WO2009094169A1 - Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1 - Google Patents

Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1 Download PDF

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WO2009094169A1
WO2009094169A1 PCT/US2009/000421 US2009000421W WO2009094169A1 WO 2009094169 A1 WO2009094169 A1 WO 2009094169A1 US 2009000421 W US2009000421 W US 2009000421W WO 2009094169 A1 WO2009094169 A1 WO 2009094169A1
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halo
alkyl
alkoxy
bond
compound
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PCT/US2009/000421
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French (fr)
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David A. Claremon
Linghang Zhuang
Yuanjie Ye
Suresh B. Singh
Colin M. Tice
Salvacion Cacatian
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Vitae Pharmaceuticals, Inc.
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Priority to US12/863,634 priority Critical patent/US8592409B2/en
Priority to EP09703823A priority patent/EP2252601B1/en
Priority to CA2712500A priority patent/CA2712500A1/en
Priority to JP2010544331A priority patent/JP5490020B2/en
Publication of WO2009094169A1 publication Critical patent/WO2009094169A1/en

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    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
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Definitions

  • the present invention relates to inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ -HSD1 ), 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.
  • 11 ⁇ -hydroxysteroid dehydrogenase pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones.
  • 11 ⁇ -HSD1 also known as 11-beta-HSD type 1 , 11 betaHSD1 , HSD11 B1 , HDL
  • 11 ⁇ -HSD1 also known as 1 1-beta-HSD type 1 , 11 betaHSD1 , HSD11 B1 , HDL, and HSD11 L
  • 1 1 ⁇ -HSD2 1 1 ⁇ -HSD2.
  • 1 1 ⁇ -HSD1 is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 11-keto forms
  • 1 1 ⁇ -HSD2 is a unidirectional dehydrogenase that inactivates biologically active Cortisol by converting it into cortisone.
  • 11 ⁇ -HSD1 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, 11 ⁇ -HSD1 may regulate intraocular pressure and may contribute to glaucoma; some data suggest that inhibition of 11 ⁇ -HSD1 may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevstev et al.
  • 11 ⁇ -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: R11-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 11 ⁇ -HSD1 or the 11 ⁇ -HSD2 genes result in human pathology.
  • individuals with mutations in 11 ⁇ -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. Natl. Acad. Sci. 95: 10200-10205).
  • H6PD cortisone reductase deficiency
  • PCOS polycystic ovary syndrome
  • 11 ⁇ -HSD1 inhibitors could be effective in combating obesity and/or aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev et al. (1997) Proc. Natl. 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 11 ⁇ -HSD1 activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin. Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275: 34841-34844).
  • Transgenic aP2-11 ⁇ HSD1 mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Moreover, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin Il and aldosterone; and treatment of the mice with an angiotensin Il antagonist alleviates the hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This suggests that hypertension may be caused or exacerbated by 11 ⁇ -HSD1 activity. Thus, 1 1 ⁇ -HSD1 inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders.
  • Inhibition of 11 ⁇ -HSD1 in mature adipocytes is also expected to attenuate secretion of plasminogen activator inhibitor 1 (PAI-1 ), which is an independent cardiovascular risk factor (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84: 4097- 4105).
  • PAI-1 plasminogen activator inhibitor 1
  • 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).
  • 11 ⁇ -HSD1 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 11 ⁇ -HSD1 inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23: 119-125).
  • 11 ⁇ -HSD1 inhibitors may also be useful for immunomodulation.
  • glucocorticoids are perceived to suppress the immune system, in actuality, there is a complex, dynamic interaction between the HPA axis and the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581 ).
  • Glucocorticoids play a role in modulating the balance between cell-mediated and humoral immune response, with high glucocorticoid activity normally associated with a humoral response. Inhibition of 11 ⁇ -HSD1 therefore can be used a means of shifting the immune response towards a cell-mediated response.
  • Certain disease states such as tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune responses that are biased towards a humoral response whereas the more effective immune response may be a cell-mediated response.
  • 1 1 ⁇ -HSD1 inhibitors may be useful for treating such diseases.
  • novel compounds of the instant invention are effective inhibitors of 11 ⁇ -HSD1.
  • Cy 1 is 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, (C 1 -C 6 )alkyl, hydroxy ⁇ - 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(
  • 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, hydroxylCi-CeJalkyl, (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 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (C 1 -C 6 JaIkOXy, (C 3 -C 6 )cycloalkoxy, (C 4 -
  • t is 1 , 2 or 3;
  • Y is (C r C 6 )alkyl or halo(C r C 6 )alkyl; n is 0, 1 or 2; E is (a) a bond or (b) (d-C 3 )alkylene or (C 1 -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;
  • R 2 is (Ci-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, (d-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 )cycloalkylalkyl, (d-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -
  • C 7 cycloalkylalkoxy, halo(C 1 -C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 - C 7 )cycloalkylalkoxy, (Ci-C 6 )alkylthio, (C 3 -C 6 )cycloalkythio, (C 4 -C 7 )cycloalkyl- alkylthio, halo(C 1 -C 6 )alkylthio, halo(C 3 -C 6 )cycloalkythio, halo(C 4 -
  • Q is O or NR 5 ;
  • R 4 is independently selected from H, (d-C 6 )alkyl, halo(C r C 6 )alkyl, amino ⁇ - C 6 )alkyl, (C r C 6 )alkylamino(Ci-C 6 )alkyl, di(CrC 6 )alkylamino(Ci-C6)alkyl, hydroxy(d- C 6 )alkyl and (C r C 6 )alkoxy(CrC 6 )alkyl;
  • R 5 is H, (Ci-C ⁇ )alkyl, halo(C r C 6 )alkyl, or hydroxy(d-C 6 )alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) a compound of Formula I 1 Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer of diastereomer thereof.
  • Another embodiment of the invention is a method of inhibiting 11 ⁇ -HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I 1 Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Another embodiment of the invention is a method of treating a subject with a disease associated with the activity or expression of 11 ⁇ -HSD1 , comprising the step of administering to the subject an effective amount of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Another embodiment of the invention is the use of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If 1 Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for inhibiting 1 1 ⁇ -HSD1 activity in a mammal in need of such treatment.
  • Another embodiment of the invention is the use of a compound of Formulas I, Ia, Ib, Ic, Id 1 Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for treating a subject with a disease associated with the activity or expression of 11 ⁇ -HSD1.
  • Another embodiment of the invention is a compound of Formulas I, Ia, Ib 1 Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in inhibiting 11 ⁇ -HSD1 activity in a mammal in need of such treatment.
  • Another embodiment of the invention is a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in for treating a subject with a disease associated with the activity or expression of 11 ⁇ -HSD1.
  • the present invention further provides methods of inhibiting 11 ⁇ -HSD1 by contacting 1 1 ⁇ -HSD1 with a compound of Formula I, Ia, Ib, Ic, Id, Ie 1 If 1 Ig, Ih or Ii of the invention.
  • the present invention further provides methods of inhibiting or reducing the conversion of cortisone to Cortisol in a subject in need of such treatment by administring to the subject an effective amount of a compound of Formula I 1 Ia 1 Ib 1 Ic, Id, Ie, If, Ig, Ih or Ii of the invention.
  • the present invention further provides methods of inhibiting or reducing production of Cortisol in a subject in need of such treatment by administring to the subject an effective amount of a compound of Formula I 1 Ia, Ib, Ic, Id, Ie If, Ig, Ih or Ii of the invention.
  • the present invention further provides methods of increasing insulin sensitivity in a subject in need thereof using a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii of the invention.
  • Another embodiment is a compound of Formula I or any one of Formulas la-i wherein: Cy 1 is phenyl, naphthyl, indanyl, tetrahydronaphthalene, 2- or 3-thienyl, 2- or
  • E is a bond or (d-C 3 )alkylene optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
  • R 3 is selected from hydrogen, (CrC 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and
  • R 1 (for Formulas I 1 la-d and Ig) is hydrogen, methyl or ethyl;
  • Cy 1 (for Formulas I, la-d and Ig) is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2- methylpropoxy, cyano, difluoromethoxy, t-butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl and methylsulfonylamino;
  • Cy 2 (for Formulas I, la-d and le-g) is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl or 2-oxo-1 ,2-dihydropyridyl, each optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylamino- methyl, methylsulfonyl, methylsulfonylamino, methylaminosul
  • E for Formulas I, la-d, le-f and Ih-i
  • R 2 for Formulas I 1 la-d, le-f and Ih-i
  • R 2 is isopropyl, thienyl, phenyl, or pyridyl, each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl
  • Q (for Formulas I and le-i) is O or NR 5 ;
  • R 5 (for Formulas I and le-i) is hydrogen or methyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • a 2 , Cy 1 , Cy 2 , E, n, Y, R 1 , R 2 , and R 3 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • a 2 , Cy 1 , Cy 2 , E, n, Y, R 1 , R 2 , R 3 and R 5 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • a 2 , Cy 1 , Cy 2 , E, n, Y, R 1 , R 2 , and R 3 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • a 2 , Cy 1 , Cy 2 , E, n,Y, R 1 , R 2 , R 3 and R 5 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • a 2 , Cy 2 , E, t, Q, R z , and R 3 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Another embodiment is a compound of Formula If:
  • a 1 Cy , E, t, Q, R 1 and R are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • R 1 , Cy 1 , A 2 , Cy 2 , t, Q, and R 3 are as defined for Formula I above; m is 0, 1 , 2, 3 or 4; and substituents X are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC 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
  • E, t, Q 1 R 2 , and R 3 are as defined for Formula I above, r and s are independently 0, 1 , 2, 3 or 4; and G 1 and G 2 are 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(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -
  • E, t, Q, R 2 , and R 3 are as defined for Formula I above, r is 0, 1 , 2, 3 or 4; and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-C ⁇ Jalkyl, hydroxy(CrC 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 )alkyl,
  • R 1 is (Ci-C 6 )alkyl.
  • R 1 is hydrogen, methyl or ethyl.
  • R 1 is methyl or ethyl.
  • 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, (d-C 6 )alkyl, hydroxy(C 1 -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,
  • Cy 1 is optionally substituted phenyl or optionally substituted pyridyl. In another alternative, Cy 1 is optionally substituted phenyl. In yet another specific embodiment, Cy 1 is substituted with fluorine chlorine, bromine, methoxy, methoxycarbonyl, carboxy, or methyl. In yet another specific embodiment, Cy 1 is substituted with fluorine or bromine.
  • Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl and methylsulfonylamino.
  • a 2 is (a) a bond, O, S or NR 4 ; or (b) (d-C 3 )alkylene or (d-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 and Cy 2 is hydrogen.
  • a 2 is a bond and Cy 2 is cyclopropyl.
  • a 2 is a bond and Cy 2 is optionally substituted aryl or optionally substituted heteroaryl.
  • a 2 is a bond and Cy 2 is optionally substituted phenyl or optionally substituted pyridyl. In another alternative, A 2 is a bond and Cy 2 is optionally substituted phenyl. In another alternative, A 2 is a bond and Cy 2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine. In yet another specific embodiment, A 2 is a bond and Cy 2 is difluorophenyl.
  • 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, (C 1 -C 6 JaIkVl 1 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 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl, (Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -
  • Cy 2 is optionally substituted phenyl.
  • Cy 2 is phenyl optonally substituted with 1-4 groups selected from chlorine and fluorine.
  • Cy 2 is difluorophenyl.
  • t is 1 , 2 or 3. In another specific embodiment t is 1. Alternatively, t is 2.
  • Y is (C r C 6 )alkyl or hak ⁇ d-CeJalkyl.
  • n is 0, 1 or 2. Alternatively, n is 0.
  • E is (a) a bond or (b) (CrC 3 )alkylene or (d ⁇ lkylenyloxy, 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 CH 2 ;.
  • E is a bond or (CrC 3 )alkylene optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo.
  • R 2 is (C ⁇ CeJalkyl, 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, (C 1 -C 6 )alkyl, hydroxy(CrC 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 )cycloalkylalkyl, (CrC 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 - C 7 )cycloalkylalkoxy, MaIo(C 1 -C 6 JaIkOXy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 - C 7 )cycloalkylalk
  • C 7 cycloalkylalkylthio, (Ci-C 6 )alkanesulfinyl, (C 3 -C 6 )cycloalkanesulfinyl, (C 4 - C 7 )cycloalkylalkanesulfinyl, halo(CrC 6 )alkane-sulfinyl, halo(C 3 - C 6 )cycloalkanesulfinyl, halo(C 4 -C 7 )cycloalkylalkanesulfinyl, (d-C 6 )alkanesulfonyl, (C 3 -C 6 )cycloalkanesulfonyl, (C 4 -C 7 )cycloalkylalkanesulfonyl, halo(Ci-
  • R 2 is optionally substituted aryl, optionally substituted heteroaryl or cycloalkyl
  • R 2 is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted thienyl.
  • R 2 is optionally substituted phenyl.
  • R 2 is fluorophenyl.
  • R 2 is isopropyl, thienyl, phenyl, or pyridyl, each optionally substituted with halo, methyl, methylthio or (4- morpholino)methyl.
  • R 3 is hydrogen. In yet another alternative, R 3 is hydroxy(C 2 -C 4 )alkyl. In yet another alternative, R 3 is ⁇ -H 2 NCO(C 1 -C 3 )alkyl. In yet another alternative, R 3 is (C 1 -C 2 )alkoxy(Ci-C 3 )alkyl. In yet another alternative, R 3 is H 2 NSO 2 O(C 2 -C 4 )alkyl. In yet another alternative, R 3 is H 2 NSO 2 NH(C 2 -C 4 )alkyl. In yet another alternative, R 3 is oxo(C 2 -C 4 )alkyl. In yet another specific embodiment, R 3 is alkenyl.
  • R 3 is allyl.
  • Q is O or NR 5 .
  • Q is O.
  • Q is N.
  • R 5 is H, (Ci-C 6 )alkyl, halo(C 1 -C 6 )alkyl, or hydroxy ⁇ -Ce ⁇ lkyl;
  • R 5 is hydrogen or methyl.
  • R 5 is hydrogen.
  • R 4 is independently selected from H, (C r C 6 )alkyl, halo(d-C 6 )alkyl, amino(C r
  • C 6 )alkyl (C 1 -C 6 )alkylamino(Ci-C 6 )alkyl, di(Ci-C 6 )alkylamino(C 1 -C 6 )alkyl, hydroxy(C r C 6 )alkyl and (Ci-CeJalkoxyCCrCeJalkyl.
  • m is O, 1 , 2, 3 or 4.
  • X is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C ⁇ )alkyl, hydroxy(CrC 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 C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkylalkyl
  • r and s are independently O, 1 , 2, 3 or 4.
  • G 1 and G 2 are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-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(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloal
  • G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -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 C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )cycloalkyl
  • alkyl means a straight or branched hydrocarbon radical having 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 an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group.
  • An aryl group is optionally substituted with 1-4 substituents.
  • substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.
  • heteroaryl means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2- pyrazinyl, 2-, A-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1 H-indol-6-yl, 1 H-indol-5-yl, 1 H- benzimidazol-6-yl, 1 H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-,
  • a heteroaryl is optionally substituted.
  • substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.
  • heterocyclyl means a A-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N 1 O, and S.
  • exemplary heterocyclyls include pyrrolidine, pyrrolidin-2- one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4-pyridone, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, piperazin-2-one, 5,6-dihydropyrimidin-4- one, pyrimidin-4-one, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1 ,3-dioxolane, 1 ,3-dithiolane, 1 ,3-dioxane, 1 ,4- dioxane, 1
  • the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included.
  • Solvates refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization.
  • Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.
  • Solvates, wherein water is the solvent molecule incorporated into the crystal lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
  • 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.
  • R * 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.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 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.
  • 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, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, s
  • Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
  • Compounds of Formula I can be prepared by several processes.
  • a 2 , Cy 1 , Cy 2 , E, Q, R 1 , R 2 , R 3 , R 5 , Y, n and t have the meanings indicated above unless otherwise noted.
  • the synthetic intermediates and final products of Formulas 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 1 wherein Q is NR 5 or O and R 1 is not hydrogen can be prepared by reaction of intermediates of Formula Il 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, CH 2 CI 2 , toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO 3 respectively, at -10 0 C to 120 0 C.
  • Z 1 and Z 2 are leaving groups such as chloride, 1- imidazolyl or aryloxide in an inert solvent such as THF, CH 2 CI 2 , toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO 3 respectively, at -10 0 C to 120 0 C.
  • 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 OCCI 3
  • III is triphosgene and as little as one third of molar equivalent can be used.
  • a hydride reagent such as BH 3 THF solution, BH 3 -Me 2 S or LiAIH 4 in an inert solvent ethereal such as THF or DME
  • One method for the synthesis of a compound of Formula V, wherein R 5 is H and n is 0, is the addition of the enolate of an ester of Formula VIII, wherein R a is (C 1 - C 6 )alkyl, to a sulfinylimine of Formula VII to give a compound of Formula IX, followed by ester hydrolysis and removal of the t-butylsulfinyl group:
  • ⁇ -Aminoesters of Formula X wherein Q is NR 5 and R 5 is H, can be prepared by reduction of ⁇ -nitroesters of Formula Xl.
  • ⁇ -Nitroesters of Formula Xl can be prepared by Michael addition of nitro compounds of Formula XII to acrylate esters of Formula XIII.
  • a borane such as disiamylborane
  • Homoallyl amines of Formula XIV, wherein R 5 is H can be prepared by addition of allylmagnesium halides to sulfinylimines of Formula XV, followed by acid treatment to remove the t-butylsulfinyl group.
  • Sulfinylimines of Formula XV can be prepared by reaction of ketones of Formula XVI with 2-methylpropane-2-sulfinamide.
  • ⁇ -hydroxyacids of Formula V wherein Q is O and t is 1
  • Additional ⁇ -hydroxyacids of Formula V, wherein Q is O and t is 1 can be prepared by diazotization of ⁇ -amino acids of Formula XVII using NaNO 2 in H 2 SO 4 :
  • ⁇ -Hydroxyacids of Formula V wherein Q is O and t is 1 , can also be prepared from ketones of Formula XVI via cyanohydrins of Formula XVIII:
  • Hydroxyacids of Formula V can also be prepared by oxidation of diols of Formula XIX with for example oxygen in the presence of a catalyst or using sodium chlorite and TEMPO:
  • Diols of Formula XIX, wherein t is 1 can be prepared by treatment of olefins of Formula XX with catalytic OsO4 in the presence of N-methylmorpholine-N-oxide.
  • Olefins of Formula XX are available from ketones of Formula XVI by Wittig reaction with methylenetriphenylphosphorane or by using the Tebbe reagent.
  • Diols of Formula XIX, wherein t is 1 are available by hydroboration of allyl alcohols of Formula XXI using, for example, disiamylborane.
  • diols of Formula XIX, wherein t is 1 are available by treatment of homoallyl alcohols of Formula XXII with ozone followed by NaBH 4 .
  • AIIyI alcohols of Formula XXI and homoallyl alcohols of Formula XXII can be prepared by treatment of ketones of Formula XVI with vinylmagnesium halide or allylmagnesium halide respectively.
  • Diols of Formula XIX, wherein t is 2 can be prepared by hydroboration of homoallyl alcohols of Formula XXII using, for example, disiamylborane.
  • Hydrazine intermediates of Formula Vl, wherein R 1 is H and Cy 1 is aryl or heteroaryl can be prepared by diazotization of amines of Formula XXIII and reduction of the diazonium salts with, for example, tin(ll) chloride.
  • Hydrazine intermediates of Formula Vl can also be prepared by reduction of nitrosamines of Formula XXXV, using for example LiAIH 4 in THF or Na in EtOH.
  • Nitrosamines of Formula XXXIV can be prepared from amines of Formula XXIV by reaction with NaNO 2 in the presence of acid.
  • Hydrazine intermediates of Formula Vl can also be prepared by amination of amines of Formula XXXIV with, for example, chloramine or hydroxylamine-O-sulfonic acid.
  • Hydrazine intermediates of Formula Vl wherein Cy 1 is aryl or heteroaryl substituted with electron withdrawing groups such as NO 2 or CF 3 and Z 3 is fluorine, chlorine or bromine, can be prepared by reaction of hydrazines of Formula XXVII with halides of Formula XXVIII.
  • Intermediates of Formula II, wherein n is O can be prepared directly by treatment of halide or sulfonate intermediates of Formula XXIX, wherein Z 4 is a halide, for example chloride, or sulfonate leaving group OSO 2 R 0 , wherein R c is alkyl, aryl or haloalkyl, for example p-toluenesulfonyloxy or methylsulfonyloxy, with a hydrazine of Formula Vl.
  • Z 4 is a halide, for example chloride, or sulfonate leaving group OSO 2 R 0 , wherein R c is alkyl, aryl or haloalkyl, for example p-toluenesulfonyloxy or methylsulfonyloxy, with a hydrazine of Formula Vl.
  • Aminoalcohols of Formula XXX, wherein Q is NR 5 and t is 2, can be prepared by hydroboration of homoallyl amines of Formula XIV.
  • Intermediates of Formula XXIX wherein Z 4 is chloride and t is 2, can be prepared by reaction of ketones of Formula XXXI with organometallics of Formula XXXII, wherein M is MgCI, MgBr, MgI or Li. In one embodiment the reaction is carried out in the presence of CeCI 3 .
  • a compound of Formula I wherein Cy 1 is cycloalkyl or heterocyclyl and R 1 is hydrogen, is prepared by reduction of a hydrazone of Formula XXXIII using, for example, hydrogen in the presence of a palladium or platinum catalyst or a hydride reagent such as LiAIH 4 , NaCNBH 3 or Bu 3 SnH.
  • Hydrazones of Formula XXXIII can be prepared from hydrazines of Formula XXXIV and ketones of Formula XXXV.
  • Hydrazines of Formula XXXIV can be prepared from cyclic intermediates of Formula XXXVI by nitrosation with, for example, NaNO 2 in the presence of acid, followed by reduction.
  • an inert solvent such as THF, CH 2 CI 2 , toluene or MeCN
  • compounds of Formula I wherein n is 0, Q is O or NR 5 , R 5 is (d-C ⁇ Jalkyl and R 1 is not hydrogen, can be prepared by treatment of compounds of Formula XXIX with isocyanates of Formula XXXVIII, wherein R 1 is not H, followed by strong bases such as NaH or DBU, in inert solvents, such as DMF.
  • Isocyanates of Formula XXXVIII, wherein R 1 is not H can be prepared by treatment of hydrazines of Formula Vl with reagents of Formula III, wherein Z 1 and Z 2 are leaving groups such as chloride, 1-imidazolyl or aryloxide.
  • compounds of Formula I wherein Cy 1 is aryl or heteroaryl
  • compounds of Formula XXXIX with halides of Formula XL, wherein Z 5 is bromide or iodide, in the presence of a copper or palladium catalyst,
  • Compounds of Formula XXXIX, wherein R 1 is (C 2 -C 6 )alkyl can be prepared by reduction of hydazones of Formula XLI, wherein R 1a is (C r C 5 )alkyl using, for example, hydrogen in the presence of a palladium or platinum catalyst or a hydride reagent such as LiAIH 4 , NaCNBH 3 or Bu 3 SnH.
  • compounds of Formula I can be prepared from other compounds 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-C 5 )alkyl using Jones reagent.
  • a compound of Formula I wherein R 1 or R 3 is ⁇ -hydroxy(C 1 -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 3 is ⁇ - amino(C 1 -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 ⁇ (CrC 6 )alkyl.
  • R 3 is ⁇ methanesulfonylamino ⁇ (C 1 -C 6 )alkyl.
  • n 0 - 4 (8) a compound of Formula I 1 wherein R 1 is (C 2 -C 6 )alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a compound of Formula I wherein R 1 is vicinal dihydroxy(C 2 -C 6 )alkyl,.
  • a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with an (d-C 6 )alkyl isocyanate to give a compound of Formula I wherein R 1 or R 3 is (C 1 -C 6 )alkylaminocarbonylamino(C 1 -C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with an (d-C 6 )alkyl chloroformate to give a compound of Formula I wherein R 1 or R 3 is (Ci-C 6 )alkoxycarbonylamino(Ci-C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(C 1 -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(C r C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is amino(C 1 -C 6 )alkyl can be reacted with a (C 1 -C 6 )alkylsulfamoyl chloride to give a compound of Formula I wherein R 1 or R 3 is (d-CeJalkylaminosulfonylamino ⁇ rCeJalkyl.
  • R 3 is ami ⁇ osulfonyloxy(d-C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is hydroxy(d-C 6 )alkyl can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (C T C ⁇ Jalkylamine or a di(Cr C 6 )alkylamine to give a compound of Formula I wherein R 1 or R 3 is aminocarboxy(C r C 6 )alkyl, (CrC 6 )alkyl aminocarboxy(C r C 6 )alkyl or di(Ci-C 6 )alkyl aminocarboxy(Ci-C 6 )alkyl.
  • 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 a cyclic amine in the presence of a palladium catalyst to give a compound of Formula I wherein A 2 is a bond and Cy 2 is a cyclic amino moiety attached through its nitrogen atom.
  • a compound of Formula I wherein Q is NR 5 and R 5 is H can be reacted with an (Ci-C 6 )alkyl halide in the presence of a strong base such as sodium hydride to afford a compound of Formula I wherein Q is NR 5 and R 5 is (Ci-C 6 )alkyl.
  • a compound of Formula I wherein R 1 or R 3 is ⁇ -H 2 NCO(Ci-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(C 1 -C 5 )alkyl.
  • a compound of Formula I 1 wherein R 1 or R 3 is ⁇ -MeO 2 C(CrC 5 )alkyl can be reacted with at least 2 equivalents of MeMgBr to afford a compound of Formula I 1 wherein R 1 or R 3 is HOC(Me) 2 (C 1 -C 5 )alkyl.
  • prep HPLC high pressure liquid chromatography
  • prep HPLC refers to preparative reverse phase HPLC on a C-18 column eluted with a water/acetonitrile gradient containing 0.01% TFA run on a Gilson 215 system.
  • Step 1 A 250-mL flask was charged with anhydrous CeCI 3 (5.58 g, 22.6 mmol) and
  • Step 3 3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (14 mg, 0.04 mmol) and triethylamine (3 drops) was dissolved in toluene (1 mL) : The solution was cooled to 0 0 C and phosgene (3 drops, 20% toluene solution) was added. After 1 h, more phosgene was added (3 drops, 20% toluene solution) and the reaction was allowed to warm to rt overnight. The solvent was evaporated and the residue was redissolved in toluene. DBU (5 drops) was added and the solution heated to reflux for 4 h.
  • Step 2 (1 ) 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (50 mg, 0.22 mmol) and 1- methyl-1-phenylhydrazine (60 mg, 0.49 mmol) were combined and heated in a microwave for 20 min at 140 0 C. Starting material was still evident by LC-MS and additional 1-methyl-1-phenylhydrazine (640 mg, 5.26 mmol) was added. The mixture was further heated in a microwave for 20 min at 140 0 C.
  • the inhibition of 11 ⁇ -HSD1 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 and 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 ++ 55.4
  • 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.
  • a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I 1 comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore.
  • the invention includes a therapeutic method for treating or ameliorating an
  • treating includes both therapeutic and prophylactic treatment.
  • Therapeutic treatment includes reducing the symptoms associated with a disease or condition and/or increasing the longevity of a subject with the disease or condition.
  • Prophylactic treatment includes delaying the onset of a disease or condition in a subject at risk of developing the disease or condition or reducing the liklihood that a subject will then develop the disease or condition in a subject that is at risk for developing the disease or condition.
  • An embodiment of the invention includes administering an 11 ⁇ -HSD1 inhibiting compound of Formula I or composition thereof 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® (EIi Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitizone 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
  • Agents for the treatment of dyslipidemia and cardiovascular disease include statins, fibrates, and ezetimbe.
  • Agents for the treatment of hypertension include alpha-blockers, beta-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 11 ⁇ -HSD1 inhibiting compound of Formula I or composition thereof in a combination therapy with one or more other 11 ⁇ -HSD1 inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCI and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCI 1 Bristol Myers Squibb); and Glucovance® (glyburide and metformin HCI, Bristol Myers Squibb).
  • Avandamet® metalformin HCI and rosiglitazone maleate, GSK
  • Avandaryl® glimepiride and rosiglitazone maleate, GSK
  • Metaglip® glipizide and metformin HCI 1 Bristol Myers Squibb
  • 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, intracutaneous ⁇ , subcutaneously, intraduodenally, or intraperitoneal ⁇ .
  • 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 dispersible 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 caboxymethylcellulose, 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 carboxymethylcellulose, and other well-known suspending agents.
  • the pharmaceutical composition is preferably in unit dosage 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.
  • 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

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Abstract

This invention relates to novel compounds of the Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), 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. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.

Description

CYCLIC CARBAZATE AND SEMICARB AZIDE INHIBITORS OF llbeta- HYDROXYSTEROID DEHYDROGENASE 1
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Serial No. 61/062,147, filed January 24, 2008, the entire teachings of which are incorporated herein by reference.
FIELD OF THE INVENTION The present invention relates to inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 ), 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 11 β-hydroxysteroid dehydrogenase (11β-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: 11 β-HSD1 (also known as 11-beta-HSD type 1 , 11 betaHSD1 , HSD11 B1 , HDL, and 11β-HSD1 (also known as 1 1-beta-HSD type 1 , 11 betaHSD1 , HSD11 B1 , HDL, and HSD11 L) and 1 1β-HSD2. 1 1β-HSD1 is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 11-keto forms, whereas 1 1β-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. 11β-HSD1 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, 11 β-HSD1 may regulate intraocular pressure and may contribute to glaucoma; some data suggest that inhibition of 11β-HSD1 may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevstev et al. (1997), Proc. Natl. Acad. Sci. USA 94(26): 14924-9). Although 1 1 β-HSD1 catalyzes both 11-beta- dehydrogenation and the reverse 11-oxoreduction reaction, 11β-HSD1 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 contradistinction, 11β-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. 11β-HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston et al. (1994) MoI. Cell. Endocrin. 105: R11-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 11 β-HSD1 or the 11β-HSD2 genes result in human pathology. For example, individuals with mutations in 11 β-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. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in 1 1 β- HSD1 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 and Chrousos (2001) Endocrinology and Metabolism, eds. FeNg and Frohman (McGraw-Hill, New York), 4th Ed.: 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 11β-HSD1 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 11β-HSD1 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 11β-HSD1 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 11 β-HSD1 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 11 β-HSD1 -deficient mice produced by homologous recombination demonstrate that the loss of 11 β-HSD1 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. Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938). -A-
The published data supports the hypothesis that increased expression of 11 β- HSD1 contributes to increased local conversion of cortisone to Cortisol in adipose tissue and hence that 11 β-HSD1 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, 11 β-HSD1 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 1β-HSD1 activity may prove beneficial in treating numerous glucocorticoid-related disorders. For example, 11β-HSD1 inhibitors could be effective in combating obesity and/or aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev et al. (1997) Proc. Natl. 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 11β-HSD1 activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin. Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275: 34841-34844).
Furthermore, given that inter-individual differences in general cognitive function have 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 resulting in chronic exposure to glucocorticoid excess in certain brain subregions has been theorized to contribute to the decline of cognitive function (McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205-216), one might predict that inhibition of 11 β-HSD1 could reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression. Notably, it is known that stress and glucocorticoids influence cognitive function (de Quervain et al. (1998) Nature 394: 787-790); and it has been shown that 11 β-HSD1 , through its control of glucocorticoid action in the brain, may have effects on neurotoxicity (Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000) Neuroendocrinol. 18:49-99).
There is also evidence that glucocorticoids and 11β-HSD1 play a role in regulation of in intra-ocular pressure (lOP) (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 eveπtually blindness. Thus, inhibition of 11β-HSD1 in the eye could reduce local glucocorticoid concentrations and lOP, and 1 1 β-HSD1 hence could potentially be used to treat glaucoma and other visual disorders.
Transgenic aP2-11βHSD1 mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Moreover, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin Il and aldosterone; and treatment of the mice with an angiotensin Il antagonist alleviates the hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This suggests that hypertension may be caused or exacerbated by 11 β-HSD1 activity. Thus, 1 1β-HSD1 inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders. Inhibition of 11 β-HSD1 in mature adipocytes is also expected to attenuate secretion of plasminogen activator inhibitor 1 (PAI-1 ), which is an independent cardiovascular risk factor (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84: 4097- 4105). 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, 11β-HSD1 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 11β-HSD1 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 11β-HSD1 is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis. 11 β-HSD1 inhibitors may also be useful for immunomodulation. Although glucocorticoids are perceived to suppress the immune system, in actuality, there is a complex, dynamic interaction between the HPA axis and the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581 ). Glucocorticoids play a role in modulating the balance between cell-mediated and humoral immune response, with high glucocorticoid activity normally associated with a humoral response. Inhibition of 11 β-HSD1 therefore can be used a means of shifting the immune response towards a cell-mediated response. Certain disease states, such as tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune responses that are biased towards a humoral response whereas the more effective immune response may be a cell-mediated response. Hence, 1 1 β-HSD1 inhibitors may be useful for treating such diseases.
It has been reported that glucocorticoids inhibit wound healing, especially in diabetic patients with ulcers (Bitar et al. (1999) J. Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar (2000) Surgery 127: 687-695; Bitar (1998) Am.
J. Pathol. 152: 547-554). Patients that exhibit impaired glucose tolerance and/or type 2 diabetes often also have impaired wound healing. Glucocorticoids have been shown to increase the risk of infection and delay wound healing (Anstead (1998) Adv.
Wound Care 11 :277-285). Moreover, there is a correlation between elevated levels of Cortisol in wound fluid and non-healing wounds (EP Patent App. No. 0 902 288).
Recent published patent applications have suggested that certain 1 1β-HSD1 inhibitors may be useful for promoting wound healing (PCT/US2006/043,951 ).
As evidenced herein, there is a continuing need for new and improved drugs that inhibit 11β-HSD1. The novel compounds of the instant invention are effective inhibitors of 11 β-HSD1.
SUMMARY OF THE INVENTION
It has now been found that compounds of Formula I or a pharmaceutically acceptable salt or prodrug thereof, are effective inhibitors of 11β-HSD1. Formula I and its constituent members are defined herein as follows:
Figure imgf000007_0001
R1 is (a) hydrogen or (b) is selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl or (CrC3)alkoxy(C1-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)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-, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino;
Cy1 is 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, (C1-C6)alkyl, hydroxy^- 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, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-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, (d-CeJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(C1-C6)alkanesulfonyl, halo(C3-
C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (d-CeJalkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (d-C6)alkoxycarbonyl, H2NCO, H2NSO2, (d-C^alkylaminocarbonyl, CIi(C1- C6)alkylaminocarbonyl, (Ci-C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclsulfonyl, (C1-C6)alkylcarbonylamino, (C1-C6)alkylcarbonylamino(C1- C6)alkyl, (d-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1- C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1- C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (Cr
Figure imgf000008_0001
amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxyl and (C1- C6)alkylcarbonyl; A2 is (a) a bond, O, S or NR4; or (b) (CrCsJalkylene or (d-C∑Jalkyleneoxy, 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, hydroxylCi-CeJalkyl, (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, (C1-C6JaIkOXy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (d-Ce^lkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (d-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C1-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(Ci-C6)alkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Cϊ-Cejalkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (d-CβJalkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclsulfonyl, (CT-CβJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(CrC6)alkyl, (C^CeJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(CrC6)alkyl, (CrCeJalkoxycarbonyKCrCeJalkoxy, (C1- C6)alkoxy(CrC6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (CrCeJalkylamino^rCeJalkyl, CJi(C1- C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(Cr C6)alkylamino(C2-C6)alkoxyl and (CrCeJalkylcarbonyl;
t is 1 , 2 or 3;
Y is (CrC6)alkyl or halo(CrC6)alkyl; n is 0, 1 or 2; E is (a) a bond or (b) (d-C3)alkylene or (C1-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, (d-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, (d-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C1-C6)alkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(d-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (C1-C6)alkylamino, di(CrC6)alkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (d-C6)alkoxycarbonyl, H2NCO, H2NSO2, (d-CeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (C1- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (d-C6)alkylcarbonylamino, (C1- C6)alkylcarbonylamino(Ci-C6)alkyl, (d-CβJalkylsulfonylamino, (C1- C6)alkylsulfonylamino(CrC6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(Cr C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(d- C6)alkylamino(C2-C6)alkoxyl and (d-C6)alkylcarbonyl; R3 is selected from hydrogen, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and
(Ci-C3)alkoxy(d-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)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);
Q is O or NR5;
R4 is independently selected from H, (d-C6)alkyl, halo(CrC6)alkyl, amino^- C6)alkyl, (CrC6)alkylamino(Ci-C6)alkyl, di(CrC6)alkylamino(Ci-C6)alkyl, hydroxy(d- C6)alkyl and (CrC6)alkoxy(CrC6)alkyl;
R5 is H, (Ci-Cβ)alkyl, halo(CrC6)alkyl, or hydroxy(d-C6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment of the present invention is a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) a compound of Formula I1 Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer of diastereomer thereof.
Another embodiment of the invention is a method of inhibiting 11 β-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I1 Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Another embodiment of the invention is a method of treating a subject with a disease associated with the activity or expression of 11β-HSD1 , comprising the step of administering to the subject an effective amount of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is the use of a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If1 Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for inhibiting 1 1 β-HSD1 activity in a mammal in need of such treatment.
Another embodiment of the invention is the use of a compound of Formulas I, Ia, Ib, Ic, Id1 Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for treating a subject with a disease associated with the activity or expression of 11β-HSD1.
Another embodiment of the invention is a compound of Formulas I, Ia, Ib1 Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in inhibiting 11β-HSD1 activity in a mammal in need of such treatment.
Another embodiment of the invention is a compound of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in for treating a subject with a disease associated with the activity or expression of 11 β-HSD1.
The present invention further provides methods of inhibiting 11 β-HSD1 by contacting 1 1 β-HSD1 with a compound of Formula I, Ia, Ib, Ic, Id, Ie1 If1 Ig, Ih or Ii of the invention. The present invention further provides methods of inhibiting or reducing the conversion of cortisone to Cortisol in a subject in need of such treatment by administring to the subject an effective amount of a compound of Formula I1 Ia1 Ib1 Ic, Id, Ie, If, Ig, Ih or Ii of the invention. The present invention further provides methods of inhibiting or reducing production of Cortisol in a subject in need of such treatment by administring to the subject an effective amount of a compound of Formula I1 Ia, Ib, Ic, Id, Ie If, Ig, Ih or Ii of the invention.
The present invention further provides methods of increasing insulin sensitivity in a subject in need thereof using a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih or Ii of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Another embodiment is a compound of Formula I or any one of Formulas la-i wherein: Cy1 is phenyl, naphthyl, indanyl, tetrahydronaphthalene, 2- or 3-thienyl, 2- or
3-furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1 H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1 H-benzimidazol-5- yl, 2-, A-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, A-, 5-, 6- , 7- or 8-quinolinyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, A-, or 5-pyrazolyl, 2-, 3-, A-, (all of which may be optionally substituted.), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidine, pyrrolidin-2- one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4-pyridone, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, piperazin-2-one, 5,6-dihydropyrimidin-4- one, pyrimidin-4-one, 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(1 H)-one, morpholine, N- methylmorpholine, morpholin-3-one, 1 ,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1 , 1 -dioxide, tetrahydro-1 ,2,5-thiaoxazole 1 ,1 -dioxide, tetrahydro-2H- 1 ,2-thiazine 1 ,1 -dioxide, hexahydro-1 ,2,6-thiadiazine 1 ,1 -dioxide, tetrahydro-1 ,2,5- thiadiazole 1,1 -dioxide or isothiazolidine 1 ,1 -dioxide, wherein each is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)alkyl, hydroxy(Cr C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-Cβ)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(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (d-CeJalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(d- 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, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(C1-C6)alkanesulfonyl, halo(C3-
C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(CrC6)alkoxy(CrC6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO1 H2NSO2, (CrC6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-C6)alkylcarbonylamino, (C1-C6)alkylcarbonylamino(C1- C6)alkyl, (CrC6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci- C6)alkoxycarbonyl(CrC6)alkoxy, (Ci-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1- C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (Cr CeJalkylamino^rCeJalkyl, di(CrC6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxyl and (C1- C6)alkylcarbonyl;
E is a bond or (d-C3)alkylene optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo; R3 is selected from hydrogen, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and
(C1-C3)alkoxy(C1-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)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) and heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H1 CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and the remainder of the variables are as described above for Formula I or below for any one of Fomrulas Ia-Ii; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula I or any one of Formulas la-i wherein:
R1 (for Formulas I1 la-d and Ig) is hydrogen, methyl or ethyl; Cy1 (for Formulas I, la-d and Ig) is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2- methylpropoxy, cyano, difluoromethoxy, t-butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl and methylsulfonylamino;
A2 (for Formulas I, la-d and le-g) is a bond, O, OCH2CO or C=O;
Cy2 (for Formulas I, la-d and le-g) is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl or 2-oxo-1 ,2-dihydropyridyl, each optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylamino- methyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylamino- sulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl and 1 -aminoethyl; n (for Formula I and la-d) is O; t (for Formulas I and le-i) is 1 , 2 or 3;
E (for Formulas I, la-d, le-f and Ih-i) is a bond or CH2; R2 (for Formulas I1 la-d, le-f and Ih-i) is isopropyl, thienyl, phenyl, or pyridyl, each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl;
R3 (for Formulas I1 la-d and le-i) is hydrogen, methyl, ethyl, propyl, butyl, vinyl, sllyl or ethoxyethyl, each optionally substituted with up to two groups independently selected from HO-, MeO-, H2N-, MeC(=O)NH-, MeS(=O)2NH-, H2NC(=O)-, MeNHC(=O)-, HO2C-, (HO)2P(=O)O-, H2NS(=O)2O-, H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=O)O- oxo, cyano, HO2C-, HOCH2CH2NH-, 4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH, MeOC(=O)NH-, MeNHC(=NC≡N)NH-, Me-, MeS-, MeSO2- MeSO2N(Me)-, MeS(=O)2NHC(=O)-, imidazolylamino-, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH- , Me2N- and MeCONMe;
Q (for Formulas I and le-i) is O or NR5;
R5 (for Formulas I and le-i) is hydrogen or methyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Ia:
Figure imgf000016_0001
wherein A2, Cy1, Cy2, E, n, Y, R1, R2, and R3 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Ib:
Figure imgf000016_0002
wherein A2, Cy1, Cy2, E, n, Y, R1, R2, R3 and R5 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Ic:
Figure imgf000017_0001
wherein A2, Cy1, Cy2, E, n, Y, R1, R2, and R3 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Id:
Figure imgf000017_0002
wherein A2, Cy1, Cy2, E, n,Y, R1, R2, R3 and R5 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Ie:
Figure imgf000017_0003
wherein A2, Cy2, E, t, Q, Rz, and R3 are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Another embodiment is a compound of Formula If:
Figure imgf000018_0001
wherein A 1 Cy , E, t, Q, R 1 and R are as defined for Formula I above; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Ig:
Figure imgf000018_0002
wherein R1, Cy1, A2, Cy2, t, Q, and R3 are as defined for Formula I above; m is 0, 1 , 2, 3 or 4; and substituents X are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)alkyl, hydroxy(Cr 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(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(d- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkane-sulfinyl, 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, (C1-C6)alkylamino, d'KC^CeJalkylamino, (C1- C6)alkoxy(CrC6)alkoxy, halo(CrC6)all<oxy(Ci-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCeOalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (C1- C3)alkoxy(C1-C3)alkylanninocarbonyl, heterocyclylcarbonyl, (CrCfOalkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (C-i-CeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(Ci-C6)alkyl, (d-CβJalkylsulfonylamino, (C1-
CeJalkylsulfonylamino^^CeJalkyl, (Ci-C6)alkoxycarbonyl(C1-C6)alkoxy, (Ci- C6)alkoxy(CrC6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amincKCrCeJalkyl, (Ci-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2- C6)alkoxyl and (d-CeJalkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. In a specific embodiment, A2-Cy2 is meta or para to the carbon atom bonded to N.
Another embodiment is a compound of Formula Ih:
Figure imgf000019_0001
wherein E, t, Q1 R2, and R3 are as defined for Formula I above, r and s are independently 0, 1 , 2, 3 or 4; and G1 and G2 are 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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (CrCeJalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Cr C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkyl- alkanesulfinyl, (CT-CβJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl- alkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4- C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, dKCrC^alkylamino, (C1- C6)alkoxy(Ci-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (d-CeJalkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(CrC6)alkylanninocarbonyl, (C1- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrCeJalkylaminosulfonyl, dKd-CeJalkylaminosulfonyl, heterocyclsulfonyl, (d-CeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(Ci-C6)alkyl, (CrCeJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(CrC6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1- C6)alkoxy(Ci-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyt, di(C1-C6)alkylamino(C1- C6)alkyl amino(C2-C6)alkoxy, (CrC6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2- C6)alkoxyl and (Cϊ-Cβjalkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment is a compound of Formula Ii:
Figure imgf000020_0001
wherein E, t, Q, R2, and R3 are as defined for Formula I above, r is 0, 1 , 2, 3 or 4; and substituents G are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-CβJalkyl, 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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (CrCeJalkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C1-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, 1IaIo(C1- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, dKd-CeJalkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO1 H2NSO2, (Ci-CeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (C1- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, (^(CrCeJalkylaminosulfonyl, heterocyclsulfonyl, (d-CeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (CrC6)alkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (d-C^alkoxycarbonyKCrCeJalkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(d-C6)alkyl, (d-CeOalkylaminotd-CeJalkyl, dKd-CeJalkylaminoζd- C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2- C6)alkoxyl and (d-C6)alkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
In certain specific embodiments of the invention, the variables in the above- described structural formulas have the following values:
R1 is (a) hydrogen or (b) is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl or (C1-C3)alkoxy(C1-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)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-, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino. In another alternative, R1 is (Ci-C6)alkyl. In another alternative, R1 is hydrogen, methyl or ethyl. In another alternative, R1 is methyl or ethyl.
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, (d-C6)alkyl, hydroxy(C1-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, (CrC6)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(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(d-C6)alkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CT-CeJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Cr
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (C1-C6)alkylamino, di(Ci-C6)alkylamino, (CrC6)alkoxy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (d-CeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (C1- C3)alkoxy(CrC3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclsulfonyl, (C1-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (Ci-
C6)alkylsulfonylamino(C1-C6)alkyl, (Ci-C6)alkoxycarbonyl(CrC6)alkoxy, (C1- C6)alkoxy(CrC6)alkyl, halo(CrC6)alkoxy(CrC6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(Cr C6)alkylamino(CrC6)alkyl amino(C2-C6)alkoxy, (CTCeJalkylamino^∑-CeJalkoxy, di(Cr C6)alkylamino(C2-C6)alkoxyl and (CrC6)alkylcarbonyl; Alternatively, Cy1 is phenyl, naphthyl, indanyl, tetrahydronaphthalene, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, A-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1 H- indol-6-yl, 1H-indol-5-yl, 1 H-benzimidazol-6-yl, 1 H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, A-, or 5-pyrazolyl, 2-, 3-, 4-, (all of which may be optionally substituted.), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidine, pyrrolidin-2-one, 1- methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4-pyridone, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, piperazin-2-one, 5,6-dihydropyrimidin-4- one, pyrimidin-4-one, 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(1 H)-one, morpholine, N- methylmorpholine, morpholin-3-one, 1 ,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1 ,1-dioxide, tetrahydro-1 ,2,5-thiaoxazole 1 ,1-dioxide, tetrahydro-2H- 1 ,2-thiazine 1 ,1-dioxide, hexahydro-1 ,2,6-thiadiazine 1 ,1-dioxide, tetrahydro-1 ,2,5- thiadiazole 1 ,1-dioxide or isothiazolidine 1 ,1-dioxide, 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(C1- 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, (d-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(d- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (C1- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkane-sulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-
C7)cycloalkylalkanesulfinyl, (C1-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-
C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (d-CeJalkylamino, di(C1-C6)alkylamino, (d-Ce^lkoxy^-CeJalkoxy, halo(Ci-C6)alkoxy(C1-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(d- C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (d-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (d-C6)alkylcarbonylamino, (CrC6)alkylcarbonylamino(d- C6)alkyl, (d-CeJalkylsulfonylamino, (d-Cβ)alkylsulfonylamino(Ci-C6)alkyl, (C1- C6)alkoxycarbonyl(d-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1- C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (C1- C6)alkylamino(CrC6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxyl and (Ci- C6)alkylcarbonyl; In another alternative, Cy1 is optionally substituted aryl or optionally substituted heteroaryl. In another alternative, Cy1 is optionally substituted phenyl or optionally substituted pyridyl. In another alternative, Cy1 is optionally substituted phenyl. In yet another specific embodiment, Cy1 is substituted with fluorine chlorine, bromine, methoxy, methoxycarbonyl, carboxy, or methyl. In yet another specific embodiment, Cy1 is substituted with fluorine or bromine. In yet another alternative, Cy1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl and methylsulfonylamino.
A2 is (a) a bond, O, S or NR4; or (b) (d-C3)alkylene or (d-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, O, OCH2CO or C=O; In another alternative, A2 is a bond and Cy2 is hydrogen. In another alternative, A2 is a bond and Cy2 is cyclopropyl. In another alternative, A2 is a bond and Cy2 is optionally substituted aryl or optionally substituted heteroaryl. In another alternative, A2 is a bond and Cy2 is optionally substituted phenyl or optionally substituted pyridyl. In another alternative, A2 is a bond and Cy2 is optionally substituted phenyl. In another alternative, A2 is a bond and Cy2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine. In yet another specific embodiment, A2 is a bond and Cy2 is difluorophenyl.
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, (C1-C6JaIkVl1 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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (d-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (d-C6)alkylamino, di(C1-C6)alkylamino, (d-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (C-r C3)alkoxy(CrC3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, clKCrCeOalkylaminosulfonyl, heterocyclsulfonyl, (d-CeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-
CeJalkylsulfonylaminoCCT-CeJalkyl, (Ci-C6)alkoxycarbonyl(CrC6)alkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl,
Figure imgf000025_0001
(Ji(C1- C6)alkylamino(CrC6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, (Ji(C1- C6)alkylamino(C2-C6)alkoxyl and (CrC6)alkylcarbonyl; Alternatively, Cy2 is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S1S- dioxothiazinyl, 2-oxo-1 ,2-dihydropyridyl optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2- methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl and 1-aminoethyl. In another alternative, Cy2 is optionally substituted phenyl. In another alternative, Cy2 is phenyl optonally substituted with 1-4 groups selected from chlorine and fluorine. In another alternative, Cy2 is difluorophenyl. t is 1 , 2 or 3. In another specific embodiment t is 1. Alternatively, t is 2. Y is (CrC6)alkyl or hak^d-CeJalkyl. n is 0, 1 or 2. Alternatively, n is 0.
E is (a) a bond or (b) (CrC3)alkylene or (d^^lkylenyloxy, 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 CH2;. In yet another alternative. E is a bond or (CrC3)alkylene optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo.
R2 is (C^CeJalkyl, 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, (C1-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(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, MaIo(C1-C6JaIkOXy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (CrCeOalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(CrC6)alkane-sulfinyl, halo(C3- C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (C1-C6)alkylamino, di(Ci-C6)alkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CT-CeJalkylaminocarbonyl, d^CrCeOalkylaminocarbonyl, (C1- C3)alkoxy(CrC3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclsulfonyl, (C^C^alkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (C^C^alkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (CrCβJalkoxycarbonyKCrCeJalkoxy, (C1- C6)alkoxy(CrC6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (CrCeJalkylamino^rCeJalkyl, di(Cτ Ce)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, Oi(C1- C6)alkylamino(C2-C6)alkoxyl and (CrC6)alkylcarbonyl; Alternatively, R2 is isopropyl, thienyl, phenyl, or pyridyl, each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl. In another alternative, R2 is optionally substituted aryl, optionally substituted heteroaryl or cycloalkyl In yet another alternative,, R2 is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted thienyl. In yet another alternative,, R2 is optionally substituted phenyl. In yet another alternative,, R2 is fluorophenyl. In yet another alternative,, R2 is isopropyl, thienyl, phenyl, or pyridyl, each optionally substituted with halo, methyl, methylthio or (4- morpholino)methyl.
R3 is selected from hydrogen, (d-CβJalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C1-C3)alkoxy(C1-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)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 selected from hydrogen, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C1- C3)alkoxy(CrC3)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)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) and 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). In another alternative, R3 is hydrogen. In yet another alternative, R3 is hydroxy(C2-C4)alkyl. In yet another alternative, R3 is ω-H2NCO(C1-C3)alkyl. In yet another alternative, R3 is (C1-C2)alkoxy(Ci-C3)alkyl. In yet another alternative, R3 is H2NSO2O(C2-C4)alkyl. In yet another alternative, R3 is H2NSO2NH(C2-C4)alkyl. In yet another alternative, R3 is oxo(C2-C4)alkyl. In yet another specific embodiment, R3 is alkenyl. In yet another alternative, R3 is allyl. In yet another alternative, R3 is MeC(=O)NH(C2-C4)alkyl. R3 is hydrogen, methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl, each optionally substituted with up to two groups independently selected from HO-, MeO-, H2N-, MeC(=O)NH-, MeS(=0)2NH-, H2NC(=O)-, MeNHC(=O)-, HO2C-, (HO)2P(=O)O-, H2NS(=O)2O-, H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=O)O- oxo, cyano, HO2C-, HOCH2CH2NH-, 4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH, MeOC(=O)NH-,
MeNHC(=NC≡N)NH-, Me-, MeS-, MeSO2- MeSO2N(Me)-, MeS(=O)2NHC(=O)-, imidazolylamino-, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH- , Me2N- and MeCONMe.
Q is O or NR5. Alternatively, Q is O. Alternatively, Q is N. R5 is H, (Ci-C6)alkyl, halo(C1-C6)alkyl, or hydroxy^-Ce^lkyl; Alternatively, R5 is hydrogen or methyl. In one specific embodiment, R5 is hydrogen. R4 is independently selected from H, (CrC6)alkyl, halo(d-C6)alkyl, amino(Cr
C6)alkyl, (C1-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(C1-C6)alkyl, hydroxy(Cr C6)alkyl and (Ci-CeJalkoxyCCrCeJalkyl. m is O, 1 , 2, 3 or 4. X is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-Cβ)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(Cr C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6JaIkOXy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-Cβ)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)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(CrC6)alkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, MaIo(C1-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(C1-C6)alkylamino, (CrC6)alkoxy(Ci- C6)alkoxy, halcKCrCeOalkoxyCCrCeJalkoxy, (C^CeJalkoxycarbonyl, H2NCO, H2NSO2,
Figure imgf000029_0001
di(Ci-C6)alkylaminocarbonyl, (C1- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrCβJalkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (CrCβJalkylcarbonylamino, (C1- CeJalkylcarbonylarnincKCrCeJalkyl, (CrCeJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, dKCrCβJalkylaminofd- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2- C6)alkoxyl and (CrC6)alkylcarbonyl.
r and s are independently O, 1 , 2, 3 or 4.
G1 and G2 are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (CrCβJalkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C-ι-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Cr
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)BIkOXy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (d-CeJalkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1- C3)alkoxy(CrC3)alkylaminocarbonyl, heterocyclylcarbonyl, (C1-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclsulfonyl, (d-CeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (d-CfOalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(Ci-C6)alkyl, (d-CeOalkoxycarbonyKd-CeOalkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2- C6)alkoxyl and (d-C6)alkylcarbonyl.
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(C1-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(Cr C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6)BIkOXy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-Cβ)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (C1-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C1-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(C1-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CTCβJalkylamino, di(C1-C6)alkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (d-CeJalkoxycarbonyl, H2NCO1 H2NSO2, (d-CeJalkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (d-CeJalkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclsulfonyl, (CrCeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(CrC6)alkyl, (C^CeJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (CrCeJalkoxycarbonyKd-CeJalkoxy, (C1- C6)alkoxy(CrC6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(d-C6)alkyl, (C^CeJalkylamino^rC^alkyl, di^rCeJalkylamino^!- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(d-C6)alkylamino(C2- C6)alkoxyl and (d-C6)alkylcarbonyl.
DEFINITIONS The term "alkyl" means a straight or branched hydrocarbon radical having 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 an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group. An aryl group is optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.
The term "heteroaryl" means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2- pyrazinyl, 2-, A-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1 H-indol-6-yl, 1 H-indol-5-yl, 1 H- benzimidazol-6-yl, 1 H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, A-, or 5-imidazolyl. A heteroaryl is optionally substituted. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.
The term "heterocyclyl" means a A-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N1 O, and S. Exemplary heterocyclyls include pyrrolidine, pyrrolidin-2- one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4-pyridone, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, piperazin-2-one, 5,6-dihydropyrimidin-4- one, pyrimidin-4-one, 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(1H)-one, morpholine, N- methylmorpholine, morpholin-3-one, 1 ,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1 ,1-dioxide, tetrahydro-1 ,2,5-thiaoxazole 1 ,1-dioxide, tetrahydro-2H- 1 ,2-thiazine 1 ,1-dioxide, hexahydro-1 ,2,6-thiadiazine 1 ,1-dioxide, tetra hydro- 1 ,2,5- thiadiazole 1 ,1-dioxide and isothiazolidine 1 ,1-dioxide. A heterocyclyl can be optionally substituted with 1-4 susbtituents. Exemplary substituents include alkyl, haloalkyl and oxo.
As used herein the terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.
When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included. "Solvates" refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
Certain of the disclosed comopounds may exist in various stereoisomer^ 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, "R*" 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.
« Ri » ,,s n ,,s* ., ..R, >, Έ „ « z » « CJSi » and "trans " indicate configurations relative to the core molecule.
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 the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 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%, 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 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 compound free from the corresponding optical isomer, a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer.
When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).
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, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.
Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
The following abbreviations have the indicated meanings:
Abbreviation Meaning
Boc te/f-butoxy carbonyl or f-butoxy carbonyl (BoC)2O di-te/Y-butyl dicarbonate
Cbz Benzyloxycarbonyl
CbzCI Benzyl chloroformate
DAST diethylaminosulfur trifluoride
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCC N.N'-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(1 H)-pyrimidinone
2,4-DNP 2,4-dinitrophenylhydrazine
DPTBS Diphenyl-t-butylsilyl
EDCHCI, EDCI 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
Equiv equivalents
Fmoc 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]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 LiAIH4 lithium aluminum hydride LC-MS liquid chromatography-mass spectroscopy
LHMDS lithium hexamethyldisilazane
Me methyl
MsCI methanesulfonyl chloride
Min minute
MS mass spectrum
NaH sodium hydride
NaHCO3 sodium bicarbonate
NaN3 sodium azide
NaOH sodium hydroxide
Na2SO4 sodium sulfate
NMM N-methylmorpholine
NMP N-methylpyrrolidinone
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
PE petroleum ether
Quant quantitative yield
Satd saturated
SOCI2 thionyl chloride
SFC supercritical fluid chromatography
SPA scintillation proximity assay
SPE solid phase extraction
TBAF tetrabutylammonium fluoride
TBS t-butyldimethylsilyl
TBDPS t-butyldiphenylsilyl
TBSCI t-butyldimethylsilyl chloride
TBDPSCI t-butyldiphenylsilyl chloride
TEA triethylamine or Et3N TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical
Teoc 1 -[2-(trimethylsilyl)ethoxycarbonyloxy]-
Teoc-OSu 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione
TFA trifluoroacetic acid
TIc, TLC thin layer chromatography
TMS trimethylsilyl
TMSCI chlorotrimethylsilane or trimethylsilyl chloride tR 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, A2, Cy1, Cy2, E, Q, R1, R2, R3, R5, Y, n and t have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products of Formulas 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 HCI in reaction mixtures are generally used in slight to substantial excess (1.05 - 5 equivalents).
In a first process, compounds of Formula I1 wherein Q is NR5 or O and R1 is not hydrogen, can be prepared by reaction of intermediates of Formula Il 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, CH2CI2, toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO3 respectively, at -10 0C to 120 0C.
Figure imgf000038_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 OCCI3, 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 hydrazides of Formula IV using a hydride reagent such as BH3THF solution, BH3-Me2S or LiAIH4 in an inert solvent ethereal such as THF or DME at 20 0C to 100 0C for between 1 h and 48 h:
Figure imgf000038_0002
Hydrazide intermediates of Formula IV can be prepared by coupling of α- (t = 1), β- (t = 2) and γ- (t = 3) amino (Q = NR5) and hydroxy (Q = O) acids of Formula V with hydrazines of Formula Vl using standard peptide coupling reagents such as EDC in the presence of HOBt and N,N-diisopropylethylamine in an inert solvent such as CH2CI2 at 0 - 30 0C for between 1 h and 24 h:
Figure imgf000039_0001
Many α-aminoacids including those of Formula V, wherein t = 1 and Q is NR5, are commercially available and methods for their synthesis are widely known in the art. (Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 1656, 5th Edition, Wiley, New York, NY, 2001).
Methods for the synthesis β-aminoacids including those of Formula V, wherein t = 2 and Q is NR5, have been reviewed (Enantioselective Synthesis of β- Amino Acids (2nd Edition) (2005), Publisher: John Wiley & Sons, Inc., Hoboken, N. J). One method for the synthesis of a compound of Formula V, wherein R5 is H and n is 0, is the addition of the enolate of an ester of Formula VIII, wherein Ra is (C1- C6)alkyl, to a sulfinylimine of Formula VII to give a compound of Formula IX, followed by ester hydrolysis and removal of the t-butylsulfinyl group:
Figure imgf000039_0002
γ-Amino acids of Formula V, wherein t = 2 and Q is NR5 and R5 is H, can be prepared hydrolysis of γ-aminoesters of Formula X, wherein Ra is lower alky!, with LiOH, NaOH or KOH.
Figure imgf000039_0003
γ-Aminoesters of Formula X, wherein Q is NR5 and R5 is H, can be prepared by reduction of γ-nitroesters of Formula Xl.
Figure imgf000040_0001
γ-Nitroesters of Formula Xl can be prepared by Michael addition of nitro compounds of Formula XII to acrylate esters of Formula XIII.
Figure imgf000040_0002
γ-Aminoacids of Formula V, wherein t = 2, Q is NR5 and R5 is H, can also be prepared from homoallyl amines of Formula XIV by hydroboration using a borane such as disiamylborane, followed by oxidation with, for example, Jones reagent.
Figure imgf000040_0003
Homoallyl amines of Formula XIV, wherein R5 is H, can be prepared by addition of allylmagnesium halides to sulfinylimines of Formula XV, followed by acid treatment to remove the t-butylsulfinyl group.
Figure imgf000040_0004
XV XIV
Sulfinylimines of Formula XV can be prepared by reaction of ketones of Formula XVI with 2-methylpropane-2-sulfinamide.
Figure imgf000041_0001
XVI XV
Certain α-hydroxyacids of Formula V, wherein Q is O and t is 1 , are commercially available. Additional α-hydroxyacids of Formula V, wherein Q is O and t is 1 , can be prepared by diazotization of α-amino acids of Formula XVII using NaNO2 in H2SO4:
Figure imgf000041_0002
α-Hydroxyacids of Formula V, wherein Q is O and t is 1 , can also be prepared from ketones of Formula XVI via cyanohydrins of Formula XVIII:
Figure imgf000041_0003
XVI XVIII
Figure imgf000041_0004
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
Hydroxyacids of Formula V can also be prepared by oxidation of diols of Formula XIX with for example oxygen in the presence of a catalyst or using sodium chlorite and TEMPO:
Figure imgf000042_0001
Diols of Formula XIX, wherein t is 1 can be prepared by treatment of olefins of Formula XX with catalytic OsO4 in the presence of N-methylmorpholine-N-oxide.
Figure imgf000042_0002
Olefins of Formula XX are available from ketones of Formula XVI by Wittig reaction with methylenetriphenylphosphorane or by using the Tebbe reagent.
Diols of Formula XIX, wherein t is 1 , are available by hydroboration of allyl alcohols of Formula XXI using, for example, disiamylborane. Alternatively, diols of Formula XIX, wherein t is 1 , are available by treatment of homoallyl alcohols of Formula XXII with ozone followed by NaBH4.
Figure imgf000042_0003
AIIyI alcohols of Formula XXI and homoallyl alcohols of Formula XXII can be prepared by treatment of ketones of Formula XVI with vinylmagnesium halide or allylmagnesium halide respectively.
Diols of Formula XIX, wherein t is 2, can be prepared by hydroboration of homoallyl alcohols of Formula XXII using, for example, disiamylborane.
Hydrazine intermediates of Formula Vl, wherein R1 is H and Cy1 is aryl or heteroaryl can be prepared by diazotization of amines of Formula XXIII and reduction of the diazonium salts with, for example, tin(ll) chloride.
Figure imgf000043_0001
XXIII Vl
Hydrazine intermediates of Formula Vl can also be prepared by reduction of nitrosamines of Formula XXXV, using for example LiAIH4 in THF or Na in EtOH. Nitrosamines of Formula XXXIV can be prepared from amines of Formula XXIV by reaction with NaNO2 in the presence of acid.
Figure imgf000043_0002
XXIV XXV Vl
Hydrazine intermediates of Formula Vl can also be prepared by amination of amines of Formula XXXIV with, for example, chloramine or hydroxylamine-O-sulfonic acid.
Hydrazine intermediates of Formula Vl, wherein Cy1 is aryl or heteroaryl substituted with electron withdrawing groups such as NO2 or CF3 and Z3 is fluorine, chlorine or bromine, can be prepared by reaction of hydrazines of Formula XXVII with halides of Formula XXVIII.
Figure imgf000043_0003
XXVII XXVIII Vl
Intermediates of Formula II, wherein n is O, can be prepared directly by treatment of halide or sulfonate intermediates of Formula XXIX, wherein Z4 is a halide, for example chloride, or sulfonate leaving group OSO2R0, wherein Rc is alkyl, aryl or haloalkyl, for example p-toluenesulfonyloxy or methylsulfonyloxy, with a hydrazine of Formula Vl.
Figure imgf000044_0001
XXIX Vl
Il
Intermediates of Formula XXIX, wherein Z4 is a sulfonate can be prepared by reaction of diols of Formula XIX or (preferably N-protected) aminoalcohols of Formula XXX with R0SO2CI or (RCSO2)2O.
Figure imgf000044_0002
XXlX
XlX Q= O XXX Q = NR5
Aminoalcohols of Formula XXX, wherein Q is NR5 and t is 2, can be prepared by hydroboration of homoallyl amines of Formula XIV.
Intermediates of Formula XXIX, wherein Z4 is chloride and t is 2, can be prepared by reaction of ketones of Formula XXXI with organometallics of Formula XXXII, wherein M is MgCI, MgBr, MgI or Li. In one embodiment the reaction is carried out in the presence of CeCI3.
Figure imgf000044_0003
XXXI XXXII XXIX
In a second process, a compound of Formula I, wherein Cy1 is cycloalkyl or heterocyclyl and R1 is hydrogen, is prepared by reduction of a hydrazone of Formula XXXIII using, for example, hydrogen in the presence of a palladium or platinum catalyst or a hydride reagent such as LiAIH4, NaCNBH3 or Bu3SnH.
Figure imgf000045_0001
XXXlII
Hydrazones of Formula XXXIII can be prepared from hydrazines of Formula XXXIV and ketones of Formula XXXV.
Figure imgf000045_0002
Hydrazines of Formula XXXIV can be prepared from cyclic intermediates of Formula XXXVI by nitrosation with, for example, NaNO2 in the presence of acid, followed by reduction.
Figure imgf000045_0003
XXXVI XXXIV
Compounds of Formula XXXVI can be prepared by reaction of aminoalcohols (Q = O) and diamines (Q = NR5) of Formula XXXVII 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, CH2CI2, toluene or MeCN, usually in the presence of an organic or inorganic base such as triethylamine or NaHCO3 respectively, at -10 0C to 120 0C.
Figure imgf000046_0001
Aminoalcohols (Q = O) and diamines (Q = NR5) of Formula XXXVII, wherein n = 0, can be prepared by reaction of of halide or sulfonate intermediates of Formula XXIX with ammonia or with sodium azide followed by reduction by catalytic hydrogenation or with Ph3P in wet THF.
Figure imgf000046_0002
Additional methods for the synthesis of 1,2-diamine intermediates, including those of Formula XXXVII wherein t = 1 and Q = NR5, are described in Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580-2617.
In a third process, compounds of Formula I wherein n is 0, Q is O or NR5, R5 is (d-CβJalkyl and R1 is not hydrogen, can be prepared by treatment of compounds of Formula XXIX with isocyanates of Formula XXXVIII, wherein R1 is not H, followed by strong bases such as NaH or DBU, in inert solvents, such as DMF.
Figure imgf000046_0003
XXlX
Figure imgf000046_0004
Isocyanates of Formula XXXVIII, wherein R1 is not H, can be prepared by treatment of hydrazines of Formula Vl with reagents of Formula III, wherein Z1 and Z2 are leaving groups such as chloride, 1-imidazolyl or aryloxide.
Figure imgf000047_0001
In a fourth process, compounds of Formula I, wherein Cy1 is aryl or heteroaryl, can be prepared by reaction of compounds of Formula XXXIX with halides of Formula XL, wherein Z5 is bromide or iodide, in the presence of a copper or palladium catalyst,
Figure imgf000047_0002
Compounds of Formula XXXIX, wherein R1 is (C2-C6)alkyl can be prepared by reduction of hydazones of Formula XLI, wherein R1a is (CrC5)alkyl using, for example, hydrogen in the presence of a palladium or platinum catalyst or a hydride reagent such as LiAIH4, NaCNBH3 or Bu3SnH.
Figure imgf000047_0003
Compounds of Formula XLI, wherein R1a is a straight chain (CrCs^lkyl can be prepared by reaction of an intermediate of Formula XXXIV with an aldehyde of Formula XLII.
Figure imgf000048_0001
In a fifth process, compounds of Formula I can be prepared from other compounds 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-C5)alkyl using Jones reagent.
(3) a compound of Formula I wherein R1 or R3 is ω-carboxy(CrC6)alkyl can be coupled with ammonia or a (d-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)(C1-C6)alkyl or . or ω-{(C1-C6)alkylNHC(=O)}(C1-C6)alkyl .
(4) a compound of Formula I wherein R1 or R3 is ω-hydroxy(C1-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 R3 is ω- amino(C1-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}(CrC6)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}(C1-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 imgf000049_0001
n = 0 - 4 (8) a compound of Formula I1 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 I1 wherein R1 is H2C=CH(Co-C4)alkyl-, can be reacted with ozone followed by NaBH4 to give a compound of Formula I wherein R1 is ω-hydroxy(CrC5)alkyl.
(11 ) a compound of Formula I, wherein R3 is H2C=CH(C0-C4)alkyl-, can be reacted with ozone followed by NaBH4 to give a compound of Formula I wherein R3 is ω-hydroxy(C1-C5)alkyl.
(12) a compound of Formula I wherein R1 or R3 is amino(C1-C6)alkyl can be reacted with an (d-C6)alkyl isocyanate to give a compound of Formula I wherein R1 or R3 is (C1-C6)alkylaminocarbonylamino(C1-C6)alkyl. (13) a compound of Formula I wherein R1 or R3 is amino(C1-C6)alkyl can be reacted with an (d-C6)alkyl chloroformate to give a compound of Formula I wherein R1 or R3 is (Ci-C6)alkoxycarbonylamino(Ci-C6)alkyl.
(14) a compound of Formula I wherein R1 or R3 is amino(C1-C6)alkyl can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I wherein R1 or R3 is aminosulfonylamino(CrC6)alkyl.
(15) a compound of Formula I wherein R1 or R3 is amino(C1-C6)alkyl can be reacted with a (C1-C6)alkylsulfamoyl chloride to give a compound of Formula I wherein R1 or R3 is (d-CeJalkylaminosulfonylamino^rCeJalkyl.
(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 amiπosulfonyloxy(d-C6)alkyl. (17) a compound of Formula I wherein R1 or R3 is hydroxy(d-C6)alkyl can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (CTCβJalkylamine or a di(Cr C6)alkylamine to give a compound of Formula I wherein R1 or R3 is aminocarboxy(CrC6)alkyl, (CrC6)alkyl aminocarboxy(CrC6)alkyl or di(Ci-C6)alkyl aminocarboxy(Ci-C6)alkyl.
(18) a compound of Formula I wherein R1 or R3 is hydroxy(Ci-C6)alkyl can be reacted with POCI3 to give a compound of Formula I wherein R1 or R3 is (HO)2P(=O)O(C1-Cβ)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 Q is NR5 and R5 is H can be reacted with an (Ci-C6)alkyl halide in the presence of a strong base such as sodium hydride to afford a compound of Formula I wherein Q is NR5 and R5 is (Ci-C6)alkyl.
(21 ) a compound of Formula I wherein R1 or R3 is ω-H2NCO(Ci-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(C1-C5)alkyl. (22) a compound of Formula I1 wherein R1 or R3 is ω-MeO2C(CrC5)alkyl can be reacted with at least 2 equivalents of MeMgBr to afford a compound of Formula I1 wherein R1 or R3 is HOC(Me)2(C1-C5)alkyl.
(23) a compound of Formula I wherein R1 or R3 is ω-hydroxy(Ci-C6)alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate and reacted with morpholine to give a compound of Formula I1 wherein R1 or R3 is ω-(4- morpholinoXCrCfOalkyl.
(24) a compound of Formula I1 wherein R1 is hydrogen, can be treated with NaH and MeI in a solvent such as DMF or THF to afford a compound of Formula I1 wherein R1 is methyl.
PURIFICATION METHODS
Compounds of the invention can be purified by high pressure liquid chromatography (prep HPLC). Unless otherwise specified, prep HPLC refers to preparative reverse phase HPLC on a C-18 column eluted with a water/acetonitrile gradient containing 0.01% TFA run on a Gilson 215 system.
LC-MS METHODS Method 1 [LC-MS (3 min)]
Column: Chromolith SpeedRod, RP-18e, 50 x 4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01 %TFA/CH3CN; Flow rate: 1 mL/min; Gradient:
EXAMPLE 1 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1 ,3-oxazinan-2-one
Figure imgf000051_0001
Step 1 A 250-mL flask was charged with anhydrous CeCI3 (5.58 g, 22.6 mmol) and
THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to -78 0C and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at -78 0C1 a solution of 3-chloro-1- (4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8 0C while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 1- chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR = 1.79 min, m/z. 213, 21 1 (M-OH)+; 1H NMR (400 MHz, CDCI3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1 H), 5.20-5.19 (m, 1 H), 5.16 (m, 1 H)1 3.59-3.52 (m, 1 H), 3.24-3.18 (m, 1 H), 2.70 (dd, J = 13.8, 5.9 Hz, 1 H), 2.50 (dd, J = 13.8, 8.5 Hz, 1 H), 2.29 (t, J = 7.9 Hz, 2H), 2.22 (s, 1 H); 19F NMR (376 MHz, CDCI3) δ -1 16.52 (m).
Step 2
1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (20 mg, 0.088 mmol) and 1-methyl- 1-phenylhydrazine (640 mg, 5.26 mmol) were combined and heated in a microwave for 10 min at 120 0C and for 20 min at 140 0C. The crude mixture was purified by chromatography on a silica gel cartridge eluted with an EtOAc/hexanes gradient followed by preparative HPLC to afford 3-(4-fluorophenyl)-1-(2-methyl-2- phenylhydrazinyl)hex-5-en-3-ol (2 mg). LC-MS Method 1 m/z = 315 (M+1).
Step 3 3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (14 mg, 0.04 mmol) and triethylamine (3 drops) was dissolved in toluene (1 mL): The solution was cooled to 0 0C and phosgene (3 drops, 20% toluene solution) was added. After 1 h, more phosgene was added (3 drops, 20% toluene solution) and the reaction was allowed to warm to rt overnight. The solvent was evaporated and the residue was redissolved in toluene. DBU (5 drops) was added and the solution heated to reflux for 4 h. The solvent was evaporated and the residue was purified by preparative HPLC to afford 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1 ,3-oxazinan-2- one (8.8 mg). LC-MS Method 1 m/z = 341 (M+1). 1H NMR (CDCI3) δ 7.43-7.37 (br m), 7.25-7.26 (m), 7.19-7.12 (m), 6.99 (t), 6.85 (m), 6.72-6.66 (m), 6.07 (d), 6.73 (m), 5.15-5.05 (m), 3.42 (m), 3.33 (m), 3.14 (s), 2.85 (s), 2.65-2.55 (m), 2.50-2.34 (m).
Alternative procedures for Step 2: (1 ) 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (50 mg, 0.22 mmol) and 1- methyl-1-phenylhydrazine (60 mg, 0.49 mmol) were combined and heated in a microwave for 20 min at 140 0C. Starting material was still evident by LC-MS and additional 1-methyl-1-phenylhydrazine (640 mg, 5.26 mmol) was added. The mixture was further heated in a microwave for 20 min at 140 0C. The crude mixture was purified by chromatography on a silica gel cartridge eluted with an EtOAc/hexanes gradient and further purified by preparative HPLC to provide 3-(4-fluorophenyl)-1-(2- methyl-2-phenylhydrazinyl)hex-5-en-3-ol (6 mg). LC-MS Method 1 m/z = 315 (M+1).
(2) 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (58 mg, 0.25 mmol), 1-methyl-1- phenylhydrazine (500 mg, 4.09 mmol), and tetrabutylammonium iodide (92 mg, 0.25 mmol) were combined and heated in a microwave for 50 min at 63 0C. The crude mixture was filtered and purified twice by chromatography on a silica gel cartridge eluted with an EtOAc/hexanes gradient to remove 1-methyl-1-phenylhydrazine. The residue was dissolved in Et2O and washed with 1 M aq HCI. The aqueous layer was treated with 1 M aq NaOH until a pH of 4 was reached, then extracted with Et2O. The organic layer was evaporated and the residue was further purified by preparative HPLC to provide 3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (6 mg). LC-MS Method 1 m/z = 315 (M+1 ).
EXAMPLE 2 6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-(methyl(phenyl)amino)-1 ,3-oxazinan-2-one
Figure imgf000053_0001
At 0 0C, 2M 2-methyl-2-butene in THF (15 mL, 30 mmol) was added to BH3OMS (1.5 mL, 15 mmol, 10M) in THF (3 mL) and stirred for 1 h to afford a 0.83 M THF solution of disiamylborane. In a separate flask, disiamylborane (0.1 mL, 0.08 mmol) was added to 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)arnino)-1 ,3-oxazinan- 2-one (6 mg, 0.018 mmol) in THF (1 mL) at 0 0C. The reaction was warmed to rt overnight. The reaction was cooled to 0 0C and quenched with H2O (1 mL) and stirred for 15 min at it NaBO3 (22 mg, 0.22 mmol) was added and the reaction was stirred for 2 h. The solvent was evaporated and the crude material purified by prep HPLC to afford 6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-(methyl(phenyl)amino)-1 ,3- oxazinan-2-one (1.16 mg). LC/MS Method 1 tR = 1 .51 min m/z = 359 (M+1 ).
BIOLOGICAL TEST EXAMPLE 1
The inhibition of microsomal preparation of 11 β-HSD1 by compounds of the invention was measured essentially as previously described (K. Solly, S. S. Mundt, H.J. Zokian, G.J. 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 HEPES, pH 7.4, 10OmM KCI, 5mM NaCI1 2mM MgCI2, 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 11β-HSD1 (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 containingiO 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 11 β-HSD1 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, H.J.;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
Compound Biological Test Example 1
IC50 Rangea % Inhibition at 100 nM
Example 1 ++ 55.4 Example 2 # 36.8 a ++ means IC50 = <100 nM, + means IC50 = 100 - 1000 nM, # means IC50 > 100 nM, nt means not tested. PROPHETIC COMPOUND TABLES
TABLE 1
Figure imgf000056_0001
t = 1 , 2 or 3
Cpd.
R1 A2 Cf E R2 R3 No. a Me 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NC(=O)CH2a Me 1 ,4-C6HA bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH(OH)CH2a Me Ph bond H bond Ph Mea Me 3-MeO-Ph bond H bond Ph Mea Me 4-MeO-Ph bond H bond Ph Mea Me Ph bond H bond 2-Me-Ph Mea Me Ph bond H bond 4-Me-Ph Mea Me Ph bond H bond 4-MeS-Ph Mea Me Ph bond H bond 2-F-Ph allyl 0a Me Ph bond H bond 4-F-Ph HOCH2CH21a Me 4-Br-Ph bond H bond 4-F-Ph allyl 2a Me 1 ,4-C6HU bond 2,4-diF-Ph bond 4-F-Ph allyl 3a Me 1 ,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH24a Me Ph bond H bond 4-F-Ph vinyl 5a Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH26a Me 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH27a Me c-hex bond H bond 4-F-Ph allyl a Me c-hex bond H bond 4-F-Ph HOCH2CH2CH2a Me 1 ,4-CeH4 bond c-Pr bond 4-F-Ph allyl a Me 4-Meθ2C-Ph bond H bond 4-F-Ph allyl a Me 1,4-CeH4 bond c-Pr bond 4-F-Ph HOCH2CH2CH2a Me 4-MeO2C-Ph bond H bond 4-F-Ph HOCH2CH2CH2a Et 4-Br-Ph bond H bond 4-F-Ph allyl a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeCH(OH)CH2a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeC(=O)CH2a Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph HOC(Me)2CH2a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeOCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHCf=O)NHCH2CH2a Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2a Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCOCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHC(=O)CH2CH2a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeCONHCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHC(=O)OCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NSO2NHCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NSO2OCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph (HO)2Pf=O)OCH2CH2a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCH2Cf=O)NHCH2CH2a Me 4-HOCH2-Ph bond H bond 4-F-Ph HOCH2CH2CH2a Me 4-HOC(Me)2-Ph bond H bond 4-F-Ph allyl a Me 4-Br-Ph bond H bond 2-thιenyl allyl a Me 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2a Me 1,4-C6H4 bond 4-F-Ph bond 2-thιenyl allyl a Me 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond Ph HOCH2CH2 48a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 2-thιenyl ally!
49a Me 1,4-C6H4 bond 4-F-Ph bond 2-thιenyl HOCH2CH2CH2
50a Me 1,4-CeH4 bond 4-F-Ph bond 2-thιenyl MeCH(OH)CH2
51a Me 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH(OH)CH2
52a Me 1,4-C6H4 bond 2,4-dιF-Ph bond Ph HOCH2CH2CH2
53a Me 1,4-C6H4 bond 2,4-dιF-Ph bond Ph MeCH(0H)CH2
54a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 2-thιenyl HOCH2CH2CH2
55a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph NCCH2CH2
56a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond Ph HOCH2CH(OH)CH2
57a Et 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2
58a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOC(=O)CH2CH2
59a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2NHCH2CH2
60a Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2C(=O)NHCH2CH2
61a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeOCf=O)NHCH2CH2
62a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph 2-(4-morpholιno)ethyl
63a Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph EtNHCONHCH2CH2
64a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHC(=NCN)NHCH2CH2
65a Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeSO2NHCH2CH2CH2
66a Me 4-CI-Ph bond H bond ι-Pr HOCH2CH2CH2
67a Me 4-Me-Ph bond H bond 4-F-Ph allyl
68a Me 4-MeO-Ph bond H bond Ph HOCH2CH2
69a Me 4-MeO-Ph bond H bond 4-F-Ph allyl
70a Me 4-HOCH2-Ph bond H bond Ph HOCH2CH2CH2
71a Me 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH2
72a Me 4-CI-Ph bond H bond 4-F-Ph allyl
73a Me c-hex bond H bond Ph HOCH2CH(OH)CH2
74a Me 4-HOCH2CH2-Ph bond H bond Ph HOCH2CH2CH2
75a Me 4-MeOCH2-Ph bond H bond Ph HOCH2CH2CH2
76a Me 4-Br-Ph bond H bond ι-Pr HOCH2CH2CH2
77a Me 4-CI-Ph bond H bond 4-F-Ph HOCH2CH2CH2 78a Me 4-CI-Ph bond H bond 4-F-Ph MeCH(OH)CH2
79a Me 4-Br-Ph bond H bond Ph sllyl
80a Me 1 ,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2
81a Me 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
82a Me 1,4-C6HU bond 2,4-diF-Ph bond i-Pr HOCH2CH2
83a Me 1 ,4-CeH4 bond ' 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2
84a Me 1,4-CeH4 bond 4-pyridyl bond Ph HOCH2CH2CH2
85a Me 1,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2CH2
86a Me 1,4-CeH4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2CH2
87a Me 1 ,4-CeH4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2
88a Me 1,4-CeH4 bond 2-thienyl bond Ph HOCH2CH2CH2
89a Me 1,4-CeH4 bond 4-morpholinyl bond 4-F-Ph SlIyI
90a Me 1,4-CeH4 bond 4-F-Ph bond 2-thienyl HOCH2CH2
91a Me 1 ,4-CeH4 bond 4-F-Ph bond Ph NCCH2CH2
92a Et 4-Br-Ph bond H bond Ph HOCH2CH2CH2
2-oxo-5-(1,2-
93a Me 1,4-CeH4 bond bond Ph HOCH2CH2CH2 dihydropyridyl)
94a Me 1,4-CeH4 bond 1-oxo-3-pyridyl bond Ph HOCH2CH2CH2
95a Me 1,4-C6H4 bond 2,4-diF-Ph bond i-Pr HOCH2CH(OH)CH2
96a Me 1,4-CeH4 bond 4-F-Ph bond Ph MeCH(OH)CH2
97a Me 1,4-C6H4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2CH2
98a Me 1,4-CeH4 bond 2,4-diF-Ph bond Ph Pr
99a Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
100a Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2CH2CH2
5-Me-1,3,4-
101a Me 1,4-CeH4 bond bond 4-F-Ph thiadiazol-2-yl sllyl
102a Me 1,4-CeH4 bond 4-F-Ph bond 2-thienyl HOCH2CH2CH2
103a Me 1,4-CeH4 bond 2,4-diF-Ph bond 2-thienyl HOCH2CH2
104a Me 1,4-CeH4 bond 4-F-Ph bond Ph H2NCOCH2CH2
105a Me 1,4-CeH4 bond 2-MeO-5-pyridyl bond Ph HOCH2CH2CH2
106a Me 1,4-CeH4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2CH2
107a Et 1,4-CeH4 bond 4-F-Ph bond Ph HOCH2CH2CH2 108a Me 1,4-CeH4 bond 4-F-Ph bond Ph HOC(Me)2CH2
109a Et 4-Br-Ph bond H bond Ph HOCH2CH(OH)CH2
110a Me 4-Br-Ph bond H bond 4-F-Ph H2NCOCH2CH2
111a Et 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
112a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph NCCH2
113a Me 1,4-CeH4 bond 2,4-dιMe-5- thiazolyl bond 4-F-Ph sllyl
114a Me 1,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
115a Me 1,4-C6H4 bond 4-F-Ph bond 2-F-Ph HOCH2CH2CH2
116a Me 1,4-CeH4 bond 4-F-Ph bond 3-F-Ph HOCH2CH2CH2
117a Me 1,4-C6H4 bond 4-F-Ph bond Ph HOC(Me)2CH2CH2
118a Me 1,4-C6H4 bond 5-MeCO-2-thιenyl bond Ph HOCH2CH2CH2
119a Me 1,4-CeH4 bond 2,4-dιF-Ph bond Ph H2NCOCH2CH2
120a Me 1,4-C6H4 bond 5-(H2NCHMe)-2- thienyl bond Ph HOCH2CH2CH2
121a Et 1,4-CeH4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
122a Et 1,4-C6H4 bond 2,4-dιF-Ph bond Ph HOCH2CH2CH2
123a Me 1,4-CeH4 bond 5-(HOCHMe)-2- thienyl bond Ph HOCH2CH2CH2
124a Et 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
125a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCH2CH2CH2
126a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHCH2CH2
127a Me 1,4-C6H4 bond 3-(CF3)-1- pyrazolyl bond 4-F-Ph sllyl
128a Me 1,4-CeH4 bond 2,4-dιF-Ph bond Ph HOC(Me)2CH2CH2
129a Et 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2CH2
130a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeSCH2CH2
131a Me Ph bond 2,4-dιF-Ph bond 4-F-Ph H2NCOCH2CH2
132a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCOCH2CH2
133a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2OCH2CH2
134a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph 2-(1-ιmιdazolyl)ethyl
135a Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeCONMeCH2CH2
136a Me 1,4-C6H4 bond 4-F-Ph bond Ph MeSO2NHCH2CH2CH2
137a Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCt=O)NHCH2CH2CH2 138a Me 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph H2NCC=O)OCH2CH2CH2
139a Me 1 ,4-C6HA bond 2,4-diF-Ph bond 4-F-Ph 2-(1-aminoimidazol-1-yl)ethyl
140a Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)NHCH2CH2CH2
141a Me 1 ,4-C6HA bond 2,4-diF-Ph bond 4-F-Ph H2NCf=O)NHCH2CH(OH)CH2
142a Me 1,4-CeH4 bond 4-F-Ph bond 4-F-Ph MeSO2NHCH2CH(OH)CH2
143a Me 1 ,4-C6H4 bond 4-F-Ph bond 4-F-Ph MeSO2NMeCH2CH(OH)CH2
144a Me 1,4-CeH4 bond 6-CF3-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
145a Me 4-MeO-Ph bond H bond Ph HOCH2CH2CH2
146a Me 3-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
147a Me 2-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
148a Me 4-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
149a Me 4-MeO-Ph bond H bond Ph HOCH2CH(OH)CH2
150a Me 4-CI-Ph bond H bond Ph H2NCOCH2CH2
151a Me 4-MeO-Ph bond H bond 4-F-Ph H2NCOCH2CH2
152a Me 4-F2HCO-Ph bond H bond 4-F-Ph allyl
153a Me Ph bond 3-pyrazolyl bond Ph HOCH2CH2CH2
154a Me 1,4-CBH4 bond 5-F-3-pyridyl bond Ph allyl
155a Me 3-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
156a Me 4-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
157a Me 1 ,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2CH2
158a Me 1,4-C6H4 bond 4-pyridyl bond Ph HOCH2CH2CH2
159a Me 1 ,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
160a Me 1,4-C6H4 bond 5-F-3-pyridyl bond Ph HOCH2CH2CH2
161a Me 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2
162a Me 1,4-C6H4 bond 5-F-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
163a Me 1 ,4-CeH4 bond 4-F-Ph bond Ph NCC(Me)2CH2
164a Me 1,4-C6H4 bond 6-MeO-3-pyridyl bond Ph H2NCOCH2CH2
165a Me 1,4-CeH4 bond 5-MeO-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
166a Me 1 ,4-C6H4 bond 5-CI-3-pyridyl bond 4-F-Ph HOCH2CH2CH2
167a Me 1,4-CeH4 bond 3-pyridyl bond Ph MeSO2NHCH2CH2 168a Me 4-F2HCO-Ph bond H bond 4-F-Ph HOCH2CH2CH2
169a Me 1 ,4-C6H4 bond 4-F-Ph bond Ph (HO)2Pf=O)OCH2CH2CH2
170a Me 1 ,4-C6H4 bond 2-Me-4-pyridyl bond 4-F-Ph HOCH2CH2CH2
4-(HOC(Me)2CH2-
171a Me bond H bond Ph HOCH2CH2CH2 Ph
1-Me-6-oxo-3-
172a Me 1 ,4-C6H4 bond (1,6- bond Ph HOCH2CH2CH2 dihydropyridyl) 173a Me 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2CH2
174a Me 4-MeO-Ph bond H bond Ph H2NCOCH2CH2
175a Me 4-F-Ph bond H bond 4-F-Ph H2NCOCH2CH2
176a Me c-hex bond H bond 4-F-Ph H2NCOCH2CH2
177a Me c-hex bond H bond 4-F-Ph MeSO2NHCH2CH2CH2
Cy1 = 1 ,4-C6H4 means
Figure imgf000062_0002
Cy
Figure imgf000062_0001
1 = 1 ,3-(4-F)C6H3 means
0
TABLE 2
Figure imgf000062_0003
5 t = 1 , 2 or 3 Cpd
No R1 A2 Cy2 E R2 R3b Me 1,4-CBH4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCf=O)CH2b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH(OH)CH2b Me Ph bond H bond Ph Meb Me 3-MeO-Ph bond H bond Ph Meb Me 4-MeO-Ph bond H bond Ph Meb Me Ph bond H bond 2-Me-Ph Meb Me Ph bond H bond 4-Me-Ph Meb Me Ph bond H bond 4-MeS-Ph Meb Me Ph bond H bond 4-F-Ph allyl 0b Me Ph bond H bond 4-F-Ph HOCH2CH21b Me 4-Br-Ph bond H bond 4-F-Ph allyl 2b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph allyl 3b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH24b Me Ph bond H bond 4-F-Ph vinyl 5b Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH26b Me 1,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH27b Me c-hex bond H bond 4-F-Ph allyl 8b Me c-hex bond H bond 4-F-Ph HOCH2CH2CH29b Me 1,4-C6H4 bond c-Pr bond 4-F-Ph allyl 0b Me 4-MeO2C-Ph bond H bond 4-F-Ph allyl 1b Me 1,4-C6H4 bond c-Pr bond 4-F-Ph HOCH2CH2CH22b Me 4-MeO2C-Ph bond H bond 4-F-Ph HOCH2CH2CH23b Et 4-Br-Ph bond H bond 4-F-Ph allyl 4b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCH2CH25b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2CH26b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeCH(OH)CH27b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeCf=O)CH28b Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOC(Me)2CH29b Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeOCH2CH2 b Me 1 ,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC)=O)NHCH2CH2b Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2b Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph H2NCOCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeNHCf=O)CH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeCONHCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeNHC(=O)OCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph H2NSO2NHCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph H2NSO2OCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph (HO)2P(=O)OCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph H2NCH2Cf=O)NHCH2CH2b Me 4-HOCH2-Ph bond H bond 4-F-Ph HOCH2CH2CH2b Me 4-HOC(Me)2-Ph bond H bond 4-F-Ph allyl b Me 4-Br-Ph bond H bond 2-lhienyl allyl b Me 1,4-CeH4 bond 4-F-Ph bond Ph HOCH2CH2b Me 1 ,4-CeH4 bond 4-F-Ph bond 2-thienyl allyl b Me 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond Ph HOCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 2-thienyl allyl b Me 1,4-CeH4 bond 4-F-Ph bond 2-thienyl HOCH2CH2CH2b Me 1,4-CeH4 bond 4-F-Ph bond 2-thienyl MeCH(OH)CH2b Me 1,4-CeH4 bond 4-F-Ph bond Ph HOCH2CH(OH)CH2b Me 1 ,4-CeH4 bond 2,4-diF-Ph bond Ph HOCH2CH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond Ph MeCH(0H)CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 2-thienyl HOCH2CH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph NCCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond Ph HOCH2CH(OH)CH2b Et 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph HOCf=O)CH2CH2b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2CH2NHCH2CH2 60b Me 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph HOCH2C(=O)NHCH2CH2
61b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeOCf=O)NHCH2CH2
62b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph 2-(4-morpholino)ethyl
63b Me 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph EtNHCONHCH2CH2
64b Me 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeNHCf=NCN)NHCH2CH2
65b Me 1,4-CeH4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2CH2
66b Me 4-CI-Ph bond H bond i-Pr HOCH2CH2CH2
67b Me 4-Me-Ph bond H bond 4-F-Ph silyl
68b Me 4-MeO-Ph bond H bond Ph HOCH2CH2
69b Me 4-MeO-Ph bond H bond 4-F-Ph sllyl
70b Me 4-HOCH2-Ph bond H bond Ph HOCH2CH2CH2
71b Me 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH2
72b Me 4-CI-Ph bond H bond 4-F-Ph allyl
73b Me c-hex bond H bond Ph HOCH2CH(OH)CH2
74b Me 4-HOCH2CH2-Ph bond H bond Ph HOCH2CH2CH2
75b Me 4-MeOCH2-Ph bond H bond Ph HOCH2CH2CH2
76b Me 4-Br-Ph bond H bond i-Pr HOCH2CH2CH2
77b Me 4-CI-Ph bond H bond 4-F-Ph HOCH2CH2CH2
78b Me 4-CI-Ph bond H bond 4-F-Ph MeCH(OH)CH2
79b Me 4-Br-Ph bond H bond Ph allyl
80b Me 1 ,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2
81b Me 4-MeO-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
82b Me 1 ,4-CBH4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2
83b Me 1,4-C6H4 bond 2,4-diF-Ph bond 4-F-Ph MeSO2NHCH2CH2
84b Me 1,4-C6H4 bond 4-pyridyl bond Ph HOCH2CH2CH2
85b Me 1,4-C6H4 bond 3-pyridyl bond Ph HOCH2CH2CH2
86b Me 1,4-CeH4 bond 2,4-diF-Ph bond i-Pr HOCH2CH2CH2
87b Me 1,4-CeH4 bond 3-pyridyl bond 4-F-Ph HOCH2CH2
88b Me 1,4-CeH4 bond 2-thienyl bond Ph HOCH2CH2CH2
89b Me 1,4-C6H4 bond 4-morpholinyl bond 4-F-Ph allyl 90b Me 1 ,4-C6HA bond 4-F-Ph bond 2-thιenyl HOCH2CH2
91b Me 1,4-CBH4 bond 4-F-Ph bond Ph NCCH2CH2
92b Et 4-Br-Ph bond H bond Ph HOCH2CH2CH2
93b 2-oxo-5-(1,2-
Me 1 ,4-CsH4 bond bond Ph HOCH2CH2CH2 dihydropyndyl)
94b Me 1 ,4-CeH4 bond 1-oxo-3-pyπdyl bond Ph HOCH2CH2CH2
95b Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond ι-Pr HOCH2CH(OH)CH2
96b Me 1 ,4-C6H4 bond 4-F-Ph bond Ph MeCH(OH)CH2
97b Me 1 ,4-C6H4 bond 3-pyπdyl bond 4-F-Ph HOCH2CH2CH2
98b Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond Ph Pr
99b Me 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
100b Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeSO2CH2CH2
5-Me-1,3,4-
101b Me 1,4-C6H4 bond bond 4-F-Ph allyl thιadιazol-2-yl
102b Me 1 ,4-C6H4 bond 4-F-Ph bond 2-thιenyl HOCH2CH2CH2
103b Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 2-thιenyl HOCH2CH2
104b Me 1 ,4-CeH4 bond 4-F-Ph bond Ph H2NCOCH2CH2
105b Me 1,4-CeH4 bond 2-MeO-5-pyrιdyl bond Ph HOCH2CH2CH2
106b Me 1 ,4-CeH4 bond 3-pyπdyl bond 4-F-Ph HOCH2CH2CH2
107b Et 1,4-CeH4 bond 4-F-Ph bond Ph HOCH2CH2CH2
108b Me 1 ,4-CeH4 bond 4-F-Ph bond Ph HOC(Me)2CH2
109b Et 4-Br-Ph bond H bond Ph HOCH2CH(OH)CH2
110b Me 4-Br-Ph bond H bond 4-F-Ph H2NCOCH2CH2
111 b Et 4-Br-Ph bond H bond 4-F-Ph HOCH2CH2CH2
112b Me 1 ,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph NCCH2
2,4-dιMe-5-
113b Me 1 ,4-C6H4 bond bond 4-F-Ph allyl thiazolyl
114b Me 1 ,4-CeH4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
115b Me 1 ,4-C6H4 bond 4-F-Ph bond 2-F-Ph HOCH2CH2CH2
116b Me 1 ,4-CeH4 bond 4-F-Ph bond 3-F-Ph HOCH2CH2CH2
117b Me 1 ,4-CeH4 bond 4-F-Ph bond Ph HOC(Me)2CH2CH2
118b Me 1 ,4-CeH4 bond 5-MeCO-2-thιenyl bond Ph HOCH2CH2CH2
119b Me 1 ,4-CeH4 bond 2,4-dιF-Ph bond Ph H2NCOCH2CH2 120b Me 1,4-CeH11 bond 5-(H2NCHMe)-2- thienyl bond Ph HOCH2CH2CH2
121b Et 1,4-C6H4 bond 4-F-Ph bond 4-F-Ph HOCH2CH2CH2
122b Et 1,4-CeH4 bond 2,4-dιF-Ph bond Ph HOCH2CH2CH2
123b Me 1,4-CeH4 bond 5-(HOCHMe)-2- thienyl bond Ph HOCH2CH2CH2
124b Et 4-Br-Ph bond H bond 4-F-Ph HOCH2CH(OH)CH2
125b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCH2CH2CH2
126b Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHCH2CH2
127b Me 1,4-CeH4 bond 3-(CF3)-1- pyrazolyl bond 4-F-Ph allyl
128b Me 1,4-CeH4 bond 2,4-dιF-Ph bond Ph HOC(Me)2CH2CH2
129b Et 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2CH2
130b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeSCH2CH2
131b Me Ph bond 2,4-dιF-Ph bond 4-F-Ph H2NCOCH2CH2
132b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCOCH2CH2
133b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph HOCH2CH2OCH2CH2
134b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph 2-(1-ιmιdazolyl)ethyl
135b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeCONMeCH2CH2
136b Me 1,4-C6H4 bond 4-F-Ph bond Ph MeSO2NHCH2CH2CH2
137b Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCf=O)NHCH2CH2CH2
138b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCf=O)OCH2CH2CH2
139b Me 1,4-CeH4 bond 2,4-dιF-Ph bond 4-F-Ph 2-(1 -amιnoιmιdazol-1 -yl)ethyl
140b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph MeNHC(=O)NHCH2CH2CH2
141b Me 1,4-C6H4 bond 2,4-dιF-Ph bond 4-F-Ph H2NCf=O)NHCH2CH(OH)CH2
142b Me 1,4-C6H4 bond 4-F-Ph bond 4-F-Ph MeSO2NHCH2CH(OH)CH2
143b Me 1,4-CeH4 bond 4-F-Ph bond 4-F-Ph MeSO2NMeCH2CH(OH)CH2
144b Me 1,4-CeH4 bond 6-CF3-3-pyπdyl bond 4-F-Ph HOCH2CH2CH2
145b Me 4-MeO-Ph bond H bond Ph HOCH2CH2CH2
146b Me 3-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
147b Me 2-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
148b Me 4-F-Ph bond H bond 4-F-Ph HOCH2CH2CH2
149b Me 4-MeO-Ph bond H bond Ph HOCH2CH(OH)CH2 150b IMe 4-CI-Ph bond H bond Ph H2NCOCH2CH2
151b Me 4-MeO-Ph bond H bond 4-F-Ph H2NCOCH2CH2
152b Me 4-F2HCO-Ph bond H bond 4-F-Ph allyl
153b Me Ph bond 3-pyrazolyl bond Ph HOCH2CH2CH2
154b Me 1,4-C6H4 bond 5-F-3-pyrιdyl bond Ph allyl
155b Me 3-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
156b Me 4-CF3-Ph bond H bond 4-F-Ph HOCH2CH2CH2
157b Me 1,4-CeH-i bond 3-pyπdyl bond Ph HOCH2CH2CH2
158b Me 1 ,4-CeH4 bond 4-pyrιdyl bond Ph HOCH2CH2CH2
159b Me 1,4-C6H4 bond 4-F-Ph bond Ph HOCH2CH2CH2
160b Me 1,4-C6H4 bond 5-F-3-pyrιdyl bond Ph HOCH2CH2CH2
161b Me 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2
162b Me 1,4-C6H4 bond 5-F-3-pyrιdyl bond 4-F-Ph HOCH2CH2CH2
163b Me 1 ,4-C6H4 bond 4-F-Ph bond Ph NCC(Me)2CH2
164b Me 1,4-C6H4 bond 6-MeO-3-pyπdyl bond Ph H2NCOCH2CH2
165b Me 1 ,4-CeH4 bond 5-MeO-3-pyπdyl bond 4-F-Ph HOCH2CH2CH2
166b Me 1,4-C6H4 bond 5-CI-3-pyrιdyl bond 4-F-Ph HOCH2CH2CH2
167b Me 1,4-C6H4 bond 3-pyrιdyl bond Ph MeSO2NHCH2CH2
168b Me 4-F2HCO-Ph bond H bond 4-F-Ph HOCH2CH2CH2
169b Me 1 ,4-C6H4 bond 4-F-Ph bond Ph (HO)2Pf=O)OCH2CH2CH2
170b Me 1AC6H4 bond 2-Me-4-pyrιdyl bond 4-F-Ph HOCH2CH2CH2
4-(HOC(Me)2CH2-
171b Me bond H bond Ph HOCH2CH2CH2 Ph
1-Me-6-oxo-3-
172b Me 1,4-CeH4 bond (1,6- bond Ph HOCH2CH2CH2 dihydropyndyl)
173b Me 4-MeO-Ph bond H bond 4-F-Ph MeSO2NHCH2CH2CH2
174b Me 4-MeO-Ph bond H bond Ph H2NCOCH2CH2
175b Me 4-F-Ph bond H bond 4-F-Ph H2NCOCH2CH2
176b Me c-hex bond H bond 4-F-Ph H2NCOCH2CH2
177b Me c-hex bond H bond 4-F-Ph MeSO2NHCH2CH2CH2 Cy1 = 1 ,3-C6H4 means
Figure imgf000069_0001
Cy ,11 _ = 1 ,4-C6H4 means )C6H3 means
Figure imgf000069_0002
= 2,6-(5-CI)-pyridyl means
Figure imgf000069_0003
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.
A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I1 comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore. The invention includes a therapeutic method for treating or ameliorating an
1 1 β-HSD1 mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof of composition thereof. As used herein, "treating" or "treatment" includes both therapeutic and prophylactic treatment. Therapeutic treatment includes reducing the symptoms associated with a disease or condition and/or increasing the longevity of a subject with the disease or condition. Prophylactic treatment includes delaying the onset of a disease or condition in a subject at risk of developing the disease or condition or reducing the liklihood that a subject will then develop the disease or condition in a subject that is at risk for developing the disease or condition.
An embodiment of the invention includes administering an 11β-HSD1 inhibiting compound of Formula I or composition thereof 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® (EIi Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitizone 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® and (glipizide, Pfizer); meglitinides, such as Prandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase®/Glucophase XR® (metformin HCI, Bristol Myers Squibb) and Glumetza (metformin HCI1 Depomed); thiazolidinediones; amylin analogs, GLP-1 analogs; DPP-IV inhibitors; PTB-1 B inhibitors; protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase kinase-3 beta inhibitors; glucose-6-phoshatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors, and alpha-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 ezetimbe. Agents for the treatment of hypertension include alpha-blockers, beta-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 11 β-HSD1 inhibiting compound of Formula I or composition thereof in a combination therapy with one or more other 11β-HSD1 inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCI and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCI1 Bristol Myers Squibb); and Glucovance® (glyburide and metformin HCI, Bristol Myers Squibb).
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, intracutaneous^, subcutaneously, intraduodenally, or intraperitoneal^. 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 dispersible 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 caboxymethylcellulose, 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 carboxymethylcellulose, 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 1 β-HSD1 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.
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 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

CLAIMSWhat is claimed is:
1. A compound of Formula (I)
Figure imgf000074_0001
R1 is (a) hydrogen or (b) is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl or (Ci-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)-, R4SC=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-, aryl, cycloalkyl, heterocyclyl, heteroaryl, arylamino and heteroarylamino;
Cy1 is 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, (d-C6)alkyl, hydroxy(Cr 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, haloiC^CeJalkoxy, 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(C1-C6)alkane-sulfinyll halo(C3-C6)cycloalkanesulfinyl, halo(C4-
C7)cycloalkylalkanesulfinyl, (d-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-
C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, (^(CrCeJalkylamino, (d-CeJalkoxytd-CeJalkoxy, halotd-CeJalkoxy^rCeJalkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, (Ji(C1- C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (d-CβJalkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclsulfonyl, (d-CβJalkylcarbonylamino, (Ci-C6)alkylcarbonylamino(C1- C6)alkyl, (d-CeJalkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1- C6)alkoxycarbonyl(d-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1- C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(d -C6)alkyl, (C1- C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C-i- C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxyl and (C1- C6)alkylcarbonyl;
A2 is (a) a bond, O, S or NR4; or (b) (CrC3)alkylene or (d-C^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, (CrC6)alkyl, hydroxy(C1-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, (C1-C6JaIkOXy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (C^CeJalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo^-CeJalkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d-CeOalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Cr
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(Ci-C6)alkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (CrCeJalkoxycarbonyl, H2NCO,
Figure imgf000076_0001
C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-CβJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (Ci-C6)alkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (C1- C6)alkoxy(CrC6)alkyl, halo(C1-C6)alkoxy(Ci-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, arnino(C1-C6)alkyl, (Ci-C6)alkylamino(C1-C6)alkyl, di(d- C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, CIi(C1- C6)alkylamino(C2-C6)alkoxyl and (Ci-C6)alkylcarbonyl;
t is 1 , 2 or 3;
Y is (CrCβ)alkyl or halo(C1-C6)alkyl;
n is O, 1 or 2;
E is (a) a bond or (b) (CT-CaJalkylene 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 (CrC6)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-Cβ)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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6)SIkOXy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (CT-C^alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(CrC6)alkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrCβJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (d-CβJalkylamino, di(Ci-C6)alkylamino, (C1-C6JaIkOXy(C1- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (d-CβJalkoxycarbonyl, H2NCO, H2NSO2, (CrC^alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1- CsJalkoxytd-C^alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, dKCrCβJalkylaminosulfonyl, heterocyclsulfonyl, (C1-C6)alkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (d-C^alkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (CrCeJalkoxycarbonyKCrCeJalkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl,
Figure imgf000077_0001
di(C1- C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(Cr C6)alkylamino(C2-C6)alkoxyl and (CrC^alkylcarbonyl;
R3 is selected from hydrogen, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C1- C3)alkoxy(CrC3)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)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);
Q is O or NR5;
R4 is independently selected from H, (d-C6)alkyl, halo(C1-C6)alkyl, amino(Cr C6)alkyl, (d-Ce^lkylamino^-CeJalkyl, dKCrCfOalkylamino^-C^alkyl, hydroxy(C1- C6)alkyl and (C1-C6)alkoxy(C1-C6)alkyl;
R5 is H, (CrC6)alkyl, halo(Ci-C6)alkyl, or hydroxy(CrC6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
2. The compound of claim 1 wherein
Cy1 is phenyl, naphthyl, indanyl, tetrahydronaphthalene, 2- or 3-thienyl, 2- or 3- furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyhmidinyl, 3- or 4-pyridazinyl, 1 H-indol-6-yl, 1 H-indol-5-yl, 1 H-benzimidazol-6-yl, 1 H-benzimidazol-5- yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6- , 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, A-, or 5-pyrazolyl, 2-, 3-, 4-, (all of which may be optionally substituted), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidine, pyrrolidin-2- one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4-pyridone, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, piperazin-2-one, 5,6-dihydropyrimidin-4- one, pyrimidin-4-one, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1 ,3-dioxolane, 1 ,3-dithiolane, 1 ,3-dioxane, 1 ,4- dioxane, 1 ,3-dithiane, 1 ,4-dithiaπe, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(1 H)-one, morpholine, N- methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1 ,1 -dioxide, tetrahydro-1,2,5-thiaoxazole 1 ,1 -dioxide, tetrahydro-2H- 1 ,2-thiazine 1 ,1 -dioxide, hexahydro-1 ,2,6-thiadiazine 1 ,1 -dioxide, tetrahyd ro- 1 ,2,5- thiadiazole 1 ,1 -dioxide or isothiazolidine 1 ,1 -dioxide, 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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (C1-C6JaIkOXy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(d-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C1- C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (C1- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkane-sulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-
C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4- C7)cycloalkylalkanesulfonyl, halo(d-C6)alkanesulfonyl, halo(C3-
C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(C1-C6)alkoxy, (d-C6)alkoxycarbonyl, H2NCO, H2NSO2, (d-CeJalkylaminocarbonyl, di(d- C6)alkylaminocarbonyl, (C1-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (d-CeJalkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclsulfonyl, (d-CeJalkylcarbonylamino, (Ci-C6)alkylcarbonylamino(d- C6)alkyl, (d-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1- C6)alkoxycarbonyl(d-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1- C6)alkyl, hydroxy(d-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (C1- C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(d-C6)alkylamino(C2-C6)alkoxyl and (C1- C6)alkylcarbonyl; and
E is a bond or (Ci-C3)alkylene optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R3 is selected from hydrogen, (d-CβJalkyl, (C2-C6)alkenyl and (C2-Cβ)alkynyl, 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)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) and 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).
3. The compound of claim 1 or 2 wherein the compound is of Formula (Ia).
Figure imgf000080_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
4. The compound of claim 1 or 2 wherein the compound is of Formula (Ib).
Figure imgf000080_0002
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
5. The compound of claim 1 or 2 wherein the compound is of Formula (Ic).
Figure imgf000081_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
6. The compound of claim 1 or 2 wherein the compound is of Formula (Id):
Figure imgf000081_0002
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
7. The compound of any one of claims 1-6 wherein R1 is (Ci-C6)alkyl.
8. The compound of claim 7, wherein R1 is methyl or ethyl.
9. The compound of claim 8, wherein R1 is unsubstituted.
10. The compound of any one of claims 1-6, wherein Cy1 is optionally substituted aryl or optionally substituted heteroaryl.
11. The compound of any one of claims 1-6, wherein Cy1 is optionally substituted phenyl or optionally substituted pyridyl.
12. The compound of claim 1 1 , wherein Cy1 is optionally substituted phenyl.
13. The compound of claim 12, wherein Cy1 is substituted with fluorine, chlorine, bromine, methoxy, methoxycarbonyl, carboxy, methyl, trifluoromethyl or difluoromethoxy.
14. The compound of claim 12, wherein A2 is a bond and Cy2 is hydrogen.
15. The compound of claim 12, wherein A2 is a bond and Cy2 is cyclopropyl.
16. The compound of claim 12, wherein A2 is a bond and Cy2 is optionally substituted aryl or optionally substituted heteroaryl.
17. The compound of claim 12, wherein A2 is a bond and Cy2 is optionally substituted phenyl or optionally substituted pyridyl.
18. The compound of claim 17, wherein Cy2 is optionally substituted phenyl.
19. The compound of claim 18, wherein Cy2 is substituted with 1 to 4 groups independently selected from chlorine or fluorine.
20. The compound of claim 18, wherein Cy2 is difluorophenyl.
21. The compound of any one of claims 1-6, wherein R3 is hydroxy(C2-C5)alkyl.
22. The compound of any one of claims 1-6, wherein R3 is dihydroxy(C3-C5)alkyl.
23. The compound of any one of claims 1-6, wherein R3 is ω-H2NCO(C1-C3)alkyl.
24. The compound of any one of claims 1 -6, wherein R3 is (C1-C2JaIkOXy(C1- C3)alkyl.
25. The compound of any one of claims 1-6, wherein R3 is H2NSO2O(C2-C4)alkyl.
26. The compound of any one of claims 1-6, wherein R3 is H2NSO2NH(C2- C4)alkyl.
27. The compound of any one of claims 1-6, wherein R3 is MeC(=O)NH(C2- C4)alkyl.
28. The compound of any one of claims 1-6, wherein R3 is MeOC(=O)NH(C2- C4)alkyl.
29. The compound of any one of claims 1-6, wherein R3 is cyanoalkyl.
30. The compound of any one of claims 1-6, wherein R3 is alkylsulfonylaminoalkyl.
31. The compound of any one of claims 1-6, wherein R3 is aminocarbonylaminoalkyl.
32. The compound of any one of claims 1-6, wherein R3 is aminocarboxyalkyl.
33. The compound of any one of claims 1-6, wherein R3 is 2-(4-morpholino)ethyl.
34. The compound of any one of claims 1-6, wherein R2 is optionally substituted aryl, optionally substituted heteroaryl or cycloalkyl.
35. The compound of claim 34, wherein R2 is optionally substituted phenyl, optionally substituted thienyl or optionally substituted pyridyl.
36. The compound of claim 35, wherein R2 is optionally substituted phenyl.
37. The compound of claim 36, wherein R2 is fluorophenyl.
38. The compound of any one of claims 1-6 wherein: R1 is hydrogen, methyl or ethyl; Cy1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl optionally substituted with 1 to 4 groups independently selected from halo, methyl, trifluoromethyl, hydroxy, methoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl and methylsulfonylamino; A2 is a bond, O, OCH2CO or C=O;
Cy2 is (a) hydrogen or (b) phenyl, thienyl, pyridyl, N-oxo-pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S1S- dioxothiazinyl, 2-oxo-1 ,2-dihydropyridyl optionally substituted by 1 to 4 groups independently selected from halo, hydroxy, methoxy, hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, (2- methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl, methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl and 1-aminoethyl; n is O; t is 1 , 2 or 3; E is a bond or CH2; R2 is isopropyl, thienyl, phenyl, or pyridyl, each optionally substituted with halo, methyl, methylthio or (4-morpholino)methyl;
R3 is hydrogen, methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl, each optionally substituted with up to two groups independently selected from HO-, MeO-, H2N-, MeC(=O)NH-, MeS(=O)2NH-, H2NC(O)-, MeNHC(=0)-, HO2C-, (HO)2P(=O)O-, H2NS(O)2O-, H2NS(O)2NH-, MeNHC(O)NH-, MeNHC(O)O- oxo, cyano, HO2C-, HOCH2CH2NH-, 4-morpholino, HOCH2C(O)NH-, H2NCH2C(O)NH-, EtNHC(O)NH, MeOC(O)NH-, MeNHC(=NC≡N)NH-, Me-, MeS-, MeSO2- MeSO2N(Me)-, MeS(O)2NHC(O)-, imidazolylamino-, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH-, Me2N- and MeCONMe.
39. The compound of claim 1 or 2 wherein the compound is of Formula (Ie)
Figure imgf000085_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
40. The compound of claim 1 or 2 wherein the compound is of Formula (If)
Figure imgf000085_0002
If
R' or a pharmaceutical acceptable salt, enantiomer or diastereomer thereof.
41. The compound of claim 1 or 2 wherein the compound is of Formula (Ig)
Figure imgf000085_0003
wherein:
m is 0, 1 , 2, 3 or 4; and
X is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)alkyl, hydroxy(C1-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(d- C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6JaIkOXy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (d-CeJalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(CrC6)alkane-sulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, FIaIo(C1-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, dKCrCeJalkylamino, (C1-C6)SIkOXy(C1- C6)alkoxy, halo(Ci-C6)alkoxy(CrC6)alkoxy, (d-CeJalkoxycarbonyl, H2NCO, H2NSO2, (CrCeJalkylaminocarbonyl, dKd-Ce^lkylaminocarbonyl, (C1- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl,
Figure imgf000086_0001
Figure imgf000086_0002
heterocyclsulfonyl, (d-CβJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(C1-C6)alkyl, (CT-CeJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(CrC6)alkyl, (CrCeJalkoxycarbonyKCrCeJalkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(CrC6)alkyl, (CrCeJalkylamino^rCeJalkyl, di(C1-C6)alkylamino(C1- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2- C6)alkoxyl and (CrC6)alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
42. The compound of claim 1 or 2 wherein the compound is of Formula (Ih)
Figure imgf000086_0003
wherein: r and s are independently 0, 1 , 2, 3 or 4; and
G1 and G2 are independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-Ce^lkyl, 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(Cr C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(d-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio, (d-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C1-C6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (d-C6)alkylamino, di(C1-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(CrC6)alkoxy, (CrCeJalkoxycarbonyl, H2NCO, H2NSO2, (Ci-CeOalkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (d-CβJalkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclsulfonyl, (Ci-CeJalkylcarbonylamino, (Ci- C6)alkylcarbonylamino(C1-C6)alkyl, (Ci-C6)alkylsulfonylamino, (C1-
C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-CβJalkoxycarbonyKCrCeJalkoxy, (Cr C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(Ci-C6)alkyl,, hydroxy(CrC6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(CrC6)alkylamino(C1- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2- C6)alkoxyl and (Ci-C6)alkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
43. The compound of claim 1 or 2 wherein the compound is of Formula (Ii)
Figure imgf000088_0001
wherein:
r is 0,1 , 2, 3 or 4;
G is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(C1-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, FIaIo(C1- C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6)BIkOXy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrCeJalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (CTCβJalkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-
C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CTCeJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (d-C6)alkylamino, di(C1-C6)alkylamino, (CrCeJalkoxy^!- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (CrCeJalkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, dKCrQOalkylaminocarbonyl, (Ci- C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclsulfonyl, (C^CeJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(CrC6)alkyl, (CrCeJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(C1-C6)alkyl, (CrCeJalkoxycarbonyKd-CeJalkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,, hydroxy(C1-C6)alkoxy, heteroaryl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1- C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-
C6)alkoxy! and (CrC6)alkylcarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
44. 6-Allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1 ,3-oxazinan-2-one or a pharmacuetically acceptable salt, enantiomer or diastereomer thereof.
45. A method of treating a subject with a disease associated with the activity or expression of 11 β-HSD1 , comprising the step of administering to the subject an effective amount of the compound of any one of claims 1-44.
46. A method of inhibiting 11 β-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of the compound of any one of claims 1-44.
47. A pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) the compound of any one of claims 1-44.
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