WO2009134387A1 - Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 - Google Patents

Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 Download PDF

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Publication number
WO2009134387A1
WO2009134387A1 PCT/US2009/002633 US2009002633W WO2009134387A1 WO 2009134387 A1 WO2009134387 A1 WO 2009134387A1 US 2009002633 W US2009002633 W US 2009002633W WO 2009134387 A1 WO2009134387 A1 WO 2009134387A1
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Prior art keywords
alkyl
halo
crc
alkoxy
cycloalkyl
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PCT/US2009/002633
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French (fr)
Inventor
David A. Claremon
Linghang Zhuang
Katerina Leftheris
Colin M. Tice
Yuanjie Ye
Suresh B. Singh
Frank Himmelsbach
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Vitae Pharmaceuticals, Inc.
Boehringer Ingelheim International Gmbh
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Priority claimed from PCT/US2008/009017 external-priority patent/WO2009017664A1/en
Application filed by Vitae Pharmaceuticals, Inc., Boehringer Ingelheim International Gmbh filed Critical Vitae Pharmaceuticals, Inc.
Priority to JP2011507445A priority Critical patent/JP5538365B2/en
Priority to EP09739190.8A priority patent/EP2291370B1/en
Priority to CA2723034A priority patent/CA2723034A1/en
Priority to US12/990,296 priority patent/US8592410B2/en
Publication of WO2009134387A1 publication Critical patent/WO2009134387A1/en

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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 (11 ⁇ -HSD) 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 , 11betaHSD1 , HSD11 B1 , HDL, and HSD11 L
  • 11 ⁇ -HSD2 also known as 11-beta-HSD type 1 , 11betaHSD1 , HSD11 B1 , HDL, and HSD11 L
  • 11 ⁇ -HSD1 is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 11-keto forms
  • 11 ⁇ -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.
  • 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.
  • 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. (1997), Proc. Natl. Acad. Sci. USA 94(26): 14924-9).
  • 11 ⁇ -HSD1 catalyzes both 11-beta-dehydrogenation and the reverse 11- oxoreduction reaction
  • 11 ⁇ -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).
  • 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.
  • 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).
  • glucocorticoids and 11 ⁇ -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 eventually blindness.
  • lOP intra-ocular pressure
  • 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, 11 ⁇ -HSD1 inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders.
  • 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 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 ⁇ -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) Banner'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.
  • 11 ⁇ -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, monocyclic cycloalkyl or monocyclic heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC ⁇ Jalkyl, hydroxy(Ci- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 - C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 - C 6 )cycloalkyl(C 2 -C 4 )alkynyl, halo(C r C 6 )alkyl, hal
  • E is (a) a bond or (b) (Ci-C 3 )alkylene or (Ci-C 2 )alkylenyloxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
  • R 2 is (C r C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(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 -
  • R 4 is independently selected from H, (Ci-C ⁇ Jalkyl, halo(CrC 6 )alkyl, amino(Ci- C 6 )alkyl, (Ci-C 6 )alkylamino(Ci-C 6 )alkyl, di(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, hydroxy(C r C 6 )alkyl and (Ci-C 6 )alkoxy(Ci-C 6 )alkyl.
  • Another embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising i) a pharmaceutically acceptable carrier or diluent, and ii) a compound of Formulas I 1 Ik, Im 3 , Im 4 , Im 6"12 , In 3 , In 4 , In 6"12 , lo 3 , lo 4 , lo 6"12 , Ip 2 , or Ip 4"7 , or a pharmaceutically acceptable salt, enantiomer or 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, Ik, Im 3 , Im 4 , Im 6"12 , In 3 , In 4 , In 6"12 , lo 3 , lo 4 , lo 6"12 , Ip 2 , or Ip 4"7 , 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, Ik, Im 3 , Im 4 , Im 6"12 , In 3 , In 4 , In 6"12 , lo 3 , lo 4 . lo 6"12 , Ip 2 , or Ip 4"7 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Another embodiment of the invention is the use of a compound of Formulas I, Ik 1
  • Another embodiment of the invention is the use of a compound of Formulas I, Ik, Im 3 , Im 4 , Im 6"12 , In 3 , In 4 , In 6"12 , lo 3 , lo 4 , lo 6 12 , Ip 2 , or Ip 4"7 , 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, Ik, Im 3 , Im 4 , Im 6 - 12 , In 3 , In 4 , In 6"12 , lo 3 , lo 4 , lo 6"12 , Ip 2 , or Ip 4"7 , 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 I, Ik 1 Im 3 , Im 4 , Im 6"12 , In 3 , In 4 , In 6"12 , lo 3 , lo 4 , lo 6"12 , Ip 2 , or Ip 4'7 , 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.
  • R 1a is absent or is methyl or ethyl
  • Cy 2 is 2,3-dihydro-3-oxopyridazinyl, 1 ,2- dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl, or 1 ,2-dihydro-2-oxopyrazinyl and is optionally substituted
  • R 2 is (CrC 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Cr C 6 )alkyl, hydroxy(CrC 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 - C 7 )cycloalkylalkyl,
  • Another embodiment of the invention is a compound of any one of Formulas Im 3 , Im 4 and Im 6'12 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
  • the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable ring nitrogen atom") with up to four substituents as described for Cy 2 in the first embodiment.
  • Suitable substituents for Cy 2 and suitable values for R 1 , R 2 , R 3 , A 1 , Cy 1 and E are as defined above in the first embodiment.
  • suitable substituents for Cy 1 and the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 3 , Im 4 and Im 6"12 are independently fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-C ⁇ )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, (C3-C 6 )cycloalkyl(C 2 )
  • suitable substituents for Cy 1 include (CrC 4 )alkyl, (CrC 4 )alkoxy, (CrC 4 )haloalkyl, (Ci-C 4 )haloalkoxy, halogen, cyano and nitro;
  • suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 3 , Im 4 and Im 6"12 include (CrC 4 )alkyl, (C 3 - C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(CrC 2 )alkyl, and (CrC 4 )haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and
  • R 1 is preferably methyl or ethyl.
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (Ci-C 4 )alkyl, (C r C 4 )haloalkyl, and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (Ci-C 4 )alkyl, (CrC 4 )haloalkyl, and SO 2 Me
  • R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methy I propyl
  • the substituent on the substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im 3 , Im 4 and Im 6"12 is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, or (C r C 2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridazinyl, oxo
  • Another embodiment of the invention is a compound of any one of Formulas In 3 , In 4 and In 6'12 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
  • the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable ring nitrogen atom") with up to four substituents as described for Cy 2 in the first embodiment.
  • Suitable substituents for Cy 2 and suitable values for R 1 , R 2 , R 3 and Cy 1 are as defined above in the first embodiment.
  • suitable substituents for Cy 1 and the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 3 , In 4 and In 6"12 are independently fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 - C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(
  • suitable substituents for Cy 1 include (CrC 4 )alkyl, (CrC 4 )alkoxy, (Ci-C 4 )haloalkyl, (CrC 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In 3 , In 4 and In 6"12 include (CrC 4 )alkyl, (C 3 - C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(CrC 2 )alkyl and (CrC 4 )haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl; and R 3 is
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (CrC 4 )alkyl, (CrC 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (C 1 -C 4 )SlKyI, (CrC 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • In 4 and In 6"12 is (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, or (Ci-C 2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodi
  • the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable ring nitrogen atom") with up to four substituents as described for Cy 2 in the first embodiment; suitable values for G 1 are fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )al
  • n is 0, 1 , 2 or 3;
  • suitable values for G 1 and substituents for the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo 3 , lo 4 and lo 6"12 are independently fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-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
  • n is O 1 1 , 2 or 3;
  • suitable values for G 1 include (CrC 4 )alkyl, (CrC 4 )alkoxy, (C 1 -C 4 )haloalkyl, (CrC 4 )haloalkoxy, halogen, cyano and nitro;
  • suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo 3 , lo 4 and lo 6 12 include CrC 4 alkyl, (C 3 - C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(CrC 2 )alkyl and CrC 4 haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridazinyl, oxodihydropyrimi
  • R 1 is preferably methyl or ethyl.
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (CrC 4 )alkyl, (d-C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (CrC 4 )alkyl, (C r C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • the substituent on the substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo 3 , lo 4 and lo 6"12 is (CrC 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C r C 2 )alkyl, or (C 1 -C 2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydro
  • n is 0 or 1 , preferably 0; each G 1 is independently (Ci-C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (CrC 4 )haloalkoxy, halogen, cyano or nitro; the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl are substituted at a substitutable ring nitrogen atom with hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkylcarbonylamino(CrC6)alkyl, (Ci- C 6 )alkylsulfonylamino(Ci-C 6
  • R 3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the First Alternate Embodiment.
  • R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the First Alternate Embodiment.
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted with methyl or ethyl; and the remainder of the variables are as described in the First Alternate Embodiment.
  • n is 0 and all of the substitutable ring carbons in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are preferably unsubstituted.
  • Another embodiment of the invention is a compound represented by any one of Formulas Ip 2 and Ip 4'7 , or a pharmaceutically acceptable salt thereof:
  • G 1 is (C r C 4 )alkyl, (CrC 4 )alkoxy, (C r C 4 )haloalkyl, (C r C 4 )haloalkoxy, halogen, cyano or nitro; n is 0, 1 or 2; G 2a is (Ci-C 4 )alkyl, (C 3 - C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl or (CrC 4 )haloalkyl; G 2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (CrC 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 - C 4 )cycloalkyl(C r C 2 )alkyl, halo(d-C 4 )alkyl, (CrC 4 )alkoxy,
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (CrC 4 )alkyl, (Ci-C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH 2 , (Ci-C 4 )alkyl, (CrC 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl; and R 3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • the substituent G 2a is selected from (CrC 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(CrC 2 )alkyl, and (Ci-C 2 )haloalkyl
  • G 2b is optionally selected from hydrogen, methyl or ethyl.
  • Embodiment is a compound represented by Structural Formulas Ip 2 and Ip 4"7 , wherein: n is O or 1 , preferably O; each G 1 is independently (CrC 4 )alkyl, (CrC 4 )alkoxy, (CrC 4 ) haloalkyl, (C r C 4 )haloalkoxy, halogen, cyano or nitro; G 2a is hydroxy(CrC 6 )alkyl, (C r C 6 )alkylcarbonylamino(CrC 6 )alkyl, (CrC 6 )alkylsulfonylamino(CrC 6 )alkyl, (Cr C 6 )alkoxy(CrC 6 )alkyl, amino(CrC 6 )alkyl, (CrC 6 )alkylamino(CrC 6 )alkyl, di(d- C 6 )alkylamino(CrC
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the Second Alternate Embodiment.
  • R 2 is phenyl or fluorophenyl; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the Second Alternate Embodiment.
  • R 2 is phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • one or two substitutable ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted with methyl or ethyl; and the remainder of the variables are as described in the Second Alternate Embodiment.
  • n O and G 2b is preferably -H.
  • Compounds of the invention are also disclosed in INHIBITORS OF 11 ⁇ - HYDROXYSTEROID DEHYDOGENASE I 1 U.S. Provisional Application No. 61/ 61/135,933, filed July 25, 2008 (Attorney Docket No. 4370.1000-000); Cyclic Inhibitors Of 11 ⁇ -Hydroxysteroid Dehydrogenase 1, U.S. Provisional Application No. 61/135,933, filed May 1 , 2008; Cyclic Inhibitors Of 11 ⁇ -Hydroxysteroid Dehydrogenase 1 , U.S.
  • 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 (c- Pr), 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 ⁇ 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-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1 H-indol-5-yl, I H-benzimidazol-6-yl, 1H- 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-
  • 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 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O 1 and S.
  • exemplary heterocyclyls include pyrrolidine, pyrrolidin-2-one, 1- methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4- oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4- oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1
  • a heterocyclyl can be optionally substituted with 1-4 substituents.
  • substituents include alkyl, haloalkyl, halogen and oxo.
  • spirocycloalkyl means a cycloalkyl group which shares one ring carbon with another alkyl or cycloalkyl group.
  • 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.
  • the term “compound” also includes labeling at one or more positions with deuterium. "Labeled with deuterium at a position” means that the amount deuterium at the position is greater than the amount that is present at natural abundance. In certain instances, the deuterium at each position in a “compound” is at natural abundance.
  • 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.
  • 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 enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • a disclosed compound 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.
  • 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 basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine 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
  • Cy 2 is an optionally substituted 3-oxo-2,3-dihydropyridazinyl, 6- oxo-1 , 6-dihydropyrimidinyl, 2-oxo-1 ,2-dihydropyrimidinyl or 2-oxo-1 ,2-dihydropyrazinyl group:
  • a compound of Formula I* can be prepared by reaction of an aminoalcohol intermediate of Formula Il with a reagent 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, CH2CI2, 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 thphosgene and as little as one third of molar equivalent can be used.
  • Aminoalcohol intermediates of Formula Il can be prepared by reduction of amides of Formula IV using 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 at 20 0 C to 100 0 C for between 1 h and 48 h:
  • a hydride reagent such as BH 3 THF solution, BH 3 -Me 2 S or LiAIH 4 in an inert solvent ethereal such as THF or DME
  • lntermediates of Formula IV can be prepared by coupling of a ⁇ -hydroxyacid of Formula V with an amine 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 CH 2 CI 2 at 0 - 30 °C for between 1 h and 24 h:
  • 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
  • Amine intermediates of Formula Vl wherein A 1 is a bond, R 1 is absent and Cy 1 is not an aromatic or heteroaromatic ring, can be prepared from ketones of formula VIII via oximes of Formula IX or by reductive amination of a ketone of Formula VIII with ammonia:
  • amine intermediates of Formula Vl wherein A 1 is CH and R 1 is methyl or ethyl, can be prepared by reduction t-butylsulfinylimines of Formula VIIIb which can be prepared from ketones of Formula Villa and f-butylsulfinamide or by addition of organometallic reagents of Formula R 1 M, wherein R1 is Me or Et and M is Li, MgCI, MgBr or MgI 1 to t-butylsulfinylimines of Formula VIIId which can be prepared from aldehydes of Formula VIIIc.
  • Intermediates of Formula Il can also be prepared by reductive amination of ⁇ - hydroxyaldehydes of Formula Xa with amines of Formula Vl.
  • Methods for the reductive amination of aldehydes are described in Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.
  • Aldehydes of Formula Xa can be prepared from homoallylic alcohols of Formula XXI by treatment with OsO 4 and NaIO 4 .
  • Epoxide compounds of formula XIV can, in turn, be prepared in a number of ways including, as described in Aube, J. "Epoxidation and Related Processes” Chapter 3.2 in Volume 1 of "Comprehensive Organic Synthesis” Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press, New York, 1992.
  • Hydroxynitrile intermediates of Formula XV can be prepared by treatment of ketones of Formula XVI with acetonitrile anion, formed by treatment of acetonitrile with n-BuLi or LDA, in an inert, anhydrous solvent such as THF at low temperature:
  • Amino-alcohol intermediates of Formula XII, wherein n is O can be prepared by treatment of sulfonate intermediates of Formula XVII, wherein R A is for example methyl, trifluoromethyl or p-methylphenyl, with ammonia:
  • XVII XII Amino-alcohol intermediates of Formula XII can be prepared by treatment of sulfonate intermediates of Formula XVII with sodium azide to give an azide intermediate of Formula XVIII, followed by catalytic hydrogenation or by Staudinger reduction with PPh 3 in wet THF:
  • Sulfonate intermediates of Formula XVII can be prepared from diol intermediates of Formula XIX with a sulfonyl chloride R A SO 2 CI:
  • Diol intermediates of Formula XIX can be prepared by hydroboration of allyl alcohols of Formula XX:
  • Diol intermediates of Formula XIX can be prepared by ozonolysis and reduction of homoallyl alcohols of Formula XXI:
  • Aminoalcohol intermediates of Formula II wherein A 1 is a bond, R 1 is absent, and Cy 1 is a heteroaryl group or an aryl group bearing at least one strongly electron withdrawing group such as CF 3 , can be prepared by reaction of an aminoalcohol intermediate of Formula XII with a compound of Formula XXII 1 wherein Cy 1 is a heteroaryl group or an aryl group bearing at least one strongly electron withdrawing group such as CF 3 and R B is a leaving group such a fluoro, chloro, bromo or iodo:
  • Aminoalcohol intermediates of Formula II, wherein A 1 is (Ci)alkylene can be prepared by reaction of an aminoalcohol of Formula XII with an aldehyde or methyl ketone of Formula XII in the presence of a reducing agent such as NaCNBH 3 or Na(OAc) 3 BH:
  • a compound of Formula I* can be prepared by reaction of a ketocarbamate of Formula XXIV, wherein R D is alkyl or arylalkyl group such as methyl, t-butyl or benzyl, with an organometallic reagent of Formula XXV wherein M includes, but is not limited to, MgCI, MgBr, MgI or Li:
  • organometallic reagent XXV is allylmagnesium bromide, allylzinc(ll) bromide, (2-methylallyl)magnesium chloride or (2-methoxy-2- oxoethyl)zinc(ll) bromide.
  • M is MgCI, MgBr or MgI
  • CeCI 3 it is advantageous to add CeCI 3 to the reaction mixture.
  • Ketocarbamates of Formula XXIV can be prepared by reaction of aminoketones of Formula XXVI with intermediates of Formula XXVII wherein R E is a leaving group such as chloride, succinyloxy, imidazolyl or t-butoxycarboxycarbonyl:
  • ⁇ -Dialkylaminoketones of Formula XXVIII are in turn derived from ⁇ , ⁇ -unsaturated ketones of Formula XXVII with dialkylamines of Formula R F NHR F .
  • a compound of Formula I* can be prepared by reaction of a compound of Formula XVII with an isocyanate of Formula XXIX in the presence of a base:
  • lsocyanates of Formula XXIX can be prepared from amines of Formula Vl by treatment with phosgene, diphosgene or triphosgene.
  • This third process is described in greater detail in U.S. Provisional Application Serial No. 61/137,013, filed July 25, 2008 entitled SYNTHESIS OF INHIBITORS OF 11 ⁇ -HYDROXYSTEROID DEHYDROGENASE TYPE 1 (Attorney Docket No. 4370.1001-000), the entire teachings of which are incorporated herein by reference.
  • a compound of Formula I* can be prepared by reaction of a halo compound of Formula, wherein Hal is chlorine or bromine, with an isocyanate of Formula XXIX in the presence of a base:
  • Halo compounds of Formula XXX can be prepared by reaction of ⁇ -haloketones of Formula XXXI with organometallic reagents of Formula XXV wherein M is a metal containing radical including MgCI, MgBr, MgI or Li. The reaction is optionally carried out in the presence of anhydrous cerium trichloride:
  • a compound of Formula I* wherein A 1 is CH 2 or CH 2 CH 2 and R 1 is absent, can be prepared by reaction of a compound of Formula XXXII, with a compound of Formula XXXIII, wherein A 1 is CH 2 or CH 2 CH 2 and R G is a leaving group such as Br, I, OSO 2 Me, OSO 2 CF 3 or OSO 2 Ph, in the presence of a base such as NaH or K 2 CO 3 :
  • a compound of Formula I* wherein A 1 is a bond and R1 is absent, can be prepared by reaction of a compound of Formula XXXII, with a compound of Formula XXII, wherein R B is a leaving group such as chloro, bromo, iodo or OSO 2 CF 3 , in the presence of a base such as K 2 CO 3 and a copper or palladium catalyst in an inert solvent such as dioxane, DMF or NMP at elevated temperature:
  • a compound of Formula I* can be prepared by Suzuki coupling of a compound of Formula XXXIV, wherein Cy 1 is aryl or heteroaryl and R x is bromo, iodo, or trifluoromethanesulfonyloxy, with a boronic acid (R ⁇ is hydrogen) or a boronate ester of Formula XXXV (R ⁇ is (C r C 6 )alkyl and the two groups R ⁇ taken together form a (CrCi 2 )alkylene group).
  • a compound of Formula XXXIV wherein Cy 1 is aryl or heteroaryl and R x is bromo, iodo, or trifluoromethanesulfonyloxy, can be reacted with bis(pinacolato)diboron in the presence of a palladium catalyst to give a boronate ester of Formula XXXVI which can be further reacted with a heterocyclic compound of Formula XXXVII, wherein R x is bromo, iodo, or trifluoromethanesulfonyloxy, again in the presence of a palladium catalyst, to give a compound of Formula I * .
  • a compound of Formula I * can be prepared from another compound of Formula I*.
  • a compound of Formula I * can be prepared from another compound of Formula I*.
  • a compound of Formula I* wherein 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 T 1 wherein R 1 or R 3 is ⁇ -hydroxy(Ci-C 6 )alkyl can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with sodium azide and reduced to give a compound of Formula I*, wherein R 1 or R 3 is ⁇ -amino(Ci- C ⁇ )alkyl.
  • a compound of Formula I* wherein R 1 or R 3 is amino(Ci-C 6 )alkyl, can be reacted with methanesulfonyl chloride to give a compound of Formula I*, wherein R 1 or R 3 is ⁇ methanesulfonylamino ⁇ (CrC 6 )alkyl.
  • a compound of Formula I*, wherein R 3 is (C 2 -C 6 )alkenyl can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a vicinal diol compound of Formula I*, wherein R 3 is vicinal dihydroxy(C 2 -C 6 )alkyl,.
  • a compound of Formula I*, wherein R 1 is (C 2 -C 6 )alkenyl can be reacted with ozone followed by NaBH 4 to give a compound of Formula I*, wherein R 1 is ⁇ - hydroxy(C r C 5 )alkyl.
  • a compound of Formula I* wherein R 3 is (C 2 -C 6 )alkenyl, can be reacted with ozone followed by NaBH 4 to give a compound of Formula I * , wherein R 3 is ⁇ - hydroxy(CrC 5 )alkyl.
  • a compound of Formula I*, wherein R 1 or R 3 is amino(C r C6)alkyl can be reacted with an (Ci-C 6 )alkyl isocyanate to give a compound of Formula I*. wherein R 1 or R 3 is (CrC6)alkylaminocarbonylamino(Ci-C 6 )alkyl.
  • R 1 or R 3 is (CrC 6 )alkoxycarbonylamino(CrC 6 )alkyl.
  • a compound of Formula I*, wherein R 1 or R 3 is amino(Ci-C 6 )alkyl can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I*, wherein R 1 or R 3 is aminosulfonylamino(CrC 6 )alkyl.
  • a compound of Formula I* wherein R 1 or R 3 is amino(Ci-C6)alkyl
  • a compound of Formula I* can be reacted with a (Ci-C 6 )alkylsulfamoyl chloride to give a compound of Formula I*, wherein R 1 or R 3 is (Ci-C 6 )alkylaminosulfonylamino(Ci-C6)alkyl.
  • a compound of Formula I* wherein R 1 or R 3 is hydroxy(Ci-C 6 )alkyl, can be reacted with chlorosulfonyl isocyanate to give a compound of Formula I*, wherein R 1 or R 3 is aminosulfonyloxy(Ci-C 6 )alkyl.
  • a compound of Formula I* wherein R 1 or R 3 is hydroxy(Ci-C6)alkyl, can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (CrC 6 )alkylamine or a di(Ci-C 6 )alkylamine to give a compound of Formula I*, wherein R 1 or R 3 is aminocarboxy(Ci-C 6 )alkyl, (d-C 6 )alkyl aminocarboxy(Ci-C 6 )alkyl or di(CrC 6 )alkyl aminocarboxy(Ci-C 6 )alkyl.
  • MeMgX wherein X is Cl, Br or I, to give a compound of Formula I*, wherein R 3 is 2- hydroxy-2-methylpropyl.
  • Halo compounds of Formula LIII can be formed by the treatment of ⁇ - haloketones of Formula XXXI with organometallic reagents of Formula LII 1 wherein M denotes MgCI 1 MgBr, MgI 1 ZnBr or ZnI and the reaction is optionally performed in the presence of anhydrous cerium trichloride in an inert anhydrous solvent, such as tetrahydrofuran, at about -25 to 0 0 C for about 0.5 h.
  • organometallic reagents of Formula LII 1 wherein M denotes MgCI 1 MgBr, MgI 1 ZnBr or ZnI and the reaction is optionally performed in the presence of anhydrous cerium trichloride in an inert anhydrous solvent, such as tetrahydrofuran, at about -25 to 0 0 C for about 0.5 h.
  • Cyclic carbamates of Formula LIV can be prepared from the reaction between ⁇ - haloalcohols of Formula LIII where Hal is a chloride and isocyanates of Formula XXXIX in the presence of a base, such as but not limited to DBU (1 ,8-diazabicyclo[5.4.0]undec- 7-ene), in a refluxing inert solvent, such as but not limited to tetrahydrofuran.
  • a base such as but not limited to DBU (1 ,8-diazabicyclo[5.4.0]undec- 7-ene
  • a refluxing inert solvent such as but not limited to tetrahydrofuran.
  • Tertiary alcohols of Formula LVII can be derived from trisubstituted alkenes of Formula LIV by first epoxidizing the alkene with an epoxidation reagent, such as m- CPBA (3-chloroperbenzoic acid), in an inert solvent, such as dichloromethane to produce the corresponding epoxides of Formula LV.
  • an epoxidation reagent such as m- CPBA (3-chloroperbenzoic acid)
  • an inert solvent such as dichloromethane
  • the resulting epoxide is then reductively ring opened to provide the corresponding tertiary alcohol I* via treatment with a strong hydride reagent, such as lithium triethylborohydride, in an anhydrous inert solvent, such as tetrahydrofuran.
  • a compound of the invention of Formula I *** is prepared by using a "Suzuki" coupling reaction of a boronate ester of Formula LIX with a haloheterocycle of Formula LX.
  • the boronate ester of Formula LIX is prepared by reaction of a bromide of Formula LVIII with bis(pinacolato)diboron.
  • LVIII is prepared by epoxidation of alkene LVII, followed by reductive epoxide opening as described above, for 2-methyl-2-hydroxypropyl group is introduced via epoxidation and hydride ring opening as described above for conversion of LIV to I**.
  • Step 1 (S)-1-bromo-4-(1-isocyanatoethyl)benzene
  • Step 2 i-chloro-S-phenylhex- ⁇ -en-S-ol
  • Step 3 (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
  • Step 4 (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3-oxazinan-2-one and 3-((R)-3-((S)-1 -(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propanal
  • (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3- oxazinan-2-one 31 g, 78 mmol
  • CuCI (19.3 g, 195 mmol) in dry DMF (150 mL) was added H 2 O (50 mL) and PdCI 2 (4.10 g, 23 mmol) at rt.
  • Step 5 (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3-oxazinan-2-one
  • Step 6 (S)-3-((S)-1- (4-bromophenyl) ethyl)-6- (2- hydroxy-2-methylpropyl)- 6- phenyl- 1 ,3- oxazinan-2- one
  • Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ⁇ 6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene.
  • the dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ⁇ 1.5 L which fine particles of a white solid developed.
  • the resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note: the wash is slightly exothermic).
  • the aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure.
  • the resulting material was subjected to flash silica chromatography (5-30 % ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt%, 3.1 :1 diastereomeric ratio favoring the desired diastereomer (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)- 6-phenyl-1 ,3-oxazinan-2-one, 32.3 % yield).
  • the material was used in Step 4 without further purification.
  • the resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1x500 mL of 30 wt% solution of sodium thiosulfate and 1x500 mL of saturated aqueous solution of sodium bicarbonate.
  • the wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is ⁇ 2.5 A% (220 nm), which in this example the wash sequence was repeated 3 times.
  • the resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer, (>99:1 dr).
  • the material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A% at 220 nm, 74:1 dr).
  • the mixture was degassed and refilled with N 2 gas 3 times. The mixture was then heated overnight at 90 0 C under protection of N 2 gas. After being cooled to rt, the mixture was diluted with EtOAc (30 ml_), washed with water (20 ml_). The aqueous layer was extracted with EtOAc (2 x 15 ml_). The combined organic layers were washed by water (15 ml_), brine (2 x 10 ml.) and dried over Na 2 SO 4 .
  • Step 2 (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3-oxazinan-2-one and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3-oxazinan-2-one.
  • Step 3 A mixture of (R)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3- oxazinan-2-one (1.067 g, 2.55 mmol, 1.0 equiv), the cobalt(ll) catalyst described in Preparation 3 (0.016 g, 0.0264 mmol, 0.010 equiv), TsCN (0.555 g, 3.06 mmol, 1.2 equiv), and PhSiH 3 (0.294 g, 2.72 mmol, 1.07 equiv) in EtOH (5 mL) was stirred at room temperature for 4 h.
  • Triphosgene (157 mg) was added to an ice-cold solution of 4-[(S)-1-(4-bromo- phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol (1 :1 diastereomeric mixture, 200 mg) and EtNZPr 2 (91 ⁇ L) in dichloromethane (5 ml_). The resulting solution was stirred with cooling for 2 h and at room temperature overnight. Then, the solution was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeCN/H 2 O/NH 3 ) to afford the title compounds in separate fractions.
  • the title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6- phenyl-3-((S)-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3- oxazinan-2-one and 5-bromo-1-methylpyrimidin-2(1 H)-one following a procedure analogous to that described in Example 1 Step 3.
  • 5-bromo-1-methylpyrimidin-2(1 H)- one was prepared from 5-bromopyrimidin-2-ol following a procedure analogous to that described in Example 1 Step 2.
  • the title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3- ((S)-I -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-6- yl)propanenitrile and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 1 Step 3.
  • 6-chloro-2-methylpyridazin-3(2H)- one was prepared from 6-chloropyridazin-3-(2H)-one following a procedure analogous to that described in Example 1 Step 2.
  • the title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1 -(4-(6-oxo-1 ,6-dihydropyrimidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan- 2-one by treatment with (i) TBSCI, (ii) NaH, MeI and (iii) Et 4 NF.
  • the title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1 -(4-(6-oxo-1 ,6-dihydropyridazin-3-yl)phenyl)ethyl)-1 ,3-oxazinan- 2-one by treatment with Ii) TBSCI, (ii) NaH, MeI and (iii) Et 4 NF.
  • the title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1 -(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one by treatment with (i) TBSCI, (ii) NaH, MeI and (iii) Et 4 NF.
  • the assay begins by dispensing 49 ⁇ l of substrate solution (5OmM HEPES, pH 7.4, 10OmM KCI, 5mM NaCI, 2mM MgCI 2 , 2 mM NADPH and 160 nM [ 3 H]cortisone (1 Ci/mmol)) and mixing in 1 ⁇ L of the test compounds in DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 ⁇ L of enzyme solution containing microsomes isolated from CHO cells overexpressing human 11 ⁇ -HSD1 (10-20 ⁇ g/ml of total protein) was added, and the plates were incubated for 90 minutes at rt.
  • substrate solution 5OmM HEPES, pH 7.4, 10OmM KCI, 5mM NaCI, 2mM MgCI 2 , 2 mM NADPH and 160 nM [ 3 H]cortisone (1 Ci/mmol)
  • the reaction was stopped by adding 50 ⁇ l of the SPA beads suspension containingiO ⁇ M 18 ⁇ -glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 ⁇ g/ml of anti-cortisol antibody (East Coast Biologies) in Superblock buffer (Bio-Rad).
  • the plates were shaken for 120 minutes at rt, and the SPA signal corresponding to [ 3 H]cortisol was measured on a Microbeta plate reader.
  • 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).
  • 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.
  • 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. Formation of [ 3 H] Cortisol was monitored by analyzing 25 ⁇ L of each supernatant in a scintillation proximity assay (SPA).
  • SPA scintillation proximity assay
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the incubation period for detection reaction was typically 2 hours.
  • the amount of Cortisol was determined by reading the time-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and 665/7.5 nm). The ratio of the two emission signals was then calculated (Em665*10000/Em615).
  • Each assay contained incubations with vehicle controls instead of compound as controls for non-inhibited Cortisol generation (100% CTL; 'high values') and incubations with carbenoxolone as controls for fully inhibited enzyme and Cortisol background (0% CTL; 'low values').
  • Each assay also contained a calibration curve with Cortisol to transform the fluorescent data into Cortisol concentrations. Percent inhibition of each compound was determined relative to the carbenoxolone signal.
  • microsomal preparation of 11 ⁇ -HSD1 in the presence of 50% human plasma by compounds of the invention was measured as follows. Microsomes from CHO cells overexpressing human 11 ⁇ -HSD1 were diluted into reaction buffer consisting of 25 mM HEPES, pH 7.4, 50 mM KCI 1 2.5 mM NaCI, 1 mM MgCI2, and 50% (v/v) human plasma (BioChemed). The assay began by dispensing 49 ⁇ l of microsome solution into 96-well polypropylene plates and adding 1 ⁇ l of the test compounds in DMSO, previously diluted in half-log increments (8 points) starting at 1.0 mM.
  • reaction was initiated with the addition of 50 ⁇ l substrate solution consisting of reaction buffer with 2 mM NADPH and 160 nM [ 3 -H]cortisone (1 Ci/mmol).
  • substrate solution consisting of reaction buffer with 2 mM NADPH and 160 nM [ 3 -H]cortisone (1 Ci/mmol).
  • the plates were incubated for 120 minutes at rt, and the reaction was quenched with the addition of 100 ⁇ l acetonitrile with 20 mM cortisone and 20 mM Cortisol. After a ten minute incubation at rt, 100 ⁇ l of each well was filtered through a Multiscreen HTS, HV filter plate (Millipore) and diluted with 100 ⁇ l of reaction buffer without human plasma.
  • [ 3 - H]cortisone and [ 3 -H]cortisol were separated by HPLC on a Zorbax SB-C8 column (4.6 x 250 mm, Agilent) with an isocratic elution at 25% acetonitrile in water with 0.01% trifluoroacetic acid, and radioactivity was quantified with an in-line ⁇ -RAM (IN/US Systems, Inc.).
  • Plasma protein binding of compounds was determined with Equilibrium Dialysis of spiked plasma against compound free dextrane buffer using a dialysis membrane with mass cutoff of 5000 Da. Compound concentrations in plasma and buffer after incubation were measured using HPLC/Mass spectrometry.
  • the assay was based on a method published by Moody et al. (Xenobiotica 1999). The inhibition of cytochrome P450 3A4-isoenzyme catalysed N-demethylation of [N-methyl-14C]-Erythromycin by the test compound was assayed at 37 0 C with human recombinant cytochrome P450 3A4. All assays were carried out on a robotic system in 96 well plates. The final incubation volume of 200 ⁇ l contains TRIS buffer (0.1 M), MgCI 2 (5 mM), recombinant protein (40 pmol/ml), Erythromycin (50 ⁇ M) and the test compound either at four different concentrations in duplicate (e.g.
  • the inhibition of recombinant CYP2C9 by compounds of the invention was measured using a commercial kit from Invitrogen (cat #2859). Supplied microsomes isolated from insect cells infected with a baculovirus engineered to express human CYP2C9 were diluted to 10 mM in reaction buffer (100 mM potassium phosphate buffer, pH 8.0) with an NADPH generation system (3.33 mM glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase).
  • 89 ⁇ l of this dilution were dispensed to each well of a 96-well, black, polystyrene plate and mixed with 1 ⁇ l of test compound previously diluted in DMSO in half log increments starting at 3 mM.
  • the assay was initiated by adding 10 ⁇ l of fluorogenic substrate n-octyloxymethylresorufin (OOMR, 20 ⁇ M.) with NADP (100 ⁇ M) diluted in reaction buffer.
  • the plate was immediately placed in a Perkin Elmer Fusion plate reader. Reaction progress was monitored by measuring fluorescence every two minutes for a total of twenty minutes (530 nM excitation filter /605 nM emission filter).
  • Example 7 Compound CYP3A4, CYP2C9, CYP2C19, CYP2C9 IC 50
  • 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 (e.g., type Il diabetes) , 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.
  • diabetes mellitus e.g., type Il diabetes
  • obesity e.g., symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease,
  • the compounds of the invention can be used as therapeutic agents for pseudo Cushing's Syndrome associated with alcoholic liver disease.
  • the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients.
  • Additional diseases or disorders that are related to 11 ⁇ -HSD1 activity include those selected from the group consisting of lipid disorders, hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X.
  • a further disease related to 11 ⁇ -HSD1 activity is pseudo Cushing's Syndrome associated with alcoholic liver disease.
  • a pharmaceutical composition of the invention may, alternatively or in addition to an 11 ⁇ -HSD1 inhibitor of the invention, comprise a pharmaceutically acceptable salt of a an 11 ⁇ -HSD1 inhibitor of the invention and one or more pharmaceutically acceptable carriers therefore.
  • a pharmaceutical composition of the invention may comprise a compound of an 11 ⁇ -HSD1 inhibitor of the invention or a pharmaceutical salt thereof as the only pharmaceutically active agent in the pharmaceutical composition.
  • the disclosed 11 ⁇ -HSD1 inhibitors can be used alone or in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma.
  • compositions of the invention are 11 ⁇ -HSD1 inhibitors.
  • Said compositions contain compounds having a mean inhibition constant (IC 50 ) against 11 ⁇ -HSD1 of below about 1 ,000 nM; preferably below about 100 nM; more preferably below about 50 nM; even more preferably below about 5 nM; and most preferably below about 1 nM.
  • IC 50 mean inhibition constant
  • the invention includes a therapeutic method for treating or ameliorating an 11 ⁇ - HSD1 mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of an 11 ⁇ -HSD1 inhibitor of the invention, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof or composition thereof.
  • "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 likelihood that a subject will then develop the disease or condition in a subject that is at risk for developing the disease or condition. - I l l -
  • An embodiment of the invention includes administering an 11 ⁇ -HSD1 inhibiting compound of the invention 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 inhibitors, 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 the invention or composition thereof in a combination therapy with one or more other 11 ⁇ -HSD1 inhibitors, or with combination products, such as Avandamet® (metformin HCI and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCI, 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.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneous ⁇ , subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
  • 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 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily.

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Abstract

This invention relates to novel compounds of the Formula I1 Ik, Im3, Im4, Im6-12, In3, In4, In6-12, lo3, lo4, lo6-12, Ip2, Ip4-7, 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 INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/206,817, filed on February 4, 2009, U.S. Provisional Application No. 61/137,148, filed on July 25, 2008, and U.S. Provisional Application No. 61/049,650, filed May 1 , 2008.
This application also claims priority to International Application No. PCT/2008/009017, which designated the United States and was filed on July 25, 2008, published in English, which claims the benefit of U.S. Provisional Application No. 61/049,650, filed May 1 , 2008.
The entire teachings of the above applications 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 (11 β-HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as 11-beta-HSD type 1 , 11betaHSD1 , HSD11 B1 , HDL, and HSD11 L) and 11β-HSD2. 11 β-HSD1 is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 11-keto forms, whereas 11 β-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, 11β-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 11β-HSD1 catalyzes both 11-beta-dehydrogenation and the reverse 11- oxoreduction reaction, 11 β-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. 11 β-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 11 β-HSD2 genes result in human pathology. For example, individuals with mutations in 11β-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 11 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 11 β-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 11β-HSD1 -deficient mice produced by homologous recombination demonstrate that the loss of 11β-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).
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 11β-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 11β-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 11β-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 eventually blindness. Thus, inhibition of 11 β-HSD1 in the eye could reduce local glucocorticoid concentrations and IOP, and 11β-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 11β-HSD1 activity. Thus, 11β-HSD1 inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders. Inhibition of 11β-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, 11 β-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 11 β-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.
11β-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) Banner'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 11β-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, 11β-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 11β-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 pharmaceutically acceptable salts thereof, are effective inhibitors of 11β-HSD1. The invention is a compound represented by Formula I:
Figure imgf000008_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;
In a first embodiment of the invention, Formula I and its constituent members are defined herein as follows:
R1 is (a) absent or (b) is selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (CrC3)alkoxy(Ci-C3)alkoxy, or (Ci-C3)alkoxy(Ci-C3)alkyl and 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)2PC=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, heteroaryl, arylamino and heteroarylamino;
A1 is (a) a bond, or (b) (d-C3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2C(=0), wherein the carbonyl carbon is attached to Cy1;
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrCβJalkyl, hydroxy(Ci- C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4- C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Cr
C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(CrC6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (CrC^alkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cr C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci- C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (CrCβJalkyl- carbonylamino(Ci-C6)alkyl, (CrCβJalkylsulfonylamino, (CrC6)alkylsulfonylamino(Ci- C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci- C6)alkoxy(CrC6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl oxo, amino(CrC6)alkyl, (d- C6)alkylamino(C1-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (d- C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy, (C3- C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkylK(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (C1- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-Ce)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(CrC6)alkyl; Cy2 in Formula I is oxodihydropyridazinyl, oxodihydropyrimidinyl or oxodihydropyrazinyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)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(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, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (d- CβJalkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci- C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (CrC6)alkoxy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cr C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (CrCeJalkylcarbonylamino, (d-CeJalkylcarbonyl- amino(CrC6)alkyl, (CrC6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(CrC6)alkyl, halo(Ci-C6)alkoxy(Cr C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (d- C6)alkylamino(CrC6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (C-i- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (C3-
C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(CrC6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(CrC6)alkyl, (d- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl(CrC6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl;
E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R2 is (CrC6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-
C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfιnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkane- sulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (CrC6)alkoxy(CrC6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (d- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrCβJalkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (Cr C6)alkylcarbonylamino(CrC6)alkyl, (CrCβJalkylsulfonylamino, (C1- C6)alkylsulfonylamino(CrC6)alkyl, (CrCβJalkoxycarbonyKCrCeJalkoxy, (Cr C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, OXO, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(CrC6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl(CrC6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl;
R3 is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C5)cycloalkyl(CrC4)alkyl, (CrC3)alkoxy(C1-C3)alkoxy, or (CrC3)alkoxy(Ci-C3)alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4C(=O)O-, 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-, spirocycloalkyl; heterocyclyl (which in turn may be optionally substituted with alkyl, haloalkyl, halogen or oxo), heteroaryl (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl- substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and
R4 is independently selected from H, (Ci-CβJalkyl, halo(CrC6)alkyl, amino(Ci- C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(Cr C6)alkyl and (Ci-C6)alkoxy(Ci-C6)alkyl.
Another embodiment of the invention is a pharmaceutical composition comprising i) a pharmaceutically acceptable carrier or diluent, and ii) a compound of Formulas I1 Ik, Im3, Im4, Im6"12, In3, In4, In6"12, lo3, lo4, lo6"12, Ip2, or Ip4"7, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Another embodiment of the invention is a method of inhibiting 11β-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, Ik, Im3, Im4, Im6"12, In3, In4, In6"12, lo3, lo4, lo6"12, Ip2, or Ip4"7, 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 β-HSD1 , comprising the step of administering to the subject an effective amount of a compound of Formulas I, Ik, Im3, Im4, Im6"12, In3, In4, In6"12, lo3, lo4. lo6"12, Ip2, or Ip4"7, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Another embodiment of the invention is the use of a compound of Formulas I, Ik1
Im3, Im4, Im6'12, In3, In4, In6'12, lo3, lo4, lo6"12, Ip2, or Ip4"7, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for inhibiting 11 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, Ik, Im3, Im4, Im6"12, In3, In4, In6"12, lo3, lo4, lo6 12, Ip2, or Ip4"7, 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 β-HSD1.
Another embodiment of the invention is a compound of Formulas I, Ik, Im3, Im4, Im6-12, In3, In4, In6"12, lo3, lo4, lo6"12, Ip2, or Ip4"7, 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 I, Ik1 Im3, Im4, Im6"12, In3, In4, In6"12, lo3, lo4, lo6"12, Ip2, or Ip4'7, 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.
DETAILED DESCRIPTION OF THE INVENTION
Another embodiment of the invention is a compound of Formula Ik:
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof;
R1a is absent or is methyl or ethyl; Cy2 is 2,3-dihydro-3-oxopyridazinyl, 1 ,2- dihydro-2-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinyl, or 1 ,2-dihydro-2-oxopyrazinyl and is optionally substituted; R2 is (CrC6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Cr 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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (d-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Cr C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(CrC6)alkylamino, (Ci-C6)alkoxy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCeJalkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Ci-C3)alkoxy(CrC3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (CrC6)alkylcarbonyl- amino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(CrC6)alkyl, (CrC6)alkoxycarbonyl(CrC6)alkoxy, (CrC6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Cr C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (d- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (CrC6)alkylcarbonyl; and R3 is as defined above in the first embodiment.
Another embodiment of the invention is a compound of any one of Formulas Im3, Im4 and Im6'12, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
Figure imgf000014_0001
Im3 Im4
Figure imgf000014_0002
Im6
Figure imgf000015_0001
Im7 Im8
Figure imgf000015_0002
Im3 Im 10
Figure imgf000015_0003
Im 11 Im 12
In Formulas Im3, Im4 and Im6'12, the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable ring nitrogen atom") with up to four substituents as described for Cy2 in the first embodiment. Suitable substituents for Cy2 and suitable values for R1, R2, R3, A1, Cy1 and E are as defined above in the first embodiment. Alternatively, suitable substituents for Cy1 and the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im3, Im4 and Im6"12 are independently fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-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(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6JaIkOXy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfιnyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Cr
C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(Ci-C6)alkylamino, (C1-C6JaIkOXy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(CrC6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO1 H2NSO2, (CrCeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (CrC3)alkoxy(CrC3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylamino- sulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci- C6)alkyl, (Ci-C6)alkylsulfonylamino, (CrC6)alkylsulfonylamino(CrC6)alkyl, (Cr C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(CrC6)alkoxy(Ci- Cβjalkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (CrC6)alkylamino(Cr C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3- C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- Cejcycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (d- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl(CrC6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; and values for R1, R2, R3, A1, Cy1 and E are as defined above in the first embodiment. Alternatively, suitable substituents for Cy1 include (CrC4 )alkyl, (CrC4 )alkoxy, (CrC4 )haloalkyl, (Ci-C4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im3, Im4 and Im6"12 include (CrC4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, and (CrC4)haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Im3, Im4 and Im6"12 include fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, halo(Cr C4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylaminocarbonyl, CIi(C1- C4)alkylaminocarbonyl and (Ci-C4)alkylcarbonylamino; and suitable values for R1, R2, R3, A1, Cy1 and E are as defined above in the first embodiment.
For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately following Formulas Im3, Im4 and Im6"12, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2l 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Im3, Im4 and Im6"12, R1 is preferably methyl or ethyl; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl. For each of the embodiments described in the paragraph immediately following
Formulas Im3, Im4 and Im6"12, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (Ci-C4)alkyl, (CrC4)haloalkyl, and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Im3, Im4 and Im6'12, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (Ci-C4)alkyl, (CrC4)haloalkyl, and SO2Me; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Im3, Im4 and Im6"12, R1 is preferably methyl or ethyl; and R3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Im3, Im4 and Im6'12, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Im3, Im4 and Im6'12, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methy I propyl; the substituent on the substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im3, Im4 and Im6"12 is (C1-C4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (CrC2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas Im3, Im4 and Im6"12 are optionally substituted with methyl or ethyl.
Another embodiment of the invention is a compound of any one of Formulas In3, In4 and In6'12, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
Figure imgf000018_0001
In3 In4
Figure imgf000018_0002
lne
Figure imgf000018_0003
In7 In8
Figure imgf000019_0001
In8 In 10
Figure imgf000019_0002
In 11 In 12 In Formulas In3, In4 and In6"12, the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable ring nitrogen atom") with up to four substituents as described for Cy2 in the first embodiment. Suitable substituents for Cy2 and suitable values for R1, R2, R3 and Cy1 are as defined above in the first embodiment. Alternatively, suitable substituents for Cy1 and the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In3, In4 and In6"12 are independently fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)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(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C1- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (CrC6)alkoxy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-CβJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(CrC3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkylamino- sulfonyl, heterocyclylsulfonyl, (Ci-Cejalkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Cr C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Cr C6)alkoxycarbonyl(C1-C6)alkoxyI (CrC6)alkoxy(Ci-C6)alkyl, halo(CrC6)alkoxy(Cr C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(CrC6)alkylamino(CrC6)alkyl amino(C2-C6)alkoxy, (CrC6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-
Cβjcycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(CrC6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(CrC6)alkyl, (d- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylanninocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; and values for R1, R2, R3 and Cy1 are as defined above in the first embodiment. Alternatively, suitable substituents for Cy1 include (CrC4 )alkyl, (CrC4 )alkoxy, (Ci-C4 )haloalkyl, (CrC4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In3, In4 and In6"12 include (CrC4 )alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl and (CrC4)haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In3, In4 and In6"12 include fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl and (CrC^alkylcarbonylamino; and suitable values for R1, R2, R3, and Cy1 are as defined above in the first embodiment. For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately following Formulas In3, In4 and In6"12, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2l H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas In3, In4 and In6"12, R1 is preferably methyl or ethyl; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas In3, In4 and In6'12, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas In3, In4 and In6"12, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (C1-C4)SlKyI, (CrC4)haloalkyl and SO2Me; and R3 is H2NCC=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas In3, In4 and In6"12, R1 is preferably methyl or ethyl; and R3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas In3, In4 and In6"12, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. For each of the embodiments described in the paragraph immediately following
Formulas In3, In4 and In6"12, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In3, In4 and In6"12 is (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C2)haloalkyl; and one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas In3, In4 and In6"12 are optionally substituted with methyl or ethyl. Another embodiment of the invention is a compound of any one for Formulas lo3, nd lo6"12, or a pharmaceutically acceptable salt thereof:
Figure imgf000022_0001
loe
Figure imgf000022_0002
los Io 10
Figure imgf000023_0001
Io 11 Io \ 1i2.
In Formulas lo3, lo4 and lo6"12, the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted (substitution at ring carbons bonded to hydrogen and at nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable ring nitrogen atom") with up to four substituents as described for Cy2 in the first embodiment; suitable values for G1 are fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2- C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfιnyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkyl- alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl- alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4- C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(CrC6)alkylamino, (Cr
C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(CrC6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-Cejalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Cr C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (Cr C6)alkylcarbonylamino(CrC6)alkyl, (CrCδJalkylsulfonylamino, (C1-
C6)alkylsulfonylamino(CrC6)alkyl, (CrCeJalkoxycarbonyKCrCeJalkoxy, (Cr C6)alkoxy(CrC6)alkyl, halo(CrC6)alkoxy(Ci-C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, amino(CrC6)alkyl, (CrC6)alkylamino(CrC6)alkyl, di(CrC6)alkylamino(CrC6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, ((C3- C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyiχ(CrC6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(C1-C6)alkyl, (Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(C1- C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; n is O, 1 , 2 or 3; and suitable substituents for Cy2 and suitable values for R1, R2 and R3 are as defined above in the first embodiment. Alternatively, n is 0, 1 , 2 or 3; suitable values for G1 and substituents for the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo3, lo4 and lo6"12 are independently 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(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, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(CrC6)alkylamino, (Ci-C6)alkoxy(Cr
C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-CeJalkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(CrC3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(CrC6)alkylamino- sulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci- C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(C1-C6)alkyll (d- C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-CeJalkoxytd-CeJalkyl, halo(CrC6)alkoxy(Ci- C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (C1-C6)alkylamino(Cr C6)alkyl, di(CrC6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (CrC6)alkylcarbonyl; and values for R1, R2 and R3 are as defined above in the first embodiment. Alternatively, n is O1 1 , 2 or 3; suitable values for G1 include (CrC4 )alkyl, (CrC4 )alkoxy, (C1-C4 )haloalkyl, (CrC4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo3, lo4 and lo6 12 include CrC4 alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl and CrC4 haloalkyl; suitable substituents for a ring carbon atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo3, lo4 and lo6"12 include fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl and (d-C^alkylcarbonylamino; and suitable values for R1, R2 and R3 are as defined above in the first embodiment.
For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately following Formulas lo3, lo4 and lo6'12, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas lo3, lo4 and lo6"12, R1 is preferably methyl or ethyl; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl. For each of the embodiments described in the paragraph immediately following
Formulas lo3, lo4 and lo6"12, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (d-C4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas lo3, lo4 and lo6'12, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas lo3, lo4 and lo6"12, R1 is preferably methyl or ethyl; and R3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas lo3, lo4 and lo6"12, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas lo3, lo4 and lo6"12, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen atom in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo3, lo4 and lo6"12 is (CrC4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, or (C1-C2 )haloalkyl; and one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings in Formulas lo3, lo4 and lo6'12 are optionally substituted with methyl or ethyl.
Another embodiment of the invention (referred to herein as the "First Alternate Embodiment") is a compound represented by Structural Formulas lo3, lo4 and lo6"12, wherein: n is 0 or 1 , preferably 0; each G1 is independently (Ci-C4 )alkyl, (C1-C4 )alkoxy, (C1-C4 )haloalkyl, (CrC4 )haloalkoxy, halogen, cyano or nitro; the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl are substituted at a substitutable ring nitrogen atom with hydroxy(Ci-C6)alkyl, (Ci-C6)alkylcarbonylamino(CrC6)alkyl, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (CrC6)alkoxy(Ci-C6)alkyl, amino(d-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkylX(Ci-C6)alkyl}arninocarbonyl(Ci-C6)alkyl or di(C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl are optionally substituted at one or more substitutable ring carbon atoms with a group independently selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1- C2)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (CrC4)haloalkoxy, CONH2, (d- C4)alkylaminocarbonyl, di(CrC4)alkylaminocarbonyl and (CrC4)alkylcarbonylamino; R1 • is methyl or ethyl; R2 is phenyl, thienyl, pyridyl or isopropyl each optionally substituted with up to three groups independently selected from halo, methyl, methylthio or (4- morpholino)methyl; and R3 is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substituted with up to two groups independently selected from methyl, HO-, MeO-, H2N-, MeC(=0)NH-, MeS(=O)2NH-, H2NC(=O)-, MeNHC(=0)-, HO2C-, (HO)2P(=O)O-, H2NSC=O)2O-, H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=0)0-, 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.
Alternatively for Structural Formulas lo3, lo4 and lo6"12, R2 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from halo, cyano, CONH2, (CrC4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NCC=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2- hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described above for the First Alternate Embodiment.
Alternatively for Structural Formulas lo3, lo4 and lo6'12, R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described above for the First Alternate Embodiment.
Alternatively for Structural Formulas lo3, lo4 and lo6"12, R2 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from halo, cyano, CONH2, (CrC4)alkyl, (d-C4)haloalkyl and SO2Me; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3- methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the First Alternate Embodiment.
Alternatively for Structural Formulas lo3, lo4 and lo6"12, R3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the First Alternate Embodiment.
Alternatively for Structural Formulas lo3, lo4 and lo6'12, R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the First Alternate Embodiment. Alternatively for Structural Formulas lo3, lo4 and lo6"12, R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted with methyl or ethyl; and the remainder of the variables are as described in the First Alternate Embodiment.
For the embodiment described in the previous seven paragraphs, n is 0 and all of the substitutable ring carbons in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are preferably unsubstituted.
Another embodiment of the invention is a compound represented by any one of Formulas Ip2 and Ip4'7, or a pharmaceutically acceptable salt thereof:
Figure imgf000028_0001
IP2
Figure imgf000028_0002
IP4
Figure imgf000028_0003
IP5 IP6
Figure imgf000029_0001
IP7.
In Formulas Ip2 and Ip4"7, G1 is (CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkyl, (Cr C4)haloalkoxy, halogen, cyano or nitro; n is 0, 1 or 2; G2a is (Ci-C4 )alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl or (CrC4)haloalkyl; G2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(CrC2)alkyl, halo(d-C4)alkyl, (CrC4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (d-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (d-C^alkylcarbonylamino; and suitable values for R1, R2 and R3 are as defined above in the first embodiment. For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately following Formulas Ip2 and Ip4'7, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Ip2 and Ip4"7, R1 is preferably methyl or ethyl; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. For each of the embodiments described in the paragraph immediately following
Formulas Ip2 and Ip4"7, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Ip2 and Ip4"7, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (Ci-C4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Ip2 and Ip4"7, R1 is preferably methyl or ethyl; and R3 is 2-hydroxy-2- methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Ip2 and Ip4'7, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. For each of the embodiment described in the paragraph immediately following
Formulas Ip2 and Ip4"7, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent G2a is selected from (CrC4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, and (Ci-C2)haloalkyl; and G2b is optionally selected from hydrogen, methyl or ethyl. Another embodiment of the invention (referred to herein as the "Second Alternate
Embodiment") is a compound represented by Structural Formulas Ip2 and Ip4"7, wherein: n is O or 1 , preferably O; each G1 is independently (CrC4 )alkyl, (CrC4 )alkoxy, (CrC4) haloalkyl, (CrC4 )haloalkoxy, halogen, cyano or nitro; G2a is hydroxy(CrC6)alkyl, (Cr C6)alkylcarbonylamino(CrC6)alkyl, (CrC6)alkylsulfonylamino(CrC6)alkyl, (Cr C6)alkoxy(CrC6)alkyl, amino(CrC6)alkyl, (CrC6)alkylamino(CrC6)alkyl, di(d- C6)alkylamino(CrC6)alkyl, cyano(CrC6)alkyl, aminocarbonyl(CrC6)alkyl, (C1- C6)alkylaminocarbonyl(CrC6)alkyl, di(CrC6)alkylaminocarbonyl(CrC6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(CrC6)alkyl or di(C3-C6)cycloalkylaminocarbonyl(CrC6)alkyl; G2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylaminocarbonyl, di(CrC4)alkylaminocarbonyl or (C1- C4)alkylcarbonylamino; R1 is methyl or ethyl; R2 is phenyl, thienyl, pyridyl or isopropyl each optionally substituted with up to three groups independently selected from halo, methyl, methylthio or (4-morpholino)methyl; and R3 is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substituted with up to two groups independently selected from methyl, 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. Alternatively for Structural Formulas Ip2 and Ip4"7, R2 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, CONH2, (Ci-C4)alkyl, (d-C4)haloalkyl and SO2Me; and R3 is is MeSO2NHCH2CH2CH2, H2NCC=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2- hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described above for the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip2 and Ip4"7, R3 is H2NC(=O)CMe2CH2, 3- hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described above for the Second Alternate Embodiment. Alternatively for Structural Formulas Ip2 and Ip4"7, R2 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from halo, cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3- methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the Second Alternate Embodiment. Alternatively for Structural Formulas Ip2 and Ip4"7, R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip2 and Ip4"7, R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of the variables are as described in the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip2 and Ip4"7, R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one or two substitutable ring carbon atoms in the oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl rings are optionally substituted with methyl or ethyl; and the remainder of the variables are as described in the Second Alternate Embodiment.
For the embodiment described in the previous seven paragraphs, n is O and G2b is preferably -H. Compounds of the invention are also disclosed in INHIBITORS OF 11 β- HYDROXYSTEROID DEHYDOGENASE I1 U.S. Provisional Application No. 61/ 61/135,933, filed July 25, 2008 (Attorney Docket No. 4370.1000-000); Cyclic Inhibitors Of 11 β-Hydroxysteroid Dehydrogenase 1, U.S. Provisional Application No. 61/135,933, filed May 1 , 2008; Cyclic Inhibitors Of 11 β-Hydroxysteroid Dehydrogenase 1 , U.S.
Provisional Application No. 61/137,148, filed July 25, 2008; and Cyclic Inhibitors Of 11 β- Hydroxysteroid Dehydrogenase 1 , International Application No. PCT/US2008/009017, filed July 25, 2008; the entire teachings of these applications are incorporated herein by reference in their entirety.
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 (c- Pr), 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, CO∑H, 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-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1 H-indol-5-yl, I H-benzimidazol-6-yl, 1H- 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-, A-, 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 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O1 and S. Exemplary heterocyclyls include pyrrolidine, pyrrolidin-2-one, 1- methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4- oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4- oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1 ,3-dioxolane, 1 ,3-dithiolane, 1 ,3-dioxane, 1 ,4- dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine- 2,4-dione, tetrahydropyrimidin-2(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 isothiazolidine 1 ,1- dioxide, 6-oxo-1 ,6-dihydropyridazin-3-yl, 6-oxo-1 ,6-dihydropyridazin-4-yl, 5-oxo-4,5- dihydro-1 H-1 ,2,4-triazol-3-yl and 5-oxo-4,5-dihydro-1H-imidazol-2-yl. A heterocyclyl can be optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, haloalkyl, halogen and oxo. The term "spirocycloalkyl" means a cycloalkyl group which shares one ring carbon with another alkyl or cycloalkyl group.
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. Some of the compounds disclosed in the exemplification may be in the anhydrous form.
The term "compound" also includes labeling at one or more positions with deuterium. "Labeled with deuterium at a position" means that the amount deuterium at the position is greater than the amount that is present at natural abundance. In certain instances, the deuterium at each position in a "compound" is at natural abundance.
Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol "*" in a structural formula represents the presence of a chiral carbon center. "R" and "S" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "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.
"R," "S," "S*," "R*," "E1" "Z," "cis," 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 enantiomer 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 basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine 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.
The following abbreviations have the indicated meanings:
Abbreviation Meaning
A% Area percentage
Boc te/t-butoxy carbonyl or f-butoxy carbonyl
(BoC)2O di-tert-butyl dicarbonate
Cbz Benzyloxycarbonyl
CbzCI Benzyl chloroformate c-Pr cyclopropyl
DAST diethylaminosulfur trifluoride
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCC N.N'-dicyclohexylcarbodiimide
DCU N,N'-dicyclohexylurea
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminum hydride
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 dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
DPTBS Diphenyl-t-butylsilyl dr diastereomer ratio
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
EDCHCI, EDCI hydrochloride
Equiv equivalents
EtOAc Ethyl acetate
Fmoc 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-
1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-
Fmoc-OSu pyrrolidinedione h, hr hour(s)
HOBt 1 -hydroxybenzotriazole
2-(7-Aza-1 H-benzotriazole-1-yl)-1 , 1 ,3,3-
H πnΔT I I U I tetramethyluronium hexafluorophosphate
2-(1 H-Benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium
H πDRT I I \J I hexafluorophosphate
KHMDS potassium hexamethyldisilazane
LAH or LiAIH4 lithium aluminum hydride
LC-MS liquid chromatography-mass spectroscopy
LHMDS lithium hexamethyldisilazane m-CPBA meta-chloroperoxybenzoic acid
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 rt room temperature
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-i-piperidinyloxy free radical
Teoc 1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu 1 -[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione
Text External temperature
Tint Internal temperature
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, A1, Cy1, E, R1 , R2, R3, Y and n have the meanings indicated above unless otherwise noted. Cy2 is an optionally substituted 3-oxo-2,3-dihydropyridazinyl, 6- oxo-1 , 6-dihydropyrimidinyl, 2-oxo-1 ,2-dihydropyrimidinyl or 2-oxo-1 ,2-dihydropyrazinyl group:
Figure imgf000039_0001
In cases where the synthetic intermediates and final products of Formula I* described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T.W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not described explicitly. Generally, reagents in the reaction schemes are used in equimolar amounts; however, in certain cases it may be desirable to use an excess of one reagent to drive a reaction to completion. This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCI in reaction mixtures are generally used in slight to substantial excess (1.05 - 5 equivalents).
In a first process a compound of Formula I*, can be prepared by reaction of an aminoalcohol intermediate of Formula Il with a reagent 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 imgf000040_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 thphosgene and as little as one third of molar equivalent can be used. Aminoalcohol intermediates of Formula Il can be prepared by reduction of amides 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 imgf000040_0002
lntermediates of Formula IV can be prepared by coupling of a β-hydroxyacid of Formula V with an amine 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 °C for between 1 h and 24 h:
Figure imgf000041_0001
Amine intermediates of Formula Vl1 wherein A1 = CH2 and R1 is absent, can be prepared by reduction of amides of Formula VII 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 imgf000041_0002
VII Vl
Amine intermediates of Formula Vl, wherein A1 is a bond, R1 is absent and Cy1 is not an aromatic or heteroaromatic ring, can be prepared from ketones of formula VIII via oximes of Formula IX or by reductive amination of a ketone of Formula VIII with ammonia:
Figure imgf000041_0003
VIII IX Vl
Methods for the conversion of ketones to oximes are described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" pp 1194-1195, 5th Edition, Wiley, New York, NY1 2001. Methods for the reduction of oximes to primary amines are described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 1555, 5th Edition, Wiley, New York, NY, 2001. Methods for the reductive amination of ketones are described in Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.
Similarly amine intermediates of Formula Vl, wherein A1 is CH and R1 is methyl or ethyl, can be prepared by reduction t-butylsulfinylimines of Formula VIIIb which can be prepared from ketones of Formula Villa and f-butylsulfinamide or by addition of organometallic reagents of Formula R1M, wherein R1 is Me or Et and M is Li, MgCI, MgBr or MgI1 to t-butylsulfinylimines of Formula VIIId which can be prepared from aldehydes of Formula VIIIc.
Figure imgf000042_0001
H2N Xy1 Cy2
Figure imgf000042_0002
VIIIc VIIId High stereoselectivity is often achieved in such reactions using chiral t- butylsulfinylimines.
Intermediates of Formula II, wherein n = 0, can be prepared by reaction of oxetanes of Formula X with amines of Formula Vl as described in Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 505, 5th Edition, Wiley, New York, NY, 2001 :
Figure imgf000042_0003
Intermediates of Formula Il can also be prepared by reductive amination of β- hydroxyaldehydes of Formula Xa with amines of Formula Vl. Methods for the reductive amination of aldehydes are described in Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed. Overman, L. E., Wiley Interscience, 2002.
Figure imgf000043_0001
Aldehydes of Formula Xa can be prepared from homoallylic alcohols of Formula XXI by treatment with OsO4 and NaIO4.
Intermediates of Formula II, wherein A1 = CH2 and R1 is absent, can be prepared by reduction of amide intermediates of formula Xl 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 imgf000043_0002
Amide intermediates of Formula Xl can be prepared by reaction of an amino- alcohol intermediate of Formula XII with activated carboxylic acid of Formula XIII wherein Z3 = chloride or an activated ester, such as an N-hydroxysuccinimide ester:
Figure imgf000043_0003
XII XIII Xl Amino-alcohol intermediates of Formula XII, wherein n = 0, can be prepared by reaction of an epoxide of Formula XIV with cyanide ion followed by reduction of the resulting hydroxynitrile of Formula XV with hydrogen gas in the presence of a catalyst or with a hydride source such as LiAIH4:
Figure imgf000044_0001
XIV XV XII
Epoxide compounds of formula XIV can, in turn, be prepared in a number of ways including, as described in Aube, J. "Epoxidation and Related Processes" Chapter 3.2 in Volume 1 of "Comprehensive Organic Synthesis" Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press, New York, 1992.
Hydroxynitrile intermediates of Formula XV can be prepared by treatment of ketones of Formula XVI with acetonitrile anion, formed by treatment of acetonitrile with n-BuLi or LDA, in an inert, anhydrous solvent such as THF at low temperature:
Figure imgf000044_0002
XVI XV
Amino-alcohol intermediates of Formula XII, wherein n is O, can be prepared by treatment of sulfonate intermediates of Formula XVII, wherein RA is for example methyl, trifluoromethyl or p-methylphenyl, with ammonia:
Figure imgf000044_0003
XVII XII Amino-alcohol intermediates of Formula XII can be prepared by treatment of sulfonate intermediates of Formula XVII with sodium azide to give an azide intermediate of Formula XVIII, followed by catalytic hydrogenation or by Staudinger reduction with PPh3 in wet THF:
Figure imgf000045_0001
XVII XVIII XIl
Sulfonate intermediates of Formula XVII can be prepared from diol intermediates of Formula XIX with a sulfonyl chloride RASO2CI:
Figure imgf000045_0002
XIX XVII
Diol intermediates of Formula XIX can be prepared by hydroboration of allyl alcohols of Formula XX:
Figure imgf000045_0003
XX XIX
Diol intermediates of Formula XIX can be prepared by ozonolysis and reduction of homoallyl alcohols of Formula XXI:
Figure imgf000045_0004
XXl XIX
Aminoalcohol intermediates of Formula II, wherein A1 is a bond, R1 is absent, and Cy1 is a heteroaryl group or an aryl group bearing at least one strongly electron withdrawing group such as CF3, can be prepared by reaction of an aminoalcohol intermediate of Formula XII with a compound of Formula XXII1 wherein Cy1 is a heteroaryl group or an aryl group bearing at least one strongly electron withdrawing group such as CF3 and RB is a leaving group such a fluoro, chloro, bromo or iodo:
Figure imgf000046_0001
Aminoalcohol intermediates of Formula II, wherein A1 is (Ci)alkylene can be prepared by reaction of an aminoalcohol of Formula XII with an aldehyde or methyl ketone of Formula XII in the presence of a reducing agent such as NaCNBH3 or Na(OAc)3BH:
Figure imgf000046_0002
Methods for the reductive amination of aldehydes and ketones are described in Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed. Overman, L. E., Wiley
Interscience, 2002.
In a second process a compound of Formula I* can be prepared by reaction of a ketocarbamate of Formula XXIV, wherein RD is alkyl or arylalkyl group such as methyl, t-butyl or benzyl, with an organometallic reagent of Formula XXV wherein M includes, but is not limited to, MgCI, MgBr, MgI or Li:
In specific examples, organometallic reagent XXV is allylmagnesium bromide, allylzinc(ll) bromide, (2-methylallyl)magnesium chloride or (2-methoxy-2- oxoethyl)zinc(ll) bromide. In certain cases when M is MgCI, MgBr or MgI, it is advantageous to add CeCI3 to the reaction mixture. Ketocarbamates of Formula XXIV can be prepared by reaction of aminoketones of Formula XXVI with intermediates of Formula XXVII wherein RE is a leaving group such as chloride, succinyloxy, imidazolyl or t-butoxycarboxycarbonyl:
Figure imgf000047_0001
Aminoketones of Formula XXVI, wherein n = O1 can be prepared by reaction of α,β-unsaturated ketones of Formula XXVIII with amines of Formula Vl:
Figure imgf000047_0002
Aminoketones of Formula XXVI, wherein n = 0, can be prepared by reaction of β- dialkylaminoketones of Formula XXVIII, wherein RF is lower alkyl especially methyl, with amines of Formula Vl:
Figure imgf000047_0003
β-Dialkylaminoketones of Formula XXVIII are in turn derived from α, β-unsaturated ketones of Formula XXVII with dialkylamines of Formula RFNHRF. In a third process a compound of Formula I* can be prepared by reaction of a compound of Formula XVII with an isocyanate of Formula XXIX in the presence of a base:
Figure imgf000048_0001
lsocyanates of Formula XXIX can be prepared from amines of Formula Vl by treatment with phosgene, diphosgene or triphosgene. This third process is described in greater detail in U.S. Provisional Application Serial No. 61/137,013, filed July 25, 2008 entitled SYNTHESIS OF INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (Attorney Docket No. 4370.1001-000), the entire teachings of which are incorporated herein by reference.
In a fourth process a compound of Formula I* can be prepared by reaction of a halo compound of Formula, wherein Hal is chlorine or bromine, with an isocyanate of Formula XXIX in the presence of a base:
Figure imgf000048_0002
Halo compounds of Formula XXX can be prepared by reaction of β-haloketones of Formula XXXI with organometallic reagents of Formula XXV wherein M is a metal containing radical including MgCI, MgBr, MgI or Li. The reaction is optionally carried out in the presence of anhydrous cerium trichloride:
Figure imgf000048_0003
XXXI XXV XXX In a fifth process a compound of Formula I*, wherein A1 is CH2 or CH2CH2 and R1 is absent, can be prepared by reaction of a compound of Formula XXXII, with a compound of Formula XXXIII, wherein A1 is CH2 or CH2CH2 and RG is a leaving group such as Br, I, OSO2Me, OSO2CF3 or OSO2Ph, in the presence of a base such as NaH or K2CO3:
Figure imgf000049_0001
XXXII XXXIII
Figure imgf000049_0002
Compounds of Formula XXXII can be prepared by treatment of compounds of
Formula XII with various 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 imgf000049_0003
In a sixth process a compound of Formula I*, wherein A1 is a bond and R1 is absent, can be prepared by reaction of a compound of Formula XXXII, with a compound of Formula XXII, wherein RB is a leaving group such as chloro, bromo, iodo or OSO2CF3, in the presence of a base such as K2CO3 and a copper or palladium catalyst in an inert solvent such as dioxane, DMF or NMP at elevated temperature:
Figure imgf000049_0004
In a seventh process a compound of Formula I* can be prepared by Suzuki coupling of a compound of Formula XXXIV, wherein Cy1 is aryl or heteroaryl and Rx is bromo, iodo, or trifluoromethanesulfonyloxy, with a boronic acid (Rγ is hydrogen) or a boronate ester of Formula XXXV (Rγ is (CrC6)alkyl and the two groups Rγ taken together form a (CrCi2)alkylene group).
Figure imgf000050_0001
In an eighth process a compound of Formula XXXIV, wherein Cy1 is aryl or heteroaryl and Rx is bromo, iodo, or trifluoromethanesulfonyloxy, can be reacted with bis(pinacolato)diboron in the presence of a palladium catalyst to give a boronate ester of Formula XXXVI which can be further reacted with a heterocyclic compound of Formula XXXVII, wherein Rx is bromo, iodo, or trifluoromethanesulfonyloxy, again in the presence of a palladium catalyst, to give a compound of Formula I*.
Figure imgf000050_0002
In a ninth process a compound of Formula I* can be prepared from another compound of Formula I*. For example:
(1) 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. (2) a compound of Formula T1 wherein R1 or R3 is ω-carboxy(Ci-C6)alkyl, can be coupled with ammonia or a (CrC6)alkylamine using a standard peptide coupling reagent such as EDC to afford a compound of Formula I*, wherein R1 or R3 is ω- H2NC(=O)(Ci-Cβ)alkyl or ω-{(C1-C6)alkylNHC(=O)}(C1-C6)alkyl. (3) a compound of Formula T1 wherein R1 or R3 is ω-hydroxy(Ci-C6)alkyl, can be converted to its methanesulfonate or trifluoromethanesulfonate, treated with sodium azide and reduced to give a compound of Formula I*, wherein R1 or R3 is ω-amino(Ci- Cβ)alkyl.
(4) 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.
(5) 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}(CrC6)alkyl. (6) a compound of Formula I*, wherein R1 is (C2-C6)alkenyl, is hydroborated to afford a compound of Formula I*, wherein R1 is hydroxy(C2-C6)alkyl.
(7) a compound of Formula I*, wherein R3 is (C2-C6)alkenyl, is hydroborated to afford a compound of Formula I*, wherein R3 is hydroxy(C2-C6)alkyl.
(8) a compound of Formula I*, wherein R1 is (C2-C6)alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a compound of Formula I*, wherein R1 is vicinal dihydroxy(C2-C6)alkyl,.
(9) a compound of Formula I*, wherein R3 is (C2-C6)alkenyl, can be reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a vicinal diol compound of Formula I*, wherein R3 is vicinal dihydroxy(C2-C6)alkyl,. (10) a compound of Formula I*, wherein R1 is (C2-C6)alkenyl, can be reacted with ozone followed by NaBH4 to give a compound of Formula I*, wherein R1 is ω- hydroxy(CrC5)alkyl.
(11) a compound of Formula I*, wherein R3 is (C2-C6)alkenyl, can be reacted with ozone followed by NaBH4 to give a compound of Formula I*, wherein R3 is ω- hydroxy(CrC5)alkyl. (12) a compound of Formula I*, wherein R1 or R3 is amino(CrC6)alkyl, can be reacted with an (Ci-C6)alkyl isocyanate to give a compound of Formula I*. wherein R1 or R3 is (CrC6)alkylaminocarbonylamino(Ci-C6)alkyl.
(13) a compound of Formula I*, wherein R1 or R3 is amino(CrC6)alkyl, can be reacted with an (Ci-C6)alkyl chloroformate to give a compound of Formula I*, wherein
R1 or R3 is (CrC6)alkoxycarbonylamino(CrC6)alkyl.
(14) a compound of Formula I*, wherein R1 or R3 is amino(Ci-C6)alkyl, can be reacted with chlorosulfonyl isocyanate or sulfamide to give a compound of Formula I*, wherein R1 or R3 is aminosulfonylamino(CrC6)alkyl. (15) a compound of Formula I*, wherein R1 or R3 is amino(Ci-C6)alkyl, can be reacted with a (Ci-C6)alkylsulfamoyl chloride to give a compound of Formula I*, wherein R1 or R3 is (Ci-C6)alkylaminosulfonylamino(Ci-C6)alkyl.
(16) a compound of Formula I*, wherein R1 or R3 is hydroxy(Ci-C6)alkyl, can be reacted with chlorosulfonyl isocyanate to give a compound of Formula I*, wherein R1 or R3 is aminosulfonyloxy(Ci-C6)alkyl.
(17) a compound of Formula I*, wherein R1 or R3 is hydroxy(Ci-C6)alkyl, can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl chloroformate or carbonyl diimidazole, followed by ammonia, a (CrC6)alkylamine or a di(Ci-C6)alkylamine to give a compound of Formula I*, wherein R1 or R3 is aminocarboxy(Ci-C6)alkyl, (d-C6)alkyl aminocarboxy(Ci-C6)alkyl or di(CrC6)alkyl aminocarboxy(Ci-C6)alkyl.
(18) a compound of Formula I*, wherein R1 or R3 is hydroxy(CrC6)alkyl, can be reacted with POCI3 to give a compound of Formula I*, wherein R1 or R3 is (HO)2P(=O)O(Ci-Cβ)alkyl.
(19) a compound of Formula I*, wherein R3 is allyl or homoallyl, can be reacted with oxygen in the presence of PdCI2 and CuCI to afford a compound of Formula I*, wherein R3 is 2-oxopropyl or 3-oxobutyl respectively.
(20) a compound of Formula I*, wherein R3 is 2-oxopropyl or 3-oxobutyl, can be reacted with MeMgX1 wherein X is Cl, Br or I, to give a compound of Formula I*, wherein R3 is 2-hydroxy-2-methylpropyl or 3-hydroxy-3-methylpropyl respectively. (21 ) a compound of Formula I*, wherein R3 is -CH2CO2Me can be treated with
MeMgX, wherein X is Cl, Br or I, to give a compound of Formula I*, wherein R3 is 2- hydroxy-2-methylpropyl. (22) a compound of Formula I*, wherein R3 is allyl or -CH2C(Me)=CH2, can be hydrocyanated with TsCN in the presence of triphenylsilane and various cobalt catalysts to afford compounds of Formula I*, wherein R3 is -CH2CH(CN)Me or -CH2CMe2CN respectively. (23) a compound of Formula I*, wherein R3 is CH2C(Me)2CN, can be treated with acetamide in the presence of PdCI2 to give a compound of Formula I*, wherein R3 is CH2CMe2CONH2.
(24) a compound of Formula I*, wherein R3 is -CH2C(Me)=CH2 can be treated with m-CPBA followed by lithium triethylborohydride to afford a compound of Formula I*, wherein R3 is 2-hydroxy-2-methylpropyl.
In a tenth process, certain compounds of the invention of Formula I** are prepared as follows:
Figure imgf000053_0002
Figure imgf000053_0001
LII
Figure imgf000053_0003
Figure imgf000053_0004
Halo compounds of Formula LIII can be formed by the treatment of β- haloketones of Formula XXXI with organometallic reagents of Formula LII1 wherein M denotes MgCI1 MgBr, MgI1 ZnBr or ZnI and the reaction is optionally performed in the presence of anhydrous cerium trichloride in an inert anhydrous solvent, such as tetrahydrofuran, at about -25 to 0 0C for about 0.5 h.
Cyclic carbamates of Formula LIV can be prepared from the reaction between β- haloalcohols of Formula LIII where Hal is a chloride and isocyanates of Formula XXXIX in the presence of a base, such as but not limited to DBU (1 ,8-diazabicyclo[5.4.0]undec- 7-ene), in a refluxing inert solvent, such as but not limited to tetrahydrofuran.
Tertiary alcohols of Formula LVII can be derived from trisubstituted alkenes of Formula LIV by first epoxidizing the alkene with an epoxidation reagent, such as m- CPBA (3-chloroperbenzoic acid), in an inert solvent, such as dichloromethane to produce the corresponding epoxides of Formula LV. The resulting epoxide is then reductively ring opened to provide the corresponding tertiary alcohol I* via treatment with a strong hydride reagent, such as lithium triethylborohydride, in an anhydrous inert solvent, such as tetrahydrofuran.
In a variation of the tenth process, a compound of the invention of Formula I*** is prepared by using a "Suzuki" coupling reaction of a boronate ester of Formula LIX with a haloheterocycle of Formula LX.
Figure imgf000054_0001
The boronate ester of Formula LIX is prepared by reaction of a bromide of Formula LVIII with bis(pinacolato)diboron. LVIII is prepared by epoxidation of alkene LVII, followed by reductive epoxide opening as described above, for 2-methyl-2-hydroxypropyl group is introduced via epoxidation and hydride ring opening as described above for conversion of LIV to I**.
This tenth process is described in greater detail in U.S. Provisional Application Serial No. 61/137,013, filed July 25, 2008 entitled SYNTHESIS OF INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (Attorney Docket No. 4370.1001-000), the entire teachings of which are incorporated herein by reference.
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:
Figure imgf000055_0001
Method2(10-80)
Figure imgf000056_0001
Method 3 (30-90)
Figure imgf000056_0002
PREPARATION 1
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1 ,3-oxazinan-
2-one
Method 1
Figure imgf000057_0001
MeMgBr
Figure imgf000057_0003
Figure imgf000057_0002
Step 1 : (S)-1-bromo-4-(1-isocyanatoethyl)benzene
To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) in methylene chloride (3 L) and satd aq NaHCO3 (3 L) solution was added triphosgene (118 g, 0.396 mol) at 0 0C. The mixture was stirred for 15 min. The organic phase was separated, dried over Na2Sθ4 and concentrated to give 1-bromo-4-(1-isocyanato-ethyl) -benzene (17O g, 63%).
Step 2: i-chloro-S-phenylhex-δ-en-S-ol
To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1mol/L) at -78 0C under nitrogen. The formed mixture was stirred for 30 min at -78 0C. The reaction was quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3- ol (180 g, 86%). 1H NMR (CDCI3): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1 H), 3.22 (m, 1 H), 3.58 (m, 1 H), 5.16 (m, 2H), 5.53 (m, 1 H), 7.23 (m, 1 H), 7.39 (m, 4H).
Step 3: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
A mixture of i-chloro-S-phenyl-hex-δ-en-S-ol (105 g, 0.050 mmol), (S)-(-)-1-(- bromophenyl)ethyl isocyanate (170 g, 0.752 mol), and DBU (228 g, 1.5 mol) in THF (1700 ml_) was heated to reflux overnight. The mixture was diluted with EtOAc and washed with 1Λ/ aq HCI. The aqueous phase was extracted with EtOAc (3 x). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column chromatography (petroleum ether/EtOAc =20:1 to 5:1) to give (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2- one (100 g, 34 %). 1H NMR (CDCI3): 1.39 (d, 3H), 2.14 (m, 1 H), 2.24 (m, 2H), 2.48-2.61 (m, 3H), 2.82 (m, 2H), 5.01 (m, 2H), 5.52 (q, 1 H), 5.73 (m, 1 H), 6.62 (d, 2H), 7.12 (m, 2H), 7.28 (m, 2H).
Step 4: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3-oxazinan-2-one and 3-((R)-3-((S)-1 -(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propanal To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3- oxazinan-2-one (31 g, 78 mmol) and CuCI (19.3 g, 195 mmol) in dry DMF (150 mL) was added H2O (50 mL) and PdCI2 (4.10 g, 23 mmol) at rt. After addition, the mixture was stirred overnight under oxygen. After TLC showed the starting material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (200 mL) was added, the organic layers were separated and the aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography (petroleum ether/EtOAc =5:1 to 1:1) to give a mixture of (S)-3-((S)-1- (4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3-oxazinan-2-one and 3-((R)- 3-((S)- 1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propanal, (26 g, 81%).
Step 5: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3-oxazinan-2-one To a mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3- oxazinan-2-one and 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3- oxazinan-6- yl)propanal (20 g, 48.2 mmol) in t-BuOH (250 ml_) and 2-methyl-2-butene (50 mL) was added a solution of NaCIO2 (19.3 g, 0.213 mol) and NaH2PO4 (28 g, 0.179 mol) in H2O (300 mL) at 0 0C. The formed mixture was stirred for 1 h at 0 0C. The mixture was treated with water (100 mL) and extracted with CH2CI2. The combined organic layer was dried over Na2SO4, filtered and concentrated to leave a residue, which was purified by column chromatography (petroleum ether/EtOAc =5:1 to 2.5:1) to afford (S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3-oxazinan-2-one (10.0 g, 83%). 1H NMR (CDCI3): 1.49 (d, 3H), 2.12 (s, 3H), 2.33 (m, 2H), 2.63 (m, 1 H), 2.86-3.08 (m, 3H), 5.57 (q, 1 H), 6.66 (d, 2H), 7.19 (m, 2H), 7.33 (m, 5H).
Step 6: (S)-3-((S)-1- (4-bromophenyl) ethyl)-6- (2- hydroxy-2-methylpropyl)- 6- phenyl- 1 ,3- oxazinan-2- one
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1 ,3- oxazinan-2-one (20 g, 46.4 mmol) in anhydrous THF (200 mL) was added dropwise methylmagnesium bromide (31 mL, 144 mmol) at -78 0C under nitrogen. Then the mixture was stirred at rt for 1 h. The reaction mixture was quenched with aq NaHCO3 (50 mL) under ice water bath. The organic layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified column chromatography (petroleum ether/EtOAc =5:1 to 2:1) to afford (S)- 3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2- one (13 g, 65%). After re-crystallization from EtOH, 4 g of the pure compound was obtained. 1H NMR (CDCI3): 1.06 (s, 3H), 1.12 (s, 3H), 1.44 (d, 3H)1 2.14 (m, 3H), 2.21 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.54 (q, 1H), 6.74 (d, 2H)1 7.16 (d, 2H), 7.28 (m, 5H).
Alternative Procedure for Method 1 Step 2
Figure imgf000059_0001
A solution of 3-chloro-i-phenylpropan-i-one (100 g, 0.595 mol) in THF (280 ml) was added dropwise to a well-stirred mixture of zinc powder (need not be activated) (40 g, 1.231 mol, satd aq NH4CI solution (1500 ml) and THF (400 ml). AIIyI bromide (143 g, 1.19 mol) was dissolved in THF (200 ml) was slowly added to the reaction mixture. The reaction was mildly exothermic, and the mixture began to reflux spontaneously. After refluxing had ceased, the mixture was stirred for 1 h. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to give 1-chloro-3-phenylhex-5- en-3-ol (122 g, 97%). 1H NMR: (400MHz, CDCI3): δ=2.24(s, 1 H), 2.34 (m, 2H), 2.53 (m, 1H)1 2.75 (m, 1H), 3.20 (m, 1H), 3.58 (m, 1H)1 5.18 (t, 1H), 5.51 (m, 1 H), 7.26 (m, 1H), 7.26-7.39 (m, 3H).
(R)-6-allyl-3-((S)-1 -(4-bromophenyl)propyl)-6-phenyl-1 ,3-oxazinan-2-one was prepared from (S)-1-(4-bromophenyl)propan-1 -amine following procedures analogous to those described in Preparation 1 Method 1 Steps 1 to 3 above.
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2- methylpropyl)-1 ,3-oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(4- bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3-oxazinan-2-one following procedures analogous to those described in Preparation 1 Method 1 Steps 4 and 6.
Method 2
Figure imgf000060_0001
THF, reflux tπphosgene, CH2CI2 sat aq NaHCO3
Figure imgf000060_0004
Figure imgf000060_0003
Figure imgf000060_0002
Figure imgf000060_0005
Step 1. i-Chloro-δ-methyl-S-phenyl-hex-S-en-S-ol
To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 mL of THF (H2O <100 ppm based on Karl Fischer titration) was charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then 3-chloro-2-methylprop-1-ene (160 g, 1.77 mol) was introduced while maintaining the internal temperature below 30 0C. The resulting solution was agitated for 2 h at rt. The solution was titrated in the presence of 1.1'-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask containing 307.0 g of anhydrous CeCI3 (1.25 mol) at rt under nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to -10 0C and agitated for 0.5 h. To the slurry was added 200 g of 3-chloro-1- phenylpropan-1-one (1.19 mol) in 200 mL of THF while maintaining the internal temperature below 0 0C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M aq HCI was added to obtain a clear solution while maintaining the internal temperature below 30 0C. After the phase cut, the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced crude 1-chloro-5-methyl-3-phenyl-hex- 5-en-3-ol, which was chased with THF to achieve H2O <500 ppm based on Karl Fischer titration. The crude product (306 g, 83wt%, 95% yield) was used directly in Step 3. 1H- NMR spectroscopy (500 MHz1 CDCI3) δ 7.38-7.37 (d. J= 7.8 Hz, 2H), 7.33 (t, J= 7.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 1 H)1 4.91 (s, 1 H), 4.76 (s, 1 H), 3.57 (ddd, J= 5.6, 10.7, and 10.7, 1 H), 3.13 (ddd, J= 4.7, 10.7 and 10.7 Hz, 1 H), 2.66 (d, J= 13.3 Hz, 1 H), 2.54 (d, J= 11.3 Hz, 1 H), 2.53 (s, 1 H), 2.36 (ddd, J= 5.4, 10.6 and 13.9 Hz. 1 H), 2.29 (ddd, J=5.6, 11.3 and 13.3 Hz, 1 H), 1.29 (s, 3H). 13C-NMR spectroscopy (125 MHz, CDCI3) δ 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2, 46.0, 39.9, 23.9.
Step 2. 1-Bromo-4-((S)-1-isocyanato-ethyl)-benzene
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(-)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to Tint=2-3 0C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ~ 6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at Tιnt=2-5 0C for 30 min, at which point HPLC analysis indicates >99 A% conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ~1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt%, 79.4 % yield). 1H-NMR spectroscopy (400 MHz, CD2CI2) δ 7.53 (d, J= 11.4 Hz, 2 H), 7.26 (d, J= 8.2 Hz, 2 H), 4.80 (q, J= 6.7 Hz, 1 H), 1.59 (d, J= 6.7 Hz, 3 H). The material was used in Step 3 without further purification.
Step 3. (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1 ,3-oxazinan-2- one
To a dried 10 L jacketed reactor under a nitrogen atmosphere was charged 1- chloro-δ-methyl-S-phenyl-hex-δ-en-S-ol (167 g, 81.7 wt%, 610 mmol, 1.00 equiv), 1- bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, 93.7 wt%, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv). The resulting solution was agitated and refluxed (Tιnt= 67-69 0C, Text= 75 0C) for 19 h, at which point HPLC analysis indicated - 1A% (220 nm) of the i-chloro-S-methyl-S-phenyl-hex-δ-en-S-ol remained. The dark solution was cooled to T,nt= 20-25 0C. Two liters of tetrahydrofuran were removed by distillation under reduced pressure. The remaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0 L of hexanes. The resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note: the wash is slightly exothermic). The aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was subjected to flash silica chromatography (5-30 % ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt%, 3.1 :1 diastereomeric ratio favoring the desired diastereomer (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)- 6-phenyl-1 ,3-oxazinan-2-one, 32.3 % yield). The material was used in Step 4 without further purification.
Analytical data for (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl- 1 ,3-oxazinan-2-one: 1H-NMR spectroscopy (500 MHz, CD2CI2) δ 7.42-7.35 (m, 3 H), 7.33-7.31 (m, 2H), 7.25-7.23 (m, 2H), 6.80-6.74 (m, 2), 5.55 (q, J= 7.1 Hz, 1 H), 5.37- 5.36 (m, 1H), 4.89 (s, 1H), 4.69 (s, 1 H), 2.96-2.93 (m, 1 H), 2.61 (dd, J= 13.8 and 26.4 Hz, 2 H), 2.37-2.25 (m, 3H), 1.68 (s, 3H), 1.50 (d, J= 7.1 Hz, 3 H). 13C-NMR spectroscopy (125 MHz, CD2CI2) δ 152.5, 141.5, 140.1 , 138.3, 130.6, 128.1 , 128.0, 126.9, 124.4, 120.2, 115.3, 82.4, 52.1 , 50.1, 35.6, 29.8, 23.4, 14.5.
Analytical data for (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl- 1 ,3-oxazinan-2-one: 1H-NMR spectroscopy (400 MHz, CD2CI2) δ 7.50-7.48 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.32 (m, 3H), 7.20-7.18 (m, 2H), 5.60 (q, J= 7.1 Hz, 1 H), 4.85 (S1 1H), 4.66 (S, 1 H), 2.73-2.67 (m, 2H), 2.60 (dd, J= 13.9 and 19.4 Hz, 2H), 2.28 (dt, J= 3.3 and 13.7 Hz, 1 H), 2.14-2.05 (m, 1 H), 1.66 (s, 3H), 1.24 (d, J= 7.2 Hz, 3 H). 13C-NMR spectroscopy (100 MHz, CD2CI2) δ 153.4, 142.5, 141.0, 140.1 , 131.8, 129.3, 128.9, 127.8, 125.3, 121.5, 116.3, 83.9, 53.2, 51.0, 36.6, 31.3, 24.3, 15.4.
Step 4. (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl- 1 ,3-oxazinan-2-one
To a 1.0 L 2-neck RBF was charged (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2- methylallyl)-6-phenyl-1 ,3-oxazinan-2-one (135.8 g, 59 wt%, 3.1 :1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 ml_), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25 0C) for 1 h, which HPLC analysis indicates >99 A% (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1x500 mL of 30 wt% solution of sodium thiosulfate and 1x500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A% (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)- 6-phenyl-1 ,3-oxazinan-2-one which was used directly in Step 5.
Step 5. (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1 ,3- oxazinan-2-one To a 2.0 L 3-neck oven-dried RBF was charged the crude (6S)-3-((S)-1-(4- bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1 ,3-oxazinan-2-one and 750 mL of anhydrous THF. The resulting solution was agitated and cooled to Tint= 2-3 0C. To the agitated clear solution was charged 1.0 M lithium triethylborohydride in tetrahydrofuran (Super Hydride, 348 mL, 348 mmol, 1.8 equiv). The addition is exothermic and addition was controlled to maintain Tint= < 8 0C. The resulting solution was agitated at Tint= 2-3 0C for 1.5 h and then allowed to warm to Tint= 10-13 0C over a 2.5 h, which HPLC analysis indicates ~94 A% (220 nm) conversion. To the agitated solution was charged a solution of hydrogen peroxide (95.7 mL of a 35 wt% aqueous solution diluted with 400 mL of water, 1.08 mol, 5.60 equiv). The addition is highly exothermic and addition was controlled to maintain Tint= < 25 0C. The resulting solution was diluted with 1.00 L of methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by 500 mL of a -30 wt% solution of sodium thiosulfate. The organic solution was dried with anhydrous sodium sulfate, filtered, and then concentrated via reduced pressure. The resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer, (>99:1 dr). The material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A% at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1 ,3- oxazinan-2-one (83.6 % yield for the two step operation). 1H-NMR spectroscopy (400 MHz, CDCI3) δ 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H), 6.82-6.79 (m, 2H), 5.61 (q, J= 6.9 Hz, 1 H), 2.83 (ddd, J= 2.5, 5.4 and 11.6 Hz, 1 H), 2.39 (ddd, J= 5.7, 12.0 and 14.1 Hz, 1 H), 2.27 (ddd, J= 2.6, 4.8 and 14.0 Hz1 1H), 2.21-2.14 (m, 3H), 2.08 (s, 1 H), 1.49 (d, J= 7.0 Hz, 3H)1 1.18 (S, 3H)1 1.13 (s, 3H). 13C-NMR spectroscopy (100 MHz, CDCI3) δ 153.2, 142.6, 138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1, 53.3, 36.4, 33.6, 32.1 , 30.8, 15.6. PREPARATION 2
(S)-6-(2-hydroxy-2-methylpropyl)- 6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborol-an-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000065_0001
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2- methylpropyl)-6-phenyl-1 ,3-oxazinan-2-one (6.6 g, 15.2 mmol) and 414,4',4I,5,5,5'15'- octamethyl- 2,2'-bi(1 ,3,2- dioxaborolane) (6.1g, 24.3 mmol) in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) and Pd(dppf)cl2 (372 mg, 0.46 mmol). After addition, the mixture was allowed to warm to 100 0C for 20 h. After TLC showed the starting material had disappeared, the solid was filtered off. Water (60 mL) and EtOAc (2OmL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 χ 15 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography to give (S)-6-(2-hydroxy-2-methylpropyl)- 6-phenyl-3-((S)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (4.4 g, 60%).
(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(4- fluorophenyl)-1 ,3-oxazinan-2-one following an analogous procedure.
(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4l5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)propyl)-1 ,3-oxazinan-2-one was prepared from (S)-3-((S)-1-(4- bromophenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1 ,3-oxazinan-2-one following an analogous procedure. (/?)-6-Methoxymethyl-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-
[1 ,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one was prepared from 3-[1-(4- bromo-phenyl)-ethyl]-6-methoxymethyl-6-phenyl-[1 ,3]oxazinan-2-one following an analogous procedure. PREPARATION 3
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)-2,2- dimethylpropanenitrile
Figure imgf000066_0001
Preparation of Cobalt(ll) Complex
A 50 mL flask was charged with Λ/,Λ/-bis(3,5-di-tert-butylsalicylidene)-1 , 1 ,2,2- tetramethylethenediamine (0.430 g, 0.78 mmol, 1.0 equiv), EtOH (17 mL), and Co(OAc)2 (0.139 g, 0.78 mmol, 1.0 equiv). The mixture was degassed and then heated to reflux under nitrogen for 3 h, cooled to room temperature. The precipitate was filtered and the purple solid was washed with EtOH (10 mL) and dried under high vacuum to give 0.353 g (75%) of the cobalt(ll) complex.
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1 ,3- oxazinan-2-one (490 mg, 1.18 mmol), the cobalt(ll) complex whose preparation is described immediately above (8 mg, 0.01 equiv), TsCN (257 mg, 1.2 equiv), and PhSiH3 (137 mg, 157 μL, 1.07 equiv) in ethanol (10 mL) was stirred 4 h at rt. After removing the solvent under reduced pressure, the residue was purified by chromatography on a 4Og silica gel column, eluted with a 25-80% EtOAc in hexanes gradient to afford 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6- yl)-2,2-dimethylpropanenitrile (267 mg, 51% yield). LC-MS (3min. method) tR = 1.89min., m/z 441 , 443 (M+1) PREPARATION 4
2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)ethyl)-1 ,3-oxazinan-6-yl)propanenitrile
Figure imgf000067_0001
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)-2,2- dimethylpropanenitrile (467 mg, 1.06 mmol), 4,4,4',4l,5,5,5',5l-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (538mg, 2equiv), KOAc (333mg, 3.2 equiv), PdCI2(dppf)CH2CI2 (27 mg, 0.033 equiv) were mixed with dry DMSO (6 ml_). The mixture was degassed and refilled with N2 gas 3 times. The mixture was then heated overnight at 90 0C under protection of N2 gas. After being cooled to rt, the mixture was diluted with EtOAc (30 ml_), washed with water (20 ml_). The aqueous layer was extracted with EtOAc (2 x 15 ml_). The combined organic layers were washed by water (15 ml_), brine (2 x 10 ml.) and dried over Na2SO4. After filtration and concentration, the residue was purified chromatography on a 4Og silica gel column, eluted with a 20-50% EtOAc in Hexanes gradient, to afford 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-6-yl)propanenitrile (393 mg, 76% yield).
PREPARATION 5 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1 ,3-oxazinan-6-yl)-2- methylpropanenitrile Method 1
Figure imgf000068_0001
CeCI3, THF DBU, THF, reflux
Figure imgf000068_0003
Figure imgf000068_0002
Figure imgf000068_0004
Step 1. 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol
A 250-mL flask was charged with anhydrous CeCb (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 THF1 21 mL, 21.0 mmol) was added. After stirring for 2 h at -78 0C, 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 of 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, 211 (M-OH)+; 1H NMR (400 MHz1 CDCI3) δ 7.37-7.32 (m, 2H), 7.07- 7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 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 -116.52 (m).
Step 2. (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3-oxazinan-2-one and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3-oxazinan-2-one.
A mixture of 1-chloro-3-(4-fIuorophenyl)hex-5-en-3-ol (0.4129 g, 1.8 mmol, 1.0 equiv), (S)-(-)-1-(4-bromophenyl)ethyl isocyanate (0.5005 g, 2.2 mmol, 1.2 equiv), and DBU (0.7375 g, 4.8 mmol, 2.7 equiv) in THF (10 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCI. The aqueous phase was extracted with EtOAc (2 x). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was directly used in the next step without further purification.
An analytical sample was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 6-allyl-3-((S)-1-(4-bromo- phenyl)ethyl)-6-(4-fluorophenyl)-1 ,3-oxazinan-2-one.
Isomer 1 : (S)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3- oxazinan-2-one. LC-MS Method 1 tR = 2.03 min, m/z 420, 418 (MH+); 1H NMR (400 MHz, CDCI3) δ 7.46 (d, J = 8.2 Hz, 2H), 7.31-7.28 (m, 2H)1 7.17 (d, J = 8.2 Hz, 2H), 7.07 (t, J = 8.5 Hz, 2H), 5.76-5.66 (m, 2H), 5.10-4.99 (m, 2H), 2.75-2.52 (m, 4H), 2.23-2.19 (m, 1 H), 2.08-2.00 (m, 1 H), 1.24 (d, J = 7.0 Hz, 3H); 19F NMR (376 MHz, CDCI3) δ - 115.07 (m).
Isomer 2: (R)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3- oxazinan-2-one. LC-MS Method 1 fe = 1.98 min, m/z 420, 418 (MH+); 1H NMR (400 MHz, CDCI3) δ 7.25-7.20 (m, 4H), 7.05-7.01 (m, 2H), 6.71 (d, J = 8.5 Hz, 2H), 5.74-5.64 (m, 1 H), 5.58 (q, J = 7.0 Hz, 1 H), 5.09-4.99 (m, 2H), 2.92-2.87 (m, 1 H), 2.63-2.50 (m, 2H), 2.33-2.16 (m, 3H), 1.47 (d, J = 7.0 Hz, 3H); 19F NMR (376 MHz, CDCI3) δ -114.91 (m).
Step 3 A mixture of (R)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3- oxazinan-2-one (1.067 g, 2.55 mmol, 1.0 equiv), the cobalt(ll) catalyst described in Preparation 3 (0.016 g, 0.0264 mmol, 0.010 equiv), TsCN (0.555 g, 3.06 mmol, 1.2 equiv), and PhSiH3 (0.294 g, 2.72 mmol, 1.07 equiv) in EtOH (5 mL) was stirred at room temperature for 4 h. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1.0130 g (89%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1 ,3- oxazinan-6-yl)-2-methylpropanenitrile as a solid. LC-MS tR = 1.83, 1.86 min in 3 min chromatography, m/z 445, 447 (MH+); 1H NMR (400 MHz, CDCI3) δ 7 '..32-7 '.22 (m, 4H), 7.13-7.05 (m, 2H), 6.80-6.73 (m, 2H), 5.60-5.56 (m, 1 H), 3.00-1.94 (m, 7H), 1.51-1.49 (m, 3H), 1.35-1.32 (m, 1.5H), 1.27-1.24 (m, 1.5H); 19F NMR (376 MHz, CDCI3) δ -113.08 (m), -113.69(m).
Step 4
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo- 1 ,3-oxazinan-6-yl)-2-methylpropanenitrile (0.332 g, 0.746 mmol) and MeI (1.40 g, 13 equiv) in THF (12 mL) at -78 0C was added 2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution in THF. The resulting mixture was stirred overnight, with the temperature slowly rising to ambient. The reaction mixture was quenched with brine (1 mL), diluted with CH2CI2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep Ci8 OBD™ 5μm 19 x 50 mm column, 10% →90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1 % CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.255 g (74%) of 3-((R)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1 ,3-oxazinan-6-yl)- 2,2-dimethylpropanenitrile. LC-MS Method 1 tR = 1.89 min, m/z 459, 461 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83 (d, J = 8.2 Hz, 2H), 5.41 (q, J = 7.0 Hz, 1 H), 3.02-2.97 (m, 1 H), 2.42-2.36 (m, 1 H), 2.29-2.08 (m, 4H), 1.42 (d, J = 7.0 Hz, 3H), 1.30 (s, 3H), 1.22 (s, 3H); 19F NMR (376 MHz, CD3OD) δ -116.50 (m). Method 2
Figure imgf000071_0001
Step i
A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol) in THF (50 ml.) was added to a well-stirred suspension of zinc power (13 g, 0.2 mol) in a mixture of aqueous saturated NH4CI solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4- fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1- ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2 x 500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/ EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4- fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76 %) as an oil.
Step 2
A mixture of 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (3.15 g, 13 mmol), (S)-(-)- 1-(- bromophenyl)ethyl isocyanate (3.5 g, 16 mmol), and DBU (8 g, 33 mmol) in THF (80 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1Λ/ aq HCI. The aqueous phase was extracted with EtOAc (3 x). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column to give (R)-3-((S)-1-(4-bromophenyl)-ethyl)-6- (4-fluorophenyl)-6-(2-methylallyl)-1 ,3-oxazinan-2-one (2.13 g, yield: 38 %). Step 3
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2- methylallyl)-1,3-oxazinan-2-one (2.13 g, 4.9 mmol), the cobalt(ll) catalyst described in Preparation 3 (0.032 g, 0.053 mmol), TsCN (1.11 g, 6.12 mmol), and PhSiH3 (0.6 g, 5.54 mmol) in EtOH (10 mL) was stirred at room temperature for 8 h. After the solvent was removed under reduced pressure, the residue was purified by column chromatography to give 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo- 1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (1.84 g, 81.1%).
PREPARATION 6
3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)-1 ,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile
Figure imgf000072_0001
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo- 1 ,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (730 mg, 1.59 mmol) in DMSO (8 mL) was added bis(pinacolato)diboron (480 mg, 1.89 mmol), KOAc (480 mg, 4.89 mmol) and Pd(dppf)CI2 (45 mg, 0.042 mmol) under nitrogen atmosphere. The formed mixture was stirred at 90 0C for 20 h. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by column chromatography to give 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (191 mg, 23.7%). PREPARATION 7
(/?)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000073_0001
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3- oxazinan-2-one (0.4910 g, 1.17 mmol, 1.0 equiv), bis(pinacolato)diboron (0.3925 g, 1.55 mmol, 1.3 equiv), KOAc (0.3696 g, 3.76 mmol, 3.2 equiv), and PdCI2(dppf) CH2CI2 (0.0316 g, 0.0386 mmol, 0.033 equiv) in DMSO (6 ml_) was heated at 90 0C under N2 for 20 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to give 0.4776 g (87%) of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1- (4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one as a white solid.
PREPARATION 8 (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000073_0002
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3-oxazinan- 2-one (5 g, 12.5 mmol) in tetrahydrofuran (60 mL) was added BH3 THF (25 ml_, I mol/L, 25 mmol) at 0 0C under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then NaOH (3 mol/L, 10 mL) and H2O2 (15 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by column chromatography to give (R)-3-((S)-1-(4- bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-pheny 1-1 ,3- oxazinan-2-one (2.5 g, 40%). 1H NMR: (400MHz, CDCI3): δ=1.48 (t, 3H)1 1.53 (m, 1 H)1 1.73 (m, 1H)1 1.93-1.98(m, 2H)1 2.17-2.28 (m,3H), 3.57 (t, 2H), 5.59 (m, 1 H), 6.72 (m, 2H), 7.20(m, 2H), 7.25-7.37 (m, 5H).
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1 ,3- oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4- fluorophenyl)-1 ,3-oxazinan-2-one following an analogous procedure.
(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1 ,3-oxazinan- 2-one was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1 ,3- oxazinan-2-one following an analogous procedure.
PREPARATION 9
(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)-1,3-oxazinan-2-one
Figure imgf000074_0001
To a solution of ((f?)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6- phenyl-1 ,3-oxazinan-2-one (2 g, 4.8 mmol) in DMSO (30 ml.) were added bis(pinacolato)diboron (1.58 g, 6.3 mmol), KOAc (1.51 g, 15.4 mmol) and PdCI2 (130 mg, 0.16 mmol) under nitrogen atmosphere. The formed mixture was stirred at 90 0C for 20 h. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by column chromatography to give(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4- (4,4,5,5-tetramethyl-i ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (1.7 g, 77%). 1H NMR: (400MHz1 CDCI3): δ=1.18 (t, 1 H), 1.33 (S, 11 H), 1.43 (m, 2H), 1.48 (m, 3H), 1.71(m, 1 H), 1.88 (m,2H), 2.1-2.3 (t, 3H), 2.7(m, 1 H)D3.5 (m, 2H), 5.5 (m, 1 H),6.72 (m, 2H), 7.25-7.37 (m, 5H),7.48(m, 2H). (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4- bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1 ,3-oxazinan-2-one following an analogous procedure. (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)propyl)-1 ,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4- bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1 ,3-oxazinan-2-one following an analogous procedure.
PREPARATION 10
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(methoxymethyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000075_0001
Step 1. 1-Methoxy-2-phenyl-pent-4-en-2-ol 2-Methoxy-1 -phenyl-ethanone (5.00 g) dissolved in tetrahydrofuran (50 mL) was added to 2 M allylmagnesium chloride in tetrahydrofuran (21 mL) at room temperature. The solution was stirred at room temperature for 3 h and then 10 % aqueous NH4CI solution (50 mL) was added. The resulting mixture was extracted with tert-butyl methyl ether (3x 50 mL) and the combined extracts were washed with water (50 mL) and brine (50 mL). The solvent was evaporated to afford the title compound as a colorless oil. Yield: 6.40 g (quantitative). Mass spectrum (ESI+): m/z = 175 [IvHH-H2O]+
Step 2. 5-Methoxy-4-phenyl-pentane-1 ,2,4-triol
OsO4 (4% in water, 2 mL; alternatively, K2OsO4 may be used) followed by N- methyl-morpholine-N-oxide (5.20 g) was added to a solution of 1-methoxy-2-phenyl- pent-4-en-2-ol (1.10 g) in tetrahydrofuran (10 mL) chilled in an ice bath. The cooling bath was removed and the solution was stirred at room temperature overnight. Then, 10% aqueous Na2S2O5 solution (10 mL) was added and the resulting mixture was stirred at room temperature for another 1.5 h. After removal of the organic solvent under reduced pressure, the remaining mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated to afford the title compound in good purity (ca. 95%). Yield: 1.20 g (96% of theory). Mass spectrum (ESI"): m/z = 225 [M-H]"
Step 3. 3-Hydroxy-4-methoxy-3-phenyl-butyraldehyde
NaIO4 (5.20 g) was added to a mixture of 5-methoxy-4-phenyl-pentane-1 ,2,4- triol (1.10 g), dichloromethane (10 mL), and water (5 mL) chilled in an ice bath. The mixture was stirred vigorously while warming to ambient temperature in the cooling bath and further stirred at this temperature overnight. Then, water (20 mL) and dichloromethane (50 mL) were added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (2x 25 mL). The combined organic phases were washed with water and dried (MgSO4). After removal of the solvent, the title compound was yielded which was directly submitted to the next reaction step (glycol cleavage). Yield: 0.94 g (quantitative)
Step 4. 4-[(S)-1-(4-Bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol
(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaB(OAc)3 (0.98 g), and acetic acid (0.27 mL) were added in the given order to a solution of 3-hydroxy-4-methoxy-3- phenyl-butyraldehyde (0.90 g) in tetrahydrofuran (20 mL) at ca. 10-15 "C. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Then, water (50 mL) and 1 M aqueous NaOH solution (20 mL) were added and the resulting mixture was stirred for another 30 min. The mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. After drying (MgSO4), the solvent was removed to give the title compound which was submitted to the subsequent reaction step without further purification. Yield: 1.80 g (quantitative). Mass spectrum (ESI+): m/z = 378/380 (Br) [M+H]+ Step 5. 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1 ,3]oxazinan- 2-one and 3-[(S)-1 -(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl- [1 ,3]oxazinan-2-one
Triphosgene (157 mg) was added to an ice-cold solution of 4-[(S)-1-(4-bromo- phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol (1 :1 diastereomeric mixture, 200 mg) and EtNZPr2 (91 μL) in dichloromethane (5 ml_). The resulting solution was stirred with cooling for 2 h and at room temperature overnight. Then, the solution was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compounds in separate fractions.
Isomer 1 : 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl- [1 ,3]oxazinan-2-one. Yield: 45 mg (21% of theory). Mass spectrum (ESI+): m/z = 404
[M+H]+ 1H NMR (400 MHz, DMSO-Cf6) δ 1.41 (d, J = 7.1 Hz, 3H), 2.19 (td, J = 11.2, 5.2 Hz, 1 H), 2.24-2.34 (m, 1 H), 2.34-2.41 (m, 1 H), 3.02-3.09 (m, 1 H), 3.27 (s, 3H), 3.49 (d, B part of an AB signal, J = 10.6 Hz, 1 H), 3.53 (d, A part of an AB signal, J = 10.6 Hz, 1 H), 5.34 (q, J = 7.0 Hz, 1 H), 6.80 (dm, J = 8.4 Hz, 2H), 7.27 (dm, J = 8.4 Hz, 2H), 7.32- 7.42 (m, 5H).
Isomer 2: 3-[(S)-1 -(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl- [1 ,3]oxazinan-2-one. Yield: 45 mg (21% of theory). Mass spectrum (ESI+): m/z = 404 [M+H]+ 1H NMR (400 MHz, DMSO-Cf6) δ 1.20 (d, J = 7.2 Hz, 3H), 2.13-2.23 (m, 1 H), 2.32-2.40 (m, 1 H), 2.63-2.72 (m, 1 H), 2.73-2.81 (m, 1 H), 3.26 (s, 3H), 3.48 (d, B part of an AB signal, J = 10.6 Hz, 1 H), 3.55 (d, A part of an AB signal, J = 10.6 Hz, 1 H), 5.35 (q, J = 7.2 Hz, 1 H), 7.19 (dm, J = 8.4 Hz, 2H), 7.32-7.45 (m, 5H), 7.53 (dm, J = 8.4 Hz, 2H).
PREPARATION 11
N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propyl)-N- methylacetamide
Figure imgf000077_0001
Step 1
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl- 1 ,3-oxazinan-2-one (200 mg, 0.48 mmol) in CH2CI2 (5 mL) was added Et3N (240 mg,
2.4 mmol) and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0 0C. The reaction solution was stirred at rt for 1 h. The reaction was quenched with H2O and the mixture was extracted with CH2CI2. The organic phase was concentrated to give 3-((R)-3-((S)- 1 -(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propyl methanesulfonate (234 mg, 98%), which was used for the next step without further purification.
Step 2
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3- oxazinan-6-yl)propyl methanesulfonate (234 mg, 0.24 mmol) in CH2CI2 (3 mL) was added NaH (82 mg, 3.4 mmol) at 0 0C. The mixture was stirred at rt for 30 min. Then
Λ/-methylacetamide (204 mg, 2.8 mmol) was added the above mixture. The formed mixture was stirred at 80 0C for 5 h. After the reaction was over, the reaction was quenched with water and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative
TLC to give Λ/-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6- yl)propyl)-Λ/-methylacetamide (150 mg, 68%). LC-MS Method 2 tR = 1.50 min, m/z = 497, 495, 475, 473. 1H NMR (400MHz, CDCI3): δ=1.41 (m, 1H), 1.48 (t, 3H), 1.73 (m,
1 H)1 1.83-1.95 (m, 2H), 2.01 (m, 3H), 2.1-2.3 (m, 3H), 2.71 (m, 1H), 2.81 (s, 3H), 3.1 (m,
1 H), 3.2 (m, 1 H), 5.5 (m, 1 H), 6.72 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.37 (m, 3H).
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl- 1 ,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3- hydroxypropyl)-6-phenyl-1 ,3-oxazinan-2-one following an analogous procedure using pyrrolidin-2-one in Step 2. PREPARATION 12
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1 ,-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1 ,3- oxazinan-2-one
Figure imgf000079_0001
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1 ,3-oxazinan- 2- one (3 g, 7.5 mmol) in CH2CI2 (50 mL) was treated with O3 at -78 0C till the mixture turned blue. Then NaBH4 (285 mg, 75 mmol) was added to the solution at O 0C, and the reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by H2O, and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (S)-3-((S)-1-(4-bromo- phenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1 ,3- oxazinan-2-one (2.5 g, 84%). 1H NMR (CDCI3): 1.48 (t, 3H), 2.05-2.41 (m, 4H), 2.71- 2.92 (m, 2H), 3.51 (m, 1 H)1 3.71 (m, 1 H), 5.58 (m, 1 H), 6.73 (d, 2H), 7.12 (m, 2H), 7.23- 7.45 (m, 6H).
PREPARATION S
(S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-(1 , 1 -dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-
1 ,3-oxazinan-2-one
Figure imgf000079_0002
Step i
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl- 1 ,3- oxazinan-2-one (300 mg, 0.75 mmol) in dichloromethane (20 mL) were added Et3N (390 mg, 3.75 mmol) and methanesulfonyl chloride (256 mg, 2.25 mmol) at 0 0C. The reaction solution was stirred at rt for 1 h. The reaction was quenched with H2O and the mixture was extracted with dichloromethane. The organic phase was concentrated to give 2-((S)-3-((S)-1 -(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)ethyl- methane sulfonate (352.8 mg, 98%), which was used for the next step without further purification.
Step 2
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3- oxazinan- 6-yl)ethyl-methanesulfonate (360 mg, 0.75 mmol) and K2CO3 (207 mg, 1.5 mmol) in acetonitrile (10 ml.) was added isothiazolidine 1 ,1-dioxide (121 mg, 4.6 mmol), and the mixture was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC to afford compound (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1 ,1-dioxo-isothiazolidin-2- yl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one (2.43 mg, 1%). LC-MS Method 2 tR = 1.37 min, m/z = 509, 507. 1H NMR (CDCI3): 1.48 (t, 3H), 2.05-2.41 (m, 7H), 2.71-2.92 (m, 2H), 3.11 (m, 3H), 3.21 (m, 2H), 5.58 (m, 1 H), 6.73 (d, 2H), 7.18 (m, 1 H), 7.23 (m, 3H);7.35 (m, 3H).
(R)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(3-(1 , 1 -dioxo-isothiazolidin-2-yl)propyl)-6- phenyl-1 ,3-oxazinan-2-one was prepared from from from (R)-3-((S)-1-(4- bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1 ,3-oxazinan-2-one following an analogous procedure.
PREPARATION 14
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-
1 ,3-oxazinan-2-one
Figure imgf000080_0001
EtMgBr
Figure imgf000080_0003
Figure imgf000080_0002
Step 1
To a solution of (f?)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1 ,3 - oxazinan-2-one (450 mg, 1.01 mmol) in acetone (10 ml_) was added a solution of KMnO4 (190 mg, 1.2 mmol) and NaIO4 (1.5 g, 7.2 mmol) in water (10 ml_). The mixture was stirred for 2 h at 0 0C. The mixture was filtered and the filtrate was adjusted to pH 5-6 with aqueous 1 N aq HCI solution. The mixture was extracted with EtOAc. The organic phase washed with brine, dried over anhydrous Na2SO4 and concentrated to give 2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6- (4-fluorophenyl)-2-oxo-1 ,3-oxazinan-6- yl)acetic acid (540 mg, crude), which was used for the next step without purification.
Step 2
To a solution of 2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6- (4-fluorophenyl)-2-oxo- 1 ,3-oxazinan-6-yl)acetic acid (540 mg, 1.24 mol) in MeOH (20 mL) was added SOCI2 (5 ml.) at 0 0C1 and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was purified by preparative TLC to give methyl 2-((S)-6- (4-fluorophenyl)-3-((S)-1 -(4-(1 -methyl-6-oxo-1 ,6-dihydropyridin-3-yl)phenyl)-ethyl)-2- oxo-1 ,3-oxazinan-6-yl)acetate (150 mg, 27%). 1H NMR (CDCI3): δ=1.49 (d, 3H), 2.19 (m, 1 H), 2.44 (m, 1 H)1 2.60 (m, 1H), 2.77-3.08 (m, 3H), 3.51 (s, 3H), 5.52 (m, 2H), 6.62 (d, 2H), 6.98 (t, 2H), 7.23 (t, 2H), 7.28 (m, 2H).
Step 3
To a solution of methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1 ,6- dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1 ,3-oxazinan-6-yl)acetate (150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) in THF (20 mL) was added 3.0 M ethylmagnesium bromide (4 mL, 12 mmol) at rt under nitrogen. Then the mixture was stirred for 2 h. The reaction was quenched with aqueous NH4CI solution, and the mixture was filtered. The filtrate was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by preparative HPLC to give (S)-3-((S)-1-(4- bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1 -hydroxycyclopropyl)methyl)-1 ,3-oxazinan-2- one (2.51 mg, 2%). 1H NMR (CDCI3): 0.03 (m, 1 H), 0.18 (m, 1 H), 0.49 (m, 1 H), 0.60 (m, 1 H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1H), 2.37 (m, 2H), 2.88 (m, 1 H), 5.53 (m, 1 H), 6.66 (d, 2H)1 6.97 (t, 2H)1 7.16 (m, 2H), 7.26 (m, 2H). PREPARATION 15
N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propyl)-N- methylmethanesulfonamide
Figure imgf000082_0001
To a solution of 3-((f?)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3- oxazinan-6-yl) propyl methanesulfonate (180 mg, 0.36 mmol) in DMF (5 mL) was added NaH (14.6 mg, 0.36 mmol) at 0 °C. The mixture was stirred at rt for 30 min. Then iodomethane (153 mg, 1.1 mmol) was added to the above mixture. The formed mixture was stirred at 40 0C for 3 h. After the reaction was over, the reaction was quenched with NH4CI solution and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give /V-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1 ,3-oxazinan-6- yl)propyl)-Λ/-methylmethanesulfonamide (100 mg, 55%). LC-MS Method 2 tR = 1.41 min, m/z = 511 , 509. 1H NMR (400MHz, CDCI3): δ=1.45 (m, 1 H)1 1.48 (t, 3H), 1.83-1.97 (m, 3H), 2.1-2.2 (m, 3H), 2.61 (s, 3H), 2.71 (s, 3H), 2.91 (m, 1H), 3.0 (m, 2H)1 5.5 (m, 1 H)1 6.72 (m, 2H)1 7.10 (m, 2H)1 7.20 (m, 2H), 7.37 (m, 3H).
EXAMPLE 1
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Figure imgf000083_0001
Step i
Concentrated H2SO4 (1 mL) was stirred at O0C, then NaNO2 (0.2 g, 2.9 mmol) was added. The mixture was heated at 50 0C until all of the NaNO2 was dissolved. The mixture was cooled to O 0C. A solution of 5-chloro-pyrazin-2-ylamine (300 mg, 2.3 mmol) in concentrated H2SO4 (2 mL) was added dropwise to the nitronium solution at 0 0C. The mixture was warmed to rt and stirred for about 15 min. before heating at 45 0C for 7 min. After being cooled to rt, the mixture was poured slowly into iced water (10 ml). The aqueous phase was neutralized to pH=4 with 20% sodium hydroxide solution and extracted with EtOAc. The organic phase was concentrated to give 5-chloro- pyrazin-2-ol (200 mg, 66%). 1H NMR (CD3OD): δ 7.81 (s, 1 H), 7.88 (s, 1 H).
Step 2
To a solution of 5-chloro-pyrazin-2-ol (100 mg, 0.76 mmol) in DMF (3 mL) was added K2CO3 (211 mg, 1.53 mmol) and CH3I (0.25 ml, 4 mmol) at room temperature. The mixture was stirred overnight, quenched by H2O1 and extracted with EtOAc. The organic phase was concentrated to give the crude product, which was purified by TLC to give 5-chloro-1-methyl-1H-pyrazin-2-one (70 mg, 64 %). 1H NMR (CD3OD): <53.52 (s, 3H), 7.78 (s, 1 H), 7.87 (s, 1 H). Step 3
A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (279 mg, 0.6 mmol) and δ-chloro-i-methyl-I H-pyrazin^-one (70 mg, 0.5 mmol), Pd(Ph3P)2CI2 (3 mg), and aq. Cs2CO3 solution (0.5 ml_, 2M) in 1 ,4-dioxane (3 mL) was stirred at reflux for 2.5 h under N2. When the reaction was over, the mixture was washed with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one (165.1 mg ,34.6 %). LC-MS Method 2 tR = 1.107 min, m/z = 404.1 ; 1H NMR (CDCI3): δ 1.11 (s, 3H), 1.18 (s, 3H), 1.54 (d, 3H), 2.35 (m, 4H), 2.87 (m, 1H)1 3.62 (s, 3H)1 5.69 (m, 1 H), 7.05 (d, 2H)1 7.34 (m, 5H), 7.45 (m, 1 H), 7.50 (d, 2H), 8.25 (s, 1 H).
EXAMPLE 2
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-oxo-4,5-dihydropyrazin-2- yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000084_0003
A microwave vial, equipped with a flea stir bar, was charged with (S)-3-((S)-1-(4- bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1 ,3-oxazinan-2-one (22 mg, 0.051 mmol), 2-tert-butoxy-5-(4,4,5l5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazine (21 mg, 0.076 mmol), Cs2CO3 (33 mg, 0.10 mmol), water (0.1 mL) and dioxane (1 mL). The mixture was sparged with N2 for 5 min and PdCI2(dppf) (4 mg, 0.005 mmol) was added. The mixture was sparged with N2 for 5 min and heated at 110 °C for 40 min in the microwave. The reaction mixture was filtered and the filtrate was purified by prep HPLC under acidic conditions, which led to loss of the t-butyl group, to afford the title compound (12.6 mg, 55%) as an oil. LC-MS Method 1 tR = 1.27 min, m/z = 448, 390; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.56 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1H), 2.47 (m, 2H), 3.02 (m, 1 H), 5.56 (q, 1 H), 7.00 (d, 2H), 7.20-7.30 (5H), 7.58 (d, 2H), 7.77 (s, 1 H), 8.14 (s, 1 H).
EXAMPLE 3
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1 -(4-(1 -methyl-2-oxo-1 ,2-dihydropyrimidin-5- yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000085_0001
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6- phenyl-3-((S)-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3- oxazinan-2-one and 5-bromo-1-methylpyrimidin-2(1 H)-one following a procedure analogous to that described in Example 1 Step 3. 5-bromo-1-methylpyrimidin-2(1 H)- one was prepared from 5-bromopyrimidin-2-ol following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR = 1.068 min, m/z = 462.1 ; 1H NMR (CD3OD) 0.95 (S, 3H), 1.28 (m, 3H), 1.54 (m, 3H), 2.15 (d, 2H), 2.20 (m, 1H), 2.47 (m, 2H), 3.04 (m, 1 H), 3.63 (s, 2H), 5.56 (m, 1 H), 7.06 (m, 2H), 7.29-7.37 (m, 7H), 8.40 (d, 1 H), 8.81 (d, 1H)
EXAMPLE 4
2,2-dimethyl-3-((R)-3-((S)-1 -(4-(1 -methyl-6-oxo-1 ,6-dihydropyridazin-3-yl)phenyl)ethyl)- 2-oxo-6-phenyl-1 ,3-oxazinan-6-yl)propanenitrile
Figure imgf000086_0001
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3- ((S)-I -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-6- yl)propanenitrile and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 1 Step 3. 6-chloro-2-methylpyridazin-3(2H)- one was prepared from 6-chloropyridazin-3-(2H)-one following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR = 1.138 min, m/z = 471.3; 1H NMR (CDCI3) 1.28 (s, 3H), 1.41 (s, 3H), 1.49 (m, 3H), 2.1 (s, 2H), 2.2 (m, 1H), 2.42 (m, 2H), 2.85 (m, 1 H)1 3.78 (s, 3H), 6.92 (m, 3H), 7.31 (m, 5H), 7.43 (d, 2H), 7.50 (d, 1 H), 7.35 (m, 8H)
EXAMPLE 5
2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1 ,6-dihydropyridazin-3-yl)phenyl)ethyl)-6- phenyl-1,3-oxazinan-6-yl)propanenitrile
Figure imgf000086_0002
A mixture of 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-6-yl)propanenitrile (150 mg, 0.31 mmol), 6-chloropyridazin-3-(2H)-one (62 mg, 0.47 mmol), Pd(Ph3P)2CI2 (15 mg), and aq. Cs2CO3 solution (2 ml_, 2M) in 1 ,4-dioxane (10 mL) was stirred at reflux for 2 h. When the reaction was finished, the mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1 ,6-dihydropyridazin-3-yl)phenyl)ethyl)-6- phenyl-1 ,3-oxazinan-6-yl)propanenitrile (18.9 mg, 15%). LC-MS Method 2 tR = 1.053 min, m/z = 457.3; 1H NMR (CDCI3): 61.16 (s, 3H), 1.25 (s, 3H), 1.38 (d, 3H), 2.21 (s, 2H), 2.24 (m, 1 H), 2.40 (m, 2H), 2.86 (m, 1 H), 5.61 (m, 1 H), 6.86 (m, 2H), 6.95 (m, 1 H), 7.29 (m, 5H), 7.32 (m, 2H),7.56 (m, 1 H).
EXAMPLE 6
4108.1002-007 EXAMPLE 539
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000087_0001
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)- 1 ,3-oxazinan-2-one and 6-chloropyridazin-3(2H)-one following a procedures analogous to that described in Example 1 Step 3. LC-MS Method 2 tR = 1.231 , m/z = 490; 1H NMR (CD3OD) 1.33 (m, 1 H), 1.56 (d, 3H), 1.61 (m, 1 H), 1.98 (m, 2H), 2.21 (m, 1H)1 2.31 (m, 1 H)1 2.43 (m, 2H)1 3.13 (m, 1H), 3.48 (m, 2H), 5.53 (m, 1 H), 6.69 (d, 1 H), 7.07-7.13 (m, 4H)1 7.32 (m, 2H)1 7.63 (m, 3H). EXAMPLE 7
4108.1002-007 EXAMPLE 579
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyrimidin-4- yl)phenyl)ethyl)-1,3-oxazinan-2-one
Figure imgf000088_0001
Step i
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (500 mg, 1.03 mmol), 2,4-dichloropyrimidine (183.7 mg, 1.24 mmol), PdCI2(PPh3J2 (41.2 mg, 5.9%) and aqueous solution of Cs2CO3 (2 mol/L, 2 mL) in 1 ,4-dioxane (5 mL) was heated to reflux overnight. The reaction was quenched with water. The organic layer was separated, dried, and concentrated to give the residue, which was purified by column chromatography to give (R)-3-((S)-1-(4-(2-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4- fluorophenyl)-6-(3-hydroxypropyl)-1 ,3-oxazinan-2-one (300 mg, 62%).
Step 2
(/?)-3-((S)-1-(4-(2-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-1 ,3-oxazinan-2-one (300 mg, 0.6 mmol) was dissolved in MeOH/NH3 (10 mL). The resulting mixture was heated to 90 0C for 24 h. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-1 ,3-oxazinan-2-one (270 mg, 90%). Step 3
To a solution of (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4- fluorophenyl)-6-(3-hydroxypropyl)-1 ,3-oxazinan-2-one (40 mg, 0.089 mmol) in CH3COOH (0.3 ml.) and H2O (0.13 mL) was added an aqueous solution of NaNO2 (2 mol/L, 0.5 mL) dropwise at 0 0C. The reaction was stirred for 10 min at this temperature before heating at 60 0C for 3 h. After the mixture was evaporated to dryness, the mixture was adjusted pH 9 with aqueous NaHCO3 solution. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3- ((S)-1-(4-(2-hydroxypyrimidin-4-yl) phenyl)ethyl)-1 ,3-oxazinan-2-one (3.18 mg, 8%). LC-MS Method 2 tR = 0.87 min, m/z = 452. 1H NMR (CD3OD): 1.19-1.23 (m, 2H), 1.48 (d, 3H), 1.82-1.86 (m, 2H), 2.05-2.41 (m, 3H)1 3.01-3.10 (m, 1 H), 3.37 (t, 2H), 5.50 (q, 1 H), 6.90 (d, 1 H), 6.95-7.02 (m, 4H), 7.18-7.22 (m, 2H), 7.00-7.05 (m, 3H), 7.21-7.24 (m, 2H), 7.80 (d, 2H).
EXAMPLE 8
4108.1002-007 EXAMPLE 580
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1 ,6-dihydropyrimidin-4- yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000089_0001
Step 1
To a mixture of ((fi)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (30 mg, 0.062 mmol), 4,6-dichloropyrimidine (12 mg, 0.081 mmol), and 2 M aqueous Cs2CO3 (1.0 mL) in dry THF (2 mL ) was added Pd(dppf)CI2 (6 mg, 0.00621 mmol) under N2 atmosphere. The mixture was heated to reflux for 2 hours. Then the solvent was evaporated, and the residue was purified by preparative TLC to afford (R)-3-((S)-1-(4-(6-chloropyrimidin- 4-yl) phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1 ,3-oxazinan-2-one (20 mg, yield 68%).
Step 2
A mixture of (R)-3-((S)-1-(4-(6-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4- fluorophenyl)-6- (3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.0426 mmol) in 15% aq NaOH (5 mL) was heated to 110 0C overnight. Then the solvent was evaporated, and the residue was washed with EtOAc. The solid was filted off and the filtrate was dried, and condensed in vacuum to give the crude product, which was purified by preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1 ,6- dihydropyrimidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (15 mg, 78%). LC-MS Method 2 tR = 0.91 min, m/z = 452, 408. 1H NMR (CD3OD): δ=1.31 (m, 1 H), 1.59 (m, 3H), 1.95 (m, 2H), 2.25 (m, 1 H)1 2.35 (m, 1 H), 2.46 (m, 1H), 3.15 (m, 1 H), 3.48 (m, 2H), 5.59 (m, 1H), 6.81 (s, 1 H), 7.12 (m, 4H), 7.33 (m, 2H), 7.79 (m, 2H), 8.25 (s, 1H).
EXAMPLE 9
4108.1002-007 EXAMPLE 591 (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1 ,6- dihydropyrirnidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000090_0001
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1 -(4-(6-oxo-1 ,6-dihydropyrimidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan- 2-one by treatment with (i) TBSCI, (ii) NaH, MeI and (iii) Et4NF. LC-MS Method 2 tR = 0.87, m/z = 452.15; 1H NMR (CD3OD) 1.20 (m, 2H), 1.49 (d, 3H), 1.83 (m, 2H), 2.15 (m, 1H), 2.22-2.41 (m, 2H), 3.07 (m, 1H), 3.38 (t, 2H)1 5.50 (m, 1H), 6.88 (d, 1H), 7.01 (m, 4H), 7.21 (m, 2H), 7.79 (m, 2H), 7.90 (s, 1 H).
EXAMPLE 10
4108.1002-007 EXAMPLE 592
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1 ,6- dihydropyridazin-3-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000091_0001
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1 -(4-(6-oxo-1 ,6-dihydropyridazin-3-yl)phenyl)ethyl)-1 ,3-oxazinan- 2-one by treatment with Ii) TBSCI, (ii) NaH, MeI and (iii) Et4NF. LC-MS Method 2 tR = 1.111 , m/z = 488; 1H NMR (CDCI3) 1.27-1.40 (m, 1H), 1.49 (d, 3H), 1.64 (m, 1 H), 1.85- 1.99 (m, 3H), 2.10-2.33 (m, 4H), 2.89 (m, 1 H), 3.51 (t, 2H), 3.80 (s, 3H)1 5.68 (m, 1 H), 6.90-7.02 (m, 5H), 7.18 (m, 2H), 7.21 (m, 1 H), 7.48 (d, 2H), 7.52 (d, 1H).
EXAMPLE 11
4108.1002-007 EXAMPLE 613
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(1 -methyl-2-oxo-1 ,2- dihydropyrimidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one
Figure imgf000091_0002
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3- hydroxypropyl)-3-((S)-1 -(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one by treatment with (i) TBSCI, (ii) NaH, MeI and (iii) Et4NF. LC-MS Method 2 tR = 1.079 min, m/z = 466.2; 1H NMR (CD3OD) 1.20 (m, 3H)1 1.49 (d, 3H), 1.78-1.91 (m, 2H), 2.08 (s, 1H), 2.14 (m, 1H)1 2.28 (m, 1H)1 2.39 (m, 1 H), 3.07 (m, 1H)1 3.36 (m, 3H), 3.50 (S1 3H)1 4.50 (S1 2H), 5.49 (m, 1 H)1 6.90 (d, 1H), 6.95-7.08 (m, 4H)1 7.21 (m, 2H), 7.80 (d, 2H), 8.06 (d, 1 H).
EXAMPLE 12
4108.1002-007 EXAMPLE 617
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000092_0001
Step 1. 6-chloro-2H-pyridazin-3-one
To a solution of 3,6-dichloro-pyridazine (1g, 0.006759mol) in AcOH/H2O (5/1)
(2OmL) was added KOAc (0.662g, 0.006759moL), and the mixture was heated to 140
0C for 70 min under microwave conditions. The vial was cooled and the solvent was evaporated in vacuo. EtOAc and H2O were added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and concentrated to give 6-chloro-2H-pyridazin-3-one (0.813g, 92.5%). 1H NMR (CDCI3): 6.96 (d, 1 H), 7.25 (d, 1 H).
Step 2. 6-chloro-2-methylpyridazin-3(2H)-one
To a solution of 6-chloropyridazin-3(2H)-one (600 mg, 4.23 mmol) were added potassium carbonate (1.2 g, 8.46 mmol) and methyl iodide (1.2 g, 8.46 mmol) in DMF (3 mL). The resulting mixture was stirred at 25 0C for 4 h. After the reaction, water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give the residue which was purified by column chromatography to give 6-chloro-2-methylpyridazin- 3(2H)-one (550 mg, 91%). 1H NMR (CDCI3): 3.76 (s, 3H), 6.92 (d, 1H), 7.19 (d, 1 H).
Step 3. (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1 ,6-dihydro pyridazin-3-yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (774 mg, 1.62 mmol), 6-chloro-2-methylpyridazin-3(2H)-one (244.8 mg, 1.7 mmol), PdCI2(PPh3)2 (77.4 mg, 10%) and aqueous solution Of Cs2CO3 (2 mol/L, 1.6 mL) in 1 ,4-dioxane (15 mL) was heated to reflux overnight. The reaction was quenched with water. The organic layer was separated, dried, and concentrated to give the residue, which was purified by column chromatography to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4- (2-methylpyhmidin-5-yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (321 mg, 43%). LC-MS
Method 2 tR = 1.158 min, m/z = 404; 1H NMR (CDCI3): 1.12 (s, 3H), 1.18 (s, 3H), 1.54 (d, 3H), 2.18-2.27 (m, 4H), 2.33-2.48 (m, 1H), 2.82-2.92 (m, 1H), 3.86 (s, 3H), 5.70 (m, 1 H), 6.99 (d, 2H), 7.05 (d, 2H), 7.26-7.50 (m, 5H), 7.51 (m, 2H), 7.57 (d, 1 H). (R)-6-(4- fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-1 ,3- oxazinan-2-one was dissolved in refluxing methyl acetate and allowed to cool slowly to rt to afford a crystalline solid with mp 166.5-167.5 0C.
EXAMPLE 13
4108.1002-007 EXAMPLE 636 (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1 -(4-(1 -methyl-6-oxo-1 ,6- dihydropyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
Figure imgf000093_0001
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2- methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3- oxazinan-2-one and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 1 Step 3. LC-MS Method 2 tR = 1.179 min, m/z = 422.1; 1H NMR (CDCI3) 1.08 (d, 6H)1 1.49 (d, 3H), 2.10 (S1 3H), 2.18 (m, 1H), 2.32- 2.41 (m, 1 H), 2.83 (m, 1 H), 3.79 (s, 3H), 5.63 (m, 1 H), 6.90-7.03 (m, 5H), 7.23 (m, 2H), 7.46-7.59 (m, 3H).
EXAMPLE 14
[4108.1002-007 EXAMPLE 650
(S)-3-((S)-1 -(4-(1 -ethyl-6-oxo-1 ,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2- methylpropyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000094_0001
The title compound was prepared following a procedure analogous to that described in Example 12 using ethyl bromide in Step 2. LC-MS Method 2 tR = 1.297 min, m/z = 418; 1H NMR (CDCI3) 1.12 (s, 3H), 1.19 (s, 3H), 1.43 (t, 3H), 1.56 (d, 3H), 2.20-2.31 (m, 4H), 2.37-2.48 (m, 1 H), 2.88 (m, 1 H), 4.29 (m, 2H), 5.70 (m, 1 H), 6.98 (d, 1 H), 7.06 (d, 2H), 7.29-7.40 (m, 5H), 7.56 (m, 3H).
EXAMPLE 15
[4108.1002-007 EXAMPLE 652 (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000094_0002
The title compound was prepared following a procedure analogous to that described in Example 12 using isopropyl iodide in Step 2. LC-MS Method 2 tR = 1.885 min, m/z = 432.1; 1H NMR (CDCI3) 1.10 (s, 3H), 1.18 (s, 3H), 1.39 (d, 6H), 1.53 (d, 3H), 2.18-2.29 (m, 4H), 2.31-2.47 (m, 1 H), 2.88 (m, 1 H), 5.32 (m, 1 H), 5.69 (m, 1 H), 6.92 (d, 1 H), 7.03 (d, 2H), 7.27-7.38 (m, 5H), 7.52 (d, 3H).
EXAMPLE 16
[4108.1002-007 EXAMPLE 653
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1 -(4-(6-oxo-1 -(2,2,2-trifluoroethyl)-1 ,6- dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one
Figure imgf000095_0001
The title compound was prepared following a procedure analogous to that described in Example 12 using 2,2,2-trifluoroethyl trifluoromethanesulfonate in Step 2. LC-MS Method 2 tR = 1.172 min, m/z = 472.1 ; 1H NMR (CD3OD) 0.93 (s, 3H), 1.28 (s, 3H), 1.54 (d, 3H), 2.04 (s, 2H), 2.20-2.31 (m, 1 H), 2.42-2.59 (m, 2H), 3.06 (m, 1 H), 4.91- 5.00 (m, 2H)1 5.59 (m, 1 H), 7.07 (d, 3H), 7.25-7.39 (m, 5H), 7.61 (d, 2H), 7.92 (d, 1 H).
EXAMPLE 17*
4108.1002-007 EXAMPLE 666
3-{(S)-1 -[4-(1 ,5-Dimethyl-6-oxo-1 ,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2- hydroxy-2-methyl-propyl)-6-phenyl-[1 ,3]oxazinan-2-one
Figure imgf000095_0002
2 M aqueous Na2CO3 solution (0.31 mL) was added to a solution of (S)-6-(2- hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl]-1 ,3-oxazinan-2-one (0.15 g) and 6-chloro-2,4-dimethyl-2H-pyridazin-3- one (75 mg) in dimethylformamide (1 mL). The resulting mixture was sparged with argon for 10 min, before [1 ,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll) dichloromethane complex (15 mg) was added. The mixture was heated to 100 0C and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2CI2/Me0H 98:2->80:20) to afford the title compound. Yield: 0.1O g (67% of theory). Mass spectrum (ESI+): m/z = 476 [M+H]+
6-Chloro-2,4-dimethyl-2H-pyridazin-3-one
Figure imgf000096_0001
Methyl iodide (1.3 mL) was added to a mixture of 6-chloro-4-methyl-2H-pyridazin-
3-one (2.70 g) and K2CO3 (3.40 g) in dimethylformamide (27 mL). The resulting mixture was stirred at ambient temperature overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the title compound was obtained as a solid. Yield: 2.97 g (100% of theory). Mass spectrum (ESI+): m/z = 159/161 (CI) [M+H]+
EXAMPLE 18*
[4108.1002-007 EXAMPLE 667 3-{(S)-1 -[4-(1 ,4-Dimethyl-6-oxo-1 ,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2- hydroxy-2-methyl-propyl)-6-phenyl-[1 ,3]oxazinan-2-one
Figure imgf000096_0002
The title compound was prepared from 3-{(S)-1-[4-(1 ,5-dimethyl-6-oxo-1 ,6- dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl- [1 ,3]oxazinan-2-one and 6-chloro-2,5-dimethylpyhdazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z = 476 [M+H]+ 6-Chloro-2,5-dimethyl-2H-pyridazin-3-one
Figure imgf000097_0001
The title intermediate was prepared from β-chloro-S-methyl^H-pyridazin-S-one following a procedure analogous to that described for intermediate 6-chloro-2,4- dimethyl-2H-pyridazin-3-one in Example 17*. Mass spectrum (ESI+): m/z = 159/161 (Cl) [M+H]+
EXAMPLE 19*
[4108.1002-007 EXAMPLE 672 3-{(S)-1-[4-(1-Cyclopropylmethyl-6-oxo-1 ,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6- (2-hydroxy-2-methyl-propyl)-6-phenyl-[1 ,3]oxazinan-2-one
Figure imgf000097_0002
The title compound was prepared from 3-{(S)-1-[4-(1 ,5-dimethyl-6-oxo-1 ,6- dihydro-pyhdazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl- [1 ,3]oxazinan-2-one and 6-chloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z = 502 [M+H]+
θ-Chloro^-cyclopropylmethyl^H-pyridazin-S-one
Figure imgf000097_0003
Cyclopropylmethyl bromide (0.82 mL) was added to a mixture of 6-chloro-2H- pyridazin-3-one (1.0 g) and K2CO3 (2.10 g) in dimethylformamide (10 mL). The resulting mixture was stirred at 60 0C overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:1:0.1) to afford the title compound as an oil. Yield: 0.85 g (60% of theory). Mass spectrum (ESI+): m/z = 185/187 (Cl) [M+H]+
EXAMPLE 20*
[4108.1002-007 EXAMPLE 673
3-{(S)-1-[4-(1-Cyclopropyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2- hydroxy-2-methyl-propyl)-6-phenyl-[1 ,3]oxazinan-2-one
Figure imgf000098_0001
The title compound was prepared from 3-{(S)-1-[4-(1 ,5-dimethyl-6-oxo-1 ,6- dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl- [1 ,3]oxazinan-2-one and 6-chloro-2-cyclopropylpyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z 488 [M+H]+
6-Chloro-2-cyclopropyl-2H-pyridazin-3-one
Figure imgf000098_0002
A microwave-suited vessel charged with a stir bar, 6-chloro-2H-pyridazin-3-one (0.15 g), cyclopropylboronic acid (0.30 g), pyridine (0.75 mL), triethylamine (0.8 mL), and tetrahydrofuran (5 mL) was sparged with argon for 5 min. Then, Cu(OAc)2 (0.42 g) was added and the mixture was stirred in a microwave oven under microwave irradiation at 140 0C for 10 min. Then, the solvent was evaporated and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and aqueous NaHCO3 solution. After drying (MgSO4) and removing the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99: 1 :0.1->9: 1 :0.1) to afford the title compound. Yield: 45 mg (23% of theory). Mass spectrum (ESI+): m/z = 171/173 (Cl) [M+H]+
BIOLOGICAL TEST EXAMPLE 1
The inhibition of a microsomal preparation of 11β-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-Hydroxyseroid Dehydrogenase Type 1 in Scintillation Proximity Assay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactions were carried out at rt 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 NaCI, 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 rt. 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 rt, and the SPA signal corresponding to [3H]cortisol was measured on a Microbeta plate reader.
BIOLOGICAL TEST EXAMPLE 2
The inhibition of 11β-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
Average %
IC50 Rangea inhibition at 10O nM
EXAMPLE 1 ++ 82.8 EXAMPLE 2 ++ 89.7 EXAMPLE 3 ++ 67.0 EXAMPLE 4 ++ 98.3
EXAMPLE 5 ++ 98.7
EXAMPLE 6 ++ 73.4 EXAMPLE 7 ++ 91.8 EXAMPLE 8 ++ 53.3 EXAMPLE 9 ++ 89.0 EXAMPLE 10 ++ 96.5 EXAMPLE 11 ++ 53.9 EXAMPLE 12 ++ 96.4 EXAMPLE 13 ++ 93.9 EXAMPLE 14 ++ 94.5 EXAMPLE 15 ++ 94.7 EXAMPLE 16 ++ 95.5 EXAMPLE 17 ++ 91.8 EXAMPLE 18 nt nt EXAMPLE 19 ++ 96.4 EXAMPLE 20 ++ 97.0 a ++ means IC50 = <100 nM, + means IC5O = 100 - 1000 nM, # means IC5O > 100 nM, means IC50 > 100O nM. BIOLOGICAL TEST EXAMPLE 3
In vitro inhibition of 11 β-HSD1 by test compounds was determined with HTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbio international, France) detecting Cortisol generated from cortisterone by human liver microsomes. Briefly, compounds were incubated for 1 hour at 37 0C in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH (200 μM) and cortisone (80 nM). Cortisol generated in the reaction is then detected with a competitive immunoassay, involving two HTRF conjugates: Cortisol linked to XL665 and anti-cortisol antibody labeled with Europium cryptate. The incubation period for detection reaction was typically 2 hours. The amount of Cortisol was determined by reading the time-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and 665/7.5 nm). The ratio of the two emission signals was then calculated (Em665*10000/Em615). Each assay contained incubations with vehicle controls instead of compound as controls for non-inhibited Cortisol generation (100% CTL; 'high values') and incubations with carbenoxolone as controls for fully inhibited enzyme and Cortisol background (0% CTL; 'low values'). Each assay also contained a calibration curve with Cortisol to transform the fluorescent data into Cortisol concentrations. Percent inhibition of each compound was determined relative to the carbenoxolone signal.
In following table the 11 β-HSD 1 inhibitory activities, determined as described above, wherein 100% indicates no inhibition and a value of zero or below zero indicates complete inhibition.
TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TEST 3
Average % control
Example inhibition at
10O nM
17* 14
18* 63
19* 10
20* 9 BIOLOGICAL TEST EXAMPLE 4
The inhibition of a microsomal preparation of 11β-HSD1 in the presence of 50% human plasma by compounds of the invention was measured as follows. Microsomes from CHO cells overexpressing human 11β-HSD1 were diluted into reaction buffer consisting of 25 mM HEPES, pH 7.4, 50 mM KCI1 2.5 mM NaCI, 1 mM MgCI2, and 50% (v/v) human plasma (BioChemed). The assay began by dispensing 49 μl of microsome solution into 96-well polypropylene plates and adding 1 μl of the test compounds in DMSO, previously diluted in half-log increments (8 points) starting at 1.0 mM. The reaction was initiated with the addition of 50 μl substrate solution consisting of reaction buffer with 2 mM NADPH and 160 nM [3-H]cortisone (1 Ci/mmol). The plates were incubated for 120 minutes at rt, and the reaction was quenched with the addition of 100μl acetonitrile with 20 mM cortisone and 20 mM Cortisol. After a ten minute incubation at rt, 100 μl of each well was filtered through a Multiscreen HTS, HV filter plate (Millipore) and diluted with 100 μl of reaction buffer without human plasma. [3- H]cortisone and [3-H]cortisol were separated by HPLC on a Zorbax SB-C8 column (4.6 x 250 mm, Agilent) with an isocratic elution at 25% acetonitrile in water with 0.01% trifluoroacetic acid, and radioactivity was quantified with an in-line β-RAM (IN/US Systems, Inc.).
BIOLOGICAL TEST EXAMPLE 5
(Fraction Unbound in Human Plasma)
Plasma protein binding of compounds was determined with Equilibrium Dialysis of spiked plasma against compound free dextrane buffer using a dialysis membrane with mass cutoff of 5000 Da. Compound concentrations in plasma and buffer after incubation were measured using HPLC/Mass spectrometry.
BIOLOGICAL TEST EXAMPLE 6
(CYP3A4 Inhibition)
The assay was based on a method published by Moody et al. (Xenobiotica 1999). The inhibition of cytochrome P450 3A4-isoenzyme catalysed N-demethylation of [N-methyl-14C]-Erythromycin by the test compound was assayed at 37 0C with human recombinant cytochrome P450 3A4. All assays were carried out on a robotic system in 96 well plates. The final incubation volume of 200 μl contains TRIS buffer (0.1 M), MgCI2 (5 mM), recombinant protein (40 pmol/ml), Erythromycin (50 μM) and the test compound either at four different concentrations in duplicate (e.g. highest concentration 10-50 μM with subsequent serial 1 :5 dilutions) or at a concentration of 10 μM in triplicate. Following a short preincubation period, reactions were started with the cofactor (NADPH, 1mM) and stopped by addition of 50 μl aqueous trichloroacetic acid (10%;w/v). An aliquot of the incubate was transferred to 96 well solid phase extraction (SPE) plates and extracted on the cartridge. The resultant [14C]-formaldehyde/formic acid was not retained on the cartridge and was therefore separated from the unmetabolized substrate by washing the SPE plates with water. An aliquot of the eluates was transferred into well plates suitable for liquid scintillation counting. The rate of formation of [14C]- formaldehyde/formic acid in these incubations was compared to a control activity containing no test compound. If the compound is tested at four concentrations, experimental IC5O values were calculated.
BIOLOGICAL TEST EXAMPLE 7
(CYP2C9 Inhibition)
Using a procedure similar to that described in Biological Test Example 6, the inhibition of cytochrome P450 2C9-isoenzyme catalysed O-demethylation of [O-methyl- 14C]-Naproxen by the test compound was assayed at 37 0C with human recombinant cytochrome P450 2C9. The experimental IC5O was calculated based on % control at four different concentrations.
BIOLOGICAL TEST EXAMPLE 8
(CYP2C19 Inhibition) Using a procedure similar to that described in Biological Test Example 6, the inhibition of cytochrome P450 2C19-isoenzyme catalysed N-demethylation of [N-methyl- 14C]-Diazepam by the test compound was assayed at 37 °C with human recombinant cytochrome P450 2C19. The experimental IC50 was calculated based on % control at four different concentrations. BIOLOGICAL TEST EXAMPLE 9
(CYP2C9 Inhibition)
The inhibition of recombinant CYP2C9 by compounds of the invention was measured using a commercial kit from Invitrogen (cat #2859). Supplied microsomes isolated from insect cells infected with a baculovirus engineered to express human CYP2C9 were diluted to 10 mM in reaction buffer (100 mM potassium phosphate buffer, pH 8.0) with an NADPH generation system (3.33 mM glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase). 89 μl of this dilution were dispensed to each well of a 96-well, black, polystyrene plate and mixed with 1 μl of test compound previously diluted in DMSO in half log increments starting at 3 mM. The assay was initiated by adding 10 μl of fluorogenic substrate n-octyloxymethylresorufin (OOMR, 20 μM.) with NADP (100 μM) diluted in reaction buffer. The plate was immediately placed in a Perkin Elmer Fusion plate reader. Reaction progress was monitored by measuring fluorescence every two minutes for a total of twenty minutes (530 nM excitation filter /605 nM emission filter).
TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 1 , 4 AND 5
Biological
Biological Biological Tpςt
Test Test
EXAMPLE Shift" Example Example 1 Example 4a 5
IC50 (nM) IC50 (nM)
(%)
1 11.35 nt
2 6.16 27.30 4.43
3 29.01 nt
4 0.93 1.95 2.09
5 0.91 2.32 2.56
6 36.96 nt
7 7.20 23.62 3.28
8 83.94 nt
9 5.02 16.36 3.26
10 1.90 8.04 4.24 11 79.64 nt 12 1.78 6.10 3.43 2.2 13 1.39 8.80 6.33 14 1.52 4.05 2.66 15 0.49 2.70 5.51 16 1.14 3.83 3.37 17 1.25 6.08 4.88 19 0.86 4.97 5.82 20 1.08 3.26 3.03 a nt means not tested; b Shift is the IC50 determined in Biological Test Example 4 divided by the IC50 determined in Biological Test Example 1.
TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 6-9
Figure imgf000106_0001
1
2
3
4
5
6
7
8
9
10 14.2
11
12 >50 >50 >50 13 >50 >50 >50
14 32.7 >50 46.3
15
16 15.6 13 18.9
17 31 >50 >50
18 >50 >50 >50
19 5.7 10.7 5.4
20 15.7 28.8 13.1
TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR COMPOUNDS IN
BIOLOGICAL TESTS 1 AND 4
Biological Biological Biological
Comparator Test Test Test Example
Figure imgf000107_0001
Compound Example 1 Example 4a 5
IC50 (nM) IC50 (nM) (%)
1 0.77 11.97 15.51
2 1.80 14.16 7.88
3 0.75 17.74 23.63 0.3
4 1.44 15.24 10.57
5 0.51 18.50 36.10
6 1.48 37.58 25.39
7 0.99 41.90 42.43
8 0.72 17.85 24.74
9 0.55 11.86 21.45 0.3
10 1.79 53.49 29.91
11 0.55 13.40 24.59 0.7
12 1.08 19.54 18.12 0.4
13 0.76 6.32 8.30
14 1.30 8.94 6.90
15 0.79 8.94 11.32 a nt means not tested; b Shift is the IC50 determined in Biological Test Example 4 divided by the IC50 determined in Biological Test Example 1.
CJ)
TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR COMPOUNDS IN
BIOLOGICAL TESTS 6-9
Biological
Biological Biological Biological Test Test Test Test Example
Comparator Example 6 Example 7 Example 8 9 Compound CYP3A4, CYP2C9, CYP2C19, CYP2C9 IC50
IP
IC50 [μM] IC50 [μM] [uM]
[μM]
1 27.0
2 1.4
3 7.4 4.1 5.7 4.9
4 5.1
5 9.9 5.1 8.3 3.7
6 4.4 2.3 8.6 5.0
7 4.0
8 5.3 2.4 5.6 3.0
7.0 3.1 9.3 2.5
10 3.6
11 14.1 6.3 12.5 5.5
12 4.9 4.6 9.5 2.5
12 4.9 3.9 10.1
13 4.4 5.6 < 0.4 7.3
14 19.7 25.9 6.4 24.6
15 3.1 7.7 < 0.4 9.5
Figure imgf000109_0001
Figure imgf000110_0001
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 (e.g., type Il diabetes) , 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 of the invention can be used as therapeutic agents for pseudo Cushing's Syndrome associated with alcoholic liver disease. In addition, the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients. Additional diseases or disorders that are related to 11β-HSD1 activity include those selected from the group consisting of lipid disorders, hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X. A further disease related to 11β-HSD1 activity is pseudo Cushing's Syndrome associated with alcoholic liver disease.
A pharmaceutical composition of the invention may, alternatively or in addition to an 11β-HSD1 inhibitor of the invention, comprise a pharmaceutically acceptable salt of a an 11β-HSD1 inhibitor of the invention and one or more pharmaceutically acceptable carriers therefore. Alternatively, a pharmaceutical composition of the invention may comprise a compound of an 11β-HSD1 inhibitor of the invention or a pharmaceutical salt thereof as the only pharmaceutically active agent in the pharmaceutical composition. The disclosed 11β-HSD1 inhibitors can be used alone or in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma.
The compositions of the invention are 11β-HSD1 inhibitors. Said compositions contain compounds having a mean inhibition constant (IC50) against 11 β-HSD1 of below about 1 ,000 nM; preferably below about 100 nM; more preferably below about 50 nM; even more preferably below about 5 nM; and most preferably below about 1 nM.
The invention includes a therapeutic method for treating or ameliorating an 11β- HSD1 mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of an 11β-HSD1 inhibitor of the invention, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof or 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 likelihood that a subject will then develop the disease or condition in a subject that is at risk for developing the disease or condition. - I l l -
An embodiment of the invention includes administering an 11β-HSD1 inhibiting compound of the invention 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 HCI, 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 inhibitors, 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 11β-HSD1 inhibiting compound of the invention or composition thereof in a combination therapy with one or more other 11β-HSD1 inhibitors, or with combination products, such as Avandamet® (metformin HCI and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCI, 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 intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can either be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and 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 11β-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.
While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula (Im3)
Figure imgf000116_0001
wherein: R1 is (a) absent or (b) is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C3)alkoxy(CrC3)alkoxy, or (CrC3)alkoxy(Ci-C3)alkyl and 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-, R4OSC=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, heteroaryl, arylamino and heteroarylamino;
A1 is (a) a bond, or (b) (CrC^alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2C(=0), wherein the carbonyl carbon is attached to Cy1;
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cydoalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C-i-CβJalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (CrC6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (d- C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(d- C6)alkylaminocarbonyl, (Ci-C3)alkoxy(CrC3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (d- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Cr C6)alkylsulfonylannino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (CrC6)alkoxycarbonyl(Ci- C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(d- C6)alkoxy, heteroaryl oxo, amino(Ci-C6)alkyl, (C1-C6)alkylamino(Ci-C6)alkyl, di(Cr C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Cr C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkylK(CrC6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Cr C6)alkylaminocarbonyl(CrC6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkyiχ(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; the oxodihydropyridazinyl ring in Formula Im3 is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(d-C6)alkyl, halo(C3- C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(d-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (d- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci- C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(d-
C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (d-CeJalkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci- C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (CrCβJalkylcarbonyl- amino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (CrC6)alkoxy(Ci-C6)alkyl, halo(d-C6)alkoxy(Ci- Cβjalkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (d- C6)alkylamino(Ci-C6)alkyl, di(C1-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (d- CeJalkylaminocarbonyKCrCeJalkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl}{(Ci-
C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(C1-C6)alkyl; E is (a) a bond or (b) (Ci-C3)alkylene or (CrC2)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 and optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (d-CβJalkyl, 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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Cr C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)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(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkane- sulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Cr C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (d- C6)alkylcarbonylamino(Ci-C6)alkyl, (CrCβJalkylsulfonylamino, (Cr C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (d- C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(CrC6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(CrC6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, ((C3- C6)cycloalkylK(CrC6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (C1- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(CrC6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- CeJcycloalkylaminocarbonyKCrCeJalkyl, {(C3-C6)cycloalkylK(Ci- C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; R3 is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C5)cycloalkyl(Ci- C4)alkyl, (Ci-C3)alkoxy(CrC3)alkoxy or (CrC3)alkoxy(Ci-C3)alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4C(=O)O-, 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-, spirocycloalkyl; heterocyclyl (optionally substituted with alkyl, haloalkyl, halogen or oxo), heteroaryl (optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (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 (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); and
R4 is independently selected from H1 (CrC6)alkyl, halo(CrC6)alkyl, amino(Ci-C6)alkyl, (CrC6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl and (Ci-C6)alkoxy(CrC6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
2. The compound of claim 1 , wherein the compound is of Formula (In3):
Figure imgf000120_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
3. The compound of claim 2, wherein the compound is of Formula (lo3):
Figure imgf000121_0001
or a pharmaceutically acceptable salt thereof; wherein: n is 0, 1 , 2 or 3; and G1 is fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Cr 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(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,
(CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C-i- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCβJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylamino- sulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (CrC6)alkylcarbonylamino(Cr C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(CrC6)alkyl, (d- C6)alkoxycarbonyl(Ci-C6)alkoxy, (CrC6)alkoxy(CrC6)alkyl, halo(CrC6)alkoxy(Ci- C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, amino(CrC6)alkyl, (Ci-C6)alkylamino(Cr C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3- C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyiχ(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl or di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl.
4. The compound of claim 3, wherein: n is 0, 1 , 2 or 3;
G1 is (Ci-C4 )alkyl, (CrC4 )alkoxy, (CrC4 )haloalkyl, (CrC4 )haloalkoxy, halogen, cyano or nitro; the oxodihydropyridazinyl in Formula lo3 is optionally substituted on a substitutable ring nitrogen atom with C1-C4 alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl or CrC4 haloalkyl; and the oxodihydropyridyl in Formula lo2 is optionally substituted on a ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-
C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2,
(Ci-C4)alkylaminocarbonyl, di(CrC4)alkylaminocarbonyl or (d-C^alkylcarbonylamino.
5. The compound of claim 4, wherein R1 is methyl or ethyl.
6. The compound of claim 4, wherein R1 is methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
7. The compound of claim 4, wherein R1 is methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2) H2NC(=O)CMe2CH2l 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
8. The compound of claim 7, wherein the compound is of the following Formula:
Figure imgf000123_0001
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 3, wherein the compound is of Formula (Ip 2\).:
Figure imgf000123_0002
or a pharmaceutically acceptable salt thereof; and wherein:
G1 is (CrC4)alkyl, (Ci-C4)alkoxy, (CrC4)haloalkyl, (Ci-C4)haloalkoxy, halogen, cyano or nitro; n is O, 1 or 2;
G2a is (C1-C4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl or (CrC4)haloalkyl;
G2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C-ι-C4)alkyl, (C3-
C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (Ci-C4)alkoxy, (C1- C4)haloalkoxy, CONH2,
Figure imgf000123_0003
di(Ci-C4)alkylaminocarbonyl or (C1-
C4)alkylcarbonylamino;
10. The compound of claim 9, wherein R1 is methyl or ethyl.
11. The compound of claim 9, wherein R1 is methyl or ethyl; and R3 is
MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
12. The compound of claim 9, wherein R1 is methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (Ci-C4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
13. The compound of claim 9, wherein R1 is methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyP, the substituent G2a is selected from (CrC4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, and (Ci-C2)haloalkyl; and G2b is optionally selected from hydrogen, methyl or ethyl.
14. The compound of claim 13, wherein the compound is of the following Formula:
Figure imgf000124_0001
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 13, wherein the compound is of the following Formula:
Figure imgf000124_0002
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is of Formula (Ik):
Figure imgf000125_0001
Ik
R1a is methyl or ethyl; R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4- C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-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,
(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)cycloalkylalkanesulfιnyl, halo(CrC6)alkanesulfinyl, 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, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (d-CeJalkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (CrC3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (CrC6)alkylcarbonylamino, (Ci-C6)alkylcarbonyl- amino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(CrC6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Cr C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (C1- C6)alkylamino(Ci-C6)alkyl, di(CrC6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy and (Ci-C6)alkylcarbonyl; and Cy2 is optionally substituted 2,3-dihydro-3-oxopyridazinyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
17. A compound of Formula (Im6)
Figure imgf000126_0001
wherein:
R1 is (a) absent or (b) is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d-
C3)alkoxy(CrC3)alkoxy, or (Ci-C3)alkoxy(CrC3)alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4J2N-, 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, heteroaryl, arylamino and heteroarylamino;
A1 is (a) a bond, or (b) (CrC3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2C(=O), wherein the carbonyl carbon is attached to Cy1;
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl and 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(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)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, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3- Cβjcycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (CrCβJalkylamino, di(Ci-C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxyl halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (C1- C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (CrC3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (C1- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(CrC6)alkyl, (C1-
C6)alkylsulfonylamino, (CrC6)alkylsulfonylamino(CrC6)alkyl, (CrC6)alkoxycarbonyl(Ci- C6)alkoxy, (CrC6)alkoxy(C1-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Cr C6)alkoxy, heteroaryl oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci- C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (CrC6)alkylamino(C2-C6)alkoxy, di(Ci- C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyKCi-CeJalkyl, (Ci-C6)alkylaminocarbonyl(CrC6)alkyl, di(Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl; the oxodihydropyrmidinyl ring in Formula Im6 is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3- C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6JaIkOXy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (Ci- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Cr C6)alkanesulfιnyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfιnyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (Ci-C6)alkoxy(Cr C6)alkoxy, halo(CrC6)alkoxy(C1-C6)alkoxyl (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrC6)alkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cr
C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrCβJalkylaminosulfonyl, di(CrC6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (C-i-CeJalkylcarbonylamino, (C-ι-C6)alkylcarbonyl- amino(CrC6)alkyl, (CrCβJalkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (CrC6)alkoxy(Ci-C6)alkyl, halo(CrC6)alkoxy(Ci- C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (d-
C6)alkylamino(C1-C6)alkyl, di(CrC6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Cr C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- Cβjcycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}anriinosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Cr C6)alkylaminocarbonyl(CrC6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(CrC6)alkyl; E is (a) a bond or (b) (CrC3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(d-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-
C7)cycloalkylalkanesulfιnyl, halo(Ci-C6)alkanesulfιnyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkane- sulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (CrCβJalkylamino, di(Ci-C6)alkylamino, (CrC6)alkoxy(CrC6)alkoxy, halo(CrC6)alkoxy(C1-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-Cejalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Cr C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrCβJalkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (Cr C6)alkylcarbonylamino(CrC6)alkyl, (Ci-C6)alkylsulfonylamino, (d- C6)alkylsulfonylamino(CrC6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Cr
C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (CrC6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, ((C3- C6)cycloalkyl}{(Ci-C6)alkyl}aιτιinocarbonyl1 di(C3-C6)cycloalkylanninocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(CrC6)alkyl}aminosulfonyl, di(C3- CβJcycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Cr C6)alkylaminocarbonyl(CrC6)alkyl, di(CrC6)alkylaminocarbonyl(CrC6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(CrC6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(CrC6)alkyl; R3 is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C5)cycloalkyl(Cr C4)alkyl, (CrC3)alkoxy(CrC3)alkoxy, or (CrC3)alkoxy(CrC3)alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4)2N-, R4O2C-, R4C(=O)O-, 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-, spirocycloalkyl; heterocyclyl (optionally substituted with alkyl, haloalkyl, halogen or oxo), heteroaryl (optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H1 CONH2, N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (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); and
R4 is independently selected from H, (Ci-C6)alkyl, halo(CrC6)alkyl, amino(CrC6)alkyl,
(CrC6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(CrC6)alkyl and
(Ci-C6)alkoxy(CrC6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
18. The compound of claim 17, wherein the compound is of Formula (In6):
Figure imgf000130_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
19. The compound of claim 18, wherein the compound is of Formula (lo6):
Figure imgf000131_0001
or a pharmaceutically acceptable salt thereof; wherein: n is 0, 1 , 2 or 3; and G1 is 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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfιnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (CrC6JaIkOXy(C1- C6)alkoxy, halo(CrC6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCeJalkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylamino- sulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (Ci-C6)alkylcarbonylamino(d- C6)alkyl, (CrC6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(CrC6)alkyl, (d- C6)alkoxycarbonyl(CrC6)alkoxy, (Ci-C6)alkoxy(C1-C6)alkyl, halo(CrC6)alkoxy(Ci- Cβjalkyl, hydroxy(CrC6)alkoxy, heteroaryl, amino(CrC6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2- C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3- C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(CrC6)alkyl, aminocarbonyl(Ci-C6)alkyl, (d- C6)alkylaminocarbonyl(CrC6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl}{(Cr
C6)alkyl}aminocarbonyl(Ci-C6)alkyl or di(C3-C6)cycloalkylaminocarbonyl(CrC6)alkyl.
20. The compound of claim 19, wherein: n is 0, 1 , 2 or 3; G1 is (C1-C4 )alkyl, (CrC4 )alkoxy, (CrC4 )haloalkyl, (CrC4 )haloalkoxy, halogen, cyano or nitro; the oxodihydropyrimidinyl in Formula lo6 is optionally substituted on a substitutable ring nitrogen atom with CrC4 alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl or CrC4 haloalkyl; and the oxodihydropyridyl in Formula lo2 is optionally substituted on a ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(CrC4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino.
21. The compound of claim 20, wherein R1 is methyl or ethyl.
22. The compound of claim 20, wherein R1 is methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
23. The compound of claim 20, wherein R1 is methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
24. The compound of claim 19, wherein the compound is of Formula (Ip4):
Figure imgf000133_0001
dp4); or a pharmaceutically acceptable salt thereof; and wherein: G1 is (CrC4)alkyl, (C1-C4JaIkOXy, (CrC4)haloalkyl, (CrC4)haloalkoxy, halogen, cyano or nitro; n is O, 1 or 2; and G2a is (C1-C4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl or (CrC4)haloalkyl.
25. The compound of claim 24, wherein R1 is methyl or ethyl.
26. The compound of claim 24, wherein R1 is methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2l 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
27. The compound of claim 24, wherein R1 is methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropylor 2-cyano-2-methylpropyl.
28. The compound of claim 24, wherein R1 is methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the substituent G2a is selected from (C1-C4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Cr C2)alkyl, and (CrC2)haloalkyl.
29. The compound of claim 28, wherein the compound is of the following Formula:
Figure imgf000134_0001
or a pharmaceutically acceptable salt thereof.
30. The compound claim 17, wherein the compound is of Formula (Ik):
Figure imgf000134_0002
R1a is methyl or ethyl; R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C-i-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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)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, (d-C6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(CrC6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(C1-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(CrC6)alkylamino, (C-ι-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (d-CeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(CrC6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (CrCeJalkylcarbonylamino, (CrC6)alkylcarbonyl- amino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Cr C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (Cr C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(CrC6)alkyl amino(C2-C6)alkoxy, (d- C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy and (CrC6)alkylcarbonyl; and Cy2 is optionally substituted 1 ,2-dihydro-2-oxopyrimidinyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
31. The compound claim 17, wherein the compound is of Formula (Ik):
Figure imgf000135_0001
R1a is methyl or ethyl; R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)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(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C-ι-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrCβJalkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, 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, (CrC6)alkylamino, di(Ci-C6)alkylamino, (CrC6)alkoxy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrCeJalkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (CrCβJalkylaminosulfonyl, di(Ci-C6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (CrC6)alkylcarbonyl- amino(CrC6)alkyl, (CrC6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (CrCeJalkoxycarbonyKd-CeJalkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(CrC6)alkoxy(Cr C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (d- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Cr C6)alkylarrιino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy and (CrC6)alkylcarbonyl; and Cy2 is optionally substituted 3,4-dihydro-4-oxopyhmidinyl; or a pharmaceutically acceptable salt thereof.
32. A compound of Formula (Im )
Figure imgf000136_0001
wherein:
R1 is (a) absent or (b) is selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C-i- C3)alkoxy(Ci-C3)alkoxy, or (CrC3)alkoxy(Ci-C3)alkyl and 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, heteroaryl, arylamino and heteroarylamino;
A1 is (a) a bond, or (b) (CrC3)alkylene, CH2CH2O, wherein the oxygen is attached to Cy1, or CH2C(=O), wherein the carbonyl carbon is attached to Cy1;
Cy1 is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C-i-CβJalkyl, 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(CrC6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (d-CβJalkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfιnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (CrC6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(CrC6)alkoxy(Ci-C6)alkoxy, (C1- C6)alkoxycarbonyl, H2NCO1 H2NSO2, (Ci-CβJalkylaminocarbonyl, di(d- C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclylsulfonyl, (Cr C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-
C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(CrC6)alkyl, (CrC6)alkoxycarbonyl(Ci- C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(CrC6)alkoxy(Ci-C6)alkyl, hydroxy(Cr C6)alkoxy, heteroaryl oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(d- C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Cr C6)alkylamino(C2-C6)alkoxy, (CrCβJalkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- Cβjcycloalkylaminocarbonyl, {(C3-C6)cycloalkylK(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3- C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl; the oxodihydropyrazinyl ring in Formula Im11 is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3- C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(CrC6)alkyl, halo(C3- C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4- C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4- C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (d- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci- C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(CrC6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (CrC6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO1 H2NSO2, (d-CeJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (CrC3)alkoxy(Ci-
C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (Ci-Cejalkylcarbonylamino, (CrC6)alkylcarbonyl- amino(CrC6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (CrC6)alkoxycarbonyl(Ci-C6)alkoxy, (CrC6)alkoxy(CrC6)alkyl, halo(Ci-C6)alkoxy(Cr C6)alkyl, hydroxy(CrC6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (CT
C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Cr C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl1 di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (Cr C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; E is (a) a bond or (b) (CrC3)alkylene or (CrC2)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 (d-CeJalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(CrC6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2- C4)alkynyl, halo(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (d- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(CrC6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkane- sulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (CrC6)alkoxy(Ci-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (d-CeJalkylaminocarbonyl, di(d-C6)alkylaminocarbonyl, (d- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(CrC6)alkylaminosulfonyl, heterocyclylsulfonyl, (CrCβJalkylcarbonylamino, (C1- C6)alkylcarbonylamino(Ci-C6)alkyl, (d-C6)alkylsulfonylamino, (C1-
C6)alkylsulfonylamino(CrC6)alkyl, (Ci-C6)alkoxycarbonyl(d-C6)alkoxy, (C1- C6)alkoxy(Ci-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(d-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(CrC6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(d-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, ((C3- C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alky!}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylanninocarbonyl(C1-C6)alkyll (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl}{(Ci- C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; R3 is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C5)cycloalkyl(Cr C4)alkyl, (Ci-C3)alkoxy(CrC3)alkoxy, or (CrC3)alkoxy(CrC3)alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, (R4J2N-, R4O2C-, R4C(=O)O-, 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-, spirocycloalkyl; heterocyclyl (optionally substituted with alkyl, haloalkyl, halogen or oxo), heteroaryl (optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo), arylamino (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 (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); and
R4 is independently selected from H, (CrC6)alkyl, halo(Ci-C6)alkyl, amino(Ci-C6)alkyl, (CrC6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl and (Ci-C6)alkoxy(CrC6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
33. The compound of claim 32, wherein the compound is of Formula (In11):
Figure imgf000141_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
34. The compound of claim 33, wherein the compound is of Formula (lo11):
Figure imgf000141_0002
or a pharmaceutically acceptable salt thereof; wherein: n is 0, 1 , 2 or 3; and G1 is fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Cr 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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C-ι-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrC6)alkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfιnyl, halo(Ci-C6)alkanesulfιnyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (d- Cβjalkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(CrC6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCβJalkylaminocarbonyl, di(CrC6)alkylaminocarbonyl, (CrC3)alkoxy(CrC3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (CrC6)alkylaminosulfonyl, di(CrC6)alkylamino- sulfonyl, heterocyclylsulfonyl,
Figure imgf000142_0001
(CrC6)alkylcarbonylamino(Ci- C6)alkyl, (CrC6)alkylsulfonylamino, (CrC6)alkylsulfonylamino(CrC6)alkyl, (C1- C6)alkoxycarbonyl(CrC6)alkoxy, (CrC6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Cr C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci- C6)alkyl, di(Ci-C6)alkylamino(CrC6)alkyl amino(C2-C6)alkoxy, (CrC6)alkylamino(C2- C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (C3- C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3-
C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(CrC6)alkyl, (d- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(CrC6)alkyl, {(C3-C6)cycloalkyl}{(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl or di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl.
35. The compound of claim 34, wherein: n is 0, 1 , 2 or 3;
G1 is (CrC4 )alkyl, (CrC4 )alkoxy, (CrC4 )haloalkyl, (CrC4 )haloalkoxy, halogen, cyano or nitro; the oxodihydropyrazinyl in Formula lo11 is optionally substituted on a substitutable ring nitrogen atom with CrC4 alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl or CrC4 haloalkyl; and the oxodihydropyridyl in Formula lo2 is optionally substituted on a ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-
C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2,
(CrC-Oalkylaminocarbonyl, di(CrC4)alkylaminocarbonyl or (CrC4)alkylcarbonylamino.
36. The compound of claim 35, wherein R1 is methyl or ethyl.
37. The compound of claim 35, wherein R1 is methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
38. The compound of claim 35, wherein R1 is methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (Ci-C4)alkyl, (CrC4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
39. The compound of claim 38, wherein the compound is of the following Formula:
Figure imgf000143_0001
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 34, wherein the compound is of Formula (Ip6):
Figure imgf000143_0002
or a pharmaceutically acceptable salt thereof; and wherein:
G1 is (CrC4)alkyl, (C1-C4JaIkOXy1 (d-C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, cyano or nitro; n is O, 1 or 2;
G2a is (CrC4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl or (d-C4)haloalkyl; G2b is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (Cr C4)haloalkoxy, CONH2, (d-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (d- C4)alkylcarbonylamino.
41. The compound of claim 40, wherein R1 is methyl or ethyl.
42. The compound of claim 40, wherein R1 is methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
43. The compound of claim 40, wherein R1 is methyl or ethyl; R2 is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, CONH2, (CrC4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2) H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
44. The compound of claim 40, wherein R1 is methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; the substituent G2a is selected from (C1-C4 )alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, and (CrC2)haloalkyl; and G2b is optionally selected from hydrogen, methyl or ethyl.
45. The compound of claim 44, wherein the compound is of the following Formula:
Figure imgf000144_0001
or a pharmaceutically acceptable salt thereof.
46. The compound claim 32, wherein the compound is of Formula (Ik):
Figure imgf000145_0001
Ik
R1a is methyl or ethyl; R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is optionally substituted with up to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (CrC6)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(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, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-C7)cycloalkylalkylthio, (CrCβJalkanesulfinyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfιnyl, halo(C4-C7)cycloalkylalkanesulfinyl, (C1- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (CrC6)alkylamino, di(CrC6)alkylamino, (Ci-C6)alkoxy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (CrCβJalkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (CrC^alkylcarbonylamino, (CrC6)alkylcarbonyl- amino(Ci-C6)alkyl, (CrC6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (CrCeOalkoxycarbonyKCrCeJalkoxy, (CrC6)alkoxy(Ci-C6)alkyl, halo(CrC6)alkoxy(Cr C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(CrC6)alkyl, (d- Ce)alkylamino(CrC6)alkyl, di(C1-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (C1- C6)alkylamino(C2-C6)alkoxy, di(CrC6)alkylamino(C2-C6)alkoxy and (d-CeJalkylcarbonyl; and Cy2 is optionally substituted 1 ,2-dihydro-2-oxopyrazinyl; or a pharmaceutically acceptable salt thereof.
47. The compound of claim 1 , wherein the compound is of the following Formula:
Figure imgf000146_0001
or a pharmaceutically acceptable salt thereof.
48. The compound of claim 1, wherein the compound is of the following Formula:
Figure imgf000146_0002
or a pharmaceutically acceptable salt thereof.
49. The compound of claim 1 , wherein the compound is of the following Formula:
Figure imgf000146_0003
or a pharmaceutically acceptable salt thereof.
50. 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 in any one of claims 1-49.
51. A method of inhibiting 11β-HSD1 activity comprising the step of administering to a mammal in need of such treatment an effective amount of the compound in any one of claims 1-49.
52. A pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) the compound in any one of claims 1-49; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
53. A method of treating a human with a disease associated with the activity or expression of 11 β-HSD1 , comprising the step of administering to the human an effective amount of the compound in any one of claims 1-49.
54. A method of inhibiting 11β-HSD1 activity comprising the step of administering to a human in need of such treatment an effective amount of the compound in any one of claims 1-49.
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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2395081T3 (en) 2007-07-26 2013-02-08 Vitae Pharmaceuticals, Inc. Synthesis of 11 beta-hydroxysteroid dehydrogenase inhibitors type 1
EP2220048B1 (en) 2007-11-16 2017-01-25 Boehringer Ingelheim International GmbH Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
TW200934490A (en) 2008-01-07 2009-08-16 Vitae Pharmaceuticals Inc Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1
CA2712500A1 (en) 2008-01-24 2009-07-30 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2245014B1 (en) * 2008-02-12 2011-11-02 Boehringer Ingelheim International GmbH Urea derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
WO2009102460A2 (en) 2008-02-15 2009-08-20 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2718264A1 (en) * 2008-03-18 2009-09-24 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
JP5538365B2 (en) 2008-05-01 2014-07-02 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8765780B2 (en) 2008-05-13 2014-07-01 Boehringer Ingelheim International Gmbh Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
EP2300437B1 (en) * 2008-06-05 2013-11-20 Glaxo Group Limited Benzpyrazol derivatives as inhibitors of pi3 kinases
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
ES2383246T3 (en) * 2008-06-05 2012-06-19 Glaxo Group Limited 4-amino-indazoles
EP2406255B1 (en) 2009-03-09 2015-04-29 Glaxo Group Limited 4-oxadiazol-2-yl-indazoles as inhibitors of pi3 kinases
EP2899191B1 (en) 2009-04-30 2017-08-09 Glaxo Group Limited Oxazole substituted indazoles as pi3-kinase inhibitors
TWI531571B (en) 2009-11-06 2016-05-01 維它藥物公司 Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
GB201018124D0 (en) 2010-10-27 2010-12-08 Glaxo Group Ltd Polymorphs and salts
TWI537258B (en) 2010-11-05 2016-06-11 百靈佳殷格翰國際股份有限公司 Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
EP2744783A1 (en) 2011-08-17 2014-06-25 Boehringer Ingelheim International GmbH Indenopyridine derivatives

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3681349A (en) * 1970-03-05 1972-08-01 Morton Norwich Products Inc 1-(substituted benzyl) tetrahydro-2-(1h) pyrimidones
EP0902288A2 (en) 1997-09-12 1999-03-17 Ethicon, Inc. Wound diagnosis by quantitating cortisol in wound fluids
EP0928789A1 (en) * 1996-07-31 1999-07-14 Nikken Chemicals Company, Limited 6-phenyltetrahydro-1,3-oxazin-2-one derivatives and medicinal compositions containing the same
US20060043951A1 (en) 2004-08-25 2006-03-02 Matsushita Electric Industrial Co., Ltd. Higher order slope compensation for fixed frequency current mode switching regulators
WO2007127693A1 (en) * 2006-04-24 2007-11-08 Eli Lilly And Company Substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
WO2008046758A2 (en) * 2006-10-19 2008-04-24 F. Hoffmann-La Roche Ag Imidazolone and imidazolidinone derivatives as 11b-hsd1 inhibitors for diabetes
WO2008106128A2 (en) * 2007-02-26 2008-09-04 Vitae Pharmaceuticals, Inc. CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1
WO2009017664A1 (en) * 2007-07-26 2009-02-05 Vitae Pharmaceuticals, Inc. CYCLIC INHIBITORS OF 11β-HYDROXYSTERIOD DEHYDROGENASE 1

Family Cites Families (193)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3378587A (en) 1963-03-14 1968-04-16 Du Pont 3, 3'-diaminomethyl-1, 1'-biadamantane
NL127995C (en) 1963-12-20 Geigy Ag J R
US3341538A (en) 1965-06-18 1967-09-12 Geigy Chem Corp Certain 2, 6-methano-3-benzazocines
DE2108954A1 (en) 1971-02-25 1972-09-07 Boehringer Sohn Ingelheim 2-(furylmethyl)-6,7-benzomorphans - useful as cns active agents
DE1801556A1 (en) 1968-10-05 1970-05-21 Huels Chemische Werke Ag Substd hexahydro-pyrimidinones
GB1304175A (en) 1969-03-31 1973-01-24
DE2105743C3 (en) 1971-02-08 1979-11-29 Boehringer Sohn Ingelheim 2- (Furylmethyl) - a -5,9-dialkyl -6,7benzomorphane, process for their preparation and their use
US4043927A (en) 1972-03-07 1977-08-23 Sun Ventures, Inc. Friction or tractive drive containing ethers of adamantanes
DE2229695A1 (en) 1972-06-19 1974-01-31 Boehringer Sohn Ingelheim 2- (HETEROARYL-METHYL) -5,9 BETA-DIALKYL6,7-BENZOMORPHANES, THEIR ACID ADDITIONAL SALTS AND THE PROCESS FOR THEIR PRODUCTION
DE2338369A1 (en) 1973-07-26 1975-02-13 Schering Ag MICROBIOLOGICAL HYDROXYLATION OF 2,6-METHANO-3-BENZAZOCINES
SU510999A3 (en) 1973-10-27 1976-04-15 К.Х.Берингер Зон, (Фирма) Method for producing (methoxymethyl-furylmethyl) 6,7-benzomorphanes of morphinanes
US4009171A (en) 1974-02-21 1977-02-22 Sterling Drug Inc. N-acylated-11-oxygenated-2,6-methano-3-benzazocine intermediates
DE2411382C3 (en) 1974-03-09 1979-09-06 C.H. Boehringer Sohn, 6507 Ingelheim 2-Tetrahydrofurfuryl-6,7-benzomorphane, process for the preparation and their use
US4136162A (en) 1974-07-05 1979-01-23 Schering Aktiengesellschaft Medicament carriers in the form of film having active substance incorporated therein
US4136145A (en) 1974-07-05 1979-01-23 Schering Aktiengesellschaft Medicament carriers in the form of film having active substance incorporated therein
DE2437610A1 (en) 1974-08-05 1976-02-26 Boehringer Sohn Ingelheim NEW 5.9-BETA-DISUBSTITUTED 2-TETRAHYDROFURFURYL-6,7-BENZOMORPHANES, THEIR ACID-ADDITIONAL SALTS, THEIR USE AS A MEDICINAL PRODUCTS AND METHOD FOR THEIR PRODUCTION
US4108857A (en) 1975-08-18 1978-08-22 Sterling Drug Inc. Imidazolylmethyl methanobenzazocines
DE2828039A1 (en) 1978-06-26 1980-01-10 Boehringer Sohn Ingelheim 2- (2-ALKOXYETHYL) -2'-HYDROXY-6,7-BENZOMORPHANES THEIR ACID ADDITION SALTS, THESE MEDICINAL PRODUCTS, AND METHOD FOR THE PRODUCTION THEREOF
CA2023492A1 (en) 1989-08-31 1991-03-01 Barry Clifford Lange Herbicidal glutarimides
US5393735A (en) 1990-08-09 1995-02-28 Rohm And Haas Company Herbicidal glutarimides
US5098916A (en) 1990-03-29 1992-03-24 G. D. Searle & Co. Propanobicyclic amine derivatives for cns disorders
EP0454444A1 (en) 1990-04-24 1991-10-30 Nissan Chemical Industries Ltd. Glutarimide derivatives and herbicides
US5215992A (en) 1990-04-30 1993-06-01 G. D. Searle & Co. Ethanobicyclic amine derivatives for CNS disorders
US5089506A (en) 1990-04-30 1992-02-18 G. D. Searle & Co. Ethanobicyclic amine derivatives for cns disorders
CA2049244A1 (en) 1990-08-16 1992-02-17 Steven H. Christiansen Process for absorption of sulfur compounds from fluids using heterocyclic compounds having at least one ring nitrogen atom
DE69109871T2 (en) 1990-10-10 1995-09-14 Schering Corp PYRIDINE AND PYRIDINE-N-OXIDE DERIVATIVES OF DIARYLMETHYL PIPERIDINES OR PIPERAZINES, THEIR COMPOSITIONS AND USE.
US5610294A (en) 1991-10-11 1997-03-11 The Du Pont Merck Pharmaceutical Company Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors
AU653896B2 (en) 1992-04-30 1994-10-13 Taiho Pharmaceutical Co., Ltd. Oxazolidine derivative and pharmaceutically acceptable salt thereof
GB9225377D0 (en) 1992-12-04 1993-01-27 Ici Plc Herbicides
AU668818B2 (en) 1993-04-07 1996-05-16 Taiho Pharmaceutical Co., Ltd. Thiazolidine derivative and pharmaceutical composition containing the same
TW280812B (en) 1993-07-02 1996-07-11 Bayer Ag
EP0640594A1 (en) 1993-08-23 1995-03-01 Fujirebio Inc. Hydantoin derivative as metalloprotease inhibitor
DE19500118A1 (en) 1994-05-18 1995-11-23 Bayer Ag Substituted diazacyclohexanedi (thi) one
US5780466A (en) 1995-01-30 1998-07-14 Sanofi Substituted heterocyclic compounds method of preparing them and pharmaceutical compositions in which they are present
FR2729954B1 (en) 1995-01-30 1997-08-01 Sanofi Sa SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
GB9510459D0 (en) 1995-05-24 1995-07-19 Zeneca Ltd Bicyclic amines
US5776959A (en) 1995-06-05 1998-07-07 Washington University Anticonvulsant and anxiolytic lactam and thiolactam derivatives
GB9517622D0 (en) 1995-08-29 1995-11-01 Univ Edinburgh Regulation of intracellular glucocorticoid concentrations
US5866702A (en) 1996-08-02 1999-02-02 Cv Therapeutics, Incorporation Purine inhibitors of cyclin dependent kinase 2
US6794390B2 (en) 1996-08-02 2004-09-21 Cv Therapeutics, Inc. Purine inhibitors of cyclin dependent kinase 2 & ikappabalpha
GB9623944D0 (en) 1996-11-15 1997-01-08 Zeneca Ltd Bicyclic amine derivatives
US6159990A (en) 1997-06-18 2000-12-12 Synaptic Pharmaceutical Corporation Oxazolidinones as α1A receptor antagonists
US5936124A (en) 1998-06-22 1999-08-10 Sepacor Inc. Fluoxetine process from benzoylpropionic acid
DE19918725A1 (en) 1999-04-24 2000-10-26 Bayer Ag New heterocyclic-substituted N-cyano-sulfonanilide compounds, useful as total or selective pre- or post-emergence herbicides, showing desiccant, defoliant, germination inhibiting and especially weed-killing activities
DE19929348A1 (en) 1999-06-26 2000-12-28 Bayer Ag Pure 2-heterocyclylmethyl-benzoic acid derivative preparation in high yield, for use as pharmaceutical or agrochemical intermediate, from phthalide compound and nitrogen-containing heterocycle
US7256005B2 (en) 1999-08-10 2007-08-14 The Chancellor, Masters And Scholars Of The University Of Oxford Methods for identifying iminosugar derivatives that inhibit HCV p7 ion channel activity
US6436928B1 (en) 1999-12-17 2002-08-20 Schering Corporation Selective neurokinin antagonists
EP1237874B1 (en) 1999-12-17 2006-02-22 Schering Corporation Selective neurokinin antagonists
GB0003397D0 (en) 2000-02-14 2000-04-05 Merck Sharp & Dohme Therapeutic agents
DE10034623A1 (en) 2000-07-17 2002-01-31 Bayer Ag New heterocyclic substituted pyridine derivatives useful as tumor necrosis factor-alpha inhibitors in treatment of e.g. atherosclerosis, arthritis, Crohn's disease, osteoporosis, transplant rejection and psoriasis
DE10034803A1 (en) 2000-07-18 2002-01-31 Bayer Ag Substituted sulfonic acid anilides
DE10034800A1 (en) 2000-07-18 2002-01-31 Bayer Ag Substituted benzo nitrogen heterocycles
DE10035908A1 (en) 2000-07-21 2002-03-07 Asta Medica Ag New heteroaryl derivatives and their use as medicines
DE10035927A1 (en) 2000-07-21 2002-03-07 Asta Medica Ag New heteroaryl derivatives and their use as medicines
DE10035928A1 (en) 2000-07-21 2002-03-07 Asta Medica Ag New heteroaryl derivatives and their use as medicines
JP2004506038A (en) 2000-08-16 2004-02-26 ニューロゲン　コーポレイション 2,4-substituted pyridine derivatives
US7294637B2 (en) 2000-09-11 2007-11-13 Sepracor, Inc. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter
AU2001290873B2 (en) 2000-09-11 2006-07-27 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission)
JP2002179572A (en) 2000-10-06 2002-06-26 Nikken Chem Co Ltd Therapeutic agent for allergic ophthalmopathy
US6841671B2 (en) 2000-10-26 2005-01-11 Pfizer Inc. Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
US20030143668A1 (en) 2001-06-18 2003-07-31 National Institute Of Advanced Industrial Guanosine triphosphate-binding protein coupled receptors
JP3873115B2 (en) 2001-09-25 2007-01-24 独立行政法人産業技術総合研究所 Cyclic urethane production method
US6653315B2 (en) 2001-10-15 2003-11-25 Schering Corporation Adenosine A2a receptor antagonists
PL370636A1 (en) 2001-11-22 2005-05-30 Ono Pharmaceultical Co, Ltd. Piperidin-2-one derivative compounds and drugs containing these compounds as the active ingredient
JP2003300884A (en) 2002-04-08 2003-10-21 Nikken Chem Co Ltd TNF-alpha PRODUCTION INHIBITOR
WO2003091258A1 (en) 2002-04-26 2003-11-06 Pfizer Products Inc. N-substituted-heteroaryloxy-aryl-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
WO2003091259A1 (en) 2002-04-26 2003-11-06 Pfizer Products Inc. Triaryl-oxy-aryl-spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors
DE60335359D1 (en) 2002-04-30 2011-01-27 Kudos Pharm Ltd phthalazinone
EP1506174B1 (en) 2002-05-17 2015-09-30 Taiwanj Pharmaceuticals Co., Ltd. Use of naltrexone for treating kidney and liver damage
WO2004004722A1 (en) 2002-07-03 2004-01-15 Schering Corporation 1-amido-4-phenyl-4-benzyloxymethyl-piperidine derivatives and related compounds as neurokinin-1(nk-1) antagonists for the treatment of emesis, depression, anxiety and cough
AU2003249812A1 (en) 2002-07-18 2004-02-09 Queen's University At Kingston Dihydrouracil compounds as anti-ictogenic or anti-epileptogenic agents
GB0218630D0 (en) 2002-08-10 2002-09-18 Tanabe Seiyaku Co Novel compounds
TWI347946B (en) 2002-10-11 2011-09-01 Otsuka Pharma Co Ltd 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compound
AU2003302027A1 (en) 2002-11-21 2004-06-15 Vicore Pharma Ab New tricyclic angiotensin ii agonists
GB0228410D0 (en) 2002-12-05 2003-01-08 Glaxo Group Ltd Novel Compounds
WO2004055008A1 (en) 2002-12-13 2004-07-01 Smithkline Beecham Corporation Compounds, compositions and methods
WO2004056744A1 (en) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
ATE474577T1 (en) 2003-03-26 2010-08-15 Merck Sharp & Dohme BICYCLIC PIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR AGONISTS
US7700583B2 (en) 2003-04-11 2010-04-20 High Point Pharmaceuticals, Llc 11β-hydroxysteroid dehydrogenase type 1 active compounds
EP1787982B1 (en) 2003-04-11 2010-05-12 High Point Pharmaceuticals, LLC 11Beta-Hydroxysteroid dehydrogenase type 1 active compounds
DE10358004A1 (en) 2003-12-11 2005-07-14 Abbott Gmbh & Co. Kg Ketolactam compounds and their use
US7186844B2 (en) 2004-01-13 2007-03-06 Mitsubishi Gas Chemical Co., Inc. Method for producing cyclic carbamate ester
JP4324669B2 (en) 2004-01-21 2009-09-02 独立行政法人産業技術総合研究所 Method for producing cyclic urethane
JP2005239670A (en) 2004-02-27 2005-09-08 Ono Pharmaceut Co Ltd Nitrogen-containing heterocyclic compound and its pharmaceutical application
JP2007528396A (en) 2004-03-09 2007-10-11 メルク　エンド　カムパニー　インコーポレーテッド HIV integrase inhibitor
US8519158B2 (en) 2004-03-12 2013-08-27 Ligand Pharmaceuticals Incorporated Androgen receptor modulator compounds and methods
JP2005272321A (en) 2004-03-23 2005-10-06 Ono Pharmaceut Co Ltd Nitrogen-containing heterocyclic compound and its medicine use
GB0411404D0 (en) 2004-05-21 2004-06-23 Glaxo Group Ltd Novel compounds
AR049344A1 (en) 2004-05-24 2006-07-19 Amgen Inc INHIBITORS OF THE 11-BETA-HYDROXI STEROID DEHYDROGENASE TYPE 1
NZ551602A (en) 2004-06-24 2010-11-26 Incyte Corp Amido compounds and their use as pharmaceuticals
GB0414438D0 (en) 2004-06-28 2004-07-28 Syngenta Participations Ag Chemical compounds
DOP2005000123A (en) 2004-07-02 2011-07-15 Merck Sharp & Dohme CETP INHIBITORS
EP1621535A1 (en) 2004-07-27 2006-02-01 Aventis Pharma S.A. Substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
EP1621539A1 (en) 2004-07-27 2006-02-01 Aventis Pharma S.A. Heterocycle -substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
EP1621536A1 (en) 2004-07-27 2006-02-01 Aventis Pharma S.A. Amino cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
MX2007001399A (en) 2004-08-02 2007-04-18 Osi Pharm Inc Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds.
AU2005290081B2 (en) 2004-08-23 2010-12-02 Merck Sharp & Dohme Corp. Inhibitors of Akt activity
BRPI0515121A (en) 2004-08-30 2008-07-08 Janssen Pharmaceutica Nv n-2 adamantyl-2-phenoxy acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US7531565B2 (en) 2004-09-10 2009-05-12 Janssen Pharmaceutica, N.V. Imidazolidin-2-one derivatives as selective androgen receptor modulators (SARMS)
DE602005012306D1 (en) * 2004-10-29 2009-02-26 Lilly Co Eli CYCLOALKYL-LACTAM DERIVATIVES AS INHIBITORS OF 11-BETA-HYDROXYSTEROIDDEHYDROGENASE 1
TWI400239B (en) 2004-11-10 2013-07-01 Incyte Corp Lactam compounds and their use as pharmaceuticals
GT200500375A (en) 2004-12-20 2006-11-28 PIPERIDINE DERIVATIVES AND THEIR USE AS ANTI-INFLAMMATORY AGENTS
AU2005318419A1 (en) 2004-12-23 2006-06-29 Chiesi Farmaceutici S.P.A. Azole derivatives with antimuscarinic activity
CA2590961C (en) 2004-12-28 2013-11-26 Exelixis, Inc. [1h-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidine or -piperazine compounds as serine-threonine kinase modulators (p70s6k, atk1 and atk2) for the treatment of immunological, inflammatory and proliferative diseases
AU2006206246A1 (en) 2005-01-19 2006-07-27 Neurogen Corporation Heteroaryl substituted piperazinyl-pyridine analogues
CA2598457A1 (en) 2005-02-16 2006-08-24 Schering Corporation Pyridyl and phenyl substituted piperazine-piperidines with cxcr3 antagonist activity
CN101146793A (en) 2005-02-16 2008-03-19 先灵公司 Novel heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity
RU2007134260A (en) 2005-02-16 2009-03-27 Шеринг Корпорейшн (US) Pyrazinyl-Substituted Piperazine-Piperidines with Antagonistic Activity Against CXCR3
RU2007134259A (en) 2005-02-16 2009-03-27 Шеринг Корпорейшн (US) HETEROCYCLIC SUBSTITUTED PIPERASINS WITH ANTAGONISTIC ACTION TO CXCR3
MX2007010068A (en) 2005-02-16 2007-10-10 Schering Corp Piperazine-piperidines with cxcr3 antagonist activity.
MX2007009948A (en) 2005-02-16 2007-09-26 Schering Corp Amine-linked pyridyl and phenyl substituted piperazine- piperidines with cxcr3 antagonist activity.
KR100890886B1 (en) 2005-02-24 2009-03-31 니혼노야쿠가부시키가이샤 Novel haloalkylsulfonanilide derivative, herbicide, and method of use thereof
WO2006104280A1 (en) * 2005-03-31 2006-10-05 Takeda Pharmaceutical Company Limited Prophylactic/therapeutic agent for diabetes
CA2604038C (en) 2005-04-12 2013-11-12 Vicore Pharma Ab New tricyclic angiotensin ii agonists
WO2007008529A2 (en) 2005-07-08 2007-01-18 Kalypsys, Inc Celullar cholesterol absorption modifiers
CN101309690A (en) 2005-08-16 2008-11-19 阿诺麦德股份有限公司 Chemokine receptor binding compounds
EP1937666B1 (en) 2005-10-11 2012-02-22 Schering Corporation Substituted heterocyclic compounds with cxcr3 antagonist activity
CN101296902A (en) 2005-10-27 2008-10-29 Ucb医药有限公司 Compounds comprising a lactam or a lactam derivative moiety, processes for making them, and their uses
JP2007140188A (en) 2005-11-18 2007-06-07 Fujifilm Corp Positive photosensitive composition and pattern forming method using the same
CA2630718A1 (en) 2005-11-22 2007-05-31 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
CA2630492C (en) 2005-12-05 2015-04-14 Incyte Corporation Spiro-lactam compounds
EP1801098A1 (en) 2005-12-16 2007-06-27 Merck Sante 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
WO2007076055A2 (en) 2005-12-22 2007-07-05 Entremed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
DE102005062990A1 (en) 2005-12-28 2007-07-05 Grünenthal GmbH New N-thiazolyl-alkyl substituted propiolamide derivatives are inhibitors of the mGluR5 receptor useful for treatment and prevention of e.g. pain, anxiety and panic attacks
CA2635087A1 (en) 2005-12-30 2007-07-19 Merck & Co., Inc. Cholesteryl ester transfer protein inhibitors
CA2635010A1 (en) 2005-12-30 2007-07-19 Amjad Ali Oxazolidinone derivatives as cetp inhibitors
NZ568904A (en) 2005-12-30 2011-05-27 Merck Sharp & Dohme 1,3-oxazolidin-2-one derivatives useful as CETP inhibitors
US7910592B2 (en) 2005-12-30 2011-03-22 Merck Sharp & Dohme Corp. CETP inhibitors
WO2007084314A2 (en) 2006-01-12 2007-07-26 Incyte Corporation MODULATORS OF 11-ß HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME
BRPI0707502A2 (en) 2006-02-27 2011-05-10 Bayer Healthcare Llc Temperature-adjusted analyte determination for biosensor systems
TW200808807A (en) 2006-03-02 2008-02-16 Incyte Corp Modulators of 11-β hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
US20070208001A1 (en) 2006-03-03 2007-09-06 Jincong Zhuo Modulators of 11- beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
WO2007109456A2 (en) 2006-03-16 2007-09-27 Pharmacopeia, Inc. Substituted biphenyl isoxazole sulfonamides as dual angiotensin endothelin receptor antagonists
JP2007254409A (en) 2006-03-24 2007-10-04 Taisho Pharmaceut Co Ltd Imidazolidinone derivative
US7435833B2 (en) 2006-04-07 2008-10-14 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
WO2007127763A2 (en) 2006-04-25 2007-11-08 Eli Lilly And Company Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8178005B2 (en) 2006-06-20 2012-05-15 Chemtura Corporation Liquid phosphite compositions having different alkyl groups
PE20080344A1 (en) 2006-06-27 2008-06-09 Sanofi Aventis 8-AZABICYCLE COMPOUNDS [3.2.1] OCT-8-IL-1,2,3,4-TETRAHYDROQUINOLINE SUBSTITUTED AS INHIBITORS 11B-HSD1
WO2008012622A2 (en) 2006-07-25 2008-01-31 Pfizer Products Inc. Azabenzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor
WO2008012623A1 (en) 2006-07-25 2008-01-31 Pfizer Products Inc. Benzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
US8927715B2 (en) 2006-08-25 2015-01-06 Vitae Pharmaceuticals, Inc. Inhibitors of 11β-hydroxysteroid dehydrogenase type 1
EP2061780A4 (en) 2006-09-14 2010-12-22 Zalicus Pharmaceuticals Ltd Diaryl piperidine compounds as calcium channel blockers
KR20090053923A (en) 2006-09-22 2009-05-28 노파르티스 아게 Heterocyclic organic compounds
DE102007005799B4 (en) 2006-10-18 2018-01-25 Heinz-Jürgen Mühlen Process for producing a hydrogen-rich product gas
TW200829171A (en) 2006-11-17 2008-07-16 Nihon Nohyaku Co Ltd Haloalkyl sulfonanilide derivatives or salts thereof, herbicide using it as effective constituent and use-method thereof
EP1935420A1 (en) 2006-12-21 2008-06-25 Merck Sante 2-Adamantyl-butyramide derivatives as selective 11beta-HSD1 inhibitors
MX2009010207A (en) 2007-03-23 2009-10-19 Schering Corp Hydrazido-peptides as inhibitors of hcv ns3-protease.
CN101646679A (en) 2007-03-29 2010-02-10 弗·哈夫曼-拉罗切有限公司 Heterocyclic antiviral compounds
WO2009020140A1 (en) 2007-08-06 2009-02-12 Dainippon Sumitomo Pharma Co., Ltd. Adamantylurea derivative
JP2009110842A (en) 2007-10-31 2009-05-21 Sumitomo Chemical Co Ltd Laminated resin body for button switch coating
AR069207A1 (en) 2007-11-07 2010-01-06 Vitae Pharmaceuticals Inc CYCLIC UREAS AS INHIBITORS OF THE 11 BETA - HIDROXI-ESTEROIDE DESHIDROGENASA 1
EP2220048B1 (en) 2007-11-16 2017-01-25 Boehringer Ingelheim International GmbH Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
WO2009075835A1 (en) 2007-12-11 2009-06-18 Vitae Pharmaceutical, Inc CYCLIC UREA INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE 1
KR101460359B1 (en) 2007-12-13 2014-11-10 삼성전자주식회사 Method and apparatus for handover in mobile telecommunication system
TW200934490A (en) 2008-01-07 2009-08-16 Vitae Pharmaceuticals Inc Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1
CA2712500A1 (en) 2008-01-24 2009-07-30 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2009102428A2 (en) 2008-02-11 2009-08-20 Vitae Pharmaceuticals, Inc. 1,3-OXAZEPAN-2-ONE AND 1,3-DIAZEPAN-2-ONE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1
EP2245014B1 (en) 2008-02-12 2011-11-02 Boehringer Ingelheim International GmbH Urea derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
WO2009102460A2 (en) 2008-02-15 2009-08-20 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8383629B2 (en) 2008-02-27 2013-02-26 Vitae Pharmaceuticals, Inc. Inhibitors of 11β-hydroxysteroid dehydrogenase type 1
JP5108557B2 (en) 2008-02-27 2012-12-26 東京エレクトロン株式会社 Load lock device and substrate cooling method
CA2718264A1 (en) 2008-03-18 2009-09-24 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
TW200944526A (en) 2008-04-22 2009-11-01 Vitae Pharmaceuticals Inc Carbamate and urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
EP2300461B1 (en) 2008-05-01 2013-04-17 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
JP5538365B2 (en) 2008-05-01 2014-07-02 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
JP5451752B2 (en) 2008-05-01 2014-03-26 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
US8765780B2 (en) 2008-05-13 2014-07-01 Boehringer Ingelheim International Gmbh Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
US20110224242A1 (en) 2008-07-23 2011-09-15 Bioalliance Pharma Styrlyquinolines, their process of preparation and their therapeutic uses
WO2010010150A1 (en) 2008-07-25 2010-01-28 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
JP5777030B2 (en) 2008-07-25 2015-09-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhibitor of 11β-hydroxysteroid dehydrogenase 1
RU2539979C2 (en) 2008-07-25 2015-01-27 Вайтаи Фармасьютиклз, Инк. Cyclic inhibitors of 11beta-hydroxysteroid-dehydrogenase 1
JP5846909B2 (en) 2008-07-25 2016-01-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 1,1'-diadamantylcarboxylic acid, medicament containing such compounds and use thereof
US8609690B2 (en) 2008-08-25 2013-12-17 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use
JP5544366B2 (en) 2008-10-23 2014-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Urea derivative of substituted nortropane, medicament containing the compound and use thereof
WO2010089303A1 (en) 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1
WO2010091067A2 (en) 2009-02-04 2010-08-12 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2405913A1 (en) 2009-03-09 2012-01-18 Bristol-Myers Squibb Company Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
UA109255C2 (en) 2009-04-30 2015-08-10 Берінгер Інгельхайм Інтернешнл Гмбх Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
KR20120061771A (en) 2009-04-30 2012-06-13 비타이 파마슈티컬즈, 인코포레이티드 Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8703765B2 (en) 2009-06-02 2014-04-22 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
AR076936A1 (en) 2009-06-02 2011-07-20 Vitae Pharmaceuticals Inc CARBAMATE AND UREA INHIBITORS OF THE 11 BETA HYDROXIESTEROID DEHYDROGENASE 1
EP2440537A1 (en) 2009-06-11 2012-04-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 based on the 1,3 -oxazinan- 2 -one structure
WO2011002910A1 (en) 2009-07-01 2011-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
KR20120104521A (en) 2009-09-11 2012-09-21 사일린 파마슈티칼스, 인크 Pharmaceutically useful heterocycle-substituted lactams
EP2496589B1 (en) 2009-11-05 2014-03-05 Boehringer Ingelheim International GmbH Novel chiral phosphorus ligands
TWI531571B (en) 2009-11-06 2016-05-01 維它藥物公司 Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
WO2011159760A1 (en) 2010-06-16 2011-12-22 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
JP5813106B2 (en) 2010-06-25 2015-11-17 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Azaspirohexanone as an inhibitor of 11-β-HSD1 for the treatment of metabolic disorders
EP2635268A1 (en) 2010-11-02 2013-09-11 Boehringer Ingelheim International GmbH Pharmaceutical combinations for the treatment of metabolic disorders

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3681349A (en) * 1970-03-05 1972-08-01 Morton Norwich Products Inc 1-(substituted benzyl) tetrahydro-2-(1h) pyrimidones
EP0928789A1 (en) * 1996-07-31 1999-07-14 Nikken Chemicals Company, Limited 6-phenyltetrahydro-1,3-oxazin-2-one derivatives and medicinal compositions containing the same
EP0902288A2 (en) 1997-09-12 1999-03-17 Ethicon, Inc. Wound diagnosis by quantitating cortisol in wound fluids
US20060043951A1 (en) 2004-08-25 2006-03-02 Matsushita Electric Industrial Co., Ltd. Higher order slope compensation for fixed frequency current mode switching regulators
WO2007127693A1 (en) * 2006-04-24 2007-11-08 Eli Lilly And Company Substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
WO2008046758A2 (en) * 2006-10-19 2008-04-24 F. Hoffmann-La Roche Ag Imidazolone and imidazolidinone derivatives as 11b-hsd1 inhibitors for diabetes
WO2008106128A2 (en) * 2007-02-26 2008-09-04 Vitae Pharmaceuticals, Inc. CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1
WO2009017664A1 (en) * 2007-07-26 2009-02-05 Vitae Pharmaceuticals, Inc. CYCLIC INHIBITORS OF 11β-HYDROXYSTERIOD DEHYDROGENASE 1

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANSTEAD, ADV. WOUND CARE, vol. 11, 1998, pages 277 - 285
BITAR ET AL., J. SURG. RES., vol. 82, 1999, pages 234 - 243
BITAR ET AL., SURGERY, vol. 125, 1999, pages 594 - 601
BITAR, AM. J. PATHOL., vol. 152, 1998, pages 547 - 554
BITAR, SURGERY, vol. 127, 2000, pages 687 - 695
ROOK, BAILLIER'S CLIN. ENDOCRINOL. METABL., vol. 13, 1999, pages 576 - 581

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors

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US20110263583A1 (en) 2011-10-27
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