WO2010010157A2 - INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 - Google Patents

INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 Download PDF

Info

Publication number
WO2010010157A2
WO2010010157A2 PCT/EP2009/059509 EP2009059509W WO2010010157A2 WO 2010010157 A2 WO2010010157 A2 WO 2010010157A2 EP 2009059509 W EP2009059509 W EP 2009059509W WO 2010010157 A2 WO2010010157 A2 WO 2010010157A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
halo
alkoxy
cycloalkyl
hydroxy
Prior art date
Application number
PCT/EP2009/059509
Other languages
French (fr)
Other versions
WO2010010157A3 (en
Inventor
Frank Himmelsbach
Matthias Eckhardt
Bradford S. Hamilton
Annette Schuler-Metz
Linghang Zhuang
Original Assignee
Boehringer Ingelheim International Gmbh
Vitae Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International Gmbh, Vitae Pharmaceuticals, Inc. filed Critical Boehringer Ingelheim International Gmbh
Priority to US13/054,954 priority Critical patent/US8846668B2/en
Priority to JP2011519178A priority patent/JP5777030B2/en
Priority to CA2729998A priority patent/CA2729998A1/en
Priority to EP09780992.5A priority patent/EP2324017B1/en
Publication of WO2010010157A2 publication Critical patent/WO2010010157A2/en
Publication of WO2010010157A3 publication Critical patent/WO2010010157A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/08—Antibacterial agents for leprosy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to inhibitors of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (1 l ⁇ -HSDl), pharmaceutical compositions thereof and methods of using the same.
  • Glucocorticoids such as Cortisol (hydrocortisone) are steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism, and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate Cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.
  • Cortisol hydrocortisone
  • glucocorticoid action was attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic -pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues.
  • HPA hypothalamic -pituitary-adrenal
  • 1 l ⁇ - hydroxysteroid dehydrogenase (l l ⁇ -HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones.
  • l l ⁇ -HSD 1 l ⁇ -HSDl
  • 11-beta-HSD type 1 l lbetaHSDl
  • HSDI lBl HDL
  • HSDl IL 11 ⁇ -HSD2.
  • 1 l ⁇ - HSDl 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 ⁇ -HSDl is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium.
  • 11 ⁇ -HSD 1 may regulate intraocular pressure and may contribute to glaucoma; some data suggest that inhibition of 11 ⁇ -HSD 1 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 ⁇ -HSD 1 catalyzes both 11 -beta-dehydrogenation and the reverse 11 -oxoreduction reaction
  • 11 ⁇ -HSD 1 acts predominantly as a NADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active Cortisol from inert cortisone (Low et al. (1994) J. MoI. Endocrin. 13: 167-174).
  • 1 l ⁇ -HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines.
  • 1 l ⁇ -HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston et al. (1994) MoI. Cell. Endocrin. 105: Rl 1 -Rl 7), 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 ⁇ -HSD 1 or the 11 ⁇ -HSD2 genes result in human pathology.
  • H6PD cortisone reductase deficiency
  • PCOS polycystic ovary syndrome
  • 1 l ⁇ -HSDl 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 1 l ⁇ -HSDl activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel and Sutter (1979) Horm. Metab. Res.
  • glucocorticoids and 1 l ⁇ -HSDl play a role in regulation of in intra-ocular pressure (IOP) (Stokes et al. (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042); if left untreated, elevated IOP can lead to partial visual field loss and eventually blindness.
  • IOP intra-ocular pressure
  • Transgenic aP2-l l ⁇ HSDl 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 II and aldosterone; and treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This suggests that hypertension may be caused or exacerbated by 11 ⁇ - HSDl activity. Thus, 1 l ⁇ -HSDl 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).
  • 1 l ⁇ -HSDl has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper et al. (2000) Bone 27: 375-381), and the 1 l ⁇ -HSDl inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23: 119-125).
  • 1 l ⁇ -HSDl inhibitors may also be useful for immunomodulation.
  • glucocorticoids are perceived to suppress the immune system, in actuality, there is a complex, dynamic interaction between the HPA axis and the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581).
  • Glucocorticoids play a role in modulating the balance between cell-mediated and humoral immune response, with high glucocorticoid activity normally associated with a humoral response.
  • Inhibition of 11 ⁇ - HSDl therefore can be used a means of shifting the immune response towards a cell- mediated response.
  • Certain disease states such as tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune responses that are biased towards a humoral response whereas the more effective immune response may be a cell-mediated response.
  • 1 l ⁇ -HSDl inhibitors may be useful for treating such diseases.
  • the invention is a compound represented by Formula I: wherein variables are defined herein as follows:
  • R 1 is (a) absent or (b) is selected from (C r C 6 )alkyl, (C r C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (Ci-C 3 )alkoxy(Ci-C 3 )alkoxy, or (Ci-C 3 )alkoxy(Ci-C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 ,
  • 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, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl,
  • Cy 2 is benzimidazolyl, benzotriazolyl and piperidinyl and is optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -
  • C 6 cycloalkylaminosulfonyl, ⁇ (C 3 -C 6 )cycloalkyl ⁇ ⁇ (Ci-C 6 )alkyl ⁇ aminosulfonyl, di(C 3 - C 6 )cycloalkylaminosulfonyl, cyano(Ci-C 6 )alkyl, aminocarbonyl(Ci-C 6 )alkyl, (Ci- C 6 )alkylaminocarbonyl(Ci-C 6 )alkyl, di(Ci-C 6 )alkylaminocarbonyl(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkylaminocarbonyl(Ci-C 6 )alkyl, ⁇ (C 3 -C 6 )cycloalkyl ⁇ ⁇ (C r C6)alkyl ⁇ aminocarbonyl(Ci-C6)alkyl and di(C 3 -C6)cycloalkyl
  • Cy is (a) halogen or -O-SO 3 -R or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 3 -C 7 )cycloalkyl(Ci-C 2 )alkyl, (C 2 -C 6 )alkenyl, halo
  • C 3 alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C 6 )alkylaminosulfonyl, di(Cp C 6 )alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C 6 )alkylcarbonylammo, (Ci-C 6 )alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci- C 6 )alkyl, (Ci-C 6 )alkoxycarbonyl(Ci-C 6 )alkoxy, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, halo(C r
  • C 6 cycloalkylaminosulfonyl, ⁇ (C 3 -C 6 )cycloalkyl ⁇ ⁇ (Ci-C 6 )alkyl ⁇ aminosulfonyl, di(C 3 - C 6 )cycloalkylaminosulfonyl, cyano(Ci-C 6 )alkyl, aminocarbonyl(Ci-C 6 )alkyl, (Ci- C 6 )alkylaminocarbonyl(Ci-C 6 )alkyl, di(Ci-C 6 )alkylaminocarbonyl(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkylaminocarbonyl(Ci-C 6 )alkyl, ⁇ (C 3 -C 6 )cycloalkyl ⁇ ⁇ (C r C6)alkyl ⁇ aminocarbonyl(Ci-C6)alkyl and di(C 3 -C6)cycloalkyl
  • Y is (Ci-C 6 )alkyl, halo(C r C 6 )alkyl or oxo; n is 0, 1 or 2; E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C 2 )alkylenyloxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
  • R 2 is (Ci-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-C6)alkyl, hydroxy(Ci-C6)alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 - C 4 )alkynyl, halo(C r C 6 )alky
  • R 3 is selected from (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 5 )cycloalkyl(C r C 4 )alkyl, (Ci-C 3 )alkoxy(C r C 3 )alkoxy, or (Ci-C 3 )alkoxy(C r C 3 )alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R 4 ,
  • heteroaryl which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo
  • aryl- amino which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N- monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino
  • R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C 4 )alkyl Or NO 2 ; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • the invention is a compound represented by Formula I
  • 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, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylal
  • Cy is benzimidazolyl, benzotriazolyl and piperidinyl 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(Ci-C6)alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, hydroxy(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl(C 2 -
  • Cy 2 is (a) halogen or -0-SO 3 -R or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C r C 2 )alkyl, (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 )cycloalky
  • Y is (Ci-C 6 )alkyl, halo(C r C 6 )alkyl or oxo; n is 0, 1 or 2; E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C 2 )alkylenyloxy, wherein the O is attached to R , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
  • R is (Ci-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-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-
  • R 3 is selected from (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 5 )cycloalkyl(Ci-C 6 )alkyl;
  • Another embodiment of the invention is a method of inhibiting 1 l ⁇ -HSDl activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 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 1 l ⁇ -HSDl, comprising the step of administering to the subject an effective amount of a compound of Formulas I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Another embodiment of the invention is the use of a compound of Formulas I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for inhibiting 11 ⁇ -HSDl activity in a mammal in need of such treatment.
  • Another embodiment of the invention is the use of a compound of Formulas I, Ia 1"10 ,
  • Another embodiment of the invention is a compound of Formulas I, Ia 1"10 , Ib 1"10 , Ic 1" 10 , Id 1"7 or Ie 1 5 Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in inhibiting 11 ⁇ -HSDl activity in a mammal in need of such treatment.
  • Another embodiment of the invention is a compound of Formulas I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 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 l l ⁇ -HSDl.
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) compound of Formulas I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 or a pharmaceutically acceptable salt, enantiomer or diastereomer, thereof.
  • a 1 is (a) a bond, (b) (C r C 2 )alkylene, or (c) CH if R 1 is present, n
  • E is a bond or CH 2 .
  • R is (Ci-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-C6)alkyl, hydroxy(Ci-C6)alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(d-C 6 )alkyl, (C r C 6 )alkoxy, (C 3 - C 6 )cycloalkoxy, halo(Ci-C 6 )alkoxy, (Ci-C 6 )alkanesulfonyl, halo(Ci-C 6 )alkanesulfonyl, halo(C 3 -C 6 )cycloalkanesulfonyl, H 2 NCO
  • C 6 alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C 6 )alkylcarbonylamino, (Ci-C 6 )alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino and oxo.
  • R 4 is independently selected from H, (Ci-C 6 )alkyl and halo(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined above for the first or second embodiment of Formula (I). In a fourth embodiment, the variables in Formula I:
  • A is (a) a bond, (b) (C r C 2 )alkylene, or (c) CH if R is present, n is 0.
  • R 2 is (Ci-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(Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(C r C 6 )alkyl, (C r C 6 )alkoxy, (C 3 - C 6 )cycloalkoxy, halo(Ci-C 6 )alkoxy, (Ci-C 6 )alkanesulfonyl, halo(Ci-C 6 )alkanesulfonyl, halo(C 3 -C 6 )cyclocyclyl and is optionally substitute
  • R 3 is methoxymethyl.
  • R 4 is independently selected from H, (d-C 6 )alkyl and halo(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined above for the first or second embodiment of Formula (I).
  • R 1 is absent or is methyl, ethyl or cyclopropyl.
  • a 1 is a bond or CH 2 or CH when R 1 is present.
  • Cy 1 is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl each optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(d- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, (C r C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, halo(C r C 6 )alkoxy, (Ci- C 6 )alkanesulfonyl, halo(Ci
  • Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(d-C 6 )alkyl, (d- Ce)alkoxy, (C 3 -C6)cycloalkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(d- C 6 )alkanesulfonyl, halo(d- C 6 )alkanesulfonyl,
  • Cy 2 is (a) halogen or -0-SO 3 -R , or (b) cycloalkyl, aryl, heterocyclyl, heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R is methyl, ethyl, propyl, phenyl, thienyl or pyridyl each optionally substituted with halo, cyano, CONH 2 , (C r C 4 )alkyl, (C r C 4 )haloalkyl, and SO 2 Me.
  • R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C ⁇ alkyl Or NO 2 ; Pharmaceutically acceptable salts, enantiomers or diastereomers thereof are also included; and values for the remaining variables are as defined for Formula (I) and for first, second, third or fourth embodiment.
  • variables of Formula I or any one of Formulas Ia l lo -Ie 1 5 are as defined in the following paragraphs: R 1 is absent or is methyl or ethyl.
  • a 1 is a bond or CH 2 or CH when R 1 is present.
  • Cy 1 is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl each optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C r C 2 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, (C r C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, halo(d-C 6 )alkoxy, (d- C 6 )alkanesulfonyl, halo(Ci-C 6
  • Cy 2 is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(C r C 6 )alkyl, (C 1 - C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, halo(Ci-C 6 )alkoxy, (Ci-C 6 )alkanesulfonyl, halo(d- C 6 )alkanesulfonyl, halo(C 3 -
  • C 6 )alkylcarbonylamino (Ci-C 6 )alkylcarbonyl, (Ci-C 6 )alkylcarbonylamino(Ci-C 6 )alkyl, (Ci- C6)alkoxycarbonyl, (Ci-C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(d- C 6 )alkyl, (Ci-C 6 )alkylaminocarbonyl(Ci-C 6 )alkyl and di(Ci-C 6 )alkylaminocarbonyl(Ci- C 6 )alkyl.
  • Cy 2 is piperidinyl, oxo is also a possible substituent.
  • R 3 is methoxymethyl
  • Cy 2 is (a) halogen or -0-SO 3 -R , or (b) cycloalkyl, aryl, heterocyclyl, heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 2 )alkyl, hydroxy(C 3 -C 6 )cycloalkyl, halo(d-C 6 )alkyl, (d-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, halo(Ci-C
  • R 2 is phenyl, thienyl or pyridyl each optionally substituted with halo, cyano, CONH 2 , (Ci-C 4 )alkyl, (C r C 4 )haloalkyl, and SO 2 Me.
  • R is methoxymethyl.
  • R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C 4 )alkyl Or NO 2 ;
  • Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl, pyrimidinyl, piperidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, nitro, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, trifluoromethyl, hydroxy, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl, methylsulfonylamino, trifluoromethoxy and 2,
  • Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci- C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C r C 2 )alkyl, (C r C 4 )alkoxy, (C 1 - C 4 )haloalkoxy, (Ci-C 4 )alkanesulfonyl, (Ci-C 4 )alkyloxycarbonyl, (Ci-C 4 )alkylcarbonyl, hydroxy(Ci-C 4 )alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH 2 , (Ci-C 4 )
  • Cy 2 is (a) halogen or -O-SO 3 -R; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, CpC 4 alkyl, (C3- C 4 )cycloalkyl, (C3-C 4 )cycloalkyl(C 1 -C 2 )alkyl, (C r C 4 )alkoxy, (C r C 4 )haloalkoxy, CONH 2 , (Ci-C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl and (Ci-C 4 )alkylcarbonylamino and C 1 -C 4 haloalkyl; and
  • R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C 4 )alkyl or NO 2 ; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined for first second, third, fourth, fifth or sixth embodiment..
  • Cy 1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl, pyrimidinyl, piperidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, nitro, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, trifluoromethyl, hydroxy, (Ci-C 4 )alkoxy, (Ci-C 4 )haloalkoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl, methylsulfonylamino, trifluoromethoxy and 2,
  • Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci- C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, (C r C 4 )alkoxy, (C 1 - C 4 )haloalkoxy, CONH 2 , (Ci-C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl, (Ci- C 4 )alkylcarbonylamino and (Ci-C 4 )haloalkyl.
  • 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci- C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C
  • Cy 2 is piperidinyl, oxo is also a possible substituent.
  • R 3 is methoxymethyl
  • Cy 2 is (a) halogen or -O-SO3-R; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, C 1 -C 4 alkyl, (C3- C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, (C r C 4 )alkoxy, (C r C 4 )haloalkoxy, CONH 2 , (Ci-C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl and (Ci-C 4 )alkylcarbonylamino and C 1 -C 4 haloalkyl; and
  • R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C 4 )alkyl Or NO 2 ; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • Values for the remaining variables are as defined for first second, third, fourth, fifth or sixth embodiment.
  • the variables Formula I or any one of Formulas Ia l lo -Ie 1 5 are as defined in the following paragraphs:
  • Cy 2 is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 - C 7 )cycloalkyl(Ci-C 2 ) alkyl, (Ci-C 4 )alkanesulfonyl, hydroxy(Ci-C 4 )alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH 2 , (Ci-C 4 )alkylaminocarbonyl, di(Cr C 4 )alkylaminocarbonyl, (Ci-C 4 )alkylcarbonyl, (Ci-C 4 )alkoxycarbonyl.
  • Cy 2 is (a) halogen or -O-SO 3 -R , wherein R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C 4 )alkyl or N ⁇ 2 ;or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl optionally substituted by 1 to 4 groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C3-C 7 )cycloalkyl(Ci-C 2 ) alkyl, (Ci-C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl, (Ci-C 4 )alkylcarbonyl, (Ci-C 4 )alkoxycarbonyl; or a pharmaceutically
  • Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -
  • Cy 2 is (a) halogen or -O-SO 3 -R , wherein R is (i) (Ci-C 4 )alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C 4 )alkyl or N ⁇ 2 ;or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl optionally substituted by 1 to 4 groups independently selected from (Ci-C6)alkyl, (C3-C 7 )cycloalkyl, (C3-C 7 )cycloalkyl(Ci-C 2 ) alkyl, (Ci-C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl, (Ci-C 4 )alkylcarbonyl, (Ci- C 4 )alkoxycarbonyl; or a pharmaceutically acceptable salt,
  • Another embodiment of the invention is a compound of any one of Formulas Ia 1"10 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; or of any one of Formulas Iba 1"10 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
  • the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, (C r C 4 )alkylcarbonyl, (C 1 - C 4 )alkoxycarbonyl or (Ci-C 4 )haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C 4 )alkyl, (C 3 - C 4 )cycloalkyl, (C3-C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C r C 4 )alkyl, (C r C 4 )
  • the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (C r C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, (C 1 - C 4 )alkylcarbonyl, (Ci-C 4 )alkoxycarbonyl or (Ci-C 4 )haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci- C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C r C 2 )alkyl, halo(C r C 4 )alkyl, (C r
  • R 1 is preferably methyl or ethyl.
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C r 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, (C r C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (C r C 4 )alkyl, (C r C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 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 isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, and (Ci-C 4 )alkyl,
  • R is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, and (Ci-C 4 )alkyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • 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, (Cl-C4)haloalkyl and SO 2 Me
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl; R 2 is isopropyl, phenyl or fluorophenyl; 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; and R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl, phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl
  • substitutable ring nitrogen atoms in the benzimidazolyl and benzotriazolyl rings in Formulas Ib 1 10 are optionally substituted with (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 - C 4 )cycloalkyl(Ci-C 2 )alkyl, or (Ci-C 2 )haloalkyl
  • substitutable ring nitrogen atoms in the piperidinyl rings in Formulas Ib 1"10 are optionally substituted with (Ci-C 2 )alkanesulfonyl, hydroxy(Ci-C 3 )alky
  • 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
  • substitutable ring nitrogen atoms in the benzimidazolyl and benzotriazolyl rings in Formulas Ib 1"10 are optionally substituted with (C r C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C r C 2 )alkyl, or (Ci-C 2 )haloalkyl
  • one or two substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ia 1"10 and Ib 1"10 are optionally substituted with methyl or ethyl;
  • Another embodiment of the invention is a compound of any one for Formulas Ic 1"10 , or a pharmaceutically acceptable salt thereof:
  • the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (Ci-C 4 )alkyl, (C3- C 4 )cycloalkyl, (C3-C 4 )cycloalkyl(C 1 -C 2 )alkyl, (C r C 4 )alkylcarbonyl, (C r C 4 )alkoxycarbonyl or (Ci-C 4 )haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C 4 )alkyl, (C3-C 4 )cycloalkyl, (C3- C 4 )cycloalkyl(Ci-C 2 )alkyl, halo(C r C 4 )alkyl, (C r C 4 )alkoxy, (C r C 4 )
  • R 1 is preferably methyl or ethyl.
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is 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 isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (Cp C 4 )alkyl, (C r C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, and (Ci- C 4 )alkyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl, phenyl or fluorophenyl
  • R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl;
  • R 2 is isopropyl, phenyl or fluorophenyl;
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;
  • substitutable ring nitrogen atoms in the benzimidazolyl and benzotriazolyl rings in Formulas Ic 1"10 are optionally substituted with (Ci-C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C r C 2 )alkyl, or (C r C 2 )haloalkyl;
  • substitutable ring nitrogen atoms in the piperidinyl rings in Formulas Ic 1"10 are optionally substituted with (Ci-C 2 )alkanesulfonyl, hydroxy(Ci-C 3 )alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH 2
  • 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 , (d-C 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 , (d-C 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, (Ci- C 4 )haloalkyl and SO 2 Me
  • R 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
  • substitutable ring nitrogen atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ic 1"10 are optionally substituted with (C r C 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 substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ic 1"10 are optionally substituted with methyl or ethyl.
  • G 1 is (C r C 4 )alkyl, (C r C 4 )alkoxy, (C 1 - C 4 )haloalkyl, (Ci-C 4 )haloalkoxy, halogen, cyano or nitro; r is 0, 1 or 2;
  • G a is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl or (Ci-C 4 )haloalkyl; each G 2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci-C 4 )alkyl, (C3-C 4 )cycloalkyl, (C3-C 4 )cycloalkyl(Ci- C 2 )alkyl, halo(C
  • R 1 , R 2 and R 3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • G 1 is (C r C 4 )alkyl, (C r C 4 )alkoxy, (C r C 4 )haloalkyl,
  • G a is (C 1 -C 4 )alkyl, (Ci- C 4 )alkanesulfonyl, hydroxy(Ci-C 4 )alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH 2 , (Ci- C 4 )alkylaminocarbonyl, di(Ci-C 4 )alkylaminocarbonyl, (Ci-C 4 )alkylcarbonyl, (Ci- C 4 )alkoxycarbonyl.; each G 2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C r C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, halo(C r C 4 )
  • R 1 is preferably methyl or ethyl.
  • R 1 is preferably methyl or ethyl
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is 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, (Ci- C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is 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, (Ci- C 4 )haloalkyl and SO 2 Me
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl or phenyl which is optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano and (Ci-C 4 )alkyl,
  • R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano and (Ci- C 4 )alkyl,
  • R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • 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 and (Ci- C 4 )alkyl, (Ci-C 4 )haloalkyl and SO 2 Me
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
  • R 1 is preferably methyl or ethyl; R 2 is isopropyl, phenyl or fluorophenyl; 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; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl, phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • the substituent G 2a is selected from (C r C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci- C 2 )alkyl, and (C 1 -C 2 )haloalkyl
  • each G 2b is independently selected from hydrogen, methyl or ethyl.
  • 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 (C r C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(Ci-C 2 )alkyl, and (C 1 -C 2 )haloalkyl
  • each G 2b is independently selected from hydrogen, methyl or ethyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl, phenyl or fluorophenyl
  • R 3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • the substituent G 2a is selected from selected from hydrogen, methyl or ethyl
  • each G 2b is independently selected from hydrogen or methyl.
  • R 1 is preferably methyl or ethyl
  • R 2 is isopropyl, phenyl or fluorophenyl
  • R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl
  • the substituent G 2a is selected from hydrogen, methyl, methanesulfonyl, acetyl, tetrahydrofuranylcarbonyl,methoxycarbonyl, methylaminocarbonyl and dimethylaminocarbonyl
  • each G 2b is independently selected from hydrogen or methyl.
  • Another embodiment of the invention is a compound represented by Formula Ie 1 or a pharmaceutically acceptable salt thereof:
  • Cy is (a) halogen or -O-SO 3 -R ; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(Ci- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, (C 3 -C 7 )cycloalkyl(Ci-C 2 )alkyl, (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 )al
  • Another embodiment of the invention is a compound represented by any one of Formulas Ie 2"5 , or a pharmaceutically acceptable salt thereof:
  • each G 1 is independently (CpC 4 )alkyl, (CpC 4 )alkoxy, (C r C 4 )haloalkyl, (Ci-C 4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for the group represented by Cy 2 are as described for Formula Ie 1 and suitable values for the remainder of the variables are as defined for the variables in Formula Ie 1 .
  • Cy 2 is preferably phenyl, thienyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benztriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl, each optionally substituted by 1 to 4 groups, wherein suitable substituents for a substitutable ring nitrogen atom are selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkyl, (Ci-C 4 )alky
  • Cy 2 is as described in the previous paragraph, and R 2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci- C 6 )alkyl, halo(C r C 6 )alkyl, hydroxy(C r C 3 )alkyl, (C r C 3 )alkoxy, halo(C r C 3 )alkoxy, CONH 2 and SO 2 Me.
  • R 2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, hydroxy(C r C 3 )alkyl, (C r C 3 )alkoxy, halo(C r C 3 )alkoxy, CONH 2 and SO 2 Me, and R 1 is methyl or ethyl.
  • R 2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH 2 , (Ci-C ⁇ alkyl, (Ci-C ⁇ haloalkyl and SO 2 Me.
  • R 2 is more preferably phenyl or fluorophenyl.
  • the present invention further provides methods of inhibiting l l ⁇ -HSDl by contacting 1 l ⁇ -HSDl with a compound of Formula I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1" 5 of the invention.
  • the present invention further provides methods of inhibiting or reducing the conversion of cortisone to Cortisol in a cell using a compound of Formula I, Ia 1"10 , Ib 1"10 , Ic 1" 10 , Id 1"7 or Ie 1"5 of the invention.
  • the present invention further provides methods of inhibiting or reducing production of Cortisol in a cell using a compound of Formula I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 of the invention.
  • the present invention further provides methods of increasing insulin sensitivity in a subject in need thereof using a compound of Formula I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 of the invention.
  • the present invention further provides methods of treating a subject with a disease associated with activity of expression of l l ⁇ -HSDl using a compound of Formula I, Ia 1"10 , Ib 1"10 , Ic 1"10 , Id 1"7 or Ie 1"5 of the invention.
  • IIbb 1 1 - " 1 1 0 0 , Ic 1"10 , Id 1"7 or Ie 1"5 are provided below:
  • 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.
  • cyclopropyl c-Pr
  • cyclobutyl cyclopentyl
  • cyclohexyl cycloheptyl
  • cyclooctyl bicyclo[2.2.2]octyl
  • bicyclo[2.2.1]heptyl 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. When substituted, an aryl group has 1-4 substituents. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl- substituted amido and N,N-dialkyl-substituted amido.
  • heteroaryl means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5- pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5-yl, lH-benzimidazol-6-yl, IH- benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl,
  • substituents for a substituted heteroaryl 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, and S.
  • heterocyclyls include pyrrolidine, 1 -methylpyrrolidine, pyrrolidin-2- one, l-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, l-(2,2,2-trifluoroethyl)piperazine, 1 ,2-dihydro-2- oxopyridine, l,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
  • Substitutable ring nitrogen atom refers to a ring nitrogen atom in a heteroaryl or heterocyclyl group that is bonded to a hydrogen atom.
  • the hydrogen atom can be replaced, i.e., substituted, with a substituent.
  • a “substitutable ring carbon atom” refers to a carbon atom in an aryl or cycloalkyl that is bonded to a hydrogen atom.
  • the hydrogen atom can be replaced, i.s., substituted, with a substituent.
  • 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. 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 “5" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "R*" and "£*” 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.
  • Tautomeric forms exist when a compound is a mixture of two or more structurally distinct compounds that are in rapid equilibrium. Certain compounds of the invention exist as tautomeric forms.
  • the following compound represented by Structural Formula (A) and (B) include at least the following tautomers forms:
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable 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
  • R D is alkyl or arylalkyl such as methyl, t-butyl or benzyl, with an organometallic reagent of Formula III wherein M includes, but is not limited to, MgCl, MgBr, MgI or Li:
  • organometallic reagent III is allylmagnesium bromide, allylzinc bromide, (2-methylallyl)magnesium chloride or (2-methoxy-2-oxoethyl)zinc bromide.
  • M is MgCl, MgBr or MgI, it is advantageous to add CeCl3 to the reaction mixture.
  • Ketocarbamates of Formula II can be prepared by reaction of aminoketones of Formula IV with intermediates of Formula V wherein R E is a leaving group such as chlorine, succinyloxy, imidazolyl or t-butoxycarboxycarbonyl:
  • Aminoketones of Formula IV wherein n is preferably but not necessarily 0, can be prepared by reaction of OC, ⁇ -unsaturated ketones of Formula V with amines of Formula VII:
  • aminoketones of Formula IV wherein n is preferably but not necessarily 0, can be prepared by reaction of ⁇ -dialkylaminoketones of Formula VI, wherein R F is lower alkyl especially methyl, with amines of Formula VII:
  • ⁇ -Dialkylaminoketones of Formula VI are in turn derived from ⁇ , ⁇ -unsaturated ketones of Formula V with dialkylamines of Formula R F NHR F .
  • organometallic allyl reagent of Formula IX wherein M includes, but is not limited to, MgCl, MgBr, MgI or Li to yield an allyl compound of Formula X.
  • organometallic reagent IX is allylmagnesium chloride, allylmagnesium bromide or allylzinc(II) bromide.
  • Allyl compound of Formula X is converted to the aldehyde of Formula XII by ozonolysis or by Os ⁇ 4 catalysed dihydroxylation followed by cleavage of the glycol of Formula XI by periodates like sodium periodate.
  • Aminocarbinol of Formula XIV can be prepared by reductive animation with an amine of Formula XIII using sodium cyanoborohydride or sodium triacetoxyborohydride as reducing agent.
  • Cyclisation of the aminocarbinol of Formula XIV to the compounds of Formula Ie 1 can be achieved by reacting with activated carbonic acid derivates such as phosgene, diphosgene, triphosgene or 1,1 '-carbonyl-diimidazol .
  • compounds of Formula (I) can be prepared from the reaction product of compounds represented by formulas II and III wherein Cy 1 is phenyl substituted with a leaving group such as bromine, for example, by using a "Suzuki"coupling reaction with Cy 2 - X [X is -B(OH) 2 ] as described in Example 111 of U.S. Provisional Patent Application No. 60/962,058, filed July 26, 2007. The entire teachings of this application are incorporated herein by reference.
  • a compound of Formula I can also be prepared by reaction of a halo compound, wherein Hal is chlorine or bromine, with an isocyanate in the presence of a base:
  • Halo compounds of this type can be prepared by reaction of ⁇ -haloketones with organometallic reagents R 3 -M, wherein M is a metal containing residue including MgCl, MgBr, MgI or Li.
  • the reaction is optionally carried out in the presence of anhydrous cerium trichloride:
  • the resulting solution was stirred at 0-5 0 C for 1 h and at ambient temperature for another 1.5 h.
  • the solution was poured into ice-cold half- saturated aqueous NH 4 Cl solution (150 mL). After addition of dichloromethane, the mixture was filtered through Celite which was extracted with an additional portion of dichloromethane. The organic phase was separated and washed with water and dried
  • the compound was obtained from [(5)-l-(4-bromo-phenyl)-ethyl]-(3,5-dihydroxy- 5-methyl-3-phenyl-hexyl)-carbamic acid methyl ester (mixture of two diastereomers) in a mixture with 3-[(5)-l-(4-bromo-phenyl)-ethyl]-(R)-6-(2-hydroxy-2-methyl-propyl)-6- phenyl-[l,3]oxazinan-2-one that was resolved into the pure diastereomers by chromatography as described above.
  • Methylamine (2 M in tetrahydrofuran, 11.4 mL) was added to a mixture of 4- bromo-2-fluoro-l-nitro-benzene (2.50 g) and K 2 CO3 (1.90 g) in N,N-dimethylformamide (40 mL). The resulting mixture was stirred at ambient temperature overnight. Then, the mixture was concentrated under reduced pressure and dichloromethane was added. The resulting mixture was washed with 0.5 M aqueous HCl solution and brine and dried (MgSO/i). The solvent was removed to give the product as a solid.
  • the resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and aqueous NaHCOs solution. After drying (MgSO 4 ) and removing the solvent, the residue was purified by chromatography on silica gel (CH 2 Cl 2 /MeOH/NH 4 OH 99:l :0.1->9:l :0.1) to afford the title compound.
  • N,N-Dimethylformamide (5 mL) was added to a flask charged with a stir bar, 3- [(5)-l-(4-bromo-phenyl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[l,3]oxazinan- 2-one (0.30 g), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridme-l- carboxylic acid tert-butyl ester (0.22 g), K 2 CO3 (0.29 g), and [l,l '-bis(diphenylphosphino)- ferrocene]-dichloropalladium(II) (57 mg) under argon atmosphere.
  • Trifluoroacetic acid (1 mL) was added to a flask charged with a stir bar and 1- cyclopropyl-4-(4-methoxy-benzyloxy)-lH-pyridin-2-one (0.17 g) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 1.5 h and at ambient temperature for another 4.5 h. Then, the solution was concentrated under reduced pressure and the residue was triturated with tert-butyl methyl ether and dried to give the title compound as a solid.
  • Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flask charged with a stir bar, l-cyclopropyl-4-hydroxy-lH-pyridin-2-one (0.10 g), NEt 3 (0.24 mL), and dichloromethane (8 mL) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 2 h and at ambient temperature for another 2 h. Then, the solution was diluted with dichloro-methane and washed in succession with water, aqueous NaHCO 3 solution, and water.
  • KO'Bu (0.68 g) was added to a solution of 5-bromo-lH-pyridin-2-one (1.00 g) in tetrahydrofuran (20 mL) at room temperature. After stirring for 30 min, cyclopropylmethyl bromide (0.77 mL) and N,N-dimethylformamide (3 mL) were added to the suspension and the resulting mixture was warmed to 70 0 C. After stirring the mixture at 70 0 C for 2 h, the reaction was finished. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2x 20 mL) and brine (20 mL).
  • NEt 3 (0.47 mL) and [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (0.15 g) were added to a solution of 3-[(5)-l-(4-bromo-phenyl)- ethyl]-(S ⁇ -6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[l,3]oxazinan-2-one (1.04 g) in MeCN (2.5 mL), methanol (20 mL), and N,N-dimethylformamide (5 mL).
  • Methyl iodide (0.9 mL) was added to a mixture of potassium carbonate (2.34 g) and 4-bromo-5-fluoro-lH-pyridin-2-one (2.50 g) in N,N-dimethylformamide (25 mL) at room temperature. The mixture was stirred at room temperature overnight and then water was added. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO/i). The solvent was evaporated to afford the crude title compound that was recrystallized from Et 2 O.
  • Trifluoroacetic acid (0.40 mL) was added to a solution of 4-(4- ⁇ (S)- ⁇ -[(S)-6-(2- hydroxy-2-methyl-propyl)-2-oxo-6-phenyl- [ 1 ,3 ] oxazinan-3 -yl] -ethyl ⁇ -phenyl)-piperidine- 1 - carboxylic acid tert-butyl ester (0.29 g) in dichloromethane (10 mL). The resulting solution was stirred at room temperature overnight. Then, more dichloromethane was added and the solution was neutralized using aqueous saturated NaHC ⁇ 3 solution. The organic phase was separated, washed with water, and dried (MgSO/i). The solvent was removed under reduced pressure to yield the title compound.
  • Triethylamine (0.10 mL), acetic anhydride (50 ⁇ L), and 4-dimethylaminopyridine (5 mg) were added consecutively to (5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(5)-l- (4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (0.12 g) dissolved in tetrahydrofuran (5 mL) at room temperature. The solution was stirred at room temperature for 4 h and then diluted with ethyl acetate. The resulting solution was washed with aqueous saturated NaHC ⁇ 3 solution and brine and dried (Na 2 SOz I ). After removal of the solvent, the residue was purified by chromatography on silica gel (CH 2 Cl 2 /Me0H 98:2->90:10) to afford the title compound as a colorless foam- like solid.
  • Acetic acid (27 ⁇ L) and NaHB(O 2 CCH 3 ) 3 (160 mg) were added to a solution of (S)- 6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(5 ⁇ )-l-(4-piperidin-4-yl-phenyl)-ethyl]- [l,3]oxazinan-2-one (200 mg) and formaldehyde (37% in water, 70 ⁇ L) in tetrahydrofuran (5 mL) at room temperature. After stirring the solution at room temperature overnight, ethyl acetate and 1 M aqueous NaOH solution were added and the resulting mixture was stirred for another 10 min.
  • Example 24 fS)-6-f2-Hvdroxy-2-methyl-propyn-6-phenyl-3-ffS)-l- ⁇ 4-ri-ffR)-tetrahvdro-furan- 2-carbonyl)-piperidin-4-yll-phenyl ⁇ -ethyl)-! " ! ,31oxazinan-2-one
  • Triphosgene (157 mg) was added to an ice-cold solution of 4-[(S)-l-(4-bromo- phenyl)-ethylamino]-l-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 (MeCNZH 2 OZNH 3 ) to afford the title compounds in separate fractions.
  • Example 31 3-[(S)-I -(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl- [l,3]oxazinan-2-one: Yield: 45 mg (21% of theory).
  • Mass spectrum (ESI + ): m/z 404 [M+H] + .
  • 1 H NMR (400 MHz, OMSO-d 6 ) ⁇ 1.20 (d, J 7.2 Hz, 3H), 2.13-2.23 (m, IH),
  • Example 36 4-ffS)-4- ⁇ l-rfS)-6-f2-Hvdroxy-2-methyl-propyn-2-oxo-6-phenyl- ⁇ .31oxazinan-3- yli-ethyll-phenyiypiperidine-l-carboxylic acid dimethylamide
  • Dimethylcarbamoyl chloride (26 ⁇ L) was added to a solution of (5)-6-(2-hydroxy- 2-methyl-propyl)-6-phenyl-3-[(5)-l-(4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (120 mg) and pyridine (40 ⁇ L) in N,N-dimethylformamide (2 mL) at room temperature.
  • the solution was stirred at room temperature for 5 h, before another portion of dimethylcarbamoyl chloride (26 ⁇ L) and pyridine (20 ⁇ L) were added.
  • the solution was stirred at room temperature overnight.
  • diluted aqueous ammonia solution was added and the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by HPLC on reversed phase (MeOH/H 2 O/NH3) to afford the title compound.
  • Step 3 To a solution of 2-(2-isopropyl-l,3-dioxolan-2-yl)-ethanol (8.0 g, 50 mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH 2 Cl 2 (120 mL) was added methanesulfonyl chloride (11.6 mL , 150 mmol) at 0 0 C, and the reaction mixture was stirred at room temperature till the reaction was finished.
  • Tetrahydrofuran (300 mL) was added, more solution of 3-chloro-2-methylprop-l-ene (15 mL) in tetrahydrofuran (20 mL) was dropped into the reaction at 0 0 C under N 2 over 30 min.
  • the reaction mixture was stirred at room temperature for 2 h.
  • the reaction was cautiously quenched with saturated aqueous NH 4 Cl, and the reaction mixture was filtered.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the incubation period for detection reaction was typically 2 hours.
  • the amount of Cortisol is 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 is 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.
  • the assay begins by dispensing 49 ⁇ l of substrate solution (5OmM HEPES, pH 7.4, 10OmM KCl, 5mM NaCl, 2mM MgCl 2 , 2 mM NADPH and 160 nM [ 3 H]cortisone (1 Ci/mmol)) and mixing in 1 ⁇ L of the test compounds in DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre- incubation, 50 ⁇ L of enzyme solution containing microsomes isolated from CHO cells overexpressing human l l ⁇ -HSDl (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 KCl, 5mM NaCl, 2mM MgCl 2 , 2 mM NADPH and 160 nM [ 3 H]cortisone (1 Ci/mmol)
  • the reaction was stopped by adding 50 ⁇ l of the SPA beads suspension containing 10 ⁇ M 18- ⁇ - glycyrrhetinic acid 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 ⁇ g/ml of anti-cortisol antibody (East Coast Biologies) in Superblock buffer (Bio-Rad).
  • the plates were shaken for 120 minutes at rt, and the SPA signal corresponding to [ 3 H] Cortisol was measured on a Microbeta plate reader.
  • the compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state.
  • the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome, infertility and hypergonadism.
  • the compounds 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 ⁇ -HSD 1 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 ⁇ -HSD 1 activity is pseudo Cushing's Syndrome associated with alcoholic liver disease.
  • a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I, comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore.
  • a pharmaceutical composition of the invention may comprise a compound of Formula I, Ia-I or a pharmaceutical salt thereof as the only pharmaceutically active agent in the pharmaceutical composition.
  • the disclosed 11 ⁇ -HSD 1 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 ⁇ -HSD 1 inhibitors.
  • Said compositions contain compounds having a mean inhibition constant (IC 5 o) against 11 ⁇ -HSD 1 of below about 1,000 nM; preferably below about 100 nM; more preferably below about 50 tiM; 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 11 ⁇ - HSDl mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof of composition thereof.
  • 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.
  • An embodiment of the invention includes administering an l l ⁇ -HSDl inhibiting compound of Formula I or composition thereof in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma.
  • Agents for the treatment of diabetes include insulins, such as Humulin® (Eli 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
  • 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 l l ⁇ -HSDl inhibiting compound of Formula I or composition thereof in a combination therapy with one or more other l l ⁇ -HSDl inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); and Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb).
  • Avandamet® metalformin HCl and rosiglitazone maleate, GSK
  • Avandaryl® glimepiride and rosiglitazone maleate, GSK
  • Metaglip® glipizide and metformin HCl,
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered intranasally or transdermally. 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.
  • 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.

Abstract

This invention relates to novel compounds of the Formula (I), (Ia1-10), (Ib1-10), (Ic1-10), (Id1-7), (Ie1-5) 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

INHIBITORS OF l lbeta-HYDROXYSTEROID DEHYDROGENASE 1
FIELD OF THE INVENTION
The present invention relates to inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 (1 lβ-HSDl), pharmaceutical compositions thereof and methods of using the same.
BACKGROUND OF THE INVENTION
Glucocorticoids, such as Cortisol (hydrocortisone), are steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism, and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate Cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.
Until recently, the major determinants of glucocorticoid action were attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic -pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues. Recently, a fourth determinant of glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 1 lβ- hydroxysteroid dehydrogenase (l lβ-HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 1 lβ-HSDl (also known as 11-beta-HSD type 1, l lbetaHSDl, HSDI lBl, HDL, and HSDl IL) and 11 β-HSD2. 1 lβ- HSDl 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. 11 β-HSDl is widely distributed in rat and human tissues; expression of the enzyme and corresponding mRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium. In adipose tissue, increased Cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity. In the eye, 11 β-HSD 1 may regulate intraocular pressure and may contribute to glaucoma; some data suggest that inhibition of 11 β-HSD 1 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 11 β-HSD 1 catalyzes both 11 -beta-dehydrogenation and the reverse 11 -oxoreduction reaction, 11 β-HSD 1 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, 1 lβ-HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines. 1 lβ-HSD2 acts as an NAD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston et al. (1994) MoI. Cell. Endocrin. 105: Rl 1 -Rl 7), 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-HSD 1 or the 11 β-HSD2 genes result in human pathology. For example, individuals with mutations in 11 β-HSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as "SAME") characterized by hypertension, hypokalemia, and sodium retention (Edwards et al. (1988) Lancet 2: 986-989; Wilson et al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in 1 lβ-HSDl and in the gene encoding a co-localized NADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD); these individuals present with ACTH-mediated androgen excess (hirsutism, menstrual irregularity, hyperandrogenism), a phenotype resembling polycystic ovary syndrome (PCOS) (Draper et al. (2003) Nat. Genet. 34: 434-439).
Notably, disruption of homeostasis in the HPA axis by either deficient or excess secretion or action results in Cushing's syndrome or Addison's disease, respectively (Miller and Chrousos (2001) Endocrinology and Metabolism, eds. Felig 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 1 lβ-HSDl activity plays an important role in obesity and metabolic syndrome (Bujalska et al. (1997) Lancet 349: 1210-1213); (Livingstone et al. (2000) Endocrinology 131 : 560-563; Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al. (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin. Endocrinol. Metab. 88: 3983- 3988).
Data from studies in mouse transgenic models supports the hypothesis that adipocyte 1 lβ-HSDl activity plays a central role in visceral obesity and metabolic syndrome (Alberts et al. (2002) Diabetologia. 45(11): 1526-32). Over- expression in adipose tissue of 1 lβ-HSDl under the control of the aP2 promoter in transgenic mice produced a phenotype remarkably similar to human metabolic syndrome (Masuzaki et al. (2001)
Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). Moreover, the increased activity of 11 β-HSDl in these mice is very similar to that observed in human obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421). In addition, data from studies with 1 lβ-HSDl -deficient mice produced by homologous recombination demonstrate that the loss of 1 lβ-HSDl leads to an increase in insulin sensitivity and glucose tolerance due to a tissue-specific deficiency in active glucocorticoid levels (Kotelevstev et al. (1997) Proc. 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 1 lβ-HSDl contributes to increased local conversion of cortisone to Cortisol in adipose tissue and hence that 1 lβ-HSDl plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17). Therefore, 1 lβ- HSDl is a promising pharmaceutical target for the treatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore, inhibition of 11 β-HSDl activity may prove beneficial in treating numerous glucocorticoid-related disorders. For example, 1 lβ-HSDl 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 1 lβ-HSDl 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 1 lβ-HSDl could reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression. Notably, it is known that stress and glucocorticoids influence cognitive function (de Quervain et al. (1998) Nature 394: 787-790); and it has been shown that 11 β- HSDl, 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 1 lβ-HSDl play a role in regulation of in intra-ocular pressure (IOP) (Stokes et al. (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042); if left untreated, elevated IOP can lead to partial visual field loss and eventually blindness. Thus, inhibition of 1 lβ-HSDl in the eye could reduce local glucocorticoid concentrations and IOP, and 1 lβ-HSDl hence could potentially be used to treat glaucoma and other visual disorders.
Transgenic aP2-l lβHSDl 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 II and aldosterone; and treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). This suggests that hypertension may be caused or exacerbated by 11 β- HSDl activity. Thus, 1 lβ-HSDl inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders. Inhibition of 11 β-HSDl 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, 1 lβ-HSDl has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper et al. (2000) Bone 27: 375-381), and the 1 lβ-HSDl inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23: 119-125). Thus, inhibition of 1 lβ-HSDl is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis. 1 lβ-HSDl inhibitors may also be useful for immunomodulation. Although glucocorticoids are perceived to suppress the immune system, in actuality, there is a complex, dynamic interaction between the HPA axis and the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13: 576-581). Glucocorticoids play a role in modulating the balance between cell-mediated and humoral immune response, with high glucocorticoid activity normally associated with a humoral response. Inhibition of 11 β- HSDl therefore can be used a means of shifting the immune response towards a cell- mediated response. Certain disease states, such as tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune responses that are biased towards a humoral response whereas the more effective immune response may be a cell-mediated response. Hence, 1 lβ-HSDl inhibitors may be useful for treating such diseases.
It has been reported that glucocorticoids inhibit wound healing, especially in diabetic patients with ulcers (Bitar et al. (1999) J. Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar (2000) Surgery 127: 687-695; Bitar (1998) Am. J. Pathol. 152: 547-554). Patients that exhibit impaired glucose tolerance and/or type 2 diabetes often also have impaired wound healing. Glucocorticoids have been shown to increase the risk of infection and delay wound healing (Anstead (1998) Adv. Wound Care 11 :277-285). Moreover, there is a correlation between elevated levels of Cortisol in wound fluid and non-healing wounds (EP Patent App. No. 0 902 288). Recent published patent applications have suggested that certain 1 lβ-HSDl 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 1 lβ-HSDl . The novel compounds of the instant invention are effective inhibitors of l lβ-HSDl. SUMMARY OF THE INVENTION It has now been found that compounds of Formula I or pharmaceutically acceptable salts or prodrugs thereof, are effective inhibitors of 11 β-HSDl . In a first embodment, the invention is a compound represented by Formula I:
Figure imgf000007_0001
wherein variables are defined herein as follows:
R1 is (a) absent or (b) is selected from (CrC6)alkyl, (CrC6)cycloalkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C3)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)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) (Ci-C3)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(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(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, (Ci- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylammo, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-
C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylammo, (Ci-C6)alkyl- sulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Cr 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, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-
Ce)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, ((C3- C6)cycloalkyl} {(Ci-C6)alkyl} aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-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(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci- C6)alkyl; Cy2 is benzimidazolyl, benzotriazolyl and piperidinyl 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(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, (Cr
Ce)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)CyC loalkylalkoxy, 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)alkanesulfmyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfmyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylammosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylammo, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci- C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(d-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(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, hydroxy(Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(d- 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, (Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl} {(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(d-
C6)alkyl; wherein the piperidinyl represented by Cy1 is attached to Cy1 through a ring carbon atom. In another embodiment, when Cy is piperidinyl, oxo is also a possible substituent. Alternatively, when R is methoxymethyl, Cy is (a) halogen or -O-SO3-R or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, 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, (C3-C7)cycloalkyl(Ci-C2)alkyl, (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(C3-C7)cycloalkyl(Ci-C2)alkyl, (C1-
Ce)alkoxy, (C3-C6)cycloalkoxy, (C3-C7)cycloalkyl(Ci-C2)alkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C7)cycloalkyl(Ci-C2)alkoxy, (CrC6)alkylthio, (C3- C6)cycloalkythio, (C3-C7)cycloalkyl(CrC2)alkylthio, halo(CrC6)alkylthio, halo(C3- C6)cycloalkythio, halo(C3-C7)cycloalkyl(CrC2)alkylthio, (Ci-C6)alkanesulfinyl, (C3- C6)cycloalkanesulfmyl, (C3-C7)cycloalkyl(Ci-C2)alkanesulfinyl, halo(d-
C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfmyl, halo(C3-C7)cycloalkyl(d- C2)alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C3- C7)cycloalkyl(Ci-C2)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C3-C7)cycloalkyl(Ci-C2)alkanesulfonyl, (Ci- C6)alkylamino, di(d-C6)alkylamino, (d-C6)alkoxy(d-C6)alkoxy, halo(Cr
C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (C1- C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cr
C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cp C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylammo, (Ci-C6)alkyl- carbonylamino(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(Cr
C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Cp 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, (Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl} {(Cr C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(d-
C6)alkyl;
Y is (Ci-C6)alkyl, halo(CrC6)alkyl or oxo; n is 0, 1 or 2; E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl 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(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, (Cr Ce)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(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Cr C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkyl- aminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkyl- aminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)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(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, (Cr C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(d-
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, (Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl} ((C1-
C6)alkyl} aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(d- 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 (Ci-C3)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
(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), aryl- amino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and R4 is independently selected from H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, amino(Ci-C6)alkyl,
(Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl and (Ci-C6)alkoxy(Ci-C6)alkyl; and R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl Or NO2; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. '
In a second embodment, the invention is a compound represented by Formula I
, wherein variables are defined herein as follows:
R1 is (a) absent or (b) is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C3)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)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) (Ci-C3)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(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)alkanesulfmyl, (C3- C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylammo, (Ci-C6)alkyl- sulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Cr 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, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylammo(C2- Ce)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3- C6)cycloalkyl} {(Ci-C6)alkyl}ammosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-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(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci- C6)alkyl;
Cy is benzimidazolyl, benzotriazolyl and piperidinyl 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(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, (Cr Ce)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(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-
C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO,
H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Cr
C6)alkoxy(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(Cr C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, ((C3- C6)cycloalkyl} {(Ci-C6)alkyl} aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylammocarbonyl(Ci- C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl} {(Cr
C6)alkyl} aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(d- Ce)alkyl; wherein the piperidinyl represented by Cy1 is attached to Cy1 through a ring carbon atom. In another embodiment, when Cy is piperidinyl, oxo is also a possible substituent. Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -0-SO3-R or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, 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, (C3-C7)cycloalkyl(CrC2)alkyl, (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(C3-C7)cycloalkyl(CrC2)alkyl, (Cr Ce)alkoxy, (C3-C6)cycloalkoxy, (C3-C7)cycloalkyl(Ci-C2)alkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C7)cycloalkyl(CrC2)alkoxy, (CrC6)alkylthio, (C3- C6)cycloalkythio, (C3-C7)cycloalkyl(CrC2)alkylthio, halo(CrC6)alkylthio, halo(C3- C6)cycloalkythio, halo(C3-C7)cycloalkyl(CrC2)alkylthio, (Ci-C6)alkanesulfmyl, (C3-
C6)cycloalkanesulfinyl, (C3-C7)cycloalkyl(Ci-C2)alkanesulfinyl, halo(Cr C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C3-C7)cycloalkyl(d- C2)alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C3- C7)cycloalkyl(Ci-C2)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C3-C7)cycloalkyl(Ci-C2)alkanesulfonyl, (Ci- C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-
C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Cr C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Cr C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cp C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-
C6)alkyl, (CrC6)alkoxycarbonyl(Ci-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(Cr C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci- C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} ((Cr
C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl} {(Cr
C6)alkyl} aminocarbonyl(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(d- C6)alkyl;
Y is (Ci-C6)alkyl, halo(CrC6)alkyl or oxo; n is 0, 1 or 2; E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R 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(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, (Cr Ce)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(Ci-C6)alkanesulfmyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci- C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4-C7)cyclo- alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (CrC6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-
C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci- C6)alkoxy(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(Cr C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl} aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, ((C3- C6)cycloalkyl} {(Ci-C6)alkyl} aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylammocarbonyl(Ci-
C6)alkyl, di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, {(C3-C6)cycloalkyl} {(Cr 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(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-, 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), aryl- amino (which in turn may be optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and heteroarylamino (which in turn may be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N- monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo); and R4 is independently selected from H, (Ci-C6)alkyl, halo(Ci-C6)alkyl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl and (Ci-C6)alkoxy(Ci-C6)alkyl; and R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C^alkyl Or NO2; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is a method of inhibiting 1 lβ-HSDl activity comprising the step of administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 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 1 lβ-HSDl, comprising the step of administering to the subject an effective amount of a compound of Formulas I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Another embodiment of the invention is the use of a compound of Formulas I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the manufacture of a medicament for inhibiting 11 β-HSDl activity in a mammal in need of such treatment. Another embodiment of the invention is the use of a compound of Formulas I, Ia1"10,
Ib1"10, Ic1"10, Id1"7 or Ie1"5 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-HSDl .
Another embodiment of the invention is a compound of Formulas I, Ia1"10, Ib1"10, Ic1" 10, Id1"7 or Ie1 5Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for use in inhibiting 11 β-HSDl activity in a mammal in need of such treatment. Another embodiment of the invention is a compound of Formulas I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 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 l lβ-HSDl. Another embodiment of the present invention is a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) compound of Formulas I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 or a pharmaceutically acceptable salt, enantiomer or diastereomer, thereof.
DETAILED DESCRIPTION OF THE INVENTION
In a third embodiment, the variables in Formula I:
R1 is (a) absent or (b) (Ci-C6)alkyl or (Ci-C6)cycloalkyl 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)2NS(=O)2NR4- and R4S(=O)2NR4-. A1 is (a) a bond, (b) (CrC2)alkylene, or (c) CH if R1 is present, n is O.
E is a bond or CH2.
R 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(Ci-C6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, halo(d-C6)alkyl, (CrC6)alkoxy, (C3- C6)cycloalkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cr
C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino and oxo.
R3 is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C5)cycloalkyl(Ci-C4)alkyl, (Ci-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-, R4S-, (R4)2N-, R4OCR4 2CR4 2NR4-, R4OCR4 2C(=O)NR4-, R4OCR4 2CR4 2O-, 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)2NS(=O)2NR4-, R4S(=O)2NR4-, R4 2NS(=O)2O-, (R4O)2P(=O)O-, R4 2NCR4 2C(=O)NR4-, N(R4)2C(=NC≡N)NR4-, R4S(=O)2NR4C(=O)-, imidazolylamino-, imidazolyl, tetrazolyl, 4-morpholino, azetidinyl, pyrrolidinyl, fluoropyrrolidinyl, oxopiperazinyl, 1 ,dioxoisothiazolidinyl, methylimidazolyl, methyloxadiazolyl, methylthiadiazolyl and (l-hydroxycyclopropy^methyl. Alternatively, R is methoxymethyl.
R4 is independently selected from H, (Ci-C6)alkyl and halo(Ci-C6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined above for the first or second embodiment of Formula (I). In a fourth embodiment, the variables in Formula I:
R1 is (a) absent or (b) (Ci-C6)alkyl 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)2NS(=O)2NR4- and R4S(=O)2NR4-.
A is (a) a bond, (b) (CrC2)alkylene, or (c) CH if R is present, n is 0.
E is a bond or CH2. 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(Ci-C6)alkyl, (C3- C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, halo(CrC6)alkyl, (CrC6)alkoxy, (C3- C6)cycloalkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Cr C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkyl- carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino and oxo.
R3 is selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C5)cycloalkyl(Ci-C4)alkyl, (C1-C3)alkoxy(C1-C3)alkoxy, or (C1-C3)alkoxy(C1-C3)alkyl and is optionally substituted with up to four groups independently selected from fluorine, cyano, oxo, R4, R4O-, R4S-, (R4)2N-, R4OCR4 2CR4 2NR4-, R4OCR4 2C(=O)NR4-, R4OCR4 2CR4 2O-, 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)2NS(=O)2NR4-, R4S(=O)2NR4-, R4 2NS(=O)2O-, (R4O)2P(=O)O-, R4 2NCR4 2C(=O)NR4-, N(R4)2C(=NC≡N)NR4-, R4S(=O)2NR4C(=O)-, imidazolylamino-, imidazolyl, tetrazolyl, 4-morpholino, azetidinyl, pyrrolidinyl, fluoropyrrolidinyl, oxopiperazinyl, 1 ,dioxoisothiazolidinyl, methylimidazolyl, methyloxadiazolyl, methylthiadiazolyl and (l-hydroxycyclopropyl)methyl.
Alternatively, R3 is methoxymethyl. R4 is independently selected from H, (d-C6)alkyl and halo(Ci-C6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined above for the first or second embodiment of Formula (I).
In a fifth embodiment, the variables in Formula I or any one of Formulas Ial lo-Ie1 5 are as defined in the following paragraphs:
R1 is absent or is methyl, ethyl or cyclopropyl. A1 is a bond or CH2 or CH when R1 is present.
Cy1 is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl each optionally substituted with 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(d- C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(Ci-C2)alkyl, hydroxy(C3-C6)cycloalkyl, halo(Ci-C6)alkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, halo(CrC6)alkoxy, (Ci- C6)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci- C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci- C6)alkylaminocarbonyl(C i -C6)alkyl and di(C i-C6)alkylaminocarbonyl(C i -C6)alkyl.
Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 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, (C3-C6)cycloalkyl(Ci-C2)alkyl, hydroxy(C3-C6)cycloalkyl, halo(d-C6)alkyl, (d- Ce)alkoxy, (C3-C6)cycloalkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(d- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (C1- C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci-C6)cycloalkylcarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkylcarbonyl, hydroxy(d- C6)alkylcarbonyl, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl, (Ci- C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl and di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl. Alternatively, when Cy2 is piperidinyl, oxo is also a possible substituent.
Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -0-SO3-R , or (b) cycloalkyl, aryl, heterocyclyl, heteroaryl, optionally substituted by 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, (C3-
C6)cycloalkyl(Ci-C2)alkyl, hydroxy(C3-C6)cycloalkyl, halo(d-C6)alkyl, (d-C6)alkoxy, (C3-C6)CyClOaIkOXy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (C1- C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci- C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci- C6)alkoxycarbonyl, (Ci-C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(Cr C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl and di(Ci-C6)alkylaminocarbonyl(Ci- C6)alkyl.
R is methyl, ethyl, propyl, phenyl, thienyl or pyridyl each optionally substituted with halo, cyano, CONH2, (CrC4)alkyl, (CrC4)haloalkyl, and SO2Me.
R 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(=0)2NH-, H2NCC=O)-, MeNHC(=0)-, HO2C-, (HO)2PC=O)O-, H2NS(=O)2O-, H2NS(=O)2NH-, MeNHC(=0)NH-, MeNHC(=0)0-, oxo, cyano, HO2C-, HOCH2CH2NH-, 4-morpholino, H0CH2C(=0)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH, Me0C(=0)NH-, MeNHC(=NC≡N)NH-, Me-, MeS-, MeSO2- MeSO2N(Me)-, MeS(=0)2NHC(=0)-, imidazolylamino-, imidazolyl, tetrazolyl, H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH-, Me2N-, MeCON(Me)-, 2-fluoroethylamino, azetidinyl, pyrrolidinyl, 3-fluoropyrrolidinyl, 3-oxopiperazinyl, l,l-dioxoisothiazolidin-2-yl, 5-methyl- lH-imidazol-2-yl, 5-methyl-l,3,4-oxadiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, EtOC(=O)NH-, fluoro or (l-hydroxycyclopropyl)methyl. Alternatively, R is methoxymethyl.
R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C^alkyl Or NO2; Pharmaceutically acceptable salts, enantiomers or diastereomers thereof are also included; and values for the remaining variables are as defined for Formula (I) and for first, second, third or fourth embodiment.
In a sixth embodiment, the variables of Formula I or any one of Formulas Ial lo-Ie1 5 are as defined in the following paragraphs: R1 is absent or is methyl or ethyl.
A1 is a bond or CH2 or CH when R1 is present.
Cy1 is phenyl, cyclohexyl, pyridyl, N-oxo-pyridyl, thiazolyl or pyrimidinyl each 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, (C3-C6)cycloalkyl(CrC2)alkyl, hydroxy(C3-C6)cycloalkyl, halo(Ci-C6)alkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, halo(d-C6)alkoxy, (d- C6)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-
C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci- C6)alkylaminocarbonyl(C i -Ce)alkyl and di(C i-C6)alkylaminocarbonyl(C i -C6)alkyl.
Cy2 is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 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, (C3-C6)cycloalkyl(Ci-C2)alkyl, hydroxy(C3-C6)cycloalkyl, halo(CrC6)alkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(d- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (C1- C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci- C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-
C6)alkylcarbonylamino, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci- C6)alkoxycarbonyl, (Ci-C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(d- C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl and di(Ci-C6)alkylaminocarbonyl(Ci- C6)alkyl. Alternatively, when Cy2 is piperidinyl, oxo is also a possible substituent. Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -0-SO3-R , or (b) cycloalkyl, aryl, heterocyclyl, heteroaryl, optionally substituted by 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, (C3- C6)cycloalkyl(Ci-C2)alkyl, hydroxy(C3-C6)cycloalkyl, halo(d-C6)alkyl, (d-C6)alkoxy, (C3-C6)cycloalkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (d-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(d- C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl, (Ci- C6)alkylsulfonylamino, oxo, cyano(Ci-C6)alkyl, aminocarbonyl(d-C6)alkyl, (Ci- C6)alkylaminocarbonyl(C i -Ce)alkyl and di(C i-C6)alkylaminocarbonyl(C i -C6)alkyl.
R2 is phenyl, thienyl or pyridyl each optionally substituted with halo, cyano, CONH2, (Ci-C4)alkyl, (CrC4)haloalkyl, and SO2Me.
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(=0)2NH-, H2NCC=O)-, MeNHC(=0)-, HO2C-, (HO)2PC=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-, MeCON(Me)-, 2-fluoroethylamino, azetidinyl, pyrrolidinyl, 3-fluoropyrrolidinyl, 3-oxopiperazinyl, l,l-dioxoisothiazolidin-2-yl, 5-methyl- lH-imidazol-2-yl, 5-methyl-l,3,4-oxadiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, EtOC(=O)NH-, fluoro or (l-hydroxycyclopropy^methyl. Alternatively, R is methoxymethyl. R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl Or NO2;
Pharmaceutically acceptable salts, enantiomers or diastereomers thereof are also included; and values for the remaining variables are as defined for first second, third or fourth embodiment.
In a seventh embodiment, the variables in Formula I or any one of Formulas Ia1"10- Ie1"5 are as defined in the following paragraphs:
Cy1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl, pyrimidinyl, piperidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, nitro, (Ci-C4)alkyl, (Ci-C4)haloalkyl, trifluoromethyl, hydroxy, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl, methylsulfonylamino, trifluoromethoxy and 2,2,2- trifluoroethoxy.
Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, (CrC4)alkoxy, (C1- C4)haloalkoxy, (Ci-C4)alkanesulfonyl, (Ci-C4)alkyloxycarbonyl, (Ci-C4)alkylcarbonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-
C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (Ci-C4)alkylcarbonylamino and (Ci- C4)haloalkyl. Alternatively, when Cy2 is piperidinyl, oxo is also a possible substituent. Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -O-SO3-R; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, CpC4 alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl and (Ci-C4)alkylcarbonylamino and C1-C4 haloalkyl; and
R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl or NO2; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined for first second, third, fourth, fifth or sixth embodiment..
In a eighth embodiment, the variables in Formula I or any one of Formulas Ia1 ^-Ie1" 5 are as defined in the following paragraphs:
Cy1 is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, pyridyl, N-oxo-pyridyl, thiazolyl, pyrimidinyl, piperidinyl, each optionally substituted with 1 to 4 groups independently selected from halo, nitro, (Ci-C4)alkyl, (Ci-C4)haloalkyl, trifluoromethyl, hydroxy, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, methoxycarbonyl, carboxy, ethoxycarbonylmethoxy, 2-hydroxy-2-methylpropoxy, cyano, difluoromethoxy, t- butoxycarbonyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, methoxymethyl, methylsulfonyl, methylsulfonylamino, trifluoromethoxy and 2,2,2- trifluoroethoxy.
Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, (CrC4)alkoxy, (C1- C4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (Ci- C4)alkylcarbonylamino and (Ci-C4)haloalkyl. Alternatively, when Cy2 is piperidinyl, oxo is also a possible substituent. Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -O-SO3-R; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, cyano, hydroxy, amino, C1-C4 alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl and (Ci-C4)alkylcarbonylamino and C1-C4 haloalkyl; and
R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl Or NO2; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. Values for the remaining variables are as defined for first second, third, fourth, fifth or sixth embodiment. In a ninth embodiment, the variables Formula I or any one of Formulas Ial lo-Ie1 5 are as defined in the following paragraphs:
Cy2 is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from (Ci-C6)alkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl(Ci-C2) alkyl, (Ci-C4)alkanesulfonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C4)alkylaminocarbonyl, di(Cr C4)alkylaminocarbonyl, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl. Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -O-SO3-R , wherein R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl or Nθ2;or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl optionally substituted by 1 to 4 groups independently selected from (Ci-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C2) alkyl, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein values for the remaining variables are as defined for first second, third, fourth, fifth, sixth seventh or eighth embodiments.
In a tenth embodiment, the variables in Formula I or any one of Formulas Ial lo-Ie1 5 are as defined in the following paragraphs:
Cy is benzimidazolyl, benzotriazolyl and piperidinyl each optionally substituted by 1 to 4 groups independently selected from (Ci-C6)alkyl, (C3-C7)cycloalkyl, (C3-
C7)cycloalkyl(Ci-C2) alkyl, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (Ci- C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl. Alternatively, when R3 is methoxymethyl, Cy2 is (a) halogen or -O-SO3-R , wherein R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl or Nθ2;or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl optionally substituted by 1 to 4 groups independently selected from (Ci-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C2) alkyl, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (Ci-C4)alkylcarbonyl, (Ci- C4)alkoxycarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein values for the remaining variables are as defined for first second, third, fourth, fifth, sixth seventh or eighth embodiments.
Another embodiment of the invention is a compound of any one of Formulas Ia1"10 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; or of any one of Formulas Iba1"10 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
In Formulas Ia1"10 and Ib1"10, the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, (CrC4)alkylcarbonyl, (C1- C4)alkoxycarbonyl or (Ci-C4)haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (C1- C4)haloalkoxy, (Ci-C4)alkanesulfonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl, (Ci- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino. Suitable values for the remainder of the variables are as defined in any one of the first, second, third, fourth fifth, sixth, seventh eighth ninth or tenth embodiments.
In another embodiment in Formulas Ia1"10 and Ib1"10, the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, (C1- C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl or (Ci-C4)haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, halo(CrC4)alkyl, (Cr C4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylcarbonyl, (CrC4)alkoxycarbonyl, (C1- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino. Suitable values for the remainder of the variables are as defined in any one of the first, second, third, fourth fifth, sixth, seventh eighth ninth or tenth embodiments.
For each of the embodiments described in the previous two paragraphs, R1 is preferably methyl or ethyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Ib1"10, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2 -hydroxy ethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is 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 -hydroxy ethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl. Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, 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.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is 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.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R 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.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, and (Ci-C4)alkyl,; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R is phenyl optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano, and (Ci-C4)alkyl,; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, 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, (Cl-C4)haloalkyl and SO2Me; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl. For each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, 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 two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl; substitutable ring nitrogen atoms in the benzimidazolyl and benzotriazolyl rings in Formulas Ib1 10 are optionally substituted with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C2)haloalkyl; substitutable ring nitrogen atoms in the piperidinyl rings in Formulas Ib1"10 are optionally substituted with (Ci-C2)alkanesulfonyl, hydroxy(Ci-C3)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci- C2)alkylaminocarbonyl, di(Ci-C2)alkylaminocarbonyl, (Ci-C2)alkylcarbonyl or (Ci-C2)alkyl; and one or two substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ia1"10 and Ib1"10 are optionally substituted with methyl or ethyl; and one substitutable ring carbon atoms in piperidinyl rings in Formulas Ia1"10 and Ib1"10 is optionally substituted with oxo;
For each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; substitutable ring nitrogen atoms in the benzimidazolyl and benzotriazolyl rings in Formulas Ib1"10 are optionally substituted with (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, or (Ci-C2)haloalkyl; and one or two substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ia1"10 and Ib1"10 are optionally substituted with methyl or ethyl; For each of the embodiments described in the two paragraphs immediately following Formulas Ia1"10 and Formulas Ib1"10, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylprop >yyll or 2-cyano-2-methylpropyl; substitutable ring nitrogen atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ib1"10 are optionally substituted with (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci- C2)alkyl, or (Ci-C2)haloalkyl; and one or two substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ia1"10 and Ib1"10 are optionally substituted with methyl or ethyl.
Another embodiment of the invention is a compound of any one for Formulas Ic1"10, or a pharmaceutically acceptable salt thereof:
Figure imgf000031_0001
Figure imgf000032_0001
In Formulas Ic " , the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (Ci-C4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, (CrC4)alkylcarbonyl, (CrC4)alkoxycarbonyl or (Ci-C4)haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, (Cr C4)alkanesulfonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci- C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl, (Ci-C^alkylaminocarbonyl, di(Cr
C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino. Suitable values for the remainder of the variables are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh eighth ninth or tenth embodiments.
For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2 -hydroxy ethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is 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.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (Cp 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.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, and (Ci- C4)alkyl,; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. For each of the embodiments described in the paragraph immediately following
Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; substitutable ring nitrogen atoms in the benzimidazolyl and benzotriazolyl rings in Formulas Ic1"10 are optionally substituted with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, or (CrC2)haloalkyl; substitutable ring nitrogen atoms in the piperidinyl rings in Formulas Ic1"10 are optionally substituted with (Ci-C2)alkanesulfonyl, hydroxy(Ci-C3)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C2)alkylaminocarbonyl, di(Cr C2)alkylaminocarbonyl, (Ci-C2)alkylcarbonyl or (Ci-C2)alkyl; and one or two substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ic1"10 are optionally substituted with methyl or ethyl; and one substitutable ring carbon atoms in piperidinyl rings in Formulas Ic1"10 is optionally substituted with oxo; Alternatively in Formulas Ic1"10, the benzimidazolyl, benzotriazolyl and piperidinyl rings are optionally substituted at each substitutable ring nitrogen atom with (Ci-C4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, (CrC4)alkylcarbonyl, (CrC4)alkoxycarbonyl or (Ci-C4)haloalkyl and optionally substituted at each substitutable ring carbon atom with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl, (Ci-C4)alkylaminocarbonyl, di(Cp C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; each G1 is independently halogen, cyano, oxo, nitro, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(d- C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, (CrC4)alkoxycarbonyl, benzoxycarbony, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (C3- C4)cycloalkylaminocarbonyl, {(Ci-C4)alkyl} {(C3-C4)cycloalkyl}aminocarbonyl and (Ci- C4)alkylcarbonylamino; r is O, 1 or 2; and suitable values for the remainder of the variables are as defined in any one of the first, second, third, fourth or fifth, embodiments. Alternatively, oxo is also a possible substituent for the piperidinyl group in Formulas Ic3, 1C840.
For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl. Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2 -hydroxy ethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl. Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (d-C4)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.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (d-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.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, 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, (Ci- C4)haloalkyl and SO2Me; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ic1"10 , R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; substitutable ring nitrogen atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ic1"10 are optionally substituted with (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(CrC2)alkyl, or (C1-C2 )haloalkyl; and one or two substitutable ring carbon atoms in the benzimidazolyl, benzotriazolyl and piperidinyl rings in Formulas Ic1"10 are optionally substituted with methyl or ethyl. Another embodiment of the invention is a compound represented by any one of Formulas Id1"7, or a pharmaceutically acceptable salt thereof:
Figure imgf000035_0001
In Formulas Id1, Id2, Id6 and Id7, G1 is (CrC4)alkyl, (CrC4)alkoxy, (C1- C4)haloalkyl, (Ci-C4)haloalkoxy, halogen, cyano or nitro; r is 0, 1 or 2; G a is (C1-C4 )alkyl, (C3-C4)cycloalkyl or (Ci-C4)haloalkyl; each G2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci- C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (C1-
C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; and suitable values for R1, R2 and R3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. In Formulas Id3, Id4, and Id5, G1 is (CrC4)alkyl, (CrC4)alkoxy, (CrC4)haloalkyl,
(Ci-C4)haloalkoxy, halogen, cyano or nitro; r is 0, 1 or 2; G a is (C1-C4 )alkyl, (Ci- C4)alkanesulfonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (Ci-C4)alkylcarbonyl, (Ci- C4)alkoxycarbonyl.; each G2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (Ci-C4)alkoxy, (CrC4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Cr C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; and suitable values for R1, R2 and R3 are as defined in any one of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiments, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
For each of the embodiments described in the previous two paragraphs, R1 is preferably methyl or ethyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; and R3 is MeSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2, 3-hydroxypropyl, 3- hydroxy-3-methylbutyl, 2 -hydroxy ethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is 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. Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"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, (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.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is 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. Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"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, (Ci- C4)haloalkyl and SO2Me; and R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2- hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl or phenyl which is optionally substituted with 1 , 2 or 3 substituents selected from halo, cyano and (Ci-C4)alkyl,; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano and (Ci- C4)alkyl,; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2 and (Ci- C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl. Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is phenyl or fluorophenyl; and R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
Alternatively, for each of the embodiment described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl, 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(Ci- C2)alkyl, and (C1-C2 )haloalkyl; and each G2b is independently selected from hydrogen, methyl or ethyl.
Alternatively, for each of the embodiment described in the two paragraphs immediately following Formulas Id1"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(Ci-C2)alkyl, and (C1-C2 )haloalkyl; and each G2b is independently selected from hydrogen, methyl or ethyl.
Alternatively, for each of the embodiments described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; in Formulas Id1, Id2, Id6 and Id7, the substituent G2a is selected from selected from hydrogen, methyl or ethyl; and each G2b is independently selected from hydrogen or methyl.
Alternatively, for each of the embodiment described in the two paragraphs immediately following Formulas Id1"7, R1 is preferably methyl or ethyl; R2 is isopropyl, phenyl or fluorophenyl; R is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; in Formulas Id3, Id4, and Id5 the substituent G2a is selected from hydrogen, methyl, methanesulfonyl, acetyl, tetrahydrofuranylcarbonyl,methoxycarbonyl, methylaminocarbonyl and dimethylaminocarbonyl; and each G2b is independently selected from hydrogen or methyl.
Another embodiment of the invention is a compound represented by Formula Ie1 or a pharmaceutically acceptable salt thereof:
Figure imgf000038_0001
Cy is (a) halogen or -O-SO3-R ; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, 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, (C3-C7)cycloalkyl(Ci-C2)alkyl, (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(C3- C7)cycloalkyl(Ci-C2)alkyl, (CrC6)alkoxy, (C3-C6)cycloalkoxy, (C3-C7)cycloalkyl(Cr C2)alkoxy, halo(CrC6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C7)cycloalkyl(Cr C2)alkoxy, (CrC6)alkylthio, (C3-C6)cycloalkythio, (C3-C7)cycloalkyl(Ci-C2)alkylthio, halo(CrC6)alkylthio, halo(C3-C6)cycloalkythio, halo(C3-C7)cycloalkyl(Ci-C2)alkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C3-C7)cycloalkyl(Ci-C2)alkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C3-C7)cycloalkyl(Cr C2)alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C3- C7)cycloalkyl(Ci-C2)alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C3-C7)cycloalkyl(Ci-C2)alkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Cr C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci- C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci- C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Cr C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Cp
C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Cr C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Cp C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(C i -C6)alkyl, (C i-C6)alkylaminocarbonyl(C i-C6)alkyl, di(C i - 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(Ci-C6)alkyl; R is (i) (Ci-C^alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C/^alkyl or NO2; the phenyl ring is optionally substituted with (C1-C4 )alkyl, (Ci-C^alkoxy, (Ci- C4)haloalkyl, (C1-C4) haloalkoxy, halogen, cyano and nitro; and suitable values for the remainder of the variables are as defined in any one of the first, second, third, fourth or fifth embodiments. For each of the embodiments described in the previous paragraph, R1 is preferably methyl or ethyl.
Another embodiment of the invention is a compound represented by any one of Formulas Ie2"5, or a pharmaceutically acceptable salt thereof:
Figure imgf000040_0001
r is 0, 1, 2 or 3; each G1 is independently (CpC4 )alkyl, (CpC4 )alkoxy, (CrC4)haloalkyl, (Ci-C4)haloalkoxy, halogen, cyano and nitro; suitable substituents for the group represented by Cy2 are as described for Formula Ie1 and suitable values for the remainder of the variables are as defined for the variables in Formula Ie1.
For each of the embodiments described in the paragraph immediately following Formulas Ie1"5, Cy2 is preferably phenyl, thienyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benztriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl, each optionally substituted by 1 to 4 groups, wherein suitable substituents for a substitutable ring nitrogen atom are selected from (Ci-C4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, (CrC4)haloalkyl, (CrC4)alkoxycarbonyl, (Ci-C4)alkylcarbonyl and benzyloxycarbonyl; and suitable substituents for a ring carbon atom in the are selected from fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, (C1- C4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl and (Ci- C4)alkylcarbonylamino.
Alternatively, for each of the embodiments described in the paragraph immediately following Formulas Ie1"5, preferably Cy2 is as described in the previous paragraph, and R2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci- C6)alkyl, halo(CrC6)alkyl, hydroxy(CrC3)alkyl, (CrC3)alkoxy, halo(CrC3)alkoxy, CONH2 and SO2Me.
For each of the embodiments described in the paragraph immediately following Formulas Ie1"5, preferably Cy2 is as described in the previous paragraph, R2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(CrC3)alkyl, (CrC3)alkoxy, halo(CrC3)alkoxy, CONH2 and SO2Me, and R1 is methyl or ethyl. More preferably, R2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (Ci-C^alkyl, (Ci-C^haloalkyl and SO2Me.
For the embodiments described in the previous paragraph, R2 is more preferably phenyl or fluorophenyl.
The present invention further provides methods of inhibiting l lβ-HSDl by contacting 1 lβ-HSDl with a compound of Formula I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1" 5 of the invention.
The present invention further provides methods of inhibiting or reducing the conversion of cortisone to Cortisol in a cell using a compound of Formula I, Ia1"10, Ib1"10, Ic1" 10, Id1"7 or Ie1"5 of the invention.
The present invention further provides methods of inhibiting or reducing production of Cortisol in a cell using a compound of Formula I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 of the invention.
The present invention further provides methods of increasing insulin sensitivity in a subject in need thereof using a compound of Formula I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 of the invention. The present invention further provides methods of treating a subject with a disease associated with activity of expression of l lβ-HSDl using a compound of Formula I, Ia1"10, Ib1"10, Ic1"10, Id1"7 or Ie1"5 of the invention.
Preferred values for the variables in the above-described structural formulas I, Ia1"10,
IIbb 11-"1100, Ic1"10, Id1"7 or Ie1"5 are provided below:
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. When substituted, an aryl group has 1-4 substituents. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl- substituted amido and N,N-dialkyl-substituted amido.
The term "heteroaryl" means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5- pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5-yl, lH-benzimidazol-6-yl, IH- benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or 5-imidazolyl. Exemplary substituents for a substituted heteroaryl 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, O, and S. Exemplary heterocyclyls include pyrrolidine, 1 -methylpyrrolidine, pyrrolidin-2- one, l-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, l-(2,2,2-trifluoroethyl)piperazine, 1 ,2-dihydro-2- oxopyridine, l,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5, 6-tetrahydro-4- oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3- dioxane, 1,4-dioxane, 1,3-dithiane, 1 ,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(lH)-one, morpholine, N-methylmorpholine, morpholin-3-one, l,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1 -dioxide, tetrahydro-l,2,5-thiaoxazole 1,1 -dioxide, tetrahydro-2H-l,2-thiazine 1,1 -dioxide, hexahydro-l,2,6-thiadiazine 1,1 -dioxide, tetrahydro-l,2,5-thiadiazole 1,1 -dioxide isothiazolidine 1,1 -dioxide, 6-oxo-l,6-dihydropyridazin-3-yl, 6-oxo- 1,6-dihy dropyridazin-4- yl, 5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl and 5-oxo-4,5-dihydro-lH-imidazol-2-yl. When substituted, a heterocyclyl has 1-4 substituents. Exemplary substituents include alkyl, haloalkyl, halogen and oxo.
"Substitutable ring nitrogen atom" refers to a ring nitrogen atom in a heteroaryl or heterocyclyl group that is bonded to a hydrogen atom. The hydrogen atom can be replaced, i.e., substituted, with a substituent. A "substitutable ring carbon atom" refers to a carbon atom in an aryl or cycloalkyl that is bonded to a hydrogen atom. The hydrogen atom can be replaced, i.s., substituted, with a substituent. 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. 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 "5" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "R*" and "£*" 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*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Tautomeric forms exist when a compound is a mixture of two or more structurally distinct compounds that are in rapid equilibrium. Certain compounds of the invention exist as tautomeric forms. For example, the following compound represented by Structural Formula (A) and (B) include at least the following tautomers forms:
Figure imgf000044_0001
It is to be understood that when one tautormeric form of a compound is depicted by name or structure, all tautomeric forms of the compound are included.
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:
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
GENERAL DESCRIPTION OF SYNTHETIC METHODS
Compounds of Formula I can be prepared by several processes. In the discussion below, A1, Cy1, Cy2, E, R1, R2, R3, Y and n have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products of Formulas I described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art (see e.g. 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 beneficial to use an excess of one reagent to drive a reaction to completion. This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCl in reaction mixtures are generally used in slight to substantial excess (1.05 - 5 equivalents). Compounds of Formula I can be prepared by reaction of a ketocarbamate of
Formula II, wherein RD is alkyl or arylalkyl such as methyl, t-butyl or benzyl, with an organometallic reagent of Formula III wherein M includes, but is not limited to, MgCl, MgBr, MgI or Li:
Figure imgf000048_0001
In specific examples, organometallic reagent III is allylmagnesium bromide, allylzinc bromide, (2-methylallyl)magnesium chloride or (2-methoxy-2-oxoethyl)zinc bromide. In certain cases when M is MgCl, MgBr or MgI, it is advantageous to add CeCl3 to the reaction mixture.
Ketocarbamates of Formula II can be prepared by reaction of aminoketones of Formula IV with intermediates of Formula V wherein RE is a leaving group such as chlorine, succinyloxy, imidazolyl or t-butoxycarboxycarbonyl:
Figure imgf000048_0002
Aminoketones of Formula IV, wherein n is preferably but not necessarily 0, can be prepared by reaction of OC,β-unsaturated ketones of Formula V with amines of Formula VII:
Figure imgf000049_0001
Alternatively, aminoketones of Formula IV, wherein n is preferably but not necessarily 0, can be prepared by reaction of β-dialkylaminoketones of Formula VI, wherein RF is lower alkyl especially methyl, with amines of Formula VII:
Figure imgf000049_0002
β-Dialkylaminoketones of Formula VI are in turn derived from α,β-unsaturated ketones of Formula V with dialkylamines of Formula RFNHRF.
Compounds of Formula Ie1 can be prepared according to the following scheme:
Figure imgf000049_0003
A methoxymethyl ketone of Formula VIII is reacted with an organometallic allyl reagent of Formula IX wherein M includes, but is not limited to, MgCl, MgBr, MgI or Li to yield an allyl compound of Formula X. In specific examples, organometallic reagent IX is allylmagnesium chloride, allylmagnesium bromide or allylzinc(II) bromide. The reaction is optionally carried out in the presence of anhydrous cerium trichloride Allyl compound of Formula X is converted to the aldehyde of Formula XII by ozonolysis or by Osθ4 catalysed dihydroxylation followed by cleavage of the glycol of Formula XI by periodates like sodium periodate. Aminocarbinol of Formula XIV can be prepared by reductive animation with an amine of Formula XIII using sodium cyanoborohydride or sodium triacetoxyborohydride as reducing agent. Cyclisation of the aminocarbinol of Formula XIV to the compounds of Formula Ie1 can be achieved by reacting with activated carbonic acid derivates such as phosgene, diphosgene, triphosgene or 1,1 '-carbonyl-diimidazol .
Alternatively compounds of Formula (I) can be prepared from the reaction product of compounds represented by formulas II and III wherein Cy1 is phenyl substituted with a leaving group such as bromine, for example, by using a "Suzuki"coupling reaction with Cy2- X [X is -B(OH)2] as described in Example 111 of U.S. Provisional Patent Application No. 60/962,058, filed July 26, 2007. The entire teachings of this application are incorporated herein by reference.
A compound of Formula I can also be prepared by reaction of a halo compound, wherein Hal is chlorine or bromine, with an isocyanate in the presence of a base:
Figure imgf000050_0001
Halo compounds of this type can be prepared by reaction of β-haloketones with organometallic reagents R3-M, wherein M is a metal containing residue including MgCl, MgBr, MgI or Li. The reaction is optionally carried out in the presence of anhydrous cerium trichloride:
Figure imgf000050_0002
Specific conditions for these reactions are described in SYNTHESIS OF INHIBITORS OF 11 BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (l lβ-HSDl), filed July 25, 2008 as U.S. Provisional Application No.61/137,013, the entire teachings of which are incorporated herein by reference.
LC-MS METHODS
LC-MS method 1 :
Figure imgf000050_0003
Figure imgf000051_0002
LC-MS method 2:
Figure imgf000051_0003
Intermediate I
3-[(S)-I -(4-Chloro-phenyl)-ethylaminol-l-phenyl-propan-l -one
Figure imgf000051_0001
NEt3 (60 mL) followed by (S)-l-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-l-phenyl-propan-l-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent.
Yield: 38.0 g (quantitative); Mass spectrum (ESI+): m/z = 288/290 (Cl) [M+H]+
The following compound was obtained in analogy to Intermediate I: (1) 3- [(S)- 1 -(4-Bromo-phenyl)-ethylamino] - 1 -phenyl-propan- 1 -one
Figure imgf000052_0001
Mass spectrum (ESI+): m/z = 332/334 (Br) [M+H]+
Intermediate II r(S)-l-(4-Chloro-phenyl)-ethyll-(3-oxo-3-phenyl-propyl)-carbamic acid methyl ester
Figure imgf000052_0002
Methyl chloroformate (15.5 mL) dissolved in dichloromethane (100 mL) was added to a mixture of 3-[(5)-l-(4-chloro-phenyl)-ethylamino]-l-phenyl-propan-l-one (38.0 g) and Na2COs (23.5 g) in a mixture of dichloromethane (100 mL) and water (100 mL) at such a rate that the solution temperature remained between 20 and 26 0C. After complete addition, the solution was stirred at ambient temperature for an additional 30 min. Then, the organic phase was separated and the aqueous phase was extracted once with dichloromethane. The combined organic phases were washed with brine and dried (MgSO/i). Then, silica gel (20 g) was added and the resulting mixture was stirred vigorously for 30 min. The silica gel was separated by filtration, washed with dichloromethane (200 mL), and the combined filtrate was concentrated under reduced pressure to give an oil. The oil was treated with z'Pr2O (150 mL) to precipitate the title compound that was separated by filtration, washed with petroleum ether (30 mL), and dried. The filtrate was concentrated and the residue was taken up in petroleum ether (60 mL). The precipitate formed after a while of stirring was separated by filtration, washed with petroleum ether (20 mL), dried, and combined with the precipitate obtained before.
Yield: 38.2 g (82% of theory); Mass spectrum (ESI+): m/z = 346/348 (Cl) [M+H]+.
The following compound was obtained in analogy to Intermediate II:
(1) [(5)-l-(4-Bromo-phenyl)-ethyl]-(3-oxo-3-phenyl-propyl)-carbamic acid methyl ester
Figure imgf000052_0003
Mass spectrum (ESI+): m/z = 390/392 (Br) [M+H]+
Intermediate III
5- IT(S)-I -(4-Chloro-phenyl)-ethyll-methoxycarbonyl-amino}-3-hvdroxy-3-phenyl- pentanoic acid methyl ester (mixture of two diastereomers)
Figure imgf000053_0001
Et2Zn (1 M in hexane, 55 mL) was added dropwise to [(S)-l-(4-chloro-phenyl)- ethyl]-(3-oxo-3-phenyl-propyl)-carbamic acid methyl ester (3.80 g) dissolved in 1,2- dichloroethane (30 mL) and chilled to 0 0C under argon atmosphere. Then, (Ph3P)3RhCl (0.50 g) was added followed by the dropwise addition of methyl bromoacetate (1.0 mL) dissolved in 1 ,2-dichloroethane (10 mL). The resulting solution was stirred at 0-5 0C for 1 h and at ambient temperature for another 1.5 h. The solution was poured into ice-cold half- saturated aqueous NH4Cl solution (150 mL). After addition of dichloromethane, the mixture was filtered through Celite which was extracted with an additional portion of dichloromethane. The organic phase was separated and washed with water and dried
(MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 85:15->70:30) to give the title compound as a mixture of two diastereomers.
Yield: 4.6 g (quantitative); Mass spectrum (ESI+): m/z = 420/422 (Cl) [M+H]+.
The following compound was obtained in analogy to Intermediate III:
(1) 5-{[(S)-l-(4-Bromo-phenyl)-ethyl]-methoxycarbonyl-amino}-3-hydroxy-3- phenyl-pentanoic acid methyl ester (mixture of two diastereomers)
Figure imgf000053_0002
Mass spectrum (ESI+): m/z = 464/466 (Br) [M+H]+
Intermediate IV \(S)-\ -(4-Chloro-phenyl)-ethyll-(3,5-dihvdroxy-5-methyl-3-phenyl-hexyl)-carbamic acid methyl ester (mixture of two diastereomers)
Figure imgf000054_0001
MeLi (1.6 M in Et2O, 5.1 mL) diluted with tetrahydrofuran (3 mL) was added to a solution of 5-{[(5')-l-(4-chloro-phenyl)-ethyl]-methoxycarbonyl-amino}-3-hydroxy-3- phenyl-pentanoic acid methyl ester (product from Intermediate III, 1.10 g) in tetrahydrofuran (8 mL) chilled to -75 0C under argon atmosphere. The solution was stirred at ca. -70 0C for 2.5 h and then poured into half-saturated aqueous NH4Cl solution (150 mL). The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 85:15->70:30) to give the title compound as a mixture of two diastereomers.
Yield: 0.62 g (56% of theory); Mass spectrum (ESI+): m/z = 420/422 (Cl) [M+H]+. The reaction may also be conducted using MeMgCl instead of MeLi as described above.
The following compound was obtained in analogy to Intermediate IV:
(1) [(S)-I -(4-Bromo-phenyl)-ethyl]-(3,5-dihydroxy-5-methyl-3-phenyl-hexyl)- carbamic acid methyl ester (mixture of two diastereomers)
Figure imgf000054_0002
Mass spectrum (ESI+): m/z = 464/466 (Br) [M+H]+.
Intermediate V
3-r(S)-l-(4-Chloro-phenyl)-ethyll-(S)-6-(2-hvdroxy-2-methyl-propyl)-6-phenyl- [l,3"|oxazinan-2-one and 3-[(S)-I -(4-chloro-phenyl)-ethyll-(R)-6-(2-hvdroxy-2-methyl- prorJyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000055_0001
NaH (60% in mineral oil, 0.15 g) was added to a solution of [(5^-1-(4-ChIoTO- phenyl)-ethyl]-(3,5-dihydroxy-5-methyl-3-phenyl-hexyl)-carbamic acid methyl ester (Intermediate IV, 0.60 g) in tetrahydrofuran (10 mL) under argon atmosphere. The resulting mixture was stirred at reflux temperature for 2.5 h. Then, aqueous NH4Cl solution 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 (cyclohexane/ethyl acetate 60:40->0:100) to separate the two title compounds. 3-[(5)-l-(4-Chloro-phenyl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-
[l,3]oxazinan-2-one: Yield: 40 mg (7% of theory). Mass spectrum (ESI+): m/z = 388/390 (Cl) [M+H]+. 1H NMR (400 MHz, DMSO-cήs) δ 0.80 (s, 3H), 1.18 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H), 2.01 (s, 2H), 2.08 (td, J= 11.5, 5.4 Hz, IH), 2.37-2.51 (m, 2H), 2.95-3.02 (m, IH), 4.23 (s, IH), 5.38 (q, J = 7.0 Hz, IH), 6.86 (d, J= 8.4 Hz, 2H), 7.14 (d, J= 8.4 Hz, 2H), 7.27-7.39 (m, 5 H).
3-[(5)-l-(4-Chloro-phenyl)-ethyl]-(R)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl- [l,3]oxazinan-2-one: Yield: 93 mg (17% of theory). Mass spectrum (ESI+): m/z = 388/390 (Cl) [M+H]+. 1H NMR (400 MHz, OMSO-d6) δ 0.81 (s, 3H), 1.16 (s, 3H), 1.18 (d, J= 7.3 Hz, 3H), 2.03 (s, 2H), 2.31-2.41 (m, 2H), 2.51-2.59 (m, IH), 2.64-2.71 (m, IH), 4.20 (s, IH), 5.31 (q, J= 7.1 Hz, IH), 7.25 (d, J= 8.4 Hz, 2H), 7.28-7.35 (m, 3H), 7.37-7.43 (m, 4 H).
The following compound was obtained in analogy to Intermediate V: (l) 3-[(5)-l-(4-Bromo-phenyl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl- [1,3] oxazinan-2 - one
Figure imgf000055_0002
The compound was obtained from [(5)-l-(4-bromo-phenyl)-ethyl]-(3,5-dihydroxy- 5-methyl-3-phenyl-hexyl)-carbamic acid methyl ester (mixture of two diastereomers) in a mixture with 3-[(5)-l-(4-bromo-phenyl)-ethyl]-(R)-6-(2-hydroxy-2-methyl-propyl)-6- phenyl-[l,3]oxazinan-2-one that was resolved into the pure diastereomers by chromatography as described above.
Intermediate VI (5)-6-(2-Hvdroxy-2-methyl-propyn-6-phenyl-3-{('5)-l-r4-('4.4.5.5-tetramethyl- ri,3,21dioxaborolan-2-yl)-phenyll-ethyl}-ri,31oxazinan-2-one
Figure imgf000056_0001
A flask charged with a stir bar, 3-[(S)-l-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy- 2-methyl-propyl)-6-phenyl-[l,3]oxazinan-2-one (4.00 g), bis(pinacolato)diboron (3.05 g), l,l '-bis(diphenylphosphino)ferrocene (0.25 g), KO2CCH3 (3.18 g), and dimethyl sulfoxide (30 mL) was sparged with argon for 15 min. Then, [l,l '-bis(diphenylphosphino)ferrocene]- dichloro-palladium(II) dichloromethane complex (0.38 g) was added and the resulting mixture was heated to 90 0C and stirred at this temperature overnight. After cooling to ambient temperature, ethyl acetate (150 mL) was added and the mixture was washed with water (3x 50 mL) and brine (50 mL) and dried (MgSO/i). The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 33:66->0:100) to give the title compound as a colorless solid. Yield: 3.50 mg (79% of theory); Mass spectrum (ESI+): m/z = 480 [M+H]+
The following compound was obtained in analogy to Intermediate VI:
(l) (R)-6-Methoxymethyl-6-phenyl-3-{(5()-l-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[l,3]oxazinan-2-one
Figure imgf000056_0002
3-[(S)-I -(4-Bromo-phenyl)-ethyll-(R)-6-methoxymethyl-6-phenyl-rL31oxazinan-2- one was used as starting compound.
Intermediate VII 6-Chloro-4-methyl-2H-pyridazin-3-one and 6-chloro-5-methyl-2H-pyridazin-3-one
Figure imgf000057_0001
A suspension of 3,6-dichloro-4-methylpyridazine (6.60 g) in 3.3 M aqueous NaOH solution (66 mL) was stirred at reflux temperature for 2 h. The heating bath was removed and 50% aqueous acetic acid (25 mL) was added. The aqueous solution was adjusted to pH value 6 and the precipitate formed thereafter was separated by filtration and washed with little water. The precipitate was chromatographed on silica gel (cyclohexane/ethyl acetate 90:10->0:100) to separate the two title compounds.
6-Chloro-4-methyl-2H-pyridazin-3-one: Yield: 2.70 g (46% of theory). Mass spectrum (ESI+): m/z = 145/147 (Cl) [M+H]+. 1H NMR (400 MHz, OMSO-d6) δ 2.06 (d, J = 1.3 Hz, 3H), 7.44 (incompletely resolved q, J = 1.3 Hz, IH), 13.03 (broad s, IH).
6-Chloro-5-methyl-2H-pyridazin-3-one: Yield: 1.90 g (32% of theory). Mass spectrum (ESI+): m/z = 145/147 (Cl) [M+H]+. 1H NMR (400 MHz, DMSO-cήs) δ 2.19 (d, J = 1.3 Hz, 3H), 6.91 (incompletely resolved q, J = 1.3 Hz, IH), 13.02 (broad s, IH).
The following compound was obtained in analogy to Intermediate VII:
(1) 6-Chloro-2H-pyridazin-3-one
Figure imgf000057_0002
Mass spectrum (ESI+): m/z = 131/133 (Cl) [M+H]+
Intermediate VIII
6-Chloro-2,4-dimethyl-2H-pyridazin-3-one
Figure imgf000057_0003
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 N,N-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 (Cl) [M+H]+.
The following compound was obtained in analogy to Intermediate VIII: (1) 6-Chloro-2,5-dimethyl-2H-pyridazin-3-one
Figure imgf000058_0001
Mass spectrum (ESI+): m/z = 159/161 (Cl) [M+H]+.
Intermediate IX (5-Bromo-2-nitro-phenyl)-methyl-amine
Figure imgf000058_0002
Methylamine (2 M in tetrahydrofuran, 11.4 mL) was added to a mixture of 4- bromo-2-fluoro-l-nitro-benzene (2.50 g) and K2CO3 (1.90 g) in N,N-dimethylformamide (40 mL). The resulting mixture was stirred at ambient temperature overnight. Then, the mixture was concentrated under reduced pressure and dichloromethane was added. The resulting mixture was washed with 0.5 M aqueous HCl solution and brine and dried (MgSO/i). The solvent was removed to give the product as a solid.
Yield: 2.60 g (99% of theory); Mass spectrum (ESI+): m/z = 231/233 (Br) [M+H]4
The following compound was obtained in analogy to Intermediate IX:
( 1 ) (4-Bromo-2-nitro-phenyl)-methyl-amine
Figure imgf000058_0003
Mass spectrum (ESI+): m/z = 231/233 (Br) [M+H]+.
Intermediate X
4-Bromo-2-methvlamino-aniline
Figure imgf000059_0004
A mixture of (5-bromo-2-nitro-phenyl)-methyl-amine (2.60 g) and Raney nickel (0.25 g) in tetrahydrofuran (100 mL) was shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to give the crude title compound as a brown oil that was used without further purification.
Yield: 2.20 g (97% of theory); Mass spectrum (ESI+): m/z = 201/203 (Br) [M+H]4
The following compound was obtained in analogy to Intermediate X: (1) 5-Bromo-2-methylamino-aniline
Figure imgf000059_0001
Mass spectrum (ESI+): m/z = 201/203 (Br) [M+H]+.
Intermediate XI 6-Bromo- 1 ,2-dimethyl- 1 H-benzoimidazole
A solution of 4-bromo-2-methylamino-aniline (1.10 g) in acetic acid (15 mL) was stirred at 130 0C for 2 h. After cooling to ambient temperature, the solution was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The resulting solution was washed with 10% aqueous K2CO3 solution and brine and dried
(MgSO4). The solvent was removed and the remainder was purified by chromatography on silica gel (CH2Cl2/Me0H/ NH4OH 99: 1 :0.1 ->9: 1 :0.1) to give the title compound as a solid.
Yield: 0.58 g (47% of theory); Mass spectrum (ESI+): m/z = 225/227 (Br) [M+H]+.
The following compound was obtained in analogy to Intermediate XI:
( 1 ) 5-Bromo- 1 ,2-dimethyl- 1 H-benzoimidazole
Figure imgf000059_0003
Mass spectrum (ESI+): m/z = 225/227 (Br) [M+H]+
Intermediate XII
6-Chloro-2-cvclopropylmethyl-2H-pyridazin-3-one
Figure imgf000060_0001
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 N,N-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]+.
Intermediate XIII
6-Chloro-2-cvclopropyl-2H-pyridazin-3-one
Figure imgf000060_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(O2CCHs)2 (0.42 g) was added and the mixture was stirred in a microwave oven under microwave irradiation at 140 0C for 10 min. After cooling to room temperature, 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 NaHCOs solution. After drying (MgSO4) and removing the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:l :0.1->9:l :0.1) to afford the title compound.
Yield: 35 mg (18% of theory); Mass spectrum (ESI+): m/z = 171/173 (Cl) [M+H]+.
The following compound was obtained in analogy to Intermediate XIII: (1) l-Cyclopropyl-4-(4-methoxy-benzyloxy)-lH-pyridin-2-one
Figure imgf000061_0001
Mass spectrum (ESI+): m/z = 272 [M+H]+.
Intermediate XIV
4-f4-{fS)-l-rfS)-6-f2-Hvdroxy-2-methyl-propyn-2-oxo-6-phenyl-ri.31oxazinan-3-yll- ethyl}-phenyl)-3,6-dihvdro-2H-pyridine-l-carboxylic acid tert-butyl ester
Figure imgf000061_0002
N,N-Dimethylformamide (5 mL) was added to a flask charged with a stir bar, 3- [(5)-l-(4-bromo-phenyl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[l,3]oxazinan- 2-one (0.30 g), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridme-l- carboxylic acid tert-butyl ester (0.22 g), K2CO3 (0.29 g), and [l,l '-bis(diphenylphosphino)- ferrocene]-dichloropalladium(II) (57 mg) under argon atmosphere. The resulting mixture was stirred at 80 0C 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 (MgSO/i), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 40:60->0:100) to afford the title compound.
Yield: 0.35 g (93% of theory); Mass spectrum (ESI+): m/z = 535 [M+H]+.
Intermediate XV
4-(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-rL31oxazinan-3-yll- ethyll-phenyP-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000061_0003
A mixture of 4-(4-{(5)-l -[(5)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl- [l,3]oxazinan-3-yl]-ethyl}-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (0.34 g) and 10% palladium on carbon (60 mg) in methanol (10 mL) was shaken in hydrogen atmosphere (50 psi) for 4 h. Then, the catalyst was separated by filtration and the filtrate was concentrated to yield the title compound.
Yield: 0.30 g (88% of theory); LC (method 1): tR = 4.31 min; Mass spectrum (ESI+): m/z = 537 [M+H]+.
Intermediate XVI
5-(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-π.31oxazinan-3-yll- ethyl} -phenyl)-pyridine-2-carboxylic acid
Figure imgf000062_0001
2 M aqueous Na2COs solution (1.3 mL) was added to a solution of (S)-6-(2- hydroxy-2-methylpropyl)-6-phenyl-3-{(5)-l-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-ethyl}-l,3- oxazinan-2-one (0.60 g) and 5-bromo-pyridine-2-carboxylic acid methyl ester (0.41 g) in N,N-dimethylformamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (61 mg) was added. The mixture was heated to 100 0C and stirred at this temperature overnight. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted with water and brine. The aqueous extracts were combined, acidified (pH ca. 5-6) using citric acid, and extracted with CH2Cl2ZMeOH (ca. 10:1). The combined organic extracts were washed with brine and dried (MgSO/i). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/Me0H 98:2->50:50) to afford the title compound as a resin- like solid.
Yield: 0.44 g (73% of theory); Mass spectrum (ESI+): m/z = 475 [M+H]+.
Intermediate XVII
3-r(S)-l-(4'-Amino-3'-nitro-biphenyl-4-yl)-ethyll-(S)-6-(2-hvdroxy-2-methyl-propyl)-6- phenyl- [1,31 oxazinan-2 - one
Figure imgf000062_0002
A flask charged with a stir bar, 3-[(5)-l-(4-bromo-phenyl)-ethyl]-(5)-6-(2- hydroxy-2-methyl-propyl)-6-phenyl-[l,3]oxazinan-2-one (1.00 g), 2-nitro-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (0.92 g), and 2 M aqueous Na2COs solution (2.3 mL) was sparged with argon for 15 min. Then, [1,1 '- bis(diphenylphosphino)ferrocene]-dichloro-palladium(II) dichloromethane complex (57 mg) was added and the mixture was stirred at 100 0C 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 (MgSO/i), and concentrated. The residue was purified by chromatography on silica gel (CH2CVMeOH 98:2->80:20) to afford the title compound as an oil that was crystallized using a mixture of ethyl acetate and zPr2O (ca. 10:1).
Yield: 0.53 g (93% of theory); Mass spectrum (ESI+): m/z = 490 [M+H]+.
Intermediate XVIII 3-r(S)-l-(3',4'-Diamino-biphenyl-4-yl)-ethyll-(S)-6-(2-hvdroxy-2-methyl-propyl)-6-phenyl-
[1,31 oxazinan-2 - one
Figure imgf000063_0001
A mixture of 3-[(5)-l-(4'-amino-3'-nitro-biphenyl-4-yl)-ethyl]-(5)-6-(2-hydroxy-2- methyl-propyl)-6-phenyl-[l,3]oxazinan-2-one (0.50 g) and 10% palladium on carbon (0.10 g) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was shaken in hydrogen atmosphere (3 bar) at room temperature for 3.5 h. Then, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to afford the title compound as an oil.
Yield: 0.46 g (97% of theory); Mass spectrum (ESI+): m/z = 460 [M+H]+.
Intermediate XIX
1 -CyclopropyM-hydroxy- 1 H-pyridin-2-one
Figure imgf000063_0002
Trifluoroacetic acid (1 mL) was added to a flask charged with a stir bar and 1- cyclopropyl-4-(4-methoxy-benzyloxy)-lH-pyridin-2-one (0.17 g) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 1.5 h and at ambient temperature for another 4.5 h. Then, the solution was concentrated under reduced pressure and the residue was triturated with tert-butyl methyl ether and dried to give the title compound as a solid.
Yield: 0.10 g (quantitative); Mass spectrum (ESI+): m/z = 152 [M+H]+.
Intermediate XX Trifluoro-methanesulfonic acid l-cvcloprorJyl-2-oxo-l,2-dihydro-rjyridin-4-yl ester
Figure imgf000064_0001
Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flask charged with a stir bar, l-cyclopropyl-4-hydroxy-lH-pyridin-2-one (0.10 g), NEt3 (0.24 mL), and dichloromethane (8 mL) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 2 h and at ambient temperature for another 2 h. Then, the solution was diluted with dichloro-methane and washed in succession with water, aqueous NaHCO3 solution, and water. The organic solution was dried (MgSO/i), the solvent was removed, and the residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1- >90:10) to afford the title compound as a resin- like solid. Yield: 0.07 g (36% of theory); Mass spectrum (ESI+): m/z = 284 [M+H]+.
The following compound was obtained in analogy to Intermediate XX:
(1) Trifluoro-methanesulfonic acid l-methyl-2-oxo-l,2-dihydro-pyridin-4-yl ester
Figure imgf000064_0002
Mass spectrum (ESI+): m/z = 258 [M+H]4
Intermediate XXI 5-Bromo- 1 -cyclopropylmethyl- 1 H-pyridin-2-one
Figure imgf000065_0001
KO'Bu (0.68 g) was added to a solution of 5-bromo-lH-pyridin-2-one (1.00 g) in tetrahydrofuran (20 mL) at room temperature. After stirring for 30 min, cyclopropylmethyl bromide (0.77 mL) and N,N-dimethylformamide (3 mL) were added to the suspension and the resulting mixture was warmed to 70 0C. After stirring the mixture at 70 0C for 2 h, the reaction was finished. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2x 20 mL) and brine (20 mL). Then, the solution was dried (MgSO4) and the solvent was removed to give the title compound as a colorless oil. Yield: 1.18 g (90% of theory); Mass spectrum (ESI+): m/z = 228/230 (Br) [M+H]+.
Intermediate XXII l-Methoxy-2-phenyl-pent-4-en-2-ol
Figure imgf000065_0002
2-Methoxy-l-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 NH4Cl 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 [M+H-H2O]+.
Intermediate XXIII
5-Methoxy-4-phenyl-pentane- 1 ,2,4-triol
Figure imgf000065_0003
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 Na2S2θ5 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 (MgSO/i). The solvent was evaporated to afford the title compound in good purity (ca. 95%).
Yield: 1.20 g (96% of theory); Mass spectrum (ESF): m/z = 225 [M-H]-.
Intermediate XXIV 3-Hvdroxy-4-methoxy-3-phenyl-butyraldehyde
Figure imgf000066_0001
Nalθ4 (5.20 g) was added to a mixture of 5-methoxy-4-phenyl-pentane-l,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 (MgSO/i). After removal of the solvent, the title compound was obtained which was used without further purification. Yield: 0.94 g (quantitative).
Intermediate XXV 4-[(S)-I -(4-Bromo-phenyl)-ethylaminol-l-methoxy-2-phenyl-butan-2-ol
Figure imgf000066_0002
(S)-l-(4-Bromo-phenyl)-ethylamine (0.93 g), NaHB(O2CH3)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 0C. 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 (MgSO/i), the solvent was removed to give the title compound which was used without further purification.
Yield: 1.80 g (quantitative); Mass spectrum (ESI+): m/z = 378/380 (Br) [M+H]+.
Intermediate XXVI
4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-ri.31oxazinan-3-yll-ethvU- benzoic acid methyl ester
Figure imgf000067_0001
NEt3 (0.47 mL) and [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (0.15 g) were added to a solution of 3-[(5)-l-(4-bromo-phenyl)- ethyl]-(S^-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[l,3]oxazinan-2-one (1.04 g) in MeCN (2.5 mL), methanol (20 mL), and N,N-dimethylformamide (5 mL). The resulting mixture was sparged with argon for 5 min and then transferred to a pressure-resistant vessel that was filled with CO (5.5. bar). The mixture was heated to 70 0C and stirred at this temperature for 18 h before another portion of [ 1 , 1 ' -bis(diphenylphosphino)ferrocene] - dichloropalladium(II) dichloromethane complex (0.15 g) was added. After stirring at 70 0C for another 4 h, the mixture was cooled to ambient temperature, filtered, and concentrated under reduced pressure. The residue was taken up in ethyl acetate and the resulting mixture was washed with water and brine and dried (MgSO/i). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 40:60- >0:100) to afford the title compound as an oil.
Yield: 0.73 g (55% of theory); Mass spectrum (ESF): m/z = 456 [M+HCOO]"
Intermediate XXVII 4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-ri.31oxazinan-3-yll-ethvU- benzoic acid
Figure imgf000067_0002
1 M aqueous NaOH solution (5 mL) was added to a solution of 4-{(5)-l-[(5)-6-(2- hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[l ,3]oxazinan-3-yl]-ethyl} -benzoic acid methyl ester (0.73 g) in tetrahydrofuran (5 mL). The resulting solution was stirred at room temperature overnight. Then, the solution was concentrated and the residue was taken up in water and filtered. The aqueous filtrate was acidified with 1 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO/i). The solvent was removed to afford the title compound as a foam- like solid.
Yield: 0.38 g (72% of theory); LC (method 1): tR = 2.60 min; Mass spectrum (ESI+): m/z = 398 [M+H]+
Intermediate XXVIII
4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-rL31oxazinan-3-yll-ethyl}- benzoic acid hydrazide
Figure imgf000068_0001
2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (0.33 g) was added to 4-{(5)-l-[(5)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[l,3]oxazinan-3-yl]- ethyl} -benzoic acid (0.37 g) and EtNzPr2 (0.41 mL) dissolved in N,N-dimethylformamide (5 mL). After stirring the solution at room temperature for 10 min, hydrazine hydrate (0.23 mL) was added. The solution was stirred at room temperature overnight and then diluted with water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO/i). The solvent was removed and the residue was purified by chromatography on silica gel (CH2CVMeOH 98:2->90:10) to afford the title compound as a colorless foam- like solid.
Yield: 0.19 g (50% of theory); Mass spectrum (ESF): m/z = 410 [M-H]-
Intermediate XXIX
4-Bromo-5-fluoro- 1 -methyl- 1 H-pyridin-2-one
Figure imgf000068_0002
Methyl iodide (0.9 mL) was added to a mixture of potassium carbonate (2.34 g) and 4-bromo-5-fluoro-lH-pyridin-2-one (2.50 g) in N,N-dimethylformamide (25 mL) at room temperature. The mixture was stirred at room temperature overnight and then water was added. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO/i). The solvent was evaporated to afford the crude title compound that was recrystallized from Et2O.
Yield: 1.22 g (45% of theory); Mass spectrum (ESI+): m/z = 206/208 (Br) [M+H]+.
Example 1
3-{(S)-l-r4-(1.5-Dimethyl-6-oxo-1.6-dihvdro-pyridazin-3-yl)-phenyll-ethvU-(S)-6-(2- hydroxy-2-methyl-rjrorJyl)-6-phenyl- [1,31 oxazinan-2-one
Figure imgf000069_0001
2 M aqueous Na2CO3 solution (0.31 mL) was added to a solution of (5)-6-(2- hydroxy-2-methylpropyl)-6-phenyl-3-[(5<)-l-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethyl]-l,3-oxazinan-2-one (0.15 g) and 6-chloro-2,4-dimethyl-2H-pyridazin-3- one (75 mg) in N,N-dimethylformamide (1 mL). The resulting mixture was sparged with argon for 10 min, before [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) 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 (MgSO/i), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/Me0H 98:2->80:20) to afford the title compound.
Yield: 0.10 g (67% of theory); LC (method 1): tR = 3.17 min; Mass spectrum (ESI+): m/z = 476 [M+H]+.
The following compounds were obtained in analogy to Example 1 : The reactions were carried out using either the bromo, chloro, or trifluoromethanesulfonyloxy derivatized coupling partners (= electrophilic component).
Example 2
3-{(S)-l-r4-(L4-Dimethyl-6-oxo-L6-dihvdro-pyridazin-3-yl)-phenyll-ethyl}-(S)-6- (2-hvdroxy-2-methyl-propyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000070_0001
LC (method 1): tR = 2.99 min; Mass spectrum (ESI+): m/z = 476 [M+H]+
Example 3
3-{(S)-l-r4-(2.3-Dimethyl-3H-benzoimidazol-5-vn-phenyll-ethvU-(S)-6-(2- hvdroxy-2-methyl-propyl)-6-phenyl- [1,31 oxazinan-2-one
Figure imgf000070_0002
Mass spectrum (ESI+): m/z = 498 [M+H]+.
Example 4
(S)-6-(2-Hvdroxy-2-methyl-propyl)-3-{(S)-l-r4-(3-methyl-3H-benzoimidazol-5-yl)- phenyl1-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000070_0003
LC (method 1): tR = 2.54 min; Mass spectrum (ESI+): m/z = 484 [M+H]4
Example 5
(S)-6-(2-Hvdroxy-2-methyl-propyl)-3 -US)-I- [4-(l -methyl- 1 H-benzoimidazol-5-vD- phenyll-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000070_0004
LC (method 1): tR = 2.44 min; Mass spectrum (ESI+): m/z = 484 [M+H]+. Example 6
3-{fS)-l-r4-π.2-Dimethyl-lH-benzoimidazol-5-vn-phenyll-ethvU-fS)-6-f2- hvdroxy-2-methyl-propyl)-6-phenyl- [1,31 oxazinan-2-one
Figure imgf000071_0001
LC (method 1): tR = 2.45 min; Mass spectrum (ESI+): m/z = 498 [M+H]+.
Example 7
3-{(S)-l-r4-(l-Cvclopropylmethyl-6-oxo-l,6-dihvdro-pyridazin-3-yl)-phenyll- ethyl}-(S)-6-(2-hvdroxy-2-methyl-propyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000071_0002
LC (method 1): tR = 3.46 min; Mass spectrum (ESI+): m/z = 502 [M+H]+.
Example 8
3-{(S)-l-^4-(l-Cvclopropyl-6-oxo-l,6-dihvdro-pyridazin-3-yl)-phenyll-ethyl}-(S)- 6-(2-hvdroxy-2-methyl-propyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000071_0003
LC (method 1): tR = 3.22 min; Mass spectrum (ESI+): m/z = 488 [M+H]+
Example 9
3-{(S)-l-r4-(l-Cvclopropyl-2-oxo-1.2-dihvdro-pyridin-4-yl)-phenyll-ethvU-(S)-6- (2-hvdroxy-2-methyl-propyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000072_0001
LC (method 2): tR = 2.41 min; Mass spectrum (ESI+): m/z = 487 [M+H]+. Trifluoro-methanesulfonic acid l-cyclopropyl-2-oxo-l,2-dihydro-pyridin-4-yl ester was employed as the coupling partner under the conditions described above
Example 10
3-{(S)-l-r4-(l-Cvclopropylmethyl-6-oxo-l,6-dihvdro-pyridin-3-yl)-phenyll-ethyl}- (S)-6-(2-hvdroxy-2-methyl-propyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000072_0002
Mass spectrum (ESI+): m/z = 501 [M+H]+.
Example 11
(R)-6-Methoxymethyl-3-{(S)-l-r4-(6-methyl-pyridazin-3-yl)-phenyll-ethyl}-6- phenyl- [1,31 oxazinan-2 - one
Figure imgf000072_0003
LC (method 1): tR = 2.92 min; Mass spectrum (ESI+): m/z = 418 [M+H]4
Example 12
(R)-6-Methoxymethyl-3-{(S)-l-r4-(l-methyl-6-oxo-L6-dihvdro-pyridin-3-yl)- phenyll-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000072_0004
LC (method 1): tR = 2.98 min; Mass spectrum (ESI+): m/z = 433 [M+H]+
Example 13
(R)-6-Methoxymethyl-3-{(S)-l-r4-(l-methyl-2-oxo-L2-dihvdro-pyridin-4-yl)- phenyl1-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000073_0001
LC (method 1): tR = 2.92 min; Mass spectram (ESI+): m/z = 433 [M+H]+ Trifluoro-methanesulfonic acid l-methyl-2-oxo-l,2-dihydro-pyridin-4-yl ester was used as the coupling partner under the conditions described above.
Example 14
3-{(S)-l-r4-(5-Fluoro-l-methyl-2-oxo-1.2-dihvdro-pyridin-4-yl)-phenyll-ethvU-(S)- 6-(2-hvdroxy-2-methyl-propyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000073_0002
Mass spectrum (ESI+): m/z = 479 [M+H]+
4-Bromo-5-fluoro-l -methyl- lH-pyridin-2-one was used as the coupling partner under the conditions described above.
Example 15 5-(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-π.31oxazinan-3-yll- ethyl}-phenyl)-pyridine-2-carboxylic acid ethylamide
Figure imgf000073_0003
2-(lH-Benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (75 mg) was added to a solution of 5-(4-{(S^-l-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl- [l,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid (0.10 g) and diisopropylethyl-amine (50 μL) in N,N-dimethylformamide (1 mL) at room temperature.
The resulting solution was stirred for 25 min, before ethylamine (70% in water, 50 μL) was added. The solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound as a foam-like solid.
Yield: 25 mg (24% of theory); TLC: rf = 0.37 (silica gel; CH2Cl2/Me0H 95:5); Mass spectrum (ESI+): m/z = 502 [M+H]+.
The following compounds were obtained in analogy to Example 15:
Example 16
5-(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-π.31oxazinan-3- yll-ethyl}-phenyl)-pyridine-2-carboxylic acid methylamide
Figure imgf000074_0001
TLC: rf = 0.37 (silica gel; CH2Cl2/Me0H 95:5); Mass spectrum (ESI+): m/z = 488
[M+H]+. Mehtylamine was the coupling partner.
Example 17
(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-rL31oxazinan-3-yll- ethyl} -phenyl)-pyridine-2-carboxylic acid dimethylamide
Figure imgf000074_0002
TLC: rf = 0.30 (silica gel; CH2Cl2MeOH 95:5); Mass spectrum (ESI+): m/z = 502 [M+H]+. Dimethylamine was the coupling partner.
Example 18
(S)-6-(2-Hvdroxy-2-methyl-propyl)-6-phenyl-3-r(S)-l-(4-piperidin-4-yl-phenyl)-ethyll-
[1,31 oxazinan-2 - one
Figure imgf000075_0001
Trifluoroacetic acid (0.40 mL) was added to a solution of 4-(4-{(S)-\-[(S)-6-(2- hydroxy-2-methyl-propyl)-2-oxo-6-phenyl- [ 1 ,3 ] oxazinan-3 -yl] -ethyl} -phenyl)-piperidine- 1 - carboxylic acid tert-butyl ester (0.29 g) in dichloromethane (10 mL). The resulting solution was stirred at room temperature overnight. Then, more dichloromethane was added and the solution was neutralized using aqueous saturated NaHCθ3 solution. The organic phase was separated, washed with water, and dried (MgSO/i). The solvent was removed under reduced pressure to yield the title compound.
Yield: 0.22 g (93% of theory); LC (method 1): tR = 2.09 min; Mass spectrum (ESI+): m/z = 437 [M+H]+.
Example 19
3-{(S)-l-r4-(l-Acetyl-piperidin-4-yl)-phenyll-ethyl}-(S)-6-(2-hvdroxy-2-methyl-propyl)-6- phenyl- [1,31 oxazinan-2 - one
Figure imgf000075_0002
Triethylamine (0.10 mL), acetic anhydride (50 μL), and 4-dimethylaminopyridine (5 mg) were added consecutively to (5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(5)-l- (4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (0.12 g) dissolved in tetrahydrofuran (5 mL) at room temperature. The solution was stirred at room temperature for 4 h and then diluted with ethyl acetate. The resulting solution was washed with aqueous saturated NaHCθ3 solution and brine and dried (Na2SOzI). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/Me0H 98:2->90:10) to afford the title compound as a colorless foam- like solid.
Yield: 80 mg (61% of theory); TLC: rf = 0.60 (silica gel; CH2Cl2/Me0H 90:10); Mass spectrum (ESI+): m/z = 479 [M+H]+.
Example 20
4-(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyl)-2-oxo-6-phenyl-rL31oxazinan-3-yll- ethyll-phenyP-piperidine-l-carboxylic acid methyl ester
Figure imgf000076_0001
Triethylamine (0.10 mL) and methyl chloroformate (24 μL) were added consecutively to (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-l-(4-piperidin-4-yl- phenyl)-ethyl]-[l,3]oxazinan-2-one (0.12 g) dissolved in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature overnight and then diluted with dichloromethane. The resulting solution was washed with water and brine and dried (Na2SOzI). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2CVMeOH 99:l->90:10) to afford the title compound as a foam- like solid.
Yield: 100 mg (70% of theory); TLC: rf = 0.60 (silica gel; CH2Cl2/Me0H 90:10); Mass spectrum (ESI+): m/z = 495 [M+H]+.
Example 21
(S)-6-(2-Hvdroxy-2-methyl-propyl)-3-{(S)-l-r4-(l-methyl-piperidin-4-yl)-phenyll- ethyl} -6-phenyl-π ,31oxazinan-2-one
Figure imgf000076_0002
Acetic acid (27 μL) and NaHB(O2CCH3)3 (160 mg) were added to a solution of (S)- 6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(5<)-l-(4-piperidin-4-yl-phenyl)-ethyl]- [l,3]oxazinan-2-one (200 mg) and formaldehyde (37% in water, 70 μL) in tetrahydrofuran (5 mL) at room temperature. After stirring the solution at room temperature overnight, ethyl acetate and 1 M aqueous NaOH solution were added and the resulting mixture was stirred for another 10 min. Then, the organic layer was separated and washed with water and brine and dried (MgSO/i). The solvent was evaporated and the residue was purified by HPLC on reversed phase (MeCN/H2O/ F3CCO2H) to afford the title compound as its trifluoroacetic acid salt.
Yield: 120 mg (46% of theory); LC (method 1): tR = 2.18 min; Mass spectrum (ESI+): m/z = 451 [M+H]+.
Example 22 (S)-6-(2-Hydroxy-2-methyl-propyl)-3 - US)- 1 - [4-0 -methanesulfonyl-piperidin-4- yl)-phenyll-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000077_0001
MeSO2Cl (29 μL) was added to a solution of (5)-6-(2-hydroxy-2-methyl-propyl)-6- phenyl-3-[(S)-l-(4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (150 mg) and triethylamine (100 μL) in dichloromethane (3 mL) at room temperature. After stirring the solution at room temperature overnight, more dichloromethane was added and the resulting solution was washed with aqueous NaHCθ3 solution, water, and brine. The organic solution was then dried (MgSO/i) and concentrated. The residue was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Yield: 52 mg (29% of theory); Mass spectrum (ESI+): m/z = 515 [M+H]+.
Example 23
(S)-6-(2-Hvdroxy-2-methyl-propyl)-6-phenyl-3-((S)-l- {4-ri-((S)-tetrahvdro-furan-2- carbonyl)-piperidin-4-yll-phenyl} -ethyl)-!"! ,31oxazinan-2-one
Figure imgf000077_0002
2-(lH-Benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (125 mg) was added to a solution of (5)-tetrahydro-furan-2-carboxylic acid (45 mg) and diisopropylethyl-amine (200 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 30 min, before (5)-6-(2-hydroxy-2-methyl-propyl)-6- phenyl-3-[(5)-l-(4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (150 mg) dissolved in dimethylformamide (1 mL) was added. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O/ NH3) to afford the title compound. Yield: 110 mg (60% of theory); LC (method 1): tR = 3.20 min; Mass spectrum
(ESI+): m/z = 535 [M+H]+
The following compounds were obtained in analogy to Example 23 : Example 24 fS)-6-f2-Hvdroxy-2-methyl-propyn-6-phenyl-3-ffS)-l- {4-ri-ffR)-tetrahvdro-furan- 2-carbonyl)-piperidin-4-yll-phenyl} -ethyl)-!"! ,31oxazinan-2-one
Figure imgf000078_0001
LC (method 1): tR = 3.20 min; Mass spectram (ESI+): m/z = 535 [M+H]+
Example 25
(S)-6-(2-Hvdroxy-2-methyl-propyn-6-phenyl-3-((S)-l- {4-ri-(2-hvdroxy-2-propyl- carbonyl)-piperidin-4-yll-phenyl}-ethyl)-ri,31oxazinan-2-one
Figure imgf000078_0002
LC (method 1): tR = 3.17 min; Mass spectram (ESI+): m/z = 535 [M+H]+
Example 26 (S)-6-(2-Hvdroxy-2-methyl-propyl)-3-((S)-l-{4-ri-((S)-l-methyl-pyrrolidine-2- carbonyl)-piperidin-4-yll-phenyl}-ethyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000078_0003
Mass spectram (ESI+): m/z = 548 [M+H]+
Example 27
(S)-6-(2-Hvdroxy-2-methyl-propyl)-3-((S)-l-{4-ri-((R)-l-methyl-pyrrolidine-2- carbonyl)-piperidin-4-yll-phenyl}-ethyl)-6-phenyl-ri,31oxazinan-2-one
Figure imgf000079_0001
LC (method 1): tR = 2.37 min; Mass spectrum (ESI+): m/z = 548 [M+H]+
Example 28 3-{(S)-l-r4-(3H-Benzotriazol-5-vn-phenyll-ethvU-(S)-6-(2-hvdroxy-2-methyl-propyn-6- phenyl- [1,31 oxazinan-2 - one
Figure imgf000079_0002
A solution of NaNθ2 (0.16 g) in water (2 mL) was added dropwise to an ice-cold solution of 3-[(5()-l-(3',4'-diamino-biphenyl-4-yl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)- 6-phenyl-[l,3]oxazinan-2-one (0.43 g) in acetic acid (10 mL). The resulting mixture was stirred with cooling for 2 h and at room temperature for another 1 h. Then, water (100 mL) was added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaHCθ3 solution, water, and brine and dried (Na2SOzI). The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/MeOH 98:2->80:20) to afford the title compound as a foam-like solid.
Yield: 0.30 g (69% of theory); LC (method 1): tR = 3.02 min; Mass spectrum (ESI+): m/z = 471 [M+H]+.
Example 29
(S)-6-(2-Hvdroxy-2-methyl-propyl)-3- US)-I - r4-(2-methyl-3H-benzoimidazol-5-yl)- phenyll-ethyl}-6-phenvl-ri,31oxazinan-2-one
Figure imgf000079_0003
3-[(5)-l-(3',4'-Diamino-biphenyl-4-yl)-ethyl]-(5)-6-(2-hydroxy-2-methyl-propyl)-6- phenyl- [1,3] oxazinan-2 -one (120 mg) taken up in acetic acid (2 mL) was stirred under microwave irradiation at 150 0C for 30 min. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound.
Yield: 77 mg (61% of theory); Mass spectrum (ESI+): m/z = 484 [M+H]+.
Examples 30 and 31
3-[(S)-I -(4-Bromo-phenyl)-ethyll-(R)-6-methoxymethyl-6-phenyl-ri,31oxazinan-2-one and 3-[(S)-I -(4-Bromo-phenyl)-ethyll-(S)-6-methoxymethyl-6-phenyl-ri,31oxazinan-2-one
Figure imgf000080_0001
Triphosgene (157 mg) was added to an ice-cold solution of 4-[(S)-l-(4-bromo- phenyl)-ethylamino]-l-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 (MeCNZH2OZNH3) to afford the title compounds in separate fractions.
Example 30: 3-[(S)-I -(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl- [l,3]oxazinan-2-one: Yield: 45 mg (21% of theory). Mass spectrum (ESI+): m/z = 404 [M+H]+. 1H NMR (400 MHz, OMSO-d6) δ 1.41 (d, J= 7.1 Hz, 3H), 2.19 (td, J = 11.2, 5.2 Hz, IH), 2.24-2.34 (m, IH), 2.34-2.41 (m, IH), 3.02-3.09 (m, IH), 3.27 (s, 3H), 3.49 (d, B part of an AB signal, J= 10.6 Hz, IH), 3.53 (d, A part of an AB signal, J= 10.6 Hz, IH), 5.34 (q, J= 7.0 Hz, IH), 6.80 (dm, J= 8.4 Hz, 2H), 7.27 (dm, J= 8.4 Hz, 2H), 7.32-7.42 (m, 5H).
Example 31 : 3-[(S)-I -(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl- [l,3]oxazinan-2-one: Yield: 45 mg (21% of theory). Mass spectrum (ESI+): m/z = 404 [M+H]+. 1H NMR (400 MHz, OMSO-d6) δ 1.20 (d, J= 7.2 Hz, 3H), 2.13-2.23 (m, IH),
2.32-2.40 (m, IH), 2.63-2.72 (m, IH), 2.73-2.81 (m, IH), 3.26 (s, 3H), 3.48 (d, B part of an AB signal, J= 10.6 Hz, IH), 3.55 (d, A part of an AB signal, J= 10.6 Hz, IH), 5.35 (q, J = 7.2 Hz, IH), 7.19 (dm, J= 8.4 Hz, 2H), 7.32-7.45 (m, 5H), 7.53 (dm, J= 8.4 Hz, 2H).
Example 32
(S)-6-(2-Methyl-allyl)-3-{(S)-l-r4-(5-methyl-ri.3.41oxadiazol-2-yl)-phenyll-ethvU-6- phenyl- [1,31 oxazinan-2 - one
Figure imgf000081_0001
A mixture of 4-{(S)-l-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl- [l,3]oxazin-an-3-yl]-ethyl} -benzoic acid hydrazide (90 mg), toluene-4-sulfonic acid monohydrate (10 mg), and 1,1,1-trimethoxy- ethane (1 ml) was stirred at room temperature for 1 h, at 80 0C for 2 h, and finally at reflux temperature for 1.5 h. After cooling to ambient temperature, ethyl acetate was added and the resulting mixture was washed with aqueous NaHCθ3 solution and brine. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2CVMeOH 99:l->95:5) to afford the title compound as a colorless resin- like solid. Yield: 55 mg (60% of theory); TLC: rf = 0.70 (silica gel; CH2Cl2/Me0H 95:5);
Mass spectrum (ESI+): m/z = 418 [M+H]+.
Example 33
(S)-6-(2-Hvdroxy-2-methyl-propyl)-3-{(S)-l-r4-(l-methyl-2-oxo-piperidin-4-yl)- phenyll-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000081_0002
PtO2 (50 mg) was added to (5)-6-(2-hydroxy-2-methyl-propyl)-3-{(5)-l-[4-(l- methyl-2-oxo-l,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-6-phenyl-[l,3]oxazinan-2-one (150 mg; the compound was obtained from (5)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(5)-l- (4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethyl]-l,3-oxazinan-2-one and 4- bromo-1 -methyl- lH-pyridin-2-one employing the procedure described for Example 1) dissolved in methanol (5 mL). The resulting mixture was shaken in hydrogen atmosphere (50 psi) for 8 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound.
Yield: 100 mg (66% of theory); LC (method 1): tR = 2.89 min; Mass spectrum (ESI+): m/z = 482 [M+NH4]+.
The following compound was obtained in analogy to Example 33: Example 34
(5)-6-(2-Hvdroxy-2-methyl-propyn-3-{('5)-l-r4-('l-methyl-6-oxo-piperidin-3-vn- phenyl1-ethyl}-6-phenyl-ri,31oxazinan-2-one
Figure imgf000082_0001
LC (method 1): tR = 2.89 min; Mass spectram (ESI+): m/z = 465 [M+H]+
The starting compound, (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-l-[4-(l-methyl-6-oxo- l,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[l,3]oxazinan-2-one, was obtained from (5)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(5)-l-(4-(4,4,5,5- tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)ethyl]-l,3-oxazinan-2-one and 5-bromo-l -methyl- lH-pyridin-2- one employing the procedure described for Example 1.
Example 35 4-(4-{(S)-l-r(S)-6-(2-Hvdroxy-2-methyl-propyn-2-oxo-6-phenyl-π.31oxazinan-3- yll-ethyl}-phenyl)-piperidine-l-carboxylic acid methylamide
Figure imgf000082_0002
MeNH2*HCl (27 mg) and K2CO3 (93 mg) were added to a solution of 4-nitrophenyl chloroformate (66 mg) in acetonitrile (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h, before (5)-6-(2-hydroxy-2-methyl-propyl)-6- phenyl-3-[(5)-l-(4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (110 mg) and NEt3 (53 μL) were added. The mixture was further stirred at room temperature overnight. Then, diluted aqueous ammonia solution was added and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeOH/H2O/NH3) to afford the title compound.
Yield: 100 mg (80% of theory); Mass spectrum (ESI+): m/z = 494 [M+H]+.
Example 36 4-ffS)-4-{l-rfS)-6-f2-Hvdroxy-2-methyl-propyn-2-oxo-6-phenyl-π.31oxazinan-3- yli-ethyll-phenyiypiperidine-l-carboxylic acid dimethylamide
Figure imgf000083_0001
Dimethylcarbamoyl chloride (26 μL) was added to a solution of (5)-6-(2-hydroxy- 2-methyl-propyl)-6-phenyl-3-[(5)-l-(4-piperidin-4-yl-phenyl)-ethyl]-[l,3]oxazinan-2-one (120 mg) and pyridine (40 μL) in N,N-dimethylformamide (2 mL) at room temperature. The solution was stirred at room temperature for 5 h, before another portion of dimethylcarbamoyl chloride (26 μL) and pyridine (20 μL) were added. The solution was stirred at room temperature overnight. Then, diluted aqueous ammonia solution was added and the resulting mixture was concentrated under reduced pressure. The residue was purified by HPLC on reversed phase (MeOH/H2O/NH3) to afford the title compound.
Yield: 70 mg (50% of theory); LC (method 1): tR = 3.17 min; Mass spectrum (ESI+): m/z = 508 [M+H]+.
Example 37
3-{(1S)-l-[4-(l,2-dimethyl-lH-benzo[d]imidazol-5-yl)phenyl]ethyl}-6-(2-hydroxy-2- methylpropyl)-6-isopropyl-l,3-oxazinan-2-one
Figure imgf000084_0001
Step 1
To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol) and ethylene glycol (56 g, 1 mol) in toluene (500 mL) was added 4-methylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was stirred at reflux with a Dean-Stark trap to remove water. The reaction mixture was washed with a small amount of water and brine, dried over anhydrous Na2SOzI, and concentrated in vacuum to give the crude (2-isopropyl-[l,3]dioxolan-2-yl)- acetic acid methyl ester (67 g 71% yield), which was used for the next step without further purification.
Step 2
In a flame-dried, three-neck flask equipped with an addition funnel, magnetic stirring bar, rubber septum, and a nitrogen inlet, was placed LiAlH4 (3.12 g, 82.1 mmol) and tetrahydrofuran (700 mL). After being cooled at 0 0C, a solution of (2-isopropyl- [l,3]dioxolan-2-yl)-acetic acid methyl ester (12 g, 63.8 mmol) in tetrahydrofuran (160 mL) was added dropwise with stirring. The mixture was warmed to room temperature and stirred for 24 hours. The reaction was quenched by adding water (5 mL), 15% aqueous NaOH (10 mL), and water (5 mL) slowly. The organic layer was separated, and the residue was extracted with EtOAc (3x100 mL). The combined organic phase was dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to give 2-(2-isopropyl-[l,3]dioxolan-2-yl)-ethanol (6.8 g, 67%). 1H NMR (CDCl3) δ 0.90 (d, J = 6.8 Hz, 6H), 1.87-1.96 (m, 3H), 2.81 (br, IH), 3.69-3.72 (m, 2H), 3.92-4.01 (m, 4H).
Step 3 To a solution of 2-(2-isopropyl-l,3-dioxolan-2-yl)-ethanol (8.0 g, 50 mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH2Cl2 (120 mL) was added methanesulfonyl chloride (11.6 mL , 150 mmol) at 0 0C, and the reaction mixture was stirred at room temperature till the reaction was finished. The reaction mixture was washed with water and brine, dried over Na2SO/), filtered, and concentrated to give the crude methanesulfonic acid 2-(2-isopropyl-[l,3]dioxolan-2-yl)-ethyl ester (12 g), which was used for the next step without further purification.
Step 4
To a solution of methanesulfonic acid 2-(2-isopropyl-[l,3]dioxolan-2-yl)-ethyl ester (12 g, 50 mmol) and (5>l-(4-bromophenyl)ethanamine (19.9 g, 100 mmol) in CH3CN (250 mL) was added K2CO3 (8 g, 58 mmol), and the mixture was refluxed for 1O h. The solution was filtered, and the filtrate was concentrated to afford the crude product, which was purified by column chromatography to give [(5<)-l-(4-bromophenyl)-ethyl]-[2-(2-isopropyl- [l,3]dioxolan-2-yl)-ethyl]-amine (6.5 g, 38%).
Step 5
To a solution of [(5)-l-(4-bromophenyl)-ethyl]-[2-(2-isopropyl-[l,3]dioxolan-2-yl)- ethyl]-amine (6.5 g, 19 mmol) in MeOH (60 mL) was added concentrated aqueous HCl (60 mL). The mixture was stirred at 65 0C till the reaction was finished. The mixture was cooled to 0 0C, and the pH of the mixture was adjusted to 7 by adding saturated aqueous NaHCO3. The mixture was concentrated, and the residue was extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine, dried over Na2Sθ4, and concentrated to give l-[(5)-l-(4-bromophenyl)-ethylamino]-4-methyl-pentan-3-one (5.5 g, 97%), which was used for the next step without further purification. 1H NMR (CDCl3): δ 1.07 (d, J= 6.8 Hz, 6H), 1.29 (d, J = 6.4 Hz, 3H), 1.89 (br, IH), 2.54-2.62 (m, 4H), 2.66-2.69 (m, IH), 3.68- 3.72 (m, IH), 7.18-7.20 (m, 2H), 7.41-7.44 (m, 2H).
Step 6
To a suspension of Mg (Hg, 458 mmol) and I2 (0.5g) in anhydrous tetrahydrofuran (50 mL) was added 3-chloro-2-methylprop-l-ene (1 mL) to initiate the reaction.
Tetrahydrofuran (300 mL) was added, more solution of 3-chloro-2-methylprop-l-ene (15 mL) in tetrahydrofuran (20 mL) was dropped into the reaction at 0 0C under N2 over 30 min. A solution of l-[(S)-l-(4-bromophenyl)-ethylamino]-4-methyl-pentan-3-one (5g) in tetrahydrofuran (5OmL) was added dropwise at -78 0C over 45 min. The reaction mixture was stirred at room temperature for 2 h. The reaction was cautiously quenched with saturated aqueous NH4Cl, and the reaction mixture was filtered. The filtrate was extracted with EtOAc (3 x 100 mL) and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3-{(5<)-2-[l-(4-bromophenyl)- ethylamino] -ethyl} -2,5-dimethyl-hex-5-en-3-ol (6.4 g, 90% yield ), which was used for the next step without further purification.
Step 7
To a solution of 3-{(5)-2-[l-(4-bromophenyl)-ethylamino]-ethyl}-2,5-dimethyl-hex- 5-en-3-ol (6.4 g, 16.8 mmol) and triethylamine (5.34 g, 52 mmol) in CH2Cl2 (260 mL) was added triphosgene (2.52 g, 8.5 mmol) at 0 0C under N2, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by column chromatography to give two isomers of 3-[(5)-l-(4-bromophenyl)ethyl]- 6-isopropyl-6-(2-methylallyl)-l,3-oxazinan-2-one. Isomer 1 : (lower rf on silica gel TLC, 1.85 g, 27% yield). 1H NMR (CDCl3) δ
0.83(d, J = 12 Hz, 3H), 0.89 (d, J = 12 Hz, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.64-1.70 (m, 2H), 1.79 (s, 3H), 1.88-1.95 (m, IH), 2.20 -2.34 (m, 2H), 2.59-2.65 (m, IH), 3.01-3.08 (m, IH), 4.70 (s, IH), 4.87 (s, IH), 5.68-5.77 (m, IH), 7.14 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H). Isomer 2: (higher rf on silica gel TLC, 1.25g, 18% yield). 1H NMR (CDCl3) δ 0.87
(d, J = 6.8 Hz, 3H), 0.92(d, J = 6.8 Hz, 3H), 1.50 (d, J = 12 Hz, 3H), 1.60-1.66 (m, IH), 1.78 (s, 3H), 1.73-1.79 (m, IH), 1.78 -2.05 (m, IH), 2.08 (d, J = 14.0 Hz, IH), 2.30 (d, J = 14.0 Hz, IH), 2.62-2.68 (m, IH), 2.98-3.05 (m, IH), 4.64 (s, IH), 4.84 (s, IH), 5.70-5.75 (m, IH), 7.13 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H).
Step 8
To a solution of 3-[(5)-l-(4-bromophenyl)ethyl]-6-isopropyl-6-(2-methylallyl)-l,3- oxazinan-2-one isomer 1 (500 mg, 1.32mmol) in dry CH2Cl2 (64 mL) was added 3- chloroperoxybenzoic acid (455 g, 2.64 mmol) at room temperature. The reaction mixture was stirred until the starting material was consumed (monitored by TLC). The mixture was diluted with (CH3)3COCH3 (70 mL), washed with 30% aqueous Na2S2O3 and aqueous NaHCO3 (3 x), dried over Na2SO4, filtered, and concentrated to give 3-[(5)-l-(4- bromophenyl)ethyl]-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-l,3-oxazinan-2-one isomer 1 (520 mg, 99%), which was used directly for the next step without further purification.
Step 9
To a solution of 3-[(5)-l-(4-bromophenyl)ethyl]-6-isopropyl-6-((2-methyloxiran-2- yl)methyl)-l,3-oxazinan-2-one isomer 1 (520 mg, 1.32 mmol) in tetrahydrofuran (32 mL) was added dropwise LiEt3BH (13.6 mL, 13.6 mmol) at 0 0C under N2 over 30 min. The resulting solution was stirred at 10-13 0C for 21.5 h. Then aqueous H2O2 (40 mL) was added to the mixture and the resulting solution was diluted with (CH3)3COCH3 (380 mL), and washed with water, 30% aqueous Na2S2O3, and brine. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography to afford 3-[(5<)-l-(4-bromophenyl)ethyl]-6-(2-hydroxy- 2-methylpropyl)-6-isopropyl-l,3-oxazinan-2-one isomer 1 (320 mg, 61%). 1H NMR (CDCl3) δ 0.82 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.51 (d, J= 10.0 Hz, 3H), 1.61 (d, J= 15.2 Hz, IH), 1.78-1.84 (m,lH), 1.91 (d, J= 15.2 Hz, IH), 2.02-2.15 (m, 2H), 2.36 (br, IH), 2.62-2.68 (m, IH), 3.03-3.09 (m, IH), 5.73 (t, J= 7.2 Hz, IH), 7.17-7.19 (m, 2H), 7.44-7.48 (m, 2H).
Step 10
To a solution of 3-[(5)-l-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methylpropyl)-6- isopropyl-l,3-oxazinan-2-one isomer 1 (315 mg, 0.793 mmol) in dimethyl sulfoxide (10 mL) was added 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (602 mg, 2.38 mmol), CH3CO2K (770 mg, 79.3 mmol), and Pd[1, 1 '- bis(diphenylphosphino)ferreocene]2Cl2 (50 mg, 0.06 mmol) under N2 and the reaction mixture was stirred at 90 0C for 4 h. The reaction was quenched with aqueous NH4Cl, and the resulting mixture was extracted with EtOAc. The combined extracts were washed with water and brine. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC to give 6-(2- hydroxy-2-methylpropyl)-6-isopropyl-3-{(5)-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl]ethyl}-l,3-oxazinan-2-one isomer 1 (250 mg, 71%).
Step 11 To a solution of 5-bromo-l,2-dimethyl-lH-benzo[</]imidazole (30 mg, 0.13 mmol),
6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-{(5)-l-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]ethyl}-l,3-oxazinan-2-one isomer 1 (15 mg, 0.034 mmol) and Na2CO3 (10.74 mg, 0.10 mmol) in toluene (3 mL), EtOH (2 mL) and H2O (1 mL) was added Pd(PPh3)4 (0.39 mg, 0.003 mmol) at room temperature. The reaction mixture was heated to 100 0C under N2 and stirred at this temperature for 2 h. The formed mixture was concentrated to afford an oil which was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated to afford an oil which was purified by preparative TLC and preparative HPLC to afford 3-{(5)-l-[4-(l,2-dimethyl-lH- benzo[d]imidazol-5-yl)phenyl]-ethyl}-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-l,3- oxazinan-2-one isomer 1 (5.5 mg, 8.9%). 1H NMR (CD3OD) δ 0.79 (d, 3H), 0.89 (d, 3H), 1.21 (s, IH), 1.22 (s, 6H), 1.51 (m, 3H), 1.62 (m, IH), 1.82 (m, 2H), 2.03 (m, IH), 2.12 (m, IH), 2.52 (m, 3H), 2.72 (m, IH), 3.72 (m, 3H), 5.62 (m, IH), 7.31 (m, 2H), 7.42 (m, 2H), 7.55 (m, 2H), 7.69 (s, IH); Mass spectrum (ESI+): m/z = 464 [M+H]+.
The following compound was obtained in analogy to Step 11 of Example 37:
Example 38
6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-{(S)-l-[4-(l-methyl-lH- benzo[d]imidazol-5-yl)phenyl]ethyl}-l,3-oxazinan-2-one
Figure imgf000088_0001
5-Bromo-l -methyl- lH-benzoimidazole was employed as the coupling partner.
1H NMR (CD3OD) 0.77 (d, 3H), 0.88 (d, 3H), 1.15-1.25 (6H), 1.55 (d, 3H), 1.60- 1.90 (3H), 2.07 (m, IH), 2.15 (m, IH), 2.74 (2H), 4.08 (s, 3H), 5.58 (q, IH), 7.40 (d, 2H), 7.64 (d, 2H), 7.87 (m, 2H), 7.94 (s, IH), 9.28 (s, IH); Mass spectrum (ESI+): m/z = 450 [M+H]+.
BIOLOGICAL TEST EXAMPLE 1
In vitro inhibition of 11 β-HSDl 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 is 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 is 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 Table 1 the 11 β-HSD 1 inhibitory activities, determined as described above, are compiled, wherein 100% indicates no inhibition and a value of zero or below zero indicates complete inhibition.
Table 1.
Figure imgf000089_0001
Figure imgf000090_0001
BIOLOGICAL TEST EXAMPLE 2
The inhibition of a microsomal preparation of l lβ-HSDl by compounds of the invention was measured essentially as previously described (K. Solly, S. S. Mundt, H.J. Zokian, GJ. Ding, A. Hermanowski-Vosatka, B. Strulovici, and W. Zheng, High- Throughput Screening of 11 -Beta-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 KCl, 5mM NaCl, 2mM MgCl2, 2 mM NADPH and 160 nM [3H]cortisone (1 Ci/mmol)) and mixing in 1 μL of the test compounds in DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre- incubation, 50 μL of enzyme solution containing microsomes isolated from CHO cells overexpressing human l lβ-HSDl (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 containing 10 μM 18-β- 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.
Table 2. l lβ-HSD 1 inhibitory activities of compounds of the invention determined as described above.
Figure imgf000090_0002
The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state. Thus, the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome, infertility and hypergonadism. 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 11 β-HSD 1 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 β-HSD 1 activity is pseudo Cushing's Syndrome associated with alcoholic liver disease.
A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I, comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefore. Alternatively, a pharmaceutical composition of the invention may comprise a compound of Formula I, Ia-I or a pharmaceutical salt thereof as the only pharmaceutically active agent in the pharmaceutical composition. The disclosed 11 β-HSD 1 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 11 β-HSD 1 inhibitors. Said compositions contain compounds having a mean inhibition constant (IC5o) against 11 β-HSD 1 of below about 1,000 nM; preferably below about 100 nM; more preferably below about 50 tiM; 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 11 β- HSDl mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof of composition thereof. As used herein, "treating" or "treatment" includes both therapeutic and prophylactic treatment. Therapeutic treatment includes reducing the symptoms associated with a disease or condition and/or increasing the longevity of a subject with the disease or condition.
Prophylactic treatment includes delaying the onset of a disease or condition in a subject at risk of developing the disease or condition or reducing the likelihood that a subject will then develop the disease or condition in a subject that is at risk for developing the disease or condition.
An embodiment of the invention includes administering an l lβ-HSDl inhibiting compound of Formula I or composition thereof in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma. Agents for the treatment of diabetes include insulins, such as Humulin® (Eli 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 HCl, Bristol Myers Squibb) and Glumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs, GLP-I analogs; DPP-IV inhibitors; PTB-IB 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 l lβ-HSDl inhibiting compound of Formula I or composition thereof in a combination therapy with one or more other l lβ-HSDl inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); and Glucovance® (glyburide and metformin HCl, 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, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can either be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and 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 l lβ-HSDl or an inhibitor in the production of Cortisol in the cell, the active ingredient is preferably administered orally in a solid dosage form as disclosed above in an amount of about 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily. All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually designated as having been incorporated by reference. It is understood that the examples and embodiments described herein are for illustrative purposes only, and it will be appreciated that the invention is susceptible to modification, variation and change without departing from the proper scope or fair meaning of the appended claims.

Claims

What is claimed is:
1. A compound of Formula (I)
Figure imgf000095_0001
wherein:
R1 is (a) absent or (b) is selected from (Ci-C6)alkyl, (Ci-C6)cycloalkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C3)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) (Ci-C3)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(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, (d-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4- C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4-
C7)cycloalkylalkanesulfinyl, halo(C i-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-
C6)alkylamino, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci- C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-
C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci- C6)alkoxy, (Ci-C6)alkoxy(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, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Cr C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-
C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Ci- C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci- C6)alkylaminocarbonyl(Ci-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl, ((C3-
C6)cycloalkyl} {(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(C i -C6)alkyl;
Cy2 is benzimidazolyl, benzotriazolyl and piperidinyl 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(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(Cr C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (d-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C i-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)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, (CrCβ^lkylamino, di(Ci-C6)alkylamino, (C1- C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-
C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (C1- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (C1- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (C1- C6)alkoxy(Ci-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, heteroaryl, oxo, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (Ci-C6)alkylamino(C2-C6)alkoxy, di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl, hydroxy(Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Cr
C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci- C6)alkylaminocarbonyl(C i-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(C i-C6)alkyl, ((C3- C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and di(C3- C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; wherein the piperidinyl represented by Cy1 is attached to Cy1 through a ring carbon atom; or when R3 is methoxymethyl, Cy2 is (a) halogen or -0-SO3-R , wherein R is (i) (Ci-C/Oalkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl or NO2;or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, 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(CrC6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1- C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C rC6)alkoxy, halo(C3-
C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4- C7)cycloalkylalkylthio, (C1-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C4- C7)cycloalkylalkanesulfinyl, halo(C i-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3- C6)cycloalkanesulfonyl, halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci- C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (C1-
C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Cr C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci- C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci- C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-
C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(Cr Ce)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, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3- C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3-
C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} ((Ci- C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl, di(Ci- C6)alkylaminocarbonyl(C i-C6)alkyl, (C3-C6)cycloalkylaminocarbonyl(C i-C6)alkyl, ((C3- C6)cycloalkyl} {(C1-C6)alkyl}aminocarbonyl(C1-C6)alkyl and di(C3-
C6)cycloalkylaminocarbonyl(C i -C6)alkyl; Y is (Ci-C6)alkyl, halo(Ci-C6)alkyl or oxo; n is 0, 1 or 2;
E is (a) a bond or (b) (Ci-C3)alkylene or (Ci-C2)alkylenyloxy, wherein the O is attached to R2, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
R2 is (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl 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(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, (C1-C6)alkoxy, (C3- C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkyl- alkylthio, halo(C rC6)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)cycloalkyl- alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl- alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C4- C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci- C6)alkoxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy(Ci-C6)alkoxy, (Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci- C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino, (Ci- C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci- C6)alkoxy(Ci-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C rC6)alkoxy, heteroaryl, oxo, amino(C i-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, (Ci-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, ((C3- C6)cycloalkyl} {(Ci-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- C6)cycloalkylaminosulfonyl, {(C3-C6)cycloalkyl} {(Ci-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-
C6)alkylaminocarbonyl(C i-C6)alkyl, di(C 1-C6)alkylaminocarbonyl(C i-C6)alkyl, (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 (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C5)cycloalkyl(C1-C4)alkyl, (C1-C3)alkoxy(C1-C3)alkoxy, or (C1-C3)alkoxy(C1-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-C6)alkyl, halo(Ci-C6)alkyl, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl and (C1- C6)alkoxy(C 1-C6)alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
The compound of Claim 1, wherein the compound is represented by one of the following structural formulas:
Figure imgf000100_0001
wherein each substitutable ring nitrogen atom in the benzimidazolyl ring is optionally substituted with (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, or (Ci-C4)haloalkyl; wherein each substitutable ring carbon atom in the benzimidazolyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl, (Ci- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci- C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
The compound of Claim 1, wherein the compound is represented by one of the following structural formulas:
Figure imgf000101_0001
wherein each substitutable ring nitrogen atom in the benzotriazolyl ring is optionally substituted with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C4)haloalkyl; wherein each substitutable ring carbon atom in the benzotriazolyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (Cr C4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylcarbonyl, (Cr C4)alkoxycarbonyl, (Ci-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
4. The compound of Claim 1 , wherein the compound is represented by one of the following structural formulas:
Figure imgf000102_0001
wherein each substitutable ring nitrogen atom in the piperidinyl ring is optionally substituted with (Ci-C4)alkyl, (Ci-C4)alkanesulfonyl, (Ci-C4)alkyloxycarbonyl, (Ci-C4)alkylcarbonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C4)alkylaminocarbonyl or di(Ci-C4)alkylaminocarbonyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
5. The compound of Claim 2, wherein the compound is represented by one of the following structural formulas:
Figure imgf000103_0001
wherein each substitutable ring nitrogen atom in the benzimidazolyl ring is optionally substituted with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C4)haloalkyl; wherein each substitutable ring carbon atom in the benzimidazolyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(C1-C4)alkyl, (d-C4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl, (Ci-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
The compound of Claim 3, wherein the compound is represented by one of the following structural formulas:
Figure imgf000104_0001
wherein each substitutable ring nitrogen atom in the benzotriazolyl ring is optionally substituted with (d-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C4)haloalkyl; wherein each substitutable ring carbon atom in the benzotriazolyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (Cr C4)alkoxy, (d-C^haloalkoxy, CONH2, (d-C4)alkylcarbonyl, (C1- C4)alkoxycarbonyl, (Ci-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
The compound of Claim 4, wherein the compound is represented by one of the following structural formulas:
Figure imgf000105_0001
wherein each substitutable ring nitrogen atom in the piperidinyl ring is optionally substituted with (Ci-C4)alkyl, (Ci-C4)alkanesulfonyl, (Ci-C4)alkyloxycarbonyl, (Ci-C4)alkylcarbonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C4)alkylaminocarbonyl or di(Ci-C4)alkylaminocarbonyl; wherein each substitutable ring carbon atom in the piperidinyl ring is optionally substituted with fluorine, hydroxy, (CrC4)alkyl or (Ci-C4)alkoxy ; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
The compound of Claim 5, wherein the compound is represented by one of the following structural formulas:
Figure imgf000106_0001
wherein each substitutable ring nitrogen atom in the benzimidazolyl ring is optionally substituted with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C4)haloalkyl; wherein each substitutable ring carbon atom in the benzimidazolyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (CrC4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl, (Ci-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; each G1 is independently halogen, cyano, oxo, nitro, hydroxy, amino, (CrC4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)haloalkoxy, (Ci-C4)alkoxycarbonyl, benzoxycarbonyl, CONH2, (Ci- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (C3-
C4)cycloalkylaminocarbonyl, {(Ci-C4)alkyl} {(C3-C4)cycloalkyl}aminocarbonyl and (Ci-C4)alkylcarbonylamino; and r is 0, 1 or 2 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
The compound of Claim 6, wherein the compound is represented by one of the following structural formulas:
Figure imgf000107_0001
wherein each substitutable ring nitrogen atom in the benzotriazolyl ring is optionally substituted with (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (Ci-C4)haloalkyl; wherein each substitutable ring carbon atom in the benzotriazolyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (C1- C4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylcarbonyl, (d- C4)alkoxycarbonyl, (Ci-C^alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; each G1 is independently halogen, cyano, oxo, nitro, hydroxy, amino, (CrC4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)haloalkoxy, (Ci-C4)alkoxycarbonyl, benzoxycarbony, CONH2, (Ci- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (C3-
C4)cycloalkylaminocarbonyl, {(Ci-C4)alkyl} {(C3-C4)cycloalkyl}aminocarbonyl and (Ci-C4)alkylcarbonylamino; and r is 0, 1 or 2 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
10. The compound of Claim 7, wherein the compound is represented by one of the following structural formulas:
Figure imgf000108_0001
wherein each substitutable ring nitrogen atom in the piperidinyl ring is optionally substituted with (Ci-C4)alkyl, (Ci-C4)alkanesulfonyl, (Ci-C4)alkyloxycarbonyl, (Ci-C4)alkylcarbonyl, hydroxy(Ci-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C4)alkylaminocarbonyl or di(Ci-C4)alkylaminocarbonyl; wherein each substitutable ring carbon atom in the piperidinyl ring is optionally substituted with fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(Ci-C2)alkyl, halo(d-C4)alkyl, (CrC4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylcarbonyl, (CrC4)alkoxycarbonyl, (CrC4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; each G1 is independently halogen, cyano, oxo, nitro, hydroxy, amino, (CrC4)alkyl, (C3- C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(Ci-C4)alkyl, (CrC4)alkoxy, (d- C4)haloalkoxy, (Ci-C4)alkoxycarbonyl, benzoxycarbony, CONH2, (Ci- C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl, (C3-
C4)cycloalkylaminocarbonyl, {(Ci-C4)alkyl} {(C3-C4)cycloalkyl}aminocarbonyl and (Ci-C4)alkylcarbonylamino; and r is 0, 1 or 2 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
11. The compound of Claim 8, wherein the compound is represented by any one of the following structural formulas:
Figure imgf000109_0001
; wherein each G1 is independently (Ci-C4)alkyl, (d-C4)alkoxy, (Ci-C4)haloalkyl, (C1-
C4)haloalkoxy, halogen, cyano or nitro; r is 0, 1 or 2;
G2a is (C1-C4 )alkyl, (C3-C4)cycloalkyl, or (CrC4)haloalkyl; and each G2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C1- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(Ci-C4)alkyl, (C1- C4)alkoxy, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl,(Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (C1- C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
12. The compound of Claim 9, wherein the compound is represented by any one of the following structural formulas:
Figure imgf000110_0001
; wherein each G1 is independently (CrC4)alkyl, (CrC4)alkoxy, (Ci-C4)haloalkyl, (C1-
C4)haloalkoxy, halogen, cyano or nitro; r is 0, 1 or 2;
G2a is (Ci-C4 )alkyl, (C3-C4)cycloalkyl, or (Ci-C4)haloalkyl; and each G2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (Cr C4)alkoxy, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl,(Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Cr C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
13. The compound of Claim 10, wherein the compound is represented by one of the following structural formulas:
Figure imgf000110_0002
or
Figure imgf000111_0001
; wherein each G1 is independently (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkyl, (Ci- C4)haloalkoxy, halogen, cyano or mtro; r is 0, 1 or 2;
G2a is (C1-C4 )alkyl, (C1-C4)alkanesulfonyl, hydroxy(C1-C4)alkylcarbonyl, tetrahydrofuranylcarbonyl, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci- C4)alkylaminocarbonyl, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl; and each G2b is independently hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci- C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, halo(CrC4)alkyl, (Cr C4)alkoxy, (Ci-C4)alkylcarbonyl, (Ci-C4)alkoxycarbonyl,(Ci-C4)haloalkoxy, CONH2, (Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl or (Cr C4)alkylcarbonylamino; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
14. The compound of any one of Claims 1-13, wherein
R2 is (Ci-C4)alkyl, phenyl, thienyl, or pyπdyl, each optionally substituted with halogen, mtro, cyano, (CrC6)alkyl, halo(CrC6)alkyl, hydroxy(Ci-C3)alkyl, (d-C3)alkoxy, halo(Ci-C3)alkoxy, CONH2 and SO2Me; and
R3 is methyl, ethyl, propyl, butyl, vinyl, allyl, propenylmethyl or ethoxyethyl each optionally substituted with up to two groups independently selected from (Ci- C4)alkyl, (Ci-C4 )alkoxy, (Ci-C4 )alkoxycarbonyl, hydroxy(Ci-C4 )alkyl, cyano(Ci- C4 )alkyl, (Ci-C4)haloalkyl, (Ci-C4)haloalkoxy, (Ci-C4)alkylarmno, di(d- C4)alkylamino, halogen, cyano, oxo, mtro, hydroxy, amino, MeSO2-, MeSO2N(Me)(C i-C4)alkyl, MeSO2NH(C i-C4)alkyl, H2NC(=O)CMe2(Ci-C4)alkyl, H2NC(=O)CHMe(Ci-C4)alkyl and H2NC(=O)CH2(Ci-C4)alkyl.
15. The compound of Claim 1-14, wherein R1 is methyl or ethyl.
16. The compound of Claim 15, wherein R3 is MeSO2NHCH2CH2CH2,
H2NCC=O)CH2CH2, H2NCC=O)CMe2CH2, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
17. The compound of Claim 16, wherein R2 is isopropyl or phenyl which is optionally substituted with 1, 2 or 3 substituents selected from halo, cyano and (Ci-C4)alkyl.
18. The compound of Claim 17, wherein R3 is H2NC(=O)CMe2CH2, 3-hydroxy-3- methylbutyl, 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
19. The compound of Claim 18, wherein R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2- methylpropyl.
20. The compound of Claim 18, wherein R2 is isopropyl, phenyl or fluorophenyl.
21. The compound of Claim 1, wherein the compound is represented by the following structural formula:
Figure imgf000112_0001
wherein Cy2 is (a) halogen or -0-SO3-R or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, 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, (C3-C7)cycloalkyl(Ci-C2)alkyl, (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(C3-C7)cycloalkyl(C1-C2)alkyl, (d-C6)alkoxy, (C3-
C6)cycloalkoxy, (C3-C7)cycloalkyl(CrC2)alkoxy, halo(CrC6)alkoxy, halo(C3- C6)cycloalkoxy, halo(C3-C7)cycloalkyl(CrC2)alkoxy, (CrC6)alkylthio, (C3- C6)cycloalkythio, (C3-C7)cycloalkyl(Ci-C2)alkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C3-C7)cycloalkyl(C1-C2)alkylthio, (C1- C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl, (C3-C7)cycloalkyl(C i -C2)alkanesulfinyl, halo(Ci-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C3- C7)cycloalkyl(Ci-C2)alkanesulfinyl, (Ci-C6)alkanesulfonyl, (C3- C6)cycloalkanesulfonyl, (C3-C7)cycloalkyl(Ci-C2)alkanesulfonyl, halo(Ci- C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, halo(C3-C7)cycloalkyl(Ci-
C2)alkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, (Ci-C6)alkoxy(Ci- C6)alkoxy, 1IaIo(C1 -C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl, di(Ci-C6)alkylaminocarbonyl, (Ci- C3)alkoxy(Ci-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (Ci- C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (Ci-
C6)alkylcarbonylamino, (Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci- C6)alkylsulfonylamino, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci- C6)alkoxycarbonyl(Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci- C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl, (Ci- C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl amino(C2-C6)alkoxy,
(C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1- C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl} {(C1-C6)alkyl}aminocarbonyl, di(C3- C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl, ((C3- C6)cycloalkyl} {(C1-C6)alkyl}aminosulfonyl, di(C3-C6)cycloalkylaminosulfonyl, cyano^i -C6)alkyl, aminocarbonyl(Ci-C6)alkyl, (Ci-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(Ci-C6)alkyl and di(C3-C6)cycloalkylaminocarbonyl(Ci- C6)alkyl; and
R is (i) (Ci-C4)alkyl optionally substituted with one or more halogen or (ii) phenyl, optionally substituted with halogen, (Ci-C4)alkyl or NO2; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
22. The compound of Claim 20, wherein the compound is represented by the following structural formula:
Figure imgf000114_0001
wherein: r is 0, 1, 2 or 3; and
G1 is independently (C1-C4 )alkyl, (C1-C4 )alkoxy, (d-C^haloalkyl, (d-C4)haloalkoxy, halogen, cyano and nitro; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
23. The compound of Claim 0, wherein the compound is represented by the following structural formula:
Figure imgf000114_0002
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
24. The compound of Claim 23, wherein the compound is represented by one of the following structural formulas:
Figure imgf000114_0003
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
25. The compound of any one of Claims 21-24 wherein:
Cy2 is (a) halogen or -0-SO3-R; or (b) cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, hydroxy(d- C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl, hydroxy(C3-C6)cycloalkyl, 1IaIo(C1 -C6)alkyl, (d-C6)alkoxy, (C3-C6)cycloalkoxy, halo(C1-C6)alkoxy, (C1- C6)alkanesulfonyl, halo(C1-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, heterocyclylcarbonyl, (C1-C6)alkylaminosulfonyl, (Ii(C1 -C6)alkylaminosulfonyl, heterocyclylsulfonyl, (C1-
C6)alkylcarbonylamino, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1- C6)alkoxycarbonyl, (C1-C6)alkylsulfonylamino, oxo, CYaUo(C1 -C6)alkyl, aminocarbony^d- C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl and di(C1-C6)alkylaminocarbonyl(C1- C6)alkyl.
26. The compound of any one of Claims 21-24 wherein Cy2 is phenyl, thienyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benztriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl, each optionally substituted by 1 to 4 groups, wherein substituents for a substitutable ring nitrogen atom are selected from (d-C^alkyl, (C3-C4)cycloalkyl, (C3- C4)cycloalkyl(C1-C2)alkyl, (CrC4)haloalkyl, (CrC4)alkoxycarbonyl, (C1-C4)alkylcarbonyl and benzyloxycarbonyl; and substituents for a ring carbon atom are selected from fluorine, chlorine, cyano, hydroxy, amino, (CrC^alkyl, (C3-C4)cycloalkyl, (C3-C4)CyClOaIkYl(C1 -C2)alkyl, halo(C1-C4)alkyl, (CrC4)alkoxy, (CrC4)haloalkoxy, CONH2, (CrC4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl and (d-C^alkylcarbonylamino.
27. The compound of any one of Claims 21-24, wherein
R2 is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C3)alkyl, (CrC3)alkoxy, halo(Cr
C3)alkoxy, CONH2 and SO2Me.
28. The compound of Claim 27, wherein R1 is methyl or ethyl.
29. The compound of Claim 28, wherein R2 is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, CONH2, (d-C^alkyl, (C1-C4)haloalkyl, and SO2Me.
30. The compound of Claim 29, wherein R2 is phenyl or fluorophenyl.
31. A compound of any one of the following structural formulas:
Figure imgf000116_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
32. A compound of any one of the following structural formulas:
Figure imgf000116_0002
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
33. A compound of the following structural formula:
Figure imgf000116_0003
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
34. A compound of any one of the following structural formulas:
Figure imgf000117_0001
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
35. A compound of any one of the following structural formulas:
Figure imgf000117_0002
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
36. A compound of any one of the following structural formulas:
Figure imgf000117_0003
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
37. A method of treating a subject with a disease associated with the activity or expression of l lβ-HSDl, comprising the step of administering to the subject an effective amount of the compound in any one of claims 1-36.
38. A method of inhibiting l lβ-HSDl 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
1-36.
39. A method of inhibiting 1 lβ-HSDl 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 1-36.
40. A pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier or diluent; and ii) the compound in any one of claims 1-36; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
PCT/EP2009/059509 2008-07-25 2009-07-23 INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 WO2010010157A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US13/054,954 US8846668B2 (en) 2008-07-25 2009-07-23 Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
JP2011519178A JP5777030B2 (en) 2008-07-25 2009-07-23 Inhibitor of 11β-hydroxysteroid dehydrogenase 1
CA2729998A CA2729998A1 (en) 2008-07-25 2009-07-23 Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP09780992.5A EP2324017B1 (en) 2008-07-25 2009-07-23 INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US13593308P 2008-07-25 2008-07-25
US61/135,933 2008-07-25
US20676709P 2009-02-04 2009-02-04
US61/206,767 2009-02-04

Publications (2)

Publication Number Publication Date
WO2010010157A2 true WO2010010157A2 (en) 2010-01-28
WO2010010157A3 WO2010010157A3 (en) 2010-04-01

Family

ID=41570653

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/059509 WO2010010157A2 (en) 2008-07-25 2009-07-23 INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1

Country Status (7)

Country Link
US (1) US8846668B2 (en)
EP (1) EP2324017B1 (en)
JP (1) JP5777030B2 (en)
AR (1) AR072753A1 (en)
CA (1) CA2729998A1 (en)
TW (1) TW201016691A (en)
WO (1) WO2010010157A2 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010089303A1 (en) * 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1
WO2010139673A1 (en) * 2009-06-02 2010-12-09 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2010127237A3 (en) * 2009-04-30 2011-08-04 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2011149822A1 (en) 2010-05-26 2011-12-01 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
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
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
CN102421773A (en) * 2008-07-25 2012-04-18 贝林格尔·英格海姆国际有限公司 Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
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
US8497281B2 (en) 2009-11-06 2013-07-30 Vitae Pharmaceuticals, Inc. Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
CN103342700A (en) * 2012-01-19 2013-10-09 通化济达医药有限公司 11[beta]-hydroxysteroid dehydrogenase type 1 inhibitor
US20140066443A1 (en) * 2011-05-03 2014-03-06 Douglas C. Beshore Aminomethyl biaryl benzotriazole 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
US8686149B2 (en) 2010-11-05 2014-04-01 Boehringer-Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US8735585B2 (en) 2011-08-17 2014-05-27 Boehringer Ingelheim International Gmbh Indenopyridine derivatives
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
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
US8829027B2 (en) 2008-10-23 2014-09-09 Boehringer Ingelheim International Gmbh Urea derivatives of substituted nortropanes, medicaments containing such compounds and their use
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8859580B2 (en) 2007-11-16 2014-10-14 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
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
AU2010242876B2 (en) * 2009-04-30 2015-06-18 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
CN104788384A (en) * 2015-03-31 2015-07-22 山东友帮生化科技有限公司 Synthesis method of 3-hydroxy-6-chloropyridazine
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE554078T1 (en) 2007-07-26 2012-05-15 Vitae Pharmaceuticals Inc SYNTHESIS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 INHIBITORS
TW200934490A (en) 2008-01-07 2009-08-16 Vitae Pharmaceuticals Inc Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1
EP2252601B1 (en) * 2008-01-24 2012-12-19 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2254872A2 (en) 2008-02-15 2010-12-01 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
WO2009134387A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0902288A2 (en) 1997-09-12 1999-03-17 Ethicon, Inc. Wound diagnosis by quantitating cortisol in wound fluids
WO2007127693A1 (en) 2006-04-24 2007-11-08 Eli Lilly And Company Substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1

Family Cites Families (227)

* 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
US3681349A (en) 1970-03-05 1972-08-01 Morton Norwich Products Inc 1-(substituted benzyl) tetrahydro-2-(1h) pyrimidones
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
SU511005A3 (en) 1973-10-27 1976-04-15 К.Х.Берингер Зон., (Фирма) The method of obtaining (methoxymethylfurylmethyl) 6,7-benzomorfan or morphinan
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
GB1513961A (en) 1975-02-25 1978-06-14 Acf Chemiefarma Nv 6,7-benzomorphans method for their preparation and intermediates
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
US5393735A (en) 1990-08-09 1995-02-28 Rohm And Haas Company Herbicidal glutarimides
CA2023492A1 (en) 1989-08-31 1991-03-01 Barry Clifford Lange 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
DK204291D0 (en) 1991-12-20 1991-12-20 Novo Nordisk As HETEROCYCLIC RELATIONSHIPS OF THEIR PREPARATION AND USE
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
US5432175A (en) 1990-10-10 1995-07-11 Schering Corporation Pyridine and pyridine N-oxide derivatives of diaryl methyl piperidines or piperazines, and compositions and methods of use thereof
GB9023583D0 (en) 1990-10-30 1990-12-12 Beecham Group Plc Novel compounds
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
HU221816B1 (en) 1991-10-11 2003-01-28 Bristol-Myers Squibb Pharma Company Cyclic carbonyls and pharmaceutical compositions
DE69329106T2 (en) 1992-04-30 2001-03-22 Taiho Pharmaceutical Co Ltd OXAZOLIDE DERIVATIVE AND ITS COMPATIBLE SALT
JPH0753721B2 (en) 1992-09-11 1995-06-07 工業技術院長 Method for producing cyclic urethane compound
GB9225377D0 (en) 1992-12-04 1993-01-27 Ici Plc Herbicides
WO1994022857A1 (en) 1993-04-07 1994-10-13 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
JPH07157681A (en) 1993-12-08 1995-06-20 Konica Corp Production of organic pigment and electrophotographic photoreceptor containing organic pigment
DE19500118A1 (en) 1994-05-18 1995-11-23 Bayer Ag Substituted diazacyclohexanedi (thi) one
JP3948744B2 (en) 1994-11-04 2007-07-25 大日本住友製薬株式会社 Novel lactam derivatives
FR2729954B1 (en) 1995-01-30 1997-08-01 Sanofi Sa SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US5780466A (en) 1995-01-30 1998-07-14 Sanofi Substituted heterocyclic compounds method of preparing them and pharmaceutical compositions in which they are present
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
JPH09151179A (en) 1995-11-30 1997-06-10 Canon Inc Optically active compound, liquid crystal composition containing the same, liquid crystal element having the composition, liquid crystal apparatus and displaying method using them
CA2249641A1 (en) 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1998004534A1 (en) 1996-07-31 1998-02-05 Nikken Chemicals Co., Ltd. 6-phenyltetrahydro-1,3-oxazin-2-one derivatives and medicinal compositions containing the same
US6794390B2 (en) 1996-08-02 2004-09-21 Cv Therapeutics, Inc. Purine inhibitors of cyclin dependent kinase 2 & ikappabalpha
US5866702A (en) 1996-08-02 1999-02-02 Cv Therapeutics, Incorporation Purine inhibitors of cyclin dependent kinase 2
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
JP2002505683A (en) 1997-06-18 2002-02-19 シナプティック・ファーマスーティカル・コーポレーション Heterocyclic-substituted piperidines and uses thereof
DE19731784A1 (en) 1997-07-24 1999-02-04 Bayer Ag Substituted N-aryl-N-thioxocarbonyl sulfonamides
GB9715892D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
US5936124A (en) 1998-06-22 1999-08-10 Sepacor Inc. Fluoxetine process from benzoylpropionic acid
US7410995B1 (en) 1998-08-14 2008-08-12 Gpi Nil Holdings Inc. N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders
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
JP2003507424A (en) 1999-08-26 2003-02-25 ブリストル−マイヤーズ スクイブ カンパニー NPY antagonist: spiroisoquinolinone derivative
US6436928B1 (en) 1999-12-17 2002-08-20 Schering Corporation Selective neurokinin antagonists
DE60026169T2 (en) 1999-12-17 2006-11-09 Schering Corp. SELECTIVE NEUROKININE ANTAGONISTS
WO2001055063A1 (en) 2000-01-25 2001-08-02 Idemitsu Petrochemical Co., Ltd. Novel bisadamantane compounds, process for preparing the same, and novel biadamantane derivatives
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
DE10035927A1 (en) 2000-07-21 2002-03-07 Asta Medica Ag New heteroaryl derivatives and their use as medicines
DE10035908A1 (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
WO2002014269A2 (en) 2000-08-16 2002-02-21 Neurogen Corporation 2,4-substituted pyridine derivatives
WO2002022572A2 (en) 2000-09-11 2002-03-21 Sepracor, Inc. Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission)
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
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
WO2003032996A1 (en) 2001-10-15 2003-04-24 Schering Corporation Imidazo (4,3-e)-1,2,4-triazolo(1,5-c) pyrimidines as adenosine a2a receptor antagonists
HUP0500027A2 (en) 2001-11-22 2005-04-28 Ono Pharmaceutical Co., Ltd. Piperidin-2-one derivative compounds and drugs containing these compounds as the active ingredient
WO2003057673A1 (en) 2001-12-28 2003-07-17 Bayer Pharmaceuticals Corporation 1h-pyrazolyl derivative compounds, for use in diseases associated with the 5-ht2c receptor
JP2003300884A (en) 2002-04-08 2003-10-21 Nikken Chem Co Ltd TNF-alpha PRODUCTION INHIBITOR
ATE304015T1 (en) 2002-04-26 2005-09-15 Pfizer Prod Inc TRIARYL-OXY-ARYL-SPIRO-PYRIMIDINE-2, 4, 6-TRION METALLOPROTEINASE INHIBITORS
CA2480092A1 (en) 2002-04-26 2003-11-06 Pfizer Products Inc. N-substituted-heteroaryloxy-aryl-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors
EP1501822B1 (en) 2002-04-30 2010-12-15 Kudos Pharmaceuticals Limited Phthalazinone derivatives
CN103405431B (en) 2002-05-17 2016-04-13 台湾J药品有限公司 Opium and opioid compounds and uses thereof
CN1678317B (en) 2002-07-03 2010-10-27 先灵公司 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
WO2004009559A2 (en) 2002-07-18 2004-01-29 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
US7276520B2 (en) 2003-03-26 2007-10-02 Merck & Co., Inc. Bicyclic piperidine derivatives as melanocortin-4 receptor agonists
EP1618090A1 (en) 2003-04-11 2006-01-25 Novo Nordisk A/S 11ß-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS
US7700583B2 (en) 2003-04-11 2010-04-20 High Point Pharmaceuticals, Llc 11β-hydroxysteroid dehydrogenase type 1 active compounds
RU2005135330A (en) 2003-04-16 2006-06-27 Мемори Фармасьютиклз Корпорейшн (Us) PHOSPHODESTHESIS INHIBITORS 4
ITMI20031292A1 (en) 2003-06-25 2004-12-26 Nikem Research Srl BICYCLIC DERIVATIVES NK-2 SELECTIVE ANTAGONISTS.
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
CN101014574A (en) 2004-03-09 2007-08-08 默克公司 HIV integrase inhibitors
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
CA2565632C (en) 2004-05-07 2013-04-23 Janssen Pharmaceutica N.V. Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
MXPA06012932A (en) 2004-05-07 2007-01-26 Janssen Pharmaceutica Nv Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors.
GB0411404D0 (en) 2004-05-21 2004-06-23 Glaxo Group Ltd Novel compounds
EA014419B1 (en) 2004-05-24 2010-12-30 Эмджен Инк. 5,5-disubstituted-2-amino-4-thiazolidinone and process for preparation thereof, pharmaceutical composition and method for treatment
EA200700118A1 (en) 2004-06-24 2007-08-31 Инсайт Корпорейшн AMIDOCIOUSNESS AND THEIR APPLICATION AS MEDICINES
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
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
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
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
JP2008508358A (en) 2004-08-02 2008-03-21 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド Aryl-amino substituted pyrrolopyrimidine multikinase inhibitor compounds
US7544677B2 (en) 2004-08-23 2009-06-09 Merck & Co., Inc. Inhibitors of Akt activity
MY141198A (en) 2004-08-30 2010-03-31 Janssen Pharmaceutica Nv Tricyclic adamantylamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
MY146435A (en) 2004-08-30 2012-08-15 Janssen Pharmaceutica Nv N-2 adamantanyl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
WO2006031715A2 (en) 2004-09-10 2006-03-23 Janssen Pharmaceutica N.V. Novel imidazolidin-2-one derivatives as selective androgen receptor modulators (sarms)
JP2008515956A (en) 2004-10-12 2008-05-15 ノボ ノルディスク アクティーゼルスカブ 11.beta.-hydroxysteroid dehydrogenase type 1 active spiro compound
AU2005296124A1 (en) 2004-10-13 2006-04-27 Neurogen Corporation Aryl substituted 8-azabicyclo[3.2.1]octane compounds as ligands of the melanin concentrating hormone receptor
US7713979B2 (en) 2004-10-29 2010-05-11 Eli Lilly And Company Cycloalkyl lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
BRPI0518022A (en) 2004-11-10 2008-10-21 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
US20090005364A1 (en) 2004-12-23 2009-01-01 Ilaria Peretto 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
BRPI0607946A2 (en) 2005-02-16 2009-10-20 Schering Corp pyrazinyl-substituted piperazine-piperidines with cxcr3 antagonist activity
CN101189238A (en) 2005-02-16 2008-05-28 先灵公司 Piperazine-piperidines with CXCR3 antagonist activity
US7417045B2 (en) 2005-02-16 2008-08-26 Schering Corporation Heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity
CA2598457A1 (en) 2005-02-16 2006-08-24 Schering Corporation Pyridyl and phenyl substituted piperazine-piperidines with cxcr3 antagonist activity
US7566718B2 (en) 2005-02-16 2009-07-28 Schering Corporation Amine-linked pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity
PE20061093A1 (en) 2005-02-16 2006-11-10 Schering Corp PIPERAZINES SUBSTITUTED WITH HETEROCYCLES WITH ANTAGONIST ACTIVITY OF CXCR3
EP1852425A1 (en) 2005-02-24 2007-11-07 Nihon Nohyaku Co., Ltd. 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
KR101284573B1 (en) 2005-04-12 2013-07-11 바이코어 파마 아베 New tricyclic angiotensin ⅱ agonists
WO2007008529A2 (en) 2005-07-08 2007-01-18 Kalypsys, Inc Celullar cholesterol absorption modifiers
US20070066624A1 (en) 2005-08-16 2007-03-22 Anormed, Inc. Chemokine receptor binding compounds
CA2625762A1 (en) 2005-10-11 2007-04-26 Schering Corporation Substituted heterocyclic compounds with cxcr3 antagonist activity
TW200804274A (en) 2005-10-27 2008-01-16 Ucb Sa Compounds comprising a lactam or a lactam derivative moiety, processes for making them, and their uses
WO2007051810A2 (en) 2005-11-01 2007-05-10 Transtech Pharma Pharmaceutical use of substituted amides
JP2007140188A (en) 2005-11-18 2007-06-07 Fujifilm Corp Positive photosensitive composition and pattern forming method using the same
US8541592B2 (en) 2005-11-22 2013-09-24 Amgen Inc. Inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1
AU2006322060A1 (en) 2005-12-05 2007-06-14 Incyte Corporation Lactam compounds and methods of using the same
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
NZ568904A (en) 2005-12-30 2011-05-27 Merck Sharp & Dohme 1,3-oxazolidin-2-one derivatives useful as CETP inhibitors
WO2007081569A2 (en) 2005-12-30 2007-07-19 Merck & Co., Inc. Cetp inhibitors
CA2635010A1 (en) 2005-12-30 2007-07-19 Amjad Ali Oxazolidinone derivatives as cetp inhibitors
WO2007081570A2 (en) 2005-12-30 2007-07-19 Merck & Co., Inc. Cholesteryl ester transfer protein 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
WO2007100651A1 (en) 2006-02-27 2007-09-07 Bayer Healthcare Llc Temperature-adjusted analyte determination for biosensor systems
US20070213311A1 (en) 2006-03-02 2007-09-13 Yun-Long Li Modulators of 11-beta 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
WO2007123853A2 (en) 2006-04-20 2007-11-01 E. I. Du Pont De Nemours And Company Five-membered heterocyclic invertebrate pest control agents
WO2007124254A2 (en) 2006-04-21 2007-11-01 Eli Lilly And Company Cyclohexylpyrazole-lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
MX2008013485A (en) 2006-04-21 2008-10-30 Lilly Co Eli Biphenyl amide lactam derivatives as inhibitors of 11- beta-hydroxysteroid dehydrogenase 1.
AU2007240450B2 (en) 2006-04-21 2011-12-22 Eli Lilly And Company Cyclohexylimidazole lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
EA015499B1 (en) 2006-04-25 2011-08-30 Эли Лилли Энд Компани Inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1
US8178005B2 (en) 2006-06-20 2012-05-15 Chemtura Corporation Liquid phosphite compositions having different alkyl groups
TW200811170A (en) 2006-06-27 2008-03-01 Sanofi Aventis Urea derivatives of tropane, their preparation and their therapeutic application
WO2008012623A1 (en) 2006-07-25 2008-01-31 Pfizer Products Inc. Benzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor
WO2008012622A2 (en) 2006-07-25 2008-01-31 Pfizer Products Inc. Azabenzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
EP2064187A2 (en) 2006-08-25 2009-06-03 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
WO2008031227A1 (en) 2006-09-14 2008-03-20 Neuromed 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
JP5079011B2 (en) 2006-10-19 2012-11-21 エフ．ホフマン−ラ ロシュ アーゲー Imidazolone and imidazolidinone derivatives as 11β-HSD1 inhibitors for diabetes
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
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
WO2008118332A2 (en) 2007-03-23 2008-10-02 Schering Corporation Hydrazido-peptides as inhibitors of hcv ns3-protease
WO2008119663A1 (en) 2007-03-29 2008-10-09 F. Hoffmann-La Roche Ag Heterocyclic antiviral compounds
ATE554078T1 (en) 2007-07-26 2012-05-15 Vitae Pharmaceuticals Inc SYNTHESIS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 INHIBITORS
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
JP5769970B2 (en) 2007-11-16 2015-08-26 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 Aryl- and heteroarylcarbonyl derivatives of benzomorphan and related skeletons, medicaments containing such compounds and their use
CA2708303A1 (en) 2007-12-11 2009-06-18 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11.beta.-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
EP2252601B1 (en) 2008-01-24 2012-12-19 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2252598A2 (en) 2008-02-11 2010-11-24 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11beta-hydroxysteroid dehydrogenase 1
JP5538239B2 (en) 2008-02-12 2014-07-02 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 Benzomorphane and related skeleton urea derivatives, medicaments containing such compounds and their use
EP2254872A2 (en) 2008-02-15 2010-12-01 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 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
WO2009108332A1 (en) 2008-02-27 2009-09-03 Vitae Pharmaceuticals, Inc. INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE TYPE 1
EP2274287B1 (en) 2008-03-18 2016-03-09 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
WO2009134384A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2009134387A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2722427A1 (en) 2008-05-01 2009-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
TW200950780A (en) 2008-05-13 2009-12-16 Boehringer Ingelheim Int 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
WO2010010149A1 (en) 2008-07-23 2010-01-28 Bioalliance Pharma Styrylquinolines, their process of preparation and their therapeutic uses
KR20110050459A (en) 2008-07-25 2011-05-13 비타이 파마슈티컬즈, 인코포레이티드 Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
TW201016691A (en) 2008-07-25 2010-05-01 Boehringer Ingelheim Int Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CN102105454A (en) 2008-07-25 2011-06-22 贝林格尔.英格海姆国际有限公司 Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
US8309597B2 (en) 2008-07-25 2012-11-13 Boehringer Ingelheim International Gmbh 1,1′-diadamantyl carboxylic acids, medicaments containing such compounds and their use
CA2735204C (en) 2008-08-25 2017-06-20 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use
TW201022266A (en) 2008-10-23 2010-06-16 Boehringer Ingelheim Int Urea derivatives of substituted nortropanes, medicaments containing such compounds and their use
WO2010089303A1 (en) 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1
US8598163B2 (en) 2009-02-04 2013-12-03 Vitae Pharmaceuticals, Inc. Derivatives of [1,3]Oxazin-2-one useful for the treatment of metabolic diseases such as lipid disorders
EP2405913A1 (en) 2009-03-09 2012-01-18 Bristol-Myers Squibb Company Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
KR20120061771A (en) 2009-04-30 2012-06-13 비타이 파마슈티컬즈, 인코포레이티드 Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
MA33216B1 (en) 2009-04-30 2012-04-02 Boehringer Ingelheim Int CYCLIC INHIBITORS OF 11BETA-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
US8703765B2 (en) 2009-06-02 2014-04-22 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
JP5656986B2 (en) 2009-06-11 2015-01-21 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 based on 1,3-oxazinan-2-one structure
JP5749263B2 (en) 2009-07-01 2015-07-15 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
SG179083A1 (en) 2009-09-11 2012-04-27 Cylene Pharmaceuticals Inc Pharmaceutically useful heterocycle-substituted lactams
JP5750449B2 (en) 2009-11-05 2015-07-22 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 New chiral phosphorus ligand
TWI531571B (en) 2009-11-06 2016-05-01 維它藥物公司 Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
JP5860042B2 (en) 2010-06-16 2016-02-16 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 Substituted 5, 6 and 7 membered heterocycles, medicaments containing such compounds and their use
WO2011161128A1 (en) 2010-06-25 2011-12-29 Boehringer Ingelheim International Gmbh Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders
AU2011325286B2 (en) 2010-11-02 2015-04-16 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0902288A2 (en) 1997-09-12 1999-03-17 Ethicon, Inc. Wound diagnosis by quantitating cortisol in wound fluids
WO2007127693A1 (en) 2006-04-24 2007-11-08 Eli Lilly And Company Substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ANSTEAD, ADV. WOUND CARE, vol. 11, 1998, pages 277 - 285
BELLOWS ET AL., BONE, vol. 23, 1998, pages 119 - 125
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 (50)

* 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
US8859580B2 (en) 2007-11-16 2014-10-14 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
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
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
US9073870B2 (en) 2008-05-13 2015-07-07 Boehringer Ingelheim International Gmbh Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CN102421773A (en) * 2008-07-25 2012-04-18 贝林格尔·英格海姆国际有限公司 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
US8829027B2 (en) 2008-10-23 2014-09-09 Boehringer Ingelheim International Gmbh Urea derivatives of substituted nortropanes, medicaments containing such compounds and their use
WO2010089303A1 (en) * 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
AU2010242876B2 (en) * 2009-04-30 2015-06-18 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2010127237A3 (en) * 2009-04-30 2011-08-04 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
WO2010139673A1 (en) * 2009-06-02 2010-12-09 Boehringer Ingelheim International Gmbh 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
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
US9328072B2 (en) 2009-11-06 2016-05-03 Vitae Pharmaceuticals, Inc. Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US9663470B2 (en) 2009-11-06 2017-05-30 Vitae Pharmaceuticals, Inc. Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US8497281B2 (en) 2009-11-06 2013-07-30 Vitae Pharmaceuticals, Inc. Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
WO2011149822A1 (en) 2010-05-26 2011-12-01 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
JP2013528652A (en) * 2010-06-16 2013-07-11 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 Substituted 5, 6 and 7 membered heterocycles, medicaments containing such compounds and their use
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
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
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
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
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
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US9120769B2 (en) 2010-11-05 2015-09-01 Boehringer-Ingelheim International Gmbh Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US8686149B2 (en) 2010-11-05 2014-04-01 Boehringer-Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline
US20140066443A1 (en) * 2011-05-03 2014-03-06 Douglas C. Beshore Aminomethyl biaryl benzotriazole derivatives
US9139576B2 (en) * 2011-05-03 2015-09-22 Merck Sharp & Dohme Corp. Aminomethyl biaryl benzotriazole derivatives
US8975405B2 (en) 2011-08-17 2015-03-10 Boehringer Ingelheim International Gmbh Indenopyridine derivatives
US8735585B2 (en) 2011-08-17 2014-05-27 Boehringer Ingelheim International Gmbh Indenopyridine derivatives
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
CN103342700A (en) * 2012-01-19 2013-10-09 通化济达医药有限公司 11[beta]-hydroxysteroid dehydrogenase type 1 inhibitor
CN103342700B (en) * 2012-01-19 2016-04-20 通化济达医药有限公司 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor
CN104788384A (en) * 2015-03-31 2015-07-22 山东友帮生化科技有限公司 Synthesis method of 3-hydroxy-6-chloropyridazine
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives
WO2017182464A1 (en) 2016-04-19 2017-10-26 Cidqo 2012, S.L. New aza- tetracyclo derivatives

Also Published As

Publication number Publication date
AR072753A1 (en) 2010-09-15
EP2324017B1 (en) 2014-12-31
US20120108578A1 (en) 2012-05-03
TW201016691A (en) 2010-05-01
US8846668B2 (en) 2014-09-30
EP2324017A2 (en) 2011-05-25
WO2010010157A3 (en) 2010-04-01
JP2011529029A (en) 2011-12-01
JP5777030B2 (en) 2015-09-09
CA2729998A1 (en) 2010-01-28

Similar Documents

Publication Publication Date Title
EP2324017B1 (en) INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1
EP2393807B1 (en) Cyclic inhibitors of 11 -hydroxysteroid dehydrogenase 1
US8242111B2 (en) Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
EP2291370B1 (en) Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
JP5670440B2 (en) Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
JP5696037B2 (en) Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
EP2252601B1 (en) Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1
EP2220052B1 (en) CYCLIC UREA INHIBITORS OF 11ß-HYDROXYSTEROID DEHYDROGENASE 1
US8138178B2 (en) Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2715290A1 (en) Inhibitors of 11beta-hydroxysteroid dehydrogenase 1

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2009780992

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2729998

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2011519178

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13054954

Country of ref document: US