WO2007121432A2 - Benzoazepin-oxy-acetic acid derivatives as ppar-delta agonists used for the increase of hdl-c, lower ldl-c and lower cholesterol - Google Patents

Benzoazepin-oxy-acetic acid derivatives as ppar-delta agonists used for the increase of hdl-c, lower ldl-c and lower cholesterol Download PDF

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WO2007121432A2
WO2007121432A2 PCT/US2007/066772 US2007066772W WO2007121432A2 WO 2007121432 A2 WO2007121432 A2 WO 2007121432A2 US 2007066772 W US2007066772 W US 2007066772W WO 2007121432 A2 WO2007121432 A2 WO 2007121432A2
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group
cpd
alkyl
substituted
compound
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PCT/US2007/066772
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French (fr)
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WO2007121432A3 (en
Inventor
Kuo Gee-Hong
Yan Zhang
Lan Shen
Songfeng Lu
Keith T. Demarest
Patricia Pelton
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Janssen Pharmaceutica N.V.
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Priority to AT07760766T priority Critical patent/ATE535282T1/en
Priority to NZ571998A priority patent/NZ571998A/en
Priority to EA200870445A priority patent/EA016583B1/en
Priority to BRPI0711695-0A priority patent/BRPI0711695A2/en
Priority to JP2009506716A priority patent/JP5232771B2/en
Priority to EP07760766A priority patent/EP2010289B1/en
Priority to CA2649700A priority patent/CA2649700C/en
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to AU2007237928A priority patent/AU2007237928B2/en
Priority to CN2007800226398A priority patent/CN101479008B/en
Priority to MX2008013534A priority patent/MX2008013534A/en
Priority to ES07760766T priority patent/ES2375754T3/en
Publication of WO2007121432A2 publication Critical patent/WO2007121432A2/en
Priority to IL194850A priority patent/IL194850A/en
Publication of WO2007121432A3 publication Critical patent/WO2007121432A3/en
Priority to ZA2008/09790A priority patent/ZA200809790B/en
Priority to NO20084847A priority patent/NO344334B1/en
Priority to HK09102249.6A priority patent/HK1124797A1/en

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Definitions

  • the peroxisome pro ⁇ ferator-activated receptors are considered to be metabolic sensors regulating the expression of genes involved in glucose and lipid homeostasis. They are members of nuclear receptor superfamily of RXR heterodimers and are ligand-activated transcription factors. Agonists of the PPAR ⁇ (e.g., Gemfibrozil) and PPAR ⁇ (e.g., Avandia® ) subtypes are used for the treatment of dyslipidemias and diabetes, respectively.
  • Each receptor has a distinct tissue distribution with PPAR ⁇ showing highest expression in liver, PPAR ⁇ in adipose tissue and PPAR ⁇ having the widest distribution being ubiquitously expressed in adult rat (Braissant et al., 1996) and in humans, expression was found in many different tissues involved in lipid metabolism including liver, kidney, abdominal adipose and skeletal muscle (Auboeuf et al., 1997). Recently, potent ligands for PPAR ⁇ have been published allowing a better understanding of its function in lipid metabolism ⁇ Barak et al, 2002; Oliver et al.
  • HDL-C high density lipoprotein cholesterol
  • triglycerides with little effect on glucose (although insulin levels were decreased in monkeys).
  • HDL-C serves to remove cholesterol from peripheral cells through a process called reverse cholesterol transport.
  • the first and rate-limiting step which is a transfer of cellular cholesterol and phospholipids to the apolipoprotein A-!
  • PPAR ⁇ activation appears to increase HDL-C through transcriptional regulation of ABCA1 (Oliver et al., 2001 ). Therefore, by inducing ABCA1 mRNA in macrophages, PPAR ⁇ agonists could increase HDL-C levels in patients and remove excess cholesterol from lipid-laden macrophages, one of the major players in atherosclerotic lesion development.
  • statin drugs which show little effect on HDL-C and mainly decrease LDL-C or the fibrates, the only marketed PPAR ⁇ agonists, having low potency and inducing only modest HDL-C elevations.
  • PPAR ⁇ agonists like the fibrates, PPAR ⁇ agonists have the potential to also reduce triglycerides, an additional risk factor for cardiovascular disease.
  • Examples of known PPAR delta agonists variously useful for hyperlipidemia, diabetes, or atherosclerosis include L-165041 (Leibowitz et al., 2000) and GW501516 (Oliver et al., 2001 ). There is a continuing need for new PPAR delta agonists. There is a further need for new PPAR delta agonists that increase HDL-C, lower LDL-C, and/or lower cholesterol.
  • PPAR delta agonists for the treatment of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL- cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL- cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.
  • the present invention is directed to a compound of Formula (I):
  • X is a covending bond, O, or S;
  • Ri and R 2 are independently selected from the group consisting of H, Ci -8 aiky1, and substituted C h alky!, or R 1 , R 2 and the carbon atom to which they are attached together may form Ca ⁇ cycloalkyl;
  • R 3 is H
  • R 4 and R 5 are independently selected from the group consisting of H, halo, Ci- ⁇ alkyl, C 3-7 cycloalkyl, C 3 -7cycloalkyl--Ci-4alky!, C 3 - 7 cycloalkyloxy-C 1-4 alkyl, Ci- 6 aikoxy-Ci- 4 alkyl, Ce-ioaryl, heteroaryl, halo substituted amino substituted Ci -4 alkyl, C 6 -ioaryl substituted Ci. 4 alkyl, cyano substituted Ci -4 alkyi, and hydroxy substituted Ci -4 alkyl;
  • R 6 and R 7 are independently selected from the group consisting of H, halo, Ci- 3 alkyl, halo substituted d-salkyt, Ci -3 alkoxy f and halo substituted Ci. 3 alkoxy; n is 1 ; and
  • Q is selected from the group consisting of
  • the present invention is further directed to pharmaceutical compositions containing one or more compounds of Formula (I), and to to use of such compounds and compositions to treat a condition directly or indirectly mediated by PPAR delta.
  • G & b ( wnere a and b are integers) refers to a radical containing from a to b carbon atoms inclusive.
  • C 1 - 3 denotes a radical containing 1 , 2 or 3 carbon atoms.
  • Alkyl refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ⁇ thanyl, ethenyl, ethynyl; propyls such as propan-1 -yl, propan-2-yi , cyciopropan-1 -yl, prop-1 -en-1 -yl, prop-1 -en-2-yi, prop-2-en-1-yi, cycloprop-1 -en-1 -yl; cyc!oprop-2-en-1 -yl, prop-1 -yn-1 -yl, prop-2 ⁇ yn-1-yl, etc.; butyls such as butan-1-yi, butan-2-yi, 2-methyl-propan-1 -yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1 -en-1-yl, but- 1 -en-2-yi, 2-methyl-prop-1 -en-1-yl, but-2
  • alkanyl alkenyt
  • alkynyi alkynyi
  • the alkyl groups are (C 1 -C 6 ) alkyl, with (Ci-C 3 ) being particularly preferred.
  • Cyclic alky! can be, for example, C3_ioalkyl; preferably, cycloalkyl is C 3 - 7 Cycloalkyl.
  • alkanyl refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1 -yl, propan-2-yl, cyclopropan-1-yi, etc.; butyanyis such as butan-1 -yl, butan-2-yi, 2-methyl-propan-1 -yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like.
  • the alkanyl groups are (Ci. 8 ) alkanyl, with (C 1 - 3 ) being particularly preferred.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent aikene.
  • the radical may be in either the cis or trans conformation about the double bond(s).
  • Typical aSkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1 -en-1 -y!; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-y!, but- 1 -en-2-yl, 2-methyl-prop-1 -en-1 -yi, but-2-en-1 -yl, but-2-en-1-yl, but-2-en-2-yi, buta-i ⁇ -dien-i-yl, buta-1 ,3-dien-2-yI, cyclobut-1 -en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1 ,3-dien-1-yl, etc.; and the like.
  • Alkvnyl refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, buM -yn-3-yl, but-3-yn-1-yl, etc.; and the like.
  • Heteroalkyl and “heteroalkanyl” refer to alkyl or alkanyi radicals, respectively, in which one or more carbon atoms (and any necessary associated hydrogen atoms) are independently replaced with the same or different heteroatoms (including any necessary hydrogen or other atoms).
  • Typical heteroatoms to replace the carbon atom ⁇ s) include, but are not limited to, N, P, O, S, Si 1 etc.
  • Preferred heteroatoms are O, N and S.
  • “Aryi” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, plei
  • “Arvialkyl” refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-i-yi, naphthylmethyl, 2-naphthylethan-1 -yi, 2-naphthylethen-1-yI, naphthobenzyl, 2-naphthophenyiethan-1 -yl and the like.
  • the arylalkyl group is ⁇ Ce- ⁇ e) arylalkyl, e.g., the alkanyl, alkenyl or aikynyl moiety of the arylalkyl group is (Ci- 6 ) and the aryi moiety is (C 5 - 2 o)-
  • the arylalkyl group is (C 6 - 13 ), e.g., the alkanyl, alkenyl or alkynyi moiety of the arylalkyl group is (C-i - 3 ) and the aryl moiety is (C 5 - 10 ).
  • Even more preferred arylalkyl groups are phenylalkanyls.
  • alkanyloxy refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen of the alcohol.
  • Typical alkanyloxy groups include, but are not limited to, methanyloxy; ethanyloxy; propanyioxy groups such as propan-1-yloxy (CH 3 CH 2 CH 2 O-), propan-2-yloxy ((CHs) 2 CHO-), cyclopropan-1-yloxy, etc.; butanyloxy groups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1 -yloxy, 2-methyl-propan-2-yloxy, cyclobutan-1 -yioxy, etc.; and the like.
  • the alkanyloxy groups are (Ci -8 ) alkanyloxy groups, with ⁇ Ci- 3 ) being particularly preferred.
  • Heteroaryl refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, radicais derived from carbazole, imidazole, indazoie, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazote, isoxazole, naphthyridine, oxadiazole, oxazoie, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like, in preferred embodiments, the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Cycloheteroalkyl refers to a saturated or unsaturated monocyclic or bicyclic alkyl radical in which one carbon atom is replaced with N, O or S. in certain specified embodiments the cycloheteroalkyl may contain up to four heteroatoms independently selected from the group consisting of N, O and S.
  • Typical cycloheteroalkyl moieties include, but are not limited to, radicals derived from imidazol ⁇ d ⁇ ne, morpholine, piperazine, piperidin ⁇ , pyrazolidine, pyrrolidine, quinuclidine, and the like.
  • the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.
  • Cycloheteroalkanyl refers to a saturated monocyclic or bicyclic alkanyS radical in which one carbon atom is replaced with N, O or S.
  • the cycloheteroalkanyl may contain up to four heteroatoms independently selected from the group consisting of N, O and S.
  • Typical cycloheteroalkanyl moieties include, but are not limited to, radicals derived from imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like, tn preferred embodiments, the cycloheteroalkanyl is a 3-6 membered cycloheteroalkanyi.
  • Cycloheteroalkenyl refers to a saturated monocyclic or bicyclic alkenyl radical in which one carbon atom is replaced with N, O or S.
  • the cycloheteroalkenyl may contain up to four heteroatoms independently selected from the group consisting of N, O and S.
  • Typical cycloheteroalkenyi moieties include, but are not limited to, radicals derived from imidazoline, pyrazoline, pyrroline, indoitne, pyran, and the like.
  • the cycloheteroalkanyl is a 3-6 membered eye loheteroa! kany i .
  • substituted refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • Preferred substituents include hydroxy j halogen, Ci. 8 aikyl, Ci -e alkanyioxy, fiuorinated alkanyloxy, fluorinated alkyl, Ci -8 alkyith! ⁇ , Ca-ecycloalkyi, C 3 .
  • substituents independently means that when more than one of such substituent is possible, such substituents may be the same or different from each other. in any structure that contains the symbol ?, that symbol designates the Iocation(s) of the open valence(s) where the partial structure attaches to the rest of the molecule.
  • phenylCi-ealkanylaminocarbonylCi.ealkyl refers to a group of the formula:
  • compositions comprising a compound of Formula (i) for uses as PPAR delta agonists:
  • X is a covalent bond, O, or S
  • R 1 and R 2 are independently selected from the group consisting of H, Ci -8 alkyl, and substituted Ci.saikyi, or Ri 1 R 2 and the carbon atom to which they are attached together may form C 3 -7Cycioa!kyl;
  • R 3 is H
  • R 4 and R 5 are independently selected from the group consisting of H, halo, Ci -8 alkyl f C 3 - 7 cycloalkyl, Ca-ycycloalkyi-Ci ⁇ alkyl, C3- 7 cycioalkyloxy-Ci -4 alkyl, C-i-ealkoxy-C-i ⁇ alkyl, Ce-ioaryl, heteroaryl, halo substituted C 1-4 alkyl, amino substituted Chalky I, CVioaryl substituted d ⁇ alkyl, cyano substituted C ⁇ alkyl, and hydroxy substituted Ci -4 aikyi;
  • R 6 and R ? are independently selected from the group consisting of H 1 halo, Ci. 3 alkyl, halo substituted Ci -3 aikyl, C 1 ⁇ aIkOXy, and halo substituted Ci- 3 alkoxy; n is 1 ; and Q is selected from the group consisting of
  • X is O;
  • R 1 and R 2 are independently selected from the group consisting of H and Ci- 8 alkyl, or R-i, R 2 and the carbon atom to which they are attached together may form Cs-scycloalkyl, and more particularly R 1 and R ⁇ are independently selected from the group consisting of H and CH 3 , or R 1 , R 2 and the carbon atom to which they are attached together may form
  • R 4 and R 5 are independently selected from the group consisting cf H and C-i- ⁇ alkyl, and more particularly R 5 is H, CH 3 , or -CH 2 CH 3 ; or
  • R 6 and R 7 are independently selected from the group consisting of H, halo, halo substituted Ci -3 aikyl, Ci -3 alkoxy, and halo substituted Ci -3 alkoxy, and more particularly R 6 is H and R 7 is selected from the group consisting of halo, halo substituted C h alky!, and halo substituted Ci. 3 alkoxy, and more particularly R 7 is selected from the group consisting of F, CF 3 , and -0-CF 3 ; or
  • Q is selected from the group consisting of
  • nd more particularly Q is selected from the group consisting of
  • the present invention is directed to a compound of Formula (I) as shown above wherein: X is O; R-i, F ⁇ 2, R 4 , and R 5 are independently selected from the group consisting of H and Ci- 3 alkyi, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3 - 5 cycloalkyl; and R 6 and R 7 are independently selected from the group consisting of H, halo, Ci. 3 afkoxy ( halo substituted C h alky!, and halo substituted Ci-3alkoxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
  • the present invention is directed to pharmaceutical compositions containing one or more compounds, salts or solvates of Formula (I) as described herein admixed with a pharmaceutically acceptable carrier, exc ⁇ pient or diluent, wherein the compositions can be used to treat a condition directly or indirectly mediated by PPAR delta.
  • the present invention is also directed to a method of treating or preventing a disease or condition in a subject, particularly a mammal and more particularly a human, which disease or condition is affected by the modulation of PPAR delta.
  • the present invention is directed to a method of treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of PPAR delta receptors, which method comprises administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I) as described herein. More particularly, the therapeutically effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 50 mg to about 1000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg.
  • the present invention is directed to a method for treating or preventing a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesteroiemia, mixed hyperlipidemia, and hypo-HDL- cholesterolemia), atherosclerosis, and obesity, said method comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I).
  • a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterol
  • the therapeutically effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 50 mg to about 1000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg.
  • the present invention is directed to a kit comprising in one or more containers an amount of the composition of Formula (I) effective to treat or prevent a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia ⁇ including hypertriglyceridemia, hypercholesteroiemia, mixed hyperlipidemia, and hypo- HDL-cholesterolemia), atherosclerosis, and obesity. More particularly, the therapeutically effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg.
  • the rapeuticaliy effective amount comprises a dose range of from about 50 mg to about 1000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg.
  • the present invention is directed to a compound of Formula (Ia)
  • R 1 and R2 are independently selected from the group consisting of H and Ci. 8 alkyl, or Ri, R 2 and the carbon atom to which they are attached together may form C ⁇ cycloalkyl;
  • R 4 and R 5 are independently selected from the group consisting of H and Ci -8 aikyl;
  • R 6 and R 7 are independently selected from the group consisting of H,
  • Ci. 3 alkyl, halo, and halo substituted C h alky!; and Q is selected from the group consisting of
  • the present invention is directed to a compound of Formula (Ib)
  • R 1 and R 2 are independently selected from the group consisting of H and CH 3 , or Ri, R 2 and the carbon atom to which they are
  • R 4 and R 5 are independently selected from the group consisting of H,
  • the present invention is directed to a compound of Formula (Ic)
  • Ri, R 2 , and R 4 are independently selected from the group consisting of H and CH 3 , or Ri, R 2 and the carbon atom to which they are
  • R 5 is selected from the group consisting of H, CH 3 , and -CH 2 CH 3 ;
  • R 7 is halo or halo substituted Chalky!; and
  • Q is selected from the group consisting of
  • the present invention is directed to compounds of Formula (Ic) hereinabove wherein: Ri or R 2 is H; Ri and R 2 are both H; i£ R 1 or R 2 is CH 3 ;
  • R 1 and R 2 are both CH 3 ;
  • R 4 is H or CH 3 ;
  • R 5 (S H 1 CH 31 Or -CH 2 CH 3 ;
  • Ri or R 2 is H and R 4 is H or CH 3 ;
  • R 1 and R 2 are both H and R 4 is H or CH 3 ;
  • R 1 or R 2 is H and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • R 1 and R 2 are both H and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • R 1 or R 2 is CH 3 and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • R 1 and R 2 are both CH 3 and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • Ri or R 2 is H, R 4 is H, and R 5 is H 1 CH 3 , or -CH 2 CH 3 ;
  • R 1 and R 2 are both H, R 4 is H, and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • R 1 or R 2 is CH 3 , R 4 is H 1 and R 5 is H, CH 3 , Or -CH 2 CH 3 ;
  • R 1 and R 2 are both CH 3 , R 4 is H, and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • R 4 is H
  • R 5 is H , CH 3 , or ⁇ CH 2 CH 3 ;
  • R 7 is CF 3 ; (t) R 7 is Cl;
  • Ri or R 2 is H, R 7 is CF 3 , and R 4 is H or CH 3 ;
  • R 1 and R 2 are both H, R 7 is CF 3 , and R 4 is H or CH 3 ;
  • R 1 or R 2 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • Ri and R 2 are both H, R 7 is CF 3 , and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • M 1 or R 2 is CH 3 , R 7 is CF 3 , and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • Ri and R 2 are both CH 3 , R 7 is CF 3 , and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • (aa) R 1 or R 2 is H, R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • R 1 and R 2 are both H, R 4 Js H, R 7 is CF 3 , and R 5 is H, CH 3 , or -
  • R 1 or R 2 is CH 3 , R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or -CH 2 CH 3 ;
  • Ri and R 2 are both CH 3 , R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or -
  • R 4 is H 1
  • R 7 is CF 3
  • R 5 is H 1 CH 3 , or -CH 2 CH 3
  • Q is selected from the group consisting of
  • Ri or R 2 is H and Q is selected from the group consisting of
  • R 1 or R 2 is CH 3 and Q is selected from the group consisting of
  • Oil Ri and R 2 are both CH 3 and Q is selected from the group consisting of
  • R 4 is H or CH 3 and Q is selected from the group consisting of
  • R 5 is H, CH 3 , Or -CH 2 CH 3 and Q is selected from the group consisting of
  • Ri or R 2 is H and R 4 is H or CH 3 and Q is selected from the group consisting of
  • R 1 and R 2 are both H and R 4 is H or CH 3 and Q is selected from the group consisting of
  • R 1 or R 2 is H and R 5 is H, CH 3 , or -CH 2 CH 3 and Q is selected from the group consisting of
  • Ri and R 2 are both H and R 5 is H, CH 3 , or -CH 2 CH 3 and Q is selected from the group consisting of
  • Ri or R 2 is CH 3 and R 5 is H 1 CH 3 , or -CH 2 CH 3 and Q is selected from the group consisting of
  • R 1 and R 2 are both CH 3 , R 5 is H, CH 3 , or -CH 2 CH 3 , andQ is selected from the group consisting of
  • Ri or R 2 is H
  • R 4 is H
  • R 5 is H, CH 3 , or -CH 2 CH 3
  • Q is selected from the group consisting of
  • Ri and R 2 are both H, R 4 is H, R 5 is H, CH 3 , or -CH 2 CH 3 , and Q is selected from the group consisting of
  • R 2 is CH 3
  • R 4 is H
  • R 5 is H, CH 3 , or -CH 2 CH 3
  • Q is selected from the group consisting of
  • Ri and R 2 are both CH 3 , R 4 is H, R 5 is H, CH 3 , or -CH 2 CH 3 , and Q is selected from the group consisting of
  • R 4 is H
  • R 5 is H, CH 3 , or -CH 2 CH 3
  • Q is selected from the group consisting of
  • R 7 is CF 3 and Q is selected from the group consisting of
  • R 7 is Cl and Q is selected from the group consisting of
  • Ri or R 2 is H
  • R 7 is CF 3
  • R 4 is H or CH 3
  • Q is selected from the group consisting of
  • R 1 or R 2 is H
  • R 7 is CF 3
  • Q is
  • Ri and R 2 are both H, R 7 is CF 3 , R 5 is H, CH 3 , Or -CH 2 CH 3 , and Q is selected from the group consisting of
  • R 1 or R 2 is CH 3
  • R 7 is CF 3
  • R 5 is H, CH 3 , or -CH 2 CH 3
  • Q is selected from the group consisting of
  • R 1 and R 2 are both CH 3 , R 7 is CF 3 , R 5 is H, CH 3 , or -CH 2 CH 3 , and Q is selected from the group consisting of is H 5 R 4 is H, R 7 is CF 3 , R 5 is H, CH 3f or -CH 2 CH 3 , and Q is selected from the group consisting of
  • R 1 and R 2 are both H, R 4 is H, R 7 is CF 3 , R 5 is H, CH 3 , or CH 2 CH 3 , and Q is selected from the group consisting of
  • R 1 or R 2 is CH 3
  • R 4 is H
  • R 7 is CF 3
  • R 5 is H, CH 3 , or -CH 2 CH 3
  • Q is selected from the group consisting of
  • R 4 is H
  • R 7 is CF 3
  • R 5 is H, CH 3 , or - CH 2 CH 3
  • Q is selected from the group consisting of
  • the present invention is directed to a compound selected from the group consisting of
  • the present invention is further directed to a compound of Formula ⁇ l)
  • X is a covalent bond, O, or S
  • Ri and R 2 are independently selected from the group consisting of H, Ci -8 alkyi, and substituted Ci -8 alkyf, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3 - 7 CycIoalkyl;
  • R 3 is H;
  • R 4 and R 5 are independently selected from the group consisting of H, halo, C 1-8 alkyi, C 3-7 Cyc!oalkyl, Cs ⁇ cycloalkyl-Ci ⁇ aikyl, C 3 . 7 cycloalkyloxy-C 1-4 alkyl, Ci-6alkoxy-Ci ⁇ alkyl, C 6-1 oaryi, heteroaryl, halo substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, C 6-10 ary! substituted Ci. 4 alkyl, heteroaryl substituted Ci ⁇ alkyl, cyano substituted C 1-4 alkyl, and hydroxy substituted Ci. 4 alkyl;
  • R 6 and R 7 are independently selected from the group consisting of H, halo, Ci ⁇ alkyl, halo substituted C h alky!, Ci ⁇ alkoxy, and halo substituted Ci. 3 alkoxy; n is 1 ; and
  • Q is C 6 -ioaryl
  • the present invention is also directed to a compound of Formula ⁇ l)
  • X is a covalent bond, O, or S
  • R 1 and R 2 are independently selected from the group consisting of H, C 1-8 alkyl, and substituted Ci-ealkyl, or Ri, R 2 and the carbon atom to which they are attached together may form C 3-7 €ycloa!kyl;
  • R 3 is H
  • R 4 and R 5 are independently selected from the group consisting of H, halo, Ci -8 alkyl, C 3 - 7 cycloalkyl, Cs-ycycloalkyl-C ⁇ alkyl, C 3- 7 cycloaikyloxy-Ci -4 alkyl, d- ⁇ alkoxy-Ci ⁇ alkyi, CVioaryl, heteroaryl, halo substituted Ci ⁇ alkyl, amino substituted Ci ⁇ alkyl, C 6-10 aryl substituted Ci- 4 alkyl, heteroaryl substituted Ci. 4 alkyi, cyano substituted Ci ⁇ alky!, and hydroxy substituted Ci ⁇ alkyl; R 6 and R 7 are independently selected from the group consisting of H, halo, Ci. 3 alkyl, halo substituted Ci- 3 alkyl, Ci ⁇ alkoxy, and halo substituted Ci -3 alkoxy; n is 1 or 2; and Q is selected from the group consisting of
  • the present invention is also directed to a compound of Formula (I)
  • X is a covalent bond, O, or S
  • R 1 and R 2 are independently selected from the group consisting of H, Ci- ⁇ alkyI, and substituted Ci- 8 aikyl, or R 1 , R 2 and the carbon atom to which they are attached together may form Cs-ycycloalkyi;
  • R 3 is H
  • R 4 and R 5 are independently selected from the group consisting of H, halo, C 1-8 alkyl, C 3-7 cycloalkyl, C 3 - 7 cycloaikyl-Ci-4alkyi, C 3 . ycycloalkyloxy-d ⁇ alkyl, Ci- 6 aikoxy-Ci. 4 alkyl, C 6 -ioaryl, heteroaryl, halo substituted Ci-4alkyl, amino substituted Ci ⁇ alkyl, Ce-ioaryl substituted Ci.
  • R 6 and R 7 are independently selected from the group consisting of H 1 halo, Ci -3 a!kyl, halo substituted Ci ⁇ alkyl ⁇ alkoxy, and halo substituted Ci-3alkoxy; n is 2; and
  • Q is selected from the group consisting of
  • the present invention is directed to a compound selected from the group consisting of
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" (Ref. international J. Pharm,, 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1).
  • Other salts well known to those in the art may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromtc, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, tactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandeiic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthaIenesulfonic, p-toluenesulfonic, cyclohexanesuffamic, salicylic, saccharinic or trtfluoroacetic acid.
  • Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term "administering" shall encompass the tfeatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administrationjojhe patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Representative hydroxy group prodrug forms include, but are not limited to, Ci. 4 a!kanyiethers, substituted Ci- 4 aikanylethers, and Ci-4alkanyl esters.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toIuoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • compositions comprising the dextrorotatory enantiomer of a compound of Formula (I), wherein said composition is substantially free from the levorotatory isomer of said compound.
  • substantially free means less than 25 %, preferably less than 10 %, more preferably less than 5 %, even more preferably less than 2 % and even more preferably less than 1 % of the levorotatory isomer calculated as.
  • compositions comprising the levorotatory enantiomer of a compound of formula ⁇ ) wherein said composition is substantially free from the dextrorotatory isomer of said compound.
  • substantially free from means less than 25 %, preferably less than 10 %, more preferably less than 5 %, even more preferably less than 2 % and even more preferably less than 1 % of the dextrorotatory isomer calculated as
  • the present invention is also directed to a compound selected from the group consisting of
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable Io protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • a pharmaceutical carrier excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipterrts or diluents.
  • the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent ⁇ s), and/or solubilising agent(s).
  • Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • the compounds of the general Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • An alternative means of transdermal administration is by use of a skin patch.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
  • compositions (as well as the compounds aione) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously.
  • the compositions will comprise a suitable carrier or diluent.
  • compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with biood.
  • a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with biood.
  • buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art.
  • the therapeutically effective dose for active compounds of the inventiom?r a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosayes to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition.
  • Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention is required for a subject in need thereof.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • a pharmaceutical composition is preferably provided in the form of tablets containing 0.01 , 10.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • condition intended to be within the scope of the present invention include, but are not limited to, diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipid ⁇ mia ⁇ including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo- HDL-choiesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.
  • Compounds of the present invention are also useful as PPAR delta agonists for treating, preventing, or inhibiting the progression of, a condition directly or indirectly mediated by PPAR delta.
  • the compounds of the present invention are partcularly useful in treating diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-choiesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL- cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.
  • a therapeutically effective dose can be determined by persons skilled in the art by the use of established animal models. Such a dose would likely fall in the range of from about 0.01 mg to about 15,000 mg of active ingredient administered 1 to 4 times per day for an average (70 kg) human.
  • Scheme 1 wherein R 1 , R 2 , R3, FU, Rs, Re, R7, X and Q are as described above, describes several general methods for the synthesis of compounds of Formula Id.
  • Method 1 alkylation of the substituted benzoazepine 1-B with a compound of Formula 1-C where Yean be a leaving group such as Br, Cl, i, mesylate, etc. under a basic condition, such as Cs 2 CO 3 in CH 3 CN, can generate the corresponding compound of Id.
  • Method 2 reductive aminatton of 1-B with aryl aldehyde 1-D (e.g.
  • reaction of 1 -B with aryl aldehyde 1-E to give the shiff-base followed by reaction with organo-alkyl reagents such as Grignard reagents, CH 3 Li or organo-cupper reagent, will also provide Id.
  • organo-alkyl reagents such as Grignard reagents, CH 3 Li or organo-cupper reagent
  • reaction of 1-B with aryl aldehyde 2-B to give the sniff-base followed by reaction with organo-alkyl reagents such as Grignard reagents, CH 3 Li or organo-cupper reagent, will also provide Ie.
  • organo-alkyl reagents such as Grignard reagents, CH 3 Li or organo-cupper reagent
  • the respective product of each process step be separated from other components of the reaction mixture and subjected to purification before its use as a starting material in a subsequent step.
  • Separation techniques typically include evaporation, extraction, precipitation and filtration.
  • Purification techniques typically include column chromatography (Still, W. C. et. a!., J. Org. Chem. 1978, 43, 2921), thin-layer chromatography, crystallization and distillation.
  • the structures of the final products, intermediates and starting materials are confirmed by spectroscopic, spectrometric and analytical methods including nuclear magnetic resonance (NMR) 1 mass spectrometry (MS) and liquid chromatography (HPLC).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC liquid chromatography
  • ethyl ether, tetrahydrofuran and dioxane are common examples of an ethereal solvent; benzene, toluene, hexanes and heptanes are typical hydrocarbon solvents and dichloromethane and dichloroethane are representative haiogenated hydrocarbon solvents, in those cases where the product is isolated as the acid addition salt the free base may be obtained by techniques known to those skilled in the art. In those cases in which the product is isolated as an acid addition salt, the salt may contain one or more equivalents of the acid. Enantiomers of the compounds of the present invention may be separated using chiral HPLC.
  • DMF ⁇ /,/V-dimethylformamide
  • DMSO dimethylsulfoxicle
  • cfppf diphenylpt ⁇ phi ⁇ oferrocene
  • LAH lithium aluminum hydride
  • Ph phenyl
  • LiN(TMS) 2 Lithium bis(trimethyls!lyl)amide
  • Cpd A1a can be prepared according to published procedures (US patent No. 4,659,706 and Eur. Pat. Appl. 204349).
  • a mixture of A2e (20 mg, 0.041 mmol) and 2 M NaOH ⁇ 41 ⁇ l_, 0.082 mmol) in THF-MeOH (0.6 mL-0.2 ml_) was stirred under N 2 for 2 h and concentrated. CH 2 CI 2 and water were added, and the mixture was acidified with concentrated HCI. The organic phase was separated and the aqueous phase was extracted with CH 2 CI 2 .
  • Cpd 2 was prepared using similar procedure as for cpd 1.
  • C 3 was prepared according to a similar procedure as for cpd 1.
  • Cpd D1 was prepared according to a similar procedure as for cpd B3.
  • Cpcl E2 was prepared from cpd E1 (Bioorg & Med. Chem. Lett., 2003, 13 (9), 1517-1521 ) following a similar procedure as for cpd A2d.
  • Cpd 5 was prepared according to a similar procedure as for cpd 1.
  • Example F Example F
  • Cpd 12 was prepared from cpd 11 ⁇ Bioorg. & Med. Chem. Lett., 2003, ?3(13), 2159-2161 ) using a similar procedure as fofecpd G2.
  • Cpd I2 was obtained as a white solid (40%);
  • Cpd 10 was prepared using a similar procedure as for cpd 2.
  • Cpd K b was prepared using a similar procedure as for cpd A1c.
  • Cpd K2c was prepared according to a simitar procedure as for ⁇ pd C2.
  • Cpd K2e was prepared according to a similar procedure as forcpd A2e.
  • Cpd K2e was obtained as a white solid (71%):
  • Cpd L1 was prepared following the same procedure as for cpd 83.
  • Cpd 02 was prepared fo ⁇ owing the same procedure as for cpd G1.
  • Cpd Q2 was prepared following the same procedure as for cpd E1.
  • Cpd Q2 was obtained as a white solid (51%):
  • Cpd 17 was prepared following the same procedure as for cpd A2e. Cpd 17 was obtained as a white solid (80%): 1 H NMR
  • Cpd R2 was prepared following the same procedure as for cpd 11.
  • Cpd R3 was reduced to give a crude alcohol intermediate following the same procedure as in the preparation of compound E1.
  • Cpd R4 was prepared following the same procedure as for cpd A2d.
  • Cpd T4 was prepared following the same procedure as for cpd A2d. Cpd T4 was obtained as a white solid (85%): 1 H NMR ⁇ 300 MHz, CDCI 3 ) ⁇ 7.95 (s, 1 H), 7.75 - 7.60 (m, 5 H), 4.43 (s, 2 H).
  • Cpd LM was prepared following the same procedure as for cpd B3.
  • Cpd W1 was prepared following the same procedure as for epd G1 Cpd W1 was obtained as a white solid ⁇ 90%): 1 H NMR (300 MHz, CDCI 3 ) ⁇ 10.00 (S, 1 H), 8.07 (s, 1 H), 7.92 (s, 1 H), 7.71 (s, 4 H).
  • Cpcf AA1 was prepared following a similar procedure as for cpd X1.
  • Cpd AA1 was obtained (3.84 g, 84%) as a pale yellow solid:
  • Cpd BB2 was prepared according to a similar procedure as for cpd 22.
  • Cpd BB2 was obtained (157 mg) in 54% yield:
  • Cpd BB3 was prepared according to a similar procedure as for ⁇ cpd Z3.
  • Cpd DD3 racemates were separated by chiral HPLC: column AD 50Og, flow rate 80 ml/min, ⁇ 220 nm, eluent: CH 3 CN.
  • Cpd EE3 was prepared according to the same procedure as for cpd X3. Cpd EE3 was obtained (0.22 g, 91%) as a brown solid: 1 H NMR (300 MHz, CD-CI 3 ) ⁇ 7.35 (m, 2 H), 7.15 (m, 2 H), 6.83 ⁇ m, 2 H), 6.50 (rn, 2 H), 3.81 (S 1 2 H), 2.80 (m, 4 H), 2.64 (m, 4 H); MS (ES) m/z: 404, 406 ⁇ M+H + ).
  • Cp FF2 was prepared according to the same procedure as for cpd EE2.
  • Cpd HH2 was prepared according to the same procedure as for cpd GG2.
  • C II2 was prepared according to the same procedure as for cpd X2.
  • Cpd JJIb was prepared according to the same procedure as for cpd EE4.
  • Cpd JJ1b was obtained (0.26 g, 100%) as pale oil:
  • Cpd JJ2 was prepared using a similar procedure as for cpd G 1a.
  • the titfe compound was made according to Schemes LL1 & LL2.
  • Cpcl LL1 was prepared according to the same procedure as for cpd KK1.
  • Cpd LL3 was prepared according to the same procedure as for cpd KK3.
  • Cpd LL6 was prepared according to the same procedure as for cpd X2.
  • 6-(4-Trifluoromethyl-phenyl)-pyrazine-2-carbaldehyde A mixture of NN2 (72 mg, 0.288 mmol), THF ⁇ 2.5 mL), water (2.5 mL), OsO 4 (2.5 wt%, 2 drops) and NaIO 4 (123 mg, 0.576 mmol) was stirred at r.t. for 18 h. The mixture was poured into aqueous NaHCOe, extracted with CH 2 CI 2 . The organic extracts were washed with water, brine, dried (NaBSO 4 ) and concentrated.

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Abstract

The invention is directed to compounds of Formula (I) useful as PPAR agonists. Pharmaceutical compositions and methods of treating one or more conditions including, but not limited to, diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof, using compounds of the invention are also described.

Description

TITLE OF THE INVENTION
BENZOAZEPiN-OXY-ACETIC ACID DERIVATIVES AS PPAR-DELTA AGONISTS USED FOR THE INCREASE OF HDL-C, LOWER LDL-C AND
LOWER CHOLESTEROL
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U. S. Provisional Application 60/793,001 , filed on April 18, 2006, which is incorporated by reference herein in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
The research and development of the invention described below was not federally sponsored,
BACKGROUND OF THE INVENTION
The peroxisome proϋferator-activated receptors (PPARs) are considered to be metabolic sensors regulating the expression of genes involved in glucose and lipid homeostasis. They are members of nuclear receptor superfamily of RXR heterodimers and are ligand-activated transcription factors. Agonists of the PPARα (e.g., Gemfibrozil) and PPARγ (e.g., Avandia® ) subtypes are used for the treatment of dyslipidemias and diabetes, respectively. Each receptor has a distinct tissue distribution with PPARα showing highest expression in liver, PPARγ in adipose tissue and PPARδ having the widest distribution being ubiquitously expressed in adult rat (Braissant et al., 1996) and in humans, expression was found in many different tissues involved in lipid metabolism including liver, kidney, abdominal adipose and skeletal muscle (Auboeuf et al., 1997). Recently, potent ligands for PPARδ have been published allowing a better understanding of its function in lipid metabolism {Barak et al, 2002; Oliver et al.r 2001 ; Tanaka et al, 2003; Wang et a!., 2003), The main effect of these compounds in db/db mice (Leibowitz et ai., 2000) and obese rhesus monkeys (Oliver et al., 2001 ) was an increase of high density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides with little effect on glucose (although insulin levels were decreased in monkeys). HDL-C serves to remove cholesterol from peripheral cells through a process called reverse cholesterol transport. The first and rate-limiting step, which is a transfer of cellular cholesterol and phospholipids to the apolipoprotein A-! component of HDL5 is mediated by the ATP binding cassette transporter A1 (ABCA1 ) (Lawn et al., 1999). PPARδ activation appears to increase HDL-C through transcriptional regulation of ABCA1 (Oliver et al., 2001 ). Therefore, by inducing ABCA1 mRNA in macrophages, PPARδ agonists could increase HDL-C levels in patients and remove excess cholesterol from lipid-laden macrophages, one of the major players in atherosclerotic lesion development. This would be an alternative therapy to the statin drugs, which show little effect on HDL-C and mainly decrease LDL-C or the fibrates, the only marketed PPARα agonists, having low potency and inducing only modest HDL-C elevations. In addition, like the fibrates, PPARδ agonists have the potential to also reduce triglycerides, an additional risk factor for cardiovascular disease.
Examples of known PPAR delta agonists variously useful for hyperlipidemia, diabetes, or atherosclerosis include L-165041 (Leibowitz et al., 2000) and GW501516 (Oliver et al., 2001 ). There is a continuing need for new PPAR delta agonists. There is a further need for new PPAR delta agonists that increase HDL-C, lower LDL-C, and/or lower cholesterol. There is a further need for new PPAR delta agonists for the treatment of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL- cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL- cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula (I):
Figure imgf000004_0001
wherein:
X is a covaient bond, O, or S;
Ri and R2 are independently selected from the group consisting of H, Ci-8aiky1, and substituted Chalky!, or R1, R2 and the carbon atom to which they are attached together may form Ca^cycloalkyl;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, Ci-βalkyl, C3-7cycloalkyl, C3-7cycloalkyl--Ci-4alky!, C3- 7cycloalkyloxy-C1-4alkyl, Ci-6aikoxy-Ci-4 alkyl, Ce-ioaryl, heteroaryl, halo substituted
Figure imgf000004_0002
amino substituted Ci-4alkyl, C6-ioaryl substituted Ci.4alkyl, cyano substituted Ci-4alkyi, and hydroxy substituted Ci-4alkyl;
R6 and R7 are independently selected from the group consisting of H, halo, Ci-3alkyl, halo substituted d-salkyt, Ci-3alkoxyf and halo substituted Ci.3alkoxy; n is 1 ; and
Q is selected from the group consisting of
Figure imgf000005_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
The present invention is further directed to pharmaceutical compositions containing one or more compounds of Formula (I), and to to use of such compounds and compositions to treat a condition directly or indirectly mediated by PPAR delta.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following underlined terms are intended to have the following meanings:
"G&b" (wnere a and b are integers) refers to a radical containing from a to b carbon atoms inclusive. For example, C1-3 denotes a radical containing 1 , 2 or 3 carbon atoms.
"Alkyl" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as θthanyl, ethenyl, ethynyl; propyls such as propan-1 -yl, propan-2-yi , cyciopropan-1 -yl, prop-1 -en-1 -yl, prop-1 -en-2-yi, prop-2-en-1-yi, cycloprop-1 -en-1 -yl; cyc!oprop-2-en-1 -yl, prop-1 -yn-1 -yl, prop-2~yn-1-yl, etc.; butyls such as butan-1-yi, butan-2-yi, 2-methyl-propan-1 -yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1 -en-1-yl, but- 1 -en-2-yi, 2-methyl-prop-1 -en-1-yl, but-2-en-1 -yl, but-2-en-2-yl, buta-1 ,3-dien-1-yl, buta-1 ,3-dien-2-y!, cyciobut-1-en-1-yi, cyclobuM -en-3-yl, cyclobuta-1 ,3-dien-1 -yl, but- 1 -yn-1-yl, but-1-yn-3-yI, but-3-yn-1-yl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature "alkanyl", "alkenyt" and/or "alkynyi" is used, as defined below. In preferred embodiments, the alkyl groups are (C1-C6) alkyl, with (Ci-C3) being particularly preferred. Cyclic alky! can be, for example, C3_ioalkyl; preferably, cycloalkyl is C3-7Cycloalkyl.
"Alkanyl" refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1 -yl, propan-2-yl, cyclopropan-1-yi, etc.; butyanyis such as butan-1 -yl, butan-2-yi, 2-methyl-propan-1 -yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like. In preferred embodiments, the alkanyl groups are (Ci.8) alkanyl, with (C1-3) being particularly preferred.
"Aikenyl" refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent aikene. The radical may be in either the cis or trans conformation about the double bond(s). Typical aSkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1 -en-1 -y!; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-y!, but- 1 -en-2-yl, 2-methyl-prop-1 -en-1 -yi, but-2-en-1 -yl, but-2-en-1-yl, but-2-en-2-yi, buta-i ^-dien-i-yl, buta-1 ,3-dien-2-yI, cyclobut-1 -en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1 ,3-dien-1-yl, etc.; and the like.
"Alkvnyl" refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, buM -yn-3-yl, but-3-yn-1-yl, etc.; and the like.
"Heteroalkyl" and "heteroalkanyl" refer to alkyl or alkanyi radicals, respectively, in which one or more carbon atoms (and any necessary associated hydrogen atoms) are independently replaced with the same or different heteroatoms (including any necessary hydrogen or other atoms). Typical heteroatoms to replace the carbon atom<s) include, but are not limited to, N, P, O, S, Si1 etc. Preferred heteroatoms are O, N and S. Thus, heteroalkanyl radicals can contain one or more of the same or different heteroatomic groups, including, by way of example and not limitation, epoxy (-0-), epidioxy (-O-O-), thioether (-S-), epidithio (-SS-), epoxythio (-0-S-), epoxyimino (-O-NR1-), imino (-NR1-), biimino (-NR'-NR1-), azino (=N-N=)} azo (-N=N-), azoxy (-N-O-N-), azimino (-NR'-N=N-), phosphano (-PH-), λ4-suifano (-SH2-), sulfonyi (-S(O)2-), and the like, where each R1 is independently hydrogen or (Ci-Ce) alkyl.
"Aryi" refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In preferred embodiments, the ary! group is (C5-2o) aryl, with (C5-10) being particularly preferred. Particularly preferred aryl groups are phenyl and naphthyl groups.
"Arvialkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-i-yi, naphthylmethyl, 2-naphthylethan-1 -yi, 2-naphthylethen-1-yI, naphthobenzyl, 2-naphthophenyiethan-1 -yl and the like. Where specific alkyl moieties are intended, the nomenclature arylaikanyl, arylakenyl and/or arylalkynyl is used, in preferred embodiments, the arylalkyl group is {Ce-εe) arylalkyl, e.g., the alkanyl, alkenyl or aikynyl moiety of the arylalkyl group is (Ci-6) and the aryi moiety is (C5-2o)- In particularly preferred embodiments the arylalkyl group is (C6-13), e.g., the alkanyl, alkenyl or alkynyi moiety of the arylalkyl group is (C-i -3) and the aryl moiety is (C5-10). Even more preferred arylalkyl groups are phenylalkanyls.
"Aikanyloxy" refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen of the alcohol. Typical alkanyloxy groups include, but are not limited to, methanyloxy; ethanyloxy; propanyioxy groups such as propan-1-yloxy (CH3CH2CH2O-), propan-2-yloxy ((CHs)2CHO-), cyclopropan-1-yloxy, etc.; butanyloxy groups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1 -yloxy, 2-methyl-propan-2-yloxy, cyclobutan-1 -yioxy, etc.; and the like. In preferred embodiments, the alkanyloxy groups are (Ci-8) alkanyloxy groups, with {Ci-3) being particularly preferred. "Heteroaryl" refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, radicais derived from carbazole, imidazole, indazoie, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazote, isoxazole, naphthyridine, oxadiazole, oxazoie, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like, in preferred embodiments, the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
"Cvcloheteroalkyl" refers to a saturated or unsaturated monocyclic or bicyclic alkyl radical in which one carbon atom is replaced with N, O or S. in certain specified embodiments the cycloheteroalkyl may contain up to four heteroatoms independently selected from the group consisting of N, O and S. Typical cycloheteroalkyl moieties include, but are not limited to, radicals derived from imidazolϊdϊne, morpholine, piperazine, piperidinβ, pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferred embodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.
"Cvcloheteroalkanyl" refers to a saturated monocyclic or bicyclic alkanyS radical in which one carbon atom is replaced with N, O or S. In certain specified embodiments the cycloheteroalkanyl may contain up to four heteroatoms independently selected from the group consisting of N, O and S. Typical cycloheteroalkanyl moieties include, but are not limited to, radicals derived from imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like, tn preferred embodiments, the cycloheteroalkanyl is a 3-6 membered cycloheteroalkanyi.
"Cvcloheteroalkenyl" refers to a saturated monocyclic or bicyclic alkenyl radical in which one carbon atom is replaced with N, O or S. In certain specified embodiments the cycloheteroalkenyl may contain up to four heteroatoms independently selected from the group consisting of N, O and S. Typical cycloheteroalkenyi moieties include, but are not limited to, radicals derived from imidazoline, pyrazoline, pyrroline, indoitne, pyran, and the like. In preferred embodiments, the cycloheteroalkanyl is a 3-6 membered eye loheteroa! kany i .
The term "substituted" refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, -X, -R, -O", =0, -OR, -0-OR1 -SR, -S", =S, -NRR, =NR, -CX3, -CN, -OCN, -SCN, -NCO, -NCS1 -NO, -NO2, =N2; -N3, -NHOH, -S(O)2O-, -S(O)2OH, -S(O)2R, -P(O)(O-)2, -P(O)(OH)2, -C(O)R, -C(O)X1 -C(S)R1 -C(S)X, -C(O)OR5 -C(O)O', -C(S)OR1 -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR and -C(NR)NRR, where each X is independently a halogen (preferably -F, -Cl or -Br) and each R is independently -H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene, aikylidyne, aryl, aryialkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein. Preferred substituents include hydroxyj halogen, Ci.8aikyl, Ci-ealkanyioxy, fiuorinated alkanyloxy, fluorinated alkyl, Ci-8alkyith!θ, Ca-ecycloalkyi, C3.8cycioalkanyloxyj nitro, amino, Ci-salkylamino, Ci-βdialkylamino, Ca-scycloalkylamino, cyano, carboxy, C^alkanyloxycarbonyl, d^alkylcarbonyloxy, formyl, carbamoyl, phenyl, aroylt carbamoyl, amidino, (Ci-salkylamtnojcarbonyi, (arylamino)carbonyl and aryi(Ci-8alkyϊ)carbonyl.
With reference to substituents, the term "independently" means that when more than one of such substituent is possible, such substituents may be the same or different from each other. in any structure that contains the symbol ?, that symbol designates the Iocation(s) of the open valence(s) where the partial structure attaches to the rest of the molecule.
Throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenylCi-ealkanylaminocarbonylCi.ealkyl" substituent refers to a group of the formula:
Figure imgf000011_0001
The present invention is directed to compositions comprising a compound of Formula (i) for uses as PPAR delta agonists:
wherein:
Figure imgf000011_0002
wherein:
X is a covalent bond, O, or S;
R1 and R2 are independently selected from the group consisting of H, Ci-8alkyl, and substituted Ci.saikyi, or Ri1 R2 and the carbon atom to which they are attached together may form C3-7Cycioa!kyl;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, Ci-8alkylf C3-7cycloalkyl, Ca-ycycloalkyi-Ci^alkyl, C3- 7cycioalkyloxy-Ci-4alkyl, C-i-ealkoxy-C-i^alkyl, Ce-ioaryl, heteroaryl, halo substituted C1-4alkyl, amino substituted Chalky I, CVioaryl substituted d^alkyl, cyano substituted C^alkyl, and hydroxy substituted Ci-4aikyi; R6 and R? are independently selected from the group consisting of H1 halo, Ci.3alkyl, halo substituted Ci-3aikyl, C1^aIkOXy, and halo substituted Ci-3alkoxy; n is 1 ; and Q is selected from the group consisting of
Figure imgf000012_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
In particular, the present invention is directed to a compound of Formula (I) wherein:
X is O; or
R1 and R2 are independently selected from the group consisting of H and Ci-8alkyl, or R-i, R2 and the carbon atom to which they are attached together may form Cs-scycloalkyl, and more particularly R1 and R^ are independently selected from the group consisting of H and CH3, or R1, R2 and the carbon atom to which they are attached together may form
Figure imgf000013_0001
R4 and R5 are independently selected from the group consisting cf H and C-i-βalkyl, and more particularly R5 is H, CH3, or -CH2CH3; or
R6 and R7 are independently selected from the group consisting of H, halo, halo substituted Ci-3aikyl, Ci-3alkoxy, and halo substituted Ci-3alkoxy, and more particularly R6 is H and R7 is selected from the group consisting of halo, halo substituted Chalky!, and halo substituted Ci.3alkoxy, and more particularly R7 is selected from the group consisting of F, CF3, and -0-CF3; or
Q is selected from the group consisting of
Figure imgf000013_0003
nd more particularly Q is selected from the group consisting of
Figure imgf000013_0002
More particularly, the present invention is directed to a compound of Formula (I) as shown above wherein: X is O; R-i, FΪ2, R4, and R5 are independently selected from the group consisting of H and Ci-3alkyi, or R1, R2 and the carbon atom to which they are attached together may form C3-5cycloalkyl; and R6 and R7 are independently selected from the group consisting of H, halo, Ci.3afkoxy( halo substituted Chalky!, and halo substituted Ci-3alkoxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
In another aspect, the present invention is directed to pharmaceutical compositions containing one or more compounds, salts or solvates of Formula (I) as described herein admixed with a pharmaceutically acceptable carrier, excϊpient or diluent, wherein the compositions can be used to treat a condition directly or indirectly mediated by PPAR delta.
The present invention is also directed to a method of treating or preventing a disease or condition in a subject, particularly a mammal and more particularly a human, which disease or condition is affected by the modulation of PPAR delta.
Therefore, in yet another aspect, the present invention is directed to a method of treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of PPAR delta receptors, which method comprises administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I) as described herein. More particularly, the therapeutically effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 50 mg to about 1000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg. In a further aspect, the present invention is directed to a method for treating or preventing a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesteroiemia, mixed hyperlipidemia, and hypo-HDL- cholesterolemia), atherosclerosis, and obesity, said method comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I). More particularly, the therapeutically effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 50 mg to about 1000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg.
fn still a further aspect, the present invention is directed to a kit comprising in one or more containers an amount of the composition of Formula (I) effective to treat or prevent a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia {including hypertriglyceridemia, hypercholesteroiemia, mixed hyperlipidemia, and hypo- HDL-cholesterolemia), atherosclerosis, and obesity. More particularly, the therapeutically effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg. More particularly, the the rapeuticaliy effective amount comprises a dose range of from about 50 mg to about 1000 mg. More particularly, the therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg. In another embodiment, the present invention is directed to a compound of Formula (Ia)
Figure imgf000016_0001
wherein
R1 and R2 are independently selected from the group consisting of H and Ci.8alkyl, or Ri, R2 and the carbon atom to which they are attached together may form C^cycloalkyl; R4 and R5 are independently selected from the group consisting of H and Ci-8aikyl; R6 and R7 are independently selected from the group consisting of H,
Ci.3alkyl, halo, and halo substituted Chalky!; and Q is selected from the group consisting of
Figure imgf000016_0002
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof. In yet another embodiment, the present invention is directed to a compound of Formula (Ib)
Figure imgf000017_0001
wherein
R1 and R2 are independently selected from the group consisting of H and CH3, or Ri, R2 and the carbon atom to which they are
attached together may form
Figure imgf000017_0003
; R4 and R5 are independently selected from the group consisting of H,
CH3, and -CH2CH3; and Q is selected from the group consisting of
Figure imgf000017_0002
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
In yet another embodiment, the present invention is directed to a compound of Formula (Ic)
Figure imgf000018_0001
Ri, R2, and R4, are independently selected from the group consisting of H and CH3, or Ri, R2 and the carbon atom to which they are
attached together may form
Figure imgf000018_0002
R5 is selected from the group consisting of H, CH3, and -CH2CH3; R7 is halo or halo substituted Chalky!; and Q is selected from the group consisting of
Figure imgf000018_0003
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
In particular, the present invention is directed to compounds of Formula (Ic) hereinabove wherein: Ri or R2 is H; Ri and R2 are both H; i£ R1 or R2 is CH3;
R1 and R2 are both CH3;
Ri, R2 and the carbon atom to which they are attached together
form
Figure imgf000018_0004
R4 is H or CH3;
R5 (S H1 CH31 Or -CH2CH3;
Ri or R2 is H and R4 is H or CH3; (i) R1 and R2 are both H and R4 is H or CH3; (j) R1 or R2 is H and R5 is H, CH3, or -CH2CH3; (k) R1 and R2 are both H and R5 is H, CH3, or -CH2CH3; (l) R1 or R2 is CH3 and R5 is H, CH3, or -CH2CH3; (m) R1 and R2 are both CH3 and R5 is H, CH3, or -CH2CH3; (n) Ri or R2 is H, R4 is H, and R5 is H1 CH3, or -CH2CH3;
R1 and R2 are both H, R4 is H, and R5 is H, CH3, or -CH2CH3;
R1 or R2 is CH3, R4 is H1 and R5 is H, CH3, Or -CH2CH3;
R1 and R2 are both CH3, R4 is H, and R5 is H, CH3, or -CH2CH3;
R1, R2 and the carbon atom to which they are attached together
form
Figure imgf000019_0001
, R4 is H, and R5 is H , CH3, or ^CH2CH3;
R7 is CF3; (t) R7 is Cl;
(u) Ri or R2 is H, R7 is CF3, and R4 is H or CH3; (v) R1 and R2 are both H, R7 is CF3, and R4 is H or CH3; (w) R1 or R2 is H, R7 is CF3, and R5 is H, CH3, or -CH2CH3; (x) Ri and R2 are both H, R7 is CF3, and R5 is H, CH3, or -CH2CH3; M R1 or R2 is CH3, R7 is CF3, and R5 is H, CH3, or -CH2CH3; (z) Ri and R2 are both CH3, R7 is CF3, and R5 is H, CH3, or -CH2CH3; (aa) R1 or R2 is H, R4 is H, R7 is CF3, and R5 is H, CH3, or -CH2CH3;
R1 and R2 are both H, R4 Js H, R7 is CF3, and R5 is H, CH3, or -
CH2CH3;
R1 or R2 is CH3, R4 is H, R7 is CF3, and R5 is H, CH3, or -CH2CH3; (dd) Ri and R2 are both CH3, R4 is H, R7 is CF3, and R5 is H, CH3, or -
CH2CH3; ee) Ri , R2 and the carbon atom to which they are attached together
form
Figure imgf000020_0004
, R4 is H1 R7 is CF3, and R5 is H1 CH3, or -CH2CH3; Q is selected from the group consisting of
Figure imgf000020_0001
Ri or R2 is H and Q is selected from the group consisting of
Figure imgf000020_0002
(hh) Ri and R2 are both H and Q is selected from the group consisting of
Figure imgf000020_0003
£ij] R1 or R2 is CH3 and Q is selected from the group consisting of
Figure imgf000021_0001
Oil Ri and R2 are both CH3 and Q is selected from the group consisting of
Figure imgf000021_0002
kk) R4 is H or CH3 and Q is selected from the group consisting of
Figure imgf000021_0003
m R5 is H, CH3, Or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000021_0004
fmm) Ri or R2 is H and R4 is H or CH3 and Q is selected from the group consisting of
Figure imgf000022_0001
fnn) R1 and R2 are both H and R4 is H or CH3 and Q is selected from the group consisting of
Figure imgf000022_0002
(00) R1 or R2 is H and R5 is H, CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000022_0003
Ri and R2 are both H and R5 is H, CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000023_0001
Ri or R2 is CH3 and R5 is H1 CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000023_0002
R1 and R2 are both CH3, R5 is H, CH3, or -CH2CH3, andQ is selected from the group consisting of
Figure imgf000023_0003
fss) Ri or R2 is H, R4 is H, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000024_0001
Ri and R2 are both H, R4 is H, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000024_0002
fuuϊ Ri or R2 is CH3, R4 is H, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000024_0003
Ri and R2 are both CH3, R4 is H, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000025_0001
Ri, R2 and the carbon atom to which they are attached together
form
Figure imgf000025_0002
, R4 is H, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000025_0004
R7 is CF3 and Q is selected from the group consisting of
Figure imgf000025_0003
(xx) R7 is Cl and Q is selected from the group consisting of
Figure imgf000026_0001
(vv) Ri or R2 is H, R7 is CF3, R4 is H or CH3, and Q is selected from the group consisting of
Figure imgf000026_0002
(zz) Ri and R2 are both H, R7 is CF3, R4 is H or CH3, and Q is selected from the group consisting of
Figure imgf000026_0003
R1 or R2 is H, R7 is CF3, R5 Js H1 CH3, or -CH 2CH3, and Q is
SΘI lected from the group consisting Of
Figure imgf000027_0001
Ri and R2 are both H, R7 is CF3, R5 is H, CH3, Or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000027_0002
R1 or R2 is CH3, R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000027_0003
(ddd) R1 and R2 are both CH3, R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000028_0001
is H5 R4 is H, R7 is CF3, R5 is H, CH3f or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000028_0002
see) R1 and R2 are both H, R4 is H, R7 is CF3, R5 is H, CH3, or CH2CH3, and Q is selected from the group consisting of
Figure imgf000028_0003
R1 or R2 is CH3, R4 is H, R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000028_0004
or Jai Ri and R2 are both CH3, R4 is H, R7 is CF3, R5 is H, CH3, or - CH2CH3, and Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
In yet another embodiment, the present invention is directed to a compound selected from the group consisting of
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
and enantfomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof. Specifically, the compound of formula (I) is
Figure imgf000033_0002
The present invention is further directed to a compound of Formula <l)
Figure imgf000033_0003
wherein;
X is a covalent bond, O, or S;
Ri and R2 are independently selected from the group consisting of H, Ci-8alkyi, and substituted Ci-8alkyf, or R1, R2 and the carbon atom to which they are attached together may form C3-7CycIoalkyl;
R3 is H; R4 and R5 are independently selected from the group consisting of H, halo, C1-8alkyi, C3-7Cyc!oalkyl, Cs^cycloalkyl-Ci^aikyl, C3. 7cycloalkyloxy-C1-4alkyl, Ci-6alkoxy-Ci^ alkyl, C6-1oaryi, heteroaryl, halo substituted C1-4alkyl, amino substituted C1-4alkyl, C6-10ary! substituted Ci.4alkyl, heteroaryl substituted Ci^alkyl, cyano substituted C1-4alkyl, and hydroxy substituted Ci.4alkyl;
R6 and R7 are independently selected from the group consisting of H, halo, Ci^alkyl, halo substituted Chalky!, Ci^alkoxy, and halo substituted Ci.3alkoxy; n is 1 ; and
Q is C6-ioaryl;
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
The present invention is also directed to a compound of Formula <l)
Figure imgf000034_0001
wherei
X is a covalent bond, O, or S;
R1 and R2 are independently selected from the group consisting of H, C1-8alkyl, and substituted Ci-ealkyl, or Ri, R2 and the carbon atom to which they are attached together may form C3-7€ycloa!kyl;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, Ci-8alkyl, C3-7cycloalkyl, Cs-ycycloalkyl-C^alkyl, C3- 7cycloaikyloxy-Ci-4alkyl, d-βalkoxy-Ci^alkyi, CVioaryl, heteroaryl, halo substituted Ci^alkyl, amino substituted Ci^alkyl, C6-10aryl substituted Ci-4alkyl, heteroaryl substituted Ci.4alkyi, cyano substituted Ci^alky!, and hydroxy substituted Ci^alkyl; R6 and R7 are independently selected from the group consisting of H, halo, Ci.3alkyl, halo substituted Ci-3alkyl, Ci^alkoxy, and halo substituted Ci-3alkoxy; n is 1 or 2; and Q is selected from the group consisting of
Figure imgf000035_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
The present invention is also directed to a compound of Formula (I)
Figure imgf000035_0002
wherein:
X is a covalent bond, O, or S;
R1 and R2 are independently selected from the group consisting of H, Ci-βalkyI, and substituted Ci-8aikyl, or R1, R2 and the carbon atom to which they are attached together may form Cs-ycycloalkyi;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, C1-8alkyl, C3-7cycloalkyl, C3-7cycloaikyl-Ci-4alkyi, C3. ycycloalkyloxy-d^alkyl, Ci-6aikoxy-Ci.4 alkyl, C6-ioaryl, heteroaryl, halo substituted Ci-4alkyl, amino substituted Ci^alkyl, Ce-ioaryl substituted Ci.4alkyl, cyano substituted d^alkyi, and hydroxy substituted Ci^alkyE; R6 and R7 are independently selected from the group consisting of H1 halo, Ci-3a!kyl, halo substituted Ci^alkyl^^alkoxy, and halo substituted Ci-3alkoxy; n is 2; and
Q is selected from the group consisting of
Figure imgf000036_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
In yet another embodiment, the present invention is directed to a compound selected from the group consisting of
Figure imgf000036_0002
Figure imgf000037_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" (Ref. international J. Pharm,, 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1). Other salts well known to those in the art may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromtc, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, tactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandeiic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthaIenesulfonic, p-toluenesulfonic, cyclohexanesuffamic, salicylic, saccharinic or trtfluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the tfeatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administrationjojhe patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Representative hydroxy group prodrug forms include, but are not limited to, Ci.4a!kanyiethers, substituted Ci- 4aikanylethers, and Ci-4alkanyl esters.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toIuoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. Thus, another embodiment of the present invention is a composition comprising the dextrorotatory enantiomer of a compound of Formula (I), wherein said composition is substantially free from the levorotatory isomer of said compound. In the present context, substantially free means less than 25 %, preferably less than 10 %, more preferably less than 5 %, even more preferably less than 2 % and even more preferably less than 1 % of the levorotatory isomer calculated as.
Figure imgf000039_0002
Another embodiment of the present invention is a composition comprising the levorotatory enantiomer of a compound of formula ^) wherein said composition is substantially free from the dextrorotatory isomer of said compound. In the present context, substantially free from means less than 25 %, preferably less than 10 %, more preferably less than 5 %, even more preferably less than 2 % and even more preferably less than 1 % of the dextrorotatory isomer calculated as
Figure imgf000039_0003
For example, the present invention is also directed to a compound selected from the group consisting of
Figure imgf000039_0001
Figure imgf000040_0001
wherin the compound is substantially free from the corresponding other enantiomer.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable Io protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Even though the compounds of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipterrts or diluents.
By way of example, in the pharmaceutical compositions of the present invention, the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent{s), and/or solubilising agent(s).
Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
Alternatively, the compounds of the general Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. An alternative means of transdermal administration is by use of a skin patch. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
For some applications, preferably the compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
The compositions (as well as the compounds aione) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. In this case, the compositions will comprise a suitable carrier or diluent.
For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with biood. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
By way of further example, pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art. it is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of the inventiom?r a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosayes to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention is required for a subject in need thereof.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing 0.01 , 10.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
Examples of condition intended to be within the scope of the present invention include, but are not limited to, diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidβmia {including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo- HDL-choiesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.
Compounds of the present invention are also useful as PPAR delta agonists for treating, preventing, or inhibiting the progression of, a condition directly or indirectly mediated by PPAR delta.
The compounds of the present invention are partcularly useful in treating diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-choiesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL- cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof.
In regard to the use of the present compounds in treatment of the disases or conditions such as those listed above, a therapeutically effective dose can be determined by persons skilled in the art by the use of established animal models. Such a dose would likely fall in the range of from about 0.01 mg to about 15,000 mg of active ingredient administered 1 to 4 times per day for an average (70 kg) human.
GENERAL SYNTHETIC METHODS Representative compounds of the present invention can be synthesized in accordance with the general syntheϋynethods described beiow as well as the illustrative examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
Scheme 1. General methods for the synthesis of Compounds of formula (Id)
Figure imgf000045_0001
Method 3,
Figure imgf000046_0001
Figure imgf000046_0002
Scheme 1 , wherein R1, R2, R3, FU, Rs, Re, R7, X and Q are as described above, describes several general methods for the synthesis of compounds of Formula Id. For example, in Method 1 , alkylation of the substituted benzoazepine 1-B with a compound of Formula 1-C where Yean be a leaving group such as Br, Cl, i, mesylate, etc. under a basic condition, such as Cs2CO3 in CH3CN, can generate the corresponding compound of Id. In Method 2, reductive aminatton of 1-B with aryl aldehyde 1-D (e.g. R5 = H) by using NaBH(OAc)3 will generate Id; or reaction of 1-B with aryi ketone (e.g. R5 = C1-C3 alky!) to give the shiff-base foϊtowed by reduction with NaCNBH3 will generate Id. In Method 3, reaction of 1 -B with aryl aldehyde 1-E to give the shiff-base followed by reaction with organo-alkyl reagents such as Grignard reagents, CH3Li or organo-cupper reagent, will also provide Id.
Scheme 2. General methods for the synthesis of Compounds of formula (Ie) Method 1 :
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0003
Scheme 2, wherein Ri, R2, Rs, R4, Rs, Re, R7, X and Q are as described above, describes several general methods for the synthesis of compounds of Formuta Ie. For example, in Method 1 , reductive amination of 1-B with aryl aldehyde 2-A (e.g. R5 = H) by using NaBH(OAc)3 will generate Ie; or reaction of 1-B with aryl ketone (e.g. R5 = CrC3 alkyi) to give the shiff- base followed by reduction with NaCNBH3 will generate Ie. In Method 2, reaction of 1-B with aryl aldehyde 2-B to give the sniff-base followed by reaction with organo-alkyl reagents such as Grignard reagents, CH3Li or organo-cupper reagent, will also provide Ie.
Compounds of Formula (I) that are chiral may be separated into their enantiomers by chromatography on a chiral stationary phase. Alternatively, the basic compounds of the present invention may be converted to diastereomeric salts by mixture with a chiral acid and resolved into their enantiomers by fractional crystallization.
It is generally preferred that the respective product of each process step be separated from other components of the reaction mixture and subjected to purification before its use as a starting material in a subsequent step. Separation techniques typically include evaporation, extraction, precipitation and filtration. Purification techniques typically include column chromatography (Still, W. C. et. a!., J. Org. Chem. 1978, 43, 2921), thin-layer chromatography, crystallization and distillation. The structures of the final products, intermediates and starting materials are confirmed by spectroscopic, spectrometric and analytical methods including nuclear magnetic resonance (NMR)1 mass spectrometry (MS) and liquid chromatography (HPLC). In the descriptions for the preparation of compounds of this invention, ethyl ether, tetrahydrofuran and dioxane are common examples of an ethereal solvent; benzene, toluene, hexanes and heptanes are typical hydrocarbon solvents and dichloromethane and dichloroethane are representative haiogenated hydrocarbon solvents, in those cases where the product is isolated as the acid addition salt the free base may be obtained by techniques known to those skilled in the art. In those cases in which the product is isolated as an acid addition salt, the salt may contain one or more equivalents of the acid. Enantiomers of the compounds of the present invention may be separated using chiral HPLC.
Abbreviations
Ac CH3ClO)-
Aq = aqueous
Cpd = Compound con = concentration
DCE = dichloroethane
DMF = Λ/,/V-dimethylformamide DMSO = dimethylsulfoxicle cfppf = diphenylptøphiπoferrocene
Et ethyt
EtOAc = ethyl acetate h or hr = hour{s)
HATU N-[(dimethylamino)(3H-1 ,2,3- triazolo{4,5-b)pyridine-3- yloxy)methyiene]-N- methylmethanaminium hexafluorophosphate
LAH = lithium aluminum hydride
Me = methyl min = minute<s)
Ph = phenyl
PPA = polyphosphortc acid psi = pascal per square inch f-Boc = terf-butoxycarbonyl t-Bu = tert-butyl
TEA = triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = (thin layer chromatography)
LiN(TMS)2 = Lithium bis(trimethyls!lyl)amide
ToI - toluene EXAMPLES
Example A
Figure imgf000050_0001
Compound 1 : {3-[3-(4-Trifluoromethyi-pheny!)-isothiazo!-5-ylmethyi]-2,3,4,5-tetrahydro- 1 H-benzo[d]azepin-7-ylo)cy}-acetic acid
The title compound was made according to Schemes A1 and A2.
Scheme A1
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000050_0004
Cpd A1a can be prepared according to published procedures (US patent No. 4,659,706 and Eur. Pat. Appl. 204349).
Figure imgf000051_0001
(4-0x0-2 ,3,4 , 5-tetrahydro- 1 H-benzo[c(lazepi n- 7-y)oxy)-acetic acid ethyl ester
To a solution of A1a (725 mg, 3.8 mmo!) in CH2Ci2 (10 mi_) at -78 0C was added BBr3 (1 M in CH2CI2, 11.4 ml, 11 ,4 mmof). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 5 h. MeOH (5 m!_) was added slowly to quench the reaction. The reaction mixture was then concentrated to give a yellow solid.
A mixture of the above crude phenol, ethyl bromoacetate {950 mg, 5.69 mmol) and CS2CO3 (2.47 g, 7.58 mmol) in CH3CN (15 ml_) was stirred at 80 °C for 20 h. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2SO^, concentrated and purified by column chromatography to give 350 mg (35%) of Cpd A1 b as a white solid: 1H NMR (300 MHz, CDCI3) δ 7.04 (d, J = 8.4 Hz, 1 H), 7.77 (del, J = 8.4, 2.7 Hz, 1 H), 6.69 {d, J = 2.5 Hz, 1 H), 5.83 (bs, 1 H), 4.59 (s, 2 H), 4.27 (q, J= 7.1 Hz, 2 H), 3.80 <s, 2 H)1 3.58 - 3.52 (m, 2 H), 3.06 (t, J = 6.0 Hz, 2 H), 1.30 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 286 (M+Na+).
Figure imgf000051_0002
(2,3,4,5-Tetrahydro-IH-benzoϊcdazepin- 7-yloxy)-acetic acid ethyl ester
1 M borane-THF solution (1 mL, 1.02 mmol) was added dropwrse to an ice-cooled and stirred solution of A1 b (ϋθ mg, 0.342 mmol) in THF (5 mL). The stirring was continued at 0 0C for 1 h and then room temperature for 20 min. The solution was cooled back to 0 0C and 1 N HCI <2 mL) was added slowly to destroy the excess borane. After stirring at room temperature for 15 min, the solution was concentrated to remove THF. The aqueous solution was washed with EtOAc and then basified with Na2CO3 until PH > 10 and then extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated and vacuum dried to give 43 mg (48%) of A1c as a yellow jelly oil: 1H NMR (300 MHz, CDCI3) δ 6.99 (d, J = 8.4 Hz1 1 H), 6.70 (s, 1 H), 6.60 (d, J = BA Hz, 1 H), 4.59 (s, 2 H), 4.28 <q, J= 7.1 Hz, 2 H)1 2.97 (bm, 4 H)1 2.84 (bm, 4 H), 2.67 (s, 1 H)1 1.30 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 250 (M+H+).
Scheme A2
Figure imgf000052_0001
Figure imgf000053_0001
5-(4-TrifIυoromethyl-phenyl)-|1 !3,4]oxathiazol-2-one
The reaction mixture of 4-trifluoromethylbenzamide (11.3 g, 59.8 mmol), chlorocarbonylsulfenyl chloride (10.1 ml_, 119.6 mmol) in toluene (120 ml_) was heated at 800C for 15 h, cooled and concentrated. The solid was transferred to a sintered funnel, washed with a small amount of ethanol and dried under vacuum to give 13.4 g (91%) of A2a as white crystals: 1H NMR (300 MHz, CDCI3) δ 8.11 <d, J= 8.2 Hz, 2 H), 7,77 <d, J= 8,3 Hz, 2 H).
Figure imgf000053_0002
3-(4-Trif!uoromethyl-phenyl)-isothiazole-5-carboxy!ic acid ethyl ester
The reaction mixture of A2a (608 mg, 2.46 mmoi) and ethyl propiolate (726 mg, 7.41 mmol) in chlorobenzene (10 mL) was heated at 135 0C for 20 h. TLC showed some of the starting material A2a still remained. More ethyl propiolate (726 mg, 7.41 mmol) and 1 ,2-dichlorobenzene <10 mL) were added and the solution was heated at 160 0C for 7 h. After cooling to room temperature, the reaction mixture was purified by column chromatography to give 229 mg (31%) of A2b as a white solid: 1H NMR (300 MHz, CDCI3) δ 8.15 (S, 1 H), 8.09 (d, J = 8.1 Hz, 2 H), 7,73 (d, J = 8.2 Hz12 H), 4.44 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 302 <M+H+).
Figure imgf000053_0003
[3- (4-Trtfluo romethyl-phen y I)- isoth iazol-5-y I]- methanol To the solution of A2b {104 mg, 0.345 mmol) in THF (2 mL) at -780C was added 1.0 M LiAIH4 (0.21 ml_s 0.21 mmol) in THF. After stirring at -78 0C for 30 min, water was slowly added and the mixture was allowed to warm uμ to room temperature. The precipitated solid was filtered and rinsed with CH2CI2. The filtrate was washed with saturated NH4Ct, and the aqueous solution was back extracted with CH2CI2. The combined organic phases were dried and concentrated to give 98 mg of crude A2c as a yellow solid: 1H NMR (300 MHz, CDCI3) δ 8.04 (d, J= 8.3 Hz5 2 H)1 7.70 {d, J= 8.4 Hz, 2 H)1 7.51 (S, 1 H), 5.06 (s, 2 H); MS (ES) m/z: 260 (M+H+).
Figure imgf000054_0001
5-B romorneth yl-3-(4-ttϊf I uororn ethy 1- phenyl)-isothiazole
To the solution of A2c (1.0 g, 3.86 mmol) in CH2Ci2 <25 mL) at 00C was added PPh3 (1.3 g, 5.01 mmol) and CBr4 (1.7 g, 5.01 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 4 h at room temperature. The reaction mixture was concentrated and purified through column chromatography to get 1.36 g (98%) A2d as a white solid:
Figure imgf000054_0002
{3-[3-(4-Trifluoromethyf-phenyl)-!sothiazol-5-yimethyl]-2,3,4,5-tetrahydro- 1 W-benzo[cQazepii>7-y!oxy}-acetic acid ethyl ester
A mixture of A1e (15 mg, 0.060 mmol), A2d<23 mg, 0.072 mmol) and Et3N (20 mg, 0.18 mmol) in CH3CN (1 mL) was stirred for 5 hours. EtOAc and H2O were added and the aqueous layer was extracted with EtOAc. The combined organic phases were dried ^Na2SO4), concentrated and purified through column chromatography to get 20 mg (68%) Cpd A2e as a white solid: 1H NMR (300 MHz, CDCI3) δ 8.05 <d, J = 8.4#z, 2 H), 7.69 <d, J = 8.4 Hz, 2 H), 7.45 (S, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.70 (d, J= 2.5 Hz1 1 H), 6.62 (dd, J= 8.2, 2.5 Hz, 1 H), 4.59 (s, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.98 (s, 2 H), 2.90 (m, 4 H), 2.70 (m, 4 H), 1.30 (t, J= 7,1 Hz, 3 H); MS (ES) m/z: 491 (M+H*).
Figure imgf000055_0001
{3-[3-(4-Triftuoromethy!-phenyl)-isothia2Ol-S-ylmethyl]-2,3,4,S-tetrahydro-1 H-benzc(cf
]azepin-7-yloxy}-acetic acid
A mixture of A2e (20 mg, 0.041 mmol) and 2 M NaOH {41 μl_, 0.082 mmol) in THF-MeOH (0.6 mL-0.2 ml_) was stirred under N2 for 2 h and concentrated. CH2CI2 and water were added, and the mixture was acidified with concentrated HCI. The organic phase was separated and the aqueous phase was extracted with CH2CI2. The combined organic layers were dried (Na2SO-O, concentrated, and purified by column chromatography to give 15 mg (80%) of Cpd 1 as a white solid: 1H NMR <300 MHz, COCi3) δ 8.05<d, J = 8.0 Hz, 2 H), 7.90 (s, 1 H), 7.71 <d, J= 8.4 Hz1 2 H)1 6.95 <d, J= 8.3 Hz1 1 H), 6.75 (dd, J= 8.1 , 2.6 Hz1 1 H)1 6.65 (d, J= 2.6 Hz1 1 H), 4.65<s, 2 H), 4.38 (s, 2 H), 3.07 (m, 4 H), 2.93 (m, 4 H); MS (ES) m/z: 463 (M+H+).
Example B
Figure imgf000055_0002
Compound 2: 2-Methyl-2-{3-[3-(4-trifluoromethyl-pheπyl)-isothiazol-S-ylmethyI]- 2,3,4,5-tetrahydro-1 W-benzoJcflazepin-y-ytoxyl-propiontc acid
The title compound was made according to Scheme 8. Scheme B
Figure imgf000056_0001
Figure imgf000056_0002
2-Methyl-2-(4-oxo-2,3!4,5-ietrahydro-1H-benzo{d ]azepin-7-yloxy)-propionic acid ethyl «ster
To a solution of A1a (4.0 g, 20.9 mmol) in CH2Cl2 (20 mL) at -78 0C was added BBr3 (1 M in CH2C)2, 62.8 mL, 62.8 mmol). The mixture was allowed to warm to room temperature and stirred at room temperature for 5 h. MeOH (5 mL) was added slowly to quench the reaction. The reactrøn mixture was then concentrated to give a yetlow solid.
A mixture of the above crude phenol, ethyl brornoisobutyrate t6.1 g, 31.4 mmol) and Cs2CO3 (20.8 g, 63.8 mmol) in CH3CN {200 mL) was stirred at 80 0C for 20 h. After cooling to room temperatuctiJhe mixture was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated and purified by coiumn chromatography to give 4.2 g (70%) of B1 as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.03 {d, J = 8,4 Hz, 1 H), 6.68 (dd, J= 8.3, 2.6 Hz, 1 H), 6.63 (d, J= 2.6 Hz1 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3,76 (s, 2 H)1 3,57 - 3.52 (m, 2 H), 3.04 <t, J= 6.0 Hz, 2 H), 1.53 (s, 6 H), 1.24 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 314 (M+Na+).
Figure imgf000057_0001
2-Methyi-2-(2J3,4!5-tetrahydro-1 H-benzo[cdazepin-7-y!ox y)-propionic acid ethyl ester
The 1 M borane-THF solution {20.5 mL, 20.5 mmol) was added dropwise to an ice-cooled and stirred solution of B1 {2.0 g, 6.85 mmot) in THF (20 mL). The stirring was continued at room temperature for 1 h. The solution was cooled back to 0 0C and 1 N HCI {25 mL) was added slowly to destroy the excess borane. After stirring at room temperature for 15 min, the solution was concentrated to remove THF. The aqueous solution was washed with EtOAc, basified with Na2CO3 until PH > 10 and then extracted with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated to give 1.5 g (79%) of B2 as a colorless jelly oil: 1H NMR (300 MHz1 CDCI3) δ 6.95 (d, J = 8.4 Hz, 1 H), 6.64 <d, J = 2.5 Hz1 1 H)16.55 (dd, J = 8.4, 2.6 Hz, 1 H), 4.22 (q, J= 7.1 Hz, 2 H), 2,99 (m, 2 H), 2.88 (m, 2 H)1 1.59 (s, 6 H), 1.25 (t, J= 7.1 Hz, 3 H); MS {ES) m/z: 278 (M+H+).
Figure imgf000058_0001
2-Methy l-2-{3- [3-{4-trif luoromethy l-pheny I)- i εoth iazol-5-y I methyi]-2,3,4,5- tetrahydro-1 H-benzo[djazepin-7-yloxy}-propionic acid ethyl ester
Cpd B3 was prepared using same procedure as for cpd A2e by replacing A1 b with B2 (white solid, 72%): 1H NMR (300 MHz1 CDCI3) δ 8.05 (d, J = 8.4 Hz, 2 H)1 7.69 (d, J = 8.4 Hz, 2 H), 7.55 (s, 1 H), 6.93 <d, J= 8.2 Hz1 1 H)1 6.64 (d, J= 2.5 Hz, 1 H), 6.57 (dd, J= 8.2, 2.5 Hz1 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 4.05 (s, 2 H)1 2.92 (m, 4 H), 2.80 (m, 4 H)1 1.57 <s, 6 H), 1.25 (t, J= 7.1 Hz1 3 H); MS (ES) m/z: 519 (M+H+).
Figure imgf000058_0002
2-Methyi-2-{3-[3-(4-trifluoromethyl-phenyl)-isothiazoI-S-ylmethy!]-2,3,4t5-tetr ahydro-1 H-benzo[d|azepin-7-yloxy}-propionic acid
Cpd 2 was prepared using similar procedure as for cpd 1. Cpd 2 was obtained as a white solid (100%): 1H NMR (300 MHz, CD3OD) δ 8.21 <d, J- 8.1 Hz1 2 H), 8.06 (s, 1 H), 7.80 (d, J= 8.2 Hz, 2 H), 7.09 (d, J= 8.2 Hz1 1 H), 6.78 (d, J = 2.5 Hz, 1 H), 6.72 (dd, J= 8.2, 2.5 Hz, 1 H), 4.74 <s, 2 H)1 3.33 (m, 4 H), 3.11 (rn, 4 H), 1.54 (s, 6 H); MS (ES) m/z: 491 (M+H+).
Example C
Figure imgf000058_0003
Compound 3: {3-[3-{4-TπfluoromethyI-phenyl)-{1,2,4]thiadiazol-5-ylmethyl]-2,3,4,S-tetrahydro-
1 H-benzo[ό]azepin-7-yioxy}-acetic acid
The title compound was made according to Scheme C. Scheme C
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0003
3-(4-Trifluoromethyl-pheπyi)-[1 ,2,4]thiadiazoie-5-carbσxylic acid ethy! ester
A reaction mixture of A2a (448 mg, 1.81 mmol) and ethyl cyanoformate (722 mg, 7.29 mmol) in 1 ,2-dtchlorobenzeπe (7 ml.) was heated at 1600C for 20 h. After cooling to room temperature, the reaction mixture was purified by column chromatography to give 505 mg <92%) of C1 as a yellow solid: 1H NMR (300 MHz1 CDCI3) δ 8.50 (d, J= 8.1 Hz, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 4.57 (q, J= 7.1 Hz, 2 H), 1.49 (t, J= 7.1 Hz, 3 H); MS (ES) m/z; 303 (M+H+).
Figure imgf000060_0001
[3- (4-Trif I uoromethy l-ph eny l)-[ 1 , 2,4]th iadiazol-5-y !]-methanoi To a solution of C1 (200 mg, 0.662 mmol) in EtOH (10 ml_) at room temperature was added NaBH4 (64 mg, 1.7 mmol). After stirring for 2 h, a few drops of water were added to quench excess of hydride. EtOH was evaporated, and the residue was partitioned between CH2Ck and water. The organic phase was dried (Na2SO4) and concentrated to provide 167 mg (97%) of C2 as off-white crystals: 1H NMR {300 MHz, CDCI3) δ 8.40 <d, J = 8.1 Hz, 2 H), 7.74 (d, J= 8.2 Hz, 2 H), 5.20 (S1 2 H), 2.65 (br, 1 H); MS <ES) m/z: 261 (M+H+).
Figure imgf000060_0002
5-Brom omethyl-3-(4-trif I uorom ethy l-phen yi)-[1 ,2 ,4]th iad tazole Cpd C3 was prepared according to a similar procedure as forcpd A2d. Cpd C3 was obtained as a white solid (96%): 1H NMR (300 MHz, CDCi3) δ 8.40 (d, J= 8.1 Hz, 2 H), 7.74 (d, J= 8.3 Hz, 2 H), 4.83 <s, 2 H); MS (ES) m/z: 321 (M-H+).
Figure imgf000060_0003
{3"{3-(4-Trifluoromethyi-phenyl)-[1 ,2,4]thtadiazol-5-yimethyi]-2,3,4,5-tetrahydro- 1 H-benzotdJazepiπ-Z-yloxyJ-acetic acid ethyl ester Cpd C4 was prepared according to a similar procedure as for cpd A2e. Cpd C4 was obtained as a white solid (50%): 1H NMR {300 MHz, CDCl3) δ 8.40 (d, J = 8.1 Hz, 2 H)1 7.73 (d, J = 8.3 Hz, 2 H), 7.02 <d, J= 8.2 Hz, 1 H)1 6.72 (d, J= 2.6 Hz, 1 H), 6.65 (dd, J= 8.2, 2.7 Hz1 1 H), 4.59 (s, 2 H)1 4.27 (q, J= 7.1 Hz1 2 H), 4.11 (s, 2 H), 2.95 - 2.83 (rn, 8 H), 1.30 <t, J = 7.1 Hz, 3 H); MS (ES) m/z: 492 (M+H+).
Figure imgf000061_0001
C 3 was prepared according to a similar procedure as for cpd 1. Cpd 3 was obtained as a white solid (85%): 1H NMR (300 MHz, CD3OD) δ 8.48 (d, J= 7.7 Hz, 2 H), 7.83 (d, J = 6.8 Hz, 2 H), 7.07 (d, J= 8.5 Hz, 1 H), 6.79 (s, 1 H)1 6.73 (d, J= 7.1 Hz, 1 H), 4.63 (s, 2 H), 4.58 <s, 2 H), 3.22 <m, 4 H), 3.07 (m, 4 H); MS (ES) m/z: 464 (M+H+).
Example D
Figure imgf000061_0002
The title compound was made according to Scheme D.
Scheme D
Figure imgf000062_0001
Figure imgf000062_0002
2-Methyi-2-{3-[3-(4-trifluoromethy!-phenyl)-[1 ,214]thiadiazol-S-ylmethyl]-2,3,4,5-tetrahydro- 1 W-benzo[o'jazepin-7-yloxy}-propionic acid ethyl ester
Cpd D1 was prepared according to a similar procedure as for cpd B3. Cpd B3 was obtained as a white solid (76%): 1H NMR (300 MHz, CDCi3) δ 8.39 <d, J = 8.2 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 6.95 <d, J = 8.2 Hz1 1 H)1 6.66 (d, J = 2.5 Hz, 1 H), 6.58 (dd, J= 8.1 , 2.6 Hz, 1 H), 4.24 (q, J= 7.1 Hz, 2 H), 4.12 (s, 2 H), 2.91 <m, 4 H), 2.88 (m, 4 H), 1.58<s, 6 H), 1.26 (t, J= 7.1 Hz1 3 H); MS (ES) m/z: 520 (M+H+).
Figure imgf000062_0003
2-Methyi-2-{3-[3-(4-trifluoromethyl-phenyi)-[1 !2,4]thiadi^ol-5-ylmethyl]-2,3>4)5- tetrahydro-1 W-benzolajazepiri-y-yloxyJ-propionic acid
Cpd 4 was prepared according to a similar procedure as for €pd 2. Cpd 4 was obtained as a white solid (94%): 1H NMR<300 MHz, CD3OD) δ 8.50 (d, J= 8.2 Hz, 2 H), 7.84 <d, J = 8.3 Hz, 2 H), 7.09 <d, J= 8.2 Hz, 1 H), 6.78 (d, J= 2.5 Hz, 1 H), 6.72 <dd, J= 8.2, 2.6 Hz, 1 H), 4.34 <s, 2 H), 3.46 (m, 4 H), 3.16 (m, 4 H), 1.55 (s, 6 H); MS (ES) m/z: 492 (M+H+).
Example E
Figure imgf000063_0001
The title compound was made according to Scheme E.
Scheme E
Figure imgf000063_0002
Figure imgf000063_0003
Figure imgf000064_0001
5-BromomethyI-4-methyl-2-(4-trifluoromethyi-phenyl)-thiazole Cpcl E2 was prepared from cpd E1 (Bioorg & Med. Chem. Lett., 2003, 13 (9), 1517-1521 ) following a similar procedure as for cpd A2d. Cpd E2 was obtained as a white solid (96%): 1H NMR (300 MHz, CDCi3) δ 8.01 {d, J = 8.7 Hz, 2 H), 7.68 (d, J = 8.6 Hz, 2 H), 4,72 (s, 2 H), 2.48 (s, 3 H).
Figure imgf000064_0002
{3-[4-Methyl-2-(4-trifluoromethy]-phenyl)-thia2θl-5-ylmethyt3-2,3,4,5- tetrahydro-1 tf-benzo[c(jazepin-7~yiσxy}-acetic acid ethyl ester
Cpd E3 was prepared according to a similar procedure as for cpd A2e. Cpd E3 was obtained as a white solid <53%): 1H NMR<300 MHz, CDCI3) δ 8.02 <d, J = 8.2 Hz, 2 H)1 7.68 (d, J= 8.3 Hz, 2 H), 7.00 (d, J= 8.2 Hz, 1 H), 6.70 (d, J= 2.5 Hz, 1 H)1 6.62 (dd, J= 8.2, 2.5 Hz, 1 H), 4.59 <s, 2 H), 4.27 <q, J = 7.1 Hz, 2 H), 3.76 (s, 2 H), 2.90 - 2.83 (m, 4 H), 2.72 - 2.64 (m, 4 H), 2.42 (s, 3 H), 1.30 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: S05 (M+H+).
Figure imgf000064_0003
{3-[4-Methyl-2-(4-trifiuoromethyl'phenyl)-thiazol-5-ylmethyl]-2,3,4,5-tetrahydro-1 H- berszo[c(|azepin-7-yloxy}-acetic acid
Cpd 5 was prepared according to a similar procedure as for cpd 1. Cpd 1 was obtained as a white solid (85%); 1H NMR <300 MHz, CDCl3) δ 8.01 (d, J= 8.2 Hz, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 6.97 <d, J= 8.3 Hz, 1 H), 6.71 (dd, J= 8.3, 2,5 Hz, 1 H), 6.66 <d, J = 2.4 Hz, 1 H), 4.63 <s, 2 H)1 4.52 (S, 2 H), 3.40 - 2.85 (m, 8 H), 2.49 (S1 3 H); MS {ES) m/z: 477 (M+H+). Example F
Figure imgf000065_0001
The title compound was made according to Scheme F,
Figure imgf000065_0002
Figure imgf000065_0003
Cpd F1 was prepared using a similar procedure as for cpd B3. Cpd F1 was obtained as a white solid (71%): 1H NMR (300 MHz, CDCi3) δ 8.02 (d, J = 8.2 Hz1 2 H)1 7.65 (d, J= 8.3 Hz, 2 H), 6.93 {ti, J = 8.2 Hz, 1 H), 6.63 (d, J= 2.4 Hz, 1 H)1 6.56 (dd, J- 8.1 , 2.5 Hz, 1 H), 4.23 <q, J= 7.1 Hz, 2 H), 3.75 (S1 2 H), 2.85 <m, 4 H), 2.88 <m, 4 H), 2.47 <s, 3 H)1 1.57 <s, 6 H), 1.25 <t, J= 7.1 Hz1 3 H); MS <£S) m/z; 533 <M+H+).
Figure imgf000066_0001
2-Methyl-2-{3-[4-methyl-2-(4-trtfluoromethyi-phenyl)-thia2Ol-5-ylmethyt]- 2,3,4,5-tetrahydro-1 W-benzo[G]azepin-7-yloxy}-proptonic acid
Cpd 6 was prepared using a similar procedure as for cpd 2. Cpd 6 was obtained as a white solid (75%): 1H NMR (300 MHz, CD3OD) δ 8.13 (d, J = 8.2 Hz1 2 H), 7.80 (d, J= 8.3 Hz1 2 H), 7.04 (d, J= 8.2 Hz, 1 H), 6.75 (d, J = 2.4 Hz, 1 H)1 6.71 (dd, J = 8.2, 2.5 Hz, 1 H), 4.50 (s, 2 H)1 3.31 - 3.24 <m, 4 H)1 3.01 - 2.97 (m, 4 H), 2.52 (s, 3 H)1 1.56 <s, 6 H); MS (ES) m/z: 505 (M+H+).
Example G
Figure imgf000066_0002
Compound 7: {3-[5-(4-Trifiuoromethyl-phenyl)-thiophen-2-ylmethyl]-2,3,4,5-tetrahydro- 1 H-benzo[d]azepin-7-yloxy}-acetic acid
The title compound was made according to Schemes G1 or<32.
Scheme G1
Figure imgf000067_0001
Figure imgf000067_0002
5-(4-Trifiuoromethyi-phenyl)-thiophene-2-carbaldehyde A mixture of S-bromothiophene-^-carboxyaldehyde (2 g, 10.5 mmol), 4-trifluoromethyi-benzeneboronic acid (2.19 g, 11.5 mmol}, Pd(PPh4)3 -(605 mg, 0.52 mmol) and 2N Na2CO3 (21 mL, 42 mmoi) in toluene/MeOH {30 ml_/15 mL) was degassed with N2 and then stirred at βO 0C for 18 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography to give G1a (2.4 g, 90%) as a white solid: 1H NMR (300 MHz, CDCI3) δ 9.92 (s, 1 H), 7.79 - 7.77 (m, 3 H), 7.70 (d, J= 8.4 Hz12 H), 7.48 (d, J= 3.9 Hz, 1 H); MS (ES) m/z: 279 (M+Na+).
Figure imgf000068_0001
mixture of A1b (100 mg, 0.401 mmoi) and G1a (113 mg, 0.442 mmo!) in dichloromethane (4 ml_) was stirred at room temperature for 1.5 h. Na(OAc)3BH (170 mg, 0.803 mmol) was added and the resulting mixture was then stirred for 17 h. Saturated NaHCO3 was added and the solution was extracted with CH2O2. The combined organic phases were dried (Na^SO4), concentrated and purified by column chromatography to give cpd 61 b (110 mg, 56%) as a white solid: 1H NMR (300 MHz, CDCf3) δ 7.67 (d, J = 8.2 Hz, 2 H)1 7.60 (d, J= 8.3 Hz, 2 H), 7.23 (d, J = 3.6 Hz, 1 H), 6.99 <d, J = 8.2 Hz, 1 H), 6.89 (d, J = 3.6 Hz, 1 H), 6.69 (d, J= 2.7 Hz, 1 H), 6.62 (dd, J = 8.2, 2.7 Hz1 1 H), 4.58 (s, 2 H), 4.26 (q, J= 7.1 Hz, 2 H), 3.85 <s, 2 H), 2.91 - 2.87 (m, 4 H), 2.71 - 2.67 (m, 4 H), 1.29 (t, J = 7.1 Hz1 3 H); MS (ES) m/z: 490 (M+H+).
Figure imgf000068_0002
7 was prepared using a similar procedure as for cpd 1. Cpd 7 was obtained as a white solid (90%): 1H NMR (300 MHz, CD3OD) δ 7.85 <d, J = 8.2 Hz, 2 H), 7.72 <d, J = 8.4 Hz, 2 H), 7,56 <d, J = 3.7 Hz, 1 H), 7.36 (d, J = 3.7 Hz, 1 H), 7.10 (d, J= 8.2 Hz, 1 H), 6.80 <d, J = 2.5 Hz1 1 H), 6.76 (dd, J = 8.2, 2.5 Hz, 1 H), 4.63 (s, 2 H)1 4.58 (s, 2 H), 3.35 - 3.28 <m, 4 H), 3.13 - 3.07 (m, 4 H); MS (ES) m/z: 462 (M+H+).
Scheme G2
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000069_0004
7-Methoxy-2,3,4,5-tetrahydro-1 H-benzo(c(|azepine
1 M borane-THF solution (1 ml_, 1.02 mmol) was added dropwise to an ice-cooled and stirred solution of A1 a (1.91 g, 10 mmol, in THF <S0 mL). A1a was prepared according to published procedures ( Eur. Pat. Appl. 204349). The ice bath was removed and the solution was heated at refiux for 3 h. Upon cooling back to 0 0C, MeOH (2 mL) was added and the reaction mixture was stirred at room temperature for 35 min and concentrated. The white solid residue was treated with 6 N HCI (50 mL) and the mixture was heated at reflux for 1 h and then room temperature overnight. The aqueous solution was washed with Et2O and then basified with 5 N NaOH until PH > 10 and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), concentrated and vacuum dried to give G2b (1.17 g, 66%) as a clear yellow oil: 1H NMR (300 MHz, CDCI3) δ 7.01 <d, J = 8.1 Hz5 1 H), 6.70 - 6.60 (m, 2 H), 3.78 (s, 3 H), 3.01 - 2.83<m, 8 H), 2.34 (br, 1 H).
Figure imgf000070_0001
7-Methoxy-3-[5-(4~irifluoromethyi-phenyl)-thiophen-2-yImethyfj- 2,3,4,5-ietrahydrO-iH-benzo[c(|azepine
To a solution of G2b (2.02 g, 11.4 mmo!) and G1 a (2.92 g, 11.4 mmo!) in dichloromethane (50 mL) was added AcOH {0.65 mL, 11.4 mmol). The reaction mixture was stirred for 1.5 h. Na(OAc)3BH (3.62 g, 17.1 mmol) was added and the reaction mixture was then stirred for another 20 h. 2 N NaOH was added (PH - 11) and the solution was extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography to give G2c <2.23 g, 47%) as a yellow solid: 1H NMR (300 MHz, CDCI3) 67.68 <d, J = 8.2 Hz, 2 H), 7.61 (d, J= 8.5 Hz, 2 H), 7.24 (d, J = 3.8 Hz, 1 H), 7.01 (d, J = 3.8 Hz, 1 H), 6.91 <m, 1 H), 6.66 - 6.62 <m, 2 H)1 3.88 (s, 2 H), 3.77 (s, 3 H), 2.91 (m, 4 H)1 2.72 (m, 4 H); MS <€S) m/z: 418 (M+H+).
Figure imgf000070_0002
3-[5-(4-Trtfluoromethy!-pheny!)-thiophen-2-ylmethyl]- 2,3,4,5-tetrahydro-1 W-benzo|of)azepin-7-ol A mixture of G2c (2,21 g, 5.30 mmoi), HBr (48%, 6.0 ml_, 53,0 mmol) and Bu4NBr (171 mg, 0.53 mmoi) in AGOH (6 mL) vygp stirred at 1000C for 16.5 h. Saturated K2CO3 was added til! PH ~ 10 and the solution extracted with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated to give G2d (1.77 g, 83%) as a biege solid: 1H NMR {400 MHz5 CDCI3) δ 7.66 (d, J = 8.4 Hz, 2 H), 7,61 <d, J= 8.4 Hz, 2 H), 7.25 (d, J = 3.6 Hz1 1 H), 6,97 (d, J= 3.3 Hz, 1 H), 6.94 (d, J= 7.7 Hz1 1 H), 6.60 -6.57 <m, 2 H), 4,01 (s, 2 H), 2.94 <m, 4 H), 2.82 (m, 4 H); MS (ES) m/z: 404 (M+H+).
Figure imgf000071_0001
{3-[5-(4-Trifluoromethyi-phenyl)-thiophen-2-ylmethyl]-2,3,4,5-tetrahydro- 1W-benzo[o]azepin-7-yfoxy}-aceik: acid ethyi ester
To a solution of NaH (60% in mineral oil, 317 mg, 7.93 mmoi) in THF (12 mL) was added G2d (1.07 g, 2.64 mmol) in THF (5 mL) followed by ethyl bromoacetate (0.35 mL, 3.17 mmol). After stirring at reflux for 1 h, the reaction mixture was cooied, quenched with saturated NH4CS solution and partitioned between ether and water. The organic phase was dried (Na2SO4), concentrated and purified by column chromatography to give 431b (1.02 g, 79%), which was further converted to Compound 7 as described above.
Example H
Figure imgf000071_0002
Compound 8: 2-Methyl-2-{3-[5-(4-trif!uoromethyl-phenyl)-thiophen-2-ylmethyl]-2,3,4,5- tetrahydro-1 H-benzof cf|azepiι>7-yioxy}-propionic acid
The title compound was made according to Scheme H. Scheme H
Figure imgf000072_0001
Figure imgf000072_0002
2-Methyl-2-{3-E5-(4-trffluoromethyl'pheny!)-thiophen-2-ylmethyI]-2,3,4,5-tetrahydro- 1 H-benzo[d]azepin-7-yloxy}-propionic acid ethyl ester
Cpd H1 was prepared according to a similar procedure as for-cpd G2. Cpd H1 was obtained as a white solid (60%): 1H NMR (300 MHz, CDCI3) δ 7.67 <d, J= BA Hz1 2 H), 7,60 (d, J= 8.5 Hz, 2 H), 7.24 (d, J= 3.6 Hz, 1 H), 6.94 - 6.91 (m, 2 H), 6.62 (d, J= 2.5 Hz, 1 H), 6.55 {dd, J= 8.2, 2.6 Hz1 1 H), 4.23 (q, J = 7.1 Hzr 2 H)1 3.90 (s, 2 H)1 2.90 (m, 4 H)1 2.74 <m, 4 H), 1.57 (s, 6 H)1 1.24 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 518 (M+H+).
Figure imgf000072_0003
2-MethyI-2-{3-[5-(4-trifluoromethyI-phenyl)-thiophen-2-yimethyt]-2,3,43- tetrahydro-1 W-benzo[d]a2epin-7-yloxy}-propionic acid
Cpd 8 was prepared according to a similar procedure as foropcl 2. Cpd 8 was obtained as a white solid (61%): 1H NMR<300 MHz1 CO3OD) δ 7.86 (d, J= 7.9 Hz, 2 H), 7.73 (d, J= 8.3 Hz, 2 H), 7.58 (d, J = 2.7 Hz, 1 H), 7.38 (d, J = 3.7 Hz, 1 H), 7.11 (d, J= 3.7 Hz, 1 H), 6.80 (d, J = 2.5 Hz1 1 H), 6.73 (dd, J= 8.2, 2.5 Hz, 1 H), 4.68 (s, 2 H), 3.21 - 3.00 (m, 8 H), 1.54 (s,6
H); MS (ES) m/z: 490 (M+H+).
Example I
Figure imgf000073_0001
The title compound was made according to Scheme
Scheme t
Figure imgf000073_0002
Figure imgf000073_0003
Cpd 12 was prepared from cpd 11 {Bioorg. & Med. Chem. Lett., 2003, ?3(13), 2159-2161 ) using a similar procedure as fofecpd G2. Cpd I2 was obtained as a white solid (40%); 1H NMR (300 MHz1 CDCi3) δ 7.72 <d, J = 8.2 Hz, 2 H), 7.60 (d, J = 8.5 Hz, 2 H), 6.98 <d, J= 8.2 Hz, 1 H)1 6.68 (m, 2 H), 6,60 <dd, J= 8,2, 2.6 Hz, 1 H), 6.30 (d, J= 3.3 Hz, 1 H), 4.56 (s, 2 H), 4.26 (q, J= 7.1 Hz, 2 H)1 3.79 (s, 2 H), 2.92 - 2.87 (m, 4 H), 2.73 - 2.67 (m, 4 H), 1.28 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 474 (M+H+).
Figure imgf000074_0001
9 was prepared according to a similar procedure as for cpd 1. Cpd 9 was obtained as a white solid (71%): 1H NMR {300 MHz, CD3OD) δ 7.89 (d, J = 8.2 Hz5 2 H), 7,69 (d, J = 8.3 Hz5 2 H), 6.98 - 6.94 (m, 2 H), 6.75 - 6.69 (m, 3 H), 4.44 (s, 2 H), 4.33 (s, 2 H)1 3.14 (m, 4 H), 2.82 <m, 4 H); MS (ES) m/z: 446 (M+H+).
Example J
Figure imgf000074_0002
The title compound was made according to Scheme J.
Scheme J
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
E5-{4-Trifiuorotnethyl-phenyl)-furan-2-yi]-methanol
Cpd J1 was prepared according to a similar procedure as for cpd €1. Cpd J1 was obtained as a white solid (75%): 1H NMR<300 MHz, CDCI3) δ 7,76 (d, J = 8.4 Hz, 2 H)1 7.62 (d, J = 8.5 Hz, 2 H), 6.73 {d, J = 3.3 Hz, 1 H), 6.42 (d, J= 3.2 Hz, 1 H), 4.69 (d, J= 5.9 Hz, 2 H), 1.75<t, J = 6.0 Hz, 1 H); MS (ES) m/z: 225 (M-OH).
Figure imgf000075_0004
2-Methyl-2-{3-I5'(4-trifiuoromethyl-phenyl)-furan-2-yimethyl]-2,3,4,5-tetrahyciro-1 H4)erβθ[ cf]azepin-7-yloxy}-propionic acid ethy! ester
A mixture of J1 (80 rng, 0.33 mmo!), methanesuifonyl chloride (38 mg, 0.33 rnmol) and triethylamine (230 μL, 1.65 mmol) in CH2Ci2 <2 mL) was stirred at room temperature for 1.5 h. Cpd B2<50 mg, 0.165 mmol) in CH3CN (1 mL) was added and the solution was stirred overnight under N2. The resulting mixture was concentrated and purified by column chromatography (EtOAc/hexane) to give 10 mg (12%, 2 steps) of J2 as a white solid: 1H NMR (300 MHz, CDCI3) δ 7.72 (d, J = 8.2 Hz, 2 H), 7,60 (d, J = 8.4 Hz, 2 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.69 (d, J= 3.3 Hz, 1 H), 6.61 <d, J = 2.3 Hz, 1 H), 6.54 (dd, J = 8.1 , 2.2 Hz, 1 H), 6.30 (d, J = 3.2 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3.79 (s, 2 H), 2.87 (m, 4 H), 2.71 (m, 4 H), 1.56 <s, 6 H), 1.23 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 502 (M+H+).
Figure imgf000076_0001
2-Methyl-2-{3-E5-{4-trifluoromethyl-phenyl)-furan-2-yimethyl]-2,3,4,5-tetrahydro- 1 H-benzo[d|azepin-7-yloxy}-propiontc acid
Cpd 10 was prepared using a similar procedure as for cpd 2. Cpd 2 was obtained as a white solid (65%): 1H NMR (300 MHz, CD3OD) δ 7.94 <d, J= 8.1 Hz, 2 H)1 7.73 (d, J= 8.2 Hz, 2 H), 7.10 - 7.05 <m, 2 H), 6.87 <d, J = 3.2 Hz, 1 H), 6.78 (d, J = 2.5 Hz, 1 H), 6.72 (dd, J = 8.1 , 2.5 Hz, 1 H)1 4.54 (S, 2 H)1 3.40 (m, 4 H), 3.11 (m, 4 H), 1.54 (s, 6 H); MS (ES) m/z: 474 (M+H+).
Example K
Figure imgf000076_0002
Compound 11 : {3'[5-(4-Trifluoromethyi-phenyl)-isoxazol-3-ylmethyl]-2,3»4,5-tetrahydro- 1 H~benzo[d]azepin-7-yloxy}-aceiic acid
The title compound was made according to Schemes K1 and K2,
Scheme K1
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0003
Cpd was prepared according to a similar procedure as for cpd A1 b. Cpd K1a was obtained as a white solid (28% over 2 steps): 1H NMR (300 MHz, CDCI3) δ 7.03 (d, J= 8,4 Hz, 1 H), 6.76 (dd, J= 8.4, 2.7 Hz, 1 H), 6.67 (d, J = 2.6 Hz, 1 H), 5.79 (brs, 1 H), 4.48 (s, 2 H), 3.79 <s, 2 H), 3.58 - 3.52 (m, 2 H), 3.06 (t, J = 6.6 Hz, 2 H), 1.49 (s, 9 H); MS (ES) m/z: 314 (M+Na+).
Figure imgf000077_0004
Cpd K b was prepared using a similar procedure as for cpd A1c. Cpd K1b was obtained as a yeiiow oil (52%): 1H NMR {300 MHz, CDCI3) 56.98 (d, J= 8.3 Hz, 1 H), 6.68 (d, J = 2.6 Hz, 1 H), 6.63 {dd, J= 8.2, 2.6 Hz, 1 H), 4,48 (S1 2 H), 2.93 - 2.84 {m, 8 H), 1.49 (s, 9 H); MS tES) m/z: 278 {M+H+). Scheme K2
Figure imgf000078_0001
Figure imgf000078_0002
4-Hydroxy-2-oxo-4-<4-trifluoromethyl-phenyl)-but-3- enoic acid methyl ester
To a solution of 1 -(4-trifiuoromethyl-pheny!)ethanone (2.0 g, 10.6 mmol) and dimethyl oxylate (1.63 g, 13.8 mmol) in toluene {50 ml_) at O 0C was added NaH portionwise {60%, 636 mg, 15.9 mmot). The mixture was stirred at room temperature for 1 h and then 60 0C for 2 h. After cooling to room temperature, H2O was added slowly to quench the reaction. The mixture was acidified with 1 N HCI and extracted with EtOAc. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography to give 2.74 g {94%) of K2a as a white solid: 1H MMR {300 MHz, CDCI3) 68.11 (d, J= 8.3 Hz, 2 H), 7.77 <d, J= 8.3 Hz, 2 H), 7.10 <s, 2 H), 3.97 (S, 3 H); MS (ES) m/z: 297 (M+Na+).
Figure imgf000079_0001
5-{4-Trifiuoromethyl-pheny!)-isoxazoIe-3-carboxytic acid ethyl ester
To a solution of K2a (2.7 g» 9.85 mmoi) in EtOH (40 mL) was added hydroxylamine hydrogen chloride {2.05 g, 29.5 mmol). The mixture was stirred at room temperature for 1 h and then 80 0C for 2 h. After Oooiing to room temperature, the precipitate was filtered and washed with EtOH. The white solid was dried under vacuum to give 2.0 g (75%) of K2b: 1H NMR (300 MHz, CDCI3) δ 7.94 (d, J= 8.2 Hz, 2 H), 7.76 <d, J= 8.3 Hz, 2 H), 7.03 (S> 1 H), 4.49 (d, J= 7.1 Hz, 2 H), 1.45 (d, J= 7.1 Hz, 3 H); MS (ES) m/z: 286 (M+H+).
Figure imgf000079_0002
[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-yl]-methanol
Cpd K2c was prepared according to a simitar procedure as for^pd C2. Cpd K2c was obtained as a white solid (98%): 1H NMR (300 MHz, CDCi3) δ 7.90 (d, J= 8.2 Hz, 2 H), 7.73 (d, J= 8.5 Hz, 2 H), 6.70 (s, 1 H), 4.84 (s, 2 H); MS (ES) m/z: 244 (M+H+).
Figure imgf000079_0003
3~Bromomethyi-5-{4-trifluoromethyl-phenyl)-isoxazole
Cpd K2d was prepared according to a similar procedure as for cpd A2d. Cpd K2d was obtained as a white solid (98%); 1H NMR 4300 MHz5 CDCI3) δ 7.91 (d, J= 8.3 Hz, 2 H), 7,75 (U1 J= 8.3 Hz5 2 H), 6.73 (s, 2 H), 4.49 (S1 2 H); MS (ES) m/z: 306 (M+H+).
Figure imgf000080_0001
{3-[5-(4-Triftuoromethyl^henyl)-isoxazol-3-yimethy!]-2,3A54etrahydro- 1 H-benzo[tf|azepin-7-yloxy}-acetic acid ferf-butyl ester
Cpd K2e was prepared according to a similar procedure as forcpd A2e. Cpd K2e was obtained as a white solid (71%): 1H NMR (300 MHz, CDCI3) δ 7.90 (d, J= 8.4 Hz1 2 H), 7.72 (d, J= 8.4 Hz, 2 H), 6.98 <d, J = 8.2 Hz1 1 H), 6.69 (S1 1 H)1 6.68 (d, J= 2.6 Hz, 1 H)1 6.61 <dd, J= 8.2, 2.6 Hz, 1 H), 4.47 (s, 2 H), 3.79 (s, 2 H)1 2.90 - 2.86 (m, 4 H), 2.72 - 2.67 (m, 4 H), 1.48 (s, 9 H); MS (ES) m/z: 503 (M+H+).
Figure imgf000080_0002
{3-t5-(4-Trifiuoromethyl-phenyI)-isoxazof-3-yimethyl]-2,3,4,5-tetrahydro- 1 H-benzo[c/|azeptn-7-yloxy}-acetic acid
To a solution of K2e (38.5 mg, 0.076 mmoi) in CH2CI2 (1 ml_) was added tπfluoroacetic acid (0.1 ml_). The mixture was stirred at room temperature for 15 h, concentrated and purified by column chromatography to give 30 mg (96%) of compound 11 as a white solid: 1H NMR (300 MHz, CD3OD) 58.08 (d, J= 8.2 Hz, 2 H), 7.86 (d, J - 8.3 Hz, 2 H), 7.17 - 7,13<m, 2 H), 6.85 (d, J= 2.5 Hz1 1 H), 6.78 (dd, J = 8.2, 2.6 Hz1 1 H)1 4,64<s, 4 H), 3.5 (m, 4 H), 3.18 (m, 4 H); MS (ES) m/z: 447 (M+H+). Example L
Figure imgf000081_0001
The title compound was made according to Scheme L.
Figure imgf000081_0002
Figure imgf000081_0003
Cpd L1 was prepared following the same procedure as for cpd 83. Cpd L1 was obtained as a white solid (68%): 1H NMR {300 MHz, CDCI3) δ 7.90 (d, J = 8.3 Hz1 2 H), 7.72 (d, J = 8.4 Hz, 2 H)1 6.93 Id, J = 8.2 Hz, 1 H), 6.71 (S, 1 H), 6.63 (d, J= 2.5 Hz, 1 H)1 6.55 (dd, J= 8.1 , 2.6 Hz, 1 H), 4.23 (q, J= 7.1 Hz, 2 H), 3.81 (s, 2 H), 2.88 - 2.86 (m, 4 H)1 2.73 - 2.7CHm1 4 H), 1.57 (S1 6 H)1 1.25 (t, J= 7.1 Hz, 3 H); MS <£S) m/z: 503 (M+H+).
Figure imgf000082_0001
2-Methyl-2-{3-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethyIJ-2,3,4,5- tetrahydro-1 H-benzo[c(]azepin-7~yloxy}-propionic acid
Cpd 12 was prepared following the same procedure as for cpd 2. Cpd 12 was obtained as a white solid (90%): 1H NMR (300 MHz, CD3OD) δ 8.08 (6, J= 8.0 Hz, 2 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.16 (s, 1 H), 7.11 <d, J = 8.3 Hz, 1 H), 6.80 (d, J= 2.5 Hz, 1 H), 6.73 (dd, J= 8.2, 2.6 Hz, 1 H)1 4.62 <s, 2 H), 3.54 (m, 4 H), 3.16 (m, 4 H), 1.55 (s, 6 H); MS (ES) m/z: 475 (M+H+).
Example M
Figure imgf000082_0002
Compound 13: {3-[3-MethyI-5-(4-trifluoromethyl-phenyl)-thiophen-2-yimethyl]-2,3,4,5- tetrahydro-1 W-benzotcflazepin-y-yloxyl-acetic acid
The title compound was made according to Scheme M.
Scheme M
Figure imgf000083_0001
3-Methyl-5-(4-trifluoromethyl-phenyi)-thtophene-2-carbatdehyde Cpd M2 was prepared from cpd M1 {J. Chem. Soc, Perkin Trans 2, 1972, 1866) following the same procedure as for€pd <31a. Cpd M2 was obtained as a white crystalline solid <65%): 1H NMR <300 MHz, CDCI3) δ 10.05 (S, 1 H), 7.75 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.26 <s, 1 H), 2.61 (S1 3 H); MS (ES) m/z: 293 (M+Na+).
Figure imgf000084_0001
[3-Methy l-5-(4-irif luoromethyl-pheπyl)-th iophen -2- yl]-methanol
Cpd M3 was prepared according to the same procedure as for cpd E1. Cpd M3 was obtained as a white solid (76%): 1H NMR (300 MHz, CDCI3) 67.65 (d, J= 8.6 Hz, 2 H), 7.60 (d, J= 8.5 Hz, 2 H)1 7.14 (s, 1 H), 4.79 <s, 2 H), 2,27 (s, 3 H), 1.68 (brs, 1 H); MS (ES) m/z: 255 (M-OH).
Figure imgf000084_0002
{3-[3-Methyt-5-(4-triftuoromethyl-phenyl)-thiophen-2-ylmethyl3-2,3,4,5-tetrah ydro1H-benzo[αf]azep!n-7-y!oxy}-acetic acid ferf-butyl ester
Cpd M4 was prepared following the same procedure as forcpd J2. Cpd M4 was obtained as a white solid (22%): 1H NMR (300 MHz, CDCI3) δ 7.65 (d, J= 8.2 Hz, 2 H), 7.58 (d, J= 8.4 Hz, 2 H), 7.11 {$, 1 H), 6.99<d, J = 8.2 Hz, 1 H), 6.68 (d, J= 2.6 Hz, 1 H), 6.61 (dd, J= 8.2, 2.7 Hz, 1 H), 4.48 (S, 2 H), 3.74 (s, 2 H), 2.88 (m, 4 H), 2.69 (m, 4 H), 2.20 is, 3 H), 1.48 <s, 9 H); MS (ES) m/z: 532 (M+H+).
Figure imgf000084_0003
{3-[3-Methyl-5-(4-trifluoromethyi-phenyt)-thiophen-2-yimethyl]-2!3,4,5-tetrah ydro-1 W-benzofc/lazepin-y-yioxyJ-acetic acid
Cpd 13 was prepared following the same procedure as for cpd 11. Cpd 13 was obtained as a white solid (71%): 1H NMR<300 MHz, CD3OD) δ 7.79 (d, J = 8.2 Hz, 2 H)1 7.67 (d, J = 8.4 Hz1 2 H), 7.36 (s, 1 H), 6.98 <d, J = 9.0 Hz, 1 H), 6.73 - 6.70 (m, 2 H), 4.45 (s, 2 H)1 4.36<s, 2 H), 3.17 (m, 4 H), 2.84 (m, 4 H), 2.29 (s, 3 H); MS (ES) m/z: 476 (M+H+).
Example N
Figure imgf000085_0001
Compound 14: 2-Methyl-2-{3-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen- 2-ylmethyi]-2,3,4,5-tetrahydro-1 H-benzo[d]a2epin-7-yloxy}-propionic acid
The title compound was made according to Scheme N.
Figure imgf000085_0002
Figure imgf000085_0003
2-MethyI-2-{3-[3-methyl-5-(4-trifiuoromethy!-phenyl)-thiophen-2-ylmethyli-2,3,4,5-te trahydro-1 H-benzo[d|azepirι-7-yloxy}-propionic acid ethy! ester
Cpd N1 was prepared following the same procedure as for€pd M4. Cpd N1 was obtained as a white solid (17%): 1H NMR {300 MHz, CDCI3) δ 7.65 (d, J = 8.2 Hz, 2 H), 7.59 (d, J = 8.3 Hz, 2 H)1 7.10 {% 1 H)1 6.92 <d, J = 8.2 Hz, 1 H), 6.62 (d, J = 2.6 Hz, 1 H), 6.55 <dd, J = 8.2, 2.7 Hz, 1 H), 4.22 (q, J= 7.1 Hz, 2 H), 3.72 (s, 2 H), 2.86 (m, 4 H), 2.70 (m, 4 H)1 2.20 <s, 3 H), 1.58 (S, 6 H), 1.25 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 532 (M+H+).
Figure imgf000086_0001
14 was prepared following the same procedure as forcpd 2, Cpd 14 was obtained as a white solid (80%): 1H NMR {300 MHz, CD3OD) δ 7.84 (d, J= 8.2 Hz, 2 H), 7.71 (d, J= 8.3 Hz, 2 H), 7.45 (s, 1 H), 7.11 <d, J = 8.3 Hz, 1 H), 6.80 (d, J= 2.5 Hz1 1 H), 6.74 (dd, J= 8.2, 2.6 Hz, 1 H), 4.60 (s, 2 H), 3,29 ((T), 4 H), 3.13 (m, 4 H), 2.35 (s, 3 H), 1.55 (s, 6 H); MS (ES) m/z: 504 (M+H+).
Example O
Figure imgf000086_0002
The title compound was made according to Scheme O.
Scheme O
Figure imgf000087_0001
Figure imgf000087_0002
4- B romo-3-methy i-th ioρhene-2-carboxy I tc acid methyl ester
To a solution of 3-methylthtophene-2-carboxylic acid methyl ester (2.0 g, 12.8 mmol) in CH2CI2 (10 rnL) and acetic acid (10 ml_) was added Br2 (0.79 mL, 15.3 mmol). The mixture was stirred at room temperature for 20 h and then partitioned between CH2CI2 and H2O. The aqueous layer was extracted with CH2Cb. The combined organic phases were washed with saturated sodium thiosuifate solution, dried (Na^SO^, concentrated and purified by column chromatography to give 1.4 g <46%) of O1 as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.41 (s, 1 H), 3.88 (s, 3 H), 2.62 <s, 3 H).
Figure imgf000088_0001
3-Methyl-4-{4-trifluoromethyl-phenyI)-thiophene- 2-carboxylic acid methyl ester
Cpd 02 was prepared foϋowing the same procedure as for cpd G1. Cpd 02 was obtained as a white solid (95%): 1H NMR (300 MHz, CDCl3) δ 7.71 <d, J = 8.2 Hz, 2 H)1 7.65 (d, J = 8.2 Hz1 2 H)1 7.40 (s, 1 H), 3.90 <s, 3 H), 2.51 (S, 3 H).
Figure imgf000088_0002
{3-[3-Methy i-4-(4-trif I uorom ethy i-pheny I )-th iophen-2-y Im ethy l]-2, 3,4,5-tetrahydro- 1 H -benzofcflazepin-y-yloxyj-acetic acid fe/t-butyl ester
To the solution of 02 (590 mg, 2.0 mmoi) in THF (10 mL) at 00C was added 1.0 M LiAIH4 (2.16 mL, 2.16 mmol) in THF. The mixture was allowed to warm up to room temperature and stirred at room temperature for 1 h. Water was slowly added and the precipitated solid was filtered and rinsed with CH2Cb. The filtrate was washed with saturated NH4CI and the aqueous solution was back extracted with CH2Ci2. The combined organic phases were dried (Na2SO4) and concentrated to give a crude solid. It was used to carry through a simitar procedure as for preparing cpd J2 and gave compound 03 as a white solid (19%): 1H NMR (300 MHz, CDCI3) δ 7.65 {ό, J= 8.2 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.16 (s, 1 H), 6.99 <d, J= 8.2 Hz, 1 H), 6.69 (d, J= 2.5 Hz, 1 H), 6.61 (dd, J= 8.1 , 2.4 Hz, 1 H), 4.48 {s, 2 H), 3.81 (S, 2 H)1 2.90 (m, 4 H)1 2.73 (m, 4 H), 2.15 <s, 3 H), 1.48 <s, 9 H); MS (ES) m/z: 532 (M+H+).
Figure imgf000089_0001
{3-[3-Methy!-4-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethyl]-2,3,4!5-tetrahydro-1H-b enzojcdazepin-y-yloxyj-acetic acid
Cpd 15 was prepared following the same procedure as for cpd11. Cpd 15 was obtained as a white solid {50%) : 1H NMR {300 MHz, CD3OD) δ 7.71 (d, J= 8.3 Hz, 2 H), 7.57 (d, J = 8.1 Hz, 2 H)1 7.46 {s, 1 H), 6.97 (ϋ, J = 8.9 Hz, 1 H)1 6.72 - 6.67 (m, 2 H), 4.40 (s, 2 H), 4.22 (s, 2 H), 3.01 (m, 4 H), 2.84 (m, 4 H), 2.21 (s, 3 H); MS (ES) m/z: 476 (M+H+).
Example P
Figure imgf000089_0002
Compound 16: 2-Methyi-2-{3-[3-methyl-4-(4-trifIuoromethyi-phenyI)-thiophen-2-ylmethyl]- 2,3,4,5-tetrahydroi W-benzo[ϋ]azepin-7-yloxy}-propionic acid
The title compound was made according to Scheme P.
Figure imgf000089_0003
Figure imgf000090_0001
Cpd P1 was prepared following the same procedure as for cpd J2. Cpd P1 was obtained as a white solid (23%); 1H NMR (300 MHz, CDCI3) δ 7.65 (d, J = 8.2 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.15 <s, 1 H), 6.93 <d, J = 8.2 Hz, 1 H)1 6.63 (d, J = 2.4 Hz5 1 H), 6.55 (dd, J = 8.1 , 2,4 Hz, 1 H)1 4.24 (q, J = 7.1 Hz, 2 H), 3.77 (ss 2 H), 2.86 (m, 4 H), 2.68 <m, 4 H)1 2.15 (s, 3 H), 1.58 (S, 6 H), 1.25 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 532 (M+H+).
Figure imgf000090_0002
2-Methyl-2-{3-[3-methy)-4-(4-trifluoromethy!-phenyi)-thiopheπ-2-ylmethyl]- 2,3,4,5-tetrahydro-i H-benzo[djazepin~7-yioxy}-propionic acid
Cpd 16 was prepared following the same procedure as for cpd 2, Cpd 16 was obtained as a white solid (80%): 1H NMR <300 MHz1 CD3OD) δ 7.73 (d, J = 8.2 Hz, 2 H), 7.72 - 7.56 (m, 3 H), 6.98 <d, J = 8.2 Hz, 1 H)1 6.73 - 6.68 (m, 2 H), 4.47 (s, 2 H)1 3.30 - 3,12 (m, 4 H), 2.95 - 2.89 (m, 4 H), 2,24 (S, 3 H), 1.57 (s, 6 H); MS (ES) m/z: 504 (M+H+).
Example Q
Figure imgf000090_0003
Compound 17: {3-[2-(4-TrifIuoromethyl-phenyI)-thiazol-4-y!rnethy!3-2,3,4,5-tetrahydro- 1 W-benzo[α]azepin-7-yloxy}-acetic acid
The title compound was made according to Scheme Q. Scheme Q
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0003
2-(4-Trif!uoromethyl-phenyi)-thiazo!e-4-carboxyltc acid ethyl ester
To a stirred solution of 4-trifluoromethylthiobenzamfcie {2.05 g, 10 mmol) in acetone (10 mL) was added ethyl bromopyruvate (1.95 g, 10 mmol) in acetone (10 mL) dropwise. The mixture was stirred under reflux for 3 h. After cooling to room temperature, the solution was concentrated and purified by column chromatography to give 1.9 g <63%) of cpd Q1 as a white solid: 1H NMR (300 MHz, CDCI3) δ 8.23 (s, 1 H), 8.14fdt J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz1 2 H), 4.46 <q, J= 7.1 Hz, 2 H), 1.44<t, J = 7,1 Hz, 3 H); MS <ES) m/z: 302 <M+H+).
Figure imgf000092_0001
[2-(4-Trifluoromethyl-phenyl)-thiazol-4-yl]-methanol
Cpd Q2 was prepared following the same procedure as for cpd E1. Cpd Q2 was obtained as a white solid (51%): 1H NMR (300 MHz1 CDCt3) δ 8.07 (d, J= 8.1 Hz, 2 H), 7.70 (d, J = 8.2 Hz, 2 H), 7.27 <s, 1 H), 4.86 (d, J = 6.0 Hz, 2 H), 2.21 (t, J= 6.0 Hz, 1 H); MS (ES) m/z: 260 (M+H+).
Figure imgf000092_0002
4-Bromomethyl-2-(4-trtfluoromethyl-phenyI)-thiazole
Cpd Q3 was prepared foilowing the same procedure as for cpd A2d. Cpd Q3 was obtained as a white solid (89%); 1H NMR (300 MHz, CDCI3) δ 8.07 (d, J= 8.1 Hz1 2 H), 7.70 (d, J= 8.2 Hz, 2 H)1 7.38 <s, 1 H), 4.64 (s, 2 H).
Figure imgf000092_0003
{3-[2-(4-Trifiuoromethy!-phenyi)-thiazol-4-ytmethyl]-2,3,4,S-tetrahydro-1 H- benzo[c(]azepin-7-yloxy}-acetic acid ethyi «ster
Cpd Q4 was prepared following the same procedure as for cpd A2e. Cpd Q4 was obtained as a white solid <54%): 1H NMR (300 MHz, CDCI3) δ 8.05 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.3 Hz, 2 H), 7.25 <s, 1 H), 6.99 <d, J = 8.2 Hz, 1 H), 6.70 (d, J= 2.6 Hz, 1 H), 6.61 (dd, J= 8.2, 2.6 Hz, 1 H)1 4.58 (S, 2 H)1 4.26 (q, J= 7.1 Hz, 2 H)1 3.91 (s, 2 H), 2.94 - 2.88 (m, 4 H), 2.79 - 2.71 (m, 4 H), 1.29 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 491 <M+H+).
Figure imgf000093_0001
{3-[2-{4-TrifiuoromethyI-phenyl)-thtazoi-4-y!methylJ-2,3,4,5-tetrahydro-1H- benzo[d|azepin-7-yloxy}-acetic acid
Cpd 17 was prepared following the same procedure as for cpd A2e. Cpd 17 was obtained as a white solid (80%): 1H NMR |300 MHz, CD3OD) δ 8.15 (d, J = 8.2 Hz, 2 H), 7.81 (S8 1 H)1 7.77 (d, J = 8.3 Hz, 2 H), 6.96 (d, J = 9.0 Hz, 1 H), 6.71 - 6.68 (m, 2 H)1 4.41 (S1 2 H), 4.33 (s, 2 H), 3.14 (m, 4 H)1 2.84 (m, 4 H); MS (ES) m/z: 463 (M+H+).
Example R
Figure imgf000093_0002
Compound 18: {3-[4-Methyl-2-(4-trif !υoromethyl-phenyi)-oxazol-5-ylmethyl3-2,3,4,5-tetrahydro-
1 H-benzo[cdazepin-7-yloxy}-acetic add
The title compound was made according to Scheme R.
Scheme R
Figure imgf000094_0001
Figure imgf000094_0002
To a solution of 2-aminopropionic acid tert-butyl ester hydrochloride (2.18 g, 12 mmol) and triethyl amine (3.03 g, 30 mmol) in CH 2CI2 (60 mL) at 0 ºC was added 4-trifluoromethylbenzoy! chloride (1 ,48 mL, 10 mmol). The mixture was stirred at room temperature for 24 h and then washed with H2O, 1 N HCl and H2O. After drying over Na2SO4, the solution was concentrated and purified by column chromatography to give 3.<\§i95%) of R1 as a white solid: 1H NMR {300 MHz, CDCI3) δ 7.92 (d, J = 8,2 Hz, 2 H), 7.70 {6, J = 8.5 Hz, 2 H)1 6.83 (brs, 1 H), 4.65 (m, 1 H), 1.51 (s, 12 H); MS {ES) nVz: 316 (M- H+).
Figure imgf000095_0001
2-(4-Trifluoromethyl-benzoyiamino)-propionic acid
Cpd R2 was prepared following the same procedure as for cpd 11. Cpd R2 was obtained as a white solid (crude): 1H NMR <300 MHz, CDCI3) δ 7.91 (d, J= 8.2 Hz, 2 H)1 7.73 (d, J= 8.3 Hz, 2 H), 6.81 {d, J = 6.7 Hz1 1 H)1 4.84 (m, 1 H), 1.62 (d, J= 7.2 Hz, 3 H).
Figure imgf000095_0002
4-Methyi-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxyl ic acid methyl ester
To a solution of R2 (1.95 g, 7.47 mmol) in toluene {30 mmot) and CH2CI2 {7.5 ml_) was added oxalyl chloride {6.52 mL, 74.7 mmol). The mixture was stirred at room temperature for 24 h and concentrated.
To the above crude intermediate at 0 0C was added Q3N <1 ,53 mL, 11.2 mmoi) followed by MeOH {56 mL). The mixture was stirred at room temperature for 3 h, concentrated and purified by column chromatography to give 1.06 g {50%) of R3 as a white solid: 1H NMR {300 MHz, CDCI3) δ 8.24 {ds J= 8.2 Hz, 2 H), 7.74 (d, J= 8.3 Hz, 2 H), 3.96<s, 3 H)1 2,56<s, 3 M); MS (ES) m/z: 286 {M+H+).
Figure imgf000096_0001
5-B romomethy I -4-methy I-2-(4-trif I uorom ethy I- phenyl)-oxazole
Cpd R3 was reduced to give a crude alcohol intermediate following the same procedure as in the preparation of compound E1. Cpd R4 was prepared following the same procedure as for cpd A2d. Cpd R4 was obtained as a white solid (61%): 1H NMR (300 MHz, CDCI3) δ 8.14<d, J = 8.6 Hz, 2 H), 7.71 (d, J= 8.4 Hz, 2 H), 4.60 (s, 2 H), 2.26 <s, 3 H).
Figure imgf000096_0002
{3-[4-Methyl-2-{4-trifluoromethyi-phenyl)-oxazol-5-ylmethyi]-2,3,4,5-tetrahydro-1H-benz o[<flazepin-7-yloxy)-acetie acid ethyl ester
Cpd R5 was prepared following the same procedure as for cpd A2e. Cpd R5 was obtained as a white solid (44%): 1H NMR (300 MHz, CDCi3) δ 8.12 (d, J= 8.4 Hz, 2 H), 7.69 (d, J= 8.5 Hz, 2 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.69 (d, J= 2.6 Hz, 1 H), 6.61 (dd, J= 8.2, 2.6 Hz, 1 H), 4.57 {s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.77 (s, 2 H), 2.92 - 2.87 <m, 4 H), 2.72 - 2.68 <m, 4 H), 2,23 (S, 3 H), 1.29 (t, J= 7.1 Hz, 3 H); MS<€S) m/z: 489 (M+H+),
Figure imgf000096_0003
{3-t4-Methyl-2-(4-trif]uoromethyl-phenyl)-oxazo)-5-ylmethyi]-2,3,4,5-tetrahydro- 1 H-benzo[d|azepin-7-yloxy}-acetic acid Cpd 18 was prepared following the same procedure as for cpd A2e. Cpd 18 was obtained as a white solid (50%): 1H NNP (300 MHz1 CD3OD) δ 8.19 (d, J = 8.1 Hz, 2 H), 7.81 (d, J= 8.3 Hz, 2 H), 6.98 <d, J= 8.0 Hz, 1 H), 6.70 - 6.67 (m, 2 H), 4.42 (s, 2 H), 4,17 (s, 2 H), 3.05 - 2,95 <m, 4 H), 2.90 - 2.80 (m, 4 H), 2.27 (s, 3 H); MS (ES) m/z: 461 (M+H+).
Example S
Figure imgf000097_0001
Compound 19: 2-Methyl-2-{3-[4-methyl-2-(4-trϊf luoromethyl-phenyi)-oxazol-5~ylmethyl]- 2r3,4,5-teirahydro-1 H-benzo[c(jazepin-7-yioxy}-proptontc acid
The title compound was made according to Scheme S.
Figure imgf000097_0002
Figure imgf000097_0003
2-Methyi-2-{3-[4-methyl-2-{4-trifiuoromethy]-phenyl)-oxazoi-5-ylmethyl]-2,3,4,5-tetrahydro- 1 W-benzo[djazepin-7-yloxy}-propionic acid ethyl ester
Cpd S1 was prepared following the same procedure as for cpd B3, Cpd S1 was obtained as a white solid <90%): 1H NMFl <300 MHz, COCI3) δ 8.12 (d, J = 8.3 Hz, 2 H), 7.68 (d, J = 8.4 Hz, 2 H)1 6.92 (d, J= 8.2 Hz, 1 H), 6.62 (d, J= 2.5 Hz, 1 H), 6.54 (dd, J= 8.1 , 2.5 Hz, 1 H), 4.22 (q, J= 7.1 Hz, 2 H), 3.76 (S, 2 H), 2.90 - 2.82 (m, 4 H), 2.70 - 2.63 (m, 4 H)1 2.23 <s, 3 H), 1.56 (S, 6 H), 1.23 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 517 (M+H÷).
Figure imgf000098_0001
2-Methyl-243-E4-methyi-2-(4-trifluoromethyI-phenyl)-oxazol-5-ylmethyl]-2,3l4,5-tetrahydro-1 H-benz o[d|azepin -7-y loxyj-propion ic acid
Cpd 19 was prepared following the same procedure as for cpd 2. Cpd 19 was obtained as a white solid (61 %): 1H NMR <300 MHz, CD3OD) δ 8.24 (d, J= 8,3 Hz1 2 H), 7.85 (d, J= 8.4 Hz, 2 H), 7.12 (d, J= 8.2 Hz, 1 H), 6.80 (d, J= 2.5 Hz, 1 H), 6.73 (dd, J= 8.2, 2.5 Hz, 1 H), 4.64 (s, 2 H), 3.85 - 3.75 (m, 2 H), 3.25 - 3.02 (m, 6 H), 2.34 (s, 3 H), 1.54 (s, 6 H); MS (ES) m/z: 489 (MH-H+).
Example 20
Figure imgf000098_0002
Compound 20: {3-[1-{4-Trifluoromethyl-phenyt)-1 H^pyrazoM-ylmethyl]- 2,3,4,5-tetrahydro-i H-benzoIcflazepin-y-yloxyJ-acetic acid
The title compound was made according to Scheme T. Scheme T
Figure imgf000099_0001
Figure imgf000099_0002
1~(4-Trifluoromethyi-pheny[)-1 W-pyrazole-4-carboxylic acid ethyl ester
To a solution of T1 (864 mg, 6 mmof, J. Org. Chem., 1982, 47, 2217- 2218) in EtOH (6 mL) at O 0C was added {4-trifiuoromethylphenyl)hydra7ine {1.06 g, 6 mmo!) in EtOH (30 mL). The mixture was stirred at room temperature for 2 days and then washed with H20, 1 N HCI and H2O, After drying over Na2SO4, the solution was concentrated and purified toy column chromatography to give 3.0 g (95%) of R1 as a white solid: 1H NMR {300 MHz, CDCI3) δ 8.47 (s, 1 H), 8.13 (s, 1 H), 7.86 <d, J = 8.6 Hz1 2 H), 7.75 <d, J = 8.6 Hz, 2 H), 4.36 (q, J = 7.1 Hz, 2 H)1 1.36 <t, J = 7.1 Hz, 3 H).
Figure imgf000100_0001
[1 -(4-Trifl uoromethy I- phenyl)- 1 H-pyrazo!-4-yl]-methanol
Cpd T3 was prepared following the same procedure as in the preparation of K2c. Cpd T3 was obtained as a white solid (83%): 1H NMR (300 MHz, CDCI3) δ 7.99 (s, 1 H), 7,81 (d, J = 8.8 Hz, 2 H), 7.75 (S, 1 H), 7.71 (d, J = 8.8 Hz, 2 H), 4.70 (d, J= 5.4 Hz, 2 H), 1.66 (t, J= 5.5 Hz, 1 H); MS (ES) m/z: 243 (M+H+).
Figure imgf000100_0002
4-Bromoιnethyl-1-(4-triflυoromethyl-phenyl)-1 H-pyrazole
Cpd T4 was prepared following the same procedure as for cpd A2d. Cpd T4 was obtained as a white solid (85%): 1H NMR <300 MHz, CDCI3) δ 7.95 (s, 1 H), 7.75 - 7.60 (m, 5 H), 4.43 (s, 2 H).
Figure imgf000100_0003
{3-[1 -(4-Trif!υoromethyi-phenyl)-1 H-pyrazol-3-ylmethyl]-2,3,4,5-tetrahydro-1 H-benzo[ d)azepin-7-yloxy}-acetic acid fert-butyl ester
Cpd T5 was prepared following the same procedure as for cpd B3. Cpd T5 was obtained as a white solid (44%): 1H NMR <300 MHz, CDCI3) δ 8.04 (s, 1 H)1 7.82 (d, J= 8.6 Hz, 2 H), 7.72 - 7.67 (m, 3 H), 6.99 <d, J = 8.2 Hz, 1 H)1 6.68 (d, J= 2.6 Hz, 1 H), 6.61 (dd, J= 8.2, 2.7 Hz, 1 H)1 4.47 (s, 2 H), 3.72 (s, 2 H), 2.93 (m, 4 H), 2.73 (m, 4 H), 1.48 (s, 9 H); MS{ΕS) m/z: 502 (M+H+).
Figure imgf000101_0001
20 was prepared following the same procedure as in the preparation of cpd 11 , Cpd 20 was obtained as a white solid (60%): 1H NMR (300 MHz, CD3OD) δ 8.59 (s, 1 H), 8,02 (d, J= 8.5 Hz1 2 H), 7.93 (m, 1 H), 7.83 (d, J= 8.6 Hz1 2 H), 7,14 (d, J= 8.3 Hz, 1 H), 6.83 (ό, J = 2.6 Hz, 1 H), 6.77 (dd, J= 8.3, 2.6 Hz, 1 H), 4.64 (s, 2 H), 4.42 (s, 2 H), 3.84 - 3.78 <m, 2 H), 3.25 - 2.99 (m, 6 H); MS (ES) m/z: 446 (M+H+).
Exampie U
Figure imgf000101_0002
The title compound was made according to Scheme U.
Scheme U
Figure imgf000101_0003
Figure imgf000102_0001
2-Methyt-2-{3-[1 -(4-trif!uoromethyl-phenyi)-1 H-pyrazol-3-ylmethyl]-2,3,4,5-tetrahydro-1 H-be nzo[c(|azepin-7-yloxy}-prOpionic acid ethyl ester
Cpd LM was prepared following the same procedure as for cpd B3. Cpd U1 was obtained as a white solid (45%): 1H NMR <300 MHz, CDCI3) δ 8.44 (S, 1 H), 7.86 (U1 J= 8.6 Hz, 2 H), 7,75 - 7.68 (m, 3 H), 6.95 (d, J - 8.2 Hz, 1 H), 6.65 (d, J = 2.6 Hz, 1 H), 6.59 (dd, J= 8.2, 2.6 Hz1 1 H), 4,23 {q, J = 7.1 Hz, 2 H), 3.91 (s, 2 H), 3.10 (m, 4 H), 2.96 (m, 4 H), 1 ,58 <$, 6 H), 1.25 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 502 (M+H+).
Figure imgf000102_0002
2-Methyl-2-{3-[1-(4-trifluoromethyl-phenyl)-1f/-pyrazol-3-ylmethyt]-2,3,4,5- tetrahydro-1 H-benzo{ήazepin-7-yloxy}-propionic acid
Cpd 21 was prepared following the same procedure as for cpd 2. Cpd 21 was obtained as a white solid (61%): 1H NMR (300 MHz, CD3OD) δ 8.54 (S1 1 H), 7.99 (d, J= 8.6 Hz, 2 H), 7.87 (s, 1 H), 7.81 <d, J= 8.7 Hz, 2 H), 6.93 (d, J = 7.6 Hz, 1 H), 6.75 - 6.67 (m, 2 H)1 4.27 (s, 2 H), 3.30 - 3.10 (m, 4 H), 2.81 (m, 4 H), 1.57 (s, 6 H); MS (ES) m/z: 474 <M+H+).
Example V
Figure imgf000102_0003
Compound 22: {3-{2-|5-(4-TrifIuoromethyl-phenyl)-thiophen-2-y!]-ethyI}- 2,3,4,5-tetrahydro-1 /-/-benzo[d)azepin-7-yioxy)-aceiic acid
The title compound was made according to Scheme V, Scheme V
Figure imgf000103_0001
Figure imgf000103_0002
A mixture of -thiophenβ acetate (1.380 g, 8.107 mmoi), CHCI3 {40 mL) and HOAc (40 mL) was cooled in ice bath. Λ/-bromosucctnamide (1.472 g, 8,269 mmol) was added. The resulting mixture was stirred at r.t. for 18 h and then poured into water {100 mL). The layers were separated and the aqueous phase was extracted with chloroform {2 x 30 mL). The combined organic layers were washed with water, brine, dried <Na2SO4) and concentrated. The residue was purified by column chromatography βluting with EtOAc/Hexane to give cpd V1 as yellow oil (1.gflJ g, 64%): 1H NMR (300 MHz1 CDCI3) δ 6.89 (dt J= 3.7 Hz, 1 H), 6.68-6.69 <m, 1 H), 4.15-4.22 (q, J = 7.2 Hz, 2 H), 3.75 (d, J = 0.7 Hz, 2 H), 1.30 <t, J = 7.1 Hz, 3 H).
Figure imgf000104_0001
[5-{4-Trifluoromethyl-phenyi)-thiophen-2-yl]-acetic acid ethyl ester
Cpd V2 (430 mg, 64%) was prepared using a similar procedure as for cpd G1. 1H NMR (300 MHz1 CDCI3) δ 7.59-7.68 (m, 4 H), 7.24 (d, J= 3.7 Hz, 1 H), 6.94 (d, J = 3.6 Hz, 1 H)1 4.18-4.25 (q, J= 7.1 Hz, 2 H), 3.84 <s, 2 H)1 1.28-1.32 (t, J= 7.1 Hz, 3 H).
Figure imgf000104_0002
2-[5-(4-Trifluoromethyl-pheny!)-thiophen-2-yl]-€thanol To a THF (5 ml_) solution of V2 (423 mg, 1.347 mmol) was added a THF solution of LAH (1.0 M, 1.62 mmol) at 00C. After stirring for 30 min, the mixture was quenched with aqueous NH4CI and then extracted with Et2O. The organic extracts were concentrated and the residue purified by column chromatography eluting with EtOAc/Hexane to give cpd V3 as yellow solid (276 mg, 75%): 1H NMR (300 MHz, CDCI3) δ 7.59-7.67 (m, 4 H)1 725 (d, J = 3.6 Hz, 1 H), 6.88 (d, J= 3.6 Hz1 1 H), 3.92 (t, J= 6,2 Hz, 2 H), 3.10 <t, J = 6.2 Hz, 2 H).
Figure imgf000104_0003
[5-(4-Trifluoromethyl-phenyI)-thtophen-2-yl]-acetaldehyde
To a mixture of V3 <194 mg, 0.713 mmol) in CH2CI2 (7 mL) at 0 0C was added Dess-Martin reagent (333 mg, 0.784 mmol). The mixture was stirred for 30 min and then washed with a mixture of aqueous NaHCO3 and aqueous Na2S2O3, followed by brine. After drying over Na2SO4, the mixture was concentrated and the resulting residue purified by column chromatography eluting with EtOAc/hexane to give cpd V4 as yellow solid (82 mg, 35%): 1H NMR (300 MHz1 CDCI3) δ 9.78 (t, J= 1.9 Hz, 1 H), 7.60- 7.68 (m, 4 H), 7.29 (d, J= 3.6 Hz, 1 H), 6.94 (d, J = 3.6 Hz, 1 H), 3.92 <d, J = 1.2 Hz, 2 H).
Figure imgf000105_0001
V5 (40 mg, 36%) was prepared according to the same procedure as for cpd G2c. 1H NMR (300 MHz, DMSO-Cf6) δ 7.71-7.82 <m, 4 H), 7.49 (d, J = 3.6 Hz, 1 H), 7.02 (d, J= 8.1 Hz, 1 H), 6.96 (d, J= 3.6 Hz, 1 H)16.71 (d, J= 2.5 Hz, 1 H), 6.62-6.66 (dd, J= 2.5, 8.1 Hz, 1 H), 3.70 <s, 3 H), 2.98 (m, 2 H), 2.83 (m, 4 H), 2.74 (m, 2 H), 2.64 (m, 4 H); MS [ES) m/z: 432.1 (M+H+).
Figure imgf000105_0002
pd V7 {13 mg, 72%) was prepared according to the ^ame procedure as for cpd G1 b. 1H NMR (300 MHz, COCI3) δ 7.58-7,66<m, 4 H), 7.22<d, J = 3.6 Hz, 1 H), 7.03 (d, J = 7.5 Hz, 1 H), 6.88 (d, J = 3.7 Hz, 1 H) , 6.72 <s, 1 H), 6.67 (br, 1 H), 4.60 (s, 2 H), 4.24-4.31 (q, J= 7.1 Hz, 2 H), 2.72-2.91 <m, 12 H), 1.30 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 604.0 tM+H+).
Figure imgf000106_0001
(3-{2-[5-(4-Trifiuoromethyl-phenyl)-thiophen-2-yl]-ettiyl}-2,3,4,5-tet rahydro-1 /-/-benzof cflazepin-7
-yloxy)-acetic acid
Cpd 22 (6mg, 60%) was prepared according to the same procedure as for cpd 7. 1H NMR (400 MHz, DMSO-cfe) δ 7.83 (d, J = 8.3 Hz, 2 H), 7.75 (d, J = 8.5 Hz, 2 H), 7.56 (d, J= 3.6 Hz, 1 H), 7.11 (d, J= 8.3 Hz, 1 H)1 7,04 (d, J= 3.5 Hz, 1 H), 6.81 (d, J= 1.9 Hz, 1 H), 6.68-6.71 <dd, J = 2.5, 8.1 Hz, 1 H)1 4.64 (S1 2 H)1 3.03-3.20 (br, 12 H); MS (ES) m/z: 476 (M+H+), 474 (M- H+).
Example W
Figure imgf000106_0002
Compound 23: {3-[4-(4-Trifiuoromethyl-phenyl)-thiophen-2-ylmethyl]-2,3,4,S-tetrahydro-1 H- benzo[G(]azepiri-7-yloxy}-acetic acid
The title compound was made according to Scheme W.
Scheme W
Figure imgf000107_0001
Figure imgf000107_0002
Cpd W1 was prepared following the same procedure as for epd G1 Cpd W1 was obtained as a white solid <90%): 1H NMR (300 MHz, CDCI3) δ 10.00 (S, 1 H), 8.07 (s, 1 H), 7.92 (s, 1 H), 7.71 (s, 4 H).
Figure imgf000107_0003
W2 was prepared following the same procedure as for cpd G2, Cpd W2 was obtained as a white solid (45%): 1H NMR (300 MHz, CDCI3) δ 7.66 (d, J= 8.8 Hz, 2 H), 7.62 <d, J = 8.7 Hz1 2 H)1 7.43 (s, 1 H), 7.20 iβ, 1 H)1 6.99 (d, J= 8.2 Hz, 1 H)1 6.69 (d, J = 2.6 Hz, 1 H), 6.62 <dd, J= 8.2, 2.6 Hz, 1 H), 4.58 <s, 2 H)1 4.26 (q, J = 7.1 Hz12. H)1 3.87 <s, 2 H)12.92 - 2.84 (m, 4 H), 2.73 - 2.-65 (m, 4 H), 129 <t, J= 7.1 Hz, 3 H); MS (ES) m/z: 490 (M+H+).
Figure imgf000108_0001
23 was prepared following the same procedure as for cpd A2e. Cpd 23 was obtained as a white solid (91%): 1H NMR (300 MHz, CD3OD) δ 7,88 (S, 1 H), 7.83 (d, J = 8.1 Hz, 2 H), 7.70 - 7.65 (m, 3 H), 6.96 <d, J = 8.9 Hz, 1 H), 6.72 - 6,68 (m, 2 H), 4.46 (s, 2 H), 4.42 (S1 2 H), 3.15 - 3.03 <m, 4 H), 2.89 - 2.75 (m, 4 H); MS (ES) m/z: 462 (M+H÷).
Example X
Figure imgf000108_0002
The title compound was made according to Scheme X.
Scheme X
Figure imgf000109_0001
Figure imgf000109_0002
Figure imgf000109_0003
2-(4-Trif I uorom eth y l-pheny l)-th iazole-5-carbaldehyde
A mixture of 2-bromo-5-formylthioazole (525 mg, 2.73 mmoi), (4- trifluoromethyl)phenylboronic acid <519 mg, 2,73 mmol), tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) and 2 N aqueous Na2CO3 {5.5 mLt 10.94 mmol) were refluxed in dioxane <8 mL) for 20 h. It was cooled and partitioned between EtOAc and waler. After separating layers, the organic phase was washed with water and orine. It was dried over Na2SO4 and concentrated under reduced pressure. T+ie crude product was purified by column chromatography fluting with EtOAc/Hexane. The title compound was obtained in yellow solWs (145 mg, 21%).
Figure imgf000110_0001
7-Methoxy-3'[2-(4-triflυoromethyi-pheny])-thia2θi-5-ylmethyl]-2,3,4,5-tetrahydro-
1H-benzo[c/|azepine
Cpd X1 (139 mg, 0.541 mmol) and cpd A1a {96 mg, 0.541 mmol) were mixed with dichloroethane (2 mL) and glacial acetic acid (0.031 mL, 0.541 mmol) was added. After the resulting mixture was stirred at r.t. for 3 h, Na(OAc)3BH (172 mg, 0.811 mmol) was added and the mixture was stirred for another 21 h. It was then basified with 2N aq. NaOH and extracted with EtOAc. The organic extracts were concentrated under reduced pressure. Purification by column chromatography gave cpd X2 as a white solid {T68 mg, 74%). 1H NMR (300 MHz, CDCI3) δ 8.04 (d, J = 8.2 Hz, 2 H), 7.69 <d, J = 8.4 Hz, 2 H)1 7.67 (s, 1 H), 7.00 (d, J= 7.8 Hz, 1 H), 6.66 - 6.63 (m, 2 H), 3.90 (S, 2 H), 3.77 (s, 3 H), 2.88 (m, 4 H), 2.87 (m, 4 H); MS (ES) m/z: 419 (M+H+).
Figure imgf000110_0002
3-[2-{4-Trifluoromethy!-phenyl)-thiazot-5-ylmethyl]-2,3,4,5-tetrahydro-1 H-benzθEo5azepin-7-ol
A mixture of cpd X2 (145 mg, 0.347 mmol), HBr<48%, 0.8 mL, 6.94 mmol), "Bu4NBr (12 mg, 0.035 mmol) and HOAc <0.4 mL) were stirred at 100 0C for 18 h. After the mixture was cooled, it was diluted with water then basified with saturated aq. K2CO3 and extracted with €tOAc. The organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with dichloromethane/acetone (10:1) to give cpd X3 as a white ^olid (100 mg, 71%). 1H NMR (300 MHz, CD3OD) δ 8.11 {d, J= 8.4 Hz, 2 H)1 7.77 (d, J = 8.4 Hz1 2 H), 7.75 (S1 1 H)1 6.88 (ό, J= 8.0 Hz, 1 H), 6.54 <d, J = 2.4 Hz, 1 H), 6.50 (dd, J = 8.0, 2,5 Hz, 1 H), 3.95 (s, 2 H), 2.83 (m, 4 H), 2.88 (m, 4 H); MS (ES) m/z: 405 (M+H+),
Figure imgf000111_0001
{3-[2-(4-Trifiuoromethyi-phenyl)-thiazoi-5-ylmethyl]-2,3,4lS-tetrahydro-1 H-benzo[c§azepi n-7-yloxy}-acetic acid ethyl ester
Cpd X3 (101 mg, 0.250 mmol) was dissolved in THF (3.0 ml_). NaH (60%, 30 mg, 0.749 mmol) was added and followed by ethy! bromoacetate (0.033 ml_, 0.297 mmol). The mixture was refluxed for 1 h. After cooling, it was treated with saturated aq. NH4CI and partitioned between water and Et2θ. The organic layers were washed with brine and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with EtOAc/Hexane to give Cpd X4 as colorless oil (60 mg, 50%). 1H NMR (300 MHz, CDCI3) δ 8.04 (d, J= 8.2 Hz12 H), 7.69 <d, J= 8.5 Hz, 2 H), 7.67 (s, 1 H), 7.00 <d, J= 8.2 Hz, 1 H), 6.69<d, J= 2.6 Hz, 1 H), 6.62 (dd, J= 8.2, 2.6 Hz, 1 H), 4.58 (s, 2 H), 4.26 <q, J= 7.1 Hz, 2 H), 3.89 (s, 2 H), 2.87 (m, 4 H), 2.68 (m, 4 H), 1.27 <t, J= 7.1 Hz, 3 H); MS (ES) m/z: 491 (M+H+).
Figure imgf000111_0002
{ 3-[2 -(4-Trif I uo romethyi-pheny l)-th iazol-5-yl methyl]-2,3 ,4,5-tetrahydro- 1 W-benzoEdJazepin-y-yloxyJ-acetic acid
A mixture of cpd X4 (50 mg, 0.102 mmol) in THF<0.3 mL) and methanol (0.3 mL) was treated with 2N aqueous NaOH<0.080 mL, 0.153 mmol). After stirring for 4 h, the mixture was acidified with 1 N HCI and extracted with dichioromethane. The organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give cpd 24 (14 mg, 30%). 1H NMR (300 MHz, CD3OD) δ 8.18 (d, J = 8.3 Hz, 2 H), β.04{s, 1 H), 7.82 (Cl, J = 8.3 Hz, 2 H), 7.12 <d, J = 8.1 Hz, 1 H), 6^1 (s, 1 H)1 6.76 <dd, J = 8,5, 2.6 Hz, 1 H), 4.67 (s, 2 H), 4.61 (s, 2 H), 3.37 (m, 4 H), 3.10 (m, 4 H); MS (ES) m/z: 463 (M+H+).
Example Y
Figure imgf000112_0001
Compound 25: {5-Methyl-3-[5-(4-trifluoromethy!-phenyl)-thiophen-2-ylmethyl]-
2,3A5-tetrahydro-1 H-benzo(c(|aze pin-7-yloxy}-acetic acid
The title compound was made according to Schemes Y1 and Y2.
Scheme Y1
Figure imgf000112_0002
Figure imgf000112_0003
2-{3-Methoxy-phenyl)-propionic acid
(3-methoxy)phenylacetic acid (4.164 g, 25.06 mmol) was refluxed in EtOH in presence of catalytic amount of cone. H2SO4. The mixture was concentrated in vacuo, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine. It was dried over Na2SO4 and concentrated to give colorless oil {4,69 g, 97%).
The above oil (1.060 g, 5.466 mmol) was dissolved in THF {20 ml.) and cooled to -700C. It was treated with a THF solution of LiN(TMS)2 (1M, 6.56 ml_). After stirring at -700C for 30 min, MeI was added and the resulting mixture was stirred for 3 h and then quenched with saturated aqueous NH4CI. The mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated in vacuo to give red oil (1.046 g, 92%).
The above oil (1.00 g, 4.807 mmol) was mixed with MeOH \3 ml_) and THF (6 ml.}. 2N aqueous NaOH was added. The mixture was stirred for 4 h and then acidified with 6N HCI till PH = 1. Extraction with dtchloromethane and subsequent concentration in vacuo gave cpd Y1a as yellow oil (869 mg, 100%). 1H NMR (400 MHz, CDCI3) δ 7.29 - 7.22 (m, 1 H)1 6.91 (d, J- 7.7 Hz, 1 H), 6.86 (s( 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 3.80 (s, 3 H)1 3.71 {% J = 7.2 Hz, 1 H), 1.50 (d, J= 7.2 Hz, 3 H); MS<ES) m/z: 181 (M+H+).
Figure imgf000113_0001
Λ/-{2,2-Dimethoxy-ethyl) -2-(3-methoxy'phenyl)-propionamide
Cpd Y1a (822 mg, 4.567 mmol) was mixed with dtehloromethane \2Q mL). Oxalyl chloride (0.60 mL, 6.85 mmol) and 2 drops of DMF were added. The mixture was stirred at r.t. for 15 h and then concentrated in vacuo. The resulting crude residue was added to a mixture of triethyiamine (0.96 mL, 6.850 mmol), (2,2-dimethoxy)ethylamine (480 mg, 4.567 mmo!) in dichϊoromethane (20 mL) and the resulting mixture was stirred at r.t. for 18 h. It was partitioned between CH2CI2 and water. The organic layer was drted (Na2SO4) and concentrated in vacuo. The crude was purified by column chromatography eluting with EtOAc/Hexane to give cpd Y1 b as colorless oil (1.015 g, 83%): 1H NMR {300 MHz1 CDCI3) 57.30 - 7.21 (m, 1 H), 6.90 - 6.79 (m, 3 H), 5.54 (brs, 1 H), 4.28 (t, J = 5.4 Hz, 1 H), 3.81 (s, 3 H), 3.53{q, J = 7.1 Hz, 1 H), 3.38 - 3.29 (m, 8 H)1 1.51 (d, J = 7.2 Hz, 3 H).
Figure imgf000114_0001
8-Methoxy-1 -methyl-1 ,3-dihydro-benzo[c(|azepin-2-one
A mixture of cpd Y1 b (3.875 g, 14.495 mmol) in cone. HCI (20 mL) and HOAc (20 mL) was stirred at room temperature for 17 h. it was then poured onto ice (66 g). The precipitates were collected by filtration and dried under vacuum at 70 0C to give cpd Y1 c (1.464 g, 50%) as a yellow solid: 1H NMR (300 MHz, DMSO-Cf6) δ 9.53 (d, J= 3.6 Hz, 1 H), 7.23 (d, J= 8.5 Hz1 1 H), 6.88 (dd, J= 8.5, 2.5 Hz, 1 H), 6.76 (d, J= 2.3 Hz, 1 H), 6.32 (d, J= 9.0 Hz, 1 H), 6.20 (dd, J = 9.0, 4.7 Hz, 1 H), 3.77 <s, 3 H), 3.15 <m, 1 H), 1.43td, J= 7.0 Hz, 3 H).
Figure imgf000114_0002
8-Methoxy-1 -methyl- 1.aAδ-tetrahydro-benzote/jazeptn^-one
Cpd Y1c (1.44 g, 7.085 mmol) was mixed with EtOAc (30 mL) and MeOH (30 mL). Pd/C (10%, 75 mg, 0.071 mmol) was added. The mixture was shaken under H2 atmosphere (45 psi) for 17 h. After filtration through celite, the solution was concentrated to give cpd Y1d (1,44 g, 100%) as a white solid: 1H NMR (300 MHz, DMSO-Cf6) δ 7.33 (brs, 1 H), 7.06 <d, J= 8.3 Hz, 1 H)1 6.75 (dd, J = 8.3, 2.5 Hz, 1 H), 6.68 <d, J = 2.4 Hz, 1 H), 4.22 <q, J = 13.8, 6.8 Hz, 1 H), 3.73 - 3.64 (m, 4 H), 3.18 - 3.10 (m, 2 H), 2.91 -2.84 (m, 1 H), 1.33 (d, J= 6.9 Hz, 3 H); MS (£S) m/z: 206 (M+H4).
Figure imgf000115_0001
8-Methoxy-1 -methyi-2,3,4,S-tetrahydro-1 H-benzo[djazep ine
To a solution of cpd Y1d (286 mg, 1.393 mmol) in THF {7 mL) was added BH3-THF (1 M, 4.18 mmol) at 0 0C. The mixture was stirred at reflux for 4 h and then cooled. MeOH <2 mL} was added to quench excessive BH3 at O 0C and the mixture was stirred at room temperature for another 30 min. After concentration, the residue was taken up with 6N HCI and stirred at 100 0C for 1 h. The mixture was extracted with Et≤O and the organic layer was discarded. The remaining aqueous phase was basified with 5N NaOH and then extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated in vacuo to give cpd Y1e (191 mg, 72%) as colorless oil: 1H NMR (300 MHz, CDCI3) δ 7.00 (d, J= 8.2 Hz, 1 H), 6.74 <d, J = 2.6 Hz, 1 H), 6.63 (dd, J= 8.2, 2.7 Hz, 1 H), 3.79 (s, 3 H), 3.05 - 2.86 <m, 6 H), 2.74 (dd, J = 13.4, 7.6 Hz, 1 H), 2.04 (brs, 1 H), 1.33<d, J= 7.2 Hz, 3 H); MS (ES) m/z; 192 (M+H+).
Scheme Y2
Figure imgf000116_0001
Figure imgf000116_0002
8-Methoxy-1-methyl-3-[5-(4-trifluoromethyl-phenyi)-thiophen-2-yimethyl]-2,3,4,5-te trahydro- 1 H-benzσf t/jazepine
A mixture of cpd Y1e (84.6 mg, 0.443 mmol), cpd G1a (113 mg, 0.443 mmol), dichloroethane (2 mL) and HOAc (0.025 mL, 0.443 mmol) was stirred at room temperature for 1 h. Na(OAc)3BH (141 mg, 0.664 mmol) was added. The mixture was continued stirring for another 20 h. After it was basified with 5N NaOH, the mixture was extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography to give cpd Y2a (154 mg, 81%) as a yellow oil: 1H NMR (300 MHz, CDCI3) δ 7.67 (d, J = 8,1 Hz, 2 H), 7.€0 (d, J ^ 8.5 Hz, 2 H), 7.23 (d, J = 3.6 Hz, 1 H), 6.99 (d, J= 8.2 Hz, 1 H), 6.88 <m, 1 H), 6.73 (d, J= 2.5 Hz, 1 H)1 6.64 (dd, J = 8.2, 2.6 Hz, 1 H), 3.83 (d, J = 4.7 Hz, 2 H), 3.78 (s, 3 H), 3.19 - 3.06 (m, 1 H), 2.99 - 2.70 {m, 4 H), 2.61 - 2.42 <m, 2 H), 1.36<d, J= 7.2 Hz, 3 H); MS (€S) m/z: 432 tM+H+).
Figure imgf000117_0001
mixture of cpd Y2a (150 mg, 0.348 mmot), HBr<48%, 0.5 mL), HOAc (0.5 mL) and "Bu4NBr (22 mg, 0.070 mmoi) was stirred at 1000C for 17 h. After it was cooled to room temperature, the mixture was basified with 5N NaOH and extracted with EtOAc. The organic extracts were washed with water, brine, dried (NazSO-O and concentrated. The resulting residue was purified by column chromatography to give cpd Y2b <98 mg, 67%) as brown oil:
Figure imgf000117_0002
a mixture of cpd Y2b (89 mg, 0.213 mmoi) in THF (1.5 ml) was added NaH (60%, 43 mg, 1.07 mmoi) and ethyl bromoacetate (0.047 mL, 0.426 mmoi) subsequently. After it was stirred at reflux for 50 min, the mixture was cooled to room temperature and quenched with aqueous NH4Ci. The resulting mixture was partitioned between water and EtsO. The layers were separated and the organic phase was dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography to give cpd Y2c (62 mg, 58%) as a yellow solid: 1H NMR (300 MHz, CDCI3) δ 7.67 (d, J= 8.2 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 2 H)1 7,24 (d, J = 3.6 Hz1 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 6.89 (m, 1 H), 6.78 <d, J = 2.4 Hz, 1 H), 6.59 (dd, J = 8.2, 2.6 Hz, 1 H), 4.58 (s, 2 H), 4.27 (q, J= 7.2 Hz, 2 H), 3.83 (s, 2 H), 3.19 - 3,05 (m, 1 H), 3.01 -2.67 {m, 4 H), 2.59 - 2.40 (m, 2 H), 1.35^d, J= 7.2 Hz, 3 H), 1.30 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 504 (M+H+).
Figure imgf000118_0001
{5-Methyl-3-[5K44riftuoromethyt-phenyt)'thiophen-2-ylmethyl]-2,3,4,5-tetrahydro-1W-benzo{cf|a2e pin-7-yloxy} -acetic acid
A mixture of cpd Y2c (56 mg, 0.111 mmol), THF (0.5 mL), MeOH <0.5 mL) and NaOH (2N, 0,11 mL, 0.22 mmol) was stirred at room temperature for 6 h. The solution was acidified with 1 N HCI and extracted with dichioromethane. The organic extracts were dried and concentrated to give cpd 25 (57 mg, 100%) as a pale pink solid: 1H NMR (300 MHz, CD3OD) δ 7.86 (d, J= 8.2 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H), 7,57 (d, J= 3.7 Hz, 1 H), 7.38 (d, J = 3.8 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 6.89 <d, J = 2,5 Hz1 1 H), 6.77 (dd, J= 8.3, 2.6 Hz, 1 H), 4.67 - 4.65 (m, 4 H), 3.76 - 3.41 (m, 4 H)1 3.25 (m, 1 H), 3.17 - 3.00 (m, 2 H), 1.46 (d, J= 7.2 Hz, 3 H); MS (€S) m/z: 476 (M+H+).
Example Z
Figure imgf000118_0002
Compound 26: {5'Methyi-3-[5-(4-trifluoromethyl-phenyl)-fυran-2-ylmethyl]-2,3,4,5-tetrahydro-
1 W-benzo[α]azepin-7-yloxy}-acetic acid
The title compound was made according to Scheme Z.
Scheme Z
Figure imgf000119_0001
Figure imgf000119_0002
A mixture of cpd Y1e (89 mg, 0.466 mmol), cpd 11 (112 mg, 0.466 mmo!), dichioroethane (2 mL ) and HOAc (0.027 mL, 0.466 mmol) was stirred at room temperature for 16 h, Na(OAc)3BH (148 mg, 0.699 mmol) was added. The resulting mixture was continued stirring for another 24 h, basified with 2N NaOH and extracted with EtOAc, The organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography to give cpd Z1 (153 mg, 79%): 1H NMR {300 MHz, CDCI3) δ 7.72 (d, J= 8.1 Hz, 2 H), 7.60 (d, J = 8.5 Hz, 2 H), 6.98 (d, J = 8.1 Hz, 1 H), 6.72 (d, J= 2.5 Hz, 1 H), 6.68 (d, J= 3.3 Hz, 1 H)1 6.62 (dd, J= 8.2, 2.6 Hz, 1 H), 6.29 (d, J = 3.1 Hz1 1 H), 3.77 (s, 5 H), 3.11 - 3.16 (m, 1 H), 2.78 - 2.99 (m, 4 H), 2.40 - 2.54 (m, 2 H), 1.35 (d, J = 7.2 Hz1 3Jd); MS (ES) rn/z: 416 (M+H+),
Figure imgf000120_0001
5-Methyl-3-[5-(4-trifluoromethyI-phenyl)-furan-2-ylmethy!]- 2,3J4,5-ietrahydro-1 H-benzo[c(|azepir!-7-o!
A mixture of cpd Z1 {140 mg, 0.337 mmol), HOAc (1 mL) and HBr (48%, 1 mL) was stirred at 800C for 17 h. Upon cooling, the mixture was diluted with EtOAc and basified with saturated aqueous K2CO3 till pH 9. It was then extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated to provide cpd Z2 (137 mg, 100%) as brown oil: 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2 H), 7.59 (d, J= 8.3 Hz, 2 H), 6.90 (d, J= 8.0 Hz, 1 H), 6.68 (d, J= 3.3 Hz, 1 H), 6.65 (d, J= 2.5 Hz, 1 H), 6.53 - 6.57 (dd, J= 8.0, 2.6 Hz, 1 H), 6.32 (s, 1 H), 3.75 - 3.80 (s, or, 2 H), 2.81 - 3.16 (m, δ H), 2.37 - 2.51 (m, 2 H), 1.34 (d, J= 7.2 Hz, 3 H); MS (ES) m/z; 402 (M+H+), 400 (M-H+).
Figure imgf000120_0002
{5-Methyl-3-[5-(4-trifluoromethyl-phenyl)-furan-2-yimethyl]-2,3,4,S-tetrahydro- 1 H-benzo[α]azepin-7-yloxy}-acetic acid ethyi ester
To a solution of cpd Z2 (108 mg, 0.269 mmol) in THF (1.5 mL) was added NaH (95%, 14 mg, 0.539 mmol) and ethyi bromoacetate <O.045 mL, 0.403 mmol). After it was stirred at room temperature for 4 h, it was quenched with aqueous NH4CI and extracted with EfeO. The organic extracts were dried, concentrated and the residue was purified by column chromatography to provide cpd Z3 (65 mg, 50%): 1H NMR<300 MHz, ODCI3) δ 7.72 (Cl1 J= 8.2 Hz, 2 H)5 7.60 (d, J= 8.3 Hz, 2 H), 6.98 <d, J= 8.2 Hz, 1 H), 6.78 (d, J= 2.6 Hz, 1 H), 6.68 (d, J = 3.3 Hz, 1 W^ 6.56 - 6.60 <dd, J = 2.7, 8.2 Hz, 1 H), 6.30 (s, 1 H)1 4.58 (s, 2 H), 4.23 - 429 <q, J= 7.2 Hz, 2 H), 3.78 (S, 2 H), 2.78 - 3.15 (m, 5 H), 2.38 - 2.51 (m, 2 H), 1.35{d, J= 7.2 Hz, 3 H), 1.26 - 1.31 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 488 (M+H+).
Figure imgf000121_0001
To a solution of cpd Z3 (60 mg, 0.123 mmol) in THF<0.5 mL) and MeOH (0.5 mL) was added NaOH (2N1 0,12 mL). The mixture was stiffed at room temperature for 2 h and then acidified with aqueous tartaric acid to pH 3-4. The mixture was extracted with EtOAc and the organic extracts were concentrated after drying over Na2SO4 to give cpd 26t60 mg, 100%) as a white powder: 1H NMR (300 MHz, CDCI3) δ 7.61 - 7.71 <m, 4 H), 6.91 <d, J = 8.2 Hz, 1 H), 6.75 (s, 3 H), 6.66 - 6.69 (dd, J= 2.3, 8.2 Hz, 1 H), 4.62 <s, 2 H), 4.27 - 4.44 (m, 2 H), 3.32 - 3.58 (m, 4 H), 2.60 -2.76 <m, 3 H), 1.32<d, J = 6.9 Hz, 3 H); MS (ES) m/z: 460 (M+H+).
Example AA
Figure imgf000121_0002
The title compound was made according to Scheme AA. Scheme AA
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Cpcf AA1 was prepared following a similar procedure as for cpd X1. Cpd AA1 was obtained (3.84 g, 84%) as a pale yellow solid:
Figure imgf000122_0004
To a mixture of cpd <32b <582 mg, 3.288 mmol), cpd AA1 <888 mg, 3.288 mmoi) and dichloroethane {30 mL) was added triethylamine {1.37 mL, 9.864 mmol) and TiCl4 (1 M in dichioromethane, 1.6IUTiL1 1.644 mmol). The resulting mixture was stirred at room temperature for 16 h. A solution of NaBH3CN (310 mg, 4.932 mmol) in MeOH (2 mL) was added and stirring was continued for another 5.5 h, The mixture was then basified with 2N NaOH and extracted with EtOAc. The organic extracts were dried and concentrated. The residue was purified by column chromatography to give cpd AA2 (487 mg, 34%) as a reddish slurry: 1H NMR {300 MHz, CDCi3) δ 7.67 (d, J = 8.9 Hz, 2 H)1 7.59 (d, J = 8.3 Hz, 2 H), 7.23 <d, J = 3.6 Hz, 1 H)1 6.99 (d, J= 8.0 Hz, 1 H), 6.84 (d, J= 3.6 Hz, 1 H), 6.66 - 6.61 <m, 2 H)1 4.15 (q, J = 7.4 Hz, 1 H), 3.77 (s, 3 H), 2.89 (m, 4 H)1 2.70 <m, 4 H), 1.41 <d, J = 6.7 Hz, 3 H); MS (ES) m/z: 432 (M+H+).
Figure imgf000123_0001
3-{1-[5-(4-Trifluoromethyl-phenyl)-thk)pherι-2-yl]-«thyl}-2,3,4,5-tetr£ϋiydro-1W- benzo[ cOazepin-7-oI
Cpd AA3 was prepared according to a similar procedure as for cpd Y2b. Cpd AA3 was obtained (249 mg, 53%) as a foam solid: 1H NMR {300 MHz, CDCl3) δ 7.67 (d, J= 8,3 Hz1 2 H), 7.59 {d, J = 8.5 Hz, 2 H)1 7.23 <d, J * 3.7 Hz, 1 H), 6.94 (d, J = 7.9 Hz, 1 H), 6.84 <d, J = 3.5 Hz, 1 H)16.59 - 6.54 (m, 2 H), 4.49 (brs, 1 H), 2.86 (m, 4 H), 2.71 (m, 4 H), 1.41 -(d, J= 6.8 Hz, 3 H); MS (ES) m/z: 418 (M+H+).
Figure imgf000123_0002
(3-{1-[5-(4-TrifluoromethyI-phenyl)-thiophen-2-yt]-ethyl}-2,3,4,S-tetrahydro-1 H- benzo[d|azepin-7-yloxy)-acetic acid ethyl ester
Cpd AA4 was prepared according to a simitar procedure as for cpd Y2c. Cpd AA4 was obtained {222 mg, 74%) as brown oil: 1H NMR {300 MHz, COCI3) δ 7.67 (d, J= 8.2 Hz1 2 H), 7.59 {d, J= 8.3 Hz, 2 H)1 7.23 <d, J = 3.6 Hz, 1 H), 6.99 (d, J= 8.2 Hz, 1 H), 6.84 (d, J = 3.5 Hz, 1 H), 6.69 <d, J= 2.6 Hz, 1 H), 6.61 (dd, J = 8.2, 2.6 Hz, 1 H)1 4.57 (s, 2 H), 4.26 (q, J= 7.1 Hz1 2 H), 4.12 (q, J = 7.1 Hz, 1 H), 2.88 (m, 4 H), 2.69 (m, 4 H), 1.41 (d, J= 6.7 Hz, 3 H), 1.29 (t, J = 7.2 Hz, 3 H); MS (ES) m/z: 504 (M-M-T).
Figure imgf000124_0001
(3-{1-[5-(4-Trifiuoromethyl-phenyl)-thiophen-2-yI]-ethyi}-2,3,4,5-tetrahydro-1H- benzo[c(|azepin-7-yloxy)-acetic acid
Cpd 27 was prepared according to a similar procedure as for cpd 25. Cpd 27 was obtained (220 mg) in 100% yield: 1H NMR {300 MHz1 COCi3) δ 7.62 (s, 4 H), 7.26 (m, 1 H), 7.17 (d, J = 3.5 Hz, 1 H), €.90 (d, J= 8.2 Hz, 1 H), 6.72 (dd, J= 8.1, 2.4 Hz, 1 H), 6.61 (d, J= 2.2 Hz, 1 H), 4.98 (m, 1 H), 4.60 (s, 2 H), 3.40 - 2.55 (m, 8 H), 1.92 (d, J= 6.9 Hz, 3 H); MS (ES) m/z: 476 (M+H*).
Cpd 27 racemates were separated by chiral HPLC. Condition used: column AD 25 cm, λ 302 nm, flow 1 ml/min; eluents: 70% of (Heptane +0.1 % TFA) and 30% of ((MeOH + EtOH)13/1 + 0.1 % TFA ) ; For cpd 27a: α = (-) 45.0 ° (c = 1 , MeOH); For cpd 27b: α = (+) 57.7 ° (c = 1 , MeOH/CHCI3).
Example BB
Figure imgf000124_0002
Compound 28: (3-{1 -[5-{4-Trifluoromethyf-phenyϊ)-furan-2-yl]-ethy!}-2,3,4,5-tetrahydro- 1 W-benzo[φzepin-7-yloxy)-acetic acid; compound with methane
The title compound was made according to Scheme BB.
Scheme BB
Figure imgf000125_0001
To a mixture of cpd 11 (750 mg» 3.124 mmoi), cpd G2b (553 mgf 3.124 mmol) and dichloroβthane (10 mL) was added triethyl orthoformate (0.52 mL, 3.124 mmol). After stirring at room temperature for 16 h, the resulting mixture was treated with MeMgSr (1.4 M in Toluene and THF, 4.5 mL, 6.25 mmol) with slow addition. The mixture was quenched with aqueous NH4CI after stirring for another 10 min and then partitioned between EtOAc and water. The organic layers were separated, dried and concentrated. The crude product was purified by column chromatography to provide cpd BB1 (646 mg, 50%) as yellow oil: 1H NMR (300 MHz, CDCI3) δ 7.68 <d, J= 8.2 Hz, 2 H)1 7.58 (d, J= BA Hz, 2 H)1 6.97 (d, J= 8.1 Hz, 1 H), 6.59-636 <m, 3 H), 6.22 (S, 1 H), 4,02-4.04 (m, 1 H), 3.74 (s, 3 H), 2.78-2.87 <m, 6 H), 2.56- 2.58 (m, 2 H), 1.49 <d, J= β.β Hz, 3 H); MS <ES) m/z: 416 (M+H+),
Figure imgf000126_0001
3-{1-t5-(4-Trifluoromethyhphenyi)-furan-2-yl]-ethyi}-2,3,4,5- tetrahydro-1 W-benzo[G]azepin-7-ol
Cpd BB2 was prepared according to a similar procedure as for cpd 22. Cpd BB2 was obtained (157 mg) in 54% yield: 1H NMR (300 MHz, CDCi3) δ 7.68 <d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H)1 6.91 <d, J= 7.9 Hz, 1 H), 6.66 (d, J= 3.3 Hz, 1 H), 6.51 -6.57 (m, 2H), 6.23 <d, J= 3.2 Hz, 1 H), 4.01-4.09 (m, 1 H)1 2.78-2.86 (m, 6 H), 2.57 - 2.68 (m, 2 H), 1.50 (d, J = 6.9 Hz, 3 H); MS (ES) m/z: 402 (M+H+).
Figure imgf000126_0002
{3-{1-[5-(4-TrifIυoromethyl-phenyl)-furan-2-yl]-ethyJ}-2,3,4,5-tetrahydro- 1 W-benzo[o[jazepin-7-yloxy)-acetic acid ethyl ester
Cpd BB3 was prepared according to a similar procedure as for<cpd Z3. Cpd BB3 was obtained (546 mg, 68%) as light brown oil: 1H NMR<300 MHz, CDCI3) δ 7.68 (d, J= 8.3 Hz, 2 H), 7.59<d, J= 8.3 Hz, 2 H), 6.96 <d, J = 8.2 Hz1 1 H), 6.60 - 6.67 (m, 2 H), 6.56 - 6.59 <m, 1 H), 6.21 (s, 1 H), 4.55 (S, 2 H), 4.21 - 4.28 (q, J= 7.2 Hz, 2 H), 4.00 - 4.11 <m, 1 H), 2.76 - 2.87 <m, 6 H), 2.55 - 2.58 (m, 2H), 1.47 - 1.50 (d, J = 6.8 Hz, 3 H), 1.23 - 1.28 <m, 3 H); MS (ES) m/z: 488 (M+H+). Cpd DD3 racemates were separated by chiral HPLC: column AD 50Og, flow rate 80 ml/min, λ 220 nm, eluent: CH3CN. One enantiomer BB3a shows optical rotation α = (+) 7.9 °<c = 1 , 100 mm, MeOH); The other enantiomer BB3b shows optical rotation a = (-) 3.8 ° (c - 1 , 100 mm, MeOH).
Figure imgf000127_0001
pcl 28 was prepared according to a similar procedure as for cpd 26. Cpd 28 was obtained (30 mg) in quantitative yield: 1H NMR (300 MHz, DMSO) δ 7.82 (d, J = 8.3 Hz, 2 H), 7.74 (d, J= 8.5 Hz, 2 H), 7.06 (d, J = 3.3 Hz, 1 H), 6.96 (d, J= 8.2 Hz, 1 H), 6.65 (d, J= 2.6 Hz, 1 H)16.55-6.57 <m, 1 H), 6.41 (d, J= 3.3 Hz, 1 H), 4.56 (s, 2 H), 4.07 (m, 1 H), 2.69 - 2.79 <m, 8 H), 1.41 {d, J= 7.0 Hz, 3 H); MS (ES) m/z: 460 (M+H+). Cpd 28a: α = (+) 19.2 ° (c = 0.4, MeOH); Cpd 28b: α = (-) 25.4 ° (c = 0.4, MeOH).
Example CC
Figure imgf000127_0002
The title compound was made according to Scheme CC.
Scheme CC
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000128_0003
1-[2-(4-Trifluoromethy!-phenyl)-trtiazol-5-yl]^etrιanol
To a solution of cpd X1 {445 mg, 1.73 rnmol) in THF <5 mL) was added MeMgBr (1.4 M, 1.48 mL, 2.078 mmol) atO 0C. After stirring at O 0C for 2 h, the mixture was quenched with aqueous NH4CI and extracted with EtOAc. The organic extracts were dried and concentrated. The residue was purified by column chromatography to give<:pd CC1 <307 mg) in€5%yield: 1H NMR {300 MHz1 CDCI3) 58.04 <d, J = 8.1 Hz, 2 H), 7.16 <s, 1 H), 7.70 <d, J = 8.2 Hz, 2H), 5.20-5.27 (q, J = 6.3 Hz, 1 H), 1.67 (d, J = 6.4 Hz, 3 H); MS (ES) m/z: 274 (M+H+).
Figure imgf000129_0001
1-[2-(4-Trif!ucromethyl-phenyl)-thiazol-5-yl]-ethanone
A mixture of cpd CC1 (302 mgt 1.106 mmol), MnO2 (1.92 g, 22.12 mmoi) in dichloromethane (20 mi_) was stirred at room temperature for 7 h. It was filtered through celite and concentrated to give cpd CC2<295 mg, 99%) as a white solid: 1H NMR (300 MHz, CDCi3) δ 8.38 (s, 1 H)1 8.12 (d, J= 8.2 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 2H), 2.64 (s, 3 H); MS (ES) rn/z: 272 (M+H+).
Figure imgf000129_0002
7-Methoxy-3-{1-[2-(4-trifluoromethyl-phenyt)4hiazol-5-yi]-ethyI}-2,3,4,5-tetrahydro-1 W-benzo[c5 azepiπe
Cpd CC3 was prepared according to a similar procedure as for cpd AA2. Cpd CC3 was obtained (130 mg, 27%) as yellow slurry: 1H NMR (300 MHz, CDCI3) δ 8.03 (d, J = 8.2 Hz, 2 H), 7.68 <d, J= 8.2 Hz, 2 H), 7.61 (s, 1 H), 6.99 (dt J = 7.9 Hz1 1 H), 6.62-6.65 (m, 2 H), 4.21 <m, 1 H), 3.77 (s, 3 H), 2.85-2.90 (m, 4 H), 2.70-2.76 (m, 4 H), 1.44<d, J= 6.7 Hz1 3H); MS<ES) m/z: 433 (M+H+).
Figure imgf000129_0003
3-{1-J2-(4-Trifluoromethyl-ρhenyl)-thiazol-5-yl]-ethyl}-2,3,4,5-tetrahydr 0-1 H-benzo[c(jazepin-7-ol
Cpd CC4 was prepared according to a similar procedure as for cpd Y2b. Cpd CC4 was obtained (38 mg) in 95% yield: 1H NMR t300 MHz, CDCI3) δ 8.03 (d, J= 8.2 Hz, 2 H), 7.68 <d, J = 8.3 Hz1 2 H), 7.61 (s, 1 H)1 6.94 (d, J= 7.9 Hz1 1 H), 6.55 - 6.S9 (m, 2 H), 4.16 - 4.22 (m, 1 H), 2.84 <m, 4 H), 2.64 - 2,68 (m, 4 H), 1.44 <d, J = 6.6 Hz, 3H); MS (ES) m/z: 419 (M+H+), 417 (M-H+).
Figure imgf000130_0001
CC5 was prepared according to a similar procedure as for cpd Y2c. Cpd CC5 was obtained (23 mg) in 70% yield: 1H NMR(300 MHz, CDCI3) δ 8.03 (d, J= 8,2 Hz, 2 H), 7.68 (d, J = 8.2 Hz, 2 H), 7.61 (s, 1 H), 7.00 (d, J = 8.1 Hz, 1 H), 6.69 (d, J = 2.5 Hz1 1 H), 6.60 - 6.64 <dd, J= 2.6, 8.2 Hz, 1 H), 4.57 (s, 2 H), 4.11 - 4.30 (m, 3 H), 2.86 (m, 4 H), 2.69 (m, 4 H), 1 ,44 (d, J = 6.6 Hz, 3H), 1.23 - 1.31 (m, 3 H); MS (ES) m/z: 505 (M+H+).
Figure imgf000130_0002
29 was prepared according to a similar procedure as for cpd 27. Cpd 29 was obtained (18 mg, 95%) as a white solid: 1H NMR ^SOO MHz, CDCt3) δ 8.03 (d, J = 8.2 Hz, 2 H), 7.75 (S1 1 H), 7.68 (d, J= 8.2 Hz, 2 H), 6.90 (d, J= 8.1 Hz, 1 H), 6.72 (m, 1 H), 6.60 <s, 1 H), 5.15 tm, 1 H), 4.61 <s, 2 H), 3.00 (m, 8 H), 1 ,90 (d, J= 6.6 Hz, 3H); MS (ES) m/z: 477<M+H+).
Example DD
Figure imgf000130_0003
The title compound was made according to Scheme OD.
Scheme DD
Figure imgf000131_0001
Figure imgf000131_0002
3-{1-[5-(4-Trifluoromethyl-phenyl)-thiophen-2-yll-propyl}-2,3,4,5-tetrahydro-1 H-benzo[d]azeptin-7
-o!
Cpd DD1 was prepared fotlowing a similar procedure as for cpd BB1. Crude cpd DD1 was subjected to the same reaction condition as for preparing cpd Z2 and cpd DD2 was obtained {64 mg, 55%) as brown oil: 1H NMR (300 MHz, CDCi3) δ 7.56-7.64 (m, 4 H), 7.21 (d, J = 3.6 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 3.3 Hz, 1 H), 6.49-6.56 (m, 2 H), 3.63 <t, J = 7.7 Hz, 1 H), 2.83-2.92 (m, 4 H), 2.70-2.80 (m, 2 H), 2.54-2.61 (m, 2 H), 1.83-1.99 (m, 2 H), 1.24-1.28 (t, J= 7.2 Hz, 3 H); MS (ES) m/z: 432 (M+H÷).
Figure imgf000132_0001
(3-{1-[5-{4-Trifluoromethyl-phenyI)-thiophen-2-yl3-propyl}-2,3,4,5-tetrahydro-1H-benzotd|a£epin-
7-yloxy)-acetic acid ethyl ester
Cpd DD3 was prepared following the same procedure as for cpd Z3. Cpd DD3 was obtained (50 mg) in 73% yield: 1H NMR (300 MHz, CDCI3) δ 7.56 - 7.64 (m, 4 H)1 7,21 (d, J = 3.6 Hz, 1 H), 6.96 (df J= 8.2 Hz, 1 H), 6.80 (dt J = 3.6 Hz, 1 H), 6.66 (d, J= 2,5 Hz, 1 H), 6.56 - 6.60 dd, J= 2.6, 8.2 Hz1 1 H), 4.55 (S, 2 H), 4.21-4.28 (q, J= 7.1 Hz, 2 H), 3.83 (m, 1 H)12.58 - 2.87 (m, 8 H), 1.81-2.11 (m, 2 H), 1.23 - 1.30 (q, J= 7.0 Hz1 3 H)1 1.01 (t, J= 7.3 Hz, 3 H); MS (ES) m/z: 518 (M+H+).
Figure imgf000132_0002
(3-{1-[5-(4-Trffluoromethyi-phenyl)-thiophen-2-yl]-propyl}-2,3,4,S-tstrahydro-
1 /-/-benzo[c(|azepin- 7-yioxy)-acetic acid
Cpd 30 was prepared according to the same procedure as for<;pd26. Cpd 30 was obtained (17 mg) in 45% yield: 1H NMR {300 MHz1 COCI3) δ 7.52-7.62 (m, 5 H), 7,12 - 7.16 (m, 1 H)1 6.91 - 6.97 (m, 1 H), 6.67 <d, J = 8.3 Hz, 1 H), 6.62 (S, 1 H), 4.65 - 4.76 (m, 1 H), 4.61 <s, 2 H)1 3.56 - 3.85 <m, 4 H)1 2.64 - 2.75 (m, 4 H), 1.90 - 2.O9 (m, 2 H), 0.95 <t, J - 6.8 Hz1 3 H); MS (ES) m/z: 490 (M+H+).
Example EE
Figure imgf000132_0003
Compound 31: {3-|5-{2,4-DichJoro-phenyl)-thiophen-2-ylmethyl]-≤,3,4,5-tetrahydro- 1 W-benzo[cflazepin-7-yloxy}-acetic add The title compound was made according to Scheme E£.
Scheme EE
Figure imgf000133_0001
Figure imgf000133_0002
3-t5-(2,4-Dichloro-phenyi)-thiophen-2-ylmethyl]-7-methoxy -2,3,4,5-tetrahydro-1 H-benzo[φzeptne
To a mixture of cpd G2b (0.15 gt 0,85 mmoϊ), 5-(dichioropheny[)~thio- phene-2-carbaldehyde (0,20 g, 0.78 mmol), CH2CI2 (15 mL) and HOAc <0.05 mL, 0.87 mmol) at room temperature was added NatOAc^BH (0.26 g, 1.17 mmot). The mixture was stirred for 2 days and additional Na(OAc)3BH<0.13 g, 0,59 mmol) was added. After the mixture was continued stirring overnight, it was basified with aqueous NaHCO3 and extracted with CH2CI2. The organic extracts were dried (MgSO4) and cor>centrated. Themide product was purified by column chromatography to give cpd 1ΞE2 {0.25 g, 78%): 1H NMR (300 MHz, CDCl3) 57.39 (m, 2 H), 7.17 (m, 2 H), 6.92 <d, 1 H, J= 7.9 Hz), 6,85 (m, 1 H)1 6.60 (m, 2 H), 3.84 (s, 2 H), 3.7d£s, 3 H), 2,85 (m, 4 H), 2.67 (m, 4 H); MS (ES) m/z: 418, 420 (M+H+).
Figure imgf000134_0001
3-[5-(2,4-Dichloro-phenyl)-thiophen-2-ytmethyl]-2,3,4,5-tetrahydro -1 W-benzo[d]azepin-7-ol
Cpd EE3 was prepared according to the same procedure as for cpd X3. Cpd EE3 was obtained (0.22 g, 91%) as a brown solid: 1H NMR (300 MHz, CD-CI3) δ 7.35 (m, 2 H), 7.15 (m, 2 H), 6.83 <m, 2 H), 6.50 (rn, 2 H), 3.81 (S1 2 H), 2.80 (m, 4 H), 2.64 (m, 4 H); MS (ES) m/z: 404, 406 {M+H+).
Figure imgf000134_0002
{3-[5-(2,4-Dichloro-phenyi)-thiophen-2-ylmethyl]-2,3,4,5-tetrahydro -1H-benzo[d!azepfn-7-yloxy}-acetic acid ethyl aster
Cpd EE4 was prepared according to the same procedure as for cpd X4. Cpd EE4 was obtained (0.17 g, 65%) as pale oil: 1H NMR <300 MHz, CDCI3) δ 7.39 (s, 1 H), 7.38 (d, J = 11 Hz, 1 H), 7.16 (m, 2 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.81 (d, J= 3.6 Hz, 1 H), 6.61 (d, J= 2.7 Hz, 1 H), 6.54 (dd, J = 8.2, 2.7 Hz, 1 H), 4.51 (s, 2 H), 4.19 (q, J = 7.1 Hz)1 3.80 (s, 2H), 2.83 (m, 4 H), 2.63 (m, 4 H); 1.22 (t, J = 7.1 Hz, 3 H); MS {ES) m/z: 490, 492 <M+H+).
Figure imgf000134_0003
{3-[5~(2,4-Dichloro-phenyI)-thiophen-2-ylmethyl]-2,3,4,5-tetra- hydro-1 H-benzo{α']azepin-7-yloxy}-aceti€ acid
A solution of cpd E€4<0.15 g, 0.31 mmol) in THF (2 mL) and methanol (2 mL) was treated with 1 N aqueous NaOH <0.60 mL, 0.60 mmol). After stirring for 1 h, the mixture was concentrated to dryness. The residue was dissolved in H2O, washed with EtzO twice and then acidified with 1 N HCI. The precipitates were collected and dried to give cpd 31 <0.13 g, 93%). 1H NMR (300 MHz, DMSO-cfe) 57.73 <d, J= 2.1 Hz, 1 H), 7.65 <d, J= 8.5 Hz, 1 H), 7.47 (dd, J= 8.3, 2.2 Hz, 1 H), 7.34 <d, J= 3.6 Hz, 1 H), 7.06 <d, J = 6.5 Hz, 1 H), 7.00 (d, J= 8.3 Hz, 1 H) 6.70 (d, J= 2.5 Hz, 1 H), 6.61 {dd, J = 8.3, 2.6 Hz, 1 H), 4.59 (s, 2 H), 3.95 (s, 2 H), 2.85 (m, 4 H), 2.68 (m, 4 H); MS (ES) m/z: 462, 464 (M+H+).
Example FF
Figure imgf000135_0001
Compound 32: {3-[5-(4-Trifluoromethoxy-phenyl)-thiophen-2-ylmethyl]- 2,3»4,5-tetrahydro-1 H-benzo[c/]azepin-7-yioxy}-acetic acid
The title compound was made according to Scheme FF.
Scheme FF
Figure imgf000136_0001
Figure imgf000136_0002
Cp FF2 was prepared according to the same procedure as for cpd EE2. Cpd FF2 was obtained (0.24 g, 71%) as a solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.8 Hz1 2 H), 7.16 (m, 2 H), 7.05<d, J= 3.6 Hz, 1 H), 6.92 {d, J= 3.6 Hz, 1 H), 6.81 (s, 1 H), 6.56 (m, 2 H), 3.79 <s, 2 H), 3.70 <s, 3 H), 2.83 (m, 4 H)1 2.63 (m, 4 H); MS (ES) m/z: 434 {M+H+).
Figure imgf000137_0001
3-[5-(4-Tπf!uoromethoxy-phenyl)-thiophen-2-ylmethyI]-2,3,4.5 -tetrahydro-1 H-benzo[c/jazepiiv7-ol
Cpd FF3 was prepared according to the same procedure as for cpd EE3. Cpd FF3 was obtained {0.17 g, 74%) as white foam: 1H NMR (300 MHz, CDCI3) 57.51 (d, J= 8.8 Hz, 2 H), 7.13 <d, J = 8.1 Hz1 2 H), 7.05 td, J = 3.6 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 6.80 <d, J = 3.3 Hz, 1 H), 6.50 (m, 2 H), 3.79 (S, 2 H), 2.80 (m, 4 H), 2.63 (m, 4 H); MS (ES) m/z: 420 (M+H+).
Figure imgf000137_0002
{3-[5-(4-Trifluoromethoxy-pheny!)-thiophen-2-ylmethyl3-2,3,4,5-tetra -hydro-1 H-benzo[d|azepin-7-yloxy}-acetic acid ethyl ester
Cpd FF4 was prepared according to the same procedure as for cpd EE4. Cpd FF4 was obtained (0.15 g, 75%) as pate oil: 1H NMR {300 MHz, CDCI3) 67.51 (d, J= 8.8 Hz, 2 H)1 7.11 (d, J= 8.0 Hz, 2 H), 7.04 (d, J= 3.6 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.78 <d, J = 3.6 Hz, 1 H), 6.61 (d, J = 2.7 Hz1 1 H), 6.54 (dd, J= 8.2, 2.7 Hz, 1 H), 4.50 (s, 2 H), 4.17 <q, J= 7.1 Hz)1 3.77 (s, 2 H), 2.81 (m, 4 H), 2.62 <m, 4 H), 1.21 (t, J= 7.1 Hz); MS (€S) m/z: 492 (M+H+).
Figure imgf000137_0003
{3-[5-(4-Trifluoromethoxy-phenyl)-thiophen-2-ylmethyl]-2,3,4,5 -tetrahydro-1 W-benzo[djazepin-7-yloxy}-acetic acid
Cpd 32 was prepared according to the same procedure as for cpd 31. Cpd 32 was obtained (0.08 g, 80%) as a white solid: 1H NMR (300 MHz, DMSO-de) δ 7.74 (d, J= 7.7 Hz, 2 H), 7.39 <m, 3 H), 6.98 <d, J= 2.7 Hz, 1 H)1 6,91 (d, J= 8.1 Hz, 1 H), 6.57 (s, 1 H), 6.49 <d, J = 8.1 Hz, 1 H), 4.02 (s, 2 H), 3.82 (S, 2 H), 2.77 (m, 4 H), 2.60 (m, 4 H); MS(ES) m/z: 478 (M+H+).
Example GG
Figure imgf000138_0001
The title compound was made according to Scheme GG .
Scheme GG
Figure imgf000138_0002
Figure imgf000139_0001
3-[5-<2,4-Dichloro-phenyl)-furan-2-ylmethyl]-7-methoxy-2,3,4,S -tetrahydro-1 H-benzo[o(|azepine
To a mixture of cpcl G2b (0.17 g, 0.96 mmol), 5-{2,4-dichlorophenyl)- furan-2-carbalclehyde (0.20 g, 0.83 mmol), CH2CI2 (15 mL) and HOAc (0.05 ml_, 0.87 mmol) at room temperature was added Na(OAc)3BH <0.30 g, 1.37 mmol). After the mixture was stirred overnight, it was basified with aqueous NaHCO3 and extracted with CH2CI2. The organic extracts were dried (MgSO4) and concentra-ted. The crude product was purified by column chromatography to give cpd GG2 (0.29 g, 88%): 1H NMR (300 MHz, COCI3) δ 7,69 (d, J = 8.6 Hz, 1 H), 7.35 <d, J= 2.1 Hz), 7.19n<m, 1 H), 6.97 <d, J = 3.4 Hz, 1 H), 6.91 (d, J = 7.9 Hz, 1 H), 6.56 (m, 2H), 6.26 (ά, J= 3.4 Hz, 1 H), 3.74 (s, 2H), 3.69 (s, 3H), 2.84 (m, 4H), 2.66 (m, 4H); MS (ES) m/z: 402, 404 (M+H+).
Figure imgf000139_0002
3-[5-(2,4-Dtchloro-phenyI)-furan-2-ylmethyl3-2,3,4,5-tetrahydro -1 W-benzo[c0azepin-7-oi
A mixture of GG2 (0.28 g, 0.70 mmol), 48% HBr (0.80 mL, 7.07 mmoi) and /T-Bu4NBr (30 mg, 0.09 mmol) in HOAc <0.8 mL) was heated at 100 0C under N2 for 18 h. After cooled to room temperature, the reaction mixture was treated with aqueous K2CO3 till pH 9. The precipitates were<x>Hected, washed with water and dried to give cpd GG3 (0.27 g, 100%) as a beige solid: 1H NMR (300 MHz, DMSO-δ6) δ 9.30 <s, 1 H), 7.91 (dt J= 8.6 Hz, 1 H), 7.77 <d, J= 2.1 Hz, 1 H), 7.60 (dd, J= 8.1 , 2.2 Hz, 1 H), 7.20 <d, J= 3,5 Hz, 1 H), 6.97 (d, J= 8.1 Hz, 1 H), 6.88 (d, J = 3.1 Hz,1 H), 6.60 :(d, J= 2.3 Hz, 1 H), 6.56 (dd, J= 8.1 , 2.3 Hz, 1 H), 4.56 (s, 2 H), 3.10 <m, 4 H), 2.94 (m, 4 H); MS (€S) m/z: 388, 390 (M+H+).
Figure imgf000140_0001
{3-[5-(2,4'Dichloro-phenyl)-furan-2-ylmethyl]-2,3(4!5-tetrahydro -1 H-benzo[c(]azepϊn-7-yloxy}-acetic acid ethyl ester
Cpd GG4 was prepared according to the same procedure as for cpd X4. Cpd GG4 was obtained (65 mg, 54%) as pale oil: 1H NMR<300 MHz, CDCI3) δ 7.69 (d, J = 8.6 Hz, 1 H)1 7.36 (d, J = 2,1 Hz, 1 H)1 7.24 (m, 1 H), 6.97 (d, J= 3.4 Hz1 1 H), 6.91 (d, J= 8.2 Hz, 1 H)16.65 (d, J= 5.01 Hz), 6.57 {dd, J= 8.2, 2.70 Hz, 1 H), 6.29 (d, J= 3.3 Hz1 1 H), 4.50 (S1 2H), 4.19 <q, J = 7.1 Hz, 2H), 3.77 (s, 2 H), 2.85 (m, 4 H), 2.68 (m, 4 H); MS (ES) m/z: 474, 476 (M+H+).
Figure imgf000140_0002
{3-[5-(2,4-DichIoro-phenyi)-furan-2-yimethyI]-2,3,4,5-tetrahydro -1 H-benzo[d]azepin-7-yioxy}-acetic acid
A mixture of cpd GG4 (50 mg, 0.10 mmol) in methanol (2 mi_) was treated with 1 N aqueous NaOH (0.30 ml, 0.30 mmol). After stirring for 1 h, the mixture was concentrated to dryness. The residue was dissolved in H2O and acidified with 1 N HCI. A brown solid was collected and dried to give cpd 33 (32 mg, 70%): 1H NMR (300 MHz, DMSO-cfe) 57.83 (d, J= 8.9 Hz1 1 H)1 7.72 (m, 1 H), 7.55 (m,1 H), 7.13 (d, J= 3.0 Hz1 1 H), 7.03 <d, J = 8.9 Hz1 1 H), 6.72 (S1 1 H), 6.63 (d, J= 6.1 Hz), 4.60 (s, 2 H), 4.61 (S1 2 H)1 3.32 <«, 2H)1 2.80 (m, 8 H); MS (ES) m/z: 446, 448 (M+H+). Example HH
Figure imgf000141_0001
The title compound was made according to Scheme HH.
Scheme HH
Figure imgf000141_0002
Figure imgf000141_0003
Figure imgf000141_0004
Cpd HH2 was prepared according to the same procedure as for cpd GG2. Cpd HH2 was obtained (0.30 g, 90%) as a yellow solid: 1H NMR {300 MHz, CDCI3) δ 7.57 (d, J= 8.8 Hz, 2 H), 7.13 (d, J= 8.2 Hz, 2 H), 6.91 {d, J = 8.2 Hz, 1 H)1 6.56 (m, 2 H), 6.49 (d, J = 3.39 Hz, 1 H), 3.72 (S1 2 H), 3,69 (s, 3 H), 2.83 <m, 4 H), 2.66 (m, 4 H); MS (ES) m/z: 418 (M+H+).
Figure imgf000142_0001
3-[5-(4-Trifluoromethoxy-phenyl)-furan-2-yimethyl]-2,3,4,5-tetrahydro
-1 W-benzotcOazepin-7-oI
A mixture of cpd HH2 (0.28 g, 0.70 mmol), 48% HBr (0.80 mL, 7.07 mmol), H-Bu4NBr (30 mg, 0.09 mmol) and HOAc (0.8 mL) was heated at 100 0C under N2 for 18 h, After cooled to room temperature, the reaction mixture was treated with aqueous K2CO3 till pH 10 and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to provide cpd HH3 {0.26 g, 93%) as a brown solid: 1H NMR (300 MHz, DMSO-S6) δ 9.04 (s, 1 H), 7.76 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 7.6 Hz, 2 H), 6.93 <s, 1 H), 6.85 <d, J - 7.6 Hz, 1 H), 6.50 (S11 H), 6.41 (m, 2 H), 3.71 (s, 2 H), 2.78 <m, 4 H), 2.53 (m, 4 H); MS (ES) m/z: 404 (M+H+).
Figure imgf000142_0002
{S-fS-tΦTrifluoromethoxy-phenyO-furan^-ylmethy^^.S^.S-tetrahydro -IH-benzoIcOazepin-y-yloxyj-acetic acid ethyl ester
Cpd HH4 was prepared according to the same procedure as for cpd X4. Cpd HH4 was obtained (55 mg, 46%) as light brown oil: 1H NMR (300 MHz, CDCI3) δ 7.57 (d, J= 8.7 Hz1 2 H), 7.13 (d, J= 8.4 Hz, 2 H), 6.91 (dd, J = 8.3, 3.3 Hz, 1 H), 6.62 (m, 1 H)1 6.54 (m, 1 H), 6.49 {d, J = 3.0 Hz, 1H), 6.21 (d, J= 3.0 Hz, 1 H), 4.50 <d, J = 5.1 Hz, 2 H), 4.11 <q, J= 7.2 Hz, 2 H), 3.72 (s, 2 H), 2.83 (mf 4 H), 2.68 <m, 4 H); MS {ES) m/z: 490<M+H+).
Figure imgf000143_0001
{3-[5-(4-Trifluoromethoxy-phenyl)-furan-2-ylmethyI]-2,3,4,5-tetrahydro -1 H-benzo[c(]azepin-7-yloxy}-acetic acid
Cpcl 34 was prepared according to the same procedure as for cpd 33. Cpd 34 was obtained {27 mg, 69%) as a light brown solid: 1H NMR <300 MHz, DMSO-δe) δ 7,78 (d, J = 6.1 Hz1 2 H), 7.41 (d, J = 6.1 Hz, 2 H), 7.00<d, J = 6.0 Hz, 1 H), 6.98 (d, J= 3.0 Hz1 1 H), 6.69 (s, 1 H), 6.59 (m, 1 H), 6.47 <s, 1 H), 4.62 {s, 2 H), 3.84 (s, 2 H), 3.33 (m, 4 H), 2.68 (m, 4 H); MS <ES) m/z: 462 (M+H+).
Exampie Il
Figure imgf000143_0002
Compound 35: {3-f5-(4-Chloro-phenyl)-furan-2-ylmethyl]-2,3,4,5-tetrahydro- 1 H-benzoIclazepin-y-yloxyJ-acetic acid
The title compound was made according to Scheme Ii,
Scheme Il
Figure imgf000144_0001
Figure imgf000144_0002
C II2 was prepared according to the same procedure as for cpd X2. Cpd II2 was obtained (0.26 g, 65%) as a brown oif: 1H NMR {300 MHz, CDCI3) δ 7.59 (d, J = 8,9 Hz, 2 H)5 7.35 (d, J = 8.9 Hz, 2 H), 7.02 <d, J = 9.1 Hz, 1 H), 6,67 (m, 1 H), 6.58 (m, 1 H)1 6.29 <d, J = 2.1 Hz1 1 H), 3.81 <s, 2 H), 3.78 (s, 3 H), 2.93 (m, 4 H), 2.75 <m, 4 H); MS <€S) m/z: 366, 368 (M+H+).
Figure imgf000144_0003
A mixture of II2 (0.25 g, 0.68 mmoi), 48% HBr (0,80 mL, 7.07 mmol) and H-Bu4NBr (26 mg, 0.08 mmo!) in HOAc (0.8 mL) was heated at 800C under N2 overnight. After cooled to room temperature, the reaction mixture was treated with aqueous K2CO3 and a brown solid was coiiected and dried (0.11 g, 46%). The aqueous layer was then extracted with CH2CI2. The CHgCb solution was concentrated and purified by column chromatography to give a brown solid (0.04 g) as second batch of the product. Overall, cpd II3 was obtained (0.15 g) in 63% yield: 1H NMR (300 MHz, CD3OD) δ 7.58 <d, J = 8.8 Hz1 2 H), 7.34 (d, J = 9.0 Hz, 1 H), 6.90 (d, J = 6.1 Hz, 1 H), 6.57 {m, 3 H)1 6.31 (d, J = 2.5 Hz, 1 H), 3.78 (s, 2 H)1 2.87 (m, 4 H), 2.73 <m, 4 H); MS (ES) m/z: 354, 356 (M+H+).
Figure imgf000145_0001
{3-[5-(4-ChlorophenyI)-furan-2-ylmethyl]-2,3,4,5-tβtrahydro-1H -benzotcdazepin-y-yloxyl-acetic acid ethyl ester
Cpd J!4 was prepared according to the same procedure as for cpd X4. Cpd II4 was obtained (96 mg, 53 %) as pale oil: 1H NMR {300 MHz1 CDCI3) δ 7.49 (d, J = 8.4 Hz, 2 H), 7.24 (d, J= 8.4 Hz, 2 H)1 6.91 (d, J= 8.0 Hz, 1 H), 6.61 (d, J = 2.4 Hz, 1 H), 6.50 (dd, J = 8.0, 2.5 Hz1 1 H), 6.49 (ύ, J = 2.4 Hz, 1 H), 6.21 (s, 1 H), 4.50 (s, 2 H), 4.20 (q, J= 7.1 Hz)1 3.70 (s, 2 H)1 2.82 (m, 4 H), 2.64 (m, 4 H); MS (ES) m/z: 440, 442 (M+H+).
Figure imgf000145_0002
{3-[5-(4-Chforo-phenyl)-furan-2-yimethyl]-2,3,4,5-tetrahydro-1 H -benzofdlazepin^-yloxyj-acetic acid
Cpd 35 was prepared according to the same procedure as for-cpd 33. Cpd 35 was obtained (70 mg, 95 %) as a light yellow solid: 1H NMR {400 MHz, DMSO-δe) δ 7.74 (d, J= 8.5 Hz, 2 H), 7.51 <d, J= 8.5 Hz, 2 H), 7.06 {<*, J= 8.2 Hz1 1 H), 7.02 <d, J= 2.8 Hz, 1 H), 6.75 (s, 1 H), 6.66 (m, 2 H), 4,61 (s, 2 H), 4.21 (bs, 2 H), 3.00 (m, 8 H); MS (ES) m/z: 412, 414 (M-t-hT).
Example JJ
Figure imgf000146_0001
Compound 36: {3-[3-Methyl-5-(4-trifluoromethyl-phenyl)-furan-2-ylmethyl]- 2,3,4,5-ietrahyd-1 H -benzofcOazepin-T-yloxyJ-acetic acid
The title compound was made according to Schemes JJ1 & JJ2.
Scheme JJ1
Figure imgf000146_0002
Figure imgf000146_0003
Figure imgf000146_0004
7-Hydroxy-1 ,2,4,5-tetrahydro-benzo[c^azepine-3-carboxyiic acid tert-butyl ester
A mixture of G2b (0.26 g, 1.47 mmoi), 48% HBr (1.7 mL, 15 mmol) and H-Bu4NBr (50 mg, 0.16 mmol) in HOAc (1.7 mL) was heated at 1000C under N2 overnight. After cooled to room temperature, the reaction mixture was treated with solid NaOH to pH 9-10. To the resulting mixture was added H2O (5 mLJ, iso-propanol (5 mL), followed by di-f-butyi dicarbonate {0.6 g, 2.8 mmoi). The mixture was stirred at room temperature overnight and then extracted with EtOAc. The organic extracts were concentrated and the residue purified by column chromato-gramphy to give Cpd JJ 1a as a white solid (0.20 g, 52%): 1H NMR (300 MHz, CDCI3) δ 6.90 (d, J= 6.0 Hz, 1 H)1 6.54 (m, 2 H), 4.52 (bs, 1 H)1 3.46 (m, 4 H), 2.75 (m, 4 H); MS (ES) m/z: 286 (M+Na).
Figure imgf000147_0001
y-Ethoxycarbonylmethoxy-I^Aδ-tetrahydro-benzotdlazepinβ-a-c arboxylic acid terf-butyl ester
Cpd JJIb was prepared according to the same procedure as for cpd EE4. Cpd JJ1b was obtained (0.26 g, 100%) as pale oil: 1H NMR (300 MHz, CDCI3) 66.95 (d, J= 8.9 Hz1 1 H), 6.65 (d, J= 2.0 Hz1 1 H)1 6.56 <m, 1 H), 6.50 (dd, J= 8.0, 2.5 Hz, 1 H), 4.52 (S1 2 H), 4.19 (q, J= 7.1 Hz1 2 H), 3.47 (m, 4 H)1 2.76 (m, 4 H)1 1.23 (t, J= 7.1 Hz1 3 H); MS {ES) m/z: 372 <M+Na).
Figure imgf000147_0002
[3-(2,2,2-TrifIuoro-acetyl)-2!3,4J5-tetrahydro-1W-benzoIc0azeptn-7-yIoxy] -acetic acid ethyl ester trifluoroacetate
A mixture of cpd JJ1 b {0.26 g, 0.76 mmol) and TFA (1.0 mL, 1.3 mmol) in CH2Ci2 (1 mL) was stirred at room temperature under N2 for 1 h. The reaction mixture was concentrated and the resulting residue was washed with Et2O, concentrated to give cpd JJ 1c {0.17 g, 100% crude yield). 1H NMR (300 MHz1 CDCI3) δ 6.99 (m, 1 H)1 6.62 (m, 2 H)1 6.56 (m, 1 H), 5.56 (bs, 1 H), 4.61 (S1 2 H), 4.19 (m, 2 H), 3.18 {m, 4 H), 3.04<m, 4 H), 1.19 (m, 3H); MS (ES) m/z: 250 {M+H÷). Scheme JJ2
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0003
3-Methyl-5-(4-trifluoromethyI-phenyl)-furan-2-carboxyiic acid methyl ester
Cpd JJ2 was prepared using a similar procedure as for cpd G 1a. Cpd JJ2 was obtained (1.17 g, 70%) as a white solid: 1H NMfξ (300 MHz, CDCl3) δ 7,78 (d, J = 8.2 Hz, 2 H), 7.58 <d, J = 8.2 Hz5 2 H), 6.«5<s, 1 H), 3.86 <s, 3 H), 2.34 (s, 3 H); MS (ES) m/z: 285 (M+H+).
Figure imgf000149_0001
[3*Methyi-5-(4-trifluoromethyl-phenyl)-furan-2-yl3-methanot To a solution of cpd JJ2 (1.17 g, 4.11 mmol) in THF ^25 mL) at O 0C under N2 was added UAIH4 (1.0 M, 2.7 mL). After stirring for 1 h, the mixture was quenched with aqueous NH4Cl solution and then extracted with EtOAc. The organic phase was dried (MgSO4) and concentrated to provide cpd JJ3 (0.95 g, 91%) as a white solid: 1H NMR (300 MHz, CDCI3) δ 7.65 (d, J= 8.3 Hz, 2 H), 7.53 (d, J = 8.3 Hz1 2 H), 6.54 (s, 1 H), 4.58 <s, 2 H), 2.04 (s, 3 H); MS (ES) m/z: 239 (M-OH").
Figure imgf000149_0002
3-Methyl-5-(4-trifluoromethyl-phenyf)-furan-2-carbaldehyde
A mixture of cpd JJ3 (0.13 g, 0.51 mmo!) and MnO2 (0.87 g, 10.0 mmol) in CH2CI2 (16 mL) was stirred at room temperature overnight, MnOa was removed by filtering the mixture through Ceiite. The filtrate was concentrated and purified by column chromatography to give cpd JJ4<0.11g, 85%) as a white solid. 1H NMR (300 MHz, CDCI3) 59.76 <s, 1 H), 7.82 <d, J = 8.2 Hz, 2 H)1 7.62 (d, J = 8.2 Hz1 2 H), 6.72 (s, 1 H)1 2.38 <s, 3 H).
Figure imgf000149_0003
{3-E3-Methyl-5-(4-trifluoromethyl-phenyl)-furan-2-ylmethy!]-2,3,4,S-tetrahydro-1H -benzofcdazepin-y-yloxyl-acetic acid ethyl -ester
Cpd JJ5 was prepared according to the same procedure as for cpd X2. Cpd JJ5 was obtained (40 mg, 45%) as a brown oil: 1H NMR<300 MHz, CDCI3) δ 7.71 (d, J= 8.2 Hz, 2 H), 7.61 (d, J= 8.2 Hz, 2 H), 7.00 <d, J = 8.2 Hz), 6.71 (d, J= 2.6 Hz, 1 H)1 6.63 (dd, J= 8.2, 2.7 Hz, 1 H), 6.60 <s, 1 H), 4.59 (S, 2 H), 4.27 (q, J= 7.1 Hz, 2 H), 3.80 (bs, 2 H)1 2.94 (m, 4 H), 2.75 (m, 4 H), 2.09 (3 H), 1.30 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 488 (M+H+).
Figure imgf000150_0001
{3-[3-Methyl-5-(4-trifluoromethyl-phenyl)-furan-2-ylmethyl3-2,3,4,5-tetrahyd- 1 H -benzo[c/)azepin-7-yloxy}-acetic acid
Cpd 36 was prepared according to the same procedure as for cpd 31. Cpd 36 was obtained (25 mg, 68%) as a light brown solid: 1H NMR {300 MHz, DMSO-δe) δ 7.83 (d, J= 8.2 Hz, 2 H), 7.75 (d, J= 8.2 Hz, 2 H), 7.00 (m, 1 H), 6.69 (d, J= 2.5 Hz, 1 H), 6.60 (dd, J= 8.2, 2.6 Hz, 1 H)1 4.S8 (s, 2 H), 3.75 (S, 2 H), 2.82 (m, 4 H), 2.64 (m, 4 H), 2.05 <s, 3 H); MS (ES) m/z: 460 (M+H+).
Exampie KK
Figure imgf000150_0002
Compound 37: 1 -{3-[5-{4-Trif luoromethyl-phenyl)-thiophen-2-ylmethyl]- 2,3,4,5-tetrahydro-1 W-benzo[djazepin-7-yloxy}-cyciopropanecarboxyltc acid
The title compound was made according to Scheme KK. Scheme KK
Figure imgf000151_0001
Figure imgf000151_0002
3-{3- [5- (4-Trif luoromethy l-pheny l)-th iophen -2~ylmethyl]-2 ,3,4 ,5-tetrahydro -1 H-benzoI^azepin-7-yloxy}-dihydro-furan-2-one
A mixture of 3-bromo-dihyclro-furan-2-one (0.62 ml_, 6.45 mmoi), cpd G2d (1 ,0 g, 2.48 mmol) and potassium carbonate {1.49 g, 9.33 mmol) in 2- butan-one (25 ml.) was heated at reflux for 6 h. After removing solvents, the residue was partitioned between H2O and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4) and purified by column chromato-graphy to give cpΦKKI (0.39 g, 32%) as a brown oil. 0.45 g of cpd G2d was recovered. 1H NMR -(300 MHz, CDCI3) δ 7.70 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz1 2 H)1 7.27 <m, 2 H), 7.03 <d, J = 8.0 Hz1 1 H), 6.92 (m, 1 H), 6,79 (m, 2 H), 4.92 <t, J= 7.8 Hz, 1 H), 4.53^m, 1 H), 4.37 (m, 1 H), 3.89 (s, 2 H), 2,92 (m, 4 H), 2.72 <m, 4 H), 2.66 (m, 1 H), 2.46 (m, 1 H); MS (ES) m/z: 404 (M+H+).
Figure imgf000152_0001
4-Hydroxy-2-{3-[5-(4-trifIuoromethy[-pheπyl)-fliiophen-2-ylmethyl]-2,3,4,S -tetrahydro-1 W- benzof c(jazepin-7-yloxy}-butyric acid methyl ester
To a solution of cpd KK1 (0.35 g, 0.72 mmol) in MeOH (7.2 ml_) at room temperature was added NaOMe (0.5 M in MeOH, 1.44 ml_, 7.2 mmol). The resulting mixture was stirred at room temperature for 30 min and quenched with aqueous NH4CI. The mixture was extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated. The^rude product was purified by column chromatography to give cpd KK2 tθ.25 g, 66%) as oil: 1H NMR (300 MHz, CDCI3) δ 7.60 (d, J = 8.3 Hz, 2 H), 7.53 (d, J= 8.3 Hz, 2 H), 7.16 (d, J= 3,6 Hz1 1 H), 6.90 (d, J= 8.2 Hz, 1 H), 6.83 <m, 1 H), 6.61 (S1 J= 2.6 Hz, 1 H), 6,52 (dd, J= 8.2, 2.7 Hz, 1 H), 4.77 (t, J = ϋ.2 Hz, 1 H), 3.79 (m, 4 H)1 3.69 (S1 3 H), 2.82 (m, 4 H), 2.63 (m, 4 H), 2.11 <m, 1 H), 1 ,63 (m, 1 H); MS (ES) m/z: 520 (M+H+).
Figure imgf000152_0002
4-Methanesulfonyioxy-2-{3»|5-(4-trifIuoromethyl-phsny])-thiophen-2-ylrnethyl] -2,3,4,5-tetrahydro-1 H-benzofdjazβpin-7-yloxy}-butyrtc acid methyl ^ester
To a solution of cpd KK2^0.23 g, 0.44 mmol), methanesulfonyl chloride (38 nL, 0.49 mmol) in CH2CI2 (13 mL) at room temperature was added Et3N (68 μl_, 0.49 mmol) and the resulting mixture was stirred for 1 h. It was partitioned between H2O and CH2Cb and the aqueous layer was extracted with CH2CI2. The combined organic layers were dried (MgSθ4) and concentrated. The crude product was purified by column chromatography to give cpd KK3 (0.18 g, 69%) as pale oil: 1H NMR (300 MHz1 CDCI3) δ 7.60 (d, J = 8.3 Hz, 2 H), 7.53 (d, J= 8.3 Hz1 2 H), 7.17 <m, 2 H), 6.90 (d, J = 8.2 Hz, 1 H), 6.83 (m, 1 H), 6.61 (s, J = 2.6 Hz, H), 6.52 (dd, J = 8.2, 2.7 Hz, 1 H), 4.77 (t, J = 6.2 Hz1 1 H), 3.79 (m, 4 H)1 3.69 <s, 3 H), 2.82 (m, 4 H), 2.63 (m, 4 H), 2.11 (m, 1 H), 1.63 (m, 1 H); MS (ES) m/z: 520 (M+H+),
Figure imgf000153_0001
1-{3-[5-(4-TrifIuoromethyi-phenyl}-thiophen-2-yimethyl]-2,3,4,S-tetrahydro-1H -benzo[ύϋazepin-7-yloxy}-cyclopropanecarboxyiic acid methyl ester
To a solution of cpd KK3 (0.18 g, 0.30 mmol) in THF (10 mL) at 00C under N2 was added f-BuOK (1 M in THF, 0.30 mL) in a dropwise fashion. The resulting mixture was stirred at 0 0C for 1 h, acidified with 1 N HCI til! pH 4 and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by column chromatography to give cpd KK4 (62 mg, 55%) as pale oil. 1H NMR <300 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz1 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.27 <m, 2 H), 6.99 (d, J = 7.8 Hz, 1 H)1 6.65 (m, 2 H)1 3.89 (s, 2 H)1 3.74 (s, 3 H), 2.91 (m, 4 H), 2.73 (m, 4 H)1 1.61 (m, 2 H), 1.32 (m, 2 H); MS (ES) m/z: 502 (M+H+).
Figure imgf000153_0002
1-{3-[5-(4-Trifluoromethyl-phenyl)-thiophen-2-ylmethyl3-2,3,4,5-t^rahydro -1 tø-benzo[cflazepin-7-yioxy}-cydopropanecarboxylic acid A mixture of cpd KK4 (38 mg, 0.76 mmol) and 1 N NaOH <4.6 ml_) in MeOH (1 mL) was stirred at room temperature oversight. The mixture was concentrated, the residue treated with tartaric acid to pH 3 and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography to give cpd 37 (12 mg, 33%) as beige solid. 1H NMR (300 MHz, DMSO-δe) δ 7.79 (d, J ~ 7.9 Hz, 2 H), 7.68 (d, J= 7.9 Hz, 2 H), 7.48 (m, 1 H)1 6.96 (m, 2 H), 6.56 (m, 2 H), 3.78 (bs, 2 H), 2.75 (m, 4 H), 2.56 (m, 4 H)1 1.41 (m, 2 H)1 1.12 (m, 2 H); MS (ES) m/z: 488 (M+H+).
Example LL
Figure imgf000154_0001
Compound 38: 1 -{3-{5-{4-Trϊfluoromethy!-phenyl)-furan-2-ylmethyl]- 2,3,4,54etrahydro-1H-benzo[φzepin-7-yloxy}-cyclopropanecarboxylic acid
The titfe compound was made according to Schemes LL1 & LL2.
Scheme LL1
Figure imgf000154_0002
Figure imgf000155_0001
7-{2-Oxo-tetrahydro-furan-3-yloxy)-1,2,4,5-tetrahydro -benzoIc/jazepine-S-carboxylic acid tert-butyl ester
Cpcl LL1 was prepared according to the same procedure as for cpd KK1. Cpd LL1 was obtained (0.65 gt 54%) as a white solid: 1H NMR {300 MHz, CDCi3) δ 7.06 (d, J = 8.0 Hz, 1 H), 6.82 (m, 2 H), 4.93 <t, J = 7.7 Hz, 1 H)1 4.53 (m, 1 H), 4.36 (m, 1 H), 3.55 (m, 4 H), 2.87 (m, 4 H), 2.73 <m, 1 H), 2.49 (rn, 1 H), 1.50 (s, 9 H); MS (ES) m/z: 370 (M+Na).
Figure imgf000155_0002
7-(3-Hydroxy-1 -methoxycarbonyl-propoxy)-1 ,2,4,5-tetrahydro -benzoIcflazepine-S-carboxylic acid te/t-butyi ester
Cpd LL2 was prepared according to the same procedure as for cpd KK2. Cpd LL2 was obtained (0.74 g, 62%): 1H NMR (300 MHz, CDCi3) 6 7.01 (d, J = 8.3 Hz, 1 H)1 6.71 (d, J = 2.5 Hz, 1 H), 6.83 <dd, J= 8.3, 2.S Hz, 1 H), 4.87 (t, J= 6.1 Hz1 1 H), 3.89 (t, J = 6.1 Hz, 2 H), 3.78 (s, 3 H), 3.54<m, 4 H), 2.85 (m, 4 H), 2.21 (q, J= 5.9 Hz, 2 H), 1.50<s, 9 H); MS tES) m/z: 402 (M+Na).
Figure imgf000155_0003
7-(3-Methanesuifonyloxy-1 -methoxycarbonyl-propoxy)-1 ,2,4,5 -tetrahydro-benzo[α^azepine-3-carboxylicacid fert-butyl ester
Cpd LL3 was prepared according to the same procedure as for cpd KK3. Cpd LL3 was obtained (0.86 g, 100%) as colorless oil: 1H NMR tSOO MHz, CDCt3) δ δ 7,03 (d, J = 8.3 Hz, 1 H), 6.71 (d, J = 2.7 Hz, 1 H), 6.63 {dd, J= 8.3, 2.7 Hz1 1 H), 4.81 (m, 1 H), 4.47 (t, J= 6.04*2, 2 H), 3.79 (s, 3 H)1 3.53 (m, 4 H), 2.99 (s, 3 H), 2.85 (m, 4 H), 2.39 (m, 2 H), 1.50 (s, 9 H); MS (ES) m/z: 480 (M+Na).
Figure imgf000156_0001
7-{1-Methoxycarbonyl-cyclopropoxy)-1,2,4,5-tetrahydro-benEO[cf]azepine -3-carboxylic acid tert-butyl ester
Cpd LL4 was prepared according to the same procedure as for cpd KK4. Cpd LL4 was obtained {0.49 g, 71%) as a white solid: 1H NMR (300 MHz, CDCI3) δ 7.05 <d, J= 8.0 Hz, 1 H), 6.80 (m, 2 H), 4.93 (t, J= 7.8 Hz, 1 H), 4.53 (m, 1 H), 4.36 (q, J = 7.7 Hz, 2 H), 3.54 (m, 4 H), 2.86 <m, 4 H), 2.71 (m, 1 H)1 2.46 (m, 1 H)1 1.50 (s, 9 H); MS (ES) m/z: 384 {M+Na).
Figure imgf000156_0002
1 -(2,3,4,5-Tetrahydro-i H-benzo[d]azepin-7-yloxy)-cyclopropane- carboxyiic acid methyl ester
A mixture of cpd LL4 (0.50 g, 1.38 mmol) and TFA (0.5 ml_) in CH2Ct2 (5 ml_) was stirred at room temperature for 30 min. After the mixture was concen-trated, the residue was treated with aqueous NaHCOe and extracted with EtOAc. The organic layer was dried (MgSCM) and concentrated to dryness to give cpd LL5 (0.36 g, 100%) as a pale solid: 1H NMR<300 MHz, CDCI3) δ 7.05 (d, J= 8,0 Hz1 1 H)1 6.80 (m, 2 H), 4.93 (t, J= 7.8 Hz, 1 H), 4.53 (m, 1 H), 4.36 (q, J= 7.7 Hz, 2 H), 3.54 (m, 4 H), 2.86 <m, 4 H), 2.71 (m, 1 H), 2.46 (m, 1 H); MS (ES) m/z: 262 (M+H+). Scheme LL2
Figure imgf000157_0001
Figure imgf000157_0002
1-{3-t5-(4-Trifluoromethyl-phenyl)-furan-2-ylmethyl]-2,3,4,5-tetrahydro-1H -benzo[Gflazepin-7-yioxy}-cyctoρroρanecarboxylic acid methyl ester
Cpd LL6 was prepared according to the same procedure as for cpd X2. Cpd MM1 was obtained (25 mg, 68%) as a light brown solid: 1H NWIR (300 MHz, CDCI3) δ 7.75 (d, J = 8.2 Hz, 2 H), 7.62 (d, J = 8.2 Hz, 2 H), 6.98 (d, J = 7.9 Hz, 1 H), 6.71 (d, J= 3.3 Hz1 1 H)1 6.64 (m, 2 H), 6.33 (d, J= 3.3 Hz), 3.83 (S, 2 H), 3.73 (s, 3 H), 2.92 (m, 4 H), 2.75 (m, 4 H), 1.60 <m, 2 H)1 1.31 (m, 2 H); MS (ES) m/z: 486 (M+H+).
Figure imgf000157_0003
1-{3-[5-(4-Trifluoromethyl-phenyl)-furan-2-ylmethyI]-2,3,4,5-t«trahydro-1 H -benzo[c$azepin-7-yloxy}-cyclopropanecarboxylic acid
A mixture of cpd MM1 (20 mg, 0.04 mmoi) and 3N NaOH {0.15 mL) in MeOH (0.5 mL) was stirred at room temperature overnight. After the mixture was concentrated, the residue was dissolved in H2O and washed with EtOAc. The aqueous layer was acidified with dilute tartaric ackJ till pH 3 and a brown solid was collected to give cpd 38 (15 mg, 79%): 1H NMR (400 MHz, DMSO-δe) δ 7.87 (d, J = 8,2 Hz, 2 H), 7.77 (6, J = 8.2 Hz, 2 H), 7.11 <d, J= 3.3 Hz, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 6.65 <d, ** 2.6 Hz, 1 H), 6.59 (dd, J= 8.2, 2.5 Hz, 1 H), 6.49 (d, J= 3.3 Hz, 1 H), 3.79 (S1 2 H), 2.82 <m, 4 H), 2.63 (m, 4 H), 1.47 (m, 2 H), 1.19 (m, 2 H); MS (ES) m/z: 472 (M+H+).
Example NN
Figure imgf000158_0001
The title compound was made according to Scheme NN.
Scheme MM
Figure imgf000158_0002
Figure imgf000158_0003
Cpd MM1 was prepared according to the same procedure as for cpd X2. Cpd MM1 was obtained (0.10 g, 53%) as a light brown solid: 1H NMR (300 MHz, CDCI3) δ 8.06 (d, J= 7.7 Hz, 2 H), 7.71 (m, 3 H), 6.99 <d, J = 8.2 Hz, 1 H), 6.67 (m, 2 H), 3.92 (s, 2 H)1 3.74 (s, 3 H), 2.89 (m, 4 H), 2.71 (m, 4 H), 1 ,63 (m, 2 H), 1.32 (m, 2 H); MS (ES) m/z: 502 (M+H+).
Figure imgf000159_0001
1-{3-[2-(4-Trifluoromethyl-phenyI)-thiazol-5-ylmethyl]-2!3,4,5-tetrahydro-1H -benzo[cfl-azepin-7-yloxy}-cyclopropanecarboxylic acid
A mixture of cpd MM1 (86 mg, 0.17 mmol), NaOH <3N, 0.50 rnL), MeOH (0.5 mL) and THF (0.5 mL) was stirred at room temperature overnight. The mixture was concentrated, the residue dissolved in H2O and washed with Et2θ. The aqueous layer was treated with tartaric acid to pH 3 and a pale solid was collected by filtration to give cpd 39 (66 mg, 80%); 1H NMR (400 MHz, CDCI3) δ 8.02 (d, J = 8.2 Hz1 2 H), 7.74 <d, J = 8.2 Hz, 2 H)1 6.92 (d, J = 8.9 Hz, 1 H), 6.75 (m, 2 H), 4.21 (s, 2 H), 2.91 (m, 4 H), 2.84 (m, 4 H), 1.59 (m, 2 H), 1.25 (m, 2 H); MS (ES) m/z: 489<M+H+).
Example QO
Figure imgf000159_0002
Compound 40: [3-(4'-Trifluoromethyl-biphenyl-4-ylmethyl)- 2,3,4, 5-tetrahydro-1 W-benzo[a]azepin-7-yIoxy3-acetic acid
The title compound was made according to Scheme OO. Scheme OO
Figure imgf000160_0001
Figure imgf000160_0002
4'-TrifluoromethyI-biphenyl-4-carbaldehyde Cpd 001 (688 mg, 79%) was prepared according to a similar procedure as for cpd G1a: 1H NMR (300 MHz, COCI3) δ 10.09 <s, 1 H), 7.99 (d, J= 8.3 Hz1 2 H)1 7.76 <d, J = 8.3 Hz, 2 H), 7.74 <s, 4 H).
Figure imgf000160_0003
3-(4'-Trifluoromethyl-biphenyl-4-ylmethyl)-2)3»4J5-tetrahydro-1 H-benzo[αf|azepin-7-ol Cpd OO3 (62%) was prepared according to a similar procedure as for cpd G2d: 1H NMR (300 MHz, DMSO) δ 9.03 <s, 1 H), 7,89 {ό, J= 8.2 Hz, 2 H), 7.80 <d, J = 8.3 Hz, 2 H), 7.70 (d, J = 8.1 Hz, 2 H), 7.46 {d, J = 8.1 Hz, 2 H), 6.86 (d, J= 8.0 Hz, 1 H)1 6.50 (d, J= 2.3 Hz, 1 H), 6.44-6.47 (dd, J =2.4, 8.0 Hz, 1 H), 3.64 (s, 2 H), 2.74 (br.s, 4 H), 2.56 (br, S, 4 H); MS <ES) m/z: 398.1 (M+H+).
Figure imgf000161_0001
004 (138 mg, 65%) was prepared according to a similar procedure as for cpd G1 b: 1H NMR (300 MHz, CDCi3) δ 7.69 (s, 4 H), 7.56 (d, J= 8.1 Hz, 2 H), 7.46 (d, J= 8.1 Hz, 2 H), 7.00 <d, J = 8.2 Hz1 1 H), 6.69 (d, J= 2.6 Hz, 1 H), 6.60-6.64 (dd, J= 2.6, 8.1 Hz, 1 H), 4.58 <s, 2 H), 4.23- 4.30 (q, J = 7.1 Hz, 2 H), 3.69 <s, 2 H), 2.89 (s, br, 4 H), 2.65 <s, br, 4 H), 1.27-1.32 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 484.0 (M+H+).
Figure imgf000161_0002
40 (125 mg, 100%) was prepared according to a similar procedure as for cpd 7: 1H NMR (400 MHz, DMSO) δ 7.93 (d, J= 8.2 Hz, 2 H), 7.81-7.85 (m, 4 H), 7.66 <d, J = 7.9 Hz, 2 H), 7.07 (d, J= 8.3 Hz, 1 H), 6.76 (d, J= 2.4 Hz, 1 H), 6.67-6.70 (dd, J = 2.4, 8.2 Hz, 1 H), 4.62 ^s, 2 H), 4.25 (s, 2 H), 3.32 (s, br, 4 H), 3.05 (s, br, 4 H); MS {ES) m/z: 456.0 (M+H+), 454.0 (M-H+). Example PP
Figure imgf000162_0001
Compound 41 : {3-[2-(4-Trifluoromethyi-phenyi)-pyrimidtn-4-yfmethyl]-2,3,4,5-tetrahydro- 1 H-benzo[α]azepin-7-yloxy}-acetic acid
The title compound was made according to Scheme PP.
Scheme PP
Figure imgf000162_0002
Figure imgf000162_0003
4-MethyI-2-(4-trifluoromethyl-phenyi)-pyrimidine Cpd PP1 (1.507 g, 86%) was prepared according to similar procedure as for cpd G1a: 1H NMR (300 MHz, CDCI3) δ 8.69 ^J= 5.0 Hz, 1 H), 8.58 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.2 Hz, 2 H), 7.13 (d, J= 5.0 Hz, 1 H), 2.62 (S1 3 H); MS (ES) m/z: 239.1 (M+H+).
Figure imgf000163_0001
2-(4-Trifluoromethyl-phenyl)-pyrimidine-4-carbalctehyde A mixture of cpd PP1 (428 mg, 1.798 mmol), SeO2 <998 mg, 8.991 mmot), dioxane (5 mL) and water (0.16 ml_) was stirred at 1000C for 16 h. After the mixture was cooled to room temperature, it was filtered to remove solids and concentrated under vacuo. The residue was purified by €oiumn chromatography eluting with EtOAc/Hexane to give cpd PPZ <291 mg, 64%) as a white solid: 1H NMR (300 MHz, CDCI3) δ 10.15 (s, 1 H), 9.11 (d, J = 4.8
Hz, 1 H), 8.68 (d, J = 8.1 Hz, 2 H), 7.75-7.81 (m/3 H).
Figure imgf000163_0002
7-Methoxy-3-E2-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]- 2, 3,4 ,5-tetrahyd ro-1 W-benzo[cflazepine
Cpd PP3 (179 mg, 43%) was prepared according to a similar procedure as for cpd G2c: 1H NMR (300 MHz, CDCt3) δ 8.80 \ύ, J = 5.0 Hz, 1 H), 8.56 (d, J= 8.2 Hz, 2 H), 7.73 (d, J= 8.3 Hz, 2 H), 7,57φs, t»r, 1 H), 7.02 (d, J= 7.8 Hz1 1 H), 6.64-6.68 (m, 2 H)1 3.86 <s, 2 H)1 3.78 fβ, 3 H)12.93 (s, br, 4 H), 2.75 (s, br, 4H); MS (ES) m/z: 414.1 (M+H+).
Figure imgf000164_0001
3-[2-(4-Trifluoromethyl-phenyi)-pyrimidin-4-yimethyl]-2,3,4,5-tetrahydro-1H-benzo[d]az epin-7-ol
Cpd PP4 (26 mg, 20%) was prepared according to a similar procedure as for cpd G2d: 1H NMR {300 MHz, CDCI3) δ 8.82 (d, J= 5.0 Hz, 1 H), 8.56 (d, J= 8.2 Hz, 2 H), 7.73 (d, J= 8.3 Hz, 2 H), 7.62 (s, br, 1 H), 6.95 (d, J = 7.8 Hz, 1 H)1 6.58-6.61 (m, 2 H)1 3.93 (s, br, 2 H), 2.94 {s, br, 4 H), 2.81 (S, br, 4 H); MS (ES) m/z: 400.0 (M+H+).
Figure imgf000164_0002
{3-[2-(4-Trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-2,3,4,5-tetrahydro- 1 H-benzo[d|azepin-7-yloxy}-acetic acid ethyi ester
Cpd PP5 (16 mg, 64%) was prepared according to a similar procedure as for cpd G1b: 1H NMR (300 MHz, CDCi3) δ 8.85 (s, br, 1 H), 8.54 (d, J= 8.1 Hz, 2 H), 7.73 <d, J = 8.3 Hz, 2 H), 7.61 ts. br, 1 H), 7.03 {d, J = 8.2 Hz, 1 H), 6.72 (d, J= 2.5 Hz, 1 H), 6.64-6.67 (m, 1 H), 4.59 <s, 2 H), 4.23- 4.30 (q, J = 7.1 Hz, 2 H), 3.92 <s, br, 2 H), 2.80-2.93 (br, 8 H), 1.29 (X, J = 7.1 Hz, 3 H); MS (ES) m/z: 486.1 (M+H+).
Figure imgf000164_0003
{3-[2-{4-TrifIuoromethyl-phenyl)-pyrimidin-4-y!methyl]-2,3,4,5-tetrahydro- 1 H-benzo[c/tazepin-7-yiQxy}-acetic acid
Cpd 41 (10 mg, 70%) was prepared according to a similar procedure as for cpd 7: 1H NMR (400 MHz, DMSO) 68.94 <d, J= 5.0 Hz, 1 H), B.S8 {ύ, J= 8.3 Hz, 2 H), 7.90 <d, J= 8.5 Hz, 2 H), 7.65 <d, J= 5.1 Hz, 1 H), 7.01 <d, J= 8.3 Hz, 1 H), 6,70 <ds J = 2.6 Hz, 1 H), 6.60-6.62 (dd, J= 2.6, 8.2 Hz, 1 H), 4.60 (S, 2 H)1 3.88 (s, 2 H), 2.86 (s, br, 4 H, 2,64£§, br, 4 H); MS (ES) m/z: 458.1 (M+H+), 456.0 (M-H+).
Example NN
Figure imgf000165_0001
The title compound was made according to Scheme NN.
Scheme NN
Figure imgf000165_0002
Figure imgf000165_0003
Figure imgf000166_0001
2-Chloro-6-(4-trifiuoromethyl-phenyl)-pyrazine Cpd NN1 (522 mg, 50%) was prepared according to a similar procedure as for cpd G1a. 1H NMR (300 MHz, CDCI3) 68.97 {s, 1 H)1 8.60 (S, 1 H), 8.15 (d, J = 8.2 Hz, 2 H), 7.78 (d, J = 8.3 Hz, 2 H).
Figure imgf000166_0002
2-(4-Trifluoromethyl-phenyl)-6-vinyl-pyrazine
A mixture of cpd NN1 (106 mg, 0.411 mmol), Pd(PPh3)4 <47 mg, 0,041 mmol), tributylvinyltin (0.18 mL, 0.616 mmol) and toluene (2.0 mL) was refluxed under N2 for 18 h. The mixture was cooled and concentrated. Cpd NN2 was obtained after column chromatography purification asslear oiK98 mg, 95%): 1H NMR (300 MHz, CDCI3) δ 8.92 (s, 1 H)1 8.58 <s, 1 H), 8.20 <d, J= 8.1 Hz, 2 H)5 7.78 (d, J= 8.2 Hz1 2 H)1 6.87-6.97 (m, 1 H), 6.49-6.55 <m, 1 H), 5.70-5.74 (m, 1 H),
Figure imgf000166_0003
6-(4-Trifluoromethyl-phenyl)-pyrazine-2-carbaldehyde A mixture of NN2 (72 mg, 0.288 mmol), THF <2.5 mL), water (2.5 mL), OsO4 (2.5 wt%, 2 drops) and NaIO4 (123 mg, 0.576 mmol) was stirred at r.t. for 18 h. The mixture was poured into aqueous NaHCOe, extracted with CH2CI2. The organic extracts were washed with water, brine, dried (NaBSO4) and concentrated. The residue was purified by column chromatography to give NN3 (60 mg, 83%) as beige solid: 1H NMR (300 MHz, CDCI3) δ 10,25 (S, 1 H), 9.28 (s, 1 H), 9.16 (S, 1 H), 8.25 (d, J = 8.1 Hz, 2 H), 7.83 <d, J = B.2 Hzt 2 H).
Figure imgf000167_0001
{3-f6-(4-Trif!uoromethyl-phenyl)-pyrazin-2-ylmethyl]-2!3,4,5-tetrahydro- 1 H-benzo[<^azepin-7-yioxy}-acetic acid ethyl ester
Cpd NN4 (38 mg, 35%) was prepared according to a similar procedure as for cpd G1b. 1H NMR {300 MHz, CDCi3) δ 8.94 <s, 1 H)1 8.81 (s, 1 H), 8.14 (d, J - 8.1 Hz, 2 H), 7.76 (d, J = 8.3 Hz, 2 H), 7,00<d, J = 8.2 Hz, 1 H), 6.70 (d, J = 2.6 Hz, 1 H), 6.61-6.65 (dd, J = 2.7, 8.2 Hz, 1 H), 4.58 (S, 2 H), 4.23-4.30 (q, J = 7.1 hz, 2 H), 3.94 <s, 2 H), 2.91 (s, br, 4 H), 2.75 (s, br, 4 H), 1.27-1.32 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 486.1 (M+H+).
Figure imgf000167_0002
{3'[6-(4-Trifluoromethyl-phenyi)-pyrazin-2-yImethyl]-2,3,4,5-tetrahydro- 1 H-benzo[d)azepin-7-yloxy}-acetic acid
Cpd 42 (21 mg, 70%) was prepared according to a similar procedure as for cpd 7. 1H NMR (400 MHz, DMSO-αfe) δ 9.40<s, 1 H), 8.894β, 1 H), 8.43 (d, J = 7.6 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.09 <d, J= 5.9 Hz, 1 H), 6.78 (S, 1 H), 6.68 (s, br, 1 H), 5.76 (s, 2 H)1 4.62<s, 2 H), 3.00 (br, 8 H); MS (ES) m/z; 458.1 (M+H+)
Example QQ
Figure imgf000167_0003
Compound 43: {3-[6-(4-Trifluoromethyi-phenyi)-pyrk-in-2-ylmethyi]- 2,3,4,5-tetra-hydro-1 H-benzof_djazepin-7-yloxy}-acetic acid The title compound was made according to Scheme QQ.
Scheme QQ
Figure imgf000168_0001
Figure imgf000168_0002
6-(4-Trifluoromethyl-phenyl)-pyridine-2-carbaldehyde Cpd QQ1 (0.78 g, 58%) was prepared according to the same procedure as for cpd G1a: 1H NMR (300 MHz, CDCI3) δ 10.2 (s, 1 H), 8.25 (d, J= 8.2 Hz, 2 H), 8.02 (m, 3 H), 7.80 (d, J= 8.2 Hz, 2 H); MS(ES) m/z: 284 (M+Na).
Figure imgf000169_0001
(2,3,4,5-Tetrahydro-1 H-benzo[c(|azepin-7-yloxy)-acetic acid ethyl ester
A mixture of cpcf JJ1 b {0.93 g, 2.66 mmol) and TFA (1.10 mL, 14.θ mmol) in CH2CI2 (1.5 mL) was stirred at room temperature under N2 for 21 h. After the mixture was concentrated, the residue was treated with aqueous NaHCθ3 and extracted with EtOAc. The organic layer was dried <MgSO4) and concentrated to give cpd A1b (0.66 g, 100%) as oil: 1H NMR (300 MHz1 CDCl3) δ 7.09 (d, J= 8.2 Hz, 1 H), 6.77 (d, J= 2.5 Hz, 1 H)1 6.71 (<jd, J = 8.2, 2.6 Hz, 1 H), 4.62 (s, 2 H)1 4.30 (q, J= 7.1 Hz, 2 H), 3.27 (m, 4 H), 3.16 (m, 4 H), 1.30 (t, J= 7,1 Hz, 3 H); MS (ES) m/z: 250 (M+H+).
Figure imgf000169_0002
{3-[6-(4-TrifluoromethyI-phenyl)-pyridin-2-ylmethyl]-2,3,4,54etrahydro-1 H -benzotαfjazeptn-y-yloxyj-acetic acid ethyl ester
Cpd QQ2 was prepared according to the same procedure as for cpd X2. Cpd QQ2 was obtained (43 mg, 45%) as an oil: 1H NMR {300 MHz, CDCi3) δ 8.13 (d, J= 8.1 Hz, 2 H), 7.81 (t, J= 7.70 Hz, 1 H)1 7.73 <d, J = 8.1 Hz, 2 H)1 7.65 (d, J= 7.6 Hz, 1 H), 7.58 (d, J= 7.6 Hz, 1 H)1 7.02 <d, J= 8.2 Hz, 1 H), 6.72 (d, J= 2.5 Hz, 1 H), 6.64 (dd, J= 8.1 , 2.6 Hz1 1 H)1 4.60-(S1 2 H), 4.28 (q, J= 7.2 Hz, 2 H)1 3.93 (s, 2 H), 2.94 (m, 4 H), 2.78 (m, 4 H), 2.09 (3 H), 1.30 (t, J= 7.2 Hz, 3 H); MS (ES) m/z; 485 (M+H+).
Figure imgf000169_0003
{3-[6-(4-Trifluoromethyl-phenyl)-pyridin-2-yImethyl]-2,3,4,5-tetra- hydro-1 H-benzo[c/]azepin-7-yloxy}-acetic acid Cpd 43 was prepared according to the same procedure as for cpd 7. Cpd 43 was obtained (31 mg, 94%) as an off-white solid: 1H NMR (400 MHz, DMSO-de) δ 8.30 (d, J= 8.1 Hz, 2 H), 7.95 <m, 2 H), 7.86 {ό, J= 8.2 Hz, 1 H), 7.58 (m, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.69 (d, J = 2.3 Hz1 1 H), 6.61 (dd, J = 8.2, 2.5 Hz, 1 H), 4.60 (s, 2 H), 3.87 (s, 2 H), 2.84 <m, 4 H), 2.67 (m, 4 H); MS (ES) m/z: 457 (M+H+),
Example RR
Figure imgf000170_0001
Compound 44: {3-[5-(4-Methoxy-phenyi)-furan-2-ylmethyl3-2,3,4,5- -1 H-benzo[d3azepin-7-yloxy}-acetic acid
The title compound was made according to Scheme RR.
Scheme RR
Figure imgf000170_0002
Figure imgf000171_0001
{3-[5-(4-Methoxyphenyl)-furan-2-ylniefnyl3-2,3,4,5-tetrahydro-1 H -benzotαjazepin-T-yloxyJ-acetic acid ethyl ester
Cpd RR1 was prepared according to the same procedure as for cpd X4. Cpd RR1 was obtained (65 mg, 68 %) as yellow oil: 1H NMR (400 MHz, CDCI3) δ 7.49 (d, J = 8.9 Hz, 2 H), 6.90 (d, J = 8.2 Hz, 1 H), 6.82 <d, J = 8.9 Hz, 2 H), 6.60 (d, J- 2.7 Hz, 1 H), 6.57 (dd, J= 8.2, 2.7 Hz1 1 H), 6.35 <d, J = 3.2 Hz, 1 H), 6.17 (d, J= 3.2 Hz, 1 H), 4.49<s, 2 H), 4.18 (q, J= 7.2 Hz, 2 H), 3.75 (S, 3 H), 3.71 (s, 2 H), 2.83 (m, 4 H), 2.65 <m, 4 H), 122 (t, J = 7.2 Hz, 3 H); MS (ES) m/z: 436 (M+H+).
Figure imgf000171_0002
{3-[5-(4-Methoxy-phenyl)-furan-2-ylmethyi]-2,3,4,5-tetrahydro-1W -benzotφzepin-7-yloxyJ-acetic acid
A solution of cpd RR1 (55 mg, 0.13 mmol) in methanol <2 rriL) was treated with 1 N aqueous NaOH (0.26 ml_, 0.26 mmol). After stirring overnight, the mixture was concentrated to dryness. The residue was dissolved in H2O, washed with Et2O twice and then acidified with 1 N HCI. The acidic solution was extracted with EtOAc. The organic extracts were dried and concentrated to give cpd 44 (42 mg, 82 %) as a yellow solid: 1H NIvIR (300 MHz, CDCI3) δ 7.46 (d, J= 8.8 Hz, 2 H), 6.92 <d, J= 7.3 Hz, 1 H), 6.85 (d, J= 8.8 Hz, 2 H), 6.62 (m, 2 H), 6.57 (d, J= 3.3 Hz, 1 H), 6.43<d, J = 3.3 Hz, 1 H), 4.56 (s, 2 H), 4.34 (s, 2 H), 3.76 (S1 3 H)1 3.63 <m, 4 H), 2.70 (m, 4 H); MS (ES) m/z: 408 (M+H+). Example SS
Figure imgf000172_0001
(3-{2-[5-(4-Trifluoromethyl-phenyi)-furan-2-yl]-ethyI}-2,3,4,5-tetrahydro- 1 H-benzo[c(!azepin-7-yloxy)-acetic acid
The title compound was made according to Scheme SS.
Scheme SS
Scheme SS
Figure imgf000172_0002
Figure imgf000173_0001
(5-Bromo-furan-2-yi)-acetic acid ethyl ester
Cpd SS 1 (765 mg, 52%) was prepared using the same procedure as for cpd V1. 1H NMR (400 MHz1 CDCi3) δ 6.25 (d, J= 3.2 Hz, 1 H), 6.22 <d, J = 3.2 Hz, 1 H), 4.16-4.22 (q, J= 7.1 Hz, 2 H)1 3.65 (s, 2 H)1 1.24-1 ,29 (t, J = 7.2 Hz, 3 H).
Figure imgf000173_0002
[5-(4-Trifluoromethyl-phenyI)-furan-2-yi]-acetic acid ethyl ester
Cpd SS2 (448 mg, 46%) was prepared using the same procedure as for cpd V2. 1H NMR (300 MHz, CDCI3) δ 7.72 (d, J= 8.2 Hz, 2 H), 7.60 (d, J = 8.3 Hz, 2 H), 6.71 (d, J= 3.3 Hz, 1 H), 6.35 (d, J = 3.3 Hz, 1 H), 4,18-4.25 (q, J= 7.2 Hz, 2 H), 3.76 (S1 2 H)1 1.27 - 1.31 {t, J = 7.1 Hz, 3 H); MS (ES) m/z: 299.1 (M+H+).
Figure imgf000173_0003
2-[5-(4-Trifluoromethyl-phenyl)-furan-2-yI]-ethanol
Cpd SS3 (249 mg, 69%) was prepared using the same procedure as for cpd V3. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J= 8.1 Hz, 2 H), 7.61 <d, J = 8.1 Hz, 2 H), 6.70 (d, J = 3.3 Hz, 1 H), 6.24 - 6.25 {m, 1 H), 3.96 (t, J= 6.2 Hz, 2 H), 2.99 (t, J = 6.2 Hz, 2 H).
Figure imgf000174_0001
[5-(4-Trifluoromethyl-phenyl)-fυran-2-yl3-acetaldehycle Cpd SS4 {144 mg, 60%) was prepared using the same procedure as for cpd V4. 1H NMR (300 MHz, CDCI3) δ 9.79 (t, J = 2.ϋ Hz, 1 H), 7.73 <d, J = 8.2 Hz, 2 H)1 7.62 (d, J = 8.4 Hz, 2 H)1 6.75 (d, J ~ 3.3 Hz, 1 H), 6.38 <d, J = 3.3 Hz, 1 H)1 3.81 (d, J- 1.9 Hz, 2 H).
Figure imgf000174_0002
7-Methoxy-3-{2-[5-(4-trifluoromethyi-pheny!)-furan-2-yl]-ethyl}-2,3,4,S-tetrahydro-1W-tenzo(αjaz epine
Cpd SS5 (81 mg, 37%) was prepared using the same procedure as for cpd G2c. 1H NMR (300 MHz1 DMSO-cfe) δ 7.84 <d, J = 8.2 Hz, 2 H)1 7.74 (d, J= 8.4 Hz1 2 H), 7.05 (d, J= 3.3 Hz, 1 H)1 7.01 (d, J= 8.2 Hz, 1 H)1 6,70 (d, J= 2.6 Hz, 1 H)1 6.62 - 6.65 (d, J= 8.1 Hz, 1 H), 6.34 (d, J= 3.2 Hz1 1 H), 3.70 (S1 3 H), 2.76 - 2.88 (m, 8 H), 2.51 - 2.65 <m, 4H); MS (ES) m/z: 416.2 (M+H+).
Figure imgf000174_0003
3-{2-[5-(4-Trifluoromethy)-phenyl)-furan-2-yl]-ethyl}-21314,5-tetrahydro- 1 H-benzo[α5azepin-7-ol
Cpd SS6 (15 mg, 20%) was prepared using the same procedure as for cpd G2d. 1H NMR (400 MHz, CDCi3) δ 7.60 - 7.68 <m, 4 H), 6.97 - 7.00 (m, 1 H)1 6.63 - 6.69 (m, 3 H)1 6.32 <ds J= 3.1 Hz, 1 H), 3.70 - 3.91 <m, 4 H), 3.41 - 3.49 (m, 4 H)1 2.78 - 2.86 <m, 4 H); MS (ES) m/z: 402.1 (M+H+).
Figure imgf000175_0001
(3-{2-[5-(4-Trifluoromethyl-phenyl)-furan-2-yl]-ethy!}-2,3,4,5-tetrahydro- 1 H-benzo[c/|azepin-7-yloxy)-acetic acid ethyl ester
Cpd SS7 (10 mg, 55%) was prepared using the same procedure as for cpd G1 b. 1H NMR {300 MHz, CDCi3) δ 7.68 (d, J= 8.6 Hz, 2 H), 7.59 - 7.62 (m, 2 H), 7.04 (d, J = 7.9 Hz, 1 H), 6.72 <s, 1 H), 6.68 <d, J - 3.3 Hz, 2 H), 6.28 (br, 1 H), 4.59 (s, 2 H), 4.23 - 4.31 (q, J = 7.1 Hz12 H), 2,87 - 3.41 (m, 12 H), 1.30 (t, J = 7.1 Hz, 3 H); MS (ES) m/z; 488.1 (M+H+).
Figure imgf000175_0002
(3-{2-[5-(4-Trifluoromethyl-phenyl)-furan-2-yI]-ethyI}-2,3,4t5-tetrahydro- 1 H-benzo[άf|azepin-7-yloxy)-acetic acid
Cpd 45 (6 mg, 60%) was prepared using the same procedure as for cpd 7. 1H NMR (400 MHz, MeOD) δ 7.83 <d, J= 8.3 Hz, 2 H), 7.67 <d, J= 8.2 Hz, 2 H), 7,11 (d, J= 8.2 Hz1 1 H)1 6.91 (d, J= 3.2 Hz1 1 H)1 6.76 - 6.81 <m, 2 H)1 6.42 (d, J= 3.0 Hz, 1 H), 4.57 <s, 2 H), 3.53 - 3.59 (m, 2 H), 3.43 (m, 2 H), 3.09 - 3.15 (m, 8 H); MS (ES) m/z: 460.0 (M+H+), 458.1 (M-H+).
Example TT
Figure imgf000175_0003
Compound 46: {3-[6-(4-Trifluoromethyl-phenyl)-pyridtn-3-yImethylJ- 2,3,4, 5-tetrahydro-1 H-benzo[d]azepin-7-yJoxy}-acetic acid
The title compound was made according to Scheme TT. Scheme TT
Figure imgf000176_0001
Figure imgf000176_0002
6-(4-TrifIuoromethyl-phenyl)-pyridine-3-carbaiclehycle
Cpd TT 1 (498 mg, 63%) was prepared using the same procedure as for cpd G1a. 1H NMR (300 MHz, CDCI3) δ 10.18 (s, 1 H), 9.18 (d, J= 1.5 Hz, 1 H), 8.29 - 8.33 (dd, J = 2.1 , 8.2 Hz, 1 H), 8.22 (d, J = 8.1 Hz, 2 H), 7.97 <d, J= 8.2 Hz, 1 H), 7.78 (d, J= 8.2 Hz, 2 H).
Figure imgf000176_0003
C TT2 (47 mg, 24%) was prepared using the same procedure as for cpd G 1b. 1H NMR (300 MHz, CDCI3) δ 8.66 (s, 1 H), 8.12 (d, J = 8.2 Hz, 2 H), 7.71 ~ 7.82 {mt 4 H), 6.99 (d, J = 8.1 Hz, 1 H), 6.69^(d, J= 2.5 Hz, 1 H), 6.61 - 6.65 <dd, J= 2.5, 8.2 Hz, 1 H), 4.58 (s, 2 H), 4.23 - 4.30<q, J= 7.1 Hz, 2 H), 3.70 (S, br, 2 H), 2.88 (s, br, 4 H)1 2.65 (s, br, 4 H), 1.29 (t, J= 7.1 Hz, 3 H); MS (ES) m/z: 485.1 (M+H+).
Figure imgf000177_0001
{3-[6-(4-Trifiuoromethyl-phenyl)-pyridiπ-3-ylmethyl]-2!3!4,5-tetrahydro- 1 W-benzoIcQazepin-y-yloxyl-acetic acid
Cpd 46 (28 mg, 70%) was prepared using the same procedure as for cpd 7. 1H NMR (400 MHz, DMSO-cfe) δ 8.87 (s, 1 H), 8.35 (d, J= 8.2 Hz, 2 H), 8.20 (s, 2 H)1 7.89 (d, J = 8.3 Hz, 2 H)1 7.09 (d, J = 8.3 Hz, 1 H), 6.79 <d, J = 2.4 Hz1 1 H), 6.69 - 6.72 (dd, J = 2.5, 8.3 Hz, 1 H), 4.63 <s, 2 H), 4.45 <s, br, 2 H), 2.98 (br, 8 H); MS (ES) m/z: 457.0 (M+H+), 455.1 (M-H+).
Example UU
Figure imgf000177_0002
Compound 47: [3-(4'-Trifluoromethyl-biphenyl-3-ylmethyl)-2,3,4,5-tetrahydro -1 H-benzo[c(jazepin-7-yloxy3-acetic acid
The title compound was made according to Scheme UU. Scheme UU
Figure imgf000178_0001
Figure imgf000178_0002
To mixture of cpd O02 (0.10 g, 0.40 mmof), 3-(4-trifluoromethyl- phenyl)-benzaldehyde (0.15 g, 0.59 mmol), CH2CI2 (10 ml_) and HOAc (0.02 mL, 0.35 mmol) at room temperature was added Na<OAc)3BH (0.13 g, 0.58 mmol). After the mixture was stirred overnight, additional Na(OAc)3BH (0.06 g, 0.27 mmol) was added. The mixture was stirred at r.t. overnight and heated at reflux for 30 min. After cooled to room temperature, it was basif Jed with aqueous NaHCO3 and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated. The crude product was purified by column chromatography to give cpd UU1 (70 mg, 37%): 1H NMR (300 MHz1 CDCI3) δ 7.72 (m, 4 H), 7.61 (s, 1 H), 7.51 <m, 1 H), 7.43<m, 2 H), 7.01 <d, J = 8.2 Hz, 1 H), 6.71 (d, J= 2.7 Hz, 1 H), 6.64 <dd, J = 8.2, 2.7 Hz, 1 H), 4.60<s, 2 H), 4.28 (q, J= 7.2 Hz, 2 H), 3.72 (s, 2 H), 2.90 <m, 4 H), 2.67 <m, 4 H), 1.32 (t, J= 7.2 Hz, 3 H); MS (ES) m/z: 484 (M+H+).
Figure imgf000179_0001
[3-{4'-Trifluoromethyl-biphenyl-3-ylmethyl)-2,3,4,5-tetrahydro -1 H-benzo[c(]azepin-7-yloxy]-acetic acid
Cpd 47 was prepared according to the same procedure as for cpd 31. Cpd 47 was obtained (41 mg, 69 %) as a beige solid: 1H NMR <300 MHz, DMSO-Cy6) δ 7.92 (d, J = 8.2 Hz, 2 H), 7.84 (m, 3 H), 7.72 (d, J= 7.3 Hz, 1 H), 7.55 (m, 2 H)1 7.04 (d, J = 8.3 Hz, 1 H), 6.72 (d, J= 2.1 Hz1 1 H), 6.65 <d, J= 8.3 Hz, 1 H), 4.61 (s, 2 H), 3.99 (bs, 2 H), 2.81 (m, 8 H); MS (ES) m/z: 456 (M+H+).
Compounds 1 through 47 of Formula (I) in Table 1 were prepared according to the methods described by the Schemes and Examples described herein.
Table 1 , Representative Compounds
Figure imgf000179_0002
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Biological Examples
Example 1 Transaction assay method for PFAB α, γ or δ receptors
HEK293 cells were grown in DMEM/F12 medium supplemented with 10% FBS and giutamine (invitrogen) and incubated in a 5% CO2 incubator at 37QC. The cells were co-transfected using DMRIE-C reagent (Invitrogen} in serum free medium (Opti-MEM, Invitrogen) with two mammalian expression plasmids, one containing the DNA sequence coding for the ligand binding domains of either PPARα, γor δ fused to the yeast GAL4 DNA binding domain and the other containing the promoter sequence of the yeast GAL4 (UAS) fused to the firefly luciferase cDNA reporter. The next day, the medium was changed to DMEM/F12 medium supplemented with 5% charcoal treated serum (Hyclone) and giutamine. After 6 hrs the cells were trypsinized and seeded at a density of 50,000 cells/weli into 96 well plates and incubated overnight as above. The celts were then treated with test compounds or vehicle and incubated for 18-24 hrs as above. Luciferase reporter activity was measured using the Steady-Glo Luciferase Assay Kit from Promega. DMRlE-C Reagent was purchased from GIBCO Cat. No.10459-014. OPTI-MEM I Reduced Serum Medium was purchased from GIBCO (Cat. No. 31985). Steady-Glo Luciferase Assay Kit was purchased from Promega (Part# E254B).
A variety of example compounds have been made and tested, with a range of in vitro results. Below, in Table 2, are representative compounds and data; in some cases, where multiple €Cso's are shown, multiple measurements were taken. Naturally, different compounds in Formula (I) may have not activities identical to any one compound betow.
Table 2. In vitro data of PPARdelta agonists
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Example 2 Rat Study of Compound 7
Figure imgf000191_0001
Rats carry the majority of serum cholesterol in the HOL lipoprotein fraction while humans carry the majority of serum cholesterol in LDL and VLDL lipoproteins. To mimic a human hypercholesterolemic state in a rodent model, Sprague Dawley rats were fed a diet high in cholesterol (Research Diets, C13002) for 6 days before treatment with the compounds for another 8 days while remaining on the diet. Under this dietary regimen, the vehicle controls (HC: High Cholesterol) typically have serum totai cholesterol and LDL-C levels that are increased by 3-8 foid and serum HDL- C is decreased by approximately 30-50% compared with chow diet <lean) controls.
Treatment of Sprague Dawley rats fed the high cholesterol diet with Compound 7 for 8 days significantly increased HDL-C levels, achieving the levels of the chow fed controls (Chow). There were also significant decreases in serum totai cholesterol and LDL-C levels. Compound 7 had no effect on serum triglycerides or liver weights. There were dose-related increases in drug plasma levels {Cmax and AUC) and there may be accumulation after multiple doses as evidenced by the differences in Cmax and AUC between the single and multiple doses at 3mg/kg. Data from this study are shown in Tables 3 and 4 below.
Table 3, Compound 7 in vivo data (\)
Figure imgf000192_0001
Table 4. Compound 7 in vivo data IW)
Figure imgf000192_0002
References:
Auboeuf et al., 1997, Diabetes 46(8):1319-1327 Braissant et al., 1996, Endocrinology 137(1 ): 354-366 Barak et al, 2002, Proc. Natl. Acad. Sci. USA 99(1 ):303-308 Lawn et ah, 1999, J. Ciin. Investigation 104(8): R25-R31 Leibowitz et ai., 2000, FEBS Lett. 473{3):333-336 Oliver et al., 2001 , Proc. Natl. Acad. Sci. USA 98(9):5306-5311 Tanaka et al, 2003, Proc. Natl. Acad. Sci. USA 100{26):15924-15929 Wang et al., 2003, Cell 113:159-170

Claims

Claims;
A compound of Formula (I)
Figure imgf000194_0001
wherein;
X is a covalent bond, O, or S;
Ri and R2 are independently selected from the group consisting of H1 d-βaikyl, and substituted C-i-aalkyl, or R1, R2 and the carbon atom to which they are attached together may form Ca^cycloalkyl;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, Ci-βalkyl, C3.7cycloaikyl, C3-7cycloalkyl-Ci-4alkyl, C3- ycycloaikyloxy-Ci^atkyl, Ci^aIkOXy-Ci-4 alkyl, Cβ-ioaryi, heteroaryl, halo substituted Ci^alkyl, amino substituted Ci^alkyl. Ce-ioaryl substituted Ci-4alkyl, cyano substituted Ci.4alkyl, and hydroxy substituted Ci^alkyl;
R6 and R7 are independently selected from the group consisting of H, hafo, Ci.3alkyl, halo substituted Ci-3alkyl, Ci.3aikoxy, and halo substituted Ci-3alkoxy; n is 1 ; and
Q is selected from the group consisting of
Figure imgf000195_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 wherein Ri and Rs are independently selected from the group consisting of H and d-salkyi, or Ri, R2 and the carbon atom to which they are attached together may form C3-5Cycloaiky!.
3. The compound according to claim 1 wherein Ri and R2 are independently selected from the group consisting of H and CH3, OrIR1, R2 and the carbon atom to which they are attached together may form
Figure imgf000195_0002
4. The compound according to claim 1 wherein R6 and R7 are independently selected from the group consisting of H, halo, hale substituted Ci-3alkyl, Ci.3alkoxy, and halo substituted C1-3alkOxy.
5. The compound according to claim 1 wherein Fl6 is H and R7 is selected from the group consisting of halo, halo substituted Ci^alkyl, and halo substituted Ci-3atkoxy.
6. The compound according to claim 5 wherein R7 is selected from the group consisting of F1 CF3, and -0-CF3.
7. The compound according to claim 1 wherein R4 and 1R5 are independently selected from the group consisting of H and Chalky!.
8. The compound according to claim 1 wherein R5 is H, CH3, or - CHbCH3,
9. The compound according to claim 1 wherein Q is selected from the group consisting of
Figure imgf000196_0001
10, The compound according to claim 1 wherein Q is selected from the group consisting of
Figure imgf000197_0001
11. The compound according to claim 1 wherein X is O.
12. A compound according to claim 1 wherein X is O;
Ri, R2, R4, and R5 are independently selected from the group consisting of H and Ci-3alkyi, or R1, R2 and the carbon atom to
which they are attached together may form
Figure imgf000197_0003
; and R6 and R7 are independently selected from the group consisting of H, haio, Ci-3alkoxy, and halo substituted d.3a!kyl, and halo substituted Ci-3alkoxy; and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
13. A compound of Formula (Ia)
Figure imgf000197_0002
wherein R1 and R2 are independently selected from the group consisting of H and Ci-8a!kyl, or R1, R2 and the carbon a^m to which they are attached together may form Cs-scycloalkyl; R6 and R7 are independently selected from the group consisting of H,
Ci-3alkyl, halo, and halo substituted
Figure imgf000198_0001
R4 and R5 are independently selected from the group consisting of H and Ci-ealkyl; and Q is selected from the group consisting of
Figure imgf000198_0002
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
14. A compound of Formula (Ib)
Figure imgf000198_0003
wherein R1 and R2 are independently selected from the group consisting of H and CH3, or Ri, R2 and the carbon atom to which they are
attached together may form
Figure imgf000199_0001
; R4 and R5 are independently selected from the group consisting of H1
CH3, and -CH2CH3; and Q is selected from the group consisting of
Figure imgf000199_0002
and enantiomers, diastereomers, tautomers, solvates, or pharmaceuticaliy acceptable salts thereof.
15. A compound of Formula (Ic)
Figure imgf000199_0003
Ri, R2, and R4, are independently selected from the group consisting of H and CH3, or R1, R2 and the carbon atom to which they are
attached together may form
Figure imgf000199_0004
; R5 is selected from the group consisting of H, CH3, and -CH2CH3; R7 is haio or halo substituted Ci.3alkyl; and Q is selected from the group consisting of
Figure imgf000200_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
16. A compound according to claim 15 wherein:
( a) Ri or R2 is H;
(b) Ri and R2 are both H;
(c) Ri or R2 is CH3;
Ri and R2 are both CH3;
R1, R2 and the carbon atom to which they are attached together form
Figure imgf000200_0002
φ R4 Is H Or CH3;
R5 is H, CH3, or -CH2CH3;
R1 or R2 is H and R4 is H or CH3; (i) R1 and R2 are both H and R4 is H or CH3; U) R1 or R2 is H and R5 is H5 CH3, or -CH2CH3; (k) Ri and R2 are both H and R5 is H, CH3, or -CH2CH3; QH R1 or R2 is CH3 and R5 is H, CH3, or --CH2CH3; fm)Ri and R2 are both CH3 and R5 is H, CH3, or -CH2CH3; (n) Ri or R2 is H, R4 is H, and R5 is H, CH3, or -CH2CH3;
R1 and R2 are both H, R4 is H, and R5 is H, CH3, or -CH2CH3; (p) R1 or R2 is CH3, R4 is H, and R5 is H, CH3, or -CH2CH3;
(q) Bi and R2 are both CH3, R4 Is H, and R5 is H, CH3, Or -CH2CH3;
(r) Ri , R2 and the carbon atom to which they are attached together form
Figure imgf000201_0002
, R4 is H, and R5 is H1 CH3, or -CH2CH3; M R7 is CF3; (t) B7 Is Cl;
(u) Ri or R2 is H, R7 is CF3, and R4 is H or CH3; ^ R1 and R2 are both H , R7 is CF3, and R4 is H or CH3; (w) Ri or R2 is H, R7 is CF3, and R5 is H, CH3, or -CH2CH3; i£ R1 and R2 are both H1 R7 is CF3, and R5 is H, CH3, or --CH2CH3; (y) Ri or R2 is CH3, R7 is CF3, and R5 is H1 CH3, or -CH2CH3; (z) R1 and R2 are both CH3, R7 is CF3, and R5 is H, CH3, or -CH2CH3; (aa) Ri or R2 is H, R4 is H, R7 is CF3, and R5 is H, CH3, or -CH2CH3; (bb) Ri and R2 are both H, R4 is H, R7 is CF3, and R5 is H, CH3, or -
CH2CH3; (cc) R1 or R2 is CH3, R4 is H, R7 is CF3, and R5 is H, CH3, or -
CH2CH3; (dd) R1 and R2 are both CH3, R4 is H, R7 is CF3, and R5 is H, CH3, or
-CH2CH3; (ee) Ri, R2 and the carbon atom to which they are attached
together form
Figure imgf000201_0001
, R4 is H, R7 is CF3, and R5 is H1 CH3, or -
CH2CH3;
Q is selected from the group consisting of
Figure imgf000202_0001
(QQ) Ri or R2 is H and Q is selected from the group consisting of
Figure imgf000202_0002
R1 and R≤ are both H and Q is selected from the group consisting of
Figure imgf000202_0003
(ii) R1 and R2 are both CH3 and Q is selected from the group consisting of
Figure imgf000203_0001
(kk) R4 is H or CH3 and Q is selected from the group consisting of
Figure imgf000203_0002
(II) R5 is H, CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000203_0003
R1 or R2 is H and R4 is H or CH3 and Q is selected from the group consisting of
Figure imgf000204_0001
fnn) R1 and R2 are both H and R4 is H or CH3 and Q is selected from the group consisting of
Figure imgf000204_0002
Ri or R2 is H and R5 is H, CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000204_0003
Ri and R2 are both H and R5 is H, CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000205_0001
Ri or R2 is CH3 and R5 is H1 CH3, or -CH2CH3 and Q is selected from the group consisting of
Figure imgf000205_0002
(xx± R1 and R2 are both CH3, R5 is H, CH3, or -CH2CH3, andQ is selected from the group consisting of
Figure imgf000205_0003
Ri or R2 is H, R4 is H8 R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000206_0001
R1 and R2 are both H, R4 is H1 R5 is H1 CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000206_0002
fuu) R1 or R2 is CH3, R4 is H1 R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000206_0003
R1 and R2 are both CH3, R4 is H1 R5 is H, CH3, Or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000207_0001
(ww) Ri, R2 and the carbon atom to which they are attached
together form
Figure imgf000207_0004
, R4 is H, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000207_0002
fxx) R7 is CF3 and Q is selected from the group consisting of
Figure imgf000207_0003
R7 is Cl and Q is selected from the group consisting of
Figure imgf000208_0001
(zz ) R1 or R2 is H, R7 is CF3, R4 is H OrCH3 , and Q is selected from the group consisting of
Figure imgf000208_0002
(aaa) Ri and R2 are both H, R 7 is CF3, R-1 is H or OH3, and Q is selected from the group consisting of
Figure imgf000208_0004
Figure imgf000208_0003
Figure imgf000208_0005
fbbb) Ri or R2 is H, R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000209_0001
Ri and R2 are both H1 R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000209_0002
fddd) R1 or R2 is CH3, R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000209_0003
teee) Ri and R2 are both CH3, R7 is CF3, R5 is H1 CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000210_0004
Ri or R2 is
H, R4 is H, R7 is CF35 R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000210_0001
R1 and R2 are both H1 R4 is H, R7 is CF3, R5 is H, CH3, or - CH2CH3, and Q is selected from the group consisting of
Figure imgf000210_0002
R1 or R2 is CH3, R4 is H, R7 is CF3, R5 is H, CH3, or -CH2CH3, and Q is selected from the group consisting of
Figure imgf000210_0003
' or fhhh) R1 and R2 are both CH3, R4 is H, R7 is CF3, R5 is H, CH3, or CH2CH3, and Q is selected from the group consisting of
Figure imgf000211_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
17. A compound selected from the group consisting of
Figure imgf000211_0002
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
18. A compound selected from the group consisting of
Figure imgf000215_0002
Figure imgf000216_0001
wherin the compound is substantially free from the corresponding other enantiomer.
19. A compound of the formufa
Figure imgf000216_0002
20. A pharmaceutical composition comprising a compound, salt or solvate according to any of claims 1 - 19 admixed with a pharmaceutically acceptable carrier, excipient or diluent.
21. A method of treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of PPAR receptors, which method comprises administering to a mammal in need of such treatment or prevention a therapeutically affective amount of a compound, salt or solvate of claim 1.
22. A method of treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of PPAR delta, which method comprises administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of claim 1.
23. The method of claim 21 or 22 wherein said therapeutically effective amount comprises a dose range of from abogLO.1 mg to about 15,000 mg.
24. The method of claim 21 or 22wherein said therapeutically effective amount comprises a dose range of from about 50 mg to about 1000 mg.
25. The method of claim 21 or 22wherein said therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg.
26. A method for treating or preventing a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterotemia, dyslipidemia {including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesteroiemia), atherosclerosis, and obesity, said method comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, salt or solvate of claim 1.
27. The method of claim 26 wherein said therapeutically -effective amount comprises a dose range of from about 0.1 mg to about 15,000 mg.
28. The method of claim 26 wherein said therapeutically effective amount comprises a dose range of from about 50 mg to about 1000 mg.
29. The method of claim 26 wherein said therapeutically effective amount comprises a dose range of from about 100 mg to about 1000 mg.
30. A kit comprising in one or more containers an amount of the composition of claim 1 effective to treat or prevent a disease or condition selected from the group consisting of diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL- choiesterolemia, dysiipidemia {including hypertriglyceridemia, hyperchoiesterolemia, mixed hyperlipidemia, and hypo-HDL- cholesteroiemia), atherosclerosis, and obesity.
31. A compound of Formula (I)
Figure imgf000218_0001
wherein:
X is a covalent bond, O, or S;
R1 and R2 are independently selected from the group consisting of H, Ci-ealkyl, and substituted Ci-8aikyl, or R1, R2 and the carbon atom to which they are attached together may form C3-7cycloalkyt;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, Ci-8alkyi, C3.7cycloalkyl, C3.7cycloalkyl-C1-4alkyl. C3- 7cycloalkyloxy-Ci-4alkyl, Ci.6alkoxy-C1-4 alkyl, Ce-ioaryl, heteroaryl, halo substituted Chalky!, amino substituted Ci-4aikyl, Ce-ioaryl substituted Ci-4alkyl, heteroaryl substituted Ci-4alkyl, cyano substituted d^alkyl, and hydroxy substituted C1-4alkyl; R6 and R7 are independently selected from the group consisting of H, halo, Ci-3alkyl, halo substituted Ci.3alkylf Ci.3aikoxy, and halo substituted Ci-3aikoxy; n is 1 ; and
Q is C6-ioaryl;
and enantiomers, diastereomers, tautomers, solvates, or pharmaceuticaliy acceptable salts thereof.
32. A compound of Formula (I)
Figure imgf000219_0001
wherein:
X is a covalent bond, O, or S;
R1 and R2 are independently selected from the group consisting of H, Ci-ealkyl, and substituted Ci-8alkyl, or Ri, R≥ and the carbon atom to which they are attached together may form C3-7cycloalkyi;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, halo, Ci.8aikyl, C3-7cyc!oaikyl, Ca^cycloalkyl-Cwalkyl, C3- 7cycioalkyloxy-Ci-4alkyl, Ci.6alkoxy-Ci-4 alkyl, Ce-ioaryl, heteroaryi, halo substituted Ci.4alkyl, amino substituted Ci-4alkyl, Ce-ioaryl substituted Ci-4alkyl, heteroaryi substituted Ci-4a!kyl, cyano substituted Ci-4alkyl, and hydroxy substituted Ci-4alkyl;
R6 and R7 are independently selected from the group consisting of H, halo, Ci.3alkyi, halo substituted Ci-aalkyl, Ci-3aikoxy, and halo substituted Ci-3alkoxy; n is 1 or 2; and
Q is selected from the group consisting of
Figure imgf000220_0001
and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
33. A compound of Formula (i)
Figure imgf000220_0002
wherein:
X is a covalent bond, O, or S;
Ri and R2 are independently selected from the group consisting of H, Ci-βalkyl, and substituted d-salkyl, or R1, R2 and the carbon atom to which they are attached together may form C3-τcyc1oalkyi;
R3 is H;
R4 and R5 are independently selected from the group consisting of H1 halo, Ci-8alkyl, C3-7Cycloalkyl, C^cycloalkyl-Ci^alkyl, C3- 7cyc!oaikyloxy-Ci.4alkyl, Ci-ealkoxy-Ci^ afkyl, C6-ioaryl, heteroaryl, halo substituted Ci^alkyl, amino substituted Ci^alkyi, Ce-ioaryl substituted Ci-4alkyl, cyano substituted Ci.4alkyl, and hydroxy substituted Ci-4alkyl;
R6 and R7 are independently selected from the group consisting of H, halo, Ci-3alkylt halo substituted Ci-3alkyl, Ci-3alkoxy, and halo substituted Ci-3alkoxy; n is 2; and
Q is selected from the group consisting of
Figure imgf000221_0001
and enantiorners, diastereomers, tautomers, solvates, or pharmaceutically acceptable saits thereof.
34. A compound according to claim 31 , 32 or 33 selected from the group consisting of
Figure imgf000221_0002
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