US20120022057A1 - Bicyclic compounds as inhibitors of diacyglycerol acyltransferase - Google Patents

Bicyclic compounds as inhibitors of diacyglycerol acyltransferase Download PDF

Info

Publication number
US20120022057A1
US20120022057A1 US13/256,468 US201013256468A US2012022057A1 US 20120022057 A1 US20120022057 A1 US 20120022057A1 US 201013256468 A US201013256468 A US 201013256468A US 2012022057 A1 US2012022057 A1 US 2012022057A1
Authority
US
United States
Prior art keywords
alkyl
phenyl
cyclohexyl
esi
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/256,468
Inventor
Gang Zhou
Grant Wishart
Pauline C. Ting
Robert G. Aslanian
Nicolas Zorn
Jianhua Cao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Priority to US13/256,468 priority Critical patent/US20120022057A1/en
Assigned to SCHERING CORPORATION reassignment SCHERING CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAO, JIANHUA, ZORN, NICOLAS, ASLANIAN, ROBERT G., TING, PAULINE C., ZHOU, GANG
Publication of US20120022057A1 publication Critical patent/US20120022057A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to certain heterocyclic compounds useful as diacylglycerol acyltransferase (“DGAT”) inhibitors, especially diacylglycerol acyltransferase 1 (“DGAT1”) inhibitors, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat or prevent various diseases including cardiovascular disease, dyslipidemia, obesity and diabetes (e.g., Type 2 diabetes).
  • DGAT diacylglycerol acyltransferase
  • DGAT1 diacylglycerol acyltransferase 1
  • Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver, and adipocytes. Triglycerides or triacylglycerols support the major functions of dietary fat absorption, packaging of newly synthesized fatty acids and storage in fat tissue (see Subauste and Burant, Current Drug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3, pp. 263-270).
  • Diacylglycerol O-acyltransferase also known as diglyceride acyltransferase or DGAT
  • DGAT diglyceride acyltransferase
  • DAG 1,2-diacylglycerol
  • DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, pp. 395-400).
  • DGAT1 and DGAT2 Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2 [see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, pp. 13018-13023, Lardizabal et al, Journal of Biological Chemistry (2001) 276, pp. 38862-38869 and Cases et al, Journal of Biological Chemistry (2001) 276, pp. 38870-38876]. Although both enzymes utilize the same substrates, there is no homology between DGAT1 and DGAT2. Both enzymes are widely expressed. However, some differences do exist in the relative abundance of expression in various tissues.
  • Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack et al, EP1219716 and Burrows et al, 26th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino-oxazines (see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, pp. 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, pp. 1340-1346), substituted benzyl-phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, pp.
  • Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et al, Biochimica et Biophysica Acta (1992) pp. 1125, 203-9), 2-bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, pp. 6528-6532), roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, pp. 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, pp.
  • DGAT inhibitors have been described. See, for example, PCT publication US 2007/0244096 (published Oct. 31, 2007; applicant: Japan Tobacco). Claim 1 therein discloses compounds of the formula:
  • DGAT inhibitors that have efficacy for the treatment of metabolic disorders such as, for example, obesity, Type II diabetes mellitus and metabolic syndrome.
  • this invention discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, or pharmaceutically acceptable salts, solvates or esters of said prodrug, the compound being represented by the Formula IA:
  • COOH bioisostere is as defined in The Practice of Medicinal Chemistry , C. G. Wermuth Ed.; Academic Press: New York, 1996, p. 203.
  • Non-limiting examples of COOH bioisosteres include —SO 3 H, —S(O) 2 NHR 7 , —S(O) 2 NHC(O)R 7 , —CH 2 S(O) 2 R 7 , —C(O)NHS(O) 2 R 7 , —C(O)NHOH, —C(O)NHCN, —CH(CF 3 )OH, —C(CF 3 ) 2 OH, —P(O)(OH) 2 and the groups listed below:
  • R 7 is selected from alkyl, aryl or heteroaryl.
  • this invention discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, or pharmaceutically acceptable salts, solvates or esters of said prodrug, the compound being represented by the Formula IB:
  • COOH bioisostere is as defined under Formula IA.
  • compositions comprising at least one compound of Formula IA or Formula IB.
  • this invention provides pharmaceutical compositions comprising at least one compound of Formula IA or Formula IB and at least one pharmaceutically acceptable carrier.
  • this invention provides a method of treating diabetes in a patient in need of such treatment using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • this invention provides a method of treating diabetes in a patient in need of such treatment, e.g., Type 2 diabetes, using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • this invention provides a method of treating metabolic syndrome in a patient in need of such treatment, using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • this invention provides a method of inhibiting DGAT using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • this invention provides a method of inhibiting DGAT1 using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • the present invention discloses compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof.
  • W is C(R 4 ).
  • W is C(R 4 R 4 ).
  • W is N.
  • W is N(R 4 ).
  • W is S.
  • W is O.
  • X is C(R 4 ).
  • X is C(R 4 R 4 ).
  • X is N.
  • X is N(R 4 ).
  • X is S.
  • X is O.
  • Y is C(R 4 ).
  • Y is C(R 4 R 4 ).
  • Y is N.
  • Y is N(R 4 ).
  • Y is S.
  • Y is O.
  • W ⁇ X ⁇ N In another embodiment, W ⁇ X ⁇ N.
  • W ⁇ Y ⁇ N In another embodiment, W ⁇ Y ⁇ N.
  • one represents a double bond and the other represents a single bond.
  • R 1 is alkyl
  • R 1 is aryl
  • R 1 is arylalkyl.
  • R 1 is cycloalkyl
  • R 1 is cycloalkylalkyl.
  • R 1 is heterocyclyl
  • R 1 is heterocyclylalkyl.
  • R 1 is heteroaryl
  • R 1 is heteroarylalkyl.
  • R 1 is alkylcarbonyl.
  • R 1 is arylcarbonyl.
  • R 1 is cycloalkylcarbonyl.
  • R 1 is (cycloalkyl)alkylcarbonyl.
  • R 1 is heteroarylcarbonyl.
  • R 1 is heterocyclylcarbonyl.
  • R 1 is (heterocyclyl)alkylcarbonyl.
  • R 1 is (aryl)alkylcarbonyl.
  • R 1 is (heteroaryl)alkylcarbonyl.
  • R 1 is (alkylthio)carbonyl-.
  • R 1 is (alkoxy)carbonyl-.
  • R 1 is (alkylamino)carbonyl.
  • R 1 is (arylamino)carbonyl-.
  • R 1 is (heteroarylamino)carbonyl-.
  • R 1 is (heterocyclylamino)carbonyl.
  • R 1 is (cycloalkylamino)carbonyl.
  • R 1 is (heterocyclylamino)sulfonyl.
  • R 1 is (arylamino)sulfonyl-.
  • R 1 is (heteroarylamino)sulfonyl.
  • R 1 comes off a ring carbon on the ring shown in Formula IA or IB.
  • R 1 comes off a ring nitrogen on the ring shown in Formula IA or IB.
  • E is C(R 4 ).
  • E is C(R 4 R 4 ).
  • E is N.
  • E is N(R 4 ).
  • E is S.
  • E is O.
  • H is C(R 4 ).
  • H is C(R 4 R 4 ).
  • H is N.
  • H is N(R 4 ).
  • H is S.
  • H is O
  • F is C(R 4 ).
  • F is C(R 4 R 4 ).
  • F is N.
  • F is N(R 4 ).
  • G is C(R 4 ).
  • G is C(R 4 R 4 ).
  • G is N.
  • G is N(R 4 ).
  • E F ⁇ N.
  • F ⁇ H ⁇ N In another embodiment, F ⁇ H ⁇ N.
  • A is C(R 5 ).
  • A is N.
  • B is C(R 5 ).
  • B is N.
  • C is C(R 5 ).
  • C is N.
  • D is C(R 5 ).
  • D is N.
  • R 5 is H.
  • R 5 is alkyl
  • R 5 is methyl
  • R 5 is cycloalkyl
  • R 5 is amino
  • R 5 is alkylamino
  • R 5 is —OH.
  • R 5 is alkoxy
  • R 5 is halo
  • R 5 is chloro
  • R 5 is R 2 , where R 2 is as defined.
  • R 2 is cycloalkyl
  • R 2 is aryl
  • R 2 is heterocyclyl
  • R 6 is H.
  • R 6 is alkyl
  • Z is a bond
  • Z is O.
  • Z is N(R 4 ).
  • Z is alkyl
  • Z is carbonyl
  • Z is sulfonyl
  • R 3 is cycloalkyl
  • R 3 is aryl
  • R 3 is heteroaryl
  • R 3 is heterocyclyl
  • R 3 is unsubstituted.
  • R 3 is substituted with one moiety as described earlier.
  • R 3 is substituted with more than one moiety as described earlier.
  • R 3 is substituted with an alkyl.
  • R 3 is substituted with a lower alkyl.
  • R 3 is substituted with a —C(O)NH(R 6 ).
  • R 3 is substituted with a —C(O)N(R 6 ) 2 .
  • R 3 is substituted with a carboxyl or carboxyester.
  • R 3 is substituted with COOH bioisostere, wherein COOH bioisostere is as defined earlier.
  • R 3 is substituted with halo.
  • R 3 is substituted with cyano.
  • R 3 is substituted with —OR 5 .
  • R 3 is substituted with —N(R 4 R 5 ).
  • R 3 is substituted with —C(O)—N(R 4 R 5 ).
  • R 3 is substituted with both halo and carboxyl.
  • R 3 is substituted with both —OR 5 and carboxyl.
  • R 3 is substituted with both carboxy and alkyl-.
  • R 3 is substituted with -alkyl)-C(O)N(R 4 R 5 ).
  • Patient includes both humans and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, pyridine, alkoxy, alkylthio, amino, oxime (e.g., ⁇ N—OH), —NH(alkyl), —NH(cycloalkyl), —N(alkyl) 2 , —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and —C(O)O-alkyl.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl).
  • substituents include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • Lower alkynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridine (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,
  • “Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
  • “Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Halogen or “halo” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroa
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, —C(CH 3 ) 2 — and the like which form moieties such as, for example:
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • “Heterocyclyl” may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • “Heterocyclenyl” may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • heteroatom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Alkoxy means an alkyl-O— group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkoxyalkyl- means an alkyl-O-alkyl- group in which the alkyl group is as previously described.
  • suitable alkoxyalkyl groups include methoxymethyl, ethoxymethyl, n-propoxyethyl, isopropoxyethyl and n-butoxymethyl. The bond to the parent moiety is through the alkyl.
  • Aryloxy means an aryl-O— group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxyalkyl- means an aryl-O-alkyl- group in which the aryl and aryl groups are as previously described.
  • suitable aryloxyalkyl groups include phenoxymethyl and naphthoxyethyl. The bond to the parent moiety is through the alkyl.
  • “Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S— group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthioalkyl- means an alkyl-S-alkyl- group in which the alkyl group is as previously described.
  • suitable alkylthioalkyl groups include methylthioethyl and ethylthiomethyl. The bond to the parent moiety is through the alkyl.
  • Arylthio means an aryl-S— group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
  • Arylthioalkyl- means an aryl-S-alkyl- group in which the aryl group is as previously described.
  • suitable arylthioalkyl groups include phenylthioethyl and phenylthiomethyl. The bond to the parent moiety is through the alkyl.
  • Alkylthio means an aralkyl-S— group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O—CO— group.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O—C(O)— group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O—C(O)— group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )— group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro - drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design , (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term “prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula IA or Formula IB or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • prodrugs are described by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 -C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alk)alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids,
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, —C(OH)C(O)OY 1 wherein Y 1 is H, (C 1 -C 6 )alkyl or benzyl, —C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 )alkyl and Y 3 is (C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, amino(C 1 -C 4 )alkyl
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci ., (2004) 93 (3), pp. 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech ., (2004) 5 (1), article 12; and A. L. Bingham et al, Chem. Commun ., (2001) pp. 603-604.
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the compounds of Formula IA or Formula IB can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula IA or Formula IB herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions may be formed and are included within the term “salt(s)” as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
  • Salts of the compounds of the Formula IA or Formula IB may be formed, for example, by reacting a compound of Formula IA or Formula IB with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate
  • the compounds of Formula IA or Formula IB may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula IA or Formula IB as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula IA or Formula IB incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula IA or Formula IB may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I, respectively.
  • Certain isotopically-labelled compounds of Formula IA or Formula IB are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 O) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula IA or Formula IB can be useful for medical imaging purposes.
  • those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single Photon Emission Computed Tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
  • Isotopically labeled compounds of Formula IA or Formula IB in particular those containing isotopes with longer half lives (T1/2>1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • Polymorphic forms of the compounds of Formula IA or Formula IB, and of the salts, solvates, esters and prodrugs of the compounds of Formula IA or Formula IB, are intended to be included in the present invention.
  • the compounds according to the invention have pharmacological properties.
  • the compounds of Formula IA or Formula IB are inhibitors of DGAT, particularly DGAT1, and can be useful for the therapeutic and/or prophylactic treatment of diseases that are modulated by DGAT, particularly by DGAT1, such as, for example, metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), obesity and the like.
  • the invention also includes methods of treating diseases that are modulated by DGAT, particularly by DGAT1.
  • the invention also includes methods of treating metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), and obesity in a patient by administering at least one compound of Formula IA or Formula IB to said patient.
  • Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose, or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Abnormal glucose homeostasis is associated with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. As such, the diabetic patient is at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Accordingly, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • Insulin resistance is not associated with a diminished number of insulin receptors but rather to a post-insulin receptor binding defect that is not well understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • Type 2 diabetes which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat.
  • sulfonylureas e.g. tolbutamide and glipizide
  • meglitinide which stimulate the pancreatic [beta]-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues.
  • the biguanides are a class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia. However, the biguanides can induce lactic acidosis and nausea/diarrhea.
  • the glitazones are a separate class of compounds with potential for the treatment of Type 2 diabetes. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia.
  • the glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype.
  • PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones.
  • Newer PPAR agonists that are being tested for treatment of Type 2 diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have been noted in some patients treated with glitazone drugs, such as troglitazone.
  • New biochemical approaches include treatment with alpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase-1B (PTP-1B) inhibitors.
  • alpha-glucosidase inhibitors e.g. acarbose
  • PTP-1B protein tyrosine phosphatase-1B
  • DPP-IV dipeptidyl peptidase-IV
  • compositions e.g., pharmaceutical compositions, comprising at least one compound of Formula IA or Formula IB.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • Other carriers include Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, or gamma-cyclodextrin or analogs thereof.
  • PEG polyethylene glycol
  • Cremophor/ethanol polyethylene glycol
  • Trappsol alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, or gamma-cyclodextrin or analogs thereof.
  • Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pa.
  • the therapeutic agents of the present invention are preferably formulated in pharmaceutical compositions and then, in accordance with the methods of the invention, administered to a subject, such as a human subject, in a variety of forms adapted to the chosen route of administration.
  • the therapeutic agents may be formulated for intravenous administration.
  • the formulations may, however, include those suitable for oral, rectal, vaginal, topical, nasal, ophthalmic, or other parenteral administration (including subcutaneous, intramuscular, intrathecal, intraperitoneal and intratumoral, in addition to intravenous) administration.
  • Formulations suitable for parenteral administration conveniently include a sterile aqueous preparation of the active agent, or dispersions of sterile powders of the active agent, which are preferably isotonic with the blood of the recipient.
  • Parenteral administration of the therapeutic agents e.g., through an I.V. drip
  • Isotonic agents that can be included in the liquid preparation include sugars, buffers, and sodium chloride. Solutions of the active agents can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions of the active agent can be prepared in water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, glycerol esters, and mixtures thereof.
  • the ultimate dosage form is sterile, fluid, and stable under the conditions of manufacture and storage.
  • the necessary fluidity can be achieved, for example, by using liposomes, by employing the appropriate particle size in the case of dispersions, or by using surfactants.
  • Sterilization of a liquid preparation can be achieved by any convenient method that preserves the bioactivity of the active agent, preferably by filter sterilization. Preferred methods for preparing powders include vacuum drying and freeze drying of the sterile injectible solutions.
  • antimicrobial agents for example, antibacterial, antiviral and antifungal agents including parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Absorption of the active agents over a prolonged period can be achieved by including agents for delaying, for example, aluminum monostearate and gelatin.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the active agent as a powder or granules, as liposomes containing the first and/or second therapeutic agents, or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught.
  • Such compositions and preparations may contain at least about 0.1 wt-% of the active agent.
  • the amounts of the therapeutic agents should be such that the dosage level will be effective to produce the desired result in the subject.
  • Nasal spray formulations include purified aqueous solutions of the active agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye. Topical formulations include the active agent dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose, or aspartame; and a natural or artificial flavoring agent.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid, and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose, or aspartame
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like.
  • a syrup or elixir may contain one or more of a sweetening agent, a preservative such as methyl- or propylparaben, an agent to retard crystallization of the sugar, an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, a dye, and flavoring agent.
  • the material used in preparing any unit dosage form is substantially nontoxic in the amounts employed.
  • the active agent may be incorporated into sustained-release preparations and devices.
  • the compound is administered orally, intraperitoneally, or intravenously or intrathecally or some suitable combination(s) thereof.
  • the therapeutic agents described in the present disclosure can be administered to a subject alone or together (coadministered, optionally but not necessarily, in a single formulation) with other active agents as described herein, and are preferably administered with a pharmaceutically acceptable buffer.
  • the therapeutic agents can be combined with a variety of physiological acceptable carriers, additives for delivery to a subject, including a variety of diluents or excipients known to those of ordinary skill in the art.
  • isotonic saline is preferred.
  • a cream including a carrier such as dimethylsulfoxide (DMSO), or other agents typically found in topical creams that do not block or inhibit activity of the peptide, can be used.
  • DMSO dimethylsulfoxide
  • Other suitable carriers include, but are not limited to, alcohol, phosphate buffered saline, and other balanced salt solutions.
  • the formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • such methods include the step of bringing the therapeutic agent (i.e., the active agent) into association with a carrier that constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing the active agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations.
  • the methods of the invention include administering the therapeutic agents to a subject in an amount effective to produce the desired effect.
  • the therapeutic agents can be administered as a single dose or in multiple doses.
  • Useful dosages of the active agents can be determined by comparing their in vitro activity and the in vivo activity in animal models.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • kits comprising a therapeutically effective amount of at least one compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • compositions comprising at least one compound of Formula IA or Formula IB and at least one other therapeutic agent in combination.
  • combination agents are described below.
  • the agents in the combination can be administered together as a joint administration (e.g., joint single pill), separately, one after the other in any order and the like as is well known in the art.
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Compounds of Formula IA or Formula IB, or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent that is not a Compound of Formula IA or Formula IB, wherein the amounts administered are together effective to treat or prevent a Condition.
  • the therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • the one or more Compounds of Formula IA or Formula IB is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) are present in the same composition.
  • this composition is suitable for oral administration.
  • this composition is suitable for intravenous administration.
  • the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) can act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • the administration of one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents.
  • the other therapeutic is an antidiabetic agent which is not a Compound of Formula IA or Formula IB.
  • the other therapeutic agent is an agent useful for reducing any potential side effect of a Compound of Formula IA or Formula IB.
  • potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
  • the other therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the other therapeutic agent is used at its normally prescribed dosage. In another embodiment, the other therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
  • Examples of antidiabetic agents useful in the present methods for treating diabetes or a diabetic complication include a sulfonylurea; an insulin sensitizer (such as a PPAR agonist, a DPP-IV inhibitor, a PTP-1B inhibitor and a glucokinase activator); a glucosidase inhibitor; an insulin secretagogue; a hepatic glucose output lowering agent; an anti-obesity agent; a meglitinide; an agent that slows or blocks the breakdown of starches and sugars in vivo; an histamine H 3 receptor antagonist; a sodium glucose uptake transporter 2 (SGLT-2) inhibitor; a peptide that increases insulin production; and insulin or any insulin-containing composition.
  • an insulin sensitizer such as a PPAR agonist, a DPP-IV inhibitor, a PTP-1B inhibitor and a glucokinase activator
  • a glucosidase inhibitor such as a PP
  • the antidiabetic agent is an insulin sensitizer or a sulfonylurea.
  • Non-limiting examples of sulfonylureas include glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide, gliclazide, glibenclamide and tolazamide.
  • Non-limiting examples of insulin sensitizers include PPAR activators, such as rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; DPP-IV inhibitors; PTP-1B inhibitors; and ⁇ -glucokinase activators, such as miglitol, acarbose, and voglibose.
  • PPAR activators such as rosiglitazone, pioglitazone and englitazone
  • biguanidines such as metformin and phenformin
  • DPP-IV inhibitors such as metformin and phenformin
  • PTP-1B inhibitors PTP-1B inhibitors
  • ⁇ -glucokinase activators such as miglitol, acarbose, and voglibose.
  • Non-limiting examples of DPP-IV inhibitors useful in the present methods include sitagliptin (JanuviaTM, Merck), saxagliptin, denagliptin, vildagliptin (GalvusTM, Novartis), alogliptin, alogliptin benzoate, ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination of sitagliptin/metformin HCl (JanumetTM, Merck).
  • Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku).
  • Non-limiting examples of hepatic glucose output lowering agents include Glucophage and Glucophage XR.
  • histamine H 3 receptor antagonist agents include the following compound:
  • Non-limiting examples of insulin secretagogues include sulfonylurea and non-sulfonylurea drugs such as GLP-1, a GLP-1 mimetic, exendin, GIP, secretin, glipizide, chlorpropamide, nateglinide, meglitinide, glibenclamide, repaglinide and glimepiride.
  • GLP-1 mimetics useful in the present methods include Byetta-Exenatide, Liraglutide, CJC-1131 (ConjuChem, Exenatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.
  • insulin as used herein, includes all pyridinones of insulin, including long acting and short acting forms of insulin.
  • Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from AutoImmune, and the compositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • the antidiabetic agent is an anti-obesity agent.
  • Non-limiting examples of anti-obesity agents useful in the present methods for treating diabetes include a 5-HT2C agonist, such as lorcaserin; a neuropeptide Y antagonist; an MCR4 agonist; an MCH receptor antagonist; a protein hormone, such as leptin or adiponectin; an AMP kinase activator; and a lipase inhibitor, such as orlistat.
  • a 5-HT2C agonist such as lorcaserin
  • a neuropeptide Y antagonist such as lorcaserin
  • an MCR4 agonist such as an MCH receptor antagonist
  • a protein hormone such as leptin or adiponectin
  • an AMP kinase activator such as orlistat
  • lipase inhibitor such as orlistat.
  • Appetite suppressants are not considered to be within the scope of the anti-obesity agents useful in the present methods.
  • Non-limiting examples of meglitinides useful in the present methods for treating diabetes include repaglinide and nateglinide.
  • Non-limiting examples of insulin sensitizing agents include biguanides, such as metformin, metformin hydrochloride (such as GLUCOPHAGE® from Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOVANCETM from Bristol-Myers Squibb) and buformin; glitazones; and thiazolidinediones, such as rosiglitazone, rosiglitazone maleate (AVANDIATM from GlaxoSmithKline), pioglitazone, pioglitazone hydrochloride (ACTOSTTM, from Takeda) ciglitazone and MCC-555 (Mitsubishi Chemical Co.)
  • biguanides such as metformin, metformin hydrochloride (such as GLUCOPHAGE® from Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOVANCETM from Bristol-Myers Squibb) and
  • the insulin sensitizer is a thiazolidinedione.
  • the insulin sensitizer is a biguanide.
  • the insulin sensitizer is a DPP-IV inhibitor.
  • the antidiabetic agent is a SGLT-2 inhibitor.
  • Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production.
  • Alpha-glucosidase inhibitors help the body to lower blood sugar by delaying the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals.
  • suitable alpha-glucosidase inhibitors include acarbose; miglitol; camiglibose; certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose.
  • Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin; pramlintide, exendin, certain compounds having Glucagon-like peptide-1 (GLP-1) agonistic activity as disclosed in WO 00/07617 (incorporated herein by reference).
  • Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from AutoImmune, and the compositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the Compound(s) of Formula IA or Formula IB and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is a tablet and one is a capsule.
  • a kit comprising the separate dosage forms is therefore advantageous.
  • a total daily dosage of the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) can, when administered as combination therapy, range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration.
  • the dosage is from about 0.2 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
  • the compounds of the invention can be made according to the processes described below.
  • the compounds of this invention are also exemplified in the examples below, which examples should not be construed as limiting the scope of the disclosure.
  • Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.
  • LCMS analyses were performed using an Agilent 6140 quadrupole mass spectrometer equipped with a Zorbax SB-C-18 C 18 column (1.8 ⁇ m, 50 ⁇ 4.6 mm) heated at 50° C.; mobile phase A: 0.1% trifluoroacetic acid in water, B: 0.1% trifluoroacetic acid in acetonitrile; gradient: 90% A and 10% B to 5% A and 95% B in 3.5 mins. Flash column chromatography was performed using Teledyne Isco RediSep silica columns and C 18 reverse phase columns.
  • Preparative HPLC separations were performed on Gilson instruments (system 1: Gilson 322 pump, UV-vis detector 156, liquid handler 215 and injector 845Z; or system 2: pumps 333 & 334, liquid handler GX281, UV-vis detector 155) using Phenomenex columns (Gemini C 18 5.0 ⁇ m, 100 ⁇ 21.2 mm or 150 ⁇ 21.2 mm or 150 ⁇ 30.0 mm or 10 ⁇ m, 250 ⁇ 50.0 mm or Gemini C 6 -phenyl 5.0 ⁇ m, 21.2 ⁇ 150 mm or Synergi Fusion-RP 4.0 ⁇ m, 21.2 ⁇ 150 mm); mobile phase A: 0.1% trifluoroacetic (or formic acid) in water, B: 0.1% trifluoroacetic (or formic acid) in acetonitrile.
  • Trimethyl phosphonoacetate (78.6 mL, 485.0 mmol) was added to a 0° C. solution of 4-(4-hydroxyphenyl)cyclohexanone A-1 (76.9 g, 404.0 mmol) in tetrahydrofuran (3.0 L) in a flame-dried 5.0 L 3-neck round bottom flask equipped with mechanical stirrer and placed under an atmosphere of nitrogen.
  • Sodium hydride (60% in mineral oil, 37.2 g) was added portionwise so that the internal temperature was maintained below 10° C. The reaction mixture was stirred at 0° C. for 20 mins and slowly warmed to room temperature and stirred for an additional 2.5 h.
  • Methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate A-3 (mixture of cis and trans isomers, 107.0 g, 430.9 mmol) was dissolved in hot ethyl acetate (90.0 mL) and the solution was allowed to cool slowly to room temperature and to stand overnight to crystallize. The white crystals were isolated by filtration, washed with an ice-cold mixture of ethyl acetate:hexanes (15:85, 100 mL) and dried to give pure isomer trans-A-3 (36.8 g).
  • the mother liquors resulting from the preparation of trans-A-3 were concentrated to dryness under reduced pressure.
  • the solid residue (10.0 g, 430.9 mmol) was dissolved in ethyl acetate (200 mL), and the solution was allowed to stand overnight at room temperature to crystallize.
  • the white crystals were isolated by filtration, washed with an ice-cold mixture of ethyl acetate:hexanes (15:85, 20 mL).
  • the filtrate was concentrated to dryness under reduced pressure, and the residual solid was recrystallized from ethyl acetate:hexanes (20:80, 10 mL) to give isomer cis-A-3.
  • Triethylamine (10.1 mL, 72.5 mmol) and trifluoromethanesulfonic anhydride (19.0 g, 67.3 mmol) were successively added dropwise to a solution of methyl 2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate trans-A-3 (12.0 g, 48.3 mmol) in methylene chloride (100.0 mL) at 0° C.
  • the reaction was stirred under a nitrogen atmosphere for 5 h, then poured into a saturated aqueous solution of NaHCO 3 (150 mL) and extracted with methylene chloride.
  • reaction was degassed under reduced pressure several times, placed under an atmosphere of nitrogen and stirred at 80° C. for 17 h. After completion, the reaction mixture was cooled, filtered through a short path silica gel column and eluted with ethyl acetate (450 mL).
  • Intermediate cis-A-5 was prepared by the sequence step a-4-step a5 described for intermediate methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5, by using methyl 2-((1s,4s)-4-(4-hydroxyphenyl)cyclohexyl)acetate cis-A-3 as starting material.
  • the reaction mixture was diluted with ethyl acetate (50 mL) and water (10 mL), then decanted, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 100 mL).
  • the combined organic extracts were successively washed with water (70 mL) then brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure.
  • N,N-diisopropylethylamine (4.3 mL, 25.0 mmol), potassium carbonate (1.7 g, 12.0 mmol) and chloroacetic acid methyl ester (1.4 g, 12.0 mmol) were successively added at room temperature to a solution of 1-(4-bromophenyl)piperazine A-9 (3.0 g, 12.0 mmol) in tetrahydrofuran (22.6 mL) and N,N-dimethylformamide (10.6 mL). The reaction mixture was stirred overnight at room temperature and quenched with water (50 mL).
  • Methyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate A-10 (240.0 mg, 1.00 mmol), bis(pinacolato)diboron (292.0 mg, 1.20 mmol), potassium acetate (376.0 mg, 3.83 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (39.1 mg, 0.048 mmol) were mixed in 1,4-dioxane (20 mL). The reaction mixture was degassed under reduced pressure three times, placed under an atmosphere of nitrogen and stirred at 80° C. for 17 h.
  • N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.34 g, 4.16 mmol) was added at 0° C. to a solution of 6-bromo-1H-indole-3-carboxylic acid A-14 (1.0 g, 4.00 mmol), aniline (0.476 mL, 5.23 mmol) and N-ethyl-N,N-diisopropylamine (0.726 mL, 4.16 mmol) in N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred overnight at room temperature and then quenched with water (50 mL).
  • Trifluoroacetic acid (0.23 mL, 3.0 mmol) was added at room temperature to a solution of 6-bromo-2-iodoquinazoline A-18 (0.50 g, 1.0 mmol) and aniline (0.16 mL, 1.8 mmol) in isopropyl alcohol (6.36 mL).
  • the reaction mixture was heated at 70° C. for 12 h, then cooled, quenched with triethylamine (1.0 mL) and concentrated to dryness under reduced pressure.
  • 1,8-Diazabicyclo[5.4.0]undec-7-ene 140.0 ⁇ L, 0.94 mmol was added at room temperature to a solution of 3-amino-6-bromopyridin-2-ol A-22 (178.0 mg, 0.94 mmol) and methyl 2-bromoacetate (81.0 ⁇ L, 0.86 mmol) in anhydrous 1-methylpyrrolidin-2-one (3.76 mL) under an argon atmosphere, in a 10 mL microwave reactor vial.
  • the sealed reaction mixture was heated at 180° C. for 3 mins under microwave irradiation and then diluted with ethyl acetate (30 mL).
  • Phenyl isocyanate (90.0 ⁇ L, 0.82 mmol) was added at room temperature to a solution of 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine A-24 (91.5 mg, 0.41 mmol) in 3:1 anhydrous methylene chloride:dimethylsulfoxide (2.0 mL) under argon. The reaction mixture was stirred at room temperature for 12 h, quenched with methanol (2.0 mL) and diluted with methylene chloride (10 mL).
  • 6-Bromo-2-chloroquinoxaline A-26 (0.20 g, 0.821 mmol), aniline (97 ⁇ L, 1.07 mmol) and N-ethyl-N,N-diisopropylamine (214 ⁇ L, 1.23 mmol) were mixed in 1-methylpyrrolidin-2-one (4.11 mL) in a 5 mL microwave reactor vial under an argon atmosphere. The reaction mixture was heated at 180° C. for 30 mins, then at 200° C. for 20 mins under microwave irradiation. The mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL), quenched with water (20 mL) and decanted.
  • a slurry of Raney nickel in water (ca. 15 mg) was suspended in ethyl acetate (5 mL) in a round-bottom flask and carefully concentrated to dryness by heating at 30° C. under reduced pressure. The procedure was repeated with toluene (10 mL) and the dry metal was then kept under an argon atmosphere.
  • a solution of 1-(5-bromo-2-nitrophenoxy)propan-2-one A-30 (30.0 mg, 0.11 mmol) in dry ethyl acetate (0.54 mL) and absolute ethanol (0.54 mL) was added at room temperature to the Raney nickel, and the reaction mixture was heated at 50° C. for 12 h under an atmosphere of hydrogen.
  • Triphenylphosphine (624.0 mg, 2.38 mmol) was added at room temperature to a solution of 5-bromo-2-nitrophenol A-32 (400.0 mg, 1.83 mmol) and methyl( ⁇ )-(S)-lactate (0.149 mL, 1.56 mmol) in anhydrous methylene chloride (18.3 mL) under an atmosphere of argon. After 10 mins of stirring, the reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.360 mL, 1.83 mmol) was added dropwise. The orange solution was warmed to room temperature, stirred for 12 h, then concentrated to ca.
  • Iron powder (1.91 g, 34.15 mmol) and (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-33 (525.0 mg, 1.71 mmol) were heated at 50° C. in glacial acetic acid (10.5 mL) for 5 h.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), filtered over a pad of celite, and rinsed with ethyl acetate (80 mL).
  • Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 0.67 mL) was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 (179.0 mg, 0.50 mmol) in anhydrous THF (10.0 mL) at ⁇ 78° C. under an atmosphere of argon. The reaction was stirred at ⁇ 78° C. for 1 h, then methyl iodide (42.0 ⁇ L, 0.67 mmol) was added.
  • the reaction was allowed to warm to room temperature and stirred overnight at room temperature, then successively quenched with water (5 mL), diluted with ethyl acetate (15 mL) and decanted. The aqueous layer was extracted with ethyl acetate (3 ⁇ 30 mL); the combined organic extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
  • Example B-4 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Lithium hydroxide monohydrate (16.8 mg, 0.4 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-3 (46.9 mg, 0.1 mmol) in tetrahydrofuran (10.0 mL) and water (1.0 mL). The reaction was stirred at room temperature overnight and quenched with an aqueous solution of hydrogen chloride (1 N, 1.0 mL).
  • 5-Bromoindoline B-1 (595.0 mg, 3.00 mmol), potassium trifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borate A-7 (1.12 g, 3.31 mmol), anhydrous potassium carbonate (1.37 g, 9.92 mmol) and palladium (II) acetate (75.0 mg, 0.33 mmol) were mixed in anhydrous methanol (12.0 mL) in a 20 mL microwave reactor vial, evacuated several times and placed under an argon atmosphere. The sealed reaction mixture was heated at 65° C.
  • 3,4-Difluorophenyl isocyanate (198.0 mg, 1.28 mmol) was added under an atmosphere of argon to a solution of methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (90.0 mg, 0.255 mmol) in anhydrous methylene chloride (1.27 mL) at room temperature.
  • Example B-7 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Lithium hydroxide monohydrate (107.0 mg, 2.55 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-6 (160.0 mg, 0.255 mmol) in a 1:1:1 mixture of tetrahydrofuran:water:methanol (5.10 mL) at room temperature. After 12 h of vigorous stirring, the reaction mixture was diluted with water (40 mL) and washed with methylene chloride (50 mL).
  • Example B-9 2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Example B-9 was prepared by the procedure described for step b3, using methyl 2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-8 as starting material.
  • the reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL).
  • the aqueous layer was extracted with methylene chloride (3 ⁇ 30 mL); the combined extracts were successively washed with an aqueous solution of pH 7 phosphate buffer (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
  • Example B-11 2-((1r,4r)-4-(4-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Example B-11 was prepared by the procedure described for step b3, using (S)-tert-butyl 2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylate B-10 as starting material.
  • Example B-12 2-((1r,4r)-4-(4-(1-((S)-pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b9
  • the aqueous layer was extracted with ethyl acetate (3 ⁇ 40 mL); the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the crude residue (43.1 mg) contained 90% pure B-12.
  • the aqueous layer was concentrated under reduced pressure to a volume of ca 2 mL, then filtered.
  • Example B-18 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-18 was prepared by the procedure described for step b6, using methyl 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-17 as starting material.
  • Example B-20 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-20 was prepared by the procedure described for step b6, using methyl 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-19 as starting material.
  • Example B-21 2-((1r,4r)-4-(4-(2-methyl-3-oxo-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b11
  • Phenyl isocyanate (9.0 ⁇ L, 0.084 mmol) was added under argon to a solution of 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid B-20 (28.9 mg, 0.076 mmol) and N,N-dimethylaminopyridine (2.0 mg, 0.016 mmol) in anhydrous methylene chloride (0.5 mL) and anhydrous DMSO (0.5 mL) at room temperature.
  • Triethylamine was added dropwise to a solution of 4-bromo-2-fluoroaniline B-22 (600 mg, 3.158 mmol) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.915 mL, 6.315 mmol) in anhydrous methylene chloride (10.2 mL) at room temperature. After 20 mins, additional methylene chloride (10.2 mL) was added, and the resulting suspension was stirred at room temperature for 90 mins. The reaction mixture was diluted with methylene chloride (50 mL), quenched with an aqueous pH 7 phosphate buffer solution (60 mL) and decanted.
  • reaction mixture was diluted with ethyl acetate (30 mL), quenched with an aqueous pH 7 phosphate buffer solution (25 mL) and decanted.
  • aqueous layer was extracted with ethyl acetate (3 ⁇ 30 mL); the combined organic extracts were then successively washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example B-27 methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b5
  • Example B-27 was prepared by the procedure described for step b5, using methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-26 as starting material.
  • Example B-28 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b14
  • Lithium hydroxide monohydrate (12.1 mg, 0.29 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-27 (ca. 100.0 mg, 0.19 mmol) in a 1:1:1 mixture of tetrahydrofuran:water:methanol (1.90 mL) at room temperature. The reaction mixture was heated at 60° C. under microwave irradiation for 30 mins.
  • Example B-34 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-34 was prepared by the procedure described for step b6, using the 1:1 mixture of regioisomers B-33 as starting material.
  • Example B-35 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-35 was prepared by the procedure described for step b6, using the 1:1 mixture of regioisomers B-33 as starting material.
  • reaction mixture was degassed several times under reduced pressure and stirred for 12 h under an atmosphere of argon.
  • the mixture was then filtered through a celite pad, washed with ethyl acetate (25 mL) and concentrated to dryness under reduced pressure.
  • Phenyl isocyanate (32.0 ⁇ L, 0.294 mmol) was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-39 (117.2 mg, 0.267 mmol) in methylene chloride (2.70 mL) at 0° C. under an atmosphere of argon. The reaction mixture was warmed slowly to room temperature, stirred for 12 h, then quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure.
  • Example B-41 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b14
  • reaction mixture was stirred for 16 h, then sequentially diluted with methylene chloride, washed with a 1 N aqueous solution of hydrogen chloride (5.0 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Example B-44 2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b14
  • N-Ethyl-N,N-diisopropylamine (64.5 mg, 0.50 mmol) was added at room temperature to a solution of aniline (465.0 mg, 0.50 mmol), 7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)quinoline-4-carboxylic acid B-46 (101.0 mg, 0.25 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (190.0 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen.
  • the reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3 ⁇ 30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Example B-48 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid—step b24
  • a 1 N aqueous solution of sodium hydroxide (3.0 mL) was added to a solution of methyl 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetate B-47 (94.0 mg, 0.20 mmol) in a 1:5 mixture of tetrahydrofuran: methanol (10.0 mL) at room temperature. After 12 h of vigorous stirring, the aqueous layer was then acidified to pH 1 using a 1 N aqueous solution of hydrogen chloride. The resulting solution was concentrated to dryness under reduced pressure.
  • Example B-52 methyl 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetate—step b27
  • reaction mixture was degassed several times under reduced pressure, heated at 120° C. and stirred for 15 h.
  • the mixture was then filtered through a celite pad, washed with ethyl acetate (30 mL) and concentrated to dryness under reduced pressure.
  • Example B-53 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Example B-53 was prepared by the procedure described for step b3, using methyl 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetate B-52 as starting material.
  • reaction mixture was allowed to warm to room temperature, then stirred for 15 mins and treated with acetic acid (47 ⁇ L, 0.80 mmol).
  • acetic acid 47 ⁇ L, 0.80 mmol.
  • the reaction mixture was stirred at room temperature for 12 h and then treated with a 10% solution of potassium carbonate (3.0 mL) and decanted.
  • the aqueous layer was extracted with methylene chloride (3 ⁇ 30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Example B-57 2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetic acid—step b24
  • Example B-57 was prepared by the procedure described for step b24, using methyl 2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate B-56 as starting material.
  • Example C-1 2-((1r,4r)-4-(4-(1-(4-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-2 2-((1r,4r)-4-(4-(1-(3-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-3 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-4 2-((1r,4r)-4-(4-(1-(pyridin-3-ylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-5 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-6 2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-7 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)phenyl)cyclohexyl)acetic acid
  • Example C-8 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-9 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-10 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-11 2-((1s,4s)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-12 2-(4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)piperazin-1-yl)acetic acid
  • Example C-13 (1R,2S)-2-(4-(1-(phenylcarbamoyl)indolin-5-yl)benzoyl)cyclopentanecarboxylic acid
  • Example C-15 2-((1r,4r)-4-(4-(4-(benzo[d]oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-16 2-((1r,4r)-4-(4-(2-(phenylamino)quinazolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-17 2-((1r,4r)-4-(4-(2-(phenylamino)benzo[d]oxazol-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-18 2-((1r,4r)-4-(4-(3-(phenylcarbamoyl)-1H-indol-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-21 2-((1r,4r)-4-(4-(4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-22 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1H-indazol-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-28 2-((1r,4r)-4-(4-(4-(4-(cyanomethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-29 2-((1r,4r)-4-(4-(4-(2-(methoxycarbonyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-31 2-((1r,4r)-4-(4-(4-(2-chloro-6-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-32 2-((1r,4r)-4-(4-(4-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-33 2-((1r,4r)-4-(4-(1-(3-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-34 2-((1r,4r)-4-(4-(1-(3-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-35 2-((1r,4r)-4-(4-(1-(2-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-36 2-((1r,4r)-4-(4-(4-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-38 2-((1r,4r)-4-(4-(1-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-40 2-((1r,4r)-4-(4-(1-(piperidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-41 2-((1r,4r)-4-(4-(1-(cyclopentylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-44 2-((1r,4r)-4-(4-(1-(phenylcarbamothioyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-45 2-((1r,4r)-4-(4-(1-(2-phenylacetyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-46 2-((1r,4r)-4-(4-(1-(morpholine-4-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-48 2-((1r,4r)-4-(4-(1-heptanoylindolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-49 2-((1r,4r)-4-(4-(1-(diisopropylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-50 2-((1r,4r)-4-(4-(2-(phenylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-51 2-((1r,4r)-4-(4-(1-(4-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-52 2-((1r,4r)-4-(4-(1-(3,5-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-53 2-((1r,4r)-4-(4-(1-(2,6-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-54 2-((1r,4r)-4-(4-(1-(2-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-55 2-((1r,4r)-4-(4-(1-(3-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-56 2-((1r,4r)-4-(4-(1-(2-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-58 2-((1r,4r)-4-(4-(1-(benzylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-60 2-((1r,4r)-4-(4-(1-(1-adamantylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-62 2-((1r,4r)-4-(4-(4-(3-fluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-66 2-((1r,4r)-4-(4-(4-(2-chlorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-68 2-((1r,4r)-4-(4-(4-(tert-butylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-70 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-72 2-((1r,4r)-4-(4-(1-(2-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-74 2-((1r,4r)-4-(4-(1-(4-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-75 2-((1r,4r)-4-(4-(1-(2-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Example C-76 2-((1r,4r)-4-(4-(4-(m-tolylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-78 2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-80 2-((1r,4r)-4-(4-(2-isopropyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-81 2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-83 2-((1r,4r)-4-(4-(2-(phenylamino)quinoxalin-6-yl)phenyl)cyclohexyl)acetic acid
  • Example C-84 2-((1r,4r)-4-(4-(4-(4-chloro-2-fluorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-86 2-((1r,4r)-4-(4-(4-(3-chloro-4-fluorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-88 2-((1r,4r)-4-(4-(4-(2-methoxy-5-methylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-96 2-((1r,4r)-4-(4-(4-(benzylsulfonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-100 2-((1r,4r)-4-(4-(4-(3,5-difluorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-101 2-((1r,4r)-4-(4-(4-(3,4-difluorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-102 2-((1r,4r)-4-(4-(4-(4-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-103 2-((1r,4r)-4-(4-(4-(3-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-104 2-((1r,4r)-4-(4-(2-ethyl-4-(4-methoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-105 2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-106 2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-110 2-((1r,4r)-4-(4-(2-methyl-4-(4-(trifluoromethoxy)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Example C-111 2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid

Abstract

The present invention relates to novel heterocyclic compounds as diacylglycerol acyltransferase (“DGAT”) inhibitors, pharmaceutical compositions comprising the heterocyclic compounds and the use of the compounds for treating or preventing a cardiovascular disease, a metabolic disorder, obesity or an obesity-related disorder, diabetes, dyslipidemia, a diabetic complication, impaired glucose tolerance or impaired fasting glucose. An illustrative compound of the invention is shown below (I).

Description

    FIELD OF THE INVENTION
  • The present invention relates to certain heterocyclic compounds useful as diacylglycerol acyltransferase (“DGAT”) inhibitors, especially diacylglycerol acyltransferase 1 (“DGAT1”) inhibitors, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat or prevent various diseases including cardiovascular disease, dyslipidemia, obesity and diabetes (e.g., Type 2 diabetes).
    • BACKGROUND OF THE INVENTION
  • There is a need for additional ways of treating diseases associated with metabolic syndrome such as, for example, dyslipidemia, cardiovascular disease, obesity and diabetes (e.g., Type 2 diabetes).
  • Triglycerides or triacylglycerols are the major form of energy storage in eukaryotic organisms. In mammals, these compounds are primarily synthesized in three tissues: the small intestine, liver, and adipocytes. Triglycerides or triacylglycerols support the major functions of dietary fat absorption, packaging of newly synthesized fatty acids and storage in fat tissue (see Subauste and Burant, Current Drug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3, pp. 263-270).
  • Diacylglycerol O-acyltransferase, also known as diglyceride acyltransferase or DGAT, is a key enzyme in triglyceride synthesis. DGAT catalyzes the final and rate-limiting step in the triacylglycerol synthesis from 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA as substrates. Thus, DGAT plays an essential role in the metabolism of cellular diacylglycerol and is critically important for triglyceride production and energy storage homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182, pp. 395-400).
  • Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2 [see Cases et al, Proceedings of the National Academy of Science, USA (1998) 95, pp. 13018-13023, Lardizabal et al, Journal of Biological Chemistry (2001) 276, pp. 38862-38869 and Cases et al, Journal of Biological Chemistry (2001) 276, pp. 38870-38876]. Although both enzymes utilize the same substrates, there is no homology between DGAT1 and DGAT2. Both enzymes are widely expressed. However, some differences do exist in the relative abundance of expression in various tissues.
  • Disorders or imbalances in triglyceride metabolism, both absorption as well as de novo synthesis, have been implicated in the pathogenesis of a variety of disease risks. These include obesity, insulin resistance syndrome, Type II diabetes, dyslipidemia, metabolic syndrome (syndrome X) and coronary heart disease [see Kahn, Nature Genetics (2000) 25, pp. 6-7, Yanovski and Yanovski, New England Journal of Medicine (2002) 346, pp. 591-602, Lewis et al, Endocrine Reviews (2002) 23, pp. 201, Brazil, Nature Reviews Drug Discovery (2002) 1, pp. 408, Malloy and Kane, Advances in Internal Medicine (2001) 47, pp. 111, Subauste and Burant, Current Drug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3, pp. 263-270 and Yu and Ginsberg, Annals of Medicine (2004) 36, pp. 252-261]. Compounds that can decrease the synthesis of triglycerides from diacylglycerol by inhibiting or lowering the activity of the DGAT enzyme would be of value as therapeutic agents for the treatment of diseases associated with abnormal metabolism of triglycerides.
  • Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack et al, EP1219716 and Burrows et al, 26th National Medicinal Chemistry Symposium (1998) poster C-22), substituted amino-pyrimidino-oxazines (see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, pp. 683-687 and Casaschi et al, Journal of Nutrition (2004) 134, pp. 1340-1346), substituted benzyl-phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, pp. 1433-1437, Goto et al, Chemistry and Pharmaceutical Bulletin (1996) 44, pp. 547-551, Ikeda et al, Thirteenth International Symposium on Atherosclerosis (2003), abstract 2P-0401, and Miyata et al, JP 2004067635), aryl alkyl acid derivatives (see Smith et al, WO2004100881 and US20040224997), furan and thiophene derivatives (see WO2004022551), pyrrolo[1,2b]pyridazine derivatives (see Fox et al, WO2005103907), and substituted sulfonamides (see Budd Haeberlein and Buckett, WO20050442500).
  • Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et al, Biochimica et Biophysica Acta (1992) pp. 1125, 203-9), 2-bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, pp. 6528-6532), roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, pp. 815-826), amidepsin (see Tomoda et al, Journal of Antibiotics (1995) 48, pp. 42-7), isochromophilone, prenylflavonoids (see Chung et al, Planta Medica (2004) 70, v58-260), polyacetylenes (see Lee et al, Planta Medica (2004) 70, pp. 97-200), cochlioquinones (see Lee et al, Journal of Antibiotics (2003) 56, pp. 967-969), tanshinones (see Ko et al, Archives of Pharmaceutical Research (2002) 25, pp. 446-448), gemfibrozil (see Zhu et al, Atherosclerosis (2002) 164, pp. 221-228), and substituted quinolones (see Ko et al, Planta Medica (2002) 68, pp. 1131-1133). Also known to be modulators of DGAT activity are antisense oligonucleotides (see Monia and Graham, US20040185559).
  • DGAT inhibitors have been described. See, for example, PCT publication US 2007/0244096 (published Oct. 31, 2007; applicant: Japan Tobacco). Claim 1 therein discloses compounds of the formula:
  • Figure US20120022057A1-20120126-C00002
  • wherein R3, R4, R5, R6, R7, X, Y, Z, L1, L2, W1, W2 and m are described.
  • See also WO 2007/126957 (published Nov. 8, 2007; applicant: Novartis Pharma). Claim 1 therein discloses compounds of the formula:

  • A-L1-B—C-D-L2-E
  • wherein A, L1, B, C, D, L2 and E are described.
  • See also WO 2008/067257 (published Jun. 5, 2008; applicant: Abbott Laboratories). Claim 1 therein discloses compounds of the formula:
  • Figure US20120022057A1-20120126-C00003
  • wherein A, Q, X, Rx, Ry, Rza, Rzb, r and s are described.
  • See also WO 2009/011285 (published Jan. 22, 2009; applicant: Taisho Pharmaceutical Co.). Claim 1 therein discloses compounds of the formula:
  • Figure US20120022057A1-20120126-C00004
  • Wherein are A, X, Y, Q, R1, R2a, and R2b are described.
  • Commonly owned U.S. provisional patent applications, Ser. Nos. 61/115,991, 61/115,995, 61/116,000, 61/115,982, 61/115,985 and 61/115,987, all filed Nov. 19, 2008, also describe DGAT inhibitors.
  • A need exists in the art, however, for additional DGAT inhibitors that have efficacy for the treatment of metabolic disorders such as, for example, obesity, Type II diabetes mellitus and metabolic syndrome.
    • SUMMARY OF THE INVENTION
  • In an embodiment, this invention discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, or pharmaceutically acceptable salts, solvates or esters of said prodrug, the compound being represented by the Formula IA:
  • Figure US20120022057A1-20120126-C00005
  • or a stereoisomer or tautomer of said compound, wherein
    • the bond denoted by
      Figure US20120022057A1-20120126-P00001
      represents a single bond or a double bond;
    • W is selected from the group consisting of C(R4), C(R4R4), N, N(R4), S or O;
    • X is selected from the group consisting of C(R4), C(R4R4), N, N(R4), S or O;
    • Y is selected from the group consisting of C(R4), C(R4R4), N, N(R4), S or O;
    • R4 is present depending on the allowed valency and R4 is selected from H, alkyl, R1, —OH, (═O), or hydroxyalkyl;
    • W, X or Y is substituted with R1 depending on the allowed valency;
    • R1 is selected from the group consisting of -alkyl, -aryl, arylalkyl-, heteroaryl-, (heteroaryl)alkyl-, cycloalkyl-, (cycloalkyl)alkyl-, heterocycloalkyl-, (heterocycloalkyl)alkyl-, (alkyl)amino-, (aryl)amino-, (arylalkyl)amino-, (heteroaryl)amino-, (heteroarylalkyl)amino-, (cycloalkyl)amino-, ((cycloalkyl)alkyl)amino-, (heterocycloalkyl)amino-, ((heterocycloalkyl)alkyl)amino-, (alkyl)carbonyl-, (cycloalkyl)carbonyl-, ((cycloalkyl)alkyl)carbonyl-, (heterocycloalkyl)carbonyl-, ((heterocyclyl)alkyl)carbonyl-, (aryl)carbonyl-, ((aryl)alkyl)carbonyl-, (heteroaryl)carbonyl-, ((heteroaryl)alkyl)carbonyl-, (alkyl)thiocarbonyl-, (cycloalkyl)thiocarbonyl-, ((cycloalkyl)alkyl)thiocarbonyl-, (heterocycloalkyl)thiocarbonyl-, ((heterocyclyl)alkyl)thiocarbonyl-, (aryl)thiocarbonyl-, ((aryl)alkyl)thiocarbonyl-, (heteroaryl)thiocarbonyl-, ((heteroaryl)alkyl)thiocarbonyl-, (alkyloxy)carbonyl-, (cycloalkyloxy)carbonyl-, (heterocycloalkyloxy)carbonyl-, (aryloxy)carbonyl-, (arylalkyloxy)carbonyl-, (heteroaryloxy)carbonyl-, (heteroarylalkyloxy)carbonyl-, (alkylamino)carbonyl-, (cycloalkylamino)carbonyl-, (heterocycloalkylamino)carbonyl-, (arylamino)carbonyl-, (arylalkylamino)carbonyl-; (heteroarylamino)carbonyl-, (heteroarylalkylamino)carbonyl-, (alkyl)sulfonyl-, (cycloalkyl)sulfonyl-, (heterocycloalkyl)sulfonyl-, (aryl)sulfonyl-, (arylalkyl)sulfonyl-, (heteroaryl)sulfonyl-, (heteroarylalkyl)sulfonyl-, (alkylamino)sulfonyl-, (cycloalkylamino)sulfonyl-, (heterocycloalkylamino)sulfonyl-, (arylamino)sulfonyl-, (arylalkylamino)sulfonyl-, (heteroarylamino)sulfonyl- and (heteroarylalkylamino)sulfonyl-, wherein each of these R1 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester, methylenedioxy, CN, cyanoalkyl-, nitro and CF3;
    • A is selected from the group consisting of C(R5) or N;
    • B is selected from the group consisting of C(R5) or N;
    • C is selected from the group consisting of C(R5) or N;
    • D is selected from the group consisting of C(R5) or N;
    • R5 is selected from H, alkyl, cycloalkyl, amino, alkylamino, hydroxy, alkoxy, halogen or R2;
    • A, B, C or D is optionally substituted, depending on the allowed vacancy, with cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each of these groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
    • R2 is selected from the group consisting of cycloalkyl, heterocyclyl, and aryl, wherein each of these R2 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
    • Z is selected from the group consisting of a bond, O, NR6, alkyl, carbonyl and sulfonyl;
    • R6 is selected from H or alkyl;
    • R3 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of these R3 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF3, —C(O)NH(R6), —CON(R6)2, —COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl, -alkyl-C(O)NH2, -alkyl-C(O)—NH—(CH2)1-3—CN, -alkyl-C(O)—NH—(CH2)1-3-(heteroaryl), —COOH bioisostere or -alkylCOOH bioisostere.
  • The term “COOH bioisostere” is as defined in The Practice of Medicinal Chemistry, C. G. Wermuth Ed.; Academic Press: New York, 1996, p. 203. Non-limiting examples of COOH bioisosteres include —SO3H, —S(O)2NHR7, —S(O)2NHC(O)R7, —CH2S(O)2R7, —C(O)NHS(O)2R7, —C(O)NHOH, —C(O)NHCN, —CH(CF3)OH, —C(CF3)2OH, —P(O)(OH)2 and the groups listed below:
  • Figure US20120022057A1-20120126-C00006
    Figure US20120022057A1-20120126-C00007
  • where R7 is selected from alkyl, aryl or heteroaryl.
  • In another aspect, this invention discloses a compound, or pharmaceutically acceptable salts, solvates, esters or prodrugs of said compound, or pharmaceutically acceptable salts, solvates or esters of said prodrug, the compound being represented by the Formula IB:
  • Figure US20120022057A1-20120126-C00008
  • or a stereoisomer or tautomer of said compound, wherein
    • the bond denoted by
      Figure US20120022057A1-20120126-P00001
      represents a single bond or a double bond;
    • E is selected from the group consisting of C(R4), C(R4R4), N, N→O, N(R4), S or O;
    • F is selected from the group consisting of C(R4), C(R4R4), N, N→O, or NR4;
    • G is selected from the group consisting of C(R4), C(R4R4), N, N→O or NR4;
    • H is selected from the group consisting of C(R4), C(R4R4), N, N→O, N(R4), S or O;
    • R4 is present depending on the allowed vacancy and is selected from H, alkyl, R1, —OH, (═O), or hydroxyalkyl;
    • E, F, G or H is substituted with R1 depending on the allowed valency;
    • R1 is selected from the group consisting of alkyl-, aryl-, arylalkyl-, heteroaryl-, (heteroaryl)alkyl-, cycloalkyl-, (cycloalkyl)alkyl-, heterocycloalkyl-, (heterocycloalkyl)alkyl-, (alkyl)amino-, (aryl)amino-, (arylalkyl)amino-, (heteroaryl)amino-, (heteroarylalkyl)amino-, (cycloalkyl)amino-, ((cycloalkyl)alkyl)amino-, (heterocycloalkyl)amino-, ((heterocycloalkyl)alkyl)amino-, (alkyl)carbonyl-, (cycloalkyl)carbonyl-, ((cycloalkyl)alkyl)carbonyl-, (heterocycloalkyl)carbonyl-, ((heterocyclyl)alkyl)carbonyl-, (aryl)carbonyl-, ((aryl)alkyl)carbonyl-, (heteroaryl)carbonyl-, ((heteroaryl)alkyl)carbonyl-, (alkyl)thiocarbonyl-, (cycloalkyl)thiocarbonyl-, ((cycloalkyl)alkyl)thiocarbonyl-, (heterocycloalkyl)thiocarbonyl-, ((heterocyclyl)alkyl)thiocarbonyl-, (aryl)thiocarbonyl-, ((aryl)alkyl)thiocarbonyl-, (heteroaryl)thiocarbonyl-, ((heteroaryl)alkyl)thiocarbonyl-, (alkyloxy)carbonyl-, (cycloalkyloxy)carbonyl-, (heterocycloalkyloxy)carbonyl-, (aryloxy)carbonyl-, (arylalkyloxy)carbonyl-, (heteroaryloxy)carbonyl-, (heteroarylalkyloxy)carbonyl-, (alkylamino)carbonyl-, (cycloalkylamino)carbonyl-, (heterocycloalkylamino)carbonyl-, (arylamino)carbonyl-, (arylalkylamino)carbonyl-, (heteroarylamino)carbonyl-, (heteroarylalkylamino)carbonyl-, (alkyl)sulfonyl-, (cycloalkyl)sulfonyl-, (heterocycloalkyl)sulfonyl-, (aryl)sulfonyl-, (arylalkyl)sulfonyl-, (heteroaryl)sulfonyl-, (heteroarylalkyl)sulfonyl-, (alkylamino)sulfonyl-, (cycloalkylamino)sulfonyl-, (heterocycloalkylamino)sulfonyl-, (arylamino)sulfonyl-, (arylalkylamino)sulfonyl-, (heteroarylamino)sulfonyl- and (heteroarylalkylamino)sulfonyl- wherein each of these R1 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester, methylenedioxy, CN, cyanoalkyl-, nitro and CF3;
    • A is selected from the group consisting of CR5 or N;
    • B is selected from the group consisting of CR5 or N;
    • C is selected from the group consisting of CR5 or N;
    • D is selected from the group consisting of CR5 or N;
    • R5 is selected from H, alkyl, cycloalkyl, amino, alkylamino, hydroxy, alkoxy, halogen or R2;
    • A, B, C or D is optionally substituted, depending on the allowed valency, with cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each of these groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
    • R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, or aryl, wherein each of these R2 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
    • Z is selected from the group consisting of a bond, O, NR6, alkyl, carbonyl and sulfonyl;
    • R6 is selected from H or alkyl; and
    • R3 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of these R3 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF3, —C(O)NH(R6), —CON(R6)2, —COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl, -alkyl-C(O)NH2, -alkyl-C(O)—NH—(CH2)1-3—CN, -alkyl-C(O)—NH—(CH2)1-3-(heteroaryl), —COOH bioisostere or -alkylCOOH bioisostere.
  • The term “COOH bioisostere” is as defined under Formula IA.
  • In another aspect, this invention provides compositions comprising at least one compound of Formula IA or Formula IB.
  • In another aspect, this invention provides pharmaceutical compositions comprising at least one compound of Formula IA or Formula IB and at least one pharmaceutically acceptable carrier.
  • In another aspect, this invention provides a method of treating diabetes in a patient in need of such treatment using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • In another aspect, this invention provides a method of treating diabetes in a patient in need of such treatment, e.g., Type 2 diabetes, using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • In another aspect, this invention provides a method of treating metabolic syndrome in a patient in need of such treatment, using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • In another aspect, this invention provides a method of inhibiting DGAT using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
  • In another aspect, this invention provides a method of inhibiting DGAT1 using therapeutically effective amounts of at least one compound of Formula IA or Formula IB, or of a composition comprising at least one compound of Formula IA or Formula IB.
    • DESCRIPTION OF THE INVENTION
  • In an embodiment, the present invention discloses compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof.
  • The following embodiments (stated as “another embodiment”) are independent of one another; different such embodiments can be independently selected and combined in various combinations. Such combinations should be considered as part of the invention. The thus described embodiments are applicable independently to Formula IA and Formula IB as appropriate.
  • In another embodiment, W is C(R4).
  • In another embodiment, W is C(R4R4).
  • In another embodiment, W is N.
  • In another embodiment, W is N(R4).
  • In another embodiment, W is S.
  • In another embodiment, W is O.
  • In another embodiment, X is C(R4).
  • In another embodiment, X is C(R4R4).
  • In another embodiment, X is N.
  • In another embodiment, X is N(R4).
  • In another embodiment, X is S.
  • In another embodiment, X is O.
  • In another embodiment, Y is C(R4).
  • In another embodiment, Y is C(R4R4).
  • In another embodiment, Y is N.
  • In another embodiment, Y is N(R4).
  • In another embodiment, Y is S.
  • In another embodiment, Y is O.
  • In another embodiment, W═X═N.
  • In another embodiment, W═Y═N.
  • In another embodiment, X═Y═N.
  • In another embodiment,
    Figure US20120022057A1-20120126-P00002
    represents a single bond.
  • In another embodiment,
    Figure US20120022057A1-20120126-P00003
    represents a double bond.
  • In another embodiment in Formula IB, both
    Figure US20120022057A1-20120126-P00001
    represent double bonds.
  • In another embodiment in Formula IB, both
    Figure US20120022057A1-20120126-P00001
    represent single bonds.
  • In another embodiment in Formula IB, one
    Figure US20120022057A1-20120126-P00001
    represents a double bond and the other
    Figure US20120022057A1-20120126-P00001
    represents a single bond.
  • In another embodiment, R1 is alkyl.
  • In another embodiment, R1 is aryl.
  • In another embodiment, R1 is arylalkyl.
  • In another embodiment, R1 is cycloalkyl.
  • In another embodiment, R1 is cycloalkylalkyl.
  • In another embodiment, R1 is heterocyclyl.
  • In another embodiment, R1 is heterocyclylalkyl.
  • In another embodiment, R1 is heteroaryl.
  • In another embodiment, R1 is heteroarylalkyl.
  • In another embodiment, R1 is alkylcarbonyl.
  • In another embodiment, R1 is arylcarbonyl.
  • In another embodiment, R1 is cycloalkylcarbonyl.
  • In another embodiment, R1 is (cycloalkyl)alkylcarbonyl.
  • In another embodiment, R1 is heteroarylcarbonyl.
  • In another embodiment, R1 is heterocyclylcarbonyl.
  • In another embodiment, R1 is (heterocyclyl)alkylcarbonyl.
  • In another embodiment, R1 is (aryl)alkylcarbonyl.
  • In another embodiment, R1 is (heteroaryl)alkylcarbonyl.
  • In another embodiment, R1 is (alkylthio)carbonyl-.
  • In another embodiment, R1 is (alkoxy)carbonyl-.
  • In another embodiment, R1 is (alkylamino)carbonyl.
  • In another embodiment, R1 is (arylamino)carbonyl-.
  • In another embodiment, R1 is (heteroarylamino)carbonyl-.
  • In another embodiment, R1 is (heterocyclylamino)carbonyl.
  • In another embodiment, R1 is (cycloalkylamino)carbonyl.
  • In another embodiment, R1 is (heterocyclylamino)sulfonyl.
  • In another embodiment, R1 is (arylamino)sulfonyl-.
  • In another embodiment, R1 is (heteroarylamino)sulfonyl.
  • In another embodiment, R1 comes off a ring carbon on the ring shown in Formula IA or IB.
  • In another embodiment, R1 comes off a ring nitrogen on the ring shown in Formula IA or IB.
  • In another embodiment, E is C(R4).
  • In another embodiment, E is C(R4R4).
  • In another embodiment, E is N.
  • In another embodiment, E is N(R4).
  • In another embodiment, E is S.
  • In another embodiment, E is O.
  • In another embodiment, H is C(R4).
  • In another embodiment, H is C(R4R4).
  • In another embodiment, H is N.
  • In another embodiment, H is N(R4).
  • In another embodiment, H is S.
  • In another embodiment, H is O.
  • In another embodiment, F is C(R4).
  • In another embodiment, F is C(R4R4).
  • In another embodiment, F is N.
  • In another embodiment, F is N(R4).
  • In another embodiment, G is C(R4).
  • In another embodiment, G is C(R4R4).
  • In another embodiment, G is N.
  • In another embodiment, G is N(R4).
  • In another embodiment, E=F═N.
  • In another embodiment, E=G=N.
  • In another embodiment, F═H═N.
  • In another embodiment, E=F=G=H.
  • In another embodiment, A is C(R5).
  • In another embodiment, A is N.
  • In another embodiment, B is C(R5).
  • In another embodiment, B is N.
  • In another embodiment, C is C(R5).
  • In another embodiment, C is N.
  • In another embodiment, D is C(R5).
  • In another embodiment, D is N.
  • In another embodiment, R5 is H.
  • In another embodiment, R5 is alkyl.
  • In another embodiment, R5 is methyl.
  • In another embodiment, R5 is cycloalkyl.
  • In another embodiment, R5 is amino.
  • In another embodiment, R5 is alkylamino.
  • In another embodiment, R5 is —OH.
  • In another embodiment, R5 is alkoxy.
  • In another embodiment, R5 is halo.
  • In another embodiment, R5 is chloro.
  • In another embodiment, R5 is R2, where R2 is as defined.
  • In another embodiment, R2 is cycloalkyl.
  • In another embodiment, R2 is aryl.
  • In another embodiment, R2 is heterocyclyl.
  • In another embodiment, R6 is H.
  • In another embodiment, R6 is alkyl.
  • In another embodiment, Z is a bond.
  • In another embodiment, Z is O.
  • In another embodiment, Z is N(R4).
  • In another embodiment, Z is alkyl.
  • In another embodiment, Z is carbonyl.
  • In another embodiment, Z is sulfonyl.
  • In another embodiment, R3 is cycloalkyl.
  • In another embodiment, R3 is aryl.
  • In another embodiment, R3 is heteroaryl.
  • In another embodiment, R3 is heterocyclyl.
  • In another embodiment, R3 is unsubstituted.
  • In another embodiment, R3 is substituted with one moiety as described earlier.
  • In another embodiment, R3 is substituted with more than one moiety as described earlier.
  • In another embodiment, R3 is substituted with an alkyl.
  • In another embodiment, R3 is substituted with a lower alkyl.
  • In another embodiment, R3 is substituted with a —C(O)NH(R6).
  • In another embodiment, R3 is substituted with a —C(O)N(R6)2.
  • In another embodiment, R3 is substituted with a carboxyl or carboxyester.
  • In another embodiment, R3 is substituted with COOH bioisostere, wherein COOH bioisostere is as defined earlier.
  • In another embodiment, R3 is substituted with halo.
  • In another embodiment, R3 is substituted with cyano.
  • In another embodiment, R3 is substituted with —OR5.
  • In another embodiment, R3 is substituted with —N(R4R5).
  • In another embodiment, R3 is substituted with —C(O)—N(R4R5).
  • In another embodiment, R3 is substituted with both halo and carboxyl.
  • In another embodiment, R3 is substituted with both —OR5 and carboxyl.
  • In another embodiment, R3 is substituted with both carboxy and alkyl-.
  • In another embodiment, R3 is substituted with -alkyl)-C(O)N(R4R5).
  • In another embodiment, in Formula IA, the moiety:
  • Figure US20120022057A1-20120126-C00009
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00010
  • In another embodiment, in Formula IA, the moiety:
  • Figure US20120022057A1-20120126-C00011
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00012
  • In another embodiment, in Formula IA, the moiety:
  • Figure US20120022057A1-20120126-C00013
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00014
  • In another embodiment, in Formula IA, the moiety:
  • Figure US20120022057A1-20120126-C00015
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00016
  • In another embodiment, in Formula IA, the moiety:
  • Figure US20120022057A1-20120126-C00017
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00018
  • In another embodiment, in Formula IB, the moiety:
  • Figure US20120022057A1-20120126-C00019
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00020
  • In another embodiment, in Formula IB, the moiety:
  • Figure US20120022057A1-20120126-C00021
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00022
  • In another embodiment, in Formula IB, the moiety:
  • Figure US20120022057A1-20120126-C00023
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00024
  • In another embodiment, in Formula IB, the moiety:
  • Figure US20120022057A1-20120126-C00025
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00026
  • In another embodiment, in Formula IB, the moiety:
  • Figure US20120022057A1-20120126-C00027
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00028
  • In another embodiment, in Formula IB, the moiety:
  • Figure US20120022057A1-20120126-C00029
  • represents the moiety:
  • Figure US20120022057A1-20120126-C00030
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is C, X is C, Y is C, Z is aryl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is C, Y is C, Z is aryl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is aryl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is aryl, R1 is (arylamino)carbonyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is aryl, R1 is (arylamino)carbonyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is aryl, R1 is arylcarbonyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is aryl, R1 is arylcarbonyl, R3 is cycloalkyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is phenyl, R1 is (arylamino)carbonyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is phenyl, R1 is (arylamino)carbonyl, R3 is cycloalkyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is biphenyl, R1 is (arylamino)carbonyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is biphenyl, R1 is (arylamino)carbonyl, R3 is cycloalkyl, and the others are as previously defined.
  • In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z, R1, R2, and R3 and any remaining moieties are independently selected, W is N, X is N, Y is C, Z is biphenyl, R1 is (arylamino)carbonyl, R3 is cycloalkyl, and the others are as previously defined.
  • Non-limiting examples of the compounds of Formula IA or Formula IB are shown below as well as in the Examples section:
  • Figure US20120022057A1-20120126-C00031
    Figure US20120022057A1-20120126-C00032
    Figure US20120022057A1-20120126-C00033
    Figure US20120022057A1-20120126-C00034
    Figure US20120022057A1-20120126-C00035
    Figure US20120022057A1-20120126-C00036
    Figure US20120022057A1-20120126-C00037
    Figure US20120022057A1-20120126-C00038
    Figure US20120022057A1-20120126-C00039
    Figure US20120022057A1-20120126-C00040
    Figure US20120022057A1-20120126-C00041
    Figure US20120022057A1-20120126-C00042
  • or pharmaceutically acceptable salts, solvates, esters and prodrugs thereof.
  • Additional non-limiting examples of the present invention are the compounds of the following formula:
  • Figure US20120022057A1-20120126-C00043
    Figure US20120022057A1-20120126-C00044
    Figure US20120022057A1-20120126-C00045
    Figure US20120022057A1-20120126-C00046
    Figure US20120022057A1-20120126-C00047
    Figure US20120022057A1-20120126-C00048
    Figure US20120022057A1-20120126-C00049
    Figure US20120022057A1-20120126-C00050
    Figure US20120022057A1-20120126-C00051
    Figure US20120022057A1-20120126-C00052
    Figure US20120022057A1-20120126-C00053
    Figure US20120022057A1-20120126-C00054
    Figure US20120022057A1-20120126-C00055
    Figure US20120022057A1-20120126-C00056
    Figure US20120022057A1-20120126-C00057
    Figure US20120022057A1-20120126-C00058
    Figure US20120022057A1-20120126-C00059
    Figure US20120022057A1-20120126-C00060
    Figure US20120022057A1-20120126-C00061
    Figure US20120022057A1-20120126-C00062
    Figure US20120022057A1-20120126-C00063
    Figure US20120022057A1-20120126-C00064
    Figure US20120022057A1-20120126-C00065
    Figure US20120022057A1-20120126-C00066
    Figure US20120022057A1-20120126-C00067
    Figure US20120022057A1-20120126-C00068
    Figure US20120022057A1-20120126-C00069
    Figure US20120022057A1-20120126-C00070
    Figure US20120022057A1-20120126-C00071
    Figure US20120022057A1-20120126-C00072
    Figure US20120022057A1-20120126-C00073
    Figure US20120022057A1-20120126-C00074
    Figure US20120022057A1-20120126-C00075
    Figure US20120022057A1-20120126-C00076
  • or pharmaceutically acceptable salts, solvates, esters and prodrugs thereof.
  • Several of the above-noted compounds exhibited IC50 values less than 3 μM in the assay described on page 84. Many compounds exhibited IC50 values less than 1 μM, with some compounds under <100 nM.
  • As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
  • “Patient” includes both humans and animals.
  • “Mammal” means humans and other mammalian animals.
  • “Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, pyridine, alkoxy, alkylthio, amino, oxime (e.g., ═N—OH), —NH(alkyl), —NH(cycloalkyl), —N(alkyl)2, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and —C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • “Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.
  • “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. Lower alkynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • “Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
  • “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridine (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • “Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • “Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • “Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, and the like.
  • “Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
  • “Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • “Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • “Halogen” or “halo” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • “Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)—NH(alkyl), oxime (e.g., ═N—OH), Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)—, Y1Y2NSO2— and —SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. “Ring system substituent” may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, —C(CH3)2— and the like which form moieties such as, for example:
  • Figure US20120022057A1-20120126-C00077
  • “Heteroarylalkyl” means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • “Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • Figure US20120022057A1-20120126-C00078
  • “Heterocyclylalkyl” means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • “Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl” may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
  • Figure US20120022057A1-20120126-C00079
  • “Heterocyclenylalkyl” means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • It should be noted that in heteroatom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
  • Figure US20120022057A1-20120126-C00080
  • there is no —OH attached directly to carbons marked 2 and 5.
  • It should also be noted that tautomeric forms such as, for example, the moieties:
  • Figure US20120022057A1-20120126-C00081
  • are considered equivalent in certain embodiments of this invention.
  • “Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • “Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • “Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
  • “Aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.
  • “Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
  • “Alkoxyalkyl-” means an alkyl-O-alkyl- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxyalkyl groups include methoxymethyl, ethoxymethyl, n-propoxyethyl, isopropoxyethyl and n-butoxymethyl. The bond to the parent moiety is through the alkyl.
  • “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
  • “Aryloxyalkyl-” means an aryl-O-alkyl- group in which the aryl and aryl groups are as previously described. Non-limiting examples of suitable aryloxyalkyl groups include phenoxymethyl and naphthoxyethyl. The bond to the parent moiety is through the alkyl.
  • “Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
  • “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
  • “Alkylthioalkyl-” means an alkyl-S-alkyl- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthioalkyl groups include methylthioethyl and ethylthiomethyl. The bond to the parent moiety is through the alkyl.
  • “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
  • “Arylthioalkyl-” means an aryl-S-alkyl- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthioalkyl groups include phenylthioethyl and phenylthiomethyl. The bond to the parent moiety is through the alkyl.
  • “Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
  • “Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • “Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • “Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • “Alkylsulfonyl” means an alkyl-S(O2)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • “Arylsulfonyl” means an aryl-S(O2)— group. The bond to the parent moiety is through the sulfonyl.
  • The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.
  • The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula IA or Formula IB, its definition on each occurrence is independent of its definition at every other occurrence.
  • As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula IA or Formula IB or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • For example, if a compound of Formula IA or Formula IB or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
  • Similarly, if a compound of Formula IA or Formula IB contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N—(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, —P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
  • If a compound of Formula IA or Formula IB incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or benzyl, —C(OY2)Y3 wherein Y2 is (C1-C4)alkyl and Y3 is (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N or di-N,N—(C1-C6)alkylaminoalkyl, —C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N—(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., (2004) 93 (3), pp. 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., (2004) 5 (1), article 12; and A. L. Bingham et al, Chem. Commun., (2001) pp. 603-604. A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • The term “effective” or ‘therapeutically effective” is used herein, unless otherwise indicated, to describe an amount of a compound or composition which, in context, is used to produce or effect an intended result or therapeutic effect as understood in the common knowledge of those skilled in the art.
  • The compounds of Formula IA or Formula IB can form salts which are also within the scope of this invention. Reference to a compound of Formula IA or Formula IB herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula IA or Formula IB contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula IA or Formula IB may be formed, for example, by reacting a compound of Formula IA or Formula IB with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) pp. 1-19; P. Gould, International J. of Pharmaceutics (1986) (2001) 33, pp. 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
  • Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di(C6-24)acyl glycerol.
  • Compounds of Formula IA or Formula IB, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • The compounds of Formula IA or Formula IB may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula IA or Formula IB as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula IA or Formula IB incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula IA or Formula IB may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
  • It is also possible that the compounds of Formula IA or Formula IB may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula IA or Formula IB incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36Cl and 123I, respectively.
  • Certain isotopically-labelled compounds of Formula IA or Formula IB (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14O) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula IA or Formula IB can be useful for medical imaging purposes. e.g., those labeled with positron-emitting isotopes like 11C or 18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula IA or Formula IB, in particular those containing isotopes with longer half lives (T1/2>1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • Polymorphic forms of the compounds of Formula IA or Formula IB, and of the salts, solvates, esters and prodrugs of the compounds of Formula IA or Formula IB, are intended to be included in the present invention.
  • The compounds according to the invention have pharmacological properties. The compounds of Formula IA or Formula IB are inhibitors of DGAT, particularly DGAT1, and can be useful for the therapeutic and/or prophylactic treatment of diseases that are modulated by DGAT, particularly by DGAT1, such as, for example, metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), obesity and the like.
  • The invention also includes methods of treating diseases that are modulated by DGAT, particularly by DGAT1.
  • The invention also includes methods of treating metabolic syndrome, diabetes (e.g., Type 2 diabetes mellitus), and obesity in a patient by administering at least one compound of Formula IA or Formula IB to said patient.
  • Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose, or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Abnormal glucose homeostasis is associated with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. As such, the diabetic patient is at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Accordingly, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissue (muscle, liver and adipose tissue), and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
  • Insulin resistance is not associated with a diminished number of insulin receptors but rather to a post-insulin receptor binding defect that is not well understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • The available treatments for Type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic [beta]-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides are a class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia. However, the biguanides can induce lactic acidosis and nausea/diarrhea.
  • The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a separate class of compounds with potential for the treatment of Type 2 diabetes. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type 2 diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have been noted in some patients treated with glitazone drugs, such as troglitazone.
  • Additional methods of treating the disease are currently under investigation. New biochemical approaches include treatment with alpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase-1B (PTP-1B) inhibitors.
  • Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type 2 diabetes.
  • The invention includes compositions, e.g., pharmaceutical compositions, comprising at least one compound of Formula IA or Formula IB. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Other carriers include Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogs thereof, or gamma-cyclodextrin or analogs thereof. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
  • The therapeutic agents of the present invention are preferably formulated in pharmaceutical compositions and then, in accordance with the methods of the invention, administered to a subject, such as a human subject, in a variety of forms adapted to the chosen route of administration. For example, the therapeutic agents may be formulated for intravenous administration. The formulations may, however, include those suitable for oral, rectal, vaginal, topical, nasal, ophthalmic, or other parenteral administration (including subcutaneous, intramuscular, intrathecal, intraperitoneal and intratumoral, in addition to intravenous) administration.
  • Formulations suitable for parenteral administration conveniently include a sterile aqueous preparation of the active agent, or dispersions of sterile powders of the active agent, which are preferably isotonic with the blood of the recipient. Parenteral administration of the therapeutic agents (e.g., through an I.V. drip) is an additional form of administration. Isotonic agents that can be included in the liquid preparation include sugars, buffers, and sodium chloride. Solutions of the active agents can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions of the active agent can be prepared in water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, glycerol esters, and mixtures thereof. The ultimate dosage form is sterile, fluid, and stable under the conditions of manufacture and storage. The necessary fluidity can be achieved, for example, by using liposomes, by employing the appropriate particle size in the case of dispersions, or by using surfactants. Sterilization of a liquid preparation can be achieved by any convenient method that preserves the bioactivity of the active agent, preferably by filter sterilization. Preferred methods for preparing powders include vacuum drying and freeze drying of the sterile injectible solutions. Subsequent microbial contamination can be prevented using various antimicrobial agents, for example, antibacterial, antiviral and antifungal agents including parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Absorption of the active agents over a prolonged period can be achieved by including agents for delaying, for example, aluminum monostearate and gelatin.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the active agent as a powder or granules, as liposomes containing the first and/or second therapeutic agents, or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught. Such compositions and preparations may contain at least about 0.1 wt-% of the active agent. The amounts of the therapeutic agents should be such that the dosage level will be effective to produce the desired result in the subject.
  • Nasal spray formulations include purified aqueous solutions of the active agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye. Topical formulations include the active agent dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
  • The tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose, or aspartame; and a natural or artificial flavoring agent. When the unit dosage form is a capsule, it may further contain a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like. A syrup or elixir may contain one or more of a sweetening agent, a preservative such as methyl- or propylparaben, an agent to retard crystallization of the sugar, an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, a dye, and flavoring agent. The material used in preparing any unit dosage form is substantially nontoxic in the amounts employed. The active agent may be incorporated into sustained-release preparations and devices.
  • Preferably the compound is administered orally, intraperitoneally, or intravenously or intrathecally or some suitable combination(s) thereof.
  • Methods of administering small molecule therapeutic agents are well-known in the art.
  • The therapeutic agents described in the present disclosure can be administered to a subject alone or together (coadministered, optionally but not necessarily, in a single formulation) with other active agents as described herein, and are preferably administered with a pharmaceutically acceptable buffer. The therapeutic agents can be combined with a variety of physiological acceptable carriers, additives for delivery to a subject, including a variety of diluents or excipients known to those of ordinary skill in the art. For example, for parenteral administration, isotonic saline is preferred. For topical administration, a cream, including a carrier such as dimethylsulfoxide (DMSO), or other agents typically found in topical creams that do not block or inhibit activity of the peptide, can be used. Other suitable carriers include, but are not limited to, alcohol, phosphate buffered saline, and other balanced salt solutions.
  • The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Preferably, such methods include the step of bringing the therapeutic agent (i.e., the active agent) into association with a carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations. The methods of the invention include administering the therapeutic agents to a subject in an amount effective to produce the desired effect. The therapeutic agents can be administered as a single dose or in multiple doses. Useful dosages of the active agents can be determined by comparing their in vitro activity and the in vivo activity in animal models.
  • The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • Another aspect of the invention includes pharmaceutical compositions comprising at least one compound of Formula IA or Formula IB and at least one other therapeutic agent in combination. Non-limiting examples of such combination agents are described below. The agents in the combination can be administered together as a joint administration (e.g., joint single pill), separately, one after the other in any order and the like as is well known in the art.
  • In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
    • Combination Therapy
  • Accordingly, in one embodiment, the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Compounds of Formula IA or Formula IB, or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent that is not a Compound of Formula IA or Formula IB, wherein the amounts administered are together effective to treat or prevent a Condition.
  • When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • In one embodiment, the one or more Compounds of Formula IA or Formula IB is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • In another embodiment, the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • In another embodiment, the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • In still another embodiment, the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • In one embodiment, the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration.
  • The one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • In one embodiment, the administration of one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents.
  • In one embodiment, when the patient is treated for diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose, the other therapeutic is an antidiabetic agent which is not a Compound of Formula IA or Formula IB.
  • In another embodiment, the other therapeutic agent is an agent useful for reducing any potential side effect of a Compound of Formula IA or Formula IB. Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
  • In one embodiment, the other therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the other therapeutic agent is used at its normally prescribed dosage. In another embodiment, the other therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
  • Examples of antidiabetic agents useful in the present methods for treating diabetes or a diabetic complication include a sulfonylurea; an insulin sensitizer (such as a PPAR agonist, a DPP-IV inhibitor, a PTP-1B inhibitor and a glucokinase activator); a glucosidase inhibitor; an insulin secretagogue; a hepatic glucose output lowering agent; an anti-obesity agent; a meglitinide; an agent that slows or blocks the breakdown of starches and sugars in vivo; an histamine H3 receptor antagonist; a sodium glucose uptake transporter 2 (SGLT-2) inhibitor; a peptide that increases insulin production; and insulin or any insulin-containing composition.
  • In one embodiment, the antidiabetic agent is an insulin sensitizer or a sulfonylurea.
  • Non-limiting examples of sulfonylureas include glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide, gliclazide, glibenclamide and tolazamide.
  • Non-limiting examples of insulin sensitizers include PPAR activators, such as rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; DPP-IV inhibitors; PTP-1B inhibitors; and α-glucokinase activators, such as miglitol, acarbose, and voglibose.
  • Non-limiting examples of DPP-IV inhibitors useful in the present methods include sitagliptin (Januvia™, Merck), saxagliptin, denagliptin, vildagliptin (Galvus™, Novartis), alogliptin, alogliptin benzoate, ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination of sitagliptin/metformin HCl (Janumet™, Merck).
  • Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku).
  • Non-limiting examples of hepatic glucose output lowering agents include Glucophage and Glucophage XR.
  • Non-limiting examples of histamine H3 receptor antagonist agents include the following compound:
  • Figure US20120022057A1-20120126-C00082
  • Non-limiting examples of insulin secretagogues include sulfonylurea and non-sulfonylurea drugs such as GLP-1, a GLP-1 mimetic, exendin, GIP, secretin, glipizide, chlorpropamide, nateglinide, meglitinide, glibenclamide, repaglinide and glimepiride.
  • Non-limiting examples of GLP-1 mimetics useful in the present methods include Byetta-Exenatide, Liraglutide, CJC-1131 (ConjuChem, Exenatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.
  • The term “insulin” as used herein, includes all pyridinones of insulin, including long acting and short acting forms of insulin.
  • Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from AutoImmune, and the compositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • In one embodiment, the antidiabetic agent is an anti-obesity agent.
  • Non-limiting examples of anti-obesity agents useful in the present methods for treating diabetes include a 5-HT2C agonist, such as lorcaserin; a neuropeptide Y antagonist; an MCR4 agonist; an MCH receptor antagonist; a protein hormone, such as leptin or adiponectin; an AMP kinase activator; and a lipase inhibitor, such as orlistat. Appetite suppressants are not considered to be within the scope of the anti-obesity agents useful in the present methods.
  • Non-limiting examples of meglitinides useful in the present methods for treating diabetes include repaglinide and nateglinide.
  • Non-limiting examples of insulin sensitizing agents include biguanides, such as metformin, metformin hydrochloride (such as GLUCOPHAGE® from Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOVANCE™ from Bristol-Myers Squibb) and buformin; glitazones; and thiazolidinediones, such as rosiglitazone, rosiglitazone maleate (AVANDIA™ from GlaxoSmithKline), pioglitazone, pioglitazone hydrochloride (ACTOST™, from Takeda) ciglitazone and MCC-555 (Mitsubishi Chemical Co.)
  • In one embodiment, the insulin sensitizer is a thiazolidinedione.
  • In another embodiment, the insulin sensitizer is a biguanide.
  • In another embodiment, the insulin sensitizer is a DPP-IV inhibitor.
  • In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.
  • Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production. Alpha-glucosidase inhibitors help the body to lower blood sugar by delaying the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. Non-limiting examples of suitable alpha-glucosidase inhibitors include acarbose; miglitol; camiglibose; certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose. Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin; pramlintide, exendin, certain compounds having Glucagon-like peptide-1 (GLP-1) agonistic activity as disclosed in WO 00/07617 (incorporated herein by reference).
  • Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 from AutoImmune, and the compositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Compound(s) of Formula IA or Formula IB and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.
  • Generally, a total daily dosage of the one or more Compounds of Formula IA or Formula IB and the additional therapeutic agent(s) can, when administered as combination therapy, range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration. In one embodiment, the dosage is from about 0.2 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
  • The compounds of the invention can be made according to the processes described below. The compounds of this invention are also exemplified in the examples below, which examples should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.
    • General Methods of Synthesis
  • The general methods described in this paragraph were used unless stated otherwise in the experimental procedures below. All solvents and reagents were used as received. Alternatively, anhydrous N,N-dimethylformamide, methylene chloride and tetrahydrofuran were obtained by drying bulk solvents purchased from Fisher Scientific on activated columns using the Pure-Solv PS-MD 3 system from Inovative Technology. Proton NMR spectra were obtained using a Varian XL-400 (400 MHz) or a Bruker Avance (500 MHz) instruments. 1H chemical shifts are reported in parts per million (ppm), measured relative to residual solvent peaks as an internal standard set to δ 7.26 ppm for chloroform-d, 3.34 for methanol-d4 and 2.50 ppm for DMSO-d6. LCMS analyses were performed using a PE SCIEX API-150EX single quadrupole mass spectrometer equipped with a Phenomenex Gemini C18 column (5.0 μm, 50×4.6 mm); mobile phase A: 0.05% trifluoroacetic acid in water, B: 0.05% trifluoroacetic acid in acetonitrile; gradient: 90% A and 10% B to 5% A and 95% B in 5 mins. Alternatively, LCMS analyses were performed using an Agilent 6140 quadrupole mass spectrometer equipped with a Zorbax SB-C-18 C18 column (1.8 μm, 50×4.6 mm) heated at 50° C.; mobile phase A: 0.1% trifluoroacetic acid in water, B: 0.1% trifluoroacetic acid in acetonitrile; gradient: 90% A and 10% B to 5% A and 95% B in 3.5 mins. Flash column chromatography was performed using Teledyne Isco RediSep silica columns and C18 reverse phase columns. Preparative HPLC separations were performed on Gilson instruments (system 1: Gilson 322 pump, UV-vis detector 156, liquid handler 215 and injector 845Z; or system 2: pumps 333 & 334, liquid handler GX281, UV-vis detector 155) using Phenomenex columns (Gemini C18 5.0 μm, 100×21.2 mm or 150×21.2 mm or 150×30.0 mm or 10 μm, 250×50.0 mm or Gemini C6-phenyl 5.0 μm, 21.2×150 mm or Synergi Fusion-RP 4.0 μm, 21.2×150 mm); mobile phase A: 0.1% trifluoroacetic (or formic acid) in water, B: 0.1% trifluoroacetic (or formic acid) in acetonitrile. Chiral resolutions of racemic mixtures were conducted on Varian HPLC systems (system 1, analytical: Varian/Dynamax pumps SD200, Varian Prostar autosampler 400 or 410, Varian Prostar PDA detector 335 and Varian Prostar CVM 500; system 2, preparative: Varian/Dynamax pumps SD200, Varian/Dynamax detector UV D-II) using Daicel Chiralpak IC columns (4.6×150 mm or 20.0×250 mm). Microwave-mediated reactions were performed using a Biotage Initiator™ Synthesis System and using the standard 2 mL, 5 mL or 20 mL vials and lids. Preparative and analytical TLC were performed using Analtech Silica gel GF plates.
    • Section A Preparation of Key Synthetic Intermediates
  • Figure US20120022057A1-20120126-C00083
    • Intermediate A-2: methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate—step a1
  • Trimethyl phosphonoacetate (78.6 mL, 485.0 mmol) was added to a 0° C. solution of 4-(4-hydroxyphenyl)cyclohexanone A-1 (76.9 g, 404.0 mmol) in tetrahydrofuran (3.0 L) in a flame-dried 5.0 L 3-neck round bottom flask equipped with mechanical stirrer and placed under an atmosphere of nitrogen. Sodium hydride (60% in mineral oil, 37.2 g) was added portionwise so that the internal temperature was maintained below 10° C. The reaction mixture was stirred at 0° C. for 20 mins and slowly warmed to room temperature and stirred for an additional 2.5 h. After disappearance of starting material on TLC (3:7 hexanes:ethyl acetate), the reaction mixture was quenched with water (200 mL), then concentrated under reduced pressure to a volume of ca. 1.5 L and diluted with water (500 mL). The aqueous layer was extracted with ethyl acetate (3×800 mL). The combined extracts were dried with anhydrous sodium sulfate and magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate A-2 (110.0 g; Yield=100%) as a white solid. MS (ESI) [M+1]+ 247.
    • Intermediate A-3: methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate—step a2
  • Into a 2.5 L hydrogenation flask, a solution of methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate A-2 (53.14 g, 215.8 mmol) in ethyl acetate (1.0 L) was degassed and placed under an atmosphere of nitrogen. A slurry of palladium on carbon (10% Pd, 5.3 g) in ethyl acetate (20 mL) was then added under an atmosphere of nitrogen. The reaction was subjected to a 35 psi hydrogen atmosphere using a Parr Shaker overnight, then filtered over a celite pad, and the celite was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure and dried under high vacuum to give methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate A-3 as a white solid (mixture of cis and trans isomers, 53.5 g; Yield=99%). MS (ESI) [M+1]+ 249.
    • Intermediate trans-A-3: methyl 2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate—step a3
  • Methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate A-3 (mixture of cis and trans isomers, 107.0 g, 430.9 mmol) was dissolved in hot ethyl acetate (90.0 mL) and the solution was allowed to cool slowly to room temperature and to stand overnight to crystallize. The white crystals were isolated by filtration, washed with an ice-cold mixture of ethyl acetate:hexanes (15:85, 100 mL) and dried to give pure isomer trans-A-3 (36.8 g). The mother liquors were concentrated to dryness under reduced pressure, and the solid residue was dissolved in a hot mixture of ethyl acetate:hexanes (1:1, 90.0 mL). The solution was allowed to cool slowly to room temperature and to stand overnight to crystallize. The colorless solid was isolated by filtration, washed with an ice-cold mixture of ethyl acetate:hexanes (15:85, 100 mL) and dried to give additional pure isomer trans-A-3 (8.60 g). Both crops were combined to give methyl 2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate trans-A-3 (45.4 g; Yield=42.4%; Purity=100%) as a white solid. MS (ESI) [M+1]+ 249.
    • Intermediate cis-A-3: methyl 2-((1s,4s)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate—step a3
  • The mother liquors resulting from the preparation of trans-A-3 were concentrated to dryness under reduced pressure. The solid residue (10.0 g, 430.9 mmol) was dissolved in ethyl acetate (200 mL), and the solution was allowed to stand overnight at room temperature to crystallize. The white crystals were isolated by filtration, washed with an ice-cold mixture of ethyl acetate:hexanes (15:85, 20 mL). The filtrate was concentrated to dryness under reduced pressure, and the residual solid was recrystallized from ethyl acetate:hexanes (20:80, 10 mL) to give isomer cis-A-3. This procedure was repeated seven times, and the combined solids were finally washed with hexanes (100 mL) and dried under high vacuum to give methyl 2-((1s,4s)-4-((4-hydroxyphenyl)cyclohexyl)acetate cis-A-3 (500 mg; Yield=4%) as white crystals. MS (ESI) [M+1]+249.
    • Intermediate A-4: methyl 2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetate—step a4
  • Triethylamine (10.1 mL, 72.5 mmol) and trifluoromethanesulfonic anhydride (19.0 g, 67.3 mmol) were successively added dropwise to a solution of methyl 2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate trans-A-3 (12.0 g, 48.3 mmol) in methylene chloride (100.0 mL) at 0° C. The reaction was stirred under a nitrogen atmosphere for 5 h, then poured into a saturated aqueous solution of NaHCO3 (150 mL) and extracted with methylene chloride. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated to a half volume. The solution was then filtered through a short path silica gel column, rinsed with methylene chloride and concentrated to dryness under reduced pressure to give methyl 2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetate A-4 (18.0 g; Yield=98%). MS (ESI) [M+1]+ 381.
    • Intermediate trans-A-5: methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate—step a5
  • Potassium acetate (15.5 g, 158 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) were successively added at room temperature to a solution of methyl 2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetate A-4 (12.0 g, 31.5 mmol) and bis(pinacolato)diboron (9.61 g, 37.8 mmol) in 1,4-dioxane (200.0 L). The reaction was degassed under reduced pressure several times, placed under an atmosphere of nitrogen and stirred at 80° C. for 17 h. After completion, the reaction mixture was cooled, filtered through a short path silica gel column and eluted with ethyl acetate (450 mL). The solvent was removed under reduced pressure, and the crude brown oil was purified by flash column chromatography on silica gel (3:1 hexanes:ethyl acetate) to give methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 as a white solid (11.0 g; Yield=100%). MS (ESI) [M+1]+ 359.
    • Intermediate cis-A-5: methyl 2-((1s,4s)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate—step a4 & a5
  • Intermediate cis-A-5 was prepared by the sequence step a-4-step a5 described for intermediate methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5, by using methyl 2-((1s,4s)-4-(4-hydroxyphenyl)cyclohexyl)acetate cis-A-3 as starting material. MS (ESI) [M+1]+ 359.
    • Intermediate A-6: 4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenylboronic acid—step a6
  • Sodium metaperiodate (896.0 mg, 4.19 mmol) was added at room temperature to a solution of methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 (500.0 mg, 1.40 mmol) in a 4:1 mixture of tetrahydrofuran and water (11.2 mL) and the reaction mixture was stirred at room temperature for 30 mins. Then, a 1 N aqueous solution of hydrogen chloride (1.12 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and water (10 mL), then decanted, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water (70 mL) then brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The solid residue was then washed with small amounts of hexanes (30 mL total) and dried under high vacuum to give 4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenylboronic acid A-6 (0.293 g; Yield=75%) as a white solid. MS (ESI) [M+1]+ 277.
    • Intermediate A-7: potassium trifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borate—step a7
  • Potassium hydrogen difluoride (2.90 g, 37.08 mmol) was added at room temperature to a solution of methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 (6.16 g, 14.83 mmol) in a 2:1 mixture of water and methanol (37.0 mL). The reaction was stirred at room temperature in a polypropylene reactor for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, the resulting solid residue was suspended in ice-cold water (150 mL), quickly filtered, washed with ice-cold diethyl ether (250 mL) and dried under high vacuum to give potassium trifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borate A-7 as a white solid (4.79 g; Yield=95%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 1.11 (dq, J=2.68, 12.61 Hz, 2H), 1.52 (dq, J=2.68, 12.60 Hz, 2H), 1.68-1.81 (m, 5H), 2.24 (d, J=6.80 Hz, 2H), 2.33 (tt, J=2.99, 12.29 Hz, 1H), 3.60 (s, 3H), 6.93 (d, J=7.41 Hz, 2H), 7.22 (d, J=7.41 Hz, 2H).
  • Figure US20120022057A1-20120126-C00084
    • Intermediate A-9: 1-(4-bromophenyl)piperazine—step a8
  • A solution of bis(2-chloroethyl)amine (4.0 g, 30.0 mmol), p-bromoaniline A-8 (5.0 g, 30.0 mmol) and potassium carbonate (4.0 g, 30.0 mmol) in diethylene glycol dimethyl ether (106 mL) was heated to reflux for 2 days. The reaction mixture was quenched with water (50 mL), and the pH was adjusted to pH 10 with a 1 N aqueous solution of NaOH (5 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (10:1 methylene chloride:methanol) to give 1-(4-bromophenyl)piperazine A-9 (5.1 g; Yield=70%). MS (ESI) [M+1]+ 241.
    • Intermediate A-10: methyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate—step a9
  • N,N-diisopropylethylamine (4.3 mL, 25.0 mmol), potassium carbonate (1.7 g, 12.0 mmol) and chloroacetic acid methyl ester (1.4 g, 12.0 mmol) were successively added at room temperature to a solution of 1-(4-bromophenyl)piperazine A-9 (3.0 g, 12.0 mmol) in tetrahydrofuran (22.6 mL) and N,N-dimethylformamide (10.6 mL). The reaction mixture was stirred overnight at room temperature and quenched with water (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined extracts were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (10:1 hexanes:ethyl acetate) to give methyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate A-10 (2.0 g; Yield=50%). MS (ESI) [M+1]+ 241.
    • Intermediate A-11: methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetate—step a10
  • Methyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate A-10 (240.0 mg, 1.00 mmol), bis(pinacolato)diboron (292.0 mg, 1.20 mmol), potassium acetate (376.0 mg, 3.83 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (39.1 mg, 0.048 mmol) were mixed in 1,4-dioxane (20 mL). The reaction mixture was degassed under reduced pressure three times, placed under an atmosphere of nitrogen and stirred at 80° C. for 17 h. After completion, the reaction mixture was cooled, filtered through a celite pad, washed with ethyl acetate (450 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetate A-11 (0.25 g; Yield=70%). MS (ESI) [M+1]+ 361.
  • Figure US20120022057A1-20120126-C00085
    • Intermediate A-13: (1R,2R)-methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopentanecarboxylate—step a11
  • (1R,2R)-methyl-2-(4-bromobenzoyl)cyclopentane-carboxylate A-12 (775.0 mg, 2.50 mmol), bis(pinacolato)diboron (734.0 mg, 2.89 mmol), potassium acetate (0.757 g, 7.71 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (78.7 mg, 0.096 mmol) were mixed in 1,4-dioxane (40.0 mL). The reaction mixture was degassed under reduced pressure three times, placed under an atmosphere of nitrogen and stirred at 80° C. for 17 h. After completion, the reaction mixture was cooled, filtered through a celite pad, washed with ethyl acetate (300 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give (1R,2R)-methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopentanecarboxylate A-13 (0.56 g; Yield=80%). MS (ESI) [M+1]+ 359.
  • Figure US20120022057A1-20120126-C00086
    • Intermediate A-15: 6-bromo-N-phenyl-1H-indole-3-carboxamide—step a12
  • N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.34 g, 4.16 mmol) was added at 0° C. to a solution of 6-bromo-1H-indole-3-carboxylic acid A-14 (1.0 g, 4.00 mmol), aniline (0.476 mL, 5.23 mmol) and N-ethyl-N,N-diisopropylamine (0.726 mL, 4.16 mmol) in N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred overnight at room temperature and then quenched with water (50 mL). The aqueous layer was extracted with methylene chloride (2×60 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude brown oil was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 6-bromo-N-phenyl-1H-indole-3-carboxamide A-15 as a white solid (0.90 g; Yield=70%). MS (ESI) [M+1]+ 315, 317.
  • Figure US20120022057A1-20120126-C00087
    • Intermediate A-17: 4-(benzo[d]oxazol-2-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a13
  • 2-Chlorobenzoxazole (0.30 g, 2.0 mmol) was added to a solution of 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.42 g, 2.0 mmol) in toluene (10.0 mL) and N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred overnight at 100° C. under an atmosphere of nitrogen and then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 4-(benzo[d]oxazol-2-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine A-17 (0.12 g; Yield=18%). MS (ESI) [M+1]+ 331, 333.
  • Figure US20120022057A1-20120126-C00088
    • Intermediate A-19: 6-bromo-N-phenylquinazolin-2-amine—step a14
  • Trifluoroacetic acid (0.23 mL, 3.0 mmol) was added at room temperature to a solution of 6-bromo-2-iodoquinazoline A-18 (0.50 g, 1.0 mmol) and aniline (0.16 mL, 1.8 mmol) in isopropyl alcohol (6.36 mL). The reaction mixture was heated at 70° C. for 12 h, then cooled, quenched with triethylamine (1.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (97:3 methylene chloride:methanol) to give 6-bromo-N-phenylquinazolin-2-amine A-19 (0.20 g; Yield=68%). MS (ESI) [M+1]+ 300, 302.
  • Figure US20120022057A1-20120126-C00089
    • Intermediate A-21: 5-bromo-N-phenyl-1H-indole-1-carboxamide—step a15
  • Sodium hydride (60% dispersion in mineral oil, 130.0 mg, 5.4 mmol) was added to a solution of 5-bromoindole A-20 (975.0 mg, 5.0 mmol) in N,N-dimethylformamide (30 mL) at 0° C. The reaction mixture was then stirred at room temperature for 3 h and phenyl isocyanate (0.54 mL, 4.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and concentrated to dryness under reduced pressure. The residue was partitioned between a 1 N aqueous hydrogen chloride solution (50 mL) and ethyl acetate (50 mL), and the aqueous layer was separated then extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 5-bromo-N-phenyl-1H-indole-1-carboxamide A-21 as yellow solid (0.88 g; Yield=56%). MS (ESI) [M+1]+ 315, 317.
  • Figure US20120022057A1-20120126-C00090
    • Intermediate A-23: 6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one—step a16
  • 1,8-Diazabicyclo[5.4.0]undec-7-ene (140.0 μL, 0.94 mmol) was added at room temperature to a solution of 3-amino-6-bromopyridin-2-ol A-22 (178.0 mg, 0.94 mmol) and methyl 2-bromoacetate (81.0 μL, 0.86 mmol) in anhydrous 1-methylpyrrolidin-2-one (3.76 mL) under an argon atmosphere, in a 10 mL microwave reactor vial. The sealed reaction mixture was heated at 180° C. for 3 mins under microwave irradiation and then diluted with ethyl acetate (30 mL). The organic layer was washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one A-23 (95.7 mg, Yield=45%). MS (ESI), [M+1]+ 229, 231.
    • Intermediate A-24: 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine—step a17
  • Borane dimethyl sulfide complex (1 M solution in THF, 0.82 mL, 0.82 mmol) was added at room temperature to a solution of 6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one A-23 (95.7 mg, 0.41 mmol) in anhydrous THF (1.23 mL) under an atmosphere of argon. The reaction mixture was heated to reflux for 2 h, cooled to room temperature, quenched with methanol (3 mL), stirred for 40 mins and concentrated to dryness under reduced pressure. The crude light beige solid 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine A-24 (91.5 mg, Yield=ca. 95%) was used as such for the next step. MS (ESI), [M+1]+ 215, 217.
    • Intermediate A-25: 6-bromo-N-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide—step a18
  • Phenyl isocyanate (90.0 μL, 0.82 mmol) was added at room temperature to a solution of 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine A-24 (91.5 mg, 0.41 mmol) in 3:1 anhydrous methylene chloride:dimethylsulfoxide (2.0 mL) under argon. The reaction mixture was stirred at room temperature for 12 h, quenched with methanol (2.0 mL) and diluted with methylene chloride (10 mL). The heavy precipitate formed was isolated by filtration, washed with small portions of methylene chloride and dried under high vacuum to give 6-bromo-N-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide A-25 (74.8 mg, Yield=55% over 2 steps). MS (ESI), [M+1]+ 334, 336.
  • Figure US20120022057A1-20120126-C00091
    • Intermediate A-27: 6-bromo-N-phenylquinoxalin-2-amine—step a19
  • 6-Bromo-2-chloroquinoxaline A-26 (0.20 g, 0.821 mmol), aniline (97 μL, 1.07 mmol) and N-ethyl-N,N-diisopropylamine (214 μL, 1.23 mmol) were mixed in 1-methylpyrrolidin-2-one (4.11 mL) in a 5 mL microwave reactor vial under an argon atmosphere. The reaction mixture was heated at 180° C. for 30 mins, then at 200° C. for 20 mins under microwave irradiation. The mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL), quenched with water (20 mL) and decanted. The aqueous layer was extracted with ethyl acetate (2×40 mL); the combined organic extracts were then successively washed with water (30 mL), brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (100:0 to 0:100 gradient of methylene chloride:ethyl acetate) to give 6-bromo-N-phenylquinoxalin-2-amine A-27 (0.13 g; Yield=53%). MS (ESI) [M+1]+ 300, 302.
  • Figure US20120022057A1-20120126-C00092
    • Intermediate A-29: 4-bromo-2-(2-methylallyloxy)-1-nitrobenzene—step a20
  • Potassium bis(trimethylsilyl)amide (solution in toluene, 5.0 mL, 2.5 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-1-nitrobenzene A-28 (500 mg, 2.273 mmol) and 2-methylprop-2-en-1-ol (dried before use over 4 Å MS, 0.212 mL, 2.50 mmol) in anhydrous THF (6.4 mL) at 0° C. under an atmosphere of argon. The reaction mixture was allowed to stir at room temperature for 12 h, then diluted with methylene chloride (50 mL), quenched with a saturated aqueous solution of NH4Cl (30 mL) and decanted. The aqueous layer was extracted with methylene chloride (2×50 mL); the combined organic extracts were then washed with brine (2×40 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (90:10 to 0:100 gradient of hexanes:ethyl acetate) to give 4-bromo-2-(2-methylallyloxy)-1-nitrobenzene A-29 (496 mg; Yield=80%). MS (ESI) [M+1]+ 272, 274.
    • Intermediate A-30:1-(5-bromo-2-nitrophenoxy)propan-2-one—step a21
  • A solution of 4-bromo-2-(2-methylallyloxy)-1-nitrobenzene A-29 (495 mg, 1.82 mmol) in anhydrous methanol (35 mL) was treated at −78° C. with ozone until a persistent blue color was observed. The ozone bubbling was then stopped. The reaction mixture was bubbled with nitrogen gas for 30 mins, and then dimethyl sulfide (2.25 mL, 30.6 mmol) was added at −78° C. The solution was allowed to warm to room temperature overnight before concentrating to dryness. The resulting oily residue was dissolved in acetone (17.5 mL) and stirred at room temperature for 18 h over wet amberlyst 15 resin (2.50 g). The solution was then filtered and concentrated to dryness. The crude residue was dissolved in diethyl ether (200 mL) and methylene chloride (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give a yellow solid. Recrystallization from pentane (200 mL) gave 1-(5-bromo-2-nitrophenoxy)propan-2-one A-30 (400.2 mg; Yield=80% over 2 steps) as a light tan solid. MS (ESI) [M+1]+ 274, 276.
    • Intermediate A-31: 7-bromo-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a22
  • A slurry of Raney nickel in water (ca. 15 mg) was suspended in ethyl acetate (5 mL) in a round-bottom flask and carefully concentrated to dryness by heating at 30° C. under reduced pressure. The procedure was repeated with toluene (10 mL) and the dry metal was then kept under an argon atmosphere. A solution of 1-(5-bromo-2-nitrophenoxy)propan-2-one A-30 (30.0 mg, 0.11 mmol) in dry ethyl acetate (0.54 mL) and absolute ethanol (0.54 mL) was added at room temperature to the Raney nickel, and the reaction mixture was heated at 50° C. for 12 h under an atmosphere of hydrogen. The solution was then placed under a nitrogen atmosphere, filtered over a celite pad while blanketing under nitrogen and rinsing with ethyl acetate (20 mL), and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (90:10 to 0:100 gradient of hexanes:ethyl acetate) to give 7-bromo-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine A-31 (14.0 mg; Yield=56%). MS (ESI) [M+1]+ 228, 230.
  • Figure US20120022057A1-20120126-C00093
    • Intermediate (R)-A-33: (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate—step a23
  • Triphenylphosphine (624.0 mg, 2.38 mmol) was added at room temperature to a solution of 5-bromo-2-nitrophenol A-32 (400.0 mg, 1.83 mmol) and methyl(−)-(S)-lactate (0.149 mL, 1.56 mmol) in anhydrous methylene chloride (18.3 mL) under an atmosphere of argon. After 10 mins of stirring, the reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.360 mL, 1.83 mmol) was added dropwise. The orange solution was warmed to room temperature, stirred for 12 h, then concentrated to ca. 1.0 mL, diluted with pentane (7 mL) and diethyl ether (8 mL), filtered and rinsed with diethyl ether-pentane (15 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-33 as a yellow solid (525.0 mg; Yield=94%). MS (ESI) [M+1]+ 304, 306.
    • Intermediate (R)-A-34: (R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one—step a24
  • Iron powder (1.91 g, 34.15 mmol) and (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-33 (525.0 mg, 1.71 mmol) were heated at 50° C. in glacial acetic acid (10.5 mL) for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), filtered over a pad of celite, and rinsed with ethyl acetate (80 mL). The filtrate was successively washed with water (2×30 mL), a saturated aqueous solution of sodium bicarbonate (40 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting white crystalline solid (R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (R)-A-34 (399.4 mg, Yield=96%) was used as such for the next step without purification. MS (ESI) [M+1]+ 242, 244.
    • Intermediate (R)-A-35: (R)-7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a17
  • Intermediate (R)-A-35 was prepared by the procedure described for step a17, using (R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (R)-A-34 as starting material. MS (ESI) [M+1]+ 228, 230; ee=96% (rt=5.195 min for (R)-A-35, rt=6.283 min for (S)-A-35; using Daicel Chiralpak AD column (4.6×150 mm) on Varian HPLC system 1 and eluting with 10% ethanol in hexanes:diethylamine 99.5:0.5, isocratic gradient at 1 mL/min).
  • Figure US20120022057A1-20120126-C00094
    • Intermediate A-36: methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoate—step a25
  • Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 0.67 mL) was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 (179.0 mg, 0.50 mmol) in anhydrous THF (10.0 mL) at −78° C. under an atmosphere of argon. The reaction was stirred at −78° C. for 1 h, then methyl iodide (42.0 μL, 0.67 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight at room temperature, then successively quenched with water (5 mL), diluted with ethyl acetate (15 mL) and decanted. The aqueous layer was extracted with ethyl acetate (3×30 mL); the combined organic extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoate A-36 (119.0 mg, Yield=80%). MS (ESI), [M+1]+ 373.
    • Section B Preparation of Example Compounds
  • Figure US20120022057A1-20120126-C00095
    • Intermediate B-2: 5-bromo-N-phenylindoline-1-carboxamide—step b1
  • Phenyl isocyanate (5.90 g, 5.0 mmol) was added dropwise to a solution of 5-bromoindoline B-1 (1.0 g, 5.0 mmol) in methylene chloride (10.0 mL). The reaction was stirred at room temperature overnight and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 5-bromo-N-phenylindoline-1-carboxamide B-2 as white solid (1.5 g; Yield=95%). MS (ESI) [M+1]+ 317, 319.
    • Intermediate B-3: methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate—step b2
  • [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.0 mg, 0.025 mmol) and an aqueous solution of sodium carbonate (307.0 mg, 2.9 mmol in 1.0 mL of water) were added to a solution of 5-bromo-N-phenylindoline-1-carboxamide B-2 (177.1 mg, 0.558 mmol) and methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 (300.0 mg, 0.840 mmol) in isopropanol (5.0 mL). The reaction was degassed several times under reduced pressure, placed under a nitrogen atmosphere and stirred at 80° C. for 10 h. After cooling, the mixture was filtered through a celite pad, washed with ethyl acetate (100 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-3 (160.0 mg; Yield=61%). MS (ESI) [M+1]+ 469.
    • Example B-4: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Lithium hydroxide monohydrate (16.8 mg, 0.4 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-3 (46.9 mg, 0.1 mmol) in tetrahydrofuran (10.0 mL) and water (1.0 mL). The reaction was stirred at room temperature overnight and quenched with an aqueous solution of hydrogen chloride (1 N, 1.0 mL). The reaction was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid B-4 (24.1 mg; Yield=53%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=11.65 Hz, 2H), 1.53 (q, J=11.65 Hz, 2H), 1.75 (br s, 1H), 1.78-1.90 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.53-2.55 (m, 1H), 3.22 (t, J=8.51 Hz, 2H), 4.18 (t, J=8.51 Hz, 2H), 7.02 (t, J=7.25 Hz, 1H), 7.25-7.35 (m, 5H), 7.38-7.63 (m, 5H), 7.91 (d, J=8.20 Hz, 1H), 8.55 (s, 1H); MS (ESI) [M+1]+ 455.
  • Figure US20120022057A1-20120126-C00096
    • Intermediate B-5: methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate—step b4
  • 5-Bromoindoline B-1 (595.0 mg, 3.00 mmol), potassium trifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borate A-7 (1.12 g, 3.31 mmol), anhydrous potassium carbonate (1.37 g, 9.92 mmol) and palladium (II) acetate (75.0 mg, 0.33 mmol) were mixed in anhydrous methanol (12.0 mL) in a 20 mL microwave reactor vial, evacuated several times and placed under an argon atmosphere. The sealed reaction mixture was heated at 65° C. for 45 mins under microwave irradiation and then diluted with methylene chloride (100 mL) and water (100 mL). The aqueous layer was separated and extracted with methylene chloride (3×100 mL). The combined organic extracts were successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) then brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methylene chloride:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 as a light yellow oil (830.0 mg, Yield=75%). MS (ESI), [M+1]+ 350.
    • Intermediate B-6: methyl 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate—step b5
  • 3,4-Difluorophenyl isocyanate (198.0 mg, 1.28 mmol) was added under an atmosphere of argon to a solution of methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (90.0 mg, 0.255 mmol) in anhydrous methylene chloride (1.27 mL) at room temperature. The reaction mixture was stirred overnight, then concentrated to dryness under reduced pressure to give methyl 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-6 as a crude solid residue (160.0 mg), sufficiently pure to be used for the next step without additional purification. MS (ESI), [M+1]+ 505.
    • Example B-7: 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Lithium hydroxide monohydrate (107.0 mg, 2.55 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-6 (160.0 mg, 0.255 mmol) in a 1:1:1 mixture of tetrahydrofuran:water:methanol (5.10 mL) at room temperature. After 12 h of vigorous stirring, the reaction mixture was diluted with water (40 mL) and washed with methylene chloride (50 mL). The aqueous layer was then acidified to pH 0 with a 1 N aqueous hydrogen chloride solution (5 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid B-7 (68.8 mg, Yield=55% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.04-1.24 (m, 2H), 1.41-1.62 (m, 2H), 1.74 (m, 1H), 1.77-1.86 (m, 4H), 2.15 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.23 (t, J=8.20 Hz, 2H), 4.15 (t, J=8.20 Hz, 2H), 7.27 (d, J=7.57 Hz, 2H), 7.34-7.40 (m, 2H), 7.42 (d, J=8.20 Hz, 1H), 7.48 (s, 1H), 7.52 (d, J=7.57 Hz, 2H), 7.74 (m, 1H), 7.91 (d, J=7.88 Hz, 1H), 8.76 (br s, 1H), 12.08 (br s, 1H); MS (ESI), [M+1]+ 491.
  • Figure US20120022057A1-20120126-C00097
    • Intermediate B-8: methyl 2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetate—step b7
  • Pyrrolidine-1-carbonyl chloride (77.3 μL, 0.70 mmol) was added under an argon atmosphere to a solution of methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (53.0 mg, 0.140 mmol), N,N-dimethylaminopyridine (8.6 mg, 0.07 mmol) and triethylamine (194.0 μL, 1.40 mmol) in anhydrous methylene chloride (1.04 mL). The reaction mixture was stirred overnight at room temperature and then heated for 5 h at 50° C. Upon cooling to room temperature, it was then diluted with ethyl acetate (30 mL) and quenched with an aqueous pH 7 phosphate buffer solution (30 mL). The aqueous layer was extracted with ethyl acetate (3×40 mL); the combined organic extracts were successively washed with an aqueous pH 7 phosphate buffer solution (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methylene chloride:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-8 (43.8 mg, Yield=70%). MS (ESI) [M+1]+ 447.
    • Example B-9: 2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Example B-9 was prepared by the procedure described for step b3, using methyl 2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetate B-8 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.45 Hz, 2H), 1.49 (q, J=11.40 Hz, 2H), 1.70-1.78 (m, 1H), 1.84 (m, 8H), 2.15 (d, J=6.94 Hz, 2H), 2.48 (m, 1H), 3.10 (t, J=8.35 Hz, 2H), 3.38 (m, 4H), 3.94 (t, J=8.35 Hz, 2H), 7.21 (d, J=8.20 Hz, 1H), 7.27 (d, J=7.57 Hz, 2H), 7.37 (d, J=8.20 Hz, 1H), 7.46 (s, 1H), 7.51 (d, J=7.25 Hz, 2H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 433.
  • Figure US20120022057A1-20120126-C00098
    • Intermediate B-10: (S)-tert-butyl 2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylate—step b8
  • Triethylamine (159 μL, 1.144 mmol) was added at room temperature to a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (92.3 mg, 0.429 mmol), methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (100.0 mg, 0.286 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (217.5 mg, 0.572 mmol) in anhydrous N,N-dimethylformamide (2.98 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with an aqueous solution of pH 7 phosphate buffer (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (methylene chloride:ethyl acetate gradient) to give (S)-tert-butyl 2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylate B-10 (128.4 mg, Yield=78%). MS (ESI) [M+1]+ 547.
    • Example B-11: 2-((1r,4r)-4-(4-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Example B-11 was prepared by the procedure described for step b3, using (S)-tert-butyl 2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylate B-10 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.25 (s, 6H), 1.40 (s, 3H), 1.48 (m, 2H), 1.70-1.95 (m, 8H), 2.15 (d, J=6.62 Hz, 2H), 2.29 (m, 1H), 2.48 (t, J=11.80 Hz, 1H), 3.23 (m, 2H), 3.32-3.47 (m, 2H), 4.17 (m, 2H), 4.49 (dd, J=7.25 Hz, J=8.20 Hz, 0.6H), 4.56 (br d, J=7.90 Hz, 0.4H), 7.28 (d, J=7.88 Hz, 2H), 7.46 (t, J=8.90 Hz, 1H), 7.50-7.57 (m, 3H), 8.10 (d, J=8.20 Hz, 0.4H), 8.14 (d, J=8.20 Hz, 0.6H), 12.11 (br s, 1H); MS (ESI) [M+1]+ 533.
    • Example B-12: 2-((1r,4r)-4-(4-(1-((S)-pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid—step b9
  • A solution of 2-((1r,4r)-4-(4-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid B-11 (75.0 mg, 0.141 mmol) in methylene chloride (1.10 mL) and 4 N hydrogen chloride in 1,4-dioxane (1.05 mL) was stirred at room temperature for 12 h, then heated to 45° C. for 2 h. The reaction mixture was then partitioned between methylene chloride (40 mL) and water (40 mL) and separated. The aqueous layer was extracted with ethyl acetate (3×40 mL); the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue (43.1 mg) contained 90% pure B-12. The aqueous layer was concentrated under reduced pressure to a volume of ca 2 mL, then filtered. The solid collected was washed with water (5 mL) then ethyl acetate (5 mL) and dried under high vacuum to give pure 2-((1r,4r)-4-(4-(1-((S)-pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid B-12 as white crystals (32.8 mg, Yield=54%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.45 Hz, 2H), 1.50 (q, J=11.50 Hz, 2H), 1.70-1.89 (m, 5H), 1.92-2.04 (m, 3H), 2.16 (d, J=6.62 Hz, 2H), 2.48 (m, 1H), 3.28 (t, J=8.50 Hz, 2H), 3.21-3.31 (m, 3H), 4.14 (q, J=8.83 Hz, 1H), 4.26 (q, J=8.72 Hz, 1H), 4.59 (m, 1H), 7.31 (d, J=7.88 Hz, 2H), 7.50-7.62 (m, 4H), 8.11 (d, J=8.20 Hz, 1H), 8.65 (br s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 433.
  • Figure US20120022057A1-20120126-C00099
    • Intermediate B-14: 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one—step a16
  • Intermediate B-14 was prepared by the procedure described for step a16, using 2-amino-5-bromophenol B-13 and ethyl 2-bromopropanoate as starting materials. MS (ESI) [M+1]+ 242, 244.
    • Intermediate B-15: 7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a17
  • Intermediate B-15 was prepared by the procedure described for step a17, using 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B-14 as starting material. MS (ESI) [M+1]+ 228, 230.
    • Intermediate B-16: methyl 2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b10
  • 7-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine B-15 (50.0 mg, 0.219 mmol), potassium trifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borate A-7 (89.0 mg, 0.263 mmol), anhydrous potassium carbonate (76.0 mg, 0.548 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (PEPPSI-iPr, 20.0 mg, 0.022 mmol) were mixed in 1:1 ethanol:water (1.10 mL) in a 5 mL microwave reactor vial, evacuated several times and placed under an argon atmosphere. The reaction mixture was sealed, heated at 65° C. for 50 mins under microwave irradiation and concentrated to dryness under reduced pressure. The crude residue was adsorbed on silica gel (5 g) and purified by flash column chromatography on silica gel (dry loading, methylene chloride:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-16 (47.8 mg, Yield=58%) as a clear oil. MS (ESI) [M+1]+ 380.
    • Intermediate B-17: methyl 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b5
  • Intermediate B-17 was prepared by the procedure described for step b5, using methyl 2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-16 and phenyl isocyanate as starting materials. MS (ESI) [M+1]+ 499.
    • Example B-18: 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-18 was prepared by the procedure described for step b6, using methyl 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-17 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.50 Hz, 2H), 1.36 (d, J=6.31 Hz, 3H), 1.49 (q, J=11.70 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d, J=10.20 Hz, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.47 (m, 1H), 3.36 (dd, J=7.57, 13.20 Hz, 1H), 4.10 (dd, J=2.20, 13.20 Hz, 1H), 4.36 (br t, J=5.83 Hz, 1H), 7.01 (t, J=7.41 Hz, 1H), 7.12-7.19 (m, 2H), 7.25-7.34 (m, 4H), 7.50 (d, J=8.20 Hz, 2H), 7.53-7.57 (m, 3H), 9.17 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 485. The two enantiomers were resolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system 1; 85:15 hexanes:isopropanol): enantiomer A (R absolute configuration, rt=13.93 min); enantiomer B (S absolute configuration, rt=18.27 min).
  • Figure US20120022057A1-20120126-C00100
    • Intermediate B-19: methyl 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b10
  • Intermediate B-19 was prepared by the procedure described for step b10, using 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B-14 as starting material. MS (ESI) [M+1]+ 394.
    • Example B-20: 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-20 was prepared by the procedure described for step b6, using methyl 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-19 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08-1.18 (q, J=11.90 Hz, 2H), 1.45 (d, J=6.62 Hz, 3H), 1.45-1.50 (m, 2H), 1.70-1.78 (m, 1H), 1.78-1.88 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 3.30-3.33 (m, 1H), 4.70 (q, J=6.62 Hz, 1H), 6.94 (d, J=8.20 Hz, 1H), 7.22-7.31 (m, 4H), 7.52 (d, J=8.20 Hz, 2H), 10.72 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 380.
    • Example B-21: 2-((1r,4r)-4-(4-(2-methyl-3-oxo-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b11
  • Phenyl isocyanate (9.0 μL, 0.084 mmol) was added under argon to a solution of 2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid B-20 (28.9 mg, 0.076 mmol) and N,N-dimethylaminopyridine (2.0 mg, 0.016 mmol) in anhydrous methylene chloride (0.5 mL) and anhydrous DMSO (0.5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, then additional phenyl isocyanate (9.0 μL, 0.084 mmol) was added. The mixture was stirred for 24 h, concentrated to yield a crude DMSO solution, which was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(2-methyl-3-oxo-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid B-21 (4.7 mg, Yield=12%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12-1.21 (m, 2H), 1.44 (d, J=6.65 Hz, 3H), 1.46-1.54 (m, 2H), 1.77-1.89 (m, 4H), 2.24 (d, J=6.31 Hz, 2H), 2.45-2.50 (m, 1H), 3.31 (br s, 1H), 4.66-4.72 (m, 1H), 6.94 (d, J=7.88 Hz, 1H), 7.00-7.04 (m, 1H), 7.22-7.32 (m, 6H), 7.52 (d, J=7.88 Hz, 2H), 7.61 (d, J=7.88 Hz, 2H), 9.89 (s, 1H), 10.72 (br s, 1H); MS (ESI) [M+1]+ 499.
  • Figure US20120022057A1-20120126-C00101
    Figure US20120022057A1-20120126-C00102
    • Intermediate B-23: 1-(4-bromo-2-fluorophenylamino)-2-methyl-1-oxopropan-2-yl acetate—step b12
  • Triethylamine was added dropwise to a solution of 4-bromo-2-fluoroaniline B-22 (600 mg, 3.158 mmol) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.915 mL, 6.315 mmol) in anhydrous methylene chloride (10.2 mL) at room temperature. After 20 mins, additional methylene chloride (10.2 mL) was added, and the resulting suspension was stirred at room temperature for 90 mins. The reaction mixture was diluted with methylene chloride (50 mL), quenched with an aqueous pH 7 phosphate buffer solution (60 mL) and decanted. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic extracts were then successively washed with water (40 mL) and brine (40 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (methylene chloride:ethyl acetate gradient) to give 1-(4-bromo-2-fluorophenylamino)-2-methyl-1-oxopropan-2-yl acetate B-23 as a white solid (956.0 mg, Yield=95%). MS (ESI) [M+1]+ 318, 320.
    • Intermediate B-24: 1-(4-bromo-2-fluorophenylamino)-2-methylpropan-2-ol—step a17
  • Intermediate B-24 was prepared by the procedure described for step a17, using 1-(4-bromo-2-fluorophenylamino)-2-methyl-1-oxopropan-2-yl acetate B-23 as starting material. MS (ESI) [M+1]+ 262, 264.
    • Intermediate B-25: 7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step b13
  • A solution of 1-(4-bromo-2-fluorophenylamino)-2-methylpropan-2-ol B-24 (97 mg, 0.35 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added via syringe at room temperature to a suspension of sodium hydride (60% disp. in oil, 35.0 mg, 0.88 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) under an atmosphere of argon. After 30 mins of vigorous stirring, the reaction mixture was heated at 65° C. overnight, followed by heating at 130° C. under microwave irradiation for 90 mins. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL), quenched with an aqueous pH 7 phosphate buffer solution (25 mL) and decanted. The aqueous layer was extracted with ethyl acetate (3×30 mL); the combined organic extracts were then successively washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (methylene chloride:ethyl acetate gradient) to give 7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine B-25 as pale yellow oil (39.1 mg, Yield=45%). MS (ESI) [M+1]+ 242, 244.
    • Intermediate B-26: methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b10
  • Intermediate B-26 was prepared by the procedure described for step b10, using 7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine B-25 as starting material. MS (ESI) [M+1]+ 394.
    • Example B-27: methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b5
  • Example B-27 was prepared by the procedure described for step b5, using methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-26 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.19 Hz, 2H), 1.34 (s, 6H), 1.49 (q, J=11.19 Hz, 2H), 1.73-1.86 (m, 5H), 2.26 (d, J=6.62 Hz, 2H), 2.45-2.49 (m, 1H), 3.61 (s, 3H), 3.64 (s, 2H), 7.00 (t, J=7.55 Hz, 1H), 7.11 (s, 1H), 7.16 (d, J=9.30 Hz, 1H), 7.26-7.31 (m, 4H), 7.46 (d, J=8.19 Hz, 1H), 7.50 (d, J=8.36 Hz, 2H), 7.55 (d, J=8.36 Hz, 2H), 9.23 (s, 1H); MS (ESI) [M+1]+ 513.
    • Example B-28: 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b14
  • Lithium hydroxide monohydrate (12.1 mg, 0.29 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-27 (ca. 100.0 mg, 0.19 mmol) in a 1:1:1 mixture of tetrahydrofuran:water:methanol (1.90 mL) at room temperature. The reaction mixture was heated at 60° C. under microwave irradiation for 30 mins. If necessary, additional portions of lithium hydroxide monohydrate were added, and subsequent heating under microwave irradiation was performed to drive the reaction to completion. The reaction mixture was then cooled to room temperature, quenched with a 1N aqueous solution of HCl (1.0 mL) and concentrated to dryness. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid B-28 (36.0 mg, Yield=38% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.15 Hz, 2H), 1.34 (s, 6H), 1.49 (q, J=11.15 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.45-2.49 (m, 1H), 3.64 (s, 2H), 7.00 (t, J=7.54 Hz, 1H), 7.12 (s, 1H), 7.16 (d, J=9.25 Hz, 1H), 7.26-7.31 (m, 4H), 7.47 (d, J=8.19 Hz, 1H), 7.50 (d, J=8.36 Hz, 2H), 7.55 (d, J=8.36 Hz, 2H), 9.24 (s, 1H), 12.25 (br s, 1H); MS (ESI) [M+1]+ 499.
  • Figure US20120022057A1-20120126-C00103
    Figure US20120022057A1-20120126-C00104
    • Intermediate B-30: 6-bromoquinoxaline-2,3(1H,4H)-dione—step b15
  • 4-Bromobenzene-1,2-diamine B-29 (232 mg, 1.24 mmol) and oxalic acid (135.0 mg, 1.24 mmol) were mixed as solids and were heated under vacuum at 160° C. for 8 h. The crude dark grey solid 6-bromoquinoxaline-2,3(1H,4H)-dione B-30 (278.0 mg, ca. 1.12 mmol) was used for next step without purification. MS (ESI) [M+1]+ 241, 243.
    • Intermediate B-31: 6-bromo-1,2,3,4-tetrahydroquinoxaline—step b16
  • Borane dimethyl sulfide complex (2 M solution in THF, 2.24 mL, 4.48 mmol) was added at room temperature to a solution of 6-bromoquinoxaline-2,3(1H,4H)-dione B-30 (278.0 mg, 1.12 mmol) in anhydrous THF (8.96 mL) under an argon atmosphere. The reaction mixture was heated to reflux for 3.5 h, then cooled to room temperature, quenched slowly with methanol (2 mL) and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (methylene chloride:ethyl acetate gradient) to give 6-bromo-1,2,3,4-tetrahydroquinoxaline B-31 as a light pink solid (181.2 mg, Yield=65% over 2 steps). MS (ESI) [M+1]+ 213, 215.
    • Intermediate B-32: methyl 2-((1r,4r)-4-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate—step b10
  • Intermediate B-32 was prepared by the procedure described for step b10, using 6-bromo-1,2,3,4-tetrahydroquinoxaline B-31 as starting material. MS (ESI) [M+1]+ 365.
    • Intermediates B-33 (mixture of regioisomers): methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate and methyl 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate—step b17
  • A solution of phenyl isocyanate (34.5 μL, 0.317 mmol) in anhydrous methylene chloride (2.3 mL) was added at room temperature over 12 h (using a syringe pump) to a solution of methyl 2-((1r,4r)-4-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate B-32 (105.0 mg, 0.288 mmol) in anhydrous methylene chloride (0.55 mL). After completion of the addition, the reaction mixture was stirred at room temperature for 12 h, quenched with methanol (2.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (90:10 to 0:100 gradient of hexanes:ethyl acetate) to give a 1:1 mixture of the two regioisomers methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate and methyl 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate B-33 (139.8 mg, Yield=94%). MS (ESI) [M+1]+ 484.
    • Example B-34: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-34 was prepared by the procedure described for step b6, using the 1:1 mixture of regioisomers B-33 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.77 Hz, 2H), 1.49 (q, J=11.77 Hz, 2H), 1.69-1.78 (m, 1H), 1.83 (br d, J=9.62 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.44-2.49 (m, 1H), 3.30 (br s, 2H), 3.68 (br s, 2H), 6.21 (br s, 1H), 6.78 (d, J=8.51 Hz, 1H), 6.88 (s, 1H), 6.97 (t, J=7.25 Hz, 1H), 7.20-7.30 (m, 4H), 7.47 (t, J=8.20 Hz, 3H), 8.79 (s, 1H), 12.13 (br s, 1H); MS (ESI) [M+1]+ 470.
    • Example B-35: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetic acid—step b6
  • Example B-35 was prepared by the procedure described for step b6, using the 1:1 mixture of regioisomers B-33 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11 (q, J=12.20 Hz, 2H), 1.45 (q, J=12.20 Hz, 2H), 1.68-1.76 (m, 1H), 1.80 (br t, J=11.03 Hz, 4H), 2.13 (d, J=6.62 Hz, 2H), 2.39-2.47 (m, 1H), 3.30 (br s, 2H), 3.70 (t, J=4.70, 2H), 6.26 (br s, 1H), 6.69 (d, J=8.51 Hz, 1H), 6.97 (t, J=7.25 Hz, 1H), 7.14 (dd, J=2.05, 8.51 Hz, 1H), 7.20 (d, J=8.20, 2H), 7.26 (d, J=7.88 Hz, 2H), 7.39 (d, J=8.20 Hz, 2H), 7.44 (d, J=1.89 Hz, 1H), 7.50 (d, J=7.88 Hz, 2H), 8.85 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 470.
  • Figure US20120022057A1-20120126-C00105
    Figure US20120022057A1-20120126-C00106
    • Intermediate B-36: diethyl 2-(5-bromo-2-nitrophenoxy)malonate—step b18
  • 5-Bromo-2-nitrophenol A-32 (0.40 g, 1.83 mmol) and diethyl 2-bromomalonate (0.470 mL, 2.75 mmol) were mixed in anhydrous 1-methylpyrrolidin-2-one (3.70 mL) under an atmosphere of argon at room temperature. Potassium fluoride (0.265 g, 4.58 mmol) was added, and the solution was heated at 70° C. for 12 h. After cooling to room temperature, the reaction mixture was successively diluted with diethyl ether (25 mL), filtered, rinsed with diethyl ether (20 mL), quenched with water (25 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic extracts were successively washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give diethyl 2-(5-bromo-2-nitrophenoxy)malonate B-36 as a yellow oil (553.0 mg, Yield=70%). MS (ESI) [M+1]+ 376, 378.
    • Intermediate B-37: ethyl 7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate—step a24
  • Intermediate B-37 was prepared by the procedure described for step a24, using diethyl 2-(5-bromo-2-nitrophenoxy)malonate B-36 as starting material. MS (ESI) [M+1]+ 300, 302.
    • Intermediate B-38: (7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol—step b16
  • Intermediate B-38 was prepared by the procedure described for step b16, using ethyl 7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate B-37 as starting material. MS (ESI) [M+1]+ 244, 246.
    • Intermediate B-39: methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b19
  • [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (16.3 mg, 0.020 mmol), potassium carbonate (139.0 mg, 1.0 mmol), 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol B-38 (115.2 mg, 0.40 mmol) and methyl 2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate trans-A-5 (260.0 mg, 0.72 mmol) were mixed in a 4:1 mixture of 1,4-dioxane:water (4.0 mL) at room temperature. The reaction mixture was degassed several times under reduced pressure and stirred for 12 h under an atmosphere of argon. The mixture was then filtered through a celite pad, washed with ethyl acetate (25 mL) and concentrated to dryness under reduced pressure. The residue was adsorbed on silica (5.0 g) and purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-39 as a light yellow solid (117.2 mg; Yield=67%). MS (ESI) [M+1]+ 396.
    • Intermediate B-40: methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b20
  • Phenyl isocyanate (32.0 μL, 0.294 mmol) was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-39 (117.2 mg, 0.267 mmol) in methylene chloride (2.70 mL) at 0° C. under an atmosphere of argon. The reaction mixture was warmed slowly to room temperature, stirred for 12 h, then quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure. The resulting purple solid methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-40 (141.6 mg, Yield=98%) was used as such for the next step without purification. MS (ESI) [M+1]+ 515.
    • Example B-41: 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b14
  • Intermediate B-41 was prepared by the procedure described for step b14, using methyl 2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-40 as starting material. 1H NMR (500 MHz, DMSO-d6)
  • δ ppm 1.14 (q, J=12.13 Hz, 2H), 1.49 (q, J=12.13 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d, J=10.56 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.49 (m, 1H), 3.52 (dd, J=7.41, 13.24 Hz, 1H), 3.60 (dd, J=6.15, 11.19 Hz, 1H), 3.70 (dd, J=4.89, 11.19 Hz, 1H), 4.13 (dd, J=2.36, 13.24 Hz, 1H), 4.19-4.25 (m, 1H), 5.09 (br s, 1H), 7.00 (t, J=7.41 Hz, 1H), 7.15-7.18 (m, 2H), 7.27-7.31 (m, 4H), 7.48-7.56 (m, 5H), 9.21 (s, 1H), 12.08 (br s, 1H); MS (ESI) [M+1]+ 501.
  • Figure US20120022057A1-20120126-C00107
    • Intermediate B-42: methyl 2-((1r,4r)-4-(4-(4-(chlorocarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b21
  • A solution of methyl 2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-16 (1.6 g, 4.2 mmol) and dry pyridine (686 μL, 8.4 mmol) in anhydrous methylene chloride (10.0 mL) was added dropwise to a solution of triphosgene (504.0 mg, 1.66 mmol) in anhydrous methylene chloride (10.0 mL) at −5° C. under an atmosphere of nitrogen. The reaction mixture was kept at −5° C. for 30 mins and was allowed to warm to room temperature over 30 mins. It was then successively diluted with methylene chloride (25 mL), quenched with a 1 N aqueous solution of hydrogen chloride (1.0 mL), diluted with water (10 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with a 1 N aqueous solution of hydrogen chloride (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The pink solid methyl 2-((1r,4r)-4-(4-(4-(chlorocarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-42 (1.74 g, Yield=94%) was used for the next step without purification and stored at −20° C. under an atmosphere of nitrogen. MS (ESI) [M+1]+ 442.
    • Intermediate B-43: methyl 2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—step b22
  • A solution of methyl 2-((1r,4r)-4-(4-(4-(chlorocarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-42 (186.0 mg, 0.42 mmol) in anhydrous methylene chloride (2.0 mL) was added dropwise to a solution of 3-phenylpropan-1-amine (85.2 mg, 0.63 mmol) and N-ethyl-N,N-diisopropylamine (104.0 μL, 0.63 mmol) in anhydrous methylene chloride (2.0 mL) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h, then sequentially diluted with methylene chloride, washed with a 1 N aqueous solution of hydrogen chloride (5.0 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue (225.0 mg) was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-43 (181.0 mg, Yield=80%) as a light pink solid. MS (ESI) [M+1]+ 541.
    • Example B-44: 2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step b14
  • Intermediate B-44 was prepared by the procedure described for step b14, using methyl 2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate B-43 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (dq, J=12.50, 2.00 Hz, 2H), 1.31 (d, J=6.50 Hz, 3H), 1.49 (dq, J=12.50, 2.00 Hz, 2H),1.69-1.88 (m, 7H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H), 2.62 (t, J=7.72 Hz, 2H), 3.22 (dd, J=13.50, 8.00 Hz, 1H), 3.97 (dd, J=13.50, 1.75 Hz, 1H), 4.20-4.30 (m, 1H), 7.00 (t, J=5.20 Hz, 1H), 7.10 (d, J=1.50 Hz, 1H), 7.13 (dd, J=8.50, 2.00 Hz, 1H), 7.18 (t, J=7.25 Hz, 1H), 7.23 (d, J=7.00 Hz, 2H), 7.25-7.31 (m, 4H), 7.53 (d, J=7.88 Hz, 2H), 7.61 (d, J=8.51 Hz, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 527.
  • Figure US20120022057A1-20120126-C00108
    • Intermediate B-46: 7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)quinoline-4-carboxylic acid—step b2
  • Intermediate B-46 was prepared by the procedure described for step b2, using 7-bromoquinoline-4-carboxylic acid B-45 as starting material. MS (ESI), [M+1]+ 404.
    • Intermediate B-47: methyl 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetate—step b23
  • N-Ethyl-N,N-diisopropylamine (64.5 mg, 0.50 mmol) was added at room temperature to a solution of aniline (465.0 mg, 0.50 mmol), 7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)quinoline-4-carboxylic acid B-46 (101.0 mg, 0.25 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (190.0 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetate B-47 (107.0 mg, Yield=90%). MS (ESI), [M+1]+ 479.
    • Example B-48: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid—step b24
  • A 1 N aqueous solution of sodium hydroxide (3.0 mL) was added to a solution of methyl 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetate B-47 (94.0 mg, 0.20 mmol) in a 1:5 mixture of tetrahydrofuran: methanol (10.0 mL) at room temperature. After 12 h of vigorous stirring, the aqueous layer was then acidified to pH 1 using a 1 N aqueous solution of hydrogen chloride. The resulting solution was concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid B-48 (65.2 mg, Yield=70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=11.5 Hz, 2H), 1.53 (q, J=11.5 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.48-2.54 (m, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.41-7.43 (m, 3H), 7.73 (d, J=8.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 5H), 8.05 (d, J=9.0 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.36 (s, 1H), 9.08 (d, J=9.0 Hz, 1H), 10.82 (s, 1H); MS (ESI) [M+1]+ 465.
  • Figure US20120022057A1-20120126-C00109
    • Intermediate B-50: tert-butyl 5-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate—step b25
  • Aniline (118.3 μL, 1.082 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (616.9 mg, 1.622 mmol) and N-ethyl-N,N-diisopropylamine (565.3 μL, 3.245 mmol) were successively added at room temperature to a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid B-49 (300.0 mg, 1.082 mmol) in methylene chloride (10.0 mL). The reaction mixture was stirred at room temperature for 12 h, then concentrated to dryness under reduced pressure and purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give tert-butyl 5-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate B-50 as a white solid (374.9 mg, Yield=98%). 1H NMR (500 MHz, CHLOROFORM-d3) δ ppm 1.51 (s, 9H), 3.09 (t, J=5.50 Hz, 2H), 3.62-3.67 (m, 2H), 4.64 (s, 2H), 7.19 (t, J=7.50 Hz, 1H), 7.25-7.31 (m, 2H), 7.39-7.43 (m, 3H), 4.64 (br s, 1H), 7.64 (d, J=7.50 Hz, 2H).
    • Intermediate B-51: N-phenyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide—step b26
  • tert-butyl 5-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate B-50 (374.9 mg, 1.352 mmol) was dissolved in a 4 N solution of hydrogen chloride in dioxane (10.0 mL) and stirred at room temperature under an atmosphere of nitrogen for 3 h. The reaction mixture was then concentrated to dryness under reduced pressure to give crude N-phenyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide B-51 (248.7 mg, Yield=81%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.10-3.13 (m, 2H), 3.34-3.37 (m, 2H), 4.33 (s, 2H), 7.10 (t, J=7.50 Hz, 1H), 7.33-7.41 (m, 3H), 7.50 (d, J=7.50 Hz, 1H), 7.74 (d, J=7.50 Hz, 2H), 9.37 (br s, 2H), 10.43 (s, 1H).
    • Example B-52: methyl 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetate—step b27
  • Palladium (II) acetate (2.90 mg, 0.013 mmol), cesium carbonate (256.9 mg, 0.789 mmol), methyl 2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)-cyclohexyl)acetate A-4 (100.0 mg, 0.263 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (13.1 mg, 0.021 mmol) and N-phenyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide B-51 (113.9 mg, 0.394 mmol) were mixed in anhydrous toluene (5.0 mL) in a sealed tube. The reaction mixture was degassed several times under reduced pressure, heated at 120° C. and stirred for 15 h. The mixture was then filtered through a celite pad, washed with ethyl acetate (30 mL) and concentrated to dryness under reduced pressure. The residue was adsorbed on silica (1.0 g) and purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetate B-52 as a yellow solid (38.5 mg; Yield=79%). 1H NMR (500 MHz, CDCl3) δ ppm 1.13-1.21 (m, 2H), 1.46-1.54 (m, 2H), 1.84-1.96 (m, 5H), 2.28 (d, J=6.50 Hz, 2H), 2.41-2.46 (m, 1H), 3.24 (t, J=6.00 Hz, 2H), 3.53 (d, J=6.00 Hz, 2H), 3.71 (s, 3H), 4.44 (s, 2H), 6.96 (d, J=8.50 Hz, 2H), 7.15-7.20 (m, 3H), 7.29-7.30 (m, 2H), 7.39-7.44 (m, 3H), 7.50 (br s, 1H), 7.65 (d, J=7.50 Hz, 2H); MS (ESI) [M+1]+ 483.
    • Example B-53: 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetic acid—step b3
  • Example B-53 was prepared by the procedure described for step b3, using methyl 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetate B-52 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.14 (m, 2H), 1.37-1.45 (m, 2H), 1.69-1.81 (m, 5H), 2.14 (d, J=7.00 Hz, 2H), 2.33-2.38 (m, 1H), 3.00 (t, J=5.50 Hz, 2H), 3.49 (t, J=5.50 Hz, 2H), 4.41 (s, 2H), 6.94-6.96 (m, 2H), 7.09-7.11 (m, 3H), 7.31-7.37 (m, 5H), 7.75 (d, J=8.00 Hz, 2H), 10.33 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 469.
  • Figure US20120022057A1-20120126-C00110
    • Intermediate B-55: methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate—step b9
  • Intermediate B-55 was prepared by the procedure described for step b9, using tert-butyl 7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)-1-(phenylcarbamoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate B-54 as starting material. MS (ESI) [M+1]+ 498.
    • Intermediate B-56: methyl 2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate—step b28
  • Sodium cyanoborohydride (40.0 mg, 0.60 mmol) was added at 0° C. to a solution of methyl 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate B-55 (99.4 mg, 0.20 mmol) and formaldehyde (20.0 mg, 0.60 mmol) in anhydrous acetonitrile (5.0 mL) under an atmosphere of argon. The reaction mixture was allowed to warm to room temperature, then stirred for 15 mins and treated with acetic acid (47 μL, 0.80 mmol). The reaction mixture was stirred at room temperature for 12 h and then treated with a 10% solution of potassium carbonate (3.0 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude methyl 2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate B-56 was used for the next step without purification. MS (ESI) [M+1]+ 512.
    • Example B-57: 2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetic acid—step b24
  • Example B-57 was prepared by the procedure described for step b24, using methyl 2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate B-56 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=12.0 Hz, 2H), 1.53 (q, J=12.0 Hz, 2H), 1.75-1.86 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.26 (s, 3H), 2.54 (m, 1H), 3.45-3.56 (m, 4H), 4.56 (s, 2H), 6.98 (t, J=7.5 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.42-7.45 (m, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.94 (s, 1H), 8.49 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 498.
    • Section C Example Compounds Preparation of Examples C-1 to C-157
  • The following examples were prepared using the general procedures outlined in section B, using reagents from commercial sources or intermediates either prepared with procedures outlined in section A or section B or published literature procedures.
    • Example C-1: 2-((1r,4r)-4-(4-(1-(4-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00111
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.98 Hz, 2H), 1.49 (q, J=11.98 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.60 Hz, 2H), 2.46-2.48 (m, 1H), 3.24 (t, J=8.50 Hz, 2H), 4.16 (t, J=8.50 Hz, 2H), 7.15 (t, J=8.83 Hz, 2H), 7.28 (d, J=8.20 Hz, 2H), 7.42 (d, J=8.51 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.56-7.61 (m, 2H), 7.91 (d, J=8.20 Hz, 1H), 8.61 (s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 473.
    • Example C-2: 2-((1r,4r)-4-(4-(1-(3-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00112
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.55 Hz, 2H), 1.49 (q, J=11.55 Hz, 2H), 1.75 (br s, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2 H), 2.45-2.48 (m, 1H), 3.26 (t, J=8.20 Hz, 2H), 4.20 (t, J=8.20 Hz, 2H), 7.29 (d, J=8.20 Hz, 2H), 7.36 (d, J=8.80 Hz, 1H), 7.44 (d, J=8.51 Hz, 1H), 7.51 (s, 1H), 7.52-7.57 (m, 3H), 7.90 (d, J=8.20 Hz, 1H), 7.93 (d, J=8.20 Hz, 1H), 8.05 (s, 1H), 8.88 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]+ 523.
    • Example C-3: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00113
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.85 Hz, 2H), 1.52 (q, J=12.00 Hz, 2H), 1.70 (br s, 1H), 1.75-1.80 (m, 4H), 2.19 (d, J=6.62 Hz, 2 H), 2.52-2.55 (m, 1H), 6.81 (d, J=3.00 Hz, 1H), 7.16 (t, J=7.50 Hz, 1H), 7.21-7.49 (m, 4H), 7.50-7.74 (m, 5H), 7.89 (s, 1H), 8.07 (d, J=3.50 Hz, 1H), 8.28 (d, J=8.00 Hz, 1H), 10.10 (s, 1H); MS (ESI) [M+1]+ 453.
    • Example C-4: 2-((1r,4r)-4-(4-(1-(pyridin-3-ylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00114
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09 (q, J=11.75 Hz, 2H), 1.53 (q, J=11.75 Hz, 2H), 1.75 (br s, 1H), 1.75-1.82 (m, 4H), 2.18 (d, J=6.94 Hz, 2H), 2.50-2.55 (m, 1H), 7.02 (m, 1H), 7.28-7.37 (m, 4H), 7.45 (d, J=8.51 Hz, 1H), 7.62 (d, J=7.25 Hz, 2H), 7.68 (s, 1H), 7.79 (d, J=8.20 Hz, 2H), 8.24 (d, J=8.51 Hz, 1H), 8.33 (br s, 1H), 9.76 (s, 1H), 11.81 (br s, 1H); MS (ESI) [M+1]+ 454.
    • Example C-5: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00115
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.40 Hz, 2H), 1.49 (q, J=11.40 Hz, 2H), 1.70-1.86 (m, 5H), 2.16 (d, J=6.94 Hz, 2H), 2.52-2.55 (m, 1H), 3.85 (t, J=4.10 Hz, 2H), 4.25 (t, J=4.10 Hz, 2H), 7.01 (t, J=7.25 Hz, 1H), 7.11-7.20 (m, 2H), 7.26-7.29 (m, 4H), 7.45-7.60 (m, 5H), 9.17 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]+ 471.
    • Example C-6: 2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00116
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.35 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.88 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.49 (br s, 1H), 3.85 (t, J=4.10 Hz, 2H), 4.25 (t, J=4.10 Hz, 2H), 6.65 (d, J=8.20 Hz, 1H), 6.92-7.07 (m, 2H), 7.17-7.35 (m, 3H), 7.43 (d, J=7.88 Hz, 2H), 7.47-7.62 (m, 2H), 9.00 (s, 1H); MS (ESI) [M+1]+ 557.
    • Example C-7: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00117
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.40 Hz, 2H), 1.52 (q, J=11.40 Hz, 2H), 1.75-1.85 (m, 5H), 2.16 (d, J=6.94 Hz, 2H), 2.53-2.56 (m, 1H), 3.85 (t, J=4.10 Hz, 2H), 4.27 (t, J=4.10 Hz, 2H), 6.90-7.03 (m, 3H), 7.24-7.32 (m, 4H), 7.38-7.51 (m, 5H), 9.15 (s, 1H); MS (ESI) [M+1]+ 471.
    • Example C-8: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00118
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.42 Hz, 2H), 1.50 (q, J=11.38 Hz, 2H), 1.73-1.85 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.52-2.55 (m, 1H), 3.87 (t, J=4.10 Hz, 2H), 4.28 (t, J=4.10 Hz, 2H), 6.94-7.03 (m, 3H), 7.21-7.33 (m, 4H), 7.39-7.48 (m, 3H), 7.52 (d, J=8.20 Hz, 1H), 7.77-7.79 (m, 1H), 9.22 (s, 1H); MS (ESI) [M+1]+ 471.
    • Example C-9: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00119
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08 (q, J=11.54 Hz, 2H), 1.57 (q, J=11.60 Hz, 2H), 1.70-1.93 (m, 5H), 1.82-1.99 (m, 2H), 2.04-2.30 (m, 2H), 2.52-2.56 (m, 1H), 2.71-2.86 (m, 2H), 3.59-3.79 (m, 2H), 6.55 (s, 1H), 6.91-7.14 (m, 1H), 7.29 (s, 4H), 7.39-7.40 (m, 2H), 7.45-7.65 (m, 4H), 8.95 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]+ 469.
    • Example C-10: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00120
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.42 Hz, 2H), 1.52 (q, J=11.58 Hz, 2H), 1.73-1.82 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.51-2.55 (m, 1H), 4.10 (t, J=4.00 Hz, 2H), 4.34 (t, J=4.00 Hz, 2H), 7.06-7.10 (m, 1H), 7.35-7.38 (m, 4H) 7.59-7.70 (m, 4H), 7.72-7.78 (m, 1H), 8.42 (s, 1H), 12.05 (br s, 1H), 12.88 (s, 1H); MS (ESI) [M+1]+ 472.
    • Example C-11: 2-((1s,4s)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00121
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.10 (q, J=11.40 Hz, 2H), 1.50 (q, J=11.35 Hz, 2H), 1.58-1.66 (m, 4H), 1.75-1.82 (m, 1H), 2.38 (d, J=6.94 Hz, 2H), 2.50-2.55 (m, 1H), 3.87 (t, J=4.10 Hz, 2H), 4.30 (t, J=4.10 Hz, 2H), 7.01 (t, J=7.25 Hz, 1H), 7.11-7.20 (m, 2H) 7.27-7.34 (m, 4H), 7.45-7.60 (m, 5H), 9.16 (s, 1H); MS (ESI) [M+1]+ 471.
    • Example C-12: 2-(4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)piperazin-1-yl)acetic acid
  • Figure US20120022057A1-20120126-C00122
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 2.53 (s, 2H), 3.58-3.62 (m, 2H), 3.80-4.20 (m, 6H), 7.02-7.09 (m, 3H), 7.36 (m, 2H), 7.40-7.47 (m, 1H), 7.50 (m, 1H), 7.47-7.63 (m, 4H), 7.93-7.98 (m, 1H), 8.56-8.60 (m, 1H), 10.5 (s, 1H); MS (ESI) [M+1]+ 457.
    • Example C-13: (1R,2S)-2-(4-(1-(phenylcarbamoyl)indolin-5-yl)benzoyl)cyclopentanecarboxylic acid
  • Figure US20120022057A1-20120126-C00123
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.55-1.70 (m, 2H), 1.70-1.87 (m, 2H), 1.98-2.06 (m, 1H), 2.13-2.22 (m, 1H), 3.22 (m, 2H), 4.04-4.12 (m, 1H), 4.20 (t, J=8.51 Hz, 2H), 7.04 (t, J=7.25 Hz, 1H), 7.31 (t, J=7.41 Hz, 2H), 7.58 (d, J=8.20 Hz, 3H), 7.64 (s, 1H), 7.82 (d, J=7.57 Hz, 2H), 7.97 (d, J=8.51 Hz, 1H), 8.06 (d, J=7.88 Hz, 2H), 8.61 (s, 1H); MS (ESI) [M+1]+ 455.
    • Example C-14: 2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)naphthalen-2-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00124
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.60 Hz, 2H), 1.53 (q, J=11.58 Hz, 2H), 1.73-1.80 (m, 5H), 2.19 (d, J=7.25 Hz, 2H), 2.54 (m, 1H), 7.12-7.18 (m, 1H), 7.36-7.54 (m, 4H), 7.59-7.70 (m, 4H), 7.74-7.90 (m, 3H), 8.13-8.39 (m, 3H), 10.61 (s, 2H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 464.
    • Example C-15: 2-((1r,4r)-4-(4-(4-(benzo[d]oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00125
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.70-1.95 (m, 5H), 2.19 (d, J=7.25 Hz, 2H), 2.53 (m, 1H), 4.22 (t, J=4.10 Hz, 2H), 4.44 (t, J=4.10 Hz, 2H), 7.10-7.33 (m, 5H), 7.46-7.62 (m, 4H), 8.38-8.54 (m, 2H); MS (ESI) [M+1]+ 469.
    • Example C-16: 2-((1r,4r)-4-(4-(2-(phenylamino)quinazolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00126
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.42 Hz, 2H), 1.54 (q, J=11.40 Hz, 2H), 1.80-1.87 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.53 (m, 1H), 7.00 (t, J=7.25 Hz, 1H), 7.29-7.41 (m, 5H), 7.68-7.76 (m, 3H), 8.00 (d, J=8.20 Hz, 2H), 8.15 (d, J=8.83 Hz, 1H), 8.20 (s, 1H), 9.36 (s, 1H), 9.93 (s, 1H); MS (ESI) [M+1]+ 438.
    • Example C-17: 2-((1r,4r)-4-(4-(2-(phenylamino)benzo[d]oxazol-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00127
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=11.62 Hz, 2H), 1.56 (q, J=11.50 Hz, 2H), 1.68-1.72 (m, 5H), 2.16 (d, J=6.62 Hz, 2H), 2.55 (m, 1 H), 3.59 (br s, 1H), 6.63 (s, 1H), 7.05 (t, J=7.09 Hz, 1H), 7.32 (d, J=7.57 Hz, 2H), 7.39 (t, J=7.57 Hz, 2H), 7.46-7.57 (m, 2H), 7.62 (d, J=7.88 Hz, 2H), 7.78 (d, J=6.62 Hz, 2H), 10.70 (s, 1H); MS (ESI) [M+1]+ 427.
    • Example C-18: 2-((1r,4r)-4-(4-(3-(phenylcarbamoyl)-1H-indol-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00128
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.15-1.19 (q, J=11.35 Hz, 2H), 1.53 (q, J=11.35 Hz, 2H), 1.85-1.95 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.53 (m, 1H), 7.12-7.18 (m, 1H), 7.30-7.40 (m, 4H), 7.50-7.70 (m, 5H), 7.91 (s, 1H), 7.95 (s, 1H), 8.00-8.20 (m, 3H); MS (ESI) [M+1]+ 453.
    • Example C-19: 2-((1r,4r)-4-(4-(2-(phenylcarbamoyl)-1H-benzo[d]imidazol-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00129
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=11.44 Hz, 2H), 1.46 (q, J=11.50 Hz, 2H), 1.83-1.85 (m, 5H), 2.16 (d, J=6.31 Hz, 2H), 2.51 (m, 1H), 6.94-7.14 (m, 1H), 7.28-7.40 (m, 5H), 7.43 (s, 1H), 7.47-7.57 (m, 4H), 8.18 (d, J=7.88 Hz, 1H), 9.45 (s, 1H), 12.26-12.64 (m, 1H); MS (ESI) [M+1]+ 454.
    • Example C-20: (1S,2S)-2-(4-(1-(phenylcarbamoyl)-1H-indol-5-yl)benzoyl)cyclopentanecarboxylic acid
  • Figure US20120022057A1-20120126-C00130
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.55-1.70 (m, 2H), 1.70-1.87 (m, 2H), 1.98-2.06 (m, 1H), 2.13-2.22 (m, 1H), 3.22-3.40 (m, 2H), 6.86 (d, J=3.50 Hz, 1H), 7.16 (t, J=7.25 Hz, 1H), 7.41 (t, J=7.41 Hz, 2H), 7.68 (d, J=8.50 Hz, 2H), 7.73 (s, 1H), 7.92 (d, J=7.57 Hz, 2H), 8.05 (s, 1H), 8.10-8.16 (m, 3H), 8.33 (d, J=8.00 Hz, 1H), 10.14 (s, 1H); MS (ESI) [M+1]+ 453.
    • Example C-21: 2-((1r,4r)-4-(4-(4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00131
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.47 (q, J=11.50 Hz, 2H), 1.72-1.80 (m, 5H), 2.15 (d, J=6.62 Hz, 2H), 2.53 (m, 1H), 3.32 (t, J=4.00 Hz, 2H), 4.15 (t, J=4.00 Hz, 2H), 6.65 (d, J=8.20 Hz, 1H), 6.94 (br s, 1H), 6.98-7.07 (m, 1H), 7.22 (d, J=8.00 Hz, 2H), 7.25-7.35 (m, 1H), 7.43 (d, J=7.88 Hz, 2H) 7.47-7.62 (m, 2H), 8.30 (s, 1H), 9.00 (s, 1H); MS (ESI) [M+1]+ 539.
    • Example C-22: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1H-indazol-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00132
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.50 Hz, 2H), 1.53 (q, J=11.50 Hz, 2H), 1.73-1.86 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.53 (m, 1H), 7.15 (t, J=7.50 Hz, 1H), 7.32-7.42 (m, 5H), 7.67 (d, J=7.88 Hz, 2H), 7.82 (d, J=8.20 Hz, 2H), 7.92 (d, J=9.50 Hz, 1H), 8.15 (s, 1H), 8.39 (d, J=5.00 Hz, 1H), 8.55 (s, 1H); MS (ESI) [M+1]+ 454.
    • Example C-23: 2-((1r,4r)-4-(4-(4-(4-ethoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00133
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.19 (t, J=7.80 Hz, 3H), 1.49 (q, J=11.50 Hz, 2H), 1.72-1.85 (m, 5H), 2.17 (d, J=6.62 Hz, 2H), 2.53 (m, 1H), 3.85 (t, J=4.00 Hz, 2H), 3.96 (q, J=7.80 Hz, 2H), 4.29 (t, J=4.00 Hz, 2H), 6.83-6.87 (m, 2H), 7.15-7.16 (m, 2H), 7.28-7.33 (m, 2H), 7.38 (d, J=9.00 Hz, 2H), 7.54 (d, J=8.00 Hz, 2H), 7.57-7.59 (m, 1H), 8.99 (s, 1H); MS (ESI) [M+1]+ 515.
    • Example C-24: 2-((1r,4r)-4-(4-(4-(4-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00134
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.50 Hz, 2H), 1.49 (q, J=11.50 Hz, 2H), 172-1.84 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.53 (m, 1H), 3.88 (t, J=4.00 Hz, 2H), 4.31 (t, J=4.00 Hz, 2H), 7.15-7.18 (m, 2H), 7.29 (d, J=7.50 Hz, 2H), 7.55 (d, J=13.50 Hz, 2H), 7.57 (d, J=9.00 Hz, 1H), 7.63-7.73 (m, 4H), 8.44 (s, 1H), 9.58 (s, 1H); MS (ESI) [M+1]+ 539.
    • Example C-25: 2-((1r,4r)-4-(4-(4-(perfluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00135
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.47 (q, J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m, 1H), 3.93 (t, J=4.00 Hz, 2H), 4.33 (t, J=4.00 Hz, 2H), 7.17-7.19 (m, 2H), 7.29 (d, J=8.50 Hz, 2H), 7.54 (d, J=8.00 Hz, 2H), 7.68 (d, J=9.00 Hz, 1H), 9.29 (s, 1H); MS (ESI) [M+1]+ 561.
    • Example C-26: 2-((1r,4r)-4-(4-(4-(2-cyanophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00136
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.46 (q, J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m, 1H), 3.93 (t, J=4.00 Hz, 2H), 4.22 (t, J=4.00 Hz, 2H), 7.18-7.20 (m, 3H), 7.28-7.34 (m, 3H), 7.54-7.58 (m, 3H), 7.68 (d, J=9.00 Hz, 1H), 7.80 (d, J=8.50 Hz, 1H), 9.46 (s, 1H); MS (ESI) [M+1]+ 496.
    • Example C-27: 2-((1r,4r)-4-(4-(4-(2-nitrophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00137
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.47 (q, J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m, 1H), 3.89 (t, J=4.00 Hz, 2H), 4.33 (t, J=4.00 Hz, 2H), 7.20 (s, 1H) 7.26-7.33 (m, 2H), 7.56 (d, J=7.57 Hz, 2H), 7.64-7.73 (m, 3H), 7.77 (d, J=8.50 Hz, 2H), 7.99 (d, J=8.20 Hz, 1H), 9.93 (s, 1H); MS (ESI) [M+1]+ 496.
    • Example C-28: 2-((1r,4r)-4-(4-(4-(4-(cyanomethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00138
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.20 (q, J=11.80 Hz, 2H), 1.58 (q, J=11.80 Hz, 2H), 1.91-2.00 (m, 5H), 2.35 (d, J=7.00 Hz, 2H), 2.56 (m, 1H), 3.75 (s, 2H), 4.01 (t, J=5.50 Hz, 2H), 4.38 (t, J=5.50 Hz, 2H), 7.20-7.24 (m, 2H), 7.21-7.33 (m, 4H), 7.38 (d, J=8.00 Hz, 1H), 7.47 (d, J=8.51 Hz, 2H), 7.53 (d, J=7.88 Hz, 2H), 8.05 (s, 1H); MS (ESI) [M+1]+ 510.
    • Example C-29: 2-((1r,4r)-4-(4-(4-(2-(methoxycarbonyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00139
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.20 (q, J=11.80 Hz, 2H), 1.57 (q, J=11.80 Hz, 2H), 1.94-2.09 (m, 5H), 2.35 (d, J=6.94 Hz, 2H), 2.56 (m, 1H), 3.83 (s, 3H), 4.00 (t, J=4.50 Hz, 2H), 4.39 (t, J=4.50 Hz, 2H), 7.06 (q, J=7.15 Hz, 1H), 7.19-7.25 (m, 2H), 7.26-7.33 (m, 2H), 7.56 (d, J=7.88 Hz, 1H), 7.64 (d, J=8.20 Hz, 1H), 8.06 (d, J=7.25 Hz, 1H), 8.02 (d, J=8.20 Hz, 1H), 8.57 (d, J=8.51 Hz, 1H), 8.55 (d, J=8.51 Hz, 1H), 10.84 (br s, 1H), 10.98 (s, 1H); MS (ESI) [M+1]+ 529.
    • Example C-30: 2-((1r,4r)-4-(4-(4-(2-fluoro-5-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00140
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.51 (q, J=11.50 Hz, 2H), 1.71-1.84 (m, 5H), 2.15 (d, J=6.00 Hz, 2H), 2.53 (m, 1H), 3.90 (t, J=4.50 Hz, 2H), 4.32 (t, J=4.50 Hz, 2H), 7.15-7.23 (m, 1H), 7.30 (d, J=8.20 Hz, 1H), 7.42-7.57 (m, 4H), 7.64-7.70 (m, 1H), 8.03 (d, J=5.67 Hz, 1H), 8.63 (d, J=5.67 Hz, 1H), 9.15 (s, 1H), 9.48-9.53 (m, 1H), 12.05 (s, 1H); MS (ESI) [M+1]+ 557.
    • Example C-31: 2-((1r,4r)-4-(4-(4-(2-chloro-6-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00141
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.50 Hz, 2H), 1.49 (q, J=11.50 Hz, 2H), 1.70-1.84 (m, 5H), 2.15 (d, J=6.00 Hz, 2H), 2.51 (m, 1H), 3.82 (t, J=4.50 Hz, 2H), 4.39 (t, J=4.50 Hz, 2H), 7.17-7.22 (m, 4H), 7.29 (d, J=8.00 Hz, 1H), 7.53-7.59 (m, 2H), 7.63 (d, J=8.00 Hz, 1H), 7.78 (d, J=8.00 Hz, 1H), 7.92 (d, J=8.00 Hz, 1H), 9.00 (s, 1H); MS (ESI) [M+1]+ 574.
    • Example C-32: 2-((1r,4r)-4-(4-(4-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00142
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.49 (q, J=11.50 Hz, 2H), 1.71-1.84 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.49 (m, 1H), 3.91 (t, J=4.50 Hz, 2H), 4.30 (t, J=4.50 Hz, 2H), 7.17-7.18 (m, 4H), 7.29 (d, J=8.50 Hz, 1H), 7.58-7.69 (m, 4H), 7.55 (d, J=8.00 Hz, 1H), 8.84 (s, 1H); MS (ESI) [M+1]+ 557.
    • Example C-33: 2-((1r,4r)-4-(4-(1-(3-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00143
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.94 Hz, 2H), 2.30 (s, 3H), 2.44-2.48 (m, 1H), 3.23 (t, J=8.51 Hz, 2H), 4.16 (t, J=8.51 Hz, 2H), 6.84 (d, J=7.57 Hz, 1H), 7.18 (t, J=7.57 Hz, 1H), 7.28 (d, J=7.88 Hz, 2H), 7.37 (d, J=8.20 Hz, 1H), 7.40-7.44 (m, 2H), 7.49 (s, 1H), 7.53 (d, J=7.88 Hz, 2H), 7.91 (d, J=8.20 Hz, 1H), 8.48 (s, 1H), 12.23 (br s, 1H); MS (ESI) [M+1]+ 469.
    • Example C-34: 2-((1r,4r)-4-(4-(1-(3-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00144
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.30 Hz, 2H), 1.75 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.94 Hz, 2H), 2.44-2.49 (m, 1H), 3.24 (t, J=8.60 Hz, 2H), 4.18 (t, J=8.60 Hz, 2H), 6.84 (t, J=8.00 Hz, 1H), 7.29 (d, J=8.10 Hz, 2H), 7.33 (br q, J=8.00 Hz, 1H), 7.40 (d, J=8.40 Hz, 1H), 7.44 (d, J=8.40 Hz, 1H), 7.50 (s, 1H), 7.54 (d, J=8.20 Hz, 2H), 7.56 (d, J=9.50 Hz, 1H), 7.92 (d, J=8.51 Hz, 1H), 8.75 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 473.
    • Example C-35: 2-((1r,4r)-4-(4-(1-(2-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00145
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.62 Hz, 2H), 2.25 (s, 3H), 2.44-2.48 (m, 1H), 3.26 (t, J=8.51 Hz, 2H), 4.17 (t, J=8.51 Hz, 2H), 7.12 (t, J=7.40 Hz, 1H), 7.20 (t, J=7.57 Hz, 1H), 7.25 (d, J=7.57 Hz, 1H), 7.28 (d, J=8.10 Hz, 2H), 7.33 (d, J=7.88 Hz, 1H), 7.40 (d, J=8.51 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=8.10 Hz, 2H), 7.87 (d, J=8.51 Hz, 1H), 8.16 (s, 1H), 12.13 (br s, 1H); MS (ESI) [M+1]+ 469.
    • Example C-36: 2-((1r,4r)-4-(4-(4-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00146
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.48 (q, J=11.50 Hz, 2H), 1.71-1.84 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.49 (m, 1H), 3.91 (t, J=4.50 Hz, 2H), 4.33 (t, J=4.50 Hz, 2H), 7.17-7.18 (m, 4H), 7.30 (d, J=8.50 Hz, 1H), 7.56 (d, J=8.00 Hz, 1H), 7.63 (d, J=8.00 Hz, 1H), 7.69 (s, 1H); 8.24 (s, 2H); 9.81 (s, 1H); MS (ESI) [M+1]+ 607.
    • Example C-37: 2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00147
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.20 (m, 5H), 1.50 (q, J=11.50 Hz, 2H), 1.71-1.83 (m, 5H), 2.15 (d, J=6.00 Hz, 2H), 2.49 (m, 1H), 2.60 (q, J=7.50 Hz, 2H), 3.90 (t, J=4.50 Hz, 2H), 4.32 (t, J=4.50 Hz, 2H), 7.14-7.20 (m, 4H), 7.22-7.33 (m, 4H), 7.54 (d, J=8.00 Hz, 1H), 7.71 (d, J=8.00 Hz, 1H), 8.56 (s, 2H), 12.05 (s, 1H); MS (ESI) [M+1]+ 499.
    • Example C-38: 2-((1r,4r)-4-(4-(1-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00148
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.10 (q, J=11.50 Hz, 2H), 1.49 (q, J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 1.94 (t, J=7.50 Hz, 2H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m, 1H), 2.84 (t, J=7.50 Hz, 2H), 3.77 (t, J=7.50 Hz, 2H), 7.18-7.36 (m, 2H), 7.41-7.67 (m, 7H), 8.02 (d, J=5.50 Hz, 1H), 8.88 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]+ 555.
    • Example C-39: 2-((1r,4r)-4-(4-(1-(cyclohexylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00149
  • 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.17-1.46 (m, 7H), 1.53-1.65 (m, 2H), 1.69 (br d, J=12.9 Hz, 1H), 1.77-1.91 (m, 3H), 1.91-2.02 (m, 6H), 2.25 (d, J=6.94 Hz, 2H), 2.53 (br s, 1H), 3.24 (t, J=8.51 Hz, 2H), 3.63-3.70 (m, 1H), 3.97 (t, J=8.51 Hz, 2H), 4.90 (br s, 2H), 7.27 (d, J=8.20 Hz, 2H), 7.37 (d, J=8.20 Hz, 1H), 7.43 (s, 1H), 7.49 (d, J=8.20 Hz, 2H), 7.86 (d, J=8.20 Hz, 1H); MS (ESI) [M+1]+ 461.
    • Example C-40: 2-((1r,4r)-4-(4-(1-(piperidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00150
  • 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.18-1.39 (m, 2H), 1.54-1.64 (m, 2H), 1.64-1.76 (m, 6H), 1.81-1.99 (m, 5H), 2.25 (d, J=6.94 Hz, 2H), 2.49-2.58 (m, 1H), 3.11 (t, J=8.20 Hz, 2H), 3.41 (d, J=5.04 Hz, 4H), 3.94 (t, J=8.20 Hz, 2H), 4.90 (br s, 1H), 7.06 (d, J=8.51 Hz, 1H), 7.25-7.30 (m, 2H), 7.40 (m, 1H), 7.46-7.52 (m, 3H); MS (ESI) [M+1]+ 447.
    • Example C-41: 2-((1r,4r)-4-(4-(1-(cyclopentylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00151
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (m, 2H), 1.50 (m, 6H), 1.68 (m, 3H), 1.83 (m, 6H), 2.15 (d, J=6.31 Hz, 2H), 2.52 (m, 1H), 3.15 (t, J=8.51 Hz, 2H), 3.92 (t, J=8.51 Hz, 2H), 4.03 (m, 1H), 6.36 (d, J=6.62 Hz, 1H), 7.26 (d, J=7.57 Hz, 2H), 7.36 (d, J=7.88 Hz, 1H), 7.42 (br s, 1H), 7.51 (d, J=7.25 Hz, 2H), 7.86 (d, J=8.20 Hz, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 447.
    • Example C-42: 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00152
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08-1.18 (m, 2H), 1.43-1.54 (m, 2H), 1.74 (m, 1H), 1.83 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.55 (m, 1H), 3.09 (t, J=7.88 Hz, 2H), 3.32 (br s, 1H), 3.90 (t, J=7.88 Hz, 2H), 6.97 (br s, 1H), 7.28 (d, J=7.88 Hz, 2H), 7.39 (d, J=7.57 Hz, 1H), 7.45-7.64 (m, 3H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 336.
    • Example C-43: 2-((1r,4r)-4-(4-(1-benzoylindolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00153
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08-1.18 (m, 2H), 1.55-1.44 (m, 2 H), 1.70-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.55 (m, 1H), 3.16 (t, J=8.80 Hz, 2H), 4.05 (m, 2H), 7.30 (d, J=7.88 Hz, 2H), 7.47-7.66 (m, 10H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 440.
    • Example C-44: 2-((1r,4r)-4-(4-(1-(phenylcarbamothioyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00154
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.56 Hz, 2H), 1.49 (q, J=11.56 Hz, 2H), 1.75 (m, 1H), 1.82 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.48 (m, 1H), 3.17 (t, J=7.88 Hz, 2H), 4.33 (t, J=7.88 Hz, 2H), 7.15 (t, J=7.09 Hz, 1H), 7.30 (d, J=8.20 Hz, 2H), 7.35 (t, J=8.05 Hz, 2H), 7.40-7.48 (m, 3H), 7.52-7.61 (m, 3H), 8.16 (d, J=8.51 Hz, 1H), 9.81 (s, 1H), 11.99 (br s, 1H); MS (ESI) [M+1]+ 471.
    • Example C-45: 2-((1r,4r)-4-(4-(1-(2-phenylacetyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00155
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.20 (m, 2H), 1.43-1.54 (m, 2H), 1.69-1.76 (m, 1H), 1.77-1.88 (m, 4H), 2.14 (d, J=5.99 Hz, 2H), 2.44-2.59 (m, 1H), 3.21 (t, J=7.50 Hz, 2H), 3.87 (s, 2H), 4.21 (t, J=7.50 Hz, 2H), 7.21-7.39 (m, 7H), 7.43 (d, J=7.88 Hz, 1H), 7.48-7.57 (m, 3H), 8.10 (d, J=8.20 Hz, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 454.
    • Example C-46: 2-((1r,4r)-4-(4-(1-(morpholine-4-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00156
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.48 (m, 2H), 1.67-1.88 (m, 5H), 2.14 (d, J=6.40 Hz, 2H), 2.42-2.57 (m, 1H), 3.06 (br s, 2H), 3.29 (br s, 4H), 3.66 (br s, 4H), 3.89 (br s, 2H), 7.13 (d, J=7.57 Hz, 1H), 7.27 (d, J=6.62 Hz, 2H), 7.40 (d, J=7.57 Hz, 1H), 7.45-7.59 (m, 3H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 449.
    • Example C-47: 2-((1r,4r)-4-(4-(1-(1H-imidazole-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00157
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.45 Hz, 2H), 1.50 (q, J=11.98 Hz, 2H), 1.75 (br s, 1H), 1.83 (m, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.48 (m, 1H), 3.25 (t, J=8.20 Hz, 2H), 3.36 (br s, 1H), 4.79 (t, J=7.88 Hz, 2H), 7.30 (d, J=7.57 Hz, 4H), 7.51 (d, J=8.51 Hz, 1H), 7.54-7.62 (m, 3H), 8.28 (d, J=7.57 Hz, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 430.
    • Example C-48: 2-((1r,4r)-4-(4-(1-heptanoylindolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00158
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.84-0.91 (m, 3H), 1.07-1.18 (m, 2H), 1.29 (m, 6H), 1.41-1.53 (m, 4H), 1.70-1.78 (m, 1H), 1.78-1.86 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.48 (m, 1H), 3.11 (q, J=6.55 Hz, 2H), 3.16 (t, J=8.50 Hz, 2H), 3.90 (t, J=8.60 Hz, 2H), 6.64 (t, J=5.20 Hz, 1H), 7.26 (d, J=7.88 Hz, 2H), 7.36 (br d, J=8.51 Hz, 1H), 7.42 (s, 1H), 7.50 (d, J=7.88 Hz, 2H), 7.87 (d, J=8.20 Hz, 1H), 11.99 (br s, 1H); MS (ESI) [M+1]+ 463.
    • Example C-49: 2-((1r,4r)-4-(4-(1-(diisopropylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00159
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.18 (m, 2H), 1.29 (d, J=6.60 Hz, 12H), 1.48 (q, J=11.60 Hz, 2H), 1.68-1.78 (m, 1H), 1.83 (t, J=11.66 Hz, 4H), 2.10 (d, J=6.94 Hz, 2H), 2.47 (m, 1H), 3.07 (t, J=8.10 Hz, 2H), 3.78 (m, 2H), 3.79 (t, J=7.95 Hz, 2H), 6.94 (d, J=8.20 Hz, 1H), 7.26 (d, J=7.57 Hz, 2H), 7.35 (d, J=8.20 Hz, 1H), 7.44 (s, 1H), 7.49 (d, J=7.57 Hz, 2H), 12.50 (br s, 1H); MS (ESI) [M+1]+ 463.
    • Example C-50: 2-((1r,4r)-4-(4-(2-(phenylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00160
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.05-1.24 (m, 2H), 1.36-1.57 (m, 2H), 1.68-1.79 (m, 1H), 1.79-1.88 (m, 4H), 2.14 (m, 1H), 2.16 (d, J=6.94 Hz, 2H), 7.12 (t, J=7.25 Hz, 1H), 7.31 (m, 2H), 7.39 (t, J=7.88 Hz, 2H), 7.49 (d, J=2.22 Hz, 1H), 7.51-7.55 (m, 2H), 7.61 (d, J=8.20 Hz, 2H), 7.83 (d, J=7.88 Hz, 2H), 7.92 (s, 1H), 10.26 (s, 1H), 11.81 (br s, 1H), 11.99 (br s, 1H); MS (ESI) [M+1]+ 453.
    • Example C-51: 2-((1r,4r)-4-(4-(1-(4-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00161
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.80 Hz, 2H), 1.49 (q, J=11.87 Hz, 2H), 1.70-1.79 (m, 1H), 1.79-1.90 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.47 (m, 1H), 3.24 (t, J=8.51 Hz, 2H), 4.17 (t, J=8.51 Hz, 2H), 7.28 (d, J=7.57 Hz, 2H), 7.36 (d, J=8.51 Hz, 2H), 7.43 (d, J=8.51 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=8.00 Hz, 2H), 7.63 (d, J=8.51 Hz, 2H), 7.91 (d, J=8.55 Hz, 1H), 8.69 (s, 1H), 12.03 (br s, 1H); MS (ESI) [M+1]+ 489.
    • Example C-52: 2-((1r,4r)-4-(4-(1-(3,5-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00162
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.35 Hz, 2H), 1.69-1.77 (m, 1H), 1.77-1.88 (m, 4H), 2.15 (d, J=5.99 Hz, 2H), 2.48 (m, 1H), 3.24 (t, J=8.20 Hz, 2H), 4.17 (t, J=8.20 Hz, 2H), 6.84 (t, J=8.35 Hz, 1H), 7.28 (d, J=7.25 Hz, 2H), 7.35-7.47 (m, 3H), 7.50 (s, 1H), 7.53 (d, J=7.57 Hz, 2H), 7.92 (d, J=8.20 Hz, 1H), 8.91 (br s, 1H), 12.18 (br s, 1H); MS (ESI) [M+1]+ 491.
    • Example C-53: 2-((1r,4r)-4-(4-(1-(2,6-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00163
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.35 Hz, 2H), 1.69-1.79 (m, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.47 (m, 1H), 3.27 (t, J=8.35 Hz, 2H), 4.15 (t, J=8.20 Hz, 2H), 7.11-7.22 (m, 3H), 7.30 (d, J=7.30 Hz, 2H), 7.41 (d, J=8.15 Hz, 1H), 7.50 (s, 1H), 7.53 (d, J=7.25 Hz, 2H), 7.84 (d, J=8.20 Hz, 1H), 8.46 (br s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 491.
    • Example C-54: 2-((1r,4r)-4-(4-(1-(2-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00164
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.30 Hz, 2H), 1.49 (q, J=11.30 Hz, 2H), 1.70-178 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.47 (m, 1H), 3.27 (t, J=8.51 Hz, 2H), 4.20 (t, J=8.51 Hz, 2H), 7.23 (br t, J=7.60 Hz, 1H), 7.28 (d, J=7.25 Hz, 2H), 7.36 (br t, J=8.05 Hz, 1H), 7.42 (d, J=8.51 Hz, 1H), 7.50 (s, 1H), 7.53 (m, 3H), 7.67 (d, J=7.88 Hz, 1H), 7.88 (d, J=8.51 Hz, 1H), 8.30 (br s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 489
    • Example C-55: 2-((1r,4r)-4-(4-(1-(3-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00165
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.19 (m, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.71-1.78 (m, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.47 (m, 1H), 3.24 (t, J=8.50 Hz, 2H), 4.18 (t, J=8.51 Hz, 2H), 7.07 (d, J=7.88 Hz, 1H), 7.28 (d, J=7.29 Hz, 2H), 7.33 (t, J=8.20 Hz, 1H), 7.44 (d, J=7.88 Hz, 1H), 7.50 (s, 1H), 7.52-7.57 (m, 3H), 7.78 (br s, 1H), 7.91 (d, J=8.20 Hz, 1H), 8.73 (s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 489.
    • Example C-56: 2-((1r,4r)-4-(4-(1-(2-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00166
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.50 Hz, 2H), 1.49 (q, J=11.77 Hz, 2H), 1.68-1.77 (m, 1H), 1.77-1.88 (m, 4H), 2.14 (d, J=5.99 Hz, 2H), 2.47 (m, 1H), 3.24 (t, J=8.30 Hz, 2H), 3.86 (s, 3H), 4.16 (t, J=8.20 Hz, 2H), 6.94 (t, J=6.46 Hz, 1H), 7.01-7.15 (m, 2H), 7.28 (d, J=7.57 Hz, 2H), 7.42 (d, J=8.20 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=7.88 Hz, 2H), 7.72 (s, 1H), 7.83 (d, J=7.57 Hz, 1H), 7.90 (d, J=8.20 Hz, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 485.
    • Example C-57: 2-((1r,4r)-4-(4-(1-(4-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00167
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.77 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.89 (m, 4H), 2.14 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.22 (t, J=8.35 Hz, 2H), 3.74 (s, 3H), 4.14 (t, J=8.51 Hz, 2H), 6.89 (d, J=8.83 Hz, 2H), 7.27 (d, J=7.88 Hz, 2H), 7.40 (d, J=8.51 Hz, 1H), 7.45 (d, J=8.83 Hz, 2H), 7.47 (s, 1H), 7.52 (d, J=7.88 Hz, 2H), 7.90 (d, J=8.51 Hz, 1H), 8.43 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]+ 485.
    • Example C-58: 2-((1r,4r)-4-(4-(1-(benzylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00168
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.35 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.13 (d, J=6.10 Hz, 2H), 2.47 (m, 1H), 3.19 (t, J=7.95 Hz, 2H), 3.99 (t, J=8.10 Hz, 2H), 4.33 (m, 2H), 7.14 (d, J=6.90 Hz, 1H), 7.19-7.38 (m, 7H), 7.44 (s, 1H), 7.51 (d, J=7.88 Hz, 2H), 7.88 (d, J=7.57 Hz, 1H), 8.79 (br s, 1H), 12.40 (br s, 1H); MS (ESI) [M+1]+ 469.
    • Example C-59: 2-((1r,4r)-4-(4-(1-(3-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00169
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.18 (m, 2H), 1.43-1.54 (m, 2H), 1.68-1.78 (m, 1H), 1.78-1.88 (m, 4H), 2.15 (br s, 2H), 2.47 (m, 1H), 3.23 (t, J=8.50 Hz, 2H), 3.95 (s, 3H), 4.17 (t, J=8.10 Hz, 2H), 6.60 (br s, 1H), 7.14-7.21 (m, 2H), 7.23-7.32 (m, 3H), 7.42 (d, J=7.57 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=7.88 Hz, 2H), 7.88 (d, J=8.15 Hz, 1H), 8.52 (s, 1H), 12.25 (br s, 1H); MS (ESI) [M+1]+ 485.
    • Example C-60: 2-((1r,4r)-4-(4-(1-(1-adamantylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00170
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.67 Hz, 2H), 1.48 (q, J=11.80 Hz, 2H), 1.59 (br s, 2H), 1.65 (br s, 4H), 1.72-1.78 (m, 1H), 1.78-1.87 (m, 6H), 1.97 (br s, 2H), 2.00-2.07 (m, 5H), 2.15 (d, J=6.62 Hz, 2H), 2.47 (m, 1H), 3.12 (t, J=8.35 Hz, 2H), 3.93 (t, J=8.51 Hz, 2H), 5.36 (br s, 1H), 7.26 (d, J=6.94 Hz, 2H), 7.35 (dd, J=1.89, 8.20 Hz, 1H), 7.42 (s, 1H), 7.51 (d, J=6.94 Hz, 2H), 7.81 (d, J=8.20 Hz, 1H), 12.08 (br s, 1H); MS (ESI) [M+1]+ 513.
    • Example C-61: 2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00171
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.66 Hz, 2H), 1.74 (br s, 1H), 1.77-1.88 (m, 4H), 2.12 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.91 (br s, 2H), 4.32 (br s, 2H), 7.15-7.23 (m, 3H), 7.29 (d, J=7.25 Hz, 2H), 7.34 (t, J=7.57 Hz, 1H), 7.50 (d, J=8.20 Hz, 1H), 7.55 (d, J=7.88 Hz, 2H), 7.68 (d, J=8.20 Hz, 1H), 7.71 (d, J=8.51 Hz, 1H), 8.79 (br s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 505.
    • Example C-62: 2-((1r,4r)-4-(4-(4-(3-fluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00172
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q, J=11.66 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.00 Hz, 2H), 2.47 (m, 1H), 3.88 (br s, 2H), 4.30 (br s, 2H), 6.82 (m, 1H), 7.16 (br s, 2H), 7.26-7.34 (m, 4H), 7.45 (d, J=11.40 Hz, 1H), 7.50-7.61 (m, 3H), 9.41 (br s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 489.
    • Example C-63: 2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00173
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.25 Hz, 3H), 1.12 (q, J=11.35 Hz, 2H), 1.23-1.33 (m, 6H), 1.43-1.53 (m, 4H), 1.74 (br s, 1H), 1.78-1.86 (m, 4H), 2.14 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.10 (m, 2H), 3.72 (t, J=3.57 Hz, 2H), 4.20 (t, J=4.10 Hz, 2H), 6.96 (t, J=4.70 Hz, 1H), 7.11 (s, 1H), 7.13 (d, J=7.88 Hz, 1H), 7.28 (d, J=7.88 Hz, 2H), 7.52 (d, J=7.57 Hz, 2H), 7.63 (d, J=8.51 Hz, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 479.
    • Example C-64: 2-((1r,4r)-4-(4-(1-(N-phenylsulfamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00174
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.60 Hz, 2H), 1.48 (q, J=11.70 Hz, 2H), 1.74 (br s, 1H), 1.77-1.88 (m, 4H), 2.15 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.03 (t, J=7.41 Hz, 2H), 3.93 (t, J=7.88 Hz, 2H), 7.02 (t, J=6.62 Hz, 1H), 7.14 (d, J=7.25 Hz, 2H), 7.20-7.31 (m, 4H), 7.34 (d, J=8.20 Hz, 1H), 7.38-7.46 (m, 2H), 7.49 (d, J=7.25 Hz, 2H), 10.70 (br s, 1H), 12.00 (br s, 1H); MS (ESI) [M+1]+ 491.
    • Example C-65: 2-((1r,4r)-4-(4-(4-(benzylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00175
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.77 Hz, 2H), 1.49 (q, J=11.55 Hz, 2H), 1.71-1.79 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.47 (m, 1H), 3.67 (t, J=4.10 Hz, 2H), 4.16 (t, J=4.10 Hz, 2H), 4.74 (s, 2H), 7.13 (d, J=8.80 Hz, 1H), 7.16 (br s, 1H), 7.30 (d, J=7.57 Hz, 2H), 7.33-7.40 (m, 5H), 7.54 (d, J=7.88 Hz, 2H), 7.62 (d, J=7.57 Hz, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 506.
    • Example C-66: 2-((1r,4r)-4-(4-(4-(2-chlorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00176
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.05 (q, J=11.70 Hz, 2H), 1.39 (q, J=11.77 Hz, 2H), 1.62 (d, J=11.98 Hz, 2H), 1.67-1.72 (m, 1H), 1.75 (d, J=11.66 Hz, 2H), 2.19 (d, J=6.94 Hz, 2H), 2.41 (t, J=11.98 Hz, 1H), 3.31 (t, J=4.10 Hz, 2H), 4.14 (t, J=3.98 Hz, 2H), 6.61 (d, J=8.20 Hz, 1H), 6.91 (br s, 1H), 6.96 (d, J=8.20 Hz, 1H), 7.19 (d, J=7.88 Hz, 2H), 7.41 (d, J=7.88 Hz, 2H), 7.61 (br t, J=7.10 Hz, 1H), 7.67-7.75 (m, 2H), 8.11 (d, J=7.88 Hz, 1H), 12.47 (br s, 1H); MS (ESI) [M+1]+ 525.
    • Example C-67: 2-((1r,4r)-4-(4-(4-(biphenyl-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00177
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.20-1.33 (m, 2H), 1.60 (q, J=11.40 Hz, 2H), 1.91-1.97 (m, 1H), 1.98-2.06 (m, 4H), 2.36 (d, J=6.94 Hz, 2H), 2.58 (t, J=11.98 Hz, 1H), 3.94 (t, J=4.10 Hz, 2H), 4.30 (t, J=4.25 Hz, 2H), 6.58 (br s, 1H), 6.71 (dd, J=2.00, 8.20 Hz, 1H), 6.77 (d, J=8.20 Hz, 1H), 7.10 (d, J=1.95 Hz, 1H), 7.16 (br t, J=7.40 Hz, 1H), 7.22 (br d, J=7.60 Hz, 1H), 7.24-7.36 (m, 6H), 7.41 (t, J=7.60 Hz, 1H), 7.46 (d, J=8.20 Hz, 2H), 7.60 (s, 1H), 8.28 (d, J=8.20 Hz, 1H), 12.00 (br s, 1H); MS (ESI) [M+1]+ 547.
    • Example C-68: 2-((1r,4r)-4-(4-(4-(tert-butylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00178
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.80 Hz, 2H), 1.32 (s, 9H), 1.49 (q, J=11.50 Hz, 2H), 1.70-1.78 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.47 (m, 1H), 3.70 (t, J=4.20 Hz, 2H), 4.19 (q, J=4.10 Hz, 2H), 6.36 (s, 1H), 7.10 (br s, 1H), 7.13 (br d, J=8.45 Hz, 1H), 7.28 (d, J=7.88 Hz, 2H), 7.52 (d, J=7.80 Hz, 2H), 7.56 (br d, J=8.51 Hz, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 451.
    • Example C-69: 2-((1r,4r)-4-(4-(4-(isopropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00179
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.07-1.19 (m, 2H), 1.14 (d, J=6.10 Hz, 6H), 1.48 (q, J=11.60 Hz, 2H), 1.70-1.77 (m, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.72 (br s, 2H), 3.85 (h, J=6.20 Hz, 1H), 4.20 (br s, 2H), 6.71 (d, J=7.25 Hz, 1H), 7.10 (s, 1H), 7.13 (d, J=8.51 Hz, 1H), 7.27 (d, J=7.57 Hz, 2H), 7.52 (d, J=7.57 Hz, 2H), 7.65 (d, J=8.20 Hz, 1H), 12.35 (br s, 1H); MS (ESI) [M+1]+ 437.
    • Example C-70: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00180
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.60 Hz, 2H), 1.50 (q, J=11.55 Hz, 2H), 1.70-1.78 (br s, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.44-2.48 (m, 1H), 3.92 (br s, 2H), 4.43 (br s, 2H), 7.03 (t, J=7.25 Hz, 1H), 7.28-7.33 (m, 4H), 7.50 (d, J=7.88 Hz, 2H), 7.54 (d, J=8.51 Hz, 1H), 7.91 (d, J=7.88 Hz, 2H), 8.05 (d, J=8.20 Hz, 1H), 9.23 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 472.
    • Example C-71: 2-((1r,4r)-4-(4-(1-(4-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00181
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.40 Hz, 2H), 1.75 (br s, 1H), 1.78-1.87 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.27 (s, 3H), 2.44-2.49 (m, 1H), 3.23 (t, J=8.20 Hz, 2H), 4.16 (t, J=8.20 Hz, 2H), 7.11 (d, J=8.20 Hz, 2H), 7.28 (d, J=8.20 Hz, 2H), 7.41 (d, J=8.50 Hz, 1H), 7.45 (d, J=8.20 Hz, 2H), 7.48 (s, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.91 (d, J=8.51 Hz, 1H), 8.46 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 469.
    • Example C-72: 2-((1r,4r)-4-(4-(1-(2-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00182
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.75 (br s, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.49 (m, 1H), 3.25 (t, J=8.51 Hz, 2H), 4.17 (t, J=8.51 Hz, 2H), 7.17-7.27 (m, 3H), 7.28 (d, J=8.20 Hz, 2H), 7.42 (d, J=8.51 Hz, 1H), 7.50 (s, 1H), 7.53-7.56 (m, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.87 (d, J=8.51 Hz, 1H), 8.41 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]+ 473.
    • Example C-73: 2-((1r,4r)-4-(4-(1-(benzo[d][1,3]dioxol-5-ylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00183
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.74 (br s, 1H), 1.79-1.88 (m, 4H), 2.15 (d, J=6.95 Hz, 2H), 2.45-2.50 (m, 1H), 3.23 (t, J=8.51 Hz, 2H), 4.13 (t, J=8.51 Hz, 2H), 5.99 (s, 2H), 6.86 (d, J=8.51 Hz, 1H), 6.96 (dd, J=1.89 and 8.51 Hz, 1H), 7.22 (d, J=1.89 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.41 (d, J=8.51 Hz, 1H), 7.48 (s, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.89 (d, J=8.51 Hz, 1H), 8.45 (s, 1H), 12.17 (br s, 1H); MS (ESI) [M+1]+ 499.
    • Example C-74: 2-((1r,4r)-4-(4-(1-(4-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00184
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q, J=11.35 Hz, 2H), 1.75 (br s, 1H), 1.79-1.88 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H), 3.25 (t, J=8.50 Hz, 2H), 4.21 (t, J=8.50 Hz, 2H), 7.29 (d, J=8.20 Hz, 2H), 7.44 (d, J=8.51 Hz, 1H), 7.51 (s, 1H), 7.54 (d, J=8.00 Hz, 2H), 7.67 (d, J=8.51 Hz, 2H), 7.84 (d, J=8.51 Hz, 2H), 7.93 (d, J=8.51 Hz, 1H), 8.93 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 523.
    • Example C-75: 2-((1r,4r)-4-(4-(1-(2-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00185
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.40 Hz, 2H), 1.48 (q, J=11.40 Hz, 2H), 1.74 (br s, 1H), 1.78-1.86 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.44-2.49 (m, 1H), 3.26 (t, J=8.51 Hz, 2H), 4.14 (t, J=8.51 Hz, 2H), 7.27 (d, J=8.20 Hz, 2H), 7.40 (d, J=8.51 Hz, 1H), 7.48 (t, J=7.57 Hz, 1H), 7.49 (s, 1H), 7.52 (d, J=8.20 Hz, 2H), 7.59 (d, J=7.88 Hz, 1H), 7.71 (t, J=7.88 Hz, 1H), 7.75 (d, J=7.88 Hz, 1H), 7.84 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 12.03 (br s, 1H); MS (ESI) [M+1]+ 523.
    • Example C-76: 2-((1r,4r)-4-(4-(4-(m-tolylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00186
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.24 (q, J=11.98 Hz, 2H), 1.59 (q, J=11.98 Hz, 2H), 1.93 (br s, 1H), 2.00 (br d, J=11.98 Hz, 4H), 2.35 (d, J=6.94 Hz, 2H), 2.37 (s, 3H), 2.52-2.60 (m, 1H), 4.01 (t, J=4.41 Hz, 2H), 4.37 (t, J=4.41 Hz, 2H), 6.91-6.93 (m, 1H), 7.19-7.26 (m, 5H), 7.27-7.30 (m, 1H), 7.31 (d, J=8.20 Hz, 2H), 7.40 (d, J=8.20 Hz, 1H), 7.54 (d, J=8.50 Hz, 2H), 9.85 (br s, 1H); MS (ESI) [M+1]+ 485.
    • Example C-77: 2-((1r,4r)-4-(4-(4-(2-fluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00187
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.40 Hz, 2H), 1.49 (q, J=11.40 Hz, 2H), 1.75 (br s, 1H), 1.78-1.87 (m, 4H), 2.16 (d, J=6.95 Hz, 2H), 2.46-2.50 (m, 1H), 3.89 (t, J=4.10 Hz, 2H), 4.31 (t, J=4.10 Hz, 2H), 7.13-7.20 (m, 4H), 7.22-7.27 (m, 1H), 7.29 (d, J=8.20 Hz, 2H), 7.54 (d, J=8.20 Hz, 2H), 7.52-7.59 (m, 1H), 7.67 (d, J=8.10 Hz, 1H), 8.87 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 489.
    • Example C-78: 2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00188
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.24 Hz, 2H), 1.35 (d, J=5.99 Hz, 3H), 1.49 (q, J=11.20 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d, J=7.57 Hz, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.42-2.49 (m, 1H), 3.41 (dd, J=13.24, 12.93 Hz, 1H), 4.08 (d, J=12.61 Hz, 1H), 4.39 (br t, J=6.20 Hz, 1H), 7.16 (s, 1H), 7.17 (d, J=9.50 Hz, 1H), 7.29 (d, J=7.88 Hz, 2H), 7.58 (d, J=6.31 Hz, 2H), 7.55 (d, J=7.88 Hz, 2H), 7.65 (m, 2H), 8.82 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 571. The two enantiomers were resolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system 1; hexanes:isopropanol:methylene chloride 87.3:2.7:10): enantiomer A (rt=12.35 min); enantiomer B (rt=14.03 min).
    • Example C-79: 2-((1r,4r)-4-(4-(2-methyl-4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00189
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.90 Hz, 2H), 1.36 (d, J=5.99 Hz, 3H), 1.49 (q, J=11.90 Hz, 2H), 1.69-1.78 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.42-2.49 (m, 1H), 3.42 (dd, J=13.40, 7.41 Hz, 1H), 4.10 (d, J=11.66 Hz, 1H), 4.39 (t, J=5.83 Hz, 1H), 7.17 (s, 1H), 7.18 (d, J=9.70 Hz, 1H), 7.29 (d, J=8.20 Hz, 2H), 7.46 (t, J=7.57 Hz, 1H), 7.53-7.59 (m, 3H), 7.65 (d, J=7.88 Hz, 1H), 7.69 (t, J=7.66 Hz, 1H), 7.74 (d, J=8.04 Hz, 1H), 8.78 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 553.
    • Example C-80: 2-((1r,4r)-4-(4-(2-isopropyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00190
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.62 Hz, 3H), 1.07 (d, J=6.62 Hz, 3H), 1.13 (q, J=11.77 Hz, 2H), 1.49 (q, J=11.77 Hz, 2H), 1.70-1.77 (m, 1H), 1.78-1.86 (m, 4H), 1.94 (m, 1H), 2.15 (d, J=6.62 Hz, 2H), 2.41-2.49 (m, 1H), 3.53 (dd, J=13.40, 7.41 Hz, 1H), 3.93 (br t, J=6.45 Hz, 1H), 4.04 (d, J=12.61 Hz, 1H), 7.01 (t, J=7.09 Hz, 1H), 7.13-7.19 (m, 2H), 7.25-7.32 (m, 4H), 7.47-7.58 (m, 5H), 9.18 (s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]+ 513.
    • Example C-81: 2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00191
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12-1.18 (m, 2H), 1.16 (t, J=7.57 Hz, 3H), 1.37 (d, J=5.99 Hz, 3H), 1.49 (q, J=11.35 Hz, 2H), 1.70-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.44-2.49 (m, 1H), 2.60 (q, J=7.57 Hz, 2H), 3.41 (dd, J=13.56, 7.57 Hz, 1H), 4.10 (d, J=12.30 Hz, 1H), 4.39 (t, J=5.67 Hz, 1H), 7.12-7.22 (m, 4H), 7.22-7.32 (m, 4H), 7.54 (d, J=7.88 Hz, 2H), 7.67 (d, J=8.20 Hz, 1H), 8.57 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 513. The two enantiomers were resolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system 1; hexanes:isopropanol 90:10): enantiomer A (R absolute configuration, rt=23.32 min); enantiomer B (S absolute configuration, rt=28.64 min).
    • Example C-82: 2-((1r,4r)-4-(4-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00192
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.13 (q, J=11.66 Hz, 2H), 1.49 (q, J=11.66 Hz, 2H), 1.62-1.77 (m, 3H), 1.78-1.87 (m, 4H), 2.15 (d, J=6.31 Hz, 2H), 2.41-2.49 (m, 1H), 3.47 (dd, J=12.61, 7.25 Hz, 1H), 4.03 (d, J=12.61 Hz, 1H), 4.16 (br s, 1H), 7.00 (t, J=7.41 Hz, 1H), 7.16 (br s, 2H), 7.26-7.33 (m, 4H), 7.45-7.59 (m, 5H), 9.17 (br s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 499. The two enantiomers were resolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system 1; hexanes:isopropanol 90:10): enantiomer A (rt=20.02 min); enantiomer B (rt=20.86 min).
    • Example C-83: 2-((1r,4r)-4-(4-(2-(phenylamino)quinoxalin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00193
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.51 Hz, 2H), 1.52 (q, J=11.51 Hz, 2H), 1.71-1.80 (m, 1H), 1.81-1.86 (m, 4H), 2.17 (d, J=6.94 Hz, 2H), 2.45-2.49 (m, 1H), 3.32 (s, 1H), 7.05 (t, J=7.41 Hz, 1H), 7.35-7.42 (m, 3H), 7.73 (d, J=7.88 Hz, 2H), 7.80 (d, J=8.51 Hz, 1H), 7.98 (d, J=8.65 Hz, 1H), 8.00 (d, J=7.88 Hz, 2H), 8.09 (s, 1H), 8.60 (s, 1H), 10.00 (s, 1H), 12.06 (s, 1H); MS (ESI) [M+1]+ 438.
    • Example C-84: 2-((1r,4r)-4-(4-(4-(4-chloro-2-fluorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00194
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=12.40 Hz, 2H), 1.35 (d, J=6.31 Hz, 3H), 1.49 (q, J=12.40 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d, J=10.56 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.49 (br s, 1H), 3.38 (dd, J=13.57, 7.72 Hz, 1H), 4.11 (d, J=11.35 Hz, 1H), 4.38 (br t, J=6.31 Hz, 1H), 7.16 (s, 1H), 7.17 (d, J=10.20 Hz, 1H), 7.26 (br d, J=8.99 Hz, 1H), 7.29 (d, J=8.04 Hz, 2H), 7.48 (dd, J=10.70, 2.21 Hz, 1H), 7.53-7.58 (m, 3H), 7.64 (d, J=8.20 Hz, 1H), 9.00 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 538.
    • Example C-85: 2-((1r,4r)-4-(4-(4-(4-fluoro-3-methylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00195
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.82 Hz, 2H), 1.35 (d, J=5.99 Hz, 3H), 1.49 (q, J=11.82 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.21 (s, 3H), 2.44-2.49 (m, 1H), 3.28-3.35 (m, 1H), 4.09 (d, J=11.82 Hz, 2H), 4.35 (br t, J=6.85 Hz, 1H), 7.06 (t, J=9.14 Hz, 1H), 7.15 (s, 1H), 7.16 (d, J=9.30 Hz, 1H), 7.29 (d, J=8.36 Hz, 2H), 7.40 (dd, J=2.36, 7.09 Hz, 1H), 7.54 (d, J=8.04 Hz, 2H), 7.56 (d, J=7.72 Hz, 1H), 9.12 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 517.
    • Example C-86: 2-((1r,4r)-4-(4-(4-(3-chloro-4-fluorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00196
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.35 (d, J=6.31 Hz, 3H), 1.49 (q, J=11.35 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.43-2.50 (m, 1H), 3.34-3.39 (m, 1H), 4.10 (dd, J=13.20, 2.36 Hz, 1H), 4.36 (dt, J=2.36, 5.80 Hz, 1H), 7.16 (s, 1H), 7.17 (dd, J=1.73, 8.99 Hz, 1H), 7.29 (d, J=8.20 Hz, 2H), 7.36 (t, J=8.99 Hz, 1H), 7.44-7.48 (m, 1H), 7.53-7.58 (m, 3H), 7.77 (dd, J=2.68, 6.94 Hz, 1H), 9.37 (s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]+ 538.
    • Example C-87: 2-((1r,4r)-4-(4-(4-(2,4-dimethylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00197
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=12.10 Hz, 2H), 1.36 (d, J=6.31 Hz, 3H), 1.49 (q, J=12.10 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d, J=9.77 Hz, 4H), 2.16 (d, J=7.09 Hz, 2H), 2.18 (s, 3H), 2.26 (s, 3H), 2.45-2.50 (m, 1H), 3.38 (dd, J=7.88, 13.56 Hz, 1H), 4.09 (dd, J=2.04, 13.08 Hz, 1H), 4.37 (dt, J=2.04, 7.08 Hz, 1H), 6.97 (d, J=8.51 Hz, 1H), 7.03 (s, 1H), 7.13-7.18 (m, 3H), 7.28 (d, J=8.20 Hz, 2H), 7.54 (d, J=8.20 Hz, 2H), 7.68 (d, J=8.51 Hz, 1H), 8.54 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 513.
    • Example C-88: 2-((1r,4r)-4-(4-(4-(2-methoxy-5-methylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00198
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.82 Hz, 2H), 1.35 (d, J=6.31 Hz, 3H), 1.50 (q, J=11.82 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d, J=9.30 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.25 (s, 3H), 2.45-2.49 (m, 1H), 3.29 (dd, J=8.10, 13.10 Hz, 1H), 3.77 (s, 3H), 4.18 (dd, J=2.04, 13.10 Hz, 1H), 4.37 (br t, J=8.10 Hz, 1H), 6.85 (br d, J=6.36 Hz, 1H), 6.92 (d, J=6.36 Hz, 1H), 7.20 (s, 1H), 7.24 (dd, J=1.26, 8.51 Hz, 1H), 7.30 (d, J=7.88 Hz, 2H), 7.56-7.60 (m, 3H), 7.70 (s, 1H), 9.37 (s, 1H), 12.14 (br s, 1H); MS (ESI) [M+1]+ 529.
    • Example C-89: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00199
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.10 Hz, 3H), 1.13 (q, J=12.13 Hz, 2H), 1.49 (q, J=12.13 Hz, 2H), 1.51-1.78 (m, 5H), 1.84 (br d, J=10.10 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H), 3.47 (dd, J=13.40, 7.41 Hz, 1H), 4.03 (d, J=11.35 Hz, 1H), 4.21-4.27 (m, 1H), 7.01 (t, J=7.41 Hz, 1H), 7.15 (s, 1H), 7.16 (d, J=8.83 Hz, 1H), 7.27-7.31 (m, 4H), 7.49 (d, J=8.20 Hz, 2H), 7.52-7.57 (m, 3H), 9.16 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 513.
    • Example C-90: 2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00200
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.09 Hz, 3H), 1.07-1.16 (m, 2H), 1.15 (t, J=7.09 Hz, 3H), 1.49 (q, J=11.03 Hz, 2H), 1.49-1.78 (m, 5H), 1.83 (br d, J=10.09 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.49 (m, 1H), 2.60 (q, J=7.46 Hz, 2H), 3.53 (dd, J=13.56, 6.94 Hz, 1H), 4.03 (d, J=12.61 Hz, 1H), 4.23-4.29 (m, 1H), 7.14-7.20 (m, 4H), 7.25 (d, J=7.57 Hz, 1H), 7.29 (d, J=8.04 Hz, 3H), 7.55 (d, J=7.57 Hz, 2H), 7.65 (d, J=8.51 Hz, 1H), 8.57 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 541.
    • Example C-91: 2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00201
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.09 Hz, 3H), 1.13 (q, J=11.50 Hz, 2H), 1.44-1.64 (m, 5H), 1.65-1.78 (m, 2H), 1.83 (br d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.44-2.49 (m, 1H), 3.49 (dd, J=13.56, 6.94 Hz, 1H), 4.06 (d, J=12.61 Hz, 1H), 4.21-4.27 (m, 1H), 7.16 (s, 1H), 7.17 (d, J=9.50 Hz, 1H), 7.29 (d, J=7.57 Hz, 2H), 7.54-7.60 (m, 4H), 7.62-7.67 (m, 2H), 8.82 (s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]+ 599.
    • Example C-92: 2-((1r,4r)-4-(4-(3-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00202
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.66 Hz, 2H), 1.21 (d, J=6.62 Hz, 3H), 1.49 (q, J=11.66 Hz, 2H), 1.79-1.78 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.31 Hz, 2H), 2.38-2.49 (m, 1H), 4.13 (d, J=10.40 Hz, 1H), 4.27 (d, J=10.4 Hz, 1H), 4.57 (br d, J=6.62 Hz, 1H), 7.00 (t, J=7.25 Hz, 1H), 7.14-7.22 (m, 2H), 7.24-7.34 (m, 4H), 7.47 (d, J=9.12 Hz, 1H), 7.51 (d, J=8.20 Hz, 2H), 7.55 (d, J=7.74 Hz, 2H), 9.14 (s, 1H); MS (ESI) [M+1]+ 485.
    • Example C-93: 2-((1r,4r)-4-(4-(2-ethyl-4-(2-ethylphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00203
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.05 (t, J=7.41 Hz, 4H), 1.16 (t, J=7.41 Hz, 4H), 1.49 (dd, J=12.50, 2.00 Hz, 2H), 1.65-1.79 (m, 3H), 1.83 (d, J=9.77 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.60 (q, J=7.57 Hz, 2H), 3.33 (br s, 1H), 3.50 (dd, J=13.56, 7.25 Hz, 1H), 4.07 (d, J=11.66 Hz, 1H), 4.17 (d, J=6.62 Hz, 1H), 7.14-7.21 (m, 4H), 7.24-7.32 (m, 4H), 7.55 (d, J=8.20 Hz, 2H), 7.66 (d, J=9.14 Hz, 1H), 8.56 (s, 1H); MS (ESI) [M+1]+ 527.
    • Example C-94: 2-((1r,4r)-4-(4-(2-ethyl-4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00204
  • 1H NMR (500 MHz, DMSO-d6)
    Figure US20120022057A1-20120126-P00004
    ppm 1.04 (t, J=7.41 Hz, 3H), 1.09-1.18 (m, 2H), 1.45-1.54 (m, 2H), 1.63-1.78 (m, 3H), 1.83 (d, J=9.46 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.47 (m, 1H), 3.48 (dd, J=13.40, 7.41 Hz, 1H), 4.09 (d, J=11.98 Hz, 1H), 4.12-4.18 (m, 1H), 7.15-7.22 (m, 2H), 7.29 (d, J=8.20 Hz, 2H), 7.56 (d, J=7.88 Hz, 2H), 7.59 (d, J=6.62 Hz, 2H), 7.65 (dd, J=8.51, 5.99 Hz, 2H), 8.82 (br s, 1H), 12.11 (br s, 1H); MS (ESI) [M+1]+ 585.
    • Example C-95: 2-((1r,4r)-4-(4-(2-ethyl-4-(2-methoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00205
  • 1H NMR (500 MHz, DMSO-d6)
    Figure US20120022057A1-20120126-P00005
    ppm 1.03 (t, J=7.41 Hz, 3H), 1.09-1.19 (m, 2H), 1.45-1.55 (m, 2H), 1.63-1.79 (m, 3H), 1.84 (br d, J=10.50 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.48 (m, 1H), 3.33 (br s, 2H), 3.40 (dd, J=13.87, 7.88 Hz, 1H), 3.81 (s, 3H), 4.13-4.20 (m, 1H), 6.92-6.96 (m, 1H), 7.03-7.08 (m, 2H), 7.21 (s, 1H), 7.24 (dd, J=7.24, 2.00, 1H), 7.30 (d, J=7.88 Hz, 2H), 7.57-7.62 (m, 3H), 7.87 (d, J=7.88 Hz, 1H), 8.30 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 529.
    • Example C-96: 2-((1r,4r)-4-(4-(4-(benzylsulfonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00206
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.41 Hz, 3H), 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.58-1.65 (m, 2H), 1.71-1.79 (m, 1H), 1.83 (br d, J=9.00 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.09 (dd, J=13.56, 8.83 Hz, 1H), 3.33 (br s, 1H), 3.85 (m, 1H), 3.91 (d, J=14.00 Hz, 1H), 4.72 (d, J=14.00 Hz, 1H), 4.80 (d, J=14.00 Hz, 1H), 7.12 (dd, J=8.50, 2.00 Hz, 1H), 7.15 (d, J=2.00 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.34-7.42 (m, 5H), 7.55 (d, J=8.20 Hz, 2H); MS (ESI) [M+1]+ 534
    • Example C-97: 2-((1r,4r)-4-(4-(2-ethyl-4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00207
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.16 (t, J=7.25 Hz, 3H), 1.27 (q, J=12.50 Hz, 2H), 1.62 (q, J=12.50 Hz, 2H), 1.71-1.88 (m, 2H), 1.90-1.98 (br m, 2H), 2.02 (d, J=12.50 Hz), 2.38 (d, J=6.62 Hz, 2H), 2.59 (t, J=11.98 Hz, 1H), 3.36 (dd, J=13.24, 8.20 Hz, 1H), 4.23 (br d, J=5.99 Hz, 1H), 4.47 (d, J=12.30 Hz, 1H), 7.21-7.27 (m, 2H), 7.29 (s, 1H), 7.30-7.37 (m, 3H), 7.44 (d, J=8.00 Hz, 1H), 7.59 (d, J=8.00 Hz, 1H), 7.63 (d, J=8.00 Hz, 2H), 7.79 (br s, 1H), 8.25 (d, J=8.20 Hz, 1H); MS (ESI) [M+1]+ 567.
    • Example C-98: 2-((1r,4r)-4-(4-(2-ethyl-4-(2-phenylacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00208
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.09 Hz, 3H),1.14 (q, J=11.75 Hz, 2H), 1.49 (q, J=11.75 Hz, 2H), 1.55-1.65 (m, 2H), 1.69-1.78 (br s, 1H), 1.78-1.87 (br s, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.46-2.50 (m, 1H), 3.28-3.41 (m, 4H), 3.98 (d, J=15.45 Hz, 1H), 4.06 (d, J=15.76 Hz, 1H), 4.22 (d, J=10.40 Hz, 1H), 7.13-7.22 (m, 2H), 7.23-7.36 (m, 7H), 7.56 (d, J=7.57 Hz, 2H), 12.11 (br s, 1H); MS (ESI) [M+1]+ 498.
    • Example C-99: 2-((1r,4r)-4-(4-(2-ethyl-4-(2-propylphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00209
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.41 Hz, 3H), 1.05 (t, J=7.41 Hz, 3H), 1.09-1.18 (m, 2H), 1.45-1.59 (m, 4H), 1.64-1.80 (m, 3H), 1.83 (d, J=9.77 Hz, 4H), 2.16 (d, J=7.25 Hz, 2H), 2.44-2.57 (m, 1H), 3.51 (dd, J=13.40, 7.09 Hz, 1H), 4.07 (dd, J=13.40, 2.00 Hz, 1H), 4.17 (qd, J=7.09, 2.00 Hz, 1H), 7.12-7.24 (m, 5H), 7.29 (d, J=8.20 Hz, 2H), 7.33 (d, J=8.20 Hz, 1H), 7.55 (d, J=8.20 Hz, 2H), 7.64 (d, J=8.20 Hz, 2H), 8.52 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 541.
    • Example C-100: 2-((1r,4r)-4-(4-(4-(3,5-difluorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00210
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.14 (q, J=12.00 Hz, 2H), 1.45 (q, J=12.00 Hz, 2H), 1.63-1.78 (m, 2H), 1.84 (br d, J=10.00 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.51 (m, 1H), 3.48 (dd, J=13.40, 7.41 Hz, 1H), 4.04 (dd, J=13.50, 2.50 Hz, 1H), 4.14-4.22 (m, 1H), 6.84 (tt, J=9.30, 2.21 Hz, 1H), 7.14-7.15 (m, 2H), 7.26 (dd, J=9.30, 2.21 Hz, 2H), 7.30 (d, J=8.00 Hz, 2H), 7.51 (d, J=9.00 Hz, 1H), 7.56 (d, J=8.00 Hz, 2H), 9.56 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 535.
    • Example C-101: 2-((1r,4r)-4-(4-(4-(3,4-difluorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00211
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.14 (q, J=11.83 Hz, 2H), 1.49 (q, J=11.83 Hz, 2H), 1.63-1.78 (m, 2H), 1.84 (br d, J=10.5 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.48 (dd, J=13.40, 7.41 Hz, 1H), 4.04 (d, J=13.40 Hz, 1H), 4.17 (q, J=7.41 Hz, 1H), 6.84 (td, J=9.30, 2.21 Hz, 3H), 7.14-7.20 (m, 2H), 7.25-7.31 (m, 3H), 7.36 (q, J=9.83 Hz, 1H), 7.58-7.52 (m, 3H), 7.63 (qd, J=7.50, 2.50 Hz, 1H), 9.56 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 535.
    • Example C-102: 2-((1r,4r)-4-(4-(4-(4-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00212
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.13 (q, J=12.17 Hz, 2H), 1.49 (q, J=12.17 Hz, 2H), 1.60-1.75 (m, 3H), 1.83 (br d, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.54 (m, 1H), 3.48 (dd, J=13.40, 7.41 Hz, 1H), 4.04 (d, J=13.40 Hz, 1H), 4.17 (q, J=7.41 Hz, 1H), 7.15-7.18 (m, 2H), 7.29 (d, J=8.50 Hz, 2H), 7.35 (d, J=8.50 Hz, 2H), 7.54 (t, J=8.50 Hz, 5H), 9.31 (s, 3H); MS (ESI) [M+1]+ 533.
    • Example C-103: 2-((1r,4r)-4-(4-(4-(3-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00213
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.63-1.78 (m, 3H), 1.83 (br d, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.48 (dd, J=13.56, 7.25 Hz, 1H), 4.04 (dd, J=13.40, 2.36 Hz, 1H), 4.17 (qd, J=7.00, 2.50 Hz, 1H), 7.17-7.22 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.33 (t, J=8.00 Hz, 1H), 7.50 (d, J=8.00 Hz, 1H), 7.56 (d, J=8.00 Hz, 1H), 7.67 (d, J=8.00 Hz, 1H), 7.69 (d, J=8.00 Hz, 1H), 9.37 (s, 1H), 12.08 (br s, 1H); MS (ESI) [M+1]+ 533.
    • Example C-104: 2-((1r,4r)-4-(4-(2-ethyl-4-(4-methoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00214
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.13 (q, J=11.50 Hz, 2H), 1.49 (q, J=11.50 Hz, 2H), 1.60-1.75 (m, 3H), 1.83 (br d, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.56 (m, 1H) 3.45 (dd, J=13.25, 6.80 Hz, 1H), 3.73 (s, 3H), 4.03 (d, J=13.50 Hz, 1H), 4.14 (q, J=6.80 Hz, 1H), 6.88 (d, J=8.83 Hz, 2H), 7.13-7.18 (m, 2H), 7.29 (d, J=7.88 Hz, 2H), 7.40 (d, J=8.83 Hz, 2H), 7.53-7.58 (m, 3H), 8.99 (s, 1H) 12.24 (br s, 1H); MS (ESI) [M+1]+ 529.
    • Example C-105: 2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00215
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=12.00 Hz, 2H), 1.37 (d, J=6.31 Hz, 3H), 1.49 (q, J=12.00 Hz, 2H), 1.70-1.80 (m, 2H) 1.83 (br d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.52 (m, 1H), 3.38 (dd, J=13.56, 7.57 Hz, 1H), 4.15 (dd, J=13.24, 2.21 Hz, 1H), 4.37-4.44 (m, 1H), 7.15-7.21 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.34 (t, J=7.50 Hz, 1H), 7.50 (d, J=8.00 Hz, 1H), 7.56 (d, J=8.00 Hz, 2H), 7.66 (d, J=8.00 Hz, 1H), 7.71 (d, J=8.00 Hz, 1H), 8.78 (s, 1H), 12.14 (br s, 1H); MS (ESI) [M+1]+ 519.
    • Example C-106: 2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00216
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=12.50 Hz, 2H),1.17 (d, J=3.00 Hz, 3H) 1.19 (d, J=3.00 Hz, 3H),1.37 (d, J=5.99 Hz, 3H), 1.49 (q, J=12.50 Hz, 2H), 1.71-1.79 (m, 1H), 1.83 (d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.14-3.19 (m, 1H), 3.44 (dd, J=13.40, 7.41 Hz, 1H), 4.08 (dd, J=13.24, 2.21 Hz, 1H), 4.37-4.43 (m, 1H), 7.14-7.25 (m, 3H), 7.23 (t, J=7.88 Hz, 2H), 7.29 (d, J=8.50 Hz, 2H), 7.33 (d, J=7.50 Hz, 1H), 7.55 (d, J=7.88 Hz, 2H), 7.67 (d, J=8.51 Hz, 1H), 8.57 (s, 2H), 12.14 (br s, 1H); MS (ESI) [M+1]+ 527.
    • Example C-107: 2-((1r,4r)-4-(4-(4-(sec-butylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00217
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (t, J=7.50 Hz, 3H), 0.89 (t, J=7.50 Hz, 3H), 1.11 (t, J=6.50 Hz, 6H), 1.07-1.18 (m, 4H), 1.30 (d, J=6.50 Hz, 3H), 1.32 (d, J=6.50 Hz, 3H), 1.38-1.55 (m, 8H), 1.71-1.79 (m, 2H), 1.80-1.86 (m, 8H), 2.15 (d, J=6.94 Hz, 4H), 2.45-2.54 (m, 1H), 3.20 (dd, J=13.40, 8.04 Hz, 1H), 3.30 (dd, J=13.75, 7.75 Hz, 1H), 3.60-3.70 (m, 2H), 3.90 (dd, J=13.24, 2.52 Hz, 1H), 3.99 (dd, J=13.40, 2.36 Hz, 1H), 4.19-4.30 (m, 2H), 6.64 (d, J=8.00 Hz, 1H), 6.65 (d, J=8.00 Hz, 1H), 7.08-7.17 (m, 4H), 7.28 (d, J=8.20 Hz, 4H), 7.53 (d, J=7.57 Hz, 4H), 7.60 (d, J=8.50 Hz, 1H), 7.17 (d, J=8.50 Hz, 1H), 12.08 (br s, 1H); MS (ESI) [M+1]+ 465.
    • Example C-108: 2-((1r,4r)-4-(4-(4-(cyclohexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00218
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.20-1.33 (m, 2H), 1.30 (d, J=6.50 Hz, 3H), 1.49 (q, J=12.50 Hz, 2H), 1.59 (br d, J=13.00 Hz, 1H), 1.59 (d, J=12.30 Hz, 2H), 1.68-1.78 (m, 2H), 1.80-1.86 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 2H), 3.22 (dd, J=13.50, 8.00 Hz, 1H), 3.47-3.54 (m, 1H), 3.95 (dd, J=13.24, 2.21 Hz, 1H), 4.21-4.27 (m, 1H), 6.69 (d, J=7.57 Hz, 1H), 7.09 (d, J=2.00 Hz, 1H), 7.12 (dd, J=8.50, 2.50 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.20 Hz, 2H), 7.61 (d, J=8.20 Hz, 1H); MS (ESI) [M+1]+ 491.
    • Example C-109: 2-((1r,4r)-4-(4-(2-methyl-4-(2-(trifluoromethoxy)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00219
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (qd, J=12.50, 3.00 Hz, 2H), 1.35 (d, J=5.99 Hz, 3H), 1.49 (qd, J=12.50, 3.00 Hz, 2H), 1.74 (td, J=7.41, 3.78 Hz, 1H), 1.84 (br d, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.41 (dd, J=13.56, 7.57 Hz, 1H), 4.10 (dd, J=13.40, 2.36 Hz, 1H), 4.36-4.41 (m, 1H), 7.15-7.19 (m, 2H), 7.26 (qd, J=8.00, 1.42 Hz, 1H), 7.30 (d, J=8.00 Hz, 2H), 7.36-7.41 (m, 2H), 7.55 (d, J=6.50 Hz, 2H), 7.59 (d, J=9.50 Hz, 1H), 7.69 (dd, J=8.04, 1.42 Hz, 3H), 8.89 (s, 1H),12.14 (br s, 1H); MS (ESI) [M+1]+ 569.
    • Example C-110: 2-((1r,4r)-4-(4-(2-methyl-4-(4-(trifluoromethoxy)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00220
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.36 (d, J=6.00 Hz, 3H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.71-1.79 (m, 1H), 1.83 (br d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.37 (dd, J=13.25, 7.75 Hz, 1H), 4.10 (dd, J=13.25, 1.75 Hz, 1H), 4.34-4.40 (m, 1H), 7.15-7.18 (m, 2H), 7.30 (t, J=8.20 Hz, 4H), 7.53-7.58 (m, 3H), 7.61 (d, J=9.00 Hz, 2H), 9.38 (s, 1H), 12.08 (br s, 1H); MS (ESI) [M+1]+ 569.
    • Example C-111: 2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00221
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.04 (t, J=7.41 Hz, 3H), 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.63-1.79 (m, 3H), 1.83 (br d, J=9.50 Hz, 4H), 2.15 (d, J=7.00 Hz, 2H), 2.45-2.55 (m, 1H), 3.48 (dd, J=13.75, 7.25 Hz, 1H), 4.12 (dd, J=13.50, 2.50 Hz, 1H), 4.15-4.23 (m, 1H), 7.17-7.21 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.34 (t, J=8.00 Hz, 1H), 7.50 (d, J=7.88 Hz, 1H), 7.56 (d, J=7.88 Hz, 2H), 7.67 (d, J=8.20 Hz, 1H), 7.69 (d, J=8.20 Hz, 1H), 8.78 (s, 1H) 12.08 (br s, 1H); MS (ESI) [M+1]+ 533.
    • Example C-112: 2-((1r,4r)-4-(4-(4-(benzylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00222
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (qd, J=12.75, 3.00 Hz, 2H), 1.32 (d, J=6.00 Hz, 3H), 1.49 (qd, J=12.75, 3.00 Hz, 2H),1.72-1.78 (m, 1H),1.80-1.88 (m, 1H), 2.15 (d, J=6.94 Hz, 2H), 2.44-2.54 (m, 1H), 3.26 (dd, J=13.56, 7.88 Hz, 1H), 4.05 (dd, J=13.40, 2.36 Hz, 1H), 4.25-4.31 (m, 1H), 4.34 (d, J=5.50 Hz, 2H), 7.12 (d, J=2.00 Hz, 1H), 7.14 (dd, J=8.50, 2.50 Hz, 1H), 7.23-7.26 (m, 1H), 7.28 (d, J=8.50 Hz, 2H), 7.30-7.36 (m, 4H), 7.53 (d, J=8.00 Hz, 2H), 7.56 (t, J=11.50 Hz, 1H), 7.66 (d, J=8.51 Hz, 1H), 12.11 (br s, 1H); MS (ESI) [M+1]+ 499.
    • Example C-113: 2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00223
  • 1H NMR (500 MHz, DMSO-ds) δ ppm 0.86 (t, J=6.75 Hz, 3H), 1.13 (br q, J=12.25 Hz, 2H), 1.26-1.33 (m, 8H), 1.44-1.53 (m, 4H),1.70-1.80 (m, 1H), 1.83 (br d, J=9.50 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H), 3.07-3.14 (m, 2H), 3.21 (dd, J=13.40, 8.04 Hz, 1H), 3.97 (dd, J=13.40, 2.36 Hz, 1H), 4.21-4.27 (m, 1H), 6.95 (t, J=5.52 Hz, 1H), 7.10 (d, J=2.50 Hz, 1H), 7.13 (dd, J=8.50, 2.50 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.51 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 12.08 (br s, 1H); MS (ESI) [M+1]+ 493.
    • Example C-114: 2-((1r,4r)-4-(4-(2-methyl-4-(pyridazin-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00224
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (d, J=11.33 Hz, 2H), 1.37 (d, J=6.00 Hz, 3H), 1.49 (d, J=11.33 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d, J=9.00 Hz, 4H), 2.16 (d, J=6.50 Hz, 2H), 3.44 (dd, J=13.24, 7.88 Hz, 1H), 4.20 (d, J=13.50 Hz, 1H), 4.37-4.47 (m, 1H), 7.19 (br s, 2H), 7.30 (d, J=8.20 Hz, 2H), 7.57 (d, J=7.88 Hz, 2H), 7.63 (d, J=8.83 Hz, 1H), 7.96-8.00 (m, 1H), 9.10 (d, J=5.99 Hz, 1H), 9.35 (d, J=2.00 Hz, 1H), 12.01 (br s, 1H); MS (ESI) [M+1]+ 487.
  • Example C-115: 2-((1r,4r)-4-(4-(2-methyl-4-(phenethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00225
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (bq, J=12.50 Hz, 2H), 1.29 (d, J=6.31 Hz, 3H), 1.49 (bq, J=12.50 Hz, 2H),1.72-1.78 (m, 1H), 1.77-1.87 (m, 4H), 2.16 (d, J=6.50 Hz, 2H), 2.81 (t, J=6.78 Hz, 2H), 3.16 (dd, J=13.56, 7.88 Hz, 1H), 3.29-3.41 (m, 4H), 3.95 (dd, J=13.40, 2.36 Hz, 1H), 4.17-4.23 (m, 1H), 7.01 (m, J=5.50 Hz, 1H), 7.08 (d, J=2.00 Hz, 1H), 7.20-7.26 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.32 (t, J=7.50 Hz, 2H), 7.47 (d, J=8.83 Hz, 1H), 7.53 (d, J=8.20 Hz, 2H), 12.03 (br s, 1H); MS (ESI) [M+1]+ 513.
    • Example C-116: 2-((1r,4r)-4-(4-(4-(heptylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00226
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.75 Hz, 3H), 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.24-1.32 (m, 10H), 1.44-1.53 (m, 4H), 1.71-1.80 (m, 1H), 1.83 (br d, J=9.46 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.54 (m, 1H), 3.07-3.14 (m, 2H), 3.21 (dd, J=13.40, 7.72 Hz, 1H), 3.97 (dd, J=13.40, 2.36 Hz, 1H), 4.21-4.27 (m, 1H), 6.94 (t, J=5.36 Hz, 1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.75, 1.75 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 12.03 (br s, 1H); MS (ESI) [M+1]+ 507.
    • Example C-117: 2-((1r,4r)-4-(4-(2-methyl-4-(4-methylphenethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00227
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (dq, J=12.50, 2.50 Hz, 2H), 1.29 (d, J=6.50 Hz, 3H), 1.49 (dq, J=12.50, 2.50 Hz, 2H),1.69-1.78 (m, 1H), 1.83 (br d, J=9.46 Hz, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.28 (s, 3H), 2.45-2.53 (m, 1H), 2.76 (t, J=7.41 Hz, 2H), 3.16 (dd, J=13.25, 7.75 Hz, 1H), 3.26-3.38 (m, 3H), 3.95 (dd, J=8.25, 1.75 Hz, 1H), 4.14-4.2 (m, 1H), 6.98 (t, J=5.50 Hz, 1H), 7.07-7.13 (m, 5H), 7.28 (d, J=8.20 Hz, 2H), 7.47 (d, J=8.20 Hz, 1H), 7.53 (d, J=8.20 Hz, 2H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 527.
    • Example C-118: 2-((1r,4r)-4-(4-(2-methyl-4-(4-phenylbutylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00228
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (br q, J=11.50 Hz, 2H), 1.30 (d, J=5.99 Hz, 3H), 1.44-1.54 (m, 4H), 1.56-1.63 (m, 2H), 1.72-1.79 (m, 1H), 1.83 (br d, J=9.00 Hz, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.45-2.50 (m, 1H), 2.61 (t, J=7.41 Hz, 2H), 3.14 (br s, 3H), 3.21 (dd, J=13.50, 2.75 Hz, 1H), 3.96 (d, J=13.00 Hz, 1H), 4.23 (t, J=5.75 Hz, 1H), 6.97 (t, J=5.25 Hz, 1H), 7.08-7.14 (m, 2H), 7.18 (t, J=7.50 Hz, 1H), 7.21 (d, J=7.00 Hz, 2H), 7.25-7.31 (m, 4H), 7.53 (d, J=7.88 Hz, 2H), 7.59 (d, J=8.20 Hz, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 541.
    • Example C-119: 2-((1r,4r)-4-(4-(2-methyl-4-(octylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00229
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (t, J=6.75 Hz, 3H), 1.13 (qd, J=12.33, 2.25 Hz, 2H), 1.20-1.33 (m, 13H), 1.43-1.54 (m, 4H), 1.70-1.79 (m, 1H), 1.83 (br d, J=9.50 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.52 (m, 1H), 3.07-3.14 (m, 2H), 3.21 (dd, J=13.24, 7.88 Hz, 1H), 3.97 (dd, J=13.24, 2.21 Hz, 1H), 4.20-4.28 (m, 1H), 6.94 (t, J=5.36 Hz, 1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.75, 1.75 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 521.
    • Example C-120: 2-((1r,4r)-4-(4-(4-(decylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00230
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.00 Hz, 3H), 1.14 (qd, J=12.13, 2.75 Hz, 2H), 1.20-1.33 (m, 16H), 1.41-1.54 (m, 4H), 1.68-1.78 (m, 1H), 1.83 (br d, J=9.50 Hz, 4H) 2.16 (d, J=6.94 Hz, 2H), 3.06-3.14 (m, 2H), 3.21 (dd, J=13.24, 7.88 Hz, 1H), 3.97 (dd, J=13.24, 2.21 Hz, 1H), 4.20-4.26 (m, 1H), 6.94 (t, J=5.50 Hz, 1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.50, 2.50 Hz, 1H), 7.28 (d, J=8.00 Hz, 2H), 7.53 (d, J=8.00 Hz, 2H), 7.60 (d, J=8.50 Hz, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 549.
    • Example C-121: 2-((1r,4r)-4-(4-(4-(3-ethoxypropylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00231
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.00 Hz, 3H), 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.31 (d, J=6.50 Hz, 3H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.67-1.78 (m, 3H), 1.83 (br d, J=9.50 Hz, 4H), 2.16 (d, J=7.00 Hz, 2H), 2.46-2.52 (m, 1H), 3.12-3.24 (m, 3H), 3.40 (q, J=13.67 Hz, 4H), 3.98 (dd, J=13.25, 2.25 Hz, 1H), 4.20-4.28 (m, 1H), 6.93 (t, J=5.25 Hz, 1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.50, 2.00 Hz, 1H), 7.28 (d, J=8.00 Hz, 2H), 7.53 (d, J=8.00 Hz, 2H), 7.61 (d, J=8.50 Hz, 1H), 12.03 (s, 1H); MS (ESI) [M+1]+ 495.
    • Example C-122: 2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00232
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (qd, J=12.50, 3.00 Hz, 2H), 1.30 (d, J=6.50 Hz, 3H), 1.47 (qd, J=12.50, 3.00 Hz, 2H), 1.68-1.78 (m, 1H), 1.82 (t, J=10.50 Hz, 4H), 2.15 (d, J=7.00 Hz, 2H), 2.45 (tt, J=12.00, 2.92 Hz, 1H), 2.95 (dd, J=11.75, 8.25 Hz, 1H), 3.33 (d, J=2.50 Hz, 1H), 3.35 (d, J=3.00 Hz, 1H), 4.07-4.18 (m, 1H), 5.88 (s, 1H), 6.62 (d, J=8.00 Hz, 1H), 6.93 (d, J=2.00 Hz, 1H), 6.97 (dd, J=8.00, 2.00 Hz, 1H), 7.22 (d, J=8.50 Hz, 2H), 7.43 (d, J=8.50 Hz, 2H),12.06 (br s, 1H); MS (ESI) [M+1]+ 495.
    • Example C-123: methyl 2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetate
  • Figure US20120022057A1-20120126-C00233
  • 1H NMR (500 MHz, CDCl3) δ ppm 1.28-1.35 (m, 4H), 1.31 (d, J=7.0 Hz, 6H), 1.59 (q, J=10.0 Hz, 1H), 1.71 (s, 1H), 1.93-2.00 (m, 3H), 2.29 (d, J=6.5 Hz, 2H), 2.57 (m, 1H), 2.82 (s, 3H), 3.13 (m, 1H), 3.72 (s, 3H), 7.29 (s, 1H), 7.32-7.42 (m, 3H), 7.47 (s, 1H), 7.76 (m, 3H), 7.85 (d, J=9.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 8.30-8.32 (m, 2H); MS (ESI) [M+1]+ 535.
    • Example C-124: 7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)quinoline-4-carboxylic acid
  • Figure US20120022057A1-20120126-C00234
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=12.5 Hz, 2H), 1.54 (q, J=12.5 Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.50 (m, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.93 (d, J=5.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.79 (d, J=9.0 Hz, 1H), 9.07 (s, 1H), 12.06 (s, 1H), 13.90 (br s, 1H); MS (ESI) [M+1]+ 390.
    • Example C-125: 2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00235
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=12.5 Hz, 2H), 1.23 (d, J=6.5 Hz, 6H), 1.54 (q, J=12.5 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 3.28-3.85 (m, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.81-7.84 (m, 4H), 8.13 (d, J=8.5 Hz, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 9.15 (d, J=4.5 Hz, 1H), 10.40 (s, 1H); MS (ESI) [M+1]+ 507.
    • Example C-126: 2-((1r,4r)-4-(4-(4-(pyridin-2-ylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00236
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=11.6 Hz, 2H), 1.54 (q, J=11.6 Hz, 2H), 1.73-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 7.23-7.26 (m, 1H), 7.42 (d, J=7.5 Hz, 2H), 7.71 (d, J=4.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.93 (t, J=8.0 Hz, 1H), 8.04 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 8.30-8.35 (m, 1H), 8.42 (d, J=4.0 Hz, 1H), 9.04 (d, J=4.0 Hz, 1H), 11.34 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 466.
    • Example C-127: 2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00237
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=12.5 Hz, 2H), 1.22 (t, J=6.5 Hz, 3H), 1.54 (q, J=12.5 Hz, 2H), 1.71-1.87 (m, 5H), 2.18 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.73 (q, J=7.5 Hz, 2H), 7.28-7.30 (m, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.53 (d, J=6.5 Hz, 1H), 7.74 (d, J=3.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 2H), 8.08 (d, J=9.0 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 9.09 (d, J=4.5 Hz, 2H), 10.32 (s, 1H); MS (ESI) [M+1]+ 493.
    • Example C-128: 2-((1r,4r)-4-(4-(4-(2,4-difluorophenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00238
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=12.0 Hz, 2H), 1.53 (q, J=12.0 Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 7.22 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 3H), 7.74 (d, J=4.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.07 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 9.07 (d, J=4.5 Hz, 1H), 10.66 (s, 1H); MS (ESI) [M+1]+ 501.
    • Example C-129: 2-((1r,4r)-4-(4-(4-(2-propylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00239
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.0 Hz, 3H), 1.17 (q, J=12.5 Hz, 2H), 1.54 (q, J=12.5 Hz, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.71-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.67 (t, J=7.5 Hz, 2H), 7.27-7.34 (m, 2H), 7.42 (d, J=7.5 Hz, 2H), 7.52 (d, J=6.5 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 8.08 (d, J=8.5 Hz, 1H), 8.29 (d, J=9.0 Hz, 1H), 8.37 (s, 1H), 9.10 (d, J=4.0 Hz, 2H), 10.34 (s, 1H); MS (ESI) [M+1]+ 507.
    • Example C-130: 2-((1r,4r)-4-(4-(4-(4-fluoro-2-methylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00240
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=10.0 Hz, 2H), 1.54 (q, J=12.0 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.35 (s, 3H), 2.54 (m, 1H), 7.11-7.15 (m, 2H), 7.22 (d, J=9.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.56 (dd, J=8.5, 7.0 Hz, 1H), 7.81-7.84 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.38 (s, 1H), 9.11 (d, J=4.0 Hz, 1H), 10.35 (s, 1H); MS (ESI) [M+1]+ 497.
    • Example C-131: 2-((1s,4s)-4-(4-(4-(2-isopropylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00241
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=12.0 Hz, 2H), 1.19 (d, J=5.5 Hz, 6H), 1.54 (q, J=12.0 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=7.5 Hz, 2H), 2.54 (m, 1H), 2.88-2.91 (m, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H), 7.70-7.73 (m, 3H), 7.82 (d, J=8.0 Hz, 2H), 8.04 (d, J=8.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 9.07 (d, J=4.5 Hz, 1H), 10.73 (s, 1H); MS (ESI) [M+1]+ 507.
    • Example C-132: 2-((1s,4s)-4-(4-(5-(2-ethylphenylcarbamoyl)naphthalen-2-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00242
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.23 (t, J=5.5 Hz, 3H), 1.53 (q, J=11.6 Hz, 2H), 1.69-1.87 (m, 5H), 2.17 (d, J=8.0 Hz, 2H), 2.54 (m, 1H), 2.64 (t, J=7.5 Hz, 2H), 6.55 (s, 1H), 7.28-7.32 (m, 2H), 7.39-7.40 (m, 3H), 7.60-7.67 (m, 3H), 7.77-7.83 (m, 3H), 8.08-8.36 (m, 2H), 10.15 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 492.
    • Example C-133: 2-((1r,4r)-4-(4-(5-(2-isopropylphenylcarbamoyl)naphthalen-2-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00243
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.22 (d, J=3.0 Hz, 6H), 1.56 (q, J=11.6 Hz, 2H), 1.52-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.72-2.77 (m, 1H), 6.55 (s, 2H), 7.26-7.52 (m, 2H), 7.60-7.65 (m, 3H), 7.77-7.79 (m, 2H), 8.08-8.15 (m, 2H), 8.31-8.37 (m, 2H), 10.09 (s, 1H),10.14 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]+ 506
    • Example C-134: 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00244
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.5 Hz, 2H), 1.53 (q, J=11.5 Hz, 2H), 1.73-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.75 (s, 3H), 7.17 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.5 Hz, 4H), 7.63 (s, 2H), 7.80 (t, J=7.0 Hz, 3H), 7.95 (d, J=9.0 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 10.78 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 479.
    • Example C-135: 2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00245
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=10.5 Hz, 2H), 1.23 (d, J=7.0 Hz, 6H), 1.54 (q, J=10.5 Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.81 (s, 3H), 3.27-3.33 (m, 1H), 7.28-7.35 (m, 2H), 7.42-7.46 (m, 2H), 7.72 (s, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.96 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.29 (s, 1H), 10.34 (br s, 1H); MS (ESI) [M+1]+ 521.
    • Example C-136: 2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00246
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (q, J=10.5 Hz, 2H), 1.22 (t, J=8.0 Hz, 3H), 1.47 (q, J=10.5 Hz, 2H), 1.76-1.87 (m, 5H), 2.08 (s, 2H), 2.54 (m, 1H), 2.69-2.75 (m, 2H), 2.77 (s, 3H), 7.27-7.30 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H), 7.63 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.97 (d, J=7.0 Hz, 1H), 8.21-8.25 (m, 2H), 10.34 (br s, 1H); MS (ESI) [M+1]+ 507.
    • Example C-137: 2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00247
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.04 (q, J=10.5 Hz, 2H), 1.48 (q, J=10.5 Hz, 2H), 1.76-1.87 (m, 5H), 1.91 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 2.75 (s, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.59 (s, 1H), 7.65-7.72 (m, 2H), 7.79 (d, J=7.5 Hz, 2H), 7.83-7.86 (m, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.23 (s, 1H), 8.31 (d, J=8.5 Hz, 1H); MS (ESI) [M+1]+ 565.
    • Example C-138: 2-((1r,4r)-4-(4-(4-(benzylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00248
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=11.6 Hz, 2H), 1.52 (q, J=11.6 Hz, 2H), 1.75-1.87 (m, 5H), 2.16 (d, J=7.0 Hz, 2H), 2.51 (m, 1H), 2.77 (s, 3H), 4.58 (d, J=6.0 Hz, 2H), 7.29-7.43 (m, 5H), 7.50-7.63 (m, 3H), 7.78 (d, J=7.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.28 (br s, 1H), 9.40 (br s, 1H); MS (ESI) [M+1]+ 493.
    • Example C-139: 2-((1r,4r)-4-(4-(2-methyl-4-(phenethylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00249
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=10.5 Hz, 2H), 1.53 (q, J=10.5 Hz, 2H), 1.75-1.86 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.47 (m, 1H), 2.75 (s, 3H), 2.82 (m, 2H), 3.63 (q, J=6.5 Hz, 2H), 7.27-7.37 (m, 5H), 7.43 (d, J=7.5 Hz, 2H), 7.47 (s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.92-7.95 (m, 2H), 8.22 (s, 1H), 8.92 (br s, 1H); MS (ESI) [M+1]+ 507.
    • Example C-140: 2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00250
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=10.5 Hz, 2H), 1.52 (q, J=10.5 Hz, 2H), 1.56-1.72 (m, 5H), 1.85 (d, J=10.5 Hz, 2H), 2.00-2.22 (m, 3H), 2.51 (m, 1H), 2.64-2.68 (m, 1H), 2.70 (s, 3H), 3.86 (m, 2H), 7.18 (m, 1H), 7.24-7.31 (m, 4H), 7.39 (d, J=6.0 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.88-7.91 (m, 1H), 8.09-8.12 (m, 1H), 8.17 (s, 1H), 8.19-8.20 (m, 1H), 8.77 (m, 1H); MS (ESI) [M+1]+ 521.
    • Example C-141: 2-((1r,4r)-4-(4-(2-methyl-4-(4-phenylbutylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00251
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=10.5 Hz, 2H), 1.53 (q, J=˜10.5 Hz, 2H), 1.24 (br s, 2H), 1.84-1.91 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.37 (m, 2H), 2.44-2.64 (m, 3H), 2.70 (s, 3H), 3.35 (m, 2H), 7.21 (t, J=6.0 Hz, 1H), 7.27-7.33 (m, 3H), 7.39 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.92 (d, J=7.0 Hz, 1H), 8.14 (d, J=5.5 Hz, 1H), 8.20 (s, 1H), 8.82 (m, 1H), 12.05 (s, 1H); MS (ESI) [M+1]+ 535.
    • Example C-142: 2-((1r,4r)-4-(4-(2-methyl-4-(5-phenylpentylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00252
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=10.5 Hz, 2H), 1.38-1.44 (m, 2H), 1.53 (q, J=10.5 Hz, 2H), 1.54-1.77 (m, 6H), 1.85 (d, J=11.5 Hz, 4H), 2.17 (d, J=7.0 Hz, 2H), 2.47-2.55 (m, 1H), 2.62 (t, J=6.5 Hz, 1H), 2.69 (s, 3H), 3.35 (m, 2H), 7.17 (t, J=7.0 Hz, 1H), 7.21-7.29 (m, 2H), 7.38-7.41 (m, 4H), 7.78 (d, J=8.0 Hz, 2H), 7.90 (d, J=7.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.20 (s, 1H), 8.74 (m, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 549.
    • Example C-143: 2-((1r,4r)-4-(4-(2-methyl-4-(6-phenylhexylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00253
  • 1H NMR (500 MHz, DMSO-d6) ppm 1.54-1.75 (m, 8H), 1.85 (d, J=11.5 Hz, 4H), 1.26-1.62 (m, 6H), 2.17 (d, J=7.0 Hz, 2H), 2.47-2.61 (m, 2H), 2.84 (s, 3H), 3.36 (m, 2H), 7.15-7.21 (m, 4H), 7.27 (t, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.65 (m, 1H), 7.78 (d, J=7.5 Hz, 1H), 8.05 (m, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.33 (s, 1H), 8.90 (brs, 1H); MS (ESI) [M+1]+ 563.
    • Example C-144: 2-((1r,4r)-4-(4-(4-(4H-1,2,4-triazol-4-ylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00254
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=10.5 Hz, 2H), 1.55 (q, J=10.5 Hz, 2H), 1.75-1.87 (m, 5H), 2.37 (s, 2H), 2.54 (m, 1H), 2.79 (s, 3H), 6.65 (d, J=8.5 Hz, 1H), 7.00 (d, J=7.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 8.30 (s, 1H), 8.35 (d, J=8.50 Hz, 1H), 8.97 (s, 1H), 12.60 (br s, 1H); MS (ESI) [M+1]+ 470.
    • Example C-145: 2-((1r,4r)-4-(4-(4-(1,3,4-thiadiazol-2-ylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00255
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=10.5 Hz, 2H), 1.55 (q, J=10.5 Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=6.0 Hz, 2H), 2.54 (m, 1H), 2.72 (s, 3H), 6.55 (s, 1H), 7.26-7.30 (m, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.76-7.79 (m, 4H), 7.87 (d, J=8.0 Hz, 1H), 8.18 (s, 1H), 12.60 (br s, 1H); MS (ESI) [M+1]+ 487.
    • Example C-146: 2-((1r,4r)-4-(4-(1-(pyridin-4-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00256
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.5 Hz, 2H), 1.52 (q, J=11.6 Hz, 2H), 1.70-1.84 (m, 4H), 1.94 (m, 2H), 2.16 (d, J=6.5 Hz, 1H), 2.52-2.56 (m, 1H), 2.82 (t, J=6.5 Hz, 2H), 3.17 (m, 2H), 3.74 (t, J=6.0 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.38-7.44 (m, 3H), 7.45-7.51 (m, 3H), 7.56 (d, J=8.5 Hz, 2H), 8.36 (br s, 1H), 9.38 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 490.
    • Example C-147: (1R,2R)-2-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzoyl)cyclopentanecarboxylic acid
  • Figure US20120022057A1-20120126-C00257
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.0 Hz, 1H), 1.56-1.86 (m, 2H), 1.97-2.03 (m, 1H), 2.13-2.20 (m, 1H), 2.73 (s, 1H), 2.89 (s, 1H), 3.89 (t, J=4.0 Hz, 2H), 4.01-4.13 (m, 1H), 4.32 (t, J=4.0 Hz, 2H), 7.03 (t, J=7.5 Hz, 1H), 7.28-7.31 (m, 4H), 7.51 (d, J=8.5 Hz, 2H), 7.66 (d, J=9.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.0 Hz, 2H), 9.21 (br s, 1H); MS (ESI) [M+1]+ 471.
    • Example C-148: (1R,2R)-2-(4-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzoyl)cyclopentanecarboxylic acid
  • Figure US20120022057A1-20120126-C00258
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.5 Hz, 3H), 1.56-1.86 (m, 3H), 1.98-2.05 (m, 1H), 2.14-2.21 (m, 1H), 2.73 (s, 1H), 2.89 (s, 1H), 3.24 (q, J=8.0 Hz, 2H), 3.49 (dd, J=7.0 Hz, 1H), 4.04-4.19 (m, 3H), 7.02 (t, J=7.0 Hz, 1H), 7.28-7.31 (m, 4H), 7.51 (d, J=8.5 Hz, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 8.05 (d, J=8.0 Hz, 2H), 9.22 (br s, 1H), 12.25 (br s, 1H); MS (ESI) [M+1]+ 499.
    • Example C-149: 2-((1r,4r)-4-(4-(2-ethyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00259
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.00 (t, J=7.41 Hz, 3H), 1.11 (q, J=11.66 Hz, 2H), 1.43-1.52 (m, 2H), 1.57-1.71 (m, 2H), 1.72-1.87 (m, 7H), 2.11 (d, J=6.62 Hz, 2H), 2.44-2.49 (m, 2H), 2.61 (t, J=7.57 Hz, 2H), 3.10-3.19 (m, 2H), 3.32 (dd, J=13.40, 7.41 Hz, 1H), 3.93 (d, J=11.66 Hz, 1H), 4.01-4.06 (m, 1H), 7.01 (t, J=5.20 Hz, 1H), 7.10-7.30 (m, 9H), 7.53 (d, J=8.20 Hz, 2H), 7.59 (d, J=8.51 Hz, 1H); MS (ESI) [M+1]+ 541.
    • Example C-150: 2-((1r,4r)-4-(4-(2-ethyl-4-(heptylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00260
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86-0.88 (m, 3H), 1.00 (t, J=7.41 Hz, 3H), 1.08-1.15 (m, 2H), 1.28 (m, 8H), 1.44-1.53 (m, 4H), 1.56-1.64 (m, 2H), 1.47 (m, 1H), 1.81-1.84 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.49 (m, 2H), 3.06-3.14 (m, 2H), 3.31 (dd, J=7.6, J=13.6, 1H), 3.90-3.92 (m, 1H), 4.02 (m, 1H), 6.94-6.96 (m, 1H), 7.12-7.14 (m, 2H), 7.26-7.28 (m, 2H), 7.51-7.59 (m, 3H); MS (ESI) [M+1]+ 521.
    • Example C-151: 2-((1r,4r)-4-(4-(2-ethyl-4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00261
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86-0.88 (m, 3H), 1.00 (t, J=7.41 Hz, 3H), 1.08-1.15 (m, 2H), 1.28 (m, 6H), 1.44-1.53 (m, 4H), 1.56-1.64 (m, 2H), 1.47 (m, 1H), 1.81-1.84 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.49 (m, 1H), 3.06-3.14 (m, 2H), 3.31 (dd, J=7.6, J=13.6, 1H), 3.90-3.92 (m, 1H), 4.02 (m, 1H), 6.94-6.96 (m, 1H), 7.10-7.14 (m, 2H), 7.26-7.28 (m, 2H), 7.51-7.59 (m, 3H); MS (ESI) [M+1]+ 507.
    • Example C-152: 2-((1r,4r)-4-(4-(4-oxo-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00262
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.5 Hz, 2H), 1.24 (s, 1H), 1.51 (q, J=11.6 Hz, 2H), 1.70-1.93 (m, 3H), 1.82-1.99 (m, 2H), 2.13 (d, J=6.5 Hz, 2H), 2.52-2.56 (m, 1H), 2.82 (t, J=5.5 Hz, 2H), 4.12 (t, J=3.0 Hz, 1H), 7.04 (t, J=6.0 Hz, 1H), 7.30-7.35 (m, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.58-7.60 (m, 3H), 7.85-7.86 (m, 2H), 8.07 (d, J=2.0 Hz, 2H), 9.55 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]+ 483.
    • Example C-153: 2-((1r,4r)-4-(4-(4-(tert-butoxycarbonyl)-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00263
  • 1H NMR (500 MHz, CDCl3) δ ppm 1.23-1.28 (m, 2H), 1.43 (s, 2H), 1.47 (s, 9H), 1.59 (q, J=11.6 Hz, 2H), 1.93-2.11 (m, 3H), 2.35 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 3.42-3.48 (m, 4H), 4.80 (br s, 2H), 7.04-7.07 (m, 3H), 7.28-7.35 (m, 5H), 7.56-7.67 (m, 4H); MS (ESI) [M+1]+ 584.
    • Example C-154: 2-((1r,4r)-4-(4-(1-(2-hydroxy-2-phenylacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00264
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.5 Hz, 2H), 1.48 (q, J=11.6 Hz, 2H), 1.70-1.84 (m, 7H), 2.16 (d, J=7.0 Hz, 2H), 2.52-2.56 (m, 1H), 2.63-2.70 (m, 2H), 3.16 (s, 1H), 3.64 (m, 2H), 7.30 (d, J=8.5 Hz, 4H), 7.39 (s, 2H), 7.45-7.47 (m, 2H), 7.55 (d, J=8.5 Hz, 4H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 484.
    • Example C-155: 2-((1s,4s)-4-(4-(4-((S)-2-amino-2-phenylacetyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamide
  • Figure US20120022057A1-20120126-C00265
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.40 (d, J=6.3 Hz, 3H), 1.53 (q, J=11.6 Hz, 2H), 1.75 (m, 1H), 1.83 (d, J=10.5 Hz, 4H), 2.16 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 3.32 (m, 1H), 4.15 (br s, 1H), 4.36 (s, 1H), 4.69 (s, 1H), 7.31-7.36 (m, 4H), 7.45 (t, J=9.0 Hz, 4H), 7.57 (d, J=7.0 Hz, 2H), 7.64 (d, J=7.5 Hz, 2H), 12.04 (br s, 1H); MS (ESI) [M+1]+ 499.
    • Example C-156: 2-((1R,4r)-4-(4-(4-((R)-2-amino-2-phenylacetyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00266
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.6 Hz, 2H), 1.22 (d, J=6.0 Hz, 1H), 1.40 (d, J=6.3 Hz, 3H), 1.48 (q, J=11.6 Hz, 2H), 1.40-1.82 (m, 5H), 2.16 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 3.61 (s, 1H), 4.34 (s, 1H), 4.39 (s, 1H), 7.10 (s, 1H), 7.17-7.22 (m, 2H), 7.29 (d, J=8.0 Hz, 3H), 7.34-7.42 (m, 4H), 7.54-7.56 (m, 2H), 12.07 (br s, 1H); MS (ESI) [M+1]+ 499.
    • Example C-157: 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)propanoic acid
  • Figure US20120022057A1-20120126-C00267
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, J=11.5 Hz, 3H), 1.23-1.26 (m, 2H), 1.50 (q, J=11.5 Hz, 2H), 1.55-1.61 (m, 4H), 1.73-1.87 (m, 1H), 2.16-2.20 (m, 1H), 2.50-2.55 (m, 1H), 3.87 (t, J=4.00 Hz, 2H), 4.30 (t, J=4.0 Hz, 2H), 7.00 (t, J=7.5 Hz, 2H), 7.15-7.17 (m, 2H), 7.28-7.31 (m, 3H), 7.50 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.57 (d, J=9.5 Hz, 1H), 9.16 s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]+ 485.
    • Section D Preparation of Additional Example Compounds
  • Figure US20120022057A1-20120126-C00268
    Figure US20120022057A1-20120126-C00269
    • Example D-1: 7-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—step d1
  • 1-Hydroxybenzotriazole (32.0 mg, 0.25 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.0 mg, 0.25 mmol) and 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid C-5 (71.0 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2.0 mL). An aqueous ammonium hydroxide solution (0.02 mL, 38% in water) was then added, and the reaction was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient) to give 7-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-1 (30.0 mg; Yield=42%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.40 Hz, 2H), 1.50 (q, J=11.40 Hz, 2H), 1.70-1.86 (m, 5H), 1.99 (d, J=6.94 Hz, 2H), 2.52-2.55 (m, 1H), 3.86 (t, J=4.10 Hz, 2H), 4.28 (t, J=4.10 Hz, 2H), 7.01 (t, J=7.25 Hz, 1H), 7.16 (s, 4H), 7.26-7.35 (m, 4H), 7.46-7.60 (m, 3H), 9.16 (s, 3H); MS (ESI) [M+1]+ 470.
    • Example D-2: 7-(4-((1r,4r)-4-(cyanomethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—step d2
  • Trifluoroacetic anhydride (20.0 mg, 0.08 mmol) and triethylaluminum (10.0 mg, 0.08 mmol) were successively added to a solution of 7-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-1 (40.0 mg, 0.04 mmol) in tetrahydrofuran (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 40 h and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient) to give 7-(4-((1r,4r)-4-(cyanomethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-2 (6.0 mg; Yield=20%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.91 (q, J=11.35 Hz, 2H), 1.30 (q, J=11.65 Hz, 2H), 1.75 (br s, 1H), 2.01-2.06 (m, 4H), 2.37 (d, J=6.50 Hz, 2H), 2.58 (t, J=11.50 Hz, 1H), 2.69 (t, J=5.51 Hz, 2H), 4.00 (t, J=4.50 Hz, 2H), 4.38 (t, J=4.00 Hz, 2H), 7.01-7.18 (m, 1H), 7.16-7.39 (m, 5H), 7.48-7.60 (m, 6H); MS (ESI) [M+1]+ 452.
    • Example D-3: 7-(4-((1r,4r)-4-((1H-tetrazol-5-yl)methyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—step d3
  • Trimethylaluminum (2 M solution in toluene, 0.50 mL, 1.0 mmol) was added at 0° C. to a solution of 7-(4-((1r,4r)-4-(cyanomethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-2 (80.0 mg, 0.20 mmol) in anhydrous toluene (3.5 mL) under an atmosphere of nitrogen. Azidotrimethylsilane (0.86 mL, 6.5 mmol) was then added, and the reaction mixture was heated at 80° C. for 48 h. The solution was cooled to room temperature, concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient) to give 7-(4-((1r,4r)-4-((1H-tetrazol-5-yl)methyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-3 (40.0 mg, Yield=60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.10 (q, J=11.4 Hz, 2H), 1.47 (q, J=11.5 Hz, 2H), 1.74-1.83 (m, 3H), 2.50-2.55 (m, 1H), 2.82 (d, J=6.5 Hz, 2H), 3.17 (d, J=5.5 Hz, 2H), 3.87 (t, J=4.0 Hz, 2H), 4.28 (t, J=4.0 Hz, 2H), 7.00 (t, J=6.5 Hz, 2H), 7.15 (s, 2H), 7.27-7.30 (m, 4H), 7.49-7.55 (m, 4H), 9.16 (s, 1H); MS (ESI) [M+1]+ 495.
  • Figure US20120022057A1-20120126-C00270
    • Example D-4: 7-(4-((1r,4r)-4-(2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—step d4
  • Diisobutylaluminum hydride (1.0 M solution in methylene chloride, 0.08 mL, 0.08 mmol) was added under a nitrogen atmosphere to a solution of 2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid C-5 (40.0 mg, 0.08 mmol) in methylene chloride (10.0 mL) at −78° C. The reaction was allowed to warm up to room temperature overnight and then quenched with methanol (1.0 mL) and solid sodium sulfate decahydrate successively. After 60 mins of additional stirring at room temperature, the solution was filtered through a celite pad and washed with ethyl acetate. The combined organic extracts were concentrated under reduced pressure, and the residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient) to give 7-(4-((1r,4r)-4-(2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-4 (20.0 mg; Yield=50%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.92 (q, J=11.35 Hz, 2H), 1.27 (m, 3H), 1.50-1.63 (m, 2H), 1.96-2.04 (m, 2H), 2.42 (d, J=6.50 Hz, 2H), 2.58 (t, J=11.00 Hz, 1H), 4.01 (t, J=4.50 Hz, 2H), 4.38 (t, J=4.50 Hz, 2H), 7.10 (t, J=7.50 Hz, 1H), 7.19-7.36 (m, 6H), 7.39-7.44 (m, 4H), 7.53 (t, J=8.00 Hz, 1H), 9.83 (s, 1H); MS (ESI) [M+1]+ 455.
    • Example D-5: 7-(4-((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—step d5
  • A solution of 7-(4-((1r,4r)-4-(2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-4 (50.0 mg, 0.1 mmol) in methanol (0.20 mL) was stirred at room temperature overnight in the presence of palladium on carbon (10% Pd, 2.0 mg) under an atmosphere of hydrogen (balloon). The reaction was then filtered through a pad of silica gel and washed with ethyl acetate (3 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give 7-(4-((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide D-5 (30.0 mg; Yield=60%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.14 (q, J=11.35 Hz, 2H), 1.27 (br s, 2H), 1.50-1.63 (m, 5H), 1.98 (t, J=14.03 Hz, 2H), 2.56 (t, J=11.00 Hz, 1H), 3.77 (t, J=7.00 Hz, 2H), 4.01 (t, J=4.50 Hz, 2H), 4.38 (t, J=4.50 Hz, 2H), 7.10 (t, J=7.50 Hz, 1H), 7.19-7.36 (m, 6H), 7.39-7.44 (m, 4H), 7.53 (t, J=7.88 Hz, 1H), 9.83 (s, 1H); MS (ESI) [M+1]+ 457.
  • Figure US20120022057A1-20120126-C00271
    • Example D-6: 2-((1r,4r)-4-(4-(4-(2-aminophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid—step d6
  • A solution of 2-((1r,4r)-4-(4-(4-(2-nitrophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid C-27 (40.0 mg, 0.08 mmol) in ethyl acetate (10.0 mL) and methanol (5.0 mL) was stirred at room temperature for 3 h in the presence of platinum dioxide (4.0 mg, 0.02 mmol) under an atmosphere of hydrogen. The reaction was filtered over a pad of celite and washed with ethyl acetate (5 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient) to give 2-((1r,4r)-4-(4-(4-(2-aminophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid D-6 (30.0 mg; Yield=80%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.50 (q, J=11.50 Hz, 2H), 1.71-1.83 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.53 (m, 1H), 3.88 (t, J=4.50 Hz, 2H), 4.33 (t, J=4.50 Hz, 2H), 7.18-7.23 (m, 2H), 7.30 (d, J=11.50 Hz, 2H), 7.55 (d, J=11.50 Hz, 2H), 7.66-7.70 (m, 3H), 7.75 (d, J=7.50 Hz, 1H), 7.99 (d, J=8.50 Hz, 1H), 9.93 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]+ 486.
  • Figure US20120022057A1-20120126-C00272
    • Example D-7: 2-(7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamido)benzoic acid—step d7
  • Lithium hydroxide monohydrate (8.4 mg, 0.2 mmol) was added at room temperature to a solution of 2-((1r,4r)-4-(4-(4-(2-(methoxycarbonyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid C-29 (30.0 mg, 0.06 mmol) in tetrahydrofuran (5.0 mL) and water (1.0 mL). The reaction was stirred at room temperature overnight, quenched with a 1 N aqueous solution of hydrogen chloride (2.0 mL) and then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient) to give 2-(7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamido) benzoic acid D-7 (20.0 mg; Yield=70%). MS (ESI) [M+1]+ 515.
  • Figure US20120022057A1-20120126-C00273
    • Example D-8: ethyl 3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoate—step d8
  • N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (244.0 mg, 0.645 mmol) was added at room temperature to a solution of 2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid C-113 (149.5 g, 0.303 mmol), ethyl 3-aminopropanoate (49.5 mg, 0.322 mmol) and N-ethyl-N,N-diisopropylamine (165.0 μL, 1.0 mmol) in methylene chloride (1.0 mL). The reaction mixture was stirred overnight at room temperature and then diluted with methylene chloride. The solution was washed with a 1 N aqueous solution of hydrogen chloride and then brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude oil was purified by flash column chromatography on silica gel (1:1 hexanes:ethyl acetate) to give ethyl 3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoate D-8 as a white solid (166.0 mg; Yield=93%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.94 (d, J=6.75 Hz, 3H), 1.20 (br q, J=11.98 Hz, 2H), 1.31-1.44 (m, 5H), 1.33 (t, J=7.00 Hz, 3H), 1.43 (d, J=6.00 Hz, 3H), 1.55-1.63 (m, 4H), 1.97 (br t, J=13.75 Hz, 5H), 2.15 (d, J=6.62 Hz, 2H), 2.55 (tt, J=10.75, 2.92 Hz, 1H), 2.61 (t, J=5.99 Hz, 2H), 3.12 (dd, J=13.40, 8.35 Hz, 1H), 3.29 (dt, J=19.00, 6.50 Hz 1H), 3.40 (dt, J=19.00, 6.50 Hz 1H), 3.59 (q, J=5.99 Hz, 2H), 4.22 (q, J=7.04 Hz, 2H), 4.29-4.35 (m, 1H), 4.45 (dd, J=13.56, 2.52 Hz, 1H), 5.46 (t, J=5.52 Hz, 1H), 6.13 (t, J=5.52 Hz, 1H), 7.17 (dd, J=8.35, 2.05 Hz, 1H), 7.21 (d, J=2.21 Hz, 1H), 7.29-7.35 (m, 2H), 7.34 (d, J=8.50 Hz, 1H), 7.54 (d, J=8.20 Hz, 1H); MS (ESI) [M+1]+ 592.
    • Example D-9: 3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoic acid—step b14
  • Example D-9 was prepared by the procedure described for step b14, using ethyl 3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoate D-8 as starting material. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.75 Hz, 3H), 1.08 (br q, J=11.83 Hz, 2H), 1.24-1.33 (m, 9H), 1.41-1.51 (m, 4H), 1.67-1.70 (m, 1H), 1.79 (t, J=14.50 Hz, 4H), 1.99 (d, J=6.62 Hz, 2H), 2.38 (t, J=6.94 Hz, 2H), 2.43-2.52 (m, 1H), 3.07-3.14 (m, 2H), 3.21 (dd, J=13.25, 7.75 Hz, 1H), 3.27 (dd, J=12.50, 6.50 Hz, 1H), 3.33 (br s, 2H), 3.97 (dd, J=13.25, 2.25 Hz, 1H), 4.21-4.26 (m, 1H), 6.95 (t, J=5.36 Hz, 1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.50, 2.50 Hz, 1H), 7.27 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 7.90 (t, J=5.52 Hz, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]+ 564.
  • Figure US20120022057A1-20120126-C00274
    • Example D-10: 2-((1r,4r)-4-(4-(4-hydroxy-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid—step d9
  • Sodium borohydride (7.4 mg, 0.20 mmol) was added at room temperature to a solution of 2-((1r,4r)-4-(4-(4-oxo-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid C-152 (96.4 mg, 0.20 mmol) in anhydrous methanol (5.0 mL) under an atmosphere of argon. The reaction mixture was stirred overnight, then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(4-hydroxy-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)acetic acid D-10 (63.0 mg, Yield=65%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.51 (q, J=11.6 Hz, 2H), 1.70-1.92 (m, 3H), 1.92-1.99 (m, 2H), 2.15 (d, J=6.5 Hz, 2H), 2.50-2.60 (m, 1H), 2.90 (t, J=6.0 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H), 4.50 (m, 1H), 7.10 (t, J=6.0 Hz, 1H), 7.25-7.35 (m, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.58-7.60 (m, 3H), 7.70-7.82 (m, 2H), 7.90 (d, J=2.5 Hz, 2H), 9.50 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]+ 485.
  • Figure US20120022057A1-20120126-C00275
    • Example: 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetic acid
  • A 4 N solution of hydrogen chloride in dioxane (3.0 mL) was added at room temperature to a solution of 2-((1r,4r)-4-(4-(4-(tert-butoxycarbonyl)-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetic acid C-153 (58.3 mg, 0.10 mmol) in dioxane (10.0 mL). After 12 h of stirring, the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetic acid D-11 (43.5 mg, Yield=90%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=12.0 Hz, 2H), 1.52 (q, J=11.58 Hz, 2H), 1.66-1.94 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 3.44-3.57 (m, 4H), 4.40 (s, 2H), 6.99 (t, J=6.5 Hz, 2H), 7.24 (t, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.41-7.44 (m, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.71-7.77 (m, 1H), 7.95 (s, 1H), 9.10 (s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]+ 484.
  • Figure US20120022057A1-20120126-C00276
    • Example D-12: 7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-2-methyl-N-phenylquinoline-4-carboxamide—step d11
  • N-Ethyl-N,N-diisopropylethylamine (50.0 μL, 0.30 mmol) was added at room temperature to a solution of 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-quinolin-7-yl)phenyl)cyclohexyl)acetic acid C-134 (47.8 mg, 0.1 mmol), (1H-tetrazol-5-yl)methanamine hydrobromide (27.7 mg, 0.15 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (64.0 mg, 0.12 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-2-methyl-N-phenylquinoline-4-carboxamide D-12 (32.2 mg, Yield=60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.0 Hz, 2H), 1.61 (q, J=11.0 Hz, 2H), 1.59-1.85 (m, 5H), 2.11 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 2.75 (s, 3H), 4.56 (d, J=5.5 Hz, 2H), 7.12-7.23 (m, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.63 (s, 1H), 7.69 (s, 1H), 7.81 (q, J=9.0 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.25 (t, J=8.5 Hz, 1H), 8.47 (s, 1H), 8.62 (t, J=5.5 Hz, 1H), 10.80 (s, 1H), 10.85 (s, 1H); MS (ESI) [M+1]+ 560.
  • Figure US20120022057A1-20120126-C00277
    • Example D-13: 7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-2-methyl-4-(phenylcarbamoyl)quinoline 1-oxide—step d12
  • m-Chloroperoxybenzoic acid (30.0 mg, 0.20 mmol) was added to a solution of 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid C-134 (47.8 mg, 0.1 mmol) in anhydrous methylene chloride (9.0 mL). The reaction was stirred at room temperature overnight, then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-2-methyl-4-(phenylcarbamoyl)quinoline 1-oxide D-13 (17.3 mg; Yield=35%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=11.6 Hz, 2H), 1.52 (q, J=11.6 Hz, 2H), 1.74-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.47-2.51 (m, 1H), 2.89 (s, 3H), 7.09-7.18 (m, 1H), 7.39-7.43 (m, 2H), 7.53-7.63 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.79-7.81 (m, 1H), 7.89-7.94 (m, 2H), 7.98 (d, J=8.5 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.86 (s, 1H), 10.74 (s, 1H); MS (ESI) [M+1]+ 495.
  • Figure US20120022057A1-20120126-C00278
    • Example D-14: 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamothioyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid—step d13
  • 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (80.0 mg, 0.20 mmol) was added dropwise to a solution of 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid C-134 (47.8 mg, 0.10 mmol) in toluene (10.0 mL). The reaction was refluxed overnight and then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamothioyl)quinolin-7-yl)phenyl)cyclohexyl)acetic acid D-14 (44.4 mg; Yield=45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (q, J=11.5 Hz, 2H), 1.53 (q, J=11.5 Hz, 2H), 1.73-1.87 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 2.72 (s, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.43 (s, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.63 (s, 1H), 7.78 (d, J=7.5 Hz, 2H), 7.93 (d, J=9.0 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.22 (s, 1H), 12.05 (s, 1H), 12.40 (br s, 1H); MS (ESI) [M+1]+ 495.
    • Section E Additional Example Compounds Preparation of Examples E-1 to E-10
  • The following examples were prepared using the general procedures outlined in section D and section B and using selected examples of section C as starting material.
    • Example E-1: 5-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenylindoline-1-carboxamide
  • Figure US20120022057A1-20120126-C00279
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=11.65 Hz, 2H), 1.50 (q, J=11.65 Hz, 2H), 1.75 (br s, 1H), 1.78-1.90 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.53-2.55 (m, 1H), 3.22 (t, J=8.51 Hz, 2H), 4.18 (t, J=8.51 Hz, 2H), 7.23-7.30 (m, 1H) 7.31-7.45 (m, 5H) 7.46-7.58 (m, 4H), 7.63-7.81 (m, 1H), 7.87-7.96 (m, 1H), 8.55 (s, 2H); MS (ESI) [M+1]+ 454.
    • Example E-2: 5-(4-((1r,4r)-4-(2-(2-cyanoethylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-phenylindoline-1-carboxamide
  • Figure US20120022057A1-20120126-C00280
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.22 (q, J=11.35 Hz, 2H), 1.50 (q, J=11.65 Hz, 2H), 1.75 (br s, 1H), 1.78-1.98 (m, 4H), 2.18 (d, J=6.50 Hz, 2H), 2.53-2.55 (m, 1H), 2.69 (t, J=5.51 Hz, 2H), 3.32 (t, J=8.51 Hz, 2H), 3.57 (q, J=6.00 Hz, 2H), 4.17 (t, J=8.51 Hz, 2H), 7.12 (t, J=7.50 Hz, 1H), 7.27-7.30 (m, 5H), 7.36 (t, J=7.50 Hz, 2H), 7.43-7.52 (s, 4H), 7.95 (d, J=8.00 Hz, 1H), 8.02 (s, 1H); MS (ESI) [M+1]+ 507.
    • Example E-3: 2-((1r,4r)-4-(4-(4-(4-Aminophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetic acid
  • Figure US20120022057A1-20120126-C00281
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (q, J=11.50 Hz, 2H), 1.48 (q, J=11.50 Hz, 2H), 1.70-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m, 1H), 3.58 (br s, 1H), 3.86 (t, J=4.50 Hz, 2H), 4.29 (t, J=4.50 Hz, 2H), 7.14-7.17 (m, 5H), 7.29 (d, J=8.00 Hz, 2H), 7.48-7.58 (m, 4H), 9.29 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]+ 486.
    • Example E-4: 7-(4-((1r,4r)-4-(2-(hydroxyamino)-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide
  • Figure US20120022057A1-20120126-C00282
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.10 (q, J=11.50 Hz, 2H), 1.47 (q, J=11.50 Hz, 2H), 1.70-1.83 (m, 5H), 1.88 (d, J=6.50 Hz, 2H), 2.50 (m, 1H), 3.58 (br s, 1H), 3.89 (t, J=4.50 Hz, 2H), 4.30 (t, J=4.50 Hz, 2H), 7.16-7.18 (m, 4H), 7.29 (d, J=8.20 Hz, 2H), 7.46-7.62 (m, 4H), 7.66 (t, J=7.41 Hz, 2H), 8.71 (br s, 1H), 8.83 (br s, 1H), 10.39 (s, 1H); MS (ESI) [M+1]+ 486.
    • Example E-5: 2-methyl-7-(4-((1r,4r)-4-(2-oxo-2-(phenylamino)ethyl)cyclohexyl)phenyl)-N-phenylquinoline-4-carboxamide
  • Figure US20120022057A1-20120126-C00283
  • 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.25-1.29 (m, 2H), 1.59-1.67 (m, 5H), 1.99-2.05 (m, 3H), 2.33 (d, J=6.5 Hz, 2H), 2.84 (s, 3H), 7.14-7.28 (m, 3H), 7.37 (d, J=8.0 Hz, 2H), 7.44-7.49 (m, 3H), 7.56 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.80 (s, 2H), 7.86 (d, J=6.0 Hz, 2H), 8.29-8.33 (m, 2H); MS (ESI) [M+1]+ 554.
    • Example E-6: 7-(4-((1r,4r)-4-(2-(methylsulfonamido)-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide
  • Figure US20120022057A1-20120126-C00284
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15-1.26 (m, 2H), 1.49 (q, J=11.5 Hz, 2H), 1.76 (s, 3H), 1.76-1.88 (m, 4H), 1.73-1.87 (m, 1H), 2.25 (d, J=7.0 Hz, 2H), 2.50-2.55 (m, 1H), 3.87 (t, J=4.0 Hz, 2H), 4.29 (t, J=4.0 Hz, 2H), 6.55 (s, 3H), 6.99-7.05 (m, 3H), 7.15 (s, 1H), 7.29 (t, J=7.5 Hz, 3H), 7.49-7.62 (m, 1H), 7.95 (s, 1H), 9.16 (s, 1H), 9.89 (br s, 1H); MS (ESI) [M+1]+ 540.
    • Example E-7: 7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylquinoline-4-carboxamide
  • Figure US20120022057A1-20120126-C00285
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 (q, J=12.5 Hz, 2H), 1.49 (q, J=12.5 Hz, 2H), 1.72-1.87 (m, 3H), 2.11 (d, J=6.5 Hz, 2H), 2.51 (m, 1H), 2.77 (s, 3H), 3.00-3.03 (m, 2H), 4.55 (d, J=5.5 Hz, 2H), 7.40 (d, J=8.00 Hz, 1H), 7.60 (s, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.73-7.83 (m, 4H), 7.97 (d, J=8.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.26 (s, 1H), 8.59 (t, J=5.5 Hz, 1H), 10.66 (s, 1H); MS (ESI) [M+1]+ 646.
    • Example E-8: 7-(4-((1r,4r)-4-(2-(1H-tetrazol-5-ylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylquinoline-4-carboxamide
  • Figure US20120022057A1-20120126-C00286
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (q, J=12.5 Hz, 2H), 1.55 (q, J=12.5 Hz, 2H), 1.87 (d, J=7.5 Hz, 5H), 2.36-2.78 (m, 3H), 2.78 (s, 3H), 7.12 (d, J=8.0 Hz, 2H), 7.63 (s, 1H), 7.73 (t, J=8.5 Hz, 1H), 7.78-7.82 (m, 4H), 8.00 (d, J=9.0 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 10.61 (s, 2H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 632.
    • Example E-9: 7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide
  • Figure US20120022057A1-20120126-C00287
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.53 (q, J=11.6 Hz, 2H), 1.73-1.80 (m, 5H), 2.19 (d, J=7.5 Hz, 2H), 2.54 (m, 1H), 3.05 (m, 2H), 3.87 (t, J=4.0 Hz, 2H), 4.30 (t, J=4.0 Hz, 2H), 7.12-7.18 (m, 1H), 7.36-7.54 (m, 2H), 7.59-7.70 (m, 2H), 7.74-7.90 (m, 2H), 8.13-8.39 (m, 3H), 10.61 (s, 2H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 638.
    • Example E-10: 7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methylquinoline 1-oxide
  • Figure US20120022057A1-20120126-C00288
  • 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (q, J=11.5 Hz, 2H), 1.52 (q, J=11.5 Hz, 2H), 1.83-1.87 (m, 4H), 2.17 (d, J=7.0 Hz, 2H), 2.37-2.67 (m, 2H), 2.89 (s, 3H), 6.99 (s, 1H), 7.08 (s, 1H), 7.19 (m, 1H), 7.45 (t, J=8.0 Hz, 2H), 7.71-7.91 (m, 2H), 8.11 (m, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.67 (s, 1H), 8.86 (s, 1H), 10.61 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]+ 581.
    • Biological Assay
  • The assay used to determine the DGAT inhibitory activity of the inventive compounds is described below:
  • The in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzyme expressed in Sf9 insect cells prepared as microsomes. The reaction was initiated by the addition of the combined substrates 1,2-dioleoyl-sn-glycerol and [14C]-palmitoyl-CoA and incubated with test compounds and microsomal membranes for 2 hours at room temperature. The assay was stopped by adding 0.5 mg wheat germ agglutinin beads in assay buffer with 1% Brij-35 and 1% 3-cholamidopropyldimethyl-ammonio-1-propane sulfonate. Plates were sealed with TopSeal and incubated for 18 hours to allow the radioactive triglyceride product to come into proximity with the bead. Plates were read on a TopCount instrument.
  • Percent inhibition was calculated as the percent of (test compound inhibition minus non-specific binding) relative to (total binding minus non-specific binding). IC50 values were determined by curve fitting the data to a Sigmoidal dose-response in GraphPad Prism utilizing the following equation:

  • Y=A+(B−A)/(1+10̂((LogIC50 −X))),
  • where A and B are the bottom and top of the curve (highest and lowest inhibition), respectively, and X is the logarithm of concentration.
  • Biological Data
    Compound human DGAT1
    Number Structure IC50 (nM)
    C-6
    Figure US20120022057A1-20120126-C00289
         		20
    B-48
    Figure US20120022057A1-20120126-C00290
         		83
    C-78 enantiomer A
    Figure US20120022057A1-20120126-C00291
         		79
    C-125
    Figure US20120022057A1-20120126-C00292
         		72
    B-18 enantiomer A
    Figure US20120022057A1-20120126-C00293
         		43
    C-82 enantiomer B
    Figure US20120022057A1-20120126-C00294
         		88
    C-81 enantiomer A
    Figure US20120022057A1-20120126-C00295
         		58
    C-129
    Figure US20120022057A1-20120126-C00296
         		94
    C-134
    Figure US20120022057A1-20120126-C00297
         		28
    C-113
    Figure US20120022057A1-20120126-C00298
         		82
    C-139
    Figure US20120022057A1-20120126-C00299
         		61
    C-116
    Figure US20120022057A1-20120126-C00300
         		71
    C-141
    Figure US20120022057A1-20120126-C00301
         		15
    C-150
    Figure US20120022057A1-20120126-C00302
         		83
    C-142
    Figure US20120022057A1-20120126-C00303
         		12
  • The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims (11)

1-12. (canceled)
13. A compound, or pharmaceutically acceptable salt of said compound, the compound being represented by the Formula IA:
Figure US20120022057A1-20120126-C00304
or a stereoisomer or tautomer of said compound, wherein
the bond denoted by
Figure US20120022057A1-20120126-P00001
represents a single bond or a double bond;
W is selected from the group consisting of N, or N(R4);
X is selected from the group consisting of C(R4), or C(R4R4);
Y is selected from the group consisting of C(R4), or C(R4R4);
R4 is present depending on the allowed valency and R4 is selected from H, alkyl, R1, —OH, (═O), or hydroxyalkyl;
W, X or Y is substituted with R1 depending on the allowed valency;
R1 is selected from the group consisting of -alkyl, -aryl, arylalkyl-, heteroaryl-, (alkylamino)carbonyl-, (cycloalkylamino)carbonyl-, (heterocycloalkylamino)carbonyl-, (arylamino)carbonyl-, (heteroarylamino)carbonyl-, wherein each of these R1 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester, methylenedioxy, CN, cyanoalkyl-, nitro and CF3;
A is C(R5);
B is C(R5);
C is C(R5);
D is C(R5);
R5 is selected from H, alkyl, cycloalkyl, amino, alkylamino, hydroxy, alkoxy, halogen or R2;
A, B, C or D is optionally substituted, depending on the allowed vacancy, with cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each of these groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
R2 is aryl, wherein the aryl is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
Z is a bond;
R6 is selected from H or alkyl;
R3 is cycloalkyl, wherein the cycloalkyl is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF3, —C(O)NH(R6), —CON(R6)2, —COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl, -alkyl-C(O)NH2, -alkyl-C(O)—NH—(CH2)1-3—CN, -alkyl-C(O)—NH—(CH2)1-3-(heteroaryl), —COOH bioisostere or -alkylCOOH bioisostere.
14. A pharmaceutical composition comprising at least one compound of claim 13 and at least one pharmaceutically acceptable carrier.
15. A method of inhibiting DGAT1 in a patient in need thereof comprising administering therapeutically effective amounts of at least one compound of claim 13 to said patient.
16. A method of treating obesity, diabetes or metabolic syndrome in a patient in need thereof comprising administering therapeutically effective amounts of at least one compound of claim 13 to said patient.
17. A compound of claim 13, selected from any of the following compounds:
Figure US20120022057A1-20120126-C00305
Figure US20120022057A1-20120126-C00306
Figure US20120022057A1-20120126-C00307
Figure US20120022057A1-20120126-C00308
Figure US20120022057A1-20120126-C00309
or a pharmaceutically acceptable salt thereof.
18. A compound, or pharmaceutically acceptable salt of said compound, the compound being represented by the Formula IB:
Figure US20120022057A1-20120126-C00310
or a stereoisomer or tautomer of said compound, wherein
the bond denoted by
Figure US20120022057A1-20120126-P00001
represents a single bond or a double bond;
E is selected from the group consisting of N, N(R4) or O;
F is selected from the group consisting of C(R4), or C(R4R4);
G is selected from the group consisting of C(R4), or C(R4R4);
H is selected from the group consisting of C(R4), C(R4R4), N or N(R4);
R4 is present depending on the allowed vacancy and is selected from H, alkyl, R1, —OH, (═O), or hydroxyalkyl;
E, F, G or H is substituted with R1 depending on the allowed valency;
R1 is selected from the group consisting of alkyl-, aryl-, arylalkyl-, heteroaryl-, (alkylamino)carbonyl-, (cycloalkylamino)carbonyl-, (heterocycloalkylamino)carbonyl-, (arylamino)carbonyl-, wherein each of these R1 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester, methylenedioxy, CN, cyanoalkyl-, nitro and CF3;
A is CR5;
B is CR5;
C is CR5;
D is CR5;
R5 is selected from H, alkyl, cycloalkyl, amino, alkylamino, hydroxy, alkoxy, halogen or R2;
A, B, C or D is optionally substituted, depending on the allowed valency, with cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each of these groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
R2 is aryl, wherein the aryl is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF3;
Z is a bond; and
R3 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of these R3 groups is unsubstituted or optionally independently substituted with 1-4 substituents independently selected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF3, —C(O)NH(R6), —CON(R6)2, —COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl, -alkyl-C(O)NH2, -alkyl-C(O)—NH—(CH2)1-3—CN, -alkyl-C(O)—NH—(CH2)1-3-(heteroaryl), —COOH bioisostere or -alkylCOOH bioisostere.
19. A pharmaceutical composition comprising at least one compound of claim 18 and at least one pharmaceutically acceptable carrier.
20. A method of inhibiting DGAT1 in a patient in need thereof comprising administering therapeutically effective amounts of at least one compound of claim 18 to said patient.
21. A method of treating obesity, diabetes or metabolic syndrome in a patient in need thereof comprising administering therapeutically effective amounts of at least one compound of claim 18 to said patient.
22. A compound selected from the compounds of the formulae:
Figure US20120022057A1-20120126-C00311
Figure US20120022057A1-20120126-C00312
Figure US20120022057A1-20120126-C00313
Figure US20120022057A1-20120126-C00314
Figure US20120022057A1-20120126-C00315
or a pharmaceutically acceptable salt thereof.
US13/256,468 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacyglycerol acyltransferase Abandoned US20120022057A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/256,468 US20120022057A1 (en) 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacyglycerol acyltransferase

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16121209P 2009-03-18 2009-03-18
US13/256,468 US20120022057A1 (en) 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacyglycerol acyltransferase
PCT/US2010/027446 WO2010107768A1 (en) 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacylglycerol acyltransferase

Publications (1)

Publication Number Publication Date
US20120022057A1 true US20120022057A1 (en) 2012-01-26

Family

ID=42134273

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/256,468 Abandoned US20120022057A1 (en) 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacyglycerol acyltransferase
US13/203,983 Active 2030-09-28 US8637507B2 (en) 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacylglycerol acyltransferase

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/203,983 Active 2030-09-28 US8637507B2 (en) 2009-03-18 2010-03-16 Bicyclic compounds as inhibitors of diacylglycerol acyltransferase

Country Status (8)

Country Link
US (2) US20120022057A1 (en)
EP (2) EP2408766A1 (en)
JP (2) JP2012520886A (en)
AR (2) AR075858A1 (en)
AU (2) AU2010226829A1 (en)
CA (2) CA2755251A1 (en)
TW (2) TW201043607A (en)
WO (2) WO2010107765A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016036636A1 (en) * 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
WO2016036633A1 (en) * 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
WO2016036638A1 (en) * 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Isoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US9556166B2 (en) 2011-05-12 2017-01-31 Proteostasis Therapeutics, Inc. Proteostasis regulators
US9849135B2 (en) 2013-01-25 2017-12-26 President And Fellows Of Harvard College USP14 inhibitors for treating or preventing viral infections
US9850262B2 (en) 2013-11-12 2017-12-26 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US10351568B2 (en) 2010-01-28 2019-07-16 President And Fellows Of Harvard College Compositions and methods for enhancing proteasome activity
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
WO2021072198A1 (en) * 2019-10-09 2021-04-15 Biocryst Pharmaceuticals, Inc. Oral complement factor d inhibitors

Families Citing this family (113)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8252812B2 (en) 2009-08-10 2012-08-28 Samumed, Llc Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof
RS56669B1 (en) 2009-12-21 2018-03-30 Samumed Llc 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
US8598156B2 (en) 2010-03-25 2013-12-03 Glaxosmithkline Llc Chemical compounds
FR2963005B1 (en) * 2010-07-23 2012-08-17 Sanofi Aventis DERIVATIVES OF OXADIAZOLES AND PYRIDAZINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
TW201236685A (en) * 2010-11-11 2012-09-16 Daiichi Sankyo Co Ltd New pyrazole amide derivatives
US9302996B2 (en) 2010-12-17 2016-04-05 Mitsubishi Tanabe Pharma Corporation Continuous arycyclic compound
WO2012088266A2 (en) 2010-12-22 2012-06-28 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3
US9051305B2 (en) 2011-03-08 2015-06-09 Eutropics Pharmaceuticals, Inc. Compositions and methods useful for treating diseases
US9062028B2 (en) 2011-04-28 2015-06-23 Bristol-Myers Squibb Company Bicyclic nitrogen containing heteroaryl TGR5 receptor modulators
MY184553A (en) 2011-05-20 2021-04-02 Glaxosmithkline Ip No 2 Ltd Novel compounds as diacylglycerol acyltransferase inhibitors
MY184882A (en) 2011-09-14 2021-04-29 Samumed Llc Indazole-3-carboxamides and their use as wnt/b-catenin signaling pathyway inhibitors
US9271969B2 (en) 2012-02-07 2016-03-01 Kainos Medicine, Inc. Compounds as inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
US8916555B2 (en) 2012-03-16 2014-12-23 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
PH12017500997A1 (en) 2012-04-04 2018-02-19 Samumed Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
RS59668B1 (en) 2012-05-04 2020-01-31 Samumed Llc 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
DK3176170T3 (en) 2012-06-13 2019-01-28 Incyte Holdings Corp SUBSTITUTED TRICYCLIC RELATIONS AS FGFR INHIBITORS
ES2690315T3 (en) 2012-06-15 2018-11-20 Mitsubishi Tanabe Pharma Corporation Imidazole and triazole compounds as DGAT-1 inhibitors
WO2013192423A2 (en) 2012-06-20 2013-12-27 Eutropics Pharmaceuticals, Inc. Methods and compositions useful for treating diseases involving bcl-2 family proteins with quinoline derivatives
WO2014026125A1 (en) 2012-08-10 2014-02-13 Incyte Corporation Pyrazine derivatives as fgfr inhibitors
EP2912036A1 (en) 2012-10-04 2015-09-02 Pfizer Limited Pyrrolo[3,2-c]pyridine tropomyosin-related kinase inhibitors
WO2014081953A1 (en) 2012-11-21 2014-05-30 Richard David J Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives
US9796729B2 (en) 2012-11-23 2017-10-24 Glaxosmithkline Llc Compounds as diacylglycerol acyltransferase inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
JP6355648B2 (en) 2013-01-08 2018-07-11 サミュメッド リミテッド ライアビリティ カンパニー 3- (Benzimidazol-2-yl) -indazole inhibitors of WNT signaling pathway and their therapeutic use
JP6669499B2 (en) 2013-02-15 2020-03-18 カラ ファーマシューティカルズ インコーポレイテッド Therapeutic compounds
JP2014156442A (en) * 2013-02-18 2014-08-28 Nippon Rikagaku Kogyo Kk Method of producing arylpiperazine derivatives or salts thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
JP2016510000A (en) 2013-02-20 2016-04-04 カラ ファーマシューティカルズ インコーポレイテッド Therapeutic compounds and uses thereof
ES2893725T3 (en) 2013-04-19 2022-02-09 Incyte Holdings Corp Bicyclic heterocyclics as FGFR inhibitors
JP6067181B2 (en) 2013-04-30 2017-01-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Aldosterone synthase inhibitor
DE102013008118A1 (en) 2013-05-11 2014-11-13 Merck Patent Gmbh Arylchinazoline
US10732182B2 (en) 2013-08-01 2020-08-04 Eutropics Pharmaceuticals, Inc. Method for predicting cancer sensitivity
NZ631142A (en) 2013-09-18 2016-03-31 Axikin Pharmaceuticals Inc Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
AU2014342269B2 (en) 2013-10-30 2020-02-27 Eutropics Pharmaceuticals, Inc. Methods for determining chemosensitivity and chemotoxicity
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
KR20160099084A (en) 2013-11-01 2016-08-19 칼라 파마슈티컬스, 인크. Crystalline forms of therapeutic compounds and uses thereof
WO2015091428A1 (en) * 2013-12-20 2015-06-25 Bayer Pharma Aktiengesellschaft Glucose transport inhibitors
WO2016040188A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040182A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine and therapeutic uses thereof
WO2016040184A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040185A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof
WO2016040181A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040193A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof
WO2016040180A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof
WO2016040190A1 (en) 2014-09-08 2016-03-17 Samumed, Llc 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
EA201790806A1 (en) 2014-11-05 2017-11-30 Флексус Байосайенсиз, Инк. IMMUNOREGULATING AGENTS
US10307480B2 (en) * 2014-11-06 2019-06-04 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
HUE049801T2 (en) 2014-12-23 2020-10-28 Sma Therapeutics Inc 3,5-diaminopyrazole kinase inhibitors
WO2016134294A1 (en) 2015-02-20 2016-08-25 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors
MA41551A (en) 2015-02-20 2017-12-26 Incyte Corp BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS
CN107438607B (en) 2015-02-20 2021-02-05 因赛特公司 Bicyclic heterocycles as FGFR inhibitors
WO2017024004A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017023987A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
WO2017023980A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
US10285983B2 (en) 2015-08-03 2019-05-14 Samumed, Llc 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof
WO2017023984A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
US10604512B2 (en) 2015-08-03 2020-03-31 Samumed, Llc 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof
US10350199B2 (en) 2015-08-03 2019-07-16 Samumed, Llc 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof
US10195185B2 (en) 2015-08-03 2019-02-05 Samumed, Llc 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof
US10463651B2 (en) 2015-08-03 2019-11-05 Samumed, Llc 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof
WO2017023993A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
WO2017024015A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10231956B2 (en) 2015-08-03 2019-03-19 Samumed, Llc 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof
US10392383B2 (en) 2015-08-03 2019-08-27 Samumed, Llc 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10519169B2 (en) 2015-08-03 2019-12-31 Samumed, Llc 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof
WO2017023988A1 (en) 2015-08-03 2017-02-09 Samumed, Llc. 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof
US10383861B2 (en) 2015-08-03 2019-08-20 Sammumed, LLC 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof
WO2017024026A1 (en) 2015-08-03 2017-02-09 Samumed, Llc 3-(1h-indol-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof
WO2017079765A1 (en) 2015-11-06 2017-05-11 Samumed, Llc Treatment of osteoarthritis
HUE060797T2 (en) 2016-06-01 2023-04-28 Biosplice Therapeutics Inc Process for preparing n-(5-(3-(7-(3-fluorophenyl)-3h-imidazo[4,5-c]pyridin-2-yl)-1h-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide
CA3036340A1 (en) 2016-09-08 2018-03-15 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
AU2017324251A1 (en) 2016-09-08 2019-03-21 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
AR109595A1 (en) 2016-09-09 2018-12-26 Incyte Corp PIRAZOLOPIRIMIDINE COMPOUNDS AND USES OF THESE AS HPK1 INHIBITORS
US20180072718A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine compounds and uses thereof
AU2017322427B2 (en) 2016-09-09 2021-12-23 Incyte Corporation Pyrazolopyridine derivatives as HPK1 modulators and uses thereof for the treatment of cancer
EP3528808B1 (en) 2016-10-21 2021-10-06 BioSplice Therapeutics, Inc. Methods of using indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors
WO2018085865A1 (en) 2016-11-07 2018-05-11 Samumed, Llc Single-dose, ready-to-use injectable formulations
CA3043203A1 (en) 2016-11-18 2018-05-24 Merck Sharp & Dohme Corp. Indazole derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
CA3043206A1 (en) 2016-11-18 2018-05-24 Merck Sharp & Dohme Corp. Indole derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
US20180228786A1 (en) 2017-02-15 2018-08-16 Incyte Corporation Pyrazolopyridine compounds and uses thereof
AR111960A1 (en) 2017-05-26 2019-09-04 Incyte Corp CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
WO2019164847A1 (en) 2018-02-20 2019-08-29 Incyte Corporation Indazole compounds and uses thereof
PL3755703T3 (en) 2018-02-20 2022-11-07 Incyte Corporation N-(phenyl)-2-(phenyl)pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
BR112020022392A2 (en) 2018-05-04 2021-02-02 Incyte Corporation solid forms of a fgfr inhibitor and processes for preparing them
MA52493A (en) 2018-05-04 2021-03-10 Incyte Corp FGFR INHIBITOR SALTS
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
MA53726A (en) 2018-09-25 2022-05-11 Incyte Corp PYRAZOLO[4,3-D]PYRIMIDINE COMPOUNDS AS ALK2 AND/OR FGFR MODULATORS
WO2020132384A1 (en) 2018-12-21 2020-06-25 Celgene Corporation Thienopyridine inhibitors of ripk2
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
WO2020223267A1 (en) 2019-05-01 2020-11-05 Boehringer Ingelheim International Gmbh (r)-(2-methyloxiran-2-yl)methyl 4-bromobenzenesulfonate
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
CA3147918A1 (en) 2019-08-06 2021-02-11 Incyte Corporation Solid forms of an hpk1 inhibitor
CR20220169A (en) 2019-10-14 2022-10-27 Incyte Corp Bicyclic heterocycles as fgfr inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021113462A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Derivatives of an fgfr inhibitor
JP2023505258A (en) 2019-12-04 2023-02-08 インサイト・コーポレイション Tricyclic heterocycles as FGFR inhibitors
TW202208355A (en) 2020-05-04 2022-03-01 美商安進公司 Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use
IL297845A (en) 2020-05-04 2023-01-01 Amgen Inc Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
WO2021257857A1 (en) 2020-06-19 2021-12-23 Incyte Corporation Naphthyridinone compounds as jak2 v617f inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
BR112023000047A2 (en) 2020-07-02 2023-03-14 Incyte Corp TRICYCLIC UREA COMPOUNDS AS JAK2 V617F INHIBITORS
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors
WO2022261160A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
WO2023078252A1 (en) 2021-11-02 2023-05-11 Flare Therapeutics Inc. Pparg inverse agonists and uses thereof

Family Cites Families (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2516040C2 (en) 1974-06-10 1984-12-20 Dr. Karl Thomae Gmbh, 7950 Biberach Benzimidazoles, processes for their preparation and pharmaceuticals containing them
GB8305245D0 (en) * 1983-02-25 1983-03-30 Fujisawa Pharmaceutical Co Imidazo-heterocyclic compounds
IL68769A (en) 1983-05-23 1986-02-28 Hadassah Med Org Pharmaceutical compositions containing insulin for oral administration
US4849405A (en) 1984-05-09 1989-07-18 Synthetic Blood Corporation Oral insulin and a method of making the same
WO1985005029A1 (en) 1984-05-09 1985-11-21 Medaphore Inc. Oral insulin and a method of making the same
US4963526A (en) 1984-05-09 1990-10-16 Synthetic Blood Corporation Oral insulin and a method of making the same
DE3903993A1 (en) * 1989-02-10 1990-08-16 Basf Ag DIARYL SUBSTITUTED HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND MEDICINAL PRODUCTS THEREOF
JP2905982B2 (en) * 1989-05-02 1999-06-14 日本農薬株式会社 Heterocycle-containing phenylpyrazole derivatives or salts thereof, process for producing the same, and herbicides
US5642868A (en) 1990-05-02 1997-07-01 The United States Of America As Represented By The Secretary Of The Navy Ceramic material
IL99699A (en) 1990-10-10 2002-04-21 Autoimmune Inc Pharmaceutical oral, enteral or by-inhalation dosage form for suppressing an autoimmune response associated with type i diabetes
US6191105B1 (en) 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
US5843866A (en) 1994-12-30 1998-12-01 Hampshire Chemical Corp. Pesticidal compositions comprising solutions of polyurea and/or polyurethane
US5824638A (en) 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US6153632A (en) 1997-02-24 2000-11-28 Rieveley; Robert B. Method and composition for the treatment of diabetes
EP1932535A3 (en) 1998-07-31 2008-10-29 Novo Nordisk A/S Stimulation of beta cell profileration
US6294503B1 (en) * 1998-12-03 2001-09-25 Ishihara Sangyo Kaisha, Ltd. Fused heterocycle compounds, process for their preparation, and herbicidal compositions containing them
JP3853655B2 (en) * 1999-11-04 2006-12-06 バジリア ファルマスーチカ アーゲー Substituted 5-benzyl-2,4-diaminopyrimidine
FR2802817B1 (en) 1999-12-23 2002-10-11 Centre Nat Rech Scient NOVEL GLYCOSIDASE INHIBITORS AND THEIR PHARMACOLOGICAL APPLICATIONS, PARTICULARLY FOR TREATING DIABETES
MXPA01012317A (en) 2000-12-28 2002-07-22 Warner Lambert Co Diacylglycerol acyltransferase (dgat) assay.
JP4164645B2 (en) 2002-08-09 2008-10-15 株式会社大塚製薬工場 DGAT inhibitor
AU2003261935A1 (en) 2002-09-06 2004-03-29 Takeda Pharmaceutical Company Limited Furan or thiophene derivative and medicinal use thereof
WO2004047755A2 (en) 2002-11-22 2004-06-10 Japan Tobacco Inc. Fused bicyclic nitrogen-containing heterocycles
BR0317430A (en) 2002-12-20 2005-10-25 Pharmacia Corp Mitogen-activated protein kinase-activated protein kinase-2 inhibitor compounds
US20040185559A1 (en) 2003-03-21 2004-09-23 Isis Pharmaceuticals Inc. Modulation of diacylglycerol acyltransferase 1 expression
AR044152A1 (en) 2003-05-09 2005-08-24 Bayer Corp RENTAL DERIVATIVES, METHOD OF PREPARATION AND USE FOR THE TREATMENT OF OBESITY
GB0325192D0 (en) 2003-10-29 2003-12-03 Astrazeneca Ab Method of use
JP2007510706A (en) 2003-11-10 2007-04-26 メルク シャープ エンド ドーム リミテッド Substituted nitrogen-containing six-membered amino heterocycles as vanilloid-1 receptor antagonists for the treatment of pain
JP2007514759A (en) * 2003-12-19 2007-06-07 タケダ サン ディエゴ インコーポレイテッド Kinase inhibitor
US20050245531A1 (en) * 2003-12-22 2005-11-03 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
KR20070007938A (en) 2004-04-21 2007-01-16 마츠시타 덴끼 산교 가부시키가이샤 Recording device, recording medium, and content protection system
JP2008500383A (en) * 2004-05-21 2008-01-10 ファイザー・プロダクツ・インク Tetrahydronaphthylpiperazines as 5-HT1B antagonists, inverse agonists and partial agonists
JP2008508314A (en) * 2004-07-28 2008-03-21 アイアールエム・リミテッド・ライアビリティ・カンパニー Compounds and compositions as modulators of steroid hormone nuclear receptors
CN102643203A (en) * 2005-01-05 2012-08-22 出光兴产株式会社 Aromatic amine derivative and organic electroluminescent element using same
US8501739B2 (en) 2005-07-04 2013-08-06 High Point Pharmaceuticals, Llc Medicaments
ES2522290T3 (en) * 2006-02-10 2014-11-14 Summit Corporation Plc Duchenne muscular dystrophy treatment
MX2008010671A (en) * 2006-02-21 2008-10-01 Amgen Inc Cinnoline derivatives as phosphodiesterase 10 inhibitors.
EP2402318A1 (en) 2006-03-31 2012-01-04 Novartis AG DGAT inhibitors
JP5420398B2 (en) * 2006-05-19 2014-02-19 アッヴィ・バハマズ・リミテッド CNS active fused bicycloheterocyclic substituted azabicyclic alkane derivatives
EP2035436B1 (en) * 2006-06-26 2011-05-25 UCB Pharma S.A. Fused thiazole derivatives as kinase inhibitors
CA2657200A1 (en) * 2006-07-28 2008-01-31 Novartis Ag 2,4-substituted quinazolines as lipid kinase inhibitors
PE20080888A1 (en) * 2006-10-18 2008-08-26 Novartis Ag HETEROCYCLIC COMPOUNDS AS ACIL-TRANSFERASE INHIBITORS OF ACIL-CoA-DIACIL-GLYCEROL 1 (DGAT1)
CA2670736A1 (en) 2006-11-29 2008-06-05 Abbott Laboratories Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme
WO2009011285A1 (en) 2007-07-13 2009-01-22 Taisho Pharmaceutical Co., Ltd. Heteroarylbenzene compounds
US7674312B2 (en) 2007-09-12 2010-03-09 Bryan Dale Evans Liquid fertilizing compositions
AR066169A1 (en) * 2007-09-28 2009-07-29 Novartis Ag DERIVATIVES OF BENZO-IMIDAZOLES, USEFUL FOR DISORDERS ASSOCIATED WITH THE ACTIVITY OF DGAT
JP2010111624A (en) * 2008-11-06 2010-05-20 Shionogi & Co Ltd Indazole derivative having ttk inhibitory action
PE20190551A1 (en) 2016-09-23 2019-04-16 Joy Global Underground Mining Llc ROCK CUTTING DEVICE
CN111448448A (en) 2017-12-11 2020-07-24 马尔文帕纳科 Determination of particle size distribution by size exclusion chromatography
CN109949347B (en) 2019-03-15 2021-09-17 百度在线网络技术（北京）有限公司 Human body tracking method, device, system, electronic equipment and storage medium
US11150645B2 (en) 2019-07-22 2021-10-19 Caterpillar Inc. Localization system for underground mining applications
JP7174266B2 (en) 2020-06-30 2022-11-17 日亜化学工業株式会社 light emitting device
US11599508B1 (en) 2022-01-31 2023-03-07 Qumulo, Inc. Integrating distributed file systems with object stores

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10351568B2 (en) 2010-01-28 2019-07-16 President And Fellows Of Harvard College Compositions and methods for enhancing proteasome activity
US10532996B2 (en) 2011-05-12 2020-01-14 Proteostasis Therapeutics, Inc. Proteostasis regulators
US9556166B2 (en) 2011-05-12 2017-01-31 Proteostasis Therapeutics, Inc. Proteostasis regulators
US9849135B2 (en) 2013-01-25 2017-12-26 President And Fellows Of Harvard College USP14 inhibitors for treating or preventing viral infections
US9850262B2 (en) 2013-11-12 2017-12-26 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US11958873B2 (en) 2013-11-12 2024-04-16 Kineta, Inc. Proteasome activity enhancing compounds
US11242361B2 (en) 2013-11-12 2022-02-08 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9877957B2 (en) 2014-09-05 2018-01-30 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2
WO2016036636A1 (en) * 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
US10568876B2 (en) 2014-09-05 2020-02-25 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2
US9828369B2 (en) 2014-09-05 2017-11-28 Merck Sharpe & Dohme Corp. Isoquinoline derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2
WO2016036638A1 (en) * 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Isoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
WO2016036633A1 (en) * 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
WO2021072198A1 (en) * 2019-10-09 2021-04-15 Biocryst Pharmaceuticals, Inc. Oral complement factor d inhibitors

Also Published As

Publication number Publication date
AU2010226829A1 (en) 2011-09-15
JP2012520886A (en) 2012-09-10
CA2755251A1 (en) 2010-09-23
TW201043607A (en) 2010-12-16
AR075858A1 (en) 2011-05-04
WO2010107765A1 (en) 2010-09-23
US8637507B2 (en) 2014-01-28
CA2755253A1 (en) 2010-09-23
EP2408766A1 (en) 2012-01-25
AU2010226826A1 (en) 2011-10-13
JP2012520887A (en) 2012-09-10
US20110319403A1 (en) 2011-12-29
WO2010107768A1 (en) 2010-09-23
TW201100408A (en) 2011-01-01
AR076126A1 (en) 2011-05-18
EP2408744A1 (en) 2012-01-25

Similar Documents

Publication Publication Date Title
US20120022057A1 (en) Bicyclic compounds as inhibitors of diacyglycerol acyltransferase
US20120172369A1 (en) Inhibitors of diacylglycerol acyltransferase
US8716312B2 (en) Inhibitors of diacylglycerol acyltransferase
US8759357B2 (en) Inhibitors of fatty acid binding protein (FABP)
US20110224136A1 (en) Inhibitors of diacylglycerol acyltransferase
US20110207734A1 (en) Azine Derivatives and Methods of Use Thereof
US20110136790A1 (en) Tricyclic Heterocyclic Derivatives and Methods of Use
US20120225885A1 (en) Imidazole derivatives and methods of use thereof
US20110224193A1 (en) Inhibitors of diacylglycerol acyltransferase
US20110130385A1 (en) Bicyclic Heterocylic Derivatives and Methods of Use
US8889683B2 (en) Substituted quinoxalines as inhibitors of fatty acid binding protein

Legal Events

Date Code Title Description
AS Assignment

Owner name: SCHERING CORPORATION, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ZHOU, GANG;TING, PAULINE C.;ASLANIAN, ROBERT G.;AND OTHERS;SIGNING DATES FROM 20110919 TO 20110923;REEL/FRAME:027029/0332

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION