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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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  • 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
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  • 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
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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

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