WO2008011131A2 - Amide compounds - Google Patents

Amide compounds Download PDF

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Publication number
WO2008011131A2
WO2008011131A2 PCT/US2007/016425 US2007016425W WO2008011131A2 WO 2008011131 A2 WO2008011131 A2 WO 2008011131A2 US 2007016425 W US2007016425 W US 2007016425W WO 2008011131 A2 WO2008011131 A2 WO 2008011131A2
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Prior art keywords
group
optionally substituted
ring
aromatic
compound
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PCT/US2007/016425
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WO2008011131A3 (en
Inventor
Shuji Kitamura
Thomas Daniel Aicher
Steve Gonzales
Yvan Le Huerou
Scott Alan Pratt
Tim Turner
Yoshihisa Nakada
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Priority to EP07810632A priority Critical patent/EP2044055A4/en
Priority to US12/309,493 priority patent/US20090286791A1/en
Priority to JP2009520851A priority patent/JP2009544616A/en
Publication of WO2008011131A2 publication Critical patent/WO2008011131A2/en
Publication of WO2008011131A3 publication Critical patent/WO2008011131A3/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel amide compound having a diacylglycerol acyl transferase (hereinafter sometimes to be abbreviated as DGAT in the present specification) inhibitory activity, which is useful for the treatment of obesity, hyperlipidemia, diabetes and the like.
  • DGAT diacylglycerol acyl transferase
  • Obesity is a state of excess accumulation of fat, mainly triglyceride, in the body, and is deeply " involved in the progression into the pathology such as arteriosclerosis, diabetes, hypertension and the like. Therefore, the development of a drug for the prophylaxis or treatment thereof has been desired.
  • two major triglyceride synthesis pathways have been biochemically clarified.
  • One is the glycelophosphoric acid pathway present in all tissues, and the other pathway is a monoglyceride pathway.
  • fatty acid in the cell is converted to acyl coenzyme A by an acyl coenzyme A synthetase and introduced into triglyceride through the both pathways.
  • DGAT As the enzyme involved in the final stage of the intracellular or intraorgan triglyceride synthesis process, DGAT has been known. As DGAT, DGATl and DGAT2 have been cloned. DGATl knockout mice have been created and analyzed. As a result, the mice did not become obese easily with high fat diet and showed promoted energy consumption and insulin sensitivity, as compared to wild-type mice. In a mating test of DGATl knockout mice and Ay/a mice, moreover, body weight gain was suppressed with a normal diet and a phenotype of promoted insulin sensitivity and elimination of leptin resistance was shown. Thus, DGATl inhibitors are expected to be antiobesity drugs.
  • DGAT is an enzyme (EC2.3.1.20) also designated as acyl coenzyme A: diacylglycerol acyl transferase.
  • cDNA cloning of DGATl is reported in Proc. Natl. Acad. Sci. USA. 95, 13018- 13023, 1998, and cDNA cloning of DGAT2 is reported in The Journal of Biological Chemistry, 276, 42, 38862-38869, 2001 and The Journal of Biological Chemistry, 276, 42, 38870-38876, 2001. Since the enzyme molecule of DGAT was not clarified for a long time, there is not much finding relating to the DGAT activity.
  • DGAT activity is detected in the endoplasmic reticulum membrane fraction, it was considered to be an endoplasmic reticulum membrane protein.
  • cDNA cloning of DGAT was reported, the properties thereof have been rapidly elucidated. For example, it has been reported to be a protein forming a tetramer in Biochem. Journal, 359, 707-714, 2001.
  • a knockout mouse of DGATl was created and its phenotype was reported in Nature Genetics, 25, 87-90, 2000, The Journal of Clinical
  • DGAT2 knockout mice were also created and their phenotype is reported in The Journal of Biological Chemistry, 279, 11767-11776 (2004) .
  • DGAT2 was clarified to be an enzyme that plays a key role in the synthesis of triglyceride in the liver.
  • DGAT expression is promoted in various pathologies and diseases such as obesity, diabetes, insulin- resistant diabetes, leptin resistance, arteriosclerosis, hypertriglyceridemia, hypercholesterolemia, arteriosclerosis, hypertension and the like
  • high expression or hyper activation of DGAT is suggested to be involved in the excess accumulation of triglyceride in the cell, tissue or organ, and closely involved in the onset and aggravation of these diseases .
  • DGAT is regulated by hormones such as insulin, leptin and the like, and DGAT is suggested to be deeply involved in the pathologies such as insulin resistance, leptin resistance and the like.
  • a compound having a DGAT inhibitory activity is effective for the treatment of obesity, insulin resistant diabetes, hyperorexia or obesity based on leptin resistance.
  • Y represents a group (CH 2 J n / wherein n represents 0, 1 or
  • R 1 is phenyl, naphthyl, a mono or bicyclic heteroaryl group; or a group NR 3 R 4 , wherein one of R 3 and R 4 is hydrogen or optionally substituted (Ci-. ⁇ j)alkyl and the other is phenyl, naphthyl or a mono or bicyclic heteroaryl group, or R 3 and R 4 together with the N atom to which they are attached form a 5 to 7-membered cyclic amine which has an optionally fused, phenyl ring; any of which R 1 groups may be optionally substituted;
  • R 2 represents phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is substituted by R 5 , and further optional substituents; or R 2 represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group;
  • R 5 represents an optionally substituted Ci- 4 alkoxy, halo, optionally substituted Ci_ 6 alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring.
  • R la and R lb is a methyl, hydroxymethyl or monohalomethyl group and the other is hydrogen;
  • X 1 is a methylene, oxy or thio linkage; m is 0 or 1;
  • RA 2 is a hydrogen, halogen or methyl group
  • RA 3 is a halogen or halomethyl group
  • R 4 is an ⁇ -halo- or ⁇ / ⁇ dihalo- (C1-3) alkyl group or a group having the formula -(X 2 J n -R 5 , where X 2 is a methylene, oxy or thio linkage, n is 0 or 1, and R 5 is an optionally substituted 5- or 6-member aromatic or heterocyclic ring.
  • X is ' S or 0;
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl-, or the like;
  • R 3 and R 4 are each independently H, alkyl, hydroxyalkyl or -C(O)-O-alkyl;
  • R 5 and R 6 are each independently H, alkyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, or the like;
  • R 7 is H, alkyl, alkenyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, (R 17 -phenyl) alkyl or -CH ⁇ -C (O) -O-alkyl; and R 8 is alkyl, heteroaryl, phenyl, cycloalkyl, or heterocycloalkyl, all optionally substituted, of a cycloalkyl- or heterocycloalkyl- substituted amide; or R 7 and R 8 and the nitrogen to which they are attached together form an optionally substituted ring;
  • R 9 is H, halo, alkyl, cycloalkyl, or the like;
  • R 10 , R 11 , and R 13 are each independently H or halo; R 17 is 1 to 3 substituents independently selected from the group consisting of H, halo, cycloalkyl, and the like.
  • R is hydrogen, - (CH 2 ) n -phenyl optionally substituted, - (CH 2 ) n -pyridinyl optionally substituted, - (CH2) n -C3-6-cycloalkyl optionally substituted, - (CH 2 ) n ⁇ N (R 1 ) -C 3 _6-cycloalkyl optionally ' substituted, - (CH 2 ) n -benzo [1, 3]-dioxolyl, - (CR' 2 ) n -thiophenyl optionally substituted, - (CR' 2 ) n -thiazolyl optionally substituted, - (CH 2 ) H -C (0) -thiophenyl optionally substituted, - (CH 2 ) n -furany1 optionally substituted, - (CH 2 ) n -C (O) - (CH 2 ) n - thiophenyl, - (CHR
  • the present inventors have searched for a compound having a DGAT inhibitory activity, and found that the compounds represented by the below-mentioned formulas (Ia) , (Ib) , (Ic) and (Id) have a superior DGAT inhibitory activity, and are superior in the properties as a pharmaceutical product, such as stability and the like, which resulted in the completion of the present invention.
  • ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted;
  • Ra 1 is a hydrogen atom or a substituent;
  • ring Aa is an optionally substituted aromatic heterocycle;
  • Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 and Ra 7 are each independently a hydrogen atom or a substituent; provided that
  • ring Aa is not the same as ring Ba; or a salt thereof (hereinafter to be abbreviated as compound (Ia));
  • ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted;
  • Ra 1 is a hydrogen atom or a substituent
  • ring Aa is an optionally substituted aromatic heterocycle
  • Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 and Ra 7 are each independently a hydrogen atom or a substituent
  • ring Ba is not oxadiazole which is optionally further substituted; 2) when ring Ba is pyrazole which is optionally further substituted, then ring Ba does not have optionally substituted tetrahydrofurylmethoxy as a substituent other than Ra 1 ;
  • ring Aa is not the same as ring Ba; ' or a salt thereof;
  • ring Bb is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted;
  • ring Cb is an optionally substituted aromatic heterocycle;
  • ring Ab is an optionally substituted aromatic hydrocarbon; provided that when ring Bb is pyrazole which is optionally further substituted, then ring Cb is not optionally substituted quinoline; or a salt thereof (hereinafter to be abbreviated as compound
  • ring Bc is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted;
  • ring Cc is an optionally substituted aromatic ring;
  • ring Ac is an optionally substituted aromatic hydrocarbon;
  • Rc 2 , Rc 3 , Rc", Rc 5 , Rc 6 and Rc 7 are each independently a hydrogen atom or a substituent, or any two of Rc 2 , Rc 3 , Rc 4 , Rc 5 , Rc 6 and Rc 7 are optionally bonded to each other to form a non-aromatic ring; provided that
  • ring Bc is not pyrazol-5-yl and 2H-1, 2, 3-triazol-4- yl, each of which is optionally further substituted;
  • ring Cc is not optionally substituted quinoline
  • Rc 2 and Rc 3 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc 2 or Rc 3 is bonded to Rc 4 or Rc 5 to form a non-aromatic ring, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle;
  • Rc 4 and Rc 5 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc 4 or Rc 5 is bonded to Rc 2 or Rc 3 to form a non-aromatic ring, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle;
  • ring Bd is an aromatic heterocycle which is optionally further substituted;
  • ring Cd is an optionally substituted aromatic ring;
  • ring Ad is an optionally substituted aromatic hydrocarbon;
  • ring Bd is not pyrazol-4-yl and pyrrol-3-yl, each of which is optionally further substituted;
  • ring Cd is not optionally substituted quinoline; 3) when ring Bd is pyridine or quinoline, each of which is optionally further substituted, then ring Bd has substituent (s) besides ring Cd; and
  • ring Bd is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted, then ring Bd does not have an optionally substituted aromatic heterocyclic group as a substituent other than ring Cd and ring Cd is an optionally substituted aromatic hydrocarbon; or a salt thereof (hereinafter to be abbreviated as compound (Id));
  • ring Ad is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom;
  • a method for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes in a mammal which comprises administering the compound of above-mentioned [1], [6], [10] or [18], or a prodrug thereof to the mammal;
  • a method of inhibiting DGAT in a mammal which comprises administering the compound of above-mentioned [1], [6], [10] or [18], or a prodrug thereof to the mammal; and the like.
  • the compound (Ia), compound (Ib), compound (Ic) and compound (Id) (these are also collectively referred to as the compound of the present invention in this specification) have a DGAT inhibitory activity and are useful for the prophylaxis, treatment or amelioration of diseases or pathologies caused by high expression or high activation of DGAT (sometimes to be abbreviated as DGAT-related diseases in this specification) .
  • DGAT-related diseases sometimes to be abbreviated as DGAT-related diseases in this specification.
  • halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.
  • the "Ci_ 3 alkylenedioxy group” means methylenedioxy, ethylenedioxy, trimethylenedioxy or the like.
  • the "Ci-6 alkyl group” means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl or the like.
  • Ci-6 alkoxy group means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or the like.
  • the ⁇ Ci-6 alkoxy-carbonyl group means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl or the like.
  • the "Ci-6 alkyl-carbonyl group” means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl or the like.
  • Ra 1 , Ra 2 , Ra 3 , Ra", Ra 5 , Ra 6 and Ra 7 are each independently a hydrogen atom or a substituent.
  • hydrocarbon group of the aforementioned “optionally substituted hydrocarbon group”
  • a Ci-io alkyl group for example, a Ci-io alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-10 cycloalkyl group, a C3- 10 cycloalkenyl group, a C4-10 cycloalkadienyl group, a C 6 - I4 aryl group, a C 7 -J -3 aralkyl group, a C 8 -i3 arylalkenyl group, a C 3 - 10 cycloalkyl-Ci- 6 alkyl group and the like can be mentioned.
  • Ci_i 0 alkyl group for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3,3- dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like can be mentioned.
  • C 2 - 1 0 alkenyl group for example, ethenyl, 1- propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1- hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned.
  • C 2 - 1 0 alkynyl group for example, ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1- octynyl and the like can be mentioned.
  • C 3 - 10 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • C3-1 0 cycloalkenyl group for example, 2- cyclopenten-1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl, 3- cyclohexen-1-yl and the like can be mentioned.
  • C 4 -. 10 cycloalkadienyl group for example, 2,4- cyclopentadien-1-yl, 2, 4-cyclohexadien-l-yl, 2,5- cyclohexadien-1-yl and the like can be mentioned.
  • C3-10 cycloalkyl group, C3-10 cycloalkenyl group and CVio cycloalkadienyl group are each optionally condensed with a benzene ring, and as such a fused ring group, for example, indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • the above-mentioned C3-10 cycloalkyl group, C3-10 cycloalkenyl group and C4-10 cycloalkadienyl group each may be a C7-10 crosslinked hydrocarbon group.
  • the C 7 -Io crosslinked 'hydrocarbon group bicyclo [2.2.1] heptyl (norbornyl) , bicyclo[2.2.2]octyl, bicyclo [3.2. l]octyl, bicyclo [3.2.2]nonyl, bicyclo [3.3.1InOHyI, bicyclo [4.2. l]nonyl, bicyclo [4.3.1] decyl, adamantyl and the like can be mentioned.
  • C3-10 cycloalkyl group, C3- ⁇ o cycloalkenyl group and C 4 - I0 cycloalkadienyl group each optionally form, together with a C3-10 cycloalkane, a C3-10 cycloalkene or a C4-10 cycloalkadiene, a spiro ring group.
  • C 3 -I 0 cycloalkane, C3-10 cycloalkene and C4-10 cycloalkadiene rings corresponding to the above-mentioned C 3 - I0 cycloalkyl group, C3-10 cycloalkenyl group and C 4 _io cycloalkadienyl group can be mentioned.
  • a spiro ring group spiro [4 ,5]decan-8-yl and the like can be mentioned.
  • C ⁇ -14 aryl group for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like can be mentioned.
  • C 7 -I 3 aralkyl group for example, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like can be mentioned.
  • C 8 -I 3 arylalkenyl group for example, styryl and the like can be mentioned.
  • C 3 -I 0 cycloalkyl-Ci-6 alkyl group for example, cyclohexylmethyl and the like can be mentioned.
  • substituents for example, (1) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclohexyl) ; (2) a C ⁇ - 14 aryl group (e.g., phenyl, naphthyl) optionally substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • a hydroxy group a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • a cyano group (e) a cyano group; (3) an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, pyrazolyl, . imidazolyl, tetrazolyl, oxazolyl, thiazolyl / oxadiazolyl/ thiadiazolyl, benzothiazolyl, pyrazinyl, quinolyl, indolyl/ pyrimidinyl, triazolyl, isoxazolyl) optionally substituted by 1 to 3 substituents selected from
  • Ci- 6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom,
  • Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci- 6 alkylsulfonyl group e.g., methylsulfonyl
  • a C 7 _i 3 aralkyl group e.g., benzyl
  • a C3-.10 cycloalkyl group e.g., cyclopropyl
  • an aromatic heterocyclic group e.g., pyridyl, thienyl, pyrimidinyl
  • a non-aromatic heterocyclic group e.g., tetrahydropyranyl
  • a non-aromatic heterocyclic group e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1, 3-dihydro-2-benzofuranyl, thiazolidinyl, tetrahydropyranyl, dihydrooxadiazolyl
  • 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • an amino group optionally mono- or di-substituted by Ci_6 alkyl group (s) optionally substituted by 1 to 3 halogen atoms
  • Ci_6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms
  • a C 6 -i4 aryl-carbonyl group e.g., benzoyl
  • a C 6 -i4 aryl-carbonyl group e.g., benzoyl
  • Ci- ⁇ alkyl groups optionally substituted by 1 to 3 halogen atoms
  • a C-7- 1 3 aralkyl-carbonyl group e.g., benzylcarbonyl
  • aralkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms
  • a C 3 - I0 cycloalkyl-carbonyl group e.g., cyclopropylcarbonyl, cyclohexylcarbonyl
  • a C 3 - I0 cycloalkyl-carbonyl group e.g., cyclopropylcarbonyl, cyclohexylcarbonyl
  • an aromatic heterocyclylcarbonyl group e.g., pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl
  • Ci- 6 alkyl groups optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclylcarbonyl group e.g., tetrahydrofurylcarbonyl, tetrahydrothiopyranylcarbonyl
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • a C 3 - 1 0 cycloalkyl group e.g., cyclopropyl
  • a C 3 - 1 0 cycloalkyl group e.g., cyclopropyl
  • 1 to 3 halogen atoms
  • a C ⁇ - 1 4 aryl group e.g., phenyl
  • Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms
  • an aromatic heterocyclic group e.g., pyrazolyl, pyrazinyl, isoxazolyl, pyridyl
  • an aromatic heterocyclic group e.g., pyrazolyl, pyrazinyl, isoxazolyl, pyridyl
  • Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms
  • Ci_ 6 alkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, and (b) a Ci-6 alkoxy group;
  • a .Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl
  • a C3-10 cycloalkylsulfonyl group e.g. / cyclopropylsulfonyl
  • Ci_ 6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • an aromatic heterocyclylsulfonyl group e.g., imidazolylsulfonyl, pyridylsulfonyl
  • an aromatic heterocyclylsulfonyl group e.g., imidazolylsulfonyl, pyridylsulfonyl
  • Ci_6 alkyl groups optionally substituted by 1 to 3 Ci_6 alkyl groups
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom,
  • an aromatic heterocyclic group e.g., pyridyl, furyl
  • a Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • an aromatic heterocyclic group e.g., pyridyl, thiadiazolyl, oxadiazolyl
  • Ci-e alkyl groups optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclic group e.g., 1,1- dioxidotetrahydrothienyl
  • a thiocarbamoyl group optionally mono- or di-substituted by Ci-e alkyl group (s) optionally substituted by 1 to 3 halogen atoms;
  • a sulfamoyl group optionally mono- or di-substituted by Q t _6 alkyl group (s) optionally substituted by 1 to 3 halogen atoms; .
  • Ci_6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • an aromatic heterocyclic group e.g., ii ⁇ idazolyl
  • Ci_6 alkyl groups optionally substituted by 1 to 3 Ci_6 alkyl groups
  • a non-aromatic heterocyclic group e.g., morpholinyl
  • a C3-10 cycloalkyloxy group e.g., cyclohexyloxy, cyclopentyloxy
  • (21) a C7-13 aralkyloxy group (e.g., benzyloxy) ;
  • (22) a C6- 1 4 aryloxy group (e.g., phenyloxy, naphthyloxy) ;
  • non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • Ci_6 alkyl-carbonyloxy group e.g., acetyloxy, tert- butylcarbonyloxy
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclylcarbonyl group e.g., pyrrolidinylcarbonyl, morpholinylcarbonyl, 1,1- dioxidothiomorpholinylcarbonyl
  • substituents selected from
  • Ci- 6 alkylthio group e.g., methylthio, ethylthio
  • a C7- 1 3 aralkylthio group e.g., benzylthio
  • a C ⁇ - 1 4 arylthio group e.g., phenylthio, naphthylthio
  • Ci- 6 alkylsulfinyl group e.g., methylsulfinyl
  • Ci- 3 alkylenedioxy group (40) an aromatic heterocyclylcarbonyl group (e.g.,- pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl) optionally substituted by 1 to 3 Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms; (41) a hydroxyimino group; and the like can be mentioned.
  • aromatic heterocyclylcarbonyl group e.g.,- pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl
  • Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl-carbonyloxy group e.g., acetyloxy
  • a non-aromatic heterocyclic group e.g., morpholinyl, pyrrolidinyl
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • heterocyclic group of the aforementioned “optionally substituted heterocyclic group”, an aromatic heterocyclic group and a non-aromatic heterocyclic group can be mentioned.
  • aromatic heterocyclic group for example, a 5- to 7-membered monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused aromatic heterocyclic group can be mentioned.
  • fused aromatic heterocyclic group for example, a group derived from a fused ring wherein a ring constituting such 5- to 7- membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6- membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are condensed, and the like can be mentioned.
  • a 5- or 6- membered aromatic heterocycle containing 1 or 2 nitrogen atoms e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle containing one sulfur atom e.g., thiophene
  • a benzene ring
  • aromatic heterocyclic group monocyclic aromatic heterocyclic groups such as furyl (e.g., 2-furyl, 3-furyl) , thienyl (e.g., 2-thienyl, 3-thienyl) , pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl) , pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl) , pyrazinyl (e.g., 2-pyrazinyl) , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imi
  • furyl e
  • heteroaryl group has the same meaning as the aromatic heterocyclic group described above .
  • non-aromatic heterocyclic group for example, a 5- to 7-membered monocyclic non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused non-aromatic heterocyclic group can be mentioned.
  • the fused non-aromatic heterocyclic group for example, a group derived from a fused ring wherein a ring constituting such 5- to 7- membered monocyclic non- aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic or non-aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are condensed, a group obtained by partial saturation of said group, and the like can be mentioned.
  • a 5- or 6-membered aromatic or non-aromatic heterocycle containing 1 or 2 nitrogen atoms e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • non-aromatic heterocyclic group tetrahydrofuryl (e.g., 2-tetrahydrofuryl) , pyrrolidinyl (e.g., 1-pyrrolidinyl) , 1, 1-dioxidotetrahydrothienyl (e.g., 1, l-dioxidotetrahydro-3-thienyl) , piperidinyl (e.g., piperidino) , morpholinyl (e.g., morpholino) , thiomorpholinyl (e.g., thiomorpholino) , 1, 1-dioxidothiomorpholinyl (e.g., 1,1- dioxidothiomorpholino) , piperazinyl (e.g., 1-piperazinyl) , hexamethyleneiminyl (e.g., hexamethyleneimin-1-yl) , oxazolidinyl (
  • non-aromatic heterocyclic group may be a heterospiro ring group.
  • the 5- to 7-membered monocyclic non-aromatic heterocyclic group and the fused non- aromatic heterocyclic group optionally form, together with a C3-10 cycloalkane, a C3-10 cycloalkene, a C4-10 cycloalkadiene or a non-aromatic heterocycle, a spiro ring group.
  • C 3 - 10 cycloalkane, C3-10 cycloalkene and C 4 -Io cycloalkadiene rings corresponding to the C3-10 cycloalkyl group, C3-10 cycloalkenyl group and C4-10 cycloalkadienyl group, which are exemplarily recited as the "hydrocarbon group" of the above-mentioned "optionally substituted hydrocarbon group", can be mentioned.
  • the non-aromatic heterocycle a ring corresponding to the above-mentioned non-aromatic heterocyclic group can be mentioned.
  • a spiro ring group 2,8- diazaspiro[4.5]decan-8-yl and the like can be mentioned.
  • the above-mentioned non-aromatic heterocyclic group may be a crosslinked non-aromatic heterocyclic group.
  • As the crosslinked non-aromatic heterocyclic group 2,5- diazabicyclo[2.2.1]heptan-2-yl and the like can be mentioned.
  • the "heterocyclic group" of the aforementioned “optionally substituted heterocyclic group” optionally has 1 to 3 substituents at substitutable position (s).
  • substituents for example, those exemplarily recited as the substituents of the C3-.10 cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned “optionally substituted hydrocarbon group” can be mentioned.
  • Ci-io alkyl group C2-10 alkenyl group, C3-10 cycloalkyl group, C3-10 cycloalkenyl group, C ⁇ -n aryl group, C7-13 aralkyl group and C ⁇ -i3 arylalkenyl group
  • those exemplarily recited as the "hydrocarbon group” of the aforementioned “optionally substituted hydrocarbon group” can be mentioned.
  • the heterocyclic group the "aromatic heterocyclic group” and “non-aromatic heterocyclic group”, which are exemplarily recited as ' the "heterocyclic group” of the aforementioned “optionally substituted heterocyclic group”, can be mentioned.
  • Ci-10 alkyl group C 2 - 1 0 alkenyl group, C 3 -Io cycloalkyl group, C3-10 cycloalkenyl group, C ⁇ -i4 aryl group, C7-.13 aralkyl group, Cg-13 arylalkenyl group, Ci- ⁇ alkyl-carbonyl group and heterocyclic group each optionally have 1 to 5 (preferably 1 to 3) substituents at substitutable position (s).
  • substituents of the C3-10 cycloalkyl group C 3 - I0 cycloalkenyl group, C ⁇ -n aryl group, C7-13 aralkyl group, C ⁇ -i3 arylalkenyl group and heterocyclic group, those exemplarily recited as the substituents of the C3_io cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group” can be mentioned.
  • a mercapto group for example, a mercapto group optionally substituted by a substituent selected from a Ci-io alkyl group, a C2-10 alkenyl group, a C 3 _io cycloalkyl group, a C 3 - I0 cycloalkenyl group, a C ⁇ -u aryl group, a C-7- ⁇ 3 aralkyl group, a C 8 _ 13 arylalkenyl group, a Ci- ⁇ alkyl-carbonyl group, a heterocyclic group and the like, each of which is optionally substituted, can be mentioned.
  • substituents those exemplarily recited as the substituents of the aforementioned "optionally substituted hydroxy group" can be mentioned.
  • Ci_io alkyl group C2-10 alkenyl group, C 3 -Io cycloalkyl group, C 3 -Io cycloalkenyl group, Ce-xi aryl group, C7-13 aralkyl group and Ce-I 3 arylalkenyl group
  • those exemplarily recited as the "hydrocarbon group” of the aforementioned “optionally substituted hydrocarbon group” can be mentioned.
  • the heterocyclic group the "aromatic heterocyclic group” and “non-aromatic heterocyclic group”, which are exemplarily recited as the "heterocyclic group” of the aforementioned “optionally substituted heterocyclic group”, can be mentioned. Of these, a 5- to 7-membered monocyclic aromatic heterocyclic group is preferable.
  • C ⁇ -10 alkyl group, C 2 - 10 alkenyl group, C 3 -I 0 cycloalkyl group, C3-10 cycloalkenyl group, C 6 - X t aryl group, C7-i 3 aralkyl group, Ce-I 3 arylalkenyl group and heterocyclic group each optionally have 1 to 3 substituents at substitutable position (s) .
  • substituents of the C3-10 cycloalkyl group C3-10 cycloalkenyl group, C ⁇ -u aryl group, C7-13 aralkyl group, Cs-i3 arylalkenyl group and heterocyclic group, those exemplarily recited as the substituents of the C 3 _ ⁇ o cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group” can be mentioned.
  • acyl group which is exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 , for example, a group represented by the formula: -COR a , -CO-OR a , - SO 3 R a , -SO 2 R 3 , -SOR a , -CO-NR 3 ' R b ', -CS-NR 3 ' R b ' or -SO 2 NR 3 ' R b ' wherein R a is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R a/ and R b ' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R a ' and R b ' optionally form, together with the adjacent nitrogen atom, an optionally substituted nitrogen-containing hetero
  • nitrogen-containing heterocycle of the "optionally substituted nitrogen-containing heterocycle” formed by R a ' and R b ' together with the adjacent nitrogen atom
  • a 5- to 7-membered nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and optionally further containing one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like can be mentioned.
  • the nitrogen-containing heterocycle optionally has 1 to 3 (preferably 1 or 2) substituents at substitutable position(s).
  • substituents those exemplarily recited as the substituents of the C 3 - 10 cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group” can be mentioned.
  • Ci-6 alkoxy-carbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl ) optionally substituted by 1 to 3 substituents selected from (a) a halogen atom,
  • a C3- 10 cycloalkyl-carbonyl group e.g./ cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl
  • a C3- 10 cycloalkyl-carbonyl group e.g./ cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl
  • a C3- 10 cycloalkyl-oxycarbonyl group e.g., cyclopentyloxycarbonyl
  • a C 6 -i 4 aryl-carbonyl group e.g., benzoyl, 1-naphthoyl, 2- naphthoyl
  • a C 6 -i 4 aryl-carbonyl group e.g., benzoyl, 1-naphthoyl, 2- naphthoyl
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups (e.g., oxooxadiazolinyl) , and (i) a carbamoyl group;
  • a C7- 13 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • substituents selected from (a) a carboxy group
  • Ci_ 6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • a halogen atom (i) a halogen atom, (ii) an aromatic heterocyclic group (e.g., pyridyl, furyl) optionally substituted by 1 to 3 Ci_6 alkyl groups, and (iii) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) ,
  • an aromatic heterocyclic group e.g., pyridyl, furyl
  • a Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • a C7- 1 3 aralkyl group e.g., benzyl
  • an aromatic heterocyclic group e.g., pyridyl, thiadiazolyl, oxadiazolyl
  • Ci-e alkyl groups optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclic group e.g., 1,1- dioxidotetrahydrothienyl
  • a C ⁇ _6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl
  • substituents selected from
  • a C 3 - I0 cycloalkylsulfonyl group e.g., cyclopropylsulfonyl
  • a C ⁇ - 14 arylsulfonyl group e.g., benzenesulfonyl
  • Ci-s alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms
  • an aromatic heterocyclylsulfonyl group e.g., thienylsulfonyl, ir ⁇ idazolylsulfonyl, pyridylsulfonyl
  • an aromatic heterocyclylsulfonyl group e.g., thienylsulfonyl, ir ⁇ idazolylsulfonyl, pyridylsulfonyl
  • a sulfamoyl group (15) a sulfamoyl group; (16) a Ci- 6 alkylsulfinyl group (e.g., methylsulfinyl) ;
  • a C7- 13 aralkyl-carbonyl group e.g., benzylcarbonyl, phenethylcarbonyl
  • an aromatic heterocyclylcarbonyl group e.g., furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurylcarbonyl, benzothienylcarbonyl, quinoxalinylcarbonyl, imidazolylcarbonyl
  • substituents selected from
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclylcarbonyl group e.g., tetrahydrofurylcarbonyl, tetrahydrothiopyranylcarbonyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, 1,1- dioxidothiomorpholinylcarbonyl
  • a non-aromatic heterocyclylcarbonyl group e.g., tetrahydrofurylcarbonyl, tetrahydrothiopyranylcarbonyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, 1,1- dioxidothiomorpholinylcarbonyl
  • a C ⁇ - 14 aryl group e.g., phenyl
  • a Ci- 6 alkyl group optionally substituted by 1 to 3 halogen atoms; and the like can be mentioned.
  • Ra 1 is preferably a hydrogen atom, an optionally substituted hydrocarbon group / an optionally substituted heterocyclic group, an acyl group and the like, more preferably a hydrogen atom, an optionally substituted Ci-io alkyl group (preferably, Cj- ⁇ alkyl group) , an optionally substituted C ⁇ -n aryl group, an optionally substituted C7-13 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C 6 -i4 aryl-carbonyl group, an optionally substituted C 6 - H arylsulfonyl group and the like.
  • Ra 1 is further preferably a hydrogen atom, an optionally substituted hydrocarbon group / an optionally substituted heterocyclic group, an acyl group and the like, more preferably a hydrogen atom, an optionally substituted Ci-io alkyl group (preferably, Cj- ⁇ alkyl group) , an optionally substituted C ⁇ -n ary
  • Ci_6 alkyl group optionally substituted by 1 to 3 aromatic heterocyclic groups (e.g., pyridyl) ;
  • an aromatic heterocyclic group e.g., pyrimidinyl
  • Ra 2 and Ra 3 are preferably both hydrogen atoms.
  • Ra 4 and Ra 5 are preferably both hydrogen atoms.
  • Ra 6 is preferably a hydrogen atom.
  • Ra 7 is preferably a hydrogen atom.
  • Ring Aa is an optionally substituted aromatic heterocycle.
  • aromatic heterocycle of the "optionally substituted aromatic heterocycle” for ring Aa
  • a ring corresponding to the aromatic heterocyclic group exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • the aromatic heterocycle can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
  • aromatic heterocycle of the “optionally substituted aromatic heterocycle” for ring Aa
  • pyridine, pyrazine, pyrimidihe, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, and pyridazine are preferable.
  • the "aromatic heterocycle” of the "optionally substituted aromatic heterocycle” for ring Aa optionally has 1 to 3 substituents at substitutable position (s).
  • substituents for example, those exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • an optionally substituted hydrocarbon group an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; a halogen atom; and the like are preferable.
  • a C ⁇ -1 4 aryl group e.g., phenyl
  • a C ⁇ -1 4 aryl group optionally substituted by 1 to 3 C ⁇ - 6 alkyl groups
  • a C7-13 aralkyl group e.g., benzyl, 2-phenethyl
  • an aromatic heterocyclic group e.g., pyrazolyl, thiazolyl, oxadiazolyl
  • a non-aromatic heterocyclic group e.g., pyrrolidinyl, morpholinyl
  • a Ci-6 alkoxy. group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from
  • a C3-10 cycloalkyl group e.g., cyclopropyl, cyclopentyl
  • a Ci-6 alkylsulfonyl group e.g./ methylsulfonyl; ethylsulfonyl
  • an aromatic heterocyclic group e.g., imidazolyl
  • Ci-6 alkyl groups optionally substituted by 1 to 3 Ci-6 alkyl groups
  • a C3- 1 0 cycloalkyloxy group e.g., cyclopentyloxy
  • a C7- 1 3 aralkyloxy group e.g., benzyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • Ci- 6 alkylthio group e.g., methylthio, ethylthio
  • a C ⁇ -14 arylthio group e.g., phenylthio
  • a Ci- 6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • (21) a carbamoyl group optionally mono- or di-substituted by Ci_6 alkyl group (s); (22) a hydroxy group; and the like are more preferable.
  • Ring Aa is preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; and a halogen atom.
  • aromatic heterocycle preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine
  • substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mer
  • Ring Aa is more preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, guinoxaline, indazole, indole/ imidazopyridine, pyridazine) optionally substituted by 1 to 3 substituents selected from
  • Ci- 6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • a C 6 -H aryl group e.g., phenyl
  • a C 7 - I3 aralkyl group e.g., benzyl, 2-phenethyl
  • an aromatic heterocyclic group e.g., pyrazolyl, thiazolyl ' , oxadiazolyl
  • Ci_e alkyl groups optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclic group e.g., pyrrolidinyl, morpholinyl
  • Ci_6 alkoxy group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from
  • a Ci-6 alkoxy group (b) a Ci-6 alkoxy group, (c) a C 3 - 10 cycloalkyl group (e.g., cyclopropyl, cyclopentyl) ,
  • Ci_6 alkylsulfonyl group e.g./ methylsulfonyl, ethylsulfonyl
  • an aromatic heterocyclic group e.g., imida ⁇ olyl
  • a C 7 -i3 aralkyloxy group e.g., benzyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • a C1-6 alkylthio group e.g., methylthio, ethylthio
  • a C 6 -i4 arylthio group e.g., phenylthio
  • a C ⁇ _6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • Ci-6 alkyl group (i) a hydroxy group, (ii) a Ci_6 alkoxy group, and (i ⁇ ) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
  • Ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted.
  • a ring corresponding to the 5-membered nitrogen-containing aromatic heterocyclic group, and a ring corresponding to the 5-membered nitrogen-containing aromatic heterocyclic group condensed with an aromatic ring selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring, can be mentioned, from among the aromatic heterocyclic
  • the 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position of the 5-membered ring thereof.
  • the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Ba pyrazole, benzimidazole, indole and indazole are preferable, and pyrazole and indole are particularly preferable.
  • the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted” for ring Ba optionally further has 1 to 3 substituents, besides Ra 1 , at substitutable position(s).
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C 3 - I0 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms;
  • C 6 -I 4 aryl group optionally substituted by 1 to 3 halogen atoms;
  • Ci-6 alkoxy-carbonyl group (b) a Ci-6 alkoxy-carbonyl group; and the like are preferable (a Ci-s alkyl group optionally substituted by 1 to 3 halogen atoms is particularly preferable) .
  • Ring Ba is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra 1 and optionally further substituted.
  • Ring Ba is more preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra 1 and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (2) a C 6 -14 aryl group;
  • Ci_ 6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • compound (Ia) As preferable examples of compound (Ia) , the following compounds can be mentioned.
  • Compound Ia-A A compound wherein ring Ba is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra 1 and optionally further substituted
  • ring Ba is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra 1 and optionally further substituted by 1 to 3 substituents selected from (1) a Ci- 6 alkyl group optionally substituted by 1 to 3 halogen atoms; (2) a C6-14 aryl group;
  • Ci- 6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ra 1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
  • Ra 1 is preferably a hydrogen atom, an optionally substituted C 1 - I0 alkyl group (preferably, a Ci_ 6 alkyl group) , an optionally substituted Ce-i4 aryl group, an optionally substituted C7- 1 3 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C6- H aryl-carbonyl group or an optionally substituted Cs-n arylsulfonyl group.
  • Ra 1 is more preferably (1) a hydrogen atom; (2) a Ci-6 alkyl group optionally substituted by 1 to 3 aromatic heterocyclic groups (e.g., pyridyl) ;
  • an aromatic heterocyclic group e.g., pyrimidinyl
  • an aromatic heterocyclic group e.g., pyrimidinyl
  • Ci-6 alkoxy group (d) a Ci-6 alkoxy group; (6) a C ⁇ - 14 aryl-carbonyl group (e.g., benzoyl) optionally substituted by 1 to 3 substituents selected from
  • ring Aa is an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted- heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; and a halogen atom
  • ring Aa is preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole) optionally substituted by 1 to 3 substituents. selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
  • a Ce- 14 aryl group e.g., phenyl
  • Ci_ 6 alkyl groups e.g., phenyl
  • a C 7 - 13 aralkyl group e.g., benzyl, 2-phenethyl
  • an aromatic heterocyclic group e.g./ pyrazolyl, thiazolyl, oxadiazolyl
  • Ci_ 6 alkyl groups optionally substituted by 1 to 3 halogen atoms
  • a non-aromatic heterocyclic group e.g., pyrrolidinyl, morpholinyl
  • Ci_6 alkoxy group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from
  • a Ci-6 alkoxy group (b) a Ci-6 alkoxy group, (c) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclopentyl) ,
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • a Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • an aromatic heterocyclic group e.g., imidazolyl
  • 1 to 3 Ci- 6 alkyl groups e.g., imidazolyl
  • a C7-13 aralkyloxy group e.g., benzyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • Ci-6 alkylthio group e.g., r ⁇ ethylthio, ethylthio
  • a C ⁇ - 1 4 arylthio group e.g., phenylthio
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • a Ce- 14 arylsulfonyl group e.g., benzenesulfonyl
  • Ci_6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci-6 alkoxy group, and (i ⁇ ) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
  • Ra 2 and Ra 3 are both hydrogen atoms; Ra 4 and Ra 5 are both hydrogen atoms; Ra 6 is a hydrogen atom; and Ra 7 is a hydrogen atom.
  • ring Ba is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra 1 and optionally further substituted
  • ring Ba is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra 1 and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ra 1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
  • Ra 1 is preferably a hydrogen atom, an optionally substituted Ci-io alkyl group (preferably, a Ci_ 6 alkyl group) , an optionally substituted C ⁇ -i 4 aryl group, an optionally substituted C7-13 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C ⁇ -n aryl-carbonyl group or an optionally substituted C 6 - H arylsulfonyl group.
  • Ra 1 is more preferably a hydrogen atom, an optionally substituted Ci-io alkyl group (preferably, a Ci_ 6 alkyl group) , an optionally substituted C ⁇ -i 4 aryl group, an optionally substituted C7-13 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C ⁇ -n aryl-carbonyl group or an optionally substituted C 6 - H arylsulfonyl group.
  • Ra 1 is more preferably
  • Ci-6 alkyl group optionally substituted by 1 to 3 aromatic heterocyclic groups (e.g., pyridyl) ;
  • Ci_6 alk ⁇ xy group (4) a C7-. 13 aralkyl group (e.g., benzyl) optionally substituted by 1 to 3 substituents selected from
  • an aromatic heterocyclic group e.g., pyrimidinyl
  • an aromatic heterocyclic group e.g., pyrimidinyl
  • a Ce- 14 arylsulfonyl group e.g., benzenesulfonyl
  • 1 to 3 substituents selected from (a) a halogen atom, (b) a hydroxy group,
  • ring Aa is an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine) optionally substituted by
  • substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; and a halogen atom
  • [ring Aa is preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom;
  • aromatic heterocycle preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine
  • Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom,
  • a non-aromatic heterocyclic group e.g., pyrrolidinyl
  • a C 7 - I3 aralkyl group e.g., benzyl, 2-phenethyl
  • an aromatic heterocyclic group e.g., pyrazolyl, thiazolyl, oxadiazolyl
  • an aromatic heterocyclic group e.g., pyrazolyl, thiazolyl, oxadiazolyl
  • a non-aromatic heterocyclic group e.g., pyrrolidinyl, morpholinyl
  • Ci-6 alkoxy group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (a) a halogen atom,
  • a C3-10 cycloalkyl group e.g., cyclopropyl, cyclopentyl
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • a Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • an aromatic heterocyclic group e.g., imidazolyl
  • Ci_ 6 alkyl groups optionally substituted by 1 to 3 Ci_ 6 alkyl groups
  • a Ce-14 aryloxy group e.g., phenoxy
  • a C 7 -i 3 aralkyloxy group e.g., benzyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • a non-aromatic heterocyclyloxy group e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy
  • Ci-6 alkylthio group e.g., methylthio, ethylthio
  • a C ⁇ -14 arylthio group e.g., phenylthio
  • a Ci-6 alkylsulfonyl group e.g., methylsulfonyl, ethylsulfonyl
  • a C ⁇ -14 arylsulfonyl group e.g., benzenesulfonyl
  • an amino group optionally mono- or di-substituted by substituent (s) selected from
  • Ra 2 and Ra 3 are both hydrogen atoms; Ra 4 and Ra 5 are both hydrogen atoms; Ra 6 is a hydrogen atom; and Ra 7 is a hydrogen atom.
  • Ring Ab is an optionally substituted aromatic hydrocarbon.
  • aromatic hydrocarbon of the "optionally substituted aromatic hydrocarbon” for ring Ab
  • a ring corresponding to the Ce-n aryl group exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • the aromatic hydrocarbon can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
  • aromatic hydrocarbon of the "optionally substituted aromatic hydrocarbon” for ring Ab, benzene is preferable.
  • the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon” for ring Ab optionally has 1 to 3 substituents at substitutable position (s) .
  • substituents for example, those exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • substituents of ring Ab an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; a halogen atom; and the like are preferable'.
  • Ci_s alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a sulfamoyl group, (7) a cyano group and the like are more preferable, and a halogen atom and a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms are particularly preferable.
  • Ring Ab is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom.
  • aromatic hydrocarbon preferably, benzene
  • substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom.
  • Ring Ab is more preferably an aromatic hydrocarbon
  • Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a cyano group particularly preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.
  • Ring Bb is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted.
  • the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring” of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted” for ring Bb optionally further has 1 to 3 substituents, besides ring Cb, at substitutable position (s).
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C 3 - I0 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra", Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Ci_ 6 alkoxy-carbonyl group (b) a Ci-6 alkoxy-carbonyl group; and the like are preferable (a Ci_ 6 alkyl group optionally substituted by 1 to 3 halogen atoms is particularly preferable) .
  • Ring Bb is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cb and optionally further substituted.
  • Ring Bb is more preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cb and optionally further substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms ;
  • Ci-6 alkoxy-carbonyl group particularly preferably, a Ci-e alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ring Cb is an optionally substituted aromatic heterocycle.
  • aromatic heterocycle of the “optionally substituted aromatic heterocycle” for ring Cb
  • a ring corresponding to the aromatic heterocyclic group exemplarily recited as the “substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • aromatic heterocycle of the "optionally substituted aromatic heterocycle” for ring Cb, indole, pyridine and pyrimidine are preferable.
  • the "aromatic heterocycle" of the "optionally substituted aromatic heterocycle” for ring Cb optionally has 1 to 3 substituents at substitutable position (s).
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra", Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • substituents of ring Cb for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra", Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • substituents of ring Cb As the substituents of ring Cb,
  • Ci- 6 alkoxy group (4) a Ci- 6 alkoxy group, and the like are preferable.
  • Ring Cb is preferably an aromatic heterocycle (preferably, indole, pyridine, pyrimidine) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom, (2) a hydroxy group, (3) a Ci-6 alkyl group, and
  • ring Bb is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cb and optionally further substituted
  • ring Bb is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , eachof which is substituted by ring Cb and optionally further substituted by 1 to 3 substituents selected from
  • Ci- 6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • ring Cb is an aromatic heterocycle (preferably, indole, pyridine, pyrimidine) optionally substituted by 1 to 3 substituents selected from
  • ring Ab is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom
  • ring Ab is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents • selected from
  • a Q L - 6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom, (2) a hydroxy group,
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a sulfamoyl group e.g., a cyano group, more preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a C ⁇ - ⁇ alkoxy group optionally substituted by 1 to 3 halogen atoms] .
  • ring Ac is an optionally substituted aromatic hydrocarbon.
  • aromatic hydrocarbon of the "optionally substituted aromatic hydrocarbon” for ring Ac, a ring corresponding to the C 6 -i4 aryl group exemplarily recited as the
  • aromatic hydrocarbon of the "optionally substituted aromatic hydrocarbon” for ring Ac optionally has 1 to 3 substituents at substitutable position (s).
  • substituents for example, those exemplarily recited as the
  • substituted for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • substituents of ring Ac an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; a halogen atom; and the like are preferable.
  • Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a sulfamoyl group
  • a cyano group and the like are more preferable, and a halogen atom and a Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms are particularly preferable.
  • Ring Ac is preferably an aromatic hydrocarbon
  • Ring Ac is more preferably an aromatic hydrocarbon
  • Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom, (2) a hydroxy group,
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a sulfamoyl group e.g., a cyano group, particularly preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci- 6 alkoxy group optionally substituted by 1 to 3 halogen atoms.
  • Ring Bc is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted.
  • w 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Be / a ring corresponding to the 5-iuembered nitrogen-containing aromatic heterocyclic group, and a ring corresponding to the 5-meitibered nitrogen-containing aromatic heterocyclic group condensed with an aromatic ring selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole/ imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring, can be mentioned, from
  • xx 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Bc
  • pyrazole, benzimidazole, indole and indazole are preferable, and pyrazole and indole are particularly preferable.
  • the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted” for ring Bc optionally further has 1 to 3 substituenfs, besides ring Cc, at substitutable position (s).
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C 3 - I0 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • substituents other than ring Cc of ring Bc are examples of substituents other than ring Cc of ring Bc.
  • Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6 alkyl group (a) a Ci-6 alkyl group, and (b) a Ci-6 alkoxy-carbonyl group and the like are preferable (a Ci_ s alkyl group optionally substituted by 1 to 3 halogen atoms is particularly preferable) .
  • Ring Bc is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole), each of which is substituted by ring Cc and optionally further substituted.
  • Ring Bc is more preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cc and optionally further substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
  • C 6 -i4 aryl group optionally substituted by 1 to 3 halogen atoms;
  • Ci_ 6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ring Cc is an optionally substituted aromatic ring.
  • aromatic ring of the "optionally substituted aromatic ring” for ring Cc, an aromatic hydrocarbon and an aromatic heterocycle can be mentioned.
  • aromatic ring of the "optionally substituted aromatic ring” for ring Cc
  • aromatic hydrocarbon is preferable, and benzene is particularly preferable.
  • the "aromatic ring" of the "optionally substituted aromatic ring” for ring Cc optionally has 1 to 3 substituents at substitutable position (s) .
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra", Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Ring Cc is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom,
  • Rc 2 , Rc 3 , Rc 4 , Rc 5 > Rc 6 and Rc 7 are each independently a hydrogen atom or a substituent, or any two of Rc 2 , Rc 3 , Rc 4 , Rc 5 , Rc 6 and Rc 7 are optionally bonded to each other to form a non-aromatic ring.
  • Rc 2 , Rc 3 , Rc 4 , Rc 5 , Rc 6 and Rc 7 those exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • non-aromatic ring formed by any two of Rc 2 , Rc 3 , Rc 4 , Rc 5 , Rc 6 and Rc 7 bonded to each other, a non-aromatic cyclic hydrocarbon and a non-aromatic heterocycle can be mentioned.
  • non-aromatic cyclic hydrocarbon for example, a C 3 _i 0 cycloalkane, C3-10 cycloalkene, C4-10 cycloalkadiene and the like, each of which is optionally condensed with a benzene ring, can be mentioned.
  • non-aromatic heterocycle a ring corresponding to the non-aromatic heterocyclic group, which is exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 , can be mentioned.
  • Rc 2 and Rc 3 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc 2 or Rc 3 is bonded to Rc 4 or Rc 5 to form a non- aromatic ring, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle.
  • Rc 2 and Rc 3 are more preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci_i 0 alkyl group (preferably, Ci-6 alkyl group) , or Rc 2 or Rc 3 is bonded to Rc 4 or Rc 5 to form a non-ar ⁇ matic hydrocarbon, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle.
  • Rc 2 and Rc 3 are particularly preferably each independently
  • Ci-6 alkyl group optionally substituted by 1 to 3 hydroxy groups ;
  • Rc 2 or Rc 3 is bonded to Rc" or Rc 5 to form a C 3 - I0 cycloalkane (e.g./ cyclohexane) ; (6) Rc 2 or Rc 3 is bonded to Rc 6 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or (7) Rc 2 or Rc 3 is bonded to Rc 7 to form a non-aromatic heterocycle (e.g./ piperidine).
  • a non-aromatic heterocycle e.g., piperidine, pyrrolidine
  • Rc 2 or Rc 3 is bonded to Rc 7 to form a non-aromatic heterocycle (e.g./ piperidine).
  • Rc 4 and Rc 5 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc 4 or Rc 5 is bonded to Rc 2 or Rc 3 to form a non- aromatic ring, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle.
  • Rc 4 and Rc 5 are more preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci-io alkyl group (preferably, Ci-e alkyl group) , or Rc 4 or Rc 5 is bonded to Rc 2 or Rc 3 to form a non-aromatic hydrocarbon, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle.
  • Rc 4 and Rc 5 are particularly preferably each independently (1) a hydrogen atom; (2) a carboxy group;
  • Ci_ 6 alkyl group optionally substituted by 1 to 3 hydroxy groups ;
  • Rc" or Rc 5 is bonded to Rc 2 or Rc 3 to form a C 3 -io cycloalkane (e.g., cyclohexane); (6) Rc 4 or Rc 5 is bonded to Rc 6 to form a non-aromatic heterocycle (e.g., piperidine); or
  • Rc" or Rc 5 is bonded to Rc 7 to form a non-aromatic heterocycle ⁇ e.g., piperidine / pyrrolidine).
  • Rc 6 is preferably a hydrogen atom or an optionally substituted hydrocarbon group, or Rc 6 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle, or bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle.
  • Rc 6 is more preferably a hydrogen atom or an optionally substituted Ci-io alkyl group (preferably, Ci-e alkyl group) , or Rc 6 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle, or bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle.
  • Rc 6 is particularly preferably (1) a hydrogen atom; or
  • Rc 6 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or
  • Rc 6 is bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle (e.g., piperidine).
  • a non-aromatic heterocycle e.g., piperidine
  • Rc 7 is preferably a hydrogen atom or an optionally substituted hydrocarbon group, or Rc 7 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle, or bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle.
  • Rc 7 is more preferably a hydrogen atom or an optionally substituted Ci_i 0 alkyl group (preferably, Ci_ 6 alkyl group) , or Rc 7 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle, or bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle.
  • Rc 7 is particularly preferably
  • Rc 7 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle (e.g., piperidine); or (4) Rc 7 is bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle (e.g./ piperidine, pyrrolidine).
  • ring Bc is not pyrazol-5-yl and 2H-1, 2, 3-triazol-4- yl, each of which is optionally further substituted (i.e., ring Bc is not pyrazole having substituent C at the 5- position, and 2H-1, 2, 3-triazole having substituent C at the A- position, each of which is optionally further substituted) ;
  • ring Cc is not optionally substituted quinoline; 3) a compound wherein Rc 2 , Rc 3 , Rc 4 , Rc 5 , Rc 6 and Rc 7 are hydrogen atoms is excluded; and
  • ring Bc is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cc and optionally further substituted
  • ring Bc is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cc and optionally further substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • ring Cc is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom, (2) a hydroxy group,
  • ring Ac is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom
  • ring Ac is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
  • Ci_6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a cyano group more preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a C ⁇ -6 alkoxy group optionally substituted by 1 to .3 halogen atoms];
  • Rc 2 and Rc 3 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc 2 or Rc 3 is bonded to Rc 4 or Rc 5 to form a non-aromatic ring, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle
  • Rc 2 and Rc 3 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci-io alkyl group
  • Rc 2 or Rc 3 is bonded to Rc 4 or Rc 5 to form a non-aromatic hydrocarbon, bonded to Rc 6 to form a non-aromatic heterocycle/ or bonded to Rc 7 to form a non- aromatic heterocycle.
  • Rc 2 and Rc 3 are more preferably each independently
  • Ci_6 alkyl group optionally substituted by 1 to 3 hydroxy groups
  • Rc 2 or Rc 3 is bonded to Rc 4 or Rc 5 to form a C3-10 cycloalkane (e.g., cyclohexane) ;
  • Rc 2 or Rc 3 is bonded to Rc 6 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or
  • Rc 2 or Rc 3 is bonded to Rc 7 to form a non-aromatic heterocycle (e.g., piperidine)];
  • Rc 4 and Rc 5 are each independently a hydrogen atom, an acyi group or an optionally substituted hydrocarbon group, or Rc 4 or Rc 5 is bonded to Rc 2 or Rc 3 to form a non-aromatic ring, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non-aromatic heterocycle
  • Rc 4 and Rc 5 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci-io alkyl group (preferably, Ci_ 6 alkyl group) , or Rc 4 or Rc 5 is bonded to Rc 2 or Rc 3 to form a non-aromatic hydrocarbon, bonded to Rc 6 to form a non-aromatic heterocycle, or bonded to Rc 7 to form a non- aromatic heterocycle
  • Rc 4 and Rc 5 are more preferably each independently
  • Ci-6 alkoxy-carbonyl group (3) a Ci-6 alkoxy-carbonyl group; or (4) a Ci-6 alkyl group optionally substituted by 1 to 3 hydroxy ⁇ groups; or
  • Rc 4 or Rc 5 is bonded to Rc 2 or Rc 3 to form a C3- 10 cycloalkane (e.g., cyclohexane) ;
  • Rc 4 or Rc 5 is bonded to Rc 6 to form a non-aromatic heterocycle (e.g., piperidine) ; or
  • Rc 4 or Rc 5 is bonded to Rc 7 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine)];
  • Rc 6 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc 6 is bonded to Rc 2 or Rc 3 to form a non- aromatic heterocycle, or bonded to Rc 4 or Rc ⁇ to form a non- aromatic heterocycle
  • Rc 6 is preferably a hydrogen atom or an optionally substituted Ci-10 alkyl group (preferably, d- ⁇ alkyl group) , or Rc 6 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle, or bonded to Rc 4 or Rc 5 to from a non-aromatic heterocycle. Rc 6 is more preferably
  • Rc 6 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or
  • Rc 6 is bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle (e.g., piperidine)];
  • Rc 7 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc 7 is bonded to Rc 2 or Rc 3 to form a non- aromatic heterocycle, or bonded to Rc 4 or Rc 5 to form a non- aromatic heterocycle
  • Rc 7 is preferably a hydrogen atom or an optionally substituted Ci-10 alkyl group (preferably, Ci-s alkyl group) , or Rc 7 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle, or bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle. Rc 7 is more preferably
  • Rc 7 is bonded to Rc 2 or Rc 3 to form a non-aromatic heterocycle (e.g., piperidine); or (4) Rc 7 is bonded to Rc 4 or Rc 5 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine)].
  • a non-aromatic heterocycle e.g., piperidine
  • a non-aromatic heterocycle e.g., piperidine, pyrrolidine
  • Ring Ad is an optionally substituted aromatic hydrocarbon.
  • aromatic hydrocarbon of the "optionally substituted aromatic hydrocarbon” for ring Ad
  • a ring corresponding to the C 6 -i4 aryl group exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • the aromatic hydrocarbon can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
  • aromatic hydrocarbon of the "optionally substituted aromatic hydrocarbon” for ring Ad
  • benzene is preferable.
  • the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon” for ring Ad optionally has 1 to 3 substituents at substitutable position (s).
  • substituents for example, those exemplarily recited as the "substituent” for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • substituents of ring Ad an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group/ an optionally substituted hydroxy group; a cyano group; an acyl group/ a halogen atom; and the like are preferable .
  • substituents of ring Ad an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group/ an optionally substituted hydroxy group; a cyano group; an acyl group/ a halogen atom; and the like are preferable .
  • Ci_ 6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a cyano group and the like are more preferable, and a halogen atom and a Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms are particularly preferable.
  • Ring Ad is preferably an aromatic hydrocarbon
  • substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom.
  • Ring Ad is more preferably an aromatic hydrocarbon
  • benzene optionally substituted by 1 to 3 substituents selected from (1) a Ci_6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
  • Ci_6 alkyl group (4) a Ci_6 alkyl group, (5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) /
  • a cyano group particularly preferably an aromatic hydrocarbon, (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci- ⁇ alkoxy group optionally substituted by 1 to 3 halogen atoms.
  • Ring Bd is an aromatic heterocycle which is optionally further substituted.
  • aromatic heterocycle of the "aromatic heterocycle which is optionally further substituted” for ring Bd
  • a ring corresponding to the aromatic heterocyclic group exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • the aromatic heterocycle can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
  • aromatic heterocycle of the "aromatic heterocycle which is optionally further substituted” for ring Bd, pyridine, pyrazole, triazole and indole are preferable.
  • the "aromatic heterocycle" of the "aromatic heterocycle which is optionally further substituted” for ring Bd optionally further has 1 to 3 substituents, besides ring Cd, at substitutable position (s).
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Ci_6 alkoxy-carbonyl group (b) a Ci_6 alkoxy-carbonyl group; and the like are preferable, and (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
  • Ring Bd is preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted.
  • Ring Bd is more preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci-6.alkoxy-carbonyl group particularly preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and (2) a C 6 -I 4 aryl group.
  • Ring Cd is an optionally substituted aromatic ring.
  • aromatic ring of the "optionally substituted aromatic ring” for ring Cd, an aromatic hydrocarbon and an aromatic heterocycle can be mentioned.
  • aromatic hydrocarbon a ring corresponding to the C 5 -U aryl group exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • aromatic heterocycle a ring corresponding- to the aromatic heterocyclic group exemplarily recited as the
  • Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • aromatic ring of the "optionally substituted aromatic ring", for ring Cd, an aromatic hydrocarbon is preferable, and benzene is particularly preferable.
  • the "aromatic ring" of the "optionally substituted aromatic ring” for ring Cd optionally has 1 to 3 substituents at substitutable position (s) .
  • substituents for example, those (except an oxo group) exemplarily recited as the substituents of the C 3 _io cycloalkyl group and the like exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Ci-6 alkoxy group and the like are preferable.
  • Ring Cd is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
  • ring Bd is not pyrazol-4-yl and pyrrol-3-yl, each of which is optionally further substituted (i.e., ring Bd is not pyrazole having substituent D at the 4-position, and pyrrole having substituent D at the 3-position, each of which is optionally further substituted) ;
  • ring Cd is not optionally substituted quinoline
  • ring Bd is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted, then ring Bd does not have an optionally substituted aromatic heterocyclic group as a substituent other than ring Cd and ring Cd is an optionally substituted aromatic hydrocarbon.
  • ring Bd is pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted
  • ring Bd is preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from
  • Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms
  • Ci- 6 alkoxy-carbonyl group more preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from (1) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms; and
  • ring Cd is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
  • Ci_6 alkoxy group (4) a Ci_6 alkoxy group; and ring Ad is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom
  • Ring Ad is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
  • an aromatic heterocyclic group e.g., imidazolyl, pyrazolyl
  • a cyano group more preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci_e alkoxy group optionally substituted by 1 to 3 halogen atoms] .
  • a pharmacologically acceptable salt is preferable.
  • a salt with inorganic base examples include a salt with inorganic base, a salt with organic base, a salt with inorganic acid/ a salt with organic acid, a salt with basic or acidic amino acid and the like.
  • the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt; ammonium salt and the like.
  • the salt with organic base include a salt with trimethylamine, triethylamine, pyridine,, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine] , tert-butylamine, cyclohexylamine, benzylamine, dieyelohexylamine, N,N- dibenzylethylenediamine or the like.
  • the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid/ nitric acid, sulfuric acid, phosphoric acid or the like.
  • the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
  • Preferable examples of the salt with basic amino acid include a salt with arginine, lysine, ornithine or the like.
  • Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid or the like.
  • a prodrug of the compound of the present invention is a compound that converts to the compound of the present invention due to the reaction by enzyme, gastric acid and the like under the physiological conditions in the body; that is, a compound that converts to the compound of the present invention by enzymatic oxidation, reduction, hydrolysis and the like, and a compound that converts to the compound of the present invention by hydrolysis and the like by gastric acid and the like.
  • Examples of a prodrug of the compound of the present invention include a compound wherein an amino group of the compound of the present invention is acylated, alkylated or phosphorylated (e.g., a compound where amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3- dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert- butylated) ; a compound wherein a hydroxy group of the compound of the present invention is acylated, alkylated, phosphorylated or borated (e.g., a compound where a hydroxy group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl
  • a prodrug of the compound of the present invention may be a compound that converts to the compound of the present invention under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, pp. 163-198, Hirokawa Shoten (1990).
  • the compound of the present invention may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I and the like) and the like.
  • an isotope e.g., 3 H, 14 C, 35 S, 125 I and the like
  • the compound of the present invention may be an . anhydride or a hydrate.
  • the compound of the present invention and a prodrug thereof show low toxicity and can be used as an agent for the prophylaxis or treatment of various diseases to be mentioned later for mammals (e.g., human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, simian) as they are or by admixing with a pharmacologically acceptable carrier and the like to give a pharmaceutical composition.
  • mammals e.g., human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, simian
  • organic or inorganic carriers conventionally used as materials for pharmaceutical preparations are used as a pharmacologically acceptable carrier, which are added as an excipient, a lubricant, a binder, a disintegrant and the like for solid preparations; and a solvent, a dissolution aid, a suspending agent, an isotonicity agent, a buffer, a soothing agent and the like for liquid preparations.
  • an additive for pharmaceutical preparations such as a preservative, an antioxidant, a coloring agent, a sweetening agent and the like can be used.
  • excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, powdered acacia, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like .
  • binder examples include pregelatinized starch, saccharose, gelatin, powdered acacia, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like.
  • disintegrant examples include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, sodium carboxymethyl starch, light anhydrous silicic acid, low- substituted hydroxypropyl cellulose and the like.
  • the solvent include water for injection, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • dissolution aid examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.
  • the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium . chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and the like; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium . chloride, benzethonium chloride, glycerol monostearate and the like
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethyl
  • the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose and the like.
  • the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer and the like.
  • the soothing agent include benzyl alcohol and the like.
  • preservative examples include p- oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite, ascorbate and the like.
  • the coloring agent include water- soluble edible tar pigments (e.g., foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake pigments (e.g./ aluminum salt of the aforementioned water- soluble edible tar pigment), natural pigments (e.g., beta carotene, chlorophil, red iron oxide) and the like.
  • water- soluble edible tar pigments e.g., foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like
  • water insoluble lake pigments e.g./ aluminum salt of the aforementioned water- soluble edible tar pigment
  • natural pigments e.g., beta carotene, chlorophil, red iron oxide
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the dosage form of the aforementioned pharmaceutical composition is, for example, an oral agent such as tablets (inclusive of sublingual tablets and orally disintegrable tablets) , capsules (inclusive of soft capsules and microcapsules) , granules, powders/ troches, syrups, emulsions, suspensions and the like; or a parenteral agent such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external agents (e.g., transdermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories) , pellets, nasal preparations, pulmonary preparations (inhalations) , ophthalmic preparations and the like. These may be administered safely via an oral or parenteral route.
  • an oral agent such as tablets (inclusive of sublingual tablets and orally disintegrable tablets) , capsules (inclusive of
  • agents may be controlled-release preparations such as rapid-release preparations and sustained-release preparations (e.g., sustained-release microcapsules).
  • the pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical preparation, such as the method described in Japan Pharmacopoeia and the like. Concrete production methods of preparations are described in detail in the following. While the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, dose of the compound of the present invention and the like, it is, for example, about 0.1-100 wt%. Where necessary, the aforementioned oral agents may be coated with a coating base for the purpose of masking taste, enteric property or sustained release.
  • the coating base examples include a sugar-coating base, a water-soluble film coating base, an enteric film coating base, a sustained-release film coating base and the like.
  • sucrose may be used, if necessary, along with one or more species selected from talc, precipitated calcium carbonate, gelatin, powdered acacia, pullulan, carnauba wax and the like.
  • water-soluble film coating base for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E, trade name, Roehm Pharma] , polyvinylpyrrolidone and the like; polysaccharides such as pullulan and the like; and the like are used.
  • cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like
  • synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E, trade name, Roehm Pharma] , polyvinylpyrrolidone and the like
  • polysaccharides
  • enteric film coating base for example, cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L, trade name, Roehm Pharma] , methacrylic acid copolymer LD [Eudragit L-30D55, trade name, Roehm Pharma], methacrylic acid copolymer S [Eudragit S, trade name, Roehm Pharma] and the like; natural products such as shellac and the like; and the like are used.
  • cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like
  • acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L, trade name,
  • sustained-release film coating base for example, cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS, trade name, Roehm Pharma] , ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE, trade name, Roehm Pharma] and the like; and the like are used. Two or more kinds of the above-mentioned coating bases may be mixed in an appropriate ratio for use.
  • a light shielding agent such as titanium oxide, ferric oxide and the like may be used during coating.
  • the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenic) , causes fewer side effects and can be used as an agent for the prophylaxis or treatment or diagnosis of various diseases for mammals (e.g., human, cattle, horse, dog, cat, simian, mouse, rat, especially human) .
  • mammals e.g., human, cattle, horse, dog, cat, simian, mouse, rat, especially human
  • the compound of the present invention has a DGAT (DGATl or DGAT2 or both) inhibitory action, and is useful for the prophylaxis, treatment or amelioration of DGAT-related diseases.
  • DGAT DGATl or DGAT2 or both
  • DGAT-related diseases for example, obesity, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes) , insulin resistance, leptin resistance, arteriosclerosis, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-cholesterolemia, postprandial hyperlipemia) , arteriosclerosis, hypertension, cardiac failure, metabolic syndrome and the like can be mentioned.
  • diabetes e.g., type 1 diabetes, type 2 diabetes, gestational diabetes
  • hyperlipidemia e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-cholesterolemia, postprandial hyperlipemia
  • arteriosclerosis hypertension
  • cardiac failure e.g., cardiac failure, metabolic syndrome and the like
  • diabetes is a condition showing any of a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test (75 g OGTT) 2 h level (glucose concentration of intravenous plasma) of not less than 200 mg/dl, and a non-fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 200 mg/dl.
  • a condition not falling under the above-mentioned diabetes and different from "a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of less than no mg/dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 h level (glucose concentration of intravenous plasma) of less than 140 mg/dl" (normal type) is called a ""borderline type".
  • ADA American Diabetes Association
  • diabetes is a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 126 ⁇ vg/dl and a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of not less than 200 mg/dl.
  • impaired glucose tolerance is a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of less than 126 mg/dl and a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of not less than 140 mg/dl and less than 200 mg/dl.
  • a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 110 mg/dl and less than 126 mg/dl is called IFG (Impaired Fasting Glucose) .
  • IFG Impaired Fasting Glucose
  • IFG Impaired Fasting Glycemia
  • the compound of the present invention can be also used as an agent for the prophylaxis or treatment of diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia), as determined according to the above-mentioned new diagnostic criteria. Moreover, the compound of the present invention can prevent progress of borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) into diabetes.
  • the compound of the present invention can be also used as an agent for the prophylaxis or treatment of, for example, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infection, inferior limb infection) , diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, peripheral blood circulation disorder], osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia or cachexia due to acquired immunodeficiency syndrome) , fatty liver, polycystic ovary syndrome, kidney disease (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hyper
  • the compound of the present invention can also be used for the secondary prophylaxis, or suppression of the progression of the above-mentioned various diseases (e.g., cardiovascular events such as cardiac infarction and the like) .
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, condition and the like, the compound of the present invention is generally given in a single dose of about 0.01-100 mg/kg body weight, preferably 0.05-30 mg/kg body weight, more preferably 0.1-10 mg/kg body weight, in the case of, for example, oral administration to adult diabetic patients. This dose is desirably given 1 to 3 times a day.
  • the compound of the present invention can be used in combination with drugs such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipemic agent, an antihypertensive agent, an antiobestic agent, a diuretic, an antithrombotic agent and the like (hereinafter to be referred to as a combination drug) , with the aim of enhancing the action of the compound, reducing the dose of the compound and the like.
  • a combination drug a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipemic agent, an antihypertensive agent, an antiobestic agent, a diuretic, an antithrombotic agent and the like
  • a combination drug a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipemic agent, an antihypertensive agent, an antiobestic agent, a diuretic, an antithrombotic agent and the like
  • the timing of administration of the compound of the present invention and a combination drug is
  • the dose of the combination drug can be determined as ' appropriate based on the dose clinically employed.
  • the proportion of the compound of the present invention and the combination drug can be appropriately determined depending on the administration subject, administration route, target disease, condition, combination and the like.
  • the combination drug is used in an amount of 0.01-100 parts by weight per 1 part by weight of the compound of the present invention.
  • insulin preparations e.g., animal insulin preparations extracted from the pancreas of bovine or pig; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-I), oral insulin preparation), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone.
  • aldose reductase inhibitors e.g., Tolrestat, Epalrestat, Zenarestat, Zopolrestat, Minalrestat, Fidarestat, CT-112, Ranirestat
  • neurotrophic factors and increasing drugs thereof e.g., NGF, NT-3, BDNF, neurotrophin production-secretion promoters described in WO01/14372 (e.g., 4- (4-chlorophenyl) -2- (2-methyl-l-imidazolyl) -5- [3- (2- methylphenoxy) propyl] oxazole)
  • ne ⁇ ranagenesis stimulators e.g., Y-128
  • PKC inhibitors e.g., ruboxistaurin mesylate
  • AGE inhibitors e.g., ALT946, pimagedine, pyratoxanthine, N- phenacylthiazolium bromide (ALT766) , ALT-7
  • antihyperlipemic agent examples include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, ⁇ rosuvastatin, pitavastatin and salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97/10224, such as N- [ [ (3R, 5S)-I- (3- acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2, 3-dii ⁇ ethoxyphenyl) - 2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzoxazepin-3-yl) acetyl] - piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinof
  • antihypertensive agent examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril) , angiotensin II receptor antagonists (e.g., candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1- [ [2' - (2, 5-dihydro-5- oxo-4H-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-lH- benzimidazole-7-carboxylic acid), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (e.g., levcromakalim, L-27152, AL 0671, NIP
  • antiobestic agent examples include antiobestic agents acting on the central nervous system (e.g., Dexfenfluramine, fenfluramine, phentermine, Sibutramine, amfepramone, dexamphetamine, Mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP- 7941; compounds encompassed in WO01/82925 and WO01/87834); neuropeptide Y antagonists (e.g., CP-422935) ; cannabinoid receptor antagonists (e.g., SR-141716, SR-147778) ; ghrelin antagonists; ll ⁇ -hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498) ) , pancreatic lipase inhibitors (e.g., orlistat, ATL- 962), ⁇ 3 agonists (e.g.,
  • diuretic examples include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide) , antialdosterone preparations (e.g., spironolactone, triamterene), carbonate dehydratase inhibitors (e.g./ acetazoland.de) , chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide) , azosemide, isosorbide, etacrynic acid, piretanide, bumetanide and
  • antithrombotic agent examples include heparins (e.g., heparin sodium, heparin calcium, dalteparin sodium), warfarins (e.g., warfarin potassium), anti-thrombin drugs (e.g., aragatroban) , thrombolytic agents (e.g., urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticl ⁇ pidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.
  • heparins e.g., heparin sodium, heparin calcium, dalteparin sodium
  • warfarins e.g., warfarin potassium
  • anti-thrombin drugs e.g
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S) -stereoisomers or as mixtures thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and diastereomers, and mixtures, racemate or otherwise, thereof. Accordingly, this invention also includes all such isomers, including diastereomeric mixtures, enantiomeric mixture, diastereomers and pure enantiomers of the compounds of this invention.
  • enantiomer refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the term "diastereomer” refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons .
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention.
  • stereochemistry is specified by a solid wedge or a hashed wedge representing a particular configuration, then that stereoisomer is so specified and defined.
  • stereochemistry is specified by a solid line or a hashed line representing a relative conformation such as cis and trans, then that conformation is so specified and defined.
  • HATU 0-(7-Azabenzotriazol-l-yl)-N,N,N / ,N / -tetramethyluronium hexafluorophosphate
  • BOP-Cl Benzotriazol-1-yl-oxytris (dimethylamino) phosphoniur ⁇ hexafluorophosphate
  • KOH Potassium hydroxide
  • K2CO3 Potassium carbonate
  • DIPEA Diisopropylethylamine
  • H2SO4 Sulfuric acid HCl : Hydrochloric acid HBr: Hydrobromic acid NH 4 Cl: Ammonium chloride
  • TFA Trifluoroacetic acid AcOH: Acetic acid TFAA: Trifluoroacetic anhydride
  • Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
  • Pd(OAc) 2 Palladium acetate
  • PdCl 2 (dppf) DichloroU, 1'- bis (diphenylphosphi.no) ferrocene]palladium
  • PdCl 2 (dppp): Dichloro [1, 3- Bis (diphenylphosphino) propane] palladium
  • CDI N,N-Carbonyldiimidazole
  • TFFH Tetramethylfluoroformamidinium hexafluorophosphate
  • Schemes 1-35 show general methods for preparing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • esters AIIb can be prepared according to one of the following references: Tetrahedron Lett. 1998, 39, 2941-2944; Eur. J. Org. Chem. 2004, 695-709; J. An. Chem. Soc. 2001, 123, 7727-7729; J. Am. Chem. Soc. 2002, 124, 11684- 11688; J. org. Chem. 2004, 69, 5578.
  • the N- arylation or N-heteroarylation of the Ba ring is performed with an aryl or hetero aryl halide (preferably iodide) in the presence of copper catalyst such as copper iodide or copper oxide, in the presence of a ligand such as substituted ethylene diamines, salicylaldoximes or other ligands reported in E ⁇ x. J. Org. Chem. 2004, 695-709.
  • copper catalyst such as copper iodide or copper oxide
  • a ligand such as substituted ethylene diamines, salicylaldoximes or other ligands reported in E ⁇ x. J. Org. Chem. 2004, 695-709.
  • the reaction requires a base such as potassium phosphate or alkali carbonates (potassium carbonate, sodium carbonate or cesium carbonate) and is performed in a degassed solvent such as acetonitrile, toluene or DMF at a temperature of 20 0 C to 150°C for 24 to 48 hours under inert atmosphere.
  • a base such as potassium phosphate or alkali carbonates (potassium carbonate, sodium carbonate or cesium carbonate)
  • a degassed solvent such as acetonitrile, toluene or DMF
  • esters AIIb can be prepared by direct alkylation with the corresponding halide or the corresponding sulfonate in the presence of a base such as alkali carbonates or hydrides (sodium hydride or potassium hydride) in a solvent such as DMF at a temperature ranging from 20°c to 130 0 C for 24 to 48 hours.
  • a base such as alkali carbonates or hydrides (sodium hydride or potassium hydride)
  • a solvent such as DMF
  • the corresponding halide may be used as the solvent at a temperature ranging from 20 0 C to 130 0 C for 10 to 48 hours.
  • esters AIIb can be prepared from the amine AIIa by opening of the corresponding epoxide in the presence of a base such as alkali carbonates in a solvent such as halogenated hydrochlorides (DCM or CHCl 3 ) or neat at a temperature from 20 0 C to 100 0 C for 1 to 48 hours.
  • a base such as alkali carbonates
  • a solvent such as halogenated hydrochlorides (DCM or CHCl 3 ) or neat at a temperature from 20 0 C to 100 0 C for 1 to 48 hours.
  • the alkylation is run in DMF or halogenated hydrocarbons with 1 equivalent of AIIa, 1.1-10 equivalents of halide, sulfonate or epoxide and 1-5 equivalents of base.
  • esters AIIb can be prepared with the corresponding acid halides or sulfonyl halides in the presence of a base such as sodium hydride, alkali carbonates, sodium hydroxide or triethylamine in a solvent such as DMF, acetone or halogenated hydrocarbons at a temperature ranging from 0 0 C to 130 0 C for 10 to 24 hours.
  • a base such as sodium hydride, alkali carbonates, sodium hydroxide or triethylamine
  • a solvent such as DMF, acetone or halogenated hydrocarbons at a temperature ranging from 0 0 C to 130 0 C for 10 to 24 hours.
  • this reaction is run in DMF or halogenated hydrocarbons with 1 equivalent of AIIa, 1.1-2 equivalents of acid halide or sulfonyl halide and 1-5 equivalents of base.
  • Compounds Ia-I can be prepared according to the sequence shown in Scheme 3. Esters AIIb, where Ra 8 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines AIIc. Compounds Ia-I can then be prepared from acids AIIIa and amines AIIc or their salts by reacting both intermediates in the presence of various condensing reagents.
  • Known condensing reagents that effect amide bond formation include, but are not limited to, N, N-carbonyldiimidazole, halopyridine salts, 2,4,6- trichlorobenzoyl chloride, HATU, BOP-Cl or EDAC -HCl/HOBt -H 2 O.
  • the preferred reagent is either HATU or EDAC -HCl/HOBt-H 2 O.
  • the reaction can be conducted in aprotic solvents such as tetrahydrofuran, halogenated hydrocarbons, acetonitrile, dimethylformamide, or a mixture of these solvents, at a temperature from 0°c to 130 0 C, preferably 20 0 C to 70 0 C, for a time ranging from 1 to 48 hours, preferably 10 to 20 hours.
  • a base such as triethylamine or diisopropylethylamine may be used especially if the reacting amine is in a salt form.
  • HATU or EDAC-HCl/HOBt-H 2 O amine or its salt (1 equivalent), acid (1 equivalent), HATU or EDAC-HCl/HOBt -H 2 O (1 to 2 equivalents), base (1 to 3 equivalents if salt form of amine is used) .
  • Compounds Ia-I can also be prepared from acid chlorides AIIIb and amines AIIc in the presence of a base such as triethylamine, diiisopropylethylamine or pyridine in an aprotic solvent such as THF, benzene, halogenated hydrocarbons at temperatures from 20 0 C to 90°C for 0.5 to 24 hours.
  • a base such as triethylamine, diiisopropylethylamine or pyridine
  • an aprotic solvent such as THF, benzene, halogenated hydrocarbons
  • esters AIIIc where Ra 8 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines AIIId.
  • Compounds Ia-I can be prepared under the conditions mentioned in Scheme 3 using an amine AIIId or its salt, and an acid AIId.
  • Acids AIId can be prepared from the corresponding esters AIIb by using a base such as lithium hydroxide, sodium hydroxide, alkali carbonates in a polar protic solvent such as methanol, ethanol, water or in mixtures of solvents including the mentioned polar protic solvent or other aproptic solvents.
  • the hydrolysis is performed in an alcohol (methanol or ethanol) or in a 1:1 mixture of alcohol/THF, with water in the presence of sodium hydroxide (1-10 equivalents) at a temperature ranging from 20 0 C to 100 0 C for 4 to 24 hours.
  • Acids AIId can also be prepared from the corresponding esters AIIb by acid hydrolysis using an acid such as TFA, HCl, H 2 SO 4 , AcOH or in a mixture of these acids in neat or aqueous condition at a temperature ranging from 20 0 C to 100 0 C for 0.5 to 24 hours.
  • acids AIId can be prepared from the corresponding esters AIIb by hydrogenolysis using catalysts such as palladium on carbon or palladium hydroxide in a protic solvent such as EtOH or aprotic solvent such as EtOAc, under hydrogen atmosphere at a pressure of 15 to 150 psi, at a temperature from 20 0 C to 100 0 C for 1 to 48 hours. Additional conditions for the hydrolysis of ester groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.
  • Compounds Ia can be prepared according to Scheme 5.
  • Compounds AIIIe can be the result of an amide coupling between a suitably protected amine AIVa, where Pg is preferably Boc or Cbz group, and an acid AIIIa in conditions commonly employed to form amide bonds (mentioned previously) , followed by the deprotection of the amino group.
  • Pg is Boc group
  • the deprotection is conveniently performed in the presence of acids such as TFA or HCl, neat or in a solvent such as ethyl ether or dioxane at a temperature from 0 0 C to 100 0 C for 5 minutes to 24 hours.
  • compounds AIIf can be the result of the coupling between a suitably protected amine ATVb, where Pg is preferably Boc or Cbz group, and an acid AIId under conditions commonly employed to form amide bonds, followed by deprotection of the amino group.
  • Compounds Ia can be produced by further coupling the amine AIIf with an acid AIIIa under conditions commonly employed to form amide bonds.
  • Scheme 7 shows a method for preparing compounds of formula Ia-V.
  • Aa is an optionally substituted 2-halo-pyridine ring
  • compounds Ia-V can be prepared by amine substitution.
  • an amine or its salt preferably sodium salt
  • a 2-halo- pyridine Ia-IV neat in an aprotic solvent such as THF, DMF, DMSO, halogenated hydrocarbons or in a protic solvent such as alcohols at temperatures from 60 0 C to 160 0 C for 1 to 24 hours.
  • the reaction is run with the appropriate amine (50 to 200 equivalents) as the solvent at a temperature from 110 0 C to 150 0 C for 18 to 24 hours.
  • the coupling can be performed under thermal conditions in the presence of a base such as potassium carbonate, potassium fluoride, hydrides or LDA in a solvent such as DMSO or dioxanes at temperatures from 100 0 C to 170 0 C for 1 to 48 hours.
  • a base such as potassium carbonate, potassium fluoride, hydrides or LDA
  • a solvent such as DMSO or dioxanes
  • the coupling can be performed under palladium or copper catalyzed-conditions as reported in J. Organomet. Chem. 1999, 576(1-2), 125; Angew. Chem. , Int. Ed. Engl. 1998, 37, 2046; Oxg. Lett. 2002, 4(4), 581.
  • Ra 10 is an optionally substituted hydroxyl group or an optionally substituted mercapto group and other symbols are as defined above.
  • compounds of formula Ia-VI can be prepared by halogen displacement.
  • an alcohol or a thiol is treated with an alkali hydride such as sodium hydride, potassium hydride or a lithium base such as LDA or BuLi to form the corresponding alkoxide or thioalkoxide, which can then react with a 2-halo-pyridine, under conditions similar to those mentioned above, to yield compounds Ia-VI.
  • an alkali hydride such as sodium hydride, potassium hydride or a lithium base such as LDA or BuLi
  • the 2-halo-pyridine can also be treated with an alcohol or a thiol in the presence of a base such as alkali carbonates in solvents such as DMF or DMSO at temperatures from 100 0 C to 170 0 C for 10 to 48 hours.
  • a base such as alkali carbonates
  • solvents such as DMF or DMSO
  • the alkoxide or thioalkoxide (1 to 5 equivalents) is formed in the presence of sodium hydride (1 to 5 equivalents) in a solvent such as THF at a temperature from 0 0 C to 30 0 C, and then reacted with a 2-halo-pyridine Ia-IV at temperatures from 60 0 C to 80 0 C for 3 to 16 hours.
  • Ra 11 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
  • the "optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” for Ra 11 those exemplarily recited as the “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”, which are those exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 5 or Ra 7 , can be mentioned.
  • Scheme 9 shows methods for preparing compounds of formula Ia-IX.
  • Compounds Ia-IX can be conveniently prepared from compounds Ia-IV under palladium-catalyzed conditions such as Suzuki (Chem. Rev. 1995, 95, 2457) or Negishi (Negishi, Ei- ichi. Handbook of Organopalladium Chemistry for Organic Synthesis (2002), 1, 767-789; John Wiley & Sons, Inc., Hoboken, N. J) .
  • the coupling is performed between a boronic acid or a zinc halide and compound Ia-IV in the presence of a catalysts such as, but not limited to, Pd ⁇ PPh3)4/ Pd(OAc) 2 / PdCl 2 (dppf) or PdCl 2 (PPh) 2 , a base such as alkali carbonates, alkali phosphates (sodium phosphate or potassium phosphate) or potassium fluoride and a ligand (J " . Am. Chem. Soc. 1999, 121, 9550 - 9561) such as phosphines in a solvent such as toluene, THF, alcohols, water or mixtures of the above solvents.
  • a catalysts such as, but not limited to, Pd ⁇ PPh3)4/ Pd(OAc) 2 / PdCl 2 (dppf) or PdCl 2 (PPh) 2
  • a base such as alkali carbonates, alkali phosphat
  • Ra 11 is an alkyl group
  • the reaction is performed using alkyl zinc bromide (2 to 3 equivalents), compound Ia-IV (1 equivalent) and PdCl 2 (dppf) - CH 2 Cl 2 (0.1 equivalents) in a solvent such as THF at a temperature from 20 0 C to 75°C for 0.5 to 24 hours.
  • a solvent such as THF
  • 9-benzyl-9-bora- bicyclo[3.3.1]nonane may be used under similar conditions to those mentioned above.
  • Ra 11 is an aromatic or hetero aromatic group
  • the reaction is performed in the presence of a boronic acid (1.5-3 equivalents), a palladium catalyst such as Pd(OAc) 2 / Pd(PPh3)4 or Pd 2 (dba)3 (0.1 to 1 equivalent), a ligand such as 2, 8, 9-triisobutyl-2, 5, 8, 9- tetraaza-l-phos ⁇ ha-bicyclo[3.3.3]undecane and a base such as alkali carbonates in a solvent such as toluene or THF at a temperature from 45°C to 120 0 C, preferably 90 0 C, for 1 to 16 hours .
  • a boronic acid 1.5-3 equivalents
  • a palladium catalyst such as Pd(OAc) 2 / Pd(PPh3)4 or Pd 2 (dba)3 (0.1 to 1 equivalent)
  • a ligand such as 2, 8, 9-triisobutyl-2, 5, 8, 9- tetra
  • Ra 12 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
  • Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Scheme 10 shows methods for preparing compounds of formula Ia-XI.
  • Compounds Ia-XI can be conveniently prepared from sulfides Ia-X, prepared according to similar conditions to those described in Scheme 8, under oxidative conditions. Suitable oxidants include, but are not limited to, KMnOo MCPBA, OXONE or hydrogen peroxide.
  • the reaction is typically performed in solvents such as THF, acetone, halogenated hydrocarbons, or a mixture of the mentioned solvents at a temperature from 0 0 C to 25°C for 1 to 24 hours.
  • An acidic co- reagent such as formic acid may be used.
  • a sulfide Ia-X (1 equivalent) is preferably treated with KMnO 4 (1.5 to 4 equivalents) and formic acid (5 to 10 equivalents) in a THF/acetone (1:2) solvent system at 25°C to 60 0 C for 8 to 48 hours.
  • Scheme 11 shows methods for preparing compounds of formula Ia-XVI where the Aa ring is substituted with a nitrile group.
  • Compounds Ia-XVI can be prepared by nucleophilic substitution in the presence of nitrile equivalents such as NaCN, KCN or CuCN in solvents such as DMF or DMSO at temperatures from 8O 0 C to 180 0 C for 1 to 48 hours.
  • Compounds Ia-XVI can also be prepared from halides Ia-IV in the presence of Zn(CN) 2 or KCN and a palladium catalyst such as Pd (PPh 3 ) 4 or Pd(OAc)2 and a phosphine in ' solvents such as DMF at 8O 0 C to 140 0 C for 1 to 24 hours (for a review on Pd-catalyzed cyanation of aryl halides see Eur. J. Inorg. Chem. 2003, 19, 3513) .
  • the reaction is performed using CuCN (1 to 2 equivalents) in a solvent such ' as DMF at a temperature from 130 0 C to 160 0 C for 16 to 48 hours.
  • Scheme 12 shows methods for preparing compounds of formula Ia-XVII where the Aa ring is substituted with a carboxylic ester group.
  • Compounds Ia-XVII can be prepared by alkoxycarbonylation of halides Ia-IV using a palladium-ligand catalyst such as (R) - (Binap) PdCl 2 or PdCl 2 (PPh 3 ) 2 in the presence of a base such as triethylamine, Hunig' s base, alkali carbonates or alkali hydroxides (lithium hydroxide, sodium hydroxide or potassium hydroxide) in solvents such as toluene or alcohols under carbon monoxide atmosphere (J " . Organomet. Chem.
  • a palladium-ligand catalyst such as (R) - (Binap) PdCl 2 or PdCl 2 (PPh 3 ) 2 in the presence of a base such as triethylamine, Hunig' s base, al
  • halides Ia-IV are preferably treated with (R)- (Binap) PdCl 2 (0.01 to 0.1 equivalents) and triethylamine (1 to 2 equivalents) in alcohol (preferably methanol or ethanol) under carbon monoxide pressure (30-100 psi) at a temperature from 20 0 C to 100 0 C for 24 to 48 hours.
  • alcohol preferably methanol or ethanol
  • Ra is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
  • Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Scheme 13 shows methods for preparing compounds of formula Ia-XVIII.
  • Compounds Ia-XVIII can be prepared by amidation of halides Ia-IV under copper-mediated or palladium- mediated conditions reported in Schemes 7 and 9 (for specific amidation coupling, see J. Am. Chem. Soc. 2002, 124(25), 7421) .
  • halides Ia-rv are treated with an amide Ra 13 CONH 2 (1 to 2 equivalents) in the presence of Pd 2 (dba) 3 (0.1 to 1 equivalents) , Xantphos (0.1 to 1 equivalent) and an alkali carbonate (1 to 3 equivalents) in a solvent such as dioxane at a temperature from 80 0 C to 120 0 C, preferably 100 0 C, for 3 to 24 hours.
  • a solvent such as dioxane
  • Scheme 14 shows methods for preparing compounds of formula Ia-XIX.
  • Compounds Ia-XIX can be prepared under Heck conditions from halides Ia-IV and vinyl alkoxides followed by hydrolysis of the resulting alkyl enol (for a description of the Heck reaction and its applications to organic synthesis see, Negishi, Ei-ichi. Handbook of Organopalladi ⁇ m Chemistry for Organic Synthesis (2002), 1, pll33-1178; John Wiley & Sons, Inc., Hoboken, N. J; Angew. Chem. , Int. Ed. Engl. 2002, 41, 4176; Tetrahedron 2001, 57, 7449) .
  • halides Ia-IV can be treated with tributyl (1-ethoxyvinyl) stannane under Stille conditions followed by hydrolysis of the resulting alkyl enol (for a description of the Stille reaction and its applications to organic synthesis see, Aqueous-Phase Organometallic Catalysis (2nd Edition) (2004), 511-523. Publisher: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany) .
  • halides Ia-IV are treated with 1- (vinyloxy) butane (1 equivalent) in the presence of Pd (OAc) 2 (0.1 to 1 equivalent), dppp (0.2 to 2 equivalents) and alkali carbonate (1 to 3 equivalents) in a solvent such as DMF, toluene, water or a mixture of the mentioned solvents at a temperature from 6O 0 C to 140 0 C, preferably 8O 0 C, for 1 to 48 hours.
  • a solvent such as DMF, toluene, water or a mixture of the mentioned solvents
  • the resulting vinyl enol can then be hydrolyzed to the acetyl group by treatment with acid, typically 2N HCl at 20 0 C for 1 to 24 hours.
  • Ra 14 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
  • Compounds of formula Ia-XX can be prepared by treating a nitrile Ia-XVI with hydroxylamine hydrochloride (1 to 1.5 equivalents) in solvents such .as aqueous alcohols (ethanol) at a temperature of 0 0 C to reflux for 1 to 24 hours.
  • solvents such .as aqueous alcohols (ethanol) at a temperature of 0 0 C to reflux for 1 to 24 hours.
  • Ra 14 is not a hydrogen atom
  • Ia-XX or its salts can be treated with an acid (Ra 14 CO 2 H), an acid anhydride ((Ra 14 CO) 2 O) or an acid chloride (Ra 14 COCl) in the presence of a base, CDI, .
  • Ia-XX is reacted with and acid chloride (Ra 14 COCl) (1-1.5 equivalents) in a base such as pyridine at a temperature from 60 0 C to 100 0 C for 1 to 24 hours.
  • a base such as pyridine
  • Ia-XX is reacted in a trialkyl orthoformate (solvent) in the presence of boron trifluoride etherate (1 equivalent) at a temperature between 60 0 C to 140 0 C for 1 to 24 hours, to yield compounds Ia-XXI.
  • Ra 15 and Ra 16 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group and other symbols are as defined above.
  • Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Compounds of formula Ia-XXIII can be prepared from compounds Ia-XVII (preferably Ra 8 is methyl or ethyl group) , ' using hydrolysis methods similar to those described in Scheme 4.
  • Compounds Ia-XXIII can be converted to the carbamates Ia- XXIV/ wherein Ra 15 is a hydrogen atom and Ra 16 is an alkoxycarbonyl group (preferably tert-butoxycarbonyl group) or vice versa, via a Curtius type rearrangement (for a description of the Curtius rearrangement and its applications to organic synthesis, see, Chem. Soc. Rev. 2006, 35(2), 146- 56).
  • acids Ia-XXIII (1 equivalent), diphenylphosphoryl azide (1 to 1.5 equivalents) and triethylamine (1 to 1.5 equivalents) are reacted in tert- 5 butanol for 1 to 3 days at 80 0 C.
  • the tert-butoxycarbonyl group is removed using acidic conditions (TFA or 4N HCl in dioxane) at room temperature to provide the unsubstituted amine Ia- XXIV, wherein Ra 15 and Ra 16 are both hydrogen atoms, or its salt.
  • Compounds Ia-XXIV, wherein Ra 15 and Ra 16 are
  • the coupling reagent of choice is HATU or EDAC -HClZHOBt 1 H 2 O in a solvent such as
  • ill transformation may also be accomplished by treating the unsubstituted amine or its salt with the corresponding acid halid ⁇ / acid anhydride, sulfonyl halide, isocyanate, carbamic halid ⁇ / haloformate or dicarbonate in the presence of an organic base such as pyridine/ triethylamine, diisopropylethylamine or an inorganic base such as alkali hydrides or alkali carbonates in a solvent such as acetone, THF, halogenated hydrocarbons or DMF at a temperature from 20 0 C to 130 0 C for 1 to 72 hours.
  • an organic base such as pyridine/ triethylamine, diisopropylethylamine or an inorganic base
  • alkali hydrides or alkali carbonates in a solvent such as acetone, THF, halogenated hydrocarbons or DMF at a temperature from 20 0 C to 130 0 C for 1 to 72 hours.
  • Compounds Ia-XXIV wherein Ra .15 and Ra 15 are independently a hydrogen atom, an optionally substituted aryl group or an optionally substituted heteroaryl group (excluding the case where Ra or Ra ,1 1 6 are both hydrogen atoms) can be prepared by reacting an unsubstituted amine Ia- XXrv or its salt with an activated aryl or heteroaryl halide under S N AT conditions (basic conditions in a polar, protic solvent; suitable bases include potassium hydride, sodium hydride, potassium tert-butoxide, lithium hydroxide or alkali carbonates in solvents such as DMF, DMSO or THF) , or an aryl or heteroaryl halide under palladium mediated conditions (conditions for these transformations can be found in Angew. Chem. Int. Ed. 1998, 37, 2046; Organomet. Chem. 1999, 576, 125) .
  • Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Compounds of formula Ia-XXV can be prepared from acids Ia-XXIII (prepared according to the method described in Scheme 16) and an amine under conditions commonly employed for the formation of amide bonds.
  • Ra 18 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
  • Scheme 18 shows a method for preparing intermediates AIIIi which are suitable for use in preparing compounds of formulas Ia and Ia-I as shown in Schemes 3, 4 and 5.
  • Compounds of formula AIIIi may be prepared from compounds AIIIh by reaction with alkyl zinc halides using Negishi conditions or with aryl/heteroaryl boronic acids using Suzuki conditions using similar methods to those described in Scheme 9.
  • the bis coupling can be achieved using excess reagent (3 to 5 equivalents) .
  • Compounds AIIIi can be converted to the corresponding acids under conditions commonly employed.
  • Ra 19 and Ra 20 are each independently an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or acyl group, and other symbols are as defined above.
  • Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 can be mentioned.
  • Scheme 19 shows a method for preparing intermediates AIIg which are suitable for use in preparing compounds of formulas Ia and Ia-I as shown in Schemes 3, 4 and 5.
  • Compounds of formula AIIg can be prepared from amines of formula AIIf using similar methods to those described in Scheme 16.
  • compounds AIIf * can be prepared according to the procedure described J. Het. Chem. 1967, pp. 325.
  • Ra 21 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • Ra 22 is a C 1 -C 2 alkoxy group, NH 2 or NMe 2 and other symbols are as defined above .
  • the "optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” for Ra 21 those exemplarily recited as the “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”, which are those exemplarily recited as the "substituent" for Ra 1 , Ra 2 , Ra 3 , Ra 4 , Ra 5 , Ra 6 or Ra 7 , can be mentioned.
  • Scheme 20 shows a method for preparing intermediates AVc which are suitable for use in preparing compounds of formula AIIb as shown in Scheme 2.
  • Compounds of formula AVb may be prepared from ⁇ -ketoesters of formula AVa.
  • Ra 22 is a C1-C2 alkoxy group
  • compounds AVb can be prepared by reacting the ⁇ -ketoester AVa (1 equivalent) with a trialkyl orthoformate (2 equivalents) and acetic anhydride (5 equivalents) at 50 0 C to 100 0 C for 4 to 24 hours.
  • compound AVb can be prepared by reacting the ⁇ -ketoester AVa (1 equivalent) in DMF-DMA (2 to 50 equivalents) in the presence of a base such as triethylamine neat or in a solvent such as THF, toluene or halogenated hydrocarbons at a temperature from O 0 C to 100 0 C for 1 to 48 hours.
  • a base such as triethylamine neat or in a solvent such as THF, toluene or halogenated hydrocarbons
  • Ra 22 is NH2 / compound AVb can be prepared by reacting the ⁇ -ketoester AVa with 3-methyl-5-nitropyrimidin-4 (3H) -one according to the procedure described in Synlett 2004, 4, 703.
  • pyrazoles AVc are conveniently prepared by reaction with hydrazine, its salts or hydrates in solvents such as alcohols or ethers at temperatures from 6O 0 C to 100 0 C for 2 to 24 hours.
  • compound AVb, where Ra 22 is a C1-C2 alkoxy group is treated with hydrazine hydrate (1 to 10 equivalents) in ethanol at reflux for 3 to 12 hours.
  • Ra 22a is a C1-C2 alkyl group
  • Ra 23 and Ra 25 are each independently an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, provided that R 23 is not optionally substituted quinolyl
  • Ra 24 is a hydrogen atom or acetyl group, and other symbols are as defined above.
  • Scheme 21 shows a method for preparing intermediates AVf which are suitable for use in preparing compounds of formulas Ia and Ia-I as shown in Schemes 3, 4 and 5.
  • Compounds of formula AVd may be prepared from alkylmalonates according to a similar method described in Scheme 20.
  • Compound AVd can be treated with substituted hydrazine or substituted acetyl hydrazide in the presence of POCI3 or a base such as sodium ethoxide following the procedures described in Tetrahedron 1977, 33, 2829; Tetrahedron 1987, 43(3), 607 and WO2001023358, to yield the pyrazolinones AVe.
  • Compound AVe can be converted to compound AVf in the presence of the corresponding activated halides and a base such as alkali hydrides or alkali carbonates in solvents such as acetonitrile or DMF at temperatures from 0 0 C to 130 0 C for 1 to 24 hours.
  • dialkyl (alkyloxy)malonates AVd are preferably treated with POCl 3 in the presence of an aryl acetylhydrazide to afford the pyrazolinones Ave, which can then be reacted with the corresponding halides (1 to 2 equivalents) in the presence of a base such as potassium carbonate (1 to 3 equivalents) at a temperature from 20 0 C to 60 0 C for 3 to 12 hours.
  • Ra 26 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic (aromatic or non- aromatic) group and other symbols are as defined above.

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Abstract

The present invention provides compounds represented by the formula (Ia) the formula (Ib) the formula (Ic) and the formula (Id) wherein each symbol is as defined in the specification. According to the present invention, these compounds have a DGAT inhibitory activity and are useful for the prophylaxis, treatment or improvement of diseases or pathologies caused by high expression or high activation of DGAT.

Description

DESCRIPTION AMIDE COMPOUNDS
TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel amide compound having a diacylglycerol acyl transferase (hereinafter sometimes to be abbreviated as DGAT in the present specification) inhibitory activity, which is useful for the treatment of obesity, hyperlipidemia, diabetes and the like. BACKGROUND OF THE INVENTION
Obesity is a state of excess accumulation of fat, mainly triglyceride, in the body, and is deeply "involved in the progression into the pathology such as arteriosclerosis, diabetes, hypertension and the like. Therefore, the development of a drug for the prophylaxis or treatment thereof has been desired. In mammals, two major triglyceride synthesis pathways have been biochemically clarified. One is the glycelophosphoric acid pathway present in all tissues, and the other pathway is a monoglyceride pathway. In any pathway, fatty acid in the cell is converted to acyl coenzyme A by an acyl coenzyme A synthetase and introduced into triglyceride through the both pathways. As the enzyme involved in the final stage of the intracellular or intraorgan triglyceride synthesis process, DGAT has been known. As DGAT, DGATl and DGAT2 have been cloned. DGATl knockout mice have been created and analyzed. As a result, the mice did not become obese easily with high fat diet and showed promoted energy consumption and insulin sensitivity, as compared to wild-type mice. In a mating test of DGATl knockout mice and Ay/a mice, moreover, body weight gain was suppressed with a normal diet and a phenotype of promoted insulin sensitivity and elimination of leptin resistance was shown. Thus, DGATl inhibitors are expected to be antiobesity drugs.
DGAT is an enzyme (EC2.3.1.20) also designated as acyl coenzyme A: diacylglycerol acyl transferase. cDNA cloning of DGATl is reported in Proc. Natl. Acad. Sci. USA. 95, 13018- 13023, 1998, and cDNA cloning of DGAT2 is reported in The Journal of Biological Chemistry, 276, 42, 38862-38869, 2001 and The Journal of Biological Chemistry, 276, 42, 38870-38876, 2001. Since the enzyme molecule of DGAT was not clarified for a long time, there is not much finding relating to the DGAT activity. Since the DGAT activity is detected in the endoplasmic reticulum membrane fraction, it was considered to be an endoplasmic reticulum membrane protein. However, ever since cDNA cloning of DGAT was reported, the properties thereof have been rapidly elucidated. For example, it has been reported to be a protein forming a tetramer in Biochem. Journal, 359, 707-714, 2001. A knockout mouse of DGATl (DGATl defective mouse) was created and its phenotype was reported in Nature Genetics, 25, 87-90, 2000, The Journal of Clinical
Investigation, 109, 175-181, 2002 and The Journal of Clinical Investigation, 109, 1049-1055, 2002. From these reports, the DGATl inhibitors have been suggested to show an antiobesity action, an anti-insulin resistance action, and an anti-leptin resistance action, and DGATl inhibitors are expected to become pharmaceutical products.
In addition, DGAT2 knockout mice were also created and their phenotype is reported in The Journal of Biological Chemistry, 279, 11767-11776 (2004) . As a result, DGAT2 was clarified to be an enzyme that plays a key role in the synthesis of triglyceride in the liver. The Journal of Biological Chemistry, 274,. 35577-35582, 1999 reports that there are a DGAT activity involved in a storage-type triglyceride synthesis in the cytoplasm side of the endoplasmic reticulum membrane and a DGAT activity that supplies triglyceride to be mobilized for lipoprotein secretion in the lumen side, which suggests that DGATl and DGAT2 play different roles as triglyceride synthases and further that DGAT2 inhibitors are effective for hypertriglyceridemia. In addition, since DGAT expression is promoted in various pathologies and diseases such as obesity, diabetes, insulin- resistant diabetes, leptin resistance, arteriosclerosis, hypertriglyceridemia, hypercholesterolemia, arteriosclerosis, hypertension and the like, high expression or hyper activation of DGAT is suggested to be involved in the excess accumulation of triglyceride in the cell, tissue or organ, and closely involved in the onset and aggravation of these diseases .
In, for example, fat organs and adipocytes, expression of DGAT is regulated by hormones such as insulin, leptin and the like, and DGAT is suggested to be deeply involved in the pathologies such as insulin resistance, leptin resistance and the like. Therefrom it is considered that a compound having a DGAT inhibitory activity is effective for the treatment of obesity, insulin resistant diabetes, hyperorexia or obesity based on leptin resistance.
As amide compounds, the following compounds are known.
(1) Amide compounds useful as leukemia therapeutic agents (Journal of Medicinal Chemistry (2005), 48(24), 7906-7910).
(2) A compound represented by the following formula (I), which is useful as an orexin receptor antagonist (WO01/96302) :
Figure imgf000005_0001
wherein: Y represents a group (CH2Jn/ wherein n represents 0, 1 or
2;
R1 is phenyl, naphthyl, a mono or bicyclic heteroaryl group; or a group NR3R4, wherein one of R3 and R4 is hydrogen or optionally substituted (Ci-.<j)alkyl and the other is phenyl, naphthyl or a mono or bicyclic heteroaryl group, or R3 and R4 together with the N atom to which they are attached form a 5 to 7-membered cyclic amine which has an optionally fused, phenyl ring; any of which R1 groups may be optionally substituted;
R2 represents phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is substituted by R5, and further optional substituents; or R2 represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group;
R5 represents an optionally substituted Ci-4 alkoxy, halo, optionally substituted Ci_6 alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring.
(3) A compound represented by the following formula, which is useful as a herbicide (WO01/46152) :
Figure imgf000006_0001
wherein: one of Rla and Rlb is a methyl, hydroxymethyl or monohalomethyl group and the other is hydrogen;
X1 is a methylene, oxy or thio linkage; m is 0 or 1;
RA2 is a hydrogen, halogen or methyl group;
RA3 is a halogen or halomethyl group; and
R4 is an <χ-halo- or α/α~dihalo- (C1-3) alkyl group or a group having the formula -(X2Jn-R5, where X2 is a methylene, oxy or thio linkage, n is 0 or 1, and R5 is an optionally substituted 5- or 6-member aromatic or heterocyclic ring. (4) A compound represented by the following formula (I), which is useful as a phosphodiesterase 4 (PDE4) inhibitor (WO2005/116009) :
Figure imgf000007_0001
wherein : the formula ( II ) is a 5-meiribered heteroaryl;
X is' S or 0; R1 is H, alkyl, cycloalkyl, cycloalkylalkyl-, or the like;
R3 and R4 are each independently H, alkyl, hydroxyalkyl or -C(O)-O-alkyl;
R5 and R6 are each independently H, alkyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, or the like;
R7 is H, alkyl, alkenyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, (R17-phenyl) alkyl or -CH∑-C (O) -O-alkyl; and R8 is alkyl, heteroaryl, phenyl, cycloalkyl, or heterocycloalkyl, all optionally substituted, of a cycloalkyl- or heterocycloalkyl- substituted amide; or R7 and R8 and the nitrogen to which they are attached together form an optionally substituted ring;
R9 is H, halo, alkyl, cycloalkyl, or the like;
R10, R11, and R13 are each independently H or halo; R17 is 1 to 3 substituents independently selected from the group consisting of H, halo, cycloalkyl, and the like.
(5) Amide compounds useful as farnesyltransferase inhibitors (Journal of Combinatorial Chemistry (2004), 6(3), 407-413).
(6) A compound represented by the following formula (I) , which is useful as an adenosine receptor ligand (WO2003/045385) :
Figure imgf000008_0001
wherein:
R is hydrogen, - (CH2) n-phenyl optionally substituted, - (CH2) n-pyridinyl optionally substituted, - (CH2)n-C3-6-cycloalkyl optionally substituted, - (CH2) n~N (R1 ) -C3_6-cycloalkyl optionally' substituted, - (CH2)n-benzo [1, 3]-dioxolyl, - (CR'2)n-thiophenyl optionally substituted, - (CR'2) n-thiazolyl optionally substituted, - (CH2)H-C (0) -thiophenyl optionally substituted, - (CH2) n-furany1 optionally substituted, - (CH2) n-C (O) - (CH2) n- thiophenyl, - (CHR1 ) n-benzofuran-2-yl, - (CH2) n-benzo [b] thiophenyl optionally substituted, - (CH2) n-N (R' ) -C (O) -phenyl optionally substituted, - (CH2) n~C (O) -phenyl optionally substituted, - (CH2Jn-C(O) -2, 3-dihydro-benzo [1, 4]dioxin-6-yl, -(CHz)n-N(R1)- C(O) -pyridinyl, - (CH2) n-tetrahydrofuranyl, -CH-bi-phenyl, - CH (phenyl) -pyridinyl, - (CH2) n-l-oxo-l73-dihydro-isoindol-2-yl, - (CH2) n-l,3-dioxo-l,3-dihydro-isoindol-2-yl, - (CH2Jn-CH (phenyl) - tetrahydropyranyl, - (CH2) n-l-oxo-l, 2, 3, 4-tetrahydro- isoquinolin-3-yl or (CH2) n-S- [1, 3, 4] thiazol-2-yl optionally substituted; R1 is hydrogen or lower alkyl, independently from each other in case R'2; and n is 0, 1, 2, 3 or 4.
(7) Amide compounds useful as synthetic intermediates for tripodal ligands (Helvetica Chimica Acta (1998), 81(2), 207- 218) .
(8) Amide compounds useful as radical scavengers (Tetrahedron (2004), 60(39), 8729-8738).
However, none of the above-mentioned prior art reports on the compound of the present invention. DISCLOSURE OF THE INVENTION
There is a demand on the development of a novel compound having a superior DGAT inhibitory activity and superior in properties (stability, solubility etc.), oral absorbability, migration to target organs and the like.
The present inventors have searched for a compound having a DGAT inhibitory activity, and found that the compounds represented by the below-mentioned formulas (Ia) , (Ib) , (Ic) and (Id) have a superior DGAT inhibitory activity, and are superior in the properties as a pharmaceutical product, such as stability and the like, which resulted in the completion of the present invention.
Accordingly, the present invention relates to [1] A compound represented by formula (Ia) :
Figure imgf000009_0001
wherein ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted; Ra1 is a hydrogen atom or a substituent; ring Aa is an optionally substituted aromatic heterocycle; and
Ra2, Ra3, Ra4, Ra5, Ra6 and Ra7 are each independently a hydrogen atom or a substituent; provided that
1) when ring Ba is pyrazole which is optionally further substituted, then ring Ba does not have optionally substituted tetrahydrofurylmethoxy as a substituent other than Ra1;
2) when ring Ba is imidazole which is optionally further substituted, then ring Ba does not have optionally substituted quinolyl as a substituent other than Ra1;
3) when ring Ba is pyrazole which is optionally further substituted, then Ra1 is not optionally substituted quinolyl; and
4) ring Aa is not the same as ring Ba; or a salt thereof (hereinafter to be abbreviated as compound (Ia));
[IA] a compound represented by formula (IaA) :
Figure imgf000010_0001
wherein ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted;
Ra1 is a hydrogen atom or a substituent; ring Aa is an optionally substituted aromatic heterocycle; and Ra2, Ra3, Ra4, Ra5, Ra6 and Ra7 are each independently a hydrogen atom or a substituent; provided that
1) ring Ba is not oxadiazole which is optionally further substituted; 2) when ring Ba is pyrazole which is optionally further substituted, then ring Ba does not have optionally substituted tetrahydrofurylmethoxy as a substituent other than Ra1;
3) when ring Ba is imidazole which is optionally further substituted, then ring Ba does not have optionally substituted quinolyl as a substituent other than Ra1;
4) when ring Ba is pyrazole which is optionally further substituted, then Ra1 is not optionally substituted quinolyl; and
5) ring Aa is not the same as ring Ba; ' or a salt thereof;
[2] The compound of above-mentioned [1], wherein ring Ba is pyrazole, benzimidazole, indole or indazole, each of which is optionally further substituted;
[3] The compound of above-mentioned [1], wherein Ra1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group; [4] The compound of above-mentioned [1], wherein ring Aa is an aromatic heterocycle optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, a cyano group, an acyl group and a halogen atom; [5] The compound of above-mentioned [1], wherein Ra2, Ra3, Ra4, Ra5, Ra6 and Ra7 are both hydrogen atoms; [6] A compound represented by formula (Ib) :
Figure imgf000011_0001
wherein ring Bb is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted; ring Cb is an optionally substituted aromatic heterocycle; and ring Ab is an optionally substituted aromatic hydrocarbon; provided that when ring Bb is pyrazole which is optionally further substituted, then ring Cb is not optionally substituted quinoline; or a salt thereof (hereinafter to be abbreviated as compound
(Ib));
[7] The compound of above-mentioned [6], wherein ring Bb is pyrazole, benzimidazole, indole or indazole, each of which is optionally further substituted; [8] The compound of above-mentioned [6], wherein ring Cb is an aromatic heterocycle optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group/ a Ci-6 alkyl group and a Ci_6 alkoxy group; [9] The compound of above-mentioned [6], wherein ring Ab is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom;
[10] A compound represented by formula (Ic) :
Figure imgf000012_0001
wherein ring Bc is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted; ring Cc is an optionally substituted aromatic ring; ring Ac is an optionally substituted aromatic hydrocarbon; and
Rc2, Rc3, Rc", Rc5, Rc6 and Rc7 are each independently a hydrogen atom or a substituent, or any two of Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 are optionally bonded to each other to form a non-aromatic ring; provided that
1) ring Bc is not pyrazol-5-yl and 2H-1, 2, 3-triazol-4- yl, each of which is optionally further substituted;
2) ring Cc is not optionally substituted quinoline;
3) a compound wherein Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 are hydrogen atoms is excluded; and
4) when Rc6 and Rc7 are bonded, then they do not form piperazine; . or a salt thereof (hereinafter to be abbreviated as compound (Ic));
[11] The compound of above-mentioned [10], wherein ring Bc is pyrazole, benzimidazole, indole or indazole, each of which is- optionally further substituted;
[12] The compound of above-mentioned [10], wherein ring Cc is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, a Ci-6 alkyl group and a Ci_6 alkoxy group; [13] The compound of above-mentioned [10], wherein ring Ac is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom;
[14] The compound of above-mentioned [10], wherein Rc2 and Rc3 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a non-aromatic ring, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle;
[15] The compound of above-mentioned [10], wherein Rc4 and Rc5 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a non-aromatic ring, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle;
[16] The compound of above-mentioned [10], wherein Rc6 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle;
[17] The compound of above-mentioned [10], wherein Rc7 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle; [18] A compound represented by formula (Id) :
Figure imgf000014_0001
wherein ring Bd is an aromatic heterocycle which is optionally further substituted; ring Cd is an optionally substituted aromatic ring; and ring Ad is an optionally substituted aromatic hydrocarbon; provided that
1) ring Bd is not pyrazol-4-yl and pyrrol-3-yl, each of which is optionally further substituted;
2) ring Cd is not optionally substituted quinoline; 3) when ring Bd is pyridine or quinoline, each of which is optionally further substituted, then ring Bd has substituent (s) besides ring Cd; and
4) when ring Bd is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted, then ring Bd does not have an optionally substituted aromatic heterocyclic group as a substituent other than ring Cd and ring Cd is an optionally substituted aromatic hydrocarbon; or a salt thereof (hereinafter to be abbreviated as compound (Id));
[19] The compound of above-mentioned [18], wherein ring Bd is pyridine, pyrazole, triazole or indole, each of which is optionally further substituted;
[20] The compound of above-mentioned [18], wherein ring Cd is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, a Ci-6 alkyl group and a Ci_6 alkoxy group;
[21] The compound of above-mentioned [18] , wherein ring Ad is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom;
[22] N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (Example A27) ;
6- (cyclopropylmethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (Example A35) ;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (3, 3, 3-trifluoropropoxy) nicotinamide (Example A42) ;
6- (2- (ethylsulfonyl) ethoxy) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide
(Example A43) ;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6-propylnicotinamide (Example A47);
1-phenyl-N- (2- ( 6- (2, 2, 2-trifluoroethoxy) nicotinamido) ethyl ) - lH-indole-3-carboxamide (Example A53) ;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6-o-tolylnicotinamide (Example A73) ; 1-benzoyl-N- (2- (6- (2, 2, 2-trifluoroethoxy) nicotinamide) ethyl) - lH-indole-3-carboxamide (Example A82);
6- (5-isopropyl-l,2, 4-oxadiazol-3-yl) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide
(Example Al03) ; or N- (2- (4-ethoxybenzamido) ethyl) -1- (pyridin-2-yl) -3-
(trifluoromethyl)-lH-pyrazole-4-carboxamide (Example B3) ; or a salt thereof;
[23] A prodrug of the compound of above-mentioned [1], [6],
[10] or [18]; [24] A pharmaceutical agent comprising the compound of above- mentioned [1], [6], [10] or [18], or a prodrug thereof; [25] The pharmaceutical agent of above-mentioned [24], which is an agent for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes; [26] A DGAT inhibitor comprising the compound of above- mentioned [1], [6], [10] or [18], or a prodrug thereof; [27] Use of the compound of above-mentioned [1], [6], [10] or [18], or a prodrug thereof for the production of an agent for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes;
[28] Use of the compound of above-mentioned [1], [6], [10] or
[18], or a prodrug thereof for the production of a DGAT inhibitor;
[29] A method for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes in a mammal, which comprises administering the compound of above-mentioned [1], [6], [10] or [18], or a prodrug thereof to the mammal;
[30] A method of inhibiting DGAT in a mammal, which comprises administering the compound of above-mentioned [1], [6], [10] or [18], or a prodrug thereof to the mammal; and the like.
The compound (Ia), compound (Ib), compound (Ic) and compound (Id) (these are also collectively referred to as the compound of the present invention in this specification) have a DGAT inhibitory activity and are useful for the prophylaxis, treatment or amelioration of diseases or pathologies caused by high expression or high activation of DGAT (sometimes to be abbreviated as DGAT-related diseases in this specification) . Detailed. Description of The Invention In the present specification, unless otherwise specified, the "halogen atom" means fluorine atom, chlorine atom, bromine atom or iodine atom.
In the present specification, unless otherwise specified, the "Ci_3 alkylenedioxy group" means methylenedioxy, ethylenedioxy, trimethylenedioxy or the like. In the present specification/ unless otherwise specified, the "Ci-6 alkyl group" means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl or the like.
In the present specification, unless otherwise specified, the "Ci-6 alkoxy group" means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or the like.
In the present specification, unless otherwise specified, the λλCi-6 alkoxy-carbonyl group" means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl or the like. In the present specification, unless otherwise specified, the "Ci-6 alkyl-carbonyl group" means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl or the like.
Each symbol in the formula (Ia) is described in detail in the following.
Ra1, Ra2, Ra3, Ra", Ra5, Ra6 and Ra7 are each independently a hydrogen atom or a substituent.
As the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra1, an "optionally substituted hydrocarbon group", an
"optionally substituted heterocyclic group", an "optionally substituted hydroxy group", an "optionally substituted amino group", an "optionally substituted mercapto group", a "cyano group", a "nitro group", an "acyl group", a "halogen atom" and the like can be mentioned.
As the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group", for example, a Ci-io alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C4-10 cycloalkadienyl group, a C6-I4 aryl group, a C7-J-3 aralkyl group, a C8-i3 arylalkenyl group, a C3-10 cycloalkyl-Ci-6 alkyl group and the like can be mentioned.
Here, as the Ci_i0 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3,3- dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like can be mentioned.
As the C2-10 alkenyl group, for example, ethenyl, 1- propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1- hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned. As the C2-10 alkynyl group, for example, ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1- octynyl and the like can be mentioned. As the C3-10 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
As the C3-10 cycloalkenyl group, for example, 2- cyclopenten-1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl, 3- cyclohexen-1-yl and the like can be mentioned.
As the C4-.10 cycloalkadienyl group, for example, 2,4- cyclopentadien-1-yl, 2, 4-cyclohexadien-l-yl, 2,5- cyclohexadien-1-yl and the like can be mentioned.
The above-mentioned C3-10 cycloalkyl group, C3-10 cycloalkenyl group and CVio cycloalkadienyl group are each optionally condensed with a benzene ring, and as such a fused ring group, for example, indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
The above-mentioned C3-10 cycloalkyl group, C3-10 cycloalkenyl group and C4-10 cycloalkadienyl group each may be a C7-10 crosslinked hydrocarbon group. As the C7-Io crosslinked 'hydrocarbon group, bicyclo [2.2.1] heptyl (norbornyl) , bicyclo[2.2.2]octyl, bicyclo [3.2. l]octyl, bicyclo [3.2.2]nonyl, bicyclo [3.3.1InOHyI, bicyclo [4.2. l]nonyl, bicyclo [4.3.1] decyl, adamantyl and the like can be mentioned.
The above-mentioned C3-10 cycloalkyl group, C3-αo cycloalkenyl group and C4-I0 cycloalkadienyl group each optionally form, together with a C3-10 cycloalkane, a C3-10 cycloalkene or a C4-10 cycloalkadiene, a spiro ring group. Here, as the C3-I0 cycloalkane, C3-10 cycloalkene and C4-10 cycloalkadiene, rings corresponding to the above-mentioned C3-I0 cycloalkyl group, C3-10 cycloalkenyl group and C4_io cycloalkadienyl group can be mentioned. As such a spiro ring group, spiro [4 ,5]decan-8-yl and the like can be mentioned. As the Cβ-14 aryl group, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like can be mentioned.
As the C7-I3 aralkyl group, for example, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like can be mentioned.
As the C8-I3 arylalkenyl group, for example, styryl and the like can be mentioned.
As the C3-I0 cycloalkyl-Ci-6 alkyl group, for example, cyclohexylmethyl and the like can be mentioned. The Ci-10 alkyl group, C2-10 alkenyl group and C2-10 alkynyl group, which are exemplarily recited as the aforementioned "hydrocarbon group", each optionally have 1 to 3 substituents at substitutable position (s) .
As such substituents, for example, (1) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclohexyl) ; (2) a Cβ-14 aryl group (e.g., phenyl, naphthyl) optionally substituted by 1 to 3 substituents selected from
(a) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a cyano group; (3) an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, pyrazolyl, . imidazolyl, tetrazolyl, oxazolyl, thiazolyl/ oxadiazolyl/ thiadiazolyl, benzothiazolyl, pyrazinyl, quinolyl, indolyl/ pyrimidinyl, triazolyl, isoxazolyl) optionally substituted by 1 to 3 substituents selected from
{a) a halogen atom,
(b) a hydroxy group,
(c) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom,
(ii) a Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(iii) a CjL_6 alkoxy-carbonyl group, and
(iv) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
(d) a Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(e) a C6-i4 aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom,
(ii) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms, and
(iii) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) ,
(f) a C7_i3 aralkyl group (e.g., benzyl), (g) a C3-.10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3 halogen atoms,
(h) an aromatic heterocyclic group (e.g., pyridyl, thienyl, pyrimidinyl) , and
(i) a non-aromatic heterocyclic group (e.g., tetrahydropyranyl) ; ^4) a non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1, 3-dihydro-2-benzofuranyl, thiazolidinyl, tetrahydropyranyl, dihydrooxadiazolyl) optionally substituted by 1 to 3 substituents selected from
(a) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(d) an oxo group, and
(e) a halogen atom;
(5) an amino group optionally mono-or di-substituted by substituent (s) selected from (a) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a hydroxyl group,
(ii) a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, (iϋ) an amino group optionally mono- or di-substituted by Ci_6 alkyl group (s) optionally substituted by 1 to 3 halogen atoms, and
(iv) a halogen atom,
(b) a Cχ~s alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(c) a Ci_6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C6-i4 aryl-carbonyl group (e.g., benzoyl) optionally substituted by 1 to 3 Ci-β alkyl groups optionally substituted by 1 to 3 halogen atoms,
(e) a C-7-13 aralkyl-carbonyl group (e.g., benzylcarbonyl) optionally substituted by 1 to 3 halogen atoms,
<f) a C3-I0 cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl) optionally substituted by 1 to 3 halogen atoms, (g) an aromatic heterocyclylcarbonyl group (e.g., pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl) optionally substituted by 1 to 3 Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms, (h) a non-aromatic heterocyclylcarbonyl group (e.g., tetrahydrofurylcarbonyl, tetrahydrothiopyranylcarbonyl) ,
(i) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) ,
(j) a Ce-14 arylsulfonyl group (e.g., benzenesulfonyl) ,
(k) an aromatic heterocyclylsulfonyl group (e.g., thienylsulfonyl) ,
(1) a C3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 to 3 halogen atoms,
(m) a Cε-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms, and
(n) an aromatic heterocyclic group (e.g., pyrazolyl, pyrazinyl, isoxazolyl, pyridyl) optionally substituted by 1 to 3 Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms; (6) an amidino group;
(7) a Ci-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(8) a Ci_6 alkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, and (b) a Ci-6 alkoxy group;
(9) a .Ci-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted by 1 to 3 halogen atoms ; (10) a C3-10 cycloalkylsulfonyl group (e.g./ cyclopropylsulfonyl) ;
(11) a C6-I4 arylsulfonyl group (e.g., benzenesulfonyl) optionally substituted by 1 to 3 substituents selected from
(a) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms, and (b) a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
(12) an aromatic heterocyclylsulfonyl group (e.g., imidazolylsulfonyl, pyridylsulfonyl) optionally substituted by 1 to 3 Ci_6 alkyl groups;
(13) a carbamoyl group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom,
(ii) an aromatic heterocyclic group (e.g., pyridyl, furyl) optionally substituted by 1 to 3 Ci_6 alkyl groups, and (iii) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) ,
(b) a Cε-14 aryl group (e.g., phenyl), (c) a C7-13 aralkyl group (e.g., benzyl),
(d) an aromatic heterocyclic group (e.g., pyridyl, thiadiazolyl, oxadiazolyl) optionally substituted by 1 to 3 Ci-e alkyl groups optionally substituted by 1 to 3 halogen atoms, and (e) a non-aromatic heterocyclic group (e.g., 1,1- dioxidotetrahydrothienyl) ;
(14) a thiocarbamoyl group optionally mono- or di-substituted by Ci-e alkyl group (s) optionally substituted by 1 to 3 halogen atoms; (15) a sulfamoyl group optionally mono- or di-substituted by Qt_6 alkyl group (s) optionally substituted by 1 to 3 halogen atoms; .
(16) a carboxy group;
(17) a hydroxy group; (18) a d-6 alkoxy group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a carboxy group,
(c) hydroxy1 group, (d) a Cχ-5 alkoxy group, (e) a Ci_6 alkoxy-carbonyl group,
(f) an amino group optionally mono- or di-substituted by substituent (s) selected from a Ci_6 alkyl group and a Ci_6 alkoxy-carbonyl group, (g) a C3-10 cycloalkyl group {e.g., cyclopropyl, cyclopentyl) ,
(h) a Ci_6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) ,
(i) an aromatic heterocyclic group (e.g., iiαidazolyl) optionally substituted by 1 to 3 Ci_6 alkyl groups, and
(j) a non-aromatic heterocyclic group (e.g., morpholinyl) ;
(19) a C2-6 alkenyloxy group (e.g., ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(20) a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy, cyclopentyloxy) ;
(21) a C7-13 aralkyloxy group (e.g., benzyloxy) ;
(22) a C6-14 aryloxy group (e.g., phenyloxy, naphthyloxy) ;
(23) a non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy) ;
(24) a Ci_6 alkyl-carbonyloxy group (e.g., acetyloxy, tert- butylcarbonyloxy) ;
(25) a C3-io cycloalkyl-oxycarbonyl group (e.g., cyclopentyloxycarbonyl) ; (26) a Ce-14 aryl-carbonyl group (e.g., benzoyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (27) a non-aromatic heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl, morpholinylcarbonyl, 1,1- dioxidothiomorpholinylcarbonyl) optionally substituted by 1 to 3 substituents selected from
(a) a C6-I4 aryl group (e.g., phenyl), and (b) a C1-G alkyl group optionally substituted by 1 to 3 halogen atoms;
(28) a mercapto group;
(29) a Ci-6 alkylthio group (e.g., methylthio, ethylthio) optionally substituted by 1 to 3 halogen atoms; (30) a C7-13 aralkylthio group (e.g., benzylthio) ;
(31) a Cβ-14 arylthio group (e.g., phenylthio, naphthylthio) ;
(32) a sulfo group;
(33) a cyano group;
(34) an azido group; (35) a nitro group;
(36) a nitroso group;
(37) a halogen atom;
(38) a Ci-6 alkylsulfinyl group (e.g., methylsulfinyl) ;
(39) a Ci-3 alkylenedioxy group; (40) an aromatic heterocyclylcarbonyl group (e.g.,- pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl) optionally substituted by 1 to 3 Ci-6 alkyl groups optionally substituted by 1 to 3 halogen atoms; (41) a hydroxyimino group; and the like can be mentioned.
The C3-10 cycloalkyl group, C3-10 cycloalkenyl group, C4-10 ' cycloalkadienyl group, Cβ-14 aryl group, C7-13 aralkyl group, C8-I3 arylalkenyl group and C3-10 cycloalkyl-Ci_6 alkyl group, which are exemplarily recited as the aforementioned ""hydrocarbon group", each optionally have 1 to 3 substituents at substitutable position (s).
As such substituents, for example,
(1) those exemplarily recited as the substituents of the aforementioned Ci_iό alkyl group and the like;
(2) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a carboxy group, (c) a hydroxy group, (d) a Ci-6 alkoxy-carbonyl group,
(e) a Ci-6 alkyl-carbonyloxy group (e.g., acetyloxy) ,
(f) a carbamoyl group,
(g) a cyano group, (h) an amino group,
(i) a hydroxyimino group, and
(j) a non-aromatic heterocyclic group (e.g., morpholinyl, pyrrolidinyl) ;
(3) a C2-6 alkenyl group (e.g.', ethenyl, 1-propenyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a carboxy group,
(c) a Ci_6 alkoxy-carbonyl group, and
(d) a carbamoyl group; (4) a C-7-13 aralkyl group (e.g., benzyl) optionally substituted by 1 to 3 substituents selected from
(a) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group, (c) a Ci-6 alkoxy group, and
(d) a halogen atom; (5) an oxo group; and the like can be mentioned.
As the "heterocyclic group" of the aforementioned "optionally substituted heterocyclic group", an aromatic heterocyclic group and a non-aromatic heterocyclic group can be mentioned.
Here, as the aromatic heterocyclic group, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused aromatic heterocyclic group can be mentioned. As the fused aromatic heterocyclic group, for example, a group derived from a fused ring wherein a ring constituting such 5- to 7- membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6- membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are condensed, and the like can be mentioned.
As preferable examples of the aromatic heterocyclic group, monocyclic aromatic heterocyclic groups such as furyl (e.g., 2-furyl, 3-furyl) , thienyl (e.g., 2-thienyl, 3-thienyl) , pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl) , pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl) , pyrazinyl (e.g., 2-pyrazinyl) , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl) , pyrazolyl (e.g., 1-pyrazolyl, 3- pyrazolyl, 4-pyrazolyl) , thiazolyl (e.g., 2-thiazolyl, 4- thiazolyl, 5-thiazolyl) , isothiazolyl (e.g., 4-isothiazolyl) , oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , isoxazolyl, oxadiazolyl (e.g., 1, 2, 4-oxadiazol-5-yl, 1,3,4- oxadiazol-2-yl) , thiadiazolyl (e.g., 1, 3, 4-thiadiazol-2-yl) , triazolyl (e.g., 1, 2, 4-triazol-l-yl, 1, 2, 4-triazol-3-yl, 1,2,3-triazol-l-yl, 1, 2, 3-triazol-2-yl, 1, 2, 3-triazol-4-yl) , tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl) , triazinyl (e.g., 1, 2, 4-triazin-l-yl, 1, 2, 4-triazin-3-yl, 1, 3, 5-triazin- 1-yl, ) and the like; fused aromatic heterocyclic groups such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6- quinolyl) , isoquinolyl (e.g., 3-isoquinolyl) , quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2- quinoxalyl, 6-quinoxalyl) , benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl) , benzothiophenyl (e.g., 2-benzothiophenyl, 3- benzothiophenyl) , benzoxazolyl (e.g., 2-benzoxazolyl) , benzisoxazolyl (e.g., 7-benzisoxazolyl) , benzothiazolyl (e.g., 2-benzothiazolyl) , benzimidazolyl (e.g., benzimidazol-1-yl, benziπiidazol-2-yl, benzimidazol-5-yl) , benzotriazolyl (e.g., IH-I, 2, 3-benzotriazol-5-yl) , indolyl (e.g., indol-1-yl, indol- 2-yl, indol-3-yl, indol-5-yl), indazolyl (e.g., lH-indazol-3- yl), pyrrolopyrazinyl (e.g., lH-pyrrolo [2, 3-b]pyrazin-2-yl, lH-pyrrolo [2, 3-b]pyrazin-6-yl) , imidazopyridinyl (e.g., IH- imidazo[4, 5-b]pyridin-2-yl, lH-imidazo [4, 5-c]pyridin-2-yl, 2H- imidazo[l, 2-a]pyridin-3-yl, 2H-imidazo[l, 2-a]pyridin-6-yl) , imidazopyrazinyl (e.g., lH-imidazo[4,5-b]pyrazin-2-yl) , pyrazolopyridinyl (e.g., lH-pyrazolo [4, 3-c]pyridin-3-yl) , pyrazolothienyl (e.g., 2H-pyrazolo [3, 4-b] thiophen-2-yl) , pyrazolotriazinyl (e.g., pyrazolo [5, 1-c] [1, 2, 4] triazin-3-yl) and the like; and the like can be mentioned.
In the present specification, the "heteroaryl group" has the same meaning as the aromatic heterocyclic group described above .
As the non-aromatic heterocyclic group, for example, a 5- to 7-membered monocyclic non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused non-aromatic heterocyclic group can be mentioned. As the fused non-aromatic heterocyclic group, for example, a group derived from a fused ring wherein a ring constituting such 5- to 7- membered monocyclic non- aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic or non-aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are condensed, a group obtained by partial saturation of said group, and the like can be mentioned.
As preferable examples of the non-aromatic heterocyclic group, tetrahydrofuryl (e.g., 2-tetrahydrofuryl) , pyrrolidinyl (e.g., 1-pyrrolidinyl) , 1, 1-dioxidotetrahydrothienyl (e.g., 1, l-dioxidotetrahydro-3-thienyl) , piperidinyl (e.g., piperidino) , morpholinyl (e.g., morpholino) , thiomorpholinyl (e.g., thiomorpholino) , 1, 1-dioxidothiomorpholinyl (e.g., 1,1- dioxidothiomorpholino) , piperazinyl (e.g., 1-piperazinyl) , hexamethyleneiminyl (e.g., hexamethyleneimin-1-yl) , oxazolidinyl (e.g., oxazolidin-3-yl) , thiazolidinyl (e.g., thiazolidin-3-yl) , imidazolidinyl (e.g., imidazolidin-3-yl) , dihydroisoindolyl (e.g., 1, 3-dihydro-2H-isoindol-2-yl) , dioxolyl (e.g., 1, 3-dioxol-4-yl) , dioxolanyl (e.g., 1,3- dioxolan-4-yl) , dihydrooxadiazolyl (e.g., 4, 5-dihydro-l, 2, 4- oxadiazol-3-yl) , thioxooxazolidinyl (e.g., 2-thioxo-l, 3- oxazolidin-5-yl) , tetrahydropyranyl (e.g., 4- tetrahydropyranyl) , tetrahydrothiopyranyl (e.g., 4- tetrahydrothiopyranyl) , 1, 1-dioxidotetrahydrothiopyranyl (e.g., 1, l-dioxidotetrahydrothiopyran-4-yl) , dihydrobenzofuranyl (e.g., 2, 3-dihydro-l-benzofuran-5-yl) , dihydrobenzodioxinyl (e.g., 2, 3-dihydro-l, 4-benzodioxin-2-yl) , dihydrobenzodioxepinyl (e.g., 3, 4-dihydro-2H-l, 5- benzodioxepin-2-yl) , tetrahydrobenzofuranyl (e.g., 4,5,6,7- tetrahydro-l-benzofuran-3-yl) , tetrahydrobenzothiazolyl (e.g.,
4, 5, 6, 7-tetrahydro-l-benzothiazol-2-yl) , tetrahydrobenzoxazolyl (e.g., 4, 5, 6, 7-tetrahydro-l-benzoxazol- 2-yl) , chromenyl (e.g., 4H-chromen-2-yl, 2H-chrσmen-3-yl) , dihydroquinolinyl (e.g., 1, 2-dihydroquinolin-2-yl) , tetrahydroquinolinyl (e.g., 1, 2, 3, 4-tetrahydroguinolin-2-yl) , dihydroisoquinolinyl (e.g., 1, 2-dihydroisoquinolin-2~yl) , tetrahydroisoquinolinyl (e.g., 1,2, 3, 4-tetrahydroisoquinolin- 4-yl, 1,2,3, 4-tetrahydroisoquinolin-2-yl) , dihydrophthalazinyl (e.g., 1, 4-dihydrophthalazin-4-yl) , pyrazolidinyl (e.g., pyrazolidin-1-yl) , tetrahydroindazolyl (e.g., 4,5,6,7- tetrahydro-2H-indazol-2-yl) , tetrahydroquinazolinyl (e.g.,
5, 6, 118-tetrahydroquinazolin-6-yl) , tetrahydrothiazolopyridinyl (e.g., 4, 5, 6, 7-tetrahydrothiazolo [5.4-c]pyridin-6-yl) , tetrahydroiiαidazopyridinyl (e.g., 1,2,3, 4-tetrahydroimidazo[4.5-c]pyridin-2-yl) , tetrahydropyrazolopyridinyl (e.g., 1,2,3,4- tetrahydropyrazolo[3.4-c]pyridin-2-yl) , tetrahydrotriazolopyrazinyl (e.g., 1,2,3,4- tetrahydrotriazolo [4.3-a]pyrazin-2-yl) , tetrahydroimidazopyrazinyl (e.g., 1,2,3,4- tetrahydroimidazo[1.2-a]pyrazin-2-yl, 1, 2, 3, 4- tetrahydroimidazo [3.4-a] pyrazin-2-yl ) , tetrahydropyridopyrimidinyl (e.g. , 5, 6, 7 , 8-tetrahydropyrido [5.4-c]pyrimidin-6-yl) and the like can be mentioned. The above-mentioned non-aromatic heterocyclic group may be a heterospiro ring group. For example, the 5- to 7-membered monocyclic non-aromatic heterocyclic group and the fused non- aromatic heterocyclic group optionally form, together with a C3-10 cycloalkane, a C3-10 cycloalkene, a C4-10 cycloalkadiene or a non-aromatic heterocycle, a spiro ring group. Here, as the C3- 10 cycloalkane, C3-10 cycloalkene and C4-Io cycloalkadiene, rings corresponding to the C3-10 cycloalkyl group, C3-10 cycloalkenyl group and C4-10 cycloalkadienyl group, which are exemplarily recited as the "hydrocarbon group" of the above-mentioned "optionally substituted hydrocarbon group", can be mentioned. As the non-aromatic heterocycle, a ring corresponding to the above-mentioned non-aromatic heterocyclic group can be mentioned. As such a spiro ring group, 2,8- diazaspiro[4.5]decan-8-yl and the like can be mentioned. The above-mentioned non-aromatic heterocyclic group may be a crosslinked non-aromatic heterocyclic group. As the crosslinked non-aromatic heterocyclic group, 2,5- diazabicyclo[2.2.1]heptan-2-yl and the like can be mentioned. The "heterocyclic group" of the aforementioned "optionally substituted heterocyclic group" optionally has 1 to 3 substituents at substitutable position (s). As such substituents, for example, those exemplarily recited as the substituents of the C3-.10 cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned.
As the aforementioned "optionally substituted hydroxy group", for example, a hydroxy group optionally substituted by a substituent selected from a Ci-αo alkyl group, a C2~io alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6- 14 aryl group, a C7-13 aralkyl group, a Ce-i3 arylalkenyl group, a Ci_6 alkyl-carbonyl group, a heterocyclic group and the like/ each of which is optionally substituted, can be mentioned.
Here, as the Ci-io alkyl group, C2-10 alkenyl group, C3-10 cycloalkyl group, C3-10 cycloalkenyl group, Cβ-n aryl group, C7-13 aralkyl group and Cβ-i3 arylalkenyl group, those exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned. As the heterocyclic group, the "aromatic heterocyclic group" and "non-aromatic heterocyclic group", which are exemplarily recited as' the "heterocyclic group" of the aforementioned "optionally substituted heterocyclic group", can be mentioned.
The aforementioned Ci-10 alkyl group, C2-10 alkenyl group, C3-Io cycloalkyl group, C3-10 cycloalkenyl group, Cε-i4 aryl group, C7-.13 aralkyl group, Cg-13 arylalkenyl group, Ci-β alkyl-carbonyl group and heterocyclic group each optionally have 1 to 5 (preferably 1 to 3) substituents at substitutable position (s). As the substituents of the Ci-10 alkyl group, C2-10 alkenyl group and Ci-6 alkyl-carbonyl group, those exemplarily recited as the substituents of the C1-I0 alkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned. As the substituents of the C3-10 cycloalkyl group, C3-I0 cycloalkenyl group, Cβ-n aryl group, C7-13 aralkyl group, Cβ-i3 arylalkenyl group and heterocyclic group, those exemplarily recited as the substituents of the C3_io cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned.
As the aforementioned ""optionally substituted mercapto group", for example, a mercapto group optionally substituted by a substituent selected from a Ci-io alkyl group, a C2-10 alkenyl group, a C3_io cycloalkyl group, a C3-I0 cycloalkenyl group, a Cβ-u aryl group, a C-7-α3 aralkyl group, a C8_13 arylalkenyl group, a Ci-β alkyl-carbonyl group, a heterocyclic group and the like, each of which is optionally substituted, can be mentioned. As the substituents, those exemplarily recited as the substituents of the aforementioned "optionally substituted hydroxy group" can be mentioned.
As the aforementioned "optionally substituted amino group", for example, an amino group optionally mono- or di- substituted by substituent (s) selected from a Ci-10 alkyl group, a C2-10 alkenyl group, a C3-10 cycloalkyl group, a €3-10 cycloalkenyl group, a Cβ-n aryl group, a C7-13 aralkyl group," a Cβ-13 arylalkenyl group and a heterocyclic group, each of which is optionally substituted; an acyl group and the like, can be mentioned.
Here, as the Ci_io alkyl group, C2-10 alkenyl group, C3-Io cycloalkyl group, C3-Io cycloalkenyl group, Ce-xi aryl group, C7-13 aralkyl group and Ce-I3 arylalkenyl group, those exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned. As the heterocyclic group, the "aromatic heterocyclic group" and "non-aromatic heterocyclic group", which are exemplarily recited as the "heterocyclic group" of the aforementioned "optionally substituted heterocyclic group", can be mentioned. Of these, a 5- to 7-membered monocyclic aromatic heterocyclic group is preferable.
The aforementioned Cα-10 alkyl group, C2-10 alkenyl group, C3-I0 cycloalkyl group, C3-10 cycloalkenyl group, C6-Xt aryl group, C7-i3 aralkyl group, Ce-I3 arylalkenyl group and heterocyclic group each optionally have 1 to 3 substituents at substitutable position (s) .
As the substituents of the Ci_io alkyl group and C2-I0 alkenyl group, those exemplarily recited as the substituents of the Ci-io alkyl group and the like exemplarily recited as the "hydrocarbon group7' of the aforementioned "optionally substituted hydrocarbon group" can be mentioned.
As the substituents of the C3-10 cycloalkyl group, C3-10 cycloalkenyl group, Cβ-u aryl group, C7-13 aralkyl group, Cs-i3 arylalkenyl group and heterocyclic group, those exemplarily recited as the substituents of the C3_χo cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned.
As the "acyl group" exemplarily recited as the substituent of the "optionally substituted amino group", those exemplarily recited as "acyl group" below, which is exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
As the "acyl group" which is exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, for example, a group represented by the formula: -CORa, -CO-ORa, - SO3Ra, -SO2R3, -SORa, -CO-NR3' Rb', -CS-NR3' Rb' or -SO2NR3' Rb' wherein Ra is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and Ra/ and Rb' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or Ra' and Rb' optionally form, together with the adjacent nitrogen atom, an optionally substituted nitrogen-containing heterocycle, and the like can be mentioned.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra, Ra' or Rb' , those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic- group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
As the "nitrogen-containing heterocycle" of the "optionally substituted nitrogen-containing heterocycle" formed by Ra' and Rb' together with the adjacent nitrogen atom, for example, a 5- to 7-membered nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and optionally further containing one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom can be mentioned. As preferable examples of the nitrogen-containing heterocycle, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like can be mentioned. The nitrogen-containing heterocycle optionally has 1 to 3 (preferably 1 or 2) substituents at substitutable position(s). As such substituents, those exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "hydrocarbon group" of the aforementioned "optionally substituted hydrocarbon group" can be mentioned.
As preferable examples of the "acyl group",
( 1 ) a forrnyl group;
(2 ) a carboxy group; (3) a Ci-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(4) a Ci-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl ) optionally substituted by 1 to 3 substituents selected from (a) a halogen atom,
(b) a carboxy group,
(c) a carbamoyl group,
(d) a thiocarbamoyl group,
(e) a Ci_6 alkoxy group, (f) a Ci_6 alkoxy-carbonyl group, and (g) a Ci-e alkyl-carbonyloxy group;
(5) a C3-10 cycloalkyl-carbonyl group (e.g./ cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl) ;
(6) a C3-10 cycloalkyl-oxycarbonyl group (e.g., cyclopentyloxycarbonyl) ;
(7) a C6-i4 aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl, 2- naphthoyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, (b) a cyano group,
(c) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(d) a Ci-6 alkoxy group,
(e) a carboxy group, (f) a Ca_6 alkoxy-carbonyl group,
(g) an aromatic heterocyclic group (e.g./ tetrazolyl, oxadiazolyl) ,
(h) a non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups (e.g., oxooxadiazolinyl) , and (i) a carbamoyl group;
(8) a Cβ-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbony1) optionally substituted by 1 to 3 substituents selected from
(a) a carboxy group, (b) a Ci_6 alkoxy-carbonyl group, and (c) a carbamoyl group;
(9) a C7-13 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) optionally substituted by 1 to 3 substituents selected from (a) a carboxy group,
(b) a carbamoyl group,
(c) a thiocarbamoyl group,
(d) a Ci_6 alkoxy-carbonyl group,
(e) a halogen atom, (f) a cyano group, (g) a nitro group, (h) a Ci-6 alkoxy group, (i) a Ci-6 alkylsulfonyl group, and (j) a Ci-6 alkyl group; (10) a carbamoyl group optionally mono- or di-substituted by substituent (s) . selected from
(a) a Ci_6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, (ii) an aromatic heterocyclic group (e.g., pyridyl, furyl) optionally substituted by 1 to 3 Ci_6 alkyl groups, and (iii) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) ,
(b) a Cβ-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom,
(ii) an aromatic heterocyclic group (e.g., pyridyl, furyl) optionally substituted by 1 to 3 Ci-6 alkyl groups, and (iii) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl),
(c) a C7-13 aralkyl group (e.g., benzyl), (d) an aromatic heterocyclic group (e.g., pyridyl, thiadiazolyl, oxadiazolyl) optionally substituted by 1 to 3 Ci-e alkyl groups optionally substituted by 1 to 3 halogen atoms, and
(e) a non-aromatic heterocyclic group (e.g., 1,1- dioxidotetrahydrothienyl) ;
(11) a Cα_6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, (b) a carboxy group,
(c) a carbamoyl group, and
(d) a Ci-6 alkoxy-carbonyl group;
(12) a C3-I0 cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl) ; (13) a CΘ-14 arylsulfonyl group (e.g., benzenesulfonyl) optionally substituted by 1 to 3 substituents selected from
(a) a Ci-s alkyl group optionally substituted by 1 to 3 halogen atoms, and
(b) a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
(14) an aromatic heterocyclylsulfonyl group (e.g., thienylsulfonyl, irαidazolylsulfonyl, pyridylsulfonyl) optionally substituted by 1 to 3 Cα_6 alkyl groups;
(15) a sulfamoyl group; (16) a Ci-6 alkylsulfinyl group (e.g., methylsulfinyl) ;
(17) a thiocarbamoyl group;
(18) a C7-13 aralkyl-carbonyl group (e.g., benzylcarbonyl, phenethylcarbonyl) optionally substituted by 1 to 3 halogen atoms; (19) an aromatic heterocyclylcarbonyl group (e.g., furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurylcarbonyl, benzothienylcarbonyl, quinoxalinylcarbonyl, imidazolylcarbonyl) optionally substituted by 1 to 3 substituents selected from
(a) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a C6-i4 aryl group,
(c) a C7-13 aralkyl group, (d) a Ci_6 alkoxy group,
(e) a carboxy group,
(f) a Ci_6 alkoxy-carbonyl group, and
(g) a carbamoyl group;
(20) a non-aromatic heterocyclylcarbonyl group (e.g., tetrahydrofurylcarbonyl, tetrahydrothiopyranylcarbonyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, 1,1- dioxidothiomorpholinylcarbonyl) optionally substituted by 1 to 3 substituents selected from
(a) a Cβ-14 aryl group (e.g., phenyl), and (b) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and the like can be mentioned.
Ra1 is preferably a hydrogen atom, an optionally substituted hydrocarbon group/ an optionally substituted heterocyclic group, an acyl group and the like, more preferably a hydrogen atom, an optionally substituted Ci-io alkyl group (preferably, Cj-β alkyl group) , an optionally substituted Cδ-n aryl group, an optionally substituted C7-13 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C6-i4 aryl-carbonyl group, an optionally substituted C6-H arylsulfonyl group and the like. Ra1 is further preferably
(1) a hydrogen atom;
(2) a Ci_6 alkyl group optionally substituted by 1 to 3 aromatic heterocyclic groups (e.g., pyridyl) ;
(3) a Cβ-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, (c) a Ci-6 alkyl group, and (d) a C1-6 alkoxy group;
(4) a C7-13 aralkyl group (e.'g., benzyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, (b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Ci-6 alkoxy group;
(5) an aromatic heterocyclic group (e.g., pyrimidinyl) optionally substituted by 1 to 3 substituents selected from (a) a halogen atom,
(b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Ci-6 alkoxy group;
(6) a Cβ-14 aryl-carbonyl group (e.g., benzoyl) optionally substituted by 1 to 3 substituents selected from (a) a halogen atom,
(b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a QL_6 alkoxy group; (7) a Cs-14 arylsulfonyl group (e.g., benzenesulfonyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group,
(c) a Ci-6 alkyl group, and (d) a Ci_6 alkoxy group; and the like.
Ra2 and Ra3 are preferably both hydrogen atoms. Ra4 and Ra5 are preferably both hydrogen atoms. Ra6 is preferably a hydrogen atom. Ra7 is preferably a hydrogen atom.
Ring Aa is an optionally substituted aromatic heterocycle.
As the "aromatic heterocycle" of the "optionally substituted aromatic heterocycle" for ring Aa, a ring corresponding to the aromatic heterocyclic group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. The aromatic heterocycle can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
As the "aromatic heterocycle" of the "optionally substituted aromatic heterocycle" for ring Aa, pyridine, pyrazine, pyrimidihe, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, and pyridazine are preferable. The "aromatic heterocycle" of the "optionally substituted aromatic heterocycle" for ring Aa optionally has 1 to 3 substituents at substitutable position (s). As such substituents, for example, those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. As the substituents of ring Aa, an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; a halogen atom; and the like are preferable.
As the substituents of ring Aa,
(1) a halogen atom;
(2) a carboxy group;
(3) a cyano group; (4) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group,
(c) a non-aromatic heterocyclic group (e.g., pyrrolidinyl) , (d) an amino group, and
(e) a hydroxyimino group;
(5) a Cε-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 Cχ-6 alkyl groups;
(6) a C7-13 aralkyl group (e.g., benzyl, 2-phenethyl) ; (7) an aromatic heterocyclic group (e.g., pyrazolyl, thiazolyl, oxadiazolyl) optionally substituted by 1 to 3 C±-β alkyl groups optionally substituted by 1 to 3 halogen atoms; (8) a non-aromatic heterocyclic group (e.g., pyrrolidinyl, morpholinyl) ; (9) a Ci-6 alkoxy. group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from
(a) a halogen atom,
(b) a Ci-6 alkoxy group,
(c) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclopentyl) , (d) a Ci-6 alkylsulfonyl group (e.g./ methylsulfonyl; ethylsulfonyl) , and
(e) an aromatic heterocyclic group (e.g., imidazolyl) optionally substituted by 1 to 3 Ci-6 alkyl groups; (10) a C3-10 cycloalkyloxy group (e.g., cyclopentyloxy) ;
(11) a Cβ-u aryloxy group (e.g., phenoxy) ;
(12) a C7-13 aralkyloxy group (e.g., benzyloxy) ;
(13) a non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy) ;
(14) a Ci-6 alkyl-carbonyl group;
(15) a Ci-6 alkoxy-carbonyl group;
(16) a Ci-6 alkylthio group (e.g., methylthio, ethylthio) ;
(17) a Cβ-14 arylthio group (e.g., phenylthio) ; (18) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) ;
(19) a Cβ-xi arylsulfonyl group (e.g., benzenesulfonyl) ;
(20) an amino group optionally mono- or di-substituted by substituent (s) selected from (a) a Ci_6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group,
(ii) a Ci-6 alkoxy group, and
(iii) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
(b) a Ci-6 alkyl-carbonyl group, and
(c) a Ci_6 alkoxy-carbonyl group;
(21) a carbamoyl group optionally mono- or di-substituted by Ci_6 alkyl group (s); (22) a hydroxy group; and the like are more preferable.
Ring Aa is preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; and a halogen atom.
Ring Aa is more preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, guinoxaline, indazole, indole/ imidazopyridine, pyridazine) optionally substituted by 1 to 3 substituents selected from
(1) a halogen atom;
(2) a carboxy group; (3) a cyano group;
(4) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, (c) a non-aromatic heterocyclic group (e.g., pyrrolidinyl) ,
(d) an amino group, and
(e) a hydroxyimino group;
(5) a C6-H aryl group (e.g., phenyl) optionally substituted by 1 to 3 Ci-6 alkyl groups; (6) a C7-I3 aralkyl group (e.g., benzyl, 2-phenethyl) ;
(7) an aromatic heterocyclic group (e.g., pyrazolyl, thiazolyl', oxadiazolyl) optionally substituted by 1 to 3 Ci_e alkyl groups optionally substituted by 1 to 3 halogen atoms;
(8) a non-aromatic heterocyclic group (e.g., pyrrolidinyl, morpholinyl) ;
(9) a Ci_6 alkoxy group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from
(a) a halogen atom,
(b) a Ci-6 alkoxy group, (c) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclopentyl) ,
(d) a Ci_6 alkylsulfonyl group (e.g./ methylsulfonyl, ethylsulfonyl) , and
(e) an aromatic heterocyclic group (e.g., imidaεolyl) optionally substituted by 1 to 3 Ci_6 alkyl groups;
(10) a C3-10 cycloalkyloxy group (e.g., cyclopentyloxy) ;
(11) a Ce-14 aryloxy group (e.g., phenoxy) ;
(12) a C7-i3 aralkyloxy group (e.g., benzyloxy) ;
(13) a non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy) ;
(14) a Ci-6 alkyl-carbonyl group;
(15) a Ci_6 alkoxy-carbonyl group;
(16) a C1-6 alkylthio group (e.g., methylthio, ethylthio) ; (17) a C6-i4 arylthio group (e.g., phenylthio) ;
(18) a Cα_6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) ;
(19) a Cβ-14 arylsulfonyl group (e.g., benzenesulfonyl) ;
(20) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a QL_6 alkyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group, (ii) a Ci_6 alkoxy group, and (iϋ) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
(b) a Ci-6 alkyl-carbonyl group, and
(c) a Cχ_6 alkoxy-carbonyl group;
(21) a carbamoyl group optionally mono- or di-substituted by Ci_6 alkyl group (s); and
(22) a hydroxy group.
Ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted. As the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Ba, a ring corresponding to the 5-membered nitrogen-containing aromatic heterocyclic group, and a ring corresponding to the 5-membered nitrogen-containing aromatic heterocyclic group condensed with an aromatic ring selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring, can be mentioned, from among the aromatic heterocyclic groups exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra"7. The 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position of the 5-membered ring thereof. As the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Ba, pyrazole, benzimidazole, indole and indazole are preferable, and pyrazole and indole are particularly preferable.
The "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Ba optionally further has 1 to 3 substituents, besides Ra1, at substitutable position(s). As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3-I0 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the substituents other than Ra1 of ring Ba,
(1) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms; (2) a C6-I4 aryl group;
(3) a Ci-6 alkoxy group;
(4) a C7_i3 aralkyloxy group (e.g., benzyloxy) ;
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from (a) a Ci-6 alkyl group, and
(b) a Ci-6 alkoxy-carbonyl group; and the like are preferable (a Ci-s alkyl group optionally substituted by 1 to 3 halogen atoms is particularly preferable) . Ring Ba is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra1 and optionally further substituted.
Ring Ba is more preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra1 and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (2) a C6-14 aryl group;
(3) a Ci-6 alkoxy group;
(4) a C7-13 aralkyloxy group (e.g., benzyloxy); and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from (a) a Ci-6 alkyl group, and
(b) a Ci_6 alkoxy-carbonyl group
(particularly preferably, a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms) .
In compound (Ia) , 1) when ring Ba is pyrazole which is optionally further substituted, then ring Ba does not have optionally substituted tetrahydrofurylmethoxy as a substituent other than Ra1;
2) when ring Ba is imidazole which is optionally further substituted/ then ring Ba does not have optionally substituted quinolyl as a substituent other than Ra1;
3) when ring Ba is pyrazole which is optionally further substituted, then Ra1 is not optionally substituted quinolyl; and 4) ring Aa is not the same as ring Ba.
As preferable examples of compound (Ia) , the following compounds can be mentioned. [Compound Ia-A] A compound wherein ring Ba is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra1 and optionally further substituted [ring Ba is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra1 and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (2) a C6-14 aryl group;
(3) a Ci-6 alkoxy group;
(4) a C-7-13 aralkyloxy group (e.g., benzyloxy) ; and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from (a) a Ci-6 alkyl group, and
(b) a Ci_6 alkoxy-carbonyl group
(particularly preferably, a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms)];
Ra1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
[Ra1 is preferably a hydrogen atom, an optionally substituted C1-I0 alkyl group (preferably, a Ci_6 alkyl group) , an optionally substituted Ce-i4 aryl group, an optionally substituted C7-13 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C6-H aryl-carbonyl group or an optionally substituted Cs-n arylsulfonyl group. Ra1 is more preferably (1) a hydrogen atom; (2) a Ci-6 alkyl group optionally substituted by 1 to 3 aromatic heterocyclic groups (e.g., pyridyl) ;
(3) a Cδ-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, (b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Ci-6 alkoxy group;
(4) a C7-13 aralkyl group (e.g., benzyl) optionally substituted' by 1 to 3 substituents selected from (a) a halogen atom,
(b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Cα_6 alkoxy group;
(5) an aromatic heterocyclic group (e.g., pyrimidinyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Ci-6 alkoxy group; (6) a Cβ-14 aryl-carbonyl group (e.g., benzoyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group,
(c) a C3.-6 alkyl group, and (d) a Ci-6 alkoxy group; or (7) a C6-H arylsulfonyl group (e.g., benzenesulfonyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, (c) a Ci-6 alkyl group, and (d) a Ci-6 alkoxy group] ; ring Aa is an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted- heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; and a halogen atom
[ring Aa is preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole) optionally substituted by 1 to 3 substituents. selected from
(1) a halogen atom;
(2) a carboxy group; (3) a cyano group;
(4) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, (c) a non-aromatic heterocyclic group (e.g., pyrrolidinyl) ,
(d) an amino group, and
(e) a hydroxyimino group;
(5) a Ce-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 Ci_6 alkyl groups; (6) a C7-13 aralkyl group (e.g., benzyl, 2-phenethyl) ; (7) an aromatic heterocyclic group (e.g./ pyrazolyl, thiazolyl, oxadiazolyl) optionally substituted by 1 to 3 Ci_6 alkyl groups optionally substituted by 1 to 3 halogen atoms;
(8) a non-aromatic heterocyclic group (e.g., pyrrolidinyl, morpholinyl) ;
(9) a Ci_6 alkoxy group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from
(a) a halogen atom,
(b) a Ci-6 alkoxy group, (c) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclopentyl) ,
(d) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) , and
(e) an aromatic heterocyclic group (e.g., imidazolyl) optionally substituted by 1 to 3 Ci-6 alkyl groups;
(10) a C3-10 cycloalkyloxy group (e.g., cyclopentyloxy) ;
(11) a Cβ-14 aryloxy group (e.g., phenoxy) ;
(12) a C7-13 aralkyloxy group (e.g., benzyloxy) ;
(13) a non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy) ;
(14) a Ci-6 alkyl-carbonyl group; (15) a Ci-6 alkoxy-carbonyl group;
(16) a Ci-6 alkylthio group (e.g., rαethylthio, ethylthio) ; (17) a Cβ-14 arylthio group (e.g., phenylthio);
(18) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) ;
(19) a Ce-14 arylsulfonyl group (e.g., benzenesulfonyl);
(20) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci_6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci-6 alkoxy group, and (iϋ) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
(b) a Ci-6 alkyl-carbonyl group, and
(c) a Ci_6 alkoxy-carbonyl group; and
(21) a carbamoyl group optionally mono- or di-substituted by Ci_6 alkyl group (s)];
Ra2 and Ra3 are both hydrogen atoms; Ra4 and Ra5 are both hydrogen atoms; Ra6 is a hydrogen atom; and Ra7 is a hydrogen atom.
[Compound Ia-B]
A compound wherein ring Ba is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra1 and optionally further substituted [ring Ba is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by Ra1 and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a C6-14 aryl group;
(3) a Ci-6 alkoxy group;
(4) a C7-i3 aralkyloxy group (e.g., benzyloxy) ; and (5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group, and
(b) a Ci_6 alkoxy-carbonyl group
(particularly preferably, a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms) ] ;
Ra1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
[Ra1 is preferably a hydrogen atom, an optionally substituted Ci-io alkyl group (preferably, a Ci_6 alkyl group) , an optionally substituted Cβ-i4 aryl group, an optionally substituted C7-13 aralkyl group, an optionally substituted aromatic heterocyclic group, an optionally substituted Cβ-n aryl-carbonyl group or an optionally substituted C6-H arylsulfonyl group. Ra1 is more preferably
(1) a hydrogen atom;
(2) a Ci-6 alkyl group optionally substituted by 1 to 3 aromatic heterocyclic groups (e.g., pyridyl) ;
(3) a C6-H aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group,
(c) a Ci_6 alkyl group, and
(d) a Ci_6 alkσxy group; (4) a C7-.13 aralkyl group (e.g., benzyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group,
(c) a Ci_6 alkyl group, and <d) a Ci_6 alkoxy group;
(5) an aromatic heterocyclic group (e.g., pyrimidinyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, (c) a C1-6 alkyl group, and
(d) a Ci-6 alkoxy group;
(6) a Ce-14 aryl-carbonyl group (e.g., benzoyl) optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, (b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Ci_6 alkoxy group; or
(7) a Ce-14 arylsulfonyl group (e.g., benzenesulfonyl) optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a hydroxy group,
(c) a Ci-6 alkyl group, and
(d) a Ci-6 alkoxy group] ; ring Aa is an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine) optionally substituted by
1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; an optionally substituted amino group; an optionally substituted mercapto group; a cyano group; an acyl group; and a halogen atom
[ring Aa is preferably an aromatic heterocycle (preferably, pyridine, pyrazine, pyrimidine, benzimidazole, quinoxaline, indazole, indole, imidazopyridine, pyridazine) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom;
(2) a carboxy group;
(3) a cyano group;
(4) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom,
(b) a hydroxy group,
(c) a non-aromatic heterocyclic group (e.g., pyrrolidinyl) ,
(d) an amino group, and
(e) a hydroxyimino group; (5) a Cβ-14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 Ci_6 alkyl groups;
(6) a C7-I3 aralkyl group (e.g., benzyl, 2-phenethyl) ;
(7) an aromatic heterocyclic group (e.g., pyrazolyl, thiazolyl, oxadiazolyl) optionally substituted by 1 to 3 Cα_6 alkyl groups optionally substituted by 1 to 3 halogen atoms; (8) a non-aromatic heterocyclic group (e.g., pyrrolidinyl, morpholinyl) ;
(9) a Ci-6 alkoxy group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from (a) a halogen atom,
(b) a Ci_6 alkoxy group,
(c) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclopentyl) ,
(d) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) , and
(e) an aromatic heterocyclic group (e.g., imidazolyl) optionally substituted by 1 to 3 Ci_6 alkyl groups;
(10) a C3-10 cycloalkyloxy group (e.g., cyclopentyloxy) ;
(11) a Ce-14 aryloxy group (e.g., phenoxy) ; (12) a C7-i3 aralkyloxy group (e.g., benzyloxy) ;
(13) a non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1- dioxidotetrahydrothiopyranyloxy) ;
(14) a C1-6 alkyl-carbonyl group; (15) a Ci-6 alkoxy-carbonyl group;
(16) a Ci-6 alkylthio group (e.g., methylthio, ethylthio) ;
(17) a Cβ-14 arylthio group (e.g., phenylthio) ;
(18) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) ; (19) a Cβ-14 arylsulfonyl group (e.g., benzenesulfonyl) ; (20) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Qt-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a hydroxy group,
(ii) a Ci_6 alkoxy group, and
(iii) an amino group optionally mono- or di-substituted by Ci-6 alkyl group (s),
■ (b) a C1-S alkyl-carbonyl group, and (c) a Ci-6 alkoxy-carbonyl group; (21) a carbamoyl group optionally mono- or di-substituted by Ci-6 alkyl group (s); and
(22) a hydroxy group];
Ra2 and Ra3 are both hydrogen atoms; Ra4 and Ra5 are both hydrogen atoms; Ra6 is a hydrogen atom; and Ra7 is a hydrogen atom.
Each symbol in the formula (Ib) is described in detail in the following.
Ring Ab is an optionally substituted aromatic hydrocarbon.
As the ""aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ab, a ring corresponding to the Ce-n aryl group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. The aromatic hydrocarbon can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
As the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ab, benzene is preferable.
The "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ab optionally has 1 to 3 substituents at substitutable position (s) . As such substituents, for example, those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the substituents of ring Ab, an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; a halogen atom; and the like are preferable'. As the substituents of ring Ab/
(1) a Ci_s alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group, (3) a halogen atom,
(4) a Ci-6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) ,
(6) a sulfamoyl group, (7) a cyano group and the like are more preferable, and a halogen atom and a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms are particularly preferable.
Ring Ab is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom.
Ring Ab is more preferably an aromatic hydrocarbon
(preferably, benzene) optionally substituted by 1 to 3 substituents selected from
(1) Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group,
(3) a halogen atom, [A) a Ci_6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) ,
(6) a sulfamoyl group, and
(7) a cyano group, particularly preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.
Ring Bb is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted.
As the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Bb, a ring corresponding to the 5-membered nitrogen-containing aromatic heterocyclic group, and a ring corresponding to the 5-membered nitrogen-containing aromatic heterocyclic group condensed with an aromatic ring selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring, can be mentioned, from among the aromatic heterocyclic groups exemplariIy recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7. The 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position of the 5-membered ring thereof.
As the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted'7 for ring Bb, pyrazole, benzimidazole, indole and indazole are preferable, and pyrazole and indole are particularly preferable.
The "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Bb optionally further has 1 to 3 substituents, besides ring Cb, at substitutable position (s). As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3-I0 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra", Ra5, Ra6 or Ra7 can be mentioned.
As the substituents other than ring Cb of ring Bb, (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a Cε-14 aryl group;.
(3) a Ci-6 alkoxy group;
(4) a C7-13 aralkyloxy group (e.g., benzyloxy) ; (5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group, and
(b) a Ci-6 alkoxy-carbonyl group; and the like are preferable (a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms is particularly preferable) .
Ring Bb is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cb and optionally further substituted.
Ring Bb is more preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cb and optionally further substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms ;
(2) a Ce-i4 aryl group;
( 3 ) a Ci-6 alkoxy group; ( 4 ) a C7-13 aralkyloxy group (e . g. , benzyloxy) ; and (5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group, and
(b) a Ci-6 alkoxy-carbonyl group (particularly preferably, a Ci-e alkyl group optionally substituted by 1 to 3 halogen atoms) .
Ring Cb is an optionally substituted aromatic heterocycle. As the "aromatic heterocycle" of the "optionally substituted aromatic heterocycle" for ring Cb, a ring corresponding to the aromatic heterocyclic group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. As the "aromatic heterocycle" of the "optionally substituted aromatic heterocycle" for ring Cb, indole, pyridine and pyrimidine are preferable.
The "aromatic heterocycle" of the "optionally substituted aromatic heterocycle" for ring Cb optionally has 1 to 3 substituents at substitutable position (s). As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra", Ra5, Ra6 or Ra7 can be mentioned. As the substituents of ring Cb,
(1) a halogen atom,
(2) a hydroxy group,
(3) a Ci-e alkyl group,
(4) a Ci-6 alkoxy group, and the like are preferable.
Ring Cb is preferably an aromatic heterocycle (preferably, indole, pyridine, pyrimidine) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom, (2) a hydroxy group, (3) a Ci-6 alkyl group, and
(4) a Ci-6 alkoxy group.
In compound (Ib) , when ring Bb is pyrazole which is optionally further substituted, then ring Cb is not optionally substituted quinoline.
As preferable examples of compound (Ib), the following compounds can be mentioned. [Compound Ib-A]
A compound wherein ring Bb is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cb and optionally further substituted [ring Bb is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , eachof which is substituted by ring Cb and optionally further substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a CΘ-14 aryl group;
(3) a Ci-6 alkoxy group;
(4) a C7-I3 aralkyloxy group (e.g., benzyloxy) ; and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group, and
(b) a Ci-6 alkoxy-carbonyl group
(particularly preferably, a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms) ] ; ring Cb is an aromatic heterocycle (preferably, indole, pyridine, pyrimidine) optionally substituted by 1 to 3 substituents selected from
(1) a halogen atom,
(2) a hydroxy group, (3) a Ci_6 alkyl group, and (4) a Ci-6 alkoxy group; and ring Ab is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom [ring Ab is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents • selected from
(1) a QL-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom, (2) a hydroxy group,
(3) a halogen atom,
(4) a Ci-6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) , (6) a sulfamoyl group, and (7) a cyano group, more preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Cχ-β alkoxy group optionally substituted by 1 to 3 halogen atoms] .
Each symbol in the formula (Ic) is described in detail in the following.
In the following explanation, a moiety in the formula (Ic) , which is represented by
Figure imgf000060_0001
wherein each symbol is as defined in the formula (Ic) , is sometimes to be referred to as substituent C.
ring Ac is an optionally substituted aromatic hydrocarbon. As the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ac, a ring corresponding to the C6-i4 aryl group exemplarily recited as the
"substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned- The aromatic hydrocarbon can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position. As the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ac, benzene is preferable .
The "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ac optionally has 1 to 3 substituents at substitutable position (s). As such substituents, for example, those exemplarily recited as the
"substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. As the substituents of ring Ac, an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; a halogen atom; and the like are preferable.
As the substάtuents of ring Ac,
(1) a Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group,
(3) a halogen atom,
(4) a Ci-6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) , (6) a sulfamoyl group,
(7) a cyano group and the like are more preferable, and a halogen atom and a Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms are particularly preferable.
Ring Ac is preferably an aromatic hydrocarbon
(preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom. Ring Ac is more preferably an aromatic hydrocarbon
(preferably, benzene) optionally substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom, (2) a hydroxy group,
(3) a halogen atom,
(4) a Ci-6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) , (6) a sulfamoyl group, and (7) a cyano group, particularly preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.
Ring Bc is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted. As the w5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Be/ a ring corresponding to the 5-iuembered nitrogen-containing aromatic heterocyclic group, and a ring corresponding to the 5-meitibered nitrogen-containing aromatic heterocyclic group condensed with an aromatic ring selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole/ imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring, can be mentioned, from among the aromatic heterocyclic groups exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7. The 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position of the 5-membered ring thereof.
As the xx5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Bc, pyrazole, benzimidazole, indole and indazole are preferable, and pyrazole and indole are particularly preferable.
The "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring" of the "5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted" for ring Bc optionally further has 1 to 3 substituenfs, besides ring Cc, at substitutable position (s). As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3-I0 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. As the substituents other than ring Cc of ring Bc,
(1) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a C6-H aryl group; (3) a Ci-6 alkoxy group;
(4) a C7-13 aralkyloxy group (e.g., benzyloxy) ; .
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group, and (b) a Ci-6 alkoxy-carbonyl group and the like are preferable (a Ci_s alkyl group optionally substituted by 1 to 3 halogen atoms is particularly preferable) .
Ring Bc is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole), each of which is substituted by ring Cc and optionally further substituted.
Ring Bc is more preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cc and optionally further substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; (2) a C6-i4 aryl group;
(3) a Ci-6 alkoxy group;
(4) a C7-α3 aralkyloxy group (e.g., benzyloxy); and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from (a) a Ci_6 alkyl group, .and
(b) a Ci-6 alkoxy-carbonyl group
(particularly preferably, a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms) .
Ring Cc is an optionally substituted aromatic ring. As the "aromatic ring" of the "optionally substituted aromatic ring" for ring Cc, an aromatic hydrocarbon and an aromatic heterocycle can be mentioned.
Here/ as the aromatic hydrocarbon, a ring corresponding to the Cs-14 aryl group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4 # Ra5, Ra6 or Ra7 can be mentioned.
As the aromatic heterocycle/ a ring corresponding to the aromatic heterocyclic group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the "aromatic ring" of the "optionally substituted aromatic ring" for ring Cc, an aromatic hydrocarbon is preferable, and benzene is particularly preferable.
The "aromatic ring" of the "optionally substituted aromatic ring" for ring Cc optionally has 1 to 3 substituents at substitutable position (s) . As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra", Ra5, Ra6 or Ra7 can be mentioned.
As the substituents of ring Cc,
(1) a halogen atom,
(2) a hydroxy group,
(3) a d-6 alkyl group, (4) a C1-6 alkoxy group and the like are preferable.
Ring Cc is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom,
(2) a hydroxy group,
(3) a Ci_6 alkyl group, and
(4) a C1-S alkoxy group.
Rc2, Rc3, Rc4, Rc5> Rc6 and Rc7 are each independently a hydrogen atom or a substituent, or any two of Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 are optionally bonded to each other to form a non-aromatic ring.
As the "substituent" for Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7, those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the "non-aromatic ring" formed by any two of Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 bonded to each other, a non-aromatic cyclic hydrocarbon and a non-aromatic heterocycle can be mentioned.
Here, as the non-aromatic cyclic hydrocarbon, for example, a C3_i0 cycloalkane, C3-10 cycloalkene, C4-10 cycloalkadiene and the like, each of which is optionally condensed with a benzene ring, can be mentioned. As the C3-10 cycloalkane, C3-10 cycloalkene and C4-10 cycloalkadiene, rings corresponding to the C3-10 cycloalkyl group, C3-10 cycloalkenyl group and C4-10 cycloalkadienyl group, which are exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned. As the non-aromatic heterocycle, a ring corresponding to the non-aromatic heterocyclic group, which is exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Rc2 and Rc3 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a non- aromatic ring, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle. Rc2 and Rc3 are more preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci_i0 alkyl group (preferably, Ci-6 alkyl group) , or Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a non-arόmatic hydrocarbon, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle. Rc2 and Rc3 are particularly preferably each independently
(1) a hydrogen atom;
(2) a carboxy group; (3) a OL-6 alkoxy-carbonyl group; or
(4) a Ci-6 alkyl group optionally substituted by 1 to 3 hydroxy groups ; or
(5) Rc2 or Rc3 is bonded to Rc" or Rc5 to form a C3-I0 cycloalkane (e.g./ cyclohexane) ; (6) Rc2 or Rc3 is bonded to Rc6 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or (7) Rc2 or Rc3 is bonded to Rc7 to form a non-aromatic heterocycle (e.g./ piperidine).
Rc4 and Rc5 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a non- aromatic ring, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle.
Rc4 and Rc5 are more preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci-io alkyl group (preferably, Ci-e alkyl group) , or Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a non-aromatic hydrocarbon, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle.
Rc4 and Rc5 are particularly preferably each independently (1) a hydrogen atom; (2) a carboxy group;
(3) a Ci-6 alkoxy-carbonyl group;, or
(4) a Ci_6 alkyl group optionally substituted by 1 to 3 hydroxy groups ; or
(5) Rc" or Rc5 is bonded to Rc2 or Rc3 to form a C3-io cycloalkane (e.g., cyclohexane); (6) Rc4 or Rc5 is bonded to Rc6 to form a non-aromatic heterocycle (e.g., piperidine); or
(7) Rc" or Rc5 is bonded to Rc7 to form a non-aromatic heterocycle {e.g., piperidine/ pyrrolidine).
Rc6 is preferably a hydrogen atom or an optionally substituted hydrocarbon group, or Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle. Rc6 is more preferably a hydrogen atom or an optionally substituted Ci-io alkyl group (preferably, Ci-e alkyl group) , or Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle. Rc6 is particularly preferably (1) a hydrogen atom; or
(2) a Ci-6 alkyl group; or
(3) Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or
(4) Rc6 is bonded to Rc4 or Rc5 to form a non-aromatic heterocycle (e.g., piperidine).
Rc7 is preferably a hydrogen atom or an optionally substituted hydrocarbon group, or Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle.
Rc7 is more preferably a hydrogen atom or an optionally substituted Ci_i0 alkyl group (preferably, Ci_6 alkyl group) , or Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle. Rc7 is particularly preferably
(1) a hydrogen atom; or
(2) a Ci-6 alkyl group; or
(3) Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle (e.g., piperidine); or (4) Rc7 is bonded to Rc4 or Rc5 to form a non-aromatic heterocycle (e.g./ piperidine, pyrrolidine).
In compound (Ic)
1) ring Bc is not pyrazol-5-yl and 2H-1, 2, 3-triazol-4- yl, each of which is optionally further substituted (i.e., ring Bc is not pyrazole having substituent C at the 5- position, and 2H-1, 2, 3-triazole having substituent C at the A- position, each of which is optionally further substituted) ;
2) ring Cc is not optionally substituted quinoline; 3) a compound wherein Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 are hydrogen atoms is excluded; and
4) when Rc6 and Rc7 are bonded, then they do not form piperazine.
As preferable examples of compound (Ic), the following compounds can be mentioned. [Compound Ic-A]
A compound wherein ring Bc is pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cc and optionally further substituted [ring Bc is preferably pyrazole, benzimidazole, indole or indazole (particularly preferably, pyrazole or indole) , each of which is substituted by ring Cc and optionally further substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a C6-14 aryl group;
(3) a Ci-6 alkoxy group; (4) a C7-i3 aralkyloxy group (e.g., benzyloxy) ; and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci_6 alkyl group, and
(b) a Cχ-6 alkoxy-carbonyl group; (particularly preferably, a Ci-e alkyl group optionally substituted by 1 to 3 halogen atoms) ] ; ring Cc is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from (1) a halogen atom, (2) a hydroxy group,
(3) a Ci-6 alkyl group, and
(4) a Cχ-6 alkoxy group; ring Ac is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom
[ring Ac is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
(1) a Ci_6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group,
(3) a halogen atom,
(4) a Ci_6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) ,
(6) a sulfamoyl group, and
(7) a cyano group, more preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Cχ-6 alkoxy group optionally substituted by 1 to .3 halogen atoms];
Rc2 and Rc3 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a non-aromatic ring, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle
[Rc2 and Rc3 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci-io alkyl group
(preferably, Ci-6 alkyl group) , or Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a non-aromatic hydrocarbon, bonded to Rc6 to form a non-aromatic heterocycle/ or bonded to Rc7 to form a non- aromatic heterocycle. Rc2 and Rc3 are more preferably each independently
(1) a hydrogen atom; (2) a carboxy group;
(3) a Ci-6 alkoxy-carbonyl group; or
(4) a Ci_6 alkyl group optionally substituted by 1 to 3 hydroxy groups; or
(5) Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a C3-10 cycloalkane (e.g., cyclohexane) ;
(6) Rc2 or Rc3 is bonded to Rc6 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or
(7) Rc2 or Rc3 is bonded to Rc7 to form a non-aromatic heterocycle (e.g., piperidine)]; Rc4 and Rc5 are each independently a hydrogen atom, an acyi group or an optionally substituted hydrocarbon group, or Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a non-aromatic ring, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle [Rc4 and Rc5 are preferably each independently a hydrogen atom, an acyl group or an optionally substituted Ci-io alkyl group (preferably, Ci_6 alkyl group) , or Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a non-aromatic hydrocarbon, bonded to Rc6 to form a non-aromatic heterocycle, or bonded to Rc7 to form a non- aromatic heterocycle.
Rc4 and Rc5 are more preferably each independently
(1) a hydrogen atom;
(2) a carboxy group;
(3) a Ci-6 alkoxy-carbonyl group; or (4) a Ci-6 alkyl group optionally substituted by 1 to 3 hydroxy ■groups; or
(5) Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a C3-10 cycloalkane (e.g., cyclohexane) ;
(6) Rc4 or Rc5 is bonded to Rc6 to form a non-aromatic heterocycle (e.g., piperidine) ; or
(7) Rc4 or Rc5 is bonded to Rc7 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine)];
Rc6 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc6 is bonded to Rc2 or Rc3 to form a non- aromatic heterocycle, or bonded to Rc4 or Rc^ to form a non- aromatic heterocycle
[Rc6 is preferably a hydrogen atom or an optionally substituted Ci-10 alkyl group (preferably, d-β alkyl group) , or Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to from a non-aromatic heterocycle. Rc6 is more preferably
(1) a hydrogen atom; or
(2) a Ci-6 alkyl group; or
(3) Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine); or
(4) Rc6 is bonded to Rc4 or Rc5 to form a non-aromatic heterocycle (e.g., piperidine)]; and
Rc7 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc7 is bonded to Rc2 or Rc3 to form a non- aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non- aromatic heterocycle
[Rc7 is preferably a hydrogen atom or an optionally substituted Ci-10 alkyl group (preferably, Ci-s alkyl group) , or Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle. Rc7 is more preferably
(1) a hydrogen atom; or
(2) a Ci_6 alkyl group; or
(3) Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle (e.g., piperidine); or (4) Rc7 is bonded to Rc4 or Rc5 to form a non-aromatic heterocycle (e.g., piperidine, pyrrolidine)].
Each symbol in the formula (Id) is described in detail in the following.
In the following explanation, a moiety in the formula (Id) , which is represented by
Figure imgf000073_0001
wherein each symbol is as defined in the formula (Id) , is sometimes to be referred to as substituent D.
Ring Ad is an optionally substituted aromatic hydrocarbon.
As the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ad, a ring corresponding to the C6-i4 aryl group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. The aromatic hydrocarbon can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position. As the "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ad, benzene is preferable.
The "aromatic hydrocarbon" of the "optionally substituted aromatic hydrocarbon" for ring Ad optionally has 1 to 3 substituents at substitutable position (s). As such substituents, for example, those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the substituents of ring Ad, an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group/ an optionally substituted hydroxy group; a cyano group; an acyl group/ a halogen atom; and the like are preferable . As the substituents of ring Ad,
(1) a Ci_6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group,
(3) a halogen atom, (4) a Ci_6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) ,
(6) a sulfamoyl group,
(7) a cyano group and the like are more preferable, and a halogen atom and a Ci_6 alkoxy group optionally substituted by 1 to 3 halogen atoms are particularly preferable.
Ring Ad is preferably an aromatic hydrocarbon
(preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom.
Ring Ad is more preferably an aromatic hydrocarbon
(preferably, benzene) optionally substituted by 1 to 3 substituents selected from (1) a Ci_6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group,
(3) a halogen atom,
(4) a Ci_6 alkyl group, (5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) /
(6) a sulfamoyl groupf and
(7) a cyano group, particularly preferably an aromatic hydrocarbon, (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci-β alkoxy group optionally substituted by 1 to 3 halogen atoms.
Ring Bd is an aromatic heterocycle which is optionally further substituted.
As the "aromatic heterocycle" of the "aromatic heterocycle which is optionally further substituted" for ring Bd, a ring corresponding to the aromatic heterocyclic group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned. The aromatic heterocycle can be bonded to a carbon atom of the adjacent carbonyl group at any bondable position.
As the "aromatic heterocycle" of the "aromatic heterocycle which is optionally further substituted" for ring Bd, pyridine, pyrazole, triazole and indole are preferable.
The "aromatic heterocycle" of the "aromatic heterocycle which is optionally further substituted" for ring Bd optionally further has 1 to 3 substituents, besides ring Cd, at substitutable position (s). As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3-10 cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the substituents other than ring Cd of ring Bd, (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms /
(2) a C6-I4 aryl group;
(3) a Ci_6 alkoxy group;
(4) a C7-13 aralkyloxy group (e.g., benzyloxy) ; (5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci_6 alkyl group, and
(b) a Ci_6 alkoxy-carbonyl group; and the like are preferable, and (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a CΘ-14 aryl group and the like are more preferable.
Ring Bd is preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted.
Ring Bd is more preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a C6-14 aryl group;
(3) a Ci-6 alkoxy group; (4) a C7-13 aralkyloxy group (e.g., benzyloxy) ; and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci_6 alkyl group, and
(b) a Ci-6.alkoxy-carbonyl group; particularly preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from (1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and (2) a C6-I4 aryl group.
Ring Cd is an optionally substituted aromatic ring. As the "aromatic ring" of the "optionally substituted aromatic ring" for ring Cd, an aromatic hydrocarbon and an aromatic heterocycle can be mentioned. Here, as the aromatic hydrocarbon, a ring corresponding to the C5-U aryl group exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the aromatic heterocycle, a ring corresponding- to the aromatic heterocyclic group exemplarily recited as the
"substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the "aromatic ring" of the "optionally substituted aromatic ring", for ring Cd, an aromatic hydrocarbon is preferable, and benzene is particularly preferable.
The "aromatic ring" of the "optionally substituted aromatic ring" for ring Cd optionally has 1 to 3 substituents at substitutable position (s) . As such substituents, for example, those (except an oxo group) exemplarily recited as the substituents of the C3_io cycloalkyl group and the like exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7 can be mentioned.
As the substituents of ring Cd, (1) a halogen atom, (2) a hydroxy group,
(3) a Ci-6 alkyl group,
(4) a Ci-6 alkoxy group and the like are preferable.
Ring Cd is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
(1) a halogen atom,
(2) a hydroxy group,
(3) a Ci-s alkyl group, and (4) a Ci_6 alkoxy group.
In compound (Id),
1) ring Bd is not pyrazol-4-yl and pyrrol-3-yl, each of which is optionally further substituted (i.e., ring Bd is not pyrazole having substituent D at the 4-position, and pyrrole having substituent D at the 3-position, each of which is optionally further substituted) ;
2) ring Cd is not optionally substituted quinoline;
3) when ring Bd is pyridine or quinoline/ each of which is optionally further substituted, then ring Bd has substituent (s) besides ring Cd; and
4) when ring Bd is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted, then ring Bd does not have an optionally substituted aromatic heterocyclic group as a substituent other than ring Cd and ring Cd is an optionally substituted aromatic hydrocarbon.
As preferable examples of compound (Id) , the following compounds can be mentioned. [Compound Id-A]
A compound wherein ring Bd is pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted
[ring Bd is preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from
(1) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a C6-14 aryl group;
(3) a Ci_6 alkoxy group;
(4) a C7_13 aralkyloxy group (e.g., benzyloxy) ; and
(5) an amino group optionally mono- or di-substituted by substituent (s) selected from
(a) a Ci-6 alkyl group, and
(b) a Ci-6 alkoxy-carbonyl group; more preferably pyridine, pyrazole, triazole or indole, each of which is substituted by ring Cd and optionally further substituted by 1 to 3 substituents selected from (1) a Ci_6 alkyl group optionally substituted by 1 to 3 halogen atoms; and
(2) a C6-I4 aryl group]; ring Cd is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
(1) a halogen atom,
(2) a hydroxy group,
(3) a Ci-6 alkyl group, and
(4) a Ci_6 alkoxy group; and ring Ad is an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted hydroxy group; a cyano group; an acyl group; and a halogen atom
[ring Ad is preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from
(1) a Cα-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a halogen atom,
(2) a hydroxy group,
(3) a halogen atom, (4) a Ci-6 alkyl group,
(5) an aromatic heterocyclic group (e.g., imidazolyl, pyrazolyl) ,
(6) a sulfamoyl group, and
(7) a cyano group, more preferably an aromatic hydrocarbon (preferably, benzene) optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ci_e alkoxy group optionally substituted by 1 to 3 halogen atoms] .
As the other preferable examples of compounds (Ia), (Ib), (Ic) and (Id), the following compounds can be mentioned.
[Compound Iz]
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (Example A27) ;
6- (cyclopropylmethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (Example A35) ;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (3, 3, 3-trifluoropropoxy) nicotinamide (Example A42) ;
6- (2- (ethylsulfonyl) ethoxy) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide
(Example A43) ;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl ) -6-propylnicotinamide (Example A47);
1-phenyl-N- (2- (6- (2, 2, 2-trifluoroethoxy) nicotinamido) ethyl) - lH-indole-3-carboxamide (Example A53) ;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6-o-tolylnicotinamide (Example A73) ; 1-benzoyl-N- (2- (6- (2, 2, 2-trifluoroethoxy) nicotinamido) ethyl) - lH-indole-3-carboxamide (Example A82) ;
6- (5-isopropyl-l, 2, 4-oxadiazol-3-yl) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide
(Example A103) ; or N- (2- (4-ethoxybenzamido) ethyl) -1- (pyridin-2-yl) -3-
(trifluoromethyl) -lH-pyrazole-4-carboxainide (Example B3) ; or a salt thereof.
As a salt of the compound of the present invention, a pharmacologically acceptable salt is preferable. Examples of such a salt include a salt with inorganic base, a salt with organic base, a salt with inorganic acid/ a salt with organic acid, a salt with basic or acidic amino acid and the like. Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt; ammonium salt and the like.
Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine,, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine] , tert-butylamine, cyclohexylamine, benzylamine, dieyelohexylamine, N,N- dibenzylethylenediamine or the like. Preferable examples Qf the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid/ nitric acid, sulfuric acid, phosphoric acid or the like.
Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
Preferable examples of the salt with basic amino acid include a salt with arginine, lysine, ornithine or the like. Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid or the like. A prodrug of the compound of the present invention is a compound that converts to the compound of the present invention due to the reaction by enzyme, gastric acid and the like under the physiological conditions in the body; that is, a compound that converts to the compound of the present invention by enzymatic oxidation, reduction, hydrolysis and the like, and a compound that converts to the compound of the present invention by hydrolysis and the like by gastric acid and the like. Examples of a prodrug of the compound of the present invention include a compound wherein an amino group of the compound of the present invention is acylated, alkylated or phosphorylated (e.g., a compound where amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3- dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert- butylated) ; a compound wherein a hydroxy group of the compound of the present invention is acylated, alkylated, phosphorylated or borated (e.g., a compound where a hydroxy group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated) ; a compound wherein a carboxyl group of the compound of the present invention is esterified or amidated (e.g., a compound where a carboxyl group of the compound of the present invention is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-l, 3- dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated) and the like. These compounds can be produced from the compound of the present invention according to a method known per se.
A prodrug of the compound of the present invention may be a compound that converts to the compound of the present invention under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, pp. 163-198, Hirokawa Shoten (1990).
The compound of the present invention may be labeled with an isotope (e.g., 3H, 14C, 35S, 125I and the like) and the like.
The compound of the present invention may be an. anhydride or a hydrate.
The compound of the present invention and a prodrug thereof (hereinafter sometimes to be simply referred to as the compound of the present invention) show low toxicity and can be used as an agent for the prophylaxis or treatment of various diseases to be mentioned later for mammals (e.g., human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, simian) as they are or by admixing with a pharmacologically acceptable carrier and the like to give a pharmaceutical composition. Here, various organic or inorganic carriers conventionally used as materials for pharmaceutical preparations are used as a pharmacologically acceptable carrier, which are added as an excipient, a lubricant, a binder, a disintegrant and the like for solid preparations; and a solvent, a dissolution aid, a suspending agent, an isotonicity agent, a buffer, a soothing agent and the like for liquid preparations. Where necessary, an additive for pharmaceutical preparations such as a preservative, an antioxidant, a coloring agent, a sweetening agent and the like can be used.
Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, powdered acacia, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like .
Preferable examples of the binder include pregelatinized starch, saccharose, gelatin, powdered acacia, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, sodium carboxymethyl starch, light anhydrous silicic acid, low- substituted hydroxypropyl cellulose and the like.
Preferable examples of the solvent include water for injection, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.
Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium . chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and the like; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
Preferable examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer and the like.
Preferable examples of the soothing agent include benzyl alcohol and the like.
Preferable examples of the preservative include p- oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite, ascorbate and the like.
Preferable examples of the coloring agent include water- soluble edible tar pigments (e.g., foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake pigments (e.g./ aluminum salt of the aforementioned water- soluble edible tar pigment), natural pigments (e.g., beta carotene, chlorophil, red iron oxide) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
The dosage form of the aforementioned pharmaceutical composition is, for example, an oral agent such as tablets (inclusive of sublingual tablets and orally disintegrable tablets) , capsules (inclusive of soft capsules and microcapsules) , granules, powders/ troches, syrups, emulsions, suspensions and the like; or a parenteral agent such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external agents (e.g., transdermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories) , pellets, nasal preparations, pulmonary preparations (inhalations) , ophthalmic preparations and the like. These may be administered safely via an oral or parenteral route.
These agents may be controlled-release preparations such as rapid-release preparations and sustained-release preparations (e.g., sustained-release microcapsules).
The pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical preparation, such as the method described in Japan Pharmacopoeia and the like. Concrete production methods of preparations are described in detail in the following. While the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, dose of the compound of the present invention and the like, it is, for example, about 0.1-100 wt%. Where necessary, the aforementioned oral agents may be coated with a coating base for the purpose of masking taste, enteric property or sustained release.
Examples of the coating base include a sugar-coating base, a water-soluble film coating base, an enteric film coating base, a sustained-release film coating base and the like.
As the sugar-coating base, sucrose may be used, if necessary, along with one or more species selected from talc, precipitated calcium carbonate, gelatin, powdered acacia, pullulan, carnauba wax and the like.
As the water-soluble film coating base, for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E, trade name, Roehm Pharma] , polyvinylpyrrolidone and the like; polysaccharides such as pullulan and the like; and the like are used.
As the enteric film coating base, for example, cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L, trade name, Roehm Pharma] , methacrylic acid copolymer LD [Eudragit L-30D55, trade name, Roehm Pharma], methacrylic acid copolymer S [Eudragit S, trade name, Roehm Pharma] and the like; natural products such as shellac and the like; and the like are used.
As the sustained-release film coating base, for example, cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS, trade name, Roehm Pharma] , ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE, trade name, Roehm Pharma] and the like; and the like are used. Two or more kinds of the above-mentioned coating bases may be mixed in an appropriate ratio for use. In addition, a light shielding agent such as titanium oxide, ferric oxide and the like may be used during coating.
The compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenic) , causes fewer side effects and can be used as an agent for the prophylaxis or treatment or diagnosis of various diseases for mammals (e.g., human, cattle, horse, dog, cat, simian, mouse, rat, especially human) .
The compound of the present invention has a DGAT (DGATl or DGAT2 or both) inhibitory action, and is useful for the prophylaxis, treatment or amelioration of DGAT-related diseases.
As the DGAT-related diseases, for example, obesity, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes) , insulin resistance, leptin resistance, arteriosclerosis, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-cholesterolemia, postprandial hyperlipemia) , arteriosclerosis, hypertension, cardiac failure, metabolic syndrome and the like can be mentioned. For diagnostic criteria of diabetes, Japan Diabetes Society reported new diagnostic criteria in 1999.
According to this report, diabetes is a condition showing any of a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test (75 g OGTT) 2 h level (glucose concentration of intravenous plasma) of not less than 200 mg/dl, and a non-fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 200 mg/dl. A condition not falling under the above-mentioned diabetes and different from "a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of less than no mg/dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 h level (glucose concentration of intravenous plasma) of less than 140 mg/dl" (normal type) is called a ""borderline type". In addition, ADA (American Diabetes Association) reported new diagnostic criteria of diabetes in 1997 and WHO in 1998.
According to these reports, diabetes is a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 126 πvg/dl and a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of not less than 200 mg/dl.
According to the above-mentioned reports, impaired glucose tolerance is a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of less than 126 mg/dl and a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of not less than 140 mg/dl and less than 200 mg/dl. According to the report of ADA, a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 110 mg/dl and less than 126 mg/dl is called IFG (Impaired Fasting Glucose) . According to the report of WHO, among the IFG (Impaired Fasting Glucose) , a condition showing a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of less than 140 mg/dl is called IFG (Impaired Fasting Glycemia) .
The compound of the present invention can be also used as an agent for the prophylaxis or treatment of diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia), as determined according to the above-mentioned new diagnostic criteria. Moreover, the compound of the present invention can prevent progress of borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) into diabetes. The compound of the present invention can be also used as an agent for the prophylaxis or treatment of, for example, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infection, inferior limb infection) , diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, peripheral blood circulation disorder], osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia or cachexia due to acquired immunodeficiency syndrome) , fatty liver, polycystic ovary syndrome, kidney disease (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end stage kidney disease) , muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular accident (e.g., cerebral infarction, cerebral apoplexy), Alzheimer's disease, Parkinson's syndrome, anxiety, dementia, insulin resistance syndrome, Syndrome X, hyperinsulinemia, hyperinsulinemia-induced sensory disorder, tumor (e.g., leukemia, breast cancer, prostatic cancer, skin cancer) , irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, postoperative or traumatic inflammation, swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis (inclusive of nonalcoholic steatohepatitis) , pneumonia, pancreatitis, enteritis, inflammatory bowel diseases (including inflammatory disease of large intestine) , ulcerative colitis, gastric mucosal injury (inclusive of gastric mucosal injury caused by aspirin) ) , small intestine mucous membrane trauma, malabsorption, testis function disorder, visceral obesity syndrome and the like. The compound of the present invention can also be used for the secondary prophylaxis, or suppression of the progression of the above-mentioned various diseases (e.g., cardiovascular events such as cardiac infarction and the like) . While the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, condition and the like, the compound of the present invention is generally given in a single dose of about 0.01-100 mg/kg body weight, preferably 0.05-30 mg/kg body weight, more preferably 0.1-10 mg/kg body weight, in the case of, for example, oral administration to adult diabetic patients. This dose is desirably given 1 to 3 times a day. The compound of the present invention can be used in combination with drugs such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipemic agent, an antihypertensive agent, an antiobestic agent, a diuretic, an antithrombotic agent and the like (hereinafter to be referred to as a combination drug) , with the aim of enhancing the action of the compound, reducing the dose of the compound and the like. In this case, the timing of administration of the compound of the present invention and a combination drug is not limited. These may be simultaneously administered to an administration subject or administered in a staggered manner. Moreover, the compound of the present invention and a combination drug may be administered as two kinds of preparations each containing an active ingredient, or may be administered as a single preparation containing both active ingredients.
The dose of the combination drug can be determined as ' appropriate based on the dose clinically employed. The proportion of the compound of the present invention and the combination drug can be appropriately determined depending on the administration subject, administration route, target disease, condition, combination and the like. When, for example, the administration subject is human, the combination drug is used in an amount of 0.01-100 parts by weight per 1 part by weight of the compound of the present invention.
As the therapeutic agent for diabetes, insulin preparations (e.g., animal insulin preparations extracted from the pancreas of bovine or pig; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-I), oral insulin preparation), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone. or a salt thereof (preferably maleate), Reglixane (JTT-501), Netoglitazone (MCC-555) , DRF- 2593, KRP-297, R-119702, Rivoglitazone (CS-OIl), FK-614, compounds described in W099/58510 (e.g., (E) -4- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy)benzyloxyimino] -4-phenylbutyric acid) , compounds described in WO01/38325, Tesaglitazar (AZ- 242), Ragaglitazar (NN-622), Muraglitazar (BMS-298585) , ONO- 5816, Edaglitazone (BM-13-1258) , LM-4156, MBX-102, Naveglitazar (LY-519818) , MX-6054, LY-510929, Balaglitazone (NN-2344), T-131 or a salt thereof, THR-0921), PPARγ agonists, PPARγ antagonists, PPARγ/α dual agonists, oc-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate) , biguanides (e.g., phenformin, metformin, buformin or salts thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogues [sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclσpyramide, glimepiride, glipizide, glybuzole) , repaglinide, senaglinide, nateglide, mitiglinide or calcium salt hydrate thereof], GPR40 agonists, GLP-I receptor agonists [e.g., GLP-I, GLP-IMR, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib(8, 35)hGLP-l (7, 37)NH2 , CJC-1131], amylin agonists (e.g., pramlintide) , phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate), dipeptidyl peptidase IV inhibitors (e.g., NVP-DPP-728, PT-100, P32/98, Vidagliptin (LAF-237), P93/01, TS-021, Sitagliptin (MK-431) , Saxagliptin (BMS-477118) , T-6666) , β3 agonists (e.g., AJ-9677, AZ4O14O) , gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists) , SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095) , llβ-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498), adiponectin or agonists thereof, IKK inhibitors (e.g., AS-2868) , leptin resistance improving drugs, somatostatin receptor agonists (compounds described in WO01/25228, WO03/42204, WO98/44921, WO98/45285 and WO99/22735) and glucokinase activators (e.g., Ro-28-1675) can be mentioned.
Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (e.g., Tolrestat, Epalrestat, Zenarestat, Zopolrestat, Minalrestat, Fidarestat, CT-112, Ranirestat) , neurotrophic factors and increasing drugs thereof (e.g., NGF, NT-3, BDNF, neurotrophin production-secretion promoters described in WO01/14372 (e.g., 4- (4-chlorophenyl) -2- (2-methyl-l-imidazolyl) -5- [3- (2- methylphenoxy) propyl] oxazole) ), neύranagenesis stimulators (e.g., Y-128) , PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, pimagedine, pyratoxanthine, N- phenacylthiazolium bromide (ALT766) , ALT-711, EXO-226, Pyridorin, Pyridoxamine) , reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190) and apoptosis signal regulating kinase-1 (ASK-I) inhibitors. Examples of the antihyperlipemic agent include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, ■ rosuvastatin, pitavastatin and salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97/10224, such as N- [ [ (3R, 5S)-I- (3- acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2, 3-diiαethoxyphenyl) - 2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzoxazepin-3-yl) acetyl] - piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate) , ACAT inhibitors (e.g./ Avasimibe, Eflucimibe) , anion exchange resins (e.g., cholestyramine) , probucol/ nicotinic acid drugs (e.g., nicomol, niceritrol), ethyl icosapentate and plant sterols (e.g., soysterol, γ-oryzanol) . Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril) , angiotensin II receptor antagonists (e.g., candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1- [ [2' - (2, 5-dihydro-5- oxo-4H-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-lH- benzimidazole-7-carboxylic acid), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (e.g., levcromakalim, L-27152, AL 0671, NIP-121) and Clonidine. Examples of the antiobestic agent include antiobestic agents acting on the central nervous system (e.g., Dexfenfluramine, fenfluramine, phentermine, Sibutramine, amfepramone, dexamphetamine, Mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP- 7941; compounds encompassed in WO01/82925 and WO01/87834); neuropeptide Y antagonists (e.g., CP-422935) ; cannabinoid receptor antagonists (e.g., SR-141716, SR-147778) ; ghrelin antagonists; llβ^-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498) ) , pancreatic lipase inhibitors (e.g., orlistat, ATL- 962), β3 agonists (e.g., AJ-9677, AZ40140), peptidic anorexiants (e.g., leptin, CNTF (Ciliary Neurotropic Factor)), cholecystokinin agonists (e.g., lintitript, FPL-15849) and feeding deterrents (e.g., P-57) .
Examples of the diuretic include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide) , antialdosterone preparations (e.g., spironolactone, triamterene), carbonate dehydratase inhibitors (e.g./ acetazoland.de) , chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide) , azosemide, isosorbide, etacrynic acid, piretanide, bumetanide and furosemide. Examples of the antithrombotic agent include heparins (e.g., heparin sodium, heparin calcium, dalteparin sodium), warfarins (e.g., warfarin potassium), anti-thrombin drugs (e.g., aragatroban) , thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticlσpidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.
Hereinafter the production methods of the compound of the present invention are explained.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S) -stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and diastereomers, and mixtures, racemate or otherwise, thereof. Accordingly, this invention also includes all such isomers, including diastereomeric mixtures, enantiomeric mixture, diastereomers and pure enantiomers of the compounds of this invention. The term "enantiomer" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. The term ""diastereomer" refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
The compounds of the present invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons .
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or a hashed wedge representing a particular configuration, then that stereoisomer is so specified and defined. When stereochemistry is specified by a solid line or a hashed line representing a relative conformation such as cis and trans, then that conformation is so specified and defined.
In the present specification, the following abbreviations may be used:
DCM: Dichloromethane MeCN: Acetonitrile
THF: Tetrahydrofuran
EtOH: Ethanol , MeOH: Methanol iPrOH: Isopropanol CHCl3: Chloroform
DCE: Dichloroethane
DMSO: Dimethyl sulfoxide
DMF: Dimethylformamide
DMA: Dimethylacetamide AcOEt: Ethyl acetate ,
Et2O: Diethyl ether
CH3CN: Acetonitrile
H2O: Water
HATU: 0-(7-Azabenzotriazol-l-yl)-N,N,N/,N/-tetramethyluronium hexafluorophosphate
BOP-Cl : Benzotriazol-1-yl-oxytris (dimethylamino) phosphoniurα hexafluorophosphate
EDAC-HCl : l-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
HOBt-H2O: Hydroxybenzotriazole monohydrate
NaOH: Sodium hydroxide
KOH: Potassium hydroxide K2CO3: Potassium carbonate
CS2CO3: Cesium carbonate
Na2Cθ3: Sodium carbonate
K3PO4 : Potassium phosphate
KF: Potassium fluoride TEA: Triethylamine-
DIPEA: Diisopropylethylamine
Py: Pyridine
NaH: Sodium hydride
LDA: Lithium diisopropylamide NaHCO3: Sodium hydrogencarbonate
H2SO4: Sulfuric acid HCl : Hydrochloric acid HBr: Hydrobromic acid NH4Cl: Ammonium chloride TFA: Trifluoroacetic acid AcOH: Acetic acid TFAA: Trifluoroacetic anhydride
Na2SO4: Sodium sulfate MgSO4: Magnesium sulfate
Pd(PPh3) 4 : Tetrakis (triphenylphosphine) palladium Pd(OAc)2: Palladium acetate PdCl2 (dppf) : DichloroU, 1'- bis (diphenylphosphi.no) ferrocene]palladium
PdCl2<PPh3) z'. Dichlorobis (triphenylphosphine) palladium
Pd2 (dba) 3: Tris (dibenzylideneacetone) dipalladium
PdCl2(dppp): Dichloro [1, 3- Bis (diphenylphosphino) propane] palladium
Xantphos : (9, 9-Dimethyl-9H-xanthene-4 , 5- diy1) bis (diphenylphosphine)
(BINAP) PdCl2: (2, 2' -Bis (diphenylphosphino) -1,1'- binaphthyl) palladium (II) chloride TsCl: p-Toluenesulfonyl chloride
MCPBA: m-Chloroperbenzoic acid
KMnCM: Potassium permanganate
CDI: N,N-Carbonyldiimidazole
PtO2: Platinum oxide Pd/C: Palladium on carbon
DMF-DMA: Dimethylformamide dimethylacetal
POCI3: Phosphorus oxychloride
TFFH: Tetramethylfluoroformamidinium hexafluorophosphate
NaCN: Sodium cyanide KCN: Potassium cyanide
CuCN: Copper cyanide
Zn(CN)2: Zinc cyanide
Boc: tert-Butoxycarbonyl Cbz : Benzyloxycarbonyl
For illustrative purposes, Schemes 1-35 show general methods for preparing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
Scheme 1
Figure imgf000098_0001
Ia
Compounds of formula Ia of this invention can be prepared by several methods generally known in- the art of organic chemistry.
Figure imgf000098_0002
Alia AIIb wherein Ra8 is a C1-C4 alkyl or benzyl group and other symbols are as defined above.
Intermediate esters AIIb, which are suitable for use in preparing compounds Ia and Ia-I can be prepared under various conditions depending on the nature of the Ra1 substituent.
In the case wherein Ra1 is an optionally substituted aryl or heteroaryl group, esters AIIb can be prepared according to one of the following references: Tetrahedron Lett. 1998, 39, 2941-2944; Eur. J. Org. Chem. 2004, 695-709; J. An. Chem. Soc. 2001, 123, 7727-7729; J. Am. Chem. Soc. 2002, 124, 11684- 11688; J. org. Chem. 2004, 69, 5578. Typically, the N- arylation or N-heteroarylation of the Ba ring is performed with an aryl or hetero aryl halide (preferably iodide) in the presence of copper catalyst such as copper iodide or copper oxide, in the presence of a ligand such as substituted ethylene diamines, salicylaldoximes or other ligands reported in Eυx. J. Org. Chem. 2004, 695-709. The reaction requires a base such as potassium phosphate or alkali carbonates (potassium carbonate, sodium carbonate or cesium carbonate) and is performed in a degassed solvent such as acetonitrile, toluene or DMF at a temperature of 200C to 150°C for 24 to 48 hours under inert atmosphere. Preferably, the N-arylation or N-heteroarylation is conducted according to the method described in J. Org. Chem. 2004, 69, 5578, in toluene with 1 equivalent of AIIa, 1.1-10 equivalents of aryl or heteroaryl halide, 2 equivalents of diamine ligand, 2-3 equivalents of base and 0.05 equivalents of copper (I) iodide, or according to the method described in Eur. J. Org. Chem. 2004, 695-709, in DMF with 1 equivalent of AIIa, 1.5-10 equivalents of aryl or heteroaryl halide, 0.2-0.4 equivalents of oxime ligand, 2-3 equivalents of base and 0.05 equivalents of copper (II) oxide. In the case where Ra1 is an optionally substituted non- aromatic hydrocarbon group or an optionally substituted non- aromatic heterocyclic group, esters AIIb can be prepared by direct alkylation with the corresponding halide or the corresponding sulfonate in the presence of a base such as alkali carbonates or hydrides (sodium hydride or potassium hydride) in a solvent such as DMF at a temperature ranging from 20°c to 1300C for 24 to 48 hours. In the case of hindered or poorly reactive halides, the corresponding halide may be used as the solvent at a temperature ranging from 200C to 1300C for 10 to 48 hours. Alternatively, esters AIIb can be prepared from the amine AIIa by opening of the corresponding epoxide in the presence of a base such as alkali carbonates in a solvent such as halogenated hydrochlorides (DCM or CHCl3) or neat at a temperature from 200C to 1000C for 1 to 48 hours. Preferably, the alkylation is run in DMF or halogenated hydrocarbons with 1 equivalent of AIIa, 1.1-10 equivalents of halide, sulfonate or epoxide and 1-5 equivalents of base.
In the case where Ra1 is an acyl group, esters AIIb can be prepared with the corresponding acid halides or sulfonyl halides in the presence of a base such as sodium hydride, alkali carbonates, sodium hydroxide or triethylamine in a solvent such as DMF, acetone or halogenated hydrocarbons at a temperature ranging from 00C to 1300C for 10 to 24 hours. Preferably, this reaction is run in DMF or halogenated hydrocarbons with 1 equivalent of AIIa, 1.1-2 equivalents of acid halide or sulfonyl halide and 1-5 equivalents of base.
Scheme 3
Figure imgf000100_0001
wherein the symbols are as defined above.
Compounds Ia-I can be prepared according to the sequence shown in Scheme 3. Esters AIIb, where Ra8 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines AIIc. Compounds Ia-I can then be prepared from acids AIIIa and amines AIIc or their salts by reacting both intermediates in the presence of various condensing reagents. Known condensing reagents that effect amide bond formation include, but are not limited to, N, N-carbonyldiimidazole, halopyridine salts, 2,4,6- trichlorobenzoyl chloride, HATU, BOP-Cl or EDAC -HCl/HOBt -H2O. In the present invention, the preferred reagent is either HATU or EDAC -HCl/HOBt-H2O. The reaction can be conducted in aprotic solvents such as tetrahydrofuran, halogenated hydrocarbons, acetonitrile, dimethylformamide, or a mixture of these solvents, at a temperature from 0°c to 1300C, preferably 200C to 700C, for a time ranging from 1 to 48 hours, preferably 10 to 20 hours. A base such as triethylamine or diisopropylethylamine may be used especially if the reacting amine is in a salt form. While the amount of reagent varies depending on the coupling reagent used, the following amounts are used preferably with HATU or EDAC-HCl/HOBt-H2O: amine or its salt (1 equivalent), acid (1 equivalent), HATU or EDAC-HCl/HOBt -H2O (1 to 2 equivalents), base (1 to 3 equivalents if salt form of amine is used) . Compounds Ia-I can also be prepared from acid chlorides AIIIb and amines AIIc in the presence of a base such as triethylamine, diiisopropylethylamine or pyridine in an aprotic solvent such as THF, benzene, halogenated hydrocarbons at temperatures from 200C to 90°C for 0.5 to 24 hours.
Scheme 4
Figure imgf000101_0001
wherein the symbols are as defined above.
Alternatively, compounds Ia-I can be prepared following the sequence described in Scheme 4. Esters AIIIc, where Ra8 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines AIIId. Compounds Ia-I can be prepared under the conditions mentioned in Scheme 3 using an amine AIIId or its salt, and an acid AIId. Acids AIId can be prepared from the corresponding esters AIIb by using a base such as lithium hydroxide, sodium hydroxide, alkali carbonates in a polar protic solvent such as methanol, ethanol, water or in mixtures of solvents including the mentioned polar protic solvent or other aproptic solvents. Typically, the hydrolysis is performed in an alcohol (methanol or ethanol) or in a 1:1 mixture of alcohol/THF, with water in the presence of sodium hydroxide (1-10 equivalents) at a temperature ranging from 200C to 1000C for 4 to 24 hours. Acids AIId can also be prepared from the corresponding esters AIIb by acid hydrolysis using an acid such as TFA, HCl, H2SO4, AcOH or in a mixture of these acids in neat or aqueous condition at a temperature ranging from 200C to 1000C for 0.5 to 24 hours. In the case where Ra8 is benzyl group, acids AIId can be prepared from the corresponding esters AIIb by hydrogenolysis using catalysts such as palladium on carbon or palladium hydroxide in a protic solvent such as EtOH or aprotic solvent such as EtOAc, under hydrogen atmosphere at a pressure of 15 to 150 psi, at a temperature from 200C to 1000C for 1 to 48 hours. Additional conditions for the hydrolysis of ester groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.
Scheme 5
Figure imgf000102_0001
wherein Pg is a protecting group an other symbols are as defined above. Compounds Ia can be prepared according to Scheme 5. Compounds AIIIe can be the result of an amide coupling between a suitably protected amine AIVa, where Pg is preferably Boc or Cbz group, and an acid AIIIa in conditions commonly employed to form amide bonds (mentioned previously) , followed by the deprotection of the amino group. In the preferred case wherein Pg is Boc group, the deprotection is conveniently performed in the presence of acids such as TFA or HCl, neat or in a solvent such as ethyl ether or dioxane at a temperature from 00C to 1000C for 5 minutes to 24 hours. Additional conditions for the deprotection of amines can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981. In the present invention, the preferred deprotection method for Boc-protected amines consists in treating the protected amine in 4N HCl in dioxanes (1-10 equivalents) at 200C for 10 minutes to 3 hours. Compounds AIIIe can be further coupled to acids AIId in conditions commonly employed to form amide bonds to produce compounds Ia.
Alternatively, compounds AIIf can be the result of the coupling between a suitably protected amine ATVb, where Pg is preferably Boc or Cbz group, and an acid AIId under conditions commonly employed to form amide bonds, followed by deprotection of the amino group. Compounds Ia can be produced by further coupling the amine AIIf with an acid AIIIa under conditions commonly employed to form amide bonds.
Scheme 6
HΑ3ι
Figure imgf000103_0001
Ia
Allte Ia-Il wherein the symbols are as defined above. Scheme 6 shows an alternative method for the preparation of compounds Ia. The amine AIIIe prepared according to Scheme 5 can be coupled to an acid AIIm under conditions commonly employed to form amide bonds. The resulting amine Ia-II can be further functionalized to compounds Ia, wherein Ra1 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group, under conditions similar to those described in Scheme 2.
Scheme 7
Figure imgf000104_0001
Ia-JV Ia-V wherein X is a halogen atom (preferably chloride, bromide or iodide) , Ra9 is an optionally substituted amino group and other symbols are as defined above.
Scheme 7 shows a method for preparing compounds of formula Ia-V. In the preferred case where Aa is an optionally substituted 2-halo-pyridine ring, compounds Ia-V can be prepared by amine substitution. Typically, an amine or its salt (preferably sodium salt) is reacted with a 2-halo- pyridine Ia-IV neat, in an aprotic solvent such as THF, DMF, DMSO, halogenated hydrocarbons or in a protic solvent such as alcohols at temperatures from 600C to 1600C for 1 to 24 hours. In the present invention, the reaction is run with the appropriate amine (50 to 200 equivalents) as the solvent at a temperature from 1100C to 1500C for 18 to 24 hours. In cases where the Aa ring is not an optionally substituted 2-halo- pyridine, the coupling can be performed under thermal conditions in the presence of a base such as potassium carbonate, potassium fluoride, hydrides or LDA in a solvent such as DMSO or dioxanes at temperatures from 1000C to 1700C for 1 to 48 hours. Alternatively, the coupling can be performed under palladium or copper catalyzed-conditions as reported in J. Organomet. Chem. 1999, 576(1-2), 125; Angew. Chem. , Int. Ed. Engl. 1998, 37, 2046; Oxg. Lett. 2002, 4(4), 581.
Scheme 8
Figure imgf000105_0001
Ia-IV Ia-Vl wherein Ra10 is an optionally substituted hydroxyl group or an optionally substituted mercapto group and other symbols are as defined above.
In the preferred case where Aa is an optionally substituted 2-halo-pyridine ring, compounds of formula Ia-VI can be prepared by halogen displacement. Typically, an alcohol or a thiol is treated with an alkali hydride such as sodium hydride, potassium hydride or a lithium base such as LDA or BuLi to form the corresponding alkoxide or thioalkoxide, which can then react with a 2-halo-pyridine, under conditions similar to those mentioned above, to yield compounds Ia-VI. The 2-halo-pyridine can also be treated with an alcohol or a thiol in the presence of a base such as alkali carbonates in solvents such as DMF or DMSO at temperatures from 1000C to 1700C for 10 to 48 hours. In the present invention, the alkoxide or thioalkoxide (1 to 5 equivalents) is formed in the presence of sodium hydride (1 to 5 equivalents) in a solvent such as THF at a temperature from 00C to 300C, and then reacted with a 2-halo-pyridine Ia-IV at temperatures from 600C to 800C for 3 to 16 hours.
Scheme 9
Figure imgf000106_0001
Ia-IV Ia-IX wherein Ra11 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above. As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra11, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra5 or Ra7, can be mentioned.
Scheme 9 shows methods for preparing compounds of formula Ia-IX. Compounds Ia-IX can be conveniently prepared from compounds Ia-IV under palladium-catalyzed conditions such as Suzuki (Chem. Rev. 1995, 95, 2457) or Negishi (Negishi, Ei- ichi. Handbook of Organopalladium Chemistry for Organic Synthesis (2002), 1, 767-789; John Wiley & Sons, Inc., Hoboken, N. J) . Typically, the coupling is performed between a boronic acid or a zinc halide and compound Ia-IV in the presence of a catalysts such as, but not limited to, Pd{PPh3)4/ Pd(OAc)2/ PdCl2 (dppf) or PdCl2(PPh)2, a base such as alkali carbonates, alkali phosphates (sodium phosphate or potassium phosphate) or potassium fluoride and a ligand (J". Am. Chem. Soc. 1999, 121, 9550 - 9561) such as phosphines in a solvent such as toluene, THF, alcohols, water or mixtures of the above solvents. In the preferred case where Ra11 is an alkyl group, the reaction is performed using alkyl zinc bromide (2 to 3 equivalents), compound Ia-IV (1 equivalent) and PdCl2 (dppf) - CH2Cl2 (0.1 equivalents) in a solvent such as THF at a temperature from 200C to 75°C for 0.5 to 24 hours. In the preferred case where Ra is benzyl group, 9-benzyl-9-bora- bicyclo[3.3.1]nonane may be used under similar conditions to those mentioned above. In the preferred case where Ra11 is an aromatic or hetero aromatic group, the reaction is performed in the presence of a boronic acid (1.5-3 equivalents), a palladium catalyst such as Pd(OAc)2/ Pd(PPh3)4 or Pd2(dba)3 (0.1 to 1 equivalent), a ligand such as 2, 8, 9-triisobutyl-2, 5, 8, 9- tetraaza-l-phosρha-bicyclo[3.3.3]undecane and a base such as alkali carbonates in a solvent such as toluene or THF at a temperature from 45°C to 120 0C, preferably 900C, for 1 to 16 hours .
Scheme 10
Figure imgf000107_0001
Ia-X Ia-Xl wherein Ra12 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra12, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1,
Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 10 shows methods for preparing compounds of formula Ia-XI. Compounds Ia-XI can be conveniently prepared from sulfides Ia-X, prepared according to similar conditions to those described in Scheme 8, under oxidative conditions. Suitable oxidants include, but are not limited to, KMnOo MCPBA, OXONE or hydrogen peroxide. The reaction is typically performed in solvents such as THF, acetone, halogenated hydrocarbons, or a mixture of the mentioned solvents at a temperature from 00C to 25°C for 1 to 24 hours. An acidic co- reagent such as formic acid may be used. In the present invention, a sulfide Ia-X (1 equivalent) is preferably treated with KMnO4 (1.5 to 4 equivalents) and formic acid (5 to 10 equivalents) in a THF/acetone (1:2) solvent system at 25°C to 600C for 8 to 48 hours.
Scheme 11
Figure imgf000108_0001
Ia-IV Ia-XVl wherein the symbols are as defined above.
Scheme 11 shows methods for preparing compounds of formula Ia-XVI where the Aa ring is substituted with a nitrile group. Compounds Ia-XVI can be prepared by nucleophilic substitution in the presence of nitrile equivalents such as NaCN, KCN or CuCN in solvents such as DMF or DMSO at temperatures from 8O0C to 1800C for 1 to 48 hours. Compounds Ia-XVI can also be prepared from halides Ia-IV in the presence of Zn(CN)2 or KCN and a palladium catalyst such as Pd (PPh3) 4 or Pd(OAc)2 and a phosphine in' solvents such as DMF at 8O0C to 1400C for 1 to 24 hours (for a review on Pd-catalyzed cyanation of aryl halides see Eur. J. Inorg. Chem. 2003, 19, 3513) . Typically, the reaction is performed using CuCN (1 to 2 equivalents) in a solvent such' as DMF at a temperature from 1300C to 1600C for 16 to 48 hours.
Scheme 12
Figure imgf000108_0002
Ia-IV Ia-XVII wherein the symbols are as defined above.
Scheme 12 shows methods for preparing compounds of formula Ia-XVII where the Aa ring is substituted with a carboxylic ester group. Compounds Ia-XVII can be prepared by alkoxycarbonylation of halides Ia-IV using a palladium-ligand catalyst such as (R) - (Binap) PdCl2 or PdCl2 (PPh3) 2 in the presence of a base such as triethylamine, Hunig' s base, alkali carbonates or alkali hydroxides (lithium hydroxide, sodium hydroxide or potassium hydroxide) in solvents such as toluene or alcohols under carbon monoxide atmosphere (J". Organomet. Chem. 2002, 641(1-2), 30; Synthesis 2002, 15, 2171). In the present invention, halides Ia-IV are preferably treated with (R)- (Binap) PdCl2 (0.01 to 0.1 equivalents) and triethylamine (1 to 2 equivalents) in alcohol (preferably methanol or ethanol) under carbon monoxide pressure (30-100 psi) at a temperature from 200C to 1000C for 24 to 48 hours.
Scheme 13
Figure imgf000109_0001
Ia-IV Ia-XVIII wherein Ra is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra13, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1,
Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 13 shows methods for preparing compounds of formula Ia-XVIII. Compounds Ia-XVIII can be prepared by amidation of halides Ia-IV under copper-mediated or palladium- mediated conditions reported in Schemes 7 and 9 (for specific amidation coupling, see J. Am. Chem. Soc. 2002, 124(25), 7421) . In the present invention, halides Ia-rv are treated with an amide Ra13CONH2 (1 to 2 equivalents) in the presence of Pd2(dba)3 (0.1 to 1 equivalents) , Xantphos (0.1 to 1 equivalent) and an alkali carbonate (1 to 3 equivalents) in a solvent such as dioxane at a temperature from 800C to 1200C, preferably 1000C, for 3 to 24 hours.
Scheme 14
Figure imgf000110_0001
Ia-IV Ia-XIX wherein the symbols are as defined above.
Scheme 14 shows methods for preparing compounds of formula Ia-XIX. Compounds Ia-XIX can be prepared under Heck conditions from halides Ia-IV and vinyl alkoxides followed by hydrolysis of the resulting alkyl enol (for a description of the Heck reaction and its applications to organic synthesis see, Negishi, Ei-ichi. Handbook of Organopalladiυm Chemistry for Organic Synthesis (2002), 1, pll33-1178; John Wiley & Sons, Inc., Hoboken, N. J; Angew. Chem. , Int. Ed. Engl. 2002, 41, 4176; Tetrahedron 2001, 57, 7449) . Alternatively, halides Ia-IV can be treated with tributyl (1-ethoxyvinyl) stannane under Stille conditions followed by hydrolysis of the resulting alkyl enol (for a description of the Stille reaction and its applications to organic synthesis see, Aqueous-Phase Organometallic Catalysis (2nd Edition) (2004), 511-523. Publisher: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany) . Preferably, halides Ia-IV are treated with 1- (vinyloxy) butane (1 equivalent) in the presence of Pd (OAc) 2 (0.1 to 1 equivalent), dppp (0.2 to 2 equivalents) and alkali carbonate (1 to 3 equivalents) in a solvent such as DMF, toluene, water or a mixture of the mentioned solvents at a temperature from 6O0C to 1400C, preferably 8O0C, for 1 to 48 hours. The resulting vinyl enol can then be hydrolyzed to the acetyl group by treatment with acid, typically 2N HCl at 200C for 1 to 24 hours.
Scheme 15
Figure imgf000111_0001
Ia-XVi Ia-XX
Figure imgf000111_0002
Ia-XXI wherein Ra14 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra14, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4,, Ra5, Ra6 or Ra7, can be mentioned.
Compounds of formula Ia-XX can be prepared by treating a nitrile Ia-XVI with hydroxylamine hydrochloride (1 to 1.5 equivalents) in solvents such .as aqueous alcohols (ethanol) at a temperature of 00C to reflux for 1 to 24 hours. In the case where Ra14 is not a hydrogen atom, Ia-XX or its salts can be treated with an acid (Ra14CO2H), an acid anhydride ((Ra14CO)2O) or an acid chloride (Ra14COCl) in the presence of a base, CDI, . DCC/benzotriazole, DCC or TFFH (Synthesis 2004, (15), 2485- 2492) in solvents such as DMF, THF, ACN or halogenated hydrocarbons to yield compounds of formula Ia-XXI. Preferably, Ia-XX is reacted with and acid chloride (Ra14COCl) (1-1.5 equivalents) in a base such as pyridine at a temperature from 600C to 1000C for 1 to 24 hours. In the case where .Ra14 is a hydrogen atom, Ia-XX is reacted in a trialkyl orthoformate (solvent) in the presence of boron trifluoride etherate (1 equivalent) at a temperature between 600C to 1400C for 1 to 24 hours, to yield compounds Ia-XXI.
Scheme 16
Figure imgf000112_0001
Ia-XVlI Ia-XXIII
Figure imgf000112_0002
Ia-XXIV wherein Ra15 and Ra16 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group"/
"optionally substituted heterocyclic group" and "acyl group" for Ra15 or Ra16, those exemplarily recited as the "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group" and "acyl group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4,
Ra5, Ra6 or Ra7, can be mentioned.
Compounds of formula Ia-XXIII can be prepared from compounds Ia-XVII (preferably Ra8 is methyl or ethyl group) , ' using hydrolysis methods similar to those described in Scheme 4. Compounds Ia-XXIII can be converted to the carbamates Ia- XXIV/ wherein Ra15 is a hydrogen atom and Ra16 is an alkoxycarbonyl group (preferably tert-butoxycarbonyl group) or vice versa, via a Curtius type rearrangement (for a description of the Curtius rearrangement and its applications to organic synthesis, see, Chem. Soc. Rev. 2006, 35(2), 146- 56). Preferably, acids Ia-XXIII (1 equivalent), diphenylphosphoryl azide (1 to 1.5 equivalents) and triethylamine (1 to 1.5 equivalents) are reacted in tert- 5 butanol for 1 to 3 days at 800C. The tert-butoxycarbonyl group is removed using acidic conditions (TFA or 4N HCl in dioxane) at room temperature to provide the unsubstituted amine Ia- XXIV, wherein Ra15 and Ra16 are both hydrogen atoms, or its salt. Compounds Ia-XXIV, wherein Ra15 and Ra16 are
10 independently a hydrogen atom, an optionally substituted non- aromatic hydrocarbon group or an optionally substituted non- aromatic heterocyclic group (excluding the case where Ra15 and Ra16 are both hydrogen atoms) , can be prepared by treating the unsubstituted amine Ia-XXIV or its salt with the corresponding
15 halide or the corresponding sulfonate in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine or an inorganic base such as alkali hydrides or alkali carbonates . Solvents include halogenated hydrochlorides, THF or DMF. The transformation can also be
20 accomplished by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent such as halogenated hydrocarbons. An acid such as acetic acid may be added to the reaction. The unsubstituted
25 amine Ia-XXTV is reacted with the corresponding aldehyde or ketone (1.1-4 equivalents) and then reduced in the presence of a reducing agent (1.5-6 equivalents) at low pH. Compounds Ia- XXIV, wherein Ra15 and Ra16 are independently a hydrogen atom or an acyl group (excluding the case where Ra15 and Ra16 are both
30 hydrogen atoms), can be prepared by treating the unsubstituted amine or its salt with the corresponding acid in the presence of a coupling reagent under conditions commonly employed to form amide bonds. In this invention, the coupling reagent of choice is HATU or EDAC -HClZHOBt1H2O in a solvent such as
^5 halogenated hydrocarbons or DMF at room temperature. The ill transformation may also be accomplished by treating the unsubstituted amine or its salt with the corresponding acid halidβ/ acid anhydride, sulfonyl halide, isocyanate, carbamic halidβ/ haloformate or dicarbonate in the presence of an organic base such as pyridine/ triethylamine, diisopropylethylamine or an inorganic base such as alkali hydrides or alkali carbonates in a solvent such as acetone, THF, halogenated hydrocarbons or DMF at a temperature from 200C to 1300C for 1 to 72 hours. Compounds Ia-XXIV, wherein Ra .15 and Ra15 are independently a hydrogen atom, an optionally substituted aryl group or an optionally substituted heteroaryl group (excluding the case where Ra or Ra ,116 are both hydrogen atoms) can be prepared by reacting an unsubstituted amine Ia- XXrv or its salt with an activated aryl or heteroaryl halide under SNAT conditions (basic conditions in a polar, protic solvent; suitable bases include potassium hydride, sodium hydride, potassium tert-butoxide, lithium hydroxide or alkali carbonates in solvents such as DMF, DMSO or THF) , or an aryl or heteroaryl halide under palladium mediated conditions (conditions for these transformations can be found in Angew. Chem. Int. Ed. 1998, 37, 2046; Organomet. Chem. 1999, 576, 125) .
Scheme 17
Figure imgf000114_0001
Ia-XXIII Ia-XXV wherein Ra11 is an optionally substituted amino group and other symbols are as defined above.
As the "optionally substituted amino group" for Ra17, those exemplarily recited as the "optionally substituted amino group", which is exemplarily recited as the "substitueht" for
Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned. Compounds of formula Ia-XXV can be prepared from acids Ia-XXIII (prepared according to the method described in Scheme 16) and an amine under conditions commonly employed for the formation of amide bonds.
Scheme 18
Figure imgf000115_0001
Figure imgf000115_0002
AIIIi wherein Ra18 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra18, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1/ Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 18 shows a method for preparing intermediates AIIIi which are suitable for use in preparing compounds of formulas Ia and Ia-I as shown in Schemes 3, 4 and 5. Compounds of formula AIIIi may be prepared from compounds AIIIh by reaction with alkyl zinc halides using Negishi conditions or with aryl/heteroaryl boronic acids using Suzuki conditions using similar methods to those described in Scheme 9. In the case where the Aa ring has more than one X atom, the bis coupling can be achieved using excess reagent (3 to 5 equivalents) . Compounds AIIIi can be converted to the corresponding acids under conditions commonly employed.
Scheme 19
Figure imgf000116_0001
AIIf AIIg wherein Ra19 and Ra20 are each independently an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or acyl group, and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra19 or Ra20, those exemplarily recited- as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the
"substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 19 shows a method for preparing intermediates AIIg which are suitable for use in preparing compounds of formulas Ia and Ia-I as shown in Schemes 3, 4 and 5. Compounds of formula AIIg can be prepared from amines of formula AIIf using similar methods to those described in Scheme 16. In the preferred case wherein Ba is an optionally substituted pyrazole ring, compounds AIIf* can be prepared according to the procedure described J. Het. Chem. 1967, pp. 325.
Scheme 20
Figure imgf000116_0002
AVa AVb AVc wherein Ra21 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, Ra22 is a C1-C2 alkoxy group, NH2 or NMe2 and other symbols are as defined above . As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra21, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 20 shows a method for preparing intermediates AVc which are suitable for use in preparing compounds of formula AIIb as shown in Scheme 2. Compounds of formula AVb may be prepared from β-ketoesters of formula AVa. In the case where Ra22 is a C1-C2 alkoxy group, compounds AVb can be prepared by reacting the β-ketoester AVa (1 equivalent) with a trialkyl orthoformate (2 equivalents) and acetic anhydride (5 equivalents) at 500C to 1000C for 4 to 24 hours. In the case where Ra22 is MMe2, compound AVb can be prepared by reacting the β-ketoester AVa (1 equivalent) in DMF-DMA (2 to 50 equivalents) in the presence of a base such as triethylamine neat or in a solvent such as THF, toluene or halogenated hydrocarbons at a temperature from O0C to 1000C for 1 to 48 hours. In the case where Ra22 is NH2/ compound AVb can be prepared by reacting the β-ketoester AVa with 3-methyl-5-nitropyrimidin-4 (3H) -one according to the procedure described in Synlett 2004, 4, 703. From the enamines or enols AVb, pyrazoles AVc are conveniently prepared by reaction with hydrazine, its salts or hydrates in solvents such as alcohols or ethers at temperatures from 6O0C to 1000C for 2 to 24 hours. Preferably, compound AVb, where Ra22 is a C1-C2 alkoxy group, is treated with hydrazine hydrate (1 to 10 equivalents) in ethanol at reflux for 3 to 12 hours.
Scheme 21
Figure imgf000118_0001
AVe wherein Ra22a is a C1-C2 alkyl group, Ra23 and Ra25 are each independently an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, provided that R23 is not optionally substituted quinolyl, Ra24 is a hydrogen atom or acetyl group, and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra23 or Ra25, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 21 shows a method for preparing intermediates AVf which are suitable for use in preparing compounds of formulas Ia and Ia-I as shown in Schemes 3, 4 and 5. Compounds of formula AVd may be prepared from alkylmalonates according to a similar method described in Scheme 20. Compound AVd can be treated with substituted hydrazine or substituted acetyl hydrazide in the presence of POCI3 or a base such as sodium ethoxide following the procedures described in Tetrahedron 1977, 33, 2829; Tetrahedron 1987, 43(3), 607 and WO2001023358, to yield the pyrazolinones AVe. Compound AVe can be converted to compound AVf in the presence of the corresponding activated halides and a base such as alkali hydrides or alkali carbonates in solvents such as acetonitrile or DMF at temperatures from 00C to 1300C for 1 to 24 hours. In the present invention, dialkyl (alkyloxy)malonates AVd are preferably treated with POCl3 in the presence of an aryl acetylhydrazide to afford the pyrazolinones Ave, which can then be reacted with the corresponding halides (1 to 2 equivalents) in the presence of a base such as potassium carbonate (1 to 3 equivalents) at a temperature from 200C to 600C for 3 to 12 hours.
Scheme 21a
Figure imgf000119_0001
AIIIj AIIIk wherein Ra26 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic (aromatic or non- aromatic) group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" for Ra25, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 21a shows methods of preparing bicyclic intermediates AIIIk. An aminopyridine Alllj may be treated with a corresponding optionally substituted α~bromo ketone in the presence of an inorganic base such as sodium bicarbonate in a polar protic solvent such as methanol or ethanol at a temperature of 400C to 800C for 4 to 24 hours to afford the imidazo [1, 2-a] pyridine AIIIk. Compounds AIIIk can be hydrolyzed to the corresponding acids under conditions commonly employed.
Scheme 21b
Figure imgf000120_0001
AlIIn wherein Ra27 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic (aromatic or non- aromatic) group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" and
"optionally substituted heterocyclic group" for Ra , those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 21b shows methods of preparing intermediates AIIIp, in which the pyridine ring is substituted with a 1,3,4- oxadiazolyl group. Compounds AIIIo can be prepared from the acid AIIIm and an acyl hydrazide (Ra27CONHNHz) in conditions commonly employed to form amide bonds. Compounds AIIIo can be treated with a reagent such as POCI3, PhP0Cl2, TFAA/Py or TsCl/Py to form the corresponding substituted 1,3,4- oxadiazoles AIIIp. Preferably, compounds AIIIo are treated with POCl3 (1.1-10 equivalents) in a solvent such as acetonitrile or neat at a temperature of 8O0C for 1 to 24 hours .
Another method consists in treating the acid AIIIm with a suitably protected hydrazine in conditions commonly employed to form amide bonds. In the present invention, the protected hydrazine is preferably Boc-hydrazine. The resulting protected hydrazide may be hydrolyzed in acidic conditions such as TFA or HCl in dioxane (2-10 equivalents) at temperatures from 200C to 900C for 1 to 24 hours to yield the hydrazide salts AIIIn. Compounds AIIIn can be reacted with a corresponding acid (Ra27COOH) under conditions commonly used to form amide bonds to give compounds AIIIo, which can be converted to compounds AIIIp under the conditions mentioned above. Compounds AIIIp may be hydrolyzed to the corresponding acids under conditions commonly employed.
Figure imgf000121_0001
wherein Rb1 is a Ci-C4 alkyl or benzyl group and other symbols are as defined above.
Intermediate esters BII and acids Bill which are suitable for use in preparing compounds of formula Ib can be prepared according to the following references: Tetrahedron Lett. 1998, 39, 2941-2944; Eur. J. Org. Chem. 2004, 695-709; J. Am. Chem. Soc 2001, 123, 7727-7729; J. Am. Chem. Soc. 2002, 124, 11684- 11688; J. Org. Chem. 2004, 69, 5578. Typically, the N- heteroarylation of the Bb ring is performed with a heteroaryl halide (preferably iodide) in the presence of copper catalyst such as copper iodide or copper oxide in the presence of a ligand such as substituted ethylene diamines, salicylaldoximes or other ligands reported in Eur. J. Org. Chem. 2004, 695-709. The reaction requires a base such as potassium phosphate or cesium carbonate and is performed in a degassed solvent such as acetonitrile, toluene or DMF at a temperature of 200C to 1500C for 0.5 to 48 hours under inert atmosphere. Preferably, the N-heteroarylation is conducted according to the method described in J. Org. Chem. 2004, 69, 5578, in toluene with 1 equivalent of BI, 1.1-10 equivalents of heteroaryl halide, 2 equivalents of diamine ligand, 2-3 equivalents of base and 0.05 equivalents of copper (I) iodide or according to the method described in Eur. J. Org. Chem. 2004, 695-709, in DMF with 1 equivalent of Bi, 1.5-10 equivalents of heteroaryl halide, 0.2-0.4 equivalents of oxime ligand, 2-3 equivalents 5 of base and 0.05 equivalents of copper (II) oxide.
Acids Bill can be prepared from the corresponding esters BII by using a base such as lithium hydroxide, sodium hydroxide, alkali carbonates (sodium carbonate, potassium carbonate or cesium carbonate) in a polar protic solvent such
10 as methanol, ethanol, water or in mixtures of solvents including alcohols and water, or aprotic solvents. Typically, the hydrolysis is performed in an alcohol (methanol or ethanol) or in a 1:1 mixture of alcohol/THF, with water in the presence of sodium hydroxide (1-10 equivalents) at a i5 temperature ranging from 200C to 1000C for 0.5 to 24 hours. Acids Bill can also be prepared from the corresponding esters BII by acid hydrolysis using an acid such as TFA, HCl, H2SO4, AcOH or in a mixture of these acids in neat or aqueous condition at a temperature ranging from 2O0C to 1000C for 0.5
20 to 24 hours. In the case where Rb1 is benzyl group, acids Bill can be prepared from the corresponding esters BII by hydrogenolysis using catalysts such as palladium on carbon or palladium hydroxide in a protic solvent such as EtOH or aprotic solvent such as EtOAc under hydrogen atmosphere at a
25 pressure of 15 to 150 psi, at a temperature of 200C to 1000C for 1 to 48 hours. Additional conditions for the hydrolysis of ester groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.
30 Scheme 23
Figure imgf000122_0001
wherein the symbols are as defined above.
Compounds Ib can be prepared according to the sequence described in Scheme 23. Esters BII, where' Rb1 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines BIV. Compounds Ib can be conveniently prepared from an amine BIV or its salt and an acid BV in the presence of various condensing reagents. Known condensing reagents that effect amide bond formation include, but are not limited to, N, N-carbonyldiimidazole, halopyridine salts, 2, 4, β-trichlorobenzoyl chloride, HATU, BOP-Cl or EDAC "HClZHOBt-H2O. In the present invention, the preferred reagent is EDAC -HCl/HOBt -H2O. The reaction can be conducted in a variety of aprotic solvents such as halogenated hydrocarbons (DCM or CHCI3) , acetonitrile or dimethylformamide, or a mixture of these solvents, at a temperature from 0°C to 1300C, preferably 200C to 70°C, for a time ranging from 0.5 to 48 hours. A base such as triethylamine or diisopropylethylamine may be used especially if the reacting amine is in a salt form. While the amount of reagent varies depending on the condensing reagent used, the following stoichiometry is used preferably with EDAC "HCl/HOBt* H2O: amine or its s.alt (1 equivalent), acid (1 equivalent), EDACΗC1 (1 to 2 equivalents), HOBt-H2O (1 to 2 equivalents) and base (1 to 3 equivalents) .
Scheme 24
Figure imgf000123_0001
wherein the symbols are as defined above. Alternatively, compounds Ib can be prepared following the sequence described in Scheme 24. Esters BVI, where Rb1 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines BVII. Compounds Ib can be prepared from the amine BVII or its salt and acid Bill in the conditions commonly employed to form amide bonds such as those mentioned in Scheme 23.
Scheme 25
Figure imgf000124_0001
wherein the symbols are as defined above.
Alternatively, compounds Ib can be prepared according to Scheme 25. The amine BVII can be coupled to the acid BVIII under conditions commonly employed to form amide bonds. The amine BVix can be further transformed to compound Ib under conditions similar to those described in Scheme 22.
Scheme 26
Figure imgf000124_0002
wherein Rc8 is a Ci-C4 alkyl or benzyl group and other symbols are as defined above.
Intermediate esters CII and acids CIII which are suitable for use in preparing compounds of formula Ic can be prepared according to the following references: Tetrahedron Lett. 1998, 39, 2941-2944; Eur. J. Org. Chem. 2004, 695-709; J. Am. Chem.
Soc 2001, 123, 7727-7729; J". Am. Chem. Soc. 2002, 124, 11684- 11688/ J. Org. Chem. 2004, 69, 5578. Typically, the N- arylation or N-heteroarylation of the Bc. ring is performed with a aryl or heteroaryl halide (preferably iodide) in the presence of copper catalyst such as copper iodide or copper oxide in the presence of a ligand such as substituted ethylene diamines, salicylaldoximes or other ligands reported in Eur. J. Org. Chem. 2004, 695-709. The reaction requires a base such as potassium phosphate or cesium carbonate and is performed in a degassed solvent such as acetonitrile, toluene or DMF at a temperature of 200C to 1500C for 0.5 to 48 hours under inert atmosphere. Preferably, the N-arylation or N-heteroarylation is conducted according to the method described in J. Org. Chem. 2004, 69, 5578, in toluene with 1 equivalent of CI, 1.1- 10 equivalents of aryl or heteroaryl halide, 2 equivalents of diamine ligand, 2-3 equivalents of base and 0.05 equivalents of copper (I) iodide or according to the method described in Eur. J. Org. Chem. 2004, 695-709, in DMF with 1 equivalent of CI, 1.5-10 equivalents of aryl or heteroaryl halide, 0.2-0.4 equivalents of oxime ligand, 2-3 equivalents of base and 0.05 equivalents of copper (II) oxide.
Acids CIII can be prepared from the corresponding esters CII by using a base such as lithium hydroxide, sodium hydroxide, alkali carbonates (sodium carbonate, potassium carbonate or cesium carbonate) in a polar protic solvent such as methanol, ethanol, water or in mixtures of solvents including alcohols and water, or aprotic solvents . Typically, the hydrolysis is performed in an alcohol (methanol or ethanol) or in a 1:1 mixture of alcohol/THF, with water in the presence of sodium hydroxide (1-10 equivalents) at a temperature ranging from 200C to 1000C for 0.5 to 24 hours. Acids CIII can also be prepared from the corresponding esters CII by acid hydrolysis using an acid such as TFA, HCl, H2SO4, AcOH or in a mixture of these acids in neat or aqueous condition at a temperature ranging from 200C to 1000C for 0.5 to 24 hours. In the case wherein Rb1 is benzyl group, acids CIII can be prepared from the corresponding esters CII by hydrogenolysis using catalysts such as palladium on carbon or palladium hydroxide in a protic solvent such as EtOH or aprotic solvent such as EtOAc under hydrogen atmosphere at a pressure of 15 to 150 psi, at a temperature of 2O0C to 1000C for- 1 to 48 hours. Additional conditions for the hydrolysis of ester groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.
Scheme 27
Figure imgf000126_0001
wherein the symbols are as defined above.
Compounds Ic can be prepared according to Scheme 27. Compounds CVI can be the result of an amide coupling between a suitably protected amine CIV (Pg is preferably Boc or Cbz group) and an acid CV in the presence of various condensing reagents followed by deprotection of the amino group. Known condensing reagents that effect amide bond formations include, but are not limited to, N, N-carbonyldiimidazole, halopyridine salts, 2, 4, 6-trichlorobenzoyl chloride, HATU, BOP-Cl or EDAC -HCl/HOBt- H2O. In the present invention, the preferred reagent is EDAC-HClZHOBt-H2O. The reaction can be conducted in a variety of aprotic solvents such as halogenated hydrocarbons (DCM or CHCI3) / acetonitrile or dimethylformamide, or a mixture of these solvents, at a temperature from 00C to 1300C, preferably 200C to 700C, for a time ranging from 0.5 to 48 hours. A base such as triethylamine or diisopropylethylamine may be used especially if the reacting amine is in a salt form. While the amount of reagent varies depending on the condensing reagent used, the following stoichiometry is used preferably with EDAC-HCl/HOBt-H2O: amine or its salt (1 equivalent), acid (1 equivalent), EDAC-HCl (1 to 2 equivalents), HOBt-H2O (1 to 2 equivalents) and base (1 to 3 equivalents) .
In the preferred case wherein Pg is Boc group, the deprotection is conveniently performed in the presence of acids such as TFA or HCl, neat or in a solvent such as ethyl ether or dioxane at a temperature from.00C to 1000C for 5 minutes to 24 hours. In the present invention, the preferred deprotection method for Boc-protected amines consists in treating the protected amine in TFA or in 4N HCl in dioxanes at 200C for 10 minutes to 24 hours. Additional conditions for the deprotection of amines can be found in T. W. Green,
Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.
Compounds CVI can be further coupled to an acid CIII in conditions commonly employed to form amide bonds to afford compounds Ic.
Alternatively, compounds CVIII can be the result of the coupling between a suitably protected amine CVII (Pg is preferably Boc or Cbz group) and an acid CIII under conditions commonly employed to form amide bonds followed by deprotection of the amino group. Compounds Ic can be produced by further coupling the amine CVIII with an acid' CV under conditions commonly employed to form amide bonds .
Scheme 28
Figure imgf000128_0001
wherein the symbols are as defined above.
Compounds of formula Ic-I can be prepared from a Pg protected diamino ester following the method described in
Scheme 27. The esters Ic-I may be hydrolyzed to the acids Ic- II using conditions commonly employed for the hydrolysis of ester. Esters Ic-I can also be reduced to the corresponding alcohols Ic-III in the presence of a reducing agent such as sodium borohydride. In the present invention, Ic-I is preferably reduced in the presence of the couple sodium borohydride/lithium chloride (1 to 3 equivalents) in a solvent system such as THF/ethanol at a temperature from 00C to 800C for 1 to 24 hours.
Scheme 29
Figure imgf000128_0002
wherein Rd1 is a Ci-C4 alkyl or benzyl group and other symbols are as defined above.
Compounds Id can be prepared according to the sequence shown in Scheme 29. Esters DIIa, where Rd1 is preferably methyl or ethyl group, can be treated with ethylehediamine at refluxing temperature to produce amines DIIb. Compounds of formula Id can then be prepared from acids DIIIa and amines DIIb or their salts by reacting both intermediates in the presence of various condensing reagents. Known condensing reagents that effect amide bond formation include N, N- carbonyldiimidazole/ halopyridine salts, 2,4,6- trichlorobenzoyl chloride, HATU, BOP-Cl, EDAC-HClZHOBt-H2O or TsClZN-methy1 imidazole. In the present invention, the preferred reagent is either PIATU or EDAC-HClZHOBt-H2O. The reaction can be conducted in aprotic solvents such as tetrahydrofuran, halogenated hydrocarbons (DCM or CHCI3) , acetonitrile, dimethylformamide, or a mixture of these solvents, at a temperature from 00C to 1300C, preferably 200C to 700C, for a time ranging from 1 to 48 hours, preferably 10 to 20 hours. A base such as triethylamine or diisopropylethylamine may be used especially if the reacting amine is in a salt form. While the amount of reagent varies depending on the coupling reagent used, the following amounts are used preferably with HATU or EDAC'HClZHOBt-H2O: amine or its salt (1 equivalent) , acid (1 equivalent) , HATU or EDAC-HClZHOBt-H2O {1 to' 2 equivalents), base (1 to 3 equivalents if salt form of amine is used) . Compounds Id. can also be prepared from acid chlorides DIIIb and amines DIIb in the presence of a base such as triethylamine, diiisopropylethylamine or pyridine in an aprotic solvent such as THF, benzene, halogenated hydrocarbons at temperatures from 20°C to 90°C for 0.5 to 24 hours.
Scheme 30
Figure imgf000130_0001
wherein the symbols are as defined above.
Alternatively, compounds Id can be prepared following the sequence described in Scheme 30. Esters DIIIc, where Rd1 is preferably methyl or ethyl group, can be treated with ethylenediamine at refluxing temperature to produce amines DIIId. Compounds Id can be prepared under the conditions mentioned in Scheme 29 using an amine DIIId or its salt form, and an acid DIIc. Acids DIIc can be prepared from the corresponding esters DIIa by using a base such as lithium hydroxide, sodium hydroxide, alkali carbonates (sodium carbonate, potassium carbonate or cesium carbonate) in a polar protic solvent such as methanol, ethanol, water or in mixtures of solvents including the mentioned polar protic solvent or other aproptic solvents. Typically, the hydrolysis is performed in an alcohol (methanol or ethanol) or in a 1:1 mixture of alcohol/THF, with water in the presence of sodium hydroxide (1-10 equivalents) at a temperature ranging from 200C to 1000C for 4 to 24 hours. Acids DIIc can also be prepared from the corresponding esters DIIa by acid hydrolysis using an acid such as TFA, HCl, H2SO4, AcOH or in a mixture of these acids in neat or aqueous condition at a temperature ranging from 200C to 1000C for 0.5 to 24 hours.. In the case where Rd1 is benzyl group, acids DIIc can be prepared from DIIa by hydrogenolysis using catalysts such as palladium on carbon or palladium hydroxide in a protic solvent such as EtOH or aprotic solvent such as EtOAc under hydrogen atmosphere at a pressure of 15 to 150 psi, at a temperature of 200C to 1000C for 1 to 48 hours. Additional conditions for the hydrolysis of ester groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.
Scheme 31
Figure imgf000131_0001
wherein the symbols are as defined above.
Compounds of formula Id can be prepared according to Scheme 31. Compounds DIIId can be the result of an amide coupling between a suitably protected ethylenediamine DIVa, where Pg is preferably Boc or Cbz group, and an acid DIIIa in conditions commonly employed to. form amide bonds, followed by the deprotection of the amino group. In the preferred case wherein Pg is Boc group, the deprotection is conveniently performed in the presence of acids such as TFA or HCl, neat or in a solvent such as ethyl ether or dioxane at a temperature from 00C to 1000C for 5 minutes to 24 hours. Additional conditions for the deprotection of amines can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981. In the present invention, the preferred deprotection method for Boc-protected amines consists in treating the protected amine in 4N HCl in dioxanes (1-10 equivalents) at 200C for 10 minutes to 3 hours. Compounds DIIId or their salts can be further coupled to acids DIIc in conditions commonly employed to form amide bonds to produce compounds Id.
Alternatively/ compounds DIIb can be the result of the coupling between a suitably protected ethylenediamine DIVa7 where Pg is preferably Boc or Cbz group, and an acid DIIc under conditions commonly employed to form amide bonds, followed by deprotection of the amino group. Compounds Id can be produced by further coupling the amine DIIb or its salt with an acid DIIIa under conditions commonly employed to form amide bonds.
Figure imgf000132_0001
wherein X is a halogen atom and other symbols are as defined above.
Scheme 32 shows a method for preparing intermediates DIIa which are suitable for use in preparing compounds of formula Id as shown in Schemes 29, 30 and 31. - Compounds DIIa can be conveniently prepared from the halogen substituted DIId under palladium-catalyzed conditions such as Suzuki {Chem. Rev. 1995, 95, 2457), Negishi (Negishi, Ei-ichi. Handbook of Organopalladium Chemistry for Organic Synthesis (2002), 1, 767-789; John Wiley & Sons, Inc., Hoboken, N. J) or Stille (Aqueous-Phase Organometallic Catalysis (2nd Edition) (2004) , 511-523. Publisher: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany) . Typically, the coupling is performed between a boronic acid, a zinc halide or a trialkylstanane and the halogen substituted DIId in the presence of a catalysts such as, but not limited to, Pd (PPh3) 4, Pd(OAc)2, PdCl2 (dppf) or PdCl2(PPh)2, a base such as alkali carbonates, alkali phosphates or potassium fluoride and a ligand [J. Mi. Chem. Soc. 1999, 121, 9550 - 9561) such as phosphines in a solvent such as toluene, THF, alcohols, water or mixtures of the above solvents.
Figure imgf000133_0001
wherein the symbols are as defined above.
Intermediate esters DVI and acids DVII which are suitable for use in preparing compounds of formula Id as shown in
Schemes 30 and 31, can be prepared according to the following references: Tetrahedron Lett. 1998, 39, 2941-2944; Eur. J. Org. Chem. 2004, 695-709; J. Am. Chem. Soc 2001, 123, 7727- 7729; J. Am. Chem. Soc. 2002, 124, 11684-11688; J. Org. Chem. 2004, 69, 5578. Typically, the N-arylation or N- heteroarylation of the Bd ring is performed with a aryl or heteroaryl halide (preferably iodide) in the presence of copper catalyst such as copper iodide or copper oxide in the presence of a ligand such as substituted ethylene diamines, salicylaldoximes or other ligands reported in Eur. J. Org. Chem. 2004, 695-709. The reaction requires a base such as potassium phosphate or cesium carbonate and is performed in a degassed solvent such as acetonitrile, toluene or DMF at a temperature of 200C to 15O0C for 0.5 to 48 hours under inert atmosphere. Preferably, the N-arylation or N-heteroarylation is conducted according to the method described in J. Org. Chem. 2004, 69, 5578, in toluene with 1 equivalent of DV, 1.1- 10 equivalents of aryl or heteroaryl halide, 2 equivalents of diamine ligand, 2-3 equivalents of base and 0.05 equivalents of copper (I) iodide or according to the method described in Eur. J. Org. Chem. 2004, 695-709, in DMF with 1 equivalent of •
DV, 1.5-10 equivalents of aryl or heteroaryl halide, 0.2-0.4 equivalents of oxime ligand, 2-3 equivalents of base and 0.05 equivalents of copper (II) oxide.
Acids DVIl can be prepared from the corresponding esters DVI by using similar methods to those described in Scheme 30.
Scheme 34
Figure imgf000134_0001
DVlII DXa DXb wherein Rd2 is an optionally substituted hydrocarbon group, Rd3 is an optionally substituted aromatic hydrocarbon group and other symbols are as defined above.
As the "optionally substituted hydrocarbon group" for Rd2, those exemplarily recited as the "optionally substituted hydrocarbon group", which is exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
As the "optionally substituted aromatic hydrocarbon group" for Rd3, groups corresponding to those exemplarily recited as the "optionally substituted aromatic hydrocarbon", which is exemplarily recited as the "optionally substituted aromatic ring" for ring Cd, can be mentioned.
Scheme 34 shows a method for preparing intermediates DXa and DXb which are suitable for use in preparing compounds of formula Id as shown in Schemes 29, 30 and 31. Compounds DXa and DXb can be conveniently prepared from enol ethers DVIII {Chem. Bex. 1982, 115(8), 2766) by reaction with a Rd3- substituted hydrazine in solvents such as alcohols at temperatures from 5O0C to 1000C for 2 to 24 hours.
Scheme 35
Figure imgf000135_0001
DXl DXIIa DXIIb wherein at least one of Rd4 and Rd5 is an optionally substituted aromatic hydrocarbon group, the other is an optionally substituted hydrocarbon group or an optionally substituted non-aromatic heterocyclic group, and other symbols are as defined above.
As the "optionally substituted aromatic hydrocarbon group" for Rd4 or Rd5, groups corresponding to those exemplarily recited as the "optionally substituted aromatic hydrocarbon", which is exemplarily recited as the "optionally substituted aromatic ring" for ring Cd, can be mentioned.
As the "optionally substituted hydrocarbon group" and "optionally substituted non-aromatic heterocyclic group" for Rd4 or Rd5, those exemplarily recited as the "optionally substituted hydrocarbon group" and "optionally substituted non-aromatic heterocyclic group", which are those exemplarily recited as the "substituent" for Ra1, Ra2, Ra3, Ra4, Ra5, Ra6 or Ra7, can be mentioned.
Scheme 35 shows a method for preparing intermediates DXIIa and DXIIb which are suitable for use in preparing compounds of formula Id as shown in Schemes 29, 30 and 31. Compounds DXIIa and DXIIb can be conveniently prepared from diketo esters DXI and Rd5-substituted hydrazines in solvents such as alcohols or mixtures of alcohols and water at temperatures from 500C to 1000C for 2 to 24 hours.' Typically, the diketo ester DXI is treated with an aryl hydrazine (1 to 3 equivalents) in ethanol at reflux temperature for 2 to 8 hours to yield a mixture of isomers DXIIa and DXIIb which can be separated by chromatography.
The conditions (solvent, reaction temperature, reaction time/ chemical equivalent ratio) for each reaction in each of the above-mentioned production methods can be appropriately determined depending on the compound to be produced, the kind of reaction and the like.
5 In the thus-obtained" compound of the present invention, the functional group in a molecule can also be converted to an • objective functional group by combining chemical reactions known per se. As such chemical reactions, oxidation reaction, reduction reaction, alkylation reaction, hydrolysis, amination
10 reaction, esterification reaction, aryl coupling reaction, deprotection and the like can be mentioned.
In the above-mentioned production method, when the starting compound has an amino group, a carboxyl group, a hydroxy group or a carbonyl group as a substituent, a
15 protecting- group generally used in peptide chemistry and the like may be introduced into these groups. By eliminating the protecting group as necessary after the reaction, the objective compound can be obtained.
As the amino-protecting group, for example, formyl group,
20 Ci_6 alkyl-carbonyl group, Ci_δ alkoxy-carbonyl group, benzoyl group, C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl) , C7-14 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, 9- fluorenylmethoxycarbonyl) , trityl group, phthaloyl group, N,N- dimethylaminomethylene group, substituted silyl group (e.g.,
25 trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl) , C2-6 alkenyl group (e.g., 1-allyl) and the like can be mentioned. These groups are optionally substituted by 1 to 3 substituents selected from halogen atom, Ci_6 alkoxy group and nitro group.
30. As the carboxyl-protecting group, for example, Cχ-6 alkyl group,' C7-H aralkyl group (e.g., benzyl), phenyl group, trityl group, substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C2-6 alkenyl group (e.g., 1-allyl) and
55 the like can be mentioned. These groups are optionally substituted by 1 to 3 substituents selected from halogen atom, Ci_6 alkoxy group and nitro group.
As the hydroxy-protecting group, for example, Ci-6 alkyl group, phenyl group, trityl group, C7TiO aralkyl group (e.g., benzyl), formyl group, Ci-β alkyl-carbonyl group, benzoyl group, C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl) , 2- tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (e.g., trirαethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- butyldiethylsilyl) , C2-6 alkenyl group (e.g., 1-allyl) and the like can be mentioned. These groups are optionally substituted by 1 to 3 substituents selected from halogen atom, Ci-e alkyl group, Ci-6 alkoxy group and nitro group.
As the carbonyl-protecting group, for example, cyclic acetal (e.g., 1, 3-dioxane) , non-cyclic acetal (e.g., di-Ci-6 alkylacetal) and the like can be mentioned.
For elimination of the above-mentioned protecting group, a method known per se, for example, a method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980) and the like can be mentioned. For example, employed is a method using acid, base, UV light, hydrazine, phenyl hydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide, (e.g., trimethylsilyl iodide, trimethylsilyl bromide and the like) and the like, reduction and the like.
In the above-mentioned production methods, the starting compound may be in the form of a salt. As such salt, those similar to the salts of the aforementioned compound of the present invention can be mentioned.
When the compound of the present invention contains an optical isomer, a stereoisomer, a positional isomer or a rotational isomer, these can be obtained as a single product according to a synthetic method and separation method known per se. The compound of the present invention may be in the form of a crystal.
The crystal of the compound of the present invention can be produced by crystallization of the compound of the present invention- according to a crystallization method known per se.
The crystal the compound of of the present invention is superior in physicochemical properties (e.g., melting point, solubility, stability and the like) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion) , efficacy expression and the like) , and is extremely useful as a pharmaceutical agent.
EXAMPIiES
The present invention is explained in more detail by referring to the following Examples, ' Formulation Examples and Experimental Example, which are not to be construed as s limitative .
In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius and ambient temperature, or room temperature, is typically 18°C to 25°C. io Starting materials, the preparation of which are not described, are commercially available or can be readily prepared by known techniques from commercially available starting materials .
. Reagents were purchased from commercial suppliers such as
/5 Aldrich Chemical Company, Lancaster, Acros international, TCI or Maybridge, and were used without further purification unless otherwise indicated.
The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube
20 (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe.
Yields are given for illustration only and are not necessarily the maximum attainable.
25 The intermediates and final products described herein may be isolated and purified by the conventional techniques known to artisans of organic chemistry. These techniques include, but are not limited to, concentration, concentration under reduced pressure, extraction with solvents, crystallization,
30 recrystallization, transfer dissolution and chromatography.
Chromatography was performed using glass column and silica gel 60 (230-400 mesh ASTM from EMD) or using medium pressure liquid chromatography (MPLC) Biotage systems (Flash+™ or Horizon™ HPFC™, manufacturer: Dyax Corporation) using normal phase
35 silica Flash+™ cartridges or reversed phase C18 Flash+™ cartridges. Reversed phase high pressure liquid chromatography (HPLC) was performed on. a Parallex Flex™ Biotage system using an Xterra® prep RP18 OBD 10 μM 19x250 mm column from Waters. 1H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H-NMR spectra were obtained as CDCI3 or DMSO-dβ solutions (reported in ppm) , using chloroform (7.25 ppm) or tetramethylsilane (0.00 ppm) as the reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet) , br (broadened) , dd (doublet of doublets) , dt (doublet of triplets) . Coupling constants, when given, are reported in Hertz (Hz) . LCMS were recorded on a Finnigan LCQduo from Thermσquest equipped with an Agilent Zorbax C18 rapid resolution 4.6x50 mm, 3.5 μm 8OA column with APCI ionization or on a Surveyor MSQ from ThermoFinnigan direct injection with ESI ionization.
Example A2
6-Methoxy-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide
Figure imgf000140_0001
Step 1
NaOH (0.36 g, 9.0 mmol) was dissolved in MeOH (5 itiL)' and water (5 mL) . Methyl 6-methoxynicotinate (1.0Og, 5.98 mmol) was added and the mixture was stirred at 700C for 90 minutes. The solution was cooled and diluted with IN NaOH (25 mL) . The solution was extracted with EtOAc and the separated aqueous layer was acidified to pH 1. The aqueous layer was extracted with EtOAc (3 times) and the combined organic layers were dried and concentrated to yield 6-methoxynicotinic acid as a white solid (0.849, 92%): m/z (APCI pos) 154.1 (100%) (M+H). -
Compounds of the following structures were prepared from the corresponding esters using a similar method to that described above.
Figure imgf000141_0001
Step 2
N- (2-Aminoethyl) -l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamide hydrochloride (0.2O g, 0.60 iπmol)., 6- methoxynicotinic acid (0.091 g, 0.60 mmol) , and HATU (0.27 g,. 0.72 rαmol) were suspended in THF (10 mL) . DIPEA (0.34 ml, 2.0 mmol) was added last. The mixture was stirred at room temperature overnight. The solution was poured into water (75 mL) and the solid was collected by filtration, dried and recrystallized in hexanes/EtOAc to provide 6-methoxy-N- (2- (1-
/0 phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.155 g, 60%): 1H NMR (400 MHz, CDCl3) δ 3.65 - 3.75 (m, 4H), 3.98 (s, 3H), 6.77 (d, J = 8.8 Hz, IH), 6.81 (br, IH), 7.12 (br, IH), 7.40 - 7.42 (m, IH), 7.49 - 7.53 (m, 2H), 7.68 - 7.71 (m, 2H), 8.00 (dd, J = 2.4, 8.4 Hz,
IS IH), 8.44 (s, IH), 8.65 (d, J = 2.0 Hz, IH): m/z (APCI pos) 434.1 (100%) (M+H) .
Compounds of the following structures were prepared from N- (2-aminoethyl) -l-phenyl-3- {trifluoromethyl) -lH-pyrazole-4-
20 carboxamide hydrochloride and the corresponding acids, using a similar method to that described above. In some cases, compounds were purified by silica gel column chromatography or preparative HPLC. In some cases, compounds were converted to an acid form by a method commonly employed.
25
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Example A5
6- (3- (Dimethylamino) propylamine?) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide
Figure imgf000150_0001
6-Chloro-N- (2- (l-phenyl-3- (triflupromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.10 g, 0.23 mmol) was suspended in Nl,Nl-dimethylpropane-l, 3-diamine (4.67 g, 45.7 mmol) . The solution was stirred at 1000C for 6 hours. The solution was cooled and concentrated. Reverse phase HPLC purification afforded 6- (3- (dimethylamino) propylamino) -N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.115 g, 27%): 1H NMR (400 MHz,
DMSOd6) δ 1.80 (t, J = 6.8 Hz, 2H), 2.33 (s, 6H), 2.51 (t, J = 6.4 Hz, 2H), 3.38 (br, 2H), 3.64 (br, 4H), 6.07 (br, IH), 6.33 (d, J = 8.4 Hz, IH), 7.37 - 7.39 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.55 (br, IH), 7.68 Cd, J = 7.6 Hz, 2H), 7.83 (d, J = 8.4 Hz, IH), 8.60 (s, IH), 8.62 (s, IH) ; m/z (APCI pos) 504.1 (35%) (M+H) .
Compounds of the following structures were prepared from 6-chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazo.le-4- carboxamido) ethyl) nicotinamide and the corresponding amines, using a similar method to that described above.
Figure imgf000151_0001
Figure imgf000152_0001
Example A30
6- (2-Ethoxyethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide
Figure imgf000152_0002
2-Ethoxyethanol (0.285 ml, 2.85 mmol) in THF (10 mL) was charged with NaH (0.058 g, 2.3 mmol) and the mixture was stirred for 30 minutes at room temperature. 6-Chloro-N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.250 g, 0.571 mmol) was added and the mixture was stirred at 75°C for 4 hours. The solution was then cooled and concentrated. The residue was diluted with water and extracted with DCM. The organic layer was then dried and concentrated. Recrystallization from DCM gave 6- (2- ethoxyethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.149 g, 53%) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 1.11 (t, J = 7.0 Hz, 3H), 3.42 (br, 4H), 3.46-3.51 (in, 2H), 3.70 (t, J = 4.6 Hz, 2H), 4.42 (t, J = 4.7 Hz, 2H), 6.90 (d, J = 8.6 Hz, IH), 7.48 (t, J = 7.2 Hz, IH), 7.61 (t, J = 7.9 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H), 8.10-8.13 (m, IH), 8.49 (br, IH), 8.60 (br, IH), 8.64 (s, IH), 9.06 (s, IH); m/z (APCI pos) 492 (M+H) .
Compounds of the following structures were prepared from 6-chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide and the corresponding alcohols or thiol, using a similar method to that described above. In some cases, compounds were purified by silica gel column chromatography or preparative HPLC. In some cases, compounds were converted to an acid form by a method commonly employed.
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Example A41
6- ( (l,l-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy) -N- (2- ( ( (1- phenyl-3- (trifluoromethyl) -lH-pyrazol-4- yl) carbonyl) amino) ethyl) nicotinamide
Figure imgf000160_0002
To a mixture of N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) -6- (tetrahydro-2H-thiopyran-4- yloxy) nicotinamide (0.20 g, 0.385 inmol), formic acid (0.15 itiL, 3.85 mmol), THF (4 mL) and acetone (8 mL) was added potassium permanganate (0.15 g, 0.96 mmol) in portions at 00C and the mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was recrystallized (EtOAc/hexanes) to afford 6- ( (1, l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy) -N- (2- ( ( (1- phenyl-3- (trifluoromethyl) -lH-pyrazol-4- yl) carbonyl) amino) ethyl) nicotinamide (0.165 g, 78%) as colorless crystals: 1H NMR (400MHz, CDCl3) δ 2.36-2.57 (4H, m) , 2.94-3.04 (2H, m) , 3.28-3.41 (2H, m) , 3.64-3.78 (4H, m) , 5.48 (IH, m) , 6.75 (IH, br) , 6.80 (IH, d, J=8.8 Hz), 7.43 (IH, t, J=7.6 Hz)7 7.52 (2H, t, J=7.6 Hz), 7.70 (2H7 d, J=7.6 Hz), 8.06 (IH, dd, J=2.4, 8.8 Hz), 8.44 (IH, s) , 8.62 (IH, d, J=2.4 H); m/z (APCI pos) 552.0 (100 %) (M+H) .
Example A43
6- (2- (Ethylsulfonyl)ethoxy)-N- (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxainido) ethyl) nicotinamide
° F r-F Stepi
Figure imgf000161_0001
Figure imgf000161_0002
Figure imgf000161_0003
Step 1 To a solution of 2- (ethylthio) ethanol (0.61 mL, 5.71 mmol) in THF (5 mL) was added NaH (0.14 g, 5.7 mmol) at 00C and the mixture was stirred for 30 min. 6-Chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl ) nicotinamide (0.5O g, 1.1 mmol) was added to the mixture and the mixture was stirred for 18h at 900C in a sealed tube. After being cooled, the mixture was poured into water, and extracted with EtOAc. The EtOAc extract was dried and concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes/EtOAc=l/4 to EtOAc/Me0H=50/l) to give 6- (2- (ethylthio) ethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (0.48 g, 83 %) as colorless crystals.
Step 2 To a mixture of 6- ( 2- (ethylthio) ethoxy) -N- ( 2- ( l-phenyl-3-
( trifluoromethyl ) -lH-pyrazole-4-carboxamido) ethyl Nicotinamide ( 0 . 36g, 0 . 71 mmol ) , formic acid ( 0 . 27 mL, 7 . 09 mmol ) , THF ( 5 mL) and acetone (10 mL) was added potassium permanganate (0.28 g, 1.77 mmol) in portions at 00C and the mixture was stirred for 12 hours at room temperature . The mixture was filtered and the filtrate was concentrated in vacuo. The residue was J partitioned between saturated aqueous sodium bicarbonate and EtOAc. The EtOAc layer was washed with brine, dried, and concentrated. Flash chromatography on silica gel (EtOAc to EtOAc/MeOH=10/l) gave 6- (2- (ethylsulfonyl) ethoxy) -N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-o carboxamido) ethyl) nicotinamide (0.30 g, 78% yield) as colorless crystals: 1H NMR (400MHz, CDCl3) δ 1.41 (3H, t, J=7.6 Hz), 3.11 (2H, q, J=7.6 Hz), 3.45 (2H, t, J=5.6 Hz), 3.66-3.78 (4H, m) , 4.83 (2H, t, J=5.6 Hz), 6.74 (IH, br) , 6.79 (IH, d, J=8.8 Hz), 7.28 (IH, br), 7.43 (IH, t, J=7.6 Hz), 7.52 (2H, t, J=7.6 Hz),5 7.71 (2H, d, J=7.6 Hz), 8.07 (IH, dd, J=2.4, 8.8 Hz), 8.45 (IH, d, J=O.8 Hz), 8.64 (IH, d, J=2.4 Hz); m/z (APCI pos) 540.1 (100 %) (M+H) .
Example A44 0 6-Chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -2- (2,2, 2-trifluoroethoxy) nicotinamide
Figure imgf000162_0001
NaH (0.085 g, 3.4 mmol) was added to THF (35 mL) . 2,2,2- Trifluoroethanol (0.244 ml, 3.39 mmol) was added and the 5 mixture was stirred at room temperature for 30 minutes. The solution was then cooled to 00C, 2, 6-dichloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxam.ido) ethyl) nicotinamide (0.320 g, 0.678 mmol) in DMF (2 mL) was added and the mixture was stirred at 00C for 2 hours. The solution was then cooled0 and diluted with water. The mixture was extracted with EtOAc, dried, and concentrated. Flash chromatography and recrystallization with hexanes/EtOAc gave 6-chloro-N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -2- (2, 2, 2-trifluoroethoxy) nicotinamide (0.250 g, 69%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 3.69 - 3.73 (m, 4H), 4.95 (q, J = 8.0, 16.0 Hz, 2H), 6.73 (br, IH), 7.18 (d, J = 8.0 Hz, IH), S 7.43 (t, J = 6.8 Hz, IH), 7.51 (t, J = 7.6 Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H), 7.80 (br, IH), 8.40 (s, IH), 8.49 (d, J = 8.4 Hz, IH); m/z (APCI pos) 536.0 (M+H) .
Example A47 o N- (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxaπtido) ethyl) -6-propylnicotinamide
Figure imgf000163_0001
6-Chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-S carboxamido) ethyl) nicotinamide (0.100 g, 0.228 xnmol) and
PdCl2 (dppf) dichloromethane adduct (0.009 g, 0.011 mtiol) were added together in degassed THF (5 inL) under argon. Propylzinc (II) bromide (1.14 ml, 0.571 mmol, 0.5 M in THF) was added and the mixture was stirred under argon at 55°C for 1 hr.0 The solution was cooled and filtered through a silica plug
(rinsing with EtOAc) and concentrated. Flash chromatography and recrystallization (EtOAc/hexanes) afforded N- (2- (1-phenyl- 3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -6- propylnicotinamide (0.020 g, 20%) as a white solid: 1H NMR (4005 MHz, CDCl3) δ 0.96 (t, J = 7.6 Hz, 3H), 1.76 (q, J = 14.8, 7.6 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H)., 3.68 - 3.77 (m, 4H), 6.75 (br, IH), 7.22 (d, J = 8.4 Hz, IH), 7.26 (br, IH), 7.42 (t, J =
7.2 Hz, IH), 7.52 (t, J = 8.0 Hz, 2H), 7.70 (d, J = 6.8 Hz, 2H),
8 . 03 ( dd, J = 8 . 4 , 2 . 4 Hz , IH) , 8 . 45 ( s , IH ) , 8 . 95 ( d, J = 2 . 40 Hz , IH) ; m/ z (APCI pos ) 44 6 . 2 (M+H ) . The compound of the following structure was prepared from 6-chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide and 2-thiazolylzinc bromide, using a similar method to that described above.
Figure imgf000164_0002
Example A49 '
N- (2- (1- (Pyrimidin-2-yl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide
Figure imgf000164_0001
To a round bottom flask were added EDAC-HCl (218 mg, 1.14 mmol) , HOBt-H2O (175 mg, 1.14 mmol) , and 1- (pyrimidin-2-yl) -3-
(trifluoromethyl) -lH-pyrazole-4-carboxylic acid (294 mg, 1.14 mmol) . These components were dissolved in DMF (3 ml) and the mixture was stirred for 5 minutes, then N- (2-aminoethyl) -6-
(2, 2, 2-trifluoroethoxy) nicotinamide (250 mg, 0.95 mmol) was added as a solution in DMF (1 ml) . The mixture was stirred for 16 h, diluted with water, and extracted with ethyl acetate several times. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (5% MeOH/DCM) to give N- (2- (1- (pyrimidin-2-yl) -3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) -6- (2,2,2- trifluoroethoxy) nicotinamide (0.178 g, 37%) as a solid: 1H NMR
(400 MHz, DMSO-de) δ 3.42 (m, 4H), 5.06 (q, 2H, J = 9.0 Hz), 7.08 (d, IH, J = 8.6 Hz), 7.66 (t, IH, J = 4.7 Hz), 8.21 (m, IH), 8.69 (m, 3H), 8.99 (d, 2H, J = 4.7 Hz), 9.41 (s, IH); m/z (APCI pos) 504.0 (100 %) (M+H) .
Compounds of the following structures were made by reacting N- (2-aminoethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide and the corresponding acids, using the procedure outlined above,
Figure imgf000165_0001
Figure imgf000166_0001
Example A52
5-Bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide
Figure imgf000166_0002
2,2,2-Trifluoroethanol (0.835 ml, 11.6 mmol) was diluted in THF (35 mL) . NaH (0.293 g, 11.6 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to 00C and 5-bromo-6-chloro-N- (2- (1-phenyl- 3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (1.20 g, 2.32 mmol) was added.
The mixture was stirred at 400C overnight. The solution was cooled, quenched with water, extracted from EtOAc, dried, and concentrated. The material was recrystallized from hexanes/EtOAc to give 5-bromo-N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -6- (2,2,2- trifluoroethoxy) nicotinamide (0.95 g, 70%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 3.66 - 3.75 (m, 4H), 4.84 (q, J = 8.0, 16.8 Hz, 2H), 6.76 (br, IH), 7.42 (t, J = 7.2 Hz, IH), 7.49 - 7.53 (m, 3H), 7.70 (d, J = 7.2 Hz, 2H), 8.35 (d, J = 2.4 Hz,
IH), 8.45 (s, IH), 8.54 (d, J = 2.0 Hz, IH); m/z (APCI pos) 580 (M+H) .
Example A53 1-Phenyl-N- (2- ( 6- (2, 2, 2-trifluoroethoxy) nicotinamide) ethyl) -IH- indole-3-carboxamide
Figure imgf000167_0001
Step 1
To a solution of lH-indole-3-carboxylic acid (0.269 g, 1.67 mmol), EDAC-HCl (0.352 g, 1.84 mmol) , and HOBt-H2O (0.281 g, 1.84 mmol) in DMF (5 ml) was added N- (2-aπri.noethyl) -6- (2, 2, 2- trifluoroethoxy) nicotinamide hydrochloride (0.500 g, 1.67 mmol) followed by DIPEA (0.87 ml, 5.0 mmol). The solution was stirred for 16 h at room temperature, diluted with EtOAc (100 ml) and washed with water (3X) , saturated aqueous sodium bicarbonate, and brine. The aqueous layer was back extracted and the combined organic layers were dried (sodium sulfate) , filtered through a short pad of silica which was rinsed with 5% MeOH/DCM, and concentrated in vacuo to give N- (2- ( 6- (2, 2, 2- trifluoroethoxy) nicotinamide) ethyl) -lH-indole-3-carboxamide (0.450 g, 66%) as a solid: 1H NMR (CDCl3) δ 3.63 (s, 4H), 4.92
(q, 2H, J = 8.59 Hz), 6.95 (m, IH), 7.16 (m, 2H), 7.41 (m, IH), 8.07 (m, IH), 8.16 (m, IH), 8.66 (m, IH); m/z (APCI pos) 407.1 (100 %) (M+H) .
Compounds of the following structures were prepared by reacting N- (2-aminoethyl) -6- (2, 2, 2-trifluoroethoxy)nicotinamide hydrochloride and the corresponding acids using the procedure outlined above.
Figure imgf000168_0001
Step 2
Following the procedure of Buchwald et al . .(J. Org. Chem. 2004, 69, 5578), to a 250 iriL sealed tube under a sweep of nitrogen were added N- (2- (6- (2, 2, 2- trifluoroethoxy) nicotinamido) ethyl) -lH-indole-3-carboxamide (0.450 g, 1.11 irimol), potassium carbonate (0.321 g, 2.33 mraol) , 1-iodobenzene (0.148 ml, 1.33 mmol), copper (I) iodide (0.0105 g, 0.06 mmol) and (IR, 2R) -Nl,N2-dimethylcyclohexane-l, 2-diaitιine (0.0315 g, 0.22 mmol). These components were dissolved in degassed (Argon) dioxane (8 ml) . The tube was sealed and the mixture was heated at 1100C for 20 h. The mixture was dissolved in EtOAc and filtered through a pad of silica, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (5% MeOH/DCM) to give 1-phenyl-N- (2- ( 6- (2, 2, 2-trifluoroethoxy)nicotinamido) ethyl) -lH-indole-3- carboxamide (0.284 g, 53% yield) as a solid: 1H NMR (CDCl3) δ 3.47 (s, 4H), 5.05 (q, 2H, J = 9.0 Hz), 7.07 (d, IH, J = 9.0 Hz), 7.25 (m, 2H), 7.49 (m, IH), 7.54 (m, IH), 7.63 (m, 4H), 8.21-8.27 (m, 3H), 8.29 (s, IH), 8.69 (m, IH), 8.72 (m, IH); m/z (APCI pos) 483.1 (100 %) (M+H) .
Compounds of the following structures were prepared using a similar method to that described above.
Figure imgf000169_0001
Figure imgf000170_0001
Example A60 tert-Butyl l-phenyl-4- (2- (6- (2, 2, 2- trifluoroethoxy) nicotinamide) ethylcarbamoyl) -lH-ρyrazol-3- ylcarbamate
Figure imgf000170_0002
Step 1
To a mixture of ethyl 3- (bis (tert-butoxycarbonyl) amino) -1- phenyl-lH-pyrazole-4-carboxylate (2.11 g, 4.89 mmol) in EtOH (20 mL) was added 2 N NaOH (12.2 ml, 24.5 mmol) and the mixture was stirred at 700C for 3 hrs . The mixture was cooled, concentrated off the EtOH, water was added and the aqueous layer was washed with EtOAc. The aqueous layer was then acidified to pH 2 using 1 N HCl. The resulting solids were filtered, washed with water and dried under high vacuum to give 3- (tert-butoxycarbonylamino) -l-phenyl-lH-pyrazole-4-carboxylic acid (1.24 g, 83%): 1H-NMR (400 MHz, DMSO-d6) δ 1.55 (s, 9H), 7.34 (t, J = 7.4 Hz, IH), 7.51 (t, J = 8.0 Hz, 2H), 7.87 (d, J = 7.6 Hz, 2H), 8.79 (s, IH), 8.91 (s, IH), 12.81 (s, IH): m/z (APCI pos) 304 (40%) (M+H) . Compounds of the following structures were prepared from the corresponding esters using a similar method to that described above.
Figure imgf000171_0001
Step 2
A mixture of N- (2-aminoethyl) -6- (2, 2, 2- trifluoroethoxy) nicotinamide hydrochloride (0.741 g, 2.47 mmol) , 3- (tert-butoxycarbonylamino) -1-phenyl~lH-pyrazole-4-carboxylie acid (0.750 g, 2.47 mmol), HATU (1.13 g, 2.97 mmol), and DIPEA (2.15 ml, 12.4 mmol) in TH.F (20 ml,) was stirred at room temperature for 3 hrs. The mixture was quenched with water (200 rtiL) and extracted with DCM, dried over Na2SO4 and concentrated to a residue that was purified by silica gel chromatography eluting with 75% EtOAc/hexanes . This material was dissolved in EtOAc and the solution was washed with water, dried and concentrated to a residue that was recrystallized from EtOAc/hexanes to give tert-butyl l-phenyl-4- (2- (6- (2, 2, 2- trifluoroethoxy) nicotinamido) ethylcarbamoyl) -lH-pyrazol-3- ylcarbamate (0.968 g, 71%) as a white solid: 1H NMR (400 MHz,
DMSO-de) δ 1.46 (s, 9H), 3.42 (br, 4H), 5.03-5.10 (m, 2H), 7.08 (d, J = 8.6 Hz, IH), 7.35 (t, J = 7.4 Hz, IH), 7.54 (t, J = 8.0 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 8.20-8.23 (m, IH), 8.40 (br, IH), 8.68-8.70 (m, 2H), 8.86 (s, IH), 9.30 (s, IH); m/z (APCI pos) 549 (M+H) .
Compounds of the following structures were prepared by reacting N- (2-aminoethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride and the corresponding acids, using the procedure outlined above.
Figure imgf000172_0001
Figure imgf000173_0001
Example A62 N- (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -5-propyl-6- (2,2,2- trifluoroethoxy) nicotinamide
Figure imgf000174_0001
5 5-Bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (0.200 g, 0.345 imtiol) and PdCl2(dppf) dichloromethane adduct (0.014 g, 0.017 mmol) were added together in degassed THF (2mL) under an argon atmosphere. Propylzinc (II) bromide (1.72 ml, 0.862 mmol, JO 0.5 M in THF) was then added. The mixture was stirred under argon at 55°C for 1 hr. The solution was cooled and filtered through a silica plug (rinsing with EtOAc) and concentrated. Flash chromatography on silica gel gave N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -5-propyl-6-
/J (2, 2, 2-trifluoroethoxy) nicotinamide (0.063 g, 34%): 1H NMR (400 MHz, CDCl3) δ .0.94 (t, J = 7.6 Hz, 3H), 1.61 - 1.66 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H), 3.71 (br, 4H), 4.80 (q, J = 8.4, 16.8 Hz, 2H), 6.81 (br, IH), 7.21 (br, IH), 7.42 (t, J = 7.2 Hz, IH), 7.51 (t, J = 7.6 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.90 (s,
20 IH), 8.44 (s, 2H); m/z (APCI pos) 544.1 (M+H) .
The compound of the following structure was prepared from 5-bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide and 25 phenethylzinc bromide, using a similar method to that described . above .
Figure imgf000175_0001
Example A63
5-Phenyl-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide
Figure imgf000175_0002
5-Bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (0.100 g, 0.172 mmol), phenylboronic acid (0.031 g, 0.26 mmol) , Pd(OAc)2 (0.004 g, 0.017 mmol), and cesium carbonate (0.112 g, 0.345 mmol) were added together under nitrogen. 2,8,9- Triisobutyl-2, 5,8, 9-tetraaza-l-phosphabicyclo [3.3.3] undecane (0.012 g, 0.035 mmol) was then added. The mixture was diluted in toluene (3 itιL) and stirred at 800C for 3 hours. The solution was filtered and concentrated. Flash chromatography on silica gel (70%-100% EtOAc/hexanes) gave 5-phenyl-N- (2- (1- phenyl-3- (trifluoromethyl) -lH~pyrazole-4-carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (0.063 g, 63%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 3.72 - 3.74 (m, 4H), 4.87 (q, J = 84, 17.2 Hz, 2H), 6.75 (br, IH), 7.34 (br, IH), 7.38 - 7.52 (rα, 6H), 7.58 - 7.60 (m, 2H), 7.65 - 7.67 (m, 2H), 8.16 (d, J = 2.4 Hz, IH), 8.40 (s, IH), 8.59 (d, J = 2.4 Hz, IH); m/z (APCI • pos) 578.1 (M+H) .
Example A66
N- (2- (3-Amino-l-phenyl-lH-pyrazole-4-carboxamido) ethyl ) -6- (2,2, 2-trifluoroethoxy) nicotinamide
Figure imgf000176_0001
To a mixture of tert-butyl l-phenyl-4- (2- ( 6- (2, 2, 2- trifluoroethoxy) nicotinamido) ethylcarbamoyl) -lH-pyrazol-3- ylcarbamate (0.200 g, 0.365 mmol) in DCM (20 iαL) was added TFA (0.140 ml, 1.82 mmol) and the mixture was stirred for 40 minutes at room temperature. TFA (5 mL) was added and the mixture was stirred for 5 hours. The mixture was concentrated to a residue and the residue dissolved in DCM. The solution was washed with saturated aqueous sodium carbonate and water, dried over Na2Sθ4 and concentrated to a residue that was recrystallized from EtOAc/hexanes to give N- (2- (3-amino-l- phenyl-lH-pyrazole-4-carboxamido) ethyl) -6- (2,2,2- trifluoroethoxy) nicotinamide (0.115 g, 70%) : 1H NMR (400 MHz,
DMSO-de) δ 3.4 (br, 4H), 5.03-5.10 (m, 2H), 5.72 (s, 2H), 7.08 (d, J = 8.7 Hz, IH), 7.24 (t, J = 7.4 Hz, IH), 7.48 (t, J = 7.9 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 8.10 (br, IH), 8.20-8.23 (m, IH), 8.68-8.71 (m, 3H): m/z (APCI pos) 449 (M+H). Example A68 l-Methyl-N-(2- (6- (2, 2, 2-trifluoroethoxy) nicotinamido) ethyl) -IH- indole-3-carboxamide
Figure imgf000177_0001
To N- (2-aminoethyl)-6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride (342 mg, 1.14 mmol) in DCM (100 mL) and DMF (10 inL) were successively added l-methyl-lH-indole-3-carboxylic acid (200 mg, 1.14 mmol), EDAC-HCl (285 mg, 1.48 mmol), HOBt-H2O (216 mg, 1.60 mmol) and triethylamine (231 mg,. 2.28 mmol). The mixture was stirred at room temperature for 18 hours and DCM
(300 mL) was added. The organic layer was successively washed with water (3x200 mL) , IN HCl (100 mL) , • 10% potassium carbonate aqueous solution (100 mL) and brine (2x200 mL) . The organic layer was dried over MgSO4 then concentrated to yield an orange solid. The crude solid was purified by silica gel chromatography (DCM/MeOH 95/5) to yield 1-methy1-N- (2- ( 6- (2,2, 2-trifluoroethoxy) nicotinamido) ethyl) -lH-indole-3- carboxamide as a white solid (120 mg, 25%) : 1H NMR (400 MHz,
DMSO-d6) δ 3.42-3.46 (m, 4H), 3.82 (s, 3H), 5.06 (q, 2H, J = 9.0 Hz), 7.08 (m, IH), 7.14 (m, IH), 7.22 (m, IH), 7.48 (m, IH), 7.94 (s, IH), 8.00-8.06 (m, IH), 8.14 (m, IH), 8.22 (m, IH), 8.68-8.73 <m, 2H); m/z (APCI pos) 421.0 (100 %) (M+H) .
The compound of the following structure was prepared from N- (2-aminoethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide hydrochloride and the corresponding acid, using a similar method to that described above.
Figure imgf000178_0002
Example A70
5-Benzyl-N- (2- ( l-phenyl-3- (trifluoroπtethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide
Figure imgf000178_0001
9-Benzyl~9-bora-bicyclo[3.3.1]nonane (0.86 ml, 1.72 mmol, 0.5 M in THF) was added to DMF (5 mL) under an argon atmosphere. 5-Bromo-N- (2- (l-phenyl-3- ( trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (0.200 g, 0.345 mmol) and PdCl2(dppf) dichloromethane adduct (0.014 g,
0.017 mmol) were then added. The mixture was heated at 600C for 90 minutes under argon. The solution was cooled and poured onto water and extracted with EtOAc. The organic layer was dried and concentrated. Reverse phase HPLC purification and recrystallization from EtOAc gave 5-benzyl-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -6- (2,2,2- trifluoroethoxy) nicotinamide (0.04Og, 20%): 1H NMR (400 MHz, DMSO-de) δ 3.40 - 3.42 (m, 4H), 3.93 (s, 2H), 5.03 (q, J = 8.8, 17.6 Hz, 2H), 7.16 - 7.28 (m, 5H), 7.47 (t, J = 7.6 Hz, IH), 7.60 (t, J = 8.4 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 8.10 (d, J = 2.4 Hz, IH), 8.48 (br, IH), 8.54 (d, J = 2.4 Hz, IH), 8.67 (br, IH), 9.05 (s, IH); m/z (APCI pos) 592.1 (M+H) .
Example A73
N- (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6-o-tolylnicotinamide
Figure imgf000179_0001
6-Chloro-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.200 g, 0.457 iranol) , o- tolylboronic acid (0.087 g, 0.640 mmol), PdCl2 (PPh3) 2 (0.096 g, 0.137 mmol), and aqueous K3PO4 (0.685 ml, 1.37 mmol, 2 M) were suspended in toluene (2 mL) . The mixture was stirred at 900C overnight. The material was filtered and concentrated.
Reverse phase HPLC purification followed by recrystallized in EtOAc/hexanes gave N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) -6-o-tolylnicotinamide (0.020 g, 9%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.47 (br, 4H), 7.27 - 7.52 (m, 8H), 7.81 (d, J = 8.0 Hz, 2H), 8.08 - 8.30 (m, IH), 8.52 (br, IH), 8.82 (br, IH), 9.07 - 9.10 (m, 2H); m/z (APCI pos) 494.2 (M+H).
Example A74 6-Ethoxy-2-phenyl-N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide
Figure imgf000179_0002
2-Chloro-6~ethoxy-N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (0.200 g, 0.415 mmol) , phenylboronic acid (0.075 g, 0.62 mmol), Pd(OAc)2 (0.009 g, 0.042 mmol) , and cesium carbonate (0.270 g, 0.830 mmol) were added together under nitrogen. 2, 8, 9-Triisobutyl-2/ 5, 8, 9- tetraaza-l-phosphabicyclo[3.3.3]undecane (0.028 g, 0.083 mmol) was then added. The mixture was diluted in toluene (3 mL) and stirred at 800C for 4 hours . The solution was cooled and filtered. Reverse phase HPLC purification and recrystallization from EtOAc/hexanes gave 6-ethoxy-2-phenyl-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.025g, 12%): 1H NMR (400 MHz,
CDCl3) δ 1.34 (t, J = 6.8 Hz, 3H), 6.26 (br, 4H), 4.40 (q, J = 7.2, 14.0 Hz, 2H), 6.79 (d, J = 8.4 Hz, IH), 7.34 - 7.38 (m, 3H), 7.48 (t, J = 7.2 Hz, IH), 7.58 - 7.65 (m, 4H), 7.76 - 7.81 (m, 3H), 8.33 - 8.36 (m, 2H), 8.99 (s, IH); m/z (APCI pos) 524.1 (M+H) .
Example A77 5-Acetamido-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide
Figure imgf000180_0001
Xantphos (0.012 g, 0.021 mmol), Pd2(dba)3 (0.006 g, 0.007 mmol) , 5-bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole- 4-carboxamido) ethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide
(0.10 g, 0.17 mmol), cesium carbonate (0.079 g, 0.241 mmol), and acetamide (0.015 g, 0.26 mmol) were added and the reaction tube was filled with argon. Dioxane (2 mL) was added via syringe and the vial was capped with a teflon sealed cap and the reaction mixture was stirred at 1000C overnight. The solution was cooled, filtered and concentrated. Flash chromatography on silica gel (2% MeOH/EtOAc) followed by recrystallization in EtOAc/hexanes gave 5-acetamido-N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) -6- ,5 (2, 2, 2-trifluoroethoxy) nicotinamide (0.047 g, 49%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 3.41 (br, 4H), 5.12 (q, J = 8.8Hz, 2H), 7.47 (t, J = 7.6 Hz, IH), 7.61 (t, J = 7.6 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H), 8.40 (d, J = 2.0 Hz, IH), 8.50 (br, IH), 8.68 (br, 2H), 9.05 (s, IH), 9.54 (br, IH); m/z 0 (APCI pos) 559.0 (M+H) .
Example A78
Methyl 5- ( (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl) -2- (2,2,2- 15 trifluoroethoxy) nicotinate
Figure imgf000181_0001
5-Bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide (0.200 g, 0.345 mmol) and triethylamine (0.0625 ml, 0.448 mmol) were
20 dissolved in MeOH (2 mL) . The solution was degassed with nitrogen for 10 minutes. (R)-(BINAP)PdCl2 (0.0138 g, 0.0172 mmol) was added and the solution was purged with nitrogen followed by CO gas (3 times) . The vessel was pressurized to 70 psi and heated at 75°C for 24 hours. The solution was cooled,
25 filtered and concentrated. Flash chromatography on silica gel (EtOAc) followed by recrystallization gave methyl 5- ((2-(I- phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl ) -2- (2,2,2- trifluoroethoxy) nicotinate (0.025 g, 13%) as a white solid: 1H
30 NMR (400 MHz, DMSO-ds) δ 3.44 (br, 4H), 3.85 (s, 3H), 5.14 (q, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, IH), 7.61 (t, J = 8.4 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 8.48 (br, IH), 8.66 (d, J = 2.4 Hz, IH), 8.85 (d, J = 2.4 Hz, IH), 8.87 (br, IH), 9.05 (s, IH); m/z (APCI pos) 560.0 (M+H) .
Example A81
5- ( (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl) picolinic acid
Figure imgf000182_0001
Ethyl 5- ( (2-(l-phenyl-3- (trifluσromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl) picolinate (0.350 g, 0.736 mmol) and lithium hydroxide monohydrate (0.0927 g, 2.21 mmol) were dissolved in EtOH (5 mL) and water (5 mL) , and the mixture was stirred at 500C for 90 minutes. The solution was cooled and concentrated. The residue was diluted with water and the mixture was extracted with EtOAc. The aqueous layer was then acidified with 6N HCl to pH < 3. The aqueous solution was then extracted with DCM and the combined organic layers were dried and concentrated to give 5- ( (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) carbamoyl)picolinic acid (0.257 g, 78%): 1H NMR (400 MHz, DMSO-d6) δ 3.46 (s, 4H), 7.48 (t, J = 7.4 Hz, IH), 7.61 (t, J = 8.0 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H), 8.12 (d, J = 8.0 Hz, IH), 8.33-8.35 (m, IH), 8.53 (s, IH), 8.96 (s, IH), 9.07-9.09 (m, 2H); m/z (APCI pos) 448 (M+H).
Example A82
1-Benzoyl-N- (2- (6- (2, 2, 2-trifluoroethoxy) nicotinamide) ethyl) -
IH-indole-3-carboxamide
Figure imgf000183_0001
Figure imgf000183_0002
Figure imgf000183_0003
Step 1
To a solution of l-benzoyl-lH-indole-3-carboxylic acid (0.200 g, 0.75 ramol) in DCM and 1 drop of DMF was added oxalyl chloride (0.132 ml, 1.51 mmol) and the mixture was stirred for 1 hour. The solvent was removed to yield the corresponding acid chloride, which was used without further purification.
Step 2 To N- (2-aminoethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride (0.226 g, 0.75 mmol) and triethylamine (0.105 ml, 0.75 mmol) in DMF (15 ml) was added l-benzoyl-lH-indole-3- carbonyl chloride (0.214 g, 0.75 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo, and the residue was dissolved in EtOAc. The mixture was then washed with water (2X) , saturated aqueous sodium bicarbonate (2X), and brine. The combined organic layers were dried (sodium sulfate) , filtered, and concentrated in vacuo to give a residue which was purified by silica gel chromatography (3-5% MeOH/DCM) and triturated with ether/methanol to give 1-benzoyl- N- (2- (6- (2, 2, 2-trifluoroethoxy) nicotinamide) ethyl) -lH-indole-3- carboxamide (0.022 g, 6%) as a solid: 1H NMR (400 MHz, DMSO-d6) 6 3.40 (m, 4H), 5.06 (q, 2H, J = 8.98 Hz), 7.06 (m, IH), 7.41 (m, 2H), 7.64 (m, 2H), 7.74 (m, IH), 7.82 (m, 2H), 8.15 (s, IH), 8.17 (m, IH), 8.27 (m, 2H), 8.51 (m, IH), 8.65 (m, IH), 8.69 (m, IH); m/z (APCI pos) 511.1 (100 %) (M+H) . Example A83
6- (Ethylthio) -N- (2- (1-phenyl-3- (trifluorornethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide
Figure imgf000184_0001
A mixture of 6-chloro-N- (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) nicotinamide (0.234 g, 0.53 mmol), sodium thioethoxide (0.17 g, 1.6 mmol) and THF (2 mL) was stirred at 800C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo. The residue was purified by Silica gel column chromatography (EtOAc to EtOAc/MeOH=10/l) to give 6- (ethylthio) -N- (2- { l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (0.23 g, 94 %) as colorless crystals: 1H NMR (400MHz, CDCl3) δ 1.38 (3H, t, J=7.6 Hz), 3.20 (2H, q, J=I. S Hz), 3.66-3.76 (4H, m) , 6.77 (IH, br) , 7.20 (IH, d, J=8.4 Hz), 7.24 (IH, m) , 7.42 (IH, t, J=7.6 Hz), 7.52 (2H, t, J=7.6 Hz), 7.70 (2H, d, J=7.6 Hz), 7.89 (IH, dd, J=2.4, 8.4 Hz), 8.44 (IH, d, J=O .4 Hz), 8.86 (IH, d, J=2.4 Hz); m/z (APCI pos) 464.1 (100 %) (M+H) .
Example A85
6- (Ethylsulfonyl) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide
Figure imgf000184_0002
To a mixture of 6- (ethylthio) -N- (2- (l-phenyl-3- ( trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide (0.21 g, 0.45 mmol) , formic acid (0.17 mL, 4.53 mmol) , acetone (4 mL) and THF (2 mL} was added potassium permanganate (0.18 g,
1.13 mmol) at 00C and the mixture was stirred for 16 h. The same amounts of reagents (formic acid and potassium permanganate) were added to the mixture at 00C and the mixture was stirred for 2 h at room temperature. This handling was repeated twice. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatograpy (EtOAc to EtOAc/MeOH=10/l) to give 6- (ethylsulfonyl) -N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.12 g, 55%) as colorless crystals: 1H NMR (400MHz, CDCl3) δ 1.31 (3H, t, J=7.6 Hz), 3.45 (2H, q, J=7.6 Hz), 3.68-3.82 (4H, m) , 6.68 (IH, br) , 7.44 (IH, t, J=7.6 Hz), 7.53 (2H, t, J=7.6 Hz), 7.72 (2H, d, J=8.4 Hz), 7.98 (IH, br) , 8.17 (IH, d, J=8.0 Hz), 8.41 (IH, dd, J=2.0, 8.0 Hz), 8.48 (IH, s)/ 9.17 (IH, d, J=2.0 Hz); m/z (APCI pos) 496.0 (100 %) (M+H) .
Example A86
N- (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (phenylsulfonyl) nicotinamide
Figure imgf000185_0001
To a solution of N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) -6- (phenylthio) nicotinamide (0.11 g, 0.21 mmol) in DCM (4 mL) was added 3-chloroperbenzoic acid
(0.13 g, 70-75%, 0.51 mmol) at 00C and the mixture was stirred for 12 h at room temperature . The mixture was washed with saturated aqueous sodium carbonate and brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatograpy (EtOAc) to give N- (2- (l-phenyl-3- (trifluororαethyl) -lH-pyrazole-4-carboxamido) ethyl) -6- (phenylsulfonyl) nicotinamide (0.06 g, 54%) as colorless crystals-: 1H NMR (400MHz, CDCl3) δ 3.64-3.76 '(4H7 m) , 6.72 (IH, br), 7.43 (IH, m) , 7.48-7.57 (4H, m) , 7.63 (IH, m) , 7.71 (2H, d, J=8.0 Hz), 7.92 (IH, m) , 8.05 (2H, d, J=8.0 Hz), 8.25 (IH, dd, J=O.8, 8.4 Hz), 8.36 (IH, dd, J=2.0, 8.4 Hz), 8.47 (IH, d, J=O.8 Hz), 9.08 (IH, dd, J=O.8, 2.0 Hz); m/z (APCI pos) 544.1
10 (100 %) (M+H) .
Example A87
5-Cyano-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide
Figure imgf000186_0001
To a solution of Cu(I)CN (0.023 g, 0.258 mmol) in DMF (1 mL) was added 5-bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) -6- (2,2,2- trifluoroethoxy) nicotinamide (0.100 g, 0.172 mmol) and the
20 solution was heated at reflux (1600C) overnight. The solution was cooled to room temperature, diluted with water, extracted with EtOAc, dried, and concentrated. Reverse phase HPLC purification gave 5-cyano-N- (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) -6- (2, 2, 2-
25 trifluoroethoxy) nicotinamide (0.045 g, 50%): 1H NMR (400 MHz,
DMSO-de) δ 3.44 (br, 4H), 5.22 (q, J = 8.8, 17.7 Hz, 2H), 7.47 (t, J = 7.4 Hz, IH), 7.61 (t, J = 7.6 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H), 8.53 (br, IH) , 8.73 (d, J = 2.3 Hz, IH), 8.87 (br, IH), 8.90 (d, J = 2.3 Hz, IH), 9.09 (s, IH); m/z (APCI pos) 527.1
30 (M+H) . Example A88
2-Cyano- 6-ethoxy-N- ( 2- ( l-phenyl-3- ( tri fluoromethyl ) -IH- pyrazole-4-carboxamido) ethyl ) nicotinamide
Figure imgf000187_0001
A solution of Cu(I)CN (0.0279 g, 0.311 mmol) in DMF (1 mL) was added to 2-chloro-6-ethoxy-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl ) nicotinamide (0.100 g, 0.208 mmol) and the solution was heated at reflux (1600C) overnight. The solution was cooled and diluted with water, extracted with EtOAc, dried, and concentrated. Flash chromatography on silica gel and recrystallization gave 2- cyano-6-ethoxy-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole- 4-carboxamido) ethyl) nicotinamide (88 mg, 83%) as a white solid: 1H NMR (400 MHz, DMSO-d«) 5 1.38 (t, J = 7.0 Hz, 3H), 3.54 (q, J = 5.9, 11.9 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 4.51 (q, J = 7.0, 14.1 Hz, 2H), 7.06 (d, J = 8.4 Hz, IH), 7.47 (t, J = 7.5 Hz, IH), 7.59 (t, J = 7.5 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.4 Hz, IH), 8.48 (t, J = 5.9 Hz, IH), 8.88 (s, IH), 9.6 (s, IH); m/z (APCI pos) 473.1 (M+H) .
Example A89
5-Acetyl-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide
Figure imgf000187_0002
5-Bromo-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxarαido) ethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide (0.490 g, 0.844 itimol), 1- (vinyloxy) butane (1.09 ml, 8.44 mmol), Pd(OAc)2 (0.0190 g, 0.0844 mmol), 1, 3-bis (diphenyl- phosphino) propane (dppp) (0.0697 g, 0.169 mmol), and potassium carbonate (0.140 g, 1.01 mmol) were diluted in DMF (12.5 mL) . Water (3.04 ml, 169 mmol) was added. The mixture was stirred in a sealed tube at 800C overnight. The mixture was cooled and diluted with water. The mixture was extracted with EtOAc, dried, and concentrated. Flash chromatography on silica gel (70% EtOAc/hexanes) gave the enol ether which was concentrated. The residue was dissolved in 2N HCl (10 mL) and stirred for 1 hr. The solution was neutralized with sodium bicarbonate and extracted with EtOAc, dried, and concentrated to afford 5- acetyl-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2,2-trifluoroethoxy) nicotinamide (0.06Og, 13%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H), 3.44 (br, 4H), 5.18 (q, J = 8.9, 17.8 Hz, 2H), 7.48 (t, J = 7.4 H, IH), 7.61 (t, J = 7.6 Hz, 2H), 7.82 (t, J = 7.6 Hz, 2H), 8.49 (br, IH), 8.57 (d, J = 2.4 Hz, IH), 8.84 (d, J = 2.4 Hz, IH), 8.87 (br, IH), 9.05 (s, IH); m/z (APCI pos) 544.0 (M+H) .
Example A90
N2-Methyl-N5- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) pyridine-2/ 5-dicarboxamide
Figure imgf000188_0001
5- ( (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl) picolinic acid (0.200 g, 0.44 mmol), HATU (0.187 g, 0.49 mmol), and methylamine (0.67 ml, 1.34 mmol, 2M in THF) were diluted in THF (5 mL) and the mixture was stirred at room temperature overnight. The solution was quenched with water, extract with DCM, dried, and concentrated. The residue was triturated with EtOAc at reflux. The solid was filtered to provide N2-methyl-N5- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl )pyridine-2, 5- dicarboxamide (0.077 g, 37%): 1H NMR (400 MHz, DMSO-d6) δ 2.83 (d, J = 4.9 Hz, 3H), 3.46 (s7 4H), 7.48 (t, J = 7.4 Hz, IH), 7.61 (t, J = 7.9 Hz, 2H), 7.80 (g, J = 7.6 Hz, 2H), 8.11 (d, J = 8.0 Hz, IH), 8.37 (d, J = 8.2 Hz, IH), 8.51 (s, IH), 8.88 (d, J = 4.9 Hz, IH), 8.93 (s, IH), 9.02 (s, IH), 9.06 (s, IH); m/z (APCI pos) 461 (M+H) .
The compound of the following structure was prepared from 5-( (2-{l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl )picolinic acid and diiαethylamine, using a similar method to that described above.
Figure imgf000189_0001
Example A91
Methyl 6-ethoxy-3- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-
4-carboxamido) ethylcarbamoyl)picolinate
Figure imgf000189_0002
2-Chloro-6-ethoxy-N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (0.300 g, 0.623 παnol) and triethylamine (0.113 ml, 0.809 mmol) were dissolved in MeOH (3 mL) . The solution was degassed with nitrogen for 10 minutes (R) -(BINAP) PdCl2 (0.024 g, 0.031 mmol) was added and the solution was purged with nitrogen followed by CO gas (2 times) . The vessel was pressurized to 70 psi and heated at 65°C for 24 hours. The solution was cooled, filtered and concentrated. Flash chromatography on silica gel (100% EtOAc) followed by recrystallization gave methyl 6-ethoxy-3- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido)ethylcarbamoyl)picolinate (0.030 g, 10%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 1.29 (t, J = 7.1 Hz, 3H), 3.43 (br, 4H), 3.73 (s, 3H), 4.40 (q, J = 7.0, 14.0 Hz, 2H), 6.98 (d, J = 8.6 Hz, IH), 7.46 (t, J = 7.4 Hz, IH), 7.61 (t, J - 7.5 Hz, 2H), 7.79 - 7.84 (m, 2H), 7.96 (d, J = 8.5 Hz, IH), 8.47 (br, IH), 8.65 (br, IH), 9.05 (s, IH); m/z (APCI pos) 506.0 (M+H) .
Example A94
6-Cyano-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide
Figure imgf000190_0001
A mixture of N- (2-aminoethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (1.00 g, 3.35 mmol), 6-cyanonicotinic acid (0.55 g, 3.69 mmol), EDACΗC1 (0.84 g, 4.36 mmol), HOBt-H2O (0.67 g, 4.36 mmol) and CH3CN (20 mL) was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic layer was then dried and concentrated. The resulting solid was washed with EtOAc and dried to give 6-cyano-N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (1.00 g, 70%) as a beige solid: 1H NMR (400MHz, CDCl3) δ 3.68-3.82 (4H, m) , 6.66 (IH, br) , 7.44 (IH, t, J=7.6 Hz), 7.53 (2H, t, J=7.6 Hz), 7.71 (2H, d, J=7.6 Hz), 7.79 (IH, d, J=8.0 Hz), 7.98 (IH, br) , 8.31 (IH, dd, J=2.4, 8.0 Hz), 8.47 (IH, s) , 9.16 (IH, d, J=2.4 Hz); m/z (APCI pos) 428.9 (25 %) (M+H) .
Example A95 6- (N'-Hydroxycarbamimidoyl) -N- (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) nicotinamide
Figure imgf000191_0001
A mixture of 6-cyano-N- (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) nicotinamide (0.50 g, 1.17 mmol) , sodium bicarbonate (0.20 g, 2.3 mmol), hydroxylamine hydrochloride (0.16 g, 2.3 mmol) and EtOH (10 iαL) was refluxed for 3 hours. After cooling, the mixture was diluted with EtOAc, washed with water and brine, dried, and concentrated. The residue was recrystallized from EtOAc to give 6- (N' - hydroxycarbamimidoyl) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide as colorless crystals (0.35 g, 65%): 1H NMR (400MHz, DMSO-d6) δ 3.45 (4H, s) , 5.91 (2H, S), 7.48 (IH, t, J=7.6 Hz), 7.61 (2H, t, J=8.4 Hz), 7.81 (2H, dd, J=O.8, 8.4 Hz), 7.93 (IH, dd, J=O.8, 8.4 Hz), 8.19 (IH, dd, J=2.0, 8.4 Hz), 8.50 (IH, br) , 8.82 (IH, br) , 8.98 (IH, dd, J=O.8, 2.0 Hz), 9.06 (IH, d, J=O .8 Hz), 10.09 (IH, s) ; m/z (APCI pos) 462.1 (100 %) (M+H).
Example A96 6- (1, 2, 4-Oxadiazol-3-yl) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4~carboxamido) ethyl) nicotinamide
Figure imgf000192_0001
A mixture of 6- (N' -hydroxycarbamimidoyl) -N- (2- (1-phenyl-3- {trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide {0.10 g, 0.22 mmol), boron trifluoride diethylether complex (0.028 itiL, 0.22 mmol) and triitvethyl orthoformate (2 mL) was stirred at 1100C for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was then dried and concentrated in vacuo. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc - EtOAc/MeOH=10/l) to afford 6- (1,2,4- oxadiazol-3-yl) -N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole- 4-carboxamido) ethyl)nicotinamide (0.022 g, 22%) as colorless crystals: 1H NMR (400MHz, DMSO-d6) δ 3.47 (4H, s) , 7.48 (IH, t, J=7.6 Hz), 7.61 (2Hr t, J=7.6 Hz), 7.81 (2H, d, J=7.6 Hz), 8.22 (IH7 d, J=8.0 Hz), 8.42 (IH, dd, J=2.0, 8.0 Hz), 8.52 (IH, br) , 8.98 (IH, br) , 9.07 (IH, s), 9.18 (IH, d, J=2.0 Hz), 9.83 (IH, s); m/z (APCI pos) 472.1 (100 %) (M+H) .
Example A97 tert-Butyl 5- ( (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl )pyridin-2-ylcarbamate
Figure imgf000192_0002
A mixture of 5- ( (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) carbamoyl) picoliriic acid (1.00 g, 2.24 mmol), diphenylphosphoryl azide (0.52 mL, 2.35 mmol), triethylamine (0.33 mL, 2.35 mmol) and t-BuOH (20 mL) was stirred at 900C in a sealed tube for 3 days. After cooling, the mixture was concentrated and recrystallized from EtOAc to give tert-butyl 5- ( (2- (l-phenyl-3- (trifluoroiαethyl ) -lH-pyrazole-4- carboxamido) ethyl) carbamoyl )pyridin-2-ylcarbamate
(0.53 g, 46%) as colorless crystals: 1H NMR (400MHz, CDCl3) δ 1.53 (9H, s), 3.64-3.78 (4H, m) , 6.82 (IH, br) , 7.24 (IH, br) ,• 7.42 (IH, t, J=I.6 Hz), 7.51 (2H, t, J=7.6 Hz), 7.65 (IH, s) , 7.70 (2H, d, J=8.0 Hz), 8.01 (IH, d, J=8.8 Hz), 8.08 (IH, dd, J=2.0, 8.8 Hz), 8.44 (IH, s) , 8.73 (IH, d, J=2.0 Hz); m/z (APCI pos) 518.8 (35 %) (M+H) .
Example A98
N- (2- (l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3- yl) nicotinamide
Figure imgf000193_0001
A mixture of 6- (N' -hydroxycarbamimidoyl) -N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide (0.10 g, 0.22 mmol), trifluoroacetic anhydride (0.15 mL, 1.08 mmol) and pyridine (2 mL) was stirred at 1000C for 6 hours.
After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to afford N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carbσxamido) ethyl ) -6- ( 5-
(trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) nicotinamide (0.065 g,
56%) as colorless crystals: 1H NMR (400MHz, CDCl3) δ 3.70-3.82 (4H, m) , 6.73 (IH, br) , 7.43 (IH, m) , 7.48-7.56 (2H, m) , 7.69- 7.75 (2H, m) , 7.93 (IH, br) , 8.27 (IH, dd, J=O.8, 8.0 Hz), 8.39 (IH, dd, J=2.4, 8.0 Hz), 8.50 (IH, d, J=O .8 Hz) , 9.27 (IH, dd,
J J=- O.8, 2.4 Hz) ; m/z (APCI pos) 540.0 (100 %) (M+H) .
Example A99
6-Acetamido-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide
Figure imgf000194_0001
Step 1 tert-Butyl 5- ( (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) carbamoyl) pyridin-2-ylcarbamate (0.450 g, 0.868 mmol) was dissolved in TFA (8 mL) . The solution was stirred at room temperature for 2 hours . The solution was concentrated, diluted in EtOAc and washed with saturated aqueous potassium carbonate and brine. The organic layer was then dried, and concentrated to give β-amino-N- (2- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxarαido) ethyl) nicotinamide (0.270 g, 74%) as a white solid: m/z (APCI pos) 419.0 (100 %) (M+H).
Step 2
6-Amino-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide (0.15 g, 0.35 mmol) in DCM (2 mL) was charged with triethylamine (0.12 ml, 0.84 mmol). The solution was cooled to 00C. Acetyl chloride (0.03 ml, 0.42 mmol) was added and the solution was warmed to room temperature, The solution was quenched with water, extracted with EtOAc, dried and concentrated. The residue was then diluted in MeOH and 2N NaOH and the mixture was stirred at room temperature for 30 minutes. The solution was extracted with EtOAc, dried, and concentrated to afford 6-acetamido-N- (2- (l-phenyl-3- (trifluoromethyl)-lH-pyrazole-4-carboxamido) ethyl) nicotinamide (0.090 g, 69%): 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 3H), 3.42 (br, 4H), 7.47 (t, J = 7.6 Hz, IH), 7.61 (t, J = 8.4 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 8.10 - 8.20 (m, 2H), 8.49 (s, IH), 8.65 (s, IH), 8.76 (d, J = 1.6 Hz, IH), 9.06 (s, IH), 10.8 (s, IH); m/z (APCI pos) 461.1 (M+H) .
Example A102
2-tert-Butyl-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) imidazo [1, 2-a] pyridine-6-carboxamide
Figure imgf000195_0001
stepS
Figure imgf000195_0002
Step 1
A mixture of methyl 6-aminonicotinate (1.50 g, 9.86 mmol) , l-bromo-3,3-dimethylbutan-2-one (1.77 g, 9.86 mmol), and NaHCO3 (0.828 g, 9.86 mmol) in MeOH (30 mL) was heated at reflux for 18 hours . The mixture was cooled and concentrated to a residue. The residue was diluted with AcOEt, and the solution was washed with water and brine, dried over Na2SO4, and concentrated to a residue. This residue was crystallized from AcOEt/EtOH to afford methyl 2-tert-butylimidazo[ 1, 2-a] pyridine- 6-carboxylate (0.690 g, 30%) as a solid: m/z (APCI pos) 233 [M+H] .
Step 2
Methyl 2-tert-butylimidazo [1, 2-a] pyridine- 6-carboxylate (0.100 g, 0.431 itimol) was dissolved in ethylenediamine (2 mL) . The solution was heated at 800C for 3 hours. The solution was concentrated and azeotroped with toluene to afford 0.126g of the crude N- (2-aminoethyl) -2-tert-butylimidazo[l, 2-a]pyridine- 6-carboxamide. Material was taken on as is: m/z (APCI pos) 261.2 (100%) (M+H) .
Step 3
N- (2-Aminoethyl) -2-tert-butylimidazo[l/ 2-a] pyridine-6- carboxamide (0.126 g, 0.484 mmol) , l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.149 g, 0.581 mmol), HOBt-H2O (0.0889 g, 0.581 mmol) and EDAC'HCl (0.111 g, 0.581 mmol) were dissolved, in DMF (2 mL) . DIPEA (0.253 ml, 1.45 mmol) was added last. The reaction was stirred at room temperature overnight. The solution was quenched with water, and extracted with EtOAc. The organic layer was dried, and concentrated. Purification by reverse phase HPLC and recrystallization with EtOAc gave 2-tert-butyl-N- (2- (1-phenyl- 3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) imidazo[l, 2-a] pyridine-6-carboxamide as a white solid (0.037 g, 15%): m/z (APCI pos) 499 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 1.32 (s, 9H), 3.44 (s, 4H), 7.46-7.53 (m, 2H), 7.58-7.62 (m, 3H), 7.78 (s, IH), 7.81 (d, J = 7.6 Hz, 2H), 8.51 (br s, IH), 8.66 (br s, IH), 9.01 (s, IH), 9.07 (s, IH).
Example Al03
6- (5-Isopropyl-l,2, 4-oxadiazol-3-yl) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxam.ido) ethyl) nicotinamide
Figure imgf000196_0001
The title compound was prepared from 6-(N1- hydroxycarbamimidoyl) -N- (2- (1-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide and isobutyryl chloride using a similar procedure described in Example A98. Colorless crystals. 1H NMR (400MHz7 CDCl3) δ 1.49 (6H, d, J=7.2 Hz), 3.34 (IH, m), 3.68-3.80 (4H, m) , 6.80 (IH, br) , 7.42 (IH, t, J=7.6 Hz), 7.51 (2H, t, J=7.6 Hz), 7.72 (2H, d, J=7.6 Hz), 7.83 (IH, br) , 8.22 (IH, d, J=8.0 Hz), 8.33 (IH, dd, J=2.4 , 8.0 Hz), 8.50 (IH, s), 9.23 (IH, m) ; m/z (APCI pos) 514.2 (100 %) (M+H) .
Example Al04
6-Hydroxy-N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) nicotinamide
Figure imgf000197_0001
The title compound was obtained in the reaction that afforded the compound of Example A42. Colorless solid. 1H NMR (400MHz, DMSO-dg) δ 3.32-3.40 (4H, in), 6.34 (IH, d, J=9.6 Hz), 7.48 (IH, t, J=7.6 Hz), 7.61 (2H, t, J=7.6 Hz), 7.81 (2H, dd, J=O.8, 8.4 Hz), 7.85 (IH, dd, J=2.4, 9.6 Hz), 7.98 (IH, d, J=2.4 Hz), 8.36 (IH, br) , 8.45 (IH, br) , 9.05 (IH, d, J=O .8 Hz), 11.95 (IH, s) ; m/z (APCI pos) 420.0 (100 %) (M+H).
Example Al05
6- (5-Isopropyl-l, 3, 4-oxadiazol-2-yl) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl ) nicotinamide
Figure imgf000197_0002
A mixture of 6- (5-isopropyl-l, 3, 4-oxadiazol-2-yl) nicotinic acid (0.13 g, 0.54mmol), N- (2-aminoethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.18 g, 0.59 mmol), EDAC-HCl (0.15 g, 0.80 mmol), HOBt-H2O (0.12 g, 0.80 mmol) and triethylamine (0.22 mL, 1.6 mmol) in CH3CN (10 mL) was stirred for 16 h at room temperature. The mixture was diluted with AcOEt, washed successively with IN HCl, saturated aqueous NaHCO3 and brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt to AcOEt/MeOH=10/l) and recrystallized from AcOEt to give 6-{5- isopropyl-1, 3, 4-oxadiazol-2-yl) -N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide (0.14 g, 51 %) as colorless crystals. 1H NMR (400MHz, CDCl3) δ 1.49 (6H, d, J=7.2 Hz), 3.30 (IH, m) , 3.70-3.82 (4H, m) , 6.80 (IH, br) , 7.42 (IH, t, J=7.2 Hz), 7.51 (2H, t, J=8.0 Hz), 7.71 (2H, d, J=8.0 Hz), 7.87 (IH, br) , 8.26-8.36 (2H, m) , 8.50 (IH, s), 9.22 (IH, d, J=I.2 Hz); m/z (APCI pos) 514.2 (100 %) (M+H) . '
6- (5-Isopropyl-l, 3, 4-oxadiazol-2-yl) nicotinic acid
Figure imgf000198_0001
Step 1
A mixture of 5- (methoxycarbonyl) picolinic acid (0.50 g, 2.62 mmol), isobutyrohydrazide (0.30 g, 2.88 mmol), EDAC-HCl (0.75 g, 3.93 mmol), HOBt-H2O (0.60 g, 3.93 mmol) and triethylamine (0.73 mL, 5.24 mmol) in CH3CN (20 mL) was stirred for 16 h at room temperature. The mixture was diluted with AcOEt, washed successively with IN HCl, saturated aqueous NaHCθ3 and brine, dried and concentrated in vacuo to give methyl 6- (N' -isobutyrylhydrazinocarbonyl) nicotinate (0.51 g, 73 %) as yellow solid. 1H NMR (400MHz, CDCl3) δ 1.27 (6H, d, J=6.8 Hz), 2.57 (IH, m) , 3.99 (3H, s), 8.22 (IH, d, J=8.0 Hz), 8.38-8.50 (2H, m) , 9.17 (IH, d, J=2.0 Hz), 10.29 (IH, s); m/z (APCI pos) 266.0 (100 %) (M+H) .
Step 2
A mixture of methyl 6- ( N' - isobutyrylhydrazinocarbonyl) nicotinate (0.51 g, 1.92 mmol) , phosphorus oxychloride (0.54 mL, 5.77 παnol) and CH3CN (10 itiL) was heated at 8O0C for 16 h. After cooling to room temperature, the mixture was diluted with AcOEt, washed with saturated aqueous NaHCO3 and brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography
(hexanes/AcOEt =2/1 to 1/1) to give methyl 6- (5-isopropyl- 1, 3, 4-oxadiazol-2-yl)nicotinate (0.28 g, y. 59 %) as pale yellow solid. 1H NMR (400MHz, CDCl3) δ 1.50 ( 6H, d, J=6.8 Hz), 3.34 (IH, m) , 4.01 (3H, s), 8.34 (IH, d, J=8.4 Hz), 8.47 (IH, dd, J=2.0, 8.4 Hz), 9.35 (IH, d, J=2.0 Hz); m/z (APCI pos) 248.2 (100 %) (M+H) .
Step 3
A mixture of methyl 6- (5-isopropyl-l, 3, 4-oxadiazol-2- yl) nicotinate (0.28 g, 1.13 mmol), IN NaOH (2.3 mL, 2.3 mmol) and MeOH (10 mL) was stirred at 500C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was neutralized with IN HCl and extracted with AcOEt. The AcOEt extract was washed with water and brine, dried and concentrated in vacuo to give 6- (5-isopropyl-l, 3, 4-oxadiazol-2- yDnicotinic acid (0.13 g, 48%) as colorless solid. 1H NMR (400MHz, CDCl3) δ 1.51 (6H, d, J=7.2 Hz), 3.36 (IH, m) , 8.40 (IH, d, J=8.4 Hz), 8.55 (IH, dd, J=2.0, 8.4 Hz), 9.43 (IH, d, J=2.0 Hz); m/z (APCI pos) 234.2 (M+H).
Example Bl
N-(2-(4-Ethoxybenzamido)ethyl)-l- (lH-indol-5-yl) -3-
(trifluoromethyl) -lH-pyrazole-4-carboxamide
Figure imgf000200_0001
To a 5 ml reacti-vial were added 1- (lH-indol-5-yl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.162 g, 0.550 iranol), HOBfH2O (0.0842 g, 0.550 mmol), and EDAC-HCl (0.105 g, 0.550 mmol). These were dissolved in DMF (1 ml) and N-(2- aminoethyl) -4-ethoxybenzamide hydrochloride (0.122 g, 0.50 mmol) was added followed by DIPEA (0.129 g, 1.00 mmol) . The mixture was stirred for 16 hours. The solvent was removed and the residue was dissolved in DCM and washed with water (2X) . The combined aqueous layers were back extracted, and the combined organic layers were washed with brine, dried (sodium sulfate) , and concentrated in vacuo. The residue was then purified by silica gel column chromatography (3% MeOH/DCM) to give N- (2- (4-ethoxybenzamido) ethyl) -1- (lH-indol-5-yl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (12 mg, 5%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, 3H, J = 7.0 Hz), 3.40 (m, 4H), 4.08 (q, 2H, J = 7.0 Hz), 6.57 (m, IH), 6.97 (d, 2H, J = 9.0 Hz), 7.53 (m, 3H), 7.82 (d, 2H, J = 9.0 Hz), 7.93 (m, IH), 8.44 (m, 2H), 8.96 (s, IH), 11.42 (br, IH); m/z (APCI pos) 486.0 (10 %) (M+H) .
Compounds of the following structures were prepared from N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride and the corresponding acids, using a similar method to that described above .
Figure imgf000201_0001
Example B5 N- ( 2- ( 4-Ethoxybenzarαido ) ethyl ) - !- (pyrimidin-2-yl ) -3- ( trifluoromethyl ) -lH-pyrazole-4-carboxamide
Figure imgf000202_0001
Step 1 To a 500 ml round-bottom flask were added 3-
(trifluoromethyl) -lH-pyrazole-4-carboxylic acid (18.8 g, 104 iranol), HOBt-H2O (16 g, 104 mmol), and EDAC-HCl (20 g, 104 mmol) . These were dissolved in DMF, and N- (2-aminoethyl) -4- ethoxybenzamide hydrochloride (23 g, 95 mmol) was added as a solid. Triethylamine (26 ml, 189 mmol) was then added and the mixture was stirred for 16 hours. The solvent was removed, the residue was dissolved in DCM and the solution was washed with water (2X) . The combined aqueous layers were back extracted, and the combined organic layers were washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was then purified by silica gel column chromatography (4% MeOH/DCM) and then triturated with ethyl acetate to give N- (2- (4- ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxamide (12 g, 34%) as a solid: 1H NMR (CDCl3) δ 1.34 (t, 3H, J = 7.0 Hz), 3.36 (m, 4H), 4.07 (q, 2H, J = 7.0 Hz), 6.96 (m, 2H), 7.80 (m, 2H), 8.34 (m, 2H), 8.41 (m, IH), 13.74 (br, IH).
Step 2
According to the procedure of Buchwald et al . (J. Am. Chem. Soc. 2001, 123, 1121-9), to a 50 mL sealed tube were added N-
(2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxamide (0.100 g, 0.270 mmol), (IR, 2R) -N1,N2- dimethylcyclohexane-1, 2-diamine (0.008 g, 0.054 mmol), copper (I) iodide (0.003 g, 0.014 mmol) , potassium carbonate (0.075 g, 0.54 inmol), and 2-bromopyrimidine (0.047 g, 0.3 mmol)
The mixture was stirred for 16 hours at 1100C, cooled to room temperature, and filtered through celite. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (9:0.5:0.5 DCM/EtOAc/MeOH) to give N- (2- (4-ethoxybenzamido) ethyl) -1- (pyrimidin-2-yl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (100 mg, 83%) as a solid: 1H NMR (400 MHz, DMSO-de) δ 1.33 (t, 3H, J = 7.0 Hz), 3.40 (s, 4H), 4.08 (q, 2H, J = 7.0 Hz), 6.97 (d, 2H, J = 9.0 Hz), 7.66 (t, IH, J = 5.0 Hz), 7.82 (d, 2H, J = 9.0 Hz), 8.44 (s, IH), 8.69 (s, IH), 8.98 (d, 2H, J = 4.7 Hz), 9.42 (s, IH); m/z (APCI pos) 449.1 (100 %) (M+H) .
The compound of the following structure was prepared using a similar method to that described above.
Figure imgf000203_0001
Example Cl ( S) -3- ( 4-Ethoxybenzamido) -2- ( l-phenyl-3- ( trifluoromethyl ) -IH- pyrazole-4-carboxamido ) propanoic acid
LiOKH2O
Figure imgf000204_0001
Figure imgf000204_0002
To (S) -methyl 3- (4-ethoxybenzamido) -2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido)propanoate (100 mg, 0.2 mmol) in MeOH (5 inL) was added lithium hydroxyde monohydrate (83 mg, 2 mmol) . The mixture was stirred for 48 hours at room temperature and concentrated. Water (10 ml) was added and the suspension was adjusted to acidic with 2N HCl. The aqueous layer was extracted with DCM (5 X 20 inL) . The combined organic layers were dried over MgSC^ and concentrated to yield (S) -3- (4-ethoxybenzamido) -2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) propanoic acid as a white solid (65 mg, 67%): 1H NMR (400 MHz, DMSO-dβ) δ 1.32 (t, 3H, J = 7.0 Hz), 3.62 (m, IH), 3.76 (m, IH), 4.07 (q, 2H, J = 7.0 Hz), 4.62 (m, IH), 6.96 (m, 2H), 7.49 (m, IH), 7.62 (m, 2H), 7.75-7.82 (m, 4H), 8.46 (t, IH, J = 5.6 Hz), 8.60 (d, IH, J = 5.6 HZ), 9.14 (S, IH), 12.80 (s, IH); m/z (APCI pos) 491.0 (100 %) (M+H) .
Compounds of the following structures were prepared from the corresponding esters, using a similar method to that described above.
Figure imgf000205_0001
Figure imgf000206_0001
Example C3
(S) -Methyl 3- (4-ethoxybenzaπtido) -2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) propanoate
Figure imgf000206_0002
Step 1
To (S) -methyl 2-amino-3- (tert- butoxycarbonylamino) propanoate hydrochloride (1.0 g, 3.9 mmol) in DCM (50 mL) were added successively l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxylic acid (1.0 g, 3,9 mmol), EDAC-HCl (0.9 g, 4.71 mmol), HOBt-H2O (0.690 g, 5.1 mmol) and triethylamine (0.8 g, 7.9 mmol). The mixture was stirred at room temperature for 12 hours and 2N HCl was added (100 mL) . The organic layer was isolated and washed with 10% aqueous K2CO3 and brine. The combined organic layers were dried over MgSO-i, concentrated and purified by silica gel column chromatography (DCM/MeOH 99/1). (S) -Methyl 3- (tert- butoxycarbonylamino) -2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) propanoate was isolated as a white solid (1.2 g, 67%): 1H NMR (CDCl3) δ 1.42 (s, 9H) > 3.64-3.68 (m, 2H), 3.80 (s, 3H), 4.74-4.82 (m, IH), 4.91-4.97 (m, IH), 7.32-7.38 (m, IH), 7.39-7.44 (m, IH), 7.48-7.54 (m, 2H), 7.69-7.72 (m, 2H), 8.44 (br, IH); m/z (APCI pos) 357.1 (100%) (M+H-Boc) .
Compounds of the following structures were prepared from the corresponding Boc-protected diamines and acids, using a similar method to that described above .
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Step 2
To (S) -methyl 3- (tert-butoxycarbonylartiino) -2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) propanoate (1.0 g,
2.2 mmol) was added TFA (10 mL) . The mixture was stirred at room temperature for 1 hour and concentrated under vaccum. The residue was dissolved in water (50 mL) and sodium carbonate was added until basic pH. After stirring 1 hour at room temperature, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSCM and concentrated to yield (S) -methyl 3-amino-2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido)propanoate as a white solid (780 mg, quant.): 1H NMR (CDCl3) δ 3.17 (dd, IH, J = 13.3, 4.7 Hz), 3.25 (dd, IH, J = 13.3, 3.9 Hz), 3.81 (s, 3H), 4.78 (dt, IH, J = 7.0,
4.3 Hz), 7.17 (br, IH), 7.39-7.44 (m, IH), 7.48-7.54 (m, 2H), 7.69-7.73 (m, 2H), 8.49 (s, IH).
Compounds of the following structures were prepared from the corresponding Boc-protected amines, using a similar method to that described above .
Figure imgf000210_0001
Figure imgf000211_0001
Step 3 Following the procedure described for the step 1 in Example C3, (S) -methyl 3- (4-ethoxybenzamido) -2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) propanoate was obtained as a white solid (1.19 g, 84%) from (S) -methyl 3- amino-2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) propanoate and 4-ethoxybenzoic acid: 1H NMR (400 MHz,
CDCl3) δ 1.41 (t, 3H, J = 7.0 Hz), 3.80 (t, 3H), 3.95 (t, 2H), 4.04 (q, 2H, J = 7.0 Hz), 4.89 (m, IH), 6.88 (m, 3H), 7.40 (m, IH), 7.49 (m, 2H), 7.64-7.74 (m, 5H), 8.43 (d, IH); m/z (APCI pos) 505 (100 %) (M+H) .
Compounds of the following structures were prepared from the corresponding amines and either 4-ethoxybenzoic acid or 1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid, using a similar method to that described above.
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
= 5 . 9 Hz ) , 9 . 01 (s ,
IH) ; m/z (APCI pos )
475 . 1 ( 100%) (M+H) .
Example C5
(S) -N- (1- (4-Ethoxybenzamido) -3-hydroxyproρan-2-yl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide
Figure imgf000215_0001
To (S) -methyl 3- (4-ethoxybenzamido) -2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxaπu.do)propanoate (647 mg, 1.3 mmol) in anhydrous THF/EtOH (2/1, 10 mL) was added lithium chloride (109 mg, 2.6 mmol). Upon dissolution, sodium borohydride (97 mg, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated to dryness, water (50 mL) was added and the pH was brought to 2-3 by addition of 2N HCl. The aqueous layer was extracted with DCM (3X50 mL) and the combined organic layers were dried over MgSCM . Concentration yielded (S)-N-(I- (4- ethoxybenzamido) -3-hydroxypropan-2-yl) -l-phenyl-3- (trifluoromethyl) ~lH-pyrazole-4-carboxanri.de as a white solid
(450 mg, 74%): 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H), 3.40 (m, IH), 3.45-3.68 (m, 3H), 4.07 (q, 2H), 4.13 (m, IH), 6.96 (m, 2H), 7.48 (m, IH), 7.61 (m, 2H), 7.78-7.82 (m, 4H), 8.08 (d, IH), 8.40 (t, IH), 9.13 (s, IH); m/z (APCI pos) 477.1 (20 %) (M+H) .
Compounds of the following structures were prepared from the corresponding esters, using a similar method to that described above.
Figure imgf000216_0001
7 . 77-7 .84 (m, 4H) ,
7 . 97 (d r IH, J = 7 . 4
Hz) , 8 . 44 (t, IH, J =
5. 9 Hz) r 9. 04 ( s , IH) ; m/z (APCI pos ) 459 . 2
( 100%) (M+H-H2O) .
Example C7
4-Ethoxy-N- (1- (l-phenyl-3- (trifluoroiαethyl) -lH-pyrazole-4- carbonyl ) piperidin-3-yl) benzamide
εtepi
Figure imgf000217_0002
Figure imgf000217_0001
Step 1
EDAC-HCl (0.1 g, 0.6 mmol) , HOBt-H2O (0.08 g, 0.6 ininol) and 4-ethoxybenzoic acid (0.09 g, 0.6 mmol) were dissolved in DMF (0.5 ml), and tert-butyl 3~aminopiperidine-l-carboxylate (0.1 g,
10 0.5 mmol) was added. The mixture was stirred for 1 h. The solvent was removed under vacuum, and the residue was placed directly on a silica column. The column was eluted with 10% ether/DCM to give 92 mg of a clear oil . The oil was dissolved in DCM (5 mL) , and TFA (5 mL) was added. The mixture was
/5 stirred for 15 min and the solvent was removed under vacuum to give 4-ethoxy-N- (piperidin-3-yl)benzamide trifluoroacetate (0.055 g, 0.2 mmol, 30%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, 3H, J = 7.0 Hz), 1.49 (m, 2H), 1.71 (m, IH), 1.84 (m, IH), 2.53 (m, 2H), 2.92 (m, IH), 3.06 (m, IH), 3.90 (m, IH),
20 4.07 (q, 2H, J = 7.0 Hz), 6.96 (m, 2H), 7.80 (m, 2H), 8.05 (m, IH) .
Compounds of the following structures were prepared from the corresponding Boc-protected diamines and either 4-
25 ethoxybenzoic acid or l-phenyl-3- (trifluoromethyl) -lH-pyrazole- 4-carboxylic acid/ using a similar method to that described above . .
Figure imgf000218_0001
Step 2
To a 5 ml reacti-vial were added l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.062 g, 0.24 mmol), EDAC-HCl (0.047 g, 0.24 mmol) , and HOBt-H2O (0.037 g, 0.24 mmol) . These were dissolved in DMF and 4-ethoxy-N-
(piperidin-3-yl) benzamide trifluoroacetate (0.055 g, 0.22 mmol) and triethylamine (33 μl, 0.24 mmol) were added to this mixture as a solution in DMF (1 mL) . The mixture was stirred for 1 hour. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (1-3% MeOH/DCM) to give a material that was triturated with ether to give 4- ethoxy-N- (1- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carbonyl)piperidin-3-yl)benzamide (0.052 g, 48%) as a crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.44 (t, 3H, J = 7.0 Hz), 1.58 (s, IH), 1.60-1.90 (m, 3H), 2.14 (br, IH), 3.19 (br, 0.5H), 3.35 (br, IH), 3.60 (br, 0.5H), 4.08 (q, 2H, J = 7.0 Hz), 4.08- 4.25 (m, 2H), 6.02 (br, 0.5H), 6.75 (br, 0.5H), 6.91 (d, 2H, J = 8.6 Hz), 7.39 (br, IH), 7.49 (m, 2H), 7.60- 7.90 (m, 4H), 8.05 (br, 0.5H), 8.36 (m, 0.5H); m/z (APCI pos) 487.0 (10 %) (M+H) .
Compounds of the following structures were prepared from, the corresponding amines which were obtained in Step 1 in Example C7 and either 4-ethoxybenzoic acid or l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid, using a similar method to that described above.
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Example Cl4
N- (2- (4-Ethoxy-N-methylbenzamido) ethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide
Figure imgf000221_0002
Step 1
To a solution of tert-butyl 2-aminoethyl (methyl) carbamate (0.174 g, 1.00 mmol) in DCM (5 ml) and saturated aqueous sodium bicarbonate (2 ml) was added l-phenyl-3- ( trifluoromethyl) -IH- pyrazole-4-carbonyl chloride (0.302 g, 1.10 mmol, prepared in the standard way from l-phenyl-3- (trifluoromethyl) -IH-pyrazole- 4-carboxylic acid and oxalyl chloride) as a solution in dichloromethane (1 ml) . The mixture was stirred for 1 hour. The layers were separated and the organic layer was dried (sodium sulfate) and the solvent was removed under vacuum to give 405 mg of the Boc protected amine. This was dissolved in DCM (5 ml) and treated with TFA (2 ml) and the mixture was stirred for 1 hour. The solvent was removed under vacuum to give N- (2- (methylamino) ethyl) -l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamide trifluoroacetate (0.426 g, 100%) as an oil: 1H NMR (400 MHz, CDCl3) 6 2.92 (s, 3H)7 3.49 (m, 2H), 3.59 (m, 2H), 7.41 (m, IH), 7.50 (m, 2H), 7.70 (m, 2H), 8.36 (m, IH)
The following compound was prepared from tert-butyl 2- aminoethyl (methyl) carbamate and 4-ethoxybenzoyl chloride in the manner described above.
Figure imgf000222_0001
Step 2
To a solution of N- (2- (methylamino) ethyl) -l-phenyl-3- (trifluσromethyl)-lH-pyrazole-4-carboxamide trifluoroacetate (0.312 g, 1.00 mmol) in DCM (10 mL) and saturated aqueous sodium bicarbonate (2 ml) was added 4-ethoxybenzoyl chloride (0.203 g, 1.10 mmol) as a solution in dichloromethane (1 ml). The mixture was stirred for 1 hour. The layers were separated, the aqueous layer was back extracted and the combined organic layers were dried (sodium sulfate) , and concentrated under vacuum. The resulting residue was triturated with ether/hexanes to give N- (2- (4-ethoxy-N-methylbenzamido) ethyl) - l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.274 g, 60%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H, J = 7.0 Hz), 3.00 (s, 3H), 3.38-3.64 (m, 4H), 4.03 (m, 2H, J = 7.0 Hz), 6.90 (s, 2H), 7.33 (s, 2H), 7.48 (m, IH), 7.61 (m, 2H), 7.80 (m, 2H), 8.51 (br, IH), 9.01 (s, IH); rα/z (APCI pos) 461.0.0 (10 %) (M+H) . The following compound was prepared from 4-ethoxy-N- (2- (methylaminό) ethyl) benzamide trifluoroacetate and l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid in the manner described above.
Figure imgf000223_0001
Example C18
(R) -Methyl 2- (4-ethoxybenzamido) -3- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) propanoate
Figure imgf000223_0002
Step 1
Following the procedure described for the step 1 in Example C3, (R) -methyl 2- (benzyloxycarbonylamino) -3- (1-phenyl- 3- (trifluoromethyl) -lH-pyrazole-4-carboxamido) propanoate was obtained as a white solid (4.6 g, 90%) from (R)-methyl 3-amino- 2- (benzyloxycarbonyl)propanoate hydrochloride and l-phenyl-3- (trifluoromethyl)-lH-pyrazole-4-carboxylic acid: 1H NMR (400
MHz, DMSO-de) δ 3.50-3.70 (m, 2H), 3.64 (s, 3H), 4.28-4.35 (m, IH), 5.05 (S, 2H), 7.25-7.37 (m, 5H), 7.45-7.51 (m, IH), 7.58- 7.63 (m, 2H), 7.70-7.75 (m, IH), 7.78-7.83 (m, 2H), 8.48 (t, IH, J = 5.9 Hz), 9.03 (s, IH) .
Step 2 To a solution of (R)-methyl 2- (benzyloxycarbonyl) -3- (1- phenyl-3- {trifluoromethyl) -lH-pyrazole-4-carboxamido)propanoate (4.5 g, 9.2 mmol) in dry THF (300 mL) was added 10%wt palladium on charcoal (dry) (1 g) under argon atmosphere. The mixture was shaken under hydrogen (45 psi) for 4 days at room temperature. The palladium was filtered off and the filtrate was concentrated and purified by silica gel column chromatography (DCM/MeOH=95/5) . (R) -Methyl 2-amino-3- (1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamido)propanoate was isolated as a white solid (2.57 g, 84 %): 1H NMR (400 MHz, DMSO-de) δ 3.17 (s, IH), 3.18 (s, IH), 3.40-3.45 (m, 2H), 3.62 (S, 3H), 4.06-4.12 (m, IH), 7.45-7.50 (m, IH), 7.58-7.63 (m, 2H), 7.81-7.85 (m, 2H), 8.37 (t, IH, J = 5.9 Hz), 9.09 (s, IH).
Step 3 Following the procedure described for the step 1 in
Example C3, (R) -methyl 2- (4-ethoxybenzamido) -3- (l-phenyl-3- (trifluoromethyl ) -lH-pyrazole-4-carboxamido) propanoate was prepared as white solid (1.35 g, 73%) from (R) -Methyl 2-amino- 3- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido)propanoate and 4-ethoxbenzoic acid: 1H NMR (400 MHz,
DMSO-de) δ 1.34 (t, 3H, J = 7.0 Hz), 3.60-3.70 (m, IH), 3.66 (s, 3H), 3.82 (dt, IH, J = 13.7, 5.8 Hz), 4.09 (q, 2H, J = 7.0 Hz), 4.62 (dt, IH, J = 7.4, 5.5 Hz), 7.00 (d, 2H, J = 9.0 Hz), 7.48 (tt, IH, J = 7.4, 1.5 Hz), 7.56-7.63 (m, 2H), 7.78-7.88 (m, 4H), 8.61 (t, IH, J = 5.9 Hz), 8.67 (d, IH, J = 7.4 Hz), 9.04 (s, IH) ; iri/z (APCI pos) .505.0 (100%) (M+H) .
The compound of the following structure was prepared from the corresponding amine, using a similar method to that described above. ■
Figure imgf000225_0002
Example Dl
N- (2- (4-Ethoxybenzamido) ethyl) -4, 6-diphenylpicolinamide
Figure imgf000225_0001
A mixture of N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride (0.16 g, 0.66 mmol) , 4, 6-diphenylpicolinic acid (0.15 g, 0.55 mmol), triethylamine (0.11 mL, 0.82 mmol), EDAC-HCl (0.14 g, 0.71 mmol), HOBt-H2O (0.1-1 g, 0.71 mmol) and DMF (6 mL) was stirred at room temperature for 4 h. The mixture was diluted with EtOAc, washed successively with water and brine, dried over MgSO,), and concentarated in vacuo. The residue was purified by silica gel column chromatography (hexanes/EtOAc=l/l-l/4) to give N- (2- (4-ethoxybenzamido) ethyl) - 4, 6-diphenylpicolinamide (0.13 g, 49%) as colorless crystals: 1H
NMR (400MHz, CDCl3) δ 1.42 (3H, t, J=7.2 Hz), 3.72-3.86 (4H, m) , 4.06 (2H, q, J=7.2 Hz), 6.90 (2H, d, J=8.4 Hz)7 7.27 (IH, πt) , 7.44-7.58 (6H, m) , 7.73-7.85 (4H, m) , 8.04-8.12 (3H, m) , 8.40
10 (IH, s), 8.74 (IH, t, J=5.8 Hz); m/z (APCI pos) 466.1 (30 %) (M+H) .
Example D2 and D3
N- (2- (4-Ethoxybenzamido) ethyl) -4-methyl-l-phenyl-lH-pyrazole-3- /5 carboxamide and
N- (2- (4-ethoxybenzamido) ethyl) -4-methyl-l-phenyl-lH-pyrazole-5- carboxamide
Figure imgf000226_0001
Step 1
20 A mixture of (E) -1-ethoxyprop-l-ene (5.00 g, 58.05 πunol) in pyridine (4.685 ml, 58.05 mmol) was added to at -100C stirring solution of 2, 2, 2-trichloroacetyl chloride (10.56 g, 58.05 mmol) in DCM (15 mL) at a rate of 6-10 drops/minute. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The resulting precipitate was filtered and washed with DCM. The filtrate was concentrated to a residue with a bath temperature of 500C and the residue was dried on high vacuum overnight to give (E) -1, 1, l-trichloro-4- ethoxy-3-methylbut-3-en-2-one (16.14 g, 120% yield). The crude material is used directly in the next step without further purification.
Step 2 A mixture of (E) -1, 1, l-trichloro-4-ethoxy-3-methylbut-3- en-2-one (16.14 g, 69.72 mmol) and 1-phenylhydrazine (9.047 g, 83.66 mmol) in EtOH (70 mL) was heated at 78°C for 4 hours. The mixture was concentrated to a residue, dissolved in DCM, washed with IN HCl and water, dried on Na∑SCj, and concentrated to a residue. The obtained residue was dissolved in minimal DCM and passed through a plug of Silica eluting with 30% EtOAc/hexanes to give 2.1g of a crude black oil containing a mixture of regio-isomers (ethyl 4-methyl-l-phenyl-lH-pyrazole- 3-carboxlate and ethyl 4-methyl-l-phenyl-lH-pyrazole-5- carboxlate) . This material was carried directly into the next step. Step 3
To a mixture of regio-isomers (ethyl 4-methyl-l-phenyl-lH- pyrazole-3-carboxlate and ethyl 4-methyl-l-phenyl-lH-pyrazole- 5-carboxlate) (2.10 g, 9.12 mmol) in EtOH (30 ml) and water (30 ml) was added lithium hydroxide monohydrate (1.15 g, 27.4 mmol) and the mixture was stirred at 500C for 90 minutes. The mixture was cooled to room temperature and the solvent was removed. Water and EtOAc were added and the layers were separated. The aqueous layer was acidified with 6N HCl and then extract with DCM. The combined organic layers were dried over Na∑SO^ and concentrated to give 1.24 g (67% yield) of a mixture of regio-isomers, 4-methyl-l-phenyl-lH-pyrazole-3- carboxylic acid and 4-methyl-l-phenyl-lH-pyrazole-5-carboxylic acid that were used directly in the next step. Step 4
The crude mixture of regio-isomers, 4-methyl-l-phenyl-lH- pyrazole-3-carboxylic acid and 4-methyl-l-phenyl-lH-pyrazole-5- carboxylic acid (300 mg, 1.48 mmol), HATU (564 mg, 1.48 mmol) , DIPEA (259 ul, 1.48 mmol), and N- (2-aminoethyl) -4- ethoxybenzamide hydrochloride (363 mg, 1.48 mmol) were combined in THF (15 ml) and stirred at room temperature for 6 hr. The mixture was quenched with water (150 ml) and extracted with DCM. The organics were dried over Na2SOo filtered, and concentrated to a residue. The obtained residue was purified by silica gel column chromatography (75% EtOAc/haxanes) to give N- (2- (4- ethoxybenzamido) ethyl) -4-methyl-l-phenyl-lH-pyrazole-3- carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 2.27 (s, 3H), 3.40-3.44 (m, 4H), 4.02-4.10 (m, 2H), 6.97
(d, J = 8.8 Hz, 2H), 7.34 (t, J = 7.3 Hz, IH), 7.52 (t, J = 7.9 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 8.37 (br, 2H), 8.44 (s, IH); m/z (APCI pos) 393 (M+H) . The other regioisomer was further purified on Prep TLC eluting with 75% EtOAc/hexanes to give N- (2- (4-ethoxybenzamido) ethyl) - 4-methyl-l-phenyl-lH-pyrazole-5-carboxamide: 1H NMR (400 MHz,
DMSO-de) δ 1.34 (t, J = 6.9 Hz, 3H), 2.10 (s, 3H), 3.38-3.39 (m, 4H), 4.05-4.11 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.29-7.33 (m, IH), 7.38-7.43 (m, 4H), 7.55 (s, IH), 7.79 (d, J = 8.8 Hz, 2H), 8.32 (s, IH), 8.66 (s, IH); m/z (APCI pos) 393 (M+H).
Example D4
N- (2- (4-Ethoxybenzamido) ethyl) -l-methyl-S-phenyl-lH-pyrazole-S- carboxamide
Figure imgf000228_0001
A mixture of HATU (0.5593 g, 1.471 mmol), DIPEA (0.7066 ml, 4.045 mmol), N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride (0.300 g, 1.226 iranol) and l-methyl-3-phenyl-lH-pyrazole-5- carboxylic acid (0.2479 g, 1.226 mmol) in THF (15 mL) was stirred at room temperature overnight. The mixture was quenched with water (150 ml) and the solid filtered, dried on high vacuum and purified on silica gel by eluting with 75% EtOAc/Hex. The pure material was recrystallized from EtOAc/hexanes to give N- (2- (4-ethoxybenzamido) ethyl) -1-methyl- 3-phenyl-lH-pyrazole-5-carboxamide (0.145 g, 30%) as a white solid: 1H NMR (400 MHz, DMSOd6) δ 1.33 (t, J = 7.0 Hz, 3H), 3.42 (br, 4H), 4.05-4.10 (m, 5H), 6.97 (d, J = 8.8 Hz, 2H), 7.23 (s, IH), 7.32 (t, J = 7.3 Hz, IH), 7.43 <t, J = 7.6 Hz, 2H), 7.74 (d, J = 7.3 Hz, 2H), 7.82 (d, J = 9.0 Hz, 2H), 8.45 (br, IH), 8.65 (br, IH); m/z (APCI pos) 393 (M+H) .
Compounds of the following structures were prepared from N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride and the corresponding acids, using a similar method to that described above .
Figure imgf000229_0001
2H) , 7 . 81 ( d, J = 8 . 4
Hz , 2H) , 8 . 04 Hz , 2H) ,
8 . 44 (br , IH) , 8 . 67
(br , IH) ; m/z (APCI pos ) 394 (M+H)
Example Sl
N- (2- (4-Ethoxybenzamido)ethyl)-l- (4-fluorophenyl ) -3- (trifluoromethyl) -lH-pyrazole-4-carbσxamide
Figure imgf000230_0001
To a 10 ml round-bottomed flask were added EDAC* HCl (0.084 g, 0.44 mmol), HOBt 'H2O (0.067 g, 0.44 mmol), and 1- (4- fluorophenyl ) -3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.100 g, 0.36 mmol). These components were dissolved in DMF (0.8 rtiL) and N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride (0.098 g, 0.40 mmol) was added, followed by DIPEA (0.13 ml, 0.73 mmol) . The mixture was stirred for 16 h. The solvent was removed in vacuo, and the residue was dissolved in DCM (80 ml) . The organic layer was washed with water, 10% HCl, and brine (~20 ml each) , dried (sodium sulfate) and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (5% MeOH/DCM and 2:1 hexanes/acetone=2/l) to give N- (2- (4-ethoxybenzamido) ethyl) -1- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.037 g, 22%) as a powder: 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, 3H, J = 7.0 Hz), 2.51 (m, 4H), 4.25 (q, 2H, J = 7.0 Hz), 7.64 (m, 4H), 7.98 (m, 4H), 8.58 (br, IH), 9.24 (br, 2H); m/z (APCI pos) 465.0 (70 %) (M+H) . Compounds of the following structures were made from N- (2- aminoethyl) -4-ethσxybenzaiuide hydrochloride and the corresponding acids according to the above procedure.
Figure imgf000231_0001
Figure imgf000232_0001
Example S5
N- (2- (4-Ethoxybenzamido) ethyl) -l-phenyl-5- (trifluoromethyl) -IH- pyrazole-4-carboxamide
Figure imgf000232_0002
To N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride (382 ing, 1.6 mmol) in DCM (50 mL) were added successively 1-phenyl- 5- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid (400 mg, 1.6 mmol), EDAC-HCl (389 mg, 20.3 mmol), HOBt-H2O (295 mg, 2.2 mmol) and triethylamine (316 mg, 3.1 mmol) . The mixture was stirred at room temperature for 12 hours and 2N HCl was added (100 mL) . The organic layer was isolated and washed with 10% aqueous potassium carbonate and brine. After concentration and purification by silica gel column chromatography • (DCM/MeOH=99/l) , N- (2- (4-ethoxybenzamido) ethyl) -l-phenyl-5-
(trifluoromethyl) -lH-pyrazole-4-carboxamide was isolated as a white solid (412 m g, 59%): 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t,
3H), 3.40 (m, 4H), 4.08 (q, 2H), 6.98 (m, 2H), 7.48-7.62 (in,
5H), 7.82 (d, 2H), 8.12 (s, IH), 8.42 (t, IH), 8.66 (t, IH); rn/e (APCI pos) 447.0 (40 %) (M+H).
Example S 6
N- ( 2- ( 4- ( 2-Hydroxyethoxy) benzamido ) ethyl ) - l-phenyl-3- ( tri fluoromethyl ) -lH-pyrazole-4-carboxamide
Figure imgf000233_0001
N- (2-Aminoethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole- 4-carboxamide hydrochloride (0.20 g, 0.60 itimol), 4- (2- hydroxyethoxy) benzoic acid (0.11 g, 0.60 mmol), and HATU (0.27 g, 0.72 mmol) were suspended in THF (10 mL) . DIPEA (0.34 ml, 2.0 mmol) was added and the mixture was stirred at room temperature overnight. The solution was quenched with water (75 mL) and the solid was collected by filtration and dried to provide N- (2- (4- (2-hydroxyethoxy) benzamido) ethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.152 g, 55% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.41 (br, 4H), 3.71 - 3.72 (m, 2H), 4.00 - 4.05 (m, 2H), 4.90 (t, J = 5.2 Hz, IH), 6.99 (d, J = 7.6 Hz, 2H), 7.45 - 7.50 (m, IH), 7.61 (t, J = 7.6 Hz, 2H), 7.80 - 7.83 (m, 4H), 8.46 - 8.50 (m, 2H), 9.07 (s, IH); m/z (APCI pos) 463.0 (100%) (M+H) .
Compounds of the following structures were prepared from N- (2-aminoethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamide hydrochloride and the corresponding acids, using a similar method to that described above. In some cases, compounds were purified by silica gel column chromatography or preparative HPLC. In some cases, compounds were converted to an acid form by a method commonly employed.
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Example S16
N- ( 2- ( 4-Ethoxybenzamido ) ethyl ) -!- { 3-hydroxyphenyl ) -3- ( trifluoromethyl ) - lH-pyra2ole~4-carboxamide
Figure imgf000239_0001
To a 50 mL sealed tube flushed with argon were added copper (I) iodide (0.00257 g, 0.014 mmol), potassium carbonate (0.0784 g, 0.567 mmol) , and N- (2- (4-ethoxybenzamido) ethyl) -3- ( trifluoromethyl) -lH-pyrazole~4-carboxamide (0.100 g, 0.27 mmol). (lS,2S)-Nl,N2-Dimethylcyclohexane-l,2-diamine {0.00768 q, 0.054 mmol) and 3-iodophenol (0.0713 g, 0.32 mmol) were then added, and these components were suspended in toluene (2 mL) . The tube was sealed and heated to 1100C overnight, then cooled to room temperature and the mixture was filtered through celite to remove the solid. The filtrate was concentrated under vacuum and the residue was purified by silicagel column chromatography (10% Et2θ/DCM) to give N-(2~(4- ethoxybenzarαido) ethyl) -1- (3-hydroxyphenyl) -3- (trifluoromethyl) - lH-pyrazole-4-carboxamide (0.024 g, 19%) as a solid: 1H NMR (400
MHz, DMSO-d6) δ 1.39 (t, 3H, J = 7.0 Hz), 3.57 (m, 4H), 4.08 (qr 2H, J = 7.0 Hz), 6.85 (m, IH), 6.95 (d, 2H, J =19. O Hz), 7.20- 7.23 (m, 2H), 7.33 (m, IH), 7.78 (d, 2H, J = 9.0 Hz); m/z (APCI pos) 463.0 (10 %) (M+H) .
Compound of the following structure was prepared from N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxamide and 3-iodobenzonitrile, using a similar method to that described above.
Figure imgf000240_0001
Example S21 and Example S34
Methyl 2- (4- (2- (4-ethoxybenzamido) ethylcarbamoyl ) -3- (trifluoroπtethyl)-lH-pyrazol-l-yl)benzoate and 2- (4- ((2- (4- ethoxybenzamido) ethyl) carbamoyl) -3- (trifluoromethyl) -IH- pyrazol-1-yl) benzoic acid
Figure imgf000240_0002
To a 50 mL sealed tube were added N- (2- (4- ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxamide (0.200 g, 0.540 mmol) , (IR, 2R) -N1,N2- dimethylcyclohexane-1, 2-diamine (0.0154 g, 0.108 mmol), copper (I) iodide (0.00514 g, 0.0270 mmol), potassium carbonate (0.149 g, 1.08 mmol), and methyl 2-iodobenzoate (1.42 g, 5.40 mmol). "The mixture was stirred for 16 hours at 1100C, cooled to room temperature, and filtered through celite. The solvent was removed under vacuum and the residue was chromatographed on silica gel (9:0.5:0.5 DCM/EtOAc/MeOH) to give methyl 2-(4-((2- (4-ethoxybenzamido) ethyl) carbamoyl) -3- (trifluoromethyl) -IH- pyrazol~l-yl)benzoate (0.017 g, 6%) as a solid: 1H NMR (400 MHz,
J DMSO-de) δ 1.42 (t, 3H, J = 7.0 Hz), 3.65 (m, 4H), 3.70 (s, 3H), 4.05 (q, 2H, J = 7.0 Hz), 6.87 (d, 2H, J = 8.6 Hz), 7.20 (s, IH), 7.33 (s, IH), 7.43 (m, IH), 7.56 (m, IH), 7.63 (m, IH), 7.75 (d, 2H, J = 8.6 Hz), 7.94 (m, IH), 8.25 (s, IH); m/z (APCI pos) 505.0 (100 %) (M+H) . 0 The column was further eluted with 10% MeOH/DCM to give the corresponding acid analog. This compound was further purified by dissolving in IN NaOH and washing with EtOAc, followed by acidification of the aqueous layer with IN HCl, filtering the resulting solid, and drying under vacuum to gives 2- (4- ( (2- (4-ethoxybenzamido) ethyl) carbamoyl) -3-
(trifluoromethyl) -lH-pyrazol-1-yl) benzoic acid (40 mg, 15%) as a solid; 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, 3H, J = 7.0 Hz), 3.39 (m, 4H), 4.07 (q, 2H, J = 7.0 Hz), 6.96 (d, 2H, J = 9.0 Hz), 7.66 (m, 2H), 7.79 (m, 3H), 7.91 (m, IH), 8.45 (m, 2H),0 8.71 (s, IH), 13.26 (s, IH); m/z (APCI neg) 489.1 {100 %) (M+H)
Example S22
1- (2- (2- (Dimethylamino) ethoxy) phenyl) -N- (2- (4- ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4-5 carboxamide
Figure imgf000241_0001
To a solution of N- (2- (4-ethoxybenzamido) ethyl) -1- (2- hydroxyphenyl ) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.050 g, 0.11 mmbl) , 2- (dimethylamino) ethanol (0.0106 g, 0.120 mτnol), and tributylphosphine (0.0405 mL, 0.162 mmol) in THF was added 1, 1' - (azodicarbonyl) dipiperidine (ADDP, 0.0409 g, 0.16 mmol) . The mixture was stirred for 1 hour. Another 1 equivalent of alcohol, ADDP, and tributylphosphine were added and the mixture was stirred overnight. The solvent was then removed under vacuum, and the residue was purified by silica gel chromatography (9:0.5:0.5 DCM/EtOAc/MeOH) to give l-(2-(2- (dimethylamino) ethoxy) phenyl) -N- (2- (^÷ethoxybenzamido) ethyl) -3- {trifluoromethyl)-lH-pyrazole-4-carboxamide (0.028 g, 48% yield) as a solid after trituration with ether: 1H NMR (400 MHz,
DMSO-de) 6 1.33 (t, 3H, J = 7.0 Hz), 2.12 (s, 6H), 2.60 (t, 2H, J = 5.5 Hz), 3.39 (m, 4H), 4.07 (q, 2H, J = 7.0 Hz), 4.19 (t, 2H, J = 5.5 Hz), 6.96 (d, 2H, J = 9.0 Hz), 7.13 (m, IH), 7.33 <m, IH), 7.48 (mf IH), 7.63 (m, IH), 7.81 (d, 2H, J = 8.6 Hz), 8.41 (m, 2H), 8.82 (s, IH); m/z (APCI pos) 534.2 (100 %) (M+H) .
Compounds of the following structures were prepared from the corresponding phenols and alcohols, using a similar method to that described above.
Figure imgf000242_0001
Figure imgf000243_0001
Example S27 and Example S20
Ethyl 2- (2- (4- (2- (4-ethoxybenzamido) ethylcarbamoyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl) phenoxy) acetate and 2-(2-(4- (2- (4-ethoxybenzamido) ethylcarbamoyl) -3- (trifluoromethyl) -IH- pyrazol-1-yl) phenoxy) acetic acid
Figure imgf000244_0001
Step 1
To a mixture of N- (2- (4-ethoxybenzamido) ethyl) -1- (2- hydroxyphenyl ) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide "(0.100 g, 0.22 mmol), and potassium carbonate (60 mg, 0.43 mmol) in DMF (1 ml) was added ethyl 2-bromoacetate (0.024 ml, 0.22 mmol) . The mixture was stirred for 1 hour then filtered through a 0.45 μM acrodisc syringe filter (Pall Co.). The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (90:5:5 DCM/EtOAc/MeOH - 10% 7N ammonia in MeOH/DCM) to give ethyl 2- (2- (4- (2- (4- ethoxybenzamido) ethylcarbamoyl) -3- (trifluoromethyl) -lH-pyrazol- l-yl)phenoxy) acetate (0.089 g, 75%) as a solid: 1H NMR (400 MHz,
CDCl3) δ 1.28 (t, 3H, J = 7.0 Hz), 1.43 (t, 3H, J = 7.0 Hz), 3.70 (m, 4H), 4.07 (q, 2H, J = 7.0 Hz), 4.25 (q, 2H, J = 7.0 Hz), 4.73 (s, 2H), 6.84 (m, IH), 6.90 (d, 2H, J = 8.6 Hz), 6.96 (m, IH), 7.05 (m, IH), 7.16 (m, IH), 7.36 (m, IH), 7.76 (d, 2H, J = 9.0 Hz), 7.86 (m, IH), 8.98 (s, IH); m/z (APCI pos) 549.1 (20 %) (M+H) .
The compound of the following structure was prepared from N- (2- (4-ethoxybenzamido) ethyl) -Ir (3-hydroxyphenyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide and ethyl 2- bromoacetate using a similar method to that described above.
Figure imgf000245_0001
Step 2
To a solution of ethyl 2- (2- (4- (2- (4- ethoxybenzamido) ethylcarbamoyl) -3- (trifluoromethyl) -lH-pyrazol- l-yl)phenoxy) acetate (0.050 g, 0.091 mmol) in MeOH was added lithium hydroxide monohydrate (0.011 g, 0.27 mmol). The mixture was stirred for 3 hours. The solvent was removed in vacuo and the residue was taken up in water and acidified with 10% HCl to pH ~4. The solid precipitate was collected and dried under vacuum to give 2- (2- (4- (2- (4- ethoxybenzamido) ethylcarbamoyl) -3- { trifluoromethyl) -lH-pyrazol- l-yl)phenoxy) acetic acid (0.031 g, 65%) as a solid: 1H NMR (400
MHz, DMSO-de) δ 1.33 (t, 3H, J = 7.0 Hz)7 3.38 (m, 4H), 4.07 (q, 2H, J = 7.0 Hz), 4.88 (s, 2H), 6.96 (d, 2H, J = 8.6 Hz), 7.15
(m, IH), 7.22 (m, IH), 7.46 (m, IH), 7.65 (m, IH), 7.81 (d, 2H, J = 8.6 Hz), .8.44 (m, IH), 8.50 (m, IH), 8.85 (s, IH); m/z
(APCI neg) 519.1 (100 %) (M-H).
The compound of the following structure was prepared from ethyl 2- (3- (4- (2- (4-ethoxybenzamido) ethylcarbamoyl) -3-
{trifluoromethyl) -lH-pyrazol-1-yl) phenoxy) acetate using a similar method to that described above.
Figure imgf000246_0001
Example S30
1-Benzyl-N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -IH- pyrazole-4-carboxamide
Figure imgf000246_0002
To a solution of N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.1 g, 0.27 mmol) in DMF were added benzyl bromide (0.03533 ml, 0.30 mmol) and potassium carbonate (75 mg, 0.54 mmol) . The mixture was stirred for 16 hours at room temperature and filtered. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (9:0.5:0.5 DCM/EtOAc/MeOH) to give 1-benzyl-N- (2- (4-ethoxybenzamido) ethyl) -3- ( trifluoromethyl) -lH-pyrazole-4-carboxamide (0.105 g, 84%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, 3H, J = 7.0 Hz), 3.34 (s, 4H), 4.08 (q, 2H, J = 7.0 Hz), 5.45 (s, 2H), 6.96 (d, 2H, J = 9.0 Hz), 7.30-7.42 (m,. 5H), 7.79 (d, 2H, J = 9.0 Hz), 8.38 (m, 3H); m/z (APCI pos) 461.1 (100 %) (M+H).- Compounds of the following structures were prepared from N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole- 4-carboxamide and the corresponding alkyl halides, using a similar method to that described above.
Figure imgf000247_0001
Figure imgf000248_0001
IH ) , 8 . 40 (m, IH) ; m/z
(APCI pos) 481 . 1
( 100 % ) (M+H) .
Example S35
N- (2- (4-Ethoxybenzamidα) ethyl) -3-πvethyl-l-phenyl-lH-pyrazole-4- carboxamide ,
Figure imgf000249_0001
A mixture N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride (200 mg, 0.981 mmol) , DIPEA (349 mg, 2.697 mmol), HATU (373 mg, 0.981 mmol), and 3-methyl-l-phenyl-lH-pyrazole-4-carboxylic acid (165 mg, 0.817 mmol) (BuJl. Soc. Chim. Fra. 1988, 540-547) in THF (15 mL) was stirred at room temperature overnight. The reaction mixture was quenched by adding water (150 mL) . The obtained solid were filtered and washed with water and dried under high vacuum to give N- (2- (4-ethoxybenzamido) ethyl) -3- methyl-l-phenyl-lH-pyrazole-4-carboxamide (146 mg, 43%) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 2.43 (s, 3H), 3.39 (s, 4H), 4.05-4.10 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 7.4 Hz, IH), 7.52 (t, J = 7.9 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 8.12 (s, IH), 8.44 (s, IH), 8.83 (s, IH); m/z (APCI pos) 393 (M+H).
Example S36
N- (2- (4-Ethoxybenzamido) ethyl) -1- (2-hydroxycyclohexyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide
Figure imgf000250_0001
To a solution of N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.100 g, 0.27 itimol) in 7-oxa-bicyclo[4.1.0] heptane (0.265 g, 2.70 ramol) was added cesium carbonate (0.0176 g, 0.05 ramol) . The mixture was stirred for 16 hours at room temperature, and then heated at
500C for 16 hours. The mixture was then diluted with EtOAc and filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography
(9:0.5:0.5 DCM/EtOAc/MeOH) to give N- ( 2- ( 4- ethoxybenzamido) ethyl) -1- (2-hydroxycyclohexyl) -3-
(trifluoromethyl ) -lH-pyrazole-4-carboxamide (0.070 g, 55%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, 3H, J = 7.0 Hz), 1.33 (m, 3H), 1.74 (m, 3H), 1.96 (m, 2H), 3.36 (m, 4H), 3.62 (m, IH), 3.95 (m, IH), 4.08 (q, 2H, J = 7.0 Hz), 4.97 (d, IH, J = 5.8 Hz), 6.96 (d, 2H, J = 8.9 Hz), 7.81 (d, 2H, J = 8.9 Hz), 8.32 (m, 2H), 8.41 (m, IH); m/z (APCI pos) 469.1 (100 %) (M+H) .
Example S41
1-Cyclopentyl-N- (2- (4-ethoxybenzamido) ethyl) -3-
(trifluoromethyl) -lH-pyrazole-4-carboxamide
Figure imgf000250_0002
To a solution of N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.1 g, 0.27 mmol) in bromocyclopentane (2 ml, excess) was added sodium bicarbonate (0.045 g, 0.54 mmol) . The mixture was stirred for 16 hours at 1200C, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (9:0.5:0.5 DCM/EtOAc/MeOH) and recrystallized from EtOAc to give 1- cyclopentyl-N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) - lH-pyrazole-4-carboxamide (0.011 g, 9%) as a solid: 1H NMR (400 MHz, DMSO-de) δ 1.34 (t, 3H, J = 7.0 Hz), 1.67 (m, 2H), 1.78 (m, 2H), 1.90 (m, 2H), 2.12 (m, 2H), 3.35 (m, 4H), 4.08 (q, 2H, J = 7.0 Hz), 4.78 (m, IH), 6.96 (d, 2H, J = 8.9 Hz), 7.80 (d, 2H, J = 8.9 Hz), 8.31 (s, IH), 8.39 (s, IH), 8.41 (s, IH); m/z (APCI pos) 439.1 (100 %) (M+H) .
Example S42
1-Cyclohexyl-N- (2- (4-ethoxybenzamido) ethyl) -3-
( trifluoromethyl ) -lH-pyrazole-4-carboxamide
Figure imgf000251_0001
To a solution of N- (2- (4-ethoxybenzamido) ethyl) -3-
(trifluoromethyl) -lH-pyrazole-4-carboxamide (0.1 g, 0.27 mmol) in bromocyclohexane (0.44 g, 2.70 mmol) was added potassium carbonate (0.11 g, 0.81 mmol). The mixture was stirred for 16 hours at 1200C. The mixture was diluted with EtOAc and filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (9:0.5:0.5 DCM/EtOAc/MeOH) then recrystallized from ethyl acetate to give 1-cyclohexyl-N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.030 g, 25%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 1.23 (m, IH), 1.34 (t, 3H, J = 7.0 Hz), 1.43 (m, 2H), 1.65 (m, 2.5H), 1.77-1.90 (m, 2.5H), 2.05 (m, 2H), 3.36 (m, 4H), 4.08 (q, 2H, J = 7.0 Hz), 4.24 (m, IH), 6.96 (d, 2H, J = 8.9 Hz), 7.80 (d, 2H, J = 8.9 Hz), 8.31 (s,' IH), 8.39 (s, IH), 8.40 (s, IH); m/z (APCI pos) 453.1 (100 %) (M+H) .
Example S43 N- (2- (4-Ethoxybenzamido) ethyl) -1- ( (tetrahydro-2H-pyran-2- yl)methyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxaiαide
Figure imgf000252_0001
To a solution of N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.100 g, 0.27 mmol) in DMF (1 ml) was added NaH (0.0119 g, 0.30 mmol) . The mixture was stirred until the gas evolution ceased, about 30 min, and 2- (bromomethyl) -tetrahydro-2H-pyran (0.0346 ml, 0.27 mmol) was added. The mixture was stirred for 16 hours at room temperature, and the mixture was heated at 800C for 2 h, then cooled to room temperature. Methanol was added (1 ml), the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (3% MeOH/DCM) to give N- (2- (4- ethoxybenzamido) ethyl) -1- ( (tetrahydro-2H-pyran-2-yl)methyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (0.025 g, 20%) as a solid: 1H NMR (400 MHz, CDCl3) δ 1.43 (t, 3H, J = 7.0 Hz), 1.52 (Si1 3H), 1.61 (m, IH), 1.86 (m, IH), 3.36 (m, IH), 3.66 (m, 6H), 3.94 (m, IH), 4.05-4.11 (m, 3H), 4.19 (m, IH), 6.69 (m, IH) , 6.91 (d, 2H, J = 8.9 Hz), 6.94 (m, IH), 7.75 (d, 2H, J = 8.9 Hz), 7.98 (m, IH); m/z (APCI pos) 469.1 (100 %) (M+H) .
The compounds of the following structures were prepared from N- (2- (4-ethoxybenzamido) ethyl ) -3- (trifluoromethyl) -IH- pyrazole-4-carboxamide and the corresponding alkyl halides, using a similar method to that described above.
Figure imgf000253_0002
Ethyl 6-ethoxy-2 , 4 -dimethylnicotinate
Figure imgf000253_0001
Step 1
(E) -Ethyl 3-aminobut-2-enoate (2.53 g, 19.6 mmol) in toluene (15 mL) was charged with 4N HCl (10 mL, 40 mmol) in dioxane. The mixture was stirred at 115°C overnight. The solution was cooled and the solid was filtered off washing with toluene. The filtrate was concentrated and the residue was purified by silica gel column chromatography (5% MeOH/EtOAc) to afford ethyl 2, 4-dimethyl-6-oxo-l, 6-dihydropyridine-3- carboxylate (1.11 g, 29%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.37 (t, J = 6.8 Hz, 3H)/ 2.29 (s, 3H), 2.47 (s, 3H), 4.33 (q, J = 7.6, 14.4 Hz, 2H), 6.25 (s, IH); m/z (APCI pos) 196.1 (100%) (M+H) .
Step 2
Ethyl 2, 4-dimethyl-6-oxo-l, 6-dihydropyridine-3-carboxylate (1.11 g, 5.69 mmol) was dissolved in DMF (5 itiL) . NaH (0.478 g, 19.9 mmol) was added and mixture was stirred for 30 minutes. Ethyl iodide (4.43 g, 28.4 mmol) was added and mixture was stirred at room temperature for 4 hours. The solution was quenched with water, extracted with EtOAc, dried, and concentrated. Flash chromatography on silica gel (5% EtOAc/hexanes) gave ethyl 6-ethoxy-2, 4-dimethylnicotinate as a clear oil (0.69 g, 54%): m/z (APCI pos) 224.1 (100%) (M+H).
Ethyl 2-chloro-6-ethoxynicotinate
Figure imgf000254_0001
' 2-Chloro-6-oxo-l, 6-dihydropyridine-3-carboxylic acid (3.00 g, 17.3 mmol, prepared according to procedure described in Ger. Offen. (1972) DE 2157289) was dissolved in DMF (10 mL) . NaH (1.53 g, 60.5 mmol) was added and the mixture was stirred for 30 minutes. Ethyl iodide (13.5 g, 86.4 mmol) was added and the mixture was stirred at room temperature overnight. The solution was quenched with water and extracted with EtOAc, dried, and concentrated. Flash chromatography on silica gel (5% EtOAc/hexanes) gave ethyl 2-chloro-6-ethoxynicotinate (2.17 g, 55%) as an oil: 1H NMR (400 MHz, CDCl3) δ 1.38 - 1.42 (m, 6H), 4.36 - 4.41 (m, 4H), 6.66 (d, J = 8.0 Hz, IH), 8.11 (d, J = 8.4 Hz, IH) .
Ethyl 6-ethoxy-2-propylnicotinate
Figure imgf000255_0001
Ethyl 2-chϊoro-6-ethoxynicotinate (0.50 g, 2.18 mmol) and PdCl2(dppf) dichloromethane adduct (0.089 g, 0.11, mmol) were dissolved in THF (30 mL) under argon. Propylzinc (II) bromide (10.9 mL, 5.44 mmol, 0.5M in THF) was added and the solution was stirred under argon at 600C for 150 minutes. The solution was cooled and filtered through a silica plug rinsing with EtOAc. The solution was concentrated and the residue was purified by silica gel column chromatography (4% EtOAc/hexanes) to give ethyl 6-ethoxy-2-propylnicotinate as an oil (0.378 g, 73%): m/z (APCI pos) 238.1 (100%) (M+H) .
Ethyl 4, 6-dipropylnicotinate
Figure imgf000255_0002
Ethyl 4, 6-dichloronicotinate (1.00 g, 4.54 mmol) and
PdCl2 (dppf) dichloromethane adduct (0.187 g, 0.227 mmol) were added together in THF (35 mL) under argon. Propylzinc (II) bromide (36.4 ml, 18.2 mmol, 0.5M in THF) was then added. The mixture was stirred under argon at 65°C for 180 minutes. The solution was filtered through a silica gel plug (rinsing with EtOAc) , and dried, and concentrated. Flash chromatography on silica gel (20 - 40% EtOAc/hexanes) gave ethyl 4, 6- dipropylnicotinate (0.49O g, 46%) as a brown oil: m/z (APCI pos) 236.2 (100%) (M+H).
Ethyl 3- (bis (tert-butoxycarbonyl) amino) -l-phenyl-lH-pyrazole-4- carboxylate
Figure imgf000256_0001
To a mixture of ethyl 3~amino-l-phenyl-lH-pyrazole-4- carboxylate (5.00 g, 21.62 mmol) (J. Het. Chem. 1967, 4, 325) in THF (50 inL) were added triethylamine (6.03 mL, 43.24 mmol) ,
S B0C2O (5.66 g, 25.95 mmol) and 50 mg of DMAP and the mixture was heated at 500C for 2 hours and then at room temperature overnight. Water and EtOAc were added and the layers were separated. The organics were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The obtained0 residue was purified on silica gel (20% EtOAc/hexanes) to give ethyl 3- (bis (tert-butoxycarbonyl) amino) -l-phenyl-lH-pyrazole-4- carboxylate (2.11 g, 30%) as a solid: 1H NMR (400 MHz, CDCl3) δ
1.35 (t, J = 7.1 Hz, 3H), 1.45 (s, 18H), 4.27-4.33 (m, 2H),
7.36 (t, J = 7.4 Hz, IH), 7.48 (t, J = 7.9 Hz, 2H), 7.69 (d, J5 = 7.8 Hz, 2H), 8.41 (s, IH); m/z (APCI pos) 331 (40%) (M+H-Boc)
Ethyl 3- (dimethylamino) -l-phenyl-lH-pyrazole-4-carboxylate
Figure imgf000256_0002
A THF (40 ml) solution of ethyl 3-amino-l-phenyl-lH-0 pyrazole-4-carboxylate (2.50 g, 10.81 mmol) was cooled in an ice bath and treated with NaH (0.6486 g, 27.03 mmol). This mixture was allowed to stir 30 minutes and then methyl iodide (1.619 ml, 25.95 mmol) was added. The mixture was allowed to warm, to room temperature and stirred for 6 hr. The mixture was5 then quenched with water, dissolved in EtOAc and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc, and the organics were combined, washed with water, dried over NaaSO^ and concentrated to a residue. The residue was purified by silica gel column chromatography (10% EtOAc/hexanes) to give ethyl 3- (dimethylamino) -1-phenyl-lH- pyrazole-4-carboxylate (0.260 g, 9%) : 1H NMR (400 MHz, CDCl3) δ s 1.37 (t, J = 7.1 Hz, 3H), 3.01 (s, 6H), 4.28-4.34 (m, 2H), 7.26 (t, J = 7.4 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 2H), 7.65-7.67 (m, 2H), 8.29 (s, IH); m/z (APCI pos) 260 (M+H) .
6- (Ethoxycarbonyl) nicotinic acid
Figure imgf000257_0001
To a mixture of pyridine-2, 5-dicarboxylic acid (30.00 g, 179.51 mmol) in ethanol (380 ml, 179.51 mmol) was slowly added sulfuric acid (3.00 ml, 56.28 mmol) and the mixture was heated to reflux for 7 hours. The solution was cooled in an ice bath 5 and diluted with water (400 mL) . The resulting suspension was stirred overnight at room temperature. The solid was filtered and washed with water. The solid was triturated in 300 ml of refluxing EtOH for 2 hours and then cooled in an ice bath and the solid was filtered to give 6- (ethoxycarbonyl) nicotinic acid 0 (16.05 g, 46% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.29 (t, J = 7.0 Hz, 3H), 4.29-4.35 (m, 2H), 8.10 (d, J = 8.0 Hz, IH), 8.39 (d, J - 8.2 Hz, IH), 9.11 (s, IH) .
Ethyl 3-isoρropyl-l-phenyl-lH-pyrazole-4-carboxylate
Figure imgf000257_0002
Step 1 A mixture of ethyl 4-methyl-3-oxopentanoate (25.00 g, 158.0 mmol) , triethyl orthoforrαate (46.84 g, 316.1 mmol) and acetic anhydride (75 ml, 794.9 mmol) was heated to reflux overnight. The volatiles were distilled off at 85°C under high vacuum. The crude material was taken on to the next step without further purification.
Step 2
To a mixture of the above crude (E/Z) -ethyl 2- (ethoxymethylene) -4-methyl-3-oxopentanσate (33.86 g, 158.0 mmol) in MeOH (500ml) was slowly added hydrazine monohydrate (15.33 ml, 316.1 mmol). The mixture was heated to reflux for 3 hours then cooled and concentrated to a residue. EtOAc (250 ml) was added and the organic layer was washed with water and brine, dried over Na∑SO,}, and concentrated to a residue that solidified upon standing to give ethyl 3-isopropyl-lH-pyrazole-
4-carboxylate (25.42 g, 88% yield): 1H NMR (400 MHz, CDCl3) δ 1.33-1.38 (m, 9H), 3.65-3.75 (m, IH), 4.28-4.33 (m, 2H), 7.96 (s, IH), 11.82 (br, IH); m/z (APCI pos) 183 (M+H) .
Step 3
To a 100 ml sealed tube flushed vigorously with nitrogen were added ethyl 3-isopropyl-lH-pyrazole-4-carboxylate (5.00 g, 27.4 mmol), 1-iodobenzene (3.67 ml, 32.9 mmol), K2CO3 (7.96 g, 57.6 mmol), copper (I) iodide (0.261 g, 1.37 mmol), and (1S,2S)- Nl,N2-dimethylcyclohexane-l,2-diamine (0.390 g, 2.74 mmol), followed by degassed toluene (25 ml) . The mixture was stirred for 24 hours at 1100C. The mixture was cooled to room temperature, and filtered through a short silica pad eluting with 25% EtOAc/hexanes . The filtrate was concentrated under high vacuum to give crude ethyl 3-isopropyl-l-phenyl-lH- pyrazole-4-carboxylate (2.31 g, 33%) that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 1.35-1.39 (m, 9H), 3.56-3.63 (m, IH), 4.29-4.35 (m, 2H), 7.26-7.42 (m, IH), 7 . 45 (t, J = 8 . 0 Hz , 2H) , 7 . 70 (d, J = 7 . 4 Hz, 2H) , 8 . 33 ( s , IH) ; m/z (APCI neg) 259 ( 100%) (M+H) .
Ethyl 3-methoxy-l~phenyl-lH-pyrazole-4-carboxylate
Figure imgf000259_0001
Step 1
Diethyl 2- (ethoxymethylene) malonate (28.80 g, 133.2 mmol) was added to N' -phenylacetohydrazide (20.00 g, 133.2 mmol) in
POCI3 (200 itiL) and the mixture was stirred at 70°C overnight 10 under nitrogen. The mixture was then cooled and carefully quenched over ice water (500 ml) to give a solution which was cooled to -100C. The resulting sticky brown solid was filtered, dissolved in DCM and dried on Na2SO4 then concentrated. The residue was purified by silica gel column chromatography (25% /5 EtOAc/hexanes ) to give ethyl 3-oxo-l-phenyl-2, 3-dihydro-lH- pyrazole-4-carboxylate (3.71 g, 12% yield) : 1H NMR (400 MHz,
CDCl3) δ 1.39 (t, J = 7.1 Hz, 3H), 4.35-4.41 (m, 2H), 7.31 (t, J = 7.4 Hz, IH), 7.45 (t, J = 8.0 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 8.12 (s, IH), 8.18 (s, IH); m/z (APCI pos) 233 (M+H) .
20
Step 2
To a mixture of ethyl 3-oxo-l-phenyl-2/ 3-dihydro-lH- pyrazole-4-carboxylate (0.750 g, 3.229 mmol) in DMF (5 inL) was added potassium carbonate (1.34 g, 9.6 mmol) followed by methyl
25 iodide (0.3 ml, 4.8 mmol) and the mixture was stirred at 400C for 3 hours. The mixture was quenched with water and the solids were filtered, washed with water and dried under high vacuum to give ethyl 3-methoxy-l-phenyl-lH-pyrazole-4- carboxylate (0.620 g, 78%): 1H NMR (400 MHz, CDCl3) δ 1.36 (t, J 30 = 7.1 Hz, 3H), 4.09 (s, 3H), 4.30-4.35' (m, 2H), 7.29 (t, J =
7.4 Hz, IH), 7.45 (t, J == 8.0 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 8.24 (s, IH). m/z (APCI pos) 247 (M+H). The compound of the following structure was prepared from ethyl 3-oxo-l-phenyl-2,3-dihydro-lH-pyrazole-4-carboxylate and benzyl bromide according to the above procedure.
Figure imgf000261_0001
Methyl l-methyl-S-phenyl-lH-pyrazole-S-carboxylate and methyl l-methyl -S-phenyl-lH-pyrazole-S-carboxylate
Figure imgf000261_0002
Methyl 2, 4-dioxo-4-phenylbutanoate (8.25 g, 40.0 imuol ) was dissolved in EtOH (50 mL) and 1-methylhydrazine (1.84 g, 40.0 mmol) was added dropwise. The resulting solution was heated at reflux for 5 hours then cooled to room temperature and concentrated to a residue. The obtained residue was purified by silicagel column chromatography (10% EtOAc/petroleum ether - 25% EtOAc/petroleum ether) . The first spot to elute was methyl l-methyl-3-phenyl-lH-pyrazole-5-carboxylate (2.84 g, 33 %) as a white solid. The next spot to elute was the regioisomer methyl l-methyl-δ-phenyl-lH-pyrazole-S-carboxylate (1.5 g, 17%) as a yellow oil . methyl l-methyl-3-phenyl-lH-pyrazole-S-carboxylate : 1H NMR (400
MHz, CDCl3) δ 3.91 (s, 3H), 4.23 (s, 3H), 7.12 (s, IH), 7.32 (t, J = 7.3 Hz, IH), 7.41 (t, J = 7.5 Hz, 2H), 7.79 (d, J = 7.0 Hz, 2H); m/z (APCI pos) 217 (100%) (M+H). methyl l-methyl-5-phenyl-lH~pyrazole-3-carboxylate: 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 3.96 (s, 3H), 6.86 (s, IH)7 7.41- 7.51 (m, 5H); m/z (APCI pos) 217 (100%) (M+H) .
l-Methyl-S-phenyl-lH-pyrazole-S-carboxylic acid
Figure imgf000262_0001
Methyl l-methyl-3-phenyl-lH-pyrazole-5-carboxylate (1.0Og, 6.23 iranol) was dissolved in EtOH (10 inL) and water (10 mL) then lithium hydroxide monohydrate (0.582 g, 13.87 mmol) was added. The mixture was stirred at 500C until complete by HPLC. The mixture was concentrated to a residue, water was added and the mixture was extracted with DCM. The aqueous layer was acidified using IN HCl and the resulting solid was filtered and dried under high vacuum to give l-methyl-3-phenyl-lH-pyrazole- 5-carboxylic acid (0.887 g, 95%) as a white solid; m/z (APCI pos) 203 (100%) (M+H) .
The compound of the following structure was prepared from the corresponding ester using a similar method to that described above.
Figure imgf000262_0002
N- (2-Aminoethyl) -l-phenyl-3- ( trifluoromethyl) -lH-pyrazole-4- carboxamide
Figure imgf000263_0001
A mixture of ethyl l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxylate (6.60 g, 23.2 mmol) and ethylenediamine (50 ml, 23.2 mmol) was heated at reflux for 3 hours. The mixture was concentrated under reduced pressure to a residue. To the residue was added toluene (50 mL) that was concentrate off, twice. The crude solid was dried under high vacuum overnight to give N- (2-aminoethyl) -l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamide (6.9 g, 99% yield) as a light tan solid. The desired product may also be isolated as the hydrochloride salt by dissolving in minimal DCM and adding IN HCl in Et2θ (3-5 molar equivalents) dropwise, filtering the solid and washing with Et2θ. 1H NMR (Free base analog) (DMSO-d6) δ 1.83 (br, 2H), 2.68 (t, J = 6.3 Hz, 2H), 3.21-3.26 (m, 2H), 7.47 (t, J = 7.4 Hz, IH), 7.60 (t, J = 8.0 Hzr 2H), 7.84 (d, J = 7.8 Hz, 2H), 8.29-8.30 (m, IH), 9.11 (s, IH); m/z (APCI pos) 299 (60%) (M+H) .
N- (2-Aminoethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide
Figure imgf000263_0002
Step 1
To a solution of 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (0.507 g, 2.29 mmol), EDAC-HCl (0.483 g, 2.52 mmol), and HOBt-H2O (0.386 g," 2.52 mmol) in DMF (5 ml) was added tert-butyl 2-aminoethylcarbamate (0.404 g, 2.52 mmol). The solution was stirred for 16 h at room temperature, diluted with EtOAc (100 ml) and washed with water (3X) , saturated aqueous sodium bicarbonate, and brine. The aqueous layer was back extracted and the combined organic layers were dried (sodium sulfate), and concentrated in vacuo to give tert-butyl 2- (6- (2, 2, 2- trifluoroethoxy) nicotinamide) ethylcarbamate (0.700 g, 84%) as a solid after trituration with ether: 1H NMR (CDCl3) δ 1.37 (s, 9H), 3.10 (m, 2H), 3.28 (m, 2H), 5.06 (q, 2H, J = 8.9 Hz), 6.91 5 <m, IH), 7.07 (d, IH, J = 8.6 Hz), 8.19 (m, IH), 8.54 (m, IH), 8.65 (m, IH) .
Step 2
To a solution of tert-butyl 2- (6- (2,2,2-
10 trifluoroethoxy) nicotinamide) ethylcarbamate (0.700 g, 1.93 mmol) in DCM (10 ml) was added TFA (1.48 ml, 19.30 mmol) . The mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo to give the product as the TFA salt, which was an intractable oil that partially crystallized
/J overnight. This material was dissolved in DCM and treated with saturated aqueous sodium bicarbonate . The aqueous layer was extracted multiple times with EtOAc. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo to give N- (2-aminoethyl) -6- (2, 2, 2-trifluoroethσxy) nicotinamide
20 (0.458 g, 90%) as an oil: 1H NMR (CDCl3) δ 3.00 (m, 2H), 3.50 (m, 2H), 5.07 (q, 2H, J = 8.9 Hz), 7.11 (m, IH), 7.84 (br, 2H), 8.22 (m, IH), 8.69 (m, IH), 8.72 (m, IH).
N- (2-Aminoethyl) -6- (2,2, 2-trifluoroethoxy) nicotinamide 25 hydrochloride
Figure imgf000264_0001
To a solution of tert-butyl 2- (6- (2, 2, 2- trifluorσethoxy) nicotinamide) ethylcarbamate (8.2 g, 23 mmol) in EtOAc was added hydrogen chloride (17 ml, 68 mmol, 4.0 M in 30 dioxane) . The solution was stirred overnight. A white solid was observed in the reaction mixture. The solid was collected by filtration and dried in vacuo to give N- (2-aminoethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride (6.8 g, 100%) as a solid: 1H NMR (400 MHz, DMSO-de) δ 2.99 (q, 2H, J = 6.2 Hz), 3.52 (q, 2H, J = 6.2 Hz) , 5.07 (q, 2H, J = 8.9 Hz) , 7.09 (m, IH), 8.03 (br, 3H) , 8.28 (m, IH), 8.75 (m, IH), 8.89 (m, IH) .
1- (Pyridin-2-ylmethyl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxylic acid
Figure imgf000265_0001
Step 1
To a solution of ethyl 3- (trifluoromethyl) -lH-pyrazole-4- carboxylate (10.0 g, 48.00 mmol) in DMF were added 2-
(bromomethyl) pyridine hydrobromide (13.4 g, 52.80 mmol) and potassium carbonate (13.3 g, 96.1 mmol). The mixture was stirred for 16 hours at room temperature and filtered. The solid was dried under vacuum to give ethyl 1- (pyridin-2- ylmethyl) -3- ( trifluoromethyl) -lH-pyrazole-4-carboxylate (12.5 g,
87%) as crystals: 1H NMR (CDCl3) δ 1.34 (t, 3H, J = 7.0 Hz), 4.32 (q, 2H, J = 7.0 Hz), 5.45 (s, 2H), 7.22 (d, IH, J = 7.8 Hz), 7.29 (m, IH), 7.72 (m, IH), 8.16 (s, IH), 8.61 (m, IH)..
Step 2
To a solution of ethyl 1- (pyridin-2-ylmethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxylate (0.273 g, 0.912 mmol) in THF was added 2N NaOH (1.37 ml, 2.74 mmol). Ethanol , was added to achieve homogeneity. The mixture was stirred for 4 hours, concentrated under vacuum, and diluted with water. Acidification to pH 3 gave a precipitate, which was filtered and dried under vacuum to give 1- (pyridin-2-ylmethyl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.203 g, 82%) as a solid: m/z (APCI neg) 226.0 (100 %) (M-CO2).
1- (Phenylsulfonyl) -lH-indole-3-carboxylic acid
Figure imgf000266_0001
To a solution of lH-indole-3-carboxylic acid (0.500 g, 3.10 itimol) in DMF at 00C was added sodium hydride (0.2606 g, 6.52 mmol) . After the gas evolution ceased (30 iriin) , benzenesulfonyl chloride (0.792 ml, 6.20 mmol) was added. The mixture was stirred for 16 hours, then partitioned between IM H3PO4 (aq.) and EtQAc. The organic layer was dried (sodium sulfate) and concentrated in vacuo and the residue was triturated with ether to give 1- (phenylsulfonyl) -lH-indole-3- carboxylic acid (0.254 g, 27%) as a solid: m/z (APCI neg) 256.0 (100 %) (M-CO2) .
The compound of the following structure was prepared by reacting lH-indole-3-carboxylic acid and benzoyl chloride using the procedure outlined above .
Figure imgf000266_0002
Ethyl 1- (lH-indol-5-yl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxylate
Figure imgf000267_0001
To a solution of ethyl 3- {trifluoromethyl) -lH-pyrazole-4- carboxylate (0.208 g, 1.0 mmol) in DMF were added lH-indol-5- ylboronic acid (0.322 g, 2.00 mmol), Cu(OAc)2 (0.136 g, 0.75 rninol)/ and pyridine (0.162 ml, 2.00 mmol) and the mixture was stirred at room temperature for 3 days . The mixture was diluted with DCM and filtered through a pad of silica gel. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (3:1 hexanes/EtOAc) to give ethyl 1- (lH-indol-5-yl) -3- (trifluoromethyl) -lH-pyrazole-4- carboxylate (0.313 g, 97%) as a solid: 1H NMR (CDCl3) δ 1.39 (t, 3H7 J = 7.0 Hz), 4.37 <q, 2H, J = 7.0 Hz), 6.64 (m, IH), 7.34 (m, IH), 7.51 (m, 2H), 7.93 (m, IH), 8.46 (m, IH).
Compounds of the following structures were made from ethyl 3- (trifluoromethyl) -lH-pyrazole-4-carboxylate and the corresponding boronic acids according to the above procedure.
Figure imgf000267_0002
Figure imgf000268_0001
Ethyl 1- (2-hydroxyphen.yl ) -3- (trif luoroinethyl ) -lH-pyra zole- 4- carbσxylate
Figure imgf000268_0002
According to the procedure of Buchwald et al . (J". Org. Chem. 2004, 69, 5578), to a 50 mL sealed tube flushed with argon were added copper(I) iodide (0.02288 g, 0.1201 mmol), potassium carbonate (0.6972 g, 5.045 mmol), and ethyl 3- (trifluoroinethyl) -lH-pyrazole-4-carboxylate (0.500 g, 2.402 mmol). (IS, 2S) -N1,N2-Dimethylcyclohexane-1, 2-diamine (0.06834 g, 0.4805 mmol) and 2-bromophenol (0.3343 ml, 2.883 mmol) were then added along with 3 ml of toluene. The tube was sealed and heated to 1100C overnight, then cooled to room temperature, the mixture was filtered through celite to remove the solid. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (10% Et2θ/DCM) to give ethyl 1- (2-hydroxyphenyl) -3- (trifluoromethyl) -lH-pyrazole- 4-carboxylate (0.660 g, 91%) as a solid: 1H NMR (CDCl3) δ 1.40 (t, 3H, J = 7.0 Hz)7 4.39 (q, 2H, J = 7.0 Hz), 7.00 (m, IH) , 7.16 (m, IH) , 7.31 (m, IH) , 7.42 (m, IH), 8.56 (m, IH) .
Compounds of the following structures were prepared from ethyl 3- (trifluoromethyl) -lH-pyrazole-4-carboxylate and the corresponding bromide or iodide, using a similar method to that described above. i
Figure imgf000269_0001
1- (lH-Indol-5-yl) -3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid
Figure imgf000270_0001
To a solution of ethyl 1- (lH-indol-5-yl) -3-
(trifluoromethyl) -lH-pyraEole-4-carboxylate (0.313 g, 0.968 mmol) in EtOH (20 ml) and THF (5 ml) was added 2M NaOH (1.45 ml, 2.90 mmol). The mixture was refluxed until TLC indicated complete consumption of ester, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in water and washed with ether. The aqueous layer was then adjusted to pH ~4 with 10% aq. HCl. The solid was collected by filtration and dried under vacuum to give 1- (lH-indol-5-yl) -3- (trifluoromethyl)-lH-pyrazole-4-carboxylic acid (0.220 g, 77%) as a powder: 1H NMR (400 MHz, CDCl3) δ 6.55 (m, IH), 7.52 (m, 2H), 7.62 (m, IH), 8.06 (m, IH), 9.08 (s, IH), 11.39 (br, IH), 13.10 (br, IH) .
Compounds of the following structures were prepared from the corresponding esters using a similar method to that described above.
Figure imgf000270_0002
Figure imgf000271_0001
Figure imgf000272_0003
N- (2-Aminoethyl) -4-ethoxybenzamide hydrochloride
Figure imgf000272_0001
Ethyl 4-ethoxybenzoate (25.4Og, 141.0 mmol) was dissolved in ethylenediamine (200 ml) and the mixture was heated at reflux for 40 hours. The mixture was concentrated under reduced pressure to a residue. The obtained residue was dissolved in DCM (100 mL) and Et2O (200 iriL) , and IN HCl in Et2O (200 mL) was added. The obtained solid was filtered, washed with DCM and dried under high vacuum to give N- {2-aminoethyl) - 4-ethoxybenzamide hydrochloride (31.78 g, 92%) as a tan solid:
1H NMR (400 MHz, CDCl3) δ 1.43 (t, J = 7.0 Hz, 3H), 2.92 (t, J = 5.9 Hz, 2H), 3.49 (t, J = 5.9 Hz, 2H), 4.05-4.10 (m, 2H), 6.88- 6.92 (m, 2H), 7.74-7.78 (m, 2H); m/z (APCI pos) 209 (M+H) .
l-Phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid
Figure imgf000272_0002
Step 1 According to the procedure of Buchwald et al. [J. Org. Chem. 2004, 6"S, 5578), to a 350 mL sealed tube flushed vigorously with nitrogen were added ethyl 3- (trifluoromethyl) - lH-pyrazole-4-carboxylate (20.0 g, 96.1 ramol) , 1-iodobenzene s (12.9 ml, 115 mmol) , potassium carbonate (27.9 g, 202 mmol), copper (I) iodide (0.915 g, 4.80 mmol), and (IS, 2S) -N1,N2- dimethylcyclohexane-l,2-diamine (1.37 g, 9.61 mmol), followed by degassed toluene (100 ml) . The mixture was stirred for 24 hours a.t 1100C7 cooled to room temperature, and filtered througho a short silica pad which was rinsed with toluene and EtOAc thoroughly. The filtrate was concentrated in vacuo to give ethyl l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylate
(21 g, 77%) as a solid: 1H NMR (400 MHz, CDCl3) δ 1.39 (t, 3H, J = 7.0 Hz), 4.37 (q, 2H, J = 7.0 Hz), 7.42 (m, IH), 7.52 (m, 2H),5 7.72 (m, 2H), 8.48 (m, IH).
Step 2
To a solution of ethyl l-phenyl-3- {trifluoromethyl) -IH- pyrazole-4-carboxylate (0.800 g, 2.81 mmol) in EtOH (20 ml) and0 THF (5 ml) was added 2N NaOH (1.69 ml, 8.44 mmol). The mixture was refluxed until TLC indicated completion, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in water and washed with ether. The aqueous layer was then adjusted to pH ~4 with 10% HCl. The solid was 5 collected by filtration and dried under vacuum to give 1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.560 g, 78%) as a powder: 1H NMR (400 MHz7 DMSO-d6) δ 7.47 (m, IH), 7.58 (m, 2H), 7.94 (m, 2H), 9.24 (br, IH); m/z 254.9 (APCI neg) (100%) (M-H) . 0
N- (2- (4-Ethoxybenzamido) ethyl) -3- (trifluoromethyl) -lH-pyrazole- 4-carboxamide
Figure imgf000274_0001
To N- (2-aminoethyl) -4-ethoxybenzamide hydrochloride (1.58 g, 6.44 mmol) in DCM (50 mL) were added successively 3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid {1.16 g, 6.44 J mmol), EDAC-HCl (1.61 g, 8.37 mmol), HOBt-H2O (1.22 g, 9.02 mmol) and triethylamine (1.3 g, 12.9 mmol). The mixture was stirred at room temperature for 12 hours then concentrated. The residue was purified by chromatography (DCM/MeOH 90/10) to yield N- (2- (4-ethoxybenzamido) ethyl) -3- (trifluoromethyl) -IH-0 pyrazole-4-carboxamide as a tan solid (1.87 g, 79%): 1H NMR (400 MHz, DMSO-de) δ 1.34 (t, 3H, J = 7.0 Hz), 3.37 (m, 4H), 4.07 (q, 2H, J = 7.0 Hz), 6.97 (m, 2H), 7.81 (m, 2H), 8.34 (m, 2H), 8.42 (m, IH); m/z 369.2 (APCI neg) (100%) (M-H) . 5 Formulation Example 1 (production of capsules)
1) compound of Example Al 30 mg
2) fine cellulose powder 10 mg
3) lactose 19 mg
4) magnesium stearate 1 mg 0 total 60 mg
1), 2), 3) and 4) are mixed and filled in gelatin capsules.
Formulation Example 2 (production of tablets)
1) compound of Example Al 30 g 5 2) lactose 50 g
3) corn starch 15 g
4) carboxymethylcellulσse calcium 44 g
5) magnesium stearate 1 g total of 1000 tablets 140 g 0 The entire amounts of 1), 2) and 3), and 30 g of 4) are kneaded with water, dried in vacuo and granulated. The granules are mixed with 14 g of 4) and 1 g of 5) and the mixture is compressed with a tableting machine, whereby 1000 tablets containing 30 mg of compound of Example Al per tablet are obtained.
Formulation Example 3 (production of capsules)
1) compound of Example Bl 30 mg
2) fine cellulose powder 10 mg
3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg
1), 2), 3) and 4) are mixed and filled in gelatin capsules.
Formulation Example 4 (production of tablets) 1) compound of Example Bl 30 g
2) lactose • 50 g
3) corn starch 15 g
4) carboxymethylcelltilose calcium 44 g
5) magnesium stearate 1 g total of 1000 tablets 140 g •
The entire amounts of 1), 2) and 3), and 30 g of 4) are kneaded with water, dried in vacuo and granulated.
The granules are mixed with 14 g of 4) and 1 g of 5) and the mixture is compressed with a tableting machine, whereby 1000 tablets containing 30 mg of compound of Example Bl per tablet are obtained.
Formulation Example 5 (production of capsules)
1) compound of Example Cl 30 mg 2) fine cellulose powder 10 mg
3) lactose 19 mg
4) magnesium stearate 1 mg
"total 60 mg
1), 2), 3) and 4) are mixed and filled in gelatin capsules, Formulation Example 6 (production of tablets)
1) compound of Example Cl 30 g
2) lactose 50 g
3) corn starch 15 g 4) carboxymethylcellulose calcium 44 g
5) magnesium stearate 1 q total of 1000 tablets 140 g
The entire amounts of 1), 2) and 3), and 30 g of 4) are kneaded with water, dried in vacuo and granulated. The granules are mixed with 14 g of 4) and 1 g of 5) and the mixture is compressed with a tableting machine, whereby 1000 tablets containing 30 mg of compound of Example Cl per tablet are obtained.
Formulation Example 7 (production of capsules)
1) compound of Example Dl 30 mg
2) fine cellulose powder 10 mg
3) lactose . 19 mg
4) magnesium stearate 1 mg total 60 mg
1), 2), 3) and 4) are mixed and filled in gelatin capsules
Formulation Example 8 (production of tablets)
1) compound of Example Dl 30 g Z) lactose 50 g
3) corn starch 15 g
4) carboxymethylcellulose calcium 44 g
5) magnesium stearate 1 g total of 1000 tablets 140 g The entire amounts of 1), 2) and 3), and 30 g of 4) are kneaded with water, dried in vacuo and granulated.
The granules are mixed with 14 g of 4) and 1 g of 5) and the mixture is compressed with a tableting machine, whereby 1000 tablets containing 30 mg of compound of Example Dl per tablet are obtained. Experimental Example 1
The genetic engineering described below followed the method described in a book (Maniatis et al . , Molecular Cloning, Cold Spring Harbor Laboratory (1989)) or a method described in the protocol attached to the reagents.
(1) Cloning of human DGATl gene and preparation of recombinant baculovirus
Human DGATl gene was cloned by PCR using human adipocyte cDNA (Clontech, QUICK-Clone cDNA, human fat cell, cat# 637220) as a template and, based on the DGATl gene information reported by Case, S. et al . (Proc. Natl. Acad. Sci. U.S.A. 95 (22), 13018-13023 (1998)), a nucleotide sequence (245-1711 of Genbank Accession No. NM_012079) encoding DGATl was amplified with the following PCR primer. The primer nucleotide sequence is shown below. DGATl-U: 5' AATTAAGAATTCATGGGCGACTACAAAGACGATGACGACGGCGACCGCGGCAGCTCCCGGCGC CGG 3' (SEQ ID N0:l), and DGAT2-L:
5' AATTAAACTAGTTCAGGCCTCTGCCGCTGGGGCCTCATAGTTGAG 3' (SEQ ID NO:2)
The PCR reaction was conducted using a KOD-plus kit (TOYOBO) . The obtained PCR product was electrophoresed on agarose gel (1%), the DNA fragment amplified by PCR was recovered from the gel, and then digested with restriction enzymes EcoRI and Spel . The DNA treated with the restriction enzymes was electrophoresed on agarose gel (1%) , and the obtained DNA fragment was recovered and ligated with plasmid pFASTBACl (Invitrogen) digested with restriction enzymes EcoRI and Spel to give expression plasmid pFB-DGATl . The nucleotide sequence of the inserted fragment was confirmed and found to be identical with the nucleotide sequence of DGATl (245-1711 of Genbank Accession No. NMJD12079) . Furthermore, using BAC-TO- BAC Baculovirus Expression System (Invitrogen) , recombinant baculovirus BAC^DGATl was prepared.
(2) Preparation of microsome of Sf9 insect cells highly expressing DGATl enzyme SF9 cells were sown at IxIO6 cells/ml on Sf-900II SFM medium (1 L, Invitrogen) containing 10% fetal calf serum (Trace), 50 mg/L gentamicin (Invitrogen) and 0.1% Pluronic F-68 (Invitrogen) , and shaking culture was performed using a 2 L volume Erlenmeyer flask at 27°C, 100 rpm. After culturing for 24 hrs, recombinant baculovirus BAC-DGATl (6.7 mL) was added, and the mixture was further cultured for 3 days . The culture medium was centrifuged at 2,000 rpm for 5 min to give virus- infected cells. The infected cells were washed with a phosphate buffered saline (Invitrogen) , centrifuged under the same conditions, and the cells were preserved at -800C. The cryopreserved cells were thawed in ice, suspended in buffer A (50 iciM Tris buffer (30 mL, pH 7.4) containing 20% glycerol, 0.15 M NaCl) supplemented with Complete Protease Inhibitor (Boehringer) , and ruptured 3 times with a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The Sf9 microsome fractions were obtained by a conventional method and cryopreserved at -800C as a DGATl high expression Sf9 microsome.
(3) Determination of DGAT inhibitory activity
As a DGATl reaction buffer, a solution having a composition of 100 mM Tris-HC.l (pH 7.5), 250 mM sucrose, 150 iriM MgCl∑, 0.01% bovine serum albumin (BSA) was used. Using this buffer, a given concentration of the test compound and a composition (100 μl) of 25 μM dioleoylglycerol, 25 μM [14C]- Oleoyl-CoA, 5 μg protein/ml DGATl high expression Sf9 microsome, and 1% acetone were subjected to a triglyceride synthesis reaction at 32°C for 20 min. A mixture of 300 μL of chloroform-.methanol (=1:2) was added to the reaction mixture to quench the reaction. The reaction mixture was sufficiently mixed and distilled water (200 μL) was added to partition the mixture between a chloroform layer (lower layer) and an aqueous layer (upper layer) . The chloroform layer (50 μL) was spotted on a thin layer chromatography silica gel plate (TLC plate, Merck) and developed with a solvent (n-hexane .'diethyl ether:ethyl acetate: acetic acid =255:30:15:0.6). The developed TLC plate was dried/ contacted with a BAS imaging plate (manufactured by FUJIFILM) and measured with BAS2500 (manufactured by FUJIFILM) 16 hr later to numerically show the amount of [14C] -triglyceride (TG amount) produced during the reaction. The inhibitory rate was calculated by the following formula:
Inhibitory rate (%) = (1-(TG amount with addition of test compound - blank TG amount) / (control TG amount - blank TG amount) ) xlOO
The count of the triglyceride produced in the solution reacted without addition of the compound was used as a "control TG amount", and the count of the triglyceride produced in the solution reacted without addition of the test compound and DGATl high expression Sf9 microsome was used as a "blank TG amount". In addition, the concentration (IC50) of the test compound necessary for inhibiting the triglyceride synthesis by 50% was calculated by PRISM 3.02 (manufactured by GraphPad Software) . The inhibitory activity. is shown in Table 1. The inhibitory activity is shown by A < 0.0lμM <B < O.lμM ≤ C < lμM <D < lOμM according to IC50.
Table 1 DGAT inhibitory activity
Figure imgf000280_0001
INDUSTRIAL APPLICABILITY
The compound of the present invention has a DGAT inhibitory activity and is useful for the prophylaxis, treatment or improvement of DGAT-related diseases. The references cited herein, including patents and patent applications/ are hereby incorporated in full by reference, to the extent that they have been disclosed herein.
It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.
This application is based on application No. 60/832,115 filed in USA, the contents of which are incorporated hereinto by reference.

Claims

1. A compound represented by formula (Ia):
Figure imgf000282_0001
wherein ring Ba is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted;
Ra1 is a hydrogen atom or a substituent; . ring Aa is an optionally substituted aromatic heterocycle; and
Ra2, Ra3, Ra4, Ra5, Ra6 and Ra7 are each independently a hydrogen atom or a substituent; provided that 1) when ring Ba is pyrazole which is optionally further substituted, then ring Ba does not have optionally substituted tetrahydrofurylmethoxy as a substituent other than Ra1;
2) when ring Ba is imidazole which is optionally further substituted, then ring Ba does not have optionally substituted quinolyl as a substituent other than Ra1;
3) when ring Ba is pyrazole which is optionally further substituted, then Ra1 is not optionally substituted quinolyl; and
4) ring Aa is not the same as ring Ba; or a salt thereof.
2. The compound of claim 1, wherein ring Ba is pyrazole, benzimidazole, indole or indazole, each of which is optionally further substituted. .
3. The compound of claim 1, wherein Ra1 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group.
4. The compound of claim 1, wherein ring Aa is an aromatic heterocycle optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, a cyano group, an acyl group and a halogen atom.
5. The compound of claim 1, wherein Ra2, Ra3, Ra4, Ra5, Ra6 and Ra7 are both hydrogen atoms .
6. A compound represented by formula (Ib) :
Figure imgf000283_0001
wherein ring Bb is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted; ring Cb is an optionally substituted aromatic heterocycle; and ring Ab is an optionally substituted aromatic hydrocarbon; provided that when ring Bb is pyrazole which is optionally further substituted, then ring Cb is not optionally substituted quinoline; or a salt thereof.
7. The compound of claim 6, wherein ring Bb is pyrazole, benzimidazole, indole or indazole, each of which is optionally- further substituted.
8. The compound of claim 6, wherein ring Cb is an aromatic heterocycle optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, a Ci-6 alkyl group and a Cα-6 alkσxy group.
9. The compound of claim 6, wherein ring Ab is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom.
10. A compound represented by formula (Ic) :
Figure imgf000284_0001
wherein ring Bc is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted; ring Cc is an optionally substituted aromatic ring; ring Ac is an optionally substituted aromatic hydrocarbon; and
Rc2, Rc3, Rc4 Rc5, Rc6 and Rc7 are each independently a hydrogen atom or a substituent, or any two of Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 are optionally bonded to each other to form a non- aromatic ring; provided that 1) ring Bc is not pyrazol-5-yl and 2H-1, 2, 3-triazol-4-yl, each of which is optionally further substituted;
2) ring Cc is not optionally substituted quinoline;
3) a compound wherein Rc2, Rc3, Rc4, Rc5, Rc6 and Rc7 are hydrogen atoms is excluded; and
4) when Rc6 and Rc7 are bonded, then they do not form piperazine; or a salt thereof.
11. The compound of claim 10, wherein ring Bc is pyrazole, benzimidazole, indole or indazole, each of which is optionally further substituted.
12. The compound of claim 10, wherein ring Cc is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, a Ci-e alkyl group and a Ci_6 alkoxy group.
13. The compound of claim 10, wherein ring Ac is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom.
14. The compound of claim 10, wherein Rc2 and Rc3 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc2 or Rc3 is bonded to Rc4 or Rc5 to form a non-aromatic ring, bonded to Rc6 to form a non- aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle.
15. The compound of claim 10, wherein Rc4 and Rc5 are each independently a hydrogen atom, an acyl group or an optionally substituted hydrocarbon group, or Rc4 or Rc5 is bonded to Rc2 or Rc3 to form a non-aromatic ring, bonded to Rc6 to form a non- aromatic heterocycle, or bonded to Rc7 to form a non-aromatic heterocycle.
16. The compound of claim. 10, wherein Rc6 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc6 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle .
17. The compound of claim 10, wherein Rc7 is a hydrogen atom or an optionally substituted hydrocarbon group, or Rc7 is bonded to Rc2 or Rc3 to form a non-aromatic heterocycle, or bonded to Rc4 or Rc5 to form a non-aromatic heterocycle.
18. A compound represented by formula (Id):
Figure imgf000286_0001
wherein ring Bd is an aromatic heterocycle which is optionally further substituted; ring Cd is an optionally substituted aromatic ring; and ring Ad is an optionally substituted aromatic hydrocarbon; provided that
1) ring Bd is not pyrazol-4-yl and pyrrol-3-yl, each of which is optionally further substituted;
2) ring Cd is not optionally substituted quinoline;
3) when ring Bd is pyridine or quinoline, each of which is optionally further substituted, then ring Bd has substituent (s) besides ring Cd; and 4) when ring Bd is a 5-membered nitrogen-containing aromatic heterocycle optionally condensed with an aromatic ring, which is optionally further substituted, then ring Bd does not have an optionally substituted aromatic heterocyclic group as a substituent other than ring Cd and ring Cd is an optionally substituted aromatic hydrocarbon; or a salt thereof.
19. The compound of claim 18, wherein ring Bd is pyridine, pyrazole, triazole or indole, each of which is optionally further substituted.
20. The compound of claim 18, wherein ring Cd is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, a Ci-6 alkyl group and .a Ci-e alkoxy group.
21. The compound of claim 18, wherein ring Ad is an aromatic hydrocarbon optionally substituted by 1 to 3 substituents selected from an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, a cyano group, an acyl group and a halogen atom.
22. N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide; 6- (cyclopropylmethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6- (3, 3, 3-trifluoropropoxy) nicotinamide;
6- (2- (ethylsulfonyl) ethoxy) -N- (2- (l-phenyl-3- (trifluoromethyl) - lH-pyrazole-4-carboxamido) ethyl) nicotinamide;
N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6-propylnicotinamide;
1-phenyl-N- (2- ( 6- (2, 2, 2-trifluoroethoxy) nicotinamide) ethyl) -IH- indole-3-carboxamide; N- (2- (l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxamido) ethyl) -6-o-tolylnicotinamide;
1-benzoyl-N- (2- (6- (2,2, 2-trifluoroethoxy)nicotinamido) ethyl) - lH-indole-3-carboxamide; 6- (5-isopropyl-l, 2, 4-oxadiazol-3-yl) -N- (2- (l-phenyl-3-
(trifluoromethyl) -lH-pyrazole-4-carboxamido) ethyl) nicotinamide; or
N- (2- (4-ethoxybenzamido) ethyl) -1- (pyridin-2-yl) -3-
(trifluoromethyl) -lH-pyrazole-4-carboxamide; or a salt thereof.
23. A prodrug of the compound of claim 1, 6, 10 or 18.
24. A pharmaceutical agent comprising the compound of claim 1, 6, 10 or 18, or a prodrug thereof.
25. The pharmaceutical agent of claim 24, which is an agent for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes .
26. A DGAT inhibitor comprising the compound of claim 1, 6, 10 or 18, or a prodrug thereof.
27. Use of the compound of claim 1, 6, 10 or 18, or a prodrug thereof for the production of an agent for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes.
28. Use of the compound of claim 1, 6, 10 or 18, or a prodrug thereof for the production of a DGAT inhibitor.
29. A method for the prophylaxis or treatment of obesity, hyperlipidemia or diabetes in a mammal, which comprises administering the compound of claim 1, 6, 10 or 18, or a prodrug thereof to the mammal .
30. A method of inhibiting DGAT in a mammal, which comprises administering the compound of claim 1, 6, 10 or 18, or a prodrug thereof to the mammal .
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