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WO2012090219A2 - COMPOSÉS THIAZOLES UTILES COMME INHIBITEURS DE L'ACÉTYL-CoA CARBOXYLASE (ACC) - Google Patents

COMPOSÉS THIAZOLES UTILES COMME INHIBITEURS DE L'ACÉTYL-CoA CARBOXYLASE (ACC) Download PDF

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Publication number
WO2012090219A2
WO2012090219A2 PCT/IN2011/000884 IN2011000884W WO2012090219A2 WO 2012090219 A2 WO2012090219 A2 WO 2012090219A2 IN 2011000884 W IN2011000884 W IN 2011000884W WO 2012090219 A2 WO2012090219 A2 WO 2012090219A2
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WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
halogen
optional
substituted
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PCT/IN2011/000884
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English (en)
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WO2012090219A3 (fr
Inventor
Pakala Kumara Savithru Sarma
Vinod Parameshwaran ACHARYA
Srinivas Rao Kasibhatla
Vellarkad Narayana Viswanadhan
Atul Tiwari
Rakesh Kumar SINGHA
Alexander Bischoff
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Jubilant Biosys Ltd.
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Publication of WO2012090219A2 publication Critical patent/WO2012090219A2/fr
Publication of WO2012090219A3 publication Critical patent/WO2012090219A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/34—Oxygen atoms
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relate to thiazole compounds, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxidcs. or prodrugs: pharmaceutical compositions containing them and methods of preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.
  • ACC Acetyl-CoA Carboxylase
  • the present invention also relates to processes for the preparation of the compounds of the present invention. These compounds are useful for preventing or treating a condition tha responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.
  • ACC Acetyl-CoA Carboxylase
  • Metabolic syndromes are associated with several diseases and disorders, such as obesity, diabetes, and diabesity (typically defined by the occurrence in a single patient of both diabetes and obesity or other overweight conditions, and characterized by elevated blood glucose levels). Metabolic syndromes are typically defined by a clustering of cardiovascular risk factors that increase the risks of coronary heart disease and/or type II diabetes. Such metabolic syndromes are often characterized by elevated insulin concentration, and arc often associated with such conditions as visceral obesity. hypcrlipidemia. atherogenic dyslipidemia, hyperglycemia, hypertension, hyperurceemia and renal dysfunction. Metabolic syndromes, together with insulin resistance, arc increasingly viewed as being major causes of type 11 diabetes and atherosclerosis.
  • Abnormal fatty acid synthesis has also been found to be a cause for obesity, as well as nonalcoholic fatty liver disease (NAFLD) and liver dysfunction (such as NAFLD- associated liver dysfunction).
  • NAFLD nonalcoholic fatty liver disease
  • Prevalence of NAFLD has markedly increased in the recent years (Cusi K.. Nonalcoholic fatty liver disease in type 2 diabetes mellitus, Curr. Opin. Endocrinol ' . Diabetes Obes.16(2), 141-9. Apr.2009).
  • Acetyl-CoA carboxylase a member of biotin-dependent carboxylases family, catalyzes the formation of malonyl-CoA, an intermediate that regulates fatty acid biosynthesis and oxidation.
  • ACC exists as two different isoenzymes, ACCl and ACC2. Both forms exhibit high sequence homology except at the N-terminal ends.
  • ACC2 a 2458 amino acid peptide, contains a 114 amino acid portion that facilitates anchoring of ACC to the mitochondrial membrane.
  • ACCl lacks this targeting sequence and thereby remains cytosolic.
  • the ACCl and ACC2 isoforms also exhibit divergent tissue expression profiles, providing the basis for different functions.
  • oxidative tissues such as heart and skeletal muscles
  • ACC2 forms malonyl- CoA which mainly regulates fatty acid oxidation through inhibition of carnityl palmitoyltransferase 1 (CPT-1) inhibition.
  • CPT-1 carnityl palmitoyltransferase 1
  • malonyl-CoA produced by ACCl is utilized as a substrate for fatty acid synthesis and chain elongation.
  • ACC acetyl-CoA carboxylase
  • the present invention provides thiazole compounds of Formula I or its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs;
  • Ai i is selected from an arylene or a heteroarylene; wherein said arylene or said heteroarylene are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; Z is Y-A12; wherein
  • Y is selected from a bond, -0-, -S(0) n , or -NH;
  • Ar2 is selected from an optionally substituted aryl, or an optional ly substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;
  • R 1 is a C
  • R 2 is selected from the group consisting of an optionally substituted l inear or branched C 1 -C2 0 alkyl, an optionally substituted linear or branched heterocyclyl, an optional ly substituted C3-C2 0 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optional ly substituted heteroaryl, an optional ly substituted heteroarylalkyl, halogen, perlluroalkyl, -N ⁇ 3 ⁇ 4 -OH, -OR3, -CN, -NH 2 , -Si(R 3 ) 3 , -S(0) n R ' ',-C(0)l i and -C(0)R 3 ; - NR R 5 , and -N(R 3 )2; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl,
  • R 3 is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-C20 alkyl, an optionally substituted, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optionally substituted aryl, an optional ly substituted arylalkyl, an optional ly substituted heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C1 -C20 alkyl, an optional ly substituted C3-C2 0 cycloalkyl, an optionally substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF 3 , -N0 2 , -Si(R 8 ) 3 , - S(0) n R 8 , -C(0)H, -C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C1 -C 4 alkoxy; R 5 is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C
  • heteroarylene contain one or more heteroatom independently selected from O. N, or
  • the present invention also provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, using an effective amount of a compound of Formula (1), its pharmaceutically acceptable salts, prodrugs, solvates, N- oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N-oxides, or prodrugs or combination or m ixtures thereof.
  • ACC Acetyl-CoA Carboxylase
  • the present further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the present invention also provides use of compound of Formu la I for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.
  • ACC Acetyl-CoA Carboxylase
  • the present invention provides thiazole compounds of Formu la I, its pharmaceutica lly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of " N- ox ides, or prodrugs;
  • An is selected from an arylene or a heteroarylene; wherein said arylene or said hcteroarylene are optional ly substituted with one or more substituents independently selected from halogen, hydroxy, Q -Ci alkyl, perhaloalkyl, or C
  • Z is Y-Ar 2 ;
  • Y is selected from a bond, -0-, -S(0) n , or -NH ;
  • Ar 2 is selected from an optionally substituted aryl, or an optional ly substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 al koxy:
  • R ' is a C, -C 6 alkyl
  • R 2 is selected from the group consisting of an optional ly substituted l inear or branched C
  • R 3 is selected from the group consisting of hydrogen, halogen, an optional ly substituted C
  • n optionally substituted heterocycloalkyl, an optional ly substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF 3 , -N0 2 , -Si(R ) 3 , - C(0)H, -C(0)R 4 , -NR 4 R 5 , and -OR 4 ; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 a lkyl, perhaloalkyl. or C 1 -C4 alkoxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C1 -C2 0 alkyl. an opt ional ly substituted C3-C2 0 cycloalkyl, an optionally substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl.
  • an optionally substituted heteroarylalkyl -CN, -CF3, -N0 2 , -Si(R 8 )3, - S(0) n R 8 , -C(0)H, -C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy; 3 is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C
  • sa id substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl.
  • each R 8 and R 9 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S.
  • An embodiment of the present invention provide the compounds of Formula I , or its pharmaceutically acceptable salts, prodrugs, solvates. N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N- oxides, or prodrugs; wherein:
  • Z is Y-Ar 2 ;
  • Y is selected from a bond, -0-, -S(0) n , or -NH;
  • Ar 2 is selected from
  • R 6 is selected from the group consisting of halogen, an optionally substituted linear or branched C
  • a 1 is a monocyclic heteroaryl ring selected from the group consisting of:
  • each m is 0. 1 or 2:
  • P, Q, R, and Z are independently selected from -CR 7 - or nitrogen;
  • R 7 is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C1-C20 alkyl. an optionally substituted heterocyclyl, an optionally substituted C3-C2 cycloalkyl. an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF 3j -NO?, -Si(R x ) 3 , - S(0) n R 8 , -C(0)H, -C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl. or C -Ci alkoxy;
  • R is Ci-C 6 alkyl
  • R 2 is selected from the group consisting of an optionally substituted linear or branched C
  • R J is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched CI-C 2 Q alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted aryl, an optional ly subst ituted arylalkyl, an optionally substituted heteroaryl.
  • an optional ly substituted heteroarylalkyl -CF 3 , -N0 2 , -Si(R 4 ) 3 , -S(0) n R 4 , -C(0)H, - C(0)R 4 , - R' ⁇ 5 , and -OR 4 ; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, an optionally substituted liner or branched C1 -C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloal kyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF 3; -N0 2 , -S i(R 8 ) 3 , -S(0) n R ' ⁇ - C(0)H, -C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl. or C 1 -C4 alkoxy;
  • R ⁇ is selected from the group consisting of hydrogen, halogen, an optiona l ly substituted l inear or branched C1 -C20 alkyl, an optional ly substituted l inear or branched C 1 -C20 heteroalkyl, an optionally substituted C 3 -C?o cycloalkyl. an optional ly substituted C 3 -C 2 o heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF 3 -NO ?
  • each R s and R 9 is, independently, selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl ; each n is, independently, 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heieroarylene contain one or more heteroatom independently selected from O, N, or S.
  • Another embodiment of the present invention provide the compounds of Form u la I, its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; wherein:
  • An is a phenylene
  • Z is Y-Ar 2 ;
  • Y is selected from a bond or -O-;
  • Ar 2 is selected from
  • A is a monocyclic heteroaryl ring selected from:
  • R 3 is independently selected from halogen or a linear or branched C 1 -C3 alkyi
  • R 4 is selected from hydrogen, a linear or a branched C 1 -C3 alkyi, or -CF 3 ;
  • R s is selected from the group consisting of hydrogen and C
  • R is methyl
  • R 2 is selected from the group consisting of C
  • Still another embodiment of the present invention provides compounds of Formula I, wherein R 2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, and butyl.
  • Yet another embodiment of the present invention provides compounds of Formula I, wherein said R 1 is methyl.
  • Another embodiment of the present invention provides compounds of Formula I, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; wherein:
  • Z is Y-Ar 2 ;
  • Y is a bond
  • Ar2 is selected from
  • each R J is selected from the group consisting of halogen, and an optionally substituted linear or branched Q-C2 0 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl. or C1-C4 alkoxy;
  • R 6 is selected from the group consisting of halogen, an optionally substituted linear or branched Ci-C 20 alkyl, an optionally substituted heterocycyi. an optional ly substituted C3-C20 cycloalkyl, an optionally substituted heterocycloalkyi, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF 3 , -N0 2 , -Si(R 8 ) 3 , -S(0) n R 8 , -C(0)R - C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, Q -C4 alkyl, perhaloalkyi, or C 1 -C4 alkoxy; each R 8 and R 9 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyi. aryl, hetero
  • P, Q, R, and Z are independently selected from -CR - or nitrogen ;
  • R 7 is selected from the group consisting of hydrogen, halogen, an optionally substituted l inear or branched C1 -C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyi, an optionally substituted arylal kyl, an optional ly substituted heteroarylalkyl, -CN, -CF 3j -N0 2 , -Si(R 8 ) 3 , -S(0) n R ' ⁇ - C(0)H, -C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloal kyi, or C 1 -C4 alkoxy;
  • R ' is C , -C 6 alkyl
  • R 2 is selected from the group consisting of an optional ly substituted l inear or branched C
  • each of P, Q, R, Z is -CR 7 and R 7 is selected from the group consisting of hydrogen, halogen, an optionally substituted l inear or branched C
  • each of P, Q, R, Z is -CR 7 ;
  • R 1 is methyl;
  • R 2 is -OR 3 and
  • R 3 is an optional ly substituted linear or branched C3-C2 0 alkyl,- or an optional ly substituted C3-C20 cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C
  • each R J is independently selected from halogen, or an optionally substituted linear or branched C r C 2 o alkyl; wherein said substituent is independently selected from halogen, hydroxy. C C 4 alkyl, perhaloalkyl, orC r C4 alkoxy;
  • R' 1 is selected from the group consisting of hydrogen, halogen and an optionally substituted linear or branched C
  • R 3 is selected from the group consisting of hydrogen, halogen and an optionally substituted linear or branched Ci-C 2 o alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and each of m and n are, independently, 0, 1, or 2.
  • R J is selected from the group consisting of chlorine, bromine, fluorine and methyl; and R 4 is selected from hydrogen, or methyl.
  • R 5 is hydrogen or methyl.
  • An another embodiment of the present invention provides the compounds of Formula I, wherein Ar 2 is
  • each R J is independently selected from halogen or an optionally substituted linear or branched C
  • R 3 is independently selected from the group consisting of chlorine, bromine, fluorine and methyl.
  • Still another embodiment of the present invention provides the compounds of Formula 1, wherein Ar 2 is each 3 is selected from halogen or an optionally substituted linear or branched C
  • R 3 is independently selected from the group consisting of chlorine, bromine, fluorine and methyl.
  • Still another embodiment of the present invention provides the compounds of Formula I, wherein Ar 2 is each R J is independently selected from halogen or an optionally substituted linear or branched C 1 -C2 0 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and R 4 is -CF3.
  • R 3 is independently selected from halogen or an optionally substituted linear or branched C,-C 2 o alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy;
  • A is ; each n is independently 0, 1 or 2, and m is independently 0, or I .
  • Yet another embodiment of the present invention provides the compounds of
  • J is independently selected from halogen or an optionally substituted l inear or branched C 1 -C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C
  • a 1 is ; each n is independently 0, 1 or 2, and m is independently 0, or 1 .
  • Particular embodiments of the present invention are the compounds of formu la 1 its pharmaceutically acceptable salts, prodrugs, solvates, " N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of N- ox ides, or prodrugs; which are:
  • An embodiment of the present invention provides compounds of Formula I, wherein free base forms of the above listed compounds can also be in the form of a pharmaceutically acceptable salt.
  • Yet another embodiment of the present invention provides compounds of Formula I, wherein the free base form of the above listed compounds is in the form of an N-oxide.
  • optical isomers can be obtained by resolution of the racemic m ixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric. ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chem ical differences by methods known to those ski lled in the art, for example, by chromatography or fractional crystallization.
  • the optical ly acjive bases or acids are then l iberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers.
  • Suitable chiral H PLC columns are manufactured by Diacel, e.g., Chiracel OD and Ch iracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivitization, are also useful.
  • the optically active compounds of Formula I can l i kewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization.
  • the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 'I f "C. l j C and/or l 4 C.
  • the compounds are deuterated.
  • Such deuterated forms can be made the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteralion can improve the efficacy and increase the duration of action of drugs.
  • Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10) (2000), 1 10 pp.; abalka, George W.; Varma, Rajendcr S., The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron ( 1989), 45(21 ), 6601 -21 ; Evans, E. Anthony, Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981 ), 64(1 -2), 9-32.]
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as base free forms, and pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobrom ic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandel ic acid, and carbonic acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g.. sodium, potassium, calcium, magnesium, ammonium, and choline salts.
  • an appropriate base e.g. sodium, potassium, calcium, magnesium, ammonium, and choline salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkal ine earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • acid salts that can be obtained by reaction with inorganic or organic acids: acetates, DIPEAtes, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopcntanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobrom ides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, n icotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persu l fates, 3- phenylpropionates, picrates, pival
  • the pharmaceutically acceptable salt can be a hydrochloride, a hydrobrom ide, a hydroformate, or a maleate.
  • the salts formed are pharmaceutically acceptable for administration to mammals.
  • pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent.
  • the free base can then, if desired, be converted to a pharmaceutically acceptable acid add ition salt.
  • polymorphism is an abi l ity of a compound to crystall ize as more than one distinct crystal l ine or "polymorphic' ' species.
  • a polymorph is a sol id crystal line phase of a compound with at least two different arrangements or polymorphic forms of that compound molecu le in the sol id state.
  • Polymorphic forms of any given compound are defined by the same chem ical formula or composition and are as distinct in chemical structure as crystal line structures of two di fferent chem ical compounds.
  • Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystall ine lattice structure of the compound molecule during the crystal lization process.
  • the present invention also includes prodrugs of compounds of Formula 1 .
  • the term prodrug is intended to represent covalently bonded carriers, wh ich are capable of releasing the active ingredient of Formula I when the prodrug is adm in istered to a mammal ian subject. Release of the active ingred ient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one ski lled in the art. These techniques general ly mod i fy appropriate functional groups in a given compound. These modi fied functional groups however regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of compounds of Formula 1 include compounds wherein a hydroxy, amino. carboxylic, or a similar group is modified.
  • prodrugs include, but are no limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g.. N,N- dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula 1 ), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g.. N,N- dimethylaminocarbonyl
  • amides e.g., trifluoroacetylamino, acetylamino, and the like
  • Prodrugs of compounds of Formula 1 are also within the scope of this invention.
  • Aromatic alcohols derived from commercially avai lable starting materials through methods known in the art, may be reacted with 2,5-dibromothiazole to render 2-aryloxy-5- bromoth iazoles.
  • Commercially available or modified methoxyarylketones (A) may be subjected to reductive am ination (e.g., with ammonium acetate and sodium cyanoborohydride) to furnish an amine which can be reacted with an appropriate substrate (e.g.. with carboxyl or carboyl halides) using methods known in the art.
  • the methoxy group may be demethylated (e.g., with boron tribromide) under reaction conditions known to one sk i l led in the art to render secondary hydroxyarylalkyalky!am ines.
  • the secondary hydroxyarylalkylam ines can be coupled (e.g., in the presence of copper iodide and an inorganic base) with 2-aryloxy-5-bromothiazoles under reaction cond itions known to one sk i l led in the art.
  • 2-Aryloxy-5-bromothiazoles can be converted to primary am ines and coupled with commercially available or modified hydroxyarylketones (B) followed by reductive amination (e.g., with ammonium acetate and sodium cyanoborohydride), or. alternatively, coupled with commercially available or modified hydroxyaryl brom ides (C).
  • B commercially available or modified hydroxyarylketones
  • C commercially available or modified hydroxyaryl brom ides
  • Schemes (2a and 2b) summarize methods for preparing phenyl thiazoyloxy compounds of Formu la I of the present invention.
  • the formulas and variables i llustrated in the section below are intended only to assist in describing the synthesis of Formu la I compounds and are not to be confused with the variables used to define Formula I compounds i n the claims or in the other sections of the specification.
  • Scheme 2a
  • 2-Amino-5-bromothiazole A which is commercially avai lable as monohydrobromide salt, may be coupled with 4-hydroxyacetophenone under coupling conditions known to the one skilled in the art. Conversion of the amine to a halide substituent may be achieved by means of a Sandmeyer reaction or other coupl ing conditions known to the one skilled in the art. The resulting bromide may be coupled with an appropriately substituted methoxyphenylboronic acid analog under coupling conditions known to the one skilled in the art.
  • Transformation of ketone B to compounds of Formula ⁇ may be carried out via reductive amination under reaction conditions known to the one skilled in the art, followed by reaction with an appropriate ketoyl chloride under reaction conditions known to the one skilled in the art.
  • the methoxy group of compounds of Formula I may be demethylated under reaction conditions known to the one skilled in the art and the resulting aromatic alcohol may be re-alkylated under reaction conditions known to the one skilled in the art.
  • the methoxy group of compounds of Formula I may be demethylated under reaction cond itions known to the one skilled in the art and the resulting aromatic alcohol may be re-alkylated under reaction conditions known to the one skilled in the art.
  • the present invention also provides a pharmaceutical composition comprisi ng at least one compound of Formula 1 and a pharmaceutically acceptable carrier.
  • An embodiment of the present invention provides a pharmaceutical composition, further comprising at least one second active ingredient.
  • Another embod iment of the present invention provides a pharmaceutical com position com prising, one or more pharmaceutically acceptable carriers.
  • Adm inistration of the compounds of the present invention may be accompl ished accord ing to patient needs, for example, orally, nasally, parenterally (subciitaneously. intraveneously, intramuscularly, intrasternally and by infusion) by inhalation, rectal ly, vaginally, topically and by ocular administration.
  • sol id oral dosage forms can be used for administering compounds of the i nvention including such solid forms as tablets, gelcaps, capsu les, caplcts, granu les, lozenges and bulk powders.
  • the compounds of the present invention can be adm in istered alone or combined with various pharmaceutical ly acceptable carriers, di luents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not l im ited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
  • l iqu id oral dosage forms can also be used for admin istering compounds of the inventions, including aqueous and non-aqueous solutions, emu lsions, suspensions, syrups, and el ixirs.
  • dosage forms can also contain suitable inert d i luents known in the art such as water and suitable excipients known in the art such as preservat i ves, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspend ing the compounds of the invention.
  • the compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic steri le solution. Other preparations are also possible.
  • Suppositories for rectal administration of the compounds of the present invention can be prepared by m ixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, past foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye. ear or nose.
  • Topical adm inistration may also involve transdermal adm inistration via means such as transdermal patches.
  • Aerosol formulations suitable for administering via inhalation also can be made.
  • the compounds of Formula 1 can be adm inistered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions.
  • the aerosol formu lation can be placed into a pressurized acceptable propel lant.
  • the present invention further provides a method for preventing or treating a cond ition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising adm in istering an effective amount of a compound of formu la (I), its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- ox ides, or prodrugs; or combination or m ixtures thereof;
  • ACC Acetyl-CoA Carboxylase
  • Aii is selected from an arylene or a heteroarylene; wherein said arylene or said heteroarylene are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy;
  • Z is Y-Ar 2 ;
  • Y is selected from a bond, -0-, -S(0) n , or -NH;
  • Ar 2 is selected from an optionally substituted aryl, or an optionally substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy;
  • R 1 is a C
  • R 2 is selected from the group consisting of an optionally substituted linear or branched C
  • R 3 is selected from the group consisting of hydrogen, halogen, an optionally substituted C
  • R 4 is selected from the group consisting of hydrogen, halogen, an optionally substituted liner or branched C
  • R 3 is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched Q -C20 alkyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted C3-C20 heterocycloalkyl, an optional ly substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF3 -NO?, -
  • aryl, heteroaryl, arylalkyl, and heteroarylalkyl wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl. and heteroarylene contain one or more heteroatom independently selected from O, N, or S.
  • An embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACQ inhibitor, said method comprising administering an effective amount ( of a compound of Formula I, its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; or combination or m ixtures thereof; wherein Z is Y-Ar 2 ; Y is selected from a bond, -0-, -S(0) N , or - Ni l; Ar 2 is selected from
  • 1 is selected from the group consisting o f halogen, an optionally substituted linear or branched C
  • a 1 is a monocyclic heteroaryl ring selected from the group consisting of:
  • each m is 0. 1 or 2;
  • P, Q, R, and Z are independently selected from -CR 7 - or nitrogen;
  • R 7 is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C
  • R 1 is C-Ce alkyl
  • R 2 is selected from the group consisting of an optionally substituted linear or branched C1-C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C 3 - C20 cycloalkyi, an optionally substituted heterocycioalkyi, an optionally substituted aiyl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF 3 , -NO2, -OH, -OR3, -CN, -Si(R 3 ) 3 , -C(0)H, and -C(0)R 3 ; - NR R ⁇ and -N(R 3 ) 2 ; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, pcrhaloalkyl, or C1-C4 alkoxy;
  • R 3 is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched Ci-C 20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyi, an optionally substituted heterocycioalkyi, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF 3 , -N0 2 , -Si(R 4 ) 3 , -S(0) n R 4 , ⁇ C(0)H, - C(0)R 4 , -NR 4 R 5 , and -OR 4 ; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C
  • R 3 is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched Q -C2 0 alkyl, an optionally substituted l inear or branched C
  • each R and R is, independently, selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; each n is, independently, 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S.
  • Another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising administering an effective amount of a compound of Formu la I, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N- oxides, or prodrugs; or combination or m ixtures thereof; wherein Z is Y-Ar 2 ;
  • Y is selected from a bond or-O-;
  • Ar2 is selected from
  • a 1 is a monocyclic heteroaryl ring selected from:
  • R 3 is independently selected from halogen or a linear or branched C 1 -C 3 alkyl
  • R 4 is selected from hydrogen, a linear or a branched C1-C 3 alkyl. or -Cl ' 3; ⁇ V is selected from the group consisting of hydrogen and C
  • R 2 is selected from the group consisting of C
  • Still another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising administering an effective amount of a compound of Formula I, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N-oxides, or prodrugs; or combination or mixtures thereof; wherein:
  • Z is Y-Ar 2 ;
  • Y is a bond
  • Ar2 is selected from
  • each R 3 is selected from the group consisting of halogen, and an optional ly substituted l inear or branched C1 -C20 alkyl; wherei n said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;
  • R 6 is selected from the group consisting of halogen, an optionally substituted l inear or branched C 1 -C2 0 alkyl, an optionally substituted heterocycyl. an optionally substituted C3-C2 0 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF 3 , -N0 2 , -Si(R 8 ) 3 , -S(0) n R 8 , -C(0)1 L - C(0)R s , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy; each R s and R 9 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl,
  • each m is 0, or 1 ;
  • An is wherein P, Q, R, and Z are independently selected from -CR 7 - or nitrogen ;
  • R ' is se lected from the group consisting of hydrogen, halogen, ai optional ly substituted l inear or branched C1 -C20 alkyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C2 0 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF 3, -N0 2 , -Si( s ) 3 , -S(0) n R 8 , - C(0)H, -C(0)R 8 , -NR 8 R 9 , and -OR 8 ; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyi, or C I -C4 alkoxy; R ' is C, -C 6 alkyl;
  • R 2 is selected from the group consisting of an optionally substituted linear or branched Ci-C 20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C 3 - C 2 0 cycloalkyl, an optional ly substituted heterocycloalkyl, an optional ly substituted aryl.
  • an optional ly substituted arylalkyl, an optional ly substituted heteroarvL an optiona l ly - substituted heteroarylalkyl, CF 3 , -N0 2, -OH, -OR3, -CN, -Si(R 3 ) , -C(0)H s -C(0)R 3 ; -
  • substituent is independently selected from halogen, hydroxy, C
  • R 4 is selected from the group consisting of hydrogen, halogen, -CF and an optionally substituted linear or branched C 3 -C 2 o alkyl, and an optional ly substituted C 3 -C?o cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C
  • R 3 is selected from the group consisting of hydrogen, halogen, and an optional ly substituted linear or branched C 3 -C 2 o alkyl, and an optional ly substituted C 3 -C 2 o cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyi, or C1 -C4 al koxy; each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S.
  • An embod iment of the present invention provides a method for preventi ng or treating a condit ion that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, sa id method comprising administering an effective amount of a compound of Formula 1, its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutical ly acceptable salts o f N- oxides, or prodrugs; or combination or mixtures thereof; wherein the Acetyl-CoA Carboxylase (ACC) is ACC- 1 or ACC-2.
  • ACC Acetyl-CoA Carboxylase
  • Effective amount means the amount of a compound of Formula I that, when adm inistered to a patient (e.g., a mammal) for treating a disease, is sufficient to effect such treatment for the disease to achieve the objectives of the invention.
  • the “effective amount” wi ll vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • Sti l l another, embodiment of the present invention provides a method for preventi ng or treating a cond ition that responds to an Acetyl-CoA Carboxylase (ACC) inh ibitor, said method comprising administering an effective amount of a compound of Formu la I, its pharmaceutically acceptable salts, prodrugs, solvates, N-ox ide thereof: solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N-oxidcs, or prodrugs; or combination or m ixtures thereof; wherein the condition is a metabol ic syndrome.
  • ACC Acetyl-CoA Carboxylase
  • Yet another embodiment of the present invention provides a method for prevent ing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising adm inistering an effective amount of a compound of F ormula I . its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N- oxides, or prodrugs; or combination or mixtures thereof; wherein the condition is selected from type I I d iabetes, obesity, diabesity, atherosclerosis, and cardiovascular d iseases.
  • ACC Acetyl-CoA Carboxylase
  • An ACC-mediated d isease or cond ition includes but is not l im ited to a disease or cond ition which is, or is related to, cardiovascular disease, dysl ipidem ias (including but not l im ited to disorders of serum levels of triglycerides, hypertriglyceridem ia, V LDL.
  • compounds of the invention will, in a patient, increase HDL levels and/or decrease triglyceride levels and/or decrease LDL or non-HDL-cholesterol levels.
  • An ACC-mediated disease or condition also includes metabol ic syndrome (including but not limited to dyslipidemia, obesity and insul in resistance, hypertension, m icroalbum inem ia, hyperuricaemia, and hypercoagulabi l ity), Syndrome X, d iabetes, prediabetes, insul in resistance, decreased glucose tolerance, non-insulin-dependent diabetes mel l itus, Type I I d iabetes, Type I diabetes, diabetic complications (such as d iabetic retinopathy, neuropathy, and nephropathy), body weight disorders (includ ing but not l i m ited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leplin related diseases.
  • the compounds of Formula I are useful in the treatment of diabetes mellitus and obesity.
  • the compounds of Formula I are useful in the treatment of obesity.
  • the term "metabolic syndrome” is a recognized cl inical term used to describe a condition comprising combinations of Type II diabetes, impaired glucose tolerance, insul in resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridem ia, low HDL, hyperuricaemia, hypercoagulabi l ity and/or m icroalbum inemia.
  • Diabestity typically involves a metabolic syndrome (such as insul in resistance syndrome or syndrome X) defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinemia, atherogenic dyslipidem ia, hypertension and hypercoagu labi l ity) that together increase the risk of developing coronary heart disease and type 2 diabetes.
  • Metabol ic syndrome is a clinical disorder where increased insu l in concentration is observed with associated conditions such as visceral obesity, hyperlipidem ia, atherogenic dyslipidemia, hyperglycemia, hypertension, hyperurecem ia and renal dysfunction.
  • An ACC-mediated disease or condition also includes fatty l iver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcohol ic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatic protoporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.
  • fatty l iver hepatic steatosis
  • hepatitis non-alcoholic hepatitis
  • non-alcoholic steatohepatitis NASH
  • alcohol ic hepatitis alcohol ic hepatitis
  • acute fatty liver fatty liver of pregnancy
  • drug-induced hepatitis erythrohepatic protoporphyria
  • iron overload disorders hereditary
  • An ACC-med iated disease or condition also includes, but is not l im ited to, a d isease or condition which is, or is related to primary hypertriglyceridem ia, or hypertriglyceridemia secondary to another disorder or disease, such as hyperl ipoproteinem ias, fami lial histiocytic reticulosis, lipoprotein lipase deficiency, apol ipoprotein deficiency (such as ApoClI deficiency or ApoE deficiency), and the l ike, or hypertriglyceridemia of unknown or unspecified etiology.
  • a d isease or condition which is, or is related to primary hypertriglyceridem ia, or hypertriglyceridemia secondary to another disorder or disease, such as hyperl ipoproteinem ias, fami lial histiocytic reticulo
  • An ACC-med iated disease or condition also includes a disorder of polyunsaturated fatty acid (PUPA) disorder, or a skin disorder, including, but not limited to, eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the l ike.
  • PUPA polyunsaturated fatty acid
  • An ACC-mediated disease or cond ition also includes inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and pre-menstrual syndrome.
  • An ACC-med iated disease or condition also includes but is not l im ited to a d isease or condition wh ich is, or is related to cancer, neoplasia, mal ignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the l ike.
  • An ACC-mediated disease or condition also includes a condition where increasi ng lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building.
  • Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT .11) are also included herein.
  • CPT I or CPT .11 carnitine palmitoyltransferase deficiency
  • Such treatments are useful in humans and in animal husbandry or companion animals, including for adm inistration to canine, feline, bovine, porcine or avian domestic animals or any other an imal to reduce triglyceride production or body weight and/or provide leaner meat products and/or healthier animals.
  • An ACC-mediated disease or condition also includes a disease or condition wh ich is, or is related to, neurological diseases, psychiatric disorders, mu ltiple sclerosis, eye diseases, and immune d isorders.
  • An ACC-mediated disease or condition also includes a disease or condition wh ich is. or is related to, viral d iseases or infections including but not l im ited to al l positive strand RNA viruses, coronaviruses, SARS virus, SARS-associated coronavirus, Togaviruses, Picornaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae, Filoviridae, ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephal itis virus, Sindbis virus, Semliki forest virus, Chikungunya virus, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIR1DAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norvvalk virus,
  • Porcine hemagglutinating encephalomyelitis virus Porcine transmissible gastroenteritis virus, Rat coronavirus, Turkey coronavirus, Rabbit coronavirus, Berne virus, Breda virus; FLAVIVIRIDAE including Hepatitis C virus, West Nile virus, Yellow Fever virus. St. Louis encephalitis virus, Dengue Group, Hepatitis G virus, Japanese B encephalitis virus, Murray Valley encephalitis virus, Central European tick-borne encephalitis virus.
  • Coxsackie B including Potyvirus, Rymovirus, Bymovirus. Additionally it can be a disease or infection caused by or linked to Hepatitis viruses, Hepatitis B virus, Hepatitis C virus, human immunodeficiency virus (HIV) and the like. Treatable viral infections include those where the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it can be a disease or infection caused by or linked to RNA negative strand viruses such as influenza and parainfluenza viruses.
  • the compounds of the inventions are useful in the treatment of elevated levels of lipids, cardiovascular diseases, diabetes, obesity, and metabolic syndrome.
  • treating means to relieve, alleviate, delay, reduce, reverse, improve or prevent at least one symptom of a condition in a subject.
  • the term ''treating may also mean to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease), manage and/or reduce the risk of developing or worsening a condition.
  • a subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment.
  • the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wi ld or in a zoological garden), research animals, such as m ice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as ch ickens, turkeys, songbirds, etc., i .e., for veterinary medical use.
  • Another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, wherein the compounds of the present invention are administered as a mono-therapy.
  • ACC Acetyl-CoA Carboxylase
  • Yet another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, wherein the compounds of the present invention are administered as part of a combination therapy.
  • ACC Acetyl-CoA Carboxylase
  • a compound of Formula I may be used in combination with other drugs or therapies that are used in the treatment/prevention/suppression or amel ioration of the diseases or conditions for which compounds of Formula I are useful.
  • Such other drug(s) may be administered, by a route and in an amount common ly used therefore, contemporaneously or sequentially with a compound of Formula 1.
  • a pharmaceutical Unit dosage form containing such other drugs in addition to the compound o f Formula I may be employed.
  • the pharmaceutical compositions o f the present invention include those that also contain one or more other active ingredients, in add ition to a compound of Formula I.
  • the present invention also provides the use of compound of Formula 1 for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inh ibitor.
  • ACC Acetyl-CoA Carboxylase
  • An embodiment of the present invention provides the use of compound of Formu la I, wherein Acetyl-CoA Carboxylase (ACC) is ACC- 1 or ACC-2.
  • ACC Acetyl-CoA Carboxylase
  • Formu la I as inhibitors of acetyl-CoA carboxylase (ACC) enzymes, for example ACC I and ACC2.
  • ACC acetyl-CoA carboxylase
  • Sti l l another embodiment of the present invention provides the use of compound of Formu la I lor preventing or treating conditions mediated by ACC I and ACC2, or a lternatively, ACC 1 or ACC2 enzymes.
  • halogen means, ⁇ unless otherwise stated, fluorine, ch lorine, bromine, or iodine atom.
  • suffix "ene” added to any of the described terms means that the substituent is connected to two other parts in the compound.
  • arylene means, unless otherwise stated, an aryl moiety that is connected to two other parts in the compound.
  • heteroarylene means, unless otherwise stated, a heteroaryl moiety that is connected to two other parts in the compound.
  • Said arylene or heteroarylene can be optional ly substituted by one or more groups that may be the same or different and which can be conceptually formed from an arylene by replacing the hydrogen atom in the aryl or heteroaryl moiety with another atom or substituent group.
  • the substituents are alkyl, cycloalkyl, heteroaikyi, heteroaryl, hcterocycloalkyl, -NH 2 , -NHR', N(R') 2 , OR', or -C(0)OR', wherein each occurrence of • R !
  • each R' is independently selected from alkyl, heteroaikyi, cycloalkyl, heteroaikyi, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and wherein each R'is optionally substituted by one or two more groups, independently selected from halogen, -R', -OR', -OH.
  • phenylene in the context of the present invention means a 1 ,2- phenylene, a 1 ,3-phenylene, or 1 ,4- phenylene, most preferably 1 ,4-phenylene.
  • alkyl means, unless otherwise stated, a hydrocarbon group that can be conceptually formed from an alkane by removing hydrogen from the structure of a hydrocarbon compound having straight or branched carbon chains, and replacing the hydrogen atom with another atom or substituent group.
  • the alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and the like.
  • heteroaikyi means, unless otherwise stated, an alkyl group consisting of one to fourteen carbon atoms and having one to six heteroatoms selected from oxygen, nitrogen, sulfur, and silicon, and wherein the nitrogen, sulfur and silicon atoms may optional ly be oxidized and the nitrogen atom may optionally be quatemized.
  • the heteroatoms O, N and S may be placed at any interior position of the heteroaikyi group.
  • the hclcroatom Si may be placed at any position of the heteroaikyi group, including the position at which the heteroalkyl group is attached to the remainder of the molecule.
  • Examples i ncl ude are not limited to 2-methoxyethyl, 2-(methylamino)ethyl, 2- (dimethylam ino)ethyl, 2-(ethylthio)methyl, 2-(methylsulfmyl)ethyl, 2-
  • substituted alkyl and “substituted heteroalkyl” denote that the alky I and the heteroal kyl group is substituted by one or more substitutents, such as halogen, hydroxy, aikoxy.
  • the substituted alkyl groups may be substituted once or more, with the same or different substitutents.
  • the substituent groups include hydroxy. fluorine, chlorine, brom ine, CF 3 , NH 2 , N HCH 3> N(CH 3 ) 2 , C0 2 CH 3 , SEt, SC i l 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
  • cycloalkyl means, unless otherwise stated, cyc l ic versions of “alkyl”, and “heteroalkyl”, respectively. Additionally, for heterocycloa lkyl, a hclcroatom can occupy the position at which the heterocycle is attached to the remai nder o f the molecule. Examples of cycloalkyl include, but are not l im ited to cyclopropyl.
  • cyclopentyl cyclohexyl, cyclohex- l -enyl, cyclohex-3-enyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamant- l -yl, adamant-2-yl, bicyc lo
  • pentyl cyclopentyl, cyclohexyl, cyclohex- l -enyl, cyclohex-3-enyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamant- l -yl, adamant-2-yl, bicyc lo
  • heterocycloalkyl examples include, but are not limited to piperidinyl, piperidin-2- yl, piperidin-3-yl, morpholin-4-yl, morpholin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran- 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, piperazin-2-yl, and the l ike.
  • aikoxy refers to those alkyl groups attached to the remainder of the molecule via an oxygen atom.
  • aikoxy groups include, but are not l i m ited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, and the like.
  • lower alkoxy refers to "C I to C7 alkoxy” such as methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, tert-butoxy, and the like.
  • C I to C7 alkoxy can be optional ly substituted, meaning that the alkyl portion of the alkoxy can be substituted to form, for example, branched alkoxy, and the l ike.
  • aryl means, unless otherwise stated, a polyunsaturated, typical ly aromatic, hydrocarbon substituent which can be a monocycl ic system or polycyclic ring system (with up to three rings) which are fused together or l inked covalently.
  • the monocycl ic or polycycl ic ring system comprises about 5 to about 1 6 carbon atoms.
  • Suitable examples of aryl groups include, but are not limited to phenyl, naphlhyl, anthracenyl, and the like.
  • heteroaryl means, unless otherwise stated, “aryl” groups that contain from one to four heteroatoms selected from nitrogen, oxygen, and su l fur, wherein the n itrogen and sulfur atoms are optionally oxidized, and one or several nitrogen atom arc optional ly quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-iimiting examples of aryl and heteroaryl groups include phenyl, 1 -naphlhyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl.
  • substituted aryl and “substituted heteroaryl” means, unless otherwise staled, that the aryl and the heteroaryl group is substituted by one or more substitutents, such as halogen, hydroxy, alkoxy, alkoxy-alkyl, oxo, cycloalkyl, napthyl, am ino, (monosubstituted) amino, (disubstituted)amino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxam ide, N-(alkyl)carboxamide, cyano, trifluoromethyl, methylsulfonylam ino, thiol, alkylthio or alkylsulfonyl .
  • the substituted alkyl groups may be substituted once or more, with the same or different substitutents.
  • arylalkyl and “heteroarylalkyl” means, unless otherwise stated, those rad ica ls in wh ich an aryl group is attached to an alkyl group (e.g.. benzyl, phcnethyl, pyridylmethyl, and the l ike) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth- l -yloxy)propyl, and the like).
  • an alkyl group e.g.. benzyl, phcnethyl, pyridylmethyl, and the l ike
  • an oxygen atom e.g., phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth- l -yloxy)prop
  • heteroatom is meant to include oxygen (O), nitrogen (N), and sul fur (S).
  • Substituted herein refers to a substituted moiety, such as a hydrocarbon, e.g., substituted alkyl or aryl wherein at least one element or rad ical, e.g., hydrogen is replaced by another, e.g., hydrogen is replaced by a halogen as in chlorobenzyl .
  • the phrases "independently selected”, “independently” and their variants, when used in reference to two or more of the same substituent group are used herein to mean that that two or more groups can be the same or different.
  • the compound of Formula 1 can comprise two R ' groups, wherein one R 3 group is hydrogen and the other R 3 group is a halogen.
  • the compound of Formula 1 can comprise two R 3 groups, wherein both J groups are -CN.
  • Hydroquinone was converted into 4-propoxyphenol using the synthetic procedure reported in J. Med.Chem., 2006, 49, 3770-3779.
  • 3-Chloro-4-propoxy-p enol 4-propoxyphenol (intermediate Via) was converted into 3-chloro-4-propoxyphenol using modification of the synthetic procedure outlined in WO 200416621 Al by using N- chlorosuccinimide instead of N-bromosuccinimide.
  • 4-isopropoxyphenol (intermediate II) was converted into 3-chloro-4-isopropoxyphenol using modification of the synthetic procedure outlined in WO 200416621 Al by using N- chlorosuccinimide instead of N-bromosuccinimide.
  • Reaction mixture was diluted with water ( 1 50ml) and extracted with diethylether (200ml X 2), washed with water, brine. dried over Na2S04 and evaporated the solvent.
  • the yellow oily crude was purified by column chromatography (Neutral AI203, Hexane) to afford l-(Methoxymethoxy)-3- (tritluoromethoxy) benzene in 60% yield.
  • Methyl hydroquinone was converted into 4-ethoxy-2-methyl-phenol using the synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779
  • Methyl hydroquinone was converted into 2-methyl-4-propoxyphenol using the synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779.
  • Methyl hydroquinone was converted into 2-methyl-4-isopropoxyphenol using synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779
  • the crude material was purified by column over silica using hexane-ethyl acetate system to afford l - ⁇ 4-[2-(4-Isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl ⁇ - ethanone in 80 % yield.
  • Borontribromide (1 .17ml, 1 1.8mmol) in 50 ml of dichloromethane was - added dropwise to a solution of N-(l- ⁇ 4-[2-(2-Chloro-4-isopropoxy-phenoxy)-thiazol-5- yloxy]-phenyl ⁇ -ethyl)-acetamide (2.6g, 5.9mmol) in 20 ml of dichloromethane at -78 °C and stirred at same temperature for 30 minutes.
  • Hydroquinone was converted into 4-cyclopentyloxyphenol using the synthetic procedure reported in J.Med. Chem, 2006, 49, 3770-3779.
  • tert-Butylnitrite (1.21 g, 0.0117 mol) was added dropwise to a stirred solution of copper(l[)bromide (2.1 g, 0.0064 mol) in 30 ml acetonitrile at -10 °C and stirred for 5 min. Then a solution of l-
  • reaction m ixture was heated at 75 °C for 15 hours.
  • the reaction mixture was cooled to room temperature and filtered through celite.
  • the solvent was evaporated under vacuum to obtain crude which was dissolved in water and extracted with ethyl acetate.
  • the combined organic extract was washed with brine and dried over anhydrous sodium sulphate and evaporated to afford crude l - ⁇ 4-[2-(2-Allyl-phenoxy)-thiazol-5-yloxy
  • -phenyl ⁇ - ethylamine which was taken into the next step without any purification.
  • Trifluoroaceticacid 120 ml, 1623 mmol was added dropwise to a solution of 2-( I - Hydroxy-ethyl)-benzene- l ,4-diol (intermediate LXXXII) (25 g, 162 mmol), triethylsi lane (26 ml, 162 mmol) in 250 ml of dichloromethane at 0 °C.
  • the reaction mixture was stirred at room temperature for 1 5 hour. Then the reaction mixture was quenched with ice-cold water and evaporated the solvent. The residue was taken in water and extarcted with ethyl acetate.
  • Methyl iodide (8.6m l, 138 mmol) was added dropwise to a mixture of p-cresol ( 1 0 g. 92.47 mmol) and potassium carbonate (25.5 g, 1 84.94 mmol) in 1 00 m l of M.N- Dimethylformamide at 0 °C. Then the reaction mixture was stirred at room temperature for 1 5 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over anhydrous sodium sulphate and evaporated to afford 1 -Methoxy-4-methyl-benzene in 88% yield.
  • the compound showed IC50 for hACC2 and hACC l of 1.84uM and >40uM respectively.
  • the compound showed IC50 for hACC2 and hACCI of 0.429 uM and 2.2uM respectively.
  • the compound showed IC50 for hACC2 and liACCl of 1.33uM and >50uM respectively.
  • the compound showed IC 50 for hACC2 and hACC l of 0.245uM and 0.57u respectively.
  • the compound showed IC 50 for hACC2 and hACCl of 0.519uM and 0.605uM respectively.
  • the compound showed IC50 for hACC2 and hACCl of 0.17uM and 0.26uM respectively.
  • the compound showed IC 50 for hACC2 and hACCl of 0.306 uM and 0.88 uM respectively.
  • the compound showed 1C 50 for hACC2 and hACCl of 0.25 uM and 0.813 uM respectively.
  • 2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl ⁇ -ethyl)-acetamide was further purified by chiral HPLC using Chiralpak IA (250mm*4.6mm) column and was eluted at 50:50 heptane: ethyl acetate.
  • the first isomer (Isomer A) was eluted at retention time (R ( ) of 11.269 min and the second isomer (Isomer B) was eluted at retention time (R t ) of 16.734 min.
  • R ( ) retention time
  • R t retention time
  • Example 16 N-( I - ⁇ 4-
  • Example 18 N-( 1 - ⁇ 4-
  • N-(l - ⁇ 4-[2-(2-Fluoro-4-hydroxy-phenoxy)-thiazol-5-yloxy]-phenyl ⁇ -ethyl)-acetamide (intermediate LXIV) was reacted with Isopropyl iodide to afford N-(1- ⁇ 4-
  • Example 19 N-( l - ⁇ 4-
  • 2-(2-Fluoro-4-hydroxy-phenoxy)-thiazol-5-yloxy]-phenyl ⁇ -ethyl)-acetamide (intermediate LXIV) was reacted with n-propyl iodide to afford N ⁇ (1 - ⁇ 4-[ 2-(2-Fluoro-4- propoxy-phenoxy)-thiazol-5-yloxy]-phenyl ⁇ -ethyl)-acetamide in 30% yield.
  • Example 20 was further purified by chiral HPLC using Chiraipak IA (250mm*4.6mm) column and was eluted at 100 % ethanol.
  • the first isomer (Isomer A) was eluted at retention time (R t ) of 8.996 minute and the second isomer (Isomer B) was eluted at retention time (R t ) of 10.357 min.
  • R t retention time
  • R t retention time
  • the compound showed IC50 for hACC2 and hACCl of>50uM and >50uM respectively.
  • the compound showed IC 50 for hACC2 and hACCl of >50uM and >50uM respectively.
  • the compound showed 1C 50 for hACC2 of 0.169 uM.
  • the compound showed IC 50 for hACC2 of 0.32 uM and hACCl of 33.4 uM.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés thiazole de formule I ou ses sels, promédicaments, solvates et N-oxydes pharmaceutiquement acceptables, des solvates des sels et N-oxydes phamaceutiquement acceptables; des sels pharmaceutiquement acceptables de N-oxydes, ou des promédicaments, ou des combinaisons ou des mélanges de ceux-ci. L'invention concerne en outre une méthode de prévention ou de traitement d'une pathologie sensible à un inhibiteur de l'acétyl-CoA carboxylase (ACC), faisant appel aux composés de formule (I) ou ses sels, promédicaments, solvates, N-oxydes pharmaceutiquement acceptables; des solvates des sels pharmaceutiquement acceptables et des N-oxydes: des sels pharmaceutiquement acceptables des N-oxydes, ou des promédicaments, ou des combinaisons ou des mélanges de ceux-ci.
PCT/IN2011/000884 2010-12-31 2011-12-21 COMPOSÉS THIAZOLES UTILES COMME INHIBITEURS DE L'ACÉTYL-CoA CARBOXYLASE (ACC) WO2012090219A2 (fr)

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WO2015036892A1 (fr) 2013-09-12 2015-03-19 Pfizer Inc. Utilisation d'inhibiteurs de l'acétyl-coa carboxylase pour traiter l'acné vulgaire
WO2016112305A1 (fr) * 2015-01-09 2016-07-14 Nimbus Apollo, Inc. Thérapie combinée à base d'un inhibiteur de l'acc utilisable en vue du traitement de la stéatose hépatique non alcoolique
WO2016159049A1 (fr) * 2015-03-31 2016-10-06 武田薬品工業株式会社 Composé monocyclique
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CN107207444A (zh) * 2014-11-26 2017-09-26 武田药品工业株式会社 二环化合物
JP2018526413A (ja) * 2015-09-09 2018-09-13 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
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US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors
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US9169205B2 (en) 2012-10-08 2015-10-27 Boehringer Ingelheim International Gmbh Pyrrolidine derivatives, pharmaceutical compositions and uses thereof
JP2015531386A (ja) * 2012-10-08 2015-11-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規ピロリジン誘導体及びそれらのアセチルｃｏａカルボキシラーゼ阻害薬としての使用
WO2014114578A1 (fr) * 2013-01-25 2014-07-31 Boehringer Ingelheim International Gmbh Dérivés de pyrrolidine, compositions pharmaceutiques les contenant et utilisations associées
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JP2016509598A (ja) * 2013-01-25 2016-03-31 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ピロリジン誘導体、その医薬組成物及び使用
WO2014170197A1 (fr) * 2013-04-17 2014-10-23 Boehringer Ingelheim International Gmbh Dérivés de pirrolidine substitués par la pyrimidine, leurs compositions pharmaceutiques et leurs utilisations
US8962641B2 (en) 2013-04-17 2015-02-24 Boehringer Ingelheim International Gmbh Pyrimidine-substituted pyrrolidine derivatives, pharmaceutical compositions and uses thereof
JP2016516790A (ja) * 2013-04-17 2016-06-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ピリミジン置換ピロリジン誘導体、医薬組成物及びこれらの使用
WO2015036892A1 (fr) 2013-09-12 2015-03-19 Pfizer Inc. Utilisation d'inhibiteurs de l'acétyl-coa carboxylase pour traiter l'acné vulgaire
KR101827660B1 (ko) 2013-12-19 2018-02-08 일라이 릴리 앤드 캄파니 플루오로페닐 피라졸 화합물
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