WO2011047481A1 - Novel spiro compounds useful as inhibitors of stearoyl-coenzyme a delta-9 desaturase - Google Patents

Novel spiro compounds useful as inhibitors of stearoyl-coenzyme a delta-9 desaturase Download PDF

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Publication number
WO2011047481A1
WO2011047481A1 PCT/CA2010/001678 CA2010001678W WO2011047481A1 WO 2011047481 A1 WO2011047481 A1 WO 2011047481A1 CA 2010001678 W CA2010001678 W CA 2010001678W WO 2011047481 A1 WO2011047481 A1 WO 2011047481A1
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group
substituted
unsubstituted
alkyl
independently selected
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PCT/CA2010/001678
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French (fr)
Inventor
Rejean Fortin
Nicolas Lachance
Chun Sing Li
Geoffrey Tranmer
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Merck Frosst Canada Ltd.
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Publication of WO2011047481A1 publication Critical patent/WO2011047481A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to heteroaromatic compounds which are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) and the use of such compounds to control, prevent and/or treat conditions or diseases mediated by SCD activity.
  • SCD stearoyl-coenzyme A delta-9 desaturase
  • the compounds of the present invention are useful for the control, prevention and treatment of conditions and diseases related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; cancer; and hepatic steatosis.
  • Co A desaturases At least three classes of fatty acyl-coenzyme A (Co A) desaturases (delta-5, delta-6 and delta-9 desaturases) are responsible for the formation of double bonds in mono- and
  • polyunsaturated fatty acyl-CoAs derived from either dietary sources or de novo synthesis in mammals.
  • the delta-9 specific stearoyl-CoA desaturases (SCDs) catalyze the rate-limiting formation of the cis-double bond at the C9-C10 position in monounsaturated fatty acyl-CoAs.
  • the preferred substrates are stearoyl-CoA and palmitoyl-CoA, with the resulting oleoyl and palmitoleoyl-CoA as the main components in the biosynthesis of phospholipids, triglycerides, cholesterol esters and wax esters (Dobr2yn and Natami, Obesity Reviews, 6: 169-174 (2005)).
  • the rat liver microsomal SCD protein was first isolated and characterized in 1974 (Strittmatter et al., PNAS. 71 : 4565-4569 (1974)).
  • a number of mammalian SCD genes have since been cloned and studied from various species. For example, two genes have been identified from rat (SCD1 and SCD2, Thiede et al., J. Biol. Chem.. 261, 13230-13235 (1986)), Mihara, K., J. Biochem. (Tokyo), 108: 1022-1029 (1990)); four genes from mouse (SCD1, SCD2, SCD3 and SCD4) (Miyazaki et al., J. Biol.
  • ASO inhibition of SCD activity reduced fatty acid synthesis and increased fatty acid oxidation in primary mouse hepatocytes.
  • Treatment of mice with SCD-ASOs resulted in the prevention of diet-induced obesity, reduced body adiposity, hepatomegaly, steatosis, postprandial plasma insulin and glucose levels, reduced de novo fatty acid synthesis, decreased the expression of lipogenic genes, and increased the expression of genes promoting energy expenditure in liver and adipose tissues.
  • SCD inhibition represents a novel therapeutic strategy in the treatment of obesity and related metabolic disorders.
  • the postprandial de novo lipogenesis is significantly elevated in obese subjects (Marques-Lopes, et al., American Journal of Clinical Nutrition, 73 : 252-261 (2001 )).
  • Knockout of the SCD gene ameliorates Metabolic Syndrome by reducing plasma triglycerides, reducing weight gain, increasing insulin sensitivity, and reduces hepatic lipid accumulation (MacDonald, et al., Journal of Lipid Research, 49(1): 217-29 (2007)).
  • There is a significant correlation between a high SCD activity and an increased cardiovascular risk profile including elevated plasma triglycerides, a high body mass index and reduced plasma HDL (Attie, et al., J. Lipid Res., 43: 1899-1907 (2002)).
  • SCD activity plays a key role in controlling the proliferation and survival of human transformed cells (Scaglia and Igal, J. Biol. Chem., (2005)). RNA interference of SCD-1 reduces human tumor cell survival (Morgan-Lappe, et al., Cancer Research, 67(9): 4390-4398 (2007)).
  • inhibitors of SCD activity include non-selective thia-fatty acid substrate analogs [B. Behrouzian and P.H. Buist,
  • SCD inhibitors are also disclosed in the following published international patent application publications: WO 2008/056687; WO 2008/096746; WO 2008/074835; WO 2008/074824; WO 2008/036715; WO 2008/044767; WO 2008/029266; WO 2008/062276; WO 2008/127349; and WO 2009/037542.
  • WO 2008/003753 (assigned to Novartis) discloses a series of pyrazolo[l,5-a]pyrimidine analogs as SCD inhibitors; WO 2007/143697 and WO 2008/024390 (assigned to Novartis and Xenon Pharmaceuticals) disclose heterocyclic derivatives as SCD inhibitors; and WO
  • the present invention is concerned with novel heteroaromatic compounds as inhibitors of stearoyl-CoA delta-9 desaturase which are useful in the treatment and or prevention of various conditions and diseases mediated by SCD activity including those related, but not limited, to elevated lipid levels, as exemplified in non-alcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, metabolic syndrome, and insulin resistance.
  • the present invention relates to heteroaromatic compounds of structural formula I:
  • heteroaromatic compounds are effective as inhibitors of SCD. They are therefore useful for the treatment, control or prevention of disorders responsive to the inhibition of SCD, such as diabetes, insulin resistance, lipid disorders, obesity, atherosclerosis, metabolic syndrome, and cancer.
  • the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also relates to methods for the treatment, control, or prevention of disorders, diseases, or conditions responsive to inhibition of SCD in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
  • the present invention also relates to methods for the treatment, control, or prevention of Type 2 diabetes, insulin resistance, obesity, lipid disorders, atherosclerosis, metabolic syndrome, and cancer by administering the compounds and pharmaceutical compositions of the present invention.
  • the present invention also relates to methods for the treatment, control, or prevention of obesity by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention also relates to methods for the treatment, control, or prevention of Type 2 diabetes by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention also relates to methods for the treatment, control, or prevention of insulin resistance by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention also relates to methods for the treatment, control, or prevention of atherosclerosis by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention also relates to methods for the treatment, control, or prevention of lipid disorders by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention also relates to methods for the treatment, control, or prevention of metabolic syndrome by administering the compounds of the present mvention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention also relates to methods for the treatment, control, or prevention of cancer by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
  • the present invention is concerned with heteroaromatic compounds useful as inhibitors of SCD.
  • Compounds of the present invention are described by structural formula I:
  • A is selected from the group consisting of:
  • g is a single bond or a double bond
  • J and K are each independently selected from the group consisting of: S, O, NH, CH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C3 ⁇ 4 is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C3 ⁇ 4 unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and K are CH;
  • L and M are each independently selected from the group consisting of: S, O, NH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2;
  • T, U, V and W are each independently selected from N and CH, wherein each CH is unsubstituted or substituted with R3, provided that at least two of T, U, V and W are CH;
  • X is CH2, wherein C3 ⁇ 4 is unsubstituted or substituted with R2;
  • Y is independently selected from the group consisting of: O, NH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with
  • Z is independently selected from the group consisting of: S, S(O), S(0)2, O, NH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2;
  • B is selected from the group consisting of:
  • each R1 is independently selected from the group consisting of: hydrogen, halogen, and Ci_3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy; each R2 is independently selected from the group consisting of:
  • each R3 is independently selected from the group consisting of:
  • alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH 2 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines;
  • R4 is selected from the group consisting of:
  • each Ra is independently selected from the group consisting of:
  • Ci-4 alkyl unsubstituted or substituted with one to five fluorines
  • Ci-4 alkoxy unsubstituted or substituted with one to five fluorines
  • C 1 _4 alky lthio unsubstituted or substituted with one to five fluorines
  • each Rh is independently selected from the group consisting of:
  • each R c is independently selected from the group consisting of:
  • any C3 ⁇ 4 in R c is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Cl-4 alkyl unsubstituted or substituted with one to five fluorines; each Rd is independently selected from the group consisting of:
  • any CH 2 in Rd is unsubstituted or substituted with one to two groups independently selected from the group consisting of: halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines; each Re is independently selected from the group consisting of:
  • alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -Ci-4 alkoxy, -Ci-4 alkylthio, -Ci-4 alkylsulfonyl, -C0 2 H, and -C0 2 Ci _4 alkyl; each Rg is independently selected from the group consisting of:
  • Ci_6 alkyl is an integer from 1 to 3;
  • n is an integer from 0 to 3;
  • p is an integer from 1 to 3;
  • q is an integer from 1 to 2;
  • t is an integer from 0 to 8.
  • d is an integer from 0 to 2;
  • e is an integer from 0 to 2
  • A is selected from the group consisting of:
  • A is:
  • A is selected from the group consisting of:
  • A is selected from the group consisting of:
  • A is selected from the group consisting of:
  • A is selected from the group consisting of: In ano ing of:
  • A is:
  • A is:
  • B is selected from the group consisting of
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of
  • B is selected from the roup consisting of:
  • B is selected from the roup consisting of:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B-R 4 is selected from the group consisting of:
  • B-R 4 is In another class of t
  • J and K are each independently selected from the group consisting of: S, O, NH, CH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C3 ⁇ 4 is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C3 ⁇ 4 unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and are CH.
  • J and K are each independently selected from the group consisting of: O, NH, CH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C3 ⁇ 4 is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C3 ⁇ 4 unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and K are CH.
  • g is a single bond
  • J is O and K is CH2, wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • g is a single bond, J is C3 ⁇ 4 and K is O, wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • g is a single bond, J is C3 ⁇ 4 and K is O.
  • g is a single bond, J is C3 ⁇ 4 and K is O, wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • g is a single bond, J and K are CH2, wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • g is a double bond
  • J and K are selected from N and CH, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH is unsubstituted or substituted with R2.
  • g is a double bond
  • J and K are CH, wherein each CH is unsubstituted or substituted with R2.
  • g is a double bond
  • J and K are CH.
  • L and M are each independently selected from the group consisting of: S, O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • M and L are each independently selected from the group consisting of: S, O, NH and C3 ⁇ 4, wherein NH is unsubstituted or substituted with Rg, and wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • M and L are each independently selected from the group consisting of: 0, NH and CH2, wherein NH is unsubstituted or substituted with Rg, and wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • g is a single bond
  • M and L are CH2, wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • g is a single bond
  • T, U, V and W are each independently selected from N and CH, wherein CH is unsubstituted or substituted with R3.
  • T, U, V and W are each CH, wherein CH is unsubstituted or substituted with R3.
  • T, U, V and W are each independently selected from N and CH, wherein CH is unsubstituted or substituted with R3, provided that at least one of T, U, V and W is N.
  • T, U, V and W are each independently selected from N and CH, wherein CH is unsubstituted or substituted with R3, provided that one of T or W is N.
  • T is N and U, V and W are CH, wherein CH is unsubstituted or substituted with R3.
  • T, U, V are CH and W is N, wherein CH is unsubstituted or substituted with R3.
  • X is CH2, wherein C3 ⁇ 4 is
  • Y is independently selected from the group consisting of: O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Z is independently selected from the group consisting of: S, S(O), S(0)2, O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Z is independently selected from the group consisting of: S, O, NH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Z is independently selected from the group consisting of: O, NH and C3 ⁇ 4, wherein each NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • X and Y are C3 ⁇ 4 and Z is O, wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • X and Y are C3 ⁇ 4 and Z is O.
  • Y is C3 ⁇ 4 and Z is O
  • C3 ⁇ 4 is unsubstituted or substituted with R.2.
  • Y is C3 ⁇ 4 and Z is O.
  • X is C3 ⁇ 4, Y is NH and Z is 0, wherein NH is unsubstituted or substituted with Rg, and wherein C3 ⁇ 4 is unsubstituted or substituted with R2.
  • X and Z are C3 ⁇ 4, and Y is NH, wherein NH is unsubstituted or substituted with Rg, and wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Y is O
  • X and Z are C3 ⁇ 4, wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Y is O and Z is CH2, wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Y is O and Z is C3 ⁇ 4.
  • X and Y are CH2and Z is S, wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Y is C3 ⁇ 4and Z is S, wherein each C3 ⁇ 4 is unsubstituted or substituted with R2.
  • Y is C3 ⁇ 4 and Z is S.
  • each Rl is independently selected from the group consisting of: hydrogen, halogen, and Ci-3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy.
  • each Rl is independently selected from the group consisting of:
  • each Rl is hydrogen.
  • each R2 is independently selected from the group consisting of: hydrogen, halogen, oxo, -Ci-6 alkyl, -OCi-6 alkyl, (CH2)nOR e , (CH 2 ) n N(Re)2, (CH 2 ) n C ⁇ N, (CH 2 ) n CORe and (CH 2 ) n S(0) q Re,
  • alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C3 ⁇ 4 in R is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci_4 alkyl unsubstituted or substituted with one to five fluorines.
  • each R2 is independently selected from the group consisting of: hydrogen, halogen, oxo, -C ⁇ -6 alkyl, -OCi-6 alkyl, (CH2) n ORe, (CH2) n N(Re)2, (CH2) n C ⁇ N, and (CH2)nCOR e , wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C3 ⁇ 4 in R2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci_4 alkyl unsubstituted or substituted with one to five fluorines.
  • each R2 is independently selected from the group consisting of: hydrogen, halogen, and oxo. In another subclass of this class, each R2 is independently selected from the group consisting of: hydrogen, bromo, chloro, fluoro, and oxo. In another subclass of this class, each R2 is independently selected from the group consisting of: hydrogen, and oxo. In another subclass of this class, each R2 is hydrogen. In another subclass of this class, each R2 is oxo.
  • R3 is independently selected from the group consisting of: hydrogen, halogen, -Ci-6 alkyl, -OCi-6 alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2) n C ⁇ N, (CH2) n CORe, and (CH2) n S(0) q Re wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any CH2 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • R is independently selected from the group consisting of: hydrogen, halogen, -Ci-6 alkyl, -OCi-6 alkyl, (CH2) n ORe, (CH2) n N(Re)2, (CH2) n C ⁇ N, and (CH2) n CORe, wherein alkyl is
  • any C3 ⁇ 4 in R is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • R3 is independently selected from the group consisting of: hydrogen, halogen, -Ci- 6 alkyl, -OH, and -OCi-6 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C3 ⁇ 4 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • R3 is independently selected from the group consisting of: hydrogen, halogen, -Ci-6 alkyl, -OH, and -OCi-6 alkyl.
  • R3 is independently selected from the group consisting of: hydrogen, halogen, -OH, and -OCi-6 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any C3 ⁇ 4 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, -OH, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • R3 is independently selected from the group consisting of: hydrogen, halogen, -OH, and -OCi-6 alkyl.
  • R is independently selected from the group consisting of: hydrogen, halogen, -OH and OCH3.
  • R3 is independently selected from the group consisting of: -OH and OCH3.
  • R is independently selected from the group consisting of: hydrogen, and halogen.
  • R is independently selected from the group consisting of: hydrogen, bromo, chloro and fluoro.
  • R3 is independently selected from the group consisting of:
  • R3 is independently selected from the group consisting of: hydrogen, and chloro. In another subclass of this class, R is chloro. In another subclass of this class, R3 is halogen. In another subclass of this class, R is
  • R independently selected from the group consisting of: bromo, chloro and fluoro.
  • R is independently selected from the group consisting of: chloro and fluoro.
  • R3 is chloro.
  • R4 is selected from the group consisting of: heteroaryl, and cycloheteroalkyl, wherein any NH group is unsubstituted or substituted with R c , and wherein any CH or CH 2 group is unsubstituted or substituted with 1 to 2 substituents selected from Rd.
  • R4 is heteroaryl, wherein any NH group is unsubstituted or substituted with R c , and wherein any CH or CH 2 group is unsubstituted or substituted with one substituent selected from Rd.
  • R4 is heteroaryl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH group is unsubstituted or substituted with one substituent selected from Rd.
  • R4 is cycloheteroalkyl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH or CH 2 group is unsubstituted or substituted with one substituent selected from Rd.
  • R4 is cycloheteroalkyl, wherein any NH group is unsubstituted or substituted with R c , and wherein any CH 2 group is unsubstituted or substituted with one to two substituents selected from Rd.
  • R4 is selected from the group consisting of
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R4 is:
  • R4 is:
  • R4 is:
  • R4 is:
  • R is:
  • R4 is:
  • each R a is independently selected from the group consisting of: hydrogen, halogen, cyano, Ci-4 alkyl, unsubstituted or substituted with one to five fluorines, Ci-4 alkoxy, unsubstituted or substituted with one to five fluorines, Ci-4 alkylthio, unsubstituted or substituted with one to five fluorines, Ci_4 alkylsulfonyl, -CO2H, Ci_ 4 alkyloxycarbonyl, and Ci_4 alkylcarbonyl.
  • Ra is independently selected from the group consisting of: hydrogen, halogen, cyano, and C[-4 alkyl, unsubstituted or substituted with one to five fluorines.
  • Ra is independently selected from the group consisting of: hydrogen, and Ci_4 alkyl, unsubstituted or substituted with one to five fluorines.
  • Ra is hydrogen.
  • R a is Ci-4 alkyl, unsubstituted or substituted with one to five fluorines.
  • R a is Ci-4 alkyl.
  • each Rb is independently selected from the group consisting of: hydrogen, and C1-.4 alkyl, wherein alkyl is unsubstituted or substituted with one to five fluorines.
  • Rb is hydrogen.
  • Rb is Ci-4 alkyl, wherein alkyl is unsubstituted or substituted with one to five fluorines.
  • Rb is C 1.4 alkyl.
  • each R c is independently selected from the group consisting of: -(CH2) m C0 2 H, -(CH2) m C02Ci-3 alkyl, -(CH2) m -NRb-(CH2)pC0 2 H,
  • R c is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1.4 alkyl unsubstituted or substituted with one to five fluorines.
  • R c is selected from the group consisting of: -(CH2)mC02H, - (CH 2 )mC02Ci- 3 alkyl, -(CH 2 ) m OCOH, -(CH 2 ) m OCOCi-3 alkyl, -(CH 2 ) m COH, - (CH 2 )mCOCi-3 alkyl, -(CH 2 )m-NRb-(CH2)pC0 2 H, -(CH2)m-NRb-(CH2)pC0 2 Ci-3 alkyl, - (CH2)m-0-(CH2)pC02H, and -(CH 2 )m-0-(CH2) p C0 2 Ci-3 alkyl, wherein any CH 2 in Rc is unsubstit
  • R c is selected from the group consisting of: -(CH2)mC02H, - (CH2)mC0 2 Ci -3 alkyl, -(CH 2 ) m OCOH, -(CH 2 ) m OCOCi_ 3 alkyl, -(CH 2 ) m COH, and - (CH 2 ) m COCi-3 alkyl, wherein any CH 2 in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • Rc is selected from the group consisting of: -(CH 2 ) m C0 2 H, -(CH 2 ) m C0 2 C i .3 alkyl, -(CH 2 ) m OCOH, -
  • Rc is selected from the group consisting of: -(CH 2 )mC0 2 H, and -(CH 2 ) m C0 2 Ci-3 alkyl, wherein any CH 2 in R c is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1.4 alkyl unsubstituted or substituted with one to five fluorines.
  • Rc is -(CH 2 )mC0 2 H.
  • Rc is -(CH ) m C0 2 Ci-3 alkyl.
  • each Rd is independently selected from the group consisting of: -(CH 2 ) n C0 2 H, -(CH 2 ) n C0 2 Ci-3 alkyl, -(CH 2 ) n -NRb-(CH 2 ) p C0 2 H, -
  • each Rd is independently selected from the group) consisting of: -(CH 2 ) n C0 2 H, -(CH 2 ) n C0 2 Ci_3 alkyl, -(CH 2 ) n -NRb-(CH 2 ) p C0 2 H, -(CH 2 ) n - NRb-(CH 2 ) p C0 2 Ci-3 alkyl, -(CH 2 ) n -0-(CH 2 ) p C0 2 H, and -(CH 2 )n-0-(CH 2 ) p C0 2 Ci-3 alkyl, wherein any CH 2 in Rd is unsubstituted or substituted with one to two grou P s independently selected from the group consisting of: halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • Rd is selected from the group consisting of: -(CH 2 ) n C0 2 H, -(CH 2 ) n C0 2 Ci-3 alkyl, -(CH 2 ) n -NRb-(CH 2 ) p C0 2 H, and -(CH 2 )n-NRb-(CH 2 ) p C0 2 Ci_3 alkyl, wherein any CH 2 in R is unsubstituted or substituted with one to two groupjs independently selected from halogen, hydroxy, and C1.4 alkyl unsubstituted or substituted with one to five fluorines.
  • Rd is selected from the group* consisting of: -(CH 2 ) n C0 2 H, and -(CH 2 ) n -NRb-(CH 2 ) p C0 2 H, wherein any CH 2 in R is unsubstituted or substituted with one to two group>s independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • Rd is selected from the group consisting of: -CH 2 C0 2 H, and - NH-CH 2 C0 2 H.
  • Rd is -CH 2 C0 2 H.
  • Rd is -NH-CH 2 C0 2 H.
  • each R e is independently selected from the group consisting of: hydrogen, and Ci_6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, cyano, -Ci-4 alkoxy, -Ci-4 alkylthio, -Ci-4 alkylsulfonyl, -CO2H, and -CO2C1.4 alkyl.
  • R e is hydrogen.
  • Re is Ci-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -Ci-4 alkoxy, -Ci-4 alkylthio, -Ci_4 alkylsulfonyl, -CO2H, and -CO2C1-4 alkyl.
  • R e is Ci-6 alkyl.
  • each Rg is independently selected from the group consisting of: hydrogen, and Ci-6 alkyl.
  • Rg is hydrogen.
  • Rg is Ci-6 alkyl.
  • g is a single bond or a double bond. In a class of this embodiment, g is a single bond. In another class of this embodiment, g is a double bond.
  • m is 1, 2, or 3.
  • s is 1 or 2.
  • m is 2 or 3.
  • m is 1 or 3.
  • m is 1.
  • m is 2.
  • m is 3.
  • n is 0, 1, 2 or 3. In a class of this embodiment, n is 0, 1 or 2. In another class of this embodiment, n is 0 or 1. In another class of this embodiment, n is 1 or 2. In another class of this embodiment, n is 0 or 2. In another class of this embodiment, n is 0. In another class of this embodiment, n is 1. In another class of this embodiment, n is 2. In another class of this embodiment, n is 3.
  • p is 1, 2, or 3. In a class of this embodiment, p is 1 or 2. In another class of this embodiment, p is 2 or 3. In another class of this embodiment, p is 1 or 3. In another class of this embodiment, p is 1. In another class of this embodiment, p is 2. In another class of this embodiment, p is 3.
  • q is 1 or 2. In another class of this embodiment, q is 1. In another class of this embodiment, q is 2.
  • r is 0, 1 , 2 or 3. In a class of this embodiment, r is 0, 1 or 2. In another class of this embodiment, r is 0 or 1. In another class of this embodiment, r is 1 or 2. In another class of this embodiment, r is 0 or 2. In another class of this embodiment, r is 0. In another class of this embodiment, r is 1. In another class of this embodiment, r is 2. In another class of this embodiment, r is 3.
  • s is 0, 1, 2, 3 or 4. In a class of this embodiment, s is 0, 1, 2 or 3. In a class of this embodiment, s is 0, 1 or 2. In another class of this embodiment, s is 0 or 1. In another class of this embodiment, s is 1 or 2. In another class of this embodiment, s is 0 or 2. In another class of this embodiment, s is 0. In another class of this embodiment, s is 1. In another class of this embodiment, s is 2. In another class of this embodiment, s is 3. In another embodiment of the present invention, t is 0, 1 , 2, 3, 4, 5, 6, 7 or 8. In a class of this embodiment, t is 0, 1 , 2, 3 or 4. In a class of this embodiment, t is 0, 1, 2 or 3.
  • t is 0, 1 or 2. In another class of this embodiment, t is 0 or 1. In another class of this embodiment, t is 1 or 2. In another class of this embodiment, t is 0 or 2. In another class of this embodiment, t is 0. In another class of this embodiment, t is 1. In another class of this embodiment, t is 2. In another class of this embodiment, t is 3. In another class of this embodiment, t is 4. In another class of this embodiment, t is 5. In another class of this embodiment, t is 6. In another class of this embodiment, t is 7. In another class of this embodiment, t is 8.
  • d is 0, 1 or 2. In a class of this embodiment, d is 0. In another class of this embodiment, d is 1. In another class of this embodiment, d is 2.
  • e is 0, 1 or 2. In a class of this embodiment, e is 0. In another class of this embodiment, e is 1. In another class of this embodiment, e is 2.
  • d is 0, and e is 2.
  • d is 1 and e is 1. In another embodiment of the present invention, d is 2 and e is 0.
  • the invention relates to compounds of structural formula I, wherein:
  • A is selected from the group consisting of:
  • R3 is independently selected from the group consisting of: hydrogen, halogen and -OCH3; and s is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • the invention relates to compounds of structural formula la:
  • the invention relates to compounds of structural formula lb:
  • the invention relates to compounds of structural formula Ic :
  • the invention relates to compounds of structural formula Id:
  • the invention relates to compounds of structural formula Ie:
  • the invention relates to compounds of structural formula If:
  • the invention relates to compounds of structural formula Ig:
  • the invention relates to compounds of structural formula Ih:
  • the invention relates to compounds of structural formula Ii:
  • the invention relates to compounds of structural formula Ij:
  • A is selected from the group consisting of:
  • B is selected from the group consisting of:
  • R3 is independently selected from the group consisting of: hydrogen, and halogen; and s is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. When no number of carbon atoms is specified, Ci-6 is intended.
  • alkenyl shall mean straight or branched-chain alkenes having the specified number of carbon atoms. Examples of alkenyl include vinyl, 1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • alkynyl refers to straight or branched-chain alkynes having the specified number of carbon atoms. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, and the like.
  • alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Ci _6 alkoxy), or any number within this range [i.e., methoxy
  • alkylthio refers to straight or branched chain alkylsulfides of the number of carbon atoms specified (e.g., Ci-6 alkylthio), or any number within this range [i.e., methylthio
  • alkylsulfonyl refers to straight or branched chain alkylsulfones of the number of carbon atoms specified (e.g., Ci -6 alkylsulfonyl), or any number within this range [i.e., methylsulfonyl (MeS02-), ethylsulfonyl, isopropylsulfonyl, etc.].
  • alkyloxycarbonyl refers to straight or branched chain esters of a carboxylic acid derivative of the present invention of the number of carbon atoms specified (e.g., Ci-6 alkyloxycarbonyl), or any number within this range [i.e., methyloxycarbonyl (MeOCO-), ethyloxycarbonyl, or butyloxycarbonyl].
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
  • Cycloalkyl means a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group generally is monocyclic unless stated otherwise. Cycloalkyl groups are saturated unless otherwise defined.
  • Cycloheteroalkyl means nonaromatic, mono- or bicyclic or bridged saturated carbocyclic rings, each having from 2 to 14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. Examples of cycloheteroalkyl include
  • cycloheteroalkyl ring may be substituted on the ring carbons and
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic.
  • heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (in particular, l,3,4-oxadiazol-2-yl and l,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphth
  • 5 membered heteroaryl ring means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N.
  • 5 membered heteroaryl rings include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (in particular, l,3,4-oxadiazol-2-yl and l,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, and the like.
  • Halogen refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine is most preferred when the halogens are substituted on an alkyl or alkoxy group (e.g. CF3O and CF3CH2O).
  • Compounds of structural formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomenc mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of structural formula I.
  • diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • any stereoisomer of a compound of the general structural formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomenc mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by
  • Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of structural formula I.
  • different isotopic forms of hydrogen (H) include protium ( H) and deuterium ( H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within structural formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • references to the compounds of structural formula I are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N- di
  • esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl
  • acyl derivatives of alcohols such as acetyl, pivaloyl, benzoyl, and aminoacyl
  • esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.
  • Solvates, in particular hydrates, of the compounds of structural formula I are included in the present invention as well.
  • the subject compounds are useful in a method of inhibiting the stearoyl-coenzyme A delta-9 desaturase enzyme (SCD) in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • SCD stearoyl-coenzyme A delta-9 desaturase enzyme
  • a condition or disease mediated by high or abnormal SCD enzyme activity is defined as any disease or condition in which the activity of SCD is elevated and/or where inhibition of SCD can be demonstrated to bring about symptomatic improvements for the individual so treated.
  • a condition or disease mediated by high or abnormal SCD enzyme activity includes, but is not limited to cardiovascular disease, dyslipidemias, (including but not limiting to disorders of serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, cholesterol, and total cholesterol, hypercholesterolemia, as well as cholesterol disorders), familial combined hyperlipidemia, coronary artery disease,
  • Atherosclerosis heart disease
  • cerebrovascular disease including but not limited to stroke, ischemic stroke, and transient ischemic attack
  • peripheral vascular disease including but not limited to stroke, ischemic stroke, and transient ischemic attack
  • ischemic retinopathy ischemic retinopathy
  • a condition or disease mediated by high or abnormal SCD enzyme activity also includes metabolic syndrome (including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cacahexia, and anorexia), weight loss, body mass index and leptin-related diseases.
  • metabolic syndrome including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability
  • Syndrome X diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cacahexia, and anorexia), weight loss, body mass index and leptin-related diseases.
  • a condition or disease mediated by high or abnormal SCD enzyme activity also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis, alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug- induced hepatitis,
  • erythrohepatic protporphyria iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.
  • one aspect of the present invention concerns a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment, which comprises administering to said patient an effective amount of a compound in accordance with structural formula I or a pharmaceutically salt or solvate thereof.
  • a second aspect of the present invention concerns a method of treating non-insulin dependent diabetes mellitus (Type 2 diabetes) in a mammalian patient in need of such treatment comprising administering to the patient an antidiabetic effective amount of a compound in accordance with structural formula I.
  • Type 2 diabetes non-insulin dependent diabetes mellitus
  • a third aspect of the present invention concerns a method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat obesity.
  • a fourth aspect of the invention concerns a method of treating metabolic syndrome and its sequelae in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat metabolic syndrome and its sequelae.
  • the sequelae of the metabolic syndrome include hypertension, elevated blood glucose levels, high triglycerides, and low levels of HDL cholesterol.
  • a fifth aspect of the invention concerns a method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia,
  • hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat said lipid disorder.
  • a sixth aspect of the invention concerns a method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount effective to treat atherosclerosis.
  • a seventh aspect of the invention concerns a method of treating cancer in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount effective to treat cancer.
  • a further aspect of the invention concerns a method of treating a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)
  • neurodegenerative disease (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with structural formula I in an amount that is effective to treat said condition.
  • Yet a further aspect of the invention concerns a method of delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) other conditions and disorders where insulin resistance is a component, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with structural formula I in an
  • Yet a further aspect of the invention concerns a method of reducing the risk of developing a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)
  • hyperlipidemia (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with structural formula I in an amount that is effective to reduce the risk of developing said condition.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent, such as a mouse, species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the present invention is further directed to a method for the manufacture of a medicament for inhibiting stearoyl-coenzyme A delta-9 desaturase enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or diluent. More particularly, the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating a condition selected from the group consisting of hyperglycemia, Type 2 diabetes, insulin resistance, obesity, and a lipid disorder in a mammal, wherein the lipid disorder is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia,
  • hypercholesterolemia low HDL, and high LDL.
  • the subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom inhibition of stearoyl-coenzyme A delta-9 desaturase enzyme activity is desired.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • SCD stearoyl-coenzyme A delta-9 desaturase
  • the potency of compounds of formula I against the stearoyl-CoA desaturase was determined by measuring the conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCD1 following previously published procedures with some modifications (Joshi, et al., J. Lipid Res., 18: 32-36 (1977); Talamo, et al., Anal. Biochem, 29: 300-304 (1969)). Liver microsome was prepared from male Wistar or Spraque Dawley rats on a high carbohydrate diet for 3 days (LabDiet # 5803, Purina).
  • the livers were homogenized (1 : 10 w/v) in a buffer containing 250 mM sucrose, 1 mM EDTA, 5 mM DTT and 50 mM Tris-HCl (pH 7.5). After a 100,000 x g centrifugation for 60 min, the liver microsome pellet was suspended in a buffer containing 100 mM sodium phosphate, 20% glycerol, 2 mM DTT, and stored at -78 °C.
  • Human SCD1 desaturase system was reconstituted using human SCD1 from a baculovirus/Sf9 expression system, cytochrome B5 and cytochrome B5 reductase. Typically, test compound in 2 ⁇ , DMSO was incubated for 15 min at room temperature with 180 ⁇ . of the
  • the culture media was removed and the labeled cells were washed with PBS (3 x 1 mL) at room temperature.
  • the labeled cellular lipids were hydrolyzed under nitrogen at 65 °C for 1 h using 400 ⁇ , of 2N sodium hydroxide plus 50 ⁇ , of L-a-phosphatidylcholine (2 mg/mL in isopropanol, Sigma #P-3556).
  • the radioactive species were extracted with 300 ⁇ , of acetonitrile and quantified on a HPLC that was equipped with a C-18 reverse phase column and a Packard Flow Scintillation Analyzer.
  • the levels of [ 1 C]-oleic acid over [ I4 C]- stearic acid, [ 1 C]-arachidonic acid over [ I4 C]-eicosatrienoic acid, and [ 14 C]-eicosatetraenoic acid (8, 11, 14, 17) over [ 14 C]-linolenic acid were used as the corresponding activity indices of SCD, delta-5 and delta-6 desaturase, respectively.
  • the SCD inhibitors of formula I including the compounds of Examples 1 to 10, exhibit an SCD inhibition constant IC50 of less than 1 ⁇ .
  • Preferred compounds of the present invention exhibit an SCD inhibition constant IC50 of less than 0.1 ⁇ .
  • the in vivo efficacy of compounds of formula I was determined by following the conversion of [l- 14 C]-stearic acid to [1- 14 C]oleic acid in animals as exemplified below. Mice were dosed with a compound of formula I and one hour later the radioactive tracer, [1- 14 C]- stearic acid, was dosed at 20 ⁇ /kg IV. At 3 h post dosing of the compound, the liver was harvested and then hydro lyzed in 10 N sodium hydroxide for 24 h at 80 °C, to obtain the total liver fatty acid pool.
  • the subject compounds are further useful in a method for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be administered in combination with a compound of formula I, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
  • troglitazone pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, and the like
  • PPARa/ ⁇ dual agonists such as KRP-297, muraglitazar, naveglitazar, Galida, TAK-559, PPARa agonists, such as fenofibric acid derivatives
  • sulfonylureas and other insulin secretagogues such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • GLP-1 GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (NN-221 1), CJC-1131, LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;
  • GIP and GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists;
  • PACAP PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/ ⁇ dual agonists, such as naveglitazar and muraglitazar, (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) HMG
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yl or Y5 antagonists, CB1 receptor inverse agonists and antagonists, ⁇ 3 adrenergic receptor agonists, melanocortin-receptor agonists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor subtype-3 agonists), and melanin-concentrating hormone (MCH) receptor antagonists;
  • MCH melanin-concentrating hormone
  • agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan), beta blockers and calcium channel blockers;
  • GKAs glucokinase activators
  • r inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib;
  • Dipeptidyl peptidase-IV inhibitors that can be combined with compounds of structural formula I include those disclosed in US Patent No. 6,699,871; WO 02/076450 (3 October 2002); WO 03/004498 (16 January 2003); WO 03/004496 (16 January 2003); EP 1 258 476 (20
  • DPP-IV inhibitor compounds include sitagliptin (M -0431); vildagliptin (LAP 237); denagliptin; P93/01; saxagliptin (BMS 477118);
  • Antiobesity compounds that can be combined with compounds of structural formula I include fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y] or Y5 antagonists, cannabinoid CB1 receptor antagonists or inverse agonists, melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists, and melanin-concentrating hormone (MCH) receptor antagonists.
  • MCH melanin-concentrating hormone
  • Patents, 11 1677- 1692 (2001 ); D. Spanswick and K. Lee, "Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237 (2003); and J.A. Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity,” Drugs, 62: 915-944 (2002).
  • Neuropeptide Y5 antagonists that can be combined with compounds of structural formula I include those disclosed in U.S. Patent No. 6,335,345 (1 January 2002) and WO
  • Cannabinoid CB 1 receptor antagonists that can be combined with compounds of formula I include those disclosed in PCT Publication WO 03/007887; U.S. Patent No. 5,624,941, such as rimonabant; PCT Publication WO 02/076949, such as SLV-319; U.S. Patent No.
  • One particular aspect of combination therapy concerns a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, in a mammalian patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of structural formula I and an HMG-CoA reductase inhibitor.
  • this aspect of combination therapy concerns a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia in a mammalian patient in need of such treatment
  • the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.
  • a method of reducing the risk of developing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelae of such conditions comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of structural formula I and an HMG- CoA reductase inhibitor.
  • a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprising administering to said patient an effective amount of a compound of structural formula I and an HMG-CoA reductase inhibitor.
  • the HMG-CoA reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.
  • a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin and further comprising administering a cholesterol absorption inhibitor.
  • a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin and the cholesterol absorption inhibitor is ezetimibe.
  • composition which comprises: (1) a compound of structural formula I;
  • DPP-IV dipeptidyl peptidase IV
  • insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, and the like) and other PPAR ligands, including PPARa/ ⁇ dual agonists, such as KRP-297, muraglitazar, naveglitazar, Galida, TAK-559, PPARa agonists, such as fenofibric acid derivatives
  • sulfonylureas and other insulin secretogogues such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;
  • a-glucosidase inhibitors such as acarbose and miglitol
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • GLP-1 GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (NN-2211), CJC-1 131, LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;
  • GIP and GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists;
  • PACAP PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;
  • statins lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins
  • sequestrants cholestyramine, colestipol, and
  • dialkylaminoalkyl derivatives of a cross-linked dextran (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/ ⁇ dual agonists, such as naveglitazar and muraglitazar, (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl
  • CoAxholesterol acyltransferase inhibitors such as avasimibe, and (viii) antioxidants, such as probucol;
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yi or Y5 antagonists, CB1 receptor inverse agonists and antagonists, ⁇ 3 adrenergic receptor agonists, melanocortin-receptor agonists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor subtype-3 agonists), and melanin-concentrating hormone (MCH) receptor antagonists;
  • agents intended for use in inflammatory conditions such as aspirin, non- steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;
  • NSAIDs non- steroidal anti-inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • antihypertensive agents such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan), beta blockers and calcium channel blockers;
  • GKAs glucokinase activators
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • topical application shall include mouthwashes and gargles.
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • diabetes mellitus and or hyperglycemia When treating or preventing diabetes mellitus and or hyperglycemia or
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of structural formula I can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific example.
  • the compound illustrated in the example is not, however, to be construed as forming the only genus that is considered as the invention.
  • the Example further illustrates details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
  • Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESMS).
  • ACN is acetonitrile; Ac 2 0 is acetic anhydride; AcOH is acetic acid; Boc is tert- butyloxycarbonyl; CeliteTMis diatomaceous earth; CuS0 4 is copper sulfate; DBU is 1,8- diazabicyclo[5.4.0]undec-7-ene; DCM is dichloromethane; DIPEA or DIEA is diisopropyl ethyl amine; DMF is N, N-dimethylformamide; equiv is equivalent(s); ESI is electrospray ionization; Et 3 N is triethylamine; EA and EtOAc is ethyl acetate; EtOH is ethyl alcohol; Et 2 0 is diethyl ether; Et 3 N is triethyl amine; g is gram(s); h is hour(s); HC1 is hydrochloric acid; K 2 C0 3 is potassium carbonate; LC is
  • MeCN is acetonitrile
  • MeOH is methyl alcohol
  • MgS0 magnesium sulfate
  • min minute(s)
  • MS mass spectrum
  • MTBE methyl tert-butyl ether
  • NaOH is sodium hydroxide
  • NaN 3 is sodium azide
  • NBS is N-bromosuccinamide
  • NMP is N-methyl-2- pyrrolidinone
  • NMR nuclear magnetic resonance spectroscopy
  • PE is pet ether
  • Ph is phenyl
  • the spiro moieties can be prepared according to the procedures described by L. Yang., et. al., Bioorg. Med. Che,. Lett., 8, 107-1 12 (1998). Here is an illustration with A-5.
  • the carbonyl of intermediate A-3 is then reduced in a 2-step sequence via alcohol A-4 to give the spiro-cyclic amine intermediate A-5 for further coupling reaction.
  • the spiro intermediate A-5 is either isolated as a free base or a salt with an acid such as HC1 or TFA.
  • R 3 OH in A-4, it can be further reacted with an alkyl or benzyl group to provide the corresponding alkylated analog.
  • Step 1 l-(2-Chloro-6-hvdroxyphenyl)ethanone.
  • DCM 500 mL
  • DIEA 554 g, 4.29 mol, 11.00 equiv
  • chloro(methoxy)methane 380 g, 10.00 equiv
  • the resulting mixture was allowed to react, with stirring, for 4 h at 20 °C.
  • the reaction mixture was then quenched with water.
  • the separated organic phase was washed with water (2x), dried over Na 2 S0 4 and then concentrated under vacuum to give l-chloro-3-(methoxymethoxy)benzene as a white oil.
  • Step 2 tert-Butyl 5 -chloro-4-oxo-3 ,4-dihydro- 1 ⁇ -spiro [chromene-2,4'-piperidinel - 1 '- carboxylate.
  • a mixture of ierf-butyl 4-oxopiperidine-l-carboxylate (14 g, 70.35 mmol, 1.00 equiv), pyrrolidine (7 g, 98.59 mmol, 1.40 equiv) and l-(2-chloro-6-hydroxyphenyl)ethanone (12 g, 70.59 mmol, 1.00 equiv) in MeOH (150 mL) was reacted at 65 °C for 20 min.
  • Step 3 tert-Butyl 5-chloro-4-hvdroxy-3,4-dihydro-rH-spiro chromene-2,4'-piperidine1-r- carboxylate.
  • tert-butyl 5-chloro-4-oxo-3,4-dihydro-l'H-spiro[chromene-2,4'- piperidine]-l'-carboxylate (30 g, 85.27 mmol, 1.00 equiv) in EtOH (300 mL) was added portionwise NaB3 ⁇ 4 (3.3 g, 87.23 mmol, 1.02 equiv) at 25 °C over 30 min.
  • Step 4 5-Chloro-3,4-dihvdrospiro[ " chromene-2,4'-piperidine] hydrochloride salt.
  • Step 1 Ethyl N- ⁇ [(2,2-dimethoxyethyl)aminolcarbonyl I glycinate To a solution of ethyl isocyanatoacetate (8.84 mL, 77 mmol) in CH 2 C1 2 (100 mL) at 0 °C was added
  • Step2 Ethyl (2-oxo-2,3-dihydro- lH-imidazol- 1 -vDacetate
  • acetic acid 20 mL
  • 80% aqueous formic acid 80 mL, 1669 mmol
  • the mixture was stirred at 65 °C for lh. Most volatile materials were removed in vacuo.
  • the residue was diluted with a small amount of water (-10 to 20 mL), and then extracted with EtOAc (3 x 50 mL).
  • Step 1 5-Chloro- 1 '-pyrazin-2-yl-3 ,4-dihydrospirorchromene-2,4'-piperidine]
  • 2-chloropyrazine 516 mg, 4.5 mmol
  • DBU 680 mg, 4.5 mmol
  • NMP 3 mL
  • Step 2 r-(5-Bromop azin-2-yl)-5-cMoro-3,4-dihydrospiro[chromene-2,4'-piperidine]
  • NBS 445 mg, 2.5 mmol
  • the mixture was stirred at 0°C over 1 hour and then warmed to 25°C, stirred for 16 h.
  • the resulting mixture was diluted with saturated NaHC0 3 , and extracted with DCM (3x).
  • the crude reaction mixture was filtered under vacuum on a sintered glass funnel, and the filter cake was rinsed with ethanol (2 x 50 mL) and hexanes (200 mL). The filter cake was further dried under vacuum to provide the title compound as a white crystalline solid.
  • Step 2 2-(Benzylamino)pyrimidine-5-carbonitrile
  • N-benzyl-5-bromopyrimidin-2- amine 150 g, 568 mmol
  • copper(I) cyanide 64 g , 710 mmol
  • DMF 1.5 L
  • the reaction mixture was heated to 150 °C for 16 h.
  • the reaction mixture was then cooled to room temperature and poured into a 3 L separatory funnel containing 750 mL of a 1 : 1 :2 solution of saturated NH 4 Cl/concentrated NH 4 0H/water.
  • the aqueous layer was extracted with MeTHF (3 x 500 mL) and the combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The resulting product was utilized in the subsequent step without further purification.
  • Step 3 N-Benzyl-5-(2H-tetrazol-5-yl)pyrimidin-2-amine
  • 2- (benzylamino)pyrimidine-5-carbonitrile 34 g, 162 mmol
  • sodium azide 13 g, 202 mmol
  • ammonium chloride 35 g , 647 mmol
  • DMF 340 mL
  • Step 4 Ethyl ⁇ 5-[2-(benzylamino)pyrimidin-5-yl1-2 /-tetrazol-2-yl
  • N-benzyl-5-(2H- tetrazol-5-yl)pyrimidin-2-amine 31.9 g, 126 mmol
  • ethyl bromoacetate 21 mL, 188 mmol
  • triethylamine 35 mL, 251 mmol
  • THF 390 mL
  • Step 5 Ethyl 5-(2-aminopyrimidin-5-yl)-2H-tetrazol-2-yl]acetate
  • MeCN 300 mL
  • water 60 mL
  • cerium ammonium nitrate 114 g, 208 mmol
  • Step 6 Ethyl 5-(2-chloropyrimidin-5-yl)-2H-tetrazol-2-yl]acetate
  • ethyl [5-(2- aminopyrimidin-5-yl)-2H-tetrazol-2-yl]acetate (16.6 g , 66 mmol) in 1 ,2-dichloroethane (330 mL) was treated with antimony (III) chloride (19.3 mL, 266 mmol).
  • the mixture was cooled to 0 °C in an ice bath and tert-butyl nitrite (44 mL, 332 mmol) was added dropwise to the reaction mixture over 15 min.
  • the mixture was diluted with saturated aqueous NaHC0 3 solution (200 mL) and CH 2 C1 2 (200 mL) and the resulting suspension was filtered through a pad of CeliteTM on a sintered glass funnel under vacuum.
  • the filtrate was poured into a 2 L separatory funnel containing saturated aqueous NaHC0 3 solution (250 mL) and the aqueous layer was extracted with CH 2 C1 2 (3 x 200 mL).
  • the combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure the crude product.
  • Step 1 Ethyl ⁇ 5- 2-(5-chloro-3,4-dihydro- 1 'H-spirorchromene-2,4'-piperidin]- 1 '-vDpyrimidin-S- yl] -2H-tetrazol-2-yl ⁇ acetate
  • ethyl [5-(2-chloropyrimidin-5-yl)-2H-tetrazol-2- yl]acetate 80 mg, 0.298 mmol
  • 5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidinium] chloride 106 mg, 0.387 mmol
  • the tube was sealed and immersed into a preheated oil bath at 130 °C, and stirred at this temperature for 20 min.
  • the reaction was diluted with EtOAc, poured into 0.5 N HCl, extracted with EtOAc, washed with water (3x) and brine, dried (Na 2 S0 4 ), filtered and concentrated.
  • the resulting residue was purified twice by flash chromatography on Si0 2 (10 g; gradient 0 to 60%
  • Step 2 5- 1 " 2-(5 -Chloro-3 ,4-dihydrospiro ⁇ 2H- 1 -benzopyran-2,4'-piperidin1 - 1 '-yl)-5-pyrimidinyl1 - 2H-tetrazole-2-acetic acid
  • Step 1 Ethyl ⁇ 3-r2-(5-chloro-3,4-dihydro- H-spiro[chromene-2 ⁇ '-piperidin]- -yl pyrimidin-5- yl]-2-oxo-2,3-dihydro-lH-imidazol-l-yl ⁇ acetate
  • a mixture of -(5-bromopyrazin-2-yl)-5- chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] 250 mg, 0.64 mmol
  • ethyl (2-oxo-2,3- dihydro-1 H-imidazol- l-yl)acetate (1 19 mg, 0.7 mmol)
  • Cul 48 mg, 0.25 mmol
  • ⁇ , ⁇ '- dimethylethylenediamine 45 mg, 0.51 mmol
  • K3PO4 270 mg, 1.27 mmol
  • Step 2 ⁇ 3-[2-(5-Chloro-3,4-dihydro-l ⁇ -spiro[chromene-2,4'-piperidinl- -yl)pyrimidin-5-yll-2- oxo-23-dihydro- lH-imidazol-1 -yl
  • Step 1 5-Chloro- -(6-iodop idazin-3-yl)-3,4-dihvdrospiro[chromene-2,4'-piperidinel
  • a mixture of 5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] TFA salt (1.00 g, 2.848 mmol), 3,6-diiodopyridazine (0.952 g, 2.877 mmol) and sodium carbonate (0.743 g, 7.006 mmol) in DMF (10 mL) was stirred overnight at 65°C. The mixture was cooled to room temperature and water (50 mL) was added.
  • Step 2 ⁇ 3 -r6-(5-Chloro-3 ,4-dihydro- 1 'H-spiro rchromene-2,4'-piperidin] - 1 '-yl)pyridazin-3 -yll-2- oxo-2,,3 -dihydro- 1 H-imidazol- 1 -yl ⁇ acetic acid
  • the title compound was prepared in a similar manner as described for Example 3 from 5-chloro-l'-(6-iodopyridazin-3-yl)-3,4- dihydrospiro[chromene-2,4'-piperidine] and ethyl (2-oxo-2,3-dihydro-lH-imidazol-l-yl)acetate.
  • Step 1 Ethyl ⁇ 4-f 5-(5-chloro-3 ,4-dihydro- 1 'H-spiro[chiomene-2,4'-piperidin "
  • Step 2 (4- 5-(5-Chloro-3 ,4-dihydro- 1 'H-spiro [chromene-2,4'-piperidin] - 1 '-yl)pyrazin-2-yl1 - 1 H- 1,2,3 -triazol-l-yl) acetic acid
  • the title compound was prepared in a similar manner as described for Example 3, Step 2 from ethyl ⁇ 4-[5-(5-chloro-3,4-dihydro-l'H-spiro[chromene-2,4'- piperidin]- 1 , -yl)pyrazin-2-yl]- IH- 1 ,2,3-triazol- 1 -yl ⁇ acetate.
  • the title compound was prepared in a similar manner as described for Example 6 from 1 '- (5-bromopyrimidin-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] and ethyl [4- (tributylstarmyl)-lH-l,2,3-triazol-l-yl]acetate.
  • the title compound was prepared in a similar manner as described for Example 6 from ⁇ - (5-bromopyrazin-2-yl)spiro[chromene-2,4'-piperidin]-4(3H)-one and ethyl [4-(tributylstannyl)- lH-l,2,3-triazol-l-yl]acetate.
  • an oral composition of a compound of the present invention 50 mg of the compound of any of the Examples is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule.
  • the pharmacologic response observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended therefore that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Abstract

Heteroaromatic compounds of structural formula I are selective inhibitors of stearoyl- coenzyme. A delta-9 desaturase (SCDl) relative to other known stearoyl-coenzyme. A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; and liver steatosis. Formula (I).

Description

TITLE OF THE INVENTION
NOVEL SPIRO COMPOUNDS USEFUL AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE FIELD OF THE INVENTION
The present invention relates to heteroaromatic compounds which are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) and the use of such compounds to control, prevent and/or treat conditions or diseases mediated by SCD activity. The compounds of the present invention are useful for the control, prevention and treatment of conditions and diseases related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; cancer; and hepatic steatosis.
BACKGROUND OF THE INVENTION
At least three classes of fatty acyl-coenzyme A (Co A) desaturases (delta-5, delta-6 and delta-9 desaturases) are responsible for the formation of double bonds in mono- and
polyunsaturated fatty acyl-CoAs derived from either dietary sources or de novo synthesis in mammals. The delta-9 specific stearoyl-CoA desaturases (SCDs) catalyze the rate-limiting formation of the cis-double bond at the C9-C10 position in monounsaturated fatty acyl-CoAs. The preferred substrates are stearoyl-CoA and palmitoyl-CoA, with the resulting oleoyl and palmitoleoyl-CoA as the main components in the biosynthesis of phospholipids, triglycerides, cholesterol esters and wax esters (Dobr2yn and Natami, Obesity Reviews, 6: 169-174 (2005)).
The rat liver microsomal SCD protein was first isolated and characterized in 1974 (Strittmatter et al., PNAS. 71 : 4565-4569 (1974)). A number of mammalian SCD genes have since been cloned and studied from various species. For example, two genes have been identified from rat (SCD1 and SCD2, Thiede et al., J. Biol. Chem.. 261, 13230-13235 (1986)), Mihara, K., J. Biochem. (Tokyo), 108: 1022-1029 (1990)); four genes from mouse (SCD1, SCD2, SCD3 and SCD4) (Miyazaki et al., J. Biol. Chem., 278: 33904-3391 1 (2003)); and two genes from human (SCD1 and ACOD4 (SCD2)), (Zhang, et al., Biochem. J., 340: 255-264 (1991); Beiraghi, et al, Gene, 309: 11-21 (2003); Zhang et al., Biochem. J., 388: 135-142
(2005)). The involvement of SCDs in fatty acid metabolism has been known in rats and mice since the 1970's (Oshino, N., Arch. Biochem. Biophys., 149: 378-387 (1972)). This has been further supported by the biological studies of a) Asebia mice that carry the natural mutation in the SCD1 gene (Zheng et al., Nature Genetics, 23: 268-270 (1999)), b) SCDl-null mice from targeted gene deletion (Ntambi, et al., PNAS, 99: 1 1482-11486 (2002), and c) the suppression of SCD1 expression during leptin-induced weight loss (Cohen et al, Science, 297: 240-243 (2002)). The potential benefits of pharmacological inhibition of SCD activity has been demonstrated with anti-sense oligonucleotide inhibitors (ASO) in mice (Jiang, et al., J. Clin. Invest., 1 15: 1030-1038 (2005)). ASO inhibition of SCD activity reduced fatty acid synthesis and increased fatty acid oxidation in primary mouse hepatocytes. Treatment of mice with SCD-ASOs resulted in the prevention of diet-induced obesity, reduced body adiposity, hepatomegaly, steatosis, postprandial plasma insulin and glucose levels, reduced de novo fatty acid synthesis, decreased the expression of lipogenic genes, and increased the expression of genes promoting energy expenditure in liver and adipose tissues. Thus, SCD inhibition represents a novel therapeutic strategy in the treatment of obesity and related metabolic disorders.
There is compelling evidence to support that elevated SCD activity in humans is directly implicated in several common disease processes. For example, there is an elevated hepatic lipogenesis to triglyceride secretion in non-alcoholic fatty liver disease patients (Diraison, et al., Diabetes Metabolism. 29: 478-485 (2003)); Donnelly, et al., J. Clin. Invest., 115: 1343-1351 (2005)). Elevated SCD activity in adipose tissue is closely coupled to the development of insulin resistance (Sjogren, et al., Diabetologia, 51(2): 328-35 (2007)). The postprandial de novo lipogenesis is significantly elevated in obese subjects (Marques-Lopes, et al., American Journal of Clinical Nutrition, 73 : 252-261 (2001 )). Knockout of the SCD gene ameliorates Metabolic Syndrome by reducing plasma triglycerides, reducing weight gain, increasing insulin sensitivity, and reduces hepatic lipid accumulation (MacDonald, et al., Journal of Lipid Research, 49(1): 217-29 (2007)). There is a significant correlation between a high SCD activity and an increased cardiovascular risk profile including elevated plasma triglycerides, a high body mass index and reduced plasma HDL (Attie, et al., J. Lipid Res., 43: 1899-1907 (2002)). SCD activity plays a key role in controlling the proliferation and survival of human transformed cells (Scaglia and Igal, J. Biol. Chem., (2005)). RNA interference of SCD-1 reduces human tumor cell survival (Morgan-Lappe, et al., Cancer Research, 67(9): 4390-4398 (2007)).
Other than the above mentioned anti-sense oligonucleotides, inhibitors of SCD activity include non-selective thia-fatty acid substrate analogs [B. Behrouzian and P.H. Buist,
Prostaglandins, Leukotrienes, and Essential Fatty Acids, 68: 107-112 (2003)], cyclopropenoid fatty acids (Raju and Reiser, J. Biol. Chem., 242: 379-384 (1967)), certain conjugated long-chain fatty acid isomers (Park, et al., Biochim. Biophys. Acta, 1486: 285-292 (2000)), and a series of heterocyclic derivatives disclosed in published international patent application publications WO 2005/011653, WO 2005/011654, WO 2005/011655, WO 2005/011656, WO 2005/011657, WO 2006/014168, WO 2006/034279, WO 2006/034312, WO 2006/034315, WO 2006/034338, WO 2006/034341, WO 2006/034440, WO 2006/034441, WO 2006/034446, WO 2006/086445; WO 2006/086447; WO 2006/101521; WO 2006/125178; WO 2006/125179; WO 2006/125180; WO 2006/125181; WO 2006/125194; WO 2007/044085; WO 2007/046867; WO 2007/046868; WO 2007/050124; WO 2007/130075; WO 2007/136746; and WO 2008/074835, all assigned to Xenon Pharmaceuticals, Inc. SCD inhibitors are also disclosed in the following published international patent application publications: WO 2008/056687; WO 2008/096746; WO 2008/074835; WO 2008/074824; WO 2008/036715; WO 2008/044767; WO 2008/029266; WO 2008/062276; WO 2008/127349; and WO 2009/037542.
A number of international patent applications assigned to Merck Frosst Canada Ltd. that disclose SCD inhibitors useful for the treatment of obesity and Type 2 diabetes have also published: WO 2006/130986 (14 Dec. 2006); WO 2007/009236 (25 Jan. 2007); WO
2007/056846 (24 May 2007); WO 2007/071023 (28 June 2007); WO 2007/134457 (29
November 2007); WO 2007/143823 (21 Dec. 2007); WO 2007/143824 (21 Dec. 2007); WO 2008/017161 (14 Feb. 2008); WO 2008/046226 (24 April 2008); WO 2008/064474 (5 June 2008); and US 2008/0182838 (31 July 2008).
WO 2008/003753 (assigned to Novartis) discloses a series of pyrazolo[l,5-a]pyrimidine analogs as SCD inhibitors; WO 2007/143697 and WO 2008/024390 (assigned to Novartis and Xenon Pharmaceuticals) disclose heterocyclic derivatives as SCD inhibitors; and WO
2008/096746 (assigned to Takeda Pharmaceutical) and WO 2008/056687 (assigned to Daiichi) disclose spiro compounds as SCD inhibitors.
Small molecule SCD inhibitors have also been described by (a) G. Liu, et al.,
"Discovery of Potent, Selective, Orally Bioavailable SCD1 Inhibitors," in J. Med. Chem., 50: 3086-3100 (2007); (b) H. Zhao, et al., "Discovery of l-(4-phenoxypiperidin-l-yl)-2- arylaminoethanone SCD 1 inhibitors," Bioorg. Med. Chem. Lett.. 17: 3388-3391 (2007); (c) Z. Xin, et al., "Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors,"
Bioorg. Med. Chem. Lett.. 18: 4298-4302 (2008); and (d) C. S. Li, et al, "Thiazole analog as stearoyl-CoA desaturase 1 inhibitor," Bioorg. Med. Chem. Lett.. 19: 5214-5217 (2009) and references therein.
The present invention is concerned with novel heteroaromatic compounds as inhibitors of stearoyl-CoA delta-9 desaturase which are useful in the treatment and or prevention of various conditions and diseases mediated by SCD activity including those related, but not limited, to elevated lipid levels, as exemplified in non-alcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, metabolic syndrome, and insulin resistance.
The role of stearoyl-coenzyme A desaturase in lipid metabolism has been described by
M. Miyazaki and J.M. Ntambi, Prostaglandins, Leukotrienes. and Essential Fatty Acids. 68: 1 13- 121 (2003). The therapeutic potential of the pharmacological manipulation of SCD activity has been described by A. Dobrzyn and J.M. Ntambi, in "Stearoyl-CoA desaturase as a new drug target for obesity treatment," Obesity Reviews. 6: 169-174 (2005).
SUMMARY OF THE INVENTION
The present invention relates to heteroaromatic compounds of structural formula I:
Figure imgf000005_0001
(I)
These heteroaromatic compounds are effective as inhibitors of SCD. They are therefore useful for the treatment, control or prevention of disorders responsive to the inhibition of SCD, such as diabetes, insulin resistance, lipid disorders, obesity, atherosclerosis, metabolic syndrome, and cancer.
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
The present invention also relates to methods for the treatment, control, or prevention of disorders, diseases, or conditions responsive to inhibition of SCD in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for the treatment, control, or prevention of Type 2 diabetes, insulin resistance, obesity, lipid disorders, atherosclerosis, metabolic syndrome, and cancer by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for the treatment, control, or prevention of obesity by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to methods for the treatment, control, or prevention of Type 2 diabetes by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to methods for the treatment, control, or prevention of insulin resistance by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to methods for the treatment, control, or prevention of atherosclerosis by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to methods for the treatment, control, or prevention of lipid disorders by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to methods for the treatment, control, or prevention of metabolic syndrome by administering the compounds of the present mvention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
The present invention also relates to methods for the treatment, control, or prevention of cancer by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with heteroaromatic compounds useful as inhibitors of SCD. Compounds of the present invention are described by structural formula I:
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof; wherein A is selected from the group consisting of:
Figure imgf000006_0002
g is a single bond or a double bond;
J and K are each independently selected from the group consisting of: S, O, NH, CH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C¾ is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C¾ unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and K are CH;
L and M are each independently selected from the group consisting of: S, O, NH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2; T, U, V and W are each independently selected from N and CH, wherein each CH is unsubstituted or substituted with R3, provided that at least two of T, U, V and W are CH; X is CH2, wherein C¾ is unsubstituted or substituted with R2;
Y is independently selected from the group consisting of: O, NH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with
R2;
Z is independently selected from the group consisting of: S, S(O), S(0)2, O, NH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2; B is selected from the group consisting of:
Figure imgf000007_0001
Figure imgf000007_0002
each R1 is independently selected from the group consisting of: hydrogen, halogen, and Ci_3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy; each R2 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) oxo,
(4) Ci_6 alkyl,
Figure imgf000007_0003
(7) (CH2)nC≡N, (8) (CH2)nCORe, and
(9) (CH2)nS(0)qRe
wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines; each R3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) -C 1-6 alkyl,
(4) -OC 1-6 alkyl,
(5) (CH2)nORe,
Figure imgf000008_0001
(7) (CH2)nC≡N,
(8) (CH2)nCORe and
(9) (CH2)nS(0)qRe
wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines;
R4 is selected from the group consisting of:
Figure imgf000008_0002
Figure imgf000009_0001
each Ra is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) cyano,
(4) Ci-4 alkyl, unsubstituted or substituted with one to five fluorines,
(5) Ci-4 alkoxy, unsubstituted or substituted with one to five fluorines, (6) C 1 _4 alky lthio, unsubstituted or substituted with one to five fluorines,
(7) Ci-4 alkylsulfonyl,
(8) -C02H,
(9) Ci-4 alkyloxycarbonyl, and
(10) Cl-4 alkylcarbonyl; each Rh is independently selected from the group consisting of:
(1) hydrogen, and
(2) Cl-4 alkyl,
wherein alkyl is unsubstituted or substituted with one to five fluorines; each Rc is independently selected from the group consisting of:
(1) -(CH2)mC02H,
(2) -(CH2)mC02Ci-3 alkyl,
(3) -(CH2)m-NRb-(CH2)pC02H,
(4) -(CH2)m-NRb-(CH2)pC02Ci-3 alkyl,
(5) -(CH2)m-0-(CH2)pC02H,
(6) -(CH2)m-0-(CH2)pC02Ci.3 alkyl,
(7) -(CH2)m-S-(CH2)pC02H, and
(8) -(CH2)m-S-(CH2)pC02Ci-3 alkyl,
wherein any C¾ in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Cl-4 alkyl unsubstituted or substituted with one to five fluorines; each Rd is independently selected from the group consisting of:
(1) -(CH2)nC02H,
(2) -(CH2)nC02Ci-3 alkyl,
(3) -(CH2)n-NRb-(CH2)pC02H,
(4) -(CH2)n-NRb-(CH2)pC02Ci-3 alkyl,
(5) -(CH2)n-0-(CH2)pC02H,
(6) -(CH2)n-0-(CH2)pC02Ci-3 alkyl,
(7) -(CH2)n-S-(CH2)pC02H, and
(8) -(CH2)n-S-(CH2)pC02Ci-3 alkyl,
wherein any CH2 in Rd is unsubstituted or substituted with one to two groups independently selected from the group consisting of: halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines; each Re is independently selected from the group consisting of:
(1) hydrogen, and
(2) Ci-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -Ci-4 alkoxy, -Ci-4 alkylthio, -Ci-4 alkylsulfonyl, -C02H, and -C02Ci _4 alkyl; each Rg is independently selected from the group consisting of:
(1) hydrogen, and
(2) Ci_6 alkyl; m is an integer from 1 to 3;
n is an integer from 0 to 3;
p is an integer from 1 to 3;
q is an integer from 1 to 2;
t is an integer from 0 to 8;
d is an integer from 0 to 2; and
e is an integer from 0 to 2,
provided that d + e is 2.
In one embodiment of the present invention, A is selected from the group consisting of:
Figure imgf000011_0001
In a class of this embodiment, A is:
Figure imgf000011_0002
In another class of this embodiment, A is selected from the group consisting of:
Figure imgf000011_0003
In another class of this embodiment, A is selected from the group consisting of:
Figure imgf000012_0001
In another class of this embodiment, A is selected from the group consisting of:
Figure imgf000012_0002
In another class of this embodiment, A is selected from the group consisting of: In ano ing of:
Figure imgf000013_0001
In another class of this embodiment, A is:
Figure imgf000013_0002
In another class of this embodiment, A is:
O
(R2)r (R3)s
Figure imgf000013_0003
Figure imgf000013_0004
In another embodiment of the present invention, B is selected from the group consisting
Figure imgf000014_0001
In a class of this embodiment, B is selected from the group consisting of:
Figure imgf000014_0002
In another class of this embodiment, B is selected from the group consisting of:
Figure imgf000014_0003
Figure imgf000014_0004
In another class of this embodiment, B is selected from the group consisting of:
Figure imgf000015_0001
In another class of this embodiment, B is selected from the group consisting
Figure imgf000015_0002
In another class of this embodiment, B is selected from the roup consisting of:
Figure imgf000015_0003
and
In another class of this embodiment, B is selected from the roup consisting of:
Figure imgf000015_0004
In another class of this embodiment, B is selected from the group consisting of:
Figure imgf000015_0005
In another class of this embodiment, B is selected from the group consisting of:
Figure imgf000015_0006
In another embodiment of the present invention, B-R4 is selected from the group consisting of:
Figure imgf000015_0007
In a class of this embodiment, B-R4 is In another class of t
Figure imgf000016_0001
In yet another class of this em is
Figure imgf000016_0002
In another embodiment of the present invention, J and K are each independently selected from the group consisting of: S, O, NH, CH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C¾ is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C¾ unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and are CH. In a class of this embodiment, J and K are each independently selected from the group consisting of: O, NH, CH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C¾ is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C¾ unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and K are CH. In another class of this embodiment, g is a single bond, J is O and K is CH2, wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, g is a single bond, J is O and K is C=0. In another class of this
embodiment, g is a single bond, J is C¾ and K is O, wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, g is a single bond, J is C¾ and K is O. In another class of this embodiment, g is a single bond, J is C¾ and K is O, wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, g is a single bond, J is C=0 and K is O. In another class of this embodiment, g is a single bond, J and K are CH2, wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, g is a single bond, J is C=0 and is C¾. In another class of this embodiment, g is a single bond, J is CH2 and K is C=0.
In another class of this embodiment, g is a double bond, J and K are selected from N and CH, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH is unsubstituted or substituted with R2. In another class of this embodiment, g is a double bond, J and K are CH, wherein each CH is unsubstituted or substituted with R2. In another class of this embodiment, g is a double bond, J and K are CH. In another embodiment of the present invention, L and M are each independently selected from the group consisting of: S, O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2. In class of this embodiment, M and L are each independently selected from the group consisting of: S, O, NH and C¾, wherein NH is unsubstituted or substituted with Rg, and wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, M and L are each independently selected from the group consisting of: 0, NH and CH2, wherein NH is unsubstituted or substituted with Rg, and wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, g is a single bond, M and L are CH2, wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, g is a single bond, M is C=0 and L is C¾.
In another embodiment of the present invention, T, U, V and W are each independently selected from N and CH, wherein CH is unsubstituted or substituted with R3. In a class of this embodiment, T, U, V and W are each CH, wherein CH is unsubstituted or substituted with R3. In another class of this embodiment, T, U, V and W are each independently selected from N and CH, wherein CH is unsubstituted or substituted with R3, provided that at least one of T, U, V and W is N. In another class of this embodiment, T, U, V and W are each independently selected from N and CH, wherein CH is unsubstituted or substituted with R3, provided that one of T or W is N. In another class of this embodiment, T is N and U, V and W are CH, wherein CH is unsubstituted or substituted with R3. In another class of this embodiment, T, U, V are CH and W is N, wherein CH is unsubstituted or substituted with R3.
In another embodiment of the present invention, X is CH2, wherein C¾ is
unsubstituted or substituted with R2.
In another embodiment of the present invention, Y is independently selected from the group consisting of: O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2.
In another embodiment of the present invention, Z is independently selected from the group consisting of: S, S(O), S(0)2, O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2. In a class of this embodiment, Z is independently selected from the group consisting of: S, O, NH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, Z is independently selected from the group consisting of: O, NH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2.
In another class of this embodiment, X and Y are C¾ and Z is O, wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X and Y are C¾ and Z is O. In another class of this embodiment, X is C=0, Y is C¾ and Z is O, wherein C¾ is unsubstituted or substituted with R.2. In another class of this embodiment, X is C=0, Y is C¾ and Z is O.
In another class of this embodiment, X is C¾, Y is NH and Z is 0, wherein NH is unsubstituted or substituted with Rg, and wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is NH and Z is O, wherein NH is unsubstituted or substituted with Rg. In another class of this embodiment, X is C=0, Y is NH and Z is O. In another class of this embodiment, X and Z are C¾, and Y is NH, wherein NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is NH and Z is CH2, wherein NH is unsubstituted or substituted with Rg, and wherein C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is NH and Z is C¾.
In another class of this embodiment, Y is O, and X and Z are C¾, wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is O and Z is CH2, wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is O and Z is C¾. In another class of this embodiment, X and Y are CH2and Z is S, wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is C¾and Z is S, wherein each C¾ is unsubstituted or substituted with R2. In another class of this embodiment, X is C=0, Y is C¾ and Z is S.
In another embodiment of the present invention, each Rl is independently selected from the group consisting of: hydrogen, halogen, and Ci-3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy. In a class of this embodiment, each Rl is independently selected from the group consisting of:
hydrogen, halogen, or C 1-3 alkyl. In another class of this embodiment, each Rl is hydrogen.
In another embodiment of the present invention, each R2 is independently selected from the group consisting of: hydrogen, halogen, oxo, -Ci-6 alkyl, -OCi-6 alkyl, (CH2)nORe, (CH2)nN(Re)2, (CH2)nC≡N, (CH2)nCORe and (CH2)nS(0)qRe,
wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C¾ in R is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci_4 alkyl unsubstituted or substituted with one to five fluorines. In a class of this embodiment, each R2 is independently selected from the group consisting of: hydrogen, halogen, oxo, -C\-6 alkyl, -OCi-6 alkyl, (CH2)nORe, (CH2)nN(Re)2, (CH2)nC≡N, and (CH2)nCORe, wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C¾ in R2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci_4 alkyl unsubstituted or substituted with one to five fluorines. In a subclass of this class, each R2 is independently selected from the group consisting of: hydrogen, halogen, and oxo. In another subclass of this class, each R2 is independently selected from the group consisting of: hydrogen, bromo, chloro, fluoro, and oxo. In another subclass of this class, each R2 is independently selected from the group consisting of: hydrogen, and oxo. In another subclass of this class, each R2 is hydrogen. In another subclass of this class, each R2 is oxo.
In another embodiment of the present invention, R3 is independently selected from the group consisting of: hydrogen, halogen, -Ci-6 alkyl, -OCi-6 alkyl, (CH2)nORe, (CH2)nN(Re)2, (CH2)nC≡N, (CH2)nCORe, and (CH2)nS(0)qRe wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any CH2 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In a class of this embodiment, R is independently selected from the group consisting of: hydrogen, halogen, -Ci-6 alkyl, -OCi-6 alkyl, (CH2)nORe, (CH2)nN(Re)2, (CH2)nC≡N, and (CH2)nCORe, wherein alkyl is
unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C¾ in R is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In a class of this embodiment, R3 is independently selected from the group consisting of: hydrogen, halogen, -Ci- 6 alkyl, -OH, and -OCi-6 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens; and wherein any C¾ in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In a subclass of this class, R3 is independently selected from the group consisting of: hydrogen, halogen, -Ci-6 alkyl, -OH, and -OCi-6 alkyl. In another subclass of this class, R3 is independently selected from the group consisting of: hydrogen, halogen, -OH, and -OCi-6 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any C¾ in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, -OH, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In another subclass of this class, R3 is independently selected from the group consisting of: hydrogen, halogen, -OH, and -OCi-6 alkyl. In another subclass of this class, R is independently selected from the group consisting of: hydrogen, halogen, -OH and OCH3. In another subclass of this class, R3 is independently selected from the group consisting of: -OH and OCH3. In another subclass of this class, R is independently selected from the group consisting of: hydrogen, and halogen. In another subclass of this class, R is independently selected from the group consisting of: hydrogen, bromo, chloro and fluoro. In another subclass of this class, R3 is independently selected from the group consisting of:
hydrogen, chloro and fluoro. In another subclass of this class, R3 is independently selected from the group consisting of: hydrogen, and chloro. In another subclass of this class, R is chloro. In another subclass of this class, R3 is halogen. In another subclass of this class, R is
independently selected from the group consisting of: bromo, chloro and fluoro. In another subclass of this class, R is independently selected from the group consisting of: chloro and fluoro. In another class of this embodiment, R3 is chloro. In another embodiment of the present invention, R4 is selected from the group consisting of: heteroaryl, and cycloheteroalkyl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH or CH2 group is unsubstituted or substituted with 1 to 2 substituents selected from Rd. In a class of this embodiment, R4 is heteroaryl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH or CH2 group is unsubstituted or substituted with one substituent selected from Rd. In a class of this embodiment, R4 is heteroaryl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH group is unsubstituted or substituted with one substituent selected from Rd. In another class of this embodiment, R4 is cycloheteroalkyl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH or CH2 group is unsubstituted or substituted with one substituent selected from Rd. In another class of this embodiment, R4 is cycloheteroalkyl, wherein any NH group is unsubstituted or substituted with Rc, and wherein any CH2 group is unsubstituted or substituted with one to two substituents selected from Rd.
In another embodiment of the present invention, R4 is selected from the group consisting
Figure imgf000020_0001
In a class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000021_0001
In another class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000021_0002
Figure imgf000022_0001
-21 -
Figure imgf000023_0001
In another class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000023_0002
In another class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000023_0003
Figure imgf000023_0004
In a class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000023_0005
In another class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000024_0001
In another class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000024_0002
In another class of this embodiment, R4 is selected from the group consisting of:
Figure imgf000024_0003
In another class of this embodiment, R4 is:
Figure imgf000024_0004
In another class of this embodiment, R4 is:
Figure imgf000024_0005
In another class of this embodiment, R4 is:
N " N
In another class of this embodiment, R4 is:
Figure imgf000024_0006
In another class of this embodiment, R is:
Figure imgf000025_0001
In another class of this embodiment, R4 is:
Figure imgf000025_0002
In another embodiment of the present invention, each Ra is independently selected from the group consisting of: hydrogen, halogen, cyano, Ci-4 alkyl, unsubstituted or substituted with one to five fluorines, Ci-4 alkoxy, unsubstituted or substituted with one to five fluorines, Ci-4 alkylthio, unsubstituted or substituted with one to five fluorines, Ci_4 alkylsulfonyl, -CO2H, Ci_ 4 alkyloxycarbonyl, and Ci_4 alkylcarbonyl. In a class of this embodiment, Ra is independently selected from the group consisting of: hydrogen, halogen, cyano, and C[-4 alkyl, unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Ra is independently selected from the group consisting of: hydrogen, and Ci_4 alkyl, unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Ra is hydrogen. In another class of this embodiment, Ra is Ci-4 alkyl, unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Ra is Ci-4 alkyl.
In another embodiment of the present invention, each Rb is independently selected from the group consisting of: hydrogen, and C1-.4 alkyl, wherein alkyl is unsubstituted or substituted with one to five fluorines. In a class of this embodiment, Rb is hydrogen. In another class of this embodiment, Rb is Ci-4 alkyl, wherein alkyl is unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rb is C 1.4 alkyl.
In another embodiment of the present invention, each Rc is independently selected from the group consisting of: -(CH2)mC02H, -(CH2)mC02Ci-3 alkyl, -(CH2)m-NRb-(CH2)pC02H,
-(CH2)m-NRb-(CH2)pC02Ci-3 alkyl, -(CH2)m-0-(CH2)pC02H, -(CH2)m-0-(CH2)pC02Ci_ 3 alkyl, -(CH2)m-S-(CH2)pC02H, and -(CH2)m-S-(CH2)pC02Ci-3 alkyl, wherein any CI¾ in
Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1.4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rc is selected from the group consisting of: -(CH2)mC02H, - (CH2)mC02Ci-3 alkyl, -(CH2)mOCOH, -(CH2)mOCOCi-3 alkyl, -(CH2)mCOH, - (CH2)mCOCi-3 alkyl, -(CH2)m-NRb-(CH2)pC02H, -(CH2)m-NRb-(CH2)pC02Ci-3 alkyl, - (CH2)m-0-(CH2)pC02H, and -(CH2)m-0-(CH2)pC02Ci-3 alkyl, wherein any CH2 in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rc is selected from the group consisting of: -(CH2)mC02H, - (CH2)mC02Ci -3 alkyl, -(CH2)mOCOH, -(CH2)mOCOCi_3 alkyl, -(CH2)mCOH, and - (CH2)mCOCi-3 alkyl, wherein any CH2 in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rc is selected from the group consisting of: -(CH2)mC02H, -(CH2)mC02C i .3 alkyl, -(CH2)mOCOH, -
(CH2)mOCOCi_3 alkyl, -(CH2)mCOH, -(CH2)mCOCi_3 alkyl, -(CH2)m-NRb-(CH2)pC02H, - (CH2)m-NRb-(CH2)pC02Ci-3 alkyl, wherein any CH2 in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C\-4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rc is selected from the group consisting of: -(CH2)mC02H, and -(CH2)mC02Ci-3 alkyl, wherein any CH2 in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1.4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rc is -(CH2)mC02H. In another class of this embodiment, Rc is -(CH )mC02Ci-3 alkyl.
In another embodiment of the present invention, each Rd is independently selected from the group consisting of: -(CH2)nC02H, -(CH2)nC02Ci-3 alkyl, -(CH2)n-NRb-(CH2)pC02H, -
(CH2)n-NRb-(CH2)pC02Ci-3 alkyl, -(CH2)n-0-(CH2)pC02H, -(CH2)n-0-(CH2)pC02Ci-3 alkyl, -(CH2)n-S-(CH2)pC02H, and -(CH2)n-S-(CH2)pC02Ci-3 alkyl, wherein any CH2 in Rd is unsubstituted or substituted with one to two grouPs independently selected from the grouP consisting of: halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, each Rd is independently selected from the group) consisting of: -(CH2)nC02H, -(CH2)nC02Ci_3 alkyl, -(CH2)n-NRb-(CH2)pC02H, -(CH2)n- NRb-(CH2)pC02Ci-3 alkyl, -(CH2)n-0-(CH2)pC02H, and -(CH2)n-0-(CH2)pC02Ci-3 alkyl, wherein any CH2 in Rd is unsubstituted or substituted with one to two grouPs independently selected from the group consisting of: halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rd is selected from the group consisting of: -(CH2)nC02H, -(CH2)nC02Ci-3 alkyl, -(CH2)n-NRb-(CH2)pC02H, and -(CH2)n-NRb-(CH2)pC02Ci_3 alkyl, wherein any CH2 in R is unsubstituted or substituted with one to two groupjs independently selected from halogen, hydroxy, and C1.4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rd is selected from the group* consisting of: -(CH2)nC02H, and -(CH2)n-NRb-(CH2)pC02H, wherein any CH2 in R is unsubstituted or substituted with one to two group>s independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines. In another class of this embodiment, Rd is selected from the group consisting of: -CH2C02H, and - NH-CH2C02H. In another class of this embodiment, Rd is -CH2C02H. In another class of this embodiment, Rd is -NH-CH2C02H.
In another embodiment of the pjresent invention, each Re is independently selected from the group consisting of: hydrogen, and Ci_6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, cyano, -Ci-4 alkoxy, -Ci-4 alkylthio, -Ci-4 alkylsulfonyl, -CO2H, and -CO2C1.4 alkyl. In a class of this embodiment, Re is hydrogen. In another class of this embodiment, Re is Ci-6 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -Ci-4 alkoxy, -Ci-4 alkylthio, -Ci_4 alkylsulfonyl, -CO2H, and -CO2C1-4 alkyl. In another class of this embodiment, Re is Ci-6 alkyl.
In another embodiment of the present invention, each Rg is independently selected from the group consisting of: hydrogen, and Ci-6 alkyl. In a class of this embodiment, Rg is hydrogen. In another class of this embodiment, Rg is Ci-6 alkyl.
In another embodiment of the present invention, g is a single bond or a double bond. In a class of this embodiment, g is a single bond. In another class of this embodiment, g is a double bond.
In another embodiment of the present invention, m is 1, 2, or 3. In a class of this embodiment, s is 1 or 2. In another class of this embodiment, m is 2 or 3. In another class of this embodiment, m is 1 or 3. In another class of this embodiment, m is 1. In another class of this embodiment, m is 2. In another class of this embodiment, m is 3.
In another embodiment of the present invention, n is 0, 1, 2 or 3. In a class of this embodiment, n is 0, 1 or 2. In another class of this embodiment, n is 0 or 1. In another class of this embodiment, n is 1 or 2. In another class of this embodiment, n is 0 or 2. In another class of this embodiment, n is 0. In another class of this embodiment, n is 1. In another class of this embodiment, n is 2. In another class of this embodiment, n is 3.
In another embodiment of the present invention, p is 1, 2, or 3. In a class of this embodiment, p is 1 or 2. In another class of this embodiment, p is 2 or 3. In another class of this embodiment, p is 1 or 3. In another class of this embodiment, p is 1. In another class of this embodiment, p is 2. In another class of this embodiment, p is 3.
In another embodiment of the present invention, q is 1 or 2. In another class of this embodiment, q is 1. In another class of this embodiment, q is 2.
In another embodiment of the present invention, r is 0, 1 , 2 or 3. In a class of this embodiment, r is 0, 1 or 2. In another class of this embodiment, r is 0 or 1. In another class of this embodiment, r is 1 or 2. In another class of this embodiment, r is 0 or 2. In another class of this embodiment, r is 0. In another class of this embodiment, r is 1. In another class of this embodiment, r is 2. In another class of this embodiment, r is 3.
In another embodiment of the present invention, s is 0, 1, 2, 3 or 4. In a class of this embodiment, s is 0, 1, 2 or 3. In a class of this embodiment, s is 0, 1 or 2. In another class of this embodiment, s is 0 or 1. In another class of this embodiment, s is 1 or 2. In another class of this embodiment, s is 0 or 2. In another class of this embodiment, s is 0. In another class of this embodiment, s is 1. In another class of this embodiment, s is 2. In another class of this embodiment, s is 3. In another embodiment of the present invention, t is 0, 1 , 2, 3, 4, 5, 6, 7 or 8. In a class of this embodiment, t is 0, 1 , 2, 3 or 4. In a class of this embodiment, t is 0, 1, 2 or 3. In a class of this embodiment, t is 0, 1 or 2. In another class of this embodiment, t is 0 or 1. In another class of this embodiment, t is 1 or 2. In another class of this embodiment, t is 0 or 2. In another class of this embodiment, t is 0. In another class of this embodiment, t is 1. In another class of this embodiment, t is 2. In another class of this embodiment, t is 3. In another class of this embodiment, t is 4. In another class of this embodiment, t is 5. In another class of this embodiment, t is 6. In another class of this embodiment, t is 7. In another class of this embodiment, t is 8.
In another embodiment of the present invention, d is 0, 1 or 2. In a class of this embodiment, d is 0. In another class of this embodiment, d is 1. In another class of this embodiment, d is 2.
In another embodiment of the present invention, e is 0, 1 or 2. In a class of this embodiment, e is 0. In another class of this embodiment, e is 1. In another class of this embodiment, e is 2.
In another embodiment of the present invention, d is 0, and e is 2. In another
embodiment of the present invention, d is 1 and e is 1. In another embodiment of the present invention, d is 2 and e is 0.
In another embodiment of the present invention, the invention relates to compounds of structural formula I, wherein:
A is selected from the group consisting of:
Figure imgf000028_0001
R3 is independently selected from the group consisting of: hydrogen, halogen and -OCH3; and s is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
In another embodiment of the present invention, the invention relates to compounds of structural formula la:
Figure imgf000029_0001
In another embodiment of the present invention, the invention relates to compounds of structural formula lb:
Figure imgf000029_0002
lb
In another embodiment of the present invention, the invention relates to compounds of structural formula Ic :
Figure imgf000029_0003
Ic
In another embodiment of the present invention, the invention relates to compounds of structural formula Id:
Figure imgf000029_0004
Id
In another embodiment of the present invention, the invention relates to compounds of structural formula Ie:
Figure imgf000030_0001
In another embodiment of the present invention, the invention relates to compounds of structural formula If:
Figure imgf000030_0002
In another embodiment of the present invention, the invention relates to compounds of structural formula Ig:
Figure imgf000030_0003
In another embodiment of the present invention, the invention relates to compounds of structural formula Ih:
Figure imgf000030_0004
In another embodiment of the present invention, the invention relates to compounds of structural formula Ii:
Figure imgf000030_0005
In another embodiment of the present invention, the invention relates to compounds of structural formula Ij:
Figure imgf000031_0001
In another embodiment of the compounds of the present invention, A is selected from the group consisting of:
Figure imgf000031_0002
B is selected from the group consisting of:
Figure imgf000031_0003
R i is
Figure imgf000031_0004
R3 is independently selected from the group consisting of: hydrogen, and halogen; and s is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
Illustrative, but nonlimiting, examples of compounds of the present invention that are useful as inhibitors of SCD are the following:
Figure imgf000031_0005
Figure imgf000032_0001
Figure imgf000033_0001
and pharmaceutically acceptable salts thereof.
As used herein the following definitions are applicable.
"Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. When no number of carbon atoms is specified, Ci-6 is intended.
The term "alkenyl" shall mean straight or branched-chain alkenes having the specified number of carbon atoms. Examples of alkenyl include vinyl, 1-propenyl, 1-butenyl, 2-butenyl, and the like.
The term "alkynyl" refers to straight or branched-chain alkynes having the specified number of carbon atoms. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, and the like. The term "alkoxy" refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Ci _6 alkoxy), or any number within this range [i.e., methoxy
(MeO-), ethoxy, isopropoxy, etc.].
The term "alkylthio" refers to straight or branched chain alkylsulfides of the number of carbon atoms specified (e.g., Ci-6 alkylthio), or any number within this range [i.e., methylthio
(MeS-), ethylthio, isopropylthio, etc.].
The term "alkylsulfonyl" refers to straight or branched chain alkylsulfones of the number of carbon atoms specified (e.g., Ci -6 alkylsulfonyl), or any number within this range [i.e., methylsulfonyl (MeS02-), ethylsulfonyl, isopropylsulfonyl, etc.].
The term "alkyloxycarbonyl" refers to straight or branched chain esters of a carboxylic acid derivative of the present invention of the number of carbon atoms specified (e.g., Ci-6 alkyloxycarbonyl), or any number within this range [i.e., methyloxycarbonyl (MeOCO-), ethyloxycarbonyl, or butyloxycarbonyl].
"Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
"Cycloalkyl" means a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group generally is monocyclic unless stated otherwise. Cycloalkyl groups are saturated unless otherwise defined.
"Cycloheteroalkyl" means nonaromatic, mono- or bicyclic or bridged saturated carbocyclic rings, each having from 2 to 14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. Examples of cycloheteroalkyl include
tetrahydrofuranyl, azetidinyl, perhydroazepinyl, dihydrofuranyl, dioxanyl, oxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, dioxidoisothiazolidinyl, azacycloheptyl, diazobicyclo[3.2.1]-octane, and hexahydroindazolyl. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens. In one embodiment of the present invention, cycloheteroalkyl is substituted or unsubstituted piperazine.
"Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (in particular, l,3,4-oxadiazol-2-yl and l,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like. For heterocycloalkyl and heteroaryl groups, rings and ring systems containing from 3- 15 atoms are included, forming 1-3 rings.
The term "5 membered heteroaryl ring" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Examples of 5 membered heteroaryl rings include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (in particular, l,3,4-oxadiazol-2-yl and l,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, and the like.
"Halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine is most preferred when the halogens are substituted on an alkyl or alkoxy group (e.g. CF3O and CF3CH2O).
The term "compounds of structural formula I" includes the compounds of structural formula I, la, lb, Ic, Id, Ie, If, Ig, Ih and Ii, and pharmaceutically acceptable salts thereof.
Compounds of structural formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomenc mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of structural formula I.
Compounds of structural formula I may be separated into their individual
diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
Alternatively, any stereoisomer of a compound of the general structural formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomenc mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by
chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
In the compounds of structural formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include protium ( H) and deuterium ( H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds within structural formula I, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
It will be understood that, as used herein, references to the compounds of structural formula I are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetyl, pivaloyl, benzoyl, and aminoacyl, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.
Solvates, in particular hydrates, of the compounds of structural formula I are included in the present invention as well.
The subject compounds are useful in a method of inhibiting the stearoyl-coenzyme A delta-9 desaturase enzyme (SCD) in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The compounds of the present invention are therefore useful to control, prevent, and/or treat conditions and diseases mediated by high or abnormal SCD enzyme activity.
As defined herein, a condition or disease mediated by high or abnormal SCD enzyme activity is defined as any disease or condition in which the activity of SCD is elevated and/or where inhibition of SCD can be demonstrated to bring about symptomatic improvements for the individual so treated. As defined herein, a condition or disease mediated by high or abnormal SCD enzyme activity includes, but is not limited to cardiovascular disease, dyslipidemias, (including but not limiting to disorders of serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, cholesterol, and total cholesterol, hypercholesterolemia, as well as cholesterol disorders), familial combined hyperlipidemia, coronary artery disease,
atherosclerosis, heart disease, cerebrovascular disease (including but not limited to stroke, ischemic stroke, and transient ischemic attack), peripheral vascular disease, and ischemic retinopathy.
A condition or disease mediated by high or abnormal SCD enzyme activity also includes metabolic syndrome (including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cacahexia, and anorexia), weight loss, body mass index and leptin-related diseases.
A condition or disease mediated by high or abnormal SCD enzyme activity also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis, alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug- induced hepatitis,
erythrohepatic protporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.
Thus, one aspect of the present invention concerns a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment, which comprises administering to said patient an effective amount of a compound in accordance with structural formula I or a pharmaceutically salt or solvate thereof.
A second aspect of the present invention concerns a method of treating non-insulin dependent diabetes mellitus (Type 2 diabetes) in a mammalian patient in need of such treatment comprising administering to the patient an antidiabetic effective amount of a compound in accordance with structural formula I.
A third aspect of the present invention concerns a method of treating obesity in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat obesity.
A fourth aspect of the invention concerns a method of treating metabolic syndrome and its sequelae in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat metabolic syndrome and its sequelae. The sequelae of the metabolic syndrome include hypertension, elevated blood glucose levels, high triglycerides, and low levels of HDL cholesterol.
A fifth aspect of the invention concerns a method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat said lipid disorder.
A sixth aspect of the invention concerns a method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount effective to treat atherosclerosis.
A seventh aspect of the invention concerns a method of treating cancer in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with structural formula I in an amount effective to treat cancer. A further aspect of the invention concerns a method of treating a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16)
neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with structural formula I in an amount that is effective to treat said condition.
Yet a further aspect of the invention concerns a method of delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) other conditions and disorders where insulin resistance is a component, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with structural formula I in an amount that is effective to delay the onset of said condition.
Yet a further aspect of the invention concerns a method of reducing the risk of developing a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)
hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) fatty liver disease, (21) polycystic ovary syndrome, (22) sleep-disordered breathing, (23) metabolic syndrome, and (24) other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with structural formula I in an amount that is effective to reduce the risk of developing said condition.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent, such as a mouse, species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
The present invention is further directed to a method for the manufacture of a medicament for inhibiting stearoyl-coenzyme A delta-9 desaturase enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or diluent. More particularly, the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating a condition selected from the group consisting of hyperglycemia, Type 2 diabetes, insulin resistance, obesity, and a lipid disorder in a mammal, wherein the lipid disorder is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, low HDL, and high LDL.
The subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom inhibition of stearoyl-coenzyme A delta-9 desaturase enzyme activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The utility of the compounds in accordance with the present invention as inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) enzyme activity may be demonstrated by the following microsomal and whole-cell based assays:
I. SCD enzyme activity assay:
The potency of compounds of formula I against the stearoyl-CoA desaturase was determined by measuring the conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCD1 following previously published procedures with some modifications (Joshi, et al., J. Lipid Res., 18: 32-36 (1977); Talamo, et al., Anal. Biochem, 29: 300-304 (1969)). Liver microsome was prepared from male Wistar or Spraque Dawley rats on a high carbohydrate diet for 3 days (LabDiet # 5803, Purina). The livers were homogenized (1 : 10 w/v) in a buffer containing 250 mM sucrose, 1 mM EDTA, 5 mM DTT and 50 mM Tris-HCl (pH 7.5). After a 100,000 x g centrifugation for 60 min, the liver microsome pellet was suspended in a buffer containing 100 mM sodium phosphate, 20% glycerol, 2 mM DTT, and stored at -78 °C. Human SCD1 desaturase system was reconstituted using human SCD1 from a baculovirus/Sf9 expression system, cytochrome B5 and cytochrome B5 reductase. Typically, test compound in 2 μΐ, DMSO was incubated for 15 min at room temperature with 180 μΐ. of the
SCD enzyme in a buffer containing 100 mM Tris-HCl (pH 7.5), ATP (5 mM), Coenzyme-A (0.1 mM), Triton X-100 (0.5 mM) and NADH (2 mM). The reaction was initiated by the addition of 20 of [3H]-stearoyl-CoA (final concentration = 2 μΜ, radioactivity concentration = 1 μα/mL). After 10 min, the reaction mixture (80 μί) was mixed with a calcium chloride/charcoal aqueous suspension (100 μΐ^ charcoal (10% w/v) plus 25 μΐ. CaCl2 (2N). After centrifugation to precipitate the radioactive fatty acid species, tritiated water released from 9,10-[ H]-stearoyI-CoA by the SCD enzyme was quantified on a scintillation counter.
II. Whole cell-based SCD (delta-9), delta-5 and delta-6 desaturase assays:
Human HepG2 cells were grown on 24-well plates in MEM media (Gibco cat# 11095-
072) supplemented with 10% heat-inactivated fetal bovine serum at 37 °C under 5% C02 in a humidified incubator. Test compound dissolved in the media was incubated with the
subconfluent cells for 15 min at 37 °C. [l-14C]-stearic acid was added to each well to a final concentration of 0.05 μΟ/ταΣ, to detect SCD-catalyzed [14C]-oleic acid formation. 0.05 μα/mL of [l-14C]-eicosatrienoic acid or [l-14C]-linolenic acid plus 10 μΜ of 2-amino-N-(3- chlorophenyl)benzamide (a delta-5 desaturase inhibitor) was used to index the delta-5 and delta-6 desaturase activities, respectively. After 4 h incubation at 37 °C, the culture media was removed and the labeled cells were washed with PBS (3 x 1 mL) at room temperature. The labeled cellular lipids were hydrolyzed under nitrogen at 65 °C for 1 h using 400 μΐ, of 2N sodium hydroxide plus 50 μΐ, of L-a-phosphatidylcholine (2 mg/mL in isopropanol, Sigma #P-3556).
After acidification with phosphoric acid (60 μΐ,), the radioactive species were extracted with 300 μΐ, of acetonitrile and quantified on a HPLC that was equipped with a C-18 reverse phase column and a Packard Flow Scintillation Analyzer. The levels of [1 C]-oleic acid over [I4C]- stearic acid, [1 C]-arachidonic acid over [I4C]-eicosatrienoic acid, and [14C]-eicosatetraenoic acid (8, 11, 14, 17) over [14C]-linolenic acid were used as the corresponding activity indices of SCD, delta-5 and delta-6 desaturase, respectively. The SCD inhibitors of formula I, including the compounds of Examples 1 to 10, exhibit an SCD inhibition constant IC50 of less than 1 μΜ. Preferred compounds of the present invention exhibit an SCD inhibition constant IC50 of less than 0.1 μΜ. In Vivo Efficacy of Compounds of the Present Invention:
The in vivo efficacy of compounds of formula I was determined by following the conversion of [l-14C]-stearic acid to [1- 14C]oleic acid in animals as exemplified below. Mice were dosed with a compound of formula I and one hour later the radioactive tracer, [1-14C]- stearic acid, was dosed at 20 μα/kg IV. At 3 h post dosing of the compound, the liver was harvested and then hydro lyzed in 10 N sodium hydroxide for 24 h at 80 °C, to obtain the total liver fatty acid pool. After phosphoric acid acidification of the extract, the amount of [1-14C]- stearic acid and [l-I4C]-oleic acid was quantified on a HPLC that was equipped with a C-l 8 reverse phase column and a Packard Flow Scintillation Analyzer.
The subject compounds are further useful in a method for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other agents.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used
contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used
contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
Examples of other active ingredients that may be administered in combination with a compound of formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
(a) dipeptidyl peptidase-IV (DPP-4) inhibitors;
(b) insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g.
troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, and the like) and other PPAR ligands, including PPARa/γ dual agonists, such as KRP-297, muraglitazar, naveglitazar, Galida, TAK-559, PPARa agonists, such as fenofibric acid derivatives
(gemfibrozil, clofibrate, fenofibrate and bezafibrate), and selective PPARy modulators
(SPPARyM's), such as disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963; (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
(c) insulin or insulin mimetics;
(d) sulfonylureas and other insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;
(e) a-glucosidase inhibitors (such as acarbose and miglitol);
(f) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
(g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (NN-221 1), CJC-1131, LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;
(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;
(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/γ dual agonists, such as naveglitazar and muraglitazar, (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoA: cholesterol acyltransferase inhibitors, such as avasimibe, and (viii) antioxidants, such as probucol; (k) PPAR8 agonists, such as those disclosed in WO 97/28149;
(1) antiobesity compounds, such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yl or Y5 antagonists, CB1 receptor inverse agonists and antagonists, β3 adrenergic receptor agonists, melanocortin-receptor agonists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor subtype-3 agonists), and melanin-concentrating hormone (MCH) receptor antagonists;
(m) ileal bile acid transporter inhibitors;
(n) agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;
(o) antihypertensive agents, such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan), beta blockers and calcium channel blockers;
(p) glucokinase activators (GKAs), such as those disclosed in WO 03/015774; WO
04/076420; and WO 04/081001 ;
(q) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 , such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741 ;
(r) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib;
(s) inhibitors of fructose 1 ,6-bisphosphatase, such as those disclosed in U.S. Patent Nos.
6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;
(t) acetyl Co A carboxylase- 1 and/or -2 inhibitors;
(u) AMPK activators; and
(v) agonists of GPR-119.
Dipeptidyl peptidase-IV inhibitors that can be combined with compounds of structural formula I include those disclosed in US Patent No. 6,699,871; WO 02/076450 (3 October 2002); WO 03/004498 (16 January 2003); WO 03/004496 (16 January 2003); EP 1 258 476 (20
November 2002); WO 02/083128 (24 October 2002); WO 02/062764 (15 August 2002); WO 03/000250 (3 January 2003); WO 03/002530 (9 January 2003); WO 03/002531 (9 January 2003); WO 03/002553 (9 January 2003); WO 03/002593 (9 January 2003); WO 03/000180 (3 January 2003); WO 03/082817 (9 October 2003); WO 03/000181 (3 January 2003); WO
04/007468 (22 January 2004); WO 04/032836 (24 April 2004); WO 04/037169 (6 May 2004); and WO 04/043940 (27 May 2004). Specific DPP-IV inhibitor compounds include sitagliptin (M -0431); vildagliptin (LAP 237); denagliptin; P93/01; saxagliptin (BMS 477118);
RO0730699; MP513; SYR-322: ABT-279; PHX1149; GRC-8200; and TS021.
Antiobesity compounds that can be combined with compounds of structural formula I include fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y] or Y5 antagonists, cannabinoid CB1 receptor antagonists or inverse agonists, melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists, and melanin-concentrating hormone (MCH) receptor antagonists. For a review of anti- obesity compounds that can be combined with compounds of structural formula I, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents, 11 : 1677- 1692 (2001 ); D. Spanswick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); and J.A. Fernandez-Lopez, et al., "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915-944 (2002).
Neuropeptide Y5 antagonists that can be combined with compounds of structural formula I include those disclosed in U.S. Patent No. 6,335,345 (1 January 2002) and WO
01/14376 (1 March 2001); and specific compounds identified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.
Cannabinoid CB 1 receptor antagonists that can be combined with compounds of formula I include those disclosed in PCT Publication WO 03/007887; U.S. Patent No. 5,624,941, such as rimonabant; PCT Publication WO 02/076949, such as SLV-319; U.S. Patent No.
6,028,084; PCT Publication WO 98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S. Patent No. 5,532,237; U.S. Patent No. 5,292,736; PCT Publication WO 03/086288; PCT Publication WO 03/087037; PCT Publication WO 04/048317; PCT Publication WO 03/007887; PCT Publication WO 03/063781 ; PCT Publication WO 03/075660; PCT Publication WO 03/077847; PCT Publication WO 03/082190; PCT Publication WO 03/082191 ; PCT Publication WO 03/087037; PCT Publication WO 03/086288; PCT Publication WO 04/012671; PCT Publication WO 04/029204; PCT Publication WO 04/040040; PCT Publication WO 01/64632; PCT Publication WO 01/64633; and PCT Publication WO 01/64634.
Melanocortin-4 receptor (MC4R) agonists useful in the present invention include, but are not limited to, those disclosed in US 6,294,534, US 6,350,760, 6,376,509, 6,410,548,
6,458,790, US 6,472,398, US 5837521, US 6699873, which are hereby incorporated by reference in their entirety; in US Patent Application Publication Nos. US 2002/0004512, US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060, US2003/0092732, US2003/109556, US 2002/0 77151, US 2002/187932, US 2003/0113263, which are hereby incorporated by reference in their entirety; and in WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO
01/70337, WO 01/91752, WO 02/068387, WO 02/068388, WO 02/067869, WO 03/007949, WO 2004/024720, WO 2004/089307, WO 2004/078716, WO 2004/078717, WO 2004/037797, WO 01/58891, WO 02/070511, WO 02/079146, WO 03/009847, WO 03/057671, WO 03/068738, WO 03/092690, WO 02/059095, WO 02/059107, WO 02/059108, WO 02/059117, WO
02/085925, WO 03/004480, WO 03/009850, WO 03/013571, WO 03/031410, WO 03/053927, WO 03/061660, WO 03/066597, WO 03/094918, WO 03/099818, WO 04/037797, WO
04/048345, WO 02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO 03/066597, WO 03/099818, WO 02/062766, WO 03/000663, WO 03/000666, WO 03/003977, WO 03/040107, WO 03/0401 17, WO 03/0401 18, WO 03/013509, WO 03/057671, WO 02/079753, WO 02//092566, WO 03/-093234, WO 03/095474, and WO 03/104761.
One particular aspect of combination therapy concerns a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, in a mammalian patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of structural formula I and an HMG-CoA reductase inhibitor.
More particularly, this aspect of combination therapy concerns a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia in a mammalian patient in need of such treatment wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.
In another aspect of the invention, a method of reducing the risk of developing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelae of such conditions is disclosed comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of structural formula I and an HMG- CoA reductase inhibitor.
In another aspect of the invention, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed comprising administering to said patient an effective amount of a compound of structural formula I and an HMG-CoA reductase inhibitor.
More particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin.
In another aspect of the invention, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin and further comprising administering a cholesterol absorption inhibitor.
More particularly, in another aspect of the invention, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin and the cholesterol absorption inhibitor is ezetimibe.
In another aspect of the invention, a pharmaceutical composition is disclosed which comprises: (1) a compound of structural formula I;
(2) a compound selected from the group consisting of :
(a) dipeptidyl peptidase IV (DPP-IV) inhibitors;
(b) insulin sensitizers including (i) PPARy agonists, such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, and the like) and other PPAR ligands, including PPARa/γ dual agonists, such as KRP-297, muraglitazar, naveglitazar, Galida, TAK-559, PPARa agonists, such as fenofibric acid derivatives
(gemfibrozil, clofibrate, fenofibrate and bezafibrate), and selective PPARy modulators
(SPPARyM's), such as disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963; (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
(c) insulin or insulin mimetics;
(d) sulfonylureas and other insulin secretogogues, such as tolbutamide, glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide and repaglinide;
(e) a-glucosidase inhibitors (such as acarbose and miglitol);
(f) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
(g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists, such as exendin-4 (exenatide), liraglutide (NN-2211), CJC-1 131, LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;
(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as those disclosed in WO 01/23420;
(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and
dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/γ dual agonists, such as naveglitazar and muraglitazar, (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl
CoAxholesterol acyltransferase inhibitors, such as avasimibe, and (viii) antioxidants, such as probucol;
(k) PPAR5 agonists, such as those disclosed in WO 97/28149;
(1) antiobesity compounds, such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Yi or Y5 antagonists, CB1 receptor inverse agonists and antagonists, β3 adrenergic receptor agonists, melanocortin-receptor agonists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, bombesin receptor agonists (such as bombesin receptor subtype-3 agonists), and melanin-concentrating hormone (MCH) receptor antagonists;
(m) ileal bile acid transporter inhibitors;
(n) agents intended for use in inflammatory conditions such as aspirin, non- steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;
(o) antihypertensive agents, such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers (losartan, candesartan, irbesartan, valsartan, telmisartan, and eprosartan), beta blockers and calcium channel blockers;
(p) glucokinase activators (GKAs), such as those disclosed in WO 03/015774;
WO 04/076420; and WO 04/081001;
(q) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 , such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741;
(r) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib; (s) inhibitors of fructose 1 ,6-bisphosphatase, such as those disclosed in U.S.
Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;
(t) acetyl CoA carboxylase- 1 and/or -2 inhibitors;
(u) AMPK activators; and
(v) agonists of GPR 1 19; and
(3) a pharmaceutically acceptable carrier.
When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm- blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require inhibition of stearoyl-CoA delta-9 desaturase enzyme activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral
administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
When treating or preventing diabetes mellitus and or hyperglycemia or
hypertriglyceridemia or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Preparation of Compounds of the Invention:
The compounds of structural formula I can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific example. The compound illustrated in the example is not, however, to be construed as forming the only genus that is considered as the invention. The Example further illustrates details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESMS).
List of Abbreviations:
ACN is acetonitrile; Ac20 is acetic anhydride; AcOH is acetic acid; Boc is tert- butyloxycarbonyl; Celite™is diatomaceous earth; CuS04 is copper sulfate; DBU is 1,8- diazabicyclo[5.4.0]undec-7-ene; DCM is dichloromethane; DIPEA or DIEA is diisopropyl ethyl amine; DMF is N, N-dimethylformamide; equiv is equivalent(s); ESI is electrospray ionization; Et3N is triethylamine; EA and EtOAc is ethyl acetate; EtOH is ethyl alcohol; Et20 is diethyl ether; Et3N is triethyl amine; g is gram(s); h is hour(s); HC1 is hydrochloric acid; K2C03 is potassium carbonate; LC is liquid chromatography; L is liter(s); M is molar; mmol is
millimole(s); MeCN is acetonitrile; MeOH is methyl alcohol; MgS0 is magnesium sulfate; min is minute(s); MS is mass spectrum; MTBE is methyl tert-butyl ether; NaOH is sodium hydroxide; NaN3 is sodium azide; NBS is N-bromosuccinamide; NMP is N-methyl-2- pyrrolidinone; NMR is nuclear magnetic resonance spectroscopy; PE is pet ether; Ph is phenyl; sat. or sat is saturated; Si02 is silicon dioxide; rt is room temperature; TEA is triethyl amine; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; THF is tetrahydrofuran; MeTHF is 2-methyltetrahydrofuran; TMP is 2,2,6,6-tetramethylpiperidine; and wt% is weight percent. Method A
The spiro moieties can be prepared according to the procedures described by L. Yang., et. al., Bioorg. Med. Che,. Lett., 8, 107-1 12 (1998). Here is an illustration with A-5. An
appropriately substituted 2'-hydroxyacetophenone A-l is reacted with an appropriately substituted cyclic ketone intermediate A-2 in the presence of a base, such as pyrrolidine, in a solvent, such as methanol, to give the spiro-intermediate A-3.
Figure imgf000053_0001
The carbonyl of intermediate A-3 is then reduced in a 2-step sequence via alcohol A-4 to give the spiro-cyclic amine intermediate A-5 for further coupling reaction. The spiro intermediate A-5 is either isolated as a free base or a salt with an acid such as HC1 or TFA. For R3 = OH in A-4, it can be further reacted with an alkyl or benzyl group to provide the corresponding alkylated analog.
Method B
Figure imgf000054_0001
An appropriately substituted spiro intermediate B-1, prepared according the Method A, is reacted with an appropriately halo-substituted (Χ' = CI, Br) heteroaryl B-2, wherein heteroaryl ring B is as previously defined, and Y' is a functional group such as halogen (CI, Br, I), ester, amide, nitrile or heterocycle which is suitable for the transformation to substituent R4 as previously defined. The functional group Y' is then converted by typical standard
transformations to substituent R4 to give the desired moiety for final product B-3. Other spiro moieties can be used to couple with B-2 to obtain the corresponding analogs.
INTERMEDIATE 1
Figure imgf000054_0002
5-Chloro-3,4-dihvdrospiro[chromene-2,4'-piperidine] hydrochloride salt
Step 1 : l-(2-Chloro-6-hvdroxyphenyl)ethanone. To a solution of 3-chlorophenol (50 g, 390.62 mmol, 1.00 equiv) in DCM (500 mL) was added DIEA (554 g, 4.29 mol, 11.00 equiv), followed by chloro(methoxy)methane (380 g, 10.00 equiv) at 20 °C. The resulting mixture was allowed to react, with stirring, for 4 h at 20 °C. The reaction mixture was then quenched with water. The separated organic phase was washed with water (2x), dried over Na2S04 and then concentrated under vacuum to give l-chloro-3-(methoxymethoxy)benzene as a white oil.
To a solution of l-chloro-3-(methoxymethoxy)benzene (24 g, 136.74 mmol, 1.00 equiv, 98%) in THF (240 mL) was added TMP (21 g, 150.00 mmol, 1.10 equiv). To the above solution was added «-BuLi (61 mL, 1.10 equiv, 2.5mol/L) dropwise with stirring at -75 °C over 30 min. After stirring for 2 h at -75 °C, the resulting mixture was treated with Ac20 (15.5 g, 148.92 mmol, 1.10 equiv, 98%) via dropwise addition with stirring at -75 °C over 30 min. The mixture was stirred for additional 30 min at room temperature, and then quenched by adding water. The resulting mixture were extracted with 2 x 300 mL of ethyl acetate. The combined organic layers was washed with H20, dried over Na2S04 and concentrated under vacuum to give l-(2-chloro-6- (methoxymethoxy)phenyl)-ethanone as a yellow oil.
To a solution of l-(2-chloro-6-(methoxymethoxy)phenyl)ethanone (38 g, 177.03 mmol, 1.00 equiv) in THF (380 mL) was added HC1 (aq. 35 g, 2.00 equiv, 36%). The resulting mixture was allowed to react, with stirring, for 3 h at 65 °C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried and concentrated under vacuum to give the crude title compound.
Step 2: tert-Butyl 5 -chloro-4-oxo-3 ,4-dihydro- 1 Ή-spiro [chromene-2,4'-piperidinel - 1 '- carboxylate. A mixture of ierf-butyl 4-oxopiperidine-l-carboxylate (14 g, 70.35 mmol, 1.00 equiv), pyrrolidine (7 g, 98.59 mmol, 1.40 equiv) and l-(2-chloro-6-hydroxyphenyl)ethanone (12 g, 70.59 mmol, 1.00 equiv) in MeOH (150 mL) was reacted at 65 °C for 20 min. The reaction mixture was cooled to room temperature and concentrated. To the resulting residue was added 500 mL of ethyl acetate. The mixture was then washed with water (2x). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a white solid.
Step 3: tert-Butyl 5-chloro-4-hvdroxy-3,4-dihydro-rH-spiro chromene-2,4'-piperidine1-r- carboxylate. To a solution of tert-butyl 5-chloro-4-oxo-3,4-dihydro-l'H-spiro[chromene-2,4'- piperidine]-l'-carboxylate (30 g, 85.27 mmol, 1.00 equiv) in EtOH (300 mL) was added portionwise NaB¾ (3.3 g, 87.23 mmol, 1.02 equiv) at 25 °C over 30 min. The resulting mixture was allowed to react, with stirring, for 1 h at room temperature. The reaction was then quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with H20 (2x), dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a white solid.
Step 4: 5-Chloro-3,4-dihvdrospiro["chromene-2,4'-piperidine] hydrochloride salt. To a mixture of tert-butyl 5-c oro-4-hydroxy-3,4-dihydro-rH-spiro[chromene-2,4'-piperidine]-l'-carboxylate (12.4 g, 35.04 mmol, 1.00 equiv) in trifluoroacetic acid (130 mL) was added triethylsilane (16.8 g, 144.48 mmol, 4.12 equiv). The resulting mixture was allowed to react, with stirring, for 5 h while the temperature was maintained at 80 °C to reflux. The resulting mixture was concentrated under vacuum. To the resulting residue were added 200 mL of Et20. The resulting solids were collected by filtration to give the TFA salt as a white solid. The TFA salt was converted to the free base by the treatment with aqueous NaOH. The free base was then dissolved in Et20 and reacted with HC1 gas to give the title compound as a white solid
INTERMEDIATE 2
Figure imgf000055_0001
Ethyl (2-oxo-2,3-dihydro- 1 H-imidazol- 1 -vDacetate
Step 1 : Ethyl N- { [(2,2-dimethoxyethyl)aminolcarbonyl I glycinate To a solution of ethyl isocyanatoacetate (8.84 mL, 77 mmol) in CH2C12 (100 mL) at 0 °C was added
aminoacetaldehyde dimethyl acetal (8.86 mL, 81 mmol) over a period of 10 min. The mixture was further stirred for 30 min, and quenched with water. The CH2C12 layer was separated, washed with water, dried (Na2S04) and concentrated to give the crude title compound as an oil. Step2: Ethyl (2-oxo-2,3-dihydro- lH-imidazol- 1 -vDacetate To a solution of ethyl N-{[(2,2- dimethoxyethyl)amino]carbonyl}glycinate (16 g, 68.3 mmol) in acetic acid (20 mL) was added 80% aqueous formic acid (80 mL, 1669 mmol). The mixture was stirred at 65 °C for lh. Most volatile materials were removed in vacuo. The residue was diluted with a small amount of water (-10 to 20 mL), and then extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were concentrated and dried in vacuo. The residue was swished with Et20 to give the title compound as a pale yellow solid. Ή NMR (500 MHz, acetone-d6): δ 9.49 (s, 1 H), 6.45 (d, 1 H), 6.40 (d, 1 H), 4.39 (s, 2 H), 4.23-4.14 (q, 2 H), 1.29-1.23 (t, 3 H).
INTERMEDIATE 3
Figure imgf000056_0001
Ethyl [4-(tributylstannvD- 1 H- 1 ,2,3 -triazol- 1 -yl] acetate
A mixture of ethyl azidoacetate (1.72 g, 13.3 mmol) and tributyl(ethynyl)stannane (4.20 g, 13.3 mmol) in 30 mL of anhydrous toluene was refluxing for 24 hours. After removing the solvent, the residue was purified by silica gel column chromatography (PE/EA = 15: 1) to afford the title compound. IHNMR (CDC13 400MHz) δ 7.53 (s, 1H), 5.13 (s, 2H), 4.17 (q, 2H), 1.56 (m, 6H), 1.20-1.28 (m, 9H), 1.03-1.07 (m, 6H), 0.75-0.82 (m, 9H). M+l : 444 and 446.
INTERMEDIATE 4
Figure imgf000056_0002
r-(5-Bromopyrimidin-2-yl)-5-cMoro-3,4-dihvdrospirorchromene-2,4'-piperidine]
A mixture of 5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] TFA salt (600 mg, 1.8 mmol), 5-bromo-2-chloro-pyrimidine (0.38 g, 2.0 mmol), Et3N (0.45 g, 4.5 mmol) and EtOH (10 ml) was stirred at 90°C for 3 hours. The solvent was removed in vacuo. The resulting residue was washed with water and dried in vacuo to give the title compound. Ή NMR (CDC13 400
MHz) δ 8.21 (s, 2H), 6.99 (t, IH), 6.88 (d, IH), 6.73 (d, IH), 4.35-4.39 (m, 2H), 3.29-3.36 (m, 2H), 2.70-2.74 (m, 2H), 1.76-1.82 (m, 4H), 1.49-1.55 (m, 2H).
INTERMEDIATE 5
Figure imgf000057_0001
-(5-Bromopyrazin-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine]
Step 1 : 5-Chloro- 1 '-pyrazin-2-yl-3 ,4-dihydrospirorchromene-2,4'-piperidine] A mixture of 5- chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] TFA salt (1 g, 3 mmol), 2-chloropyrazine (516 mg, 4.5 mmol) and DBU (680 mg, 4.5 mmol) in NMP (3 mL) was heated at 150°C over 18 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with water, dried over Na2S04 and concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the title compound. Ή NMR (CDC13 400 MHz) δ 8.11 (s, IH), 7.99 (s, IH), 7.75 (d, IH), 6.99 (t, IH), 6.88 (d, IH), 6.72 (d, IH), 4.01-4.05 (m, 2H), 3.30-3.36 (m, 2H), 2.71-2.75 (m, 2H), 1.77- 1.87 (m, 4H), 1.53-1.62 (m, 2H).
Step 2: r-(5-Bromop azin-2-yl)-5-cMoro-3,4-dihydrospiro[chromene-2,4'-piperidine] To a solution of 5-chloro- -pyrazin-2-yl-3,4-dihydrospiro[chromene-2,4'-piperidine] (660 g, 2.1 mmol) in DCM (20 mL) was added NBS (445 mg, 2.5 mmol) at 0°C. The mixture was stirred at 0°C over 1 hour and then warmed to 25°C, stirred for 16 h. The resulting mixture was diluted with saturated NaHC03, and extracted with DCM (3x). The combined organic extracts were concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound. Ή NMR (CDC13 400 MHz) δ 8.12 (s, IH), 7.90 (s, IH), 7.05 (t, IH), 6.96 (d, IH), 6.79 (d, IH), 4.02-4.06 (m, 2H), 3.34-3.42 (m, 2H), 2.78-2.82 (m, 2H), 1.84-1.90 (m, 4H), 1.56-1.68 (m, 2H).
INTERMEDIATE 6
Figure imgf000057_0002
Ethyl [5-(2-chloropyrimidin-5-yl)-2H-tetrazol-2-yl acetate Step 1 : N"-Benzyl-5-bromopyrimidin-2-amine Into a 2 L round-bottom flask equipped with a heating mantle, reflux condenser and under N2 was added 2-chloro-5-bromopyrimidine (125 g, 646 mmol), DIPEA (251 mL, 1435 mmol) and benzylamine (95 mL, 872 mmol) in 2-propanol (250 mL). The reaction mixture was heated to 100 °C for 1 h and then cooled to room temperature and stirred for 16 h. The crude reaction mixture was filtered under vacuum on a sintered glass funnel, and the filter cake was rinsed with ethanol (2 x 50 mL) and hexanes (200 mL). The filter cake was further dried under vacuum to provide the title compound as a white crystalline solid.
Step 2: 2-(Benzylamino)pyrimidine-5-carbonitrile Into a 5 L round-bottom flask equipped with a reflux condenser and heating mantle, under N2, was added N-benzyl-5-bromopyrimidin-2- amine (150 g, 568 mmol), copper(I) cyanide (64 g , 710 mmol) and DMF (1.5 L). The reaction mixture was heated to 150 °C for 16 h. The reaction mixture was then cooled to room temperature and poured into a 3 L separatory funnel containing 750 mL of a 1 : 1 :2 solution of saturated NH4Cl/concentrated NH40H/water. The aqueous layer was extracted with MeTHF (3 x 500 mL) and the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting product was utilized in the subsequent step without further purification.
Step 3: N-Benzyl-5-(2H-tetrazol-5-yl)pyrimidin-2-amine A suspension of 2- (benzylamino)pyrimidine-5-carbonitrile (34 g, 162 mmol), sodium azide (13 g, 202 mmol) and ammonium chloride (35 g , 647 mmol) in DMF (340 mL) was heated at 100 °C. A steady flow of N2 (170 iriL/min) was placed above the reaction mixture and the reaction flask was kept open and well- vented. At 1.5 h, 3 h, and 4 h, an additional 1 equiv of sodium azide (10.5 g, 162 mmol) was added to the mixture. After 5 h total reaction time, the mixture was allowed to cool to room temperature. The reaction was poured into a 2 L separatory funnel containing aqueous 1 N NaOH solution (750 mL) and the aqueous layer was extracted with MTBE (2 x 200 mL). The aqueous layer was cooled to 0 °C in an ice bath and acidified to pH 1-2 with aqueous 2 M HC1 solution. During the acidification, the internal temperature was maintained below 15 °C. The aqueous mixture was poured into a separatory funnel and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford to the title compound as a beige solid.
Step 4: Ethyl {5-[2-(benzylamino)pyrimidin-5-yl1-2 /-tetrazol-2-yl| acetate To a 2 L round- bottom flask equipped with a heating mantle and reflux condenser was added N-benzyl-5-(2H- tetrazol-5-yl)pyrimidin-2-amine (31.9 g, 126 mmol), ethyl bromoacetate (21 mL, 188 mmol), triethylamine (35 mL, 251 mmol) and THF (390 mL). The reaction mixture was heated to 65 °C for 1 h and then cooled to room temperature. Water (1 L) was added and the mixture was stirred at room temperature for 1 h, then filtered under vacuum on a sintered glass funnel. The filter cake was further washed with water/THF (2.5: 1 , 300 mL), and then with water (500 mL). The resulting cake was re-suspended in THF (320 mL) and then water (640 mL) was added gradually over 0.5 h. The suspension was stirred an additional 0.5 h at room temperature and then filtered under vacuum on a sintered glass funnel. The filter cake was washed with 2: 1 watenTHF (2 x 200 mL) and dried under vacuum for several hours, affording the title compound as white powder.
Step 5: Ethyl 5-(2-aminopyrimidin-5-yl)-2H-tetrazol-2-yl]acetate Into a 1 L round-bottom flask was dissolved ethyl {5-[2-(benzylamino)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate (30.7 g, 90 mmol) in MeCN (300 mL) and water (60 mL). To this solution was added cerium ammonium nitrate (114 g, 208 mmol) portion wise over 15 min. The mixture was stirred at room
temperature for 1 h, and then poured into a separatory funnel containing water (500 mL). The aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with aqueous 0.1 N HCl solution / brine (1 : 1 ; 250 mL), brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the title compound.
Step 6: Ethyl 5-(2-chloropyrimidin-5-yl)-2H-tetrazol-2-yl]acetate A solution of ethyl [5-(2- aminopyrimidin-5-yl)-2H-tetrazol-2-yl]acetate (16.6 g , 66 mmol) in 1 ,2-dichloroethane (330 mL) was treated with antimony (III) chloride (19.3 mL, 266 mmol). The mixture was cooled to 0 °C in an ice bath and tert-butyl nitrite (44 mL, 332 mmol) was added dropwise to the reaction mixture over 15 min. After 3 h, the mixture was diluted with saturated aqueous NaHC03 solution (200 mL) and CH2C12 (200 mL) and the resulting suspension was filtered through a pad of Celite™ on a sintered glass funnel under vacuum. The filtrate was poured into a 2 L separatory funnel containing saturated aqueous NaHC03 solution (250 mL) and the aqueous layer was extracted with CH2C12 (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure the crude product.
Purification of the crude product by column chromatography through silica gel, eluting with 85: 15 hexanes/EtOAc to 50:50 hexanes/EtOAc as a gradient afforded the title compound as an off-white solid. 1H NMR ( 6-DMSO, 400 MHz): δ 9.40 (2H, s), 6.01 (2H, s), 4.24 (2H, q, J 7.0 Hz), 1.25 (3H, t, J= 7.0 Hz). MS (ESI, Q+) m/z 269, 271 (M + 1, 35C1, 37C1).
EXAMPLE 1
Figure imgf000059_0001
5-[2-(5-CMoro-3,4-dihydrospiro 2H-l-benzop an-2,4'-piperidinl-l l)-5-pyrimidinyl]-2H- tetrazole-2-acetic acid
Step 1 : Ethyl {5- 2-(5-chloro-3,4-dihydro- 1 'H-spirorchromene-2,4'-piperidin]- 1 '-vDpyrimidin-S- yl] -2H-tetrazol-2-yl } acetate To a solution of ethyl [5-(2-chloropyrimidin-5-yl)-2H-tetrazol-2- yl]acetate (80 mg, 0.298 mmol) and 5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidinium] chloride (106 mg, 0.387 mmol) in NMP (1.25 mL) was added DBU (1 15 μί, 0.763 mmol). The tube was sealed and immersed into a preheated oil bath at 130 °C, and stirred at this temperature for 20 min. The reaction was diluted with EtOAc, poured into 0.5 N HCl, extracted with EtOAc, washed with water (3x) and brine, dried (Na2S04), filtered and concentrated. The resulting residue was purified twice by flash chromatography on Si02 (10 g; gradient 0 to 60%
EtOAc/hexanes) to give the title compound as an off white solid.
Step 2: 5- 1"2-(5 -Chloro-3 ,4-dihydrospiro \2H- 1 -benzopyran-2,4'-piperidin1 - 1 '-yl)-5-pyrimidinyl1 - 2H-tetrazole-2-acetic acid A solution of ethyl {5-[2-(5-chloro-3,4-dihydro-rH-spiro[chromene- 2,4'-piperidin]- -yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate (95 mg, 0.202 mmol) in THF (4 mL) was treated with IN NaOH (2 mL). After 30 min, the reaction was poured into aqueous IN HCl, extracted with EtOAc and washed with brine. The organic layer was dried (Na2S04) and filtered. The resulting residue was purified by trituration with Et20/heptane to give the title compound as a white solid. Ή NMR (500 MHz, DMSO-d6): δ 13.78 (br s, 1H), 8.97 (s, 2 H),
7.15 (t, 1 H), 7.01 (d, 1 H), 6.86 (d, 1 H), 5.74 (s, 2 H), 4.52-4.45 (m, 2 H), 3.53-3.45 (m, 2 H), 2.74 (t, 2 H), 1.90 (t, 2 H), 1.81 (d, 2 H), 1.72-1.65 (m, 2 H). LC-MS: m/z = 444.1, 442.1
(MH+).
EXAMPLE 2
Figure imgf000060_0001
{5-r2-(5-Chloro-4-oxo-3,4-dihydro-l^-spiro[chromene-2,4'-piperidinl-r-yl)pyrimidin-5-yl]-2H- tetrazol-2-v acetic acid
The title compound was prepared in a similar manner as described for Example 1 from 5- chlorospiro[chromene-2,4'-piperidin]-4(3H)-one and ethyl [5-(2-chloropyrimidin-5-yl)-2H- tetrazol-2-yl]acetate. 1H NMR (500 MHz, DMSO-d6): δ 8.96 (s, 2 H), 7.53 (t, 1 H), 7.12 (t, 2 H), 5.49 (s, 2 H), 4.50 (d, 2 H), 3.49 (t, 2 H), 2.92 (s, 2 H), 2.00 (d, 2 H), 1.78 (t, 2 H).
EXAMPLE 3
Figure imgf000060_0002
{3-r2-(5-Crrtoro-3^-dihydro-17/-spiro[cfa^
dihvdro- 1 H-imidazol- 1 -yl ) acetic acid
Step 1 : Ethyl {3-r2-(5-chloro-3,4-dihydro- H-spiro[chromene-2^'-piperidin]- -yl pyrimidin-5- yl]-2-oxo-2,3-dihydro-lH-imidazol-l-yl}acetate A mixture of -(5-bromopyrazin-2-yl)-5- chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] (250 mg, 0.64 mmol), ethyl (2-oxo-2,3- dihydro-1 H-imidazol- l-yl)acetate (1 19 mg, 0.7 mmol), Cul (48 mg, 0.25 mmol), Ν,Ν'- dimethylethylenediamine (45 mg, 0.51 mmol) and K3PO4 (270 mg, 1.27 mmol) in dioxane (10 mL) was stirred at 80°C for 7 hours under Argon. After cooling, the solid was filtered off and the residue was concentrated in vacuo and the residue was purified by preparative TLC to give the title compound. Ή NMR (CDC13 400 MHz) δ 8.47 (s, 2H), 7.06 (t, IH), 6.95 (d, IH), 6.80 (d, IH), 6.42-6.44 (m, 2H), 4.50-4.53 (m, 2H), 4.45 (s, 2H), 4.22-4.28 (m, 2H), 3.42-3.48 (m, 2H), 2.78-2.82 (m, 2H), 1.84-1.89 (m, 4H), 1.55-1.65 (m, 2H), 1.38 (t, 3H).
Step 2: {3-[2-(5-Chloro-3,4-dihydro-l^-spiro[chromene-2,4'-piperidinl- -yl)pyrimidin-5-yll-2- oxo-23-dihydro- lH-imidazol-1 -yl| acetic acid A mixture of ethyl {3-[2-(5-chloro-3,4-dihydro- 17/-spiro[chromene-2,4'-piperidin]-l '-yl)pyrimidin-5-yl]-2-oxo-2,3-dihydro- 1 H-imidazol- 1 - yl} acetate (100 mg, 0.21 mmol) and 1M LiOH (0.6 mL, 1 M) in THF (3 mL) was stirred at room temperature for 2 hours. Volatile materials were removed under vacuum. The residue was adjusted to pH of 5 with 1 M HC1. The resulting solid was collected, washed with water and dried to afford the title compound. 1H NMR (DMSO-d6 400 MHz) δ 8.57 (s, 2H), 7.10 (t, IH), 6.95 (d, IH), 6.89 (d, IH), 6.80 (d, IH), 6.70 (d, IH), 4.30-4.33 (m, 4H), 3.36-3.42 (m, 2H), 2.67-2.70 (m, 2H), 1.82-1.86 (m, 2H), 1.71-1.75 (m, 2H), 1.56-1.64 (m, 2H).
EXAMPLE 4
Figure imgf000061_0001
(3-f5-(5-CMoro-3,4-dihydro-rH-spiro[chromene-2,4'-piperidin1-r-yl)pyrazin-2-yll-2-oxo-2,3- dihydro- 1 H-imidazol- 1 -yl } acetic acid
The title compound was prepared in a similar manner as described for Example 3 from 1 '-
(5-bromopyrazin-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] and ethyl (2-oxo- 2,3-dihydro-lH-imidazol-l-yl)acetate. 1H NMR (DMSO-d6, 400 MHz): δ 8.92 (s, IH), 8.16 (s, IH), 7.09 (d, IH), 6.92-6.96 (m, 2H), 6.80 (d, IH), 6.56 (d, IH), 3.96-4.00 (m, 2H), 3.78 (s, 2H), 3.35-3.39 (m, 2H), 2.67-2.71 (m, 2H), 1.83-1.86 (m, 2H), 1.64-1.76 (m, 4H).
EXAMPLE 5
Figure imgf000062_0001
{ 3 - |~6-(5-Chloro-3 ,4-dihydro- 1 'H-spiro rchromene-2,4'-piperidinl - 1 '-yl)pyridazin-3 -yl"|-2-oxo-2,3 - dihydro- 1 H-imidazol- 1 -yl ) acetic acid
Step 1 : 5-Chloro- -(6-iodop idazin-3-yl)-3,4-dihvdrospiro[chromene-2,4'-piperidinel A mixture of 5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] TFA salt (1.00 g, 2.848 mmol), 3,6-diiodopyridazine (0.952 g, 2.877 mmol) and sodium carbonate (0.743 g, 7.006 mmol) in DMF (10 mL) was stirred overnight at 65°C. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was acidified with IN HC1, filtered, and the resulting precipitate was washed with hexane to afford the title compound. 1H NMR (CDC13 400 MHz) δ 7.45 (d, IH), 7.06 (t, IH), 6.95 (d, IH), 6.79 (d, IH), 6.66 (d, IH), 4.10 (d, 2H), 3.44 (t, IH), 2.79 (t, 2H), 1.91 (d, 2H), 1.85 (t, 2H), 1.61-1.71 (m, 2H).
Step 2: { 3 -r6-(5-Chloro-3 ,4-dihydro- 1 'H-spiro rchromene-2,4'-piperidin] - 1 '-yl)pyridazin-3 -yll-2- oxo-2,,3 -dihydro- 1 H-imidazol- 1 -yl} acetic acid The title compound was prepared in a similar manner as described for Example 3 from 5-chloro-l'-(6-iodopyridazin-3-yl)-3,4- dihydrospiro[chromene-2,4'-piperidine] and ethyl (2-oxo-2,3-dihydro-lH-imidazol-l-yl)acetate. 1HNMR (DMSO-d6, 400 MHz) δ 8.20 (d, IH), 7.49 (d, IH), 7.24 (d, IH), 7.10 (t, IH), 6.96 (d, IH), 6.80 (d, IH), 6.76 (d, IH), 4.32 (s, 2H), 3.98-4.07 (m, 2H), 3.35 (t, 2H), 2.69 (t, 2H), 1.81- 1.88 (m, 2H), 1.62-1.78 (m, 4H).
EXAMPLE 6
Figure imgf000062_0002
14- r5-(5-Chloro-3 ,4-dihydro- 1 'H-spiro rchromene-2,4'-piperidinl - 1 '-yl)pyrazin-2-yll- 1 H-l.2.3- triazol-l-yU acetic acid
Step 1 : Ethyl { 4-f 5-(5-chloro-3 ,4-dihydro- 1 'H-spiro[chiomene-2,4'-piperidin"|- 1 '-yl)pyrazin-2- yl] - 1 H- 1 ,2,3 -triazol- 1 -yl ) acetate A mixture of l'-(5-bromopyrazin-2-yl)-5-chloro-3,4- dihydrospiro[chromene-2,4'-piperidine] (300 mg, 0.76 mmol), ethyl [4-(tributylstannyl)-lH- l,2,3-triazol-l-yl]acetate (442 mg, 0.99 mmol) and Pd(PPh3)4 (80 mg, 0.076 mmol) in DMF (6 mL) was stirred at 80°C for 8 hours under argon. After cooling, the mixture was diluted with water and extracted with EtOAc (2x). Solvent was removed in vacuo and the residue was purified by preparative TLC to give the title compound. 1H NMR (CDC13 400 MHz) δ 8.88 (s, IH), 8.14 (s, IH), 8.07 (s, IH), 7.07 (t, IH), 6.96 (d, IH), 6.80 (d, IH), 5.20 (s, 2H), 4.26-4.31 (m, 2H), 4.14-4.18 (m, 2H), 3.42-3.48 (m, 2H), 2.79-2.83 (m, 2H), 1.93-1.96 (m, 2H), 1.86-1.89 (m, 2H), 1.65-1.73 (m, 2H), 1.30 (t, 3H).
Step 2: (4- 5-(5-Chloro-3 ,4-dihydro- 1 'H-spiro [chromene-2,4'-piperidin] - 1 '-yl)pyrazin-2-yl1 - 1 H- 1,2,3 -triazol-l-yl) acetic acid The title compound was prepared in a similar manner as described for Example 3, Step 2 from ethyl {4-[5-(5-chloro-3,4-dihydro-l'H-spiro[chromene-2,4'- piperidin]- 1 ,-yl)pyrazin-2-yl]- IH- 1 ,2,3-triazol- 1 -yl} acetate. 1H NMR (DMSO_t/6 400 MHz) δ 8.65 (s, IH), 8.37 (s, IH), 8.35 (s, IH), 7.10 (t, J= 8 Hz, IH), 6.96 (d, J= 8 Hz, IH), 6.81 (d, J= 8 Hz, IH), 5.20 (s, 2H), 4.08-4.1 1 (m, 2H), 3.36-3.39 (m, 2H), 2.68-2.71 (m, 2H), 1.84-1.87 (m, 2H), 1.65-1.71 (m, 4H).
EXAMPLE 7
Figure imgf000063_0001
{4-[2-(5-Chloro-3,4-dihydro-l^-spiro[cfa
triazol-l-yl} acetic acid
The title compound was prepared in a similar manner as described for Example 6 from 1 '- (5-bromopyrimidin-2-yl)-5-chloro-3,4-dihydrospiro[chromene-2,4'-piperidine] and ethyl [4- (tributylstarmyl)-lH-l,2,3-triazol-l-yl]acetate. 1H NMR (CD3OD 400 MHz) δ 8.72 (s, 2H), 8.20 (s, IH), 7.06 (t, IH), 6.91 (d, IH), 6.80 (d, IH), 5.02 (s, 2H), 4.49-4.53 (m, 2H), 3.43-3.49 (m, 2H), 2.77-2.81 (m, 2H), 1.82-1.89 (m, 4H), 1.62-1.69 (m, 2H).
EXAMPLE 8
Figure imgf000063_0002
(4- Γ5-(3 ,4-Dihydro- 1 'H-spiro rchromene-2,4'-piperidin|- 1 '-yl pyrazin-2-yn - IH- 1.2,3 -triazol- 1 - yl} acetic acid
The title compound was prepared in a similar manner as described for Example 6 from Γ-
(5-bromopyrazin-2-yl)-3,4-dihydrospiro[chromene-2,4'-piperidine] and ethyl [4-(tributylstannyl)- lH-l,2,3-triazol-l-yl]acetate. !HNMR (MeOH-cL, 400MHz): δ 8.68 (s, IH), 8.29 (s, IH), 8.26(s, IH), 7.03-7.06 (m, 2H), 6.78-6.82 (m, 2H), 5.30 (s, 2H), 4.21 (d, 2H), 3.42-3.49 (m, 2H), 2.81 (t, 2H), 1.82-1.92 (m, 4H), 1.66-1.74 (m, 2H). MS: m/z 407 (MH+).
EXAMPLE 9
Figure imgf000064_0001
{ 4- [5-(4-Oxo-3.4-dihydro- 1 'H-spiro [chromene-2.4'-piperidin|- 1 '-vDpyrazin-2-yl] - 1 H- 1 ,2,3 - triazol- 1 -yl } acetic acid
The title compound was prepared in a similar manner as described for Example 6 from Γ- (5-bromopyrazin-2-yl)spiro[chromene-2,4'-piperidin]-4(3H)-one and ethyl [4-(tributylstannyl)- lH-l,2,3-triazol-l-yl]acetate. 'HNMR (MeOH-d4, 400MHz): 6 8.69 (s, IH), 8.30 (s, IH), 8.27 (s, IH), 7.80-7.83 (m, IH), 7.53-7.58 (m, IH), 7.01-7.09 (m, 2H), 5.29 (s, 2H), 4.22 (d, 2H), 3.46 t, 2H), 2.80 (s, 2H), 2.13 (d, 2H), 1.76-1.84 (m, 2H). MS: m/z 421(MH+).
EXAMPLE 10
Figure imgf000064_0002
(4- Γ6-( 5 -Chloro-3.4-dihvdro- 1 'H-spiro rchromene-2,4'-piperidin1- 1 '-yl)pyridazin-3 -yll- 1 H- 1.2.3- triazol- 1-vU acetic acid
The title compound was prepared in a similar manner as described for Example 6 from 5- cUoro-r-(6-iodopyridazin-3-yl)-3,4-dihydrospiro[chromene-2,4'-piperidine], Example 6, step 1, and ethyl [4-(tributylstannyl)-lH- 1,2,3 -triazol- l-yl]acetate. 'HNMR (DMSO-d6, 400 MHz) δ 8.45 (s, IH), 7.94 (d, IH), 7.42 (d, IH), 7.13 (t, IH), 6.99 (d, IH), 6.84 (d, I H), 4.98 (s, 2H), 4.14
(d, 2H), 3.44-3.54 (m, 2H), 2.73 (t, 2H), 1.88 (d, 2H), 1.66-1.83 (m, 4H).
EXAMPLE OF A PHARMACEUTICAL FORMULATION
As a specific embodiment of an oral composition of a compound of the present invention, 50 mg of the compound of any of the Examples is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule. While the invention has been described and illustrated in reference to specific embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the human being treated for a particular condition. Likewise, the pharmacologic response observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended therefore that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of structural formula I:
Figure imgf000066_0001
or a pharmaceutically acceptable salt thereof; wherein A is selected from the group consisting of:
Figure imgf000066_0002
g is a single bond or a double bond; J and K are each independently selected from the group consisting of: S, O, NH, CH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH and C¾ is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is C¾ unsubstituted or substituted with R2, and further provided that when g is a double bond then both J and K are CH;
L and M are each independently selected from the group consisting of: S, O, NH and C¾, wherein each NH is unsubstituted or substituted with Rg, and wherein each C¾ is unsubstituted or substituted with R2; T, U, V and W are each independently selected from N and CH, wherein each CH is
unsubstituted or substituted with R3, provided that at least two of T, U, V and W are CH;
X is CH2, wherein C¾ is unsubstituted or substituted with R2; Y is independently selected from the group consisting of: O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH2 is unsubstituted or substituted with
R2;
Z is independently selected from the group consisting of: S, S(O), S(0)2, O, NH and CH2, wherein each NH is unsubstituted or substituted with Rg, and wherein each CH2 is unsubstituted or substituted with R2;
B is selected from the group consisting of:
Figure imgf000067_0001
each R1 is independently selected from the group consisting of: hydrogen, halogen, and Ci-3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy; each R2 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) oxo,
(4) Ci-6 alkyl,
(5) (CH2)nORe,
Figure imgf000067_0002
(7) (CH2)nC≡N,
(8) (CH2)nCORe, and
Figure imgf000067_0003
wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C\-4 alkyl unsubstituted or substituted with one to five fluorines; each R3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) -Ci-6 alkyl,
(4) -OCi-6 alkyl,
(5) (CH2)nORe,
Figure imgf000068_0001
(7) (CH2)nC≡N,
(8) (CH2)nCORe, and
Figure imgf000068_0002
wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci -4 alkyl unsubstituted or substituted with one to five fluorines;
R4 is selected from the group consisting of:
Figure imgf000068_0003
Figure imgf000069_0001
each Ra is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) cyano,
(4) Ci-4 alkyl, unsubstituted or substituted with one to five fluorines,
(5) C 1 -4 alkoxy, unsubstituted or substituted with one to five fluorines,
(6) C i -4 alkylthio, unsubstituted or substituted with one to five fluorines, (7) Ci-4 alkylsulfonyl,
(8) -C02H,
(9) Ci-4 alkyloxycarbonyl, and
(10) Ci-4 alkylcarbonyl; each Rb is independently selected from the group consisting of:
(1) hydrogen, and
(2) Ci-4 alkyl,
wherein alkyl is unsubstituted or substituted with one to five fluorines; each Rc is independently selected from the group consisting of:
(1) -(CH2)mC02H,
(2) -(CH2)mC02Ci-3 alkyl,
(3) -(CH2)m-NRb-(CH2)pC02H,
(4) -(CH2)m-NRb-(CH2)pC02Ci-3 alkyl,
(5) -(CH2)m-0-(CH2)pC02H,
(6) -(CH2)m-0-(CH2)pC02Ci_3 alkyl,
(7) -(CH2)m-S-(CH2)pC0 H, and
(8) -(CH2)m-S-(CH2)pC02Ci.3 alkyl,
wherein any CH2 in Rc is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Ci-4 alkyl unsubstituted or substituted with one to five fluorines; each d is independently selected from the group consisting of:
(1) -(CH2)nC02H,
(2) -(CH2)nC02Ci_3 alkyl, (3) -(CH2)n-NRb-(CH2)pC02H,
(4) -(CH2)n-NRb-(CH2)pC02Ci-3 alkyl,
(5) -(CH2)n-0-(CH2)pC02H,
(6) -(CH2)n-0-(CH2)pC02Ci_3 alkyl,
(7) -(CH2)n-S-(CH2)pC02H, and
(8) -(CH2)n-S-(CH2)pC02Ci-3 alkyl,
wherein any Cl¾ in Rd is unsubstituted or substituted with one to two groups independently selected from the group consisting of: halogen, hydroxy, and C]_4 alkyl unsubstituted or substituted with one to five fluorines; each Re is independently selected from the group consisting of:
(1) hydrogen, and
(2) Ci-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -Cl-4 alkoxy, -Ci-4 alkylthio, -Ci-4 alkylsulfonyl, -CO2H, and -CO2C1-4 alkyl; each Rg is independently selected from the group consisting of:
(1) hydrogen, and
(2) Ci-6 alkyl; m is an integer from 1 to 3;
n is an integer from 0 to 3;
p is an integer from 1 to 3;
q is an integer from 1 to 2;
t is an integer from 0 to 8;
d is an integer from 0 to 2; and
e is an integer from 0 to 2,
provided that d + e is 2.
2. The compound of Claim 1 wherein t is 0, d is 1, and e is 1 ; or a
pharmaceutically acceptable salt thereof.
3. The compound of Claim 2 wherein T, U, V and W are CH, wherein CH is unsubstituted or substituted with R3; or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 1 wherein A is selected from the group consisting of:
Figure imgf000071_0001
or a pharmaceutically acceptable salt thereof.
5. The compound of Claim 9 wherein A is selected from the group consisting of:
Figure imgf000071_0002
or a pharmaceutically acceptable salt thereof.
6. The compound of Claim 1 wherein B is selected from the group consisting of:
Figure imgf000071_0003
or a pharmaceutically acceptable salt thereof.
7. The compound of Claim 4 wherein B is selected from the group consisting of:
Figure imgf000072_0001
or a pharmaceutically acceptable salt thereof.
8. The compound of Claim 5 wherein B is selected from the group consisting of:
Figure imgf000072_0002
or a pharmaceutically acceptable salt thereof.
The compound of Claim 1 wherein R4 is selected from the group consisting of:
Figure imgf000072_0003
or a pharmaceutically acceptable salt thereof.
The compound of Claim 7 wherein R.4 is selected from the group consisting of:
Figure imgf000072_0004
or a pharmaceutically acceptable salt thereof.
1 1. The compound of Claim 9 wherein r is 1 or 0; s is 0 or 1 ; R2 is independently selected from the group consisting of: hydrogen, and oxo; and R3 is independently selected from the group consisting of: hydrogen, and halogen; or a pharmaceutically acceptable salt thereof.
12. The compound of Claim 1 wherein:
A is selected from the group consisting of:
Figure imgf000073_0001
B is selected from the group consisting of:
Figure imgf000073_0002
R4 is
Figure imgf000073_0003
R3 is independently selected from the group consisting of: hydrogen, and halogen; and s is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
13. The compound of Claim 12 selected from the group consisting of:
Figure imgf000073_0004
Figure imgf000074_0001
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of Claim 1 in combination with a pharmaceutically acceptable carrier.
15. Use of a compound of Claim 1 for the treatment in a mammal of a disorder, condition, or disease responsive to inhibition of stearoyl-coenzyme A delta-9 desaturase.
16. The use of Claim 15 wherein said disorder, condition, or disease is selected from the group consisting of Type 2 diabetes, insulin resistance, a lipid disorder, obesity, metabolic syndrome, liver steatosis, and non-alcoholic steatohepatitis.
17. The use of Claim 16 wherein said lipid disorder is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, atherosclerosis,
hypercholesterolemia, low HDL, and high LDL.
18. Use of a compound of Claim 1 in the manufacture of a medicament for use in treating Type 2 diabetes, insulin resistance, a lipid disorder, obesity, metabolic syndrome, liver steatosis, and non-alcoholic steatohepatitis in a mammal.
19. The use of Claim 18 wherein said lipid disorder is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, atherosclerosis,
hypercholesterolemia, low HDL, and high LDL.
PCT/CA2010/001678 2009-10-23 2010-10-20 Novel spiro compounds useful as inhibitors of stearoyl-coenzyme a delta-9 desaturase WO2011047481A1 (en)

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WO2013056148A2 (en) 2011-10-15 2013-04-18 Genentech, Inc. Methods of using scd1 antagonists
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