WO2004100875A2 - Benzimidazoles, compositions containing such compounds and methods of use - Google Patents

Benzimidazoles, compositions containing such compounds and methods of use Download PDF

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Publication number
WO2004100875A2
WO2004100875A2 PCT/US2004/013874 US2004013874W WO2004100875A2 WO 2004100875 A2 WO2004100875 A2 WO 2004100875A2 US 2004013874 W US2004013874 W US 2004013874W WO 2004100875 A2 WO2004100875 A2 WO 2004100875A2
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groups
optionally substituted
alkyl
halo
group
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PCT/US2004/013874
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French (fr)
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WO2004100875A3 (en
Inventor
Emma R. Parmee
Ronald M. Kim
Rui Liang
Jiang Chang
Elizabeth Ashley Rouse
Kevin T. Chapman
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Merck & Co., Inc.
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Priority to AU2004238240A priority Critical patent/AU2004238240A1/en
Priority to JP2006532564A priority patent/JP2006528687A/en
Priority to CA002524436A priority patent/CA2524436A1/en
Priority to US10/556,230 priority patent/US7563815B2/en
Priority to EP04751318A priority patent/EP1626717A4/en
Publication of WO2004100875A2 publication Critical patent/WO2004100875A2/en
Publication of WO2004100875A3 publication Critical patent/WO2004100875A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to substituted benzimidazole derivatives, compositions containing such compounds and methods of treating type 2 diabetes mellitus.
  • Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or following glucose administration during an oral glucose tolerance test.
  • Frank diabetes mellitus e.g., a blood glucose level >126 mg/dL in a fasting state
  • Type 2 diabetes mellitus Patients with non-insulin dependent diabetes mellitus (type 2 diabetes mellitus), approximately 95% of patients with diabetes mellitus, frequently display elevated levels of serum lipids, such as cholesterol and triglycerides, and have poor blood-lipid profiles, with high levels of LDL- cholesterol and low levels of HDL-cholesterol.
  • Those suffering from Type 2 diabetes mellitus are thus at an increased risk of developing macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension (for example, blood pressure > 130/80 mmHg in a resting state), nephropathy, neuropathy and retinopathy.
  • Type 2 diabetes at least early in the natural progression of the disease is characterized primarily by insulin resistance rather than by a decrease in insulin production, resulting in insufficient uptake, oxidation and storage of glucose in muscle, inadequate repression of lipolysis in adipose tissue, and excess glucose production and secretion by the liver.
  • the net effect of decreased sensitivity to insulin is high levels of insulin circulating in the blood without appropriate reduction in plasma glucose (hyperglycemia). Hyperinsulinemia is a risk factor for developing hypertension and may also contribute to vascular disease.
  • Glucagon serves as the major regulatory hormone attenuating the effect of insulin in its inhibition of liver gluconeogenesis and is normally secreted by pancreatic islet cells in response to falling blood glucose levels.
  • the hormone binds to specific receptors in liver cells that triggers glycogenolysis and an increase in gluconeogenesis through cAMP-mediated events. These responses generate glucose (e.g. hepatic glucose production) to help maintain euglyce ia by preventing blood glucose levels from falling significantly.
  • type II diabetics In addition to elevated levels of circulating insulin, type II diabetics have elevated levels of plasma glucagon and increased rates of hepatic glucose production. Antagonists of glucagon are useful in improving insulin responsiveness in the liver, decreasing the rate of gluconeogenesis and lowering the rate of hepatic glucose output resulting in a decrease in the levels of plasma glucose.
  • the present invention is directed to a compound represented by formula I:
  • R 1 represents H or is independently selected from the group consisting of: a) OH, halo, C0 2 R ⁇ C ⁇ NR'R 0 , NR b R c , CN or S(0) p R d ; b) .ioalkyl, C 2 - ⁇ 0 alkenyl, C 2 . ⁇ oalkynyl, OC ⁇ _ ⁇ 0 alkyl, OC 3 .
  • alkenyl and OC 3 _ ⁇ 0 alkynyl said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 C ⁇ - ⁇ 0 alkoxy groups, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C0 2 R a group; (5) 1 C0 2 R a or S(0) p R d ; (6)1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C0 2 R a , CN, S(0) p R d , N0 2 or C(0)NR b R c group, (c) 1-2 Q.ioalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C
  • HAR group each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C0 2 R a , CN, S(0) p R d , N0 2 or C(0)NR b R c group, (c) 1-2 C ⁇ _ ⁇ 0 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C0 2 R a groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Ci.ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo; and 1-2 hydroxy or C0 2 R a groups; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set forth below: (1) 1-3 C ⁇ - ⁇ -
  • R 3 represents H or is selected from the group consisting of: a) C ⁇ _ ⁇ 0 alkyl or C 2 - ⁇ o lkenyl, each optionally substituted with 1-5 halo groups up to perhalo; 1-2 OH, C ⁇ _ 3 alkoxy or haloC ⁇ _ 3 alkoxy groups; 1-2 NR c R d groups; and 1-2 Aryl, HAR or Hetcy groups, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N0 2 , C ⁇ _ 3 alkyl, haloC ⁇ _ 3 alkyl, C ⁇ - 3 alkoxy and haloC ⁇ - 3 alkoxy groups; and b) Aryl, HAR or Hetcy, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N0 2 , C ⁇ _ 3 alkyl, haloC ⁇ _ 3 alkyl, C ⁇ _ 3 alkoxy and haloC ⁇ _ 3 alkoxy groups; R
  • R 5 represents H or C ⁇ - 6 alkyl
  • R 6 is selected from the group consisting of H, OH, F or C ⁇ _ 3 alkyl;
  • R 7 is H or F, or R 6 and R 7 are taken in combination and represent oxo;
  • R 8 represents H or C ⁇ _ ⁇ alkyl, optionally substituted with OH and 1-5 halo groups up to perhalo;
  • R 9 represents H, halo, OH, C ⁇ _ 6 alkyl, optionally substituted with 1-5 halo groups up to perhalo, or C ⁇ _
  • R 8 and R 9 can be taken together and represent a -(CH 2 ) 24 - or a -0-(CH 2 ) ⁇ _ 3 - group;
  • R a is H or C ⁇ - ⁇ 0 alkyl, optionally substituted with phenyl, OH, OC ⁇ - 6 alkyl, C0 2 H, C0 2 C ⁇ _ 6 alkyl and 1-3 halo groups;
  • R b is H or C 0 alkyl
  • R c is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OC ⁇ - 6 alkyl, C0 2 H, C0 2 C ⁇ . 6 alkyl, and 1-3 halo groups; (b) Aryl or Ar-C ⁇ _ 6 alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, C ⁇ _ ⁇ 0 alkyl and OCi.jo alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-C ⁇ - 6 alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, C ⁇ - ⁇ 0 alkyl and OC MO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-C ⁇ .
  • alkyl optionally substituted with 1-5 halo groups and 1-3 groups selected from: C ⁇ - ⁇ 0 alkyl and OC MO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
  • R d is Ci_i 0 alkyl, Aryl or Ax-C]_i 0 alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C0 2 R a , 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
  • Alkyl as well as other groups having the prefix "alk”, such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-10 carbon atoms are intended for linear or branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.
  • Cycloalkyl is a subset of alkyl; if no number of atoms is specified, 3-10 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. "Cycloalkyl” also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
  • Aryl (Ar) means mono- and bicyclic aromatic rings containing 6-12 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like.
  • Heteroaryl means a mono- or bicyclic aromatic ring or ring system containing at least one heteroatom selected from O, S and N, with each ring containing 5 to 6 atoms. Examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl and the like.
  • Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium.
  • Heterocyclyl (Hetcy) means mono- and bicyclic saturated rings and ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH,3H)-pyrimidine-2,4-diones (N-substituted uracils).
  • Heterocyclyl moreover includes such moieties in charged form, e.g., piperidinium.
  • Halogen includes fluorine, chlorine, bromine and iodine, preferably F and Cl, more preferably F.
  • the invention is directed to a compound represented by formula I:
  • R 1 represents H or is independently selected from the group consisting of: a) OH, halo, C0 2 R a , C(0)NR b R c , NR 1 ⁇ 0 , CN or S(0) p R d ; b) C ⁇ _ ⁇ 0 alkyl, C 2 _ ⁇ oalkenyl, C 2 - ⁇ oalkynyl, OC ⁇ _ ⁇ 0 alkyl, OC 3 _ ⁇ 0 alkenyl and OC 3 _ ⁇ 0 alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 C ⁇ _ ⁇ 0 alkoxy groups, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C0 2 R a group; (5) 1 C0 2 R a or S(0) p R d ; (6)1-2 A
  • alkyl or C ⁇ - 6 alkoxy groups the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C0 2 R a ; CN or S(0) p R d groups; and (2) 1-3 C ⁇ . ⁇ 0 alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH; phenyl optionally substituted with 1-3 halo, C ⁇ .
  • R 3 represents H or is selected from the group consisting of: a) C]. ⁇ 0 alkyl or C 2 - ⁇ oalkenyl, each optionally substituted with 1-5 halo groups up to perhalo; 1-2 OH, C ⁇ . 3 alkoxy or haloC ⁇ . 3 alkoxy groups; 1-2 NR c R d groups; and 1-2 Aryl, HAR or Hetcy groups, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N0 2 , C ⁇ - 3 alkyl, haloC ⁇ - 3 alkyl, C ⁇ .
  • Aryl, HAR or Hetcy each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N0 2 , C ⁇ - 3 alkyl, haloC ⁇ - 3 alkyl, C ⁇ - 3 alkoxy and haloC ⁇ - 3 alkoxy groups;
  • R 4 is independently selected from the group consisting of: a) C ⁇ - ⁇ 4 alkyl, C 2 - ⁇ oalkenyl and C 2 . ⁇ 0 alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 C ⁇ - ⁇ 0 alkoxy groups, each optionally substituted with up to five halo or a perhaloalkoxy, 1 OH or C0 2 R a group; (5) 1 C0 2 R a or S(0) p R d ; (6) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 OH, C0 2 R a , CN, S(0) p R d , N0 2 or C(0)NR b R c group, (iii) 1-2 C ⁇ . ⁇ 0 alkyl or alkoxy groups,
  • R 5 represents H or C ⁇ . 6 alkyl
  • R 6 is selected from the group consisting of H, OH, F or C ⁇ - 3 alkyl
  • R 7 is H or F, or R 6 and R 7 are taken in combination and represent oxo;
  • R 8 represents H or - ⁇ alkyl, optionally substituted with OH and 1-5 halo groups up to perhalo;
  • R 9 represents H, halo, OH, C ⁇ - 6 alkyl, optionally substituted with 1-5 halo groups up to perhalo, or Q. 6 alkoxy, optionally substituted with 1-3 halo groups up to perhalo, or when R 9 is ortho to the benzylic group, R 8 and R 9 can be taken together and represent a -(CH 2 ) 2 . 4 - or a -0-(CH 2 ) ⁇ - 3 - group;
  • R a is H or C ⁇ - ⁇ 0 alkyl, optionally substituted with phenyl, OH, OC ⁇ alkyl, C0 2 H, C0 2 C ⁇ . ⁇ alkyl and 1-3 halo groups;
  • R b is H or Ci-ioalkyl
  • R c is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OC ⁇ - 6 alkyl, C0 2 H, C0 2 C ⁇ . 6 alkyl, and 1-3 halo groups; (b) Aryl or Ar-C ⁇ . 6 alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, C ⁇ - ⁇ 0 alkyl and OC MO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-C ⁇ .
  • 6 alkyl optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, C ⁇ - ⁇ 0 alkyl and OC MO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-C ⁇ . 6 alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: C ⁇ - ⁇ 0 alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
  • R d is Ci.ioalkyl, Aryl or Ar-C ⁇ - ⁇ 0 alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C0 2 R a , 5-tetrazolyl and
  • One aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 1 represents H. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
  • Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein one R 2 represents H, halo or d- 6 alkyl, and the other is selected from the group consisting of: H, halo, OH, optionally substituted with 1-3 halo groups, C ⁇ alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C . 4 alkenyl or OC - alkenyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
  • R 3 is selected from the group consisting of: H, C 2 . 4 alkenyl and C ⁇ . 6 alkyl optionally substituted as follows: a) up to 3 halo groups; b) NR c R d wherein R c and R d are H or C ⁇ . 4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C M alkyl, OC ⁇ . 3 alkyl, CN, N0 2 , haloC ⁇ - 3 alkyl or 0-haloC ⁇ _ 3 alkyl.
  • all other variables are as originally defined with respect to formula I.
  • R 4 is independently selected from the group consisting of:
  • (a) C]- ⁇ 4 alkyl optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 C ⁇ - ⁇ 0 alkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N0 2 , (iii) 1-2 C ⁇ .
  • ⁇ oalkyl or alkoxy groups each optionally substituted with: 1-5 halo, up to perhaloalkyl; and (b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 C ⁇ - ⁇ 0 alkyl or C 2 - ⁇ 0 alkenyl groups, optionally substituted with 1-5 halo groups, phenyl or C0 2 R a groups; (2) 1-2 .
  • ⁇ 0 alkoxy groups the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Ci.ioalkyl or C 2 . ⁇ 0 alkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 .
  • Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 9 represents H or halo.
  • R 9 represents H or halo.
  • Yet another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 8 and R 9 are taken in combination and represent -(CH 2 ) 2 . 4 -- More particularly, an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R 8 and R 9 are taken in combination and represent ethylene.
  • all other variables are as originally defined with respect to formula I.
  • an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein
  • R 1 represents H
  • one R 2 represents H, halo or Ci- ⁇ alkyl, and the other is selected from the group consisting of: H, halo, OH, optionally substituted with 1-3 halo groups, C ⁇ - 6 alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C 2 . 4 alkenyl or OC 2 . 4 alkenyl;
  • R 3 is selected from the group consisting of: H, C 2 . 4 alkenyl and C ⁇ . 6 alkyl optionally substituted as follows: a) up to 3 halo groups; b) NR c R d wherein R c and R d are H or C ⁇ - 4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C ⁇ - 3 alkyl, OC ⁇ - 3 alkyl, CN, N0 2 , haloC ⁇ - 3 alkyl or 0-haloC ⁇ - 3 alkyl; ⁇
  • R 4 is independently selected from the group consisting of:
  • Aryl, HAR or Hetcy each optionally substituted as follows: (1) 1-2 Ci.ioalkyl or C 2 . l oalkenyl, optionally substituted with 1-5 halo groups, phenyl or C0 2 R a groups; (2) 1-2 Ci-ioalkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 C ⁇ - ⁇ 0 alkyl or C 2 - ⁇ oalkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 C ⁇ . ⁇ 0 alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and (iv) 1-2 C0 2 R a , S(0) p R d , CN, NR
  • R 8 represents H or C ⁇ _ 6 alkyl
  • R 9 represents H or halo
  • R 5 represents H or C]- 6 alkyl
  • R 6 is selected from the group consisting of H, OH, F or C ⁇ - 3 alkyl;
  • R 7 is H or F, or R 6 and R 7 are taken in combination and represent oxo;
  • R a is H or Ci.ioalkyl, optionally substituted with phenyl, OH, OC ⁇ - 6 alkyl, C0 2 H, C0 2 C ⁇ - 6 alkyl and 1-3 halo groups;
  • R is H or Ci-ioalkyl
  • R c is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OC ⁇ - 6 alkyl, C0 2 H, C0 2 C ⁇ . 6 alkyl, and 1-3 halo groups; (b) Aryl or Ar-C ⁇ - 6 alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, C ⁇ . ⁇ 0 alkyl and OC MO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Ci- ⁇ alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, C ⁇ - ⁇ 0 alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-C ⁇ .
  • alkyl optionally substituted with 1-5 halo groups and 1-3 groups selected from: C ⁇ - ⁇ 0 alkyl and OC MO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
  • R d is Ci.ioalkyl, Aryl or Ar-C ⁇ - ⁇ 0 alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C0 2 R a , 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
  • all other variables are as originally defined with respect to formula I.
  • Another more particular aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein:
  • alkenyl and Cj- ⁇ alkyl optionally substituted as follows: a) up to 3 halo groups; b) NR c R d wherein R c and R d are H or C M alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C ⁇ - 3 alkyl, OC ⁇ - 3 alkyl, CN, N0 2 , haloC ⁇ .
  • R 4 is independently selected from the group consisting of: a) C].
  • ⁇ 4 a ⁇ kyl optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1- 2 Ci-ioalkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N0 2 , and (iii) 1-2 Ci- ⁇ 0 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 C ⁇ - ⁇ 0 alkyl or C 2 - i 0 alkenyl, optionally substituted with 1-5 halo groups, phenyl or C0 2 R a groups; (2)
  • R 8 and R 9 are taken in combination and represent -(CH 2 ) 2 . 4 -;
  • R 5 represents H or C ⁇ . ⁇ alkyl;
  • R 6 is selected from the group consisting of H, OH, F or C ⁇ . 3 alkyl
  • R 7 is H or F, or R 6 and R 7 are taken in combination and represent oxo;
  • R a is H or Ci.ioalkyl, optionally substituted with phenyl, OH, OC ⁇ alkyl, C0 2 H, C0 2 C ⁇ . 6 alkyl and 1-3 halo groups;
  • R D is H or C,., 0 alkyl;
  • R c is H or is independently selected from: (a) C ⁇ - ⁇ 0 alkyl, optionally substituted with OH, OC ⁇ . 6 alkyl, C0 2 H, C0 2 C ⁇ - 6 alkyl, and 1-3 halo groups; (b) Aryl or Ar-C ⁇ .
  • R d is Ci-ioalkyl, Aryl or Ar-C ⁇ . ⁇ 0 alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C0 2 R a , 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
  • all other variables are as originally defined with respect to formula I
  • the invention further includes a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • disorders include diseases and conditions selected from the group consisting of: dyslipidemias, (e.g., hyperlipidemia), such as elevated levels of cholesterol (hypercholesterolemia), triglycerides (hypertriglyceridemia) or low density lipoproteins (LDL) (high LDL levels), low levels of high density lipoprotein (HDL), microvascular or macrovascular changes and the sequellae of such conditions, such as coronary heart disease, stroke, peripheral vascular disease, hypertension, renal hypertension, nephropathy, neuropathy and retinopathy.
  • dyslipidemias e.g., hyperlipidemia
  • hyperlipidemia such as elevated levels of cholesterol (hypercholesterolemia), triglycerides (hypertriglyceridemia) or low density lipoproteins (LDL) (high LDL levels), low levels of high density lipoprotein (HDL)
  • LDL low density lipoproteins
  • HDL high density lipoprotein
  • microvascular or macrovascular changes and the sequellae of such conditions such as coronar
  • the method entails administering to a type 2 diabetic patient, e.g., a human patient, an amount of a compound of formula I that is effective for treating, preventing or delaying the onset of such diseases or conditions. Also included is a method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat atherosclerosis.
  • a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia,
  • a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia,
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • salts refers to salts prepared from pharmaceutically acceptable substantially non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, as well as salts that can be converted into pharmaceutically acceptable salts.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, 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, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, pipe
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Solvates as used herein refers to the compound of formula I or a salt thereof, in association with a solvent, such as water. Representative examples include hydrates, hemihydrates, trihydrates and the like.
  • references to the compounds of Formula I include the pharmaceutically acceptable salts and solvates.
  • This invention relates to method of antagonizing or inhibiting the production or activity of glucagon, thereby reducing the rate of gluconeogenesis and glycogenolysis, and the concentration of glucose in plasma.
  • the compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals caused by elevated levels of glucose, comprised of combining the compound of formula I with the carrier materials to provide the medicament.
  • the prophylactic or therapeutic dose of the compound of formula I will, of course, vary with the nature of the condition to be treated, the particular compound selected and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight, preferably about 0.01 mg to about 50 mg per kg, and more preferably 0.1 to 10 mg per kg, in single or divided doses. It may be necessary to use dosages outside of these limits in some cases.
  • the terms "effective amount” "anti-diabetic effective amount” and the other terms appearing throughout the application addressing the amount of the compound to be used refer to the dosage ranges provided, taking into account any necessary variation outside of these ranges, as determined by the skilled physician.
  • Representative dosages for adults range from about 0.1 mg to about 1.0 g per day, preferably about 1 mg to about 200 mg, in single or divided doses.
  • a representative dosage range is from about 0.001 mg to about 100 mg (preferably from 0.01 mg to about 10 mg) of a compound of Formula I per kg of body weight per day, and more preferably, about 0.1 mg to about 10 mg of a compound of Formula I per kg of body weight per day.
  • the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
  • composition encompasses a product comprising the active and inert ingredient(s), (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from the 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 between ingredients.
  • the composition is comprised of a compound of formula I in an amount that is effective to treat, prevent or delay the onset of type 2 diabetes mellitus, in combination with the pharmaceutically acceptable carrier.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like, with oral tablets being preferred.
  • a compound of formula I for preparing a pharmaceutical composition which is comprised of combining the compound of formula I with the carrier.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquids, e.g., suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solids, e.g., powders, capsules and tablets, with the solid oral preparations being preferred. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 1 mg to about lg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
  • Combination Therapy Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/delaying the onset of type 2 diabetes mellitus, as well as the diseases and conditions associated with type 2 diabetes mellitus, for which compounds of Formula I are useful.
  • Other drugs 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 containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions include, but are not limited to: (a) bis-guanides (e.g., buformin, metformin, phenformin), (b) PPAR agonists (e.g., troglitazone, pioglitazone, rosiglitazone), (c) insulin, (d) somatostatin, (e) D-glucosidase inhibitors (e.g., voglibose, miglitol, acarbose), (f) DP-1V inhibitors, (g) LXR modulators and (h) insulin secretagogues (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypin
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied within wide limits and depends upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a PPAR agonist the weight ratio of the compound of the Formula I to the PPAR agonist 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 Formula I 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. For combination products, the compound of formula I may be combined with any other active ingredients and then added to the carrier ingredients; alternatively the order of mixing may be varied.
  • Examples of pharmaceutical combination compositions include: 1) a compound according to formula I, 2) a compound selected from the group consisting of: a) DP-IV inhibitors; b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; c) insulin and insulin mimetics; d) sulfonylureas and other insulin secretagogues; e) alpha glucosidase inhibitors; f) glucagon receptor antagonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; h) GIP, G1P mimetics, and GIP receptor agonists; i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; j) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic
  • a method that is of particular interest relates to a method of treating, preventing or delaying the onset of diabetes, and in particular, type 2 diabetes, in a mammalian patient in need thereof, comprising administering to the patient 1) a compound according to formula I, and 2) a compound selected from the group consisting of: a) DP-1N inhibitors; b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; c) insulin and insulin mimetics; d) sulfonylureas and other insulin secretagogues; e) alpha glucosidase inhibitors; f) glucagon receptor antagonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; h) GIP, GIP mimetics, and GIP receptor agonists; i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; j) cholesterol lowering agents selected from the group consisting
  • PPAR alpha/gamma dual agonists (vi) inhibitors of cholesterol absorption, (vii) acyl CoA: cholesterol acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (m) an ileal bile acid transporter inhibitor; (n) anti-inflammatory agents other than glucocorticoids; and (o) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; said compounds being administered in an amount that is effective to treat, prevent or delay the onset of type 2 diabetes.
  • PTP-1B protein tyrosine phosphatase-lB
  • one method that is of interest relates to 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, (11) 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) Syndrome X, 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 an effective amount of a compound of formula I and a compound selected from the group consisting of: (a) DP-IV inhibitors; (b) insulin sensitizers selected from the group consisting of (i) PP
  • a method that is of interest relates to 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 mammalina patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I and an HMG-CoA reductase inhibitor.
  • the method that is of interest comprises administering to the patient a therapeutically effective amount of a compound of formula I and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin, and even more particularly, the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
  • a different aspect of the invention relates to 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 formula I and an HMG-CoA reductase inhibitor.
  • Another aspect of the invention relates to 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 formula I and an HMG-CoA reductase inhibitor. More particularly, the method comprises administering an effective amount of a compound of formula I and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin.
  • the method comprises administering a compound of formula I and a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. Still more particularly, the method comprises administering a compound of formula I and the statin known as simvastatin.
  • Another aspect of the invention relates to 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 formula I and a cholesterol absorption inhibitor.
  • the method comprises administering an effective amount of a compound of formula I and the cholesterol absorption inhibitor known as ezetimibe.
  • a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment comprises administering to said patient an effective amount of a compound of formula I and a cholesterol absorption inhibitor. More particularly, the method comprises administering a compound of formula I and the cholesterol absorption inhibitor known as ezetimibe.
  • the compounds (la) where R 3 is hydrogen may be prepared from ester Ha (vide infra),
  • R l , R 2 , R 4 , R 8 , and R 9 are as defined above and R 10 represents an alkyl or aryl group.
  • Amine 1 may be commercially available or readily prepared via a reductive amination sequence by treating, for example, carbomethoxy benzaldehyde 2 (if R 8 and R 9 are hydrogen) and an amine 3 with a reducing agent such as sodium triacetoxyborohydride or cyanoborohydride in a solvent such as dichloroethane at ambient temperature.
  • a reducing agent such as sodium triacetoxyborohydride or cyanoborohydride in a solvent such as dichloroethane at ambient temperature.
  • the benzylamine 4 can be reacted with the appropriate R 4 carbonyl containing substituent under the same conditions to give amine I.
  • Amine 1 is then treated with thiophosgene in the presence of a base such as diethylisopropylamine (DIEA) in a nonpolar aprotic solvent such as dichloromethane at temperatures of zero to 25° C followed by direct addition of a 1,2-diaminobenzene and either mercury (II) trifluoroacetate or methyl iodide (for example /. Med. Chem., 1985, 28, 1925 and Synthesis, 1974, 41). The reaction is stirred a further 30 min to 6h before isolation of benzimidazole 5 with an aqueous work-up.
  • a base such as diethylisopropylamine (DIEA) in a nonpolar aprotic solvent such as dichloromethane
  • a nonpolar aprotic solvent such as dichloromethane
  • 1,2-Diaminobenzene analogs are commercially available, or readily prepared by those skilled in the art by reduction of the corresponding 2-nitroaniline with, for example hydrogen and a palladium catalyst or stannous chloride. Either reaction is effected in an alcoholic solvent such as methanol or ethanol.
  • An alternative approach to synthesizing benzimidazole Ha involves reaction of amine 1 with triphosgene in the presence of a base, such as triethylamine, in a nonpolar aprotic solvent such as dichloromethane at temperatures of zero to 25 °C, as shown in Scheme 2.
  • a base such as triethylamine
  • a nonpolar aprotic solvent such as dichloromethane
  • the carbamoyl chloride 6 formed in the reaction can be readily isolated and treated with a 1,2-diaminobenzene to give the urea which is treated directly with a dehydrating agent, usually phosphorus oxychloride, at elevated temperatures for 6 - 24h, followed by an aqueous work-up to yield the benzimidazole 5.
  • Coupling of the acid with an amine is then achieved using l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 3 to 48 hours at ambient temperature to yield the compounds Ia-7 and Ia-8.
  • EDC l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide
  • HOBt 1-hydroxybenzotriazole
  • a base generally diisopropylethylamine
  • the product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, J. Org. Chem., 43, 2923, (1978), or HPLC.
  • Compounds purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
  • enantiomerically pure compounds enantiomerically pure starting materials should be used for the preparation of enantiomerically pure compounds.
  • intermediates such as 5 can be undertaken in one of several different ways. These manipulations may include, but are not limited to substitution, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are commonly known to those skilled in the art.
  • the compounds (lb) (which are defined as compounds of formula I wherein R 3 is not hydrogen) may be prepared from ester lib (vide infra),
  • R 1 , R 2 , R 3 , R 4 , R 8 , and R 9 are as defined above and R 10 represents an alkyl or aryl group.
  • N-alkylated 1 ,2-diaminobenzene K are commercially available or readily prepared by those skilled in art.
  • One such method involves alkylation of a 2-nitro aniline. This is effected by deprotonation with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide (DMF) at 0 - 25 °C for 15min to 2h, followed by addition of an electrophile such as an alkyl iodide, Scheme 5. The reaction is stirred for an additional 1 - 24 h to give intermediate J_l , which can be reduced with, for example hydrogen and a palladium catalyst or stannous chloride in an alcoholic solvent.
  • the alkylated 2-nitro aniline JJ. can also be prepared by nucleophilic displacement of fluorine from a 2-fluoronitrobenzene 12 with an amine as described in J. Org. Chem., 1999, 64, 3060. This is achieved in a solvent such as methylene chloride or DMF with a base such as DIEA, at temperatures of 25 - 80 °C for l-6h, Scheme 5.
  • the diaminobenzene H) can then be converted to the benzimidazole 9 using amine 1 or carbamoyl chloride 6 in an identical fashion to that described above and illustrated in Schemes 6 and 7.
  • a third route to intermediates Hb involves alkylation of the 2-aminobenzimdazole 3 with a benzylic bromide, for example carbomethoxy benzyl-bromide, as illustrated in Scheme 8.
  • Amine 3 is converted to the isothiocyanate by reaction with thiophosgene in the presence of a base such as DIEA in a nonpolar aprotic solvent such as dichloromethane at temperatures of zero to 25° C followed by addition of diamine 10 and cyclization with an agent such as methyl iodide. This reaction is effected at 25 - 50 °C for 1 - 24 h to give amine 13.
  • Deprotonation is achieved with a base such as sodium hydride or potassium carbonate in a nonpolar aprotic solvent such as DMF to give a mixture of the desired compound 9 and its isomer 14.
  • a base such as sodium hydride or potassium carbonate
  • a nonpolar aprotic solvent such as DMF
  • ester 9 Conversion of ester 9 to the final products is achieved by saponification of the ester using a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, methanol, ethanol or a mixture of similar solvents, Scheme 9.
  • a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, methanol, ethanol or a mixture of similar solvents, Scheme 9.
  • Coupling of the acid with an amine is then achieved using l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 3 to 48 hours at ambient temperature to yield the compounds Ib-7 and Ib-8.
  • EDC l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
  • HOBt 1-hydroxybenzotriazole
  • a base generally diisopropylethylamine
  • DMF N,N-dimethylformamide
  • methylene chloride methylene chloride
  • the product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, /. Org. Chem., 43, 2923, (1978), or HPLC.
  • Compounds purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
  • Deprotection of a methoxy ether is routinely effected by treatment of the compound with boron tribromide in a solvent such as methylene chloride for a period of 1 - 16h at ambient temperatures. Finally, if the alcohol is protected as an allyl ether, this is removed by treatment with dimethylbarbituric acid and a palladium catalyst, routinely tris(dibenzylideneacetone)dipalladium(0), with a ligand such as l,4-bis-(diphenylphospino)butane in an aprotic solvent such as methylene chloride for 15min to 2h. See “Protective Groups in Organic Synthesis", Greene, published by Wiley and Sons.
  • the free hydroxyl group may then be further modified to prepare ethers using an alcohol and coupling agent, such as diisopropylazodicarboxylate, and triphenylphosphine in a non polar solvent such as methylene chloride at temperatures of 0 to 40°C for 1 to 16h, Scheme 10.
  • an alcohol and coupling agent such as diisopropylazodicarboxylate, and triphenylphosphine in a non polar solvent such as methylene chloride at temperatures of 0 to 40°C for 1 to 16h, Scheme 10.
  • Intermediates J_6 and 17 can then be converted to the desired products as previously described, vide supra.
  • R 4 contains an aromatic halide as in 18, Scheme 11
  • R 4 contains an aromatic halide as in 18, Scheme 11
  • the halide is coupled with a boronic acid, exemplified here with phenyl boronic acid, using a palladium catalyst such as palladium acetate and tris-o-tolylphosphine or triphenyl phosphine.
  • the solvent is generally DMF or ethanol, and cesium carbonate or aqueous sodium carbonate is also added to the reaction, which is performed at elevated temperatures for 12-24 h (see Helv. Chim.
  • R and R 9 form a 5-membered ring alternate conditions were used for the synthesis of the amine intermediate 21, Scheme 12.
  • commercially available ketone 22 was converted to amine 23 by a reductive amination sequence using a Lewis acid such as titanium isopropoxide in ethanol at ambient temperature for 6 - 24 h, followed by further reduction with a hydride reducing agent such as sodium borohydride ( J. C. S., Perkin Trans 1, 1998, 2527-2531).
  • a hydride reducing agent such as sodium borohydride
  • decaborane in methanol at ambient temperature can be used for the reductive amination (J.C.S. Perkin Trans 1, 2000 145-146).
  • ester linkage is then installed by treatment of the bromide with a base such as butyl lithium at -78 °C in a polar aprotic solvent such as THF, followed by quenching the reaction with solid carbon dioxide to give the acid.
  • a base such as butyl lithium at -78 °C in a polar aprotic solvent such as THF
  • THF polar aprotic solvent
  • Intermediate 21 can then be converted to the desired products as previously described, vide supra.
  • Condition B 20 to 60% acetonitrile in water (each containing 0.1% trifluoroacetic acid).
  • Condition C 20 to 80% acetonitrile in water (each containing 0.1% trifluoroacetic acid).
  • Condition D 20 to 100% acetonitrile in water (each containing 0.1% trifluoroacetic acid).
  • Step A l-Isothiocyanato-2-nitrobenzene.
  • 2-nitroaniline 10 mmol, 1.38 g
  • DIEA 15 mmol, 2.6 mL
  • thiophosgene 15 mmol, 1.14 mL
  • HPLC A 2.24 min.
  • Step B Methyl 4- (r(4-tert-butylcyclohexyl)aminol methyl Ibenzoate
  • the reaction mixture was stirred at ambient temperature for 1.5 h, then concentrated under reduced pressure to ca. 25 % of the initial volume. 400 mL of EtOAc was added to the solution and the mixture was washed with 3 x 200 mL of 5 % NaHC0 3 followed by brine. The organic phase was dried over MgS0 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes to afford the trans isomer as a white solid.
  • Step C Methyl 4- ⁇ riH-benzimidazol-2-yl(4-tert-butylcvclohexyl)amino1methyl)-benzoate
  • DIEA 0.8 mL
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was taken up in 5 mL of DMF containing 0.4 mL of H 2 0, and SnCl 2 (2 g) was added (exothermic).
  • the crude thiourea was concentrated under reduced pressure and the residue was taken up in 10 mL of EtOH.
  • Step D 4- ⁇ riH-Benzimidazol-2-yl(4-tgrt-butylcvclohexyl)aminolmethyl)benzoic acid
  • Step E 4- ⁇ riH-Benzimidazol-2-yl(4-tgrt-butylcvclohexyl)aminolmethyIl-N-(lH-tetra-azol-5- vDbenzamide
  • DIEA 0.5 mmol, 90 ⁇ L
  • Step A 4- ⁇ r(4-tgrt-Butylcvclohexyl)(l-methyl-lH-benzimidazol-2-v ⁇ aminolmethv ⁇ -benzoic acid
  • Step B N-(4- (4-tgrt-ButylcvclohexylKl-methyl-lH-benzimidazol-2-yl)aminolmethyll-benzoylVD- alanine
  • Step A Methyl 4-(r(4-fgrt-butylcvclohexyl ' )(l-(2-r(trimethylsilyl ' )oxylethyll-lH-benz-imidazol-2- yDaminol methyl Ibenzoate
  • Step B 4- ⁇ r(4-tgrt-Butylcvclohexyl)(l-l2-hydroxyethyU-lH-benzimidazol-2-yl ' )-aminolmethyllbenzoic acid
  • Step C 4-( ⁇ (4-tgrt-Butylc vclohexyl) I " 1 -(2-hvdroxyethvD- lH-benzimidazol-2-y 11 amino ) -methyl)-N-( 1H- tetraazol-5 -vDbenzamide
  • Example 1 Step A To the product of Example 1 Step A (3 mmol, 910 mg) and DIEA (3.6 mmol, 626 ⁇ L) in 12 mL of DCM was added thiophosgene (3 mmol, 229 ⁇ L). After 1 h additional DIEA (3.6 mmol) and the title compound of Example 11 Step C (2.75 mmol, 489 mg) were added. After 1.5 h Hg(0 2 CCF 3 ) 2 (3 mmol, 1.27 g) was added (exothermic), and the slurry was allowed to stand overnight. HPLC analysis revealed the cyclization was incomplete, so additional Hg(0 2 CCF 3 ) 2 (1.5 mmol, 650 mg) was added to the reaction.
  • Step E 4-f rf6-(Allyloxy)-l-methyl-lH-benzimidazol-2-yll(4-tgrt-butylcvclohexyl)aminolmethyl Ibenzoic acid
  • a solution of LiOH 0.4 mmol, 10 mg
  • H 2 400 ⁇ L
  • the resulting solution was stirred at ambient temperature overnight.
  • the reaction mixture was taken up in a pH 7 buffer solution and EtOAc.
  • Step F 4-1 rr6-(AlIyloxy)-l-methyl-lH-benzimidazol-2-yll(4-tgrt-butylcvclohexyl ' )-aminolmethvU-N- ( lH-tetraazol-5-yl)benzamide
  • 1H- tetraazol-5-amine monohydrate (0.12 mmol, 12 mg)
  • ⁇ OBt (0.08 mmol, 12 mg
  • EDC 0.08 mmol, 15 mg
  • Step A Methyl 4- ( r(4-tgrt-butylcvclohexyl )(6-hvdroxy- 1 -methyl- 1 H-benzimidazol-2- yl , a ⁇ -inol methyl 1 benzoate
  • Step B 4-(r(4-tgrt-Butylcyclohexyl)(6-hydroxy-l-methyl-lH-benzimidazol-2-yl)aminol-methyl)benzoic acid
  • Step C 4- ⁇ r(4-tgrt-Butylcyclohe ⁇ yl)(6-hvdroxy-l-methyl-lH-benzimidazol-2-yl)amino1-methyll-N-(lH- tetraazol-5-yl)benzamide
  • lH-tetraazol-5 -amine monohydrate (0.12 mmol, 12 mg)
  • HOBt (0.08 mmol, 12 mg
  • EDC 0.08 mmol, 15 mg
  • Step A Methyl 4-1 f (4-tgrt-butylcvclohexyl)(l-methyl-6-propoxy-lH-benzimidazol-2- yDaminol methyl Ibenzoate
  • n- propanol 0.25 mmol, 19 ⁇ L
  • diisopropyl azodicarboxylate 0.2 mmol, 37 ⁇ L
  • Step B 4- ⁇ r(4-tert-Butylcvclohexyl)(l-methyl-6-propoxy-lH-benzimidazol-2-yl)aminol- methyl ibenzoate
  • Step A ⁇ -Methyl-4-methoxy-2-nitroaniline.
  • Step B N-Methyl-4-methoxy-1.2-phenylenediamine.
  • Step D 4-1 f (4-tgrt-Butylcvclohexyl)( 5-methoxy-l-methyl-lH-benzimidazol-2-yl)aminolmethyl)benzoic acid
  • Step E 4-( f(4-tgrt-Butylcvclohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2-yl)-aminolmethyl ⁇ -N-(lH- tetraazol-5-yl)benzamide
  • Step A Methyl 4-( [(4-tgrt-butylcvclohexyl)( 5-hvdroxy-l-methyl-lH-benzimidazol-2- yl.aminolmethyl Ibenzoate
  • BBr 3 5 mmol, 5 mL of a IM solution in DCM
  • Step C 4-(r(4-tgrt-Butylcvclohexyl)(5-hydroxy-l-methyl-lH-benzimidazol-2-yl)-amino-lmethy ⁇ -N-(lH- tetraazol-5-yl .benzamide
  • EDC 0.2 mmol, 38 mg
  • Step A Methyl 4-1 r(4-tgrt-butylcvclohexyl)( 5-benzyloxy-l-methyl-lH-benzimidazol-2- yl .aminolmethyl Ibenzoate
  • Step B 4-(r(4-tert-Butylcvclohexyl)( 5 -benzyloxy-1 -methyl- 1 H-benzimidazol-2-yl.- aminol methyl I benzoic acid
  • Step C 4-(r(4-tgrt-Butylcyclohexyl)(5-benzyloxy-l-methyl-lH-benzimidazol-2-yl)-aminolmethyll-N- ( lH-tetraazol-5-yl)benzamide
  • Step B l-
  • Step C 4-Cvclohex-l-en-l-ylphenylamine The title compound from Example 221 Step B was taken up in a solution of 150 mL of
  • Step D N-(4-Cvclohex- 1 -en- 1 -ylpheny 1)- 1 -methyl- lH-benzimidazol-2-amine
  • Step E Methyl 4-(r(4-cvclohex-l-en-l-ylphenyl)(l-methyl-li t - ' -benzi idazol-2-yl)- aminolmethyl 1 benzoate
  • To the title compound from Example 221 Step D (0.53 mmol, 161 mg) and NaH (0.80 mmol, 32 mg of a 60% dispersion in mineral oil) was added 1 mL of DMF (gas evolution). The mixture was stirred for 30 min at ambient temperature, then methyl 4-(bromomethyl)benzoate (0.80 mmol, 182 mg) was added.
  • Step F 4- ⁇ f(4-Cvclohex-l-en-l-ylphenyl (l-methyl-l//-benzimidazol-2-yl)amino1-methyl
  • a solution of LiOH 2.6 mmol, 62 mg
  • the reaction was stirred at 50°C for 30 min.
  • the dioxane was removed under reduced pressure and the remaining aqueous solution was acidified with 2 N HCl.
  • the resulting precipitate was filtered, washed with H 2 0 and dried under reduced pressure, affording the product as a white solid.
  • HPLC A 2.11 min.
  • Step G 4-( r(4-Cvclohex-l-en-l-ylphenyl)(l-methyl-lH-benzimidazol-2-yl)aminol-methyll-N-(lH- tetraazol-5 -vDbenzamide
  • Step B Methyl 4-( r(3.5-dichlorophenyl)(l-methyl-lH-benzimidazol-2-yl)aminol-methyl Ibenzoate
  • ⁇ aH 0.24 mmol, 6 mg of a 60% slurry in mineral oil
  • DMF gas evolution
  • methyl-4-(bromomethyl)benzoate 0.24 mmol, 55 mg was added and the reaction mixture was allowed to stand at ambient temperature overnight.
  • the mixture was partitioned between DCM and ⁇ aHC0 3 .
  • the organic phase was collected and the aqueous phase was extracted 2 x with DCM.
  • Step C 4-f r(3,5-Dichlorophenyl)(l -methyl- lH-benzimidazol-2-yl)aminolmethyl I -benzoic acid
  • a solution of LiOH 0.8 mmol, 19 mg
  • the reaction was allowed to stir at ambient temperature overnight.
  • the crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation.
  • the organic phase was collected and the aqueous phase was extracted twice with EtOAc.
  • the combined organic phase was dried over MgS0 , then concentrated under reduced pressure to afford the product as a white foam.
  • HPLC A 1.79 min.
  • Step P 4- ⁇ [(3,5-Dichlorophenyl)(l-methyl-lH-benzimidazol-2-yl)aminolmethyl)-N-(l, I - f -tetraazol-5- vDbenzamide
  • DIEA 0.48 mmol, 83 ⁇ L
  • Step P Methyl 3-bromo-4- ⁇ r(4-t g rt-butylcvclohexyl)(5-methoxy-l-methyl-lH-benz-imidazol-2- vDaminol methyl Ibenzoate
  • Step F 3-Bromo-4- ⁇ f(4-tgrt-butylcvcIohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2- yl .aminolmethyl 1 -N-( lH-tetraazol-5-yl)benzamide
  • Step A Methyl 3-bromo-4- ⁇ r(4-tgrt-butylcvclohexyl)(5-hvdroxy-l-methyl-lH-benz-imidazol-2- vDaminolmethyl 1 benzoate
  • Step B Methyl 3-bromo-4- ⁇ r(4-tgrt-butylcvclohexyl)(5-cvclopentyloxy-l-methyl-lH-benz-imidazol-2- yDaminol methyl Ibenzoate
  • Step C 3-Bromo-4- ⁇ r(4-tgrt-butylcyclohexyl)(5-cyclopentyloxy-l -methyl- lH-benz-imidazol -2- y Daminol methyl Ibenzoic acid
  • Step D 3-Bromo-4-l r(4-tgrt-butylcvclohexyl)(5-cvclopentyloxy-l-methyl-lH-benzimidazol-2- y 1. aminol methyl ) -N-( 1 H-tetraazol-5 -vDbenzamide
  • Step A Ethyl 4-1 l-f(tr ⁇ fi-.-4-tgrt-butylcvclohexyl)aminolethyl Ibenzoate
  • Step B Ethyl 4-1 H(tr ⁇ n,y-4-tgrt-butylcvclohexyl)(l-methyl-lH-benzimidazol-2- vDaminolethyl Ibenzoate
  • ethyl 4- ⁇ l-[(tran-;-4-tgrt-butylcyclohexyl)amino]ethyl ⁇ benzoate (0.55 g, 1.66 mmol) and DIEA (0.35 mL, 1.99 mmol) in dry dichloromethane (15 mL) was slowly added thiophosgene (0.13 mL, 1.66 mmol).
  • Step C 4-1 l-r(tr ⁇ w-.-4-tgrt-ButylcvcIohexyl)(l-methyl-lH-benzimidazol-2-yl)amino1ethyll-N-lH- tetrazol-5-ylbenzamide. isomer A and B.
  • Step A (5-Bromo-2,3-dihydro- lH-inden- 1 -ylXtrans -4-tgrt-butylcvclohexyl)amine
  • 5-bromoindan-l-one (6.33 g, 30.0 mmol)
  • titanium (IV) isopropoxide (17.8 mL, 60.0 mmol)
  • 4-tgrt-butylcyclohexyl amine (9.32 g, 60.0 mmol) in absolute ethanol (200 mL) was stirred under nitrogen at room temperature for 12 h.
  • Sodium borohydride (1.70 g, 45.0 mmol) was then added and the resulting mixture was stirred for an additional 8 h at room temperature.
  • Step B Methyl l-r(tr ⁇ n-.-4-tgrt-butylcvclohexyl)aminolindane-5-carboxylate
  • Step C Methyl l-r(tr ⁇ » -4-tgrt-butylcvclohexyl)(l-methyl-lH-benzimidazol-2-yl)aminolindane-5- carboxylate
  • Step P l-[(tr ⁇ n-.-4-tgrt-Butylcvclohexyl)(l-methyl-lH-benzimidazol-2-yl)aminol-N-lH-tetrazol-5- ylindane-5-carboxamide.
  • Step B Butyl l-[(4-cvclohexylphenyl)(l-methyl-lH-benzimidazol-2-yl)aminolindane-5-carboxyIate To a 0°C solution of butyl l-[(4-cyclohexylphenyl)amino]indane-5-carboxylate (0.50 g,
  • Step C l-f(4-Cvclohexylphenyl " )(l-methyl-lH-benzimidazol-2-yl)aminol-N-lH-tetrazol-5-ylindane-5- carboxamide. isomer B.
  • Butyl l-[(4-cyclohexylphenyl)(l-methyl-lH-benzimidazol-2-yl)amino]indane-5- carboxylate (0.10 g, 0.18 mmol) was dissolved in EtO ⁇ /n- ⁇ eptane (1: 1, 4 mL) and eluted with 10% isopropanol in n- ⁇ eptane on ChiralPak AD column. The fast moving component was collected as isomer A and the slow moving component as isomer B.
  • Step A Butyl l-r(tr ⁇ n-.-4-tgrt-butylcyclohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2- yl)aminolindane-5-carboxylate
  • Step B Butyl l-l(tr ⁇ n .-4-t g rt-butylcvclohexyl)(5-hydroxy-l-methyl-lH-benzimidazol-2- yl)aminolindane-5-carboxylate
  • Butyl l-[(tr n-.-4-tgrt-butylcyclohexyl)(l-methyl-5-propoxy-lH-benzimidazol-2- yl)amino]indane-5-carboxylate (36.0 mg, 0.06 mmol) was dissolved in T ⁇ F/MeO ⁇ (1:1, 6 mL) and aq. LiO ⁇ (1.0 M, 3 mL) was added. After stirred at room temperature for 16 h, the reaction was neutralized with aqueous ⁇ C1 (IN, 3.5 mL) until white precipitate started to appear. The resulting mixture was poured into brine (10 mL) and extracted with EtOAc (3x10 mL).
  • BIOLOGICAL ASSAYS The ability of the compounds of the present invention to inhibit the binding of glucagon and their utility in treating or preventing type 2 diabetes mellitus and the related conditions can be demonstrated by the following in vitro assays.
  • Glucagon Receptor Binding Assay A stable CHO (Chinese hamster ovary) cell line expressing cloned human glucagon receptor was maintained as described (Chicchi et al._J Biol Chem 272, 7765-9(1997); Cascieri et al. J Biol Chem 274, 8694-7(1999)).
  • Glucagon-stimulated Intracellular cAMP Formation Exponentially growing CHO cells expressing human glucagon receptor were harvested with the aid of enzyme-free dissociation media (Specialty Media), pelleted at low speed, and re- suspended in the Cell Stimulation Buffer included in the Flash Plate cAMP kit (New England Nuclear, SMP0004A). The adenylate cyclase assay was setup as per manufacturer instructions. Briefly, compounds were diluted from stocks in DMSO and added to cells at a final DMSO concentration of 5%.
  • Cells prepared as above were preincubated in flash plates coated with anti-cAMP antibodies (NEN) in presence of compounds or DMSO controls for 30 minutes, and then stimulated with glucagon (250 pM) for an additional 30 minutes.
  • the cell stimulation was stopped by addition of equal amount of a detection buffer containing lysis buffer as well as 1 5 I-labeled cAMP tracer (NEN). After 3 hours of incubation at room temperature the bound radioactivity was determined in a liquid scintillation counter (TopCount-Packard Instruments). Basal activity (100% inhibition) was determined using the DMSO control while 0% inhibition was defined at the amount of pmol cAMP produced by 250pM glucagon.

Abstract

The present invention relates to substituted benzimidazoles, compositions containing such compounds and methods of treatment The compounds are glucagon receptor antagonists and thus are useful for . treating, preventing or delaying the onset of type 2 diabetes mellitus

Description

TITLE OF THE INVENTION
BENZIMIDAZOLES, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE
BACKGROUND OF THE INVENTION
The present invention relates to substituted benzimidazole derivatives, compositions containing such compounds and methods of treating type 2 diabetes mellitus.
Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or following glucose administration during an oral glucose tolerance test. Frank diabetes mellitus (e.g., a blood glucose level >126 mg/dL in a fasting state) is associated with increased and premature cardiovascular morbidity and mortality, and is related directly and indirectly to various metabolic conditions, including alterations of lipid, lipoprotein and apolipoprotein metabolism. Patients with non-insulin dependent diabetes mellitus (type 2 diabetes mellitus), approximately 95% of patients with diabetes mellitus, frequently display elevated levels of serum lipids, such as cholesterol and triglycerides, and have poor blood-lipid profiles, with high levels of LDL- cholesterol and low levels of HDL-cholesterol. Those suffering from Type 2 diabetes mellitus are thus at an increased risk of developing macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension (for example, blood pressure > 130/80 mmHg in a resting state), nephropathy, neuropathy and retinopathy.
Patients having type 2 diabetes mellitus characteristically exhibit elevated plasma insulin levels compared with nondiabetic patients; these patients have developed a resistance to insulin stimulation of glucose and lipid metabolism in the main insulin-sensitive tissues (muscle, liver and adipose tissues). Thus, Type 2 diabetes, at least early in the natural progression of the disease is characterized primarily by insulin resistance rather than by a decrease in insulin production, resulting in insufficient uptake, oxidation and storage of glucose in muscle, inadequate repression of lipolysis in adipose tissue, and excess glucose production and secretion by the liver. The net effect of decreased sensitivity to insulin is high levels of insulin circulating in the blood without appropriate reduction in plasma glucose (hyperglycemia). Hyperinsulinemia is a risk factor for developing hypertension and may also contribute to vascular disease.
Glucagon serves as the major regulatory hormone attenuating the effect of insulin in its inhibition of liver gluconeogenesis and is normally secreted by pancreatic islet cells in response to falling blood glucose levels. The hormone binds to specific receptors in liver cells that triggers glycogenolysis and an increase in gluconeogenesis through cAMP-mediated events. These responses generate glucose (e.g. hepatic glucose production) to help maintain euglyce ia by preventing blood glucose levels from falling significantly.
In addition to elevated levels of circulating insulin, type II diabetics have elevated levels of plasma glucagon and increased rates of hepatic glucose production. Antagonists of glucagon are useful in improving insulin responsiveness in the liver, decreasing the rate of gluconeogenesis and lowering the rate of hepatic glucose output resulting in a decrease in the levels of plasma glucose.
SUMMARY OF THE INVENTION
The present invention is directed to a compound represented by formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 represents H or is independently selected from the group consisting of: a) OH, halo, C02R\ C^NR'R0, NRbRc, CN or S(0)pRd; b) .ioalkyl, C2-ι0alkenyl, C2.ιoalkynyl, OCι_ι0alkyl, OC3.]0alkenyl and OC3_ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 Cι-ι0alkoxy groups, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6)1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (c) 1-2 Q.ioalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo, 1-3 Ci.ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (e) -NRa-C(0)- NRDRC; (f) -NRa-C02Rc; (g) -NRa-C(0)Rc; (h) - NR°RC; (i) -NRaS02Rc; (j) -SOz-NR^; (k) - C(0)NRbRc and (1) -OC(0)-NRbRc; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set forth below: (1) 1-3 Cι_ι0alkyl, C2-ιoalkenyl or C2..oalkynyl groups optionally substituted with 1-5 halo groups; 1-2 OH groups; phenyl optionally substituted with 1-3 halo, C].6 alkyl or Cι-6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C02Ra; CN or S(0)pRd groups; and (2) 1-3 Cι_ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH; phenyl optionally substituted with 1-3 halo, Cι_6 alkyl or Cι_6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C02Ra; CN or S(0)pRd groups; said Aryl, HAR, Hetcy -O-Aryl, -O-HAR and -O-Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of: (3) 1-5 halo groups; (4) 1-2 OH groups; (5) 1 S(0)pRd, N02 or CN group; (6) 1-2 C02Ra; (7) -NR (0)-NRbRc; (8) -NRa-C02Rc; (9) -NRa-C(0)Rc; (10) -NRbRc; (11) -NRaS02Rc; (12) -S02-NRbRc; and (13) -C(0)NRbRc; and when R1 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(0)NRbRc; (b) - C02Rc; (c) -C(0)Rc; and (d) -S02Rc; each R2 represents H or is independently selected from the group consisting of: a) OH, halo, C02Ra, C(O)NRbR0, NRbRc, CN or S(0)pRd; b) Ci.ioalkyl, C2-ιoalkenyl, C2-10alkynyl, O .ioalkyl, OC3_ι0alkenyl and OC3_ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1 OH group; (4) 1 Cι_ι0alkoxy group, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6) 1 Aryl, Hetcy or
HAR group, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (c) 1-2 Cι_ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Ci.ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo; and 1-2 hydroxy or C02Ra groups; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set forth below: (1) 1-3 Cι-ι0alkyl, C2_ιoalkenyl or C2-ιoalkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; (2) 1-3 Cι-ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; said Aryl, HAR or Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of: (3) 1-5 halo groups up to perhalo; (4) 1 OH group; (5) 1 S(0)pRd, N02 or CN group; and (6) 1 C02Ra;
R3 represents H or is selected from the group consisting of: a) Cι_ι0alkyl or C2-ιo lkenyl, each optionally substituted with 1-5 halo groups up to perhalo; 1-2 OH, Cι_3alkoxy or haloCι_3alkoxy groups; 1-2 NRcRd groups; and 1-2 Aryl, HAR or Hetcy groups, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N02, Cι_3alkyl, haloCι_3alkyl, Cι-3alkoxy and haloCι-3 alkoxy groups; and b) Aryl, HAR or Hetcy, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N02, Cι_3alkyl, haloCι_3alkyl, Cι_3alkoxy and haloCι_3 alkoxy groups; R4 is independently selected from the group consisting of: a) Cι_ι alkyl, C2-ιoalkenyl and C2_ιoalkynyl, said groups being optionally substituted with:
(1) 1-5 halo groups up to perhaloalkyl; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 Cι_ι0alkoxy groups, each optionally substituted with up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (iii) 1-2 Cι-ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (iv) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Cι_ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-3 Cι_ι4alkyl, C2. ι0alkenyl or C2_ιoalkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, C02Ra, CN or S(0)pRd groups or phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Cι-ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or Cθ2Ra groups; (2) 1-3 Cι_ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, C02Ra, CN, S(0)pRd , and phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Cι_ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Cι-ι0alkyl, C2. ι0alkenyl or C _ιoalkynyl groups each optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; (iii) 1-2 Cι_ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; and (iv) 1-2 C02R\ S(0)pRd, CN, NR^, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) - NRbRc; (12) -NRaS02Rc; (13) -SOz-NR'Tl0; (14) -C^ NR and -OC(0)-NRbRc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NR1^.0; (b) - C02Rc; (c) - C(0)Rc; and (d) -S02Rc;
R5 represents H or Cι-6 alkyl;
R6 is selected from the group consisting of H, OH, F or Cι_3alkyl; R7 is H or F, or R6 and R7 are taken in combination and represent oxo;
R8 represents H or Cι_β alkyl, optionally substituted with OH and 1-5 halo groups up to perhalo;
R9 represents H, halo, OH, C ι_6alkyl, optionally substituted with 1-5 halo groups up to perhalo, or Cι_
6alkoxy, optionally substituted with 1-3 halo groups up to perhalo, or when R9 is ortho to the benzylic group, R8 and R9 can be taken together and represent a -(CH2)24- or a -0-(CH2)ι_3- group; Ra is H or Cι-ι0alkyl, optionally substituted with phenyl, OH, OCι-6alkyl, C02H, C02Cι_ 6alkyl and 1-3 halo groups;
Rb is H or C 0alkyl;
Rc is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OCι-6alkyl, C02H, C02Cι.6alkyl, and 1-3 halo groups; (b) Aryl or Ar-Cι_6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Cι_ι0alkyl and OCi.jo alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Cι-6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-Cι.6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
Rd is Ci_i0alkyl, Aryl or Ax-C]_i0alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02Ra, 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
"Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-10 carbon atoms are intended for linear or branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like. Cycloalkyl is a subset of alkyl; if no number of atoms is specified, 3-10 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
"Aryl" (Ar) means mono- and bicyclic aromatic rings containing 6-12 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like.
"Heteroaryl" (HAR) means a mono- or bicyclic aromatic ring or ring system containing at least one heteroatom selected from O, S and N, with each ring containing 5 to 6 atoms. Examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl and the like. Heteroaryl also includes aromatic heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium.
"Heterocyclyl" (Hetcy) means mono- and bicyclic saturated rings and ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples of "heterocyclyl" include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH,3H)-pyrimidine-2,4-diones (N-substituted uracils). Heterocyclyl moreover includes such moieties in charged form, e.g., piperidinium.
"Halogen" (Halo) includes fluorine, chlorine, bromine and iodine, preferably F and Cl, more preferably F.
In one aspect, the invention is directed to a compound represented by formula I:
Figure imgf000007_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 represents H or is independently selected from the group consisting of: a) OH, halo, C02Ra, C(0)NRbRc, NR1^0, CN or S(0)pRd; b) Cι_ι0alkyl, C2_ιoalkenyl, C2-ιoalkynyl, OCι_ι0alkyl, OC3_ι0alkenyl and OC3_ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 Cι_ι0alkoxy groups, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6)1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (c) 1-2 Cι-ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo, 1-3 Cι.ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or Cθ2Ra groups; (e) -NRa-C(0)- NR ; (f) -NRa-C02Rc; (g) -NRa-C(0)Rc; (h) - NR Rc; (i) -NRaS02Rc; (j) -S02-NRbRc; (k) - C(0)NRbRc and (1) -OC(0)-NRbRc; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set • forth below: (1) 1-3 Ci.ioalkyl, C2-ι0alkenyl or C2.ιoalkynyl groups optionally substituted with 1-5 halo groups; 1-2 OH groups; phenyl optionally substituted with 1-3 halo, .6 alkyl or Cι-6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C02Ra; CN or S(0)pRd groups; and (2) 1-3 Cι.ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH; phenyl optionally substituted with 1-3 halo, Cι.6 alkyl or Cι-6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C02Ra; CN or S(0)pRd groups; said Aryl, HAR, Hetcy -O-Aryl, -O-HAR and -O-Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of: (3) 1-5 halo groups; (4) 1-2 OH groups; (5) 1 S(0)pRd, N02 or CN group; (6) 1-2 C02Ra; (7) -NRa-C(0)-NRbRc; (8) -NRa-C02Rc; (9) -NRa-C(0)Rc; (10) -NRbRc; (11) -NRaS02Rc; (12) -S02-NRbRc; and (13) -C(0)NRbRc; and when R1 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(0)NRbRc; (b) -C02Rc; (c) - C(0)Rc; and (d) -S02Rc; each R2 represents H or is independently selected from the group consisting of: a) OH, halo, C02Ra, C(0)NRbRc, NRbRc, CN or S(0)pRd; b) Ci.ioalkyl, C2-ιoalkenyl, C_-ιoalkynyl, OCι-ι0alkyl, OC3_ι0alkenyl and OC3.ιoalkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1 OH group; (4) 1 Cι.ι0alkoxy group, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)„Rd; (6) 1 Aryl, Hetcy or HAR group, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (c) 1-2 Ci.ioalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Ci.ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo; and 1-2 hydroxy or C02Ra groups; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set forth below: (1) 1-3 Cι-ι0alkyl, C2-ιoa- enyl or C2-ioalkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; (2) 1-3 Cι-ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; said Aryl, HAR or Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of; (3) 1-5 halo groups up to perhalo; (4) 1 OH group; (5) 1 S(0)pRd, N02 or CN group; (6) 1 C02Ra;
R3 represents H or is selected from the group consisting of: a) C].ι0alkyl or C2-ιoalkenyl, each optionally substituted with 1-5 halo groups up to perhalo; 1-2 OH, Cι.3alkoxy or haloCι.3alkoxy groups; 1-2 NRcRd groups; and 1-2 Aryl, HAR or Hetcy groups, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N02, Cι-3alkyl, haloCι-3alkyl, Cι.3alkoxy and haloCι-3 alkoxy groups; and b) Aryl, HAR or Hetcy, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N02, Cι-3alkyl, haloCι-3alkyl, Cι-3alkoxy and haloCι-3 alkoxy groups;
R4 is independently selected from the group consisting of: a) Cι-ι4alkyl, C2-ιoalkenyl and C2.ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 Cι-ι0alkoxy groups, each optionally substituted with up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (iii) 1-2 Cι.ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (iv) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Cι-ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-3 Cι.ι4alkyl, C2- i0alkenyl or C2.ιoalkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, C02Ra, CN or S(0)pRd groups or phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Cι-ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (2) 1-3 Cι-ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, C02Ra, CN, S(0)pRd , and phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Ci.ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Cι-ι0alkyl, C2.ι0alkenyl or C .ι0alkynyl groups each optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; (iii) 1-2 Cι-ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; and (iv) 1-2 C02Ra, S(0)pRd, CN, NR^, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) - NRbRc; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(0) NRbRc and -OC^-NR^0; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NRbRc; (b) - C02Rc; (c) - C(0)Rc; and (d) -S02Rc;
R5 represents H or Cι.6 alkyl;
R6 is selected from the group consisting of H, OH, F or Cι-3alkyl;
R7 is H or F, or R6 and R7 are taken in combination and represent oxo; R8 represents H or -β alkyl, optionally substituted with OH and 1-5 halo groups up to perhalo; R9 represents H, halo, OH, C ι-6alkyl, optionally substituted with 1-5 halo groups up to perhalo, or Q. 6alkoxy, optionally substituted with 1-3 halo groups up to perhalo, or when R9 is ortho to the benzylic group, R8 and R9 can be taken together and represent a -(CH2)2.4- or a -0-(CH2)ι-3- group;
Ra is H or Cι-ι0alkyl, optionally substituted with phenyl, OH, OC^alkyl, C02H, C02Cι. βalkyl and 1-3 halo groups;
Rb is H or Ci-ioalkyl;
Rc is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OCι-6alkyl, C02H, C02Cι.6alkyl, and 1-3 halo groups; (b) Aryl or Ar-Cι.6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Cι.6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-Cι.6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: Cι-ι0alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
Rd is Ci.ioalkyl, Aryl or Ar-Cι-ι0alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02Ra, 5-tetrazolyl and
5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
One aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R1 represents H. Within this aspect of the invention, all other variables are as originally defined with respect to formula I. Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein one R2 represents H, halo or d-6alkyl, and the other is selected from the group consisting of: H, halo, OH,
Figure imgf000011_0001
optionally substituted with 1-3 halo groups, C^alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C . 4alkenyl or OC - alkenyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R3 is selected from the group consisting of: H, C2.4alkenyl and Cι.6alkyl optionally substituted as follows: a) up to 3 halo groups; b) NRcRd wherein Rc and Rd are H or Cι.4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, CM alkyl, OCι.3alkyl, CN, N02, haloCι-3alkyl or 0-haloCι_3alkyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R4 is independently selected from the group consisting of:
(a) C]-ι4alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 Cι-ι0alkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N02, (iii) 1-2 C\. ιoalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and (b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 Cι-ι0alkyl or C2- ι0alkenyl groups, optionally substituted with 1-5 halo groups, phenyl or C02Ra groups; (2) 1-2 . ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Ci.ioalkyl or C2.ι0alkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 . ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and (iv) 1-2 C02Ra, S(0)pRd, CN, NR°RC, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of ; (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) - NRbRc; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(O) NRbRc and (15) -OC(0)-NR Rc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(0)NRbRc; (b) - Cθ2Rc; (c) -C(0)RC; and (d) -Sθ2Rc. Within this aspect of the invention, all other variables are as originally defined with respect to formula I. Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R8 represents H or C].6 alkyl. More particularly, R represents H or methyl. Within these aspects of the invention, all other variables are as originally defined with respect to formula I.
Another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R9 represents H or halo. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Yet another aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R8 and R9 are taken in combination and represent -(CH2)2.4-- More particularly, an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein R8 and R9 are taken in combination and represent ethylene. Within these aspects of the invention, all other variables are as originally defined with respect to formula I.
More particularly, an aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein
R1 represents H; one R2 represents H, halo or Ci-βalkyl, and the other is selected from the group consisting of: H, halo, OH,
Figure imgf000012_0001
optionally substituted with 1-3 halo groups, Cι-6alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C2.4alkenyl or OC2.4alkenyl;
R3 is selected from the group consisting of: H, C2.4alkenyl and Cι.6alkyl optionally substituted as follows: a) up to 3 halo groups; b) NRcRd wherein Rc and Rd are H or Cι-4 alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, Cι-3 alkyl, OCι-3alkyl, CN, N02, haloCι-3alkyl or 0-haloCι-3alkyl; ■
R4 is independently selected from the group consisting of:
(a) Cι-ι4alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 Ci-ioalkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N02, (iii) 1-2 Ci- loalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and
(b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 Ci.ioalkyl or C2. loalkenyl, optionally substituted with 1-5 halo groups, phenyl or C02Ra groups; (2) 1-2 Ci-ioalkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Cι-ι0alkyl or C2-ιoalkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 Cι.ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and (iv) 1-2 C02Ra, S(0)pRd, CN, NRbRc, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) -NR"RC; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(O) NRbRc and (15) -OC(0)-NR°Rc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NRbRc; (b) - C02Rc; (c) -C(0)Rc; and (d) -S02Rc;
R8 represents H or Cι_6 alkyl;
R9 represents H or halo;
R5 represents H or C]-6 alkyl;
R6 is selected from the group consisting of H, OH, F or Cι-3alkyl; R7 is H or F, or R6 and R7 are taken in combination and represent oxo;
Ra is H or Ci.ioalkyl, optionally substituted with phenyl, OH, OCι-6alkyl, C02H, C02Cι- 6alkyl and 1-3 halo groups;
R is H or Ci-ioalkyl;
Rc is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OCι-6alkyl, C02H, C02Cι.6alkyl, and 1-3 halo groups; (b) Aryl or Ar-Cι-6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Cι.ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Ci-βalkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Cι-ι0alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-Cι.6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
Rd is Ci.ioalkyl, Aryl or Ar-Cι-ι0alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02Ra, 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl). Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Another more particular aspect of the invention that is of interest relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein:
R1 represents H; one R2 represents H, halo or C).6alkyl, and the other is selected from the group consisting of: H, halo, OH, Cι.6alkyl optionally substituted with 1-3 halo groups, Cι-6alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C2-4alkenyl or OC^alkenyl; R3 is selected from the group consisting of: H, C2. alkenyl and Cj-βalkyl optionally substituted as follows: a) up to 3 halo groups; b) NRcRd wherein Rc and Rd are H or CM alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, Cι-3 alkyl, OCι-3alkyl, CN, N02, haloCι.3alkyl or 0-haloCι-3alkyl; R4 is independently selected from the group consisting of: a) C].ι4aιkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1- 2 Ci-ioalkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N02, and (iii) 1-2 Ci- ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 Cι-ι0alkyl or C2- i0alkenyl, optionally substituted with 1-5 halo groups, phenyl or C02Ra groups; (2) 1-2 Cι-ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (a) 1-3 halo groups; (b) 1-2 Cι_ι0alkyl or C2-ιoalkenyl, each optionally substituted with 1-3 halo groups; (c) 1-2 Cι.ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and (d) 1-2 C02R\ S(0)pRd, CN, NRbRc, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) - NRbRc; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(O) NRbRc and (15) -OC(0)-NRbRc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NR°RC; (b) - C02Rc; (c) - C(0)Rc; and (d) -S02Rc;
R8 and R9 are taken in combination and represent -(CH2)2.4-; R5 represents H or Cι.β alkyl;
R6 is selected from the group consisting of H, OH, F or Cι.3alkyl;
R7 is H or F, or R6 and R7 are taken in combination and represent oxo;
Ra is H or Ci.ioalkyl, optionally substituted with phenyl, OH, OC^alkyl, C02H, C02Cι. 6alkyl and 1-3 halo groups; RD is H or C,.,0alkyl;
Rc is H or is independently selected from: (a) Cι-ι0alkyl, optionally substituted with OH, OCι.6alkyl, C02H, C02Cι-6alkyl, and 1-3 halo groups; (b) Aryl or Ar-Cι.6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Cι-6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Cι-ι0alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-Cι-6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
Rd is Ci-ioalkyl, Aryl or Ar-Cι.ι0alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02Ra, 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl). Within this aspect of the invention, all other variables are as originally defined with respect to formula I
Selected compounds of the invention that are of interest are shown in the table below.
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0002
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
as well as the pharmaceutically acceptable salts and solvates thereof.
The invention further includes a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
Also included is a method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount that is effective to treat type 2 diabetes mellitus.
Also included is a method of preventing or delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to said patient a compound of formula I in an amount that is effective to prevent or delay the onset of type 2 diabetes mellitus.
Also included is 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 of formula I. Also included is a method of treating, preventing or delaying the onset of diseases or conditions that are associated with type 2 diabetes mellitus. Examples include diseases and conditions selected from the group consisting of: dyslipidemias, (e.g., hyperlipidemia), such as elevated levels of cholesterol (hypercholesterolemia), triglycerides (hypertriglyceridemia) or low density lipoproteins (LDL) (high LDL levels), low levels of high density lipoprotein (HDL), microvascular or macrovascular changes and the sequellae of such conditions, such as coronary heart disease, stroke, peripheral vascular disease, hypertension, renal hypertension, nephropathy, neuropathy and retinopathy. The method entails administering to a type 2 diabetic patient, e.g., a human patient, an amount of a compound of formula I that is effective for treating, preventing or delaying the onset of such diseases or conditions. Also included is a method of treating atherosclerosis in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat atherosclerosis.
Also included is 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, (11) 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) Syndrome X, 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 formula I in an amount that is effective to treat said condition. Also included is 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, (11) 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) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalian patient in need thereof, comprising administering to the patient a compound of formula I in an amount that is effective to delay the onset of said condition.
Also included is 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, (11) 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) Syndrome X, 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 of formula I in an amount that is effective to reduce the risk of developing said condition.
Optical Isomers - Diastereomers - Geometric Isomers - Tautomers Many of the compounds of formula I contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all such isomeric forms of the compounds, in pure form as well as in mixtures.
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 with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
Salts and Solvates
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable substantially non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, as well as salts that can be converted into pharmaceutically acceptable salts. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, 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, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. Solvates as used herein refers to the compound of formula I or a salt thereof, in association with a solvent, such as water. Representative examples include hydrates, hemihydrates, trihydrates and the like.
References to the compounds of Formula I include the pharmaceutically acceptable salts and solvates.
This invention relates to method of antagonizing or inhibiting the production or activity of glucagon, thereby reducing the rate of gluconeogenesis and glycogenolysis, and the concentration of glucose in plasma.
The compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals caused by elevated levels of glucose, comprised of combining the compound of formula I with the carrier materials to provide the medicament.
Dose Ranges
The prophylactic or therapeutic dose of the compound of formula I will, of course, vary with the nature of the condition to be treated, the particular compound selected and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight, preferably about 0.01 mg to about 50 mg per kg, and more preferably 0.1 to 10 mg per kg, in single or divided doses. It may be necessary to use dosages outside of these limits in some cases. The terms "effective amount" "anti-diabetic effective amount" and the other terms appearing throughout the application addressing the amount of the compound to be used refer to the dosage ranges provided, taking into account any necessary variation outside of these ranges, as determined by the skilled physician.
Representative dosages for adults range from about 0.1 mg to about 1.0 g per day, preferably about 1 mg to about 200 mg, in single or divided doses. When intravenous or or oral administration is employed, a representative dosage range is from about 0.001 mg to about 100 mg (preferably from 0.01 mg to about 10 mg) of a compound of Formula I per kg of body weight per day, and more preferably, about 0.1 mg to about 10 mg of a compound of Formula I per kg of body weight per day.
Pharmaceutical Compositions
As mentioned above, the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. The term "composition" encompasses a product comprising the active and inert ingredient(s), (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from the 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 between ingredients. Preferably the composition is comprised of a compound of formula I in an amount that is effective to treat, prevent or delay the onset of type 2 diabetes mellitus, in combination with the pharmaceutically acceptable carrier.
Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Examples of dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like, with oral tablets being preferred. Thus, one aspect of the invention that is of interest is the use of a compound of formula I for preparing a pharmaceutical composition which is comprised of combining the compound of formula I with the carrier.
In preparing oral compositions, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquids, e.g., suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solids, e.g., powders, capsules and tablets, with the solid oral preparations being preferred. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about lg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient. The following are examples of pharmaceutical dosage forms for the compounds of
Formula I:
Injectable Suspension (I.M.) mg/mL Tablet mg/tablet
Compound of Formula I 10.0 Compound of Formula I 25
Methy -cellulose 5.0 Microcrystalline Cellulose 415
Tween 80 0.5 Povidone 14.0
Benzyl alcohol 9.0 Pregelatinized Starch 43.5
Benzalkonium chloride 1.0 Magnesium Stearate 2.5
Water for injection to make 1.0 mL Total 500mg
Capsule mg/capsule Aerosol Per canister
Compound of Formula I 25.0 Compound of Formula I 24 mg
Lactose Powder 573.5 Lecithin, NF Liq. Cone. 1.2 mg
Magnesium Stearate 1.5 Trichlorofluoromethane, NF 4.025 g
Total 600mg Dichlorodifluoromethane, NF 12.15 g
Combination Therapy Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/delaying the onset of type 2 diabetes mellitus, as well as the diseases and conditions associated with type 2 diabetes mellitus, for which compounds of Formula I are useful. Other drugs 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 with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I 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 Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) bis-guanides (e.g., buformin, metformin, phenformin), (b) PPAR agonists (e.g., troglitazone, pioglitazone, rosiglitazone), (c) insulin, (d) somatostatin, (e) D-glucosidase inhibitors (e.g., voglibose, miglitol, acarbose), (f) DP-1V inhibitors, (g) LXR modulators and (h) insulin secretagogues (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide and repaglinide).
The weight ratio of the compound of the Formula I to the second active ingredient may be varied within wide limits and depends upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a PPAR agonist the weight ratio of the compound of the Formula I to the PPAR agonist 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 Formula I 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. For combination products, the compound of formula I may be combined with any other active ingredients and then added to the carrier ingredients; alternatively the order of mixing may be varied.
Examples of pharmaceutical combination compositions include: 1) a compound according to formula I, 2) a compound selected from the group consisting of: a) DP-IV inhibitors; b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; c) insulin and insulin mimetics; d) sulfonylureas and other insulin secretagogues; e) alpha glucosidase inhibitors; f) glucagon receptor antagonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; h) GIP, G1P mimetics, and GIP receptor agonists; i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; j) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR alpha agonists, (v) PPAR alpha/gamma dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA: cholesterol acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (m) an ileal bile acid transporter inhibitor; (n) anti-inflammatory agents other than glucocorticoids; and (o) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; and 3) a pharmaceutically acceptable carrier.
A method that is of particular interest relates to a method of treating, preventing or delaying the onset of diabetes, and in particular, type 2 diabetes, in a mammalian patient in need thereof, comprising administering to the patient 1) a compound according to formula I, and 2) a compound selected from the group consisting of: a) DP-1N inhibitors; b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; c) insulin and insulin mimetics; d) sulfonylureas and other insulin secretagogues; e) alpha glucosidase inhibitors; f) glucagon receptor antagonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; h) GIP, GIP mimetics, and GIP receptor agonists; i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; j) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR alpha agonists, (v)
PPAR alpha/gamma dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA: cholesterol acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (m) an ileal bile acid transporter inhibitor; (n) anti-inflammatory agents other than glucocorticoids; and (o) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; said compounds being administered in an amount that is effective to treat, prevent or delay the onset of type 2 diabetes. In accordance with the methods described herein one method that is of interest relates to 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, (11) 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) Syndrome X, 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 an effective amount of a compound of formula I and a compound selected from the group consisting of: (a) DP-IV inhibitors; (b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) alpha glucosidase inhibitors; (f) glucagon receptor antagonists; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GIP,GIP mimetics, and GIP receptor agonists; (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol lowering agents selected from the group consisting of: (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts thereof, (iv) PPAR alpha agonists, (v) PPARalpha/gamma dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA holesterol acyltransferase inhibitors, (viii) anti-oxidants and (ix) LXR modulators; (k) PPAR delta agonists; (1) antiobesity compounds; (m) an ileal bile acid transporter inhibitor; (n) anti-inflammatory agents excluding glucocorticoids; and (o) protein tyrosine phosphatase- IB (PTP- IB) inhibitors, said compounds being administered to the patient in an amount that is effective to treat said condition.
More particularly, a method that is of interest relates to 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 mammalina patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I and an HMG-CoA reductase inhibitor.
Even more particularly, the method that is of interest comprises administering to the patient a therapeutically effective amount of a compound of formula I and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin, and even more particularly, the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
A different aspect of the invention relates to 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 formula I and an HMG-CoA reductase inhibitor.
Another aspect of the invention relates to 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 formula I and an HMG-CoA reductase inhibitor. More particularly, the method comprises administering an effective amount of a compound of formula I and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase inhibitor is a statin. Even more particularly, the method comprises administering a compound of formula I and a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. Still more particularly, the method comprises administering a compound of formula I and the statin known as simvastatin.
Another aspect of the invention relates to 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 formula I and a cholesterol absorption inhibitor. In particular, the method comprises administering an effective amount of a compound of formula I and the cholesterol absorption inhibitor known as ezetimibe.
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 described which comprises administering to said patient an effective amount of a compound of formula I and a cholesterol absorption inhibitor. More particularly, the method comprises administering a compound of formula I and the cholesterol absorption inhibitor known as ezetimibe.
Throughout the instant application, the following abbreviations are used with the following meanings unless otherwise indicated:
Figure imgf000034_0001
Figure imgf000035_0002
Compounds of the present invention may be prepared according to the methodology outlined in the following general synthetic schemes.
In one embodiment of the present invention, the compounds (la) where R3 is hydrogen may be prepared from ester Ha (vide infra),
Figure imgf000035_0001
where Rl, R2, R4, R8, and R9 are as defined above and R10 represents an alkyl or aryl group.
Compounds 11a are known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art as described in "Comprehensive Organic Chemistry", Katritzky et. al., Vol 5. One such route is illustrated in Scheme 1. Amine 1 may be commercially available or readily prepared via a reductive amination sequence by treating, for example, carbomethoxy benzaldehyde 2 (if R8 and R9 are hydrogen) and an amine 3 with a reducing agent such as sodium triacetoxyborohydride or cyanoborohydride in a solvent such as dichloroethane at ambient temperature. Alternatively, the benzylamine 4 can be reacted with the appropriate R4 carbonyl containing substituent under the same conditions to give amine I. Amine 1 is then treated with thiophosgene in the presence of a base such as diethylisopropylamine (DIEA) in a nonpolar aprotic solvent such as dichloromethane at temperatures of zero to 25° C followed by direct addition of a 1,2-diaminobenzene and either mercury (II) trifluoroacetate or methyl iodide (for example /. Med. Chem., 1985, 28, 1925 and Synthesis, 1974, 41). The reaction is stirred a further 30 min to 6h before isolation of benzimidazole 5 with an aqueous work-up. 1,2-Diaminobenzene analogs are commercially available, or readily prepared by those skilled in the art by reduction of the corresponding 2-nitroaniline with, for example hydrogen and a palladium catalyst or stannous chloride. Either reaction is effected in an alcoholic solvent such as methanol or ethanol. SCHEME 1
Figure imgf000036_0001
An alternative approach to synthesizing benzimidazole Ha involves reaction of amine 1 with triphosgene in the presence of a base, such as triethylamine, in a nonpolar aprotic solvent such as dichloromethane at temperatures of zero to 25 °C, as shown in Scheme 2. The carbamoyl chloride 6 formed in the reaction can be readily isolated and treated with a 1,2-diaminobenzene to give the urea which is treated directly with a dehydrating agent, usually phosphorus oxychloride, at elevated temperatures for 6 - 24h, followed by an aqueous work-up to yield the benzimidazole 5.
Figure imgf000036_0002
Preparation of the desired compounds la (which are defined as compounds of formula I wherein R3 represents H) is then achieved by saponification of the ester 5 using a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, methanol, ethanol or a mixture of similar solvents, Scheme 3. Coupling of the acid with an amine, generally 5-aminotetrazole 7 or a beta alanine derivative 8 which may be substituted at the 2-position, is then achieved using l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 3 to 48 hours at ambient temperature to yield the compounds Ia-7 and Ia-8. Other peptide coupling conditions may also be used. The product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, J. Org. Chem., 43, 2923, (1978), or HPLC. Compounds purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner. As will be understood by those skilled in the art, for the preparation of enantiomerically pure compounds, enantiomerically pure starting materials should be used.
In some cases further modification of intermediates such as 5 can be undertaken in one of several different ways. These manipulations may include, but are not limited to substitution, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are commonly known to those skilled in the art.
SCHEME 3
Figure imgf000037_0001
In another embodiment of the present invention, the compounds (lb) (which are defined as compounds of formula I wherein R3 is not hydrogen) may be prepared from ester lib (vide infra),
Figure imgf000037_0002
where R1, R2, R3, R4, R8, and R9 are as defined above and R10 represents an alkyl or aryl group.
Compounds lib may be conveniently prepared by a variety of methods known to those skilled in the art. One such example, shown in Scheme 4, involves alkylation of intermediate 5 by deprotonation with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide (DMF) at 0 - 25 °C for 15min to 2h, followed by addition of an electrophile such as an alkyl iodide. The reaction is stirred, with heating if necessary, for an additional 1 - 24 h to give intermediate 9.
SCHEME 4
Figure imgf000038_0001
An alternative route goes via the N-alkylated 1 ,2-diaminobenzene K). These are commercially available or readily prepared by those skilled in art. One such method involves alkylation of a 2-nitro aniline. This is effected by deprotonation with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide (DMF) at 0 - 25 °C for 15min to 2h, followed by addition of an electrophile such as an alkyl iodide, Scheme 5. The reaction is stirred for an additional 1 - 24 h to give intermediate J_l , which can be reduced with, for example hydrogen and a palladium catalyst or stannous chloride in an alcoholic solvent. The alkylated 2-nitro aniline JJ. can also be prepared by nucleophilic displacement of fluorine from a 2-fluoronitrobenzene 12 with an amine as described in J. Org. Chem., 1999, 64, 3060. This is achieved in a solvent such as methylene chloride or DMF with a base such as DIEA, at temperatures of 25 - 80 °C for l-6h, Scheme 5. The diaminobenzene H) can then be converted to the benzimidazole 9 using amine 1 or carbamoyl chloride 6 in an identical fashion to that described above and illustrated in Schemes 6 and 7.
SCHEME 5
Figure imgf000038_0002
SCHEME 6
Figure imgf000039_0001
SCHEME 7
Figure imgf000039_0002
A third route to intermediates Hb involves alkylation of the 2-aminobenzimdazole 3 with a benzylic bromide, for example carbomethoxy benzyl-bromide, as illustrated in Scheme 8. Amine 3 is converted to the isothiocyanate by reaction with thiophosgene in the presence of a base such as DIEA in a nonpolar aprotic solvent such as dichloromethane at temperatures of zero to 25° C followed by addition of diamine 10 and cyclization with an agent such as methyl iodide. This reaction is effected at 25 - 50 °C for 1 - 24 h to give amine 13. Deprotonation is achieved with a base such as sodium hydride or potassium carbonate in a nonpolar aprotic solvent such as DMF to give a mixture of the desired compound 9 and its isomer 14. These are generally separable by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel or HPLC.
SCHEME 8
Figure imgf000039_0003
Conversion of ester 9 to the final products is achieved by saponification of the ester using a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, methanol, ethanol or a mixture of similar solvents, Scheme 9. Coupling of the acid with an amine, generally 5-aminotetrazole 7 or a beta alanine derivative 8 which may be substituted at the 2-position, is then achieved using l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 3 to 48 hours at ambient temperature to yield the compounds Ib-7 and Ib-8. Other standard peptide coupling conditions may also be used. The product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, /. Org. Chem., 43, 2923, (1978), or HPLC. Compounds purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
SCHEME 9
Figure imgf000040_0001
In some cases further modification of intermediates such as 9 can be undertaken in one of several different ways. These manipulations may include, but are not limited to substitution, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are commonly known to those skilled in the art. One such modification, illustrated here when R1 or R2 is a protected alcohol as in 15, involves release of the alcohol and subsequent etherification. The hydroxyl group may be protected as a silyl ether, in which case a fluoride source, generally hydrofluoric acid or tetrabutylammonium fluoride is used for the reaction. Deprotection of a methoxy ether is routinely effected by treatment of the compound with boron tribromide in a solvent such as methylene chloride for a period of 1 - 16h at ambient temperatures. Finally, if the alcohol is protected as an allyl ether, this is removed by treatment with dimethylbarbituric acid and a palladium catalyst, routinely tris(dibenzylideneacetone)dipalladium(0), with a ligand such as l,4-bis-(diphenylphospino)butane in an aprotic solvent such as methylene chloride for 15min to 2h. See "Protective Groups in Organic Synthesis", Greene, published by Wiley and Sons.
SCHEME 10
Figure imgf000041_0001
The free hydroxyl group may then be further modified to prepare ethers using an alcohol and coupling agent, such as diisopropylazodicarboxylate, and triphenylphosphine in a non polar solvent such as methylene chloride at temperatures of 0 to 40°C for 1 to 16h, Scheme 10. Intermediates J_6 and 17 can then be converted to the desired products as previously described, vide supra.
Another such modification, illustrated here when R4 contains an aromatic halide as in 18, Scheme 11, involves coupling reactions either with a boronic acid in a Suzuki type coupling or a vinyl stannane to give products such as .19 and 20. For the former reaction, the halide is coupled with a boronic acid, exemplified here with phenyl boronic acid, using a palladium catalyst such as palladium acetate and tris-o-tolylphosphine or triphenyl phosphine. The solvent is generally DMF or ethanol, and cesium carbonate or aqueous sodium carbonate is also added to the reaction, which is performed at elevated temperatures for 12-24 h (see Helv. Chim. Ada, 1992, 75, 855). Preparation of intermediates 20 is carried out by reaction with a vinyl stannane in the presence of a palladium catalyst such as palladium tris-o-tolylphosphine. The solvent is generally DMF, and the reaction is performed at elevated temperatures for 1-8 h. Intermediates 19 and 20 can then be converted to the desired products as previously described, vide supra. SCHEME 11
Figure imgf000042_0001
In cases where R and R9 form a 5-membered ring alternate conditions were used for the synthesis of the amine intermediate 21, Scheme 12. For example, commercially available ketone 22 was converted to amine 23 by a reductive amination sequence using a Lewis acid such as titanium isopropoxide in ethanol at ambient temperature for 6 - 24 h, followed by further reduction with a hydride reducing agent such as sodium borohydride ( J. C. S., Perkin Trans 1, 1998, 2527-2531). Alternatively, decaborane in methanol at ambient temperature can be used for the reductive amination (J.C.S. Perkin Trans 1, 2000 145-146). The requisite ester linkage is then installed by treatment of the bromide with a base such as butyl lithium at -78 °C in a polar aprotic solvent such as THF, followed by quenching the reaction with solid carbon dioxide to give the acid. Esterification, with TMS diazomethane for example, gives amine 21. Intermediate 21 can then be converted to the desired products as previously described, vide supra.
SCHEME 12
Figure imgf000042_0002
The following examples are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way. General experimental: Analytical HPLC analysis for examples 1 - 274 (HPLC A) was performed on a YMC Combiscreen ODS-A column (50 x 4.6 mm i.d.) at a flow rate of 4 mL/min using a gradient elution of 10 - 100% acetonitrile in water containing 0.1% trifluoroacetic acid. Preparative HPLC was performed on a YMC-Pack Pro C18 column (150 x 20 mm i.d.) at an initial flow rate of 4 mL/min for 1.35 min, followed by 20 rnL/min for 10.6min. Various concentration gradients were used during the faster part of the run (see below), and all runs were followed with 100% organic for 0.5 min.
Condition A: 10 to 90% acetonitrile in water (each containing 0.1% trifluoroacetic acid).
Condition B: 20 to 60% acetonitrile in water (each containing 0.1% trifluoroacetic acid).
Condition C: 20 to 80% acetonitrile in water (each containing 0.1% trifluoroacetic acid). Condition D: 20 to 100% acetonitrile in water (each containing 0.1% trifluoroacetic acid).
EXAMPLE 1
Figure imgf000043_0001
Step A. l-Isothiocyanato-2-nitrobenzene. To a solution of 2-nitroaniline (10 mmol, 1.38 g) and DIEA (15 mmol, 2.6 mL) in 10 mL of DCM at 0°C was added thiophosgene (15 mmol, 1.14 mL). The reaction was brought to 65° for 45 min. Purification by flash chromatography on silica eluting with 10% EtOAc/hexanes afforded the isothiocyanate as a gold solid. HPLC A: 2.24 min.
Step B. Methyl 4- (r(4-tert-butylcyclohexyl)aminol methyl Ibenzoate
To a solution of methyl-4-formylbenzoate (73 mmol, 12 g) in 200 L of MeOH was added 4-tert-butylcyclohexylamine (74 mmol, 13.2 mL) via syringe. The reaction mixture was heated to reflux for 0.75 h, then was cooled in an ice bath. The resulting precipitate was filtered and the filter cake was washed with 2 x 20 mL of cold MeOH. The solid was dried under reduced pressure, then suspended in 224 mL of MeOH. HOAc (652 mmol, 37.4 mL) was added to the solution, followed by NaBH3CN (42.7 mmol, 2.68 g) in several portions. The reaction mixture was stirred at ambient temperature for 1.5 h, then concentrated under reduced pressure to ca. 25 % of the initial volume. 400 mL of EtOAc was added to the solution and the mixture was washed with 3 x 200 mL of 5 % NaHC03 followed by brine. The organic phase was dried over MgS0 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes to afford the trans isomer as a white solid. 1H NMR (500 MHz, CDC13): δ 8.00 (d, 2H), 7.40 (d, 2H), 3.92 (s, 3H), 3.88 (s, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.79 (m, 2H), 0.95 - 1.15 (overlapping m, 5H), 0.85 (s, 9H).
Step C. Methyl 4-{ riH-benzimidazol-2-yl(4-tert-butylcvclohexyl)amino1methyl)-benzoate To the title compound of Example 1 Step B (2.13 mmol, 721 mg) in 2.5 mL of DMF was added DIEA (0.8 mL), followed by the title compound of Example 1 Step A (2.5 mmol, 450 mg). The reaction mixture was concentrated under reduced pressure. The residue was taken up in 5 mL of DMF containing 0.4 mL of H20, and SnCl2 (2 g) was added (exothermic). The crude thiourea was concentrated under reduced pressure and the residue was taken up in 10 mL of EtOH. Mel (400 μL) was added and the resulting mixture was heated at 60° for 1 h and concentrated under reduced pressure. The product was purified by flash chromatography on silica eluting with 30% EtOAc/hexanes affording a slightly pink solid. *H NMR (500 MHz, CD3OD): 6 8.00 (d, 2H), 7.43 (d, 2H), 7.29 (m, 2H), 7.14 (m, 2H), 4.86 (s, 2H), 4.04 (m, 1H), 3.89 (s, 3H), 1.82 - 1.95 (overlapping m, 4H), 1.57 (m, 2H), 1.29 (m, 2H), 1.05 (m, 1H), 0.89 (s, 9H). MS (ESI): m/z 420 (M + H). HPLC A: 2.30 min.
Step D. 4-{riH-Benzimidazol-2-yl(4-tgrt-butylcvclohexyl)aminolmethyl)benzoic acid
To the title compound of Example 1 Step C (0.21 mmol, 90 mg) in 2 mL of dioxane was added a solution of LiOΗ (2.1 mmol, 52 mg) in 0.6 mL of Η20. The reaction was stirred at 40°C for 3 h. The product was partitioned into EtOAc/H20 acidified with 2 N HC1. The aqueous phase was washed with EtOAc and the combined organic phase was dried with MgS0 and concentrated under reduced pressure affording a yellow solid. HPLC A: 1.98 min.
Step E. 4-{ riH-Benzimidazol-2-yl(4-tgrt-butylcvclohexyl)aminolmethyIl-N-(lH-tetra-azol-5- vDbenzamide To a solution of the title compound of Example 1 Step D (0.1 mmol, 41 mg), 1H- tetraazol-5-amine monohydrate (0.2 mmol, 21 mg), ΗOBt (0.25 mmol, 38 mg) and EDC (0.4 mmol, 77 mg) in 1 mL of DMF was added DIEA (0.5 mmol, 90 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/Η20, acidified with TFA, and purified by reverse-phase chromatography (Condition A). Lyophilization afforded the product as a white solid. MS (ESI): m/z 473 (M + H). HPLC A: 1.86 min. EXAMPLE 2
Figure imgf000045_0001
N-(4-f T lH-Benzimidazol-2-yl(4-tgrt-butylcvclohexyl)aminolmethyl }benzoyl)-β-alanine To a solution of the title compound of Example 1 Step D (0.1 mmol, 41 mg), the hydrochloride salt of β-alanine tert-butyl ester (0.15 mmol, 27 mg), HOBt (0.25 mmol, 38 mg) and EDC (0.4 mmol, 77 mg) in 1 mL of DMF was added DIEA (0.5 mmol, 90 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then partitioned into EtOAc/H20. The aqueous phase was washed with EtOAc, and the combined organic phase was dried with MgS0 and the solvent was removed under reduced pressure. The residue was treated with 3 mL of 2:30:68 H20/TFA/DCM for 1 hr and the solution was concentrated under reduced pressure. Purification by reverse-phase chromatography (Condition A), followed by lyophilization, afforded the product as a white solid. MS (ESI): m/z 477 (M + H). HPLC A: 1.70 min.
EXAMPLE 3
Figure imgf000045_0002
4-([lH-Benzinτidazol-2-yl(4-tert-butylcvclohexyl)aminolmethyll-N-(lH-tetraazol-5-ylmethyl)benzamide
To a solution of the title compound of Example 1 Step D (0.04 mmol, 16 mg), 1H- tetraazol-5-yImethylamine (0.06 mmol, 8 mg), ΗOBt (0.1 mmol, 15 mg) and EDC (0.12 mmol, 23 mg) in 0.4 mL of DMF was added DIEA (0.2 mmol, 35 μL). After 3 h the reaction mixture was concentrated under reduced pressure. The product was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 487 (M + Η). ΗPLC A: 1.58 min. EXAMPLE 4
Figure imgf000046_0001
(2R)-3-r(4-( riH-Benzimidazol-2-yl(4-tgrt-butylcvclohexyl)aminolmethyllbenzoyl)-aminol-2- hydroxypropanoic acid To a solution of the title compound of Example 1 Step D (0.04 mmol, 16 mg), the hydrochloride salt of 2-hydroxy β-alanine methyl ester (0.06 mmol, 9 mg), HOBt (0.1 mmol, 15 mg), and EDC (0.12 mmol, 23 mg) in 0.4 mL of DMF was added DIEA (0.2 mmol, 35 μL). After 3 h the reaction was partitioned into EtO Ac/brine. The organic phase was dried with MgS04 and concentrated under reduced pressure. The residue was taken up in 1 mL of dioxane and a solution of LiOH (1 mmol, 24 mg) in 0.5 mL of H20 was added. The reaction was stirred at ambient temperature overnight, acidified with TFA and the product was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 493 (M + H). HPLC A: 1.73 min.
EXAMPLE 5
Figure imgf000046_0002
Step A. 4-{ r(4-tgrt-Butylcvclohexyl)(l-methyl-lH-benzimidazol-2-vπaminolmethvπ-benzoic acid
To the title compound from Example 1 Step C (0.72 mmol, 300 mg) in 5 mL of THF was added Mel (1 mmol, 67 μL), followed by NaH (1 mmol, 40 mg of 60% dispersion in mineral oil) (exothermic, H2 evolution). After 1 h starting benzimidazole was still present, so the reaction was treated with additional Mel (1 mmol) and NaH (1 mmol). After 1 h the reaction was complete (HPLC A: 2.38). The mixture was concentrated under reduced pressure and the residue was taken up in 6 mL of dioxane. A solution of LiOH (7 mmol, 172 mg) in 2 mL of H20 was added and the resulting mixture was stirred at ambient temperature overnight. The mixture was poured into EtOAc/ H20, and acidified with 2 N HC1 until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic phase was dried with MgS0 and concentrated under reduced pressure affording product as a yellow solid. MS (ESI): m/z 420 (M + H). HPLC A: 2.09 min.
Step B. N-(4- (4-tgrt-ButylcvclohexylKl-methyl-lH-benzimidazol-2-yl)aminolmethyll-benzoylVD- alanine
To a solution of the title compound of Example 5 Step A (0.06 mmol, 24 mg), the hydrochloride salt of β-alanine tert-butyl ester (0.09 mmol, 16 mg), HOBt (0.15 mmol, 23 mg) and EDC (0.18 mmol, 35 mg) in 0.8 mL of DCM was added DIEA (0.3 mmol, 52 μL). The reaction mixture was allowed to stand at ambient temperature for 3 h, then partitioned into EtOAc/brine. The aqueous phase was washed with EtOAc, and the combined organic phase was dried with MgS04 and the solvent was removed under reduced pressure. The residue was treated with 3 mL of 2:30:68 H20/TFA/DCM for 1 hr and the solution was concentrated under reduced pressure. The crude product was purified by reverse- phase chromatography (Condition A), then lyophilized, affording the title compound as a white solid. MS (ESI): m/z 491 (M + H). HPLC A: 1.92 min.
EXAMPLE 6
Figure imgf000047_0001
4-f f (4-tgrt-Butylcvclohexyl)( 1 -methyl-lH-benzimidazol-2-yl)aminolmethyl 1 -N-( lH-tetraazol-5- vDbenzamide
To a solution of the product of Example 5 Step A (0.14 mmol, 64 mg), lH-tetraazol-5- amine monohydrate (0.28 mmol, 29 mg), HOBt (0.35 mmol, 53 mg) and EDC (0.56 mmol, 108 mg) in 1 mL of DMF was added DIEA (0.7 mmol, 122 μL). The reaction was allowed to stand at ambient temperature for 21 h, then concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/ H20 and acidified with TFA, then purified by reverse-phase chromatography (Condition A). The product was lyophilized, affording a white solid. 1H ΝMR (500 MHz, CD3OD): δ 8.01 (d, 2H), 7.52 - 7.62 (overlapping m, 3H), 7.35 - 7.50 (overlapping m, 3H), 3.87 (s, 3H), 3.76 (m, 1H), 2.16 (m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.30 (m, 2H), 1.14 (m, IH), 0.92 (s, 9H). MS (ESI): m/z 487 (M + H). HPLC A: 1.97 min.
EXAMPLE 7
Figure imgf000048_0001
Methyl (2R -3-r(4-{f(4-fert-butylcyclohexyl)(l-methyl-lH-benzimidazol-2-yl')amino1- methyl)benzoyl)aminol-2-hvdroxypropanoate
To a solution of the title compound of Example 5 Step A (0.32 mmol, 145 mg), the hydrochloride salt of 2-hydroxy β-alanine methyl ester (0.48 mmol, 74 mg), HOBt (0.8 mmol, 121 mg) and EDC (0.96 mmol, 183 mg) in 2 mL of DMF was added DIEA (1.6 mmol, 0.28 mL). After 3 h the reaction was partitioned into EtO Ac/brine. The organic phase was dried with MgS0 and concentrated under reduced pressure. The product was purified by flash chromatography on silica eluting with 1:25:74 MeOH/EtOAc/DCM, affording the title compound as a foamy solid. 1H.NMR (500 MHz, DMSO-d6): δ 8.47 (t, IH), 7.75 (d, 2H), 7.60 (m, IH), 7.48 (m, IH), 7.45 (d, 2H), 7.30 - 7.37 (overlapping m, 2H), 4.80 (s, 2H), 3.76 (s, 3H), 3.70 (m, IH), 3.60 (s, 3H), 3.50 (m, IH), 3.39 (m, IH), 2.02 (m, 2H), 1.82 (m, 2H), 1.71 (m, 2H), 1.18 (m, 2H), 1.03 (m, IH), 0.85 (s, 9H). MS (ESI): m/z 521 (M + H). HPLC A: 1.94 min.
EXAMPLE 8
Figure imgf000048_0002
(2R)-3-r(4-i r(4-tgrt-Butylcvclohexyl)(l-methyl-lH-benziπ-idazol-2-yl)arnino1methvU-benzoyπaminol-2- hydroxypropanoic acid
To a solution of the title compound of Example 7 (0.1 mmol, 50 mg) in 2 mL of MeOΗ was added LiOΗ (0.5 mmol, 12 mg). Η20 was added dropwise until the reaction became slightly cloudy, then the mixture was sonicated to dissolve the LiOH. The reaction was stirred at 40°C for 2 h. The reaction was concentrated under reduced pressure and the residue was taken up in dioxane/H20 and acidified with TFA. Purification by reverse-phase HPLC (Condition A), followed by lyophilization, afforded the title compound as a white solid. 1H NMR (500 MHz, CD30D): δ 7.79 (d, 2H), 7.58 (m, IH), 7.39 - 7.52 (overlapping m, 5H), 4.86 (s, 2H), 4.34 (m, IH), 3.87 (s, 3H), 3.52 - 3.84 (overlapping m, 3H), 2.16 (m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.31 (m, 2H), 1.14 (m, IH), 0.92 (s, 9H). MS (ESI): m/z 487 (M + H). MS (ESI): m/z 507 (M + H). HPLC A: 1.84 min.
EXAMPLE 9
Figure imgf000049_0001
4-f r(4-tgrt-Butylcvclohexyl)(l-methyl-lH-benzimidazol-2-yl)aminolmethyll-N-(lH-tetraazol-5- ylmethvDbenzamide
To a solution of the title compound of Example 5 Step A (0.06 mmol, 25 mg) 1H- tetraazol-5-ylmethylamine (0.09 mmol, 12 mg), HOBt (0.15 mmol, 23 mg) and EDC (0.18 mmol, 35 mg) in 0.5 mL of DMF was added DIEA (0.3 mmol, 52 μL). The reaction was allowed to proceed overnight at ambient temperature. The mixture was partitioned between EtOAc/brine. The organic phase was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 517 (M + H). HPLC A: 1.94min.
EXAMPLE 10
Figure imgf000050_0001
Step A. Methyl 4-(r(4-fgrt-butylcvclohexyl')(l-(2-r(trimethylsilyl')oxylethyll-lH-benz-imidazol-2- yDaminol methyl Ibenzoate
To the title compound from Example 1 Step C (0.5 mmol, 210 mg) in 1 mL of THF was added a solution of NaH (1 mmol, 40 mg of 60% slurry in mineral oil) in 1 mL of DMF (exothermic, H2 evolution). After gas evolution ceased for several minutes, (2-bromoethoxy)(trimethyl)silane was added to the solution via syringe. The reaction mixture was heated to 40°C. After 2.5 h the reaction was quenched by addition of saturated ammonium chloride. The product was extracted 3x with EtOAc and the organic phase was dried over MgS04 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 5 % EtOAc/hexanes. HPLC A: 3.14 min.
Step B. 4-{ r(4-tgrt-Butylcvclohexyl)(l-l2-hydroxyethyU-lH-benzimidazol-2-yl')-aminolmethyllbenzoic acid
To the title compound of Example 10 Step A (0.13 mmol, 73 mg) in 2 mL of dioxane was added a solution of LiOH (1.25 mmol, 30 mg) in 1 mL of H20. The resulting solution was stirred at 40°C overnight. The reaction mixture was taken up in a pH 7 buffer solution and EtOAc. The mixture was acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgS0 and concentrated under reduced pressure to afford the acid as a beige solid. MS (ESI): m/z 450 (M + H). HPLC A: 2.05 min.
Step C. 4-( { (4-tgrt-Butylc vclohexyl) I" 1 -(2-hvdroxyethvD- lH-benzimidazol-2-y 11 amino ) -methyl)-N-( 1H- tetraazol-5 -vDbenzamide
To a solution of the title compound of Example 10 Step B (0.04 mmol, 19 mg) 1H- tetraazol-5-amine monohydrate (0.13 mmol, 13 mg), HOBt (0.085 mmol, 13 mg) and EDC (0.17 mmol, 33 mg) in 0.5 mL of DMF was added DIEA (0.21 mmol, 36 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/H20 and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized, affording the title compound as a white solid. MS (ESI): m/z 517 (M + H). HPLC A: 1.81 min.
EXAMPLE 11
Figure imgf000051_0001
Step A. 4-Allyloxy-2-fluoro-nitrobenzene
To a solution of 3-fluoro-4-nitrophenol (17.5 mmol, 2.75 g) and allyl bromide (17.5 mmol, 1.5 mL) in 10 mL of DMF was added K2C03 (21 mmol, 2.9 g). The slurry was stirred at ambient temperature overnight, and partitioned into NaHC03 (aq)/DCM. The organic phase was removed under reduced pressure affording the product as a brown oil. HPLC A: 2.19 min.
Step B. 5-(Allyloxy)-N-methyl-2-nitroaniline
The title compound of Example 11 Step A (15.2 mmol, 3.01 g) was stirred in 15 mL of 2 M methylamine in THF at 0°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was partitioned into DCM/brine. The organic phase was concentrated under reduced pressure affording the product as a bright yellow solid. 1H ΝMR (500 MHz, d6-DMSO): δ 8.03 (d, IH), 6.30 - 6.36 (overlapping m, 2H), 6.06 (m, IH), 5.44 (m, IH), 5.31 (m, IH), 2.96 (d, 3H). MS (ESI): m/z 209 (M + H). HPLC A: 2.20 min.
Step C. 5-(Allyloxy)-N-methyl-2-aminoaniline
To a solution of the title compound in Example 11 Step B (7.2 mmol, 1.50 g) in 14.6 mL of 10:1 DMF/H2O was added SnCl2 (anhydrous) (5 mmol, 8.1 g). The reaction mixture was heated at 45°C overnight. DCM, followed by ΝaHC03 (aq) was added slowly to the reaction. The resulting precipitate was removed by filtration over celite. The filter cake was washed with DCM, and the combined organic phase was dried with MgS0 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 20% EtOAc/hexanes, then 30 % EtOAc/hexanes, affording the desired product as a brown oil. MS (ESI): m/z 179 (M + H). HPLC A: 0.89 min. Step P. Methyl 4-{rf6-(allyloxy)-l-methyl-lH-benzimidazol-2-yll(4-tgrt- butylc vclohexyDaminolmethyl I benzoate
To the product of Example 1 Step A (3 mmol, 910 mg) and DIEA (3.6 mmol, 626 μL) in 12 mL of DCM was added thiophosgene (3 mmol, 229 μL). After 1 h additional DIEA (3.6 mmol) and the title compound of Example 11 Step C (2.75 mmol, 489 mg) were added. After 1.5 h Hg(02CCF3)2 (3 mmol, 1.27 g) was added (exothermic), and the slurry was allowed to stand overnight. HPLC analysis revealed the cyclization was incomplete, so additional Hg(02CCF3)2 (1.5 mmol, 650 mg) was added to the reaction. After 2 h the solution was poured into NaHCOβ (aq) containing Na2S, and the slurry was filtered through celite, and the filter cake was washed with DCM. The organic phase was collected and the aqueous phase was extracted with 2x DCM. The combined organic phase was dried with MgS04 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 20 % EtOAc/hexanes, then 30 % EtOAc/hexanes affording the product as a foamy solid. 1H NMR (500 MHz, d6-DMSO): δ7.82 (d, 2H), 7.44 (d, 2H), 7.23 (d, IH), 6.94 (d, IH), 6.69 (dd, IH), 6.06 (m, IH), 5.40 (m, IH), 5.24 (m, IH), 4.56 (m, 2H), 4.51 (s, 2H), 3.79 (s, 3H), 3.57 (s, 3H), 3.16 (m, IH), 1.96 (m, 2H), 1.79 (m, 2H), 1.58 (m, 2H), 0.94 - 1.12 (overlapping m, 3H), 0.83 (s, 9H). MS (ESI): m/z 490 (M + H). HPLC A: 2.58 min.
Step E. 4-f rf6-(Allyloxy)-l-methyl-lH-benzimidazol-2-yll(4-tgrt-butylcvclohexyl)aminolmethyl Ibenzoic acid To the title compound of Example 11 Step D (0.1 mmol, 51 mg) in 800 μL of dioxane was added a solution of LiOH (0.4 mmol, 10 mg) in 400 μL of H20. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was taken up in a pH 7 buffer solution and EtOAc.
The mixture was acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgS0 and concentrated under reduced pressure to afford the acid as a white solid. MS (ESI): m/z
476 (M + H).HPLC A: 2.33 min.
Step F. 4-1 rr6-(AlIyloxy)-l-methyl-lH-benzimidazol-2-yll(4-tgrt-butylcvclohexyl')-aminolmethvU-N- ( lH-tetraazol-5-yl)benzamide To a solution of the title compound of Example 11 Step E (0.04 mmol, 20 mg), 1H- tetraazol-5-amine monohydrate (0.12 mmol, 12 mg), ΗOBt (0.08 mmol, 12 mg) and EDC (0.08 mmol, 15 mg) in 1 mL of DMF was added DIEA (0.08 mmol, 14 μL). The reaction was heated at 40°C for 2 h, then concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/ Η20 and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized, affording the title compound as a white solid. lH ΝMR (500 MHz, d6-DMSO): δ 12.33 (br s, IH), 8.01 (d, 2H), 7.52 (d, 2H), 7.35 (d, IH), 7.23 (br unres. m, IH), 6.91 (br unres. m, IH), 6.06 (m, IH), 5.41 (dd, IH), 5.27 (dd, IH), 4.75 (s, 2H), 4.62 (d, 2H), 3.73 (s, 3H), 2.01 (m, 2H), 1.82 (m, 2H), 1.69 (m, 2H), 1.16 (m, 2H), 1.03 (m, IH), 0.85 (s, 9H). one proton obscured by water. MS (ESI): m/z 543 (M + H). HPLC A: 2.19 min.
EXAMPLE 12
Figure imgf000053_0001
Step A. Methyl 4- ( r(4-tgrt-butylcvclohexyl )(6-hvdroxy- 1 -methyl- 1 H-benzimidazol-2- yl , aπ-inol methyl 1 benzoate
To a solution of the title compound of Example 11 Step D (0.6 mmol, 300 mg) and 1,3- dimethylbarbituric acid (0.72 mmol, 112 mg) in 3 mL of DCM was added under N2 a solution of Pd2dba3 ( 0.025 mmol, 23 mg) and l,4-bis(diphenylphosphino)-butane (0.05 mmol, 21 mg) in 0.5 mL of dry THF which had been incubated under N2 for 15 min. After 30 min the reaction mixture was concentrated under reduced pressure, then purified by flash chromatography on silica eluting with a step gradient of 1% MeOH/DCM to 4 % MeOH/DCM, affording the product as a white solid. MS (ESI): m/z 450 (M + H). HPLC A: 2.26 min.
Step B. 4-(r(4-tgrt-Butylcyclohexyl)(6-hydroxy-l-methyl-lH-benzimidazol-2-yl)aminol-methyl)benzoic acid
To the title compound of Example 12 Step A (0.1 mmol, 50 mg) in 800 μL of dioxane was added LiOH (0.4 mmol, 10 mg) in 400 μL of H20. The resulting solution was stirred at 40°C overnight. The reaction mixture was taken up in aqueous pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic layers were dried with MgS0 and concentrated under reduced pressure to afford the acid as a white solid, which was used without further purification. (HPLC A: 1.97 min).
Step C. 4-{r(4-tgrt-Butylcycloheχyl)(6-hvdroxy-l-methyl-lH-benzimidazol-2-yl)amino1-methyll-N-(lH- tetraazol-5-yl)benzamide To the product of Example 12 Step B (0.04 mmol), lH-tetraazol-5 -amine monohydrate (0.12 mmol, 12 mg), HOBt (0.08 mmol, 12 mg) and EDC (0.08 mmol, 15 mg) in 1 mL of DMF was added DIEA (0.08 mmol, 14 μL). The reaction was heated at 40°C for 2.5 h, then concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/ H2O and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized directly, affording the title compound as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 12.35 (br s, IH), 9.81 (br s, IH), 8.01 (d, 2H), 7.52 (d, 2H), 7.28 (d, 2H), 6.91 (unres. d, IH), 6.79 (dd, IH), 4.75 (s, 2H), 3.69 (s, 3H), 2.01 (m, 2H), 1.83 (m, 2H), 1.69 (m, 2H), 1.16 (m, 2H), 1.04 (m, IH), 0.85 (s, 9H). One proton obscured by H20. MS (ESI): m/z 503 (M + H). HPLC A: 1.85 min.
Figure imgf000054_0001
Step A. Methyl 4-1 f (4-tgrt-butylcvclohexyl)(l-methyl-6-propoxy-lH-benzimidazol-2- yDaminol methyl Ibenzoate To a solution of the title compound of Example 12 Step A (0.1 mmol, 45 mg), n- propanol (0.25 mmol, 19 μL) and diisopropyl azodicarboxylate (0.2 mmol, 37 μL) in 1 mL of DCM was added solid Ph3P (exothermic). After 20 min the reaction was complete. The product was isolated by flash chromatography on silica eluting with 10% EtOAc/hexanes, then 25% EtOAc/hexanes, affording the product as a clear oil. MS (ESI): m/z 492 (M + Η). ΗPLC A: 2.68 min.
Step B 4-{ r(4-tert-Butylcvclohexyl)(l-methyl-6-propoxy-lH-benzimidazol-2-yl)aminol- methyl ibenzoate
To the title compound of Example 13 Step A (0.07 mmol, 36 mg) in 0.8 mL of dioxane was added LiOΗ (0.3 mmol, 7 mg) in 0.4 mL of Η20. The resulting solution was stirred at ambient temperature for 5 h. The reaction mixture was taken up in aqueous pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2x with EtOAc. The combined organic layers were dried with MgS04 and concentrated under reduced pressure to afford the acid as a white solid, which was used without further purification. (HPLC A: 2.42 min). Step C. 4-( r(4-tgrt-Butylcyclohexyl¥l-methyl-6-propyloxy-lH-benzimidazol-2-yl)-aminolmethyl|-N- ( lH-tetraazol-5-yl)benzamide
To a solution of the title compound of Example 13 Step B (0.02 mmol, 10 mg), 1H- tetraazol-5-amine monohydrate (0.06 mmol, 6 mg), HOBt (0.04 mmol, 6 mg) and DIEA (0.06 mmol, 10 μL) in 1 mL of DMF was added EDC (0.04 mmol, 8 mg). The reaction was allowed to stand at ambient temperature overnight, then concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/ H20 and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized affording the title compound as a white solid. 1H ΝMR (500 MHz, d6- DMSO): δ 12.34 (s, IH), 8.00 (d, 2H), 7.53 (d, 2H), 7.43 (d, IH), 7.20 (br m, IH), 6.88 (m, IH), 4.75 (s, IH), 3.97 (t, 2H), 3.73 (s, 3H), 3.57 (br m, IH), 2.01 (m, 2H), 1.82 (m, 2H), 1.62 - 1.78 (overlapping m, 4H), 1.16 (m, 2H), 0.95 - 1.08 (overlapping m, 4H), 0.85 (s, 9H). MS (ESI): m/z 545 (M + H). HPLC A: 2.28 min.
EXAMPLE 14
Figure imgf000055_0001
Step A. Ν-Methyl-4-methoxy-2-nitroaniline.
To 4-methoxy-2-nitroaniline (10 mmol, 1.68 g) in 20 mL of DMF was added NaH (12 mmol, 480 mg of a 60 % dispersion in mineral oil) (exothermic, H2 evolution), affording a deep red slurry. After 15 min Mel (20 mmol, 1.2 mL) was added (exothermic). After 30 min the reaction was poured into a solution of brine and NaHC03, resulting in formation of a bright orange precipitate. The slurry was filtered and the filter cake was washed with H20. The solid was dried under reduced pressure, affording a bright orange solid. HPLC A: 1.77 min.
Step B. N-Methyl-4-methoxy-1.2-phenylenediamine.
The title compound of Example 14 Step A (3 mmol, 547 mg) and 10 % Pd-C (ca. 50 mg) were stirred in 10 mL of MeOH under H2 (balloon). After 3 h the solution was nearly colorless. The reaction mixture was filtered over celite and filter cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure affording a slightly orange solid. HPLC A: 0.44 min. Step C. Methyl 4-ir(4-tgrt-butylcyclohexyl,( 5-methoxy-l-methyl-lH-benzimidazol-2- yl.aminol methyl Ibenzoate
To a solution of the title compound of Example 1 Step B (2.5 mmol, 759 mg) and DIEA (3 mmol, 0.52 mL) in 10 mL of DCM was added thiophosgene (2.5 mmol, 0.19 mL) (exothermic). After 15 min the title compound of Example 14 Step B (3 mmol, 456 mg) and DIEA (3 mmol, 0.52 mL) were added to the solution. After 30 min Ηg(02CCF3)2 (2.5 mmol, 1.1 g) was added (exothermic), resulting in formation of an orange precipitate. After 30 min the solution was poured into NaHC03 (aq) containing Na2S, and the slurry was filtered through celite, and the filter cake was washed with DCM. The organic phase was collected and the aqueous phase was extracted with 2x DCM. The combined organic phase was dried with Na2S0 and concentrated under reduced pressure affording a tan solid. Purification by flash chromatography on silica eluting with 25 % EtOAc/hexanes afforded the product as a white solid. 1H NMR (500 MHz, CDC13) δ 7.92 (d, 2H), 7.45 (d, 2H), 7.20 (d, IH), 7.08 (d, IH), 6.84 (dd, IH), 4.63 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.18 (m, IH), 2.11 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H), 0.96 - 1.15 (overlapping m, 3H), 0.87 (s, 9H). MS (ESI): m/z 464 (M + H). HPLC A: 2.45 min.
Step D. 4-1 f (4-tgrt-Butylcvclohexyl)( 5-methoxy-l-methyl-lH-benzimidazol-2-yl)aminolmethyl)benzoic acid
To a solution of the title compound of Example 14 Step C (0.2 mmol, 93 mg) in 2 mL of dioxane was added LiOH (2 mmol, 48 mg) in 1 mL of H20. The reaction mixture was stirred at 40°C for 1 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2x with EtOAc. The combined organic layers were dried with Na2S0 and concentrated under reduced pressure to afford the acid as a white solid. HPLC A: 2.17 min.
Step E. 4-( f(4-tgrt-Butylcvclohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2-yl)-aminolmethyl \-N-(lH- tetraazol-5-yl)benzamide
To a solution of the title compound of Example 14 Step D (0.1 mmol, 45 mg), 1H- tetraazol-5 -amine monohydrate (0.2 mmol, 21 mg), ΗOBt (0.2 mmol, 31 mg) and DIEA (0.3 mmol, 52 μL) in 1 mL of DMF was added EDC (0.2 mmol, 38 mg). The reaction was heated to 40°C for 3 h, then concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/ Η20 and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized affording a white solid. 1H NMR (500 MHz, d6-DMSO): δ 12.35 (s, IH), 8.02 (d, 2H), 7.50-7.56 (overlapping m, 3H), 7.00 (d, IH), 6.96 (m, IH), 4.81 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.65 (m, IH), 2.02 (m, 2H), 1.83 (m, 2H), 1.71 (m, 2H), 1.17 (m, 2H), 1.04 (m, IH), 0.85 (s, 9H). MS (ESI): m/z 517 (M + H). HPLC A: 2.03 min.
Figure imgf000057_0001
Step A. Methyl 4-( [(4-tgrt-butylcvclohexyl)( 5-hvdroxy-l-methyl-lH-benzimidazol-2- yl.aminolmethyl Ibenzoate To a stirring solution of the title compound of Example 14 Step C (1 mmol, 464 mg) in 5 mL of DCM at -78°C under N2 was added dropwise BBr3 (5 mmol, 5 mL of a IM solution in DCM). The reaction was allowed to warm to ambient temperature. After 15 min the reaction was poured into stirring NaHC03 (gas evolution), and the product was extracted with DCM. The organic layer was dried with Na2S04 and concentrated under reduced pressure, affording the product as a white solid. 1H NMR (500 MHz, CDC13): δ 7.90 (d, 2H), 7.44 (d, 2H), 7.28 (unres. m, IH), 7.01 (d, IH), 6.83 (dd, IH), 4.64 (s, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 3.20 (m, IH), 2.10 (m, 2H), 1.89 (m, 2H), 1.59 (m, 2H), 0.98 - 1.14 (overlapping m, 3H), 0.86 (s, 9H). MS (ESI): m/z 450 (M + H). HPLC A: 2.30 min.
Step B.4-. r(4-tgrt-Butylcyclohexyl)( 5-hvdroxy-l-methyl-lH-benzimidazol-2-yl)aminolmethyl}benzoic acid
To a solution of the title compound of Example 15 Step A (0.09 mmol, 40 mg) in 1 mL of dioxane was added LiOH (1 mmol, 24 mg) in 0.5 mL of H20. The reaction mixture was stirred at 40°C for 1 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2x with EtOAc. The combined organic layers were dried with Na2S0 and concentrated under reduced pressure to afford the acid as a beige solid. HPLC A: 2.01 min.
Step C. 4-(r(4-tgrt-Butylcvclohexyl)(5-hydroxy-l-methyl-lH-benzimidazol-2-yl)-amino-lmethyπ-N-(lH- tetraazol-5-yl .benzamide To a solution of the title compound of Example 15 Step B (0.02 mmol, 10 mg), 1H- tetraazol-5-amine monohydrate (0.2 mmol, 21 mg), HOBt (0.2 mmol, 31 mg) and DIEA (0.3 mmol, 52 μL) in 0.5 mL of DMF was added EDC (0.2 mmol, 38 mg). The reaction was heated to 40°C 15 min, then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/H20 and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized affording the title compound as a white solid. MS (ESI): m/z 503 (M + H). HPLC A: 1.88 min.
Figure imgf000058_0001
Step A. Methyl 4-1 r(4-tgrt-butylcvclohexyl)( 5-benzyloxy-l-methyl-lH-benzimidazol-2- yl .aminolmethyl Ibenzoate
To a solution of the title compound of Example 15 Step A (0.2 mmol, 90 mg), benzyl alcohol (0.5 mmol, 52 μL) and diisopropyl azodicarboxylate (0.4 mmol, 78 μL) in 1 mL of DCM was added solid Ph3P (0.4 mmol, 104 mg) (exothermic). After 1 h the product was isolated by flash chromatography on silica eluting with 10% EtOAc/hexanes, then 25% EtOAc/hexanes, affording the product as a waxy solid. HPLC A: 2.76 min.
Step B. 4-(r(4-tert-Butylcvclohexyl)( 5 -benzyloxy-1 -methyl- 1 H-benzimidazol-2-yl.- aminol methyl I benzoic acid
To a solution of the title compound of Example 16 Step A (0.2 mmol, 123 mg) in 2 mL of dioxane was added LiOH (2 mmol, 48 mg) in 1 mL of H20. The reaction mixture was stirred at 40°C for 1.5 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2x with EtOAc. The combined organic layers were dried with Na2S04 and concentrated under reduced pressure to afford the acid as a white solid. (HPLC A: 2.49 min).
Step C. 4-(r(4-tgrt-Butylcyclohexyl)(5-benzyloxy-l-methyl-lH-benzimidazol-2-yl)-aminolmethyll-N- ( lH-tetraazol-5-yl)benzamide
To a solution of the title compound of Example 16 Step B (0.07 mmol, 37 mg), 1H- tetraazol-5 -amine monohydrate (0.4 mmol, 41 mg), ΗOBt (0.4 mmol, 62 mg) and DIEA (0.6 mmol, 104 μL) in 1 mL of DMF was added EDC (0.4 mmol, 76 mg). The reaction was heated to 40°C for 1 h, then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ca. 2: 1 dioxane/ Η20 and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized affording the title compound as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 12.35 (s, IH), 8.01 (d, 2H), 7.53 (d, 2H), 7.51 (unres m, IH), 7.43 (dd, 2H), 7.38 (dd, 2H), 7.32 (tt, IH), 7.0-7.6 (overlapping m, 2H), 5.16 (s, 2H), 4.79 (s, 2H), 3.73 (s, 3H), 3.63 (m, IH), 2.01 (m, 2H), 1.82 (m, 2H), 1.69 (m, 2H), 1.16 (m, 2H), 1.03 (m, IH), 0.85 (s, 9H). MS (ESI): m/z 593 (M + H). HPLC A: 2.38 min.
Following the procedures outlined for Examples 1 - 16 the compounds listed in Tables 1 - 9 were prepared
TABLE 1
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
TABLE 2
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000069_0002
TABLE 3
Figure imgf000069_0001
Figure imgf000069_0003
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0002
TABLE 4
Figure imgf000076_0001
Figure imgf000076_0003
Figure imgf000077_0002
Figure imgf000077_0001
Figure imgf000077_0003
Figure imgf000078_0001
TABLE 6
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0002
Figure imgf000080_0001
Figure imgf000080_0003
Figure imgf000081_0002
TABLE 8
Figure imgf000081_0001
Figure imgf000081_0003
Figure imgf000082_0002
TABLE 9
Figure imgf000082_0001
Figure imgf000082_0003
Figure imgf000083_0002
EXAMPLE 221
Figure imgf000083_0001
Step A. (lE)-l-(4-Bromophenyl)-3-cyclopentyltriaz-l-ene
Synthesis of 4-cyclohex-l-en-l-ylphenylamine described below followed the procedure in J.Org. Chem., 1993, 58, 2104.
To a suspension of 4-bromoaniline (58 mmol, 10 g) in 12 mL of cone. HCl at 0°C was added dropwise an icecold solution of NaN02 (58 mmol, 4 g) in 5 mL of H20. The resulting mixture was stirred at 0°C for 10 min, then poured into a solution of pyrrolidine (64 mmol, 5.33 mL) in 50 mL of 1 N KOH in an icebath, and the reaction mixture was stirred for 30 min. The resulting brown precipitate was filtered, washed with H20, then recrystallized from 50 mL of EtOH, affording the product as a brown crystalline solid. HPLC A: 2.41 min.
Step B. l-|4-r(l-- )-3-Cvclopentyltriaz-l-enyllphenyllcvclohexanol
To a stirring solution of the title compound in Example 221 Step A (3.9 mmol, 1 g) in 30 mL of ether cooled to -78°C was added dropwise -.gc-butyllithium (7.8 mmol, 6.6 mL of a 1.3 M solution in hexanes). The resulting dark red solution was stirred for 30 min at -78°C. Cyclohexanone (7.9 mmol, 820 μL) was added dropwise, and the reaction mixture was allowed to warm to ambient temperature. The reaction was quenched by the addition of 30 mL of H20, and the reaction mixture was extracted with 2 x 30 mL of ether. The combined extracts were dried over MgS0 and concentrated under reduced pressure, affording a brown oil, which was taken on to Step C without further purification.
Step C. 4-Cvclohex-l-en-l-ylphenylamine The title compound from Example 221 Step B was taken up in a solution of 150 mL of
MeOH and 150 mL of 1 N KOH and cooled in an ice bath. To the stirring solution was added in portions Al-Ni catalyst (10 g) (gas evolution). The reaction mixture was allowed to warm to ambient temperature and stirred for 5 h, after which time a grey precipitate formed. The slurry was filtered over celite and the filtrate was concentrated under reduced pressure to remove most of the MeOH. The remaining solution was extracted with 2 x 100 mL of ether. The organic phase was concentrated under reduced pressure affording a green oil. The oil was dissolved in 100 mL of benzene, and 50 mg of TsOH, followed by 1 mL of cone. HCl were added to the solution. The resulting reaction mixture was heated to reflux for 30 min, then allowed to cool to ambient temperature. The solution was washed with 100 mL of saturated NaHCθ3, and the organic layer was dried over MgS0 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 10% EtOAc/hexanes, then 15% EtOAc/hexanes, affording the product as a light amber oil. MS (ESI): m/z 174 (M + H). HPLC A: 1.30 min.
Step D. N-(4-Cvclohex- 1 -en- 1 -ylpheny 1)- 1 -methyl- lH-benzimidazol-2-amine
To a solution of the title compound from Example 221 Step C (0.59 mmol, 102 mg) and DIEA (0.65 mmol, 113 DL) in 1 mL of DCM was added thiophosgene (0.62 mmol, 43 μL). After 30 min, Ν-methyl-l,2-phenylenediamine (0.9 mmol, 100 μL) was added and the reaction was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was taken up in 1 mL of DMF. Mel (5.9 mmol, 360 μL) was added, and the solution was warmed to 50°C for 30 min. The reaction mixture was concentrated under reduced pressure, and crude product was purified by flash chromatography on silica eluting with 0.5: 1:98.5 Et3N/MeOH/DCM, affording the product as a white solid. MS (ESI): m/z 304 (M + H). HPLC A: 1.90 min.
Step E. Methyl 4-(r(4-cvclohex-l-en-l-ylphenyl)(l-methyl-lit-'-benzi idazol-2-yl)- aminolmethyl 1 benzoate To the title compound from Example 221 Step D (0.53 mmol, 161 mg) and NaH (0.80 mmol, 32 mg of a 60% dispersion in mineral oil) was added 1 mL of DMF (gas evolution). The mixture was stirred for 30 min at ambient temperature, then methyl 4-(bromomethyl)benzoate (0.80 mmol, 182 mg) was added. After 30 min the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with a step gradient of 10% EtOAc/hexanes, 15% EtOAc/hexanes, and 20% EtOAc/hexanes, affording the product as a white solid. 1H NMR (500 MHz, CDC13) D 8.02 (d, 2H), 7.77 (m, IH), 7.58 (d, 2H), 7.36 (d, 2H), 7.20 - 7.36 (overlapping m, 4H), 6.93 (d, 2H)6.16 (m, IH), 5.44 (s, 2H), 3.93 (s, 3H), 3.31 (s, 3H), 2.40 (m, 2H), 2.25 (m, 2H), 1.82 (m, 2H), 1.69 (m, 2H). MS (ESI): m z 452 (M + H). HPLC A: 2.42 min.
Step F. 4-{ f(4-Cvclohex-l-en-l-ylphenyl (l-methyl-l//-benzimidazol-2-yl)amino1-methyl|benzoic acid To the title compound of Example 221 Step E (0.26 mmol, 117 mg) in 2 mL of dioxane was added a solution of LiOH (2.6 mmol, 62 mg) in 1 mL of H20. The reaction was stirred at 50°C for 30 min. The dioxane was removed under reduced pressure and the remaining aqueous solution was acidified with 2 N HCl. The resulting precipitate was filtered, washed with H20 and dried under reduced pressure, affording the product as a white solid. HPLC A: 2.11 min.
Step G. 4-( r(4-Cvclohex-l-en-l-ylphenyl)(l-methyl-lH-benzimidazol-2-yl)aminol-methyll-N-(lH- tetraazol-5 -vDbenzamide
To a solution of the title compound of Example 221 Step F (0.11 mmol, 50 mg), \H- tetraazol-5-amine monohydrate (0.23 mmol, 24 mg), ΗOBt (0.29 mmol, 43 mg) and EDC (0.46 mmol, 88 mg) in 1 mL of DMF was added DIEA (0.57 mmol, 100 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then poured into a mixture of dilute pΗ 7 buffer/EtOAc, which was acidified with 2 Ν ΗC1 until two clear layers formed after agitation. The organic phase was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography (Condition B) and lyophilized, affording a white solid. 1H ΝMR (500 MHz, DMSO) δ 8.06 (d, 2H), 7.68 (d, 2H), 7.55 (m, 2H), 7.42 (d, 2H), 7.34 (m, 2H), 7.20 (d, 2H), 6.18 (m, IH), 5.38 (s, 2H), 3.31 (s, 3H), 2.35 (m, 2H), 2.18 (m, 2H), 1.73 (m, 2H), 1.60 (m, 2H). MS (ESI): m/z 505 (M + H). HPLC A: 1.99 min.
EXAMPLE 222
Figure imgf000085_0001
N-(4-(r(4-Cvclohex-l-en-l-ylphenyl)(l-methyl-lH-benzimidazol-2-yl)aminolmethyl)-benzoyl)-D- alanine
To a solution of the title compound of Example 1 Step F (0.01 mmol, 5 mg), the hydrochloride salt of β-alanine tert-butyl ester (0.02 mmol, 4 mg), HOBt (0.03 mmol, 4 mg) and EDC (0.05 mmol, 9 mg) in 0.1 mL of DMF was added DIEA (0.06 mmol, 10 μL). The reaction mixture was allowed to stand at ambient temperature for 4 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was concentrated under reduced pressure. The residue was treated with 0.5 mL of 2:30:68 H20/TFA/DCM for 30 min and the solution was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Condition B) and then lyophilized, affording a white solid. 1H NMR (500 MHz, CD3OD) δ 7.82 (d, 2H), 7.58-7.43 (m, 8H), 7.32 (d, 2H), 6.21 (m, IH), 5.38 (s, 2H), 3.61 (2H, t), 3.37 (s, 3H), 2.63 (2H, t), 2.40 (m, 2H), 2.23 (m, 2H), 1.81 (m, 2H), 1.70 (m, 2H). MS (ESI): m/z 509 (M + H). HPLC A: 1.92 min.
EXAMPLE 223
Figure imgf000086_0001
Step A. N-(3,5-Dichlorophenyl)-l-methyl-lH-benziιτ-idazol-2-amine
To a solution of 3,5-dichloroaniline (6.2 mmol, 1.0 g) and DIEA (6.8 mmol, 1.2 mL) in 10 mL of DCM was slowly added thiophosgene (6.2 mmol, 472 μL) (exothermic). After 30 min, Ν- methyl- 1,2-phenylenediamine (6.2 mmol, 704 μL) was added and the reaction mixture was allowed to stand at ambient temperature for 1 h. Mel (6.2 mmol, 386 μL), followed by DIEA (6.8 mmol, 1.2 mL) were then added, and the reaction mixture was allowed to stand at ambient temperature overnight. The crude reaction was partitioned between DCM/brine. The organic layer was collected and the aqueous phase was extracted twice with DCM. The combined organic layer was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 2% MeOH/DCM and 4% MeOH/DCM, affording the product as a tan solid, H ΝMR (500 MHz, d6-DMSO) δ 9.35 (s, IH), 8.04 (s, 2H), 7.48 (m, 2H), 7.36 (m, 2H), 7.08 - 7.14 (overlapping m, 2H), 3.73 (s, 3H). MS (ESI): m/z 292 (M + H). HPLC A: 1.38 min.
Step B. Methyl 4-( r(3.5-dichlorophenyl)(l-methyl-lH-benzimidazol-2-yl)aminol-methyl Ibenzoate To the title compound from Example 223 Step A (0.21 mmol, 60 mg) and ΝaH (0.24 mmol, 6 mg of a 60% slurry in mineral oil) was added 0.5 mL of DMF (gas evolution). After 15 min, methyl-4-(bromomethyl)benzoate (0.24 mmol, 55 mg) was added and the reaction mixture was allowed to stand at ambient temperature overnight. The mixture was partitioned between DCM and ΝaHC03. The organic phase was collected and the aqueous phase was extracted 2 x with DCM. After 30 min the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 2% MeOH/DCM. The product was further purified by reverse phase HPLC (Condition B). The combined HPLC fractions were neutralized with saturated NaHC03 and extracted with DCM. The organic phase was dried over MgS04 and concentrated under reduced pressure to afford the product as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.94 (d, 2H), 7.68 (d, 2H), 7.61 (d, IH), 7.52 (d, IH), 7.21 - 7.29 (overlapping m, 2H), 7.10 (t, IH), 6.79 (d, 2H), 5.27 (s, 2H), 3.83 (s, 3H), 3.50 (s, 3H). MS (ESI): m/z 440 (M + H). HPLC A: 2.16 min.
Step C. 4-f r(3,5-Dichlorophenyl)(l -methyl- lH-benzimidazol-2-yl)aminolmethyl I -benzoic acid To the title compound of Example 223 Step B (0.2 mmol, 85 mg) in 1.6 mL of dioxane was added a solution of LiOH (0.8 mmol, 19 mg) in 0.8 mL of H20. The reaction was allowed to stir at ambient temperature overnight. The crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over MgS0 , then concentrated under reduced pressure to afford the product as a white foam. MS (ESI): m/z 426 (M + H). HPLC A: 1.79 min.
Step P. 4-{ [(3,5-Dichlorophenyl)(l-methyl-lH-benzimidazol-2-yl)aminolmethyl)-N-(l,I-f-tetraazol-5- vDbenzamide To a solution of the title compound of Example 223 Step C (0.16 mmol, 68 mg), 1H- tetraazol-5-amine monohydrate (0.48 mmol, 49 mg), ΗOBt (0.32 mmol, 49 mg) and EDC (0.32 mmol, 61 mg) in 1 mL of DMF was added DIEA (0.48 mmol, 83 μL). The reaction mixture was warmed to 40°C for 2 h, then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Condition B). The product was lyophilized, affording a white solid. *Η ΝMR (500 MHz, d6-DMSO) δ 12.38 (s, IH), 8.07 (d, 2H), 7.73 (d, 2H), 7.63 (m, IH), 7.56 (m, IH), 7.24 - 7.33 (overlapping m, 2H), 7.15 (t, IH), 6.90 (d, 2H), 5.31 (s, 2H), 3.53 (s, 3H). MS (ESI): m/z 493 (M + H). HPLC A: 1.69 min.
EXAMPLE 224
Figure imgf000087_0001
Step A. Methyl 3-bromo-4-methylbenzoate
To a solution of 2.0 g (9.3 mmol) of 3-bromo-4-methylbenzoic acid in 25 mL of dichloromethane was added 5.6 mL (11.2 mmol) of oxalyl chloride and 100 μL of Ν,Ν- dimethylformamide. The resultant mixture was stirred at ambient temperature for 2 hours, concentrated in vacuo, and the residue suspended in methanol. The solution was concentrated in vacuo and the residue purified by flash column chromatography (biotage) using 5% ethyl acetate/ hexanes as eluent to provide the title compound. 1H NMR (500 MHz, CDC13) δ 8.23 (s, IH), 7.90 (d, IH, J=8 Hz), 7.33 (d, IH, J=8 Hz), 3.94 (s, 3H), 2.48 (s, 3H). HPLC/MS (ESI) m/z (M + H) = 231.0 (3.63 min).
Step B. Methyl 3-bromo-4-bromomethy Ibenzoate To a solution of 1.09g (4.76 mmol) of the product from Example 224 Step A in 7 mL of carbon tetrachloride was added 847 mg (4.76 mmol) of N-bromosuccinimide and 78 mg (0.48 mmol) of 2,2'-azobisisobutyronitrile. The resultant mixture was heated at reflux for 2 5 hours, cooled to ambient temperature, diluted with carbon tetrachloride and filtered through celite. The filtrate was concentrated in vacuo and carried on without purification assuming 100% conversion. HPLC/MS (ESI) m/z (M+ H) = 310.9 (3.68 min).
Step C. Methyl 3-bromo-4-{ r(4-tgrt-butylcvclohexyl)aminolmethyl Ibenzoate
To a solution of the product from Example 224 Step B (assume 4.76 mmol) in 5 mL of N,N-dimethylformamide was added 1.02 mL (5.71 mmol) of 4-tgrt-butylcyclohexylamine and 1.7 mL (9.76 mmol) of N,N-diisopropylethylamine. The resultant mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate and the organic layer washed sequentially with three portions of water and one portion of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (biotage) using 5% ethyl acetate/hexanes as eluent to provide both the cis isomer and the desired trans isomer. 1H NMR (500 MHz, CD3OD) δ 8.18 (s, IH), 7.97 (d, IH, J=8 Hz), 7.58 (d, IH, J=8 Hz), 3.93 (s, 2H), 3.91 (s, 3H), 2.43-2.37 (m, IH), 2.08-2.01 (m, 2H), 1.85-1.79 (s, 2H), 1.19-0.99 (m, 5H), 0.86 (s, 9H). HPLC/MS (ESI) m/z (M+H) = 384.2 (2.47 min.).
Step P. Methyl 3-bromo-4-{r(4-tgrt-butylcvclohexyl)(5-methoxy-l-methyl-lH-benz-imidazol-2- vDaminol methyl Ibenzoate
To a solution of the title compound from Example 224 Step C (0.5 mmol, 191 mg) and DIEA (0.6 mmol, 104 μL) in 2 mL of DCM was added thiophosgene (0.5 mmol, 38 μL) (exothermic). After 15 min, the title compound from Example 14 Step B (0.6 mmol, 91 mg) was added to the reaction, followed by DIEA (0.6 mmol, 104 μL). The reaction mixture was allowed to stand at ambient temperature for 1 h, then Hg(02CCF3)2 (0.6 mmol, 256 mg) was added (exothermic), affording a pinkish precipitate. After 30 min the solution was poured into saturated NaHC03 containing Na2S, and the slurry was filtered through celite. The filter cake was washed with DCM. The organic layer of the filtrate and washings was collected and the aqueous phase was extracted with 2x DCM. The combined organic phase was dried with Na2S04 and concentrated under reduced pressure affording a brown residue. Purification by flash chromatography on silica eluting with 20% EtOAc/hexanes afforded the product as a slightly green foam. MS (ESI): m/z 542 (M + H), 544. HPLC A: 2.67 min. Step E. 3-Bromo-4-{ r(4-tgrt-butylcyclohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2- yl.aπύnolmethyllbenzoic acid
To the title compound of Example 224 Step D (0.07 mmol, 40 mg) in 2 mL of dioxane was added a solution of LiOΗ (1 mmol, 24 mg) in 1 mL of Η20. The reaction was allowed to stir at 40°C for 1.5 h. The crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over Na2S04, then concentrated under reduced pressure to afford the product as a slightly yellow-green foam. HPLC A: 2.32 min.
Step F. 3-Bromo-4-{ f(4-tgrt-butylcvcIohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2- yl .aminolmethyl 1 -N-( lH-tetraazol-5-yl)benzamide
To a solution of the title compound of Example 223 Step E (0.07 mmol, 40 mg), 1H- tetraazol-5 -amine monohydrate (0.2 mmol, 21 mg), ΗOBt (0.2 mmol, 31 mg) and EDC (0.2 mmol, 38 mg) in 1 mL of DMF was added DIEA (0.3 mmol, 52 μL). The reaction mixture was warmed to 40°C for 2 h, then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Condition C). The product was lyophilized, affording a white solid. 1H ΝMR (500 MHz, d6-DMSO) δ 12.50 (s, IH), 8.36 (d, IH), 7.98 (dd, 2H), 7.60 (d, 2H), 7.51 (dd, IH), 7.01 (d, IH), 6.95 (d, IH), 4.78 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 1.98 (m, 2H), 1.80 (m, 2H), 1.61 (m, 2H), 1.15 (m, 2H), 1.03 (m, IH), 0.84 (s, 9H). MS (ESI): m/z 595 (M + H), 597. HPLC A: 2.17 min.
EXAMPLE 225
Figure imgf000089_0001
Step A. Methyl 3-bromo-4-{ r(4-tgrt-butylcvclohexyl)(5-hvdroxy-l-methyl-lH-benz-imidazol-2- vDaminolmethyl 1 benzoate
To a stirring solution of the title compound of Example 224 Step D (0.1 mmol, 54 mg) in 1 mL of DCM cooled to -78°C under Ν2 was added dropwise BBr3 (0.3 mmol, 0.3 mL of a IM solution in DCM). The reaction was allowed to warm to ambient temperature. After 1 h the reaction was taken up in 10 mL of MeOH and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 50% EtOAc/hexanes, affording the product as a white solid. HPLC A: 2.54 min.
Step B. Methyl 3-bromo-4-{ r(4-tgrt-butylcvclohexyl)(5-cvclopentyloxy-l-methyl-lH-benz-imidazol-2- yDaminol methyl Ibenzoate
To a solution of the title compound of Example 225 Step A (0.08 mmol, 43 mg), cyclopentyl alcohol (0.25 mmol, 23 μL) and diisopropyl azodicarboxylate (0.25 mmol, 49 μL) in 0.7 mL of DCM was added Ph3P (0.25 mmol, 66 mg) (exothermic). After 2 h the product was isolated by flash chromatography on silica eluting with 10% EtOAc/hexanes, then 20% EtOAc/hexanes, affording a waxy yellow solid. HPLC A: 2.97 min.
Step C. 3-Bromo-4-{ r(4-tgrt-butylcyclohexyl)(5-cyclopentyloxy-l -methyl- lH-benz-imidazol -2- y Daminol methyl Ibenzoic acid
To the title compound of Example 225 Step B (0.07 mmol, 57 mg) in 2 mL of dioxane was added a solution of LiOH (1 mmol, 24 mg) in 1 mL of H20. The reaction was allowed to stir at 40°C for 10 min, then stirred at ambient temperature overnight. The crude reaction mixture was poured into pH
7 buffer/EtOAc, then was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over Na2S04, then concentrated under reduced pressure to afford an oily residue.
The residue was triturated in hexanes to afford a beige solid. MS (ESI): m/z 582 (M + H), 584. HPLC A:
2.66 min.
Step D. 3-Bromo-4-l r(4-tgrt-butylcvclohexyl)(5-cvclopentyloxy-l-methyl-lH-benzimidazol-2- y 1. aminol methyl ) -N-( 1 H-tetraazol-5 -vDbenzamide
To a solution of the title compound of Example 225 Step C (0.06 mmol, 36 mg), 1H- tetraazol-5-amine monohydrate (0.2 mmol, 21 mg), HOBt (0.2 mmol, 31 mg) and EDC (0.2 mmol, 38 mg) in 1 mL of DMF was added DIEA (0.3 mmol, 52 μL). The reaction mixture was warmed to 40°C for 1 h, then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Condition D). Lyophilization afforded the product as a white solid. 1H ΝMR (500 MHz, d6-DMSO) δ 12.49 (s, IH), 8.35 (d, 2H), 7.97 (dd, 2H), 7.59 (d, IH), 7.49 (d, IH), 6.96 (d, IH), 6.91 (dd, IH), 4.83 (m, IH), 4.77 (s, 2H), 3.74 (s, 3H), 3.64 (m, IH), 1.96 (m, 2H), 1.88 (m, 2H), 1.64 - 1.74 (overlapping m , 4H), 1.52 - 1.64 (overlapping m, 4H), 1.13 (m, 2H), 1.01 (m, IH), 0.82 (s, 9H). MS (ESI): m/z 649 (M + H), 651. HPLC A: 2.51 min. Following the procedures outlined for Examples 1 - 16 and 221 - 225, the compounds listed in Tables 10 - 12 were prepared
TABLE 10
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000092_0002
TABLE 11
Figure imgf000092_0001
Figure imgf000092_0003
Figure imgf000093_0001
Figure imgf000094_0001
TABLE 12
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000096_0002
EXAMPLE 275 / 276
Figure imgf000096_0001
Step A. Ethyl 4-1 l-f(trαfi-.-4-tgrt-butylcvclohexyl)aminolethyl Ibenzoate
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.6 mmol), titanium (IV) isopropoxide (9.30 mL, 31.2 mmol), 4-tgrt-butylcyclohexyl amine (4.85 g, 31.2 mmol) in absolute ethanol (100 mL) was stirred under nitrogen at room temperature for 10 h. Sodium borohydride (0.88 g, 23.4 mmol) was then added and the resulting mixture was stirred for an additional 8 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 225 mL). The resulting inorganic precipitate was filtered off and washed with dichloromethane (100 mL). The organic layer was separated and the remaining aqueous layer was extracted once with dichloromethane (100 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated. Chromatography (20% EtOAc in Hexane) afforded ethyl 4-{ l-[(trαn-.-4-tgrt-butylcyclohexyl)amino]ethyl}benzoate. HPLC/MS: m/z = 332.3 (M+1), R, = 2.74 min. Η NMR (500 MHz, CDC13): δ 8.01 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.0 Hz), 4.37 (2H, q, J = 7.1 Hz), 4.02 (IH, q, J = 6.6 Hz), 2.18-2.06 (2H, m), 1.77-1.67 (4H, m), 1.39 (3H, t, J = 7.1 Hz), 1.32 ( 3H, d, J = 6.6 Hz), 1.22 (IH, br s), 1.09-0.85 (4 H, m), 0.79 (9H, s).
Step B. Ethyl 4-1 H(trαn,y-4-tgrt-butylcvclohexyl)(l-methyl-lH-benzimidazol-2- vDaminolethyl Ibenzoate To a 0°C solution of ethyl 4-{ l-[(tran-;-4-tgrt-butylcyclohexyl)amino]ethyl}benzoate (0.55 g, 1.66 mmol) and DIEA (0.35 mL, 1.99 mmol) in dry dichloromethane (15 mL) was slowly added thiophosgene (0.13 mL, 1.66 mmol). After stirring at 0°C for 10 min and then at room temperature for 45 min, a solution of N-methylbenzene-l,2-diamine (0.22 g, 1.83 mmol) and DIEA (0.35 mL, 1.99 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with dichloromethane (20 mL) and poured into aqueous HCl (IN, 20 mL). The organic layer was separated and washed with aqueous HCl (IN, 20 mL), saturated aqueous NaHC03 (20 mL), brine (20 mL), dried over Na2S04 and then concentrated to dryness. The residue was dissolved in dichloromethane (20 mL) and mercury (II) trifluoroacetate (0.80 g, 1.86 mmol) was added. The reaction mixture was stirred for 30 min at room temperature and then filtered through Celite. The organic solution was washed with saturated NaHC03 (20 mL), dried over Na2S0 and concentrated. Chromatography (15% EtOAc in Hexane) afforded ethyl 4-{ l-[(tranj-4-tert-butylcyclohexyl)(l-methyl- lH-benzimidazol-2-yl)amino]ethyl}benzoate. HPLC/MS: m/z = 462.4 (M+1), Rt = 3.46 min. Η NMR (500 MHz, CDC13): D 8.03 (2H, d, J = 8.2 Hz), 7.78 (IH, m), 7.52 (2H, d, J = 8.2 Hz), 7.28 (3H, m), 4.80 (IH, q, = 6.5 Hz), 4.39 (2H, q, J = 7.5 Hz), 3.72 (3H, s), 2.86 (IH, m), 2.14 (IH, m), 1.94 (IH, m), 1.72-1.64 (2H, m), 1.48 (IH, m), 1.41 (3H, t, J = 7.5 Hz), 1.17 (3H, d, / = 6.5 Hz), 0.95-0.75 (4H, m), 0.73 (9H, s).
Step C. 4-1 l-r(trαw-.-4-tgrt-ButylcvcIohexyl)(l-methyl-lH-benzimidazol-2-yl)amino1ethyll-N-lH- tetrazol-5-ylbenzamide. isomer A and B.
Ethyl 4-{ l-[(trαπ5-4-tgrt-butylcyclohexyl)(l-methyl-lH-benzimidazol-2- yl)amino]ethyl Jbenzoate (0.22 g, 0.48 mmol) was dissolved in EtOΗ/n-Ηeptane (1:1, 9 mL) and eluted with 5% isopropanol in n-Ηeptane on ChiralPak AD column. The fast moving component was collected as isomer A and the slow moving component as isomer B. Ethyl 4-{ l-[(trαn-.-4-tert-butylcyclohexyl)(l-methyl-lH-benzimidazol-2- yl)amino]ethyl}benzoate, isomer A (0.10 g, 0.22 mmol) was dissolved in TΗF/MeOΗ (1: 1, 6 mL) and aq. LiOΗ (1.0 M, 3 mL) was added. After stirred at room temperature for 16 h, the reaction was neutralized with aqueous ΗC1 (IN, 3.5 mL) until white precipitate started to appear. The resulting mixture was poured into brine (10 mL) and extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over Νa2S04 and then concentrated. The residue was dissolved in dry DMF (6 mL) and divided into 3 portions for amide coupling reaction under standard conditions (EDC/ΗOBt/DIEA in DMF) with 5-amino tetrazole, β-alanine methyl ester and β-hydroxyl β-alanine methyl ester, respectively. For the tetrazole coupling, reaction mixture was loaded directly on ΗPLC (Xterra C]8 column from Waters) and eluted with CΗ3CN in H20 containing 0.1% TFA (20% to 95% over 12 min). Product was freeze-dried from dioxane as a white powder. For coupling reactions with β-alanine methyl ester and β- hydroxyl β-alanine methyl ester, products were purified on silica gel (35% to 45% EtOAc in Hexane). Methyl ester was subsequently removed with 1.0 M aq. LiOH in THF/MeOH. The resulting carboxylic acids were obtained without further purification.
Isomer A. HPLC/MS: m/z = 501.4 (M+1), R, = 3.01 min. Η NMR (DMSO-d6): δ 12.40 (IH, s), 8.07 (2H, d, J = 8.3 Hz), 7.70-7.67 (2H, m), 7.66 (2H, d, J = 8.5 Hz), 7.47-7.42 (2H, m), 4.90 (IH, q, J = 6.5 Hz), 3.14 (IH, t, J = 11.5 Hz), 2.53 (3H, s), 2.02 (2H, m), 1.68 (2H, m), 1.35 (3H, d, J = 6.4Hz), 1.32-1.24 (IH, m), 1.13-1.06 (IH, m), 0.96-0.78 (3H, m), 0.73 (9H, s).
Isomer B. HPLC/MS: m/z = 501.4 (M+1), Rt = 3.02 min. Η NMR (DMSO-d6): δ 12.40 (IH, s), 8.07 (2H, d, J = 8.3 Hz), 7.70-7.67 (2H, m), 7.66 (2H, ά, J = 8.5 Hz), 7.47-7.42 (2H, m), 4.90 (IH, q, J = 6.5 Hz), 3.14 (IH, t, J = 11.5 Hz), 2.53 (3H, s), 2.02 (2H, m), 1.68 (2H, m), 1.35 (3H, d, J = 6.4Hz), 1.32-1.24 (IH, m), 1.13-1.06 (IH, m), 0.96-0.78 (3H, m), 0.73 (9H, s).
EXAMPLE 277/278
Figure imgf000098_0001
Step A. (5-Bromo-2,3-dihydro- lH-inden- 1 -ylXtrans -4-tgrt-butylcvclohexyl)amine A mixture of 5-bromoindan-l-one (6.33 g, 30.0 mmol), titanium (IV) isopropoxide (17.8 mL, 60.0 mmol), 4-tgrt-butylcyclohexyl amine (9.32 g, 60.0 mmol) in absolute ethanol (200 mL) was stirred under nitrogen at room temperature for 12 h. Sodium borohydride (1.70 g, 45.0 mmol) was then added and the resulting mixture was stirred for an additional 8 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 300 mL). The resulting inorganic precipitate was filtered off and washed with dichloromethane (150 mL). The organic layer was separated and the remaining aqueous layer was extracted once with dichloromethane (150 mL). The combined organic extracts were dried over Na2S0 , filtered and concentrated. Chromatography (10% to 20% EtOAc in Hexane) afforded (5-Bromo-2,3-dihydro-lH-inden-l-yl)(trαn-.-4-tgrt-butylcyclohexyl)amine and the corresponding cis product (less polar). HPLC/MS: m/z = 350.1 (M+1), R, = 3.01 min.
Step B. Methyl l-r(trαn-.-4-tgrt-butylcvclohexyl)aminolindane-5-carboxylate
(5-Bromo-2,3-dihydro-lH-inden-l-yl)(trαn-.-4-tgrt-butylcyclohexyl)amine (1.20 g, 3.42 mmol) was dried azeotropically from dry THF in toluene (3x) and kept under high vacuum for 2 h before use. It was then dissolved in anhydrous THF (20 mL) and cooled to -78 °C. n-Butyl lithium (1.6 M solution in Hexane, 8.40 mL, 13.68 mmol) was added over 15 min. After stirring at -78 °C for 30 min, excess dry ice cubes were then added. The reaction mixture was allowed to warm up slowly and then quenched at -20 °C with saturated aqueous NH4CI (20 mL). Extractions with EtOAc (3x15 mL), drying (Na2S0 ), filtration and removal of solvent gave the crude carboxylic acid. The crude carboxylic acid was dissolved in MeOH/DCM (1:2, 10 mL) and then (trimethylsilyl)diazomethane (2.0 M solution in Hexane) was added until gas bubbling ceased and the yellow color sustained. Concentration and chromatography (35% EtOAc in Hexane) afforded methyl l-[(tπm-.-4-tgrt- butylcyclohexyl)amino]indane-5-carboxylate. HPLC/MS: m/z = 330.3 (M+1), R, = 2.85 min.
Step C. Methyl l-r(trα» -4-tgrt-butylcvclohexyl)(l-methyl-lH-benzimidazol-2-yl)aminolindane-5- carboxylate
To a 0°C solution of methyl l-[(tr n-.-4-tgrt-butylcyclohexyl)amino]indane-5-carboxylate (0.43 g, 1.30 mmol) and DIEA (0.27 mL, 1.56 mmol) in dry dichloromethane (20 mL) was added thiophosgene (0.11 mL, 1.36 mmol) slowly. After stirring at 0°C for 10 min and then at room temperature for 45 min, a solution of /V-methylbenzene-l,2-diamine (0.38 g, 3.12 mmol) and DIEA (0.53 mL, 3.12 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred for 1 h at room temperature, then diluted with dichloromethane (30 mL) and poured into aqueous HCl (IN, 30 mL). The organic layer was separated and washed with aqueous HCl (IN, 30 mL), saturated aqueous NaHC03 (30 mL), brine (30 mL), dried over Na2S04 and then concentrated to dryness. The residue was dissolved in dichloromethane (30 mL) and mercury (II) trifluoroacetate (0.61 g, 1.43 mmol) was added. The reaction mixture was stirred for 30 min at room temperature and then filtered through Celite. The organic solution was washed once with saturated NaHC03 (30 mL), dried over Na2S04 and concentrated. Chromatography (15% EtOAc in Hexane) afforded methyl l-[(trαn-.-4-tgrt-butylcyclohexyl)(l-methyl- l//-benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC/MS: m/z = 460.3 (M+1), Rt = 3.46 min. Η NMR (CDCI3): δ 7.85 (IH, s), 7.78 (IH, d, J = 8.0 Hz), 7.71 (IH, m), 7.27 (IH, d, J = 8.5 Hz), 7.25-7.18 (3H, m), 5.04 (IH, dd, J = 7.5, 5.0 Hz), 3.90 (3H, s), 3.48 (3H, s), 3.24 (IH, m), 3.10 (IH, m), 2.83 (IH, m), 2.66 (IH, m), 2.39 (IH, m), 2.21 (IH, m), 1.94 (IH, m), 1.85-1.75 (2H, m), 1.50 (IH, m), 1.36 (IH, m), 1.10-0.94 (2H, m), 0.84 (9H, s).
Step P. l-[(trαn-.-4-tgrt-Butylcvclohexyl)(l-methyl-lH-benzimidazol-2-yl)aminol-N-lH-tetrazol-5- ylindane-5-carboxamide.
Methyl 1 -[(trαn-.-4-tgrt-butylcyclohexyl)( 1 -methyl- lH-benzimidazol-2-yl)amino] indane-
5-carboxylate (0.43 g, 0.48 mmol) was dissolved in EtOH/n-Heptane (1:1, 9 mL) and eluted with 5% isopropanol in n-Heptane on ChiralPak AP column. The fast moving component was collected as isomer
A and the slow moving component as isomer B. Methyl l-[(trαn_.-4-tgrt-butylcyclohexyl)(l-methyl-lH-benzimidazol-2-yl)amino]indane-
5-carboxylate, isomer A (0.10 g, 0.22 mmol) was dissolved in THF/MeOH (1: 1, 6 mL) and aq. LiOH (1.0 M, 3 mL) was added. After stirred at room temperature for 16 h, the reaction was neutralized with aqueous HCl (IN, 3.5 mL) until white precipitate started to appear. The resulting mixture was poured into brine (10 mL) and extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over Na2S04 and then concentrated. The residue was dissolved in dry PMF (6 mL) and divided into 3 portions for amide coupling reaction under standard conditions (EDC/HOBt/D-EA in DMF) with 5- amino tetrazole, β-alanine methyl ester and β-hydroxyl β-alanine methyl ester, respectively. For the tetrazole coupling, reaction mixture was loaded directly on HPLC (Xterra 8 column from Waters) and eluted with CH3CN in H 0 containing 0.1% TFA (5% to 70% over 12 min). Product was freeze-dried from dioxane as a white powder. For coupling reactions with β-alanine methyl ester and β-hydroxyl β- alanine methyl ester, products were purified on silica gel (50% to 60% EtOAc in Hexane). Methyl ester was subsequently removed with 1.0 M aq. LiOH in THF/MeOH. The resulting carboxylic acids were obtained without further purification.
Isomer A: HPLC/MS: m/z = 513.3 (M+1), R, = 3.09 min. Η NMR (DMSO-d6): δ 10.97 (IH, br s), 7.92 (IH, s), 7.78 (H, d, J = 7.7 Hz), 7.60 (IH, d, J = 8.0 Hz), 7.48 (IH, d, J = 8.0 Hz), 7.42 (IH, d, / = 8.0 Hz), 7.40-7.33 (2H, m), 5.35 (IH, t, J = 7.8 Hz), 3.72 (3H, s), 3.74-3.52 (2H, m), 3.24- 3.18 (IH, m), 3.01-2.94 (IH, m), 2.64-2.58 (2H, m), 2.09 (2H, m), 1.87 (2H, m), 1.68 (2H, m), 1.65 (2H, m), 1.05 (IH, m), 0.87 (9H, s).
Isomer B: HPLC/MS: m/z = 513.3 (M+1), R, = 3.10 min. Η NMR (DMSO-d6): δ 10.97 (IH, br s), 7.92 (IH, s), 7.78 (H, d, J = 7.7 Hz), 7.60 (IH, d, J = 8.0 Hz), 7.48 (IH, d, J = 8.0 Hz), 7.42 (IH, d, J = 8.0 Hz), 7.40-7.33 (2H, m), 5.35 (IH, t, J = 7.8 Hz), 3.72 (3H, s), 3.74-3.52 (2H, m), 3.24- 3.18 (IH, m), 3.01-2.94 (IH, m), 2.64-2.58 (2H, m), 2.09 (2H, m), 1.87 (2H, m), 1.68 (2H, m), 1.65 (2H, m), 1.05 (lH, m), 0.87 (9H, s).
Following the procedures outlined above the compounds listed in Tables 13 - 14 were prepared.
TABLE 13
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000101_0002
TABLE 14
Figure imgf000101_0001
Figure imgf000101_0003
HPLC/MS: m/z = 533.3 (M+1),
286 B ,CO2H
HN' Rt = 2.93 min.
OH
EXAMPLE 287
Figure imgf000102_0001
Step A. Butyl l-r(4-cvclohexylphenyl)aminolindane-5-carboxylate
To a solution of butyl l-oxoindane-5-carboxylate (2.0 g, 8.60 mmol) and 4-cyclohexylaniline (2.28 g, 20.64 mmol) in 30 mL of anhydrous MeOH was added decaborane B]0Hι4 (0.32 g, 2.6 mmol) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 16-48 h. Product butyl l-[(4-cyclohexylphenyl)amino]indane-5-carboxylate was collected by filtration as a white solid. HPLC/MS: m/z = 392.3 (M+1), R, = 4.97 min. Η NMR (CDC13): δ 7.80 (IH, s), 7.97 (IH, d, 7 = 8.0 Hz), 7.48 (IH, d, 7 = 8.0 Hz), 7.14 (2H, d, 7 = 8.5 Hz), 6.74 (2H, d, J = 8.5 Hz), 5.07 (IH, t, 7 = 7.1 Hz), 4.39 (2H, t, 7 = 6.7 Hz), 3.92 (IH, br s), 3.10 (IH, m), 2.97 (IH, m), 2.69 (IH, m), 2.49 (IH, m),2.02- 1.80 (8H, m), 1.60-1.31 (7H, m), 1.08 (3H, t, 7 = 7.3 Hz).
Step B. Butyl l-[(4-cvclohexylphenyl)(l-methyl-lH-benzimidazol-2-yl)aminolindane-5-carboxyIate To a 0°C solution of butyl l-[(4-cyclohexylphenyl)amino]indane-5-carboxylate (0.50 g,
1.27 mmol) and DIEA (0.33 mL, 1.90 mmol) in dry dichloromethane (15 mL) was added thiophosgene (0.10 mL, 1.34 mmol) slowly. After stirring at 0°C for 10 min and then at room temperature for 1 h, a solution of N-methylbenzene-l,2-diamine (0.23 g, 1.90 mmol) and DIEA (0.33 mL, 1.90 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred for 1 h at room temperature and then diluted with dichloromethane (30 mL) and poured into aqueous HCl (IN, 30 mL). The organic layer was separated and washed with aqueous HCl (IN, 30 mL), saturated aqueous NaHC03 (30 mL), brine (30 mL), dried over Na2S0 and then concentrated to dryness. The residue was dissolved in dichloromethane (30 mL) and excess of mercury (II) trifluoroacetate was added. The reaction mixture was stirred for 30 min at ambient temperature and then filtered through Celite. The organic solution was washed with saturated NaHC03 (30 mL), dried over Na2S0 and concentrated. Chromatography (8% to 15% EtOAc in Hexane) afforded butyl l-[(4-cyclohexylphenyl)(l-methyl-lH-benzimidazol-2- yl)amino]indane-5-carboxylate. HPLC/MS: m/z = 552.4 (M+1), R, = 2.58 min. Η NMR (CDC13): δ 7.96 (IH, d, 7 = 7.8 Hz), 7.91 (IH, s), 7.70 (IH, d, 7 = 7.5 Hz), 7.55 (IH, d, 7 = 7.5 Hz), 7.27-7.20 (2H, m), 7.18 (IH, d, 7 = 7.5 Hz), 7.01 (2H, d, 7 = 8.5 Hz), 6.67 (2H, d, J = 8.5 Hz), 6.20 (IH, t, 7 = 7.5 Hz), 4.37 (IH, t, 7 = 6.5 Hz), 3.21 (3H, s), 2.91-2.85 (IH, m), 2.77-2.64 (2H, m), 2.46-2.34 (2H, m), 1.86-1.75 (8H, m), 1.54 (2H, m), 1.41-1.24 (6H, m), 1.04 (3H, t, 7 = 7.5 Hz).
Step C. l-f(4-Cvclohexylphenyl")(l-methyl-lH-benzimidazol-2-yl)aminol-N-lH-tetrazol-5-ylindane-5- carboxamide. isomer B.
Butyl l-[(4-cyclohexylphenyl)(l-methyl-lH-benzimidazol-2-yl)amino]indane-5- carboxylate (0.10 g, 0.18 mmol) was dissolved in EtOΗ/n-Ηeptane (1: 1, 4 mL) and eluted with 10% isopropanol in n-Ηeptane on ChiralPak AD column. The fast moving component was collected as isomer A and the slow moving component as isomer B.
Butyl l-[(4-cyclohexylphenyl)(l-methyl-lH-benzimidazol-2-yl)amino]indane-5- carboxylate, isomer B (44.0 mg, 0.07 mmol) was dissolved in TΗF/MeOΗ (1: 1, 6 mL) and aq. LiOΗ (1.0 M, 3 mL) was added. After stirred at room temperature for 16 h, the reaction was neutralized with aqueous ΗC1 (IN, 3.5 mL) until white precipitate started to appear. The resulting mixture was poured into brine (10 mL) and extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over Νa2S04 and then concentrated. The residue was dissolved in dry DMF (2 mL) and coupled with 5- amino tetrazole. Product was purified on ΗPLC (Xterra Cι8 column from Waters) with CΗ3CN in H20 containing 0.1% TFA (5% to 80% over 12 min) and freeze-dried from dioxane to yield l-[(4- cyclohexy lphenyl)( 1 -methyl- lH-benzimidazol-2-yl)amino] -N- 1 H-tetrazol-5-y lindane-5 -carboxamide, isomer B. HPLC/MS: m/z = 533.4 (M+1), Rt = 2.05 min. 1H ΝMR (DMSO-d6): δ 12.38 (IH, s), 7.97 (IH, d, 7 = 8.0 Hz), 7.96 (IH, s), 7.77 (IH, d, J = 7.5 Hz), 7.56 (IH, dd, 7 = 6.0, 3.5 Hz), 7.51 (IH, m), 7.31 (2H, m), 7.17 (2H, d, 7 = 8.5 Hz), 6.92 (2H, d, 7 = 8.0 Hz), 5.98 (IH, t, J = 7.5 Hz), 3.17 (3H, s), 2.91-2.84 (IH, m), 2.72 (IH, m), 2.61 (IH, m), 2.46 (IH, m), 2.33 (IH, m), 1.77-1.18 (11H, m).
EXAMPLE 288
Figure imgf000103_0001
Step A. Butyl l-r(trαn-.-4-tgrt-butylcyclohexyl)(5-methoxy-l-methyl-lH-benzimidazol-2- yl)aminolindane-5-carboxylate
To a 0°C solution of butyl l-[(tran-r-4-tgrt-butylcyclohexyl)amino]indane-5-carboxyIate (0.93 g, 2.5 mmol) and DIEA (0.52 mL, 3.00 mmol) in anhydrous dichloromethane (20 mL) was added thiophosgene (0.20 mL, 2.60 mmol) slowly. After stirring at 0°C for 30 min, a solution of 4-methoxy-N1- methylbenzene-l,2-diamine (0.46 g, 3.00 mmol) and DIEA (0.52 mL, 3.00 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred for 30 min at room temperature and then diluted with dichloromethane (30 mL) and poured into saturated aqueous ΝaHC03 (30 mL). The organic layer was separated, dried over Na2S0 and then concentrated to dryness. Chromatography afforded 0.94 g (66%) of a mixture of two thiourea intermediates. The mixture of two thioureas was dissolved in dichloromethane (50 mL) and mercury (II) trifluoroacetate (0.78 g, 1.82 mmol) was added. The reaction mixture was stirred for 1 h at room temperature and then filtered through Celite. The filtrate was washed once with saturated NaHC03 (30 mL), dried over Na2S0 and concentrated. Chromatography (15% to 20% EtOAc in Hexane) afforded butyl l-[(tr-ιn5-4-tgrt-butylcyclohexyl)(5-methoxy-l-methyl-lH- benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC MS: m/z = 532.4 (M+1), Rt = 3.92 min.
Step B. Butyl l-l(trαn .-4-tgrt-butylcvclohexyl)(5-hydroxy-l-methyl-lH-benzimidazol-2- yl)aminolindane-5-carboxylate
To a solution of butyl l-[(trα«5-4-tgrt-butylcyclohexyl)(5-methoxy-l-methyl-lH- benzimidazol-2-yl)amino]indane-5 -carboxylate (0.40 g, 0.75 mmol) in 20 mL of anhydrous dichloromethane at -78 °C was slowly added BBr3 (1.0 M solution in CH2C12, 3.8 mL, 3.8 mmol) over 10 min. The reaction mixture was stirred at -78 °C for 30 min and then the cold bath was removed. The reaction was quenched after 20 min with saturated aqueous NaHC03 (20 mL) and extracted with EtOAc (3x15 mL). The organic layers were combined, dried over Na2S04 and concentrated. Chromatography afforded butyl l-[(tr «5-4-tgrt-butylcyclohexyl)(5-hydroxy-l-methyl-lH-benzimidazol-2- yl)amino]indane-5-carboxylate. HPLC/MS: m/z = 518.4 (M+1), Rt = 2.45 min.
Step C. Butyl l-r(tra« -4-tgrt-butylcyclohexyl)(l-methyI-5-propoxy-lH-benzimidazol-2- yDaminol indane-5 -carboxylate To a solution of butyl l-[(trαn-.-4-tgrt-butylcyclohexyl)(5-hydroxy-l-methyl-lH- benzimidazol-2-yl)amino]indane-5-carboxylate (49.0 mg, 0.095 mmol) in dry dichloromethane was added 1-propanol (18.0 GL, 0.24 mmol), diisopropyl azodicarboxylate (37.0 μL, 0.19 mmol) and Ph3P
(50.0 mg, 0.19 mmol). After stirring at room temperature for 2 h, solvent was removed.
Chromatography (15% EtOAc in Hexane) afforded butyl l-[(trαns-4-tert-butylcyclohexyl)(l-methyl-5- propoxy-lH-benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC/MS: m/z = 560.5 (M+1), Rt = 2.43 min. Step D. l-r(trαn-.-4-tgrt-Butylcvclohexyl)(l-methyl-5-propoxy-l-t -benzimidazol-2-yl)aminol-N-lH- tetrazol-5-ylindane-5-carboxamide
Butyl l-[(tr n-.-4-tgrt-butylcyclohexyl)(l-methyl-5-propoxy-lH-benzimidazol-2- yl)amino]indane-5-carboxylate (36.0 mg, 0.06 mmol) was dissolved in TΗF/MeOΗ (1:1, 6 mL) and aq. LiOΗ (1.0 M, 3 mL) was added. After stirred at room temperature for 16 h, the reaction was neutralized with aqueous ΗC1 (IN, 3.5 mL) until white precipitate started to appear. The resulting mixture was poured into brine (10 mL) and extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over Νa2S04 and then concentrated. The residue was dissolved in dry DMF (2 mL) and coupled with 5-amino tetrazole (EDC/ΗOBt/DBEA). Product was purified on ΗPLC (Xterra C]8 column from Waters) with CΗ3CN in H20 containing 0.1% TFA (20% to 95% over 12 min) and freeze-dried from dioxane to yield l-[(tran-.-4-tgrt-Butylcyclohexyl)(l-methyl-5-propoxy-lH-benzimidazol-2-yl)amino]-N- lH-tetrazol-5-ylindane-5-carboxamide. HPLC/MS: m/z = 571.5 (M+1), R, = 2.16 min. Η ΝMR (DMSO-d6): δ 12.34 (IH, s), 7.98 (IH, s), 7.86 (IH, d, 7 = 8.5 Hz), 7.52 (IH, m), 7.42 (IH, d, 7 = 8.0 Hz), 7.03 (IH, d, 7 = 2.0 Hz), 6.98 (IH, d, J = 7.5 Hz), 5.30 (IH, m), 3.67-3.45 (2H, m), 3.95 (2H, t, J = 7.0 Hz), 3.71 (3H, s), 3.36 (IH, m), 3.16-3.11 (IH, m), 2.95-2.88 (IH, m), 2.56 (2H, m), 2.00 (2H, m), 1.79-1.70 (4H, m), 1.66-1.51 (2H, m), 1.12-1.05 (2H, m), 0.98 ( 3H, t, 7 = 7.5 Hz), 0.82 (9H, s).
BIOLOGICAL ASSAYS The ability of the compounds of the present invention to inhibit the binding of glucagon and their utility in treating or preventing type 2 diabetes mellitus and the related conditions can be demonstrated by the following in vitro assays.
Glucagon Receptor Binding Assay A stable CHO (Chinese hamster ovary) cell line expressing cloned human glucagon receptor was maintained as described (Chicchi et al._J Biol Chem 272, 7765-9(1997); Cascieri et al. J Biol Chem 274, 8694-7(1999)). To determine antagonistic binding affinity of compounds 0.002 mg of cell membranes from these cells were incubated with 125I-Glucagon (New England Nuclear, MA) in a buffer containing 50mM Tris-HCl (pH 7.5), 5mM MgCl2, 2mM EDTA, 12% Glycerol, and 0.200 mg WGA coated PVT SPA beads (Amersham), +/- compounds or 0.001 mM unlabeled glucagon. After 3 hours incubation at room temperature, the radioactivity bound to the cell membranes was determined in a radioactive emission detection counter (Wallac-Microbeta). Data were analyzed using the software program Prism® from GraphPad. The IC50 were calculated using non-linear regression analysis assuming single site competition.
Inhibition of Glucagon-stimulated Intracellular cAMP Formation Exponentially growing CHO cells expressing human glucagon receptor were harvested with the aid of enzyme-free dissociation media (Specialty Media), pelleted at low speed, and re- suspended in the Cell Stimulation Buffer included in the Flash Plate cAMP kit (New England Nuclear, SMP0004A). The adenylate cyclase assay was setup as per manufacturer instructions. Briefly, compounds were diluted from stocks in DMSO and added to cells at a final DMSO concentration of 5%. Cells prepared as above were preincubated in flash plates coated with anti-cAMP antibodies (NEN) in presence of compounds or DMSO controls for 30 minutes, and then stimulated with glucagon (250 pM) for an additional 30 minutes. The cell stimulation was stopped by addition of equal amount of a detection buffer containing lysis buffer as well as 1 5I-labeled cAMP tracer (NEN). After 3 hours of incubation at room temperature the bound radioactivity was determined in a liquid scintillation counter (TopCount-Packard Instruments). Basal activity (100% inhibition) was determined using the DMSO control while 0% inhibition was defined at the amount of pmol cAMP produced by 250pM glucagon.
Certain embodiments of the invention has been described in detail; however, numerous other embodiments are contemplated as falling within the invention. Thus, the claims are not limited to the specific embodiments described herein. All patents, patent applications and publications of any kind that are cited herein are hereby incorporated by reference in their entirety.

Claims

WHAT IS CLAMED IS:
1. A compound represented by formula I:
Figure imgf000107_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 represents H or is independently selected from the group consisting of: a) OH, halo, C02R\ C(0)NRbRc, NRbRc, CN or S(0)pRd; b) Ci-ioalkyl, C2-ιoalkenyl, C2-ι0alkynyl, OCj-ioalkyl, OC3-ι0alkenyl and OC3.ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 Cι-ι0alkoxy groups, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6)1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (c) 1-2 Cι-ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo, 1-3 Ci-i0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (e) -NRa-C(0)- NR"RC; (f) -NRa-C02Rc; (g) -NRa-C(0)Rc; (h) - NRbRc; (i) -NRaS02Rc; (j) -S02-NRbRc; (k) - C(0)NRbRc and (1) -OC(0)-NRbRc; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set forth below: (1) 1-3 Ci.ioalkyl, C2-ιoalkenyl or C2-ιoalkynyl groups optionally substituted with 1-5 halo groups; 1-2 OH groups; phenyl optionally substituted with 1-3 halo, Cι_6 alkyl or C].6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C02Ra; CN or S(0)pRd groups; and (2) 1-3 Ci-ioalkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH; phenyl optionally substituted with 1-3 halo, Cι-6 alkyl or C].6 alkoxy groups, the alkyl and alkoxy groups being further optionally substituted with 1-3 halo groups; C02Ra; CN or S(0)pRd groups; said Aryl, HAR, Hetcy -O-Aryl, -O-HAR and -O-Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of: (3) 1-5 halo groups; (4) 1-2 OH groups; (5) 1 S(0)pRd, N02 or CN group; (6) 1-2 C02Ra; (7) -NRa-C(0)-NRbRc; (8) -NRa-C02Rc; (9) -NRa-C(0)Rc; (10) -NR ; (11) -NRaS02Rc; (12) -SOz-NR^0; and (13) -C(0)NRbRc; and when R1 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(0)NRbRc; (b) -C02Rc; (c) - C(0)Rc; and (d) -S02Rc; each R2 represents H or is independently selected from the group consisting of: a) OH, halo, C02R\ C(0)NRbRc, NRbRc, CN or S(0)pRd; b) Ci-ioalkyl, C2.ι0alkenyl, C2.]0alkynyl, OCι-ι0alkyl, OC3.ι0alkenyl and OC3-ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) 1 oxo group; (3) 1 OH group; (4) 1 Cι.ι0alkoxy group, each optionally substituted with: up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02R or S(0)pRd; (6) 1 Aryl, Hetcy or HAR group, each optionally substituted as follows: (a) 1-5 halo groups, (b) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (c) 1-2 Cι-ι0alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (d) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Ci-ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo; and 1-2 hydroxy or C02Ra groups; c) Aryl, HAR, Hetcy, -O-Aryl, -O-HAR and -O-Hetcy, each optionally substituted as set forth below: (1) 1-3 Cι.ι0alkyl, C2.ι0alkenyl or C2_ι0alkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; (2) 1-3 Cι.ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; said Aryl, HAR or Hetcy group c) being further optionally substituted on carbon by a group selected from the group consisting of; (3) 1-5 halo groups up to perhalo; (4) 1 OH group; (5) 1 S(0)pRd, N02 or CN group; (6) 1 C02Ra;
R3 represents H or is selected from the group consisting of: a) .ioalkyl or C2.ι0alkenyl, each optionally substituted with 1-5 halo groups up to perhalo; 1-2 OH,
Figure imgf000108_0001
or haloCι-3alkoxy groups; 1-2 NRcRd groups; and 1-2 Aryl, HAR or Hetcy groups, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N02, Cι-3alkyl, haloCι-3alkyl, Cι-3alkoxy and haloCι-3 alkoxy groups; and b) Aryl, HAR or Hetcy, each optionally substituted with 1-3 halo groups and 1-2 groups selected from CN, N02, Cι-3alkyl,
Figure imgf000108_0002
Cι-3alkoxy and haloC]-3 alkoxy groups; R4 is independently selected from the group consisting of: a) Cι-ι alkyl, C2-ι0alkenyl and C2-ι0alkynyl, said groups being optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1 oxo group; (3) 1-2 OH groups; (4) 1-2 Cι.ι0alkoxy groups, each optionally substituted with up to five halo or a perhaloalkoxy, 1 OH or C02Ra group; (5) 1 C02Ra or S(0)pRd; (6) 1-2 Aryl, Hetcy or HAR groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 OH, C02Ra, CN, S(0)pRd , N02 or C(0)NRbRc group, (iii) 1-2 Q.ioalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or C02Ra groups; and (iv) 1-2 phenyl rings, each of which is optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Ci-ioalkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-3 Cι-ι4alkyl, C2- loalkenyl or C2-ιoalkynyl groups optionally substituted with 1-5 halo groups, 1-2 OH, C02Ra, CN or S(0)pRd groups or phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 Cι.ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (2) 1-3 Cι-ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups, 1-2 OH, C02Ra, CN, S(0)pRd , and phenyl optionally substituted as follows: 1-5 halo groups up to perhalo; 1-3 C].ι0alkyl or alkoxy groups, each being further optionally substituted with 1-5 halo up to perhalo, or 1-2 hydroxy or C02Ra groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Ci-ioalkyl, C2-ιoalkenyl or C2.ιoalkynyl groups each optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; (iii) 1-2 C].ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-5 halo groups, 1-2 OH, phenyl, C02Ra, CN or S(0)pRd groups; and (iv) 1-2 C02R\ S(0)pRd, CN, NRbRc, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) - NRbRc; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(0) NRbRc and -OC^-NR1^0; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NRbRc; (b) - C02Rc; (c) - C(0)Rc; and (d) -S02Rc;
R5 represents H or Q-β alkyl; R6 is selected from the group consisting of H, OH, F or Cι_3alkyl;
R7 is H or F, or R6 and R7 are taken in combination and represent oxo;
R8 represents H or Cι-6 alkyl, optionally substituted with OH and 1-5 halo groups up to perhalo; R9 represents H, halo, OH, C i-βalkyl, optionally substituted with 1-5 halo groups up to perhalo, or Ci. 6alkoxy, optionally substituted with 1-3 halo groups up to perhalo,
or when R9 is ortho to the benzylic group, R8 and R9 can be taken together and represent a -(CH2)2.4- or a -0-(CH2)i-3- group;
Ra is H or Ci-ioalkyl, optionally substituted with phenyl, OH, OC^al- yl, C02H, C02Cι- 6alkyl and 1-3 halo groups; Rb is H or C,.10alkyl;
Rc is H or is independently selected from: (a) Cι-ι0alkyl, optionally substituted with OH, OCι.6alkyl, C02H, C02C1.6alkyl, and 1-3 halo groups; (b) Aryl or Ar-C].6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Cι-ι0alkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Cι.6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Ci.ioalkyl and OC].ι0 alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-Cι.6alkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: Ci.ioalkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo;
Rd is Cι-I0alkyl, Aryl or Ar-C].ι0alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02R\ 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
2. A compound in accordance with claim 1 wherein R1 represents H.
3. A compound in accordance with claim 1 wherein one R2 represents H, halo or . βalkyl, and the other is selected from the group consisting of: H, halo, OH, Cι-6alkyl optionally substituted with 1-3 halo groups, Cι.6alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C2. alkenyl or OC2- alkenyl.
4. A compound in accordance with claim 1 wherein R3 is selected from the group consisting of: H, C2- alkenyl and Cι-6alkyl optionally substituted as follows: a) up to 3 halo groups; b)
NRcRd wherein Rc and Rd are H or Cι--j alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, Cι-3 alkyl, OCι.3alkyl, CN, N02, haloCι-3alkyl or 0-haloCi.3alkyl.
5. A compound in accordance with claim 1 wherein R4 is independently selected from the group consisting of:
(a) Cι-ι4alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1-2 Ci-ioalkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N02, (iii) 1-2 . loalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and (b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 Cι.10alkyl or C2.ιoalkenyl groups, optionally substituted with 1-5 halo groups, phenyl or C02Ra groups; (2) 1-2 . ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii) 1-2 Ci.ioalkyl or C2-ιoalkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 Q. ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and (iv) 1-2 C02Ra, S(0)pRd, CN, NR1*0, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) -NRbRc; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(O) NRbRc and (15) -OC(0)-NRbRc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NRbRc; (b) - C02Rc; (c) -C(0)Rc; and (d) -S02Rc.
Figure imgf000111_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 represents H; one R2 represents H, halo or Cι.6alkyl, and the other is selected from the group consisting of: H, halo, OH, Cι-6alkyl optionally substituted with 1-3 halo groups, Cι.6alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C2. alkenyl or OC2.4alkenyl;
R3is selected from the group consisting of: H, C2. alkenyl and Cι-6alkyl optionally substituted as follows: a) up to 3 halo groups; b) NRcRd wherein Rc and Rd are H or C alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, Cι.3 alkyl, OCι-3alkyl, CN, N02, haloCι.3alkyl or
0-haloCi.3alkyl; R4 is independently selected from the group consisting of:
(a) Cu4alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2)
1-2 .ioalkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2
Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N02, (iii) 1-2 . ιoalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and (b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 Cι-ι0alkyl or C2. ι0alkenyl, optionally substituted with 1-5 halo groups, phenyl or C02Ra groups; (2) 1-2 Cι.ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or
Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (i) 1-3 halo groups; (ii)
1-2 Ci.ioalkyl or C2-ι0alkenyl, each optionally substituted with 1-3 halo groups; (iii) 1-2 Cι.ι0alkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and (iv) 1-2 C02Ra,
S(0)pRd, CN, NRbRc, N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups;
(6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NR Rc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) -NR'ft0; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(O) NR Rc and (15) -OC(0)-NRbRc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: -C(O) NRbRc; (b) -C02Rc; (c) -C(0)Rc; and (d) -S02Rc;
R8 represents H or .6 alkyl;
R9 represents H or halo; R5 represents H or Cι-6 alkyl;
R6 is selected from the group consisting of H, OH, F or Cι.3alkyl;
R7 is H or F, or R6 and R7 are taken in combination and represent oxo;
Ra is H or Ci-ioalkyl, optionally substituted with phenyl, OH, OC^alkyl, C02H, COz - 6alkyl and 1-3 halo groups; Rb is H or Ci.ioalkyl;
Rc is H or is independently selected from: (a) Ci.ioalkyl, optionally substituted with OH, OCι-6alkyl, C02H, C02Cι-6alkyl, and 1-3 halo groups; (b) Aryl or Ar-Cι-6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Ci-ioalkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Ci-βalkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Ci-ioalkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-C^alkyl, optionally substituted with
1-5 halo groups and 1-3 groups selected from: Cι-ι0alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; Rd is Ci.ioalkyl, Aryl or Ar-Cι-ι0alkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02Ra, 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
7. A compound represented by formula I:
Figure imgf000113_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 represents H; one R2 represents H, halo or -βalkyl, and the other is selected from the group consisting of: H, halo, OH, Ci-βalkyl optionally substituted with 1-3 halo groups, Cι-6alkoxy optionally substituted with 1-3 halo groups or 1 phenyl or heterocyclic ring, C2.4alkenyl or OC2-4alkenyl;
R3 is selected from the group consisting of: H, C2- alkenyl and Ci-βalkyl optionally substituted as follows: a) up to 3 halo groups; b) NRcRd wherein Rc and Rd are H or Cι- alkyl; c) OH; and d) Aryl optionally substituted with 1-3 halo groups, C].3 alkyl,
Figure imgf000113_0002
or 0-haloCi-3alkyl;
R4 is independently selected from the group consisting of: a) Cι.ι4alkyl, optionally substituted with: (1) 1-5 halo groups up to perhaloalkyl; (2) 1- 2 Ci-ioalkoxy groups, each optionally substituted with 1-5 halo groups up to perhaloalkoxy; (3) 1-2 Aryl groups, each optionally substituted as follows: (i) 1-5 halo groups, (ii) CN or N02, and (iii) 1-2 . lo lkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl; and b) Aryl, HAR or Hetcy, each optionally substituted as follows: (1) 1-2 Cι-ι0alkyl or C . i0alkenyl, optionally substituted with 1-5 halo groups, phenyl or C02Ra groups; (2) 1-2 Cι.ι0alkoxy groups, the alkyl portion of which is optionally substituted with 1-5 halo groups; (3) 1-2 Aryl, HAR or Hetcy, OAryl, OHAR or OHetcy groups, each optionally substituted as follows: (a) 1-3 halo groups; (b) 1-2 Ci-ioalkyl or C2-ιoalkenyl, each optionally substituted with 1-3 halo groups;
(c) 1-2 Ci-ioalkoxy groups the alkyl portion of which being optionally substituted with 1-3 halo groups, and
(d) 1-2 C02Ra, S(0)pRd, CN, NR , N02 or OH groups; said Aryl, HAR or Hetcy group b) being further optionally substituted on carbon by a group selected from the group consisting of: (4) 1-5 halo groups; (5) 1-2 OH groups; (6) 1 S(0)pRd, N02 or CN group; (7) 1-2 C02Ra; (8) -NRa-C(0)-NRbRc; (9) -NRa-C02Rc; (10) -NRa-C(0)Rc; (11) -NR^0; (12) -NRaS02Rc; (13) -S02-NRbRc; (14) -C(O) NR"RC and (15) -OC(0)-NRbRc; and when R4 represents Hetcy containing a nitrogen atom, said nitrogen atom can be optionally substituted with a member selected from the group consisting of: (a) -C(O) NR^; (b) - C02Rc; (c) - C(0)Rc; and (d) -S02Rc;
R8 and R9 are taken in combination and represent -(CH2)2.4-; R5 represents H or C].6 alkyl; R6 is selected from the group consisting of H, OH, F or Cι_3alkyl;
R7 is H or F, or R6 and R7 are taken in combination and represent oxo;
Ra is H or C Oalkyl, optionally substituted with phenyl, OH, OCι-6alkyl, C02H, CO2 . 6alkyl and 1-3 halo groups; Rb is H or CMOalkyl;
Rc is H or is independently selected from: (a) Ci-ioalkyl, optionally substituted with OH, OC].6alkyl, C02H, CO^^a- yl, and 1-3 halo groups; (b) Aryl or Ar-Cι-6alkyl, each optionally substituted with 1-5 halos and 1-3 members selected from the group consisting of: CN, OH, Cι.ι0alkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; (c) Hetcy or Hetcy-Ci-βalkyl, optionally substituted with 1-5 halo groups and 1-3 groups selected from: oxo, Ci-ioalkyl and OCMO alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; and (d) HAR or HAR-Cι.6alkyl, optionally substituted with
1-5 halo groups and 1-3 groups selected from: CM0 lkyl and OC O alkyl, said alkyl and alkoxy being further optionally substituted with 1-5 halo groups up to perhalo; Rd is d-ioalkyl, Aryl or Ar-C Oalkyl; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 to 6; p is an integer selected from 0, 1 and 2, and when at least one of m and n is other than 0, Z is selected from C02Ra, 5-tetrazolyl and 5-(2-oxo-l,3,4-oxadiazolyl), and when both m and n are 0, Z is selected from 5-tetrazolyl and 5-(2-oxo- 1,3,4-oxadiazolyl).
8. A compound falling within table A below:
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
or a pharmaceutically acceptable salt or solvate thereof.
9. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
10. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat type 2 diabetes mellitus.
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JP2006528687A (en) 2006-12-21
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CN1784226A (en) 2006-06-07
EP1626717A4 (en) 2009-09-09
WO2004100875A3 (en) 2005-03-17
CA2524436A1 (en) 2004-11-25

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