WO2009082152A2 - Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient - Google Patents

Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient Download PDF

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WO2009082152A2
WO2009082152A2 PCT/KR2008/007585 KR2008007585W WO2009082152A2 WO 2009082152 A2 WO2009082152 A2 WO 2009082152A2 KR 2008007585 W KR2008007585 W KR 2008007585W WO 2009082152 A2 WO2009082152 A2 WO 2009082152A2
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Prior art keywords
dihydro
thiazol
indol
ethyl
cyclopentylamino
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PCT/KR2008/007585
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French (fr)
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WO2009082152A3 (en
Inventor
Soon Ha Kim
Sung Bae Lee
Seung Hyun Yoon
Mi Kyoung Cho
Kyoung Hee Kim
Heui Sul Park
Hyoung Jin Kim
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Lg Life Sciences Ltd.
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Priority to JP2010539310A priority Critical patent/JP5364103B2/en
Priority to US12/742,991 priority patent/US20100267708A1/en
Priority to CN2008801208137A priority patent/CN101896483B/en
Priority to EP08864050A priority patent/EP2220081A4/en
Priority to BRPI0819655-9A priority patent/BRPI0819655B1/en
Publication of WO2009082152A2 publication Critical patent/WO2009082152A2/en
Publication of WO2009082152A3 publication Critical patent/WO2009082152A3/en
Priority to US13/329,831 priority patent/US8309586B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new compounds exhibiting excellent activity for glucokinase (glucokinase activators, GKAs), and pharmaceutical compositions comprising the same as an active ingredient.
  • GKAs glucokinase activators
  • Diabetes affects harmful influences on human health, causing various complications. Diabetes may be classified into type 1 diabetes where insulin is not excreted due to the destruction of pancreatic cells, and type 2 diabetes where insulin is not produced due to the other conditions or the body does not response to insulin. The type 2 diabetes occupies 90% or more of the total patients suffered from diabetes. Typical complications accompanied with diabetes include hyperlipidemia, hypertension, retinosis, renal failure, etc. (Zimmer P., et al., Nature, 2001, 414, 782).
  • sulfonyl ureas facilitating insulin secretion in the pancreatic cells
  • biguanides suppressing glucose production in the liver
  • ⁇ - glucosidase inhibitors suppressing glucose uptake in the bowels
  • PPAR Y peroxisome proliferator-activated receptor gamma
  • these agents show some side effects, such as weight gain, according to the respective mechanisms of action (Moller D.E., Nature, 2001, 414, 821).
  • PPAR Y peroxisome proliferator-activated receptor gamma
  • glucose is accurately controlled within a safe and narrow physiological range by means of various endocrine glucostatic systems. If such glucostatic systems do not work, glucose intolerance occurs first, which is gradually grown to the type 2 diabetes. Dysfunction of such control mechanism is resulted from (i) decrease of secretion of insulin from the pancreatic cells, (ii) increases of insulin resistance in the liver, cells of adipose tissue, and cells of skeletal muscle, and (iii) excess production of blood glucose by the liver.
  • glucokinase that belongs to hexokinase IV series are involved in the first step of glucose metabolism to directly control the glucose content in the blood, whereby it plays an important role in the maintenance of glucose homeostasis in the body.
  • the glucokinase in the pancreatic cells can determine the thresholds of glucose- stimulated insulin release (GSIR) by acting as a glucose sensor.
  • GSIR glucose- stimulated insulin release
  • the glucokinase decreases blood glucose by phosphorylating glucose into glucose-6-phosphate consuming ATP, and keeping glucose-6-phosphate in the cells (Meglasson M.D. and Matschinsky F.M., Diabetes Metab Rev, 1986, 2, 163).
  • the glucokinase in hepatocytes has the feature of being short- term controlled by glucokinase regulatory protein.
  • Glucokinase regulatory protein forms a 1:1 complex with glucokinase, and acts as a "competitive inhibitor" against glucose to confine the inactivated glucokinase within the nucleus and to protect and stabilize it from other proteins such as decomposition enzymes, etc. It has been reported that fructose-6-phosphate further stabilizes glukinase regulatory protein, whereas fructose- 1 -phosphate separates glucokinase from glucokinase regulatory protein and transfers it from nucleus to cytoplasm to keep its activated state (Van Schaftingen E., Eur J Biochem, 1989, 179). The glucokinase in hepatocytes appropriately controls the glucose metabolism in the liver. That is, glucose uptake and production are effectively controlled under the satiation or fast state (Agius L., et al., J Biol Chem, 1996, 271, 30479).
  • glucokinase activates the two functions of (i) direct control of blood glucose in the liver, and (ii) facilitation of insulin secretion within the physiological range after detection of glucose concentration in the pancreas, and thus, plays a very important role in the maintenance of glucose homeostasis.
  • glucokinase is a key regulator in the maintenance of glucose homeostasis. Rats lacking the glucokinase gene function in pancreatic beta cells show a significant hyperglycemic symptom, and rats lacking the glucokinase gene function in hepatocytes show depressed glucose uptake and hyperglycemic symptom. On the other hand, when the glucokinase gene is over expressed in hepatocytes of normal rats, amelioration effect of glucose tolerance is shown (Rossetti L., et al., Am J Physiol, 1997, 273, E743). And, the over expression of glucokinase in diabetic rats induces amelioration of glucose tolerance and blood glucose lowering effect under the fast state (Desai UJ., et al., Am J Diabetes, 2001, 50, 2285).
  • glucokinase gene mutants have been clinically reported for humans.
  • patients of PNDM (permanent neonatal diabetes) and PHHI (persistent hyperinsulinemia hypoglycemia of infancy) showed serious hypoglycemia due to the glucokinase activation based on the gain-of-function mutation (Matsinsky F.M., et al., Frontiers in Daibetes, 2004, 16, chapter 4-7).
  • glucokinase-associated diseases suggest that glucokinase plays an important role in the maintenance of glucose homeostasis in the body, which leaves a clue to develop a drug for enhancing the glucokinase activity.
  • glucokinase activators facilitate pancreatic beta cell division to improve the glucose metabolism by maintaining the pancreatic cell mass.
  • the present inventors extensively studied glucokinase activators, and as a result have confirmed that the indole compounds of formula (1) are effective as glucokinase activators. Thus, they completed the present invention that relates to glucokinase activators based on indole structure.
  • the object of the present invention is to provide glucokinase activators of the indole compounds of formula (1). It is also another object of the present invention to provide a composition for the prevention or treatment of diseases caused by the decline of glucokinase activity, which comprises said compounds as an active ingredient.
  • the present invention provides the compounds of the following formula (1): [Formula 1] in which
  • X represents O or NH
  • n denotes a number of 0 to 3
  • Y represents a direct bond, -(CH 2 ) P O-, -(CH 2 ),-, or -(CH 2 ) q SO 2 -
  • p denots a number of 0 to 2
  • q denotes a number of 1 to 3
  • Rl represents hydrogen, -(CR4R5) P -A-R6 or ⁇ (CR4R5) q -R6, p and q are as defined above, R4 and R5 independently of one another represent hydrogen or Ci-C 5 -alkyl,
  • A represents 6-12 membered aryl or optionally oxo-containing C 3 -C 8 - cycloalkyl, or represents 3-10 membered heterocyclyl or heteroaryl each of which has 1 to 3 hetero atoms selected from O, S, and N,
  • R6 represents hydrogen, hydroxy, halogen, nitro, d-C ⁇ -alkylcarbonyl, C 1 - C 6 -alkylsulfonyl, Q-C ⁇ -alkoxycarbonyl or carboxy,
  • R2 represents hydrogen, nitro, halogen, Ci-C 6 -alkyl or trifluoromethyl, represents 5-12 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally Ci-C 6 -alkylsulfonyl-substituted 6-12 membered aryl, R3 represents R7-X-B-X'-,
  • B represents a direct bond, or represents 3-10 membered heterocyclyl or heteroaryl each of which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, O and S
  • X and X' independently of one another represent a direct bond, or are selected from the group consisting of -CO-, -(CH 2 ),-, -NR4C(O)-, -NR4-, -OC(O)-, -O-, - (CH 2 ) P C(O)-, -(CH 2 ) P O-, -(CH 2 ) P NR4-, -C(0)NR4- and -S(OV, wherein p and q are as defined above, r denotes a number of O to 2, and R4 represents hydrogen or Ci-C 5 -alkyl, R7 represents hydrogen, hydroxy, Ci-C 6 -alkyl, Cj-C 6 -alkoxy, halogeno-Ci-
  • C 6 -alkyl or C 3 -C 6 -cycloalkyl represents 6-12 membered aryl, or represents 4-8 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O, where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, d-C ⁇ -alkylamino, di(Ci-C 6 -alkyl)amino,
  • Ci-C ⁇ -alkyl Ci-C ⁇ -alkyl, halogeno-Q-C ⁇ -alkyl, Ci-C 6 -alkylsulfonyl, aryl-Q-C ⁇ -alkoxy and oxo, pharmaceutically acceptable salts or isomers thereof.
  • alkyl' means an aliphatic hydrocarbon radical.
  • Alkyl may be saturated alkyl that does not comprise alkenyl or alkynyl moiety, or unsaturated alkyl that comprises at least one alkenyl or alkynyl moiety.
  • Alkenyl means a group containing at least one carbon-carbon double bond
  • alkynyl means a group containing at least one carbon-carbon triple bond.
  • Alkyl may be branched or straight-chain when used alone or in a composite form such as alkoxy.
  • Alkyl group may have 1 to 20 carbon atoms unless otherwise defined. Alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms. Otherwise, alkyl group may be a lower alkyl having 1 to 6 carbon atoms. Typical examples thereof include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, etc.
  • Ci-C 4 -alkyl has 1 to 4 carbon atoms in the alkyl chain, and is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
  • alkoxy means an alkyloxy having 1 to 10 carbon atoms unless otherwise defined.
  • 'cycloalkyl' means a saturated aliphatic 3-10 membered cycle unless otherwise defined. Typical examples thereof include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • aryl' includes at least one ring having covalent ⁇ electron system, for example, monocyclic or fused polycyclic (i.e., cycles that share the adjacent carbon atom pairs) group.
  • aryl means an aromatic 4-10 membered, preferably 6-10 membered, monocyclic or multicyclic ring including phenyl, naphthyl, etc., unless otherwise defined.
  • heteroaryl means an aromatic 3-10 membered, preferably 4-8 membered, more preferably 5-6 membered cycle that has 1 to 3 hetero atoms selected from N, O and S, and may be fused with benzo or C 3 -C 8 cycloalkyl, unless otherwise defined.
  • the monocyclic heteroaryl includes, but not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like.
  • the bicyclic heteroaryl includes, but not limited to, indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, puropyridine and the like.
  • heterocycle means a 3-10 membered, preferably 4-8 membered, more preferably 5-6 membered cycle that has 1 to 3 hetero atoms selected from N, O and S, may be fused with benzo or C 3 -C 8 cycloalkyl, and is saturated or contains 1 or 2 double bonds, unless otherwise defined.
  • the heterocycle includes, but not limited to, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran and the like.
  • Preferred compounds among the compounds of formula (1) above are those wherein
  • X represents O or NH
  • n denotes a number of 0 to 3
  • Y represents a direct bond, -(CH 2 ) P O, -(CH 2 ) q -, or -(CH 2 ) q SO 2 -, p denotes a number of 0 to 2, q denotes a number of 1 to 3,
  • Rl represents -(CR4R5) P -A-R6 or -(CR4R5) q -R6, p and q are as defined above,
  • R4 and R5 independently of one another represent hydrogen or Ci-C 5 -alkyl
  • A represents 6—12 membered aryl or optionally oxo-containing C 3 -C 7 - cycloalkyl, or represents 4-8 membered heterocyclyl or heteroaryl each of which has 1 to 3 hetero atoms selected from O, S, and N,
  • R6 represents hydrogen, hydroxy, halogen, nitro, Ci-C 6 -alkylcarbonyl, C 1 - C ⁇ -alkylsulfonyl, Ci-C ⁇ -alkoxycarbonyl or carboxy,
  • R2 represents hydrogen, halogen, Q-C ⁇ -alkyl or trifluoromethyl, represents 5-8 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally Ci-C 6 -alkylsulfonyl-substituted 6-10 membered aryl,
  • R3 represents R7-X-B-X'-
  • B represents a direct bond, or represents 4-10 membered heterocyclyl or heteroaryl each of which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, O and S,
  • X and X' independently of one another represent a direct bond, or are selected from the group consisting of -CO-, -(CH 2 ) q -, -NR4C(O)-, -NR4-, -OC(O)-, -O-, - (CH 2 ) P C(O)-, -C(0)NR4- and -S(O) r , wherein p and q are as defined above, r denotes a number of 0 to 2, and R4 represents hydrogen or Q-Cs-alkyl, R7 represents hydrogen, hydroxy, Ci-C 6 -alkyl, halogeno-Ci-C 6 -alkyl or C 3 -
  • C 6 -cycloalkyl represents 6-12 membered aryl, or represents 4-8 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O, where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, Ci-C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, Ci-C ⁇ -alkyl, halogeno-C ! -C 6 -alkyl, Ci-C 6 -alkylsulfonyl, aryl-C ! -C 6 -alkoxy and oxo.
  • the substituent Y more preferably represents a direct bond, -O-, -(CH 2 )O-, -(CH 2 )- or -(CH 2 )SO 2 -.
  • Rl more preferably represents -(CH 2 ) P -A-R6 or -(CR4R5) q -R6, wherein p denotes a number of O to 2, q denotes a number of 1 to 3, R4 and R5 independently of one another represent hydrogen or d-C 5 -alkyl, A represents 6-12 membered aryl or optionally oxo-containing C 3 -C 6 -cycloalkyl or represents 5 ⁇ 6 membered heterocyclyl which has 1 to 2 hetero atoms selected from O, S, and N, and R6 represents hydrogen, halogen, nitro, Ci-C ⁇ -alkylcarbonyl, Ci-C 6 -alkylsulfonyl, Ci-C 6 - alkoxycarbonyl or carboxy.
  • Rl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, difluorocyclohexyl, tetrahydrofuran, tetrahydropyran, (tetrahydropyran-4-yl)methyl, tetrahydrothiopyran, 4-oxo-cyclohexyl, (l-methanesulfonyl)pyrrolidine, (l-acetyl)piperidine, 4-nitrophenyl and methylpropiolate.
  • the substituent R2 more preferably represents hydrogen, halogen, Ci-C 3 -alkyl or trifluoromethyl, represents 5 ⁇ 6 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally methanesulfonyl-substituted 6 ⁇ 10 membered aryl.
  • R2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, phenyl, methanesulfonylphenyl, pyridine, morpholine, 1,2-imidazole, 1,3-imidazole, pyrrolidine and pyrrole.
  • the substituent B more preferably represents a direct bond, represents pyrazole, imidazole or oxadiazole each of which is optionally substituted by Q-C ⁇ -alkyl, or represents 5 ⁇ 9 membered heterocyclyl which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, S and O.
  • B represents a direct bond, or may be a structure selected from the following formulae (i) to (xi)
  • the substituent X' more preferably represents a direct bond, or is selected from the group consisting of -CO-, - NR4CO-, -SO 2 - and -0-.
  • the substituent X more preferably represents a direct bond, or is selected from the group consisting of -C(0)NR4-, -NR4-, -OC(O)-, -NR4C(0)-, -(CH 2 )C(O)-, - S(O) 2 - and -C(O)-.
  • X represents a direct bond, or is selected from the group consisting of -C(O)NH-, -C(O)N(Me)-, -NH-, -N(Me)-, -OC(O)-, - N(Me)C(O)-, -(CH 2 )C(O)-, -S(O) 2 - and -C(O)-.
  • the substituent R7 more preferably represents hydrogen, hydroxy, Ci-C ⁇ -alkyl, halogeno-Ci-C 6 -alkyl or C 4 -C 6 -cycloalkyl, represents optionally halogen-substituted 6—10 membered aryl, or represents 5-6 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O.
  • R7 is selected from the group consisting of hydrogen, hydroxy, methyl, trifluoromethyl, ethyl, t-butyl, cyclohexyl, pyrrolidine, phenyl, 2-fluorophenyl, piperidine, pyridine, 1,3-pyrazine, 1,4- pyrazine, furan, trifluoromethyl, 1,2,3,4-tetrazole and tetrahydrofuran.
  • Typical compounds among the compounds of formula (1) are those selected from the following:
  • the compounds of formula (1) according to the present invention can also form a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example, a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid,
  • the pharmaceutically acceptable carboxylic acid salt includes a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.
  • the compounds of formula (I) of the present invention may be converted to their salts according to any of the conventional methods.
  • the compounds of formula (1) of the present invention may have an asymmetric carbon center(s) in the structure, and so may exist in the form of R or S isomer, racemate, mixture of diastereomers, or individual diastereomer, etc. All the isomers are also covered by the present invention.
  • the present invention also provides processes for preparing the compounds of formula (1).
  • the processes for preparing the compounds of formula (1) are illustrated by exemplary reaction schemes for the purpose of better understanding.
  • a skilled artisan in the field to which the present invention pertains may prepare the compounds of formula (1) via various routes according to their structures, and such processes should be construed to fall under the scope of the present invention.
  • the compounds of formula (1) may be prepared by optionally combining various synthetic methods which are described in the present specification or disclosed in the prior arts.
  • the processes for preparing the compounds of formula (1) cover even such processes, and are not limited to those explained below.
  • the compounds of formula (1) can be prepared according to the following
  • Reaction Scheme (1) by reducing the nitro group of Compound (2) to give an amine Compound (3), and introducing Rl substituent to the resulting amine group.
  • the compounds of formula (1) can be prepared according to the following
  • Compound (5) can be prepared according to the following Reaction Schemes (8) and (9).
  • Compound (7) can be prepared according to the following Reaction Scheme (10), and
  • Compound (20) can be prepared according to the following Reaction Scheme (11).
  • a represents Fe, Zn, Pd/C, etc.
  • Rl, R2, and R3 are as defined in formula (1)
  • R8 represents Y-R2, wherein Y and R2 are as defined in formula (1).
  • Compound (2) can be prepared according to the following Reaction Schemes (2) to (9).
  • Compound (3) can be prepared by reducing the Compound (2).
  • the reduction reaction may be carried out using an acid catalyst and metal, or using a metal catalyst in the presence of hydrogen gas.
  • the acid that can be used in the reduction reaction using an acid catalyst and metal includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic carboxylic acids such as acetic acid, trifluoroacetic acid, etc., aminates such as ammonium chloride, preferably hydrochloric acid, acetic acid, ammonium chloride, etc.
  • the acid is typically used in the amount of 0.01 ⁇ 10 eq., preferably 0.1 - 5 eq., with respect to 1 eq. of the Compound (2).
  • the metal that can be used includes, for example, iron, zinc, lithium, sodium, tin (usually, tin chloride), etc., particularly preferably iron, zinc, tin chloride, etc.
  • the metal is typically used in the amount of 1 ⁇ 20 eq., preferably 1 - 10 eq., with respect to 1 eq. of the Compound (2).
  • the reaction of metal in the presence of an acid catalyst may be carried out in an inert solvent.
  • alkyl alcohols such as methanol, ethanol, etc.
  • ethers such as tetrahydrofuran, diethylether, etc.
  • alkyl esters such as ethyl acetate, etc., preferably methanol, ethanol, tetrahydrofuran, ethyl acetate, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the metal catalyst that can be used in the reduction reaction using a metal catalyst in the presence of hydrogen gas includes palladium, nickel, platinum, ruthenium, rhodium, etc., particularly preferably palladium, nickel, etc.
  • the metal catalyst is typically used in the amount of 0.001 ⁇ 2 eq., preferably 0.01 ⁇ 1 eq., with respect to 1 eq. of the Compound (2).
  • the hydrogen gas pressure is typically in the range of 1 ⁇ 10 atm, preferably 1 ⁇ 3 atm.
  • the reaction may be carried out in an inert solvent, for example, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc., alkyl acetates such as methyl acetate, ethyl acetate, etc., preferably methanol, ethanol, ethyl acetate, etc.
  • the reaction temperature using the metal catalyst is typically in the range of -10 ⁇ 200 " C, preferably 25 ⁇ 50 ° C, and the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (4) can be prepared via a reductive alkylation reaction of the Compound (3).
  • the reductive alkylation on the amine group of the Compound (3) may be carried out with a ketone using a reducing agent, and if necessary, using an acid catalyst.
  • the ketone is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (3).
  • the reducing agent that can be used includes sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.
  • the reducing agent is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (3).
  • the acid catalyst that can be used includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic carboxylic acids such as acetic acid, trifluoroacetic acid, etc., aminates such as ammonium chloride, particularly preferably hydrochloric acid, acetic acid, etc.
  • the acid is typically used in the amount of 0.1 ⁇ 10 eq., preferably 1 ⁇ 5 eq., with respect to 1 eq. of the Compound (3).
  • the reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc., chloroalkanes such as dichloromethane, chloroform, dichloroethane, etc., preferably dichloroethane, chloroform, etc.
  • the reaction temperature is typically in the range of - 10 ⁇ 100 ° C , preferably -10 - 50 "C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the Compound (1) or (2) of the present invention can be prepared according to the processes that are specifically exemplified in the following Reaction Schemes (2) to (9).
  • a represents a metal hydroxide (for example, NaOH, LiOH)
  • b represents a coupling agent (for example, EDC, CDI, BOP-Cl) and Compound (7)
  • c represents PCl 5 or Tf 2 O and Ph 3 PO
  • d represents a coupling agent (for example, EDC, CDI, BOP-Cl) and
  • R8 is as defined in the Reaction Scheme (1), R9 represents Ci-C 6 -alkyl,
  • RlO represents NO 2 or Rl-X, wherein X and Rl are as defined in formula
  • RI l represents p-MeOBn or Ph 3 C
  • R3' and R3" independently of one another represent R7-X-B-, wherein R7, X and B are as defined in formula (1).
  • Compound (5) can be prepared according to Reaction Schemes (8) and (9).
  • Compound (6) can be prepared via hydrolysis reaction of the Compound (5) using a base.
  • the base that can be used includes lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.
  • the base is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (5).
  • the hydrolysis reaction may be carried out in an inert solvent selected, for example, from water, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 ⁇
  • reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (8) can be prepared via a coupling reaction of the carboxylic acid of
  • the known coupling agent that can be used in the coupling reaction includes, but not limited to, carboimides such as dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), l,r-dicarbonyldiimidazole (CDI), etc.
  • DCC dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • CDI l,r-dicarbonyldiimidazole
  • the coupling agent is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (6).
  • the amount of HOBT or HOAT used is typically in the range of 1 - 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (6).
  • the base that can be used includes organic bases such as triethylamine, diisopropylethylamine.
  • the base is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (7).
  • the coupling reaction may be carried out in an inert solvent selected from tetrahydrofuran, diethylether, N,N-dimethylformamide, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 "C, preferably 25 ⁇ 120 ° C, and the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (9) can be prepared by cyclizing the Compound (8) as described in Journal of Organic Chemistry, 68(24), 2003, 9506-9509, Tetrahedron, 55(34), 1999, 10271-10282, etc.
  • PCI 5 is typically used in the amount of 1 - 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (8).
  • the reaction temperature is typically in the range of -10 - 50 ° C , preferably 0 - 25 ° C, and the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
  • Rl 1 is triphenylmethyl (Ph 3 C) group
  • the cyclization reaction is carried out in dichloromethane solvent using trifluoromethanesulfonic-anhydride (Tf 2 O) and triphenylphosphineoxide (Ph 3 PO), which are typically used in the amount of 1 - 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (8).
  • the reaction temperature is typically in the range of -10 ⁇ 50 ° C , preferably 0 - 25 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (11) is an amine compound that is commercially available.
  • Compound (12) can be prepared via a coupling reaction of the carboxylic acid of the Compound (10) with the Compound (11) according to the preparing process of the Compound (8).
  • a represents a reducing agent (for example, NaBH 4 , LiAlH 4 ), b represents I 2 or MsCl, etc., c represents a base and the Compound (11), d represents a base and Compound (15), R8 is as defined in Reaction Scheme (1),
  • R9 represents d-C 6 -alkyl
  • RlO represents NO 2 or Rl-X, wherein X and Rl are as defined in formula
  • R12 represents Ci -C ⁇ -alkoxy, cyano or 5-6 membered heteroaryl
  • R' and R" are as defined in the Reaction Scheme (2), and W represents a leaving group, for example, halides such as chloride, bromide, iodide, etc., or sulfonates such as methane sulfonate, p-toluene sulfonate, etc.
  • Compound (13) can be prepared by converting the ester group of Compound (9) to an alcohol group.
  • the reducing agent that can be used to reduce the ester group to the alcohol group includes, for example, sodium borohydride, lithium borohydride, borane, lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL-H), etc.
  • the reducing agent is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (9).
  • the reaction may be carried out in an inert solvent selected, for example, from alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc., preferably tetrahydrofuran, diethylether, etc.
  • the reaction temperature is typically in the range of -78 ⁇ 100 °C, preferably -78 - 50 ° C, and the reaction time is typically in the range of 10 min — 60 h, preferably 10 min - 12 h.
  • Compound (14) can be prepared by converting the alcohol group of the Compound (13) to a leaving group W.
  • the leaving group W can be introduced via halogenation or sulfonation reaction.
  • the halogenation reaction may be carried out using a halogenating agent selected from iodine, bromine, N-iodosuccimide (NIS), N- bromosuccimide (NBS), carbon tetrachloride (CCl 4 ), carbon tetrabromide (CBr 4 ), etc. in the presence of a base such as imidazole, dimethylaminopyridine (DMAP), etc.
  • phosphines such as triphenylphosphine (Ph 3 P), tributylphosphine (Bu 3 P), etc.
  • Each of the halogenating agent, base and phosphine is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (13).
  • This reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc. and dichloromethane, chloroform, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 0 - 50 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the sulfonation reaction may be carried out using a sulfonating agent selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. in the presence of an organic base such as pyridine, triethylamine, etc.
  • a sulfonating agent selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.
  • an organic base such as pyridine, triethylamine, etc.
  • Each of the sulfonating agent and base is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 5 eq., with respect to 1 eq. of the Compound (13).
  • This reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc., chloroalkanes such as dichloromethane, dichloroethane, chloroform, etc., preferably dichloromethane, dichloroethane, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 0 ⁇ 50 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (16) can be prepared by a coupling reaction of the Compound (11) with the Compound (14) using a base.
  • a base for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, etc., organic bases such as triethylamine, diisopropylethylamine, l,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), etc. can be mentioned.
  • the base is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 5 eq., with respect to 1 eq. of the Compound (14).
  • This reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc., alkyl nitriles such as acetonitrile, propionitrile, etc., amides such as N,N-dimethylformamide, etc., preferably tetrahydrofuran, acetonitrile, N,N- dimethylformamide, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (17) can be prepared via a coupling reaction of the Compound (14) with the Compound (15) according to the preparing process of the Compound (16).
  • a represents a coupling agent (for example, EDC, CDI, BOP-Cl) and
  • R8 is as defined in the Reaction Scheme (1), RlO represents NO 2 or Rl-X, wherein X and Rl are as defined in formula
  • Rl 3 represents C 3 -C 6 -cyc loalkyl or piperidinyl.
  • Compound (18) can be prepared according to a method known in Heterocycles, 60(10), 2087, 2003 or Bioorganic & Medicinal Chemistry Letters, 11(24), 3164, 2001.
  • Compound (19) can be prepared via a coupling reaction of the Compound (10) with the Compound (18).
  • the coupling agent dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), l,l'-dicarbonyldiimidazole (CDI), etc. can be used, but not limited thereto.
  • the coupling agent is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (10).
  • This reaction may be carried out in an inert solvent selected from tetrahydrofuran, diethylether, N,N-dimethylformamide, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • a represents a coupling agent (for example, EDC, CDI, BOP-Cl)
  • b represents PCl 5 or Tf 2 O and Ph 3 PO
  • c represents a metal hydroxide (for example, NaOH, LiOH)
  • d represents I 2 or MsCl, etc.
  • e represents a base and the Compound (11), R8 is as defined in the Reaction Scheme (1),
  • RlO represents NO 2 or Rl-X, wherein X and Rl are as defined in formula
  • Rl 1 represents p-MeOBn or Ph 3 C
  • R14 represents Ci-C 6 -alkyl
  • R' and R" are as defined in the Reaction Scheme (2), and
  • W represents a leaving group, for example, halides such as chloride, bromide, iodide, etc., or sulfonates such as methane sulfonate, p-toluene sulfonate, etc.
  • Compound (21) can be prepared using the Compounds (6) and (20) according to the preparing process of the Compound (8) in the Reaction Scheme (2).
  • Compound (22) can be prepared using the Compound (21) according to the preparing process of the Compound (9) in the Reaction Scheme (2).
  • Compound (23) can be prepared using the Compound (22) according to the preparing process of the Compound (6) in the Reaction Scheme (2).
  • Compound (24) can be prepared using the Compound (23) according to the preparing process of the Compound (14) in the Reaction Scheme (3).
  • Compound (25) can be prepared using the Compound (24) according to the preparing process of the Compound (16) in the Reaction Scheme (3).
  • a represents di-t-butyloxy-dicarbonyl (BoC 2 O), a base (for example,
  • b represents a brominating agent (for example, N-bromosuccinimide
  • NBS sodium acetate
  • d represents an acid (for example, hydrochloric acid, trifluoroacetic acid)
  • e represents a metal hydroxide (for example, NaOH, LiOH)
  • f represents a coupling agent (for example, EDC, CDI, BOP-Cl) and
  • R2 is as defined in formula (1)
  • R9 represents Ci-C 6 -alkyl
  • Rl 1 represents p-MeOBn
  • R15 represents CrC ⁇ -alkoxycarbonyl or Ci-C ⁇ -alkylcarbonyloxy.
  • Compound (27) can be prepared by protecting the amine group of the
  • Boc 2 O used in the protection reaction of amine group is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (26).
  • the base is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (26).
  • a catalyst may be used for facilitating the reaction.
  • the catalyst used is dimethylaminopyridine (DMAP), and typically used in the amount of
  • This reaction may be carried out in an inert solvent selected from tetrahydrofuran, diethylether, N,N-dimethylformamide, dichloromethane, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 25 ⁇ 120 " C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the brominating agent used in the bromomethylation reaction includes N- bromosuccinimide (NBS) and l,3-dibromo-5,5-dimethylhydantoin, and is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound
  • a catalyst may be used for facilitating the reaction.
  • the catalyst used is 2,2'- azidobis(2-methylpropionitrile) (AIBN) or benzoyl peroxide, and typically used in the amount of 0.001 ⁇ 2 eq., preferably 0.01 ⁇ 0.3 eq., with respect to 1 eq. of the
  • This reaction may be carried out in an inert solvent selected from benzene, toluene, carbon tetrachloride, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 - 120 " C, and the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (28) can be prepared by reacting sodium acetate (NaOAc) with the Compound (27).
  • Sodium acetate is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 5 eq., with respect to 1 eq. of the Compound (27).
  • This reaction may be carried out in an inert solvent, for example, selected from ethers such as tetrahydrofuran, diethylether, etc., alkyl nitriles such as acetonitrile, propionitrile, etc., amides such as N,N-dimethylformamide, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (29) can be prepared by removing the BOC group using an acid, and hydrolysis reaction using a base, in the order.
  • the acid used in the removal of BOC group is hydrochloric acid, trifiuoroacetic acid, etc.
  • the acid is typically used in the amount of 1 ⁇ 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (28).
  • This reaction may be carried out in an inert solvent, for example, selected from ethers such as tetrahydrofuran, diethylether, dioxane, etc., alkyl alcohols such as methanol, ethanol, etc., chloroalkanes such as dichloromethane, chloroform, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the base used in the hydrolysis reaction includes lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.
  • the base is typically used in the amount of 2 ⁇ 20 eq., preferably 2 - 10 eq., with respect to 1 eq. of the Compound (28).
  • This hydrolysis reaction may be carried out in an inert solvent, for example, selected from alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (30) can be prepared according to Reaction Schemes (10) and (11).
  • Compound (31) can be prepared via a coupling reaction of the Compound (29) with the Compound (30) according to the preparing process of the Compound (8) in the Reaction Scheme (2).
  • Compound (32) can be prepared by reacting PClswith the Compound (31). hi this reaction of using PCl 5 , cyclization and chlorination of the alcohol group occur simultaneously.
  • PCl 5 is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (31).
  • This reaction may be carried out in a solvent selected from dichloromethane, chloroform, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 0 ⁇ 50 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (33) is commercially available.
  • Compound (34) can be prepared via a coupling reaction of the Compound (32) with the Compound (33) according to the preparing process of the Compound (16).
  • a represents an acylating agent [for example, Rl 1 -CO-Cl, (Rl 1-CO) 2 O]
  • b represents PCl 5
  • c represents a metal hydroxide (for example, NaOH, LiOH)
  • Rl 1 represents p-MeOBn
  • Rl 4 represents Ci-C 6 -alkyl
  • Rl 5 represents C ! -C 6 -alkoxycarbonyl or Ci-C ⁇ -alkylcarbonyloxy.
  • Compound (35) can be prepared by protecting the alcohol group of the Compound (31) with an acyl group, and cyclizing using PCl 5 .
  • the protection reaction of the alcohol group is carried out using a base and an acylating agent.
  • the base used includes organic bases such as triethylamine, diisopropylethylamine, pyridine, etc.
  • the base is typically used in the amount of 1 - 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (31).
  • the acylating agent is typically used in the amount of 1 ⁇ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (31).
  • This reaction may be carried out in a solvent selected from dichloromethane, chloroform, dichloroethane, etc.
  • the reaction temperature is typically in the range of - 10 - 200 ° C , preferably 0 - 50 ° C, and the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the cyclization reaction uses PCl 5 .
  • PCl 5 is typically used in the amount of 1 - 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (31).
  • This reaction may be carried out in a solvent selected from dichloromethane, chloroform, etc.
  • the reaction temperature is typically in the range of -10 - 200 ° C, preferably 0 - 50 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min - 12 h.
  • Compound (36) can be prepared via a deprotection reaction of the hydroxyl group of the Compound (35) using a base.
  • the base used in the deprotection reaction includes lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.
  • the base is typically used in the amount of 1 - 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (35).
  • This reaction may be carried out in an inert solvent, for example, selected from water, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc.
  • the reaction temperature is typically in the range of -10 - 200 ° C , preferably 25 - 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • a represents sodium nitrite (NaNO 2 ); tin chloride (SnCl 2 ), b represents a ketone compound (39), a base (for example, NaOAc), c represents an acid (for example, polyphosphoric acid PPA), d represents NaNO 2 , e represents Compound (42), a base (for example, NaOH),
  • R8 is as defined in the Reaction Scheme (1), and
  • R9 and RlO are as defined in the Reaction Scheme (2).
  • Compound (37) is commercially available, or can be prepared by a method known in Heterocycles, 68(11), 2285-99, 2006, or Bioorganic & Medicinal Chemistry Letters, 14(19), 4903-4906, 2004.
  • Compound (38) is commercially available, or can be prepared by converting the amine group of the Compound (37) to hydrazine group according to a method known in Journal of the American Chemical Society, 198(48), 15374-75, 2006.
  • the hydrazine Compound (38) can be prepared by reacting the amine group of the Compound (37) with NaNO 2 in the presence of hydrochloric acid to give a diazonium salt (41), which is not separated and reduced by using SnCl 2 .
  • NaNO 2 is typically used in the amount of 1 ⁇ 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (37).
  • SnCl 2 is typically used in the amount of 1 ⁇ 10 eq., preferably 2 ⁇
  • reaction temperature is in the range of -10 ⁇ 50 ° C
  • reaction time is typically in the range of 10 min ⁇ 6O h, preferably 10 min ⁇ 6 h.
  • Compound (39) is commercially available.
  • Hydrazone Compound (40) can be prepared via a coupling reaction of the Compound (38) with the ketone Compound (39).
  • a base is not used when the Compound (38) is in neutral form, but should be used when the Compound (38) is in the form of an acid salt to make the neutral form.
  • the base for example, metal hydroxides such as sodium hydroxide, lithium hydroxide, etc., metal carbonates such as sodium bicarbonate, potassium carbonate, etc., metal acetates such as sodium acetate, etc., organic bases such as triethylamine, pyridine, etc., preferably sodium acetate, sodium bicarbonate, etc. can be used.
  • the base is typically used in the amount of 1 ⁇ 5 eq., preferably 1 - 2 eq., with respect to 1 eq. of the Compound (38).
  • This reaction may be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, etc.
  • the reaction temperature is in the range of -10 ⁇ 100 "C, and the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the Compound (40) can also be prepared by reacting the diazonium salt (41) with the Compound (42) in the presence of a base according to Japp-Klingemann rearrangement method described in Organic Process Research & Development, 2, 1988,
  • Hydrochloric acid is used in the preparation of the diazonium salt (41) typically in the amount of 1 ⁇ 10 eq., preferably 2 ⁇ 4 eq., with respect to 1 eq. of the
  • the base used in the reaction of the Compounds (41) and (42) is sodium hydroxide, which is typically used in the amount of 1 ⁇ 20 eq., preferably 1 ⁇ 10 eq., with respect to 1 eq. of the Compound (42).
  • 80% aqueous ethanol solution is used as the solvent, and the reaction temperature is in the range of -10 ⁇ 50 ° C .
  • the reaction time is typically in the range of 10 mim ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (5) can be prepared using an acid catalyst and the Compound (40).
  • the acid used in the synthesis is polyphosphoric acid, hydrochloric acid, p- toluenesulfonic acid, sulfuric acid, acetic acid, etc., preferably polyphosphoric acid.
  • Polyphosphoric acid can be used alone, or as a mixture with aromatic hydrocarbons such as benzene, toluene, etc.
  • the reaction temperature is in the range of 25 - 150 ° C, and the reaction time is typically in the range of 5 mim ⁇ 60 h, preferably 5 min - 12 h.
  • a represents a sodium alkoxide (for example, sodium methoxide)
  • b represents heat
  • Rl is as defined in formula (1)
  • R8 is as defined in the Reaction Scheme (1), and R9 represents Ci-C 6 -alkyl.
  • Compound (43) is commercially available.
  • Compound (44) can be prepared by a method known in Journal of Medicinal Chemistry, 31(11), 2145, 1988.
  • Compound (45) is commercially available, or can be prepared by a method known in WO 2007040289, WO200601079 or Organic Letters 9(3), 397-400, 2007.
  • the Compound (45) can be prepared via a coupling reaction of the
  • the base used is sodium methoxide, sodium ethoxide, etc.
  • the base is typically used in the amount of 1 ⁇ 10 eq., preferably 1 ⁇ 3 eq., with respect to 1 eq. of the Compound (43).
  • This reaction may be carried out in an inert solvent, for example, selected from alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably -10 - 25 ° C
  • the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
  • Compound (46) can be prepared by cyclizing the Compound (45).
  • the cyclization reaction may be carried out by dissolving the Compound (45) in an inert solvent, and heating the solution.
  • the inert solvent that can be used includes tetrahydrofuran, benzene, toluene, etc.
  • the reaction temperature is typically in the range of 25 ⁇ 200 ° C , preferably 50 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • a represents p-methoxybenzylchloride (PMBCl) or triphenylmethyl- chloride (TrCl), a base (for example, NaOH), b represents di-t-butyloxy-dicarbonyl (BoC 2 O), a base (for example,
  • c represents an alkylchloroformate (for example, EtOCOCl), a base (for example, N-methylmorpholine), d represents diazomethane (CH 2 N 2 ), a base (for example, KOH), e represents a silver ion (for example, silver benzoate), f represents an acid, g represents MsCl, Et 3 N, h represents p-methoxybenzylthiol (PMBSH), NaH, R9 represents Ci-C 6 -alkyl, and Rl 1 represents p-MeOBn or Ph 3 C.
  • alkylchloroformate for example, EtOCOCl
  • a base for example, N-methylmorpholine
  • d represents diazomethane (CH 2 N 2 )
  • a base for example, KOH
  • e represents a silver ion (for example, silver benzoate)
  • f represents an acid
  • g represents MsCl
  • Et 3 N
  • h represents
  • Compound (47) can be prepared by protecting the thiol group of cysteine using p-methoxybenzyl chloride (PMBCl) or triphenylmethyl chloride (TrCl) in the presence of a base.
  • PMBCl p-methoxybenzyl chloride
  • TrCl triphenylmethyl chloride
  • PMBCl or TrCl used in the protection reaction of the thiol group is typically used in the amount of 1 ⁇ 5 eq., preferably 1 - 2 eq., with respect to 1 eq. of cysteine.
  • the base used is sodium hydroxide, potassium carbonate, etc., and is typically used in the amount of 1 ⁇ 5 eq, preferably 1 ⁇ 2 eq., with respect to 1 eq. of cysteine.
  • This reaction may be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, water, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 0 ⁇ 50 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (48) can be prepared by protecting the amine group of the Compound (47) using BOC group.
  • Boc 2 O used in the protection reaction of the amine group is typically used in the amount of 1 ⁇ 5 eq., preferably 1 ⁇ 2 eq., with respect to 1 eq. of cysteine.
  • the base used is selected, for example, from hydroxides such as sodium hydroxide, lithium hydroxide, etc., carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc., organic bases such as diisopropylethylamine, triethylamine, etc., preferably potassium carbonate, triethylamine, etc.
  • This reaction may be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, water, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 0 ⁇ 50 " C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • Compound (49) can be prepared by a method known in Helvetica Chimica Acta, 87, 2004, 3131-3159.
  • an Ag ion for example, silver trifluoroacetate (CF 3 CO 2 Ag), silver benzoate, etc.
  • an alkyl alcohol for example, methanol, ethanol, etc.
  • the reaction for removing the BOC group can be made using an acid.
  • the acid used includes hydrochloric acid, trifluoroacetic acid, etc.
  • the acid is typically used in the amount of 1 - 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (48).
  • This reaction may be carried out in an inert solvent, for example, selected from ethers such as tetrahydrofuran, diethylether, dioxane, etc., alkyl alcohols such as methanol, ethanol, etc., chloroalkanes such as dichloromethane, chloroform, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C, preferably 25 ⁇ 120 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min - 12 h.
  • Compound (50) can be prepared from glutamic acid or aspartic acid by a method known in Synlett, 15, 2005, 2397-2399, Journal of Organic Chemistry, 66(5), 2001, 1919-1923, etc.
  • Compound (51) can be prepared by sulfonating the Compound (50).
  • the sulfonation reaction may be carried out using methanesulfonyl chloride in the presence of an organic base such as pyridine, triethylamine, etc.
  • the sulfonylating agent and base each are used in the amount of 1 ⁇ 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (50).
  • This reaction may be carried out in an inert solvent selected from dichloromethane, dichloroethane, etc.
  • the reaction temperature is typically in the range of -10 - 200 ° C , preferably 0 - 50 ° C, and the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
  • the Compound (7) can be prepared by reacting p-methoxybenzylthiol
  • PMBSH PMBSH with the Compound (51) in the presence of a base, and removing the BOC group using an acid.
  • the base used is sodium hydride, potassium carbonate, cesium carbonate, etc., preferably sodium hydride.
  • the base is typically used in the amount of 1 - 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (51).
  • p- Methoxybenzylthiol (PMBSH) is typically used in the amount of 1 ⁇ 10 eq., preferably 2 ⁇ 5 eq., with respect to 1 eq. of the Compound (51).
  • This reaction may be carried out in an inert solvent selected from tetrahydrofuran, dimethylformamide, N- methylpyrrolidinone, etc.
  • the reaction temperature is typically in the range of -10 ⁇ 200 ° C , preferably 25 ⁇ 100 ° C
  • the reaction time is typically in the range of 10 min ⁇ 60 h, preferably 10 min ⁇ 12 h.
  • the reaction for removing BOC group may be carried out in the same manner as the removal of BOC group explained in the preparing process of the Compound (49).
  • a represents an alkyl alcohol (for example, methanol, ethanol), acetyl chloride or thionyl chloride, b represents di-t-butyloxy-dicarbonyl (BoC 2 O), a base (for example,
  • c represents a reducing agent (for example, NaBH 4 )
  • d represents an alkylcarbonyl chloride (for example, t-butylcarbonyl chloride ( 1 BuCOCl))
  • a base for example, Et 3 N
  • e represents an acid
  • R9 represents Ci-C 6 -alkyl
  • Rl 1 represents p-MeOBn or Ph 3 C
  • R14 represents Ci-C 6 -alkyl
  • Compound (52) can be prepared by esterifying the carboxylic group of the Compound (47), and protecting the amine group with BOC group.
  • the esterification reaction may be carried out using acetyl chloride or thionyl chloride in an alkyl alcohol solvent.
  • Acetyl chloride or thionyl chloride is used in the amount of 1 ⁇ 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (47).
  • the reaction temperature is typically in the range of 25 - 200 ° C, preferably 25 - 100 ° C
  • the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
  • the protection reaction of the amine group may be carried out in the same manner as the preparing process of the Compound (48).
  • the Compound (20) can be prepared from the starting Compound (52) via reduction of the ester group, protection of the alcohol group, and removal of BOC, in the order.
  • the reduction reaction of the ester group may be carried out by reacting with an alkylchloro formate (for example, ethylchloroformate, isobutylchloroformate) in tetrahydrofuran solvent of room temperature in the presence of 1 ⁇ 5 eq. of a base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, etc.) to give an anhydride, which is then reacted with 1 - 5 eq. of lithium borohydride or sodium borohydride in aqueous tetrahydrofuran solution of 0 ⁇ 25 "C for 10 min — 12 h.
  • an alkylchloro formate for example, ethylchloroformate, isobutylchloroformate
  • the protection reaction of the alcohol group may be carried out by reacting with an alkylcarbonylchloride, for example, t-BuCOCl, in dichloromethane solvent of 0 ⁇ 25 ° C in the presence of 1 ⁇ 5 eq. of a base selected from triethylamine, pyridine, etc. for 10 min ⁇ 12 h.
  • an alkylcarbonylchloride for example, t-BuCOCl
  • the reaction for removing BOC group may be carried out by dissolving the reactant in an inert solvent selected from tetrahydrofuran, dioxane, ethyl acetate, dichloromethane, etc. and reacting with 1 ⁇ 10 eq. of hydrochloric acid or trifluoroacetic acid at 0 ⁇ 50 ° C for lO min - 12 h.
  • an inert solvent selected from tetrahydrofuran, dioxane, ethyl acetate, dichloromethane, etc.
  • the compounds whose preparation methods are not specifically explained in the present specification are known per se, or can be prepared from a known compound according to a known process or a similar process thereto.
  • the compounds of formula (1) obtained by the above processes may be separated or purified from the reaction product by various methods such as recrystallization, ionophoresis, silica gel column chromatography, ion exchange chromatography, etc.
  • the compounds according to the present invention may be obtained by various processes, and such processes for preparing the compounds of formula (1) should be construed to fall under the scope of the present invention.
  • the present invention further provides a pharmaceutical composition for the activation of glucokinase, which comprises the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
  • Diseases which are caused by the deactivation of glucokinase, and can be prevented or treated by the pharmaceutical composition of the present invention include, but not limited to, diabetes, complications of diabetes, obesity, etc.
  • the pharmaceutical composition of the present invention can be used for the prevention or treatment of type 1 diabetes or type 2 diabetes, and is particularly preferable for type 2 diabetes.
  • the complications of diabetes that can be prevented or treated by the pharmaceutical composition of the present invention include, but not limited to, hyperlipidemia, hypertension, retinosis, renal failure, etc.
  • the present invention further provides a hypoglycemic composition which comprises the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
  • the present invention further provides a process for preparing a pharmaceutical composition for the activation of glucokinase, more specifically, for the prevention or treatment of diabetes, complications of diabetes, or obesity, which comprises the step of mixing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
  • compositions may comprise pharmaceutically acceptable carriers, diluents, excipients, or their combinations, if needed, together with the compounds of the present invention.
  • Pharmaceutical composition facilitates the administration of the compound into a living organism. There exist a number of techniques to administer the compound, and they include, but not limited to, oral, injectable, aerosol, parenteral and topical administration.
  • carrier means a substance which facilitates the incorporation of the compound into the cells or tissues.
  • DMSO dimethylsulfoxide
  • carrier is a typical carrier which is used to facilitate the introduction of various organic compounds into the cells or tissues of living organisms.
  • diluent is defined as a substance that is diluted in water which dissolves the compound, as well as stabilizes the biologically active form of the subject compound.
  • the salts dissolved in buffer solution are utilized as diluents in the art.
  • buffer solution is phosphate buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
  • pharmaceutically acceptable means the property that does not impair the biological activities and physical properties of the compound.
  • the compounds of the present invention can be formulated as various pharmaceutical dosage forms according to the purpose.
  • the active ingredient specifically, the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof are mixed together with various pharmaceutically acceptable carriers which can be selected according to the formulation to be prepared.
  • the pharmaceutical composition of the present invention can be formulated as injectable preparation, oral preparation, etc., according to the purpose.
  • the compounds of the present invention can be formulated by the methods known in the art, which utilize pharmaceutical carriers and excipients known in the art, and be incorporated into the containers of unit dose form or multi-dose form.
  • the form of the preparation can be solutions, suspensions or emulsions in oily or aqueous media, and may contain typical dispersing agents, suspending agents or stabilizers. Further, for example, it can be a form of dry powder which is intended to be reconstructed by dissolving in sterile, pyrogen-free water prior to use.
  • the compounds of the present invention also can be formulated into suppository forms utilizing typical suppository bases such as cocoa butter or other glycerides.
  • solid dosage forms for oral administration capsules, tablets, pills, powder and granule can be prepared, and capsules and tablets are especially useful.
  • tablets and pills are prepared as enteric coated forms.
  • Solid dosage forms can be prepared by mixing the compounds of the present invention together with carriers, for example, one or more inert diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrant, binder, etc.
  • the compounds of the present invention or the pharmaceutical compositions containing the same can also be administered in combination with other active agents, for example, other agents for treating diabetes.
  • the dosage of the compounds of formula (1) depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, and severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 1 to 500 mg per day, depending on the intensity and frequency of the administration. When administered to an adult via intramuscular or intravenous routes, total dosage typically from about 5 to 300 mg per day will be sufficient when separately administered in a single dosage, but for some patients a higher daily dosage may be desirable.
  • the present invention further provides a method for the prevention or treatment of diseases which are caused by the deactivation of glucokinase, using effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient.
  • the present invention further provides a process for preparing a pharmaceutical composition for the prevention or treatment of diseases which are caused by the deactivation of glucokinase, which comprises the step of mixing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
  • treatment means the interrupting or delaying the progress of the disease when applied to the subject showing the onset of disease symptoms
  • prevention means the interrupting or delaying the sign of the onset of disease when applied to the subject that does not show, but is at risk of, the onset of disease symptoms.
  • M means molar concentration
  • N means normal concentration
  • the resulting acetamide compound was dissolved in dichloromethane (200ml), and fuming nitric acid (13ml, 0.29 mol) was added in drops thereto at 0 ° C .
  • the mixture was stirred for 1 h at 0 " C ⁇ room temperature.
  • Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • the resulting nitrate compound was dissolved in methanol (100ml) and tetrahydrofuran (100ml), and 6N sodium hydride was added in drops thereto. The mixture was stirred for 6 h at room temperature. After completion of the reaction, the reaction solution was neutralized to about pH 7 using 6N hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound (44g, Yield 83%).
  • the compound thus obtained was dissolved using water (100ml), tetrahydrofuran (100ml) and methanol (100ml). Iron powder (103g, 1.84 mol) and ammonium chloride (99g, 1.84 mol) were added thereto, and the mixture was stirred using a mechanical stirrer for 3 h at 80 "C . After completion of the reaction, the reaction solution was filtered through a celite, washed with methanol, and concentrated.
  • Step 2 nylann ⁇ no-3-(4 yl)-prop ⁇ on ⁇ c
  • the compound (30.7g, 127.3mmol) prepared in Step 1 was dissolved in tetrahydrofuran (150ml) and water (150ml). Potassium carbonate (26.4g, 190mmol) and di-t-butyloxy-dicarbonyl (27.7g, 127.3mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The residue was cooled to 0 ° C , and acidified to pH 3 using 3N aqueous hydrochloric acid solution.
  • the compound prepared in Step 3 was dissolved in methanol (1000ml), silver benzoate (7.1g, 31.1mmol) was added thereto, and the mixture was sonicated for 1 h.
  • the compound prepared in Step 1 was dissolved in tetrahydrofuran (200ml) and water (200ml). Triethylamine (87ml, 621.6mmol) was added thereto, and di-t- butyloxy-dicarbonyl (43.Og, 196.8mmol) dissolved in tetrahydrofuran (100ml) was added in drops thereto while stirring. The mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added to the reaction solution, which was then extracted with ethyl acetate.
  • Triethylamine (58ml, 414.4mmol) and trimethylacetyl chloride (28ml, 227.9mmol) were added thereto, and the mixture was stirred for 6 h at 0 ° C . After completion of the reaction, water was added, and the reaction solution was extracted with ethyl acetate.
  • the compound (900mg, 2.7mmol) prepared in Preparation 19 was dissolved in 1 ,2-dichloroethane (100ml). Tetrahydro-4H-pyran-4-one (0.8ml, 8.13mmol), sodium triacetoxyborohydride (1.72g, 8.13mmol) and acetic acid (0.47ml, 8.13mmol) were added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered.
  • the compound prepared in Step 1 was dissolved in methanol (32ml), tetrahydrofuran (32ml) and water (16ml). IN sodium hydroxide (7ml) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (700mg, Yield 78%).
  • the compound (460mg, 0.9mmol) prepared in Step 1 was dissolved in methanol (50ml), and 4N hydrochloric acid solution (0.8ml, 2.7mmol) was added thereto. The mixture was stirred for 8 h at room temperature, distilled under reduced pressure, and purified by column chromatography.
  • Example 8 Synthesis of ⁇ (R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -methanol ⁇ (R)-2-[5-Chloro-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl ⁇ -methanol
  • Example 14 Synthesis of ⁇ (R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran- 4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -methanoI H-indol-2-
  • Example 17 Synthesis of cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5- dihydro-thiazol-2-yl)-lH-indol-7-yl]-amine Cyclopentyl-[2-((R)-4-dimethylamino methyl-4,5-dihydro-thiazol-2-yl)-1H
  • the compound (24.Og, lOOmmol) prepared in Preparation 7 was dissolved in dichloromethane (500ml). Triethylamine (84ml, ⁇ Olmmol) and 4- (dimethylamino)pyridine (600mg, 5mmol) were added, and di-t-butyloxy-dicarbonyl (43. Ig, 200mmol) dissolved in dichloromethane (100ml) was added in drops thereto. The mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added.
  • Preparation 29 Synthesis of 2,2-dimethyl-propionic acid (R)-2-(5- chIoromethyl-7-nitro-lH-indol-2-yI)-4,5-dihydro-thiazol-4-ylmethyl ester acid (R)-2-( e
  • the compound (1.Og, 1.9mmol) prepared in Preparation 28 was dissolved in dichloromethane (30ml). Phosphorus pentachloride (0.8g, 3.9mmol) was added thereto, and the mixture was stirred for 6 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound (0.7g, Yield 90%).
  • Step 1 2,2-Dimethyl-propionic acid (R)-2-( 7-nitro-5-pyrazol-1 -ylmethyl-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-ylme thyl ester
  • Step 1 The compound (300mg, 0.68mmol) prepared in Step 1 was reacted according to the same procedures as Step 4 of Preparation 19, Preparation 20 and Example 1 in the order to give the title compound (42mg, Yield 24%).
  • Example 25 Synthesis of [7-cyclopentylamino-2-((R)-4-hydroxymethyl-4,5- dihydro-thiazol-2-yl)-l H-indoI-5-yl] -methanol [7-Cyclopentylam ⁇ no-2-((R)-4-hydrox ymethyl-4,5-d ⁇ hydro-th ⁇ azol-2-yl)-1
  • Step 2 The compound (15. Ig, 60.8mmol) prepared in Step 1 was reacted according to the same procedures as Preparation 23 and Preparation 24 to give the title compound (6.3g, Yield 24%).
  • Preparation 33 Synthesis of S-chloro- ⁇ -nitro-lH-indole- ⁇ -carboxylic acid -7-n ⁇ tro-1 H- ⁇ ndole-2-carbox
  • the compound (15.Og, 59.1mmol) prepared in Preparation 5 was dissolved in tetrahydrofuran (300ml) and methanol (100ml).
  • Lithium hydroxide monohydrate (7.43g, 177mmol) was dissolved in water (100ml), and added to the reaction solution, which was then stirred for 3 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. The residue was neutralized to about pH 6 using 3N hydrochloric acid solution. The resulting solid was filtered and dried to give the title compound (13. Ig, Yield 92%).
  • Step 2 ⁇ H ⁇ --i ⁇ n ⁇ iduoul ⁇ --2. yl]-acet ⁇ es cf t ⁇ e r r
  • dichloromethane 200ml
  • Phosphorus pentachloride 17. Ig, 82mmol
  • the reaction solution was concentrated, and diethylether (200ml) was added.
  • Example 26 The compound (1.5g, 3.83mmol) prepared in Example 26 was dissolved in tetrahydrofuran (100ml) and methanol (50ml). Lithium hydroxide monohydrate (640mg, 15.3mmol) was dissolved in water (50ml) and added to the reaction solution, which was then stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. IN hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (13. Ig, Yield 92%).
  • Example 28 Synthesis of [(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid ethyl ester
  • the compound (l.Og, 3.1mmol) prepared in Preparation 34 was dissolved in 1,2- dichloroethane (100ml). Tetrahydro-4H-pyran-4-one (0.57ml, 6.18mmol), sodium triacetoxyborohydride (1.31g, 6.18mmol) and acetic acid (0.18ml, 3.09mmol) were added thereto, and the mixture was stirred for 24 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (0.5g, Yield 40%).
  • Example 30 The compound (400mg, l.Ommol) prepared in Example 30 was reacted according to the same procedure as Example 27 to give the title compound (360mg, Yield 92%).
  • Example 30 The compound (2.5g, 6.12mmol) prepared in Example 30 was reacted according to the same procedure as Example 29 to give the title compound (2.19g, 5.76mmol, Yield 94%).
  • Example 34 Synthesis of 2-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-l,3-thiazol-4-yl]-ethanol 2-[(R)-2-(5-Bromo-7-cyclopentylamin o-1 H-indol-2-yl)-4,5-dihydro-thiazo l-4-yl]-ethanol
  • Example 35 Synthesis of ⁇ (R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)- lH-indoI-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid ⁇ (R)-2-[5-Bromo-7-(tetrahydro-pyran -4-ylamino)-1 H-indol-2-yl]-4,5-dihy dro-thiazol-4-yl ⁇ -acetic acid
  • Example 37 The compound (80mg, 0.22mmol) prepared in Example 37 was dissolved in ethanol (2ml). Acetyl chloride (0.1ml) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (50mg, Yield 58%).
  • Example 40 Synthesis of ⁇ (R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid ⁇ (R)-2-[5-Fluoro-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl ⁇ -acetic acid
  • Step 2 The compound prepared in Step 1 was reacted according to the same procedure as Example 27 to give the title compound (5.44g, 2 steps, Yield 91%).
  • Example 43 Synthesis of [(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid ethyl ester [(R)-2-(7-Cyclopentylamino-1 H-indol -2-yl)-4,5-dihydro-thiazol-4-yl]-ac etic acid ethyl ester
  • Example 42 The compound (500mg, 1.46mmol) prepared in Example 42 was reacted according to the same procedure as Example 38 to give the title compound (420mg, Yield 78%).
  • Example 48 Synthesis of [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl] -acetic acid [(R)-2-(7-Cyclopentylam ⁇ no-5-methox y-1 H- ⁇ ndol-2-yl)-4,5-d ⁇ hydro-th ⁇ azo l-4-yl]-acet ⁇ c acid
  • Example 47 The compound (300mg, 0.78mmol) prepared in Example 47 was reacted according to the same procedure as Example 27 to give the title compound (240mg, Yield 82%).
  • Example 48 The compound (200mg, 0.54mmol) prepared in Example 48 was reacted according to the same procedure as Example 38 to give the title compound (124mg, Yield 57%).
  • Example 50 Synthesis of ⁇ (R)-2-[5-methoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid methyl ester
  • Example 51 Synthesis of ⁇ (R)-2-[5-methoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid
  • Example 52 Synthesis of [(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid [(R)-2-(7-Cyclopentylam ⁇ no-5-ethoxy -1H- ⁇ ndol-2-yl)-4,5-d ⁇ hydro-th ⁇ azol
  • Example 55 Synthesis of ⁇ (R)-2-[5-phenoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid
  • Example 56 Synthesis of ⁇ (R)-2-[7-cycIopentylamino-5-(pyridin-3-yloxy)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid methyl ester ⁇ (R)-2-[7-Cyclopentylam ⁇ no-5-(pyr ⁇ d ⁇ n-3-yloxy)-1 H- ⁇ ndol-2-yl]-4,5-d ⁇ hy dro-th ⁇ azol-4-yl ⁇ -acet ⁇ c acid methy I ester
  • Example 56 The compound (35mg, 0.08mmol) prepared in Example 56 was reacted according to the same procedure as Example 27 to give the title compound (15mg, Yield 44%).
  • Example 58 Synthesis of ⁇ (R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran- 4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid methyl ester ⁇ (R)-2-[5-(Py ⁇ d ⁇ n-3-yloxy)-7-(tetr ahydro-pyran-4-ylam ⁇ no)-1 H- ⁇ ndol-2- yl]-4,5-d ⁇ hydro-th ⁇ azol-4-yl ⁇ -acet ⁇ c acid methyl ester
  • Example 58 The compound (25mg, 0.05mmol) prepared in Example 58 was reacted according to the same procedure as Example 27 to give the title compound (15mg, Yield 58%).
  • Example 60 The compound (12mg, 0.03mmol) prepared in Example 60 was reacted according to the same procedure as Example 27 to give the title compound (5mg, Yield 43%).
  • Example 62 Synthesis of ⁇ (R)-2-[5-methyI-7-(tetrahydro-pyran-4-ylamino)- 1 H-indol-2-yl] -4,5-dihydro-thiazol-4-yl ⁇ -acetic acid
  • Example 64 Synthesis of ⁇ (R)-2-[7-cycIopentylamino-5-(4-methanesulfonyl- phenoxy)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl ⁇ -acetic acid
  • Example 65 The compound (l lmg, 0.02mmol) prepared in Example 65 was reacted according to the same procedure as Example 27 to give the title compound (5mg, Yield 45%).
  • Example 68 The compound (29mg, 0.07mmol) prepared in Example 68 was reacted according to the same procedure as Example 27 to give the title compound (19mg, Yield 67%).
  • Example 68 The compound (720mg, l. ⁇ Ommol) prepared in Example 68 was dissolved in tetrahydrofuran (20ml). 2 M lithium borohydride tetrahydrofuran solution (1.6ml, 3.2mmol) was added thereto, and the mixture was stirred for 3 h at room temperature.
  • Example 70 The compound (178mg, 0.42mmol) prepared in Example 70 was dissolved in tetrahydrofuran (10ml). Iodine (161mg, 0.63mmol), triphenylphosphine (166mg,
  • Example 72 Synthesis of l-(4- ⁇ 2-[(R)-2-(7-cyclopentylamino-5- methanesulfonylmethyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl ⁇ -piperazin-l- yl)-ethanone 1-(4- ⁇ 2-[(R)-2-(7-Cyclopentylamino- 5-methanesulfonylmethyl-1 H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-ethyl ⁇ -piperazin-1-yl)-ethanone
  • Example 27 The compound (50mg, 0.13mmol) prepared in Example 27 was dissolved in

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Abstract

The present invention relates to new compounds of formula (1) exhibiting excellent activity for glucokinase, and pharmaceutical compositions comprising the same as an active ingredient.

Description

[SPECIFICATION] [Title of Invention]
GLUCOKINASE ACTIVATORS AND PHARMACEUTICAL
COMPOSITIONS CONTAINING THE SAME AS AN ACTIVE INGREDIENT
[Technical Field]
The present invention relates to new compounds exhibiting excellent activity for glucokinase (glucokinase activators, GKAs), and pharmaceutical compositions comprising the same as an active ingredient.
[Background Art]
Diabetes affects harmful influences on human health, causing various complications. Diabetes may be classified into type 1 diabetes where insulin is not excreted due to the destruction of pancreatic cells, and type 2 diabetes where insulin is not produced due to the other conditions or the body does not response to insulin. The type 2 diabetes occupies 90% or more of the total patients suffered from diabetes. Typical complications accompanied with diabetes include hyperlipidemia, hypertension, retinosis, renal failure, etc. (Zimmer P., et al., Nature, 2001, 414, 782). As the therapeutic agents for diabetes, sulfonyl ureas (facilitating insulin secretion in the pancreatic cells), biguanides (suppressing glucose production in the liver), α - glucosidase inhibitors (suppressing glucose uptake in the bowels), etc. are used, among which peroxisome proliferator-activated receptor gamma (PPAR Y ) agonists (thiazolidinediones, increased insulin sensitivity) are recently focused. However, these agents show some side effects, such as weight gain, according to the respective mechanisms of action (Moller D.E., Nature, 2001, 414, 821). Thus, there has been a need for the development of an agent for the treatment of diabetes, which does not cause such side effects.
For a normal healthy person, blood glucose is accurately controlled within a safe and narrow physiological range by means of various endocrine glucostatic systems. If such glucostatic systems do not work, glucose intolerance occurs first, which is gradually grown to the type 2 diabetes. Dysfunction of such control mechanism is resulted from (i) decrease of secretion of insulin from the pancreatic cells, (ii) increases of insulin resistance in the liver, cells of adipose tissue, and cells of skeletal muscle, and (iii) excess production of blood glucose by the liver.
According to many research outputs obtained during the past forty years, glucokinase that belongs to hexokinase IV series are involved in the first step of glucose metabolism to directly control the glucose content in the blood, whereby it plays an important role in the maintenance of glucose homeostasis in the body.
The glucokinase in the pancreatic cells can determine the thresholds of glucose- stimulated insulin release (GSIR) by acting as a glucose sensor. The glucokinase decreases blood glucose by phosphorylating glucose into glucose-6-phosphate consuming ATP, and keeping glucose-6-phosphate in the cells (Meglasson M.D. and Matschinsky F.M., Diabetes Metab Rev, 1986, 2, 163). On the other hand, the glucokinase in hepatocytes has the feature of being short- term controlled by glucokinase regulatory protein. Glucokinase regulatory protein forms a 1:1 complex with glucokinase, and acts as a "competitive inhibitor" against glucose to confine the inactivated glucokinase within the nucleus and to protect and stabilize it from other proteins such as decomposition enzymes, etc. It has been reported that fructose-6-phosphate further stabilizes glukinase regulatory protein, whereas fructose- 1 -phosphate separates glucokinase from glucokinase regulatory protein and transfers it from nucleus to cytoplasm to keep its activated state (Van Schaftingen E., Eur J Biochem, 1989, 179). The glucokinase in hepatocytes appropriately controls the glucose metabolism in the liver. That is, glucose uptake and production are effectively controlled under the satiation or fast state (Agius L., et al., J Biol Chem, 1996, 271, 30479).
As explained above, glucokinase activates the two functions of (i) direct control of blood glucose in the liver, and (ii) facilitation of insulin secretion within the physiological range after detection of glucose concentration in the pancreas, and thus, plays a very important role in the maintenance of glucose homeostasis.
The experimental results in many rodent models suggested that glucokinase is a key regulator in the maintenance of glucose homeostasis. Rats lacking the glucokinase gene function in pancreatic beta cells show a significant hyperglycemic symptom, and rats lacking the glucokinase gene function in hepatocytes show depressed glucose uptake and hyperglycemic symptom. On the other hand, when the glucokinase gene is over expressed in hepatocytes of normal rats, amelioration effect of glucose tolerance is shown (Rossetti L., et al., Am J Physiol, 1997, 273, E743). And, the over expression of glucokinase in diabetic rats induces amelioration of glucose tolerance and blood glucose lowering effect under the fast state (Desai UJ., et al., Am J Diabetes, 2001, 50, 2285).
Hitherto, about 200 glucokinase gene mutants have been clinically reported for humans. Patients of MODY (maturity onset diabetes of the young)-2, a subtype of type 2 diabetes, showed some decrease of glucokinase activity due to the loss-of-function mutation and hyperglycemia due to the decrease of insulin secretion. On the contrary, patients of PNDM (permanent neonatal diabetes) and PHHI (persistent hyperinsulinemia hypoglycemia of infancy) showed serious hypoglycemia due to the glucokinase activation based on the gain-of-function mutation (Matsinsky F.M., et al., Frontiers in Daibetes, 2004, 16, chapter 4-7). Such phenotypes of glucokinase-associated diseases suggest that glucokinase plays an important role in the maintenance of glucose homeostasis in the body, which leaves a clue to develop a drug for enhancing the glucokinase activity.
According to the recent studies (Nakamura A., et al., Impact of small molecule glucokinase activator on glucose metabolism and beta cell mass, Endocrinology, 2008, Nov.), glucokinase activators facilitate pancreatic beta cell division to improve the glucose metabolism by maintaining the pancreatic cell mass. Also, it has been reported that glucose metabolism and hyperglycemia can be normalized by the restoration of hepatocellular glucokinase activity only in 20 week old ZDF (Zucker diabetic fatty) rat model (Torres T.P., et al., Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalize plasma glucose in zucker diabetic fatty rats, 2008, Endocrinology, Oct.), which suggests that hepatocyte-specifϊc glucokinase activators may be developed as a therapeutic agent that can be used for the type 1 diabetics as well as the chronic type 2 diabetics in the future.
A lot of researches for glucokinase activators have been reported. As the recently published patents, WO2007/007910A1, WO2006/112549A1, WO2007/031739, WO2007/037534, WO2007/043638, WO2007/028135, US20070099930, WO2007/041365, WO2007/051847, WO2007/053345, WO2007/007910, WO2006/049304, etc. may be mentioned.
The present inventors extensively studied glucokinase activators, and as a result have confirmed that the indole compounds of formula (1) are effective as glucokinase activators. Thus, they completed the present invention that relates to glucokinase activators based on indole structure.
[Detailed Description of the Invention] [Technical Subject to be Solved]
The object of the present invention is to provide glucokinase activators of the indole compounds of formula (1). It is also another object of the present invention to provide a composition for the prevention or treatment of diseases caused by the decline of glucokinase activity, which comprises said compounds as an active ingredient.
[Means for Solving the Technical Subject]
The present invention provides the compounds of the following formula (1): [Formula 1]
Figure imgf000007_0001
in which
X represents O or NH, n denotes a number of 0 to 3, Y represents a direct bond, -(CH2)PO-, -(CH2),-, or -(CH2)qSO2-, p denots a number of 0 to 2, q denotes a number of 1 to 3,
Rl represents hydrogen, -(CR4R5)P-A-R6 or ~(CR4R5)q-R6, p and q are as defined above, R4 and R5 independently of one another represent hydrogen or Ci-C5-alkyl,
A represents 6-12 membered aryl or optionally oxo-containing C3-C8- cycloalkyl, or represents 3-10 membered heterocyclyl or heteroaryl each of which has 1 to 3 hetero atoms selected from O, S, and N,
R6 represents hydrogen, hydroxy, halogen, nitro, d-Cό-alkylcarbonyl, C1- C6-alkylsulfonyl, Q-Cό-alkoxycarbonyl or carboxy,
R2 represents hydrogen, nitro, halogen, Ci-C6-alkyl or trifluoromethyl, represents 5-12 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally Ci-C6-alkylsulfonyl-substituted 6-12 membered aryl, R3 represents R7-X-B-X'-,
B represents a direct bond, or represents 3-10 membered heterocyclyl or heteroaryl each of which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, O and S, X and X' independently of one another represent a direct bond, or are selected from the group consisting of -CO-, -(CH2),-, -NR4C(O)-, -NR4-, -OC(O)-, -O-, - (CH2)PC(O)-, -(CH2)PO-, -(CH2)PNR4-, -C(0)NR4- and -S(OV, wherein p and q are as defined above, r denotes a number of O to 2, and R4 represents hydrogen or Ci-C5-alkyl, R7 represents hydrogen, hydroxy, Ci-C6-alkyl, Cj-C6-alkoxy, halogeno-Ci-
C6-alkyl or C3-C6-cycloalkyl, represents 6-12 membered aryl, or represents 4-8 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O, where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, d-Cό-alkylamino, di(Ci-C6-alkyl)amino,
Ci-Cό-alkyl, halogeno-Q-Cό-alkyl, Ci-C6-alkylsulfonyl, aryl-Q-Cό-alkoxy and oxo, pharmaceutically acceptable salts or isomers thereof.
In the above definitions for the compounds of formula (1), the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be saturated alkyl that does not comprise alkenyl or alkynyl moiety, or unsaturated alkyl that comprises at least one alkenyl or alkynyl moiety. "Alkenyl" means a group containing at least one carbon-carbon double bond, and "alkynyl" means a group containing at least one carbon-carbon triple bond. Alkyl may be branched or straight-chain when used alone or in a composite form such as alkoxy.
Alkyl group may have 1 to 20 carbon atoms unless otherwise defined. Alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms. Otherwise, alkyl group may be a lower alkyl having 1 to 6 carbon atoms. Typical examples thereof include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, etc. For example, Ci-C4-alkyl has 1 to 4 carbon atoms in the alkyl chain, and is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
The term 'alkoxy' means an alkyloxy having 1 to 10 carbon atoms unless otherwise defined.
The term 'cycloalkyl' means a saturated aliphatic 3-10 membered cycle unless otherwise defined. Typical examples thereof include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
The term 'aryl' includes at least one ring having covalent π electron system, for example, monocyclic or fused polycyclic (i.e., cycles that share the adjacent carbon atom pairs) group. In the present specification, aryl means an aromatic 4-10 membered, preferably 6-10 membered, monocyclic or multicyclic ring including phenyl, naphthyl, etc., unless otherwise defined.
The term 'heteroaryl' means an aromatic 3-10 membered, preferably 4-8 membered, more preferably 5-6 membered cycle that has 1 to 3 hetero atoms selected from N, O and S, and may be fused with benzo or C3-C8 cycloalkyl, unless otherwise defined. The monocyclic heteroaryl includes, but not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. The bicyclic heteroaryl includes, but not limited to, indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, puropyridine and the like.
The term 'heterocycle' means a 3-10 membered, preferably 4-8 membered, more preferably 5-6 membered cycle that has 1 to 3 hetero atoms selected from N, O and S, may be fused with benzo or C3-C8 cycloalkyl, and is saturated or contains 1 or 2 double bonds, unless otherwise defined. The heterocycle includes, but not limited to, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran and the like.
Other terms and abbreviations in the present specification may be understood to have the meaning conventionally used in this field by a skilled artisan, unless otherwise defined.
Preferred compounds among the compounds of formula (1) above are those wherein
X represents O or NH, n denotes a number of 0 to 3,
Y represents a direct bond, -(CH2)PO, -(CH2)q-, or -(CH2)qSO2-, p denotes a number of 0 to 2, q denotes a number of 1 to 3,
Rl represents -(CR4R5)P-A-R6 or -(CR4R5)q-R6, p and q are as defined above,
R4 and R5 independently of one another represent hydrogen or Ci-C5-alkyl, A represents 6—12 membered aryl or optionally oxo-containing C3-C7- cycloalkyl, or represents 4-8 membered heterocyclyl or heteroaryl each of which has 1 to 3 hetero atoms selected from O, S, and N,
R6 represents hydrogen, hydroxy, halogen, nitro, Ci-C6-alkylcarbonyl, C1- Cδ-alkylsulfonyl, Ci-Cβ-alkoxycarbonyl or carboxy,
R2 represents hydrogen, halogen, Q-Cό-alkyl or trifluoromethyl, represents 5-8 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally Ci-C6-alkylsulfonyl-substituted 6-10 membered aryl,
R3 represents R7-X-B-X'-,
B represents a direct bond, or represents 4-10 membered heterocyclyl or heteroaryl each of which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, O and S,
X and X' independently of one another represent a direct bond, or are selected from the group consisting of -CO-, -(CH2)q-, -NR4C(O)-, -NR4-, -OC(O)-, -O-, - (CH2)PC(O)-, -C(0)NR4- and -S(O)r, wherein p and q are as defined above, r denotes a number of 0 to 2, and R4 represents hydrogen or Q-Cs-alkyl, R7 represents hydrogen, hydroxy, Ci-C6-alkyl, halogeno-Ci-C6-alkyl or C3-
C6-cycloalkyl, represents 6-12 membered aryl, or represents 4-8 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O, where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, Ci-C6-alkylamino, di(C1-C6-alkyl)amino, Ci-Cό-alkyl, halogeno-C!-C6-alkyl, Ci-C6-alkylsulfonyl, aryl-C!-C6-alkoxy and oxo.
In the compounds of formula (1) of the present invention, the substituent Y more preferably represents a direct bond, -O-, -(CH2)O-, -(CH2)- or -(CH2)SO2-.
The substituent Rl more preferably represents -(CH2)P-A-R6 or -(CR4R5)q-R6, wherein p denotes a number of O to 2, q denotes a number of 1 to 3, R4 and R5 independently of one another represent hydrogen or d-C5-alkyl, A represents 6-12 membered aryl or optionally oxo-containing C3-C6-cycloalkyl or represents 5~6 membered heterocyclyl which has 1 to 2 hetero atoms selected from O, S, and N, and R6 represents hydrogen, halogen, nitro, Ci-Cό-alkylcarbonyl, Ci-C6-alkylsulfonyl, Ci-C6- alkoxycarbonyl or carboxy. Most preferably, Rl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, difluorocyclohexyl, tetrahydrofuran, tetrahydropyran, (tetrahydropyran-4-yl)methyl, tetrahydrothiopyran, 4-oxo-cyclohexyl, (l-methanesulfonyl)pyrrolidine, (l-acetyl)piperidine, 4-nitrophenyl and methylpropiolate.
The substituent R2 more preferably represents hydrogen, halogen, Ci-C3-alkyl or trifluoromethyl, represents 5~6 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally methanesulfonyl-substituted 6~10 membered aryl. Most preferably, R2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, phenyl, methanesulfonylphenyl, pyridine, morpholine, 1,2-imidazole, 1,3-imidazole, pyrrolidine and pyrrole.
In the group R7-X-B-X'- of the substituent R3, the substituent B more preferably represents a direct bond, represents pyrazole, imidazole or oxadiazole each of which is optionally substituted by Q-Cό-alkyl, or represents 5~9 membered heterocyclyl which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, S and O. Most preferably, B represents a direct bond, or may be a structure selected from the following formulae (i) to (xi)
Figure imgf000013_0001
0) (ϋ) (iii) (iv) (V)
Figure imgf000013_0002
(vi) (vii) (viϋ) (ix) (x)
Figure imgf000013_0003
(xi) in which R7 is as defined above.
The substituent X' more preferably represents a direct bond, or is selected from the group consisting of -CO-, - NR4CO-, -SO2- and -0-.
The substituent X more preferably represents a direct bond, or is selected from the group consisting of -C(0)NR4-, -NR4-, -OC(O)-, -NR4C(0)-, -(CH2)C(O)-, - S(O)2- and -C(O)-. Most preferably, X represents a direct bond, or is selected from the group consisting of -C(O)NH-, -C(O)N(Me)-, -NH-, -N(Me)-, -OC(O)-, - N(Me)C(O)-, -(CH2)C(O)-, -S(O)2- and -C(O)-.
The substituent R7 more preferably represents hydrogen, hydroxy, Ci-Cβ-alkyl, halogeno-Ci-C6-alkyl or C4-C6-cycloalkyl, represents optionally halogen-substituted 6—10 membered aryl, or represents 5-6 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O. Most preferably, R7 is selected from the group consisting of hydrogen, hydroxy, methyl, trifluoromethyl, ethyl, t-butyl, cyclohexyl, pyrrolidine, phenyl, 2-fluorophenyl, piperidine, pyridine, 1,3-pyrazine, 1,4- pyrazine, furan, trifluoromethyl, 1,2,3,4-tetrazole and tetrahydrofuran.
Typical compounds among the compounds of formula (1) are those selected from the following:
[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-l,3-thiazol-4-yl]- methanol;
{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -methanol; {(R)-2-[7-(tetrahydro-furan-3-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -methanol;
{(R)-2-[7-(l-methanesulfonyl-pyrrolidin-3-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- methanol;
{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- methanol;
{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
{(R)-2-[5-chloro-7-(tetrahydro-thiopyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol; [(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- methanol;
{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -methanol;
{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol; Cyclopentyl-[2-((R)-4-pyrrolidin-l-ylmethyl-4,5-dihydro-thiazol-2-yl)-lH- indol-7-yl] -amine;
Cyclopentyl-[2-((R)-4-moφholin-4-ylmethyl-4,5-dihydro-thiazol-2-yl)-lH- indol-7-yl] -amine;
Cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5-dihydro-thiazol-2-yl)-lH- indol-7-yl]-amine;
{(R)-2-[5-morpholin-4-ylmethyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2- yl]-4,5-dihydro-thiazol-4-yl}-methanol;
[(R)-2-[7-cyclopentylamino-5-pyrazol-l-ylmethyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
[(R)-2-(7-cyclopentylamino-5-imidazol-l-ylmethyl-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl} -methanol;
{(R)-2-[7-cyclopentylamino-5-(lH-pyrrol-3-ylmethyl)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol; [(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-methanol;
[7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5 -dihydro-thiazol-2-yl)- 1 H- indol-5 -yl] -methanol;
[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid methyl ester;
[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-ylj- acetic acid;
[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid ethyl ester; 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-l,3-thiazol-
4-yl]-ethanol;
{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid methyl ester;
{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -ethanol;
[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
2-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-l,3-thiazol- 4-yl]-ethanol;
{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; 2-{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -ethanol;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid ethyl ester;
2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethanol;
{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; 2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -ethanol;
[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid;
[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid ethyl ester;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;
{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -acetic acid; 2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl}-ethanol;
[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid ethyl ester;
{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid methyl ester; {(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
[(R)-2-(7-cyclopentylamino-5-propoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-acetic acid;
[(R)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
{(R)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; {(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid methyl ester;
{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; {(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -acetic acid methyl ester;
{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -acetic acid;
[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
{(R)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; {(R)-2-[5-methyl-7-(4-oxo-cyclohexylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(R)-2-[7-cyclopentylamino-5-(4-methanesulfonyl-phenoxy)-lH-indol-2-yl]- 455-dihydro-thiazol-4-yl} -acetic acid;
[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -acetic acid;
[(R)-2-(7-cyclopentylamino-5-pyrrolidin-l-ylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -acetic acid methyl ester; [(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-455- dihydro-thiazol-4-yl] -acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid; 2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethanol;
Cyclopentyl-{5-methanesulfonylmethyl-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl} -amine; l-(4-{2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)- 4,5 -dihydro-thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-mdol-2-yl)-4,5-dihydro-thiazol-4- yl]- 1 -morpholin-4-yl-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-(2-moφholin-4-yl-ethyl)-acetamide; 2-[(R)-2-(5-chloro-7-cyclopentylamino- lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -N-(3 -morpholin-4-yl-propyl)-acetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-mdol-2-yl)-4,5-dihydro-thiazol-4- yl] -N-methyl-acetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N,N-dimethyl-acetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(4-methyl-piperazin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(3 -dimethylamino-pyrrolidin- 1 -yl)-ethanone; 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(3 -hydroxy-pyrrolidin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -piperidin- 1 -yl-ethanone; 2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl}-N-methyl-acetamide;
2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} - 1 -morpholin-4-yl-ethanone;
2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-l -(4-methyl-piperazin-l-yl)-ethanone;
2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;
1 -(4-Acetyl-piperazin- 1 -yl)-2-[(R)-2-(7-cyclopentylamino-5-fluoro- 1 H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-ethanone; 2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -N-methyl-acetamide;
2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -morpholin-4-yl-ethanone;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-ethyl- acetamide;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N- methyl-acetamide;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-l- moφholin-4-yl-ethanone; N-methyl-2- {(R)-2-[7-(tetrahydro-pyran-4-ylamino)- 1 H-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-acetamide; l-Moφholin-4-yl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethanone; {5-Chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4?5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -cyclopentyl-amine;
{5-Chloro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -cyclopentyl-amine;
{5-Chloro-2-[(R)-4-(2-ρiρerazin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -cyclopentyl-amine; l-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazin-l-yl)-ethanone;
(5-Chloro-2-{(R)-4-[2-(4-ethanesulfonyl-piperazin-l-yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine; l-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-2-hydroxy-ethanone;
(5-Chloro-2-{(R)-4-[2-(4-methyl-piperazin-l-yl)-ethyl]-4,5-dihydro-thiazol-2- yl} - 1 H-indol-7-yl)-cyclopentyl-amine; l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl}-piperidin-4-ol;
(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol- 4-yl]-ethyl} -piperazin-2-one;
(5-Chloro-2-{(R)-4-[2-(3-dimethylamino-pyrrolidin-l-yl)-ethyl]-4,5-dihydro- thiazol-2-yl} - 1 H-indol-7-yl)-cyclopentyl-amine; {5-Chloro-2-[(R)-4-(2-piperidin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -cyclopentyl-amine;
(5-Chloro-2-{(R)-4-[2-(l,l-dioxo-thiomoφholin-4-yl)-ethyl]-4,5-dihydro- thiazol-2-yl} - 1 H-indol-7-yl)-cyclopentyl-amine; {5-Chloro-2-[(R)-4-(2-pyrazol-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7- yl} -cyclopentyl-amine;
(S)-l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -pyrrolidine-2-carboxylic acid;
{5-Chloro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -cyclopentyl-amine;
3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester;
3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl} -5-methyl-3H-imidazole-4-carboxylic acid; l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-
4-yl] -ethyl} -pyrrolidin-2-one; l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperidine-3-carboxylic acid; l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylic acid dimethylamide;
[(S)-l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamic acid t-butyl ester;
(2-{(R)-4-[2-((S)-3-amino-pyrrolidin-l-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5- chloro- 1 H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine; N-[(S)-l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]- 4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-acetamide;
{5-Chloro-2-[(R)-4-(2-piperazin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl}-(tetrahydro-pyran-4-yl)-amine; l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-2-hydroxy-ethanone; l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperazin- 1 -yl] -2-tetrazol- 1 -yl-ethanone; l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-3,3,3-trifluoro-propan-l-one;
[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperazin- 1 -yl]-furan-2-yl-methanone;
(5-Chloro-2- {(R)-4-[2-(2,3,5,6-tetrahydro-[ 1 ,2']bipyrazinyl-4-yl)-ethyl]-4,5- dihydro-thiazol-2-yl}-lH-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine; (5-Chloro-2-{(R)-4-[2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-lH-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;
{2-[(R)-4-(2-amino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-lH-indol-7-yl}- cyclopentyl-amine; l-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazin-l-yl)-ethanone;
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2- yl]-l H-indol-7-yl} -amine;
Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5- fluoro- 1 H-indol-7-yl} -amine; Cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol-2- yl] - 1 H-indol-7-yl} -amine;
Cyclopentyl-(2- {(R)-4-[2-(l , 1 -dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-5-fluoro-lH-indol-7-yl)-amine; 4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl} -piperazin-2-one;
1 -(4- {2-[(R)-2-(7-cyclopentylamino-5-fluoro- lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-2-hydroxy-ethanone;
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol- 2-yl]-lH-indol-7-yl}-amine;
{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-lH-indol- 7-yl}-(tetrahydro-pyran-4-yl)-amine;
{5-Fluoro-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-diliydro-thiazol-2-yl]-lH-indol- 7-yl}-(tetrahydro-pyran-4-yl)-amine; {5-Fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-
7-yl}-(tetrahydro-pyran-4-yl)-amine; l-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl-piperazin- 1 -yl)-ethanone;
(2- {(R)-4-[2-(l , 1 -dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl} -5- fluoro-lH-indol-7-yl)-(tetrahydropyran-4-yl)-amine;
(5-Fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;
4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one; l-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-2-hydroxy-ethanone;
Cyclopentyl-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7- yl} -amine; Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -amine;
Cyclopentyl-{2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -amine;
Cyclopentyl-{2-[(R)-4-(2-piρeridin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -amine;
{2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}- (tetrahydro-pyran-4-yl)-amine; l-(4-{2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazin-l-yl)-2-hydroxy-ethanone; 2-Hydroxy- 1 -[4-(2- {(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)- 1 H- indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-ethanone;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propionic acid;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propan-l-ol;
3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -propionic acid; 3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl } -prop an- 1 -ol ;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-(2-morpholin-4-yl-ethyl)-propionamide; 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(4-methyl-piperazin- 1 -yl)-propan- 1 -one; l-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-propyl}-piperazin-l-yl)-ethanone;
{5-Chloro-2-[(R)-4-(3-moφholin-4-yl-propyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -cyclopentyl-amine;
3-[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propionic acid; 3-[(R)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid; 3-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid; 3-[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -propionic acid;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- ylmethoxy]-acetic acid ethyl ester; [(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- ylmethoxy] -acetic acid;
Cyclopentyl-{2-[(R)-4-(3-cyclopentyl-[l,2,4]oxadiazol-5-ylmethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl} -amine;
Cyclopentyl-{2-[(R)-4-(3-piperidin-l-yl-[l,2,4]oxadiazol-5-ylmethyl)-4,5- dihydro-thiazol-2-yl]- 1 H-indol-7-yl} -amine;
[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid; l-(4-{2-[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}- piperazin- 1 -yl)-ethanone;
2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-7-phenoxy-lH- indole;
7-Phenoxy-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indole;
Dimethyl-{2-[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- ethyl} -amine;
[(S)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
{(S)-2-[7-(l-acetyl-piperidin-4-ylamino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; ((S)-2-{7-[(tetrahydro-pyran-2-ylmethyl)-amino]-lH-indol-2-yl}-4,5-dihydro- thiazol-4-yl)-acetic acid;
((S)-2-{7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2-yl}-4,5-dihydro- thiazol-4-yl)-acetic acid;
{(S)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -acetic acid;
{(S)-2-[7-(l-acetyl-pyrrolidin-3-ylamino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(S)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid; ((S)-2- {5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2-yl} -
4,5-dihydro-thiazol-4-yl)-acetic acid;
{(S)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(S)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(S)-2-(7-cyclobutylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
{(S)-2-[5-methyl-7-(tetrahydro-furan-3-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(S)-2-[7-(cyclopropylmethyl-amino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
((S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2-yl}-4,5- dihydro-thiazol-4-yl)-acetic acid; {(S)-2-[5-methyl-7-(tetrahydro-pyran-4-ylaniino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(S)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid methylester;
[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
(2-{(S)-4-[2-((R)-3-amino-pyrrolidin-l-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5- chloro- 1 H-indol-7-yl)-cyclopentyl-amine; (5-Chloro-2-{(S)-4-[2-((R)-3-dimethylamino-pyrrolidin-l-yl)-ethyl]-4,5- dihydro-thiazol-2-yl} - 1 H-indol-7-yl)-cyclopentyl-amine; l-(4-{2-[(S)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-ethanone; l-(4-{2-[(S)-2-(7-amino-5-chloro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- ethyl} -piperazin- 1 -yl)-ethanone; l-(4-{2-[(S)-2-(5-methyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethyl} -piperazin- l-yl)-ethanone;
{5-Methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -(tetrahydro-pyran-4-yl)-amine; l-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-2-hydroxy-ethanone;
Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-piperazin-l-yl-ethyl)-4,5-dihydro-thiazol- 2-yl]-lH-indol-7-yl} -amine; 4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazine-l-carboxylic acid t-butyl ester;
Cyclopentyl-(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3- a]pyrazin-7-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-phenoxy-lH-indol-7-yl)-amine;
4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin-2-one;
(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-(tetrahydro-furan-2-yl)-methanone;
Cyclopentyl-(5-phenoxy-2-{(S)-4-[2-(4-pyridin-2-yl-piperazin-l-yl)-ethyl]-4,5- dihydro-thiazol-2-yl}-lH-indol-7-yl)-amine; Cyclopentyl-[2-((S)-4-{2-[4-(2-fluoro-phenyl)-piperazin-l-yl]-ethyl}-4,5- dihydro-thiazol-2-yl)-5-phenoxy- 1 H-indol-7-yl)-amine; l-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-ethanone;
{(R)-l-[2-[(S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol- 2-yl}-4,5-dihydro-thiazol-4-yl]-ethyl]-pyrrolidin-2-yl}-methanol;
N-((R)-l-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-3-yl)-acetamide;
(2-{(S)-4-[2-(4-benzyl-piperazin-l-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5- phenoxy- 1 H-indol-7-yl)-cyclopentyl- amine;
{5-Methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)methyl-amine;
{2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-5-phenoxy-lH- indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)-amine; 4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2- yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one;
Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol- 2-yl] - 1 H-indol-7-yl)-amine;
(4,4-Difluoro-cyclohexyl)-{2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro- thiazol-2-yl]-lH-indol-7-yl)-amine;
(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3-pyrazin-7-yl]-ethyl)- 4,5-dihydro-thiazol-2-yl} -5-phenoxy- 1 H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl)- amine;
4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2- yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one; and
4-(2-{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-phenoxy-7-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one.
Other terms and abbreviations in the present specification may be understood to have the meaning conventionally used in this field by a skilled artisan, unless otherwise defined.
The compounds of formula (1) according to the present invention can also form a pharmaceutically acceptable salt. Such a pharmaceutically acceptable salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example, a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Also, for example, the pharmaceutically acceptable carboxylic acid salt includes a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compounds of formula (I) of the present invention may be converted to their salts according to any of the conventional methods.
The compounds of formula (1) of the present invention may have an asymmetric carbon center(s) in the structure, and so may exist in the form of R or S isomer, racemate, mixture of diastereomers, or individual diastereomer, etc. All the isomers are also covered by the present invention. The present invention also provides processes for preparing the compounds of formula (1). Hereinafter, the processes for preparing the compounds of formula (1) are illustrated by exemplary reaction schemes for the purpose of better understanding. However, a skilled artisan in the field to which the present invention pertains may prepare the compounds of formula (1) via various routes according to their structures, and such processes should be construed to fall under the scope of the present invention.
In other words, the compounds of formula (1) may be prepared by optionally combining various synthetic methods which are described in the present specification or disclosed in the prior arts. The processes for preparing the compounds of formula (1) cover even such processes, and are not limited to those explained below.
The compounds of formula (1) can be prepared according to the following
Reaction Scheme (1) by reducing the nitro group of Compound (2) to give an amine Compound (3), and introducing Rl substituent to the resulting amine group.
Alternatively, the compounds of formula (1) can be prepared according to the following
Reaction Schemes (2) to (7) by modifying Rl, R2 and R3 substituents in Compound (4).
Compound (5) can be prepared according to the following Reaction Schemes (8) and (9). Compound (7) can be prepared according to the following Reaction Scheme (10), and Compound (20) can be prepared according to the following Reaction Scheme (11).
Reaction Scheme 1
Figure imgf000035_0001
(2) (3) (4) in the above Reaction Scheme (1), a represents Fe, Zn, Pd/C, etc., b represents a ketone compound in the form of Rl=O, sodium triacetoxyborohydride (NaBH(OAc)3), sodium cyanoborohydride (NaBH3CN), etc., Rl, R2, and R3 are as defined in formula (1), and R8 represents Y-R2, wherein Y and R2 are as defined in formula (1).
Compound (2) can be prepared according to the following Reaction Schemes (2) to (9).
Compound (3) can be prepared by reducing the Compound (2). The reduction reaction may be carried out using an acid catalyst and metal, or using a metal catalyst in the presence of hydrogen gas.
The acid that can be used in the reduction reaction using an acid catalyst and metal includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic carboxylic acids such as acetic acid, trifluoroacetic acid, etc., aminates such as ammonium chloride, preferably hydrochloric acid, acetic acid, ammonium chloride, etc. The acid is typically used in the amount of 0.01 ~ 10 eq., preferably 0.1 - 5 eq., with respect to 1 eq. of the Compound (2). The metal that can be used includes, for example, iron, zinc, lithium, sodium, tin (usually, tin chloride), etc., particularly preferably iron, zinc, tin chloride, etc. The metal is typically used in the amount of 1 ~ 20 eq., preferably 1 - 10 eq., with respect to 1 eq. of the Compound (2). The reaction of metal in the presence of an acid catalyst may be carried out in an inert solvent. As the inert solvent, for example, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc., alkyl esters such as ethyl acetate, etc., preferably methanol, ethanol, tetrahydrofuran, ethyl acetate, etc. can be mentioned. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 25 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The metal catalyst that can be used in the reduction reaction using a metal catalyst in the presence of hydrogen gas includes palladium, nickel, platinum, ruthenium, rhodium, etc., particularly preferably palladium, nickel, etc. The metal catalyst is typically used in the amount of 0.001 ~ 2 eq., preferably 0.01 ~ 1 eq., with respect to 1 eq. of the Compound (2). The hydrogen gas pressure is typically in the range of 1 ~ 10 atm, preferably 1 ~ 3 atm. The reaction may be carried out in an inert solvent, for example, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc., alkyl acetates such as methyl acetate, ethyl acetate, etc., preferably methanol, ethanol, ethyl acetate, etc. The reaction temperature using the metal catalyst is typically in the range of -10 ~ 200 "C, preferably 25 ~ 50 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (4) can be prepared via a reductive alkylation reaction of the Compound (3). The reductive alkylation on the amine group of the Compound (3) may be carried out with a ketone using a reducing agent, and if necessary, using an acid catalyst. The ketone is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (3). The reducing agent that can be used includes sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. The reducing agent is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (3). The acid catalyst that can be used includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic carboxylic acids such as acetic acid, trifluoroacetic acid, etc., aminates such as ammonium chloride, particularly preferably hydrochloric acid, acetic acid, etc. The acid is typically used in the amount of 0.1 ~ 10 eq., preferably 1 ~ 5 eq., with respect to 1 eq. of the Compound (3). The reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc., chloroalkanes such as dichloromethane, chloroform, dichloroethane, etc., preferably dichloroethane, chloroform, etc. The reaction temperature is typically in the range of - 10 ~ 100 °C , preferably -10 - 50 "C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The Compound (1) or (2) of the present invention can be prepared according to the processes that are specifically exemplified in the following Reaction Schemes (2) to (9).
Reaction Scheme 2
Figure imgf000038_0001
in the above Reaction Scheme (2), a represents a metal hydroxide (for example, NaOH, LiOH), b represents a coupling agent (for example, EDC, CDI, BOP-Cl) and Compound (7), c represents PCl5 or Tf2O and Ph3PO, d represents a coupling agent (for example, EDC, CDI, BOP-Cl) and
Compound (11),
R8 is as defined in the Reaction Scheme (1), R9 represents Ci-C6-alkyl,
RlO represents NO2 or Rl-X, wherein X and Rl are as defined in formula
(1),
RI l represents p-MeOBn or Ph3C, and
R3' and R3" independently of one another represent R7-X-B-, wherein R7, X and B are as defined in formula (1).
Compound (5) can be prepared according to Reaction Schemes (8) and (9). Compound (6) can be prepared via hydrolysis reaction of the Compound (5) using a base. The base that can be used includes lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. The base is typically used in the amount of 1 ~ 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (5). The hydrolysis reaction may be carried out in an inert solvent selected, for example, from water, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc.
The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 ~
120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (7) can be prepared according to the following Reaction Schemes (10) and (11).
Compound (8) can be prepared via a coupling reaction of the carboxylic acid of
Compound (6) with the amine group of the Compound (7). The known coupling agent that can be used in the coupling reaction includes, but not limited to, carboimides such as dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), l,r-dicarbonyldiimidazole (CDI), etc. mixed with 1-hydroxy-benzotriazole (HOBT) or l-hydroxy-7-azabenzotriazole (HOAT), or bis-(2-oxo-3-oxazolidinyl)- phosphinic acid chloride (BOP-Cl), diphenylphosphorylazide (DPPA), N- [dimethylamino-lH-l,2,3-triazole[4,5-b]-pyridin-l-ylmethylene]-N- methylmethaneaminium (HATU), etc. The coupling agent is typically used in the amount of 1 ~ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (6). The amount of HOBT or HOAT used is typically in the range of 1 - 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (6). When an amine hydrochloride is used in the coupling reaction, the acid should be removed by using a base. The base that can be used includes organic bases such as triethylamine, diisopropylethylamine. The base is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (7). The coupling reaction may be carried out in an inert solvent selected from tetrahydrofuran, diethylether, N,N-dimethylformamide, etc. The reaction temperature is typically in the range of -10 ~ 200 "C, preferably 25 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (9) can be prepared by cyclizing the Compound (8) as described in Journal of Organic Chemistry, 68(24), 2003, 9506-9509, Tetrahedron, 55(34), 1999, 10271-10282, etc.
When RI l is p-methoxybenzyl (p-MeOBn) group, the cyclization reaction is carried out in dichloromethane solvent using phosphorus pentachloride (PCI5). PCI5 is typically used in the amount of 1 - 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (8). The reaction temperature is typically in the range of -10 - 50 °C , preferably 0 - 25 °C, and the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
When Rl 1 is triphenylmethyl (Ph3C) group, the cyclization reaction is carried out in dichloromethane solvent using trifluoromethanesulfonic-anhydride (Tf2O) and triphenylphosphineoxide (Ph3PO), which are typically used in the amount of 1 - 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (8). The reaction temperature is typically in the range of -10 ~ 50 °C , preferably 0 - 25 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (11) is an amine compound that is commercially available.
Compound (12) can be prepared via a coupling reaction of the carboxylic acid of the Compound (10) with the Compound (11) according to the preparing process of the Compound (8).
Reaction Scheme 3
Figure imgf000041_0001
(9) (13)
Figure imgf000041_0002
(17) in the above Reaction Scheme (3), a represents a reducing agent (for example, NaBH4, LiAlH4), b represents I2 or MsCl, etc., c represents a base and the Compound (11), d represents a base and Compound (15), R8 is as defined in Reaction Scheme (1),
R9 represents d-C6-alkyl,
RlO represents NO2 or Rl-X, wherein X and Rl are as defined in formula
(1), R12 represents Ci -Cό-alkoxy, cyano or 5-6 membered heteroaryl,
R' and R" are as defined in the Reaction Scheme (2), and W represents a leaving group, for example, halides such as chloride, bromide, iodide, etc., or sulfonates such as methane sulfonate, p-toluene sulfonate, etc.
Compound (13) can be prepared by converting the ester group of Compound (9) to an alcohol group. The reducing agent that can be used to reduce the ester group to the alcohol group includes, for example, sodium borohydride, lithium borohydride, borane, lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL-H), etc. The reducing agent is typically used in the amount of 1 ~ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (9). The reaction may be carried out in an inert solvent selected, for example, from alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc., preferably tetrahydrofuran, diethylether, etc. The reaction temperature is typically in the range of -78 ~ 100 °C, preferably -78 - 50 °C, and the reaction time is typically in the range of 10 min — 60 h, preferably 10 min - 12 h.
Compound (14) can be prepared by converting the alcohol group of the Compound (13) to a leaving group W. The leaving group W can be introduced via halogenation or sulfonation reaction. The halogenation reaction may be carried out using a halogenating agent selected from iodine, bromine, N-iodosuccimide (NIS), N- bromosuccimide (NBS), carbon tetrachloride (CCl4), carbon tetrabromide (CBr4), etc. in the presence of a base such as imidazole, dimethylaminopyridine (DMAP), etc. and phosphines such as triphenylphosphine (Ph3P), tributylphosphine (Bu3P), etc. Each of the halogenating agent, base and phosphine is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (13). This reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc. and dichloromethane, chloroform, etc. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 0 - 50 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The sulfonation reaction may be carried out using a sulfonating agent selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. in the presence of an organic base such as pyridine, triethylamine, etc. Each of the sulfonating agent and base is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 5 eq., with respect to 1 eq. of the Compound (13). This reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc., chloroalkanes such as dichloromethane, dichloroethane, chloroform, etc., preferably dichloromethane, dichloroethane, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 0 ~ 50 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (16) can be prepared by a coupling reaction of the Compound (11) with the Compound (14) using a base. As the base, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, etc., organic bases such as triethylamine, diisopropylethylamine, l,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), etc. can be mentioned. The base is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 5 eq., with respect to 1 eq. of the Compound (14). This reaction may be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethylether, etc., alkyl nitriles such as acetonitrile, propionitrile, etc., amides such as N,N-dimethylformamide, etc., preferably tetrahydrofuran, acetonitrile, N,N- dimethylformamide, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (17) can be prepared via a coupling reaction of the Compound (14) with the Compound (15) according to the preparing process of the Compound (16).
Reaction Scheme 4
Figure imgf000044_0001
(10) (19) in the above Reaction Scheme (4), a represents a coupling agent (for example, EDC, CDI, BOP-Cl) and
Compound (18),
R8 is as defined in the Reaction Scheme (1), RlO represents NO2 or Rl-X, wherein X and Rl are as defined in formula
(1), and
Rl 3 represents C3-C6-cyc loalkyl or piperidinyl. Compound (18) can be prepared according to a method known in Heterocycles, 60(10), 2087, 2003 or Bioorganic & Medicinal Chemistry Letters, 11(24), 3164, 2001.
Compound (19) can be prepared via a coupling reaction of the Compound (10) with the Compound (18). As the coupling agent, dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), l,l'-dicarbonyldiimidazole (CDI), etc. can be used, but not limited thereto. The coupling agent is typically used in the amount of 1 ~ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (10). This reaction may be carried out in an inert solvent selected from tetrahydrofuran, diethylether, N,N-dimethylformamide, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 ~ 120 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Reaction Scheme 5
Figure imgf000045_0001
(22) (23)
Figure imgf000045_0002
(24) (25) in the above Reaction Scheme (5), a represents a coupling agent (for example, EDC, CDI, BOP-Cl), b represents PCl5 or Tf2O and Ph3PO, c represents a metal hydroxide (for example, NaOH, LiOH), d represents I2 or MsCl, etc., e represents a base and the Compound (11), R8 is as defined in the Reaction Scheme (1),
RlO represents NO2 or Rl-X, wherein X and Rl are as defined in formula
(1),
Rl 1 represents p-MeOBn or Ph3C, R14 represents Ci-C6-alkyl, R' and R" are as defined in the Reaction Scheme (2), and
W represents a leaving group, for example, halides such as chloride, bromide, iodide, etc., or sulfonates such as methane sulfonate, p-toluene sulfonate, etc.
Compound (20) can be prepared according to the Reaction Scheme (11).
Compound (21) can be prepared using the Compounds (6) and (20) according to the preparing process of the Compound (8) in the Reaction Scheme (2).
Compound (22) can be prepared using the Compound (21) according to the preparing process of the Compound (9) in the Reaction Scheme (2).
Compound (23) can be prepared using the Compound (22) according to the preparing process of the Compound (6) in the Reaction Scheme (2). Compound (24) can be prepared using the Compound (23) according to the preparing process of the Compound (14) in the Reaction Scheme (3).
Compound (25) can be prepared using the Compound (24) according to the preparing process of the Compound (16) in the Reaction Scheme (3).
Reaction Scheme 6
Figure imgf000047_0001
in the above Reaction Scheme (6), a represents di-t-butyloxy-dicarbonyl (BoC2O), a base (for example,
NaOH, K2CO3), b represents a brominating agent (for example, N-bromosuccinimide
(NBS)), c represents sodium acetate (NaOAc), d represents an acid (for example, hydrochloric acid, trifluoroacetic acid), e represents a metal hydroxide (for example, NaOH, LiOH), f represents a coupling agent (for example, EDC, CDI, BOP-Cl) and
Compound (33), g represents PCl5, h represents a base and the Compound (33),
R2 is as defined in formula (1),
R9 represents Ci-C6-alkyl, Rl 1 represents p-MeOBn, and
R15 represents CrCβ-alkoxycarbonyl or Ci-Cβ-alkylcarbonyloxy.
Compound (26) can be prepared according to Reaction Scheme (9).
Compound (27) can be prepared by protecting the amine group of the
Compound (26) using BoC2O in the presence of a base, and converting the methyl group to bromomethyl group using a brominating agent, in the order.
Boc2O used in the protection reaction of amine group is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (26).
The base is typically used in the amount of 1 ~ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (26). A catalyst may be used for facilitating the reaction. The catalyst used is dimethylaminopyridine (DMAP), and typically used in the amount of
0.01 ~ 2 eq., preferably 0.1 ~ 0.3 eq., with respect to 1 eq. of the Compound (26). This reaction may be carried out in an inert solvent selected from tetrahydrofuran, diethylether, N,N-dimethylformamide, dichloromethane, etc. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 25 ~ 120 "C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h. The brominating agent used in the bromomethylation reaction includes N- bromosuccinimide (NBS) and l,3-dibromo-5,5-dimethylhydantoin, and is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound
(26). A catalyst may be used for facilitating the reaction. The catalyst used is 2,2'- azidobis(2-methylpropionitrile) (AIBN) or benzoyl peroxide, and typically used in the amount of 0.001 ~ 2 eq., preferably 0.01 ~ 0.3 eq., with respect to 1 eq. of the
Compound (26). This reaction may be carried out in an inert solvent selected from benzene, toluene, carbon tetrachloride, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 - 120 "C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (28) can be prepared by reacting sodium acetate (NaOAc) with the Compound (27). Sodium acetate is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 5 eq., with respect to 1 eq. of the Compound (27). This reaction may be carried out in an inert solvent, for example, selected from ethers such as tetrahydrofuran, diethylether, etc., alkyl nitriles such as acetonitrile, propionitrile, etc., amides such as N,N-dimethylformamide, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (29) can be prepared by removing the BOC group using an acid, and hydrolysis reaction using a base, in the order. The acid used in the removal of BOC group is hydrochloric acid, trifiuoroacetic acid, etc. The acid is typically used in the amount of 1 ~ 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (28). This reaction may be carried out in an inert solvent, for example, selected from ethers such as tetrahydrofuran, diethylether, dioxane, etc., alkyl alcohols such as methanol, ethanol, etc., chloroalkanes such as dichloromethane, chloroform, etc. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 25 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The base used in the hydrolysis reaction includes lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. The base is typically used in the amount of 2 ~ 20 eq., preferably 2 - 10 eq., with respect to 1 eq. of the Compound (28). This hydrolysis reaction may be carried out in an inert solvent, for example, selected from alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (30) can be prepared according to Reaction Schemes (10) and (11).
Compound (31) can be prepared via a coupling reaction of the Compound (29) with the Compound (30) according to the preparing process of the Compound (8) in the Reaction Scheme (2).
Compound (32) can be prepared by reacting PClswith the Compound (31). hi this reaction of using PCl5, cyclization and chlorination of the alcohol group occur simultaneously. PCl5 is typically used in the amount of 1 ~ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (31). This reaction may be carried out in a solvent selected from dichloromethane, chloroform, etc. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 0 ~ 50 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (33) is commercially available.
Compound (34) can be prepared via a coupling reaction of the Compound (32) with the Compound (33) according to the preparing process of the Compound (16).
Reaction Scheme 7
Figure imgf000051_0001
in the above Reaction Scheme (7), a represents an acylating agent [for example, Rl 1 -CO-Cl, (Rl 1-CO)2O], b represents PCl5, c represents a metal hydroxide (for example, NaOH, LiOH),
Rl 1 represents p-MeOBn,
Rl 4 represents Ci-C6-alkyl, and
Rl 5 represents C!-C6-alkoxycarbonyl or Ci-Cό-alkylcarbonyloxy.
Compound (35) can be prepared by protecting the alcohol group of the Compound (31) with an acyl group, and cyclizing using PCl5. The protection reaction of the alcohol group is carried out using a base and an acylating agent. The base used includes organic bases such as triethylamine, diisopropylethylamine, pyridine, etc. The base is typically used in the amount of 1 - 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (31). The acylating agent used is a compound in the form of R14-CO-C1 or (R14-CO)2O (R14=Ci~C6-alkyl). The acylating agent is typically used in the amount of 1 ~ 10 eq., preferably 1 - 3 eq., with respect to 1 eq. of the Compound (31). This reaction may be carried out in a solvent selected from dichloromethane, chloroform, dichloroethane, etc. The reaction temperature is typically in the range of - 10 - 200 °C , preferably 0 - 50 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The cyclization reaction uses PCl5. PCl5 is typically used in the amount of 1 - 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (31). This reaction may be carried out in a solvent selected from dichloromethane, chloroform, etc. The reaction temperature is typically in the range of -10 - 200 °C, preferably 0 - 50 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min - 12 h.
Compound (36) can be prepared via a deprotection reaction of the hydroxyl group of the Compound (35) using a base. The base used in the deprotection reaction includes lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. The base is typically used in the amount of 1 - 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (35). This reaction may be carried out in an inert solvent, for example, selected from water, alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc. The reaction temperature is typically in the range of -10 - 200 °C , preferably 25 - 120 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Reaction Scheme 8
Figure imgf000053_0001
(37) (38) (40) (5)
Figure imgf000053_0002
in the above Reaction Scheme (8), a represents sodium nitrite (NaNO2); tin chloride (SnCl2), b represents a ketone compound (39), a base (for example, NaOAc), c represents an acid (for example, polyphosphoric acid PPA), d represents NaNO2, e represents Compound (42), a base (for example, NaOH),
R8 is as defined in the Reaction Scheme (1), and
R9 and RlO are as defined in the Reaction Scheme (2).
Compound (37) is commercially available, or can be prepared by a method known in Heterocycles, 68(11), 2285-99, 2006, or Bioorganic & Medicinal Chemistry Letters, 14(19), 4903-4906, 2004.
Compound (38) is commercially available, or can be prepared by converting the amine group of the Compound (37) to hydrazine group according to a method known in Journal of the American Chemical Society, 198(48), 15374-75, 2006. Alternatively, the hydrazine Compound (38) can be prepared by reacting the amine group of the Compound (37) with NaNO2 in the presence of hydrochloric acid to give a diazonium salt (41), which is not separated and reduced by using SnCl2. NaNO2 is typically used in the amount of 1 ~ 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (37). SnCl2 is typically used in the amount of 1 ~ 10 eq., preferably 2 ~
5 eq., with respect to 1 eq. of the Compound (37). This reaction is carried out in 1 ~
12N, preferably 4 ~ 8N, aqueous hydrochloric acid solution. The reaction temperature is in the range of -10 ~ 50 °C , and the reaction time is typically in the range of 10 min ~ 6O h, preferably 10 min ~ 6 h.
Compound (39) is commercially available.
Hydrazone Compound (40) can be prepared via a coupling reaction of the Compound (38) with the ketone Compound (39). A base is not used when the Compound (38) is in neutral form, but should be used when the Compound (38) is in the form of an acid salt to make the neutral form. As the base, for example, metal hydroxides such as sodium hydroxide, lithium hydroxide, etc., metal carbonates such as sodium bicarbonate, potassium carbonate, etc., metal acetates such as sodium acetate, etc., organic bases such as triethylamine, pyridine, etc., preferably sodium acetate, sodium bicarbonate, etc. can be used. The base is typically used in the amount of 1 ~ 5 eq., preferably 1 - 2 eq., with respect to 1 eq. of the Compound (38). This reaction may be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, etc. The reaction temperature is in the range of -10 ~ 100 "C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The Compound (40) can also be prepared by reacting the diazonium salt (41) with the Compound (42) in the presence of a base according to Japp-Klingemann rearrangement method described in Organic Process Research & Development, 2, 1988,
214-220. Hydrochloric acid is used in the preparation of the diazonium salt (41) typically in the amount of 1 ~ 10 eq., preferably 2 ~ 4 eq., with respect to 1 eq. of the
Compound (37). The base used in the reaction of the Compounds (41) and (42) is sodium hydroxide, which is typically used in the amount of 1 ~ 20 eq., preferably 1 ~ 10 eq., with respect to 1 eq. of the Compound (42). 80% aqueous ethanol solution is used as the solvent, and the reaction temperature is in the range of -10 ~ 50 °C . The reaction time is typically in the range of 10 mim ~ 60 h, preferably 10 min ~ 12 h.
Compound (5) can be prepared using an acid catalyst and the Compound (40). The acid used in the synthesis is polyphosphoric acid, hydrochloric acid, p- toluenesulfonic acid, sulfuric acid, acetic acid, etc., preferably polyphosphoric acid. Polyphosphoric acid can be used alone, or as a mixture with aromatic hydrocarbons such as benzene, toluene, etc. The reaction temperature is in the range of 25 - 150 °C, and the reaction time is typically in the range of 5 mim ~ 60 h, preferably 5 min - 12 h.
Reaction Scheme 9
Figure imgf000055_0001
in the above Reaction Scheme (9), a represents a sodium alkoxide (for example, sodium methoxide), b represents heat,
Rl is as defined in formula (1),
R8 is as defined in the Reaction Scheme (1), and R9 represents Ci-C6-alkyl.
Compound (43) is commercially available.
Compound (44) can be prepared by a method known in Journal of Medicinal Chemistry, 31(11), 2145, 1988.
Compound (45) is commercially available, or can be prepared by a method known in WO 2007040289, WO200601079 or Organic Letters 9(3), 397-400, 2007.
Alternatively, the Compound (45) can be prepared via a coupling reaction of the
Compound (43) with the Compound (44) in the presence of a base. The base used is sodium methoxide, sodium ethoxide, etc. The base is typically used in the amount of 1 ~ 10 eq., preferably 1 ~ 3 eq., with respect to 1 eq. of the Compound (43). This reaction may be carried out in an inert solvent, for example, selected from alkyl alcohols such as methanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably -10 - 25 °C, and the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
Compound (46) can be prepared by cyclizing the Compound (45). The cyclization reaction may be carried out by dissolving the Compound (45) in an inert solvent, and heating the solution. The inert solvent that can be used includes tetrahydrofuran, benzene, toluene, etc. The reaction temperature is typically in the range of 25 ~ 200 °C , preferably 50 ~ 120 °C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Reaction Scheme 10
Figure imgf000057_0001
(47) (48) (49)
Figure imgf000057_0002
(50) <51) (J) in the above Reaction Scheme (10), a represents p-methoxybenzylchloride (PMBCl) or triphenylmethyl- chloride (TrCl), a base (for example, NaOH), b represents di-t-butyloxy-dicarbonyl (BoC2O), a base (for example,
NaOH, K2CO3 ), c represents an alkylchloroformate (for example, EtOCOCl), a base (for example, N-methylmorpholine), d represents diazomethane (CH2N2), a base (for example, KOH), e represents a silver ion (for example, silver benzoate), f represents an acid, g represents MsCl, Et3N, h represents p-methoxybenzylthiol (PMBSH), NaH, R9 represents Ci-C6-alkyl, and Rl 1 represents p-MeOBn or Ph3C.
Compound (47) can be prepared by protecting the thiol group of cysteine using p-methoxybenzyl chloride (PMBCl) or triphenylmethyl chloride (TrCl) in the presence of a base.
PMBCl or TrCl used in the protection reaction of the thiol group is typically used in the amount of 1 ~ 5 eq., preferably 1 - 2 eq., with respect to 1 eq. of cysteine. The base used is sodium hydroxide, potassium carbonate, etc., and is typically used in the amount of 1 ~ 5 eq, preferably 1 ~ 2 eq., with respect to 1 eq. of cysteine. This reaction may be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, water, etc. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 0 ~ 50 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (48) can be prepared by protecting the amine group of the Compound (47) using BOC group.
Boc2O used in the protection reaction of the amine group is typically used in the amount of 1 ~ 5 eq., preferably 1 ~ 2 eq., with respect to 1 eq. of cysteine. The base used is selected, for example, from hydroxides such as sodium hydroxide, lithium hydroxide, etc., carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc., organic bases such as diisopropylethylamine, triethylamine, etc., preferably potassium carbonate, triethylamine, etc. This reaction may be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, water, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 0 ~ 50 "C, and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
Compound (49) can be prepared by a method known in Helvetica Chimica Acta, 87, 2004, 3131-3159.
1 Eq. of the Compound (48) is reacted with 1 ~ 2 eq. of ethylchloroformate
(EtOCOCl) or isobutylchloroformate (1BuOCOCl) in tetrahydrofuran solvent maintained at room temperature in the presence of 1 ~ 2 eq. of a base {for example, N-methylmorpholine (NMM), triethylamine, etc.} to give an anhydride compound. The resulting anhydride compound is reacted with 1 ~ 5 eq. of diazomethane and 1 - 5 eq. of aqueous potassium hydroxide solution in diethylether solvent maintained at 0 °C , and then reacted with 0.1 - 2 eq. of an Ag ion (for example, silver trifluoroacetate (CF3CO2Ag), silver benzoate, etc.) and 1 - 10 eq. of an alkyl alcohol (for example, methanol, ethanol, etc.) under the dark condition at room temperature to give an alkyl ester.
The reaction for removing the BOC group can be made using an acid. The acid used includes hydrochloric acid, trifluoroacetic acid, etc. The acid is typically used in the amount of 1 - 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (48). This reaction may be carried out in an inert solvent, for example, selected from ethers such as tetrahydrofuran, diethylether, dioxane, etc., alkyl alcohols such as methanol, ethanol, etc., chloroalkanes such as dichloromethane, chloroform, etc. The reaction temperature is typically in the range of -10 ~ 200 °C, preferably 25 ~ 120 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min - 12 h.
Compound (50) can be prepared from glutamic acid or aspartic acid by a method known in Synlett, 15, 2005, 2397-2399, Journal of Organic Chemistry, 66(5), 2001, 1919-1923, etc.
Compound (51) can be prepared by sulfonating the Compound (50). The sulfonation reaction may be carried out using methanesulfonyl chloride in the presence of an organic base such as pyridine, triethylamine, etc. The sulfonylating agent and base each are used in the amount of 1 ~ 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (50). This reaction may be carried out in an inert solvent selected from dichloromethane, dichloroethane, etc. The reaction temperature is typically in the range of -10 - 200 °C , preferably 0 - 50 °C, and the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
The Compound (7) can be prepared by reacting p-methoxybenzylthiol
(PMBSH) with the Compound (51) in the presence of a base, and removing the BOC group using an acid. The base used is sodium hydride, potassium carbonate, cesium carbonate, etc., preferably sodium hydride. The base is typically used in the amount of 1 - 10 eq., preferably 2 - 5 eq., with respect to 1 eq. of the Compound (51). p- Methoxybenzylthiol (PMBSH) is typically used in the amount of 1 ~ 10 eq., preferably 2 ~ 5 eq., with respect to 1 eq. of the Compound (51). This reaction may be carried out in an inert solvent selected from tetrahydrofuran, dimethylformamide, N- methylpyrrolidinone, etc. The reaction temperature is typically in the range of -10 ~ 200 °C , preferably 25 ~ 100 °C , and the reaction time is typically in the range of 10 min ~ 60 h, preferably 10 min ~ 12 h.
The reaction for removing BOC group may be carried out in the same manner as the removal of BOC group explained in the preparing process of the Compound (49).
Reaction Scheme 11
Figure imgf000061_0001
(47) (52) (20) in the above Reaction Scheme (11), a represents an alkyl alcohol (for example, methanol, ethanol), acetyl chloride or thionyl chloride, b represents di-t-butyloxy-dicarbonyl (BoC2O), a base (for example,
NaOH, K2CO3), c represents a reducing agent (for example, NaBH4), d represents an alkylcarbonyl chloride (for example, t-butylcarbonyl chloride (1BuCOCl)), a base (for example, Et3N), e represents an acid,
R9 represents Ci-C6-alkyl, Rl 1 represents p-MeOBn or Ph3C, and R14 represents Ci-C6-alkyl.
Compound (52) can be prepared by esterifying the carboxylic group of the Compound (47), and protecting the amine group with BOC group. The esterification reaction may be carried out using acetyl chloride or thionyl chloride in an alkyl alcohol solvent. Acetyl chloride or thionyl chloride is used in the amount of 1 ~ 10 eq., preferably 1 - 5 eq., with respect to 1 eq. of the Compound (47). The reaction temperature is typically in the range of 25 - 200 °C, preferably 25 - 100 °C , and the reaction time is typically in the range of 10 min - 60 h, preferably 10 min - 12 h.
The protection reaction of the amine group may be carried out in the same manner as the preparing process of the Compound (48).
The Compound (20) can be prepared from the starting Compound (52) via reduction of the ester group, protection of the alcohol group, and removal of BOC, in the order. The reduction reaction of the ester group may be carried out by reacting with an alkylchloro formate (for example, ethylchloroformate, isobutylchloroformate) in tetrahydrofuran solvent of room temperature in the presence of 1 ~ 5 eq. of a base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, etc.) to give an anhydride, which is then reacted with 1 - 5 eq. of lithium borohydride or sodium borohydride in aqueous tetrahydrofuran solution of 0 ~ 25 "C for 10 min — 12 h.
The protection reaction of the alcohol group may be carried out by reacting with an alkylcarbonylchloride, for example, t-BuCOCl, in dichloromethane solvent of 0 ~ 25 °C in the presence of 1 ~ 5 eq. of a base selected from triethylamine, pyridine, etc. for 10 min ~ 12 h.
The reaction for removing BOC group may be carried out by dissolving the reactant in an inert solvent selected from tetrahydrofuran, dioxane, ethyl acetate, dichloromethane, etc. and reacting with 1 ~ 10 eq. of hydrochloric acid or trifluoroacetic acid at 0 ~ 50 °C for lO min - 12 h.
The compounds whose preparation methods are not specifically explained in the present specification are known per se, or can be prepared from a known compound according to a known process or a similar process thereto.
The compounds of formula (1) obtained by the above processes may be separated or purified from the reaction product by various methods such as recrystallization, ionophoresis, silica gel column chromatography, ion exchange chromatography, etc.
As explained above, the compounds according to the present invention, starting materials, intermediates, etc. for the preparation thereof may be obtained by various processes, and such processes for preparing the compounds of formula (1) should be construed to fall under the scope of the present invention.
[Effect]
The present invention further provides a pharmaceutical composition for the activation of glucokinase, which comprises the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
Diseases which are caused by the deactivation of glucokinase, and can be prevented or treated by the pharmaceutical composition of the present invention include, but not limited to, diabetes, complications of diabetes, obesity, etc. The pharmaceutical composition of the present invention can be used for the prevention or treatment of type 1 diabetes or type 2 diabetes, and is particularly preferable for type 2 diabetes. The complications of diabetes that can be prevented or treated by the pharmaceutical composition of the present invention include, but not limited to, hyperlipidemia, hypertension, retinosis, renal failure, etc.
The present invention further provides a hypoglycemic composition which comprises the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
The present invention further provides a process for preparing a pharmaceutical composition for the activation of glucokinase, more specifically, for the prevention or treatment of diabetes, complications of diabetes, or obesity, which comprises the step of mixing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
The above-mentioned "pharmaceutical composition" or "hypoglycemic composition" may comprise pharmaceutically acceptable carriers, diluents, excipients, or their combinations, if needed, together with the compounds of the present invention. Pharmaceutical composition facilitates the administration of the compound into a living organism. There exist a number of techniques to administer the compound, and they include, but not limited to, oral, injectable, aerosol, parenteral and topical administration.
As used herein, "carrier" means a substance which facilitates the incorporation of the compound into the cells or tissues. For example, dimethylsulfoxide (DMSO) is a typical carrier which is used to facilitate the introduction of various organic compounds into the cells or tissues of living organisms.
As used herein, "diluent" is defined as a substance that is diluted in water which dissolves the compound, as well as stabilizes the biologically active form of the subject compound. The salts dissolved in buffer solution are utilized as diluents in the art. Typically used buffer solution is phosphate buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
As used herein, "pharmaceutically acceptable" means the property that does not impair the biological activities and physical properties of the compound.
The compounds of the present invention can be formulated as various pharmaceutical dosage forms according to the purpose. In preparing the pharmaceutical composition of the present invention, the active ingredient, specifically, the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof are mixed together with various pharmaceutically acceptable carriers which can be selected according to the formulation to be prepared. For example, the pharmaceutical composition of the present invention can be formulated as injectable preparation, oral preparation, etc., according to the purpose.
The compounds of the present invention can be formulated by the methods known in the art, which utilize pharmaceutical carriers and excipients known in the art, and be incorporated into the containers of unit dose form or multi-dose form. The form of the preparation can be solutions, suspensions or emulsions in oily or aqueous media, and may contain typical dispersing agents, suspending agents or stabilizers. Further, for example, it can be a form of dry powder which is intended to be reconstructed by dissolving in sterile, pyrogen-free water prior to use. The compounds of the present invention also can be formulated into suppository forms utilizing typical suppository bases such as cocoa butter or other glycerides. As solid dosage forms for oral administration, capsules, tablets, pills, powder and granule can be prepared, and capsules and tablets are especially useful. Preferably, tablets and pills are prepared as enteric coated forms. Solid dosage forms can be prepared by mixing the compounds of the present invention together with carriers, for example, one or more inert diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrant, binder, etc.
If needed, the compounds of the present invention or the pharmaceutical compositions containing the same can also be administered in combination with other active agents, for example, other agents for treating diabetes.
The dosage of the compounds of formula (1) depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, and severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 1 to 500 mg per day, depending on the intensity and frequency of the administration. When administered to an adult via intramuscular or intravenous routes, total dosage typically from about 5 to 300 mg per day will be sufficient when separately administered in a single dosage, but for some patients a higher daily dosage may be desirable.
The present invention further provides a method for the prevention or treatment of diseases which are caused by the deactivation of glucokinase, using effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient.
The present invention further provides a process for preparing a pharmaceutical composition for the prevention or treatment of diseases which are caused by the deactivation of glucokinase, which comprises the step of mixing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
As used herein, "treatment" means the interrupting or delaying the progress of the disease when applied to the subject showing the onset of disease symptoms, and "prevention" means the interrupting or delaying the sign of the onset of disease when applied to the subject that does not show, but is at risk of, the onset of disease symptoms.
The present invention will be more specifically explained by the following preparations and examples. However, it should be understood that they are intended to illustrate the present invention but not in any manner to limit the scope of the present invention. In the following preparations and examples, M means molar concentration, and N means normal concentration.
[Best Mode for Carrying Out the Invention]
Preparation 1: Synthesis of 2-[(4-fluoro-2-nitro-phenyl)-hydrazono]- propionic acid ethyl ester
2-[(4-Fluoro-2-nitro-phenyl)-hydraz
Figure imgf000068_0001
ono]-propionic acid ethyl ester
4-Fluoro-2-nitroaniline (1Og, 64mmol) was dissolved in 6N hydrochloric acid (64ml, 0.27mol), sodium nitrate (4.4g, 64mmol) dissolved in water (50ml) was slowly added in drops thereto at 0 "C , and the mixture was stirred for 30 min at 0 °C ~ room temperature. Simultaneously, ethyl 2-methylacetoacetate (9.2ml, 64mmol) and sodium hydroxide (19g, 0.34mol) were dissolved in 80% aqueous ethanol solution (95ml), and stirred for 10 min at 0 °C . The two solutions thus prepared were mixed, and stirred for 8 h at 0 "C ~ room temperature. Water was added to the reaction solution, and the insoluble solid was collected. The solid was washed with water, and dried to give the title compound (7.9g, Yield 46%).
1H-NMR (400HMz, CDCl3); δ 10.81(br s, IH), 8.05(m, IH), 7.90(m, IH), 7.41(m, IH), 4.36(q, 2H), 2.22(S, 3H), 1.38(t, 3H)
Preparation 2: Synthesis of S-fluoro-T-nitro-lH-indole-l-carboxylic acid ethyl ester
5-Fluoro-7-nitro-1 H-indole-2-carbox ylic acid ethyl ester
Figure imgf000069_0001
The compound (8.8g, 33mmol) prepared in Preparation 1 was mixed with polyphosphoric acid (50ml), and stirred for 7 h at 60 °C . Water was added to the reaction solution, and the insoluble solid was collected. The solid was washed with water, and dried to give the title compound (3.4g, Yield 41%). 1H-NMR (400HMz, DMSOd6); δ 11.55(br s, IH), 8.16(m, IH), 8.10(m, IH),
7.42(s, IH), 4.40(q, 2H), 1.36(t, 3H)
Preparation 3: Synthesis of (4-chloro-2-nitro-phenyl)-hydrazine hydrochloride
rin (4-Chloro-2-nitro-phenyl)-hydrazine
Figure imgf000069_0002
4-Chloro-2-nitroaniline (4Og, 0.23 mol) was dissolved in 12N hydrochloric acid
(100ml). At 0 °C , sodium nitrate (16g, 0.23 mol) dissolved in water (50ml) was slowly added in drops thereto, and the mixture was stirred for 30 min at 0 °C ~ room temperature. The temperature was lowered to 0 °C , and tin(II) chloride (132g, 0.70mol) dissolved in 12N hydrochloric acid (100ml) was slowly added in drops thereto. The mixture was stirred for 3 h at 0 °C ~ room temperature. The resulting yellow solid was filtered, washed with a small quantity of 6N HCl, and dried to give the title compound (3Og, Yield 63%).
1H-NMR (400HMz, DMSOd6); δ 9.21(s, IH), 7.98(d, J=2.4Hz, IH), 7.66 (d, J=9.6Hz, IH), 7.55(dd, J=2.4, 9.6Hz, IH), 4.74(br s, 2H)
Preparation 4: Synthesis of 2-[(4-chloro-2-nitro-phenyl)-hydrazono]- propionic acid methyl ester
2-[(4-Chloro-2-nitro-phenyl)-hydraz ono]-propionic acid methyl ester
Figure imgf000070_0001
The hydrazine (3Og, 0.14mol) prepared in Preparation 3 and methyl pyruvate
(14.4ml, 0.16mol) were dissolved in methanol (300ml), and sodium acetate (14.2g, 0.17mol) was added thereto. The mixture was stirred for 8 h at room temperature.
The resulting yellow solid was filtered, washed with water and methanol, and dried to give the title compound (3Og, Yield 82%).
1H-NMR (400HMz, CDCl3); δ 10.88(s, IH), 8.21 (d, J=2.4Hz, IH), 8.01(d, J=9.2Hz, IH), 7.56(dd, J=2.4,9.2Hz, IH), 3.90(s, 3H), 2.23(s, 3H). Mass Spectrum (ESI, m/z): Calculated for Ci0H10ClN3O4 271.04, Found 271.66
Preparation 5: Synthesis of S-chloro^-nitro-lH-indole^-carboxylic acid methyl ester
5-Chloro-7-nitro-1 H-indole-2-carbox ylic acid methyl ester
Figure imgf000070_0002
To the compound (13 g, 46 mmol) prepared in Preparation 4 was added polyphosphoric acid (100ml), which was then heated at 100 "C for 4 h. After completion of the reaction, water was added to the reaction solution, and the insoluble solid was collected. The solid was washed with water, and dried to give the title compound (6.Og, Yield 49%).
1H-NMR (400HMz, CDCl3); δ 10.32(br s, IH), 8.29(d, IH), 8.03(d, J=2.4Hz, IH), 7.3 l(d, J=2.0Hz, IH), 4.01 (s, 3H) Mass Spectrum (ESI, m/z): Calculated 254.01, Found 254.63
Preparation 6: Synthesis of S-bromo^-nitro-lH-indole-Z-carboxylic acid methyl ester
5-Bromo-7-nitro-1 H-indole-2-carboxy lie acid methyl ester
Figure imgf000071_0001
4-Bromo-2-nitroaniline (15.6g, 71.9 mmol) was reacted according to the same procedures as Preparations 3 to 5 to give the title compound (7.2g, Yield 73%).
1H-NMR (400HMz, CDCl3); δ 10.33(br s, IH), 8.41(s, IH), 8.18(s, IH), 7.30(d, J=4.0Hz, IH), 4.01(s, 3H)
Preparation 7: Synthesis of 5-methyl-7-nitro-lH-indole-2-carboxylic acid methyl ester
Figure imgf000071_0002
4-Methyl-2-nitroaniline (4Og, 0.26mol) was reacted according to the same procedures as Preparations 3 to 5 to give the title compound (2Og, Yield 32%). 1H-NMR (500HMz, DMSOd6); δ 11.25(br s, IH), 8.08(3, IH), 7.96(s, IH),
7.32(s, IH), 3.87(s, 3H), 2.44(s, 3H) Preparation 8: Synthesis of 7-nitro-lH-indole-2-carboxylic acid methyl ester
7-Nitro-1 H-indole-2-carboxylic acid methyl ester
Figure imgf000072_0001
2-Nitroaniline (3Og, 0.21mol) was reacted according to the same procedures as
Preparations 3 to 5 to give the title compound (1 Ig, Yield 23%).
1H-NMR (500HMz, DMSOd6); δ 11.36(br s, IH), 8.23(d, IH), 8.17(d, IH), 7.42(s, IH), 7.32(t, IH), 3.88(s, 3H)
Preparation 9: Synthesis of 5-methoxy-7-nitro-lH-indoIe-2-carboxylic acid methyl ester
0Vo" j* 5-Methoxy-7-nitro-1 H-indole-2-carbo
0^ / N~~T| > | χy''c ac'd methyl ester
< ΛAΛ0.
4-Methoxy-2-nitrophenylamine (3Og, 0.18mol) was reacted according to the same procedures as Preparations 3 to 5 to give the title compound (12g, Yield 27%).
Preparation 10: Synthesis of 4-ethoxy-2-nitro-phenylamine
Figure imgf000072_0002
4-Ethoxy-phenylamine 4-Ethoxy-2-nitro-phenylamine
4-Ethoxyaniline (4Og, 0.29mol) and triethylamine (61ml, 0.44 mol) were dissolved in dichloromethane (200ml). Acetic anhydride (30ml, 0.32 mmol) was added in drops thereto, and the mixture was stirred for 1 h at 0 °C ~ room temperature. IN hydrochloric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.
The resulting acetamide compound was dissolved in dichloromethane (200ml), and fuming nitric acid (13ml, 0.29 mol) was added in drops thereto at 0 °C . The mixture was stirred for 1 h at 0 "C ~ room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.
The resulting nitrate compound was dissolved in methanol (100ml) and tetrahydrofuran (100ml), and 6N sodium hydride was added in drops thereto. The mixture was stirred for 6 h at room temperature. After completion of the reaction, the reaction solution was neutralized to about pH 7 using 6N hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound (44g, Yield 83%).
Preparation 11: Synthesis of S-ethoxy-T-nitro-lH-indole-Z-carboxylic acid methyl ester
5-Ethoxy-7-nitro-1 H-indole-2-carbox ylic acid methyl ester
Figure imgf000073_0001
4-Ethoxy-2-nitroaniline (4Og, 0.22 mol) prepared in Preparation 10 was reacted according to the same procedures as Preparations 3 to 5 to give the title compound (13g, Yield 22%).
1H-NMR (400HMz, DMSOd6); δ 10.20(br s, IH), 7.86(s, IH), 7.51(s, IH), 7.26(s, IH), 4.13(m, 2H), 3.98(s, 3H), 1.47(m, 3H)
Preparation 12: Synthesis of T-nitro-S-phenoxy-lH-indole^-carboxylic acid methyl ester
7-Nitro-5-phenoxy-1H-indole-2-carbo xylic acid methyl ester
Figure imgf000074_0001
4-Aminophenyl phenyl ether (2Og, 0.11 mol) was reacted according to the same procedures as Preparation 10 and Preparations 3 to 5 in the order to give the title compound (5g, Yield 15%).
1H-NMR (400HMz, CDCl3); δ 10.26(br s, IH), 8.05(s, IH), 7.69(s, IH), 7.39(m, 2H), 7.26(s, IH), 7.15(m, IH), 7.01(m, 2H), 4.00(s, 3H)
Preparation 13: Synthesis of 7-nitro-5-(pyridin-3-yloxy)-lH-indole-2- carboxylic acid ethyl ester
7-Nitro-5-(pyridin-3-yloxy)-1 H-indo le-2-carboxylic acid ethyl ester
Figure imgf000074_0002
(Step 1)
Figure imgf000075_0001
3-(4-Nitro-phenoxy)-pyridine 4-(Pyridin-3-yloxy)-phenylamine l-Chloro-4-nitrobenzene (4Og, 0.25 mol) and 3-hydroxypyridine (36g, 0.38 mol) were dissolved in N,N-dimethylformamide (100ml). Potassium carbonate (52.6g, 0.38 mol) was added thereto, and the mixture was stirred for 20 h at 100 °C . Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give 3-(4-nitro-phenoxy)-pyridine.
The compound thus obtained was dissolved using water (100ml), tetrahydrofuran (100ml) and methanol (100ml). Iron powder (103g, 1.84 mol) and ammonium chloride (99g, 1.84 mol) were added thereto, and the mixture was stirred using a mechanical stirrer for 3 h at 80 "C . After completion of the reaction, the reaction solution was filtered through a celite, washed with methanol, and concentrated.
The resulting solid was filtered, washed with ether, and dried to give 4-(pyridin-3- yloxy)-phenylamine ( 17g, Yield 36%).
(Step 2)
Figure imgf000075_0002
7-Nitro5-(pyridin-3-yloxy)-1 H-indo le-2-carboxylic acid ethyl ester
4-(Pyridin-3-yloxy)-phenylamine (25g, 0.13 mol) prepared in Step 1 was reacted according to the same procedures as Preparation 10 and Preparations 3 to 5 in the order to give the title compound (4.2g, Yield 10%).
1H-NMR (400HMz, CDCl3); δ 10.32(br s, IH), 8.51~8.47(m, 2H), 8.05(d, J=2.4Hz, IH), 7.73(d, J=2.0Hz, IH), 7.42~7.35(m, 2H), 7.3 l(d, J=2.4Hz, IH), 4.48(q, 2H), 1.47(t, 3H)
Preparation 14: Synthesis of 5-(4-methanesulfonyl-phenoxy)-7-nitro-lH- indole-2-carboxylic acid methyl ester
5-(4-Methanesulfonyl-phenoxy)-7-nit ro-1 H-indole-2-carboxylic acid meth yl ester
Figure imgf000076_0001
(Step 1)
Figure imgf000076_0002
l-Chloro-4-nitrobenzene (15g, 95 mmol) and 4-(methylmercapto)phenol (13.3g,
95 mmol) were dissolved in dimethylsulfoxide (100ml). Potassium carbonate (15.8g, 134 mmol) was added thereto, and the mixture was stirred for 12 h at 100 °C . After completion of the reaction, excess water was added to give precipitated solid. The solid was filtered, and dried to give l-(4-methylsulfanylphenoxy)-4-nitrobenzene.
The compound thus obtained was dissolved in dichloromethane (500ml). mCPBA (3-chloroperbenzoic acid) (83g, 330 mmol) was added thereto, and the mixture was stirred for 2 h at 0 °C ~ room temperature. After completion of the reaction, excess 6N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate and dichloromethane. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give l-(4- methylsulfonylphenoxy)-4-nitrobenzene (28g, Yield 100%). (Step 2)
Figure imgf000077_0001
4-(4-Methanesulfonyl-phenoxy)-pheny lamine l-(4-Methylsulfonylphenoxy)-4-nitrobenzene (28g) prepared in Step 1 was dissolved in methanol (500ml) and ethyl acetate (500ml). 10% Pd/C (1.Og) was added thereto, and the mixture was stirred for 3 h under hydrogen gas of normal pressure. After completion of the reaction, the reaction solution was filtered through a celite, washed with methanol, concentrated, and dried to give 4-(4-methanesulfonylphenoxy)- phenylamine (25g, Yield 100%).
(Step 3)
Figure imgf000077_0002
4-(4-Methanesulfonylphenoxy)-phenylamine (25g, 95 mmol) was reacted according to the same procedures as Preparation 10 and Preparations 3 to 5 in the order to give the title compound (0.9g, Yield 2.4%).
Preparation 15: Synthesis of (R)-3-amino-4-(4-methoxy-benzylsulfanyi)- butyric acid methyl ester hydrochloride
(R)-3-Amino-4-(4-methoxy-benzylsulf
Figure imgf000077_0003
u, anyl)-butyric acid methyl ester
Cl (Step 1)
(R)-2-Amιno-3-(4-methoxy-benzylsulf anyl)-propιonιc acid
Figure imgf000078_0001
To a solvent mixture of diethylether (400ml) and cone, hydrochloric acid
(400ml) was added in drops 4-methoxybenzylalcohol (28Og, 1780mmol) dissolved in diethylether (400ml) for 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197g, 1625mmol) and 2N aqueous sodium hydroxide solution (980ml) in ethanol (1890ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was cooled to 0 °C, and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered, and dried to give (R)-2-amino-3-(4- methoxy-benzylsulfanyl)-propionic acid (25Og, 1035mmol, Yield: 64%).
(Step 2) nylannιno-3-(4 yl)-propιonιc
Figure imgf000078_0002
The compound (30.7g, 127.3mmol) prepared in Step 1 was dissolved in tetrahydrofuran (150ml) and water (150ml). Potassium carbonate (26.4g, 190mmol) and di-t-butyloxy-dicarbonyl (27.7g, 127.3mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The residue was cooled to 0 °C , and acidified to pH 3 using 3N aqueous hydrochloric acid solution. The resulting solid was washed with water, and dried to give (R)-2-t- butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propionic acid (43 g, 126mmol, Yield 99%).
(Step 3)
[(R)-3-Diazo-1-(4-methoxy-benzylsul fanylmethyl)-2-oxo-propyl]-carbamic acid tert-butyl ester
Figure imgf000079_0001
The compound (43g) prepared in Step 2, 1-methylmorpholine (14.5ml, 132mmol) and ethylchloroformate (14.1ml, 132mmol) were dissolved in tetrahydrofuran (500ml), and stirred for 1 h at -25 °C . Simultaneously, potassium hydroxide (75g, 1336mmol) was dissolved in water (75ml) and diethylether (750ml), N-methyl- nitrosourea (26g, 252mmol) was added in drops thereto for 2 h at 0 °C, and the mixture was stirred for 30 min. Thus prepared two solutions were mixed, and stirred for 3 h at - 25 °C ~ room temperature. After completion of the reaction, water was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous ammonium chloride solution in the order. The organic layer was concentrated to give [(R)-3-diazo-l-(4-methoxy-benzylsulfanylmethyl)-2-oxo-propyl]- carbamic acid t-butyl ester.
1H-NMR (400HMz, CDCl3); δ 7.25(d, J=8.8Hzm 2H), 6.86(d, J=8.8Hz, 2H), 5.48(br s IH), 5.29(m, IH), 4.3 l(m, IH), 3.79(s, 3H), 3.69(s, 2H), 2.76(d, J-6.0Hz, 2H), 1.45(s, 9H)
(Step 4) (R)-3-tert-Butoxycarbonylamino-4-(4 -methoxy-benzylsulfanylj-butyric ac id methyl ester
Figure imgf000080_0001
The compound prepared in Step 3 was dissolved in methanol (1000ml), silver benzoate (7.1g, 31.1mmol) was added thereto, and the mixture was sonicated for 1 h.
After completion of the reaction, the reaction solution was concentrated, and separated by column chromatography to give (R)-3-t-butoxycarbonylamino-4-(4-methoxy- benzylsulfanyl)-butyric acid methyl ester (35.2g, 95.3mmol, Yield 76%).
1H-NMR (500HMz, CDCl3); δ 7.24(d, J=8.6Hz, 2H), 6.83(d, J=8.6Hz, 2H), 5.09(m, IH), 4.08(m, IH), 3.79(s, 3H), 3.68(s, 2H), 3.66(s, 3H), 2.70~2.52(m, 4H), 1.44(s, 9H)
(Step 5)
The compound (35.2g) prepared in Step 4 was dissolved in dichloromethane (70ml), 4N hydrochloric acid/l,4-dioxane solution (71ml) was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was concentrated. Dichloromethane (30ml) and diethylether (150ml) were added to the residue, and the resulting solid was filtered and dried to give the title compound (25.5g, 83.3mmol, Yield 87%).
1K NMR (400MHz, DMSOd6); δ 8.21(br s, 3H), 7.25(d, 2H), 6.83(d, 2H), 3.78(s, 3H), 3.68(s, 2H), 3.65(s, 3H), 3.29(m, IH), 2.51-2.48(m, 2H), 2.35-2.31(m, 2H)
Preparation 16: Synthesis of (R)-3-amino-4-(4-methoxy-benzylsulfanyl)- butyric acid ethyl ester hydrochloride (R)-3-Amino-4-(4-methoxy-benzylsulf
Figure imgf000081_0001
-. 0 anyl)-butyric acid ethyl ester
Cl
L-cysteine (5Og, 0.41mol) was reacted according to the same procedure as Preparation 15 except that ethanol was used instead of methanol in Step 4 of Preparation 15 to give the title compound (5.2g, Yield 40%). 1H NMR (400MHz, CDCl3); δ 8.37(br s, 3H), 7.28(d, J=8.0Hz, 2H), 6.87(d,
J=8.0Hz, 2H), 4.1 l(m, 2H), 3.73(s, 3H), 3.70(s, 2H), 2.81~2.67(m, 4H), 1.18(t, 3H)
Preparation 17: Synthesis of (R)-4-amino-5-(4-methoxy-benzylsulfanyi)- pentanoic acid ethyl ester hydrochloride
(R)-4-Amino-5-(4-methoxy-benzylsulf anyl)-pentanoic acid ethyl ester
Figure imgf000081_0002
(Step 1)
(R)-4-tert-Butoxycarbonylamino-5-me thanesulfonyloxy-pentanoic acid eth y' ester
Figure imgf000081_0003
droxy-pentanoic acid ethyl ester
(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester (36g, 137.8mmol) that can be obtained by a known method and triethylamine (38.4ml, 275.5 mol) were dissolved in dichloromethane (200ml). Methanesulfonylchloride (11.7ml, 151.5 mmol) was added in drops thereto, and the mixture was stirred for 1 h at 0 °C ~ room temperature. IN hydrochloric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give (R)-4-t- butoxycarbonylamino-5-methanesulfonyloxy-pentanoic acid ethyl ester.
(Step 2)
(R)-4-tert-Butoxycarbonylamino-5-(4 .methoxy-benzylsulfanyl)-pentanoic
Figure imgf000082_0001
acid ethyl este7
Sodium hydride (5.5g, 137.8mmol) and 4-methoxybenzylmercaptan (15.4ml, 110.2mmol) were dissolved in N,N-dimethylformamide (150ml), and stirred for 10 min at 0 °C . To thus obtained solution was added in drops the methanesulfonate prepared in Step 1. The mixture was stirred for 4 h at 0 °C . After completion of the reaction, water was added, and the reaction solution was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and separated by column chromatography to give (R)-4-t- butoxycarbonylamino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid ethyl ester (21.Og, Yield 38%). 1H-NMR (400HMz, CDCl3); δ 7.25(d, J=8.8Hz, 2H), 6.85(d, J=8.8Hz, 2H),
4.56(m, IH), 4.12(m, 2H), 3.79(s, 3H), 3.69(s, 2H), 2.53(m, 2H), 2.33(t, 2H), 1.93(m, IH), 1.70(m, IH), 1.44(s, 9H), 1.25(t, 3H)
(Step 3)
Figure imgf000082_0002
The compound (Hg, 62.7mmol) prepared in Step 2 was dissolved in dichloromethane (200ml), and 4N hydrochloric acid/ethyl acetate solution (20ml) was added thereto. The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was thoroughly concentrated, and diethylether (150ml) was added thereto. The resulting solid was filtered and dried to give the title compound (2Og, Yield 96%).
1H NMR (400 MHz, DMSOd6); δ 8.69(br s, 3H), 7.29(d, J=8.0Hz, 2H), 6.89(d, J=8.0Hz, 2H), 4.08(m, 2H), 3.74(m, 5H), 3.26(m, IH), 2.76~2.63(m, 2H), 2.49~2.40(m, 2H), 1.89(m, 2H), 1.20(t, 3H)
Preparation 18: Synthesis of 2,2-dimethyl-propionic acid (R)-2-amino-3-(4- methoxy-benzylsulfanyl)-propyl ester
„, 2,2-Dimethyl-propionic acid (R)-2-a Cl mmiinnoo--33--((44--nmethoxy-benzylsulfanyl)-p ropyl ester
Figure imgf000083_0001
(Step 1)
Figure imgf000083_0002
(R)-2-Amino-3-(4-methoxy-benzylsulf anyl)-propionic acid methyl ester
The compound (5Og, 207.2mmol) prepared in Step 1 of Preparation 15 was dissolved in methanol (300ml). Acetyl chloride (21ml, 207.2mmol) was added in drops thereto, and stirred for 12 h at 50 °C . After completion of the reaction, the reaction solution was thoroughly concentrated, to which was added diethylether. The resulting solid was filtered and dried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)- propionic acid methyl ester.
1H NMR (400 MHz, DMSO-(I6, HCl salt); δ 8.81(br s, 3H), 7.29(d, J=8.4Hz, 2H), 6.91(d, J=8.4Hz, 2H), 4.28(m, IH), 3.18(br s, 8H), 2.95(m, 2H)
(Step 2) (R)-2-tert-Butoxycarbonylamino-3-(4 -methoxy-benzylsulfanyl)-propionic acid methyl ester
Figure imgf000084_0001
The compound prepared in Step 1 was dissolved in tetrahydrofuran (200ml) and water (200ml). Triethylamine (87ml, 621.6mmol) was added thereto, and di-t- butyloxy-dicarbonyl (43.Og, 196.8mmol) dissolved in tetrahydrofuran (100ml) was added in drops thereto while stirring. The mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give (R)-2-t- butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propionic acid methyl ester.
(Step 3)
[(R)-2-Hydroxy-1-(4-methoxy-benzyls
Figure imgf000084_0002
ulfanylmethyl)-ethyl]-carbamic acid tert-butyl ester
The compound prepared in Step 2 was dissolved in tetrahydrofuran (300ml).
Lithium borohydride (9.Og, 414.4mmol) was added thereto, and the mixture was stirred for 3 h at 0 °C . After completion of the reaction, water was added, and the reaction solution was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give [(R)-2- hydroxy- l-(4-methoxy-benzylsulfanylmethyl)-ethyl]-carbamic acid t-butyl ester.
1H NMR (500MHz, DMSOd6); δ 7.24(d, J=8.6Hz, 2H), 6.84(d, J=8.6Hz, 2H), 4.96(br s, IH), 3.78(s, 3H), 3.76(br s, IH), 3.70(s, 2H), 3.7~3.66(m, 3H), 2.58(m, 2H), 1.44(s, 9H)
(Step 4)
2,2-Dimethyl-propionic acid (R)-2-t ert-butoxycarbonylamino-3-(4-methox
Figure imgf000085_0001
y-benzylsulfanyl)-propyl ester
The compound prepared in Step 3 was dissolved in dichloromethane (300ml).
Triethylamine (58ml, 414.4mmol) and trimethylacetyl chloride (28ml, 227.9mmol) were added thereto, and the mixture was stirred for 6 h at 0 °C . After completion of the reaction, water was added, and the reaction solution was extracted with ethyl acetate.
The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and separated by column chromatography to give 2,2-dimethyl- propionic acid (R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propyl ester (81.Og, Yield 95%).
1R NMR (400 MHz, CDCl3); δ 7.25(d, J=8.8Hz, 2H), 6.85(d, J=8.8Hz, 2H),
4.71(m, IH), 4.1 l(m, 2H), 3.79(s, 3H), 3.70(s, 2H), 2.55(d, J=6.4Hz, 2H), 1.52(s, (H,
1.27(s, 9H)
(Step 5)
Figure imgf000085_0002
The compound (8 Ig, 196mmol) prepared in Step 4 was dissolved in dichloromethane (300ml). 4N hydrochloric acid/1, 4-dioxane solution (100ml) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was thoroughly concentrated, and diethylether was added. The resulting solid was filtered and dried to give the title compound (68g, Yield 95%).
1H NMR (400MHz, DMSOd6, free form ); δ 7.24(d, J=12.0Hz, 2H), 6.85(dd, J=4.0, 8.0Hz, 2H), 4.04(m, IH), 3.95(m, IH), 3.80(s, 3H), 3.68(s, 2H), 3.10(m, IH), 2.60(m, IH), 2.36(m, IH)5 1.18(s, 9H)
Preparation 19: Synthesis of 2,2-dimethyl-propionic acid (R)-2-(7-amino-
1 H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester
2,2-Dimethyl-propionic acid (R)-2-( 7-amino-1H-indol-2-yl)-4,5-dihydro-
Figure imgf000086_0001
thiazol-4-ylmethyl ester
(Step 1)
Figure imgf000086_0002
Methyl 7-nitroindole-2-carboxylate (13g, 59 mmol) prepared in Preparation 8 was dissolved in a solvent mixture of tetrahydrofuran and water (1 :1, 300ml), and IN aqueous sodium hydroxide solution (180ml, 177 mmol) was added thereto. The mixture was stirred for 3 h at room temperature, excess 6N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give 7-nitro-lH-indole-2- carboxylic acid (12g, Yield 99%). (Step 2)
2,2-Dιmethyl-propιonιc acid (R)-3-( 4-methoxy-benzylsulfanyl)-2-[(7-nιt ro-1 H-ιndolθ-2-carbonyl)-amιno]-pro pyl ester
Figure imgf000087_0001
7-Nitroindole-carboxylic acid compound (8.2g, 22.7mmol) prepared in Step 1 and the amine compound (13.2g, 27.2mmol) prepared in Preparation 18 were dissolved in N,N-dimethylformamide (100ml), and EDC (6.6g, 25.0mmol) and HOBT (4.6g,
25.0mmol) were added thereto. The mixture was stirred for 8 h at room temperature, and saturated sodium bicarbonate solution was added thereto. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, concentrated, and the residue was purified by column chromatography to give 2,2-dimethyl-propionic acid (R)-3-(4-methoxy- benzylsulfanyl)-2-[(7-nitro-lH-indole-2-carbonyl)-amino-propyl ester (8.1g, Yield 71%).
1H-NMR (400HMz, CDCl3); δ 10.47(br s, IH), 8.27(d, J=8.0Hz, IH), 8.01 (d,
J=8.0Hz, IH), 7.26(m, 2H), 6.93(d, J=4.0Hz, IH), 6.83(m, 2H), 6.74(d, J=8.0Hz, IH), 4.56(m, IH), 4.44(m, IH), 4.24(m, IH), 3.74(m, 5H), 2.77(m, IH), 2.62(m, IH), 1.18(s,
9H)
2,2-Dιmethyl-propionιc acid (R)-2-( 7-nιtro-1 H-ιndol-2-yl)-4,5-dιhydro-
Figure imgf000087_0002
thιazol-4-ylmethyl ester The compound (1.6g, 3.2mmol) prepared in Step 2 was dissolved in dichloromethane (50ml). Phosphorus pentachloride (1.3g, 6.4mmol) was added thereto, and the mixture was stirred for 5 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added thereto. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, concentrated, and the residue was purified by column chromatography to give 2,2-dimethyl-propionic acid (R)-2-(7-nitro-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester (0.8g, Yield 69%).
1H-NMR (400HMz, CDCl3); δ 10.53(br s, IH), 8.26(d, J=8.0Hz, IH), 7.99(d, J=8.0Hz, IH), 7.04(d, J=2.0Hz, IH), 6.90(d, J=7.6Hz, IH), 4.78(m, IH), 4.46(m, IH), 4.30(m, IH), 3.59(m, IH), 3.36(m, IH), 1.20(s, 9H)
(Step 4)
2,2-Dimethyl-propionic acid (R)-2-( 7-amino-1 H-indol-2-yl)-4,5-dihydro-
Figure imgf000088_0001
thiazol-4-ylmethyl ester
The compound (2.7g, 7.5mmol) prepared in Step 3 was dissolved in a solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 150ml). iron powder (4.2g, 74.7mmol) and ammonium chloride (4.Og, 74.7mmol) were added, and the mixture was stirred for 30 min at 60 °C using a mechanical stirrer. After completion of the reaction, water was added thereto. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (2.Og, Yield 81%). 1H-NMR (400HMz, CDCl3); δ 9.86(br s, IH), 7.30(d, J=7.6Hz, IH), 7.14(d,
J=8.0Hz, IH), 6.89(d, J=2.0Hz, IH), 6.61(dd, J=0.8,7.2Hz, IH), 4.96(m, IH), 4.36(m, 2H), 3.55(m, IH), 3.33(m, IH)9 1.18(s, 9H) Preparation 20: Synthesis of 2,2-dimethyl-propionic acid (R)-2-(7- cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester
2,2-Dimethyl-propionic acid (R)-2-( 7-cyclopentylamino-1 H-indol-2-yl)-4 ,5-dihydro-thiazol-4-ylmethyl ester
Figure imgf000089_0001
The compound (2.Og, 5.0 mmol) prepared in Preparation 19 was dissolved in 1 ,2-dichloroethane (100ml). Cyclopentanone (0.8g, 7.5 mmol) and sodium triacetoxyborohydride (1.9g, 7.5 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added thereto.
The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.3g, Yield 54%).
Example 1: Synthesis of [(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5- dihydro-l,3-thiazol-4-yl]-methanoI
[(R)-2-(7-Cyclopentylamino-1 H-indol
-2-yl)-4,5-dihydro-thiazol-4-yl]-me
Figure imgf000089_0002
thanol The compound (1.3g, 3.3mmol) prepared in Preparation 20 was dissolved in tetrahydrofuran (10ml), methanol (10ml) and water (10ml). Lithium hydroxide hydrate (0.4g, 9.8mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. The reaction solution was concentrated by distillation under reduced pressure. IN hydrochloric acid was added to the residue, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (820mg, Yield 80%). 1H-NMR(SOOHMz, CDCl3); δ 11.17-11.08(m, IH), 7.09(m, IH), 6.99(t, IH), 6.96(s, IH), 6.52(m, IH), 4.72(m, IH), 4.04(m, IH), 3.75(m, IH), 3.65(m, IH), 3.51(m, IH), 3.40(m, IH), 1.90(m, 2H), 1.60~1.49(m, 4H), 1.41~1.24(m, 2H)
Mass Spectrum (ESI, m/z): Calculated 315.14, Found 315.44
Example 2: Synthesis of {(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol- 2-yl]-4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[7-(Tetrahydro-pyran-4-ylamι nnoo))--11HH--ιιnnddooll--22--yyll]]--44,5-dιhydro-thιa
Figure imgf000090_0001
zol-4-yl}-methanol
(Step 1)
2,2-Dιmethyl-propιonιc acid (R)-2-[ 7-(tetrahydro-pyran-4-ylamιno)-1H-ι ndol-2-yl]-4,5-dιhydro-thιazol-4-yl
Figure imgf000090_0002
methvl ester
The compound (900mg, 2.7mmol) prepared in Preparation 19 was dissolved in 1 ,2-dichloroethane (100ml). Tetrahydro-4H-pyran-4-one (0.8ml, 8.13mmol), sodium triacetoxyborohydride (1.72g, 8.13mmol) and acetic acid (0.47ml, 8.13mmol) were added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give 2,2-dimethylpropionic acid (R)-2-[7-(tetrahydro-pyran- 4-ylamino)-lΗ-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethyl ester.
1H-NMR (400HMz, CDCl3); δ 10.91(br s, IH), 7.01~6.91(m, 3H), 6.48(d, J=7.2Hz, IH), 4.86(m, IH), 4.34(m 2H), 4.00(m, 2H), 3.61(m, IH), 3.54(m, 3H), 3.31(m, IH), 2.05(m, 2H), 1.55(m, 2H), 1.16(s, 9H)
(Step 2)
Figure imgf000091_0001
The compound prepared in Step 1 was dissolved in methanol (32ml), tetrahydrofuran (32ml) and water (16ml). IN sodium hydroxide (7ml) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (700mg, Yield 78%).
1H-NMR (SOOHMz, CDCl3); δ 11.04~10.95(m, IH), 7.11(m, IH), 6.99(t, IH), 6.96(s, IH), 6.52(m, IH), 4.74(m, IH), 4.02(m, IH), 3.92(m, 2H), 3.68(m, IH), 3.46~3.30(m, 5H), 1.91(m, 2H), 1.28(m, 2H) Mass Spectrum (ESI, m/z): Calculated 331.14, Found 331.44
Example 3: Synthesis of {(R)-2-[7-(tetrahydro-furan-3-ylamino)-lH-indol- 2-yl]-4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[7-(Tetrahydro-furan-3-ylami no)-1 H-indol-2-yl]-4,5-dihydro-thia zol-4-yl}-methanol
Figure imgf000091_0002
The compound (940mg, 2.9mmol) prepared in Preparation 19 and tetrahydrofuran-3-one instead of tetrahydro-4H-pyran-4-one were reacted according to the same procedure as Example 2 to give the title compound (650mg, Yield 69%). 1H-NMR (500HMz, CDCl3); δ 10.58(br s, IH), 7.14(d, J=7.95Hz, IH), 7.00(m, IH), 6.94(m, IH), 6.48(d, J=7.35Hz, IH), 4.79(m, IH), 4.15~3.95((m, 3H), 3.90~3.65(m, 4H), 3.50~3.39(m, 2H), 2.20(m, IH), 1.83(m, IH)
Example 4: Synthesis of {(R)-2-[7-(l-methanesulfonyl-pyrrolidin-3- ylamino)-! H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[7-(1-Methanesulfonyl-pyrrol idin-3-ylamino)-1 H-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-methanol
Figure imgf000092_0001
(Step 1)
A 3-{2-[(R)-4-(2,2-Dimethyl-propionyl oxymethyl)-4,5-dihydro-thiazol-2-yl ]-1 H-indol-7-ylamino}-pyrrolidine-1 -carboxylic acid tert-butyl ester
Figure imgf000092_0002
The compound (l.Omg, 3.0mmol) prepared in Preparation 19 and 3-oxo- pyrrolidine-1 -carboxylic acid t-butyl ester (l.lg, ό.Ommol) instead of tetrahydro-4H- pyran-4-one were reacted according to the same procedure as Step 1 of Example 2 to give a pyrrolidine compound (853mg, Yield 57%).
(Step 2)
2,2-Dimethyl-propionic acid (R)-2-[ 7-(1-methanesulfonyl-pyrrolidin-3-y lamino)-1Η-indol-2-yl]-4,5-dihydro- thiazol-4-ylmethyl ester
Figure imgf000092_0003
The compound (460mg, 0.9mmol) prepared in Step 1 was dissolved in methanol (50ml), and 4N hydrochloric acid solution (0.8ml, 2.7mmol) was added thereto. The mixture was stirred for 8 h at room temperature, distilled under reduced pressure, and purified by column chromatography.
Thus purified compound (313mg, 0.8mmol) was dissolved in dichloromethane (50ml). Triethylamine (158mg, l.όmmol) and methanesulfonyl chloride (90mg, O.δmmol) were added, and the mixture was stirred for 30 min at 0 °C ~ room temperature. After completion of the reaction, water was added to the reaction solution, which was then extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give a sulfonamide compound (223mg, Yield 58%).
(Step 3)
The compound (223mg, 0.47mmol) prepared in Step 2 was reacted according to the same procedure as Example 1 to give the title compound (152mg, Yield 82%).
1H-NMR (500HMz, CDCl3); δ 10.50(br s, IH), 7.15(d, J=7.95Hz, IH), 7.00(dd, IH), 6.93(s, IH), 6.46(d, J=7.35Hz, IH), 4.77(m, IH), 4.18(m, IH), 4.08(dd, IH), 3.75(dd, IH), 3.59~3.36(m, 6H), 3.48(s, 3H), 2.27(m, IH), 1.95(m, IH)
Preparation 21: Synthesis of 2,2-dimethyl-propionic acid (R)-2-[7-amino-
5-fluoro-lH-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethyl ester
2,2-Dιmethyl-propιonιc acid (R)-2-( 7-amιno-5-fluoiO-1 H-ιndol-2-yl)-4,5
Figure imgf000093_0001
-dιhydro-thιazol-4-ylmethyl ester
Ethyl 5-fluoro-7-nitro-lH-indole-2-carboxylate (6.Og, 23.8mmol) prepared in Preparation 2 was reacted according to the same procedure as Preparation 19 to give the title compound (2.3g, Yield 28%).
Example 5: Synthesis of [(R)-2-(7-cycIopentylamino-5-fluoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-methanol
N^^ [(R)-2-(7-Cyclopentylamino-5-fluoro
~--s. M w X -1 H-indol-2-yl)-4,5-dihydro-thiazol
T y / J] I -4-yl]-methanol
The amine compound (l.lg, 3.1mmol) prepared in Preparation 21 was reacted according to the same procedures as Preparation 20 and Example 1 to give the title compound (600mg, Yield 58%). 1H-NMR (400HMz, CDCl3); δ 10.73(br s, IH), 6.91(s, IH), 6.72(m, IH),
6.33(m, IH), 4.78(m, IH), 4.12(m, IH), 3.97(br s, IH), 3.79(m, IH), 3.75(m, IH), 3.49(m, 2H), 2.0 l(m, 2H), 1.62(m, 4H), 1.41(m, 2H)
Example 6: Synthesis of {(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)- 1 H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[5-Fluoro-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl}-methanol
Figure imgf000094_0001
The amine compound (l.lg, 3.1mmol) prepared in Preparation 21 was reacted according to the same procedure as Example 2 to give the title compound (750mg, Yield 68%). 1H-NMR (400HMz, CDCl3); δ 10.45(br s, IH), 6.90(s, IH), 6.75(m, IH),
6.34(m, IH), 4.82(m, IH), 4.12(m, IH), 4.01(m, 2H), 3.94(m, IH), 3.78(m, IH), 3.54~3.43(m, 5H), 2.03(m, 2H), 1.50(m, 2H)
Example 7: Synthesis of [(R^-β-chloro-J-cyclopentylamino-lH-indol-I- yl)-4,5-dihydro-thiazol-4-yl]-methanol
[(R)-2-(5-Chloro-7-cyclopentylamιno
-1 H-ιndol-2-yl)-4,5-dιhydro-thιazol
-4-yl]-methanol
Figure imgf000095_0001
(Step 1)
2,2-Dιmethyl-propιonιc acid (R)-2-( 7-amιno-5-chloro-1 H-ιndol-2-yl)-4,5
Figure imgf000095_0002
-dιhydro-thιazol-4-ylmethyl ester
Methyl S-chloro-V-nitro-lH-indole^-carboxylate (3.Og, 11.8 mmol) prepared in Preparation 5 was reacted according to the same procedure as Preparation 19 to give an amine compound (2.4g, Yield 56%).
(Step 2)
The amine compound (150mg, 0.4 mmol) prepared in Step 1 was reacted according to the same procedures as Preparation 20 and Example 1 to give the title compound (50mg, Yield 36%).
1H-NMR (500HMz, CDCl3); δ 10.53(br s, IH), 7.24(s, IH), 6.84(d, IH), 6.45(s, IH), 4.74(m, IH), 4.06(m, IH), 3.81(m, IH), 3.71(m, IH), 3.45(dd, 2H), 1.99(m, 2H), 1.60(m, 4H), 1.37(m, 2H)
Example 8: Synthesis of {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol {(R)-2-[5-Chloro-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl}-methanol
Figure imgf000096_0001
The amine compound (150mg, 0.4 mmol) prepared in Step 1 of Example 7 was reacted according to the same procedure as Example 2 to give the title compound (40mg, Yield 27%).
Example 9: Synthesis of {(R)-2-[5-chloro-7-(tetrahydro-thiopyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yI}-methanol
{(R)-2-[5-Chloro-7-(tetrahydro-thio pyran-4-ylamino)-1 H-indol-2-yl]-4,5 -dihydro-thiazol-4-yl}-methanol
Figure imgf000096_0002
The amine compound (150mg, 0.4 mmol) prepared in Step 1 of Example 7 and tetrahydro-thiopyran-4-one instead of tetrahydro-4H-pyran-4-one were reacted according to the same procedure as Example 2 to give the title compound (130mg, Yield 85%).
1H-NMR (400ΗMz, CDCl3); δ 10.87(br s, IH), 7.01(s, IH), 6.89(s, IH), 6.40(s, IH), 4.80(m, IH), 4.10(m, IH), 3.80(m, IH), 3.50(m, 2H), 3.32(m, IH), 2.76(m, 4H), 2.29(m, 2H), 1.56 (m, 2H)
Example 10: Synthesis of [(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-methanol
[(R)-2-(5-Bromo-7-cyclopentylamino-
1 H-indol-2-yl)-4,5-dihydro-thiazol-
4-yl]-methanol
Figure imgf000096_0003
Methyl 5-bromo-7-nitro-lH-indole-2-carboxylate (1.3g, 4.3mmol) prepared in Preparation 6 was reacted according to the same procedures as Preparation 19, Preparation 20 and Example 1 in the order to give the title compound (lOOmg, Yield 6%).
1H-NMR (400HMz, CDCl3); δ 10.59(br s, IH), 7.23(s, IH), 6.88(s, IH), 6.64(d, IH), 4.77(m, IH), 4.14(m, IH), 3.82(m, IH), 3.76(m, IH), 3.49(dd, 2H), 2.04(m, 2H), 1.65(m, 4H), 1.41(m, 2H)
Example 11: Synthesis of {(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[5-Bromo-7-(tetrahydro-pyran
-4-ylamino)-1 H-indol-2-yl]-4,5-dihy dro-thiazol-4-yl}-methanol
Figure imgf000097_0001
Methyl 5-bromo-7-nitro-lH-indole-2-carboxylate (1.3g, 4.3mmol) prepared in
Preparation 6 was reacted according to the same procedures as Preparation 19 and Example 2 in the order to give the title compound (70mg, Yield 4%).
1H-NMR (400HMz, CDCl3); δ 10.53(br s, IH), 7.25(s, IH), 6.87(s, IH), 6.63(d, IH), 4.80(m, IH), 4.14(m, IH), 4.03(m, 2H), 3.79(m, IH), 3.56-3.3.44(m, 4H), 2.02(m, 2H), 1.45(m, 2H)
Example 12: Synthesis of [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-methanoI
[(R)-2-(7-Cyclopentylamino-5-methox y-1H-indol-2-yl)-4,5-dihydro-thiazo l-4-yl]-methanol
Figure imgf000097_0002
Methyl 5-methoxy-7-nitro-lH-indole-2-carboxylate (700mg, 2.8mmol) prepared in Preparation 9 was reacted according to the same procedures as Preparation 19,
Preparation 20 and Example 1 in the order to give the title compound (80mg, Yield 8%).
1H-NMR (500HMz, DMSO-d6); δ 11.23(br s, IH), 6.60(s, IH), 6.23(s, IH),
5.89(m, IH), 5.84(m, IH), 4.96(m, IH), 4.65(m, IH), 3.77(m, IH), 3.70(m, IH), 3.45(m, IH), 3.33(m, IH), 3.29(s, 3H), 1.91(m, 2H), 1.67(m, 2H), 1.53(m, 4H)
Example 13: Synthesis of {(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[7-Cyclopentylamino-5-(pyrid in-3-yloxy)-1 H-indol-2-yl]-4,5-dihy dro-thiazol-4-yl}-methanol
Figure imgf000098_0001
7-Nitro-5-(pyridin-3-yloxy)-lH-indole-2-carboxylic acid ethyl ester (500mg,
1.5mmol) prepared in Preparation 13 was reacted according to the same procedures as Preparation 19, Preparation 20 and Example 1 in the order to give the title compound (35mg, Yield 6%).
1H-NMR (400HMz, CDCl3); δ 11.16(br s, IH), 8.42(d, IH), 8.28(m, IH), 7.30(m, IH), 7.22(m, IH), 6.88(s, IH), 6.67(d, IH), 6.28(d, IH), 4.83(m, IH), 4.02(m, IH), 3.75(m, 2H), 3.46(m, 2H), 1.97(m, 2H), 1.63(m, 4H), 1.43(m, 2H)
Example 14: Synthesis of {(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran- 4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanoI H-indol-2-
Figure imgf000098_0002
7-Nitro-5-(pyridin-3-yloxy)-lH-indole-2-carboxylic acid ethyl ester (500mg, 1.5mmol) prepared in Preparation 13 was reacted according to the same procedures as Preparation 19 and Example 2 in the order to give the title compound (40mg, Yield 6%). 1H-NMR (400HMz, CDCl3); δ 10.96(br s, IH), 8.36(d, J=2.4Hz, IH), 8.26(m, IH), 7.27(m, IH), 7.19(m, IH), 6.83(s, IH), 6.63(d, J=1.6Hz, IH), 6.24(d, JNl.όHz, IH), 4.81(m, IH), 4.01~3.94(m, 3H), 3.75(m, IH), 3.47(s, 3H), 3.48~3.29(m, 5H), 1.93(m, 2H), 1.52(m, 2H)
Preparation 22: Synthesis of methanesulfonic acid (R)-2-(7- cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester
Methanesulfonic acid (R)-2-(7-cyclo pentylamino-1H-indol-2-yl)-4,5-dihy dro-thiazol-4-ylmethyl ester
Figure imgf000099_0001
The compound (820mg, 2.6mmol) prepared in Example 1 was dissolved in dichloromethane (50ml). Methanesulfonyl chloride (0.24ml, 3.1mmol) and triethylamine (0.81ml, 3.1mmol) were added thereto, and the mixture was stirred for 30 min at 0 °C . After completion of the reaction, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (600mg, Yield 60%).
Example 15: Synthesis of cyclopentyl-[2-((R)-4-pyrrolidin-l-ylmethyl-4,5- dihydro-thiazol-2-yl)-lH-indol-7-yl]-amine
Cyclopentyl-[2-((R)-4-pyrrolidin-1- ylmethyl-4,5-dihydro-thiazol-2-yl)- 1 H-indol-7-yl]-amine
Figure imgf000099_0002
The compound (150mg, 0.38mmol) prepared in Preparation 22 was dissolved in N,N-dimethylformamide (5ml). Pyrrolidine (0.08ml, l.lmmol) was added thereto, and the mixture was stirred for 4 h at 70 °C . After completion of the reaction, water was added, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (20mg, Yield 14%).
1H-NMR (400HMz, DMSOd6); δ 11.37(br s, IH), 6.83(m, IH), 6.75(d, J=2.0Hz, IH), 6.29(d, J=8.0Hz, IH), 5.86(d, J=8.0Hz, IH), 4.80(m, IH), 3.87(m, IH), 3.52(m, IH), 3.43(m, IH), 3.33(m, 2H), 2.78(m, 2H), 2.61(m, 2H), 1.99(m, 2H), 1.72(m, 6H), 1.60(m, 4H)
Example 16: Synthesis of cyclopentyl-[2-((R)-4-morpholin-4-ylmethyl-4,5- dihydro-thiazol-2-yl)-l H-indol-7-yl] -amine
Cyclopentyl-[2-((R)-4-morpholin-4-y lmethyl-4,5-dihydro-thiazol-2-yl)-1 H-indol-7-yl]-amine
Figure imgf000100_0001
The compound (150mg, 0.38mmol) prepared in Preparation 22 and morpholine instead of pyrrolidine were reacted according to the same procedure as Example 15 to give the title compound (50mg, Yield 34%).
1H-NMR (400HMz, DMSOd6); δ 11.37(br s, IH), 6.83(m, IH), 6.75(m, IH), 6.29(d, J=8.0Hz, IH), 5.85(d, J=8.0Hz, IH), 4.87(m, IH), 3.87(m, IH), 3.61(m, 4H), 3.35(m, 3H), 2.71(m, IH), 2.54(m, 2H), 2.44(m, 2H), 1.99(m, 2H), 1.74(m, 6H), 1.59(m, 4H)
Example 17: Synthesis of cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5- dihydro-thiazol-2-yl)-lH-indol-7-yl]-amine Cyclopentyl-[2-((R)-4-dimethylamino methyl-4,5-dihydro-thiazol-2-yl)-1H
-indol-7-yl]-amine
Figure imgf000101_0001
The compound (150mg, 0.38mmol) prepared in Preparation 22 and dimethylamine instead of pyrrolidine were reacted according to the same procedure as Example 15 to give the title compound (20mg, Yield 15%). 1H-NMR (400HMz, CDCl3); δ 9.87(br, IH), 7.05(d, J=8.0Hz, IH), 6.99(t,
IH), 6.89(s, IH), 6.52(d, J=8.0Hz, IH), 4.83(m, IH), 3.91(m, IH), 3.50(t, IH), 3.29(t, IH), 2.63(m, IH), 2.44(m, IH), 2.29(s, 6H), 2.04(m, 2H), 1.70(m, 2H), 1.50(m, 4H)
Example 18: Synthesis of 2-[2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2- yl)-lH-indol-7-ylamino]-propionic acid
2-[2-((R)-4-Hydroxymethyl-4,5-dihyd ro-thiazol-2-yl)-1H-indol-7-ylamino
Figure imgf000101_0002
]-propionic acid
The compound prepared in Preparation 19 and methyl pyruvate were reacted according to the same procedures as Preparation 20 and Example 1 consecutively to give the title compound. 1H-NMR (400HMz, CDCl3); δ 11.16 (m, IH), 10.43 (br, IH), 7.04 (m, IH),
7.00 (m, IH), 6.97 (m, IH), 6.53(m, IH), 4.74 (m, IH), 4.14 (m, IH), 4.05 (m, IH), 3.77(m, IH), 3.57 (m, IH), 3.42(m, IH), 1.43(d, 3H)
Example 19: Synthesis of {(R)-2-[7-(4-nitro-phenylamino)-lH-mdol-2-yl]- 4,5-dihydro-thiazol-4-yl}-methanol
Figure imgf000102_0001
The compound prepared in Preparation 19 and 4-fluoro-nitrobenzene were reacted in the presence of a base Cs2CO3 according to the same procedure as Example 15 to give the title compound. 1H-NMR ^OOHMZ9 CDCI3); δ 11.15(br, IH), 7.85(d, 2H), 7.04 (m, IH), 6.97
(m, IH), 6.96(m, IH), 6.65(d, 2H), 6.53(m, IH), 4.73(m, IH), 4.10(m, IH), 3.78 (m, IH), 3.52(m, IH), 3.38(m, IH)
Preparation 23: Synthesis of S-methyl-^-nitro-indole-l^-dicarboxylic acid 1-t-butyl ester 2-methyl ester
5-Methyl-7-nitro-indole-1 ,2-dicarbo xylic acid 1-tert-butyl ester 2-met hyl ester
Figure imgf000102_0002
The compound (24.Og, lOOmmol) prepared in Preparation 7 was dissolved in dichloromethane (500ml). Triethylamine (84ml, όOlmmol) and 4- (dimethylamino)pyridine (600mg, 5mmol) were added, and di-t-butyloxy-dicarbonyl (43. Ig, 200mmol) dissolved in dichloromethane (100ml) was added in drops thereto. The mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound (34.Og, Yield 100%). 1H-NMR (500HMz, CDCl3); δ 7.80(s, IH), 7.67(s, IH), 7.15(s, IH), 3.93(s,
3H), 2.51 (s, 3H), 1.62(s, 9H) Preparation 24: Synthesis of 5-bromomethyl-7-nitro-indole-l,2- dicarboxylic acid 1-t-butyl ester 2-methyl ester
5-Bromomethyl-7-nitro-indole-1 ,2-di carboxylic acid 1-tert-butyl ester 2-methyl ester
Figure imgf000103_0001
The compound (34g, lOUmmol) prepared in Preparation 23 was dissolved in carebon tetrachloride (100ml). N-bromosuccinimide (27.2g, 152.6mmol) and AIBN (1.7g, 10.2mmol) were added thereto, and the mixture was stirred for 5 h at 80 °C . After completion of the reaction, the reaction solution was distilled under reduced pressure, and purified by column chromatography to give the title compound (48.Og, Yield 100%).
1H-NMR (500HMz, CDCl3); δ 8.01(s, IH), 7.90(s, IH), 7.21(s, IH), 4.60(s, 2H), 3.93(s, 3H), 1.62(s, 9H)
Preparation 25: Synthesis of 5-acetoxymethyl-7-nitro-indole-l,2- dicarboxylic acid 1-t-butyl ester 2-methyl ester
5-Acetoxymethyl-7-nitro-indole-1,2- dicarboxylic acid 1-tert-butyl este r 2-methyl ester
Figure imgf000103_0002
The compound (10. Og, 24.2mmol) prepared in Preparation 24 was dissolved in
N,N-dimethylformamide (50ml). Sodium acetate (2.4g, 29.0mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and purified by column chromatography to give the title compound (4.7g, Yield 50%).
1H-NMR (500HMz, CDCl3); δ 7.99(s, IH), 7.90(s, IH), 7.21(s, IH), 5.22(s, 2H), 3.94(s, 3H), 2.12(s, 3H), 1.63(s, 9H)
Preparation 26: Synthesis of 5-acetoxymethyl-7-nitro-lH-indoIe-2- carboxylic acid methyl ester
5-Acetoxymethyl-7-nitro-1 H-indole-2 -carboxylic acid methyl ester
Figure imgf000104_0001
The compound (4.7g, 12.0mmol) prepared in Preparation 25 was dissolved in dichloromethane (50ml). 2N hydrochloric acid solution (30ml, 60mmol) was added thereto, and the mixture was stirred for 12 h at room temperature and distilled under reduced pressure to give the title compound (3.5g, Yield 100%) as a solid.
1H-NMR (500HMz, CDCl3); δ 10.33(br s, IH), 8.32(s, IH), 8.06(s, IH), 7.34(s, IH), 5.24(s, 2H), 3.99(s, 3H), 2.12(s, 3H)
Preparation 27: Synthesis of 5-hydroxymethyl-7-nitro-lH-indole-2- carboxylic acid
5-Hydroxymethyl-7-nitro-1 H-indole-2 -carboxylic acid
Figure imgf000104_0002
The compound (3.5g, 12.0mmol) prepared in Preparation 26 was dissolved in a solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 100ml). Lithium hydroxide hydrate (1.5g, 35.9mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After distillation of the mixture under reduced pressure, 1 N hydrochloric acid was added to the residue. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (2.3g, Yield 81%).
1H-NMR (500HMz, DMSOd6); δ 11.02(br s, IH), 8.21(s, IH), 8.10(s, IH), 7.34(s, IH), 5.43(br s, IH), 4.64(s, 2H)
Preparation 28: Synthesis of 2,2-dimethyl-propionic acid (R)-2-[(5- hydroxymethyl-7-nitro-lH-indole-2-carbonyl)-amino]-3-(4-methoxy- benzylsulfanyl)-propyl ester
2,2-Dimethyl-propionic acid (R)-2-[ (5-hydroxymethyl-7-nitro-1 H-indole- 2-carbonyl)-amino]-3-(4-methoxy-ben zylsulfanyl)-propyl ester
Figure imgf000105_0001
The compound (2.2g, 9.3mmol) prepared in Preparation 27 was reacted according to the same procedure as Step 2 of Preparation 19 to give the title compound (4.Og, Yield 84%).
Preparation 29: Synthesis of 2,2-dimethyl-propionic acid (R)-2-(5- chIoromethyl-7-nitro-lH-indol-2-yI)-4,5-dihydro-thiazol-4-ylmethyl ester acid (R)-2-( e
Figure imgf000105_0002
The compound (1.Og, 1.9mmol) prepared in Preparation 28 was dissolved in dichloromethane (30ml). Phosphorus pentachloride (0.8g, 3.9mmol) was added thereto, and the mixture was stirred for 6 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound (0.7g, Yield 90%).
1H-NMR (500HMz, CDCl3); δ 12.89(br s, IH), 8.40(s, IH), 7.98(s, IH), 7.42(s, IH), 5.30(m, IH), 4.73(s, 2H), 4.61(m, IH), 4.54(m, IH), 3.97(m, IH), 3.62(m, IH), 1.20(s, 9H)
Example 20: Synthesis of {(R)-2-[5-morpholin-4-ylmethyl-7-(tetrahydro- pyran-4-ylamino)-lH-indoI-2-yl]-4,5-dihydro-thiazol-4-yI}-methanol
H-indol
Figure imgf000106_0001
The compound prepared in Preparation 29, morpholine and tetrahydropyran-4- one were reacted according to the same procedures as Example 15, Preparation 20 and Example 1 in the order to give the title compound (20mg, Yield 12%).
1H-NMR (400HMz, CDCl3); δ 10.77(br s, IH), 7.06(s, IH), 6.95(s, IH), 6.62(s, IH), 4.80(m, IH), 4.1 l(m, IH), 3.99(m, 2H), 3.76(m, IH), 3.75(m, 4H), 3.51(s, 2H), 3.45(m, 5H), 2.51(br s, 4H), 2.00(m, 2H), 1.45(m, 2H)
Example 21: Synthesis of [(R)-2-[7-cyclopentylamino-5-pyrazol-l-ylmethyl- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol
[(R)-2-(7-Cyclopentylamino-5-pyrazo l-1-ylmethyl-1 H-indol-2-yl)-4,5-dih ydro-thiazol-4-yl]-methanol
Figure imgf000106_0002
(Step 1) 2,2-Dimethyl-propionic acid (R)-2-( 7-nitro-5-pyrazol-1 -ylmethyl-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-ylme
Figure imgf000107_0001
thyl ester
The compound (300mg, 0.73mmol) prepared in Preparation 29 was dissolved in N,N-dimethylformamide (10ml). Potassium carbonate (300mg, 2.2mmol) and pyrazole (149mg, 2.2mmol) were added thereto, and the mixture was stirred for 1 h at room temperature. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give a pyrazole compound (225mg, Yield
%).
(Step 2)
The compound (300mg, 0.68mmol) prepared in Step 1 was reacted according to the same procedures as Step 4 of Preparation 19, Preparation 20 and Example 1 in the order to give the title compound (42mg, Yield 24%).
1H-NMR (500HMz, CDCl3); δ 11.05(brs, IH), 7.52(s, IH), 7.34(s, IH), 6.93(s, IH), 6.87(s, IH), 6.34(s, IH), 6.23(m, IH), 5.30(s, 2H), 4.71(m, IH), 3.99(m, IH), 3.66(m, 2H), 3.42(m, 2H), 1.86(m, 2H), 1.52(m, 4H), 1.26(m, 2H)
Example 22: Synthesis of [(R)-2-(7-cyclopentylamino-5-imidazol-l- ylmethyI-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl}-methanol
[(R)-2-(7-Cyclopentylamino-5-imidaz ol-1-ylmethyl-1H-indol-2-yl)-4,5-di hydro-thiazol-4-yl]-methanol
Figure imgf000107_0002
The compound (300mg, 0.73mmol) prepared in Preparation 29 and imidazole instead of pyrazole were reacted according to the same procedure as Example 21 to give the title compound (65mg, Yield 23%).
1H-NMR (500HMz, CDCl3); δ 11.10(brs, IH), 8.20(s, IH), 7.25(s, IH), 7.23(s, IH), 6.87(m, 2H), 6.16(s, IH), 5.05(s, 2H), 4.77(m, IH), 3.96(m, IH), 3.73(m, 2H), 3.43(m, 2H), 1.92(m, 2H), 1.59(m, 4H), 1.38(m, 2H)
Example 23: Synthesis of {(R)-2-[7-cyclopentylamino-5-(lH-pyrrol-3- yImethyl)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol
{(R)-2-[7-Cyclopentylamino-5-(1 H-py rrol-3-ylmethyl)-1H-indol-2-yl]-4,5 -dihydro-thiazol-4-yl}-methanol
Figure imgf000108_0001
The compound (300mg, 0.73mmol) prepared in Preparation 29 and pyrrole instead of pyrazole were reacted according to the same procedure as Example 21 to give the title compound (65mg, Yield 23%).
1H-NMR (500HMz, CDCl3); δ 11.04(brs, IH), 7.85(s, IH), 6.88(m, 2H), 6.61(s, IH), 6.36(s, IH), 6.13(m, IH), 6.00(s, IH), 4.71(m, IH), 4.04(m, IH), 3.99(s, 2H), 3.69(m, 2H), 3.45(m, 2H), 1.90(m, 2H), 1.55(m, 4H), 1.32(m, 2H)
Example 24: Synthesis of [(R)-2-(7-cyclopentylamino-5- methanesulfonylmethyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol
[(R)-2-(7-Cyclopentylamino-5-methan esulfonylmethyl-1H-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-methaπol
Figure imgf000108_0002
The compound (330mg, 0.81mmol) prepared in Preparation 29 and sodium methanesulfinate instead of pyrazole were reacted according to the same procedure as Example 21 to give the title compound (152mg, Yield 46%).
1H-NMR (500HMz, CDCl3); δ 11.10(brs, IH), 7.01(s, IH), 6.88(m, IH), 6.49(s, IH), 4.76(m, IH), 4.26(s, 2H), 3.99(m, IH), 3.79(m, IH), 3.68(m, IH), 3.43(m, 2H), 2.73(s, 3H), 1.96(m, 2H), 1.57(m, 4H), 1.35(m, 2H)
Preparation 30: Synthesis of 2,2-dimethyl-propionic acid (R)-2-{[5-(2,2- dimethyl-propionyIoxymethyl)-7-nitro-lH-indole-2-carbonyl]-amino}-3-(4- methoxy-benzylsulfanyl)-propyl ester 2,2-Dimethyl-propionic acid (R)-2-{ [5-(2,2-dimethyl-propionyloxymethyl
)-7-nitro-1 H-indole-2-carbonyl]-anni no}-3-(4-methoxy-benzylsulfanyl)-pr opyl ester
Figure imgf000109_0001
The compound (3.1g, ό.Ommol) prepared in Preparation 28 was dissolved in dichloromethane (50ml). Triethylamine (1.2g, 12.0mmol) and pivaloyl chloride (0.8g, 6.6mmol) were added thereto, and the mixture was stirred for 8 h at 0 °C . After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (3.6g, Yield 98%). 1H-NMR (400HMz, CDCl3); δ 10.47(brs, IH), 8.27(s, IH), 8.01(s, IH),
7.27(d, J=8.0Hz, 2H), 6.92(s, IH), 6.83(d, J=8.0Hz, 2H), 6.76(d, J=8.0Hz, IH), 5.25(s, 2H), 4.56(m, IH), 4.42(m, IH), 4.22(m, IH), 3.75(s, 3H), 3.74(s, 2H), 2.82(m, IH), 2.69(m, IH), 1.25(s, 9H), 1.20(s, 9H)
Preparation 31: Synthesis of 2,2-dimethyl-propionic acid (R)-2-[5-(2,2- dimethyl-propionyloxymethyl)-7-nitro-lH-indol-2-yl]-4,5-dihydro-thiazol-4- ylmethyl ester 2,2-Dimethyl-propionic acid (R)-2-[
5-(2,2-dimethyl-propionyloxymethyl)
-7-nitro-1 H-indol-2-yl]-4,5-dihydro
-thiazol-4-ylmethyl ester
Figure imgf000110_0001
The compound (3.6g, 5.9mmol) prepared in Preparation 30 was reacted according to the same procedure as Step 3 of Preparation 19 to give the title compound (2.Og, Yield 72%). 1H-NMR (400HMz, CDCl3); δ 12.91(brs, IH), 8.35(s, IH), 7.96(s, IH),
7.46(s, IH), 5.40(m, IH), 5.23(s, 2H), 4.64(m, 2H), 4.09(m, IH), 3.64(m, IH), 1.27(s, 9H), 1.19(s, 9H)
Preparation 32: Synthesis of 2,2-dimethyl-propionic acid (R)-2-[7-amino- 5-(2,2-dimethyl-propionyloxymethyl)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethyl ester
2,2-Dimethyl-propionic acid (R)-2-[
7-amino-5-(2,2-dimethyl-propionylox ymethyl)-1 H-indol-2-yl]-4,5-dihydro -thiazol-4-ylmethyl ester
Figure imgf000110_0002
The compound (2.Og, 4.2mmol) prepared in Preparation 31 was reacted according to the same procedure as Step 4 of Preparation 19 to give the title compound (LOg, Yield 53%).
1H-NMR (400HMz, CDCl3); δ 10.08(brs, IH), 7.26(s, IH), 6.87(s, IH), 6.60(s, IH), 5.09(s, 2H), 4.95(m, IH), 4.40(m, 2H), 3.58(m, IH), 3.35(m, IH), 1.20(s, 9H), 1.12(s, 9H)
Example 25: Synthesis of [7-cyclopentylamino-2-((R)-4-hydroxymethyl-4,5- dihydro-thiazol-2-yl)-l H-indoI-5-yl] -methanol [7-Cyclopentylamιno-2-((R)-4-hydrox ymethyl-4,5-dιhydro-thιazol-2-yl)-1
H-ιndol-5-yl]-methanol
Figure imgf000111_0001
The compound (lOOmg, 0.22mmol) prepared in Preparation 34 was reacted according to the same procedures as Preparation 20 and Example 1 to give the title compound (lOmg, Yield 13%).
1H-NMR (400HMz, CDCl3); δ 9.63(brs, IH), 7.40(s, IH), 7.18(s, IH), 6.90(s, IH), 4.80(m, IH), 4.73(s, 2H), 4.06(m, IH), 3.84(m, IH), 3.66(m, 2H), 3.48(m, IH), 3.31(m, IH), 1.79(m, 2H), 1.43(m, 4H), 1.26(m, 2H)
Preparation 35: Synthesis of 5-bromomethyl-7-nitro-indole-l,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester
5-Bromomethyl-7-nιtro-ιndole-1,2-dι carboxylic acid 1-tert-butyl ester 2-ethyl ester
Figure imgf000111_0002
(Step 1)
5-Methyl-7-nιtro-1 H-ιndole-2-carbox ylic acid ethyl ester
Figure imgf000111_0003
4-Methyl-2-nitroaniline (2Og, 131mmol) was reacted according to the same procedures as Preparation 1 and Preparation 2 to give 5-methyl-7-nitro-lH-indole-2- carboxylic acid ethyl ester (16g, Yield 49%).
(Step 2) The compound (15. Ig, 60.8mmol) prepared in Step 1 was reacted according to the same procedures as Preparation 23 and Preparation 24 to give the title compound (6.3g, Yield 24%).
Preparation 33: Synthesis of S-chloro-^-nitro-lH-indole-^-carboxylic acid -7-nιtro-1 H-ιndole-2-carbox
Figure imgf000112_0001
The compound (15.Og, 59.1mmol) prepared in Preparation 5 was dissolved in tetrahydrofuran (300ml) and methanol (100ml). Lithium hydroxide monohydrate (7.43g, 177mmol) was dissolved in water (100ml), and added to the reaction solution, which was then stirred for 3 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. The residue was neutralized to about pH 6 using 3N hydrochloric acid solution. The resulting solid was filtered and dried to give the title compound (13. Ig, Yield 92%).
Preparation 34: Synthesis of [(R)-2-(7-amino-5-chloro-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(7-Amιno-5-chloro-1H-ιndol-2 -yl)-4,5-dιhydro-thιazol-4-yl]-acet
Figure imgf000112_0002
IC acid methyl ester
(Step 1) H-ιndole- en methyl es
Figure imgf000112_0003
The compound (12.5g, 52.0mmol) prepared in Preparation 33 and the compound
(19. Ig, 62.4mmol) prepared in Preparation 15 were dissolved in N,N- dimethylformamide (200ml). Triethylamine (8.7ml, 62.4mmol), HOBT (14.Og, 104mmol) and EDC (16.9g, 88.4mmol) were added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was concentrated, extracted with ethyl acetate, and washed using saturated sodium bicarbonate solution and saturated aqueous ammonium chloride solution, respectively. The organic layer was concentrated and separated by column chromatography to give (R)-3-[(5-chloro-7-nitro-lH-indole-2-carbonyl)-amino]-4-(4-methoxy-benzylsulfanyl)- butyric acid methyl ester (20.2g, 41.0mmol, Yield 79%).
1H-NMR (500HMz, CDCl3); δ 10.47(br s, IH), 8.24(d, J=I.9Hz, IH), 7.96(d, J=I .9Hz, IH), 7.24(d, J=8.6Hz, 2H), 6.89(s, IH), 6.81(d, J=8.6Hz, 2H), 4.58(m, IH), 3.75(s, 3H), 3.73(s, 2H), 3.71(s, 3H), 2.86(m, IH), 2.80(m, IH), 2.73(m, IH), 2.70(m, IH)
(Step 2) ιHπ--iιnιiduoulι--2. yl]-acet
Figure imgf000113_0001
α escftαerr The compound prepared in Step 1 was dissolved in dichloromethane (200ml). Phosphorus pentachloride (17. Ig, 82mmol) was added thereto, and the mixture was stirred for 1 h at room temperature. After completion of the reaction, the reaction solution was concentrated, and diethylether (200ml) was added. The resulting solid was filtered and dried to give [(R)-2-(5-chloro-7-nitro-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-acetic acid methyl ester.
1H-NMR (500HMz, CDCl3); δ 10.48(br s, IH), 8.22(d, J=1.8Hz, IH), 7.94(d, J=I.8Hz, IH), 7.29(d, J=8.6Hz, 2H), 6.96(d, J=2.5Hz, IH), 6.89(d, J=8.6Hz, 2H), 5.00(m, IH), 3.76(s, 3H), 3.71(m, IH), 3.26(m, IH), 2.99(m, IH), 2.67(m, IH)
(Step 3)
[(R)-2-(7-Amino-5-chloro-1 H-indol-2 -yl)-4,5-dihydro-thiazol-4-yl]-acet
Figure imgf000114_0001
ic acid methyl ester The compound prepared in Step 2 was dissolved in tetrahydrofuran (200ml), methanol (200ml) and water (200ml). Iron powder (22.9g, 410mmol) and ammonium chloride (21.9g, 410mmol) were added thereto, and the mixture was stirred for 1 h at 60 °C using a mechanical stirrer. After completion of the reaction, tetrahydrofuran (300ml) was added thereto. The mixture was filtered through a celite, washed with tetrahydrofuran (100ml), distilled under reduced pressure, and concentrated. The residue was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (9.Og, Yield 68%).
Example 26: Synthesis of [(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid methyl ester
[(R)-2-(5-Chloro-7-cyclopentylamino -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid methyl ester
Figure imgf000114_0002
The compound (4.9g, 15.1mmol) prepared in Preparation 34 was dissolved in dichloroethane (100ml). Cyclopentanone (2.7ml, 30.3mmol), acetic acid (0.86ml,
15.1mmol) and sodium triacetoxyborohydride (6.42g, 30.3mmol) were added thereto, and the mixture was stirred for 36 h at room temperature. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution (200ml), concentrated, and separated by column chromatography to give the title compound (5.15g, Yield 87%).
1R NMR (DMSOd6, ppm); δ 11.51(s, IH), 6.79(s, IH), 6.79(s, IH), 6.16(s, IH), 6.13(d, IH), 4.85(m, IH), 3.80(m, IH), 3.62(m, IH), 3.58(s, 3H), 3.19(m, IH), 2.71(m, IH), 2.63(m, IH), 1.93(m, 2H), 1.69(m, 2H), 1.56(m, 4H)
FAB MS(m/e) = 392
Example 27: Synthesis of [(R)-2-(5-chloro-7-cyclopentyIamino-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid
[(R)-2-(5-Chloro-7-cyclopentylamino -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid
Figure imgf000115_0001
The compound (1.5g, 3.83mmol) prepared in Example 26 was dissolved in tetrahydrofuran (100ml) and methanol (50ml). Lithium hydroxide monohydrate (640mg, 15.3mmol) was dissolved in water (50ml) and added to the reaction solution, which was then stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. IN hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (13. Ig, Yield 92%).
1H NMR (DMSO-d6, ppm); δ 12.51(br s, IH), 11.51(s, IH), 6.79(s, IH), 6.79(s, IH), 6.16(s, IH)5 6.14(d, IH), 4.87(m,lH), 3.80(m, IH), 3.61(m, IH), 3.19(m, IH), 2.72(m, IH), 2.64(m, IH), 1.93(m, 2H), 1.69(m, 2H), 1.56(m, 4H) FAB MS(m/e) = 378
Example 28: Synthesis of [(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid ethyl ester
[(R)-2-(5-Chloro-7-cyclopentylamino -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid ethyl ester
Figure imgf000116_0001
The compound (4.5g, 18.7mmol) prepared in Preparation 33 and the compound (6.3g, 19.7mmol) prepared in Preparation 16 were reacted according to the same procedures as Preparation 34 and Example 26 to give the title compound (840mg, Yield 11%).
1H-NMR (500HMz, CDCl3); δ 10.01(brs, IH), 6.99(s, IH), 6.80(s, 2H), 6.43(s, IH), 5.03(m, IH), 4.07(q, 2H), 3.81(m, IH), 3.64(m, IH), 3.21(m, IH), 2.81(m, IH), 2.67(m, IH), 2.04(m, 2H), 1.64(m, 4H), 1.49(m, 2H), 1.20(t, 3H)
Example 29: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-
2-yl)-4,5-dihydro-l,3-thiazol-4-yl]-ethanol
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-ethanol
Figure imgf000116_0002
The compound (550mg, 1.4mmol) prepared in Example 26 was dissolved in tetrahydrofuran (50ml). 1 M lithium borohydride tetrahydrofuran solution (2.11ml, 2.11mmol) was added thereto, and the mixture was stirred for 1 h while raising the reaction temperature from -60 °C to 0 "C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (510mg, Yield 100%). 1H NMR (DMSO-d6, ppm); δ 11.47(1H, s), 6.79(1H, s), 6.67(1H, s), 6.11(1H, s),
6.09(1H, m), 4.65(1H, t), 4.54(1H, m), 3.80(2H, m), 3.61(2H, m), 3.52(1H, m), 3.15(1H, m), 2.47(1H, m), 1.97(2H, m), 1.68(2H, m), 1.54(4H, m) FAB MS(m/e) = 364
Example 30: Synthesis of {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)- lH-indoI-2-yl]-4,5-dihydro-thiazoI-4-yl}-acetic acid methyl ester
{(R)-2-[5-Chloro-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl}-acetic acid meth yl ester
Figure imgf000117_0001
The compound (l.Og, 3.1mmol) prepared in Preparation 34 was dissolved in 1,2- dichloroethane (100ml). Tetrahydro-4H-pyran-4-one (0.57ml, 6.18mmol), sodium triacetoxyborohydride (1.31g, 6.18mmol) and acetic acid (0.18ml, 3.09mmol) were added thereto, and the mixture was stirred for 24 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (0.5g, Yield 40%).
1H NMR (DMSO-d6, ppm); δ 11.52(1H, s), 6.81(1H, s), 6.71(1H, s), 6.28(1H, s), 6.07(1H, d), 4.9O(1H, m), 3.86(2H, m), 3.64(3H, s), 3.62(2H, m), 3.44(2H, t), 2.82- 2.71(2H, m), 1.94(2H, m), 1.40(2H, m) FAB MS(m/e) = 408
Example 31: Synthesis of {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-yIamino)- lH-indoI-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[5-Chloro-7-(tetrahydro-pyra n-4-ylamino)-1H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl}-acetic acid
Figure imgf000118_0001
The compound (400mg, l.Ommol) prepared in Example 30 was reacted according to the same procedure as Example 27 to give the title compound (360mg, Yield 92%).
1H NMR (DMSO-d6, ppm); δ 12.43(1H, s, br), 11.53(1H, s), 6.81(1H, s), 6.71(1H, s), 6.28(1H, s), 6.06(1H, d), 4.87(1H, m), 3.87(2H, m), 3.62(2H, m), 3.44(2H, t), 3.19(1H, m), 3.74(1H, m), 2.63(1H, m), 1.94(2H, m), 1.41(2H, m)
FAB MS(m/e) = 394
Example 32: Synthesis of 2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol
2-{(R)-2-[5-Chloro-7-(tetrahydro-py ran-4-ylamino)-1H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-ethanol
Figure imgf000118_0002
The compound (2.5g, 6.12mmol) prepared in Example 30 was reacted according to the same procedure as Example 29 to give the title compound (2.19g, 5.76mmol, Yield 94%). 1H NMR (DMSO-d6, ppm); δ 11.48(1H, s), 6.81(1H, s), 6.68(1H, s), 6.28(1H, s),
6.05(1H, d), 4.66(1H, quin), 4,54(1H, t), 3.87(2H, m), 3.61-3.54(3H, m), 3.44(2H, t), 3.15(1H, m), 1.99-1.93(3H, m), 1.73(1H, m), 1.40(2H, m), 1.2O(1H, m) FAB MS(m/e) = 380
Preparation 35: Synthesis of [(R)-2-(7-amino-5-bromo-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(7-Amino-5-bromo-1 H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-aceti c acid methyl ester
Figure imgf000119_0001
Methyl 5-bromo-7-nitro-lH-indole-2-carboxylate (2.7g, 9.0mmol) prepared in Preparation 6 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (585mg, Yield 18%).
Example 33: Synthesis of [(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2- yl)-4,5-dihy dro-thiazol-4-yl] -acetic acid
[(R)-2-(5-Bromo-7-cyclopentylamino- 1 H-indol-2-yl)-4,5-dihydro-thiazol- 4-yl]-acetic acid
Figure imgf000119_0002
The compound (340mg, 0.9mmol) prepared in Preparation 35 was reacted according to the same procedures as Example 26 and Example 27 to give the title compound (250mg, Yield 66%).
1H-NMR (400HMz, CDCl3); δ 12.50(br s, IH), 7.10(sm IH), 7.06(s, IH), 6.56(s, IH), 5.3 l(m, IH), 3.89(m, 2H), 3.40(m, IH), 2.99(m, IH), 2.83(m, IH), 2.08(m, 2H), 1.86(m, 2H), 1.66(m, 4H)
Example 34: Synthesis of 2-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-l,3-thiazol-4-yl]-ethanol 2-[(R)-2-(5-Bromo-7-cyclopentylamin o-1 H-indol-2-yl)-4,5-dihydro-thiazo l-4-yl]-ethanol
Figure imgf000120_0001
(Step 1)
The compound (582mg, 1.58mmol) prepared in Preparation 35 was reacted according to the same procedure as Example 26 to give a cyclopentylamine compound (430mg, Yield 62%).
(Step 2)
The compound (150mg, 0.34mmol) prepared in Step 1 was dissolved in tetrahydrofuran (8ml). Lithium borohydride (15mg, 0.69mmol) was added thereto, and the mixture was stirred for 1 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (135mg, Yield 96%).
1H-NMR (400HMz, CDCl3); δ 10.42(br s, IH), 7.18(s, IH), 6.87(s, IH), 6.59(d, IH), 4.67(m, 2H), 4.02(m, 2H), 3.91(m, IH), 3.63(m, IH), 3.16(t, IH), 2.10(m, 4H), 1.74(m, 2H), 1.4(m, 4H)
Example 35: Synthesis of {(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)- lH-indoI-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid {(R)-2-[5-Bromo-7-(tetrahydro-pyran -4-ylamino)-1 H-indol-2-yl]-4,5-dihy dro-thiazol-4-yl}-acetic acid
Figure imgf000121_0001
The compound (50mg, 0.14mmol) prepared in Preparation 44 was reacted according to the same procedures as Example 30 and Example 27 to give the title compound (54mg, Yield 88%). 1H-NMR (400HMz, CDCl3); δ 7.07(m, 2H), 6.50(s, IH), 5.10(m, IH), 4.03(m,
2H), 3.91(m, IH), 3.70-3.41(m, 4H), 3.1 l(m, IH), 2.83(m, 2H), 2.52(m, IH), 2.04(m, 2H), 1.69(m, 2H)
Example 36: Synthesis of 2-{(R)-2-[5-bromo-7-(tetrahydro-pyran-4- ylamino)-! H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-ethanol
2-{(R)-2-[5-Bromo-7-(tetrahydro-pyr an-4-ylamino)-1 H-indol-2-yl]-4,5-di hydro-thiazol-4-yl}-ethanol
Figure imgf000121_0002
The compound (50mg, 0.14mmol) prepared in Preparation 35 was reacted according to the same procedures as Example 30 and Step 2 of Example 34 to give the title compound (35mg, Yield 59%). 1H-NMR (400HMz, CDCl3); δ 10.50(br s, IH), 7.19(s, IH), 6.89(s, IH),
6.59(d, IH), 4.67(m, 2H), 4.05(m, 4H), 3.63(m, 4H), 3.18(t, IH), 2.12(m, 4H), 1.64(m, 4H)
Preparation 36: Synthesis of [(R)-2-(7-amino-5-fluoro-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid methyl ester [(R)-2-(7-Amino-5-fluoro-1 H-indol-2 -yl)-4,5-dihydro-thiazol-4-yl]-acet
Figure imgf000122_0001
ic acid methyl ester
Ethyl S-fluoro^-nitro-lH-indole^-carboxylate (2.3g, 9.1mmol) prepared in Preparation 2 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (650mg, Yield 23%).
Example 37: Synthesis of [(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid
[(R)-2-(7-Cyclopentylamino-5-fluoro -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid
Figure imgf000122_0002
The compound (361mg, 1.2mmol) prepared in Preparation 36 was reacted according to the same procedures as Example 26 and Example 27 to give the title compound (189mg, Yield 44%).
1H-NMR (400HMz, CDCl3); δ 11.09(br s, IH), 6.73(s, IH), 6.45(dd, IH), 6.07(dd, IH), 4.98(m, IH), 3.79(m, IH), 3.59(m, IH), 3.16(m, IH), 2.79(m, IH), 2.60(m, IH), 1.96(m, 2H), 1.71(m, 2H), 1.58(m, 4H)
Example 38: Synthesis of [(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-acetic acid ethyl ester
[(R)-2-(7-Cyclopentylamino-5-fluoro -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid ethyl ester
Figure imgf000122_0003
The compound (80mg, 0.22mmol) prepared in Example 37 was dissolved in ethanol (2ml). Acetyl chloride (0.1ml) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (50mg, Yield 58%).
1H-NMR (400HMz, CDCl3); δ 10.71(br s, IH), 6.86(s, IH), 6.64(dd, IH), 6.23(dd, IH), 5.07(m, IH), 3.99(q, 2H), 3.91(m, IH), 3.76(m, IH), 3.64(m, IH), 3.22(m, IH), 2.88(m, IH), 2.65(m, IH), 2.00(m, 2H), 1.63(m, 4H), 1.40(m, 2H), 1.12(t, 3H)
Example 39 : Synthesis of 2- [(R)-2-(7-cyclopentylamino-5-fluoro-l H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-ethanol
2-[(R)-2-(7-Cyclopentylamino-5-fluo ro-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-ethanol
Figure imgf000123_0001
The compound (90mg, 0.29mmol) prepared in Preparation 36 was reacted according to the same procedures as Example 26 and Step 2 of Example 34 to give the title compound (46mg, Yield 46%).
1H-NMR (400HMz, CDCl3); δ 10.90(br s, IH), 6.91(s, IH), 6.65(dd, IH), 6.26(dd, IH), 4.68(m, IH), 4.08(m, 2H), 3.88(m, IH), 3.62(m, IH), 3.15(t, IH), 2.10(m, 4H), 1.74(m, 2H), 1.62(m, 4H)
Example 40: Synthesis of {(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid {(R)-2-[5-Fluoro-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih ydro-thiazol-4-yl}-acetic acid
Figure imgf000124_0001
The compound (852mg, 2.8mmol) prepared in Preparation 36 was reacted according to the same procedures as Example 30 and Example 27 to give the title compound (970mg, Yield 92%). 1H-NMR (400HMz, DMSO-d6); δ 11.45(s, IH), 6.75(d, IH), 6.22(dd, IH),
6.16(d, J=6.8Hz, IH), 4.91(m, IH), 3.88(m, 2H), 3.66(m, IH), 3.61(m, IH), 3.48(m, 2H), 3.22(m, IH), 2.80(m, IH), 2.65(m, IH), 2.99(m, 2H), 1.40(m, 2H)
Example 41: Synthesis of 2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol
2-{(R)-2-[5-Fluoro-7-(tetrahydro-py ran-4-ylamino)-1 H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-ethanol
Figure imgf000124_0002
The compound (1.24g, 4.0mmol) prepared in Preparation 36 was reacted according to the same procedures as Example 30 and Step 2 of Example 34 to give the title compound (810mg, Yield 55%). 1H-NMR (400HMz, CDCl3); δ 10.69(br s, IH), 6.87(s, IH), 6.63(d, IH),
6.22(d, IH), 4.87(m, IH), 4.66(m, IH), 4.02(m, 4H), 3.55(m, 4H), 3.15(m, IH), 2.04(m, 4H), 1.54(m, 2H)
Preparation 37: Synthesis of [(R)-2-(7-amino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-acetic acid methyl ester [(R)-2-(7-Amino-1 H-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid m
Figure imgf000125_0001
ethyl ester
Methyl 7-nitro-lH-indole-2-carboxylate (14.Og5 63.6mmol) prepared in Preparation 8 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (6.5g, Yield 35%).
Example 42: Synthesis of [(R)-2-(7-cyclopentylamino-lH-indol-2-yI)-4,5- dihydro-thiazol-4-yI]-acetic acid pentylamino-1 H-indol ro-thiazol-4-yl]-ac
Figure imgf000125_0002
(Step 1)
The compound (5.Og, 17.3mmol) prepared in Preparation 37 was reacted according to the same procedure as Example 26 to give a methyl ester compound.
(Step 2) The compound prepared in Step 1 was reacted according to the same procedure as Example 27 to give the title compound (5.44g, 2 steps, Yield 91%).
1H-NMR (400HMz, CDCl3); δ 11.77(br s, IH), 7.04(d, IH), 6.97(m, 2H), 6.43(d, IH), 5.34(m, IH), 3.88(m, IH), 3.69(m, IH), 3.19(m, IH), 2.72(m, IH), 2.60(m, IH), 2.01(m, 2H), 1.74(m, 2H), 1.59(m, 4H)
Example 43: Synthesis of [(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid ethyl ester [(R)-2-(7-Cyclopentylamino-1 H-indol -2-yl)-4,5-dihydro-thiazol-4-yl]-ac etic acid ethyl ester
Figure imgf000126_0001
The compound (500mg, 1.46mmol) prepared in Example 42 was reacted according to the same procedure as Example 38 to give the title compound (420mg, Yield 78%). 1H-NMR (400HMz, CDCl3); δ 10.12(br s, IH), 7.05(m, IH), 6.99(m, IH),
6.91(d, IH), 6.51(d, IH), 5.07(m, IH), 4.09(q, 2H), 3.87(m, IH), 3.65(m, IH), 3.21(m, IH), 2.86(m, IH), 2.65(m, IH), 2.01(m, 2H), 1.74(m, 2H), 1.62(m, 4H), 1.46(m, 2H), 1.81(t, 3H)
Example 44: Synthesis of 2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -eth anol
2-[(R)-2-(7-Cyclopentylamino-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-yl]- ethanol
Figure imgf000126_0002
The compound (1.46g, 5.06mmol) prepared in Preparation 37 was reacted according to the same procedures as Example 26 and Step 2 of Example 34 to give the title compound ( 1.44g, Yield 78%).
1H NMR (DMSOd6, ppm); δ 11.28(1H, s), 6.77-6.74(2H, m), 6.69(1H, s), 6.25(1H, d), 5.78(1H, d), 4.65(1H, quin), 4.53(1H, t), 3.82(1H, m), 3.60(2H, m), 3.51(1H, m), 3.11(1H, m), 1.99-1.91(3H, m), 1.75-1.67(3H, m), 1.56-1.54(4H, m)
FAB MS(m/e) = 330
Example 45: Synthesis of {(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol- 2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[7-(Tetrahydro-pyran-4-ylami no)-1 H-indol-2-yl]-4,5-dihydro-thia zol-4-yl}-acetic acid
Figure imgf000127_0001
The compound (1.32g, 4.58mmol) prepared in Preparation 37 was reacted according to the same procedures as Example 30 and Example 27 to give the title compound (1.25g, Yield 76%).
1H NMR (DMSOd6, ppm); δ 12.42(1H, s, br), 11.34(1H, s), 6.8O(1H, d), 6.72(1H, s), 6.33(1H, d), 5.79(1H, d), 4.86(1H, quin), 3.88(2H, m), 3.60-3.52(2H, m), 3.42(2H, t), 3.17(1H, m), 2.74(1H, m), 2.59(1H, m), 1.94(2H, m), 1.39(2H, m)
FAB MS(m/e) = 360
Example 46: Synthesis of 2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH- indol-2-yI]-4,5-dihydro-thiazol-4-yl}-ethanol
2-{(R)-2-[7-(Tetrahydro-pyran-4-yla mino)-1 H-indol-2-yl]-4,5-dihydro-th iazol-4-yl}-ethanol
Figure imgf000127_0002
The compound (529mg, 1.83mmol) prepared in Preparation 37 was reacted according to the same procedures as Example 30 and Step 1 of Example 34 to give the title compound (340mg, Yield 54%).
1H NMR (DMSO-d6, ppm); δ 11.29(1H, s), 6.79(2H, m), 6.7O(1H, s), 6.33(1H, d), 5.76(1H, d), 4.66(1H, quin), 4.54(1H, t), 3.88(2H, m), 3.62-3.59(3H, m), 3.53(1H, t), 3.43(2H, m), 3.12(1H, m), 1.96(3H, m), 1.75(1H, m), 1.40(2H, m) FAB MS(m/e) = 346 Preparation 38: Synthesis of [(R)-2-(7-amino-5-methoxy-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -acetic acid methyl ester
[(R)-2-(7-Amιnc-5-methoxy-1 H-ιndol- 2-yl)-4,5-dιhydro-thιazol-4-yl]-ace tic acid methyl ester
Figure imgf000128_0001
Methyl 5-methoxy-7-nitro-lH-indole-2-carboxylate (2.5g, ό.Ommol) prepared in Preparation 9 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (1.Og, Yield 52%).
Example 47: Synthesis of [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(7-Cyclopentylamιno-5-methox y-1H-ιndol-2-yl)-4,5-dιhydro-thιazo l-4-yl]-acetιc acid methyl ester
Figure imgf000128_0002
The compound (1.Og, 3.13mmol) prepared in Preparation 38 was reacted according to the same procedure as Example 26 to give the title compound (49Og, Yield 40%).
1H NMR (DMSOd6, ppm); δ 11.24(1H, s), 6.62(1H, s), 6.22(1H, s), 5.89(1H, d), 5.84(1H, s), 4.83(1H, quin), 3.77(1H, m), 3.64(3H, s), 3.59(3H, s), 3.56(1H, m), 3.15(1H, m), 2.69(1H, m), 2.58(1H, m), 1.90(2H, m), 1.67(2H, m), 1.51(4H, m)
FAB MS(m/e) = 388
Example 48: Synthesis of [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl] -acetic acid [(R)-2-(7-Cyclopentylamιno-5-methox y-1 H-ιndol-2-yl)-4,5-dιhydro-thιazo l-4-yl]-acetιc acid
Figure imgf000129_0001
The compound (300mg, 0.78mmol) prepared in Example 47 was reacted according to the same procedure as Example 27 to give the title compound (240mg, Yield 82%). 1H NMR (DMSOd6, ppm); δ 12.54(1H, s, br), 11.21(1H, s), 6.63(1H, s),
6.23(1H, s), 5.89(1H, d), 5.84(1H, s), 4.84(1H, quin), 3.77(1H, m), 3.64(3H, s), 3.56(1H, m), 3.15(1H, m), 2.69(1H, m), 2.58(1H, m), 1.90(2H, m), 1.67(2H, m), 1.52(4H, m)
FAB MS(m/e) = 374
Example 49: Synthesis of [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-
2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid ethyl ester
[(R)-2-(7-Cyclopentylamιno-5-methox y-1 H-ιndol-2-yl)-4,5-dιhydro-thιazo l-4-yl]-acetιc acid ethyl ester
Figure imgf000129_0002
The compound (200mg, 0.54mmol) prepared in Example 48 was reacted according to the same procedure as Example 38 to give the title compound (124mg, Yield 57%).
1H-NMR (400HMz, CDCl3); δ 10.73(br s, IH), 6.83(s, IH), 6.43(s, IH), 6.16(s, IH), 5.07(m, IH), 4.00-3.88(m, 3H), 3.80(s, 3H), 3.76(m, IH), 3.62(m, IH), 3.20(m, IH), 2.83(m, IH), 2.63(m, IH), 1.98(m, 2H), 1.61(m, 4H), 1.40(m, 2H), 1.12(t, 3H)
Example 50: Synthesis of {(R)-2-[5-methoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid methyl ester
{(R)-2-[5-Methoxy-7-(tetrahydro-pyr an-4-ylamιno)-1 H-ιndol-2-yl]-4,5-dι hydro-thιazol-4-yl}-acelιc acid met hyl ester
Figure imgf000130_0001
The compound (4.8g, 14.8mmol) prepared in Preparation 38 was reacted according to the same procedure as Example 30 to give the title compound (2.5g, Yield 42%).
Example 51: Synthesis of {(R)-2-[5-methoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[5-Methoxy-7-(tetrahydro-pyr an-4-ylamιno)-1 H-ιndol-2-yl]-4,5-dι hydro-thιazol-4-yl}-acetιc acid
Figure imgf000130_0002
The compound (30mg, 0.07mmol) prepared in Example 50 was reacted according to the same procedure as Example 27 to give the title compound (8.7g, Yield
30%).
1H-NMR (500HMz, DMSOd6); δ 11.21(br s, IH), 6.64(m, IH), 6.26(m, IH),
5.95(m, IH), 5.84(m, IH), 4.85(m, IH), 3.85(m, IH), 3.64(s, 3H), 3.63-3.49(m, 2H), 3.43(m, 2H), 3.17(m, IH), 2.73(m, IH), 2.62(m, IH), 1.94(m, 2H), 1.72(m, IH), 1.38(m,
2H)
Example 52: Synthesis of [(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid [(R)-2-(7-Cyclopentylamιno-5-ethoxy -1H-ιndol-2-yl)-4,5-dιhydro-thιazol
-4-yl]-acetιc acid
Figure imgf000131_0001
Methyl 5-ethoxy-7-nitro-lH-indole-2-carboxylate (1.5g, 5.7mmol) prepared in Preparation 11 was reacted according to the same procedures as Preparation 33, Preparation 34, Example 26 and Example 27 in the order to give the title compound (150mg, Yield 7%).
1H-NMR (400HMz, DMSOd6); δ 11.24(br s, IH), 6.65(d, J=2.0Hz, IH), 6.26(d, J=2.0Hz, IH), 5.92(d, J=6.0Hz, IH), 5.88(d, J=2.0Hz, IH), 4.89(m, IH), 3.94(q, 2H), 3.81(m, IH), 3.65(m, IH), 3.20(m, IH), 2.74(m, IH), 2.62(m, IH), 1.94(m, 2H), 1.72(m, 2H), 1.61(m, 4H), 1.31(t, 3H)
Preparation 39: Synthesis of T-nitro-S-propoxy-lH-indoIe-l-carboxylic acid ethyl ester
7-Nιtro-5-propoxy-1H-ιndole-2-carbo xylic acid ethyl ester
Figure imgf000131_0002
2-Nitro-4-propoxy-phenylamine (2Og, 102mmol) was reacted according to the same procedures as Preparation 1 and Preparation 2 to give the title compound (1.5g, Yield 5%).
Example 53: Synthesis of [(R)-2-(7-cyclopentylamino-5-propoxy-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid
X, > [(R)-2-(7-Cyclopentylamιno-5-propox j y-1 H-ιndol-2-yl)-4,5-dιhydro-thιazo
■ • "lϊ η l-4-yl]-acetιc acid s *—^o^
Ethyl 5-propoxy-7-nitro-lH-indole-2-carboxylate (1.4g, 4.82mmol) prepared in Preparation 39 was reacted according to the same procedures as Preparation 33, Preparation 34, Example 26 and Example 27 in the order to give the title compound (70mg, Yield 4%).
1H-NMR (500HMz, CDCl3); δ 12.79(br s, IH), 7.05(s, IH), 6.26(s, IH), 6.22(s, IH), 5.14(br s, IH), 3.88(m, 3H), 3.41(m, 2H), 3.07(m, IH), 2.83(m, IH), 2.03(m, 2H), 1.82(m, 3H), 1.69(m, 2H), 1.60(m, 2H), 1.04(t, 3H)
Preparation 40: Synthesis of [(R)-2-(7-amino-5-phenoxy-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -acetic acid methyl ester
[(R)-2-(7-Amιno-5-phenoxy-1 H-ιndol- 2-yl)-4,5-dιhydro-thιazol-4-yl]-ace tic acid methyl ester
Figure imgf000132_0001
Methyl 5-phenoxy-7-nitro-lH-indole-2-carboxylate (550mg, 1.84mmol) prepared in Preparation 12 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (150mg, Yield 16%).
Example 54: Synthesis of [(R)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-
2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid
[(R)-2-(7-Cyclopentylamino-5-phenox y-1H-ιndol-2-yl)-4,5-dιhydro-thιazo l-4-yl]-acetιc acid
Figure imgf000132_0002
The compound (65mg, 0.13mmol) prepared in Preparation 40 was reacted according to the same procedures as Example 26 and Example 27 to give the title compound (20mg, Yield 35%).
1H-NMR (400HMz, CDCl3); δ 11.92(br s, IH), 7.28(m, 2H), 7.00(m, 4H), 6.56(s, IH), 6.22(s, IH), 5.34(br s, IH), 3.81(br s, IH), 3.70(m, IH), 3.22(d, J=12.0Hz, IH), 2.76~2.62(m, 2H), 1.96(m, 2H), 1.73(m, 2H), 1.58(m, 4H)
Example 55: Synthesis of {(R)-2-[5-phenoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[5-Phenoxy-7-(tetrahydro-pyr an-4-ylamιno)-1H-ιndol-2-yl]-4,5-dι hydro-thιazol-4-yl}-acetιc acid
Figure imgf000133_0001
The compound (65mg, 0.13mmol) prepared in Preparation 40 was reacted according to the same procedures as Example 30 and Example 27 to give the title compound (13mg, Yield 22%).
1H-NMR (400HMz, CDCl3); δ 11.98(br s, IH), 7.28(m, 2H), 7.00(m, 4H), 6.58(s, IH), 6.22(s, IH), 5.34(br s, IH), 3.98(br s, 2H), 3.70(m, IH), 3.50(m, 3H), 3.21(m, 2H), 2.74(m, IH), 2.66(m, IH), 2.05(m, 2H), 1.58(m, 2H)
Preparation 41: Synthesis of {(R)-2-[7-amino-5-(pyridin-3-yloxy)-lH-indol- 2-yl]-4,5-dihydro-thiazol-4-yI}-acetic acid methyl ester
{(R)-2-[7-Amιno-5-(pyrιdιn-3-yloxy) -1 H-ιndol-2-yl]-4,5-dihydro-thιazol -4-yl}-acetιc acid methyl ester
Figure imgf000133_0002
7-Nitro-5-(pyridin-3-yloxy)-lH-indole-2-carboxylic acid ethyl ester (l.Og,
3.1mmol) prepared in Preparation 13 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (160mg, Yield 14%).
Example 56: Synthesis of {(R)-2-[7-cycIopentylamino-5-(pyridin-3-yloxy)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid methyl ester {(R)-2-[7-Cyclopentylamιno-5-(pyrιd ιn-3-yloxy)-1 H-ιndol-2-yl]-4,5-dιhy dro-thιazol-4-yl}-acetιc acid methy
Figure imgf000134_0001
I ester
The compound (80mg, 0.21mmol) prepared in Preparation 41 was reacted according to the same procedure as Example 26 to give the title compound (45mg, Yield 48%). 1H-NMR (400HMz, CDCl3); δ 10.89(br s, IH), 8.41(d, IH), 8.26(m, IH),
7.27(m, IH), 7.19(m, IH), 6.85(s, IH), 6.62(d, IH), 6.22(m, IH), 5.04(m, IH), 4.13(br s, IH), 3.78(m, IH), 3.65(m, IH), 3.59(s, 3H), 3.20(m, IH), 2.83(m, IH), 2.67(m, IH), 1.98(m, 2H), 1.61(m, 4H), 1.46(m, 2H)
Example 57: Synthesis of {(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)- lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[7-Cyclopentylamιno-5-(pyrιd ιn-3-yloxy)-1H-ιndol-2-yl]-4,5-dιhy dro-thιazol-4-yl}-acetιc acid
Figure imgf000134_0002
The compound (35mg, 0.08mmol) prepared in Example 56 was reacted according to the same procedure as Example 27 to give the title compound (15mg, Yield 44%).
1H-NMR (400HMz, CDCl3); δ 11.86(br s, IH), 8.40(d, IH), 8.26(m, IH), 7.25(m, IH), 7.17(m, IH), 6.96(s, IH), 6.57(d, IH), 6.18(d, IH), 5.33(br s, IH), 3.80(br s, IH), 3.70(m, IH), 3.21(m, IH), 2.73(m, IH), 2.65(m, IH), 1.96(m, 2H), 1.72(m, 2H), 1.58(m, 4H)
Example 58: Synthesis of {(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran- 4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid methyl ester {(R)-2-[5-(Pyπdιn-3-yloxy)-7-(tetr ahydro-pyran-4-ylamιno)-1 H-ιndol-2- yl]-4,5-dιhydro-thιazol-4-yl}-acetι c acid methyl ester
Figure imgf000135_0001
The compound (48Og, 0.21mmol) prepared in Preparation 41 was reacted according to the same procedure as Example 30 to give the title compound (35mg, Yield 36%). 1H-NMR (400HMz, DMSO-d6); δ 11.48(br s, IH), 8.3O(d, IH), 8.25(m, IH),
7.34(m, IH), 7.29(m, IH), 6.76(d, IH), 6.46(d, IH), 6.18(d, IH), 4.93(m, IH), 3.87(m, 3H), 3.66(s, 3H), 3.59(m, IH), 3.44(m, 2H), 3.23(m, IH), 2.81(m, 2H), 1.95(m, 2H), 1.43(m, 2H)
Example 59: Synthesis of {(R)-2-[5-(pyridin-3-yLoxy)-7-(tetrahydro-pyran-
4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[5-(Pyrιdιn-3-yloxy)-7-(tetr ahydro-pyran-4-ylamιno)-1H-ιndol-2- yl]-4,5-dιhydro-thιazol-4-yl}-acetι
Figure imgf000135_0002
cacιd
The compound (25mg, 0.05mmol) prepared in Example 58 was reacted according to the same procedure as Example 27 to give the title compound (15mg, Yield 58%).
1H-NMR (400HMz, MeOH-d4); δ 8.14(s, IH), 8.07(s, IH), 7.25(m, 2H), 6.76(s, IH), 6.45(s, IH), 6.12(d, IH), 4.84(m, IH), 3.85(m, IH), 3.83(m, IH), 3.53(m, IH), 3.40(m, 2H), 3.21(m, 2H), 3.12(m, IH), 2.73(m, IH), 2.59(m, IH), 1.93(m, 2H), 1.46(m, 2H)
Preparation 42: Synthesis of [(R)-2-(7-amino-5-methyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid methyl ester [(R)-2-(7-Amino-5-methyl-1 H-indol-2 -yl)-4,5-dihydro-thiazol-4-yl]-acet ic acid methyl ester
Figure imgf000136_0001
Methyl 5-methyl-7-nitro-lH-indole-2-carboxylate (3.4g, 14.5mmol) prepared in Preparation 7 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (1.7g, Yield 39%).
Example 60: Synthesis of [(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(7-Cyclopentylamino-5-methyl -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid methyl ester
Figure imgf000136_0002
The compound (1.7g, 5.67mmol) prepared in Preparation 42 was reacted according to the same procedure as Example 26 to give the title compound (1.2g, Yield 58%).
1H NMR (DMSO-d6, ppm); δ 11.19(1H, s), 6.62(1H, s), 6.55(1H, s), 6.07(1H, s), 5.75(1H, d), 4.88(1H, quin), 3.79(1H, m), 3.63-3.57(5H, m), 3.17(1H, m), 2.82-2.73(2H, m), 2.23(3H, s), 1.94(2H, m), 1.68(2H, m), 1.55(3H, m) FAB MS(m/e) = 372
Example 61: Synthesis of [(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid
[(R)-2-(7-Cyclopentylamino-5-methyl -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-yl]-acetic acid
Figure imgf000136_0003
The compound (12mg, 0.03mmol) prepared in Example 60 was reacted according to the same procedure as Example 27 to give the title compound (5mg, Yield 43%).
1H NMR (DMSOd6, ppm); δ 12.42(1H, s, br), 11.21(1H, s), 6.61(1H, s), 6.54(1H, s), 6.02(1H, s), 5.76(1H, d), 4.87(1H, quin), 3.77(1H, m), 3.62(2H, t), 3.16(1H, m), 2.81-2.72(2H, m), 2.23(3H, s), 1.94(2H, m), 1.68(2H, m), 1.55(3H, m)
FAB MS(m/e) = 358
Example 62: Synthesis of {(R)-2-[5-methyI-7-(tetrahydro-pyran-4-ylamino)- 1 H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[5-Methyl-7-(tetrahydro-pyra n-4-ylamino)-1 H-indol-2-yl]-4,5-dih
Figure imgf000137_0001
ydro-thiazol-4-yl}-acetic acid
The compound (55mg, O.lδmmol) prepared in Preparation 42 was reacted according to the same procedures as Example 30 and Example 27 to give the title compound (47mg, Yield 70%).
1H-NMR (500HMz, CDCl3); δ 11.85(br s, IH), 6.97(d, IH), 6.76(s, IH), 6.26(s, IH), 5.32(m, IH), 3.99(m, 2H), 3.71(m, IH), 3.65(m, IH), 3.54(m, 2H), 3.23(m, IH), 2.76(m, IH), 2.64(m, IH), 2.3 l(s, 3H), 2.06(m, 2H), 1.58(m, 2H)
Preparation 43: Synthesis of {(R)-2-[7-(l,4-dioxa-spiro[4,5]dec-8-ylamino)- 5-methyl-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid methyl ester
{(R)-2-[7-(1 ,4-Dioxa-spiro[4.5]dec- 8-ylamino)-5-methyl-1 H-indol-2-yl]- 4,5-dihydro-thiazol-4-yl}-acetic ac id methyl ester
Figure imgf000137_0002
The compound (98mg, 0.32mmol) prepared in Preparation 42 and 1,4- cyclohexandione monoethylene acetal instead of cyclopentanone were reacted according to the same procedure as Example 26 to give the title compound (31mg, Yield 23%).
1H-NMR (500HMz, CDCl3); δ 10.62(br s, IH), 6.85(s, IH), 6.77(s, IH), 6.31(s, IH), 4.98(m, IH), 3.96(m, 4H), 3.72(s, 3H), 3.64(m, IH), 3.55(m, IH), 3.21(m, IH), 2.89(m, IH), 2.66(m, IH), 2.37(s, 3H), 2.08(m, 2H), 1.99(m, 2H), 1.69(m, 4H)
Example 63: Synthesis of {(R)-2-[5-methyl-7-(4-oxo-cyclohexylamino)-lH- indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
{(R)-2-[5-Methyl-7-(4-oxo-cyclohexy lamino)-1 H-indol-2-yl]-4,5-dihydro- thiazol-4-yl}-acetic acid
Figure imgf000138_0001
The compound (40mg, 0.09mmol) prepared in Preparation 43 was dissolved in tetrahydrofuran (2ml), methanol (2ml) and water (2ml). Lithium hydroxide monohydrate (8mg, O.lδmmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, IN hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography.
Thus purified compound was dissolved in acetone (5ml). p-Toluenesulfonic acid (5mg) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (7mg, Yield 20%). 1H-NMR (500HMz, CDCl3); δ 11.99(br s, IH), 7.00(s, IH), 6.79(s, IH), 6.30(s, IH), 5.34(m, IH), 3.89(m, IH), 3.71(m, IH), 3.21(m, IH), 2.66(m, 2H), 2.59(m, 2H), 2.43-2.35(m, 5H), 2.26(m, 2H), 1.97(m, 2H)
Preparation 44: Synthesis of {(R)-2-[7-amino-5-(4-methanesulfonyl- phenoxy)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid methyl ester
{(R)-2-[7-Amino-5-(4-methanesulfony l-phenoxy)-1 H-indol-2-yl]-4,5-dihyd ro-thiazol-4-yl}-acetic acid methyl
Figure imgf000139_0001
ester
The compound (900mg, 2.30mmol) prepared in Preparation 14 was reacted according to the same procedures as Preparation 33 and Preparation 34 to give the title compound (328mg, Yield 31 %).
Example 64: Synthesis of {(R)-2-[7-cycIopentylamino-5-(4-methanesulfonyl- phenoxy)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid
Figure imgf000139_0002
The compound (320mg, 0.7mmol) prepared in Preparation 44 was reacted according to the same procedures as Example 26 and Example 27 to give the title compound (45mg, Yield 13%).
1H-NMR (500HMz, DMSOd6); δ 11.71(br s, IH), 7.81(d, 2H), 7.05(m, 2H), 6.65(s, IH), 6.49(s, IH), 6.35(m, IH), 5.96(s, IH), 4.86(m, IH), 3.75(m, IH), 3.52(m, IH), 3.17(m, IH), 3.12(s, 3H), 1.87(m, 2H), 1.67(m, 2H), 1.53(m, 4H)
Preparation 45: Synthesis of (R)-3-[(5-hydroxymethyl-7-nitro-lH-indole-2- carbonyl)-amino]-4-(4-methoxy-benzyIsulfanyl)-butyric acid methyl ester
(R)-3-[(5-Hydroxymethyl-7-nitrc~1 H- indole-2-carbonyl)-amino]-4-(4-meth oxy-benzylsulfanyl)-butyric acid me thyl ester
Figure imgf000140_0001
The compound (12.9g, 54.8mmol) prepared in Preparation 27 was reacted according to the same procedure as Step 1 of Preparation 34 to give the title compound (15.3g, Yield 57%).
1H-NMR (500HMz, CDCl3); δ 10.43(br s, IH), 8.28(s, IH), 8.00(s, IH), 7.25(m, 2H), 6.92(d, IH), 6.84(s, IH), 6.82(s, IH), 4.86(m, 2H), 4.59(m, IH), 3.76(s, 3H), 3.73(s, 2H), 3.69(s, 3H), 2.88(m, IH), 2.82(m, 2H), 2.73(m, IH), 2.69(m, IH)
Preparation 46: Synthesis of [(R)-2-(5-chloromethyl-7-nitro-lH-indol-2-yl)-
4,5-dihydro-thiazol-4-yl] -acetic acid methyl ester
[(R)-2-(5-Chloromethyl-7-nitro-1 H-i ndol-2-yl)-4,5-dihydro-thiazol-4-yl
Figure imgf000140_0002
]-acetic acid methyl ester
The compound (4.8g, 0.8mmol) prepared in Preparation 45 was reacted according to the same procedure as Preparation 29 to give the title compound (3.2g, Yield 88%).
1H-NMR (500HMz, CDCl3); δ 12.82(br s, IH), 8.43(s, IH), 8.04(s, IH), 7.49(s, IH), 5.25(m, IH), 4.74(s, 2H), 4.03(m, IH), 3.57(m, IH), 3.45(m, IH), 2.99(m, IH)
Preparation 47: Synthesis of [(R)-2-(7-nitro-5-phenoxymethyl-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl] -acetic acid methyl ester [(R)-2-(7-Nitro-5-phenoxymethyl-1 H- indol-2-yl)-4,5-dihydro-thiazol-4-y l]-acetic acid methyl ester
Figure imgf000141_0001
The compound (500mg, 1.4mmol) prepared in Preparation 46 was dissolved in N,N-dimethylformamide (10ml). Potassium hydride (82mg, 2.0mmol) and phenol (192mg, 2.0mmol) were added thereto, and the mixture was stirred for 8 h at 0 °C ~ room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound (55mg, Yield
<%ι.
1H-NMR (500HMz, CDCl3); δ 10.46(br s, IH), 8.34(s, IH), 8.06(s, IH), 7.31(m, 2H), 7.25(s, IH), 7.00(m, 3H), 5.19(s, 2H), 5.06(m, IH), 3.77(s, 3H), 3.71(m, IH), 3.26(m, IH), 2.97(m, IH), 2.69(m, IH)
Example 65: Synthesis of [(R)-2-(7-cyclopentylamino-5-phenoxymethyl-lH- indol-2-yI)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester ox es
Figure imgf000141_0002
The compound (33mg, 0.08mmol) prepared in Preparation 47 was reacted according to the same procedures as Step 3 of Preparation 34 and Example 26 to give the title compound (16mg, Yield 43%).
1H-NMR (500HMz, CDCl3); δ 9.49(br s, IH), 7.27(m, 2H), 7.10(s, IH), 7.01(m, 2H), 6.93(m, IH), 6.89(s, IH), 6.59(s, IH), 5.07(s, 2H), 5.02(m, IH), 3.93(m, IH), 3.71(s, 3H), 3.65(m, IH), 3.21(m, IH), 2.88(m, IH), 2.68(m, IH), 2.04(m, 2H), 1.75(m, 2H), 1.58(m, 4H) Example 66: Synthesis of [(R^-CT-cyclopentylamino-S-phenoxymethyl-lH- indol-2-yl)-4,5-dihydro-thiazoI-4-yl]-acetic acid
[(R)-2-(7-Cyclopentylamino-5-phenox ymethyl-1 H-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-acetic acid
Figure imgf000142_0001
5 The compound (l lmg, 0.02mmol) prepared in Example 65 was reacted according to the same procedure as Example 27 to give the title compound (5mg, Yield 45%).
1H-NMR (500HMz, CDCl3); δ 11.79(br s, IH), 7.26(m, 2H), 7.02(m, 2H), 6.99(s, IH), 6.92(m, IH), 6.48(s, IH), 5.35(m, IH), 5.07(s, 2H), 3.89(m, IH), 3.71(m, 10 IH), 3.21(m, IH), 2.75(m, IH), 2.63(m, IH), 2.00(m, 2H), 1.73(m, 2H), 1.59(m, 4H), 1.75(m, 2H)
Preparation 48: Synthesis of [(R)-2-(7-nitro-5-pyrrolidin-l-ylmethyl-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(7-Nitro-5-pyrrolidin-1-ylme thyl-1H-indol-2-yl)-4,5-dihydro-thi
-, ,-
Figure imgf000142_0002
azol-4-yl]-acetic acid methyl ester
The compound (87mg, 0.24mmol) prepared in Preparation 46 and pyrrolidine instead of dimethylamine were reacted according to the same procedure as Example 15 to give the title compound (56mg, Yield 58%).
1H-NMR (500HMz, CDCl3); δ 8.28(s, IH), 8.26(s, IH), 7.00(s, IH), 5.03(m, 20 IH), 4.10(s, 2H), 3.74(s, 3H), 3.68(m, IH), 2.94(m, IH), 2.92(m, 4H), 2.66(m, IH), 1.98(m, 4H) Example 67: Synthesis of [(R)-2-(7-cycIopentylamino-5-pyrrolidin-l- ylmethyl-lH-indol-2-yl)-4,5-dihydro-thiazoI-4-yI]-acetic acid methyl ester
[(R)-2-(7-Cyclopentylamino-5-pyrrol idin-1-ylmethyl-1 H-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid m
Figure imgf000143_0001
ethyl ester
The compound (56mg, 0.14mmol) prepared in Preparation 48 was reacted according to the same procedures as Step 3 of Preparation 34 and Example 26 to give the title compound (13mg, Yield 21%).
1H-NMR (400HMz, CDCl3); δ 10.20(br s, IH), 6.97(s, IH), 6.88(s, IH), 6.73(s, IH), 5.01(m, IH), 4.04(s, 2H), 4.02(m, IH), 3.73(s, 3H), 3.65(m, IH), 3.22(m, IH), 3.10(m, 4H), 2.87(m, IH), 2.68(m, IH), 2.06(m, 3H), 1.95(m, 4H), 1.65(m, 3H), 1.47(m, 2H)
Preparation 49: Synthesis of [(R)-2-(5-methanesulfonylmethyl-7-nitro-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(5-Methanesulfonylmethyl-7-n itro-1 H-indol-2-yl)-4,5-dihydro-thi
Figure imgf000143_0002
azol-4-yl]-acetic acid methyl ester The compound (HOmg, 0.30mmol) prepared in Preparation 55 and sodium methanesulfmate instead of dimethylamine were reacted according to the same procedure as Example 15 to give the title compound (92mg, Yield 74%).
1H-NMR (500HMz, CDCl3); δ 10.55(br s, IH), 8.26(s, IH), 8.08(s, IH), 7.04(s, IH), 5.06(m, IH), 4.40(s, 2H), 3.77(s, 3H), 3.48(m, IH), 3.27(m, IH), 2.99(m, IH), 2.86(s, 3H), 2.71(m, IH)
Example 68: Synthesis of [(R)-2-(7-cyclopentylamino-5- methanesulfonylmethyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester
[(R)-2-(7-Cyclopentylamino-5-methan esulfonylmethyl-1H-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid m
Figure imgf000144_0001
ethyl ester
The compound (92mg, 0.22mmol) prepared in Preparation 49 was reacted according to the same procedures as Step 3 of Preparation 34 and Example 26 to give the title compound (31mg, Yield 31%).
1H-NMR (500HMz, CDCl3); δ 10.22(br s, IH), 7.00(s, IH), 6.87(s, IH), 6.50(s, IH), 5.05(m, IH), 4.27(s, 2H), 3.87(m, IH), 3.61(s, 3H), 3.22(m, IH), 2.83(m, IH), 2.72(s, 3H), 2.66(m, IH), 2.03(m, 2H), 1.64(m, 4H), 1.46(m, 2H)
Example 69: Synthesis of [(R)-2-(7-cyclopentylamino-5- methanesulfonylmethyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid
[(R)-2-(7-Cyclopentylamino-5-methan esulfonylmethyl-1 H-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid
Figure imgf000144_0002
The compound (29mg, 0.07mmol) prepared in Example 68 was reacted according to the same procedure as Example 27 to give the title compound (19mg, Yield 67%).
1H-NMR (400HMz, DMSOd6); δ 11.68(br s, IH), 6.85(s, IH), 6.71(s, IH), 6.33(s, IH), 6.18(m, IH), 4.88(m, IH), 4.35(s, 2H), 3.84(m, IH), 3.56(m, IH), 3.20(m, IH), 2.84(s, 3H), 2.55(m, IH), 2.09(m, IH), 1.97(m, 2H), 1.73(m, 2H), 1.58(m, 4H)
Example 70: Synthesis of 2-[(R)-2-(7-cyclopentylamino-5- methanesulfonylmethyl-lH-indoI-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol
2-[(R)-2-(7-Cyclopentylamino-5-meth anesulfonylmethyl-1 H-indol-2-yl)-4,
5-dihydro-thiazol-4-yl]-ethanol
Figure imgf000145_0001
The compound (720mg, l.όOmmol) prepared in Example 68 was dissolved in tetrahydrofuran (20ml). 2 M lithium borohydride tetrahydrofuran solution (1.6ml, 3.2mmol) was added thereto, and the mixture was stirred for 3 h at room temperature.
After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (292mg, Yield 43%). 1H-NMR (500HMz, CDCl3); δ 10.41(br s, IH), 6.98(s, IH), 6.90(s, IH),
6.49(s, IH), 4.68(m, IH), 4.28(s, 2H), 3.96(m, 3H), 3.59(m, IH), 3.13(m, IH), 2.05(m,
4H), 1.72(m, 2H), 1.60(m, 4H)
Preparation 50: Synthesis of cycIopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5- dihydro-thiazol-2-yl] -5-methanesulf onyImethyl-1 H-indol-7-yl}-amine
i
Figure imgf000145_0002
The compound (178mg, 0.42mmol) prepared in Example 70 was dissolved in tetrahydrofuran (10ml). Iodine (161mg, 0.63mmol), triphenylphosphine (166mg,
0.63mmol) and imidazole (86mg, 1.23mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added.
The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (120mg, Yield 54%).
Example 71: Synthesis of cyclopentyl-{5-methanesuIfonylmethyl-2-[(R)-4-
(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{5-methanesulfonylmethy l-2-[(R)-4-(2-morpholin-4-yl-ethyl) -4,5-dihydro-thiazol-2-yl]-1 H-indol
Figure imgf000146_0001
-7-yl}-amine
The compound (116mg, 0.22mmol) prepared in Preparation 50 was dissolved in N,N-dimethylformamide (4ml). Morpholine (57mg, 0.66mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound (68mg, Yield 64%).
1H-NMR (500HMz, CDCl3); δ 10.60(br s, IH), 6.99(s, IH), 6.89(s, IH), 6.49(s, IH), 4.79(m, IH), 4.26(s, 2H), 3.86(m, IH), 3.57(m, 5H), 3.19(m, IH), 2.72(s, 3H), 2.45(m, 2H), 2.32(m, 2H), 2.26(m, 2H), 2.04(m, 2H), 1.80(m, 2H), 1.66(m, 4H), 1.41(m, 2H)
Example 72: Synthesis of l-(4-{2-[(R)-2-(7-cyclopentylamino-5- methanesulfonylmethyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-l- yl)-ethanone 1-(4-{2-[(R)-2-(7-Cyclopentylamino- 5-methanesulfonylmethyl-1 H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-ethyl }-piperazin-1-yl)-ethanone
Figure imgf000147_0001
The compound (129mg, 0.24mmol) prepared in Preparation 50 and 1- acetylpiperazine instead of morpholine were reacted according to the same procedure as Example 71 to give the title compound (54mg, Yield 42%). 1H-NMR (500HMz, CDCl3); δ 10.62(br s, IH), 6.99(s, IH), 6.89(s, IH),
6.46(s, IH), 4.77(m, IH), 4.26(s, 2H), 3.87(m, IH), 3.57(m, IH), 3.30(m, 2H), 3.16(m, IH), 2.72(s, 3H), 2.46(m, 2H), 2.31(m, 2H), 2.21(m, 2H), 2.04(s, 3H), 2.03(m, 2H), 1.79(m, 2H), 1.64(m, 4H), 1.45(m, 2H)
Example 73: Synthesis of 2-[(R)-2-(5-chloro-7-cycIopentylamino-lH-indol-
2-yl)-4,5-dihydro-thiazol-4-yl]-l-morpholin-4-yl-ethanone
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-1-morpholin-4-yl-ethanone
Figure imgf000147_0002
The compound (50mg, 0.13mmol) prepared in Example 27 was dissolved in
N,N-dimethylformamide (2ml). Morpholine (17mg, 0.20mmol), EDC (43mg, 0.23mmol) and HOBT (36mg, 0.26mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (22mg, Yield 37%).
1H-NMR (500HMz, DMSO-d6); δ 11.52(br s, IH), 6.80(s, IH), 6.69(s, IH), 6.16(s, IH), 6.12(m, IH), 4.95(m, IH), 3.81(m, IH), 3.63(m, IH), 3.41(m, 8H), 3.12(m, IH), 2.85(m, IH)5 2.69(m, IH), 1.93(m, 2H), 1.68(m, 2H), 1.56(m, 4H)
Example 74: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yI]-N-(2-morpholin-4-yl-ethyl)-acetamide
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-N-(2-morpholin-4-yl-ethyl) -acetamide
Figure imgf000148_0001
The compound (50mg, 0.13mmol) prepared in Example 27 and 4-(2- aminoethyl)morpholine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (22mg, Yield 34%). 1H-NMR (500HMz, DMSOd6); δ 11.53(br s, IH), 7.91(m, IH), 6.80(s, IH),
6.70(s, IH), 6.16(s, IH), 6.12(m, IH), 4.93(m, IH), 3.80(m, IH), 3.53(m, 5H), 3.20(m, 3H), 2.60(m, IH), 2.32(m, 7H), 1.93(m, 2H), 1.68(m, 2H), 1.53(m, 4H)
Example 75: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl] -N-(3-morpholin-4-yl-propyl)-acetamide
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-N-(3-morpholin-4-yl-propyl )-acetamide
Figure imgf000148_0002
The compound (50mg, 0.13mmol) prepared in Example 27 and 4-(3- aminopropyl)morpholine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (23mg, Yield 35%). 1H-NMR (500HMz, DMSOd6); δ 11.52(br s, IH), 7.94(m, IH), 6.79(s, IH),
6.70(s, IH), 6.16(s, IH), 6.12(m, IH), 4.93(m, IH), 3.80(m, IH), 3.51(m, 5H), 3.10(m, 3H), 2.59(m, IH), 2.37(m, IH), 2.25(m, 6H), 1.93(m, 2H), 1.68(m, 2H)5 1.53(m, 6H)
Example 76: Synthesis of 2-[(R)-2-(5-chloro-7-cycLopentylamino-lH-indol- 2-yI)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-N-methyl-acetamide
Figure imgf000149_0001
The compound (50mg, 0.13mmol) prepared in Example 27 and methylamine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (45mg, Yield 87%).
1H-NMR (500HMz, DMSOd6); δ 11.52(br s, IH), 7.90(m, IH), 6.80(s, IH), 6.69(s, IH), 6.16(s, IH), 6.13(m, IH), 4.93(m, IH), 3.80(m, IH), 3.55(m, IH), 3.15(m, IH), 2.58(m, 4H), 2.39(m, IH), 1.93(m, 2H), 1.68(m, 2H), 1.56(m, 4H)
Example 77: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-N,N-dimethyl-acetamide
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-N,N-dimethyl-acetamide
Figure imgf000149_0002
The compound (50mg, 0.13mmol) prepared in Example 27 and dimethylamine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (26mg, Yield 49%).
1H-NMR (500HMz, DMSOd6); δ 11.53(br s, IH), 6.79(s, IH), 6.69(s, IH), 6.16(s, IH), 6.12(m, IH), 4.93(m, IH), 3.81(m, IH), 3.63(m, IH), 3.15(m, IH), 2.95(s, 3H), 2.87(m, IH), 2.83(s, 3H), 2.65(m, IH), 1.93(m, 2H), 1.69(m, 2H), 1.53(m, 4H) Example 78: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-l-(4-methyI-piperazin-l-yl)-ethanone
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-1-(4-methyl-piperazin-1-yl )-ethanone
Figure imgf000150_0001
The compound (40mg, O.l lmmol) prepared in Example 27 and 1- methylpiperazine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (21mg, Yield 43%).
1H-NMR (500HMz, DMSOd6); δ 11.52(br s, IH), 6.80(s, IH), 6.69(s, IH), 6.16(s, IH), 6.12(m, IH), 4.94(m, IH), 3.80(m, IH), 3.62(m, IH), 3.42(m, 4H), 3.35(m, IH), 3.15(m, IH), 2.85(m, IH), 2.66(m, IH), 2.24(m, 4H), 2.13(s, 3H), 1.93(m, 2H), 1.68(m, 2H), 1.55(m, 4H)
Example 79: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-l-(3-dimethylamino-pyrrolidin-l-yl)-ethanone
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-1-(3-dimethylamino-pyrroli din-1-yl)-ethanone
Figure imgf000150_0002
The compound (40mg, O.l lmmol) prepared in Example 27 and 3- dimethylaminopyrrolidine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (24mg, Yield 48%).
1H-NMR (500HMz, DMSO-d6); δ 11.53(br s, IH), 6.80(s, IH), 6.69(s, IH), 6.16(s, IH), 6.12(m, IH), 4.94(m, IH), 3.81(m, IH), 3.62(m, 3H), 3.30(m, IH), 3.17(m,
2H), 2.78(m, IH), 2.53(m, 2H), 2.1 l(s, 3H), 2.07(s, 3H), 1.93(m, 2H), 1.69(m, 3H), 1.59(m, 5H)
Example 80: Synthesis of 2-[(R)-2-(5-chloro-7-cycIopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yI]-l-(3-hydroxy-pyrrolidin-l-yl)-ethanone
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-1 -(3-hydroxy-pyrrolidin-1 - yl)-ethanone
Figure imgf000151_0001
The compound (40mg, O.l lmmol) prepared in Example 27 and 3-pyrrolidinol instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (19mg, Yield 40%).
1H-NMR (500HMz, DMSOd6); δ 11.54(br s, IH), 6.80(s, IH), 6.69(s, IH), 6.16(s, IH), 6.12(m, IH), 4.93(m, IH), 4.25(m, IH), 3.81(m, IH), 3.63(m, 3H), 3.47(m, 2H), 3.32(m, 2H), 3.17(m, IH), 2.79(m, IH), 2.59(m, IH), 1.93(m, 3H), 1.80(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Example 81: Synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yI)-4,5-dihydro-thiazol-4-yl]-l-piperidin-l-yl-ethanone
2-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-1 -piperidin-1 -yl-ethanone
Figure imgf000151_0002
The compound (40mg, O.l lmmol) prepared in Example 27 and piperidine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (27mg, Yield 57%). 1H-NMR (500HMz, DMSO-d6); δ 11.52(br s, IH), 6.80(s, IH), 6.69(s, IH),
6.16(s, IH), 6.12(m, IH), 4.94(m, IH), 3.81(m, IH), 3.63(m, IH), 3.45(m, IH), 3.38(m, 3H), 3.14(m, IH), 2.85(m, IH), 1.93(m, 2H), 1.68(m, 2H), 1.48(m, 10H)
Example 82: Synthesis of 2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-N-methyl-acetamide
Figure imgf000152_0001
The compound (44mg, O.l lmmol) prepared in Example 31 was dissolved in N,N-dimethylformamide (2ml). Methylamine (0.08ml, 2M in THF, 0.17mmol), EDC (36mg, 0.19mmol) and HOBT (30mg, 0.22mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18mg, Yield 37%).
1H-NMR (500HMz, DMSO-d6); δ 11.54(br s, IH), 7.91(m, IH), 6.81(s, IH), 6.70(s, IH), 6.28(s, IH), 6.08(m, IH), 4.93(m, IH), 3.85(m, 2H), 3.56(m, 2H), 3.44(m, 2H), 3.15(m, IH), 2.06(m, 4H), 2.37(m, IH), 1.93(m, 2H), 1.39(m, 2H)
Example 83: Synthesis of 2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indoI-2-yl]-4,5-dihydro-thiazol-4-yl}-l-morpholin-4-yl-ethanone
2-{(R)-2-[5-Chloro-7-(tetrahydro-py ran-4-ylamino)-1 H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-1 -morpholin-4- yl-ethanone
Figure imgf000152_0002
The compound (44mg, O.l lmmol) prepared in Example 31 and morpholine instead of methylamine were reacted according to the same procedure as Example 82 to give the title compound (35mg, Yield 68%).
1H-NMR (500HMz, DMSO-d6); δ 11.53(br s, IH), 6.81(s, IH), 6.70(s, IH), 6.28(s, IH), 6.08(m, IH), 4.96(m, IH), 3.86(m, 2H), 3.47(m, 12H), 3.15(m, IH), 2.85(m, IH), 2.69(m, IH), 1.94(m, 2H), 1.39(m, 2H)
Example 84: Synthesis of 2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-l-(4-methyI-piperazin-l-yl)-ethanone
2-[(R)-2-(7-Cyclopentylamino-5-fluo ro-1H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-1 -(4-methyl-piperazin-1 -yl
Figure imgf000153_0001
)-ethanone
The compound (lOOmg, 0.28mmol) prepared in Example 37 was dissolved in
N,N-dirnethylformamide (3ml). 1-Methylpiperazine (36mg, 0.36mmol), EDC (90mg, 0.47mmol) and HOBT (75mg, 0.55mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (78mg, Yield 64%).
1H-NMR (400HMz, DMSOd6); δ 11.44(br s, IH), 6.73(s, IH), 6.52(dd, IH), 6.19(d, J=1.2Hz, IH), 6.07(dd, IH), 4.99(m, IH), 3.84(m, 2H), 3.65(m, IH), 3.49(m, 4H), 3.20(m, IH), 2.88(m, IH), 2.71(m, IH), 2.28(m, 4H), 2.17(s, 3H), 1.98(m, 2H), 1.72(m, 2H), 1.58(m, 4H)
Example 85: Synthesis of 2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yI-ethyl)-acetamide
2-[(R)-2-(7-Cyclopentylamino-5-fluo ro-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-N-(2-morpholin-4-yl-ethyl) -acetamide
Figure imgf000154_0001
The compound (lOOmg, 0.28nimol) prepared in Example 37 and 4-(2- aminoethyl)morpholine instead of 1-methylpiperazine were reacted according to the same procedure as Example 84 to give the title compound (80mg, Yield 60%).
1H-NMR (400HMz, DMSOd6); δ 11.46(br s, IH), 7.95(m, IH), 6.75(s, IH), 6.73(dd, IH), 6.18(d, J=4.0Hz, IH), 6.07(dd, IH), 5.00(m, IH), 3.84(m, IH), 3.58(m, IH), 3.53(m, 4H), 3.20(m, 3H), 2.73(m, IH), 2.45(m, 3H), 2.34(m, 4H), 1.98(m, 2H), 1.72(m, 2H), 1.59(m, 4H)
Example 86: Synthesis of l-(4-acetyl-piperazm-l-yl)-2-[(R)-2-(7- cyclopentylamino-5-fluoro-lH-mdol-2-yl)-4,5-dihydro-thiazoI-4-yl]-ethanone
1 -(4-Acetyl-piperazin-1 -yl)-2-[(R)- 2-(7-cyclopentylamino-5-fluoro-1 H-i ndol-2-y I )-4 , 5-d ihyd ro-th iazol-4-y I
Figure imgf000154_0002
]-ethanone
The compound (lOOmg, 0.28mmol) prepared in Example 37 and 1- acetylpiperazine instead of 1-methylpiperazine were reacted according to the same procedure as Example 84 to give the title compound (60mg, Yield 55%).
Example 87: Synthesis of 2-[(R)-2-(7-cycIopentylamino-5-methoxy-lH- indoI-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide 2-[(R)-2-(7-Cyclopentylamino-5-meth oxy-1 H-indol-2-yl)-4,5-dihydro-thia zol-4-yl]-N-methyl-acetamide
Figure imgf000155_0001
The compound (83mg, 0.22mmol) prepared in Example 48 was dissolved in N,N-dimethylformamide (3ml). Methylamine (0.17ml, 2M in THF, 0.33mmol), EDC (72mg, 0.38mmol) and HOBT (60mg, 0.44mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39mg, Yield 46%). 1H-NMR (500HMz, DMSOd6); δ 11.22(br s, IH), 7.90(m, IH), 6.61(s, IH),
6.23(s, IH), 5.87(m, IH), 5.85(s, IH), 4.90(m, IH), 3.76(m, IH), 3.64(s, 3H), 3.52(m, IH), 3.12(m, IH), 2.58(m, 4H), 2.35(m, IH), 1.91(m, 2H), 1.67(m, 2H), 1.53(m, 4H)
Example 88: Synthesis of 2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-l-morpholin-4-yl-ethanone
2-[(R)-2-(7-Cyclopentylamino-5-meth oxy-1H-indol-2-yl)-4,5-dihydro-thia zol-4-yl]-1-morpholin-4-yl-ethanone
Figure imgf000155_0002
The compound (83mg, 0.22mmol) prepared in Example 48 and morpholine instead of methylamine were reacted according to the same procedure as Example 87 to give the title compound (24mg, Yield 24%). 1H-NMR (500HMz, DMSOd6); δ 11.21(br s, IH), 6.62(s, IH), 6.24(s, IH),
5.87(m, IH), 5.85(s, IH), 4.92(m, IH), 3.77(m, IH), 3.65(s, 3H), 3.60(m, IH), 3.58- 3.33(m, 8H), 3.13(m, IH), 2.84(m, IH), 2.66(m, IH), 1.91(m, 2H), 1.67(m, 2H), 1.53(m, 4H)
Example 89: Synthesis of 2-[(R)-2-(7-cydopentylamino-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -N-ethyl-acetamide
2-[(R)-2-(7-Cyclopentylamino-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-yl]-
N-ethyl-acetamide
Figure imgf000156_0001
The compound (9mg, 0.03mmol) prepared in Example 42 was dissolved in N5N- dimethylformamide (ImI). Ethylamine hydrochloride (3mg, 0.03mmol), EDC (8mg, 0.04mmol), HOBT (5mg, 0.04mmol) and triethylamine (8mg, 0.08mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (4mg, Yield 41%). 1H-NMR (400HMz, CDCl3); δ 9.66, 7.08~6.99(m, 2H), 6.92(d, IH), 6.55(d,
J=7.2Hz, IH), 5.88(m, IH), 5.02(m, IH), 4.13(m, IH), 3.61(m, IH), 3.32-3.18(m, 3H), 2.67(1H, m), 2.52(m, IH), 2.04(m, IH), 1.72~1.53(m, 6H), 1.08(m, 3H)
Example 90: Synthesis of 2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -N-methyl-acetamide
2-[(R)-2-(7-Cyclopentylamino-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-yl]-
Figure imgf000156_0002
N-methyl-acetamide The compound (97mg, 0.28mmol) prepared in Example 42 and methylamine instead of ethylamine were reacted according to the same procedure as Example 89 to give the title compound (34mg, Yield 34%).
1H-NMR (500HMz, DMSOd6); δ 11.33(br s, IH), 7.90(m, IH), 6.78(m, IH), 6.71(s, IH), 6.24(s, IH), 5.80(m, IH), 4.93(m, IH), 3.81(m, IH), 3.54(m, IH), 3.14(m, IH), 2.62(m, IH), 2.58(m, 3H), 2.38(m, IH), 1.93(m, 2H), 1.69(m, 2H), 1.54(m, 4H)
Example 91: Synthesis of 2-[(R)-2-(7-cyclopentylammo-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-l-morpholin-4-yl-ethanone
2-[(R)-2-(7-Cyclopentylamino-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-yl]- 1 -morpholin-4-yl-ethanone
Figure imgf000157_0001
The compound (97mg, 0.28mmol) prepared in Example 42 and morpholine instead of ethylamine were reacted according to the same procedure as Example 89 to give the title compound (19mg, Yield 16%).
1H-NMR (500HMz, DMSOd6); δ 11.32(br s, IH), 6.78(m, IH), 6.71(s, IH), 6.24(s, IH), 5.81(m, IH), 4.95(m, IH), 3.81(m, IH), 3.61(m, IH), 3.59-3.39(m, 8H), 3.15(m, IH), 2.87(m, IH), 2.68(m, IH), 1.93(m, 2H), 1.68(m, 2H), 1.54(m, 4H)
Example 92: Synthesis of N-methyl-2-{(R)-2-[7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetamide
N-Methyl-2-{(R)-2-[7-(tetrahydro-py ran-4-ylamino)-1 H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-acetamide
Figure imgf000157_0002
The compound (80mg, 0.22mmol) prepared in Example 45 instead of the compound prepared in Example 48 was reacted according to the same procedure as Example 87 to give the title compound (17mg, Yield 20%).
1H-NMR (500HMz, DMSOd6); δ 11.34(br s, IH), 7.90(m, IH), 6.79(m, IH), 6.72(s, IH), 6.33(m, IH), 5.76(m, IH), 4.93(m, IH), 3.86(m, IH), 3.54(m, 2H), 3.43(m, 2H), 3.14(m, IH), 2.61(m, IH), 2.59(m, 3H), 2.38(m, IH), 1.95(m, 2H), 1.40(m, 2H)
Example 93: Synthesis of l-morpholin-4-yl-2-{(R)-2-[7-(tetrahydro-pyran- 4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanone H-indol-2-y
Figure imgf000158_0001
The compound (80mg, 0.22mmol) prepared in Example 45 instead of the compound prepared in Example 42 was reacted according to the same procedure as Example 91 to give the title compound (12mg, Yield 13%).
1H-NMR (500HMz, DMSO-d6); δ 11.34(br s, IH), 6.79(m, IH), 6.72(s, IH), 6.33(m, IH), 5.77(m, IH), 4.95(m, IH), 3.87(m, IH), 3.61(m, IH), 3.57-3.38(m, HH), 3.15(m, IH), 2.87(m, IH), 2.68(m, IH), 1.95(m, 2H), 1.40(m, 2H)
Preparation 51: Synthesis of {5-chloro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro- thiazol-2-yl]-lH-indoI-7-yl}-cyclopentyl-amine
{5-Chloro-2-[(R)-4-(2-iodo-ethyl)-4 ,5-dihydro-thiazol-2-yl]-1 H-indol-7 -yl}-cyclopentyl-amine
Figure imgf000158_0002
The compound (520mg, 1.43mmol) prepared in Example 28 was reacted according to the same procedure as Preparation 50 to give the title compound (524mg, Yield 77%).
Example 94: Synthesis of {5-chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-cyclopentyl-amine
{5-Chloro-2-[(R)-4-(2-dimethylamino
-ethyl)-4,5-dihydro-thiazol-2-yl]-1
H-indol-7-yl}-cyclopentyl-amine
Figure imgf000159_0001
The compound (52mg, O.l lmmol) prepared in Preparation 51 was dissolved in N,N-dimethylformamide (4ml). Dimethylamine (1.1ml, 2M in THF, 2.2mmol) and potassium carbonate (300mg, 2.17mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (29mg, Yield 68%).
1H-NMR (500HMz, CDCl3); δ 10.07(br s, IH), 6.99(s, IH), 6.80(s, IH), 6.42(s, IH), 4.67(m, IH), 3.54(m, IH), 3.16(m, IH), 2.46(m, IH), 2.37(m, IH), 2.19(s, 6H), 2.02(m, 3H), 1.81(m, 4H), 1.69(m, 4H)
Example 95: Synthesis of {5-chloro-2-[(R)-4-(2-morpholin-4-yI-ethyI)-4,5- dihydro-thiazol-2-yl] - 1 H-indol-7-yl} -cyclopentyl- amine
{5-Chloro-2-[(R)-4-(2-morpholin-4-y l-ethyl)-4,5-dihydro-thiazol-2-yl]- 1 H-indol-7-yl}-cyclopentyl-amine
Figure imgf000159_0002
The compound (52mg, O.l lmmol) prepared in Preparation 51 and morpholine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (18mg, Yield 38%).
1H NMR (DMSO-d6, ppm); δ 11.46(1H, s), 6.79(1H, s), 6.68(1H, s), 6.11(1H, s), 6.09(1H, d), 4.61(1H, quin), 3.81(1H, m), 3.57(4H, m), 3.15(1H, m), 2.50-2.43(3H, m), 2.35(4H, m), 1.95(2H, m), 1.8O(1H, m), 1.68(2H, m), 1.57-1.49(4H, m), 1.21(1H, m) FAB MS(m/e) = 434
Example 96: Synthesis of {5-chloro-2-[(R)-4-(2-piperazin-l-yl-ethyl)-4,5- dihydro-thiazol-2-yI]-lH-indol-7-yl}-cyclopentyl-amine
{5-Chloro-2-[(R)-4-(2-piperazin-1-y l-ethyl)-4,5-dihydro-thiazol-2-yl]-
1 H-indol-7-yl}-cyclopentyl-amine
Figure imgf000160_0001
The compound (250mg, 0.53mmol) prepared in Preparation 51 was dissolved in tetrahydrofuran (10ml). 1-t-Butoxycarbonylpiperazine (980mg, 5.28mmol) and potassium carbonate (730mg, 5.28mmol) were added thereto, and the mixture was stirred for 8 h at 80 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure.
Thus obtained compound was dissolved in dichloromethane (50ml), and 4N hydrochloric acid ethyl acetate solution (1.3ml, 5.28mmol) was added thereto. The mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to give a solid. The solid was washed with ethylether, and dried to give the title compound (125mg, Yield 55%).
1H NMR (DMSOd6, ppm); δ 11.48(1H, s), 6.79(1H, s), 6.67(1H, s), 6.11(1H, s), 6.1O(1H, d), 4.61(1H, m), 3.80(1H, m), 3.54(1H, m), 3.15(1H, m), 2.93(2H, m), 2.50- 2.41(2H, m), 2.31(3H, m), 1.95(4H, m), 1.79(1H, m), 1.68(3H, m), 1.57-1.50(4H, m), 1.20(lH, m)
FAB MS(m/e) = 432
Example 97: Synthesis of l-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyI}-piperazin-l-yl)-ethanone
1-(4-{2-[(R)-2-(5-Chloro-7-cyclopen tylamino-1 H-indol-2-yl)-4,5-dihydro -thiazol-4-yl]-ethyl}-piperazin-1 -y l)-ethanone
Figure imgf000161_0001
The compound (80mg, 0.22mmol) prepared in Preparation 51 and 1- acetylpiperazine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (26mg, Yield 33%).
1H-NMR (500HMz, DMSOd6); δ 11.47(br s, IH), 6.79(s, IH), 6.68(s, IH), 6.16(s, IH), 6.1 l(m, IH), 4.62(m, IH), 3.80(m, IH), 3.55(m, IH), 3.39(m, 4H), 3.15(m, IH), 2.46(m, IH), 2.32(m, 4H), 1.95(m, 4H), 1.80(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Example 98: Synthesis of (5-chloro-2-{(R)-4-[2-(4-ethanesulfonyl-piperazin- l-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine
(5-Chloro-2-{(R)-4-[2-(4-ethanesulf onyl-piperazin-1-yl)-ethyl]-4,5-dih ydro-thiazol-2-yl}-1 H-indol-7-yl)-c yclopentyl-amine
Figure imgf000161_0002
The compound (40mg, O.l lmmol) prepared in Preparation 51 and 1- ethylsulfonylpiperazine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (17mg, Yield 39%). 1H-NMR (500HMz, CDCl3); δ 11.29(br s, IH), 6.97(s, IH), 6.86(s, IH), 6.37(s, IH), 4.93(m, IH), 3.92(br s, IH), 3.77(m, IH), 3.57(m, IH), 3.16(m, IH), 2.95(m, 2H), 2.80(m, 4H), 2.42-2.28(m, 4H), 2.03(m, 4H), 1.74(m, 3H), 1.63(m, 4H), 1.43(m, IH), 1.32(t, 3H)
Example 99: Synthesis of l-(4-{2-[(R)-2-(5-chloro-7-cycIopentyIamino-lH- indoI-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-l-yl)-2-hydroxy-ethanone
1 -(4-{2-[(R)-2-(5-Chloro-7-cyclopen tylamino-1H-indol-2-yl)-4,5-dihydro -thiazol-4-yl]-ethyl}-piperazin-1-y l)-2-hydroxy-ethanone
Figure imgf000162_0001
The compound (85mg, 0.20mmol) prepared in Example 96 was dissolved in N,N-dimethylformamide (ImI). Glycolic acid (22mg, 0.30mmol), EDC (64mg,
0.33mmol) and HOBT (53mg, 0.39mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (41mg, Yield 44%).
1H-NMR (500HMz, DMSOd6); δ 11.47(br s, IH), 6.79(s, IH), 6.68(s, IH), 6.16(s, IH), 6.10(m, IH), 4.63(m, IH), 4.50(m, IH), 4.04(m, 2H), 3.81(m, IH), 3.55(m, IH), 3.43(m, 2H), 3.16(m, IH), 2.52(m, 2H), 2.35(m, 4H), 1.95(m, 3H), 1.81(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Example 100: Synthesis of (5-chloro-2-{(R)-4-[2-(4-methyl-piperazin-l-yl)- ethyl]-4,5-dihydro-thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine (5-Chloro-2-{(R)-4-[2-(4-methyl-pip erazin-1-yl)-ethyl]-4,5-dihydro-thi azol-2-yl}-1 H-indol-7-yl)-cyclopent
Figure imgf000163_0001
yl-amine
The compound (80mg, 0.22mmol) prepared in Preparation 51 and 1- methylpiperazine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (24mg, Yield 32%). 1H-NMR (500HMz, DMSOd6); δ 11.47(br s, IH), 6.79(s, IH), 6.67(s, IH),
6.16(s, IH), 6.10(m, IH), 4.59(m, IH), 3.80(m, IH), 3.54(m, IH), 3.15(m, IH), 2.40(m, 10H), 2.13(s, 3H), 1.95(m, 3H), 1.78(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Example 101: Synthesis of l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperidin-4-ol
1-{2-[(R)-2-(5-Chloro-7-cyclopentyl amino-1 H-indol-2-yl)-4,5-dihydro-th iazol-4-yl]-ethyl}-piperidin-4-ol
Figure imgf000163_0002
The compound (80mg, 0.22mmol) prepared in Preparation 51 and 4- hydroxypiperidine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (28mg, Yield 37%). 1H-NMR (500HMz, DMSOd6); δ 11.48(br s, IH), 6.79(s, IH), 6.68(s, IH),
6.16(s, IH), 6.10(m, IH), 4.60(m, IH), 3.80(m, IH), 3.54(m, IH), 3.32(m, 4H), 3.16(m, IH), 2.71(m IH), 2.60(m, IH), 2.32(m, 5H), 1.71(m, 5H), 1.57(m, 5H)
Example 102: Synthesis of (4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one 4-{2-[(R)-2-(5-Chloro-7-cyclopentyl amino-1 H-indol-2-yl)-4,5-dihydro-th iazol-4-yl]-ethyl}-piperazin-2-one
Figure imgf000164_0001
The compound (80mg, 0.22mmol) prepared in Preparation 51 and 2- oxopiperazine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (38mg, Yield 51%). 1H-NMR (500HMz, DMSOd6); δ 11.48(br s, IH), 7.71(s, IH), 6.79(s, IH),
6.68(s, IH), 6.16(s, IH), 6.10(m, IH), 4.61(m, IH), 3.81(m, IH), 3.55(m, IH), 3.13(m, 3H), 2.92(m, 2H), 2.56(m 3H), 1.96(m, 3H), 1.80(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Example 103: Synthesis of (5-chloro-2-{(R)-4-[2-(3-dimethylamino- pyrrolidin-l-yl)-ethyI]-4,5-dihydro-thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine
(5-Chloro-2-{(R)-4-[2-(3-dimethylam ino-pyrrolidin-1-yl)-ethyl]-4,5-dih ydro-thiazol-2-yl}-1 H-indol-7-yl)-c yclopentyl-amine
Figure imgf000164_0002
The compound (80mg, 0.22mmol) prepared in Preparation 51 and 3- dimethylaminopyrrolidine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (21mg, Yield 27%). 1H-NMR (500HMz, DMSO-d6); δ 11.47(br s, IH), 6.79(s, IH), 6.67(s, IH),
6.16(s, IH), 6.11(m, IH), 4.62(m, IH), 3.80(m, IH), 3.52(m, IH), 3.15(m, IH), 2.66(m, 2H), 2.56(m 2H), 2.41(m, 2H), 2.27(m, IH), 1.93(m, 3H), 1.71(m, 4H), 1.53(m, 4H)
Example 104: Synthesis of {5-chloro-2-[(R)-4-(2-piperidin-l-yI-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-cyclopentyl-amine {5-Chloro-2-[(R)-4-(2-piperidin-1-y l-ethyl)-4,5-dihydro-thiazol-2-yl]-
1 H-indol-7-yl}-cyclopentyl-amine
Figure imgf000165_0001
The compound (80mg, 0.22mmol) prepared in Preparation 51 and piperidine instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (30mg, Yield 41%). 1H-NMR (500HMz, DMSO-d6); δ 11.52(br s, IH), 6.80(s, IH), 6.70(s, IH),
6.16(s, IH), 6.12(m, IH), 4.63(m, IH), 3.80(m, IH), 3.57(m, IH), 3.29(m, 4H), 3.17(m, IH), 2.60(m, 4H), 1.95(m, 3H), 1.68(m, 2H), 1.58(m, 9H)
Example 105: Synthesis of (5-chloro-2-{(R)-4-[2-(l,l-dioxo-thiomorpholin-4- yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine
(5-Chloro-2-{(R)-4-[2-(1 , 1 -dioxo-11 ambda*6*-thiomorpholin-4-yl)-ethyl] -4,5-dihydro-thiazol-2-yl}-1 H-indol -7-yl)-cyclopentyl-amine
Figure imgf000165_0002
The compound (80mg, 0.22mmol) prepared in Preparation 51 and thiomorpholine- 1,1 -dioxide instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (31mg, Yield 38%). 1H-NMR (500HMz, DMSO-d6); δ 11.48(br s, IH), 6.79(s, IH), 6.68(s, IH),
6.16(s, IH), 6.09(m, IH), 4.61(m, IH), 3.80(m, IH), 3.56(m, IH), 3.16(m, IH), 3.07(m, 4H), 2.89(m, 4H), 2.67(m, 2H), 1.94(m, 3H), 1.81(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Example 106: Synthesis of {5-chloro-2-[(R)-4-(2-pyrazol-l-yl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-cyclopentyl-amine {5-Chloro-2-[(R)-4-(2-pyrazol-1-yl- ethyl)-4,5-dihydro-thiazol-2-yl]-1 H -indol-7-yl}-cyclopentyl-amine
Figure imgf000166_0001
The compound (81mg, O.l lmmol) prepared in Preparation 51 was dissolved in tetrahydrofuran (4ml). Pyrazole (58mg, 0.85mmol) and sodium hydride (21mg, 60%, 0.85mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (24mg, Yield 34%).
1R NMR (DMSOd6, ppm); δ 11.5O(1H, s), 7.76(1H, s), 7.42(1H, s), 6.8O(1H, s), 6.7O(1H, s), 6.22(1H, s), 6.17(1H, s), 6.11(1H, d), 4.49(1H, quin), 4.32(2H, m), 3.8O(1H, m), 3.53(1H, t), 3.12(1H, t), 2.38(1H, m), 2.14(1H, m), 1.92(2H, m), 1.68(2H, m), 1.59- 1.50(4H, m)
FAB MS(m/e) = 414
Example 107: Synthesis of (S)-l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyI}-pyrrolidine-2-carboxylic acid
(S)-1 -{2-[(R)-2-(5-Chloro-7-cyclope ntylamino-1 H-indol-2-yl)-4,5-dihydr o-thiazol-4-yl]-ethyl}-pyrrolidine-
Figure imgf000166_0002
2-carboxylic acid
The compound (200mg, 0.42mmol) prepared in Preparation 51 was dissolved in tetrahydrofuran (20ml). Pyrrolidine-2-carboxylic acid methyl ester hydrochloride (700mg, 4.22mmol) and potassium carbonate (1.2g, 8.44mmol) were added thereto, and the mixture was stirred for 8 h at 80 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure.
Thus obtained compound was dissolved in tetrahydrofuran (10ml), methanol (10ml) and water (10ml). Lithium hydroxide monohydrate (71mg, 1.70mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, IN hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (34mg,
Yield 18%).
1H NMR (CDCl3, ppm); δ 12.04(1H, s), 11.02(1H, s), 6.85(1H, s), 6.69(1H, s), 6.31(1H, s), 6.24(1H, m), 4.37(1H, m), 4.1O(1H, m), 3.86(1H, m), 3.79(1H, m), 3.59(1H, m), 3.28(1H, m), 3.17(1H, m), 2.88(2H, m), 2.59(1H, m), 2.21(1H, m), 2.06-1.59(11H, m), 1.23(1H, m)
FAB MS(m/e) = 461
Example 108: Synthesis of {5-chloro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-cycIopentyl-amine
{5-Chloro-2-[(R)-4-(2-methanesulfon yl-ethyl)-4,5-dihydro-thiazol-2-yl]
-1 H-indol-7-yl}-cyclopentyl-amine
Figure imgf000167_0001
The compound (50mg, O.l lmmol) prepared in Preparation 51 was dissolved in N,N-dimethylformamide (2ml). Sodium methanesulfmate (54mg, 0.55mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (19mg, Yield 45%). 1H-NMR (400HMz, CDCl3); δ 10.39(br s, IH), 7.03(s, IH), 6.89(s, IH),
6.48(s, IH), 6.17(s, IH), 4.77(m, IH), 3.87(m, IH), 3.59(m, IH), 3.29(m, IH), 3.17(m, 2H), 2.86(s, 3H), 2.26(m, 2H), 2.10(m, 2H), 1.70(m, 4H), 1.51(m, 2H)
Example 109: Synthesis of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indoI-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester
3-{2-[(R)-2-(5-Chloro-7-cyclopentyl amino-1 H-indol-2-yl)-4,5-dihydro-th iazol-4-yl]-ethyl}-5-methyl-3H-imid azole-4-carboxylic acid ethyl ester
Figure imgf000168_0001
The compound (150mg, 0.31mmol) prepared in Preparation 51 and 5-methyl-3H- imidazole-4-carboxylic acid ethyl ester instead of pyrazole were reacted according to the same procedure as Example 106 to give the title compound (74mg, Yield 47%).
1H-NMR (500HMz, DMSO-d6); δ 11.49(br s, IH), 7.71(s, IH), 6.80(s, IH), 6.72(s, IH), 6.17(s, IH), 6.08(m, IH), 4.56(m, IH), 4.16(m, 4H), 3.81(m, IH), 3.58(m, IH), 3.18(m, IH), 2.46(s, 3H), 2.1 l(m, 2H), 1.95(m, 2H), 1.68(m, 2H), 1.53(m, 4H), 1.22(m, 3H)
Example 110: Synthesis of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic acid
3-{2-[(R)-2-(5-Chloro-7-cyclopentyl amino-1 H-indol-2-yl)-4,5-dihydro-th iazol-4-yl]-ethyl}-5-methyl-3H-imid azole-4-carboxylic acid
Figure imgf000169_0001
The compound (35mg, 0.07mmol) prepared in Example 109 was dissolved in tetrahydrofuran (10ml), methanol (10ml) and water (10ml). Lithium hydroxide monohydrate (29mg, OJOmmol) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, IN hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (17mg, Yield 52%).
1H NMR (DMSOd6, ppm); δ 11.5O(1H, s), 7.71(1H, s), 6.8O(1H, s), 6.72(1H, s), 6.17(1H, s), 6.08(1H, m), 4.55(1H, m), 4.13(2H, m), 3.8O(1H, m), 3.55(2H, m), 2.19- 2.15(2H, m), 1.95(3H, m), 1.68(3H, m), 1.51(5H, m)
FAB MS(m/e) = 472
Example 111: Synthesis of l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-2-one
1-{2-[(R)-2-(5-Chloro-7-cyclopentyl amino-1 H-indol-2-yl)-4,5-dihydro-th iazol-4-yl]-ethyl}-pyrrolidin-2-one
Figure imgf000169_0002
The compound (80mg, 0.22mmol) prepared in Preparation 51 and pyrrolidinone instead of dimethylamine were reacted according to the same procedure as Example 94 to give the title compound (17mg, Yield 36%). 1H-NMR (500HMz, DMSO-d6); δ 11.49(br s, IH), 6.80(s, IH), 6.69(s, IH), 6.16(s, IH), 4.51(m, IH), 3.80(m, IH), 3.57(m, IH), 3.46(m, IH), 3.32(m, IH), 3.15(m, IH), 2.18(m, 2H), 1.91(m, 5H), 1.80(m, IH), 1.68(m, 2H), 1.53(m, 4H)
Preparation 52: Synthesis of {5-chloro-2-[(R)-4-(2-iodo-ethyI)-4,5-dihydro- thiazol-2-yI]-lH-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine
{5-Chloro-2-[(R)-4-(2-iodo-ethyl)-4 ,5-dihydro-thiazol-2-yl]-1 H-indol-7
-yl}-(tetrahydro-pyran-4-yl)-amine
Figure imgf000170_0001
The compound (3.7g, 10.2mmol) prepared in Example 32 was dissolved in tetrahydrofuran (100ml). Imidazole (2.1g, 30.6mmol), triphenylphosphine (4.Og, 15.3mmol), and iodine (3.9g, 15.3mmol) were added thereto, and the mixture was stirred for 8 h at 0 °C ~ room temperature. After completion of the reaction, ethyl acetate (100ml) was added, and the mixture was washed with water (2 x 100ml). The organic layer was concentrated, and the residue was separated by column chromatography to give the title compound (2.Og, 4.07mmol, Yield 40%).
Preparation 53: Synthesis of l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylic acid ethyl ester
este
Figure imgf000170_0002
The compound (300mg, 0.63mmol) prepared in Preparation 52 was dissolved in
N,N-dimethylformamide (20ml). Piperidine-3-carboxylic acid ethyl ester (1.97ml, 12.7mmol) and potassium carbonate (1.75g, 12.7mmol) were added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, IN hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (150mg, Yield 46%).
1K NMR (DMSOd6, ppm); δ 11.48(1H, s), 6.82(1H, s), 6.67(1H, s), 6.29(1H, s), 6.04(1H, d), 4.61(1H, quin), 4.47(1H, m), 3.87(2H, m), 3.62(2H, q), 3.56(2H, m), 3.44-3.39(4H, m), 3.14(2H, m), 2.52(1H, m), 2.37-2.30(6H, m), 1.96-1.92(3H, m), 1.81(1H, m), 1.42(2H, m), 1.28(3H, t) FAB MS(m/e) = 519
Example 112: Synthesis of l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylic acid
1 -(2-{(R)-2-[5-Chloro-7-(tetrahydro -pyran-4-ylamino)-1 H-indol-2-yl]-4, 5-dihydro-thiazol-4-yl}-ethyl)-pipe ridine-3-carboxylic acid
Figure imgf000171_0001
The compound (135mg, 0.28mmol) prepared in Preparation 53 was reacted according to the same procedure as Example 110 to give the title compound (90mg, Yield 58%). 1H NMR (DMSO-d6, ppm); δ 13.17(1H, s), 11.94(1H, s), 6.8O(1H, s), 6.68(1H, s), 6.28(1H, s), 6.04(1H, d), 4.62(1H, quin), 4.47(1H, m), 3.87(2H, m), 3.56(2H, m), 3.44-3.39(4H, m), 3.14(2H, m), 2.52(1H, m), 2.37-2.30(6H, m), 1.96-1.92(3H, m), 1.80(lH, m), 1.40(2H, m) FAB MS(m/e) = 491
Example 113: Synthesis of l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylic acid dimethylamide
Figure imgf000172_0001
The compound (84mg, O.lδmmol) prepared in Example 112 was dissolved in N,N-dimethylformamide (4ml). Dimethylamine (0.13ml, 2M in THF, 0.27mmol), EDC (58mg, 0.30mmol) and HOBT (48mg, 0.35mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18mg, Yield 20%). 1H NMR (DMSO-d6, ppm); δ 11.48(1H, s), 6.81(1H, s), 6.69(1H, s), 6.28(1H, s),
6.04(1H, d), 4.6O(1H, quin), 3.87(2H, m), 3.56(2H, m), 3.44(2H, t), 3.16(1H, m), 2.97(3H, s), 2,95(1H, m), 2.88-2.76(2H, m), 2.74(5H, m), 1.96(4H, m), 1.80(2H, m), 1.66(2H, m), 1.50-1.37(3H, m), 1.23(1H, m) FAB MS(m/e) = 518
Example 114: Synthesis of [(S)-l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- yIamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamic acid t-butyl ester [(S)-I -(2-{(R)-2-[5-Chloro-7-(tetra hydro-pyran-4-ylamino)-1 H-indol-2-y l]-4,5-dihydro-thiazol-4-yl}-ethyl) -pyrrolidin-3-yl]-carbamic acid ter t-butyl ester
Figure imgf000173_0001
The compound (300mg, 0.63mmol) prepared in Preparation 52 and (S)- pyrrolidin-3-yl-carbamic acid t-butyl ester instead of piperidine-3-carboxylic acid ethyl ester were reacted according to the same procedure as Preparation 53 to give the title compound (21 Omg, Yield 61 %).
1H-NMR (500HMz, DMSOd6); δ 11.48(br s, IH), 6.92(m, IH), 6.81(s, IH), 6.68(s, IH), 6.28(m, IH), 6.05(m, IH), 4.63(m, IH), 3.86(m, 3H), 3.59(m, IH), 3.54(m, IH), 3.44(m, 2H), 3.14(m, IH), 2.71-2.58(m, 2H), 2.25(m, IH), 1.95(m, 4H), 1.75(m, IH), 1.52(m, IH), 1.39(m, 2H), 1.37-1.32(m, HH)
Example 115: Synthesis of (2-{(R)-4-[2-((S)-3-amino-pyrrolidin-l-yI)-ethyI]- 4,5-dihydro-thiazol-2-yl}-5-chloro-lH-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine
(2-{(R)-4-[2-((S)-3-Amino-pyrrolidi n-1-yl)-ethyl]-4,5-dihydro-thiazol- 2-yl}-5-chloro-1 H-indol-7-yl)-(tetr ahydro-pyran-4-yl)-amine
Figure imgf000173_0002
The compound (150mg, 0.27mmol) prepared in Example 114 was dissolved in dichloromethane (30ml). 4N hydrochloric acid dioxane solution (0.34ml, 1.35mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to give a solid. The solid was washed with ethylether, and dried to give the title compound (92mg, Yield 75%). 1H NMR (DMSOd6, ppm); δ 1O.92(1H, s), 8.63(2H, s, br), 6.86(1H, s), 6.83(1H, s), 6.43(1H, s), 6.11(1H, m), 4.72(1H, m), 3.65(5H, m), 3.45(5H, m), 3.22(3H, m), 2.37(2H, m), 2.19(3H, m), 1.90(2H, m), 1.49(2H, m) FAB MS(m/e) = 448
Example 116: Synthesis of N-[(S)-l-(2-{(R)-2-[5-chloro-7-(tetrahydro- pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]- acetamide
N-[(S)-1-(2-{(R)-2-[5-Chloro-7-(tet rahydro-pyran-4-ylamino)-1 H-indol-2
-yl]-4,5-dihydro-thiazol-4-yl}-ethy l)-pyrrolidin-3-yl]-acetamide
Figure imgf000174_0001
The compound (85mg, 0.19mmol) prepared in Example 115 was dissolved in dichloromethane (10ml). Diisopropylethylamine (0.13ml, 0.75mmol) and acetyl chloride (0.013ml, 0.19mmol) were added thereto, and the mixture was stirred for 30 min at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39mg,
Yield 42%).
1R NMR (DMSOd6, ppm); δ 11.49(1H, s), 7.97(1H, s), 6.81(1H, s), 6.69(1H, s), 6.28(1H, s), 6.05(1H, d), 4.64(1H, quin), 4.12(1H, m), 3.85(2H, m), 3.53(2H, m), 3.44(2H, t), 3.34(2H, m), 3.15(1H, t), 2.72-2.60(3H, m), 2.39(1H, m), 2.05-1.87(4H, m), 1.80-1.72(4H, m), 1.53(1H, m), 1.37(2H, m), FAB MS(m/e) = 490
Example 117: Synthesis of {5-chloro-2-[(R)-4-(2-piperazin-l-yl-ethyl)-4,5- dihydro-thiazol-2-yl]~lH-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine
{5-Chloro-2-[(R)-4-(2-piperazin-1 -y l-ethyl)-4,5-dihydro-thiazol-2-yl]- 1 H-indol-7-yl}-(tetrahydro-pyran-4- yl)-amine
Figure imgf000175_0001
The compound (lOOmg, 0.2mmol) prepared in Preparation 52 was reacted according to the same procedure as Example 96 to give the title compound (25mg, Yield 30%).
1H NMR (DMSOd6, ppm); δ 11.42(1H, s), 6.83(1H, s), 6.74(1H, s), 6.3O(1H, s), 6.02(1H, d), 4.69(1H, m), 3.85(1H, m), 3.52-3.42(6H, m), 3.35(3H, m), 3.20(2H, m), 2.16(2H, m), 1.92(3H, m), 1.42(3H, m)
FAB MS(m/e) = 448
Example 118: Synthesis of l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-2-hydroxy- ethanone
1-[4-(2-{(R)-2-[5-Chloro-7-(tetrahy dro-pyran-4-ylamino)-1 H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-ethyl)-p iperazin-1-yl]-2-hydroxy-ethanone
Figure imgf000175_0002
The compound (23mg, 0.05mmol) prepared in Example 117 was dissolved in
N,N-dimethylformamide (5ml). Glycolic acid (15.1mg, 0.2mmol), triethylamine (28ul, 0.2mmol), EDC (45mg, 0.23mmol) and HOBT (40mg, 0.29mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, IN hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (5mg, Yield 19%).
1H-NMR (500HMz, DMSOd6); δ 11.48(br s, IH), 6.81(s, IH), 6.69(d, J=I.8Hz, IH), 6.29(s, IH), 6.05(d, J=7.4Hz, IH), 4.62(m, IH), 4.49(t, IH), 4.04(m, 2H), 3.87(m, 2H), 3.56(m, IH), 3.45(m, 4H), 3.29(m, 4H), 3.16(m, IH), 2.36(m, 4H). 1.96(m, 5 3H), 1.80(m, IH), 1.40(m, 2H)
Example 119: Synthesis of l-[4-(2-{(R)-2-[5-ch!oro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-2-tetrazoI- 1-yl-ethanone l] -yl-etha
Figure imgf000176_0001
The compound (61mg, 0.14mmol) prepared in Example 117 and lH-tetrazole-1- acetic acid instead of glycolic acid were reacted according to the same procedure as Example 118 to give the title compound (31mg, Yield 48%).
1H NMR (DMSOd6, ppm); δ 11.48(1H, s), 9.26(1H, s), 6.81(1H, s), 6.7O(1H, s), 15 6.29(1H, s), 6.04(1H, d), 5.60(2H, s), 4.64(1H, quin), 3.87(2H, m), 3.57(2H, m), 3.47- 3.41(7H, m), 3.17(2H, m), 2.58(1H, m), 2.39(2H, m), 1.99-1.93(4H, m), 1.81(1H, m), 1.40(2H, m)
FAB MS(m/e) = 558 0 Example 120: Synthesis of l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yI]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-3,3,3- trifluoro-propan-1 -one
Figure imgf000177_0001
The compound (66mg, 0.15mmol) prepared in Example 117 was dissolved in dichloromethane (10ml). Diisopropylethylamine (0.08ml, 0.44mmol) and 3,3,3- trifluoropropionic acid 2,5-dioxo-pyrrolidin-l-yl ester (29mg, 0.13mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (6mg, Yield 9%). 1H NMR (DMSOd6, ppm); δ 11.47(1H, s), 6.81(1H, s), 6.69(1H, s), 6.28(1H, s),
6.09(1H, d), 4.62(1H, quin), 3.87(2H, m), 3.56(4H, m), 3.47-3.38(7H, m), 3.16(1H, m), 2.53(1H, m), 2.3702.30(4H, m), 1.94(3H, m), 1.81(1H, m), 1.40(2H, m) FAB MS(m/e) = 558
Example 121: Synthesis of [4-(2-{(R)-2-[5-chIoro-7-(tetrahydro-pyran-4- ylamino)-lH-mdoI-2-yl]-4,5-dihydro-thiazoI-4-yl}-ethyl)-piperaziii-l-yl]-furan-2-yl- inethaiione
[4-(2-{(R)-2-[5-Chloro-7-(tetrahydr o-pyran-4-ylamino)-1H-indol-2-yl]-4 ,5-dihy .dro-thiazol-4-y .l} .-ethy .l .)-pip
Figure imgf000177_0002
eerraazziinn--11 --yvll]l--ffuurraann--22--yvll--mmeetthhaannoonnee
The compound (lOOmg, 0.20mmol) prepared in Preparation 52 and furanoylpiperazine instead of piperidine-3-carboxylic acid ethyl ester were reacted according to the same procedure as Preparation 53 to give the title compound (19mg, Yield 17%).
1H-NMR (500HMz, DMSOd6); δ 11.48(br s, IH), 7.79(s, IH), 6.81(s, IH), 6.69(s, IH), 6.59(m, IH), 6.28(s, IH), 6.05(m, IH), 4.63(m, IH), 3.86(m, 2H), 3.57(m, 6H), 3.44(m, 2H), 3.16(m, 2H), 2.56(m, IH), 1.96(m, 3H), 1.83(m, IH), 1.41(m, 2H)
Example 122: Synthesis of (5-chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro- [l,2']bipyrazinyl-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-lH-indol-7-yl)-(tetrahydro- pyran-4-yI)-amine
H-ind
Figure imgf000178_0001
The compound (lOOmg, 0.20mmol) prepared in Preparation 52 and l-(2- pyrazinyl)piperazine instead of piperidine-3-carboxylic acid ethyl ester were reacted according to the same procedure as Preparation 53 to give the title compound (13mg, Yield 12%).
1H-NMR (500HMz, DMSO-d6); δ 11.48(br s, IH), 8.27(s, IH), 8.04(s, IH), 7.80(s, IH), 6.81(s, IH), 6.69(s, IH), 6.29(s, IH), 6.05(m, IH), 4.64(m, IH), 3.86(m, 2H), 3.57(m, 2H), 3.53(m, 4H), 3.18(m, IH), 2.57(m, IH). 1.99(m, IH), 1.95(m, 2H), 1.83(m, IH), 1.40(m, 2H)
Example 123: Synthesis of (5-chloro-2-{(R)-4-[2-(4-pyrimidin-2-yl- piper azin- 1 -yl)-ethyl] -4,5-dihydro-thiazol-2-yl} - 1 H-indol-7-yl)-(tetr ahydro-py ran- 4-yl)-amine (5-Chloro-2-{(R)-4-[2-(4-pyrimidin- 2-yl-piperazin-1-yl)-ethylj-4,5-dih ydro-thiazol-2-yl}-1 H-indol-7-yl)-( tetrahydro-pyran-4-yl)-amine
Figure imgf000179_0001
The compound (lOOmg, 0.20mmol) prepared in Preparation 52 and l-(2- pyrimidyl)piperazine instead of piperidine-3-carboxylic acid ethyl ester were reacted according to the same procedure as Preparation 53 to give the title compound (lOmg, Yield 9%).
1H-NMR (500HMz, DMSOd6); δ 11.49(br s, IH), 8.31(m, IH), 6.81(s, IH), 6.69(s, IH), 6.58(m, IH), 6.28(s, IH), 6.06(m, IH), 4.65(m, IH), 3.86(m, 2H), 3.69(m, 4H), 3.58(m, 2H), 3.45(m, 2H), 3.35(m, IH), 3.18(m, IH), 2.56(m, IH). 2.43(m, 3H), 2.00(m, IH), 1.96(m, 2H), 1.40(m, 2H)
Preparation 54: Synthesis of cyclopentyl-{5-fluoro-2-[(R)-4-(2-iodo-ethyI)- 4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-i odo-ethyl)-4,5-dihydro-thiazol-2-yl ]-1 H-indol-7-yl}-amine
Figure imgf000179_0002
The compound (120mg, 0.35mmol) prepared in Example 39 was reacted according to the same procedure as Preparation 50 to give the title compound (HOmg, Yield 70%).
Example 124: Synthesis of {2-[(R)-4-(2-amino-ethyl)-4,5-dihydro-thiazol-2- yI]-5-fluoro-lH-indol-7-yl}-cyclopentyl-amine {2-[(R)-4-(2-Amino-ethyl)-4,5-dihyd ro-thiazol-2-yl]-5-fluoro-1 H-indol-
7-yl}-cyclopentyl-amine
Figure imgf000180_0001
(Step 1)
{2-[(R)-4-(2-Azido-ethyl)-4,5-dihyd ro-thiazol-2-yl]-5-fluoro-1 H-indol-
7-yl}-cyclopentyl-amine
Figure imgf000180_0002
The compound (lOOmg, 0.22mmol) prepared in Preparation 54 was dissolved in N,N-dimethylformamide (2ml). Sodium azide (43mg, 0.66mmol) was added thereto, and the mixture was stirred for 1 h at 70 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give an azido compound (75mg, Yield 9%).
(Step 2)
The compound (70mg, 0.19mmol) prepared in Step 1 was dissolvd in tetrahydrofuran (3ml). Water (4ul, 0.21mmol) and triphenylphosphine (55mg, 0.31mmol) were added thereto, and the mixture was stirred for 2 h at 80 °C . After completion of the reaction, the reaction solution was distilled under reduced pressure, and purified by column chromatography to give the title compound (45mg, Yield 69%).
1H-NMR (400HMz, CDCl3/DMSO-d6); δ 11.28(br s, IH), 6.80(br s, 2H), 6.80(d, J=2.0Hz), 6.50(dd, IH), 6.16(dd, IH), 4.58(m, IH), 3.81(m, IH), 3.54(m, IH), 3.24(m, 2H), 3.02(m, IH), 2.13~1.55(m, 10H) Preparation 55: Synthesis of methanesulfonic acid 2-[(R)-2-(7- cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl ester
Methanesulfonic acid 2-[(R)-2-(7-cy clopentylamino-5-fluoro-1 H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-ethyl
Figure imgf000181_0001
ester
The compound (1.Og, 2.87mmol) prepared in Example 39 was reacted according to the same procedure as Preparation 22 to give the title compound (l.lg, Yield 90%).
Example 125: Synthesis of l-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-l-yl)-ethanone
1-(4-{2-[(R)-2-(7-Cyclopentylamino- 5-fluoro-1 H-indol-2-yl)-4,5-dihydro -thiazol-4-yl]-ethyl}-piperazin-1-y l)-ethanone
Figure imgf000181_0002
The compound (lOOmg, 0.23mmol) prepared in Preparation 55 was dissolved in
N,N-dimethylformamide (10ml). Triethylamine (48mg, 0.47mmol) and 1- acetylpiperazine (92mg, 0.70mmol) were added thereto, and the mixture was stirred for 8 h at 50 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (60mg, Yield 56%).
1H-NMR (400HMz, CDC13); δ 10.47(br s, IH), 6.87(s, IH), 6.66(d, J=8.0Hz, IH), 6.26(d, J=12.0Hz, IH), 4.80(m, IH), 3.92(m, IH), 3.81(m, IH), 3.59(m, 2H), 3.49(m, IH), 3.28(m, IH), 3.18(m, IH), 2.44(m, 2H), 2.34(m, IH), 2.23(m, 2H), 2.14(m, IH), 2.05(s, 3H), 1.93(m, IH), 1.81(m, IH), 1.71(m, 5H), 1.48(m, 2H) Example 126: Synthesis of cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholin-4-yl- ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-m orpholin-4-yl-ethyl)-4,5-dihydro-th iazol-2-yl]-1 H-indol-7-yl}-amine
Figure imgf000182_0001
The compound (lOOmg, 0.23mmol) prepared in Preparation 55 and morpholine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (50mg, Yield 52%).
1H-NMR (400HMz, CDC13); δ 10.92(br s, IH), 6.87(s, IH), 6.64(d, J=8.0Hz, IH), 6.24(d, J=12.0Hz, IH), 4.83(m, IH), 3.93(m, IH), 3.77(m, IH), 3.54(m, 4H), 3.47(m, IH), 3.17(m, IH), 2.38(m, IH), 2.33(m, 2H), 2.16(m, 2H), 2.04(m, 3H), 1.77(m, IH), 1.65(m, 4H), 1.47(m, IH), 1.35(m, IH)
Example 127: Synthesis of cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)- 4,5-dihydro-thiazol-2-yl]-5-fluoro-lH-indol-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(2-dimethylam ino-ethyl)-4,5-dihydro-thiazol-2-yl ]-5-fluoro-1 H-indol-7-yl}-amine
Figure imgf000182_0002
The compound (lOOmg, 0.23mmol) prepared in Preparation 55 and dimethylamine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (40mg, Yield 47%).
1H-NMR (400HMz, CDC13); δ 10.99(br s, IH), 6.80(s, IH), 6.60(d, J=8.0Hz, IH), 6.22(d, J=12.0Hz, IH), 4.59(m, IH), 4.13(m, IH), 3.47(m, IH), 3.03(m, IH), 2.90(m, IH), 2.55(m, IH), 2.42(s, 6H), 2.01(m, 3H), 1.81(m, IH), 1.62(m, 2H), 1.55(m, 4H) Example 128: Synthesis of cycIopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-l-yl- ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-p yrrolidin-1-yl-ethyl)-4,5-dihydro-t hiazol-2-yl]-1 H-indol-7-yl}-amine
Figure imgf000183_0001
The compound (lOOmg, 0.23mmol) prepared in Preparation 55 and pyrrolidine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (30mg, Yield 33%).
1H-NMR (400HMz, CDC13); δ 11.39(br s, IH), 6.81(s, IH), 6.63(dd, IH), 6.25(dd, IH), 4.59(m, IH), 4.17(m, IH), 3.89(m, IH), 3.32(m, IH), 3.07(m, 3H), 2.71(m, IH), 2.09(m, 2H), 1.95(m, 4H), 1.77(m, 2H), 1.65(m, 4H)
Example 129: Synthesis of cyclopentyl-(2-{(R)-4-[2-(l,l-dioxo- thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-lH-indol-7-yl)-amine
Cyclopentyl-(2-{(R)-4-[2-(1 ,1-dioxo -1lambda*6*-thiomorpholin-4-yl)-eth yl]-4,5-dihydro-thiazol-2-yl}-5-flu oro-1 H-indol-7-yl)-amine
Figure imgf000183_0002
The compound (lOOmg, 0.23mmol) prepared in Preparation 55 and thiomorpho line- 1,1 -dioxide instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (10mg, Yield 9%).
1H-NMR (400HMz, CDC13); δ 11.05(br s, IH), 6.94(s, IH), 6.60(d, J=8.0Hz, IH), 6.26(d, J=12.0Hz, IH), 4.74(m, IH), 3.85(m, IH), 3.62(t, IH), 3.49(q, IH), 3.18(q, IH), 3.00(m, 8H), 2.74(m, 2H), 2.05(m, 3H), 1.79(m, 2H), 1.63(m, 4H) Example 130: Synthesis of 4-{2-[(R)-2-(7-cyclopentyIamino-5-fluoro-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one
4-{2-[(R)-2-(7-Cyclopentylamino-5-f luoro-1 H-indol-2-yl)-4,5-dihydro-th iazol-4-yl]-ethyl}-piperazin-2-one
Figure imgf000184_0001
The compound (200mg, 0.44mmol) prepared in Preparation 55 was dissolved in tetrahydrofuran (5ml). 2-Oxopiperazine (87mg, 0.88mmol) and potassium carbonate
(118mg, 0.88mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (650mg, Yield 27%).
1H-NMR (400HMz, CDC13); δ 11.26(br s, IH), 7.26(br s, IH), 6.87(s, IH), 6.58(d, J=8.0Hz, IH), 6.22(d, J=12.0Hz, IH), 4.73(m, IH), 3.84(m, IH), 3.53(t, IH), 3.19(m, 5H), 2.57(m, 4H), 2.04(m, 3H), 1.95(m, IH), 1.74(m, 2H), 1.62(m, 2H)
Example 131: Synthesis of l-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-l-yl)-2-hydroxy-ethanone
1 -(4-{2-[(R)-2-(7-Cyclopentylamino- 5-fluoro-1 H-indol-2-yl)-4,5-dihydro -thiazol-4-yl]-ethyl}-piperazin-1-y l)-2-hydroxy-ethanone
Figure imgf000184_0002
The compound (500mg, 1.09mmol) prepared in Preparation 55 was reacted according to the same procedures as Example 96 and Example 99 to give the title compound (1 OOmg, Yield 19%).
1H-NMR (400HMz, CDC13); δ 11.26(br s, IH), 6.89(s, IH), 6.63(d, J=8.0Hz, IH), 6.22(d, J=12.0Hz, IH), 4.85(m, IH), 4.10(s, 2H), 3.77(m, IH), 3.57(m, 2H), 3.41(m, IH), 3.14(q, IH), 3.00(m, IH), 2.91(m, IH), 2.38(m, 3H), 2.12(m, 2H), 2.02(m, 4H), 1.85(m, IH), 1.77(m, IH), 1.63(m, 4H), 1.36(m, IH), 1.26(m, IH)
Example 132: Synthesis of cyclopentyl-{5-fluoro-2-[(R)-4-(2- methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yI}-amine
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-m ethanesulfoπyl-ethyl)-4,5-dihydro-t hiazol-2-yl]-1H-ιndol-7-yl}-amine
Figure imgf000185_0001
The compound (50mg, 0.12mmol) prepared in Preparation 55 and sodium iodide (88mg, 0.59mmol) were dissolvd in N,N-dimethylformamide (5ml), and stirred for 6 h at 50 °C . Sodium methanesulfmate (60mg, 0.59mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (14mg, Yield 29%). 1H-NMR (400HMz, CDCl3); δ 9.89(br s, IH), 6.87(s, IH), 6.67(dd, IH),
6.28(dd, IH), 4.77(m, IH), 3.83(t, IH), 3.59(m, IH), 3.31(m, IH), 3.13(m, 2H), 2.84(s, 3H), 2.27(m, 2H), 2.04(m, 2H), 1.68(m, 6H), 1.51(m, 2H)
Preparation 56: Synthesis of methanesulfonic acid 2-{(R)-2-[5-fluoro-7- (tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl ester
Methanesulfonic acid 2-{(R)-2-[5-fl uoro-7-(tetrahydro-pyran-4-ylamino)
-1 H-indol-2-yl]-4,5-dihydro-thiazol
-4-yl}-ethyl ester
Figure imgf000185_0002
The compound (740mg, 2.03mol) prepared in Example 44 was reacted according to the same procedure as Preparation 22 to give the title compound (750mg, Yield 84%).
Example 133: Synthesis of {2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro- thiazol-2-yl]-5-fluoro-lH-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine
{2-[(R)-4-(2-Dimethylamino-ethyl)-4 ,5-dihydro-thiazol-2-yl]-5-fluoro-1 H-indol-7-yl}-(tetrahydro-pyran-4-y l)-amine
Figure imgf000186_0001
The compound (lOOmg, 0.23mmol) prepared in Preparation 56 and dimethylamine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (21mg, Yield 23%). 1H-NMR (400HMz, CDC13); δ 11.27(br s, IH), 6.79(s, IH), 6.60(d, J=8.0Hz,
IH), 6.22(d, J=12.0Hz, IH), 4.61(m, IH), 4.13(m, 2H), 3.59(m, 4H), 3.04(m, IH), 2.55(s, 4H), 2.04(m, 6H), 1.65(m, 2H), 1.26(m, 2H)
Example 134: Synthesis of {5-fluoro-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine
{5-Fluoro-2-[(R)-4-(2-pyrrolidin-1- yl-ethyl)-4,5-dihydro-thiazol-2-yl] -1H-indol-7-yl}-(tetrahydro-pyran-4
-yl)-amine
Figure imgf000186_0002
The compound (lOOmg, 0.23mmol) prepared in Preparation 56 and pyrrolidine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (29mg, Yield 30%). 1H-NMR (400HMz, CDC13); δ 11.16(br s, IH), 6.87(s, IH), 6.68(d, J=8.0Hz,
IH), 6.26(d, J=12.0Hz, IH), 4.69(m, IH), 4.17(d, J=8.0Hz, 2H), 3.60(m, 5H), 3.17(m, IH), 2.90(m, IH), 2.67(m, 5H), 2.09(m, 3H), 1.90(m, 4H), 1.57(m, 2H)
Example 135: Synthesis of {5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5- dihydro-thiazoI-2-yl]-lH-indoI-7-yl}-(tetrahydro-pyran-4-yl)-amine
{5-Fluoro-2-[(R)-4-(2-morpholin-4-y l-ethyl)-4,5-dihydro-thiazol-2-yl]- 1 H-indol-7-yl}-(tetrahydro-pyran-4- yl)-amine
Figure imgf000187_0001
The compound (lOOmg, 0.23mmol) prepared in Preparation 56 and morpholine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (16mg, Yield 16%).
1H-NMR (400HMz, CDC13); δ 11.16(br s, IH), 6.86(s, IH), 6.64(d, J=8.0Hz, IH), 6.23(d, J=12.0Hz, IH), 4.75(m, IH), 4.02(m, IH), 3.66(m, 4H), 3.51(m, 4H),
3.18(m, IH), 2.60(m, IH), 2.49(m, 4H), 2.07(m, 4H), 1.80(m, IH), 1.54(m, 2H)
Example 136: Synthesis of l-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazoI-4-yl}-ethyl-piperazin-l-yl)-ethanone
1-[4-(2-{(R)-2-[5-Fluoro-7-(tetrahy dro-pyran-4-ylamino)-1 H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-ethyl)-p iperazin-1 -yl]-ethanone
Figure imgf000187_0002
The compound (lOOmg, 0.23mmol) prepared in Preparation 56 and 1- acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (24mg, Yield 22%).
1H-NMR (400HMz, CDC13); δ 10.20(br s, IH), 6.87(s, IH), 6.68(d, J=8.0Hz, IH), 6.27(d, J=12.0Hz, IH), 4.76(m, IH), 4.01(m, 3H), 3.61(m, 4H), 3.30(m, 2H), 3.20(m, IH), 2.51(m, 2H), 2.33(m, 4H), 2.06(m, 7H), 1.99(m, IH), 1.49(m, 2H) Example 137: Synthesis of (2-{(R)-4-[2-(l,l-dioxo-thiomorphoIin-4-yl)- ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-lH-indol-7-yl)-(tetrahydropyran-4-yl)- amine - H-indol
Figure imgf000188_0001
The compound (lOOmg, 0.23mmol) prepared in Preparation 56 and thiomorpholine- 1,1 -dioxide instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (28mg, Yield 25%).
1H-NMR (400HMz, CDC13); δ 6.93(s, IH), 6.64(d, J=8.0Hz, IH), 6.28(d, J=12.0Hz, IH), 4.68(m, IH), 4.03(m, 2H), 3.55(m, 3H), 3.26(m, 2H), 3.17(m, 3H), 3.05(m, 4H), 2.95(m, IH), 2.82(m, IH), 2.09(m, 4H), 1.82(m, IH), 1.65(m, 2H)
Example 138: Synthesis of (5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine
{5-Fluoro-2-[(R)-4-(2-methanesulfon yl-ethyl)-4,5-dihydro-thiazol-2-yl]
-1H-indol-7-yl}-(tetrahydro-pyran-4
-yl)-amine
Figure imgf000188_0002
The compound (50mg, O.l lmmol) prepared in Preparation 56 was reacted according to the same procedure as Example 132 to give the title compound (18mg, Yield 38%).
1H-NMR (400HMz, CDCl3); δ 10.15(br s, IH), 6.86(s, IH), 6.65(dd, IH), 6.26(dd, IH), 4.77(m, IH), 4.05(m, IH), 3.56(m, 4H), 3.36(m, IH), 3.24(m, 2H), 3.12(m, IH), 2.91(s, 3H), 2.32(m, IH), 2.22(m, IH), 2.13(m, IH), 2.02(m, IH), 1.54(m, 2H) Preparation 57: Synthesis of {5-fluoro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro- thiazol-2-yI]-lH-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine
{5-Fluoro-2-[(R)-4-(2-iodo-ethyl)-4 ,5-dihydro-thiazol-2-yl]-1 H-indol-7 -yl}-(tetrahydro-pyran-4-yl)-amine
Figure imgf000189_0001
The compound (3.2g, 8.82mol) prepared in Example 41 was reacted according to the same procedure as Preparation 50 to give the title compound (1.9g, Yield 46%).
Example 139: Synthesis of 4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one
4-(2-{(R)-2-[5-Fluoro-7-(tetrahydro -pyran-4-ylamino)-1H-indol-2-yl]-4, 5-dihydro-thiazol-4-yl}-ethyl)-pipe razin-2-one
Figure imgf000189_0002
The compound (200mg, 0.44mmol) prepared in Preparation 57 was reacted according to the same procedure as Example 130 to give the title compound (50mg, Yield 51%).
1H-NMR (400HMz, CDC13); δ 11.07(br s, IH), 7.70(br s, IH), 6.83(s, IH), 6.61(d, J=8.0Hz, IH), 6.22(d, J=12.0Hz, IH), 5.19(m, IH), 4.71(m, IH), 4.05(d, J=12.0Hz, 2H), 3.55(m, 4H), 3.33(m, 3H), 3.14(m, IH), 2.73(m, 4H), 2.10(m, 2H), 1.98(m, 2H), 1.58(m, 4H)
Example 140: Synthesis of l-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4- ylamino)-l H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-l -yl] -2-hydroxy- ethanone 1 -[4-(2-{(R)-2-[5-Fluoro-7-(tetrahy dro-pyran-4-ylamino)-1 H-indol-2-yl]
-4,5-dihydro-thiazol-4-yl}-ethyl)-p iperazin-1-yl]-2-hydroxy-ethanone
Figure imgf000190_0001
The compound (500mg, l.Oόmmol) prepared in Preparation 57 was reacted according to the same procedures as Example 96 and Example 97 to give the title compound (lOOmg, Yield 19%). 1H-NMR (400HMz, CDC13); δ 11.19(br s, IH), 6.89(s, IH), 6.65(d, J=8.0Hz,
IH), 6.23(d, J=12.0Hz, IH), 4.82(m, IH), 4.20(m, IH), 4.18(s, 2H), 3.98(m, 2H), 3.61(m, 2H), 3.47(m, 4H), 3.16(m, 3H), 2.42(m, 3H), 2.17(m, 5H), 1.90(m, 2H), 1.40(m, 2H)
Preparation 58: Synthesis of cyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(2-iodo-ethyl )-4,5-dihydro-thiazol-2-yl]-1 H-indo l-7-yl}-amine
Figure imgf000190_0002
The compound (1.68g, 5.10mol) prepared in Example 44 was reacted according to the same procedure as Preparation 50 to give the title compound (1.75g, Yield 78%).
Example 141: Synthesis of cyclopentyl-{2-[(R)-4-(2-methoxy-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(2-methoxy-et hyl)-4,5-dihydro-thiazol-2-yl]-1 H-i ndol-7-yl}-amine
Figure imgf000190_0003
The compound (lOOmg, 0.23mmol) prepared in Preparation 58 was dissolved in tetrahydrofuran (20ml). Sodium methoxide (61mg, 1.15mmol) was added thereto, and the mixture was stirred for 8 h at 80 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (15mg, Yield 19%).
1H-NMR (500HMz, DMSOd6); δ 10.62(br s, IH), 7.03(d, J=7.95Hz, IH), 6.99(t, IH), 6.93(s, IH), 6.48(d, J=7.35Hz, IH), 4.83(m, IH), 3.83(m, IH), 3.56(m, IH), 3.46(m, 2H), 3.20(m, 4H), 2.05~1.87(m, 4H), 1.70~1.38(m, 6H)
Example 142: Synthesis of cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-
4,5-dihydro-thiazol-2-yl] -1 H-indol-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(2-dimethylam ino-ethyl)-4,5-dihydro-thiazol-2-yl ]-1 H-indol-7-yl}-amine
Figure imgf000191_0001
The compound (150mg, 0.34mmol) prepared in Preparation 58 and dimethylamine instead of 2-oxopiperazine were reacted according to the same procedure as Example 130 to give the title compound (38mg, Yield 31%).
1H-NMR (500HMz, DMSOd6); δ 11.28(br s, IH), 6.78(m, 2H), 6.24(m, 2H), 5.80(m, IH), 4.59(m, IH), 3.81(m, IH), 3.51(m, IH), 3.13(m, IH), 2.50(m, IH), 2.37(m, IH), 2.17(s, 6H), 1.93(m, 3H). 1.79-1.65(m, 3H), 1.54(m, 4H)
Example 143: Synthesis of cyclopentyl-{2-[(R)-4-(2-morpholin-4-yl-ethyl)-
4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine Cyclopentyl-{2-[(R)-4-(2-morpholin- 4-yl-ethyl)-4,5-dihydro-thiazol-2-y l]-1 H-indol-7-yl}-amine
Figure imgf000192_0001
The compound (150mg, 0.34mmol) prepared in Preparation 58 and morpholine instead of 2-oxopiperazine were reacted according to the same procedure as Example 130 to give the title compound (48mg, Yield 35%). 1H-NMR (500HMz, DMSO-d6); δ 11.27(br s, IH), 6.78(m, 2H), 6.70(m, IH),
6.24(m, IH), 5.80(m, IH), 4.60(m, IH), 3.81(m, IH), 3.55-3.49(m, 4H), 3.13(m, IH), 2.46(m, IH), 2.36(m, 4H), 1.96(m, 3H). 1.80(m, IH), 1.68(m, 2H), 1.54(m, 4H)
Example 144: Synthesis of cyclopentyl-{2-[(R)-4-(2-piperidin-l-yl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(2-piperidin- 1-yl-ethyl)-4,5-dihydro-thiazol-2-y l]-1 H-indol-7-yl}-amine
Figure imgf000192_0002
(Step 1)
Methyl ester compound (68mg, 0.19mmol) prepared from the compound of Step 1 of Example 42 was dissolved in dichloromethane (4ml). Diisobutylaluminum hydridie
(0.13ml, 1.5M in CH2Cl2, 0.21mmol) was added at -78 °C , and the mixture was stirred for 2 h. After completion of the reaction, potassium sodium tartrate solution was added.
The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give an aldehyde compound (62mg, Yield 100%). (Step 2)
The aldehyde compound (23mg, 0.07mmol) prepared in Step 1 was dissolved in dichloroethane (2ml). Piperidine (9mg, O.l lmmol) and sodium triacetoxyborohydride (19mg, 0.09mmol) were added thereto, and the mixture was stirred for 30 min at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (lOmg, Yield 36%).
1H-NMR (400HMz, CDCl3); δ 10.34(br s, IH), 7.04(d, IH), 6.99(t, IH), 6.49(d, IH), 4.72(m, IH), 3.86(m, IH), 3.51(m, IH), 3.15(m, IH), 2.30~2.00(m, 8H), 2.69-1.40(m, 14H)
Preparation 59: Synthesis of {2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2- yl]-lH-indol-7-yI}-(tetrahydro-pyran-4-yl)-amine
{2-[(R)-4-(2-lodo-ethyl)-4,5-dihydr o-thiazol-2-yl]-1 H-indol-7-yl}-(tet rahydro-pyran-4-yl)-amine
Figure imgf000193_0001
The compound (340mg, 0.98mol) prepared in Example 46 was reacted according to the same procedure as Preparation 50 to give the title compound (370mg, Yield 83%).
Example 145: Synthesis of {2-[(R)-4-(2-methanesuIfonyl-ethyl)-4,5-dihydro- thiazoI-2-yl]-lH-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine ) H-indol
Figure imgf000193_0002
The compound (50mg, O.l lmmol) prepared in Preparation 59 was reacted according to the same procedure as Example 108 to give the title compound (18mg, Yield %).
1H-NMR (400HMz, CDCl3); δ 10.02(br s, IH), 7.08(d, IH), 7.00(t, IH), 6.95(s, IH), 6.54(d, IH), 4.78(m, IH), 4.01(m, 2H), 3.61-3.47(m, 4H), 3.33(m, IH), 3.15(m, 2H), 2.85(s, 3H), 2.25(m, 2H). 2.05(m, 2H), 1.51(m, 2H)
Preparation 60: Synthesis of 2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH- indol-2-yl}-4,5-dihydro-thiazol-4-yl]-ethanol
2-[(R)-2-(7-Cyclopentylamino-5-meth oxy-1 H-indol-2-yl)-4,5-dihydro-thia zol-4-yl]-ethanol
Figure imgf000194_0001
The compound (2.4Og, 6.19mmol) prepared in Example 47 was reacted according to the same procedure as Example 70 to give the title compound (1.2Og, Yield 54%).
Preparation 61: Synthesis of cyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5- dihydro-thiazol-2-yl]-5-methoxy-lH-indol-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(2-iodo-ethyl )-4,5-dihydro-thiazol-2-yl]-5-metho xy-1 H-indol-7-yl}-amine
Figure imgf000194_0002
The compound (1.2Og, 3.34mmol) prepared in Preparation 60 was reacted according to the same procedure as Preparation 50 to give the title compound (1.23g, Yield 78%). Example 146: Synthesis of l-(4-{2-[(R)-2-(7-cyclopentylamino-5-methoxy- lH-indol-2-yl)-4,5-dihydro-thiazoI-4-yl]-ethyl}-piperazin-l-yl)-2-hydroxy-ethanone
1-(4-{2-[(R)-2-(7-Cyclopentylamino- 5-methoxy-1 H-indol-2-yl)-4,5-dihydr o-thiazol-4-yl]-ethyl}-piperazin-1- yl )-2-hyd roxy-ethanone
Figure imgf000195_0001
The compound (500mg, 1.07mmol) prepared in Preparation 61 was reacted according to the same procedures as Example 96 and Example 97 to give the title compound (20mg, Yield 4%).
1H-NMR (400HMz, CDC13); δ 11.13(br s, IH), 6.98(s, IH), 6.42(s, IH), 6.13(d, IH), 4.85(m, IH), 4.07(s, 2H), 3.81(m, 8H), 3.55(m, 2H), 3.39(m, IH), 3.13(m, IH), 2.96(m, IH), 2.90(m, IH), 2.35(m, 3H), 2.10(m, 2H), 1.99(m, 3H), 1.84(m, IH), 1.75(m, IH), 1.62(m, 4H), 1.44(m, IH), 1.35(m, IH)
Preparation 62: Synthesis of 2-{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazoI-4-yl}-ethanol
2-{(R)-2-[5-Methoxy-7-(tetrahydro-p yran-4-ylamino)-1 H-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethanol
Figure imgf000195_0002
The compound (4.0Og, 9.91mmol) prepared in Example 50 was reacted according to the same procedure as Example 70 to give the title compound (2.8Og, Yield
75%).
Preparation 63: Synthesis of {2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2- yl]-5-methoxy-lH-indol-7-yl}-(tetrahydro-pyran-4-yI)-amine {2-[(R)-4-(2-lodo-ethyl)-4,5-dihydr o-thiazol-2-yl]-5-methoxy-1 H-indol-
7-yl}-(tetrahydro-pyran-4-yl)-amine
Figure imgf000196_0001
The compound (2.8Og, 7.46mmol) prepared in Preparation 62 was reacted according to the same procedure as Preparation 50 to give the title compound (2.65g, Yield 73%).
Example 147: Synthesis of 2-hydroxy-l-[4-(2-{(R)-2-[5-methoxy-7- (tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)- piperazin-l-yl]-ethanone
2-Hydroxy-1-[4-(2-{(R)-2-[5-methoxy -7-(tetrahydro-pyran-4-ylamino)-1 H- indol-2-yl]-4,5-dihydro-thiazol-4-y l}-ethyl)-piperazin-1-yl]-ethanone
Figure imgf000196_0002
The compound (500mg, 1.03mmol) prepared in Preparation 63 was reacted according to the same procedures as Example 96 and Example 97 to give the title compound (50mg, Yield 10%).
1H-NMR (400HMz, CDC13); δ 11.13(br s, IH), 6.91(s, IH), 6.47(s, IH), 6.17(s, IH), 4.86(m, IH), 4.13(m, 2H), 3.97(m, 3H), 3.84(m, 3H), 3.62(m, 2H), 3.47(m, 4H), 3.03(m, 3H), 2.43(m, 3H), 2.17(m, 5H), 1.98(m, 3H), 1.44(m, 2H)
Preparation 64: Synthesis of 3-[(R)-2-(7-amino-5-chloro-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -propionic acid ethyl ester
3-[(R)-2-(7-Amino-5-chloro-1 H-indol -2-yl)-4,5-dihydro-thiazol-4-yl]-pr opionic acid ethyl ester
Figure imgf000196_0003
The acid compound (2.Og, 8.3mmol) prepared in Preparation 33 and the compound (R)-4-amino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid ethyl ester hydrochloride (3.4g, 10.2mmol) prepared in Preparation 17 were reacted according to the same procedure as Preparation 34 to give the title compound (0.76g, Yield: 26%).
1H-NMR (400HMz, CDCl3); δ 10.00(br s, IH), 7.08(s, IH), 6.80(s, IH), 6.57(s, IH), 4.71(m, IH), 4.07(m, 2H), 3.88(br s, 2H), 3.55(m, IH), 3.1 l(m, IH), 2.50(t, 2H), 2.05(m, 2H), 1.22(t, 3H)
Example 148: Synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid ethyl ester
3-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid ethyl ester
Figure imgf000197_0001
The compound (760mg, 2.1mmol) prepared in Preparation 64 was reacted according to the same procedure as Example 26 to give the title compound (450mg, Yield 51%).
Preparation 65: Synthesis of (R)-4-amino-5-(4-methoxy-benzylsulfanyl)- pentanoic acid cyclohexyl ester hydrochloride )-4-Amino-5-(4-methoxy-benzylsulf yl)-pentanoic acid cyclohexyl est
Figure imgf000197_0002
(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid cyclohexyl ester (6.5g, 20.6mmol) was reacted according to the same procedure as Preparation 17 to give the title compound (7.5g, Yield 97%). Preparation 66: Synthesis of 3-[(R)-2-(7-amino-5-chloro-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -propionic acid cyclohexyl ester
3-[(R)-2-(7-Amino-5-chloro-1 H-indol -2-yl)-4,5-dihydro-thiazol-4-yl]-pr opionic acid cyclohexyl ester
Figure imgf000198_0001
The compound (3.9g, 16.2mmol) prepared in Preparation 33 and the compound (7.5g, 19.5mmol) prepared in Preparation 65 were reacted according to the same procedure as Preparation 34 to give the title compound (2.6g, Yield 40%).
Preparation 67: Synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid cyclohexyl ester
3-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid cyclohexyl
Figure imgf000198_0002
ester
The compound (1.3Og, 3.20mmol) prepared in Preparation 66 was reacted according to the same procedure as Example 29 to give the title compound (1.15g, Yield 76%).
Example 149: Synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-
2-yl)-4,5-dihydro-thiazol-4-yl] -propionic acid
3-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz
Figure imgf000198_0003
ol-4-yl]-propionic acid
The ester compound (500mg, 1.05mmol) prepared in Preparation 67 was reacted according to the same procedure as Example 27 to give the title compound (400mg, Yield 97%). 1H-NMR (400HMz, DMSOd6, Na salt); δ 11.69(br s, IH), 6.82(d, J=4.0Hz, IH), 6.68(s, IH), 6.27(s, IH), 6.18(s, IH), 4.63(m, IH), 3.83(m, IH), 3.50(m, IH), 3.13(m, IH), 2.08~1.96(m, 6H), 1.72(m, 2H), 1.58(m, 4H)
Example 150: Synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-
2-yI)-4,5-dihydro-thiazol-4-yl]-propan-l-ol
3-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propan-1-ol
Figure imgf000199_0001
The compound (650mg, 1.37mmol) prepared in Preparation 67 was reacted according to the same procedure as Example 70 to give the title compound (210mg, Yield 41%).
1H-NMR (400HMz, CDC13); δ 10.42(br s, IH), 6.94(s, IH), 6.82(s, IH), 6.37(s, IH), 4.58(m, IH), 4.56(m, IH), 3.75(m, 2H), 3.65(m, IH), 1.95(m, 7H), 1.51(m, 4H), 1.31 (m, 2H)
Preparation 68: Synthesis of 3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-prop ionic acid cyclohexyl ester
3-{(R)-2-[5-Chloro-7-(tetrahydro-py ran-4-ylamino)-1 H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-propionic acid cyclohexyl ester
Figure imgf000199_0002
The compound (1.3Og, 3.20mmol) prepared in Preparation 66 was reacted according to the same procedure as Example 30 to give the title compound (1.24g, Yield 79%). Example 151: Synthesis of 3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-lH-indoI-2-yl]-4,5-dihydro-thiazol-4-yl}-propionic acid
3-{(R)-2-[5-Chloro-7-(tetrahydro-py ran-4-ylamino)-1 H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-propionic acid
Figure imgf000200_0001
The ester compound (500mg, 1.05mmol) prepared in Preparation 68 was reacted according to the same procedure as Example 27 to give the title compound (250mg, Yield 59%).
1H-NMR (400HMz, DMSOd6, Na salt); δ 11.53(br s, IH), 6.86(s, IH), 6.76(s, IH), 6.34(s, IH), 4.67(m, IH), 3.91(m, 2H), 3.49(m, 4H), 3.21(m, IH), 2.50(m, 2H), 2.01(m, 4H), 1.43(m, 2H)
Example 152: Synthesis of 3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4- ylamino)-l H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}-propan-l -ol
3-{(R)-2-[5-Chloro-7-(tetrahydro-py ran-4-ylamino)-1H-indol-2-yl]-4,5-d ihydro-thiazol-4-yl}-propan-1-ol
Figure imgf000200_0002
The compound (650mg, 1.33mmol) prepared in Preparation 68 was reacted according to the same procedure as Example 70 to give the title compound (150mg, Yield 29%).
1H-NMR (400HMz, CDC13); δ 11.00(br s, IH), 6.93(s, IH), 6.82(s, IH), 6.31(s, IH), 4.89(br s, IH), 4.56(m, IH), 3.95 (m, IH), 3.85(m, IH), 3.77(m, IH), 3.65(m, IH), 3.51(m, 4H), 3.10(m, IH), 1.97(m, 2H), 1.83(m, 3H), 1.74(m, IH), 1.44(m, IH), 1.40(m, IH) Example 153: Synthesis of 3-[(R)-2-(5-chIoro-7-cycIopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazoI-4-yl]-N-(2-morphoIin-4-yl-ethyl)-propionamide
3-[(R)-2-(5-Chloro-7-cyclopentylami no-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-N-(2-morpholin-4-yl-ethyl) -propionamide
Figure imgf000201_0001
The compound (150mg, 0.38mmol) prepared in Example 149 and 4-(2- aminoethyl)moφholine instead of morpholine were reacted according to the same procedure as Example 70 to give the title compound (50mg, Yield 26%).
1H-NMR (400HMz, CDC13); δ 11.13(br s, IH), 7.06(br s, IH), 6.93(s, IH), 6.82(s, IH), 6.39(s, IH), 4.61(m, IH), 3.88(m, 2H), 3.77(s, 4H), 3.45(m, 2H), 3.07(m, IH), 2.70(m, 6H), 2.44(m, 2H), 2.10(m, 3H), 1.95(m, IH), 1.71(m, 2H), 1.64(m, 2H), 1.54(m, 2H)
Example 154: Synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-l-(4-methyl-piperazin-l-yl)-propan-l-one
3-[(R)-2-(5-Chloro-7-cyclopentylami nnoo--11 HH--iinnddooll--22--yyll)-4,5-dihydra-thiaz ooll--44--yyll]]--11 --((44--mmeetthyl-piperazin-1 -yl ) )--pprrooppaann--11--oonnee
Figure imgf000201_0002
The compound (150mg, 0.38mmol) prepared in Example 149 and 1- methylpiperazine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (50mg, Yield 28%).
1H-NMR (400HMz, CDC13); δ 11.26(br s, IH), 6.93(s, IH), 6.85(s, IH), 6.38(s, IH), 4.73(m, IH), 3.83(m, IH), 3.59(m, 3H), 3.30(m, 2H), 3.14(m, IH), 2.45(m, 4H), 2.30(m, 5H), 2.04(m, 4H), 1.70(m, 4H), 1.52(m, 2H) Preparation 69: Synthesis of methanesulfonic acid 3-[(R)-2-(5-chIoro-7- cycIopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propyl ester
Methanesulfonic acid 3-[(R)-2-(5-ch loro-7-cyclopentylamino-i H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-propy I ester
Figure imgf000202_0001
The compound (140mg, 0.37mmol) prepared in Example 154 was reacted according to the same procedure as Preparation 22 to give the title compound (120mg, Yield 71%).
Example 155: Synthesis of l-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamino-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propyl}-piperazin-l-yl)-ethanone
1 -(4-{3-[(R)-2-(5-Chloro-7-cyclopen tylamino-1H-indol-2-yl)-4,5-dihydro -thiazol-4-yl]-propyl}-piperazin-1- yl)-ethanone
Figure imgf000202_0002
The compound (lOOmg, 0.22mmol) prepared in Preparation 69 was reacted according to the same procedure as Example 125 to give the title compound (49mg, Yield 46%).
1H-NMR (400HMz, CDC13); δ 10.33(br s, IH), 6.97(s, IH), 6.81(s, IH), 6.42(s, IH), 4.64(m, IH), 3.85(m, IH), 3.65(m, 2H), 3.56(m, IH), 3.45(m, 2H), 3.13(m, IH), 2.43(m, 6H), 2.04(m, 2H), 1.72(m, 8H), 1.54(m, 2H)
Example 156: Synthesis of {5-chloro-2-[(R)-4-(3-morpholin-4-yl-propyl)- 4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-cyclopentyl-amine {5-Chloro-2-[(R)-4-(3-morpholin-4-y l-propyl)-4,5-dihydro-thiazol-2-yl] -1 H-indol-7-yl}-cyclopentyl-amine
Figure imgf000203_0001
The compound (lOOmg, 0.22mmol) prepared in Preparation 69 and morpholine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 125 to give the title compound (43mg, Yield 44%). 1H-NMR (400HMz, CDC13); δ 11.07(br s, IH), 6.90(s, IH), 6.74(s, IH),
6.36(s, IH), 4.61(m, IH), 3.94(m, 4H), 3.55(m, IH), 3.04(m, 3H), 2.04(m, 7H), 1.71(m, 3H), 1.61(m, 4H), 1.26(m, 3H)
Example 157: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl] -propionic acid ethyl ester
3-[(R)-2-(7-Cyclopentylamino-5-meth yl-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid ethyl ester
Figure imgf000203_0002
The compound (2.Og, 8.6mmol) prepared in Preparation 7 and the compound (3.4g, 10.2mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (500mg, Yield 15%).
1H-NMR (400HMz, CDCl3); δ 10.75(br s, IH), 6.82(d, 2H), 6.32(s, IH), 4.71(m, IH), 4.01(q, 2H), 3.83(m, IH), 3.53(m, IH), 3.1 l(m, IH), 2.44(m, 2H), 2.37(s, 3H), 2.0 l(m, 4H), 1.64(m, 4H), 1.40(m, 2H)
Example 158: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-
2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid 3-[(R)-2-(7-Cyclopentylamino-5-meth yl-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid
Figure imgf000204_0001
The compound (300mg, 0.75mmol) prepared in Example 157 was dissolved in tetrahydrofuran (25ml) and methanol (25ml). IN aqueous sodium hydroxide solution (4.0ml, 4mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, IN hydrochloric acid was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (235mg, Yield 84%).
1H-NMR (400HMz, CDCl3); δ 11.34(br s, IH), 6.56(s, IH), 6.54(s, IH), 6.06(s, IH), 5.05(br d, IH), 4.60(m, IH), 3.81(m, IH), 3.45(m, IH), 3.06(m, IH), 2.28(s, 3H), 2.09-1.93(m, 5H), 1.78~1.54(m, 7H)
Preparation 70: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-phenoxy-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl] -propionic acid ethyl ester en este
Figure imgf000204_0002
The compound (2.6g, 8.4mmol) prepared in Preparation 12 and the compound (3.4g, 10.2mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (1.Og, Yield 25%).
Example 159: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-phenoxy-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid
3-[(R)-2-(7-Cyclopentylamino-5-phen oxy-1 H-indol-2-yl)-4,5-dihydro-thia zol-4-yl]-propionic acid
Figure imgf000205_0001
The compound (600mg, 1.26mmol) prepared in Preparation 70 was reacted according to the same procedure as Example 158 to give the title compound (430mg, Yield 76%).
1H-NMR (400HMz, DMSOd6); δ 11.59(br s, IH), 7.29(m, 2H), 7.01(m, IH), 6.92(m, 2H), 6.67(s, IH), 6.40(d, IH), 6.21(d, IH), 5.99(d, IH), 4.63(m, IH), 3.75(m, IH), 3.50(m, IH), 3.11(m, IH), 2.08(m, 2H), 2.03(m, IH), 1.90(m, 2H), 1.81(m, IH), 1.71(m, 2H), 1.56(m, 4H)
Example 160: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol- 2-yI)-4,5-dihydro-thiazol-4-yl] -propionic acid ethyl ester
3-[(R)-2-(7-Cyclopentylamino-5-fluo ro-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid ethyl ester
Figure imgf000205_0002
The compound (2.2g, 8.9mmol) prepared in Preparation 2 and the compound (3.6g, 10.7mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (l.lg, Yield 31%).
1H-NMR (400HMz,CDCl3); δ 10.48(br s, IH), 6.91(s, IH), 6.69(m, IH), 6.30(m, IH), 4.77(m, IH), 4.19~4.02(m, 3H), 3.84(m, IH), 3.60(m, IH), 3.18(m, IH), 2.51(m, 2H), 2.07(m, 4H), 1.74~1.46(m, 6H), 1.21(m, 3H) Example 161: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indoI- 2-yl)-4,5-dihydro-thiazol-4-yl] -propionic acid
3-[(R)-2-(7-Cyclopentylamino-5-fluo ro-1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid
Figure imgf000206_0001
The compound (1.Og, 2.48mmol) prepared in Example 160 was reacted according to the same procedure as Example 158 to give the title compound (430mg, Yield 46%).
1H-NMR (400HMz5DMSOd6); δ 11.63(br s, IH), 6.49(m, IH), 6.33(m, IH), 6.09(m, IH), 6.66(m, IH), 4.61(m, IH), 3.85(m, IH), 3.52(m, IH), 3.1 l(m, IH), 2.09-1.74(m, 12H),
Example 162: Synthesis of 3-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol- 2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid ethyl ester
3-[(R)-2-(5-Bromo-7-cyclopentylamin o-1 H-indol-2-yl)-4,5-dihydro-thiazo l-4-yl]-propionic acid ethyl ester
Figure imgf000206_0002
The compound (2.1g, 7.01mmol) prepared in Preparation 6 and the compound (2.3g, 6.89mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (530mg, Yield 16%).
1H-NMR (400HMz, CDC13); δ 10.02(br s, IH), 7.16(s, IH), 6.81(s, IH), 6.57(s, IH), 4.74(m, IH), 4.1 l(m, 2H), 4.02(m, 2H), 3.59(q, IH), 3.16(q, IH), 2.52(m, 2H), 2.06(m, 4H), 1.72(m, 3H), 1.49(m, 2H), 1.19(t, 3H) Example 163: Synthesis of 3-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indoI- 2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid
3-[(R)-2-(5-Bromo-7-cyclopentylamin o-1 H-indol-2-yl)-4,5-dihydro-thiazo l-4-yl]-propionic acid
Figure imgf000207_0001
The compound (420mg, 0.88mmol) prepared in Example 162 was reacted according to the same procedure as Example 158 to give the title compound (350mg, Yield 91%).
1H-NMR (400HMz, DMSOd6); δ 11.77(br s, IH), 6.96(s, IH), 6.68(s, IH), 6.3 l(m, IH), 6.29(s, IH), 4.64(m, IH), 3.82(m, IH), 3.53(m, IH), 3.13(m, IH), 2.05(m, 2H), 1.97(m, 2H), 1.77(m, 3H), 1.58(m, 4H)
Preparation 71: Synthesis of 3-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)- 4,5-dihydro-thiazol-4-yl] -propionic acid ethyl ester
3-[(R)-2-(7-Cyclopentylamino-1 H-ind ol-2-yl )-4 ,5-d i hyd ro-thiazol-4-yl]- propionic acid ethyl ester
Figure imgf000207_0002
The compound (1.64g, 7.49mmol) prepared in Preparation 8 and the compound (3.5Og, 10.46mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (1.23g, Yield 43%).
Example 164: Synthesis of 3-[(R)-2-(7-cyclopentylamino-lH-mdol-2-yl)-4,5- dihydro-thiazol-4-yl]-propionic acid 3-[(R)-2-(7-Cyclopentylamino-1 H-ind ol-2-yl)-4,5-dihydro-thiazol-4-yl]- propionic acid
Figure imgf000208_0001
The compound (1.Og, 2.59mmol) prepared in Preparation 71 was reacted according to the same procedure as Example 158 to give the title compound (560mg, Yield 60%). 1H-NMR (400HMz, DMSO-d6); δ 11.46(br s, IH), 6.85(m, 2H), 6.70(s, IH)9
6.27(d, J=4.0Hz, IH), 5.94(d, J=8.0Hz, IH), 4.65(m, IH), 3.86(m, IH), 3.52(m, IH), 3.1 l(m, IH), 2.05(m, 2H), 1.97(m, 3H), 1.78(m, 3H), 1.56(m, 4H)
Preparation 72: Synthesis of 3-[(R)-2-(7-cycIopentylamino-5-methoxy-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yI]-propionic acid ethyl ester
3-[(R)-2-(7-Cyclopentylamino-5-meth oxy-1H-indol-2-yl)-4,5-dihydro-thia zol-4-yl]-propionic acid ethyl este
Figure imgf000208_0002
The compound (2.1g, 8.5mmol) prepared in Preparation 9 and the compound (3.4g, 10.2mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (700mg, Yield 20%).
Example 165: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-methoxy-lH- indol-2-yl)-4,5-dihydro-thiazol-4-yl] -propionic acid
3-[(R)-2-(7-Cyclopentylamino-5-meth oxy-1 H-indol-2-yl)-4,5-dihydro-thia zol-4-yl]-propionic acid
Figure imgf000208_0003
The compound (700mg, 1.69mmol) prepared in Preparation 72 was reacted according to the same procedure as Example 158 to give the title compound (430mg, Yield 66%).
1H-NMR (400HMz, DMSO-d6); δ 11.28(br s, IH), 6.61(s, IH), 6.27(s, IH), 5.97(m, IH), 5.88(s, IH), 4.59(m, IH), 3.75(m, IH), 3.68(s, 3H), 3.48(m, 2H), 3.08(m, IH), 2.00(m, 5H), 1.75(m, 3H), 1.57(m, 4H)
Example 166: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol- 2-yl)-4,5-dihydro-thiazoI-4-yl]-propionic acid ethyl ester
3-[(R)-2-(7-Cyclopentylamino-5-etho xy"1 H-indol-2-yl)-4,5-dihydro-thiaz ol-4-yl]-propionic acid ethyl ester
Figure imgf000209_0001
The compound (2.4g, 9.0mmol) prepared in Preparation 11 and the compound (3.Og, 8.98mmol) preared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (600mg, Yield 16%). 1H-NMR (500HMz, CDCl3); δ 9.79(br s, IH), 6.80(s, IH), 6.44(s, IH), 6.19(s,
IH), 4.69(m, IH), 4.1 l(q, 2H), 4.03(q, 2H), 3.83(m, IH), 3.54(m, IH), 3.1 l(m, IH), 2.49(m, 2H), 2.02(m, 4H), 1.69(m, 2H), 1.60(m, 2H), 1.48(m, 2H), 1.25(t, 3H), 1.19(t, 3H)
Example 167: Synthesis of 3-[(R)-2-(7-cyclopentyIamino-5-ethoxy-lH-indol-
2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid 3-[(R)-2-(7-Cyclopentylamιno-5-etho xy-1 H-ιndol-2-yl)-4,5-dιhydro-thιaz ol-4-yl]-propιonιc acid
The compound (300mg, 0.70mmol) prepared in Example 166 was reacted according to the same procedure as Example 158 to give the title compound (210mg, Yield 71%). 1H-NMR (400HMz, DMSO-d6); δ 11.37(br s, IH), 6.78(s, IH), 6.30(s, IH),
5.94(s, IH), 4.64(m, IH), 3.93(q, 2H), 3.82(m, IH), 3.60(m, IH), 3.21(m, IH), 2.44(m, 2H), 1.97(m, 4H), 1.71(m, 2H), 1.57(m, 4H), 1.32(t, 3H)
Preparation 73: Synthesis of 7-nitro-5-trifluoromethoxy-lH-indole- carboxylic acid methyl ester
7-Nιtro-5-trιfluoromethoxy-1 H-ιndol e-2-carboxylιc acid methyl ester
Figure imgf000210_0002
4-Trifluoromethoxy-2~nitroaniline (10. Og, 45.0 mmol) was reacted according to the same procedures as Preparations 3 to 5 to give the title compound (3.0g, Yield 22%).
Example 168: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5- trifluoromethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid ethyl ester
3-[(R)-2-(7-Cyclopentylamιno-5-tπf luoromethoxy-1 H-ιndol-2-yl)-4,5-dιh ydro-thiazol-4-yl]-propionic acid e thyl ester
Figure imgf000210_0003
The compound (2.7g, 8.96mmol) prepared in Preparation 73 and the compound
(3.0g, 8.98mmol) prepared in Preparation 17 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (900mg, Yield 21%).
1H-NMR (500HMz, CDCl3); δ 10.97(br s, IH), 6.93(s, IH), 6.86(s, IH), 6.30(s, IH), 4.76(m, IH), 4.05-3.89(m, 3H), 3.78(m, IH), 3.57(m, IH), 3.16(m, 2H), 2.42(m, 2H), 2.00(m, 4H), 1.63(m, 2H), 1.45(m, IH), 1.34(m, IH)
Example 169: Synthesis of 3-[(R)-2-(7-cyclopentylamino-5- trifluoromethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic acid
3-[(R)-2-(7-Cyclopentylamino-5-trif luoromethoxy-1 H-indol-2-yl)-4,5-dih ydro-thiazol-4-yl]-propionic acid
Figure imgf000211_0001
The compound (750mg, l.όOmmol) prepared in Example 168 was reacted according to the same procedure as Example 158 to give the title compound (600mg, Yield 5%).
1H-NMR (40HMz, DMSOd6) 11.61(br s, IH), 6.85(d, IH), 6.77(s, IH), 6.16(s, IH), 4.66(m, IH), 3.85(m, IH), 3.60(m, 2H), 3.20(m, IH), 2.42(m, 2H), 1.99(m, 4H), 1.71(m, 2H), 1.58(m, 4H)
Example 170: Synthesis of [(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-ylmethoxy] -acetic acid ethyl ester
est
Figure imgf000211_0002
The compound (50mg, 0.15mmol) prepared in Example 5 was dissolved in tetrahydrofuran (5ml). Bromoacetic acid ethyl ester (30mg, 0.18mmol) and sodium hydride (8mg, 0.18mmol) were added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, IN hydrochloric acid was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (15mg, Yield 24%) and the acid compound (40mg, Yield 68%) of Example 171.
1H-NMR (400HMz, CDCl3); δ 10.16(br s, IH), 6.87(s, IH), 6.66(dd, J=2.4? 9.2Hz, IH), 6.30(dd, J=2.4, 11.8Hz, IH), 4.94(m, IH), 4.25(q, 2H), 4.13(d, J=5.6Hz, 2H), 3.87(m, IH), 3.76(d, J=6.4Hz, 2H), 3..56(m, IH), 3.44(m, IH), 2.07(m, 2H), 1.67(m, 4H), 1.51(m, 2H), 1.30(t, 3H)
Example 171: Synthesis of [(R)-2-(7-cyclopentylamino-5-fIuoro-lH-indol-2- yl)-4,5-dihydro-thiazol-4-ylmethoxy] -acetic acid
[(R)-2-(7-Cyclopentylamino-5-fluoro -1 H-indol-2-yl)-4,5-dihydro-thiazol -4-ylmethoxy]-acetic acid
Figure imgf000212_0001
The title compound was additionally obtained in the process of Example 170. 1H-NMR (400HMz, DMSO-d6); δ 12.70(br s, IH), 7.07(s, IH), 6.57(d,
J=8.8Hz, IH), 6.23(d, J=12Hz, IH), 5.13(m, IH), 4.34(m, IH), 4.07(m, 2H), 3.89(m, IH), 3.63(m, 3H), 2.03(m, 2H), 1.58(m, 6H)
Example 172: Synthesis of cyclopentyl-{2-[(R)-4-(3-cyclopentyl- [l,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine Cyclopentyl-{2-[(R)-4-(3-cyclopenty l-[1 ,2,4]oxadiazol-5-ylmethyl)-4,5- dihydro-thiazol-2-yl]-1 H-indol-7-yl }-amine
Figure imgf000213_0001
The compound (140mg, 0.41mmol) prepared in Example 42 was dissolved in N,N-dimethylformamide (5ml). l,l'-Dicarbonyldiimidazole (73mg, 0.45mmol) was added thereto, and the mixture was stirred for 30 min at room temperature. N-hydroxy- cyclopentanecarboxamidine (260mg, 2.03mmol) was added thereto, and the mixture was stirred for 5 h at 80 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (lOOmg, Yield 56%). 1H-NMR (400HMz, CDCl3); δ 10.62(br s, IH), 7.04(d, IH), 6.97(t, IH),
6.92(d, IH), 6.49(d, IH), 5.20(m, IH), 3.83(m, 2H), 3.64(m, IH), 3.39(m, IH), 3.31(m, IH), 3.17(m, IH), 3.01(m, IH), 1.97(m, 4H), 1.73(m, 4H), 1.60(m, 6H), 1.46(m, 2H), 1.34(m, 2H)
Example 173: Synthesis of cyclopentyl-{2-[(R)-4-(3-piperidin-l-yI-
[l,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-lH-indoI-7-yl}-amine
Cyclopentyl-{2-[(R)-4-(3-piperidin-
1 -yl-[1 ,2,4]oxadiazol-5-ylmethyl)-4 ,5-dihydro-thiazol-2-yl]-1 H-indol-7 -yl}-amine
Figure imgf000213_0002
The compound (140mg, 0.41mmol) prepared in Example 42 and N- hydroxypiperidinecarboxamidine instead of N-hydroxycyclopentanecarboxamidine were reacted according to the same procedure as Example 172 to give the title compound (lOOmg, Yield 54%).
1H-NMR (400HMz, CDCl3); δ 10.56(br s, IH), 7.01(d, IH), 6.96(t, IH), 6.90(d, IH), 6.46(d, IH), 5.23(m, IH), 3.83(m, 2H), 3.64(m, IH), 3.36(m, IH), 3.31(m, IH), 3.17(m, 2H), 3.01(m, IH), 1.95(m, 2H), 1.68-1.43(m, HH), 1.35(m, IH)
Preparation 74: Synthesis of 7-phenoxy-lH-indole-2-carboxylic acid methyl ester
7-Phenoxy-1 H-indole-2-carboxylic ac id methyl ester
Figure imgf000214_0001
(Step 1)
(Z)-2-Azido-3-(3-phenoxy-phenyl)-ac rylic acid methyl ester
Figure imgf000214_0002
3-Phenoxy-benzaldehyde (16. Ig, 81.3mmol) was dissolved in methanol (300ml). Sodium methoxide (70.3g, 25%, 325.3mmol) and methyl azidoacetate (42.Og, 325.3mmol) were added thereto, and the mixture was stirred for 5 h at -10 "C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give an azido compound (18.5g, Yield 77%).
(Step 2)
The compound (18.5g, 62.6mmol) prepared in Step 1 was dissolved in xylene (100ml), and stirred for 4 h at 120 °C . After completion of the reaction, and reaction solution was distilled under reduced pressure, and purified by column chromatography to give the title compound (4.9g, Yield 29%).
Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acid methyl ester hydrochloride
Ph^Ph
J. (R)-3-Amino-4-tritylsulfanyl-butyri
U c acid methyl ester
Cl
(Step 1) L-cysteine hydrochloride (5Og, 284.7mmol) was dissolved in N,N- dimethylformamide (200ml). Trityl chloride (119g, 427.0mmol) was added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, 10% sodium acetate (1.5L) was added. The mixture was filtered to give a solid, which was then added to acetone (1.5L), and stirred for 30 min at 50 °C . The insoluble solid was filtered, and dried to give a trityl compound (80g, Yield 78%).
(Step 2)
The compound (34g, 154mmol) prepared in Step 1 was reacted according to the same procedures as Steps 2 ~ 5 of Preparation 15 to give the title compound (26g, Yield 39%).
Preparation 76: Synthesis of [(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-acetic acid methyl ester [(R)-2-(7-Phenoxy-1 H-indoj-2-yl)-4, 5-dihydro-thiazol-4-yl]-acetic acid methyl ester
Figure imgf000216_0001
The compound (4.9g, 18.3mmol) prepared in Preparation 74 and the compound (10.4g, 24.3mmol) prepared in Preparation 75 were reacted according to the same procedures as Preparation 33, Preparation 34 and Example 26 in the order to give the title compound (4.48g, Yield 57%).
Example 174: Synthesis of [(R)-2-(7-phenoxy-lH-indoI-2-yl)-4,5-dihydro- thiazol-4-yl] -acetic acid
[(R)-2-(7-Phenoxy-1 H-indol-2-yl)-4, δ-dihydro-thiazoM-ylJ-acetic acid
Figure imgf000216_0002
The compound (500mg, 1.36mmol) prepared in Preparation 76 was reacted according to the same procedure as Example 27 to give the title compound (300mg, Yield 63%).
1H-NMR (400HMz, DMSOd6); δ 12.17(br s, IH), 7.51(d, J=8.0Hz, IH), 7.41(t, IH), 7.28(br s, IH), 7.16(m, 2H), 7.08(m, 2H), 6.84(d, J=8.0Hz, IH), 4.95(m, IH), 3.77(m, IH), 3.37(m, IH)3 2.86(m, IH), 2.75(m, IH)
Preparation 77: Synthesis of 2-[(R)-2-(7-phenoxy-lH-indoI-2-yl)-4,5- dihydro-thiazoI-4-yl]-ethanol
2-[(R)-2-(7-Phenoxy-1 H-indol-2-yl)- 4,5-dihydro-thiazol-4-yl]-ethanol
Figure imgf000216_0003
The compound (2.56g, 6.99mmol) prepared in Preparation 76 was dissolved in tetrahydrofuran (20ml). Lithium borohydride (7ml, 2.0M in THF, 14.0mmol) was added thereto, and the mixture was stirred for 4 h at 0 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (2.2Og5 Yield 93%).
Preparation 78: Synthesis of 2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2- yl]-7-phenoxy-lH-indole
2-[(R)-4-(2-lodo-ethyl)-4,5-dihydro -thiazol-2-yl]-7-phenoxy-1H-indole
Figure imgf000217_0001
The compound (2.2Og, 6.50mmol) prepared in Preparation 77 was reacted according to the same procedure as Preparation 50 to give the title compound (1.80g, Yield 62%).
Example 175: Synthesis of l-(4-{2-[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethyl}-piperazin-l-yl)-ethanone
1-(4-{2-[(R)-2-(7-Phenoxy-1 H-indol-
2-yl)-4,5-dihydro-thiazol-4-yl]-eth yl}-piperazin-1-yl)-ethanone
Figure imgf000217_0002
The compound (lOOmg, 0.22mmol) prepared in Preparation 78 was dissolved in acetonitrile (3ml). 1-Acetylpiperazine (29mg, 2.2mmol) and potassium carbonate
(93mg, 0.67mmol) were added thereto, and the mixture was stirred for 8 h at 80 °C . After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (40mg, Yield 41%). 1H-NMR (400HMz, CDCl3); δ 9.73(br s, IH), 7.55(d, J=8.0Hz, IH), 7.41(m,
2H), 7.1 l(t, IH), 7.07(m, 3H), 6.91(s, IH), 6.78(d, J=8.0Hz, 2H), 4.71(m, IH), 3.58(m, 2H), 3.48(m, IH), 3.38(m, 2H), 3.1 l(t, IH), 2.56(m, 2H), 2.50(m, 4H), 2.06(s, 3H), 1.98(m, IH), 1.82(m, IH)
Example 176: Synthesis of 2-[(R)-4-(2-morphoIin-4-yl-ethyl)-4,5-dihydro- thiazol-2-yl] -7-phenoxy-l H-indole
2-[(R)-4-(2-Morpholin-4-yl-ethyl)-4 ,5-dihydro-thiazol-2-yl]-7-phenoxy- 1 H-indole
Figure imgf000218_0001
The compound (lOOmg, 0.22mmol) prepared in Preparation 78 and morpholine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 175 to give the title compound (40mg, Yield 45%).
1H-NMR (400HMz, CDCl3); δ 9.17(br s, IH), 7.42(d, J=8.0Hz, IH), 7.34(t, 2H), 7.13(t, IH), 7.05(m, 3H), 6.93(s, IH), 6.80(d, J=8.0Hz, 2H), 4.68(m, IH), 3.72(m, 4H), 3.70(t, IH), 3.14(t, IH), 2.62(m, 2H), 2.51(m, 4H), 2.07(m, IH), 1.85(m, IH)
Example 177: Synthesis of 7-phenoxy-2-[(R)-4-(2-pyrroIidin-l-yl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indole 7-Phenoxy-2-[(R)-4-(2-pyrrolidin-1- yl-ethyl)-4,5-dihydro-thiazol-2-yl]
-1H-indole
Figure imgf000219_0001
The compound (lOOmg, 0.22mmol) prepared in Preparation 78 and pyrrolidine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 175 to give the title compound (80mg, Yield 93%). 1H-NMR (400HMz, CDCl3); δ 9.37(br s, IH), 7.41(d, J=8.0Hz, IH), 7.34(t,
2H), 7.10(t, IH), 7.05(m, 3H), 6.92(s, IH), 6.80(d, J=8.0Hz, 2H), 4.67(m, IH), 3.54(t, IH), 3.14(t, IH), 2.57(m, 2H), 2.51(m, 4H), 2.07(m, IH), 1.89(m, IH), 1.77(m, 4H)
Example 178: Synthesis of dimethyl- {2- [(R)-2-(7-phenoxy-lH-indol-2-yl)- 4,5-dihydro-thiazoI-4-yl]-ethyl}-amine
Dimethyl-{2-[(R)-2-(7-phenoxy-1 H-in dol-2-yl)-4,5-dihydro-thiazol-4-yl]
-ethyl}-amine
Figure imgf000219_0002
The compound (lOOmg, 0.22mmol) prepared in Preparation 78 and dimethylamine instead of 1-acetylpiperazine were reacted according to the same procedure as Example 175 to give the title compound (70mg, Yield 87%). 1H-NMR (400HMz, CDCl3); δ 9.31(br s, IH), 7.41(d, J=8.0Hz, IH), 7.43(t,
2H), 7.10(t, IH), 7.05(m, 3H), 6.92(s, IH), 6.80(d, J=8.0Hz, 2H), 4.65(m, IH), 3.54(t, IH), 3.14(t, IH), 2.57(m, 2H), 2.27(s, 6H), 2.04(m, IH), 1.85(m, IH)
Preparation 79: Synthesis of (S)-3-amino-4-(4-methoxy-benzylsulfanyl)- butyric acid isopropyl ester (S)-3-Amino-4-(4-methoxy-benzylsulf
Figure imgf000220_0001
anyl)-butyric acid isopropyl ester
(Step 1)
The commercially available (S)-2-BOC-amino-succinic acid 1 -methyl ester (2.4g, lOmmol) was dissolved in DCM (30ml), and triethylamine (2.8ml, 20mmol) was added thereto. Isopropanol (660mg, l lmmol), EDC (2.5g, 26mmol) and HOBt (2.3g, 30mmol) were added, and the mixture was stirred for 4 h at room temperature. The reaction was quenched by saturated aqueous NaHCO3 solution. The organic material was extracted with EtOAc, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give a compound (2.5g, Yield 87%).
(Step 2) The compound (57.8g, 200mmol) prepared in Step 1 was dissolved in methanol
(200ml). LiBH4 (IN THF solution, 400ml) was added thereto, and the mixture was stirred for 2 h while maintaining the temperature at 10°C or less. After completion of the reaction, the reaction solution was cooled to 0 "C . Water was slowly added to quench the reaction, and methanol was removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 solution. The organic material was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give a compound (39g, Yield 75%). (Step 3)
The compound (36g, 137.8mmol) prepared in Step 2 and triethylamine (38.4ml, 275.5mmol) were dissolved in dichloromethane (200ml). Methanesulfonyl chloride (11.7ml, 151.5mmol) was added in drops thereto, and the mixture was stirred for 1 h at 0 °C ~ room temperature. After completion of the reaction, IN hydrochloric acid solution was added. The organic material was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate to give a compound.
(Step 4)
Sodium hydride (5.5g, 137.8mmol) and 4-methoxybenzylmercaptan (15.4ml, 110.2mmol) were dissolved in N,N-dimethylformamide (150ml), and the mixture was stirred for 10 min at 0 "C . To the resulting solution was added in drops the compound (46.7g, 137.8mmol) prepared in Step 3, and the mixture was stirred for 4 h at 0 "C . Water was added thereto to quench the reaction. The organic material was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give a compound.
(Step 5)
The compound (24g, 62.7mmol) prepared in Step 4 was dissolved in dichloromethane (200ml). 4N hydrochloric acid/ethyl acetate solution (20ml) was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was thoroughly removed under reduced pressure. The residue was recrystallized from diethylether (150ml), and dried to give the title compound (2Og, Yield 96%).
Examples 179 to 196:
Indole carboxylic acids prepared in Preparations 5, 7, 8 and 12 and the amine compound prepared in Preparation 79 were reacted according to the same procedure as Preparation 34 to give indole derivatives, which were then reacted with commercially available carbonyl compounds according to the same procedures as Examples 26 and 27 in the order to give the Example compounds as shown in the following table.
Figure imgf000222_0001
Figure imgf000222_0002
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Examples 197 to 222:
The intermediate esters for preparing the compounds of Examples 179, 185, 186, 192, 193, 195 and 196 and commercially available amine compounds were reacted according to the same procedures as Example 129, Preparation 50 and Example 71 in the order to give the Example compounds as shown in the following table.
Figure imgf000226_0001
Figure imgf000226_0002
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
1.81(d, 2H), 1.39(m, 2H)
222 2-oxopiperazin-4-yl phenoxy 4,4-difluorocyclohexyl- 1 -yl
(400MHz, CDCl3); δ 10.14 (brs , IH), 6 .82 (s, IH), 6. 80 (s, IH) 6.31 (s, IH), 4 .65
(m, IH), 3.54 (m, IH) 3.53 (dd, J=8Hz, IH), 3 39 (m, 2H), 3.30 (m, IH), 3.22-3 .08
(m, 4H), 2.78-2.65 (m, 4H), 2.38 (s, 3H), 2.28-2 .04 (m, 4H), 1.96-1.86 (m, 2H), 1 .73
(m, 2H)
The compounds according to the present invention were tested in the enzyme and animal model experiments in the following Experiments 1 and 2 to evaluate their efficacies.
Experiment 1 : Glucokinase enzymatic activity assay
Glucokinase known as hexokinase IV (human GK isoform 1, pancreas form and human GK isoform 2, liver form) was cloned into an expression vector pET15 fx (Novagen Co.), transformed to E. coli BL21 (DE3) (Invitrogen Co.) strain, expressed, and purified using a nickel column. Then, the glucokinase obtained from dialysis was used in the following assay.
Glucokinase assay was performed by measuring absorbance according to the conventional manner. Briefly speaking, glucokinase converts the substrate glucose to glucose-6-phosphate under certain conditions, and glucose-6-phosphate dehydrogenase irreversibly converts glucose-6-phosphate to gluconate-6-phosphate. During this procedure, NADH is formed, and its absorbance is measured to calculate the enzymatic activity. In the measurement of the enzymatic activity, each compound was diluted by two-fold from the maximum to the minimum concentrations, and 2 μi of each solution was added to 96 well UV plate (BD bioscience). 60 μi of the first mixture (final concentrations 25mM Hepes, 25mM KCl, 2mM MgCl2, ImM DTT) was added, and thoroughly mixed. 38 μi of the enzyme mixture (final concentrations ImM ATP, ImM NAD, 5mM glucose, 0.85U G6PDH, 37nM GK) was added (final volume lOOμβ), and the mixture was reacted for 10 min at room temperature. The absorbance of NADH was measured at 340nm using a UV spectrometer (Molecular Device).
The enzyme activating abilities of the compounds according to the present invention are represented as AC 1.5 (the compound concentration at which the enzymatic activity is increased by 1.5 times, nM), which is in the range of 0.001 uM to 30 uM or less, preferably 0.001 uM to 10 uM, more preferably 0.001 uM to 1 uM. The enzyme activating abilities of the representative compounds are shown in Table 1.
Table 1
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Experiment 2: Blood glucose lowering abilities of glucokinase activators after their single oral administration in male C57BL/6 mouse
The glucokinase activators according to the present invention were orally administered in a single dose in the amount of 30 mg/kg body weight to male C57BL/6 mice for 24 h. The media were selected depending on their solubilities from distilled water, pH 1.2 HCl buffer solution, 0.5% methyl cellulose distilled water solution, 10%
Gelucire/pH 1.2 HCl buffer solution (1/1). The glucokinase activators were dissolved in the selected media to the medium volume of O.lml/lOg body weight on the basis of the body weight measured on the day of experiment.
Blood glucose was measured by cutting the tail vein before 1 h (time = -1) from the measurement of blood glucose, collecting blood from the tail vein at immediately before the administration of the glucokinase activator (time = 0), and at 1, 2, 4, 8, 12, 24 h after administration, loading on the automatic glucometer (Accu-Chek® Active, Roche, USA), dropping 5 μJt of the blood to a yellow pad of the Accu-Chek® Active glucose strip, and recording the measured value.
Mice involved in the experiment were divided into groups (n=10, in the case of media group n=4) on one day before the experiment so that each group has uniform average and standard deviation for blood glucose after 4 hour fasting. Mice were fed ad libitum.
Blood glucose-area under the curve (AUC) with respect to the media control was calculated for 24 h after administration of the glucokinase activators. The blood glucose lowering abilities in % of the representative compounds with respect to the 100% of media control were shown in the following Table 2.
Table 2
Figure imgf000236_0001
Figure imgf000237_0001

Claims

[CLAIMS] [Claim 1 ]
Indole compounds of the following formula (1): [Formula 1]
Figure imgf000238_0001
in which
X represents O or NH, n denotes a number of 0 to 3,
Y represents a direct bond, -(CH2)PO-, -(CH2),-, or -(CH2)qSO2-, p denots a number of 0 to 2, q denotes a number of 1 to 3,
Rl represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, p and q are as defined above,
R4 and R5 independently of one another represent hydrogen or d-C5-alkyl, A represents 6—12 membered aryl or optionally oxo-containing C3-C8- cycloalkyl, or represents 3-10 membered heterocyclyl or heteroaryl each of which has 1 to 3 hetero atoms selected from O, S, and N,
R6 represents hydrogen, hydroxy, halogen, nitro, Ci-Cβ-alkylcarbonyl, C1- Cό-alkylsulfonyl, Ci-Cό-alkoxycarbonyl or carboxy, R2 represents hydrogen, nitro, halogen, Ci-C6-alkyl or trifluoromethyl, represents 5-12 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally Ci-C6-alkylsulfonyl-substituted 6—12 membered aryl, R3 represents R7-X-B-X'-,
B represents a direct bond, or represents 3-10 membered heterocyclyl or heteroaryl each of which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, O and S, X and X' independently of one another represent a direct bond, or are selected from the group consisting of -CO-, -(CH2)q-, -NR4C(0)-, -NR4-, -OC(O)-, -O-, - (CH2)PC(O)-, -(CH2)pO-, -(CH2)PNR4-, -C(O)NR4- and -S(O)1--, wherein p and q are as defined above, r denotes a number of 0 to 2, and R4 represents hydrogen or Ci-C5-alkyl,
R7 represents hydrogen, hydroxy, Q-Cδ-alkyl, Q-Q-alkoxy, halogeno-d- Cό-alkyl or C3-C6-cycloalkyl, represents 6-12 membered aryl, or represents 4~8 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O, where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, Ci-C6-alkylamino, di(C1-C6-alkyl)amino,
Ci-C6-alkyl, halogeno-Ci-C6-alkyl, C!-C6-alkylsulfonyl, aryl-Q-Q-alkoxy and oxo, pharmaceutically acceptable salts or isomers thereof.
[Claim 2] The compounds of Claim 1 wherein
X represents O or NH, n denotes a number of 0 to 3,
Y represents a direct bond, -(CH2)PO-, -(CH2)q-, or -(CH2)qSO2-, p denotes a number of 0 to 2, q denotes a number of 1 to 3,
Rl represents -(CR4R5)P-A-R6 or -(CR4R5)q-R6, p and q are as defined above,
R4 and R5 independently of one another represent hydrogen or Ci-C5-alkyl, A represents 6-12 membered aryl or optionally oxo-containing C3-C7- cycloalkyl, or represents 4~8 membered heterocyclyl or heteroaryl each of which has 1 to 3 hetero atoms selected from O, S, and N,
R6 represents hydrogen, hydroxy, halogen, nitro, C)-C6-alkylcarbonyl, C1- C6-alkylsulfonyl, Ci-C6-alkoxycarbonyl or carboxy, R2 represents hydrogen, halogen, Ci-C6-alkyl or trifluoromethyl, represents
5-8 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally Ci-C6-alkylsulfonyl-substituted 6-10 membered aryl,
R3 represents R7-X-B-X'-, B represents a direct bond, or represents 4-10 membered heterocyclyl or heteroaryl each of which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, O and S,
X and X' independently of one another represent a direct bond, or are selected from the group consisting of -CO-, -(CH2),-, -NR4C(0)-, -NR4-, -OC(O)-, -O-, - (CH2)PC(O)-, -C(0)NR4- and -S(O)r-, wherein p and q are as defined above, r denotes a number of 0 to 2, and R4 represents hydrogen or Ci-C5-alkyl, and
R7 represents hydrogen, hydroxy, d-Cβ-alkyl, halogeno-Ci-C6-alkyl or C3- C6-cycloalkyl, represents 6-12 membered aryl, or represents 4-8 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O.
[Claim 3]
The compounds of Claim 2 wherein Rl represents -(CH2)P-A-R6 or -(CR4R5)q- R6, wherein p denotes a number of 0 to 2, q denotes a number of 1 to 3, R4 and R5 independently of one another represent hydrogen or Ci-Cs-alkyl, A represents 6-12 membered aryl or optionally oxo-containing C3-C6-cycloalkyl or represents 5-6 membered heterocyclyl which has 1 to 2 hetero atoms selected from O, S, and N, and R6 represents hydrogen, halogen, nitro, Ci-Cό-alkylcarbonyl, Ci-C6-alkylsulfonyl, C1-C6- alkoxycarbonyl or carboxy.
[Claim 4]
The compounds of Claim 3 wherein Rl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, difluorocyclohexyl, tetrahydrofuran, tetrahydropyran, (tetrahydropyran-4-yl)methyl, tetrahydrothiopyran, 4-oxo-cyclohexyl, (l-methanesulfonyl)pyrrolidine, (l-acetyl)piperidine, 4-nitrophenyl and methylpropiolate.
[Claim 5]
The compounds of Claim 2 wherein Y represents a direct bond, -O-, -(CH2)O-, - (CH2)- or -(CH2)SO2-.
[Claim 6]
The compounds of Claim 2 wherein R2 represents hydrogen, halogen, Ci-C3- alkyl or trifluoromethyl, represents 5-6 membered heteroaryl or heterocyclyl each of which has 1 to 3 hetero atoms selected from N and O, or represents optionally methanesulfonyl-substituted 6-10 membered aryl.
[Claim 7] The compounds of Claim 6 wherein R2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, phenyl, methanesulfonylphenyl, pyridine, morpholine, 1,2-imidazole, 1,3-imidazole, pyrrolidine and pyrrole.
[Claim 8] The compounds of Claim 2 wherein B represents a direct bond, represents pyrazole, imidazole or oxadiazole each of which is optionally substituted by d-C6-alkyl, or represents 5-9 membered heterocyclyl which optionally contains oxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, S and O.
[Claim 9]
The compounds of Claim 8 wherein B represents a direct bond, or is selected from the following formulae (i) to (xi)
Figure imgf000243_0001
0) (ϋ) (iii) (iv) (V)
Figure imgf000243_0002
(vi) (vϋ) (viϋ) (ix) (X)
Figure imgf000243_0003
(xi) in which R7 is as defined in Claim 1 or 2.
[Claim 10] The compounds of Claim 2 wherein X' represents a direct bond, or is selected from the group consisting of -CO-, - NR4CO-, -SO2- and -O-.
[Claim 11 ]
The compounds of Claim 2 wherein X represents a direct bond, or is selected from the group consisting of -C(O)NR4-, -NR4-, -OC(O)-, -NR4C(O)-, -(CH2)C(O)-, - S(O)2- and -C(O)-.
[Claim 12]
The compounds of Claim 11 wherein X represents a direct bond, or is selected from the group consisting of -C(O)NH-, -C(O)N(Me)-, -NH-, -N(Me)-, -OC(O)-, - N(Me)C(O)-, -(CH2)C(O)-, -S(O)2- and -C(O)-.
[Claim 13]
The compounds of Claim 2 wherein R7 represents hydrogen, hydroxy, Ci-C6- alkyl, halogeno-Ci-C6-alkyl or C4-C6-cycloalkyl, represents optionally halogen- substituted 6—10 membered aryl, or represents 5-6 membered heteroaryl or heterocyclyl each of which has 1 to 4 hetero atoms selected from N and O.
[Claim 14] The compounds of Claim 13 wherein R7 is selected from the group consisting of hydrogen, hydroxy, methyl, trifluoromethyl, ethyl, t-butyl, cyclohexyl, pyrrolidine, phenyl, 2-fluorophenyl, piperidine, pyridine, 1,3-pyrazine, 1,4-pyrazine, furan, trifluoromethyl, 1,2,3,4-tetrazole and tetrahydrofuran.
[Claim 15]
The compounds of Claim 2 which are selected from the goup consisting of
[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-l,3-thiazol-4-yl]- methanol;
{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -methanol;
{(R)-2-[7-(tetrahydro-furan-3-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -methanol;
{(R)-2-[7-(l-methanesulfonyl-pyrrolidin-3-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol; [(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- methanol;
{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol; [(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- methanol;
{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
{(R)-2-[5-chloro-7-(tetrahydro-thiopyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl } -methanol;
[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- methanol;
{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol; [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -methanol;
{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol;
Cyclopentyl- [2-((R)-4-pyrrolidin- 1 -ylmethyl-4,5 -dihydro-thiazol-2-yl)- 1 H- indol-7-yl] -amine;
Cyclopentyl-[2-((R)-4-morpholin-4-ylmethyl-4,5-dihydro-thiazol-2-yl)-lH- indol-7-yl]-amine; Cydopentyl-[2-((R)-4-dimethylammomethyl-4,5-dihydro-thiazol-2-yl)-lH- indol-7-yl] -amine;
{(R)-2-[5-morpholin-4-ylmethyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2- yl] -4, 5 -dihydro-thiazol-4-yl } -methanol ; [(R)-2-[7-cyclopentylamino-5-pyrazol-l-ylmethyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -methanol;
[(R)-2-(7-cyclopentylamino-5-imidazol-l-ylmethyl-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl} -methanol;
{(R)-2-[7-cyclopentylamino-5-(lH-pyrrol-3-ylmethyl)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -methanol;
[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -methanol;
[7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-lH- indol-5-yl] -methanol; [(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid methyl ester;
[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid ethyl ester;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-l,3-thiazol- 4-yl]-ethanol;
{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid methyl ester; {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -ethanol; [(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
2-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-l,3-thiazol- 4-yl]-ethanol;
{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylaniino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
2-{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -ethanol;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid; [(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid ethyl ester;
2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethanol;
{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -ethanol;
[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl] -acetic acid; [(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid ethyl ester;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;
{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -acetic acid;
2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl}-ethanol;
[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid methyl ester; [(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-acetic acid ethyl ester;
{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid methyl ester;
{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid; [(R)-2-(7-cyclopentylamino-5-propoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
[(R)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
{(R)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid methyl ester;
{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -acetic acid methyl ester;
{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -acetic acid; [(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
{(R)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(R)-2-[5-methyl-7-(4-oxo-cyclohexylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(R)-2-[7-cyclopentylamino-5-(4-methanesulfonyl-phenoxy)-lH-indol-2-yl]- 4,5-dihydro-thiazol-4-yl} -acetic acid; [(R)-2-(7-cyclopentylamino-5-phenoxymethyl- 1 H-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -acetic acid;
[(R)-2-(7-cyclopentylamino-5-pyrrolidin-l-ylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -acetic acid methyl ester;
[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl] -acetic acid;
2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethanol;
Cyclopentyl-{5-methanesulfonylmethyl-2-[(R)-4-(2-moφholin-4-yl-ethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl} -amine; 1 -(4- {2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl- lH-indol-2-yl)-
4,5-dihydro-thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -morpholin-4-yl-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -N-(3 -morpholin-4-yl-propyl)-acetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-methyl-acetamide; 2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -N,N-dimethyl-acetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]- 1 -(4-methyl-piperazin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]- 1 -(3-dimethylamino-pyrrolidin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(3 -hydroxy-pyrrolidin- 1 -yl)-ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-l-piperidin-l-yl-ethanone;
2-{(R)-2-[5-chloro-7-(tetrahydro-ρyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl}-N-methyl-acetamide;
2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} - 1 -morpholin-4-yl-ethanone; 2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(4-methyl-piperazin- 1 -yl)-ethanone;
2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;
1 -(4- Acetyl -piperazin- 1 -yl)-2-[(R)-2-(7-cyclopentylamino-5-fluoro- 1 H-indol-2- yl)-4,5-dihydro-thiazol-4-yl]-ethanone;
2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro~thiazol-4- yl]-N-methyl-acetamide;
2-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -morpholin-4-yl-ethanone; 2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-ethyl- acetamide;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N- methyl-acetamide;
2-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-l- morpholin-4-yl-ethanone;
N-methyl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-acetamide;
1 -Morpholin-4-yl-2- {(R)-2-[7-(tetrahydro-ρyran-4-ylamino)- lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethanone;
{5-Chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -cyclopentyl-amine;
{5-Chloro-2-[(R)-4-(2-moφholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -cyclopentyl-amine; {5-Chloro-2-[(R)-4-(2-piperazin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-
7-yl} -cyclopentyl-amine; l-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-ethanone;
(5-Chloro-2- {(R)-4-[2-(4-ethanesulfonyl-piperazin- 1 -yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine; l-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazin-l-yl)-2-hydroxy-ethanone;
(5-Chloro-2- {(R)-4-[2-(4-methyl-piperazin- 1 -yl)-ethyl]-4,5-dihydro-thiazol-2- yl}-lH-indol-7-yl)-cyclopentyl-amine; l-{2-[(R)-2-(5-chloro-7-cycloρentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl} -piperidin-4-ol;
(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol- 4-yl]-ethyl} -piperazin-2-one;
(5-Chloro-2-{(R)-4-[2-(3-dimethylamino-ρyrrolidin-l-yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine;
{5-Chloro-2-[(R)-4-(2-piperidin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -cyclopentyl-amine;
(5-Chloro-2-{(R)-4-[2-(l,l-dioxo-thiomoφholin-4-yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine;
{5-Chloro-2-[(R)-4-(2-pyrazol-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7- yl } -cyclopentyl-amine;
(S)-l-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -pyrrolidine-2-carboxylic acid; {5-Chloro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -cyclopentyl-amine;
3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester;
3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic acid;
1 - {2-[(R)-2-(5-chloro-7-cyclopentylamino- lH-indol-2-yl)-4,5-dihydro-thiazol- 4-yl]-ethyl} -pyrrolidin-2-one; l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperidine-3-carboxylic acid; l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperidine-3-carboxylic acid dimethylamide;
[(S)-l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamic acid t-butyl ester;
(2- {(R)-4-[2-((S)-3-amino-pyrrolidin- 1 -yl)-ethyl]-4,5-dihydro-thiazol-2-yl} -5- chloro- 1 H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;
N-[(S)-l-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]- 4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-acetamide;
{5-Chloro-2-[(R)-4-(2-piperazin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -(tetrahydro-pyran-4-yl)-amine; l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-ρyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperazin- 1 -yl]-2-hydroxy-ethanone; l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperazin- 1 -yl]-2-tetrazol- 1 -yl-ethanone; l-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-3,3,3-trifluoro-propan-l-one;
[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-ρyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-furan-2-yl-methanone;
(5-Chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-yl)-ethyl]-4,5- dihydro-thiazol-2-yl}-lH-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;
(5-Chloro-2-{(R)-4-[2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-4,5-dihydro- thiazol-2-yl} - 1 H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;
{2-[(R)-4-(2-amino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-lH-indol-7-yl}- cyclopentyl-amine; l-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-ethanone;
Cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2- yl]-l H-indol-7-yl} -amine;
Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5- fluoro-lH-indol-7-yl} -amine;
Cycloρentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol-2- yl] - 1 H-indol-7-yl} -amine;
Cyclopentyl-(2-{(R)-4-[2-(l,l-dioxo-thiomoφholin-4-yl)-ethyl]-4,5-dihydro- thiazol-2-yl}-5-fluoro-lH-indol-7-yl)-amine;
4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -ethyl} -piperazin-2-one; l-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazin-l-yl)-2-hydroxy-ethanone; Cyclopentyl-{5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-
2-yl] - 1 H-indol-7-yl} -amine;
{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-lH-indol- 7-yl}-(tetrahydro-pyran-4-yl)-amine;
{5-Fluoro-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl} -(tetrahydro-pyran-4-yl)-amine;
{5-Fluoro-2-[(R)-4-(2-moφholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol- 7-yl}-(tetrahydro-pyran-4-yl)-amine; l-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-ρyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl-piperazin- 1 -yl)-ethanone; (2-{(R)-4-[2-(l,l-dioxo-thiomoφholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5- fluoro- 1 H-indol-7-yl)-(tetrahydropyran-4-yl)-amine;
(5-Fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;
4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one; l-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl} -ethyl)-piperazin- 1 -yl]-2-hydroxy-ethanone;
Cyclopentyl-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7- yl} -amine;
Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -amine;
Cyclopentyl-{2-[(R)-4-(2-moφholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -amine; Cyclopentyl-{2-[(R)-4-(2-piperidin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -amine;
{2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH-indol-7-yl}- (tetrahydro-pyran-4-yl)-amine;
1 -(4- {2-[(R)-2-(7-cyclopentylamino-5-methoxy- 1 H-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-2-hydroxy-ethanone;
2-Hydroxy-l-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-lH- indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-l-yl]-ethanone;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester; 3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propionic acid;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-propan-l-ol;
3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -propionic acid;
3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -propan- 1 -ol;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl]-N-(2-morpholin-4-yl-ethyl)-propionamide;
3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] - 1 -(4-methyl-piperazin- 1 -yl)-propan- 1 -one; l-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-propyl} -piperazin- 1 -yl)-ethanone; {5-Chloro-2-[(R)-4-(3-morρholin-4-yl-propyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl} -cyclopentyl-amine;
3-[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester; 3-[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(5-bromo-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-methoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid;
3-[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-ethoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -propionic acid; 3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-propionic acid ethyl ester;
3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -propionic acid;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- ylmethoxy] -acetic acid ethyl ester;
[(R)-2-(7-cyclopentylamino-5-fluoro-lH-indol-2-yl)-4,5-dihydro-thiazol-4- ylmethoxyj-acetic acid;
Cyclopentyl- {2-[(R)-4-(3-cyclopentyl-[ 1 ,2,4]oxadiazol-5-ylmethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine; Cyclopentyl-{2-[(R)-4-(3-piperidin-l-yl-[l,2,4]oxadiazol-5-ylmethyl)-4,5- dihydro-thiazol-2-yl]-lH-indol-7-yl}-amine;
[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid; l-(4-{2-[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}- piperazin- 1 ~yl)-ethanone; 2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-7-phenoxy-lH- indole;
7-Phenoxy-2-[(R)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indole; Dimethyl-{2-[(R)-2-(7-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- ethyl} -amine;
[(S)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid;
{(S)-2-[7-(l-acetyl-piperidin-4-ylaniino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
((S)-2-{7-[(tetrahydro-pyran-2-ylmethyl)-amino]-lH-indol-2-yl}-4,5-dihydro- thiazol-4-yl)-acetic acid;
((S)-2-{7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2-yl}-4,5-dihydro- thiazol-4-yl)-acetic acid; {(S)-2-[7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro-thiazol-4- yl} -acetic acid;
{(S)-2-[7-(l-acetyl-pyrrolidin-3-ylammo)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(S)-2-(7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid;
((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2-yl}- 4,5-dihydro-thiazol-4-yl)-acetic acid;
{(S)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid; {(S)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(S)-2-(7-cyclobutylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid; {(S)-2-[5-methyl-7-(tetrahydro-furan-3-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
{(S)-2-[7-(cyclopropylmethyl-amino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
((S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2-yl}-4,5- dihydro-thiazol-4-yl)-acetic acid;
{(S)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
[(S)-2-(7-cyclopentylamino-5-methyl-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- acetic acid methylester; [(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro-thiazol-4- yl] -acetic acid;
{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-methyl-lH-indol-2-yl]-4,5-dihydro- thiazol-4-yl} -acetic acid;
(2-{(S)-4-[2-((R)-3-amino-pyrrolidin-l-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5- chloro-lH-indol-7-yl)-cyclopentyl-amine;
(5-Chloro-2- {(S)-4-[2-((R)-3-dimethylamino-pyrrolidin- 1 -yl)-ethyl]-4,5- dihydro-thiazol-2-yl}-lH-indol-7-yl)-cyclopentyl-amine; l-(4-{2-[(S)-2-(5-chloro-7-cyclopentylamino-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazin-l-yl)-ethanone; l-(4-{2-[(S)-2-(7-amino-5-chloro-lH-indol-2-yl)-4,5-dihydro-thiazol-4-yl]- ethyl} -piperazin- 1 -yl)-ethanone; l-(4-{2-[(S)-2-(5-methyl-7-(tetrahydro-pyran-4-ylamino)-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethyl}-piperazin-l-yl)-ethanone; {5-Methyl-2-[(S)-4-(2-moφholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl}-(tetrahydro-pyran-4-yl)-amine; l-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-2-hydroxy-ethanone;
Cyclopentyl- {5-phenoxy-2-[(S)-4-(2 -piperazin- 1 -yl-ethyl)-4,5-dihydro-thiazol- 2-yl]-lH-indol-7-yl}-amine;
4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazine- 1 -carboxylic acid t-butyl ester;
Cyclopentyl-(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3- a]pyrazin-7-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-phenoxy-lH-indol-7-yl)-amine; 4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl}-piperazin-2-one;
(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl] -ethyl} -piperazin- 1 -yl)-(tetrahydro-furan-2-yl)-methanone;
Cyclopentyl-(5-phenoxy-2-{(S)-4-[2-(4-pyridin-2-yl-piperazin-l-yl)-ethyl]-4,5- dihydro-thiazol-2-yl} - 1 H-indol-7-yl)-amine;
Cyclopentyl-[2-((S)-4-{2-[4-(2-fluoro-phenyl)-piperazin-l-yl]-ethyl}-4,5- dihydro-thiazol-2-yl)-5-phenoxy-lH-indol-7-yl)-amine; l-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5-dihydro- thiazol-4-yl]-ethyl} -piperazin- 1 -yl)-ethanone; {(R)-l-[2-[(S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol- 2-yl}-4,5-dihydro-thiazol-4-yl]-ethyl]-pyrrolidin-2-yl} -methanol;
N-((R)-l-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-lH-indol-2-yl)-4,5- dihydro-thiazol-4-yl]-ethyl}-pyπOlidin-3-yl)-acetamide; (2-{(S)-4-[2-(4-benzyl-piperazin-l-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5- phenoxy- 1 H-indol-7-yl)-cyclopentyl-amine;
{5-Methyl-2-[(S)-4-(2-moφholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-lH- indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)methyl-amine;
{2-[(S)-4-(2-moφholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-5-phenoxy-lH- indol-7-yl} -(tetrahydro-pyran-4-ylmethyl)-amine;
4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2- yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one;
Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-pyrrolidin-l-yl-ethyl)-4,5-dihydro-thiazol- 2-yl]- lH-indol-7-yl)-amine; (4,4-Difluoro-cyclohexyl)- {2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro- thiazol-2-yl]-lH-indol-7-yl)-amine;
(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[l,2,4]triazolo[4,3-pyrazin-7-yl]-ethyl)- 4,5-dihydro-thiazol-2-yl}-5-phenoxy-lH-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl)- amine; 4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-indol-2- yl} -4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one; and
4-(2-{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-phenoxy-7-lH-indol-2-yl]-4,5- dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one.
[Claim 16]
A pharmaceutical composition for the activation of glucokinase, which comprises the compounds of formula (1) as defined in Claim 1, pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
[Claim 17]
The composition of Claim 16 for the prevention or treatment of diabetes, complications of diabetes, diabetes related diseases, or obesity.
[Claim 18]
The composition of Claim 17 wherein diabetes is type 1 diabetes.
[Claim 19] The composition of Claim 17 wherein diabetes is type 2 diabetes.
[Claim 20]
The composition of Claim 17 wherein complications of diabetes are neurogenic disease, hyperlipidemia, hypertension, retinosis, or renal failure.
[Claim 21 ]
The composition of Claim 16 which is a hypoglycemic composition.
[Claim 22] A process for preparing a pharmaceutical composition for the prevention or treatment of the diseases caused by deactivation of glucokinase, which comprises the step of mixing the compounds of formula (1) as defined in Claim 1, pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.
PCT/KR2008/007585 2007-12-20 2008-12-22 Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient WO2009082152A2 (en)

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CN2008801208137A CN101896483B (en) 2007-12-20 2008-12-22 Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient
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Cited By (13)

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WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
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