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WO2012091010A1 - Dérivé de pyrimidine bicyclique - Google Patents

Dérivé de pyrimidine bicyclique Download PDF

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Publication number
WO2012091010A1
WO2012091010A1 PCT/JP2011/080207 JP2011080207W WO2012091010A1 WO 2012091010 A1 WO2012091010 A1 WO 2012091010A1 JP 2011080207 W JP2011080207 W JP 2011080207W WO 2012091010 A1 WO2012091010 A1 WO 2012091010A1
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group
phenyl
methyl
hydrogen atom
alkyl group
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Japanese (ja)
Inventor
篤志 諏訪
貴士 ▲高▼田
友明 西田
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having a monoacylglycerol acyltransferase (hereinafter also referred to as “MGAT”) inhibitory activity and having a bicyclic pyrimidine structure, or a physiologically acceptable salt thereof, and a pharmaceutical composition containing the same. .
  • MGAT monoacylglycerol acyltransferase
  • BMI body mass index
  • type 2 diabetes impaired glucose tolerance
  • abnormal lipid metabolism hypertension
  • hyperuricemia / gout coronary artery disease
  • brain Obesity is caused by infarction, sleep apnea syndrome, fatty liver, orthopedic disease, menstrual abnormalities, or urine protein.
  • obesity is considered to be a visceral fat type obesity.
  • Neutral fat (triglycerol (TG)) ingested by meals is broken down into fatty acids and monoacylglycerol (MG) by pancreatic lipase in the digestive tract, forming micelles, and absorbed by small intestinal epithelial cells.
  • the absorbed fatty acid becomes acyl-CoA by acyl-CoA synthase.
  • diacylglycerol (DG) is synthesized from MG and acyl-CoA by monoacylglycerol acyltransferase (MGAT), and TG is re-synthesized from DG and acyl-CoA by diacylglycerol acyltransferase (DGAT).
  • MTP microsomal triglycerol transfer protein
  • chylomicron is secreted into the blood via lymphatic vessels, and is transported to peripheral tissues.
  • MGAT catalyzes the reaction of synthesizing DG from MG and acyl-CoA, and plays an important role in the process of fat absorption from the small intestine.
  • research has not progressed due to the difficulty of purification, and genes have recently been identified.
  • MGAT1 Three types of molecular species (MGAT1, MGAT2, and MGAT3) have been cloned and reported so far (Proceedings of the Narional Academy of Sciences, 99, 8512-8517, 2002; Jounal of Biological Chemistry, 278, 18532-18537, 2003; Journal of Biological Chemistry, 278, 13860-13866, 2003; American Journal of Physiology, 285, E927-E937, 2003; Journal of Biological Chemistry, 278, 13611-13614, 2003).
  • MGAT1 was expressed in the stomach and kidney and was not detected in the small intestine.
  • MGAT2 was highly expressed in the small intestine.
  • the gene of MGAT3 has been reported only in humans and was specifically expressed in the small intestine. Therefore, it is speculated that MGAT2 and MGAT3 are involved in fat absorption in the small intestine.
  • Patent Documents 1 and 2 have been reported as compounds having an MGAT inhibitory action and a bicyclic pyrimidine structure.
  • compounds described in Patent Documents 3 and 4 have been reported as compounds having a GPR119 action and having a bicyclic pyrimidine structure.
  • specific compounds having an azetidine structure which is one of the features of the present invention, are not described in these patent documents.
  • An object of the present invention is to provide a compound having an MGAT inhibitory action useful as a pharmaceutical or a physiologically acceptable salt thereof, and a pharmaceutical composition containing the same.
  • the inventors of the present invention have considered that if MGAT activity in the small intestine is inhibited, fat absorption from the small intestine is suppressed and effective against obesity, and as a result of intensive studies, the present inventors have expressed two formulas (I) below.
  • a compound having a cyclic pyrimidine structure hereinafter also referred to as “the compound of the present invention” and physiologically acceptable salts thereof have an MGAT inhibitory action and a fat absorption inhibitory action, thereby completing the present invention. did. That is, the present invention is as follows.
  • R 1 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower cycloalkyl group, an optionally substituted lower cycloalkenyl group, a substituted An optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted saturated or unsaturated heterocyclic group
  • R 2 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group, a substituted An optionally substituted lower alkenyl group, an optionally substituted lower alkanoyl group, an optionally substituted phenylcarbonyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group or
  • R 3 is not benzoyl
  • R 4 and R 5 are each independently a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted C 3-6 cycloalkyl group, OH or OR 4b (wherein R 4b represents an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-6 cycloalkyl group),
  • X is an oxygen atom, a sulfur atom, -N (R 6 )-or -C (R 7 ) (R 8 )-(wherein R 6 is a hydrogen atom, an optionally substituted lower alkyl group or a substituted R 2 and R 6 may be combined to form a cyclic amino
  • R 7 and R 8 are each independently a hydrogen atom, a halogen atom
  • Y represents any one selected from the following formulas (II), (III), (IV) or (V): Wherein R 9 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted saturated or unsaturated group.
  • Z represents an oxygen atom or a sulfur atom), m represents 1, n represents 2.
  • R 1 is a group represented by any one of the following formulas (2a ′), (2b ′), (2c ′), (2d ′), (2e ′), (2f ′) or (2g ′) Representation: [Where: R a2a, R a2b, R a2c , R a2d, R b2, R a2f and R A2G are each independently a hydrogen atom, a halogen atom, CF 3, CN, OH, C 1-6 alkyl groups, C 1- 6 alkoxy groups (wherein the C 1-6 alkyl group and the C 1-6 alkoxy group may be substituted with CO 2 H or CO 2 CR 1g1 R 1g2 R 1g3 (where R 1g1 , R 1g2 and Each R 1g3 is independently Hydrogen atom, C 1-4 alkyl group (the group is an OH, C 1-4 alkoxy group, C 3-6 cycloalkyl group optionally substituted with C 1-4 alkoxy group
  • Each of the carbon atoms together may form a 3- to 8-membered cycloalkyl ring or a 5- or 6-membered saturated heterocycle,
  • two R d4g , R d4h , R f4h , R h4h , R j4h , R d4i or R f4i bonded to adjacent carbon atoms through 0-3 carbon atoms are the two carbons to which they are bonded.
  • R 1 represents a group represented by any of the following formulas (2a ′), (2b ′), (2c ′), (2d ′), (2e ′) or (2g ′): [Where: R a2a, R a2b, R a2c , R a2d, R b2 and R A2G are each independently a hydrogen atom, a halogen atom, CF 3, C 1-6 alkyl, or C 1-6 alkoxy groups (here The C 1-6 alkyl group and C 1-6 alkoxy group may be substituted with CO 2 H or CO 2 CR 1g1 R 1g2 R 1g3 (wherein R 1g1 , R 1g2 and R 1g3 are each independently do it, Hydrogen atom or a C 1-4 alkyl (in which the group OH, C 1-4 alkoxy group, may be substituted with a saturated heterocyclic group, or NR 1b1 R 1b2 of 5- or 6-membered, R 1b1 and R 1
  • R a3a , R a3c, and R a3d may be substituted at any position as long as they are chemically acceptable
  • X 3d represents an oxygen atom, a sulfur atom or —N (R c3 ) —
  • R c3 represents a hydrogen atom or a C 1-6 alkyl group
  • n 3a represents an integer of 0 to 4
  • n 3c represents an integer of 1 to 6
  • m 3d represents an integer of 1 to 3
  • n 3d represents an integer of 0 to 3
  • n 3e represents an integer of 0 to 8]
  • R 3 represents a group represented by any of the following formulas (4g), (4h) or (4i): [Where: Arm represents a benzene ring or a heteroaromatic ring, R a4g and R a4h each independently represent a hydrogen atom, a halogen atom, CF 3 , CN, OH, a C 1-6 alkyl group
  • R d4g and R e4g , R d4h , R e4h , R f4h , R g4h , R h4h , R i4h , R j4h and R k4h , and R d4i , R e4i , R f4i and R g4i Independently of each other, and when there are a plurality of groups, each independently represents a hydrogen atom, a C 1-6 alkyl group, a CO 2 H or a CO 2 -C 1-6 alkyl group, Alternatively, R d4g and R e4g , R d4h and R e4h , R f4h and R g4h , R h4h and R i4h , R j4h and R k4h , R d4i and R e4i , and R f4i and R g4i are combined.
  • Y is the formula (II), (III) or (IV): [Wherein each symbol is as defined in [1]]
  • Y is the formula (III): The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [1] to [5], which is a group represented by the formula:
  • R 3 has the formula (4g): [Where: Arm is a benzene ring or a pyridine ring, R a4g is a hydrogen atom, a halogen atom, CN, OH, CO 2 H, CO 2 —C 1-4 alkyl group, or CH ⁇ CH—R 3af (wherein R 3af is CO 2 H or CO 2 —C 1-4 represents an alkyl group) R d4g and R e4g each independently represent a hydrogen atom, a C 1-4 alkyl group, CO 2 H, or CO 2 -C 1-4 when there are a plurality of groups. Represents an alkyl group, m 4g represents an integer of 1 to 3]
  • the bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [3] to [6], which is a group represented by the formula:
  • R 3 is the formula (4h): [Where: Arm is a benzene ring or a pyridine ring, m 4h , n 4h , p 4h and q 4h each independently represent an integer of 0 to 3 (provided that m 4h + n 4h + p 4h + q 4h is an integer of 0 to 10; r 4h is 1 If, m 4h represents an integer of 2 or 3), Each other symbol is as defined in [4]]
  • the bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [3] to [6], which is a group represented by the formula:
  • R a4h is a hydrogen atom, a halogen atom, CF 3 , a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R B4h is (vi) CO 2 H, or (xi) CO 2 CR 3g1 R 3g2 R 3g3
  • R 3g1, R 3g2 and R 3G3 are each independently A hydrogen atom, or A C 1-4 alkyl group (the group may be substituted with OH, a C 1-4 alkoxy group, a 5- or 6-membered saturated heterocyclic group, or NR 3b8 R 3b9 , each of R 3b8 and R 3b9 is Independently represents a hydrogen atom or a C 1-4 alkyl group
  • Represents) R d4h , R e4h , R f4h , R g4h , R h4h , R i4h , R j4h and R k4h are Independently of each other
  • R b4h is (xi) CO 2 CR 3g1 R 3g2 R 3g3 (Here, R 3g1, R 3g2 and R 3G3 is [9] As a is defined to) represented by, [8] or [9] bicyclic pyrimidine compound or a physiologically according to any one of Acceptable salt.
  • R b4h is (xi) CO 2 CR 3g1 R 3g2 R 3g3 (Here, R 3g1, R 3g2 and R 3G3 are each independently A hydrogen atom or a C 1-4 alkyl group (the group may be substituted with OH or a C 1-4 alkoxy group)
  • R 1 is represented by the following formula (2a ′) or (2b ′): [Where: R a2a and R a2b are each independently a hydrogen atom, a halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group, n 2a and n 2b are 0]
  • the bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [3] to [12], which is a group represented by the formula:
  • R 1 is the following formula (2c ′): [Where: R a2c is a hydrogen atom or a fluorine atom (a plurality of such groups may be substituted at any position as long as it is chemically acceptable); p 2c is 0, n 2c is an integer of 1 to 4]
  • R 1 is represented by the following formula (2d ′) or (2g ′): [Where: R a2d and R a2g are hydrogen atoms, X 2d and X 2g are oxygen atoms, p 2d and n 2g are 1, m 2d is an integer of 2 to 3, n 2d is an integer from 0 to 1]
  • the bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [3] to [12],
  • R 1 is represented by the following formula (2e ′): [Where: R b2 is a C 1-4 alkoxy group, R d2e and R e2e are each independently a hydrogen atom or a C 1-4 alkyl group when there are a plurality of groups, n 2e is an integer of 2 to 4]
  • R 2 is represented by the following formula (3c) or (3d): [Where each symbol is as defined in [4]]
  • R 2 is represented by the following formula (3c): [ Wherein R a3c is a hydrogen atom, and n 3c is an integer of 1 to 4]
  • R 2 is represented by the following formula (3a): [ Wherein R a3a is a hydrogen atom or a C 1-6 alkoxy group which may be substituted with a C 1-4 alkoxy group, and n 3a is 0]
  • R 1 represents any of the following formulas (2a), (2b), (2c), (2d), (2e), (2f), or (2g): [Where: R a2a, R a2b, R a2c , R a2d, R b2, R a2f and R A2G are each independently a hydrogen atom, a halogen atom, CF 3, CN, OH, C 1-6 alkyl groups, C 1- 6 alkoxy group, C 1-6 alkylcarbonyl group, CO 2 R 1a , NR 1b R 1c or C ( ⁇ O) NR 1d R 1e , R a2n represents a hydrogen atom, CF 3 , CN, C 1-6 alkyl group, C 1-6 alkylcarbonyl group, CO 2 R 1a , NR 1b R 1c or C ( ⁇ O) NR 1d R 1e , R 1a , R 1b , R 1c , R 1d and R 1e each independently represent a hydrogen atom
  • X 2d represents an oxygen atom or —N (R c2 ) — (wherein R c2 represents a hydrogen atom or a C 1-10 alkyl group), X 2g represents an oxygen atom or a sulfur atom, n 2c represents an integer of 1 to 6, m 2d represents an integer of 1 to 3, n 2d represents an integer of 0 to 3, n 2e represents an integer of 0 to 8]; R 2 represents any of the following formulas (3a), (3b), (3c), (3d) or (3e): [Where: R a3a , R a3b , R a3c , R a3d and R b3 each independently represent a hydrogen atom, a halogen atom, CF 3 , CN, OH, a C 1-6 alkyl group, a C 1-6 alkoxy group, C 1 Represents a -6 alkylcarbonyl group,
  • X 3d represents an oxygen atom, a sulfur atom, or —N (R c3 ) — (wherein R c3 represents a hydrogen atom or a C 1-10 alkyl group), n 3a represents an integer of 0 to 6; n 3b represents an integer of 0 to 6; n 3c represents an integer of 1 to 6, m 3d represents an integer of 1 to 3, n 3d represents an integer of 0 to 3, n 3e represents an integer of 0 to 8]; R 3 represents any of the following formulas (4a), (4b), (4c), (4d) or (4e): [Where: R a4a , R a4b , R a4c and R a4d are each independently a hydrogen atom, a halogen atom, CF 3 , CN, OH, a C 1-10 alkyl group, a C 3-6 cycloalkyl group, a C
  • R d4a , R d4b , R d4c , R f4c , R d4d , R f4d, or R f4e bonded to adjacent carbon atoms through 0 to 3 carbon atoms are the two carbons to which they are bonded.
  • Y is the formula (II), (III) or (V): [Wherein each symbol is as defined in [1]]
  • Y is the formula (III): The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [1], [2], [21] or [22], which is represented by:
  • R 3 is the formula (4a), (4b), (4c) or (4e): [Where: m 4a and m 4b each independently represent an integer of 0 to 8, m 4c and n 4c each independently represents an integer of 0 to 10 (provided that m 4c + n 4c is 10 or less), Each other symbol is as defined in [21]]
  • R 3 is the formula (4a) or (4b): [Where: R a4a and R a4b are each independently a hydrogen atom, a halogen atom, CN, OH, a C 1-6 alkyl group, a C 1-6 alkoxy group, CO 2 H or CO 2 -C 1-6 alkyl. , m 4a and m 4b are each independently an integer of 1 to 3, Other symbols are as defined in [21]] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [21] to [24],
  • R a4a and R a4b are each independently a hydrogen atom, OH, or a C 1-4 alkoxy group, and m 4a and m 4b are each independently an integer of 1 or 2, 25]
  • R 3 is the formula (4c): [Where: m 4c and n 4c each independently represent an integer of 0 to 6 (provided that m 4c + n 4c is 10 or less), Each other symbol is as defined in [21]]
  • R a4c is a hydrogen atom, a halogen atom, OH, a C 1-6 alkyl group, a C 1-6 alkoxy group, CO 2 H or CO 2 -C 1-6 alkyl
  • R d4c , R e4c , R f4c and R g4c are all hydrogen atoms
  • m 4c is an integer of 1 or 2
  • R a4c is a hydrogen atom
  • R b4c is (vi) CO 2 H
  • R 1 is represented by the following formula (2a), (2b) or (2g): [Wherein each symbol is as defined in [21]]
  • R 1 is represented by the following formula (2a): [Wherein R a2a is as defined in [21]] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [21] to [30],
  • R 2 represents the following formula (3c) or (3d): [Wherein each symbol is as defined in [21]] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [21] to [32],
  • R 2 is represented by the following formula (3c): [ Wherein R a3c is a hydrogen atom, and n 3c is an integer of 1 to 4]
  • R p1 may be substituted by C 1-4 alkyl (in which the group 1-3 halogen atoms, provided that when the base is a methyl group, 1 to 3 halogen atoms, a phenyl group or a 9- Which may be substituted with a fluorenyl group) or a C 1-4 alkenyl group
  • R p2 represents a hydrogen atom, a C 1-4 alkyl group (the group may be substituted with 1 to 3 halogen atoms, provided that when the group is a C 1-2 alkyl group, 1 to 3 A halogen atom, or a C 1-4 alkanoyloxy group) or a phenyl group
  • R 1 , R 2 , R 4 , R 5 and X are as defined in [4]].
  • a pharmaceutical composition comprising the bicyclic pyrimidine compound according to any one of [1] to [40] or [49] or a physiologically acceptable salt thereof.
  • An agent for preventing and / or treating MGAT-related diseases comprising as an active ingredient the bicyclic pyrimidine compound or physiologically acceptable salt thereof according to any one of [1] to [40] or [49]. .
  • Obesity, metabolic syndrome, hyperlipidemia comprising as an active ingredient the bicyclic pyrimidine compound according to any one of [1] to [40] or [49] or a physiologically acceptable salt thereof, A prophylactic and / or therapeutic agent for hypertriglyceridemia, hyperVLDL, hyperfattyemia, diabetes or arteriosclerosis.
  • R 1 is represented by the following formula (2a ′) or (2b ′): [Where: R a2a and R a2b are each independently a hydrogen atom, a halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group, n 2a and n 2b are 0], The following formula (2c ′): [Where: R a2c is a hydrogen atom or a fluorine atom (a plurality of such groups may be substituted at any position as long as it is chemically acceptable); p 2c is 0, n 2c is an integer from 1 to 4], or The following formula (2d ′): [Where: R a2d is a hydrogen atom, X 2d is an oxygen atom, p 2d is 1, m 2d is an integer of 2 to 3, n 2d is an integer from 0 to 1] A group represented by R 2 is represented by the following formula (3c): [ Wherein , R a3c is a hydrogen atom,
  • Bicyclic pyrimidine derivatives of the present invention and physiologically acceptable salts thereof have an MGAT inhibitory action, obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, high fatty acid It is useful as a prophylactic and / or therapeutic agent for blood glucose, diabetes and arteriosclerosis.
  • Alkyl group and “alkyl” moiety means, for example, a linear or branched alkyl group having 1 to 10 carbon atoms (also referred to herein as “C 1-10 ”). Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, octyl, nonyl, decyl and the like.
  • R 1 , R 2 , R 4 and R 5 have 1 to 6 carbon atoms (also referred to herein as “C 1-6 ”), and R 3 has 1 to 10 carbon atoms. (C 1-10 ). More preferably, it has 1 to 6 carbon atoms (C 1-6 ) in R 3 .
  • Preferable specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.
  • “Lower alkyl group” and “lower alkyl” moiety means a linear or branched alkyl group having 1 to 8 carbon atoms (also referred to as “C 1-8 ” in this specification), specifically Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, octyl and the like.
  • it has 1 to 6 carbon atoms (C 1-6 ) in R 1 , R 2 , R 4 and R 5 , and 1 to 8 carbon atoms (C 1-8 ) in R 3 . More preferably, it has 1 to 6 carbon atoms (C 1-6 ) in R 3 . More preferably, it is 1 to 4 carbon atoms in R 1 , R 2 , R 3 , R 4 and R 5 (also referred to as “C 1-4 ” in this specification).
  • Preferable specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.
  • alkenyl group and the “alkenyl” part include, for example, at least a carbon-carbon single bond of an “alkyl group” having 2 to 10 carbon atoms (also referred to herein as “C 2-10 ”). This means a carbon chain in which one place is replaced with a double bond.
  • alkyl group having 2 to 10 carbon atoms (also referred to herein as “C 2-10 ”).
  • C 2-10 carbon atoms
  • Specific examples include vinyl, allyl, 3-butenyl, isobutenyl, 3-pentenyl, 8-nonenyl, 1,4-heptadienyl, 2,4,7- Decatrienyl and the like can be mentioned.
  • R 1 , R 2 , R 4 and R 5 have 2 to 6 carbon atoms (also referred to herein as “C 2-6 ”), and R 3 has 3 to 10 carbon atoms. (Also referred to as “C 3-10 ” in this specification). Preferred examples include vinyl, isobutenyl, 1,4-heptadienyl, 8-nonenyl and the like.
  • the “lower alkenyl group” and the “lower alkenyl” moiety are carbon-carbon single bonds of the “lower alkyl group” having 2 to 8 carbon atoms (also referred to as “C 2-8 ” in this specification).
  • Means a carbon chain in which at least one site is replaced with a double bond and specific examples include vinyl, allyl, 3-butenyl, isobutenyl, 1,4-heptadienyl, and the like.
  • R 1 , R 2 , R 4 and R 5 have 2 to 6 carbon atoms (C 2-6 ), and R 3 has 2 to 8 carbon atoms (C 2-8 ). More preferably, it has 3 to 6 carbon atoms (also referred to as “C 3-6 ” in this specification) in R 3 .
  • Preferable specific examples include vinyl, isobutenyl, 1,4-heptadienyl and the like.
  • Alkynyl group and “alkynyl” part is a carbon chain in which at least one of carbon-carbon single bonds of an “alkyl group” having 2 to 10 carbon atoms (C 2-10 ) is replaced with a triple bond
  • Specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl, 4-heptynyl, 3-hexynyl, 2,4-octadiynyl and the like.
  • Preferable specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl and the like.
  • the “lower alkynyl group” and “lower alkynyl” moiety is a carbon-carbon single bond of a “lower alkyl group” having 2 to 8 carbon atoms (C 2-8 ), wherein at least one site is replaced with a triple bond.
  • Specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl, 4-heptynyl and the like.
  • R 1, R 2, R 4 and 6 from the two carbon atoms at R within 5 (C 2-6), it is in the R 3 is eight from 2 carbon atoms (C 2-8). More preferably, it has 3 to 6 carbon atoms (C 3-6 ) in R 3 .
  • Preferable specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl and the like.
  • the “lower cycloalkyl group” and the “lower cycloalkyl” part mean a cyclic alkyl group having 3 to 8 carbon atoms (also referred to herein as “C 3-8 ”). , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, it has 5 to 7 carbon atoms (also referred to as “C 5-7 ” in this specification). Preferably, it has 3 to 6 carbon atoms (C 3-6 ) in R 2 , more preferably 5 or 6 carbon atoms (also referred to as “C 5-6 ” in this specification). is there. Preferred specific examples include cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • the “lower cycloalkenyl group” and the “lower cycloalkenyl” moiety are defined by attaching one or two of the carbon-carbon single bonds of the “lower cycloalkyl group” having 3 to 8 carbon atoms (C 3-8 ). This means a carbon chain replaced with a double bond, and specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. Preferably, it has 5 or 6 carbon atoms (C 5-6 ). Preferable specific examples include cyclopentenyl, cyclohexenyl and the like.
  • the “lower alkoxy group” and the “lower alkoxy” part mean a straight or branched alkoxy group having 1 to 8 carbon atoms (C 1-8 ). Specific examples thereof include methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Preferably, it has 1 to 6 carbon atoms (C 1-6 ) in R 1 , R 2 , R 4 and R 5 , and 1 to 8 carbon atoms (C 1-8 ) in R 3 . More preferably, it has 1 to 6 carbon atoms (C 1-6 ) in R 3 . More preferably, it has 1 to 4 carbon atoms (C 1-4 ) in R 1 , R 2 , R 3 , R 4 and R 5 .
  • the “lower alkylthio group” means a group in which one sulfur atom is bonded to the bonding site of a linear or branched alkyl group having 1 to 8 carbon atoms (C 1-8 ).
  • methylthio examples include ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.
  • it has 1 to 6 carbon atoms (C 1-6 ) in R 1 , R 2 , R 4 and R 5 , and 1 to 8 carbon atoms (C 1-8 ) in R 3 .
  • R 3 More preferably, it has 1 to 6 carbon atoms (C 1-6 ) in R 3 . More preferably, it has 1 to 4 carbon atoms (C 1-4 ) in R 1 , R 2 , R 3 , R 4 and R 5 . .
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • R 1, R 2 and R 3 preferably a fluorine atom and a chlorine atom, more preferably a fluorine atom.
  • the “cyclic amino group” and the “cyclic amino” moiety contain at least one nitrogen atom and optionally contain a 4- to 7-membered cyclic amino group which may contain an oxygen atom or a sulfur atom, or at least 1 nitrogen atom.
  • the thing of a 5-membered ring or a 6-membered ring is mentioned.
  • lower alkanoyl group and “lower alkanoyl” moiety means a straight or branched alkanoyl group having 1 to 8 carbon atoms (C 1-8 ). Specific examples thereof include formyl, acetyl, propionyl, Examples include butyryl, isobutyryl, valeryl, pivaloyl and the like. Preferably, one having 1 to 6 carbon atoms (C 1-6 ) is used. More preferably, it has 1 to 4 carbon atoms (C 1-4 ).
  • aryl group and the “aryl” moiety are also referred to as “C 6-14 aryl” in the present specification as a 6- to 14-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbon.
  • aryl Preferably 6- to 10-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbons (also referred to herein as “C 6-10 aryl”) .
  • Specific examples include phenyl, naphthyl, phenanthryl, anthryl and the like. Preferred are phenyl, 1-naphthyl, 2-naphthyl and the like, and more preferred is phenyl.
  • the “benzene ring” represented as a preferred embodiment of Arm in the formulas (4g) and (4h) is an alkylene which may be mediated by oxygen as described in the formula Benzene substituted at any substitutable position by one or two side chains.
  • Arm represents phenylene
  • the bonding positions of the two side chains are the ortho (o) position (1, 2 position), the meta (m) position (1 , 3 position) or para (p) position (1, 4 position), preferably meta position (1, 3 position) or para position (1, 4 position), more preferably para position. (1st, 4th).
  • Heteroaryl and “heteroaryl” moieties are 4- to 10-membered monocyclic or bicyclic aromatics containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Means a heterocyclic group. Specific examples include, for example, pyrrolyl, furanyl (furyl), thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, indolyl, azaindolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, Examples thereof include isoquinolyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, indazolyl
  • it is a 5-membered or 6-membered monocyclic aromatic heterocyclic group.
  • Preferable specific examples include pyrrolyl, furanyl (furyl), thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and the like. More preferred specific examples include pyridyl, furanyl (furyl), thienyl and the like.
  • R 1 is pyrrolyl, furanyl (furyl), thienyl and pyridyl. More preferably, R 1 is furanyl (furyl) and pyridyl.
  • heteromatic ring represented as an embodiment of Arm in the formulas (4g) and (4h) is an alkylene which may be mediated by oxygen as described in the formula in addition to the substituent R a4g or R a4h.
  • Unsaturated heterocycle substituted at any substitutable position by one or two side chains and containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Means a 5- to 10-membered monocyclic or bicyclic aromatic heterocycle.
  • pyrrole furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, isothiazole, pyrazole, indole, azaindole, imidazole, isoxazole, triazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, Examples thereof include quinoline, isoquinoline, benzothiazoline, thiazolopyridine, thiazolopyrazine, thiazolopyrimidine, indazoline, benzodiazine, benzofuran, benzothiophene, benzimidazole, and benzoxazole.
  • it is a 5-membered or 6-membered monocyclic aromatic heterocycle.
  • Preferable specific examples include pyrrole, furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyridazine, pyrazine and the like. More preferably, it is a 5-membered or 6-membered monocyclic aromatic heterocycle containing only 1 or 2 nitrogen atoms as a hetero atom.
  • More preferable specific examples include pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyridazine, pyrazine and the like, more preferably a pyrazole ring and a pyridine ring, and most preferably a pyridine ring.
  • the bonding positions of these side chains May be any arrangement that can be combined.
  • Arm is a “pyridine ring”
  • Arm is a pyridine ring substituted at any position on the carbon atom that can be substituted by the side chain described in the formula, and as described in formula (4h)
  • the bonding positions of the two side chains are other than the nitrogen atom, and are any two positions selected from the 2nd to 6th positions of the pyridine ring, Preferred are 2,4, 3,5, 4,6, 2,5 or 3,6, more preferably 2,5 or 3,6.
  • Heterocyclic group and “heterocyclic” moiety are 3- to 12-membered monocyclic, bicyclic or tricyclic containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. It means a cyclic saturated or unsaturated heterocyclic group.
  • pyrrolyl furanyl (furyl), thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, indolyl, azaindolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, Isoquinolyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, indazolyl, benzodiazinyl, benzofuranyl, benzodioxalyl, benzothienyl, benzimidazolyl, benzoxazolyl, oxetanyl, azetidinyl,
  • the “optionally substituted lower alkyl group” or “optionally substituted alkyl group” includes a halogen atom, a lower cycloalkyl group, and a phenyl group (the phenyl group is a halogen atom; CF 3 ; a lower alkoxy group; Substituted with 1 to 3 substituents selected from a carboxyl group; a lower alkoxycarbonyl group; a cyano group; a hydroxyl group; and an alkyl group optionally substituted with either a halogen atom, a carboxyl group or a lower alkoxycarbonyl group May be substituted), phenyloxy group, lower alkoxy group (the lower alkoxy group may be substituted with a lower alkoxycarbonyl group), trifluoromethoxy group, lower alkylthio group, hydroxyl group, nitro group, cyano group, Carboxyl group, lower alkoxycarbonyl group, benzyloxycarbon
  • Lower alkyl group or alkyl group which may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, chloromethyl, methoxymethyl, 2-methoxyethyl, 2-methoxy Propyl, cyclopropylmethyl, benzyldiphenylmethyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, hydroxymethyl, methoxycarbonylmethyl, hydroxycarbonylmethyl, carbamoylmethyl, 2-chloroethyl, 2-bromoethyl, 2,2- Dichloroethyl, 2,2,2 Trifluoroethyl, 2-aminoethyl, 3-chloropropyl, 3-nitropropyl, 3-cyanopropyl, 3- (methylamino) propyl, 3- (dimethylamino) propyl, 3- (1
  • R 3 is an “optionally substituted alkyl group”
  • the substituent in R 3 includes a phenyl group, a phenyloxy group, a phenyl lower alkoxy group, a heteroaryl group, a heteroaryloxy group, or a heteroaryl.
  • the lower alkoxy group are, for example, 5 to 10 members, preferably 5 or 6 members, more preferably pyridyl or pyrazolyl, and more preferably pyridyl.
  • Each substituent in R 3 is independently at any position on the aromatic ring (ie, phenyl or heteroaryl), as long as it is chemically acceptable, 3, CN, OH, carboxyl group, lower alkoxycarbonyl group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, lower The lower alkyl group, lower alkoxy group, lower alkenyl group, lower cycloalkyl group and lower alkoxyalkyl group may be further substituted with one or two substituents selected from a cycloalkyl group and a lower alkoxyalkyl group; Carboxyl group, aminocarbonyl group, mono- or di-substituted lower alkylaminocarbonyl group, lower alkoxycarbonyl group, C 1-4 alkoxy-C 2-4 alkoxycarbonyl group or hydroxy- It may be substituted with a C 2-4 alkoxycarbonyl group or the like.
  • the “optionally substituted lower alkenyl group” or “optionally substituted alkenyl group” is a halogen atom, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethoxy group, lower alkylthio group.
  • the “optionally substituted lower cycloalkyl group” is a halogen atom, lower alkyl group, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethyl group, trifluoromethoxy group, lower alkylthio group.
  • a lower cycloalkyl group such as 3,3-difluorocyclobutyl, 2- or 3-methylcyclopentyl, 2- or 3-fluorocyclohexyl, 2-, 3- or 4-methylcyclohexyl, 2 -, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 2- or 3-methoxycyclohexyl and the like.
  • the “optionally substituted lower cycloalkenyl group” is a halogen atom, a lower alkyl group, a lower cycloalkyl group, a phenyl group, a phenyloxy group, a lower alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group.
  • a lower cycloalkenyl group which may be, for example, 2-methylcyclohexen-2-yl, 3-methylcyclohexen-2-yl, 4-methylcyclohexen-2-yl, 4-methylcyclohexen-3-yl, 4, 4-dimethylcyclohexen-2-yl and the like can be mentioned.
  • the “optionally substituted lower alkynyl group” or “optionally substituted alkynyl group” is a halogen atom, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethoxy group, lower alkylthio group.
  • the “optionally substituted lower alkanoyl group” includes halogen atom, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethoxy group, lower alkylthio group, hydroxyl group, nitro group, cyano group, carboxyl Group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino group, lower alkylsulfonylamino Group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or di-substituted lower alkylaminocarbonylamino
  • the "optionally substituted phenyl group” and the “optionally substituted phenyl” moiety are a halogen atom, an alkyl group (the alkyl group may be substituted with a lower alkoxycarbonyl group), a phenyl group, a phenyl group Oxy group, lower alkoxy group (the alkoxy group may be substituted with lower alkoxy group or lower alkoxycarbonyl group), trifluoromethyl group, trifluoromethoxy group, lower alkylthio group, hydroxyl group, hydroxy lower alkyl group, nitro Group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino Group, lower al Rusulfonyla
  • the “optionally substituted naphthyl group” is a halogen atom, a lower alkyl group, a phenyl group, a phenyloxy group, a lower alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group, a hydroxyl group, a hydroxy lower alkyl group.
  • the “saturated or unsaturated heterocyclic group which may be substituted” means a halogen atom, an alkyl group (the alkyl group may be substituted with a lower alkoxycarbonyl group), a phenyl group, a phenyloxy group, a lower group.
  • an alkoxy group (the alkoxy group may be substituted with a lower alkoxy group or a lower alkoxycarbonyl group), a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group, a hydroxyl group, a hydroxy lower alkyl group, a nitro group, a cyano group; , Carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino group, lower alkyl Sulfonylami Group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono or disub
  • the “mono- or di-substituted lower alkylamino group” and the “mono- or di-substituted lower alkylamino” moiety mean a group in which one or two lower alkyl groups are substituted on the amino group, for example, methylamino, dimethylamino, Examples include ethylamino, diethylamino, isopropylamino and the like.
  • each substituent is, for example, Y, R 4 , R 5 , R a2a , R a2b , R a2c , R a2d , R a2f , R a2g , R a3a , R a3b , R a3c , R a3d , R a4a , R a4b , R a4c , R a4d , R a4g and R a4h groups each May be combined at an arbitrary position as long as it is allowed.
  • the protection generally used for these groups It may be protected by introducing a group, and in that case, the target compound can be obtained by removing the protecting group as appropriate.
  • amino-protecting group examples include substituents that can be easily removed by reduction or hydrolysis, such as Protective Groups In ⁇ Organic Synthesis (Theodora W. Greene, Peter G. M). In addition to the protecting groups described by Wuts, John Wiley & Sons, Inc., 1999), it means a substituent that can be removed enzymatically or non-enzymatically in vivo.
  • amino-protecting group examples include methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, isobutoxycarbonyl group, allyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group , Vinyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, formyl group, acetyl group, propionyl group, benzoyl group, trifluoroacetyl group, p-toluenesulfonyl group, benzenesulfonyl group, methanesulfonyl group, benzyl group, 4 -Methoxybenzyl group, 2,4-dimethoxybenzyl group, diphenylmethyl group, triphenylmethyl group, pivaloyloxymethyl group, acetoxymethyl group, acetoxymethoxycarbonyl group, 1-acetoxycarbonyl group,
  • P 2 in the intermediate of the compound of the present invention represented by the formula (Ib) described in [41] is 1 to 3 phenyl groups (the phenyl group is substituted with 1 to 2 methoxy groups).
  • a methyl group substituted with a C 1-4 alkanoyloxy group, (C ⁇ O) OR p1 , or (C ⁇ O) R p2 R p1 may be substituted by C 1-4 alkyl (in which the group 1-3 halogen atoms, provided that when the base is a methyl group, 1 to 3 halogen atoms, a phenyl group or a 9- Which may be substituted with a fluorenyl group) or a C 1-4 alkenyl group
  • R p2 represents a hydrogen atom, a C 1-4 alkyl group (the group may be substituted with 1 to 3 halogen atoms, provided that when the group is a C 1-2 alkyl group, 1 to 3 A halogen
  • Examples thereof include a xycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a formyl group, an acetyl group, a trifluoroacetyl group, a benzyl group and a triphenylmethyl group, and more preferably a tert-butoxycarbonyl group, a benzyloxy group.
  • Examples thereof include a carbonyl group, a trifluoroacetyl group, a benzyl group, and the like, and most preferred is a tert-butoxycarbonyl group or a benzyloxycarbonyl group.
  • the method for producing the compound of the present invention is described below.
  • the compound of the present invention represented by the formula (Ia) can be produced, for example, by the following production methods A to G.
  • the compound represented by the formula (Ia) will be mainly described.
  • the compounds represented by the formula (I) are also obtained from the corresponding regioisomer raw materials. It can be similarly produced by the following production method.
  • a compound represented by the formula [A] wherein X is —N (R 6 ) — and Y is —CO— (hereinafter also referred to as “compound A”) Can be produced, for example, by the following production method. (Wherein R 1 to R 6 are as defined in [1] above, R is a lower alkyl group, and P 1 and P 2 are amino-protecting groups)
  • Step A-1 This step is a step of obtaining compound a2 by reacting compound a1 with ammonia in a suitable solvent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methanol or water. More specifically, this step is performed, for example, by the method described in Step (i) of Reference Example 1 described later or a method analogous thereto.
  • Step A-2 This step is a step of obtaining compound a3 by reacting compound a2 with compound a2 obtained in step A-1. This step is performed by the method described in Heterocycles, 55 (2001) 115-126 or step (ii) of Reference Example 1 described later, or a method analogous thereto.
  • Step A-3 This step is a step of obtaining compound a4 by reacting compound a3 obtained in step A-2 with methyl iodide in the presence of various bases in an appropriate solvent.
  • the base used in this step is selected from the bases exemplified below, but is preferably 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • the solvent used in this step is selected from the solvents exemplified below, and preferably N, N-dimethylformamide (DMF). More specifically, this step is performed, for example, by the method described in Step (iii) of Reference Example 1 described later or a method analogous thereto.
  • Step A-4 This step is a step of obtaining compound a5 by reacting compound a4 obtained in step A-3 with various oxidizing agents in an appropriate solvent.
  • the oxidizing agent used in this step is, for example, m-chloroperbenzoic acid, hydrogen peroxide, etc., preferably m-chloroperbenzoic acid.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride. More specifically, this step is performed, for example, by the method described in Step (iv) of Reference Example 1 described later or a method analogous thereto.
  • Step A-5 This step is a step of obtaining compound a6 by reacting compound a5 obtained in step A-4 with compound a11 in a suitable solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine and / or 4-dimethylaminopyridine (DMAP).
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably dioxane. More specifically, this step is performed, for example, by the method described in Step (v) of Reference Example 1 described later or a method analogous thereto.
  • Step A-6 This step is a protecting group P 1 of the amino group of the compound a6 obtained above Step A-5, is deprotected, to give compound compound a7.
  • This step is carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) or step (vi) of Reference Example 1 described later. be able to.
  • Step A-7 This step is a step of obtaining compound a8 by reacting compound a12 obtained in step A-6 with compound a12 in a suitable solvent in the presence of various condensing agents.
  • the condensing agent used in this step is selected from various materials exemplified in the following (step A-9 ′), and preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride). Included).
  • the solvent used in this step is selected from the solvents exemplified below. More specifically, this step is performed, for example, by the method described in Example 1 below or a method analogous thereto.
  • Step A-8 This step is a protecting group P 2 of the amino group of the compound a8 obtained in A-7 process, by deprotection, to give compound compound a9.
  • This step should be carried out according to the method described in Example 2 or Reference Example 3 below, and Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). Can do.
  • the substitution reaction (i) is carried out in an appropriate solvent in the presence of various bases as necessary, and the base and the solvent are selected from those exemplified below. More specifically, for example, It is carried out by the method described in Example 3 or a method analogous thereto.
  • the substitution reaction (i) can be used in the method for producing a compound represented by the formula (Id) in item [42].
  • Represents an alkyl group (the “heteroaryl group” and “heteroaryl” are preferably 5- to 10-membered, more preferably Or a 6-membered, more preferably a pyridyl or pyrazolyl
  • R 3 ′′ represents a hydrogen atom, a lower alkyl group or an optionally substituted phenyl group as described above, and is preferably a hydrogen atom or a lower alkyl group.
  • R 3 ′ —C ( ⁇ O) —R 3 ′′ a compound represented by the formula (VIb) of the item [43]
  • R 3p1 —C ( ⁇ O) —R 3p2 can be given. That is, the reductive amination reaction of (ii) can be used in the method for producing a compound represented by the formula (Ie) in item [43].
  • R 3p1 represents a group represented by any one of the formulas (4gp), (4hp), and (4ip) in the term [43], and preferably in the formula (4gp) or (4hp) Represents a group represented by formula (4hp), more preferably a group represented by formula (4hp).
  • m 4hp represents an integer of 0 to 4 (provided that when r 4h is 1, m 4hp represents an integer of 1 to 4), preferably an integer of 0 to 2 (provided that In this case, n 4h , p 4h and q 4h each independently represent an integer of 0 to 3, and m 4hp + n 4h + p 4h + q 4h is an integer of 0 to 9; r 4h is 1 M 4hp represents an integer of 1 or 2, more preferably an integer of 0 or 1 (provided that when r 4h is 1, m 4hp is 1); Arm, R a4h , R b4h , R d4h , R e4h , R f4h , R g4h , R h4h , R i4h , R j4h , R k4h , n 4h , p 4h , q 4h , r 4
  • m 4gp represents an integer of 0 to 5, preferably an integer of 0 to 2
  • Arm, R a4g , R d4g and R e4g are as defined in the above item [4].
  • Yes preferably as defined in paragraph [7].
  • R 3p2 is a hydrogen atom or a C 1-6 alkyl group as described in Item [43], preferably a hydrogen atom.
  • the reductive amination reaction (ii) is carried out in a suitable solvent using various boron-based reducing agents or formic acid, and the solvent is selected from those exemplified below. More specifically, for example, The method described in Example 19 or Reference Example 7 (r7-i) described later, or a method analogous thereto.
  • the reductive amination reaction may be carried out by (a) dehydrating with a Dean-Stark apparatus or a dehydrating agent in the presence of various acid or base catalysts, if necessary, or using them together to convert the carbonyl compound and the amine compound to an imine.
  • iminium is formed, and (b) this is reduced with a boron-based reducing agent or formic acid, and consists of two steps, (a) and (b) may be performed in the same system, and after (a) is performed If necessary, isolation, purification, solvent substitution, etc. may be carried out to carry out (b).
  • a boron reducing agent include sodium cyanoborohydride and sodium triacetoxyborohydride, sodium borohydride, 2-picoline-borane and the like.
  • the acid catalyst include organic acids such as acetic acid, and Lewis acids such as titanium (IV) tetrachloride. Base catalysts are selected from the bases exemplified below.
  • dehydrating agent examples include molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and the like.
  • the compound represented by formula (Ib) of item [41] can be synthesized in the same manner as the compounds b3, c3 or d3 described below in addition to a8.
  • R d4g , R e4g , R d4h , R e4h , R f4h , R g4h , R h4h , R i4h , R j4h , R k4h , R d4i , R e4i , R f4i and R g4i are as defined in the terms [3], [4], [7], [9], etc., and are preferably independent of each other.
  • R f4h and R g4h may form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are bonded, as described in item [9], and the cycloalkyl ring is preferably Is 3 to 5 members, more preferably 3 members (ie, cyclopropane ring).
  • r 4h and s 4h each independently represent 0 or 1 as described in the term [3] or [4], and preferably both are 0 or one is 1, and the other is 0 is represented.
  • r 4h and s 4h are preferably such that r 4h represents 0 and s 4h represents 0 or 1.
  • Step A-9 ' This step is an embodiment different from the above-described method for producing Compound A.
  • this step is a step of obtaining compound A by reacting compound a13 obtained in step A-6 with compound a13 in an appropriate solvent in the presence of various condensing agents.
  • the condensing agent used in this step is selected from various compounds exemplified below, but is preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride).
  • the solvent used in this step is selected from the solvents exemplified below.
  • this step is performed, for example, by the method described in Example 1 or Example 87 described later, or a method analogous thereto, as in step A-7 above. More specifically, this step is not limited to the method using the condensing agent, but a condensation reaction in which compound a13 or a salt thereof is activated and reacted with compound a7 or a salt thereof in the presence of a base as necessary. It is. Examples of the method for activating compound a13 or a salt thereof include a method for converting the carboxyl group into an acid halide, mixed acid anhydride, or the like, or a method using the above condensing agent.
  • compound a13 is added in an inert solvent, if necessary, in the presence or absence of an additive, such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc.
  • an additive such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc.
  • a halogenated reagent is reacted to obtain an acid halide.
  • the additive include N, N-dimethylformamide, N, N-diethylformamide and the like.
  • the inert solvent examples include halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, and esters such as ethyl acetate.
  • halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform
  • aromatic hydrocarbon solvents such as toluene and xylene
  • esters such as ethyl acetate.
  • the reaction solution is concentrated under reduced pressure in the presence of a hydrocarbon solvent such as benzene or toluene, and the resulting acid halide is added in an inert solvent, if necessary, in the presence of a base.
  • Compound A or a salt thereof can be obtained by reacting with compound a7 or a salt thereof.
  • the base and the solvent include those exemplified below.
  • compound a13 or a salt thereof is reacted with an acid halide in the presence of a base to form a mixed acid anhydride, and then reacted with compound a7 or a salt thereof to give compound A or a salt thereof.
  • a base for converting the acid halide to methoxycarbonyl chloride to methoxycarbonyl chloride to methoxycarbonyl chloride.
  • ethoxycarbonyl chloride isopropyloxycarbonyl chloride, isobutyloxycarbonyl chloride, paranitrophenoxycarbonyl chloride, t-butylcarbonyl chloride, and the like.
  • the base and the solvent include those exemplified below.
  • compound A13 or a salt thereof and compound a7 or a salt thereof can be reacted in an inert solvent, if necessary, in the presence of a base using various condensing agents to produce compound A or a salt thereof.
  • a phase transfer catalyst and other additives may be used. Examples of the condensing agent include those described in Experimental Chemistry Course (Edited by The Chemical Society of Japan, Maruzen) Vol.
  • phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide
  • carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HCl), dicyclohexylcarbodiimide (DCC), 2 , 2'-dipyridyldisulfide and other disulfides and triphenylphosphine and other phosphines, N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl) and other phosphorus halides, azo Combinations of azodicarboxylic acid diesters such as diethyl dicarboxylate and phosphines such as triphenylphosphine, 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 1,1'
  • Examples of the inert solvent and the base include those exemplified below.
  • Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide or benzyltriethylammonium bromide, or crown ethers such as 18-crown-6-ether, and are used when the base is an inorganic base.
  • Examples of other additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like, and the condensing agent is 1-ethyl-3- (3-dimethylaminopropyl). Used in the case of carbodiimides such as carbodiimide hydrochloride (WSC ⁇ HCl).
  • the condensation reaction (that is, the above-mentioned acid halide method, mixed acid anhydride method, and method using a condensing agent) of the present A-9 ′ step is the same as that of the compound represented by formula (If) in item [45]. It can be used in a manufacturing method.
  • Step A-10 In this step, compound A obtained in the above step A-9 (wherein R 1 , R 2 , R 3 , R 4 , R 5 or R 6 contains an ester group) is added as necessary.
  • Te, Q in is a process of converting a corresponding carboxylic acid compound a 1 (the reaction formula represents a portion other than the ester group in the compounds a, R a represents a chemical group in the ester group ).
  • This step can be performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). More specifically, this step is performed, for example, by the method described in Example 20 below or a method analogous thereto.
  • Manufacturing method B Of the compounds represented by the formula (Ia), a compound represented by the formula [B] wherein X is —S— and Y is —CO— (hereinafter also referred to as “compound B”) is, for example, It can manufacture by the manufacturing method of. (Wherein R 1 to R 5 are as defined in [1] above, Hal is a halogen atom, and P 1 and P 2 are amino-protecting groups)
  • Step B-1 This step is a step of obtaining compound b1 by reacting compound b5 obtained in step A-2 with compound b5 in the same manner as in step A-3.
  • Step B-2 This step is a step of obtaining compound b2 by treating compound b1 obtained in step B-1 in the same manner as in step A-6.
  • Step B-3 This step is a step of obtaining compound b3 by treating compound b2 obtained in step B-2 with the same method as in step A-7.
  • Step B-4 This step is a step of obtaining compound b4 by treating compound b3 obtained in step B-3 with a method similar to step A-8.
  • Step B-5 This step is represented by the formula [B] by treating the compound b4 obtained in the above step B-4 by the same method as the above step A-9 (and step A-10 if necessary). This is a step of obtaining a compound.
  • compound C a compound represented by the formula [C] wherein X is —C (R 7 ) (R 8 ) — and Y is —CO— (hereinafter referred to as “compound C For example, can be produced by the following production method. (Wherein, R 1 ⁇ R 5, R 7 and R 8 are as defined above [1], Hal is a halogen atom, P 1 and P 2 means a protecting group of amino group)
  • Step C-1 This step is a step of obtaining compound c1 by reacting compound c5 with compound a5 obtained in step A-4. More specifically, this step is performed by, for example, the method described in the step (xv) of Example 18 described later or a method analogous thereto.
  • Step C-2 This step is a step of obtaining compound c2 by treating compound c1 obtained in step C-1 in the same manner as in step A-6.
  • Step C-3 This step is a step of obtaining compound c3 by treating compound c2 obtained in step C-2 with the same method as in step A-7.
  • Step C-4 This step is a step of obtaining compound c4 by treating compound c3 obtained in step C-3 with a method similar to step A-8.
  • Step C-5 This step is represented by the formula [C] by treating the compound c4 obtained in the above step C-4 by the same method as the above step A-9 (and step A-10 if necessary). This is a step of obtaining a compound.
  • R 7 and R 8 are as defined in the item [1] or the item [4], and preferably, R 7 and R 8 each independently represent a hydrogen atom or a C 1-4 alkyl group. More preferably, at least one of R 7 and R 8 represents a hydrogen atom, and the other represents a hydrogen atom or a C 1-4 alkyl group.
  • Manufacturing method D Of the compounds represented by the formula (Ia), a compound represented by the formula [D] wherein X is —O— and Y is —CO— (hereinafter also referred to as “compound D”) is, for example, It can manufacture by the manufacturing method of. (Wherein R 1 to R 5 are as defined in [1] above, and P 1 and P 2 are amino-protecting groups)
  • Step D-1 This step is a step of obtaining compound d1 by reacting compound d5 obtained in step A-4 with compound d5 in the presence of various bases in a suitable solvent.
  • the base used in this step is selected from the bases exemplified below, and is preferably sodium hydride.
  • Step D-2 This step is a step of obtaining compound d2 by treating compound d1 obtained in step D-1 with the same method as in step A-6.
  • Step D-3 This step is a step of obtaining compound d3 by treating compound d2 obtained in step D-2 with the same method as in step A-7.
  • Step D-4 This step is a step of obtaining a compound d4 by treating the compound d3 obtained in the step D-3 with the same method as in the step A-8.
  • Step D-5 This step is represented by the formula [D] by treating the compound d4 obtained in the above step D-4 in the same manner as in the above step A-9 (and step A-10 if necessary).
  • This is a step of obtaining a compound.
  • the production method D below preparation H or preparation J, or can be produced using these according method, etc.
  • the compound X is represented by -O-, R 2 is Terms [1], [3], [4], as defined in [17] to [20] etc., preferably R 2 is as defined in term [20], more preferably In formula (3a) of item [20], R a3a represents a meta-position (3-position) substituted C 1-6 alkoxy group which may be substituted with a C 1-4 alkoxy group.
  • Step E-1 In this step, compound e2 is obtained by adding triphosgene to compound a7, b2, c2 or d2 obtained by production methods A to D in the presence of various bases and stirring, and then adding compound e4. More specifically, this step is performed, for example, by the method described in Example 84, or a method analogous thereto.
  • Step E-2 This step is a step of obtaining a compound e3 by treating the compound e2 obtained in the step E-1 with a method similar to the step A-8.
  • Step E-3 This step is represented by the formula [E] by treating the compound e3 obtained in the step E-2 with the same method as the step A-9 (and step A-10 if necessary). This is a step of obtaining a compound. More specifically, the pre-E-2 step and this step are performed, for example, by the method described in Example 85, or a method analogous thereto.
  • Step Ea-1 The above-mentioned [E In this step, compound e2a is obtained by the same method as in Step-1.
  • Step E-2] to [Step E-3] These steps are a step of obtaining a compound represented by the formula [Ea] by treating the compound e2a obtained in the step Ea-1 with a method similar to the steps E-2 and E-3. is there.
  • Compound E and Compound Ea are compounds in which Y is represented by Formula (II) and Formula (V) among the compounds represented by Formula (I) in Item [1].
  • R 9 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower cycloalkyl group, an optionally substituted phenyl group or a substituted group.
  • Z represents an oxygen atom or a sulfur atom, preferably an oxygen atom.
  • Step F-1 compound f2 is obtained by reacting compound a7, b2, c2 or d2 obtained by the above production methods A, B, C and D with compound f4 in the presence of various bases in an appropriate solvent. It is.
  • the solvent used in this step is selected from the solvents exemplified below. More specifically, this step is performed, for example, by the method described in the step (ex208-i) of Example 208 described later or a method analogous thereto.
  • Step F-2 This step is a protecting group P 2 of the amino group of the compound f2 obtained in the above F-1 step, by deprotection, to give compound compound f3.
  • Step F-3 In this step, compound f3 obtained in step F-2 is treated in the same manner as in step A-9 or step 208 (ex208-iii) in Example 208 (and step A-10 if necessary). This is a step of obtaining a compound represented by the formula [F].
  • the compounds B, C and D obtained by the production methods B, C and D can be produced, for example, by the following production method.
  • X represents an oxygen atom, a sulfur atom or —CR 7 R 8 —, and R 1 to R 5 , R 7 and R 8 are as defined in the above [1]
  • Step G-1 This step is a step of obtaining compound B, C or D by reacting compound b2, c2 or d2 obtained by the above production methods B, C and D with compound a13 in the same manner as in step A-9 ′ above. is there.
  • Manufacturing method H Compound a6, b1, or d1 that is an intermediate of production method A, B, or D can also be produced, for example, by the following production method.
  • X represents an oxygen atom, a sulfur atom or —N (R 6 ) —
  • R 1 , R 2 and R 6 are as defined in [1] above, and R represents a lower alkyl group.
  • P 1 means an amino-protecting group
  • Step H-1 This step is a step of obtaining compound h1 by reacting compound h2 obtained in step A-1 with compound h2 in the same manner as in step A-2. More specifically, this step is performed, for example, by the method described in Step (r4-i) of Reference Example 4 described later or a method analogous thereto.
  • Step H-2 This step is a step for obtaining compound a6, b1 or d1 by reacting compound a11, h3 or d5 with compound h1 obtained in step H-1. This step is performed by the method described in The Journal of Organic Chemistry, 72 (2007) 10194-10210 or step (r4-ii) of Reference Example 4 described later, or a method analogous thereto.
  • Manufacturing method I Compound c1, which is an intermediate of production method C, can also be produced, for example, by the following production method. (Wherein, R i and R ii represents a lower alkyl group, or, taken together with the N to which they are attached represent a cyclic amino group, R 1, R 2, R 7, and R 8 in the above [1] As defined, and P 1 means an amino protecting group)
  • Step I-1 This step is a step of obtaining compound i2 by reacting compound i1 with amine i7 in an appropriate solvent in the presence of an acid catalyst.
  • the acid catalyst used in this step is preferably tosylic acid.
  • the amine i7 used in this step is a secondary amine, preferably morpholine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably toluene.
  • Step I-2 This step is a step of obtaining compound i3 by reacting compound i2 obtained in the above step I-1 with isocyanate h2 in a suitable solvent. This step is performed by the method described in the document Tetrahedron, 45, 3189 (1989) or a method analogous thereto.
  • Step I-3 This step is a step of obtaining compound i4 by treating compound i3 obtained in step I-2 with an aqueous acid solution in a suitable solvent.
  • the acid aqueous solution is preferably hydrochloric acid.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably toluene. More specifically, the above steps I-1 to this step are performed, for example, by the method described in the step (r5-i) of Reference Example 5 described later or a method analogous thereto.
  • Step I-4 This step is a step of obtaining compound i5 by treating compound i4 obtained in step I-3 above in the same manner as in step A-1.
  • Step I-5 This step is a step of obtaining compound i6 by treating compound i5 obtained in the above step I-4 with various carboxylic acids i8 and phosphorus oxychloride in the presence of a base.
  • the base used in this step is selected from the bases exemplified below, and is preferably pyridine. More specifically, this step is performed, for example, by the method described in the step (r5-iii) of Reference Example 5 described later or a method analogous thereto.
  • Step I-6 This step is a step of obtaining compound c1 from compound i6 obtained in the above step I-5. More specifically, this step is performed by, for example, the method described in the document Tetrahedron, 61, 4297 (2005) or the step (r5-iv) of Reference Example 5 described later, or a method analogous thereto.
  • Manufacturing method J Compound d1, which is an intermediate of production method D, can also be produced, for example, by the following production method. (Wherein R 1 and R 2 are as defined in [1] above, and P 1 means an amino-protecting group)
  • Step J-1 This step is a step of obtaining compound d1 by reacting compound h1 obtained in step H-1 with an alkylating agent in the presence of various bases in a suitable solvent.
  • the alkylating agent used in this step (that is, also denoted as “R 2 -L”; L is a leaving group, and represents a halogen atom or OSO 2 R L described below) is an organic halogen compound (that is, R 2 -Hal; where Hal means a halogen atom, preferably a chlorine atom, bromine atom or iodine atom) or an organic sulfate compound (ie R 2 -OSO 2 R L ; L represents a C 1-4 alkyl group which may be substituted with a fluorine atom or a phenyl group which may be substituted with C 1-4 alkyl, and examples thereof include methyl, trifluoromethyl, 4-methylphenyl, and phenyl.
  • an alkyl iodide or the like Preferably an alkyl iodide or the like.
  • the base used in this step is selected from the bases exemplified below, and is preferably potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably N, N-dimethylformamide. More specifically, this step is performed by, for example, the method described in the step (r6-ii) of Reference Example 6 described later or a method analogous thereto.
  • Manufacturing method K Compound a13, which is an intermediate between production methods A and G, can be produced, for example, by the following production method.
  • R is a lower alkyl group or a benzyl group, and R 3 , R 4 , and R 5 are as defined in [1] above).
  • Step K-1 This step is a step of obtaining compound a13 from compound k1 by a reductive amination reaction using a compound having a formyl group or a ketone group and a reducing agent such as NaBH (OAc) 3 or NaBH 3 CN.
  • the reductive amination reaction is the same as (ii) in step A-9. More specifically, this step is performed, for example, by the method described in the step (r7-i) of Reference Example 7 described later or a method analogous thereto.
  • R 3 '' is a hydrogen atom, means a lower alkyl group or an optionally substituted phenyl group, R 3 'is' from R 3 as defined above [1] -C (R 3 '' ) H- ”part.
  • R 3 ′ is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower cycloalkyl group, or optionally substituted.
  • R 31 is a hydrogen atom, C 1-6 An alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkoxy-C 1-6 alkyl group, wherein the hydrogen atom, C 1-6 alkyl group, C 1-6 alkoxy group, and C 1-6 alkoxy-
  • the C 1-6 alkyl group may be further substituted with CO 2 R 32 , OCOR 33 or C ( ⁇ O) NR 34 R 35 ; each of R 32 , R 33 , R 34 and R 35 is independently , A hydrogen atom, or a lower alkyl group, and the lower alkyl group may be further substituted with one or more lower alkoxy groups or OH at any position as long as it is chemically acceptable.
  • R 3 ′ is a phenyl group, a phenyloxy lower alkyl group, a phenyl lower alkoxy lower alkyl group, a heteroaryl group (the “heteroaryl group” is preferably pyridyl or pyrazolyl, more preferably pyridyl
  • Each group of R 3 ′ is independently at any position on the aromatic ring (ie, phenyl or heteroaryl), as long as it is chemically acceptable, and a halogen atom, CF 3 CN, OH, carboxyl group, lower alkoxycarbonyl group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower cycloalkyl group and lower alkoxy lower alkyl group may be substituted with 1 to 2 substituents.
  • R 3 ′′ is preferably a hydrogen atom or a lower alkyl group.
  • the substitution reaction in this step is carried out in an appropriate solvent in the presence of various bases, and the base and the solvent are selected from those exemplified below, and more specifically, for example, as described in Example 3 below It is performed by a method or a method according to this.
  • the protection and deprotection of the carboxylic acid can be performed according to the method described in the Protective Groups in Organic Synthesis.
  • Compound a13 that can be produced by this production method K includes the compound represented by formula (VII) in item [44], and R 3 of compound a13 is represented by formula (4h) in item [4].
  • R b4h is as defined in [44], preferably CO 2 R 3g4 (where R 3g4 represents a C 1-4 alkyl group). .
  • Arm, R a4h , R d4h , R e4h , R f4h , R g4h , R h4h , R i4h , R j4h , R k4h , m 4h , n 4h , p 4h , q 4 h r 4h , s 4h , R 4 and R 5 are as defined in [4] above, preferably as defined in [8], [9], [12] or [39].
  • the compound represented by the formula [a13a] contained in the compound a13 which is an intermediate between the production methods A and G (hereinafter also referred to as “compound a13a”) can be produced, for example, by the following production method.
  • R b4h is an ester defined in [44] above
  • Arm, R a4h , R d4h , R f4h , R g4h , R 4 and R 5 are as defined in [4] above. )
  • This step is a step of obtaining compound k2a by reacting compound k1a with compound k1 in the same manner as in step K-1. More specifically, this step is performed, for example, by the method described in the step (r7-i) of Reference Example 7 described later or a method analogous thereto.
  • the compound k2a obtained in the above Ka-1 step is subjected to a reduction reaction of a double bond to a single bond, for example, a hydrogenation reaction in the presence of various metal catalysts (palladium carbon, platinum carbon, etc.), or hydride reduction.
  • compound a13a is obtained by a reduction reaction using an agent or the like.
  • this step is performed, for example, by the method described in the step (r7-ii) of Reference Example 7 described later or a method analogous thereto.
  • the compound a13a which can be manufactured with this manufacturing method Ka is contained in the compound represented by Formula (VII) of said [44] as one preferable aspect.
  • Step M-1 The compound represented by compound a10 of production method A can be produced, for example, by the following production method.
  • R 1 is as defined in [1] above
  • Step M-1 This step is a step of obtaining compound a10 by reacting compound m1 with thiophosgene in a suitable solvent.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably a two-layer system of methylene chloride and water. More specifically, this step is performed by, for example, the method described in Reference Example 8 described later or a method analogous thereto.
  • substitution reaction with azetidine nitrogen using the reaction agent R 3 -L described in the above production method A, production method K, etc. is also an aromatic halogen compound represented by the Buchwald-Hartwig reaction. Even if R 3 is substituted by using conditions for various general coupling reactions in which an aromatic sulfate ester compound and an amine are combined in the presence of a metal catalyst such as a palladium catalyst or a copper catalyst and an appropriate base, etc.
  • a metal catalyst such as a palladium catalyst or a copper catalyst and an appropriate base, etc.
  • compounds of the present invention that are good alkyl groups for example, compounds of the present invention in which R 3 is an optionally substituted aryl group, an optionally substituted heteroaryl group, and the like can be produced.
  • the compound used in each of the above production methods may form a salt, and examples of such a salt include the same salts as the salts of the compound of the present invention.
  • alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate
  • Alkali carbonates such as: metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali alkoxides such as sodium methoxide and sodium tert-butoxide
  • Organometallic bases such as butyllithium and lithium diisopropylamide; triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU)
  • DMAP 1,8-diazabicyclo [5.4.0] -7-undecene
  • the solvent used in each of the above production methods should be appropriately selected depending on the reaction, the type of raw material compound, etc., for example, alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ketone; Halogenated hydrocarbons such as methylene and chloroform; Ethers such as tetrahydrofuran (THF) and dioxane; Aromatic hydrocarbons such as toluene and benzene; Aliphatic hydrocarbons such as hexane and heptane; Ethyl acetate Esters such as propyl acetate; Amides such as N, N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitriles such as acetonitrile Yes; these solvents may be used alone or in combination of two or more. Depending on the type of reaction, organic bases may be used as a solvent.
  • the reaction temperature in each of the above production methods should be appropriately selected according to the reaction, the raw material compound or the type of solvent used, and is usually -100 ° C to 200 ° C, preferably -70 ° C to 100 ° C. It is.
  • the reaction time in each of the above production methods should be selected in a timely manner depending on the reaction, the raw material compound or the type of solvent used, and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours. .
  • the functional group in the molecule is obtained by a known method such as ComprehensivehenOrganic Transformations (Richard C. Larock, John Wiley & Sons, Inc., 1999). ) Can be converted into the desired functional group.
  • a known method such as ComprehensivehenOrganic Transformations (Richard C. Larock, John Wiley & Sons, Inc., 1999).
  • another compound of the present invention having various esters, amides, carbamates and the like, useful as an MGAT2 inhibitor, using the compound having a carboxylic acid, alcohol or primary or secondary amine as an intermediate in the present invention can be converted to
  • the product obtained in each of the above production methods can be isolated and purified according to conventional methods such as extraction, column chromatography, recrystallization, reprecipitation and the like.
  • “Physiologically acceptable salt” means a physiologically acceptable acid addition salt, alkali metal salt, alkaline earth metal salt or salt with an organic base.
  • the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and oxalate, maleate, and fumarate.
  • organic acid salts such as malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, and gluconate.
  • Examples of the alkali metal salt include inorganic alkali salts such as sodium salt and potassium salt.
  • the alkaline earth metal salt include calcium salt and magnesium salt.
  • the salt as the organic base include And salts with ammonia, methylamine, triethylamine, N-methylmorpholine.
  • the compound of this invention can be made into an acid addition salt as one preferable aspect,
  • the acid used includes hydrochloric acid, phosphoric acid, fumaric acid, and the like.
  • “Chemically stable salt” means an acid addition salt, alkali metal salt, alkaline earth metal salt, or salt with an organic base having storage stability to the extent acceptable as an intermediate of a chemical reaction.
  • examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, trifluoroacetate, and oxalate.
  • Organic acid salts such as salts can be mentioned.
  • alkali metal salts include inorganic alkali salts such as sodium salts and potassium salts.
  • alkaline earth metal salts include calcium salts and magnesium salts.
  • salts as organic bases include Examples include, but are not limited to, salts with ammonia, methylamine, triethylamine, and N-methylmorpholine.
  • the compound represented by the formula (I) may have one or more asymmetric carbon atoms, and may cause geometric isomerism and axial chirality, and thus may exist as several stereoisomers. . These stereoisomers, mixtures thereof and racemates are also included in the compounds of the present invention. Furthermore, the present invention includes all tautomers of the compounds of the present invention.
  • the present invention also includes a prodrug of the compound represented by formula (I) or a physiologically acceptable salt thereof.
  • the present invention also includes these hydrates and / or solvates.
  • the term “prodrug of the compound represented by formula (I)” is a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, for example, A compound that is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted to a compound of formula (I); a compound that is hydrolyzed by gastric acid or the like to be converted to a compound of formula (I).
  • the compounds of the present invention include ante-drugs.
  • the term “ante-drug” refers to the expression of a desired action, followed by a reaction with an enzyme or the like (eg, enzymatic oxidation, reduction, hydrolysis, etc.) under physiological conditions in the living body. It means a compound that is quickly converted to a compound with relatively low burden (such as undesirable side effects).
  • Specific examples include compounds such as esters, amides, carbamates and the like that can be easily hydrolyzed by reactions with enzymes in the living body among the compounds of the present invention, with esters being preferred.
  • a deuterium converter obtained by converting any one or two or more 1 H of the compounds of the present invention into 2 H (D) is also included in the compounds of the present invention.
  • deuterated reducing agents eg, sodium deuteride borohydride
  • the compounds of the present invention can be obtained in the form of salts, free acids or free bases depending on the reaction conditions. These compounds can be converted into the desired salts, free acids or free bases by conventional methods.
  • the compound of the present invention or a physiologically acceptable salt thereof may be a crystal, and these can be obtained by a known crystallization method or the like.
  • the compound of the present invention or a physiologically acceptable salt thereof can take a plurality of crystal forms, all forms of the crystal form are also included in the compound of the present invention.
  • an optical isomer, a stereoisomer, a rotational isomer and / or a positional isomer when an optical isomer, a stereoisomer, a rotational isomer and / or a positional isomer can exist, these are also included in the compound of the present invention. These can be obtained by a known method such as a synthesis from an optically active raw material compound or a separation method such as an optical resolution method or a preferential crystallization method.
  • MGAT-related disease means a disease caused by excessive triglyceride accumulation in the body due to excessive intake of triglyceride or abnormal metabolism of triglyceride, such as obesity, metabolic syndrome, high Lipemia, hypertriglyceridemia, hyperVLDL (where "VLDL” stands for very low-density lipoprotein), hyperfattyemia, diabetes, arteriosclerosis Etc.
  • the compounds of the present invention and physiologically acceptable salts thereof are obesity, metabolic syndrome, hyperlipidemia, hypertriglyceremia, hyperVLDL, hyperfattyemia, diabetes, arteriosclerosis. It is useful as a prophylactic and / or therapeutic agent.
  • any of oral administration, parenteral administration and rectal administration may be used, but oral administration is preferred.
  • the dose varies depending on the administration method, patient symptom / age, treatment mode (prevention or treatment), etc., but is usually 10 ng / kg / day to 10 mg / kg / day, preferably 0.1 ⁇ g / kg / day to 1 mg. / Kg / day, more preferably 1 ⁇ g / kg / day to 100 ⁇ g / kg / day is administered once a day or divided into 2 to 3 times a day. It can also be administered once every few days to several weeks.
  • 1 ⁇ g / day to 1 g / day preferably 10 ⁇ g / day to 100 mg / day, more preferably 100 ⁇ g / day to 10 mg / day per adult is administered once or twice or three times a day. To do. It can also be administered once every few days to several weeks.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier.
  • a pharmaceutical carrier a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose , Gelatin, gum arabic, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, lauryl Sodium sulfate, glycerin, fatty acid glycerin ester,
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, it is prepared by dissolving the compound represented by formula (I) or a physiologically acceptable salt thereof in water, but an isotonic agent may be dissolved if necessary. In addition, pH adjusting agents, buffers and preservatives may be added.
  • compositions can contain the compound of the present invention or a physiologically acceptable salt thereof in an amount of 0.01% by weight or more, preferably 0.05 to 70% by weight. These formulations may also contain other therapeutically effective ingredients.
  • the compounds of the present invention are drugs such as anti-obesity agents, anti-diabetic agents, anti-diabetic complication agents, anti-hyperlipidemic agents, antihypertensive agents, diuretics, anti-ventilants, etc. , Abbreviated as “concomitant drug”).
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of the compound of this invention and a concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the administration subject is a human
  • 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • anti-obesity agents examples include dexfenfluramine, fenfluramine, phentermine, topiramate, bupropion, sibutramine, lorcaserine, amphetapramone, dexamphetamine, mazindol, tesofensin, phenylpropanolamine, Clobenzolex, zonisamide, MCH receptor antagonist (eg, BMS-830216, etc.), neuropeptide Y5 receptor antagonist (eg, S-2367, etc.), neuropeptide Y2 receptor agonist (eg, AC-162352, etc.) ), Opioid ⁇ receptor antagonists (eg, naltrexone, etc.), opioid ⁇ receptor inverse agonists (eg, GSK-15151498, etc.), histamine H3 receptor antagonists (eg, HPP-404, etc.), etc.
  • MCH receptor antagonist eg, BMS-830216, etc.
  • neuropeptide Y5 receptor antagonist eg
  • Peptide appetite suppressants eg, , Leptin, etc.
  • GLP-1 analogues eg, liraglutide, etc.
  • cannabinoid receptor antagonists eg, TM38883, etc.
  • agouti related protein (AgRP) inhibitors eg, TTP-435, etc.
  • pancreatic lipase inhibitors eg, Eg, orlistat, cetiristat, etc.
  • glucokinase activator eg, AZD-5658, etc.
  • microsomal triglyceride transfer protein (MTP) inhibitor eg, JNJ-16269110, etc.
  • acylcoenzyme A: diacylglycerol acyltran Ferrase (DGAT) inhibitors eg, AZD-5658, etc.
  • sodium-dependent glucose transporter (SGLT) 2 inhibitors eg, canagliflozin, etc.
  • ⁇ 3 agonists eg
  • Antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas, human insulin preparations genetically engineered using E. coli / yeast, insulin zinc, protamine insulin zinc, insulin fragments or Derivatives, oral insulin preparations), insulin sensitizers (eg, pioglitazone or its hydrochloride, rosiglitazone or its maleate, alleglitazar, ZYH1, robeglitazone, valaglitazone, THR-0921, GFT-505, indeglita Saar, siglitazar, MBX-2044, MBX-102, INT-131, DSP-8658, etc.), ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides Eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclam
  • aldose reductase inhibitors eg, epalrestat, lanirestat, etc.
  • neurotrophic factors eg, NGF, TAK-428, etc.
  • PKC inhibitors eg, ruboxistaurine mesylate, etc.
  • AGE inhibitors eg, pyridoxamine, etc.
  • active oxygen scavengers eg, thioctic acid, etc.
  • cerebral vasodilators eg, thioprid, mexiletine, etc.
  • angiogenesis inhibitors eg, defibrotide, ranibizumab, etc.
  • Nrf2 activator eg, RTA-402, etc.
  • endothelin antagonist eg, atrasentan, etc.
  • phosphodiesterase inhibitor eg, PF-489791, etc.
  • CCR2 receptor antagonist eg, CCX-140, etc.
  • T-type calcium channel antagonists eg, ABT-639,
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin or salts thereof (eg, sodium salt, calcium salt)), fibrates Compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), anion exchange resins (eg, cholestyramine, etc.), cholesterol absorption inhibitors (eg, ezetimibe, etc.), probucol, nicotinic acid drugs (eg, niacin) And icosapentate, etc.), CETP inhibitors (eg, anacetrapib, darcetrapib, etc.), ACAT inhibitors (eg, K604 etc.), and the like.
  • HMG-CoA reductase inhibitors eg, pravastatin,
  • Antihypertensive agents include angiotensin-converting enzyme inhibitors (eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (eg, olmesartan medoxomilrexilmil, candesalcimilrexilmil) Azilsartan medoxomil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonist (eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.), renin inhibitor (eg, aliskiren
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.
  • thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide, Methiclotiazide, etc.
  • anti-aldosterone preparations eg, eplerenone, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetazolamide, etc.
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide, etc.
  • azosemide examples include isosorbide, ethacrynic acid, piretanide, bumetanide
  • anti-ventilating agent examples include allopurinol, probenecid, colchicine, benzbromarone, febuxostat, citrate and the like.
  • Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. Therefore, side effects that may be caused by these drugs can be safely prevented.
  • Example 1 tert-butyl 3- ⁇ [2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Il] carbonyl ⁇ azetidine-1-carboxylate
  • N-dimethylformamide 5 mL
  • 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid 201 mg
  • triethylamine 0.16 mL
  • 1-hydroxybenzotriazole 405 mg
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (619 mg) were added.
  • Example Compound 1 (335 mg).
  • Example 2 6- (azetidin-3-ylcarbonyl) -2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H) -ON Production of hydrochloride To a solution of Example Compound 1 (270 mg) in 1,4-dioxane (4 mL) was added 4 mol / L dioxane hydrochloride solution (4 mL). The reaction mixture was stirred at 25 ° C. for 1 hr and concentrated under reduced pressure to give Example Compound 2 (330 mg).
  • Example 3 6-[(1-Benzylazetidin-3-yl) carbonyl] -2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] Production of pyrimidine-4 (3H) -one
  • N N-dimethylformamide
  • benzyl bromide 0.065 mL
  • diisopropylethylamine (0.33 mL).
  • the reaction mixture was stirred at 25 ° C. for 16 hours, water was added, and the mixture was extracted with ethyl acetate.
  • Example Compound 3 (98 mg).
  • Examples 4 to 16 The compounds of Examples 4 to 16 were synthesized according to the method of Example 3 and Example Compound 2 synthesized in Example 2.
  • Example 17 6-[(1-Benzylazetidin-3-yl) carbonyl] -2- (cyclohexylsulfanyl) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] Production of pyrimidine-4 (3H) -one Steps (xi) to (xiv) were synthesized according to steps (vi) to (ix) of Reference Example 1 and Examples 1 to 3, and the compound of Example 17 was obtained.
  • Example 18 6-[(1-Benzylazetidin-3-yl) carbonyl] -2-pentyl-3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H) -ON production Process (xv): A solution of compound V (780 mg) in tetrahydrofuran (10 mL) was cooled to ⁇ 78 ° C. under a nitrogen atmosphere, and 2 mol / L pentylmagnesium bromide in diethyl ether (1.0 mL) was added dropwise. The reaction mixture was stirred at ⁇ 78 ° C.
  • Steps (xvi) to (xix) were synthesized according to steps (vi) to (ix) of Reference Example 1 and Examples 1 to 3, and the compound of Example 18 was obtained.
  • Example 19 Methyl (2E) -3- ⁇ 4-[(3- ⁇ [2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3 -D] Preparation of Pyrimidin-6 (4H) -yl] carbonyl ⁇ azetidin-1-yl) methyl] phenyl ⁇ prop-2-enoate Add (E) -methyl 3- (4-formylphenyl) acrylate (47 mg) and diisopropylethylamine (0.050 mL) to a solution of compound XVI (135 mg) in dichloromethane (2 mL), and add nitrogen at 25 ° C for 30 minutes.
  • Example 20 (2E) -3- ⁇ 4-[(3- ⁇ [2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3- d] Preparation of pyrimidin-6 (4H) -yl] carbonyl ⁇ azetidin-1-yl) methyl] phenyl ⁇ prop-2-enoic acid To a solution of Example Compound 19 (20 mg) in methanol (3 mL) was added 1 mol / L aqueous sodium hydroxide solution (1 mL). The reaction mixture was stirred at 50 ° C.
  • Example Compound 20 (12 mg).
  • 1 H-NMR (400 MHz, DMSO-d 6 ): ⁇ (ppm) 7.65-7.52 (m, 6H), 7.34-7.27 (m, 4H), 6.52-6.47 (m, 1H), 4.26-3.24 (m , 10H), 2.68-2.59 (m, 2H), 1.97-1.90 (m, 2H), 1.60-1.15 (m, 10H).
  • Examples 21-75 The compounds of Examples 21 to 75 were synthesized according to the method of Example 3, Example 17, Example 19 or Example 20.
  • Example 84 tert-butyl 3-( ⁇ [2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl ⁇ amino) azetidine-1-carboxylate
  • Tetrahydrofuran 8 mL was added to Compound VII (150 mg), and the mixture was stirred under ice-water cooling. Furthermore, diisopropylethylamine (312 mg) and triphosgene (41 mg) were added and stirred for 30 minutes.
  • Example Compound 84 (90 mg).
  • Example 85 2- (cyclohexylamino) -N- [1- (4-fluorobenzyl) azetidin-3-yl] -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidine-6 (4H) -carboxamide
  • Toluene (3 mL) was added to Example Compound 84 (100 mg), and the mixture was stirred under ice-water cooling. Furthermore, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether (5 mL) was added to the resulting residue, and the precipitated solid was filtered.
  • N, N-dimethylformamide (5 mL) and potassium carbonate (87 mg) were added to the obtained solid, and the mixture was stirred at room temperature.
  • a solution of 4-fluorobenzyl bromide (appropriate amount) in N, N-dimethylformamide (1 mL) was added dropwise and stirred for 4 hours.
  • the reaction mixture was quenched by adding water and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 86 6-[(1-Benzylazetidin-2-yl) carbonyl] -2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] Production of pyrimidine-4 (3H) -one
  • 1-Benzylazetidine-2-carboxylic acid 34 mg
  • diisopropylethylamine 58 mg
  • 1-hydroxybenzotriazole 34 mg
  • compound VII 54 mg
  • N, N-dimethylformamide 3 mL
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 43 mg was added.
  • Step (r6-iii): Compound XXIX (105 mg) was dissolved in ethanol (2.5 mL), and 10% Pd / C (50% water-containing product) (40 mg) was added. The reaction vessel was purged with hydrogen and stirred at room temperature and normal pressure for 8 hours. After Pd / C was filtered off, the filtrate was concentrated under reduced pressure to obtain Compound XXXI (70 mg). Compound XXX was used in the next reaction without purification. LC / MS: m / z 312 (MH + )
  • Example 87 Ethyl 3- ⁇ 4-[(3- ⁇ [2- (cyclopentyloxy) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine Preparation of -6 (4H) -yl] carbonyl ⁇ azetidin-1-yl) methyl] phenyl ⁇ propanoate
  • compound XXX 34 mg
  • compound XXXIII 49 mg
  • triethylamine 0.2 mL
  • 1-hydroxybenzotriazole (16 mg) and 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride 25 mg was added and stirred overnight at room temperature.
  • Example Compound 87 13 mg.
  • Examples 88-200 Examples 88 to 96 were synthesized by a method according to Example 87 using a compound synthesized according to Reference Example 1 or Reference Example 4 and a compound synthesized according to Reference Example 7.
  • Examples 97 to 124 were synthesized according to Example 17 or Example 19.
  • Examples 125 to 153 were synthesized by a method according to Example 87 using a compound synthesized according to Reference Example 7 and a compound synthesized according to the production method of Compound IX of Example 17.
  • Examples 154 to 160 were synthesized by a method according to Example 87 using a compound synthesized according to the production method of compound XXV of Reference Example 5 and a compound synthesized according to Reference Example 7.
  • Example 161 was synthesized by the method according to Example 87 using the compound synthesized according to Reference Example 7 and compound XXX.
  • Examples 162 to 200 were synthesized by a method according to Example 20 using the corresponding ester compounds described in this Example.
  • the corresponding isothiocyanate was used instead of phenylisothiocyanate in Step (ii) of Reference Example 1 as necessary.
  • the commercial item which can be obtained was used, or what was prepared according to the method of Reference Example 8 or this was used.
  • Example 201 2- (cyclohexylsulfanyl) -6- ⁇ [1- (2-hydroxyethyl) azetidin-3-yl] carbonyl ⁇ -3-phenyl-5,6,7,8-tetrahydropyrido [4 Preparation of 3-d] pyrimidin-4 (3H) -one
  • THF 3N lithium hydroxide aqueous solution
  • Example 201 (19 mg).
  • Example 202 2- (cyclohexylsulfanyl) -6- ⁇ [1- (4-hydroxybutyl) azetidin-3-yl] carbonyl ⁇ -3-phenyl-5,6,7,8-tetrahydropyrido [4 Preparation of 3-d] pyrimidin-4 (3H) -one
  • Example 202 (68 mg) was obtained according to Example 201 using Example Compound 122.
  • Example 203 2-methoxyethyl 3- ⁇ 4-[(3- ⁇ [2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3- d] Preparation of pyrimidin-6 (4H) -yl] carbonyl ⁇ azetidin-1-yl) methyl] phenyl ⁇ propanoate To a solution of Example Compound 64 (50 mg) in N, N-dimethylformamide (2 mL) was added 2-methoxyethanol (65 mg), 1-hydroxybenzotriazole (17 mg) and 1-ethyl-3- (3-dimethyl).
  • Examples 204-206 According to the method of Example 203, the compounds of Examples 204 to 206 were synthesized from the corresponding carboxylic acid described in this Example and ethylene glycol, dimethylamine or ammonia.
  • Example 207 Methyl (3- ⁇ 6 [(1-benzylazetidin-3-yl) carbonyl] -2- (cyclohexylsulfanyl) -4-oxo-5,6,7,8-tetrahydropyrido [4 Preparation of 3-d] pyrimidine-3 (4H) -yl ⁇ phenyl) acetate
  • the compound of Example 207 was obtained by the method according to Reference Example 1, Reference Example 2, and then Example 17 using Compound XXXVIII obtained in Reference Example 9.
  • Example 208 Ethyl 3- ⁇ 4-[(3- ⁇ [2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine Preparation of -6 (4H) -yl] sulfonyl ⁇ azetidin-1-yl) methyl] phenyl ⁇ propanoate Process (ex208-i) Compound IX (75 mg) was dissolved in N, N-dimethylformamide (2 mL), and triethylamine (0.07 mL) was added dropwise under ice water cooling.
  • step (ex208-ii) compound XXXXII was obtained according to the method of Reference Example 3.
  • Step (ex208-iii) Example Compound 208 (51 mg) was synthesized according to the method of Example 19 using Compound XXXXII and Compound XXXX obtained in Reference Example 10.
  • Example 209 methyl ⁇ 4-[(3- ⁇ [2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido
  • a solution of Example Compound 135 (200 mg) in ethyl acetate (8 mL) is heated to 40 ° C., and fumaric acid (39 mg) is added.
  • Example Compound 209 (195 mg).
  • XRD X-ray diffraction
  • X-ray Diffraction system X'pert MPD (PANAlytical) is used, anode material is Copper, K-Alpha1 is 1.54 angstrom, Tension is 45 kV, Current is 40 mA, Start Angle (2 ⁇ ) was measured at 4 °, End Angle (2 ⁇ ) at 40 °, step size (2 ⁇ ) at 0.017 °, and Time per step at 100 s.
  • a non-reflective Si plate was used as the measurement sample plate, about 5 mg of the measurement sample was applied to the non-reflective Si plate, and the measurement was performed under the above measurement conditions. The following X-ray diffraction measurement was performed in the same manner.
  • Examples 210-213 The compounds of Examples 210 to 213 were synthesized according to the method of Example 209 using the corresponding Example compounds (Examples 65, 142, 59 and 118).
  • Example 214 is according to Reference Example 4 except that a compound synthesized using 3-butoxyphenol instead of cyclohexylamine in Step (r4-ii) is used in Steps (xi) to (xii) of Example 17. This was synthesized according to Reference Example 3 and then Example 19. Examples 215 and 216 were synthesized by the method according to Example 20 using the corresponding ester compounds of Example 95 and Example 214, respectively.
  • Test Example 1 (1) Preparation of human MGAT2 recombinant protein
  • the human MGAT2 gene described in the literature (American Journal of Physiology, 285, E927-E937, 2003) was introduced into a cell line according to a standard method to prepare a human MGAT2 recombinant protein.
  • Radioactivity determined by (Condition A) or (Condition B) was defined as MGAT activity.
  • Test Example 2 Fat absorption inhibitory action in the small intestine
  • the fat absorption inhibitory action in the small intestine of the bicyclic pyrimidine compound of the present invention can be confirmed as follows. Mice (ICR, 8-9 weeks old, male, Japan SLC) are fasted overnight (about 24 hours), and the test compound (eg, 30 mg / kg) is suspended in 5% methylcellulose (MC) solution and administered. (Note that the MC solution may be a diluted MC solution of 0.5% or the like, or a 5% gum arabic solution or the like may be used instead). Ten minutes later, intralipid 20% (Terumo) (10 mL / kg) is administered by oral gavage (this time is 0 min).
  • TG plasma triglyceride
  • the compound of the present invention has an action as an MGAT inhibitor and is expected to be effective as a prophylactic and / or therapeutic agent for MGAT-related diseases.
  • the bicyclic pyrimidine derivative and the physiologically acceptable salt thereof of the present invention have an MGAT inhibitory action and are obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDL, high fatty acid It is useful as a prophylactic and / or therapeutic agent for blood glucose, diabetes and arteriosclerosis.

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Abstract

La présente invention vise à fournir un composé qui a un effet inhibiteur sur les enzymes MGAT et qui peut être utilisé comme produit pharmaceutique, ou encore un sel physiologiquement acceptable dudit composé ; et une composition pharmaceutique qui contient ledit composé ou un sel physiologiquement acceptable de celui-ci. L'invention concerne donc un composé de pyrimidine bicyclique de formule (I) ou l'un de ses sels physiologiquement acceptables. (Dans la formule, R1 représente un groupe alkyle inférieur éventuellement substitué ou équivalent ; R2 représente un atome d'hydrogène ou équivalent ; R3 représente un atome d'hydrogène ou équivalent ; R4 et R5 représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou équivalent ; X représente un atome d'oxygène ou équivalent ; Y représente -N(R9)C(=Z)- (où R9 représente un atome d'hydrogène ou équivalent et Z représente un atome d'oxygène ou équivalent) ou équivalent ; m est égal à 1 ; et n est égal à 2.)
PCT/JP2011/080207 2010-12-28 2011-12-27 Dérivé de pyrimidine bicyclique Ceased WO2012091010A1 (fr)

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WO2013112323A1 (fr) * 2012-01-23 2013-08-01 Eli Lilly And Company Dérivés de phényle méthanesulfonamide utilisés comme inhibiteurs mgat - 2
WO2014133134A1 (fr) * 2013-02-28 2014-09-04 味の素株式会社 Nouveau dérivé de tétrahydropyridopyrimidinone
US8993568B2 (en) 2012-01-31 2015-03-31 Eli Lilly And Company Morpholinyl derivatives useful as MOGAT-2 inhibitors
WO2015129845A1 (fr) * 2014-02-28 2015-09-03 味の素株式会社 Nouveau dérivé de tétrahydro-pyrido-pyrimidinone
WO2019013312A1 (fr) * 2017-07-14 2019-01-17 塩野義製薬株式会社 Dérivé à cycle condensé ayant une activité inhibitrice de ｍｇａｔ２
US10335401B2 (en) 2015-12-21 2019-07-02 Shionogi & Co., Ltd. Non-aromatic heterocyclic derivative having MGAT2 inhibitory activity
WO2020145369A1 (fr) 2019-01-11 2020-07-16 塩野義製薬株式会社 Dérivé de dihydropyrazolopyrazinone présentant une activité inhibitrice sur mgat2
RU2803743C2 (ru) * 2019-01-11 2023-09-19 Сионоги Энд Ко., Лтд. Производное дигидропиразолопиразинона, обладающее ингибирующей активностью в отношении mgat-2

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WO2014133134A1 (fr) * 2013-02-28 2014-09-04 味の素株式会社 Nouveau dérivé de tétrahydropyridopyrimidinone
WO2015129845A1 (fr) * 2014-02-28 2015-09-03 味の素株式会社 Nouveau dérivé de tétrahydro-pyrido-pyrimidinone
US10335401B2 (en) 2015-12-21 2019-07-02 Shionogi & Co., Ltd. Non-aromatic heterocyclic derivative having MGAT2 inhibitory activity
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JP7493635B2 (ja) 2017-07-14 2024-05-31 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する縮合環誘導体
KR20200029549A (ko) 2017-07-14 2020-03-18 시오노기 앤드 컴파니, 리미티드 Mgat2 저해 활성을 갖는 축합환 유도체
JPWO2019013311A1 (ja) * 2017-07-14 2020-05-07 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する縮合環誘導体
US12454533B2 (en) 2017-07-14 2025-10-28 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity
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JP7060298B1 (ja) 2017-07-14 2022-04-26 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する縮合環誘導体
JP2022068347A (ja) * 2017-07-14 2022-05-09 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する縮合環誘導体
EP4043463A1 (fr) 2017-07-14 2022-08-17 Shionogi & Co., Ltd Dérivé à cycle condensé ayant une activité inhibitrice de mgat2
US12024519B2 (en) 2017-07-14 2024-07-02 Shionogi & Co., Ltd. Fused ring derivative having MGAT-2 inhibitory activity
JP7224086B2 (ja) 2017-07-14 2023-02-17 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する縮合環誘導体
JP2023055851A (ja) * 2017-07-14 2023-04-18 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する縮合環誘導体
KR20210114001A (ko) 2019-01-11 2021-09-17 시오노기 앤드 컴파니, 리미티드 Mgat2 저해 활성을 갖는 다이하이드로피라졸로피라지논 유도체
RU2803743C2 (ru) * 2019-01-11 2023-09-19 Сионоги Энд Ко., Лтд. Производное дигидропиразолопиразинона, обладающее ингибирующей активностью в отношении mgat-2
EP3909583A4 (fr) * 2019-01-11 2022-08-17 Shionogi & Co., Ltd Dérivé de dihydropyrazolopyrazinone présentant une activité inhibitrice sur mgat2
US12227509B2 (en) 2019-01-11 2025-02-18 Shionogi & Co., Ltd. Dihydropyrazolopyrazinone derivative having MGAT2 inhibitory activity
WO2020145369A1 (fr) 2019-01-11 2020-07-16 塩野義製薬株式会社 Dérivé de dihydropyrazolopyrazinone présentant une activité inhibitrice sur mgat2

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