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HK1033670A - 2,3-substituted indole compounds as cox-2 inhibitors - Google Patents

2,3-substituted indole compounds as cox-2 inhibitors Download PDF

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Publication number
HK1033670A
HK1033670A HK01104208.9A HK01104208A HK1033670A HK 1033670 A HK1033670 A HK 1033670A HK 01104208 A HK01104208 A HK 01104208A HK 1033670 A HK1033670 A HK 1033670A
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Hong Kong
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indol
acetic acid
chloro
carbonyl
alkyl
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HK01104208.9A
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Chinese (zh)
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K‧中生
R‧W‧斯蒂温斯
K‧川村
C‧内田
H‧小池
S‧卡罗恩
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辉瑞大药厂
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Description

2, 3-substituted indole compounds as cyclooxygenase-2 inhibitors
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Technical Field
The present invention relates to novel 2, 3-substituted indole pharmaceuticals. The invention particularly relates to compounds, compositions and methods for treating or reducing pain and inflammation and other inflammation-related disorders, such as arthritis.
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat pain and the symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is well recognized that the action of conventional NSAIDs is to block the activity of Cyclooxygenase (COX), also known as prostaglandin G/H synthase (PGHS), an enzyme that converts eicosatetraenoic acid to prostanoids. Prostaglandins, in particular prostaglandin E2(PGE2) Eicosanoids, the major eicosanoids detected under inflammatory conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of prostaglandin biosynthesis has been a therapeutic goal in the discovery of anti-inflammatory drugs. However, conventional NSAIDs have limited therapeutic use due to drug-related side effects including life-threatening ulcers and renal toxicity. An alternative to NSAIDs is the use of corticosteroids, however, long-term treatment can also produce serious side effects.
Recently, two COX's were identified, one structural isoform (COX-1) and one inducible isoform (COX-2), the expression of which is up-regulated at the site of inflammation (Vane, j.r., Mitchell, j.a., Appleton, i., Tomlinson, a., Bishop-Bailey, d., croutoll, j., Willoughby, d.a. proc.natl.acad.sci.usa, 1994, 91, 2046). COX-1 is thought to exert certain physiological effects and is responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathogenic role and is the major isoform present under inflammatory conditions. The pathogenic effects of prostaglandins are associated with a variety of human conditions including rheumatoid and osteoarthritis, fever, asthma, bone resorption, cardiovascular disease, nephrotoxicity, atherosclerosis, hypertension, shock, pain, cancer and alzheimer's disease. NSAIDs currently on the market inhibit both COX isoforms simultaneously, optionally with little change, explaining their good (COX-2 inhibition) and bad (COX-1 inhibition) effects. It is believed that compounds capable of optionally inhibiting the biosynthesis of prostaglandins by interfering with the induction phase of the inducible enzyme cyclooxygenase-2 and/or by interfering with the activity of the enzyme cyclooxygenase-2 which acts on eicosatetraenoic acid would provide an alternative treatment to the use of NSAIDs and corticosteroids in which these compounds would exert an anti-inflammatory effect without the side effects associated with COX-1 inhibition.
A variety of indole compounds are known and have been disclosed in several patent applications. International patent application No. WO96/32379 discloses N-substituted indole compounds as cGMP-PDE inhibitors. International patent application Nos. WO96/37467, WO96/37469, British patent publication No. GB2283745A and US5510368 disclose 2-methyl-N-substituted indole compounds as cyclooxygenase-2 inhibitors. Various indole compounds are also disclosed by Konya, Kazumi et al in european patent publication No. 0556949a2 as agents for controlling underwater mold-forming microorganisms. Specifically, an indole compound is disclosed as a neuropeptide antagonist in International patent publication No. WO 97/09308. In addition, a method for preparing 2-ester substituted indoles is disclosed in sci.pharm.64, 577 (1996).
Brief disclosure of the invention
The present invention provides a compound of the formula:or pharmaceutically acceptable salts thereof, wherein Z is OH or C1-6Alkoxy, -NR2R3Or a group of formula (II) or (III):wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4And W is OH or-NR2R3(ii) a Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen or the likeSubstituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) A 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; r4Is H or C1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C 1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4.
The indole compounds of the present invention inhibit the activity of COX. Preferred compounds of the invention have COX-2 inhibitory activity and more preferably COX-2 selective compounds.
Accordingly, the present invention also provides a pharmaceutical composition useful for treating medical conditions in which prostaglandins are the etiological agent, comprising a compound of formula (I) and pharmaceutically acceptable salts thereof.
The present invention also provides a method of treating a medical condition in a mammalian subject in which prostaglandins are the causative agent, comprising administering to said subject a therapeutically effective amount of said pharmaceutical composition.
Medical conditions in which prostaglandins are pathogenic include pain relief, fever and various inflammations including rheumatic fever, symptoms associated with influenza or other viral infections, cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout, ankylosis, spondylitis, systemic lupus erythematosus and juvenile arthritis, bursitis, burns, injuries following surgical and dental procedures.
The compounds and pharmaceutical compositions of the present invention inhibit cellular neoplastic transformation and the growth of metastatic tumors and are therefore useful in the treatment and/or prevention of cancer in the colon, breast, skin, esophagus, stomach, bladder, lung and liver. The compounds and pharmaceutical compositions of the invention are useful in the treatment and/or prevention of cyclooxygenase-mediated proliferative diseases such as those which occur in diabetic retinopathy and in tumor angiogenesis.
The compounds and pharmaceutical compositions of the present invention inhibit prostaglandin-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and are therefore useful in the treatment of dysmenorrhea, premature labor, asthma and eosinophil-associated diseases as well as in the treatment of neurodegenerative diseases such as alzheimer's disease and parkinson's disease, in the treatment of bone loss disease (osteoarthritis), stroke, seizures, migraine, multiple sclerosis, aids and encephalopathy.
In terms of COX-2 activity and/or specificity for COX-2 over COX-1, these compounds will prove to be an alternative to conventional NSAIDs, particularly when the NSAID is contraindicated, e.g., patients with ulcers (e.g., peptic and gastric), gastritis, regional enteritis, ulcerative colitis, diverticulitis or with GI damage, GI bleeding, a recurrent history of coagulation including anemias such as hypoprothrombinemia, hemophilia and other bleeding problems, renal disease; prior to surgery where anticoagulant is administered.
The present invention also provides a compound of formulae 7-VI:wherein B is a suitable protecting group; q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3 and 4.
The present invention also provides a compound of formula 7-V:wherein B is a suitable protecting group; q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7CycloalkanesThe base group is a group of a compound,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C 1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7CycloalkanesA group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-C6An alkyl group; and n is 0, 1, 2, 3 or 4.
Detailed disclosure of the invention
"halogen" as used herein is fluorine, chlorine, bromine or iodine.
The term "C" as used herein1-4Alkyl "means a straight or branched chain saturated radical containing 1 to 4 carbon atoms and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
Examples of "propyl" as used herein are n-propyl and isopropyl.
Examples of "butyl" as used herein are n-butyl, isobutyl, sec-butyl and tert-butyl.
Examples of "alkoxy" as used herein are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
Examples of "alkylthio" as used herein are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.
As used herein, "di- (C)1-4Examples of "alkyl) amino" are dimethylamino, diethylamino, dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-butylamino, N-ethyl-N-propylamino and the like.
As used herein, "C1-4Examples of the alkylamino group "are a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, a sec-butylamino group, a tert-butylamino group and the like.
As used herein, "HO-C1-4Examples of alkylamino are hydroxymethyl, hydroxyethyl (e.g. 1-hydroxyethyl and 2-hydroxyethyl), hydroxypropyl (e.g. 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl).
As used herein, "C1-4alkoxy-C 1-4Examples of alkyl are methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl and the like.
The term "halogen-substituted alkyl" as used herein refers to the above alkyl groups substituted with 1 or more halogens, including but not limited to chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trichloroethyl, and the like.
Examples of "halogen-substituted alkoxy" as used herein are chloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethyloxy, 2, 2, 2-trichloroethoxy and the like.
The term "C" as used herein3-7Cycloalkyl "refers to carbocyclic groups containing 3 to 7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
Examples of "aryl" as used herein are phenyl and naphthyl.
As used herein, a 5-membered monocyclic aryl group typically contains one heteroatom selected from O, S and N in its ring. In addition to the heteroatoms, the monocyclic aryl groups optionally contain up to 3N atoms in their ring. For example, 5-membered monocyclic aryl includes thienyl, furyl, thiazolyl (e.g., 1, 3-thiazolyl, 1, 2-thiazolyl), imidazolyl, pyrrolyl, oxazolyl (e.g., 1, 3 oxazolyl, 1, 2 oxazolyl, isoxazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1, 2, 3-triazolyl, 1, 2, 4-triazolyl), oxadiazolyl (e.g., 1, 2, 3-oxadiazolyl), thiadiazolyl (e.g., 1, 3, 4-thiadiazolyl, 1, 2, 3-thiadiazolyl), and the like.
As used herein, a 6-membered monocyclic aryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (e.g., 1, 3, 5-triazinyl), tetrazinyl, and the like.
Examples of benzo-fused heterocyclic groups for use herein include quinolyl, isoquinolyl, 1, 2-diazanaphthyl, quinoxalyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, quinazolinyl, 2, 3-diazanaphthyl, and the like.
Examples of the (ethyl) (ethoxy) pyridyl group used herein include a 3-ethoxy-4-ethyl-2-pyridyl group, a 4-ethoxy-3-ethyl-2-pyridyl group and the like.
Examples of the (chloro) (ethyl) pyridyl group used herein include 3-chloro-4-ethyl-2-pyridyl group, 4-chloro-3-ethyl-2-pyridyl group and the like.
Examples of the (fluoro) (ethyl) pyridyl (phenyl) group used herein include 3-fluoro-4-ethyl-2-pyridyl, 4-fluoro-3-ethyl-2-pyridyl and the like.
Preferred compounds of the invention are those of formula (I) wherein Z is OH, C1-6Alkoxy, dimethylamino, methylamino, amino, N-methoxy-N-methylamino, 2-cyanoethylamino, 2-hydroxyethylamino, pyrrolidinyl, piperidino, piperazinylN-methylpiperazinyl, morpholino, methoxyamino, piperazinyl (piperazynyl), aminopyrrolidinyl or aminoethylamino.
More preferred compounds of the invention are those of formula (I) wherein Z is OH or C1-6Alkoxy and Q is selected from the group consisting of:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 independently selected fromHalogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) c selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl3-7Cycloalkyl, and said cycloalkyl is optionally substituted by 1 member selected from the group consisting of OH, methyl, ethyl, propyl, F, Cl and CF3Substituted with the substituent(s); and
(e) a benzo-fused heterocycle selected from the group consisting of quinolyl, isoquinolyl, 1, 2-naphthyridinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, and indolyl, and said benzo-fused heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group of (a-1) above.
More preferred compounds of the invention are those of formula (I) wherein Q is selected from the group consisting of:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl radical) Amino group, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) cyclopropyl, cyclobutyl, and cyclohexyl; and
(e) quinolyl or isoquinolyl, and said quinolyl or isoquinolyl being optionally substituted by 1 member selected from halogen, C1-4Alkyl, NH2、OH、C1-4Alkoxy and C1-4Substituted with a haloalkyl.
More preferred compounds of the invention are those of formula (I) wherein Z is OH or C1-6Alkoxy and Q is selected from the group consisting of:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4Alkyl group), C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) A 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above; and
(e) an isoquinolinyl group; r1Is H or C1-4An alkyl group; r2And R3Independently is H or methyl; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOR4, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2 or 3.
More preferred compounds of the invention are of formula (I) wherein Z is OH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; a compound wherein Q is selected from the group consisting of:
(a) Phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl, -COOH, C1-4Alkylsulfonylamino group, NO2、C1-4An alkylsulfonyl group and a CN group,
(a-2) phenyl or benzyloxy and the phenyl group of phenyl or benzyloxy is optionally substituted by 1 group selected from C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy and NH2The substituent (b) of (a) is substituted,
(a-3) a 5-membered monocyclic aryl group selected from imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, and the 5-membered monocyclic aryl group is optionally substituted with 1 member selected from C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy and NH2The substituent (b) of (a) is substituted,
(a-4) a 6-membered monocyclic aryl group selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, and the 6-membered monocyclic aryl group is optionally substituted with 1 member selected from C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy and NH2The substituent (b) of (a) is substituted,
(b) a 6-membered monocyclic aryl group selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, and said monocyclic aryl group is optionally substituted with 1 or 2 substituents independently selected from the group of (a-1), (a-2), (a-3) or (a-4) above,
(c) a 5-membered monocyclic aryl group selected from the group consisting of imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, and said monocyclic aryl group is optionally substituted with 1 or 2 substituents independently selected from the group of (a-1), (a-2), (a-3) or (a-4) above; r1Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl and aminosulfonyl; and n is 0, 1, 2 or 3.
More preferred compounds of the invention are compounds of formula (I) wherein Z is OH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; q is selected from the following groups:
(a) Phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
(a-1) fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, butyl, CH2F、CHF2、CF3Methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, CH2F-O-、CHF2-O-、CF3-O-, methylthio, ethylthio, hydroxymethyl, methoxymethyl, methoxyethyl, ethoxymethyl, OH, NO2Methanesulfonyl, CN, (HO) (H)3C)2C-, acetyl and methylsulfonylamino,
(a-2) phenyl or benzyloxy and the phenyl moiety of phenyl or benzyloxy is optionally substituted by 1 substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl,Propyl, CF3F, Cl, OH, methoxy, ethoxy and NH2The substituent (b) of (a) is substituted,
(a-3) a 5-membered monocyclic aryl group selected from furyl, thienyl and pyrrolyl, and the 5-membered monocyclic aryl group is optionally substituted with 1 group selected from methyl, ethyl, propyl, CF3F, Cl, OH, methoxy, ethoxy and NH2The substituent (b) of (a) is substituted,
(a-4) is optionally substituted by 1 member selected from methyl, ethyl, propyl, CF3F, Cl, OH, methoxy, ethoxy and NH2A pyridyl group substituted with the substituent(s) of (a),
(b) pyridyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the above-mentioned (a-1), (a-2), (a-3) or (a-4),
(c) Imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1, 2, 3-thiadiazolyl or pyrrolyl, and said imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1, 2, 3-thiadiazolyl or pyrrolyl is optionally substituted with 1 or 2 substituents independently selected from the group of (a-1), (a-2), (a-3) or (a-4) above; r1Is H, methyl, ethyl, n-propyl, isopropyl; x is independently selected from F, Cl, Br, methyl, ethyl, propyl, butyl, CH2F、CHF2、CF3Methoxy, CF3-O-or ethoxy; and n is 0, 1 or 2.
More preferred compounds of the invention are compounds of formula (I) wherein: z is OH, ethoxy or methoxy; q is phenyl, chlorophenyl, fluorophenyl, bromophenyl, tolyl, methoxyphenyl, (furyl) phenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, dimethylpyridyl, chloropyridyl, fluoropyridyl, trifluoromethylpyridyl, methoxypyridyl, (ethyl) (ethoxy) pyridyl, (chloro) (ethyl) pyridyl, thiazolyl, methylthiazolyl, furyl, methoxymethylfuryl, isoquinolyl, cyclohexyl, methoxyphenyl, (fluoro) (ethyl) pyridyl, trifluoromethylpyridyl, pyridylquinolyl, pyridyl, Dimethylpyridyl or (ethoxy) (ethyl) pyridyl; r1Is H; x is F, Cl, methyl, ethyl, isopropyl, tert-butyl, CF3Or a methoxy group; and n is 1 or 2.
More preferred compounds of the invention are compounds of formula (I) wherein: z is OH, ethoxy or methoxy; q is phenyl, chlorophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl or chloropyridyl; r1Is H; x is F, Cl, methyl or CF3(ii) a And n is 1 or 2.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, sodium salt [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, and, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-7-chloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the less polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the more polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl acetate, ethyl acetate, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl (2-benzoyl-6-chloro-1H-indol-3-yl) acetate, methyl (2-benzoyl-6-chloro-1H-indol-3-yl) -N, N-dimethylacetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) -N-methylacetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) acetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) -N-methoxy-N-methylacetamide, methyl acetate, ethyl acetate, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1-piperidino-1-ethanone, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1- (4-methyl-1-piperazinyl) -1-ethanone, (2-benzoyl-6-chloro-1H-indol-3-yl) -N- (2-cyanoethyl) acetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) -N- (2-hydroxyethyl) acetamide, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) ) -1-morpholino-1-ethanone, [2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol- 3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl ester, [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetate, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl ] acetate, methyl [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl, [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate -yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, Methyl [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl-2- (4-methylpyridine-, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid methyl ester [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate -yl ] acetic acid, methyl [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, methyl (2-benzoyl-1H-indol-3-yl ] acetate, methyl (I) indole-3-yl) acetate, methyl (I) indole-3-yl ] acetate, methyl (I) indole-2-yl ] acetate, methyl (I), (2-benzoyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetate, methyl [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, methyl [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, methyl [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl acetate, [2- (4-chlorobenzoyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl ] ethyl acetate Acid methyl ester, [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-methoxybenzoyl) -1H-indole-3-yl ] acetic acid Indole-3-yl acetic acid methyl ester, [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl ester, and salts thereof, [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester -yl ] acetic acid, [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester -indol-3-yl acetic acid, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [ (4-methanesulfonyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [ (4-methanesulfonyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (methanesulfonylamino) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (methanesulfonylamino) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, [ 6-chloro-2-2- (chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-cyanobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [ 4-bromobenzoyl ] -1H-indol-3-yl ] acetic acid methyl ester -3-yl methyl acetate, [ 6-chloro-2- [4- (2-thienyl) benzoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (2-thienyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] -1H-indol-3-yl ] acetate [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-thiazolyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (2-thiazolyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-bromobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- [3- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, methyl acetate, and mixtures thereof, [ 6-chloro-2- [3- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, dl-2- [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] propionic acid methyl ester, dl-2- [2- (4-chlorobenzoyl) -6-chloro-1H-indol-3-yl ] propionic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl ester, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, acetic acid, [ 6-chloro-2- (2-thienyl) carbonylindol-3-yl ] acetic acid, methyl [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indazol-3-yl ] acetate Indole-3-yl acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [3- (ethoxycarbonyl) isoxazole-5-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- [3- (carboxy) isoxazole-5-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl ] acetate, methyl [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl ] acetic acid, methyl [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, methyl [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N, n-dimethylacetamide, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N-methylacetamide, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N- (2-hydroxyethyl) acetamide, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N-methoxyacetamide, 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -1-piperazinyl-1-ethanone, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N- (2-aminoethyl) acetamide, 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -1- (3-amino-1-pyrrolidinyl) -1-ethanone, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-nitrobenzoyl) -1H-indol-3- Yl ] acetic acid, [ 6-chloro-2- (2, 4-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-difluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 5-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluorobenzoyl) -5-indol-3-yl ] acetic acid -1H-indol-3-yl ] acetic acid methyl ester, [ 6-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-methylsulfanyl-1H-indol-3-yl ] acetic acid, methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-methylsulfanyl-1H-indol-3-yl ] acetic acid, and salts thereof.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, sodium salt, [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, and, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-7-chloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the less polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the more polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl acetate, ethyl acetate, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl (2-benzoyl-6-chloro-1H-indol-3-yl) acetate, [2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl (I) and (II) methyl (III) acetate, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl acetic acid, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] ethylidene ] acetic acid Acids, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, (2-benzoyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] ethyl acetate Acids, [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl ] ethyl ] acetic acid Acids, [ 6-chloro-2- [ (4-methanesulfonylamino) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-cyanobenzoyl) -1H-indol-3-yl ] acetic acid Indole-3-yl methyl acetate, [ 6-chloro-2- [ 4-bromobenzoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (2-thienyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (2-thiazolyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-bromobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [3- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, dl-2- [2- (4-chlorobenzoyl) -6-chloro-1H-indol-3-yl ] propionic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid -yl ] acetic acid, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-thienyl) carbonylindol-3-yl ] acetic acid, [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, and salts thereof, [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [3- (carboxy) isoxazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl ] acetic acid, [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 4-ethyl-3-fluoropyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-nitrobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 4-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-difluoromethoxybenzoyl) -1H-indol-3-yl ] ethyl ] acetic acid Acids, [ 6-chloro-2- (2, 5-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid and salts thereof.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl (I) acetate, methyl (II) acetate, methyl (III) acetate, and mixtures thereof, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, less polar enantiomer 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, and salts thereof, The more polar enantiomers 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetate, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, methyl, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester Esters, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, salts of these compounds, and their use as medicaments, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [2- (4-methylpyridine-2-carbonyl) -, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate Acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid methyl ester, acetic acid methyl ester, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid methyl ester -yl ] acetic acid, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, a salt thereof, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, salts thereof, solvates thereof, and pharmaceutical compositions comprising the same, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 4-ethyl-3-fluoropyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, and [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid methyl ester, and salts thereof.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl (I) acetate, methyl (II) acetate, methyl (III) acetate, and mixtures thereof, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, less polar enantiomer 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, and salts thereof, The more polar enantiomers 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid -3-yl acetic acid, [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid 3-yl acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid An alkyl ] acetic acid, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, 2- { 6-chloro-2- [ 4-ethyl-3-fluoro-2-pyridyl) carbonyl ] -1H-indol-3-yl ] acetic acid -3-yl } acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetate and salts thereof.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] ethylidene Acids, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, salts thereof, and salts thereof, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 2-methyl-2- (2-carbonyl) -1H-indol-3-, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate Esters, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, esters, salts of the corresponding compounds, and pharmaceutical compositions containing the same, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, and methyl [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) acetate 1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate Acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate Indol-3-yl acetic acid, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 2-methyl-2- (4-methylthiazole-2-carbonyl) -1, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid methyl ester and salts thereof.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] ethylidene Acids, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, salts thereof, solvates thereof, and pharmaceutical compositions containing the same, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3- Yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid Yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid -3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (2-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (2-methylimidazole-2-carbonyl) -, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl ] -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and salts thereof.
Preferred individual compounds of the invention are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl acetate, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, methyl-2- (4-methylpyridine-2-carbonyl) -1, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid (cj-020,099), [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and salts thereof.
The most preferred individual compounds are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid -indol-3-yl acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, and salts thereof.
Preferred pharmaceutical compositions of the invention contain a compound of formula (I) as defined above.
The most preferred individual compounds comprised in the pharmaceutical composition are: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid -indol-3-yl acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, and salts thereof.
The present invention also provides a process for preparing a compound of the formula:q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 and 4, the method comprising the steps of:
i) reacting a compound of the formula:
wherein B is a suitable protecting group, R5Is C1-6Alkyl, X and n are as defined above, with a compound of the formula:
wherein E is halogen and Q is as defined above;
ii) reacting the product of step i) with a second base;
iii) reacting the product of step ii) with an acid.
Preferably the above process is wherein said first base is potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or cesium carbonate.
Preferably the above process is wherein said first base is potassium carbonate.
Preferred is the above process wherein said second base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium pentaalkoxide (then water), sodium methoxide (then water) or potassium tert-butoxide in water (then water).
Preferably said process is wherein said second base is sodium hydroxide.
Preferred above processes are those wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid or aqueous ammonium chloride.
The above method is preferred wherein the acid is aqueous hydrochloric acid.
The above method is preferred wherein the solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
The above method is preferred wherein the solvent is N, N-dimethylacetamide.
The present invention also provides a process for preparing a compound of the formula:wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen radicalsSubstituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) Optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3, and 4, the method comprising reacting a compound of the formula:
wherein R is5Is C1-6Alkyl, X and n are as defined above, with a base in a suitable solvent.
The above method is preferred wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium tert-amylate, sodium methoxide, sodium ethoxide or potassium tert-butoxide.
Preferably said process is wherein said base is sodium hydroxide.
Preferred above processes are those wherein the solvent is methanol, ethanol, isopropanol or a mixture of tetrahydrofuran and water.
The above method is preferred wherein the solvent is methanol containing water.
The present invention also provides a process for preparing a compound of the formula:wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r 2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of the formula:
wherein B, Q, X, n and R5As defined above, with a base in a suitable solvent.
A preferred method as described above is wherein said base is 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 3, 3-tetramethylguanidine, sodium tert-amylate, sodium methoxide or potassium tert-butoxide.
A preferred such method is wherein the base is 1, 8-diazabicyclo [5.4.0] undec-7-ene or potassium tert-butoxide.
The above method is preferred wherein the solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
The above method is preferred wherein the solvent is N, N-dimethylacetamide.
The present invention also provides a process for preparing a compound of the formula:
wherein B is a suitable protecting group;
wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO 2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C 1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3, and 4, the method comprising reacting a compound of the formula:
wherein B, Q, X, n and R5As defined above, with a base in the presence of a solvent.
Preferably the above process is wherein the base is potassium carbonate, potassium bicarbonate, sodium carbonate or cesium carbonate.
A preferred such process is wherein the base is potassium carbonate.
The above method is preferred wherein the solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
The above method is preferred wherein the solvent is N, N-dimethylacetamide.
The present invention also provides a process for preparing a compound of the formula: Wherein B is a suitable protecting group; wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of the formula:
wherein B, X, n and R5As previously defined, with a compound of the formula:
wherein E is halogen and Q is as defined above.
Preferably the above process is wherein the base is potassium carbonate, potassium bicarbonate, sodium carbonate or cesium carbonate.
A preferred such process is wherein the base is potassium carbonate.
The above method is preferred wherein the solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
The above method is preferred wherein the solvent is N, N-dimethylacetamide.
The present invention also provides a process for preparing a compound of the formula:wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen、C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) A 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; r5Is C1-6An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C 1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which comprises treating a compound of the formula (X):
wherein R is1、R5X, Q and n are as previously defined and B is a suitable protecting group to give a compound of formula (XII).
The present invention also provides a process for preparing a compound of the formula: wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH、C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C 1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; r5Is C1-6An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of formula (IX):
wherein R is1、R5X and n are as defined above and B is a suitable protecting group, with a compound (XI) of the formula:
wherein E is halogen and Q is as defined above, to give a compound of formula (XII).
Preferred is the above process wherein the reaction is carried out at a temperature of from 0 to 100 ℃.
Preferred above processes are those wherein the suitable base is potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride or potassium fluoride.
The above method is preferred in which the reaction is first carried out in the presence of a base for 2 minutes to 1 day, and then another base is added to the reaction mixture.
The above-mentioned method is preferred in which the reaction is carried out for 30 minutes to 8 hours.
Preferred above processes are those wherein a suitable protecting group is methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl.
Preferred above processes are those wherein a suitable protecting group is a phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl group.
Preferred above processes are those wherein the first base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine and diethylisopropylamine; and the second base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, and diethylisopropylamine.
Preferred above processes are those wherein the first base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydride and potassium fluoride; and the second base is selected from the group consisting of 1, 8-diazabicyclo [5.4.0] undec-7-ene, cesium carbonate, pyrrolidine, diisopropylamine, triethylamine, diethylisopropylamine and diisopropylethylamine.
Preferred above processes are those wherein the first base is potassium carbonate, cesium carbonate or potassium fluoride; and the second base is 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium tert-butoxide or cesium carbonate.
A preferred such method is where the combination of the first base and the second base (first base/second base) is selected from the group consisting of potassium carbonate/1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate/cesium carbonate, cesium carbonate/potassium tert-butoxide, cesium carbonate/1, 8-diazabicyclo [5.4.0] undec-7-ene and potassium fluoride/cesium carbonate.
A preferred such process is one wherein the combination of the first base and the second base (first base/second base) is selected from the group consisting of potassium carbonate/1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate/cesium carbonate and cesium carbonate/potassium tert-butoxide.
The present invention also provides a process for preparing a compound of the formula: Wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which process comprises treating a compound of formula (X) with a suitable base under hydrolysis conditions:
wherein R is1、R5X, Q and n are as defined above to give a compound of formula (VIII).
The present invention also provides a process for preparing a compound of formula (VIII): wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH、C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N atoms, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) Optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0,1. 2, 3 or 4, the process comprising hydrolyzing a compound of the formula (XII):
wherein R is5Is C1-6Alkyl radical, R1X, Q and n are as previously defined.
General Synthesis
The compounds of formula (I) can be prepared from structurally related compounds using synthetic methods known to those skilled in the art. The following representative examples are illustrative and are not intended to limit the scope of the present invention. Q, X, Z, R unless otherwise stated 1And n is as defined above.Scheme 1:
for example, in one embodiment, the compound of formula (VI) may be prepared according to the reaction sequence depicted in scheme 1. (Compound (VI) corresponds to R in Compound (I)1Is H and Z is OH).
[R4H or halogen] [R5＝C1-6Alkyl radical]
Scheme 1
Briefly, the compound of formula (III) is oxidatively homolytic malonylated (see, for a primary reference, can. j. chem., 70, 1838,1992and e.baciocchi et al j.org.chem., 58, 7610,1993). In one embodiment, a compound of formula (III) is reacted with a compound of formula C (R)4)H(CO2R5) In R4Is H or halogen, preferably chlorine, and R5Is C1-6The alkyl compound is reacted with a suitable malonyl and manganese (III) reagent, preferably manganese (III) triacetate. Manganese (III) reagent in amountsUsually stoichiometric, but can also be varied to catalytic amounts by the use of suitable reoxidants, such as sodium persulfate, and is usually employed in the presence of a promoter, such as a silver (I) salt, e.g., silver nitrate. The preferred reaction solvent is acetic acid, but acetic acid-acetic anhydride or other protic solvents such as propionic acid may be used. The reaction is preferably carried out in the presence of sodium acetate or potassium acetate, but may be carried out in a solvent alone. The reaction temperature is generally in the range of room temperature (e.g., 25 ℃) to the reflux temperature of the solvent, preferably 60 to 100 ℃, but higher or lower temperatures may be used if necessary. The reaction time is generally 1 hour to 1 day, preferably 4 to 16 hours, however, longer or shorter times may be used if necessary. In the case of intermediates, the α -acetoxy compound of formula (IV) is usually obtained as the main product. The compounds of formula (IV) can be readily converted to compounds of formula (V) by reduction with a suitable reducing agent such as trialkylsilane, α - (dimethylamino) naphthyl sodium, lithium in liquid ammonia, sodium naphthyl sodium, preferably triethylsilane in a suitable protic solvent such as trifluoroacetic acid. Alternatively, the reaction may be carried out in a co-solvent which is inert to the reaction, for example dichloromethane or 1, 2-dichloroethane. The reaction temperature is generally in the range of room temperature to the reflux temperature of the solvent, preferably at 15 to 100 ℃, but higher or lower temperatures may be used if necessary. The reaction time is generally from several minutes to 1 day, preferably from 20 minutes to 5 hours, however, longer or shorter times may be used if necessary. Alternatively, the compound of formula (V) may be derived directly from a compound of formula (III), (i) from the malonyl group generated from a suitable monohalomalonate, preferably a bromomalonate, mediated by air oxidation of a trialkylborane such as triethylborane (see Radials in organic synthesis: formation of carbon-carbon bases. Pergamon Press, Oxford. pp.86-89, 1986And j.chem.soc. (B), 1126,1960) Or (ii) from malonyl groups generated from malonates in the presence of a cerium (IV) salt, e.g., ammonium cerium (IV) nitrate (see, e.g., E.Baciocchi et alTetrahedron Lett.，2763， 1986). The compound of formula (V) can be readily converted to the compound of formula (VI) by subjecting it to standard saponification/decarboxylation conditions.Scheme 2
Alternatively, as shown in scheme 2, in a manner similar to the preparation of the compound of formula (VI), using suitable reaction conditions as described above, one can prepare from a suitable monoalkylmalonate ester wherein R is1Is C1-4Alkyl, W is H or halogen, preferably bromine, and R5Is C1-6Alkyl, preparation of R in formula (VIII) from a compound of formula (III)1Is C1-4Alkyl compounds (compound (I) wherein Z is OH).
Scheme 2
In scheme 2, for example, the oxidizing agent is a manganese (III) reagent such as manganese (III) triacetate or a cerium (IV) reagent such as ammonium cerium (IV) nitrate or cerium (IV) sulfate.Scheme 3:
in another embodiment, the compound of formula (VIII) is readily obtained from the appropriate 2-aminocinnamate (IX) wherein B is a suitable protecting group, e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, methanesulfonyl or trifluoromethanesulfonyl (preferably benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl).
Scheme 3
In scheme 3, the requisite 2-aminocinnamate (IX) is reacted with a compound of formula (XI) wherein Q is as defined above and E is halogen, preferably iodine, bromine or chlorine, in the presence of a suitable base. Suitable bases are, for example, alkali metal or alkaline earth metal alkoxides, carbonates, fluorides or hydrides, for example sodium tert-butoxide,Potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium fluoride or potassium hydride. Preferred reaction-inert solvents include, but are not limited to, acetone, methyl ethyl ketone, acetonitrile, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dioxane, or Tetrahydrofuran (THF). The reaction temperature is preferably from-40 ℃ to the reflux temperature of the solvent (e.g., 200 ℃), and is typically in the range of 0 to 100 ℃, although higher or lower temperatures may be used if necessary. The reaction time is generally from 2 minutes to 1 day, preferably from 30 minutes to 8 hours, although longer or shorter times may be used. For example, when the reaction is carried out at room temperature (e.g., 25 ℃), the intermediate indoline (X) can be isolated. Indole (XII) may be formed by conducting the reaction at higher temperatures (e.g., 40-100 ℃). The intermediate indoline (X) is generally not isolated but is either (i) directly hydrolysed to the compound of formula (VIII) under standard conditions known to those skilled in the art with concomitant formation of the indole ring, or (ii) by use of a suitable base, for example an alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate or caesium carbonate, or an organic base such as 1, 8-diazabicyclo [5.4.0 ] ]Undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, diethylisopropylamine, Hunig's base, potassium tert-butoxide, sodium tert-butoxide or the like, or a suitable oxidizing agent such as ammonium cerium (IV) nitrate (CAN), manganese (IV) oxide, manganese (III) triacetate, copper (II)/air, chloranil, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), N-methylmorpholine-N-oxide or the like converts it to a compound of formula (XII) (see, for example, J.heterocyclic. chem., 32, 1703,1995(ii) a Tetrahedron lett et al, 5053,1991(ii) a Helm.acta, 77, 111, of p.martin et al,1994(ii) a J.chem.soc.perkins Trans 1, 7, 1401,1984(ii) a Tetrahedron lett, 6567, goti et al,1996(ii) a J.org.chem., 61, 2594, l.s.liebeckind et al,1996). Preferred reactionInert solvents include, but are not limited to, acetone, methyl ethyl ketone, acetonitrile, dioxane, or Tetrahydrofuran (THF). The reaction temperature is preferably from 0 ℃ to the reflux temperature of the solvent, generally in the range of from 15 to 60 ℃, although higher or lower temperatures may be used if necessary. The reaction time is generally from several minutes to 1 day, preferably from 30 minutes to 8 hours, but longer or shorter times may be used if necessary. The compound of formula (XII) can be readily hydrolyzed to the compound of formula (VIII) under standard conditions. Reaction formula 4:
in another embodiment, Q, X, R in formula (VIII)1And n is as defined above, may be prepared according to the method shown in scheme 4:
scheme 4
For example, R in formula (XIII) is treated with a trialkyltin hydride, e.g. tributyltin hydride, generally in the presence of a free radical initiator, e.g. 2, 2' -Azabicyclooisobutyronitrile (AIBN), according to the method described in T.Fukuyama, J.Am.chem.Soc., 116, 3127, (1994)1、R5X and n are as defined above, by an intramolecular free radical cyclisation to give the intermediate 2-stannyl indole (XIV). The in situ generated intermediate (XIV) is then treated with an acid halide wherein Q and E are as defined above in the presence of a suitable palladium catalyst according to the method of Stille (see, for example, j.am. chem. soc., 109, 813, 5478, (1987) and j.am. chem. soc., 106, 813, 4833, (1984)) to give indole (XII) which can be hydrolysed to the compound of formula (VIII) by conventional means.
Examples of palladium catalysts are tetrakis (triphenylphosphine) palladium (O), bis (triphenylphosphine) palladium (II) dichloride, bis (dibenzylideneacetone) palladium (O), benzyl (chloro) bis (triphenylphosphine) palladium (II), bis (acetonitrile) palladium (II) dichloride. 5, preparing ammonia:
in another embodiment, Q, X, R in formula (VIII)1And n is as defined aboveThe compounds may be prepared according to the method shown in scheme 5:
scheme 5
For example, let R in formula (XV)1Compounds of formula Q-C (O) -A are reacted with compounds of formula Q-C (O) -A to give compounds of formula (VIII) or compounds of formula (XVI) (see, for example, U.Pindru et al, Liebigs Ann. chem., 601(1991) and C.J.Moody et al, J.chem.Soc.Perkin Trans.1, 3249(1988)), which can be hydrolyzed to compounds of formula (VIII) by conventional methods (see, for example, E.B.Fray et al, Tetrahedron, 49, 439(1993) and U.Pindru et al, J.heterocyclic. chem., 29, 145 (1992)). In the compounds of the formula A-C (O) -Q, A is defined such that the compound of A-C (O) -Q is, for example, an acid halide, a carboxylic acid anhydride, a mixed carboxylic acid sulfonic acid anhydride or the like. The reaction may be carried out in the presence or absence of a catalyst, preferably in the presence of a catalyst such as boron trifluoride-ethyl ether, tin (IV) chloride, aluminum chloride, ferric chloride, zinc chloride, iodine, iron or the like. Preferred reaction-inert solvents include, but are not limited to, diethyl ether, dichloromethane, 1, 2-dichloroethane, carbon disulfide, nitrobenzene or nitromethane. The reaction temperature is preferably in the range of-78-210 deg.C, usually-10 deg.C-the reflux temperature of the solvent, but higher or lower temperatures may be used if necessary. The reaction time is generally from several minutes to 1 day, preferably from 30 minutes to 8 hours, but longer or shorter times may be used if necessary. Scheme 6:
the acetic acid compounds of formulae (VI) and (VII) described in the above schemes can be readily converted to the corresponding amides, compounds or esters of formulae (XVII) and (XVIII), compounds of formula (XII) according to conventional methods known to those skilled in the art.
Scheme 6
As shown in scheme 6, by using a compound wherein R2、R3Compounds of formula (XVII) and (XVIII) can be readily prepared by treating the requisite acetic acid compounds of formulae (VI) and (VIII) with a suitable amine, Y and r being as hereinbefore defined, in the presence of a suitable coupling agent, examples being but not limited to 1- (dimethylaminopropyl) -3-ethylcarbodiimide (WSC), N' -Dicyclohexylcarbodiimide (DCC), carbonyldiimidazole, diethylphosphoryl cyanate (DEPC) and the like. Preferred reaction-inert solvents include, but are not limited to, acetone, acetonitrile, dichloromethane, 1, 2-dichloroethane, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), Dimethylsulfoxide (DMSO), dioxane, Tetrahydrofuran (THF), or pyridine. The reaction temperature is preferably in the range of-40 to 150 deg.C, usually in the range of 15 deg.C to the reflux temperature of the solvent, but higher or lower temperatures may be used if necessary. The reaction time is generally from several minutes to 1 day, preferably from 30 minutes to 8 hours, but longer or shorter times may be used if necessary. The compounds of formulae (VI) and (VIII) can also be readily converted to the corresponding esters by conventional methods. Scheme 7(wherein B is a suitable protecting group, R5Is C1-6Alkyl, E is halogen, Q, X and n are as defined above).
In scheme 7, the reaction starting material of formula 7-I can be prepared according to methods well known to those skilled in the art, including r.w. carling, p.d. leeson, k.moore, j.d. smith, c.r. moyes inJ.Med.Chem.1993, p 3397-3408.
Compounds of formula 7-II may be prepared by treating a compound of formula 7-I with a base and an electrophile in a suitable solvent. Suitable bases include, for example, triethylamine, diisopropylethylamine or optionally substituted by 1 to 3 (C)1-C4) Alkyl substituted pyridines, preferably pyridine. Suitable electrophiles include methanesulfonyl chloride or methanesulfonic anhydride, or benzenesulfonyl chloride wherein the phenyl group in said benzenesulfonyl group optionally contains 1 or2 are selected from halogen, nitro and (C)1-C4) An alkyl substituent. Suitable solvents include dichloromethane, dichloroethane, methyl tert-butyl ether, diisopropyl ether or toluene, preferably dichloromethane. The reaction temperature may be 0 to 50 ℃ as described above, and the reaction is preferably carried out at about room temperature (20 to 25 ℃) for about 1 to 30 hours, preferably 18 hours.
Compounds of formula 7-IV can be prepared from compounds of formula 7-II by treating with a first base and an alkylating agent of formula 7-III in the presence of a solvent, followed by reaction with a second base and then with an acid. Suitable first bases include potassium carbonate, potassium bicarbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate. Suitable solvents include N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or Tetrahydrofuran (THF), preferably N, N-dimethylacetamide. The reaction described above is carried out at a temperature of about 0-100 c, preferably at room temperature (20-25 c) for a period of about 10 minutes to 5 hours, typically 15 minutes. Suitable second bases include a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium tert-amylate (then water), sodium methoxide (then water) or potassium tert-butoxide (then water) in water, preferably sodium hydroxide in water. The reaction with the second base is carried out at a temperature of about 20 to 120 c, preferably 100 c, for a period of about 1 hour to 24 hours, typically 8 hours. Suitable acids include aqueous hydrochloric, hydrobromic, sulfuric or ammonium chloride, preferably aqueous hydrochloric acid. The reaction with the acid is carried out at a temperature of about 0 to 50 c, preferably about 20 to 25 c, for a period of about 1/2 hours to 6 hours, typically about 1 hour.
Alternatively, the compounds of formula 7-II may be converted stepwise to compounds of formula 7-IV. Compounds of formula 7-V can be prepared from compounds of formula 7-II by treatment with a base and an alkylating agent of formula 7-III in the presence of a solvent. Suitable bases include potassium carbonate, potassium bicarbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate. Suitable solvents include N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N, N-dimethylacetamide. The reaction described above may be carried out at a temperature of about 0 to 50 deg.C, preferably at room temperature (20 to 25 deg.C) for a period of about 10 minutes to 40 minutes, typically 30 minutes.
Compounds of formulae 7-VI can be prepared from compounds of formulae 7-V by reaction with a base in the presence of a solvent. Suitable bases include potassium carbonate, potassium bicarbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate. Suitable solvents include N, N-Dimethylacetamide (DMA), N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N, N-dimethylacetamide. The above reaction may be carried out at a temperature of about 0 to 50 deg.C, preferably at room temperature (20 to 25 deg.C) for a period of about 1 hour to 6 hours, preferably 4 hours.
Compounds of formulae 7-VII may be prepared from compounds of formulae 7-VI by reaction with a base in a suitable solvent. Suitable bases include 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 3, 3-tetramethylguanidine, sodium tert-amylate, sodium methoxide or potassium tert-butoxide, preferably 1, 8-diazabicyclo [5.4.0] undec-7-ene, sodium methoxide or potassium tert-butoxide. Suitable solvents include N, N-dimethylformamide, N-dimethylacetamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N, N-dimethylacetamide. The above reaction may be carried out at a temperature of about 0 to 100 deg.C, preferably at room temperature (20 to 25 deg.C) for a period of about 30 minutes to 5 hours, preferably 1 hour.
The compounds of formula 7-IV can be prepared from the compounds of formula 7-VII by treatment with a base in a suitable solvent. Suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-amylate, sodium methoxide, sodium ethoxide or potassium tert-butoxide, preferably sodium hydroxide. Suitable solvents include methanol, ethanol, isopropanol or a mixture of tetrahydrofuran and water, preferably methanol containing water. The reaction described above may be carried out at a temperature of about 10 to 100 deg.C, preferably at room temperature (20 to 25 deg.C) for a period of about 12 to 48 hours, preferably 24 hours, to give the carboxylic acid salt of the compound of formula 7-IV, which is then treated with an acid to give the compound of formula 7-IV.
The compounds of formulae 7-VI contain asymmetric atoms and therefore exist in different enantiomeric and diastereomeric forms. Depending on the physicochemical properties of the diastereomers, mixtures of diastereomers may be separated into the individual diastereomers by methods well known to those skilled in the art, for example, by chromatography or fractional crystallization. The use of all such isomers, including diastereomeric mixtures and pure enantiomers, is considered to be part of the invention.
The starting materials used in the above general syntheses may be obtained by conventional methods known to those skilled in the art. The methods for preparing these materials are described in the accompanying non-limiting examples, which are provided for illustration only. In addition, the necessary raw materials can be obtained by a method similar to that described later or a modification thereof.
The products described in the general syntheses above and in the experimental examples which follow may be isolated by standard methods and purified by conventional means known to those skilled in the art, for example by distillation, crystallization or chromatographic techniques.
Certain of the compounds described therein contain one or more asymmetric centers and can exist in various stereoisomeric forms. The present invention contemplates all such possible stereoisomers and racemates thereof as well as resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Certain compounds of the present invention are capable of forming addition salts with inorganic or organic acids. Pharmaceutically acceptable acid salts of the compounds of formula (I) are those which form non-toxic addition salts and include, but are not limited to, the hydrochloride, hydrobromide, sulfate or bisulfate salts, acetate, benzoate, benzenesulfonate, citrate, fumarate, glucuronate, hippurate, lactate, tartrate, saccharate, succinate, maleate, methanesulfonate, p-toluenesulfonate, phosphate and pamoate salts (i.e., 4' -methylene-bis (3-hydroxy-2-naphthoate)). The pharmaceutically acceptable acid salts may be prepared according to conventional techniques.
Certain compounds of the present invention are capable of forming pharmaceutically acceptable, non-toxic cations. The pharmaceutically acceptable non-toxic cations of the compounds of formula (I) may be prepared according to conventional techniques, for example by contacting the compounds with a stoichiometric amount of the appropriate alkali or alkaline earth metal (sodium, potassium, calcium and magnesium) hydroxide or alkoxide in water or a suitable organic solvent such as ethanol, isopropanol or mixtures thereof.
The scope of protection of the present invention also includes the biological precursors (also called prodrugs) of the compounds of formula (I). A bioprecursor of a compound of formula (I) is a chemical derivative of a compound of formula (I) that readily reverts to the parent compound of formula (I) in a biological system. In particular, when a biological precursor of a compound of formula (I) is administered to and absorbed by a mammalian subject, such as a human, it returns to the parent compound of formula (I). When the compound of formula (I) of the present invention may form a solvate, such as a hydrate, such a solvate is included in the scope of the present invention.
An example of a prodrug of a compound of formula (I) is a compound of formula (I) wherein the 1-position of the indole ring is substituted with a substituent selected from the group consisting of hydroxymethyl, -C (O) -C1-4Alkyl, -C (O) - (NH)2)CH-(C1-4Alkyl), -C (O) -phenyl, -CH2NHC (O) -aryl, -CH2-C1-4alkyl-O-C (O) -C1-4Alkyl, -C1-4Alkyl-pyridyl, -C (O) CH2NR2and-CH2N(C1-4Alkyl radical)2A compound substituted with the group (1).
Another example of a prodrug of a compound of formula (I) is a compound of formula (I) wherein the carboxyl group is replaced by a group selected from C1-4Alkyl, -CH2-C1-4alkyl-O-C (O) -C1-4Alkyl, -CH2-C1-4alkyl-O-C (O) -N (C)1-4Alkyl radical)2、-CH2C(O)N(C1-4Alkyl radical)2、-CH2-C1-4alkyl-O-C (O) -O-C1-4Alkyl, ethyl-OH and CH2CO2A compound substituted with a group of H.
The compounds of formula (I) of the present invention may be administered to a mammal by oral, parenteral or topical administration. In general, it is most desirable to administer these compounds to humans at a dose of 0.01mg to 100mg per kg of body weight per day, although the dose will vary depending on the body weight, sex and physical condition of the subject to be treated, the condition of the disease to be treated and the mode of administration selected, as necessary. However, for the treatment of the above diseases, a dosage level of 0.01mg to 10mg/kg body weight/day, single or divided doses are most desirable.
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the routes of administration described above, and such administration may be accomplished in a single dose or in multiple doses. More particularly, the novel therapeutic agents of the present invention may be administered in a variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, gels, jellies, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, and the like. Furthermore, oral pharmaceutical compositions may be suitably sweetened and/or flavored. Generally, the therapeutically effective compound of the present invention is present in such dosage forms at concentration levels ranging from 5% to 70% by weight, preferably from 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium hydrogen phosphate and glycine may be employed together with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates and particulate binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used to make tablets. Similar solid compositions may also be employed as fillers in gelatin capsules, preferred such materials also including lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are to be used for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, emulsifying and/or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.
For parenteral administration, solutions of the compounds of the invention in sesame or peanut oil or in aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably pH > 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-arterial injection, intramuscular injection and subcutaneous injection. All of these solutions are readily prepared under sterile conditions according to standard pharmaceutical techniques well known to those skilled in the art. In addition, when treating skin inflammation, the compounds of the present invention may also be administered topically, and preferably in the form of creams, jellies, gels, pastes, ointments and the like, following standard pharmaceutical procedures.
The compounds of formula (I) may also be administered in the form of suppositories for rectal or vaginal administration of the active ingredient. The active ingredient is released by mixing it with a suitable non-irritating excipient which is solid at room temperature (e.g. 10-32℃.) but liquid at the rectal temperature and will melt in the rectum or vagina. Such materials are polyethylene glycols, cocoa butter, suppositories and waxes.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. In combination with other drugs:
the compounds of formula I are useful in, but not limited to, treating inflammation in a subject, in treating other inflammation-related disorders such as for example, as analgesics for treating pain and headache, or as antipyretics for treating fever. For example, the combinations of the present invention may be used to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. These combinations of the invention will be useful in the treatment of asthma, bronchitis, menstrual cramping pain, tendonitis, bursitis and skin conditions such as psoriasis, eczema, burns and dermatitis. The combination of the invention is also useful for the treatment of gastrointestinal disorders such as inflammatory bowel disease, crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, for the prevention of colorectal cancer. The combinations of the invention are useful in the treatment of inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, allergy, conjunctivitis, post-traumatic swelling, myocardial ischemia, and the like. The combinations of the invention are useful in the treatment of certain central nervous system disorders such as Alzheimer's disease and dementia. The combination of the invention is useful as an anti-inflammatory agent, for example for the treatment of arthritis, and also has the additional advantage of having significantly fewer harmful side effects. These combinations are also useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, atherosclerosis and central nervous system injury caused by stroke, ischemia and trauma.
The compounds of formula (I) will be useful as a partial or complete replacement for NSAID's commonly used in formulations where they are administered simultaneously with other agents or components. Accordingly, the present invention includes pharmaceutical compositions for treating the COX-2 mediated diseases described above, comprising a non-toxic therapeutically effective amount of a compound of formula (I) and one or more components such as another analgesic, including acetaminophen and phenacetin; synergists, including caffeine; h2-antagonists, aluminium or magnesium hydroxide, dimethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudoephedrine, phentolazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine or levo-oxidized epinephrine; an antitussive comprises codeine, hydrocodone, caramiphene, carbetapentane or dextromethorphan; a prostaglandin comprises misoprostol, enprost, lioprost, and unoprostLinalool or roxaprost; a diuretic agent; an antihistamine with or without sedative effect; an anticancer agent such as angiostatin and an internal inhibitor; anti-alzheimer's agents such as Doepezil and tacrine hydrochloride; and TNF-alpha inhibitors such as Etanercept.
The cyclooxygenase inhibitors may also be used in combination with a nitric oxide inhibitor as disclosed in WO 96/28145.
The invention also includes pharmaceutical compositions for treating the COX-2 mediated diseases described above comprising a non-toxic therapeutically effective amount of a compound of formula (I) and one or more anti-ulcer agents and/or prostaglandins as disclosed in WO 97/11701.
Prostaglandins that may be used include misoprostol, plus-minus 11 α, 16-dihydroxy-16-methyl-9-oxoprostaglandin-13E-ene-1-oic acid methyl ester; enisoprost and 7- [2B- [6- (1-cyclopenten-1-yl) -4-hydroxy-4-methyl-1E, 5E-hexadiene ] -3 α -hydroxy-5-oxo-1R, 1 α -cyclopentyl ] -4Z-heptenoic acid methyl ester. Prostaglandins falling within the scope of the present invention also include abaprost, enprost, lioprost, nochloroprost, mexiprost, oloprost, dimoproprost, tiprost and roxaprost.
The compounds of the invention may also be used in co-therapy, partially or completely replacing other commonly used anti-inflammatory agents, for example with steroids, 5-lipoxygenase inhibitors, LTB4Antagonists and LTA4The hydrolase inhibitors are used together.
LTB is disclosed in WO97/297744Examples of (3). Suitable LTB 4Examples of inhibitors include ebuximab, Bayer Bay-x-1005, Ciba Geigy CGS-25019C, LeoDenmark compound ETH-615, Lilly Compound LY-293111, Ono Compound ONO-4057, Terumo Compound TMK-688, Lilly Compound LY-213024, 264086 and 292728, Ono Compound ONO-LB457, Searle Compound SC-S3228, calcitriol, Lilly Compound LY-210073, LY-223982, LY233469 and LY255283, Ono Compound ONO-LB-448, Searle Compound SC-41930, SC-50605 and SC-51146, and SK&SKF-1044 of compound F93. Preferably, LTB4The inhibitor is selected from the group consisting of ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688.
Examples of 5-LO inhibitors are disclosed in WO 97/29776. Examples of suitable 5-LO inhibitors include maxoprocol, tenidapa, zileuton, pranlukast, tipaxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.
LTA is disclosed in WO97/297744Examples of hydrolase inhibitors, suitable LTA4The hydrolase inhibitor comprises Rhone-Poulene Rorer RP-64966.
Administration of the compounds of the invention may be for prophylactic or therapeutic purposes. The methods and compositions used herein may be used alone or in combination with other therapeutic methods known to those skilled in the art for preventing or treating angiogenesis. In addition, the methods and compositions described herein may be used as an adjunct therapy. For example, the cyclooxygenase-2 inhibitor can be administered alone or in combination with other antineoplastic agents or other growth inhibitory agents or other drugs or nutrients.
A large number of antineoplastic agents have been commercially, clinically evaluated and preclinically developed from which agents for use in the treatment of angiogenesis can be selected for use with pharmacological chemotherapy. Such antitumor agents are classified into several broad classes, i.e., antibiotic-type agents, alkylating agents, antimetabolite agents, hormones, immunological agents, interferon-type agents, and miscellaneous agents. Other antineoplastic agents such as metal-matrix protease inhibitors (MMPs), e.g., MMP-13 inhibitors including batiastat, marimastat, Agouron Pharmaceuticals AG-3340 and Roche R0-32-3555 or alpha, beta inhibitors, may additionally be used.
The first family of antineoplastic agents that can be used in combination with an optional cyclooxygenase-2 inhibitor consists of antimetabolite antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from the group consisting of 5-Fu-fibrinogen, echinocandic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-GeityCGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugate, Lilly DATHF, Merrel Dow DDFC, dizazyganine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, deoxyfluorouridine, Wellcome EHNA, Merck & Co.EX-015, fazabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2' -furyl) -5-fluorouracil, Daiichi Seiyaku F0-152, ispyproly, LillyLY-188011, Lilly-36LY 82, methobenzapine, ZPES, WellNCI, NCNCI-264880, NSInNCI-264880, NSIcC-59 39661, and NCC-5-fluorouracil, Warner-Lambert PALA, pentostatin, pirbecsin, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, thiazolorubin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, and uricytin.
The second family of antineoplastic agents which can be used in combination with an optional cyclooxygenase-2 inhibitor consists of alkylated antineoplastic agents. Suitable alkylated antineoplastic agents may be selected from the group consisting of Shionogi254-S, oxophosphoramide analogs, hexamethylmelamine, Analoxidone, Boehringer Mannheim BBR-2207, bestrabuchil, Brodotetitanium, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American cyanamid CL-286558, Sanofi CY-233, cytoplatite, Degussa D-19-384, Sumimoto DACHP (Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba ristomycin derivatives, Chugai DWA-2114R, ITI E09, emetine, ErbamentFCE-24517, estramustine, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, Isobutidoxuron-17230, Isochrysin, Nakamural-121, dulafamium, platinum-2, and their pharmaceutically acceptable salts, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-II9, ranimustine, semustine, SmithKline SK & F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, taurocastine, temozolomide, tiroxilone, tetraplatin and trimelamol.
The family III antineoplastic agents that can be used in combination with an optional cyclooxygenase-2 inhibitor consist of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the group consisting of Taiho4181-A, adroxicin, actinomycin D, actinoplanone, Erbamont ADR-456, aerolysin derivatives, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycin, anthracycline, azinomycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMy-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryonine-1, Taiho C-1-2, Kyowa KkoDC-79, yowa Hakko DC-88A, Kyowa A-89, Shisano Hakko A-92, Shisanorin B, Shisanorin-3641, Shisanomycin B-92, Shisanomycin B-3641, Shisanomysin, Shistol-B, Shisanomycin, and optionally, Epirubicin, erbstatin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostricin, Fujisawa FR-900482, glidobacter, gregatin-A, grincamycin, herbicidin, idarubicin, cryptomerin, kazusamycin, kesarrhodin, Kyowa HakkokKM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, Ameri Cyanumi LL-D49194, Meijiseika ME 3, minoritrin, mitomycin, mitoxantrone, Smitym-smith, Klenosin, Klenosine-Al, esperamicin-Alb, Brazimin-N-S-D-49194, Meijikutsin-S-K-D-2303, Meijiika ME 3, mitomycin, Smithm-SM-S-B-K, Klenomycin-313, rapamycin, Brazizanin, Brazicin, rapamycin-S-D-Na-D-Na-, Snow Brand SN-07, sorangin-A, sparamycin, SSpharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSpharmaceutical SS-9816B, spartinamycin B, Taiho 4181-2, talithromycin, TakedaTAN-868A, terpentitecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-2S024, and zorubicin.
A fourth family of antineoplastic agents which may be used in combination with the optional cyclooxygenase-2 inhibitor consists of a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, Averme A, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphetamine, amsacrine, angiostatin, ancinomycin, antitumor AIO, antitumor A2, antitumor A3, antitumor A5, antitumor AS2-1, Henkel APD, aphidicolin, glycinate, asparaginase, avarol, swallow, balamin, benflurron, chlorophenyl tryptophan, Ipsen-BeauFOur BIM-23015, Bisheng, Bri-Myers BMY-40481, Vestar boron-IO, bromothiophonamide, Wembo BW-502, carboxim-BW-3, carboximes hydrochloride, carboximes 773, carboximes-772, carboximes-CDQ, ChloroE-D, ChloroE-2, ChloroE-D, ChloroE-2, ChloroE-D, ChloroE-D, E, Chemes CHX-i00, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claveridonone, ICN compound 1259, ICH compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, BIS maleate, dacarbazine, dacchloramine, didemnin-B, hematoporphyrin ether, lentilone, denalin, stemycin, Toyo GR-75, Daiichi Seiyaku-9693, ellimirabin, eletamine, VIRU, VITAMIN 221, EPIPAI, EPAIGRAIA 56, CbaI-3643, Gliavorax-7, Cbax-0, Gliavorax-7, Csajou-5, Glabrodensine, Glyphene-N-A-36633635, Glyphene-7, Glyphene-A-III, Glyphene-N-III, Glyphenyl-N-A-III, Glyphenyl-7, Glyphenyl-L, and S, Homoharringtonine, hydroxyurea, BTG ICRF-187, isomofoxin, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukaregulin, Ionidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medmedr-340, merbarone, merocanine derivatives, methylanilide, Molecular Genetics MGI-136, minovirin, mitonaphthylamine, mitoquinolone, mopidanol, muvian amine, Zenyakya Kogyal T-16, N- (MSYnoyl) MGI-02132, Nosidaco, Novonamic-145813, Novozac-N-6, Novozac, Novonamine, Novozac-35, Novozac-2, Novozac, NCI NSC-361456, NCI NSC-604782, NCINSC-95580, octreotide, Ono ONO-112, oquinazocine, Akzo Org-10172, pancreatin, pazestin, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT polypeptide D, piroxantrone, polyhedrosophiline, polypreoic acid, phenoxypropylamine porphyrin, probamazine, procarbazine, progluride, Invitron protease nexin I, Tobishira-700, Razoxan, sapphire Brweries RBS, restrictocin-P, retelliptine, retinoic acid, Rholenone-Poulenc-49532, Rhone-Poulenc RP-56976, Smith SM & Klitron S-104864, Surveitchinson S-10094, Suremtrol S-023, Skomatrypsin-S-10, Skomato S-6, Skomato-S-10, Skomatoxib, Skomato S-6, Skomatoxib, Skomato S-6, Skomatoxib-S2, Skomatoxib-S2, Skomato, Suntory SUN2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, TeijinTEI-0303, teniposide, thalblitine, Eastman Kodak TJB-29, tocotrienol, Topottin, Teijin TT-82, Kyowa Hakko UCN-O1, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolide and Yamanouchi YM-534.
Examples of radioprotectants that may be used with the chemotherapy of the present invention are AD-5, adchnon, amifostine analogs, bone aminoglycosides, dimesna, 1-102, MN-159, N-acylated-dehydroalanine, TGF-Genentech, tiaprofenic, amifostine, WR-151327, FUT-187, transdermal ketoprofen, nabumetone, superoxide dismutase (Chiron), and superoxide dismutase Enzon.
Methods for preparing the above-mentioned antineoplastic agents can be found in the literature. Processes for the preparation of doxorubicin are described, for example, in USP3,590,028 and US4,012,448; methods for preparing metal-matrix protease inhibitors are described in EP780386, WO97/20824, WO 96/15096; a process for the preparation of SOD mimetics is described in EP524,101; methods for preparing alpha, beta inhibitors are described in WO 97/08174.
In addition, selective COX-2 inhibitors may be administered with other anti-inflammatory agents for the safest and most effective treatment. These anti-inflammatory agents include: NSAID's, selective inhibitors of COX-1, and inhibitors of the leukotriene pathway, including 5-lipoxygenase inhibitors. Examples of NSAID's include indomethacin, naproxen, ibuprofen, salicylic acid derivatives such as aspirin, diclofenac, ketorolac, piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium, zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulide, zaltoprofen and letodolac.
Methods for evaluating biological activity:
the activity of the compounds of formula (I) according to the invention is demonstrated by the following tests. In vitro assay based on COX-1 assay in human cells
Human peripheral blood obtained from healthy volunteers was diluted to 1/10 volumes with a 3.8% sodium citrate solution. The platelet-rich plasma just obtained was washed with 0.14M sodium chloride containing 12mM Tris-HCl (pH7.4) and 1.2mM EDTA. The platelets were then washed with platelet buffer (Hanks buffer containing 0.2% BSA and 20mM Hepes (Ca free)). Finally, the washed human platelets (HWP) were suspended at a concentration of 2.85X 108Cells/ml in platelet buffer, stored at room temperature until use. HWP suspension (70. mu.l each, final concentration 2.0X 10)7One cell/ml) was placed in a 96-well U-shaped bottom plate, and 10. mu.l of 12.6mM CaCl was added to each portion2Platelets were incubated with A23187 (final concentration 10. mu.M, Sigma) and test compound (0.1-100. mu.M) in DMSO (final concentration less than 0.01%) for 15 minutes at 37 ℃. The reaction was stopped by addition of EDTA (final concentration 7.7mM) and TxB2 in the supernatant was quantitated using a radioimmunoassay kit (Amersham) following the manufacturer's protocol. COX-2 assay based on human cells Inhibition of COX-2 activity following COX-2 induction with hIL-1 betaSystem for making
Human cell-based COX-2 assays were performed as previously described (Moore et al Inflam. Res, 45, 54, 1996). Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in 96-well U-bottomed dishes were washed with 100. mu.l of RPMI1640 containing 2% FCS at 37 ℃ with hIL-1. beta. (final concentration 300 units/ml, R)&D Systems) were incubated together for 24 hours. After washing, activated HUVECs were stimulated for 15 minutes at 37 ℃ with A23187 (final concentration 30. mu.M) in Hanks buffer containing 0.2% BSA, 20mM Hepes and test compound (0.1 nM-100. mu.M) in DMSO (final concentration less than 0.01%). After sufficient dilution, 6-keto-PGF 1 α, a stable metabolite of PGI2, was quantitatively determined in the supernatant using a radioimmunoassay kit (Amersham) following the manufacturer's procedure.Inhibition of COX-2 during induction
Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in 96-well U-bottomed dishes were washed with 100. mu.l RPMI1640 containing 2% FCS and test compound (0.1 nM-100. mu.M) in DMSO (final concentration < 0.01%) and incubated with hIL-1. beta. (final concentration 300 units/ml, R & D Systems) for 24 hours at 37 ℃. After washing, HUVECs were challenged with A23187 (final concentration 30. mu.M) in Hanks buffer containing 0.2% BSA and 20mM Hepes for 15 min at 37 ℃. After sufficient dilution, 6-keto-PGF 1 α, a stable metabolite of PGI2, was quantitatively determined in the supernatant using a radioimmunoassay kit (Amersham) following the manufacturer's procedure. In vivo test carrageenan-induced foot edema in rats
Male Sprague-Dawley rats (aged 5 weeks, Charles River Japan) were fasted overnight. The paw volume was measured by draining with a plethysmometer (Muromachi) by drawing a line above the ankle of the right hind paw with a marker (V0). Animals were dosed orally with vehicle (0.1% methylcellulose or 5% Tween80) or test compound (2.5ml/100g body weight). After 1 hour, the right hind paw of the animal was injected subcutaneously with lambda carrageenan (0.1ml of 1% w/V saline suspension, Zushikagaku) (Winter et al, Proc. Soc. exp. biol. Med., 111, 544, 1962; Lombardino et al, Arzneim. Forsch., 25, 1629, 1975) and paw volumes (V3) were measured after 3 hours and volume increase values (V3-V0) were calculated. Since the maximum inhibition obtained with classical NSAIDs is 60-70%, the ED30 value was calculated. Gastric ulcer in rat
The gastric ulcer-inducing effects of the test compounds were evaluated by modified conventional methods (Ezer et al, J.Pharm.Pharmacol., 28, 655, 1976; Cashin et al, J.Pharm.Pharmacol., 29, 330-336, 1977). Male Sprague-Dawley rats (age 5 weeks, Charles River Japan) after an overnight fast were given either oral vehicle (0.1% methylcellulose or 5% Tween80) or test compound (1ml/100g body weight). After 6 hours, animals were killed by cervical approach. The stomach was removed and expanded with formalin solution (10 ml). The stomach was cut along the stomach bay. The incidence of ulcers was calculated from the number of rats with at least one gastric ulcer or hemorrhagic erosion, including plaque. Animals were not allowed to feed or water during the test period. Data analysis
Statistical packages SYSTAT (SYSTAT, INC.) and StatView (Abacus centers, Inc.) for Macintosh were used. The ANOVA was used to test the difference between the group treated with the test compound and the control group. Calculation of IC from the equation of the log linear regression line of concentration (dose) with percent inhibition50(ED30)。
Some of the compounds prepared in the working examples described later were tested by these methods, indicating IC's for COX-2 inhibition50The value is 0.001. mu.M to 10. mu.M.
The most preferred compounds described above were also tested by these methods, indicating IC for COX-2 inhibition50The value is 0.001. mu.M-0.5. mu.M.
By COX-1 inhibiting IC50IC of value and COX-2 inhibition50The ratio of values may determine the selectivity to COX-2. In summary, it can be said that compounds with COX-1/COX-2 inhibition ratios greater than 2 have good COX-2 selectivity.
Some of the compounds prepared in the examples have COX-1/COX-2 inhibition ratios greater than 10.
The following examples contain detailed descriptions of the preparation of the compounds of formula (I). These detailed descriptions, which fall within the scope of the present invention, are intended to exemplify the general synthetic methods described above and form part of the present invention. The detailed description is provided for illustration only and is not intended to limit the scope of the invention.
Examples
The invention is illustrated in the following non-limiting examples, all operations being carried out at room or ambient temperature, i.e. in the range of from 18 to 25 ℃ unless otherwise indicated; evaporation of the solvent is carried out under reduced pressure with a rotary evaporator at bath temperatures up to 60 ℃; the reaction was monitored by thin layer chromatography (tlc), the reaction times given are for illustration only; the melting points given (m.p.) were not corrected (polymorphism would result in different melting points); the structure and purity of all isolated compounds was confirmed by at least one of the following techniques: tlc (Merck silica gel 60F-254 pre-coated plate), mass spectrometry, Nuclear Magnetic Resonance (NMR), or microanalysis. The yields are given for illustration only. Flash column chromatography was performed using Merck silica gel 60(230 and 400 mesh ASTM). Low resolution mass spectral data (EI) were obtained on an automated 120(JEOL) mass spectrometer. Low resolution mass spectral data (ESI) were obtained on a Quattro II (Micromass) mass spectrometer. Unless otherwise indicated, NMR data were measured at 270MHz (JEOLJNM-LA 270 spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent, expressed in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard, commonly used abbreviations are: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, etc. Example 1 (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester Step 1. trans-4-chloro-2-nitrocinnamic acid ethyl ester
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 4.4g, 0.11mol) in THF (150ml) was added dropwise a solution of triethyl phosphonoacetate (25.0g, 0.11mol) in THF (50ml) at room temperature. After stirring for 1 hour, a solution of 4-chloro-2-nitrobenzaldehyde (19.0g, 0.10mol) in THF (50ml) was added. After stirring for a further 1 hour, addSaturated aqueous ammonium chloride (50ml) was added to the solution, and the resulting mixture was extracted with ethyl acetate (300 ml. times.2). The combined organic extracts were dried (magnesium sulfate) and concentrated to give 27g (quantitative) of the title compound as a brown solid.1H-NMR(CDCl3)δ：8.04(1H，d，J＝15.8Hz)，8.03(1H，d，J＝1.8Hz)，7.64-7.58(2H，m)，6.36(1H，d，J＝15.8Hz)，4.30(2H，q，J＝7.0Hz)，1.35(3H，t，J＝7.0Hz).Step 2. trans-2-amino-4-chlorocinnamic acid ethyl ester
Ethyl trans-4-chloro-2-nitrocinnamate (step 1, 27.0g, 0.11mol) and sodium hydrosulfide (92g, 0.53mol) in THF-H were stirred at room temperature2O (1: 1, 500ml) solution for 1 hour. Then, saturated aqueous sodium hydrogencarbonate (300ml) was added and the mixture was extracted with ethyl acetate (300 ml. times.2). The combined organic extracts were dried (magnesium sulfate) and concentrated to give 16.7g (67%) of the title compound as a yellow solid.1H-NMR(CDCl3)δ：7.72(1H，d，J＝15.8Hz)，7.27(1H，d，J＝8.4Hz)，6.78-6.68(2H，m)，6.31(1H，d，J＝15.8Hz)，4.27(2H，q，J＝7.0Hz)，1.33(3H，t，J＝7.0Hz).Step 3, trans-4-chloro-2-formylaminocinnamic acid ethyl ester
A mixture of acetic anhydride (20ml) and formic acid (10ml) was heated at 60 ℃ for 2 hours. After cooling to 0 ℃ a solution of ethyl trans-2-amino-4-chlorocinnamate (step 2, 15.5g, 0.069mol) in THF (80ml) was carefully added. The resulting mixture was allowed to warm to room temperature. After stirring overnight, the mixture was concentrated, the precipitate collected by filtration, and the solid was washed with hexane to give 9.6% (55%) of the title compound.1H-NMR(CDCl3)δ：9.40-9.15(1H，m)，8.51-8.40(1H，m)，8.10-7.80(2H，m)，7.60-7.47(1H，m)，7.28-7.12(1H，m)，6.40(1H，d，J＝15.8Hz)，4.25(2H，q，J＝7.3Hz)，1.34(3H，t，J＝7.3Hz).Step 4, trans-4-chloro-2-isocyano ethyl cinnamate
To a solution of triphenylphosphine (5.3g, 20mmol) in dichloromethane (80ml) cooled to 0 deg.C was added dropwise a solution of triphosgene (2.0g, 6.7mmol) in dichloromethane (20 ml). The ice bath was removed and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was then cooled to 0 ℃ and a solution of ethyl trans-4-chloro-2-carboxamido cinnamate (step 3, 5.2g, 0.020mol) in dichloromethane (80ml) was added. The mixture was allowed to warm to room temperature overnight and then concentrated. The residue was partitioned between water (80ml) and ethyl acetate (100ml), the aqueous layer was separated and extracted with ethyl acetate (100 ml). The combined organic extracts were dried (magnesium sulfate), the solvent was evaporated and the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 6) to give 3.9g (83%) of the title compound as a white solid. 1H-NMR(CDCl3)δ：7.89(1H，d，J＝16.1Hz)，7.60(1H，d，J＝8.8Hz)，7.45(1H，d，J＝1.8Hz)，7.42(1H，dd，J＝1.8，8.8Hz)，6.52(1H，d，J＝16.1Hz)，4.30(2H，q，J＝7.0Hz)，1.35(3H，t，J＝7.0Hz).(2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester
A mixture of ethyl trans-4-chloro-2-isocyano cinnamate (step 4, 1.2g, 5.1mmol), tributyltin hydride (1.6g, 5.6mmol) and AIBN (43mg, 0.26mmol) in acetonitrile (30ml) was heated at 100 ℃. After 1h tetrakis (triphenylphosphine) palladium (580mg, 0.50mmol) and benzoyl chloride (0.65ml, 5.6mmol) were added and the mixture heated for an additional 17 h. The mixture was cooled, poured into 2N aqueous HCl (50ml) and extracted with ether (80 ml. times.2). The combined organic extracts were extracted with saturated aqueous potassium fluoride (50ml) and dried (magnesium sulphate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 5) to give 0.43g (25%) of the title compound as a white solid. Melting point: 160 ℃ and 163 ℃.1H-NMR(CDCl3)δ：8.94(1H，br s)，7.82-7.75(2H，m)，7.67-7.47(4H，m)，7.37(1H，d，J＝1.8 Hz)，7.13(1H，dd，J＝1.8，8.4Hz)，4.11(2H，q，J＝7.3Hz)，3.78(2H，s)，1.22(3H，t，J＝7.3Hz).Example 2 (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acidMethod A
To a solution of ethyl (2-benzoyl-6-chloro-1H-indol-3-yl) acetate (example 1, 380mg, 0.11mmol) in ethanol (15ml) was added 2N KOH (5 ml). After heating at 80 ℃ for 1 hour, the mixture was cooled and concentrated, then 2N was carefully addedAqueous HCl (15ml), the mixture was extracted with ether (50 ml. times.2), the combined organic extracts were dried (magnesium sulfate) and concentrated. The remaining solid was recrystallized from ethyl acetate/hexane to yield 60mg (17%) of the title compound as a pale yellow solid. m.p.: 183 ℃.1R (KBr) v: 1700, 1610, 1520, 1425, 1330, 1000cm -1.1H-NMR(DMSO-d6) δ: 12.26(1H, br s), 11.76(1H, s), 7.77-7.66(4H, m), 7.62-7.54(2H, m), 7.48(1H, d, J ═ 1.8Hz), 7.13(1H, dd, J ═ 1.8, 8.7Hz), 3.80(2H, s)Step 1.6-chloro-1- (phenylsulfonyl) indole
6-chloroindole (Y.Watanabe et al, J.org.chem., 1990,55580, 36.2g, 0.24mol), tetrabutylammonium hydrogensulphide (8.1g, 0.024mol) and 50% KOH (160ml) in benzene (500ml) were mixed for 10 minutes, then the mixture was cooled to 0 ℃ and a solution of benzenesulfonyl chloride in benzene (20ml) was added. After stirring at room temperature for 3 hours, the mixture was poured into water (200ml), the organic layer was separated, and the aqueous layer was extracted with ether (200 ml. times.2). The combined organic extracts were washed with brine (200ml), dried (magnesium sulfate) and concentrated. The remaining solid was washed with ethanol (100 ml. times.3) to give 58g (83%) of the title compound as an off-white solid.1H-NMR(CDCl3)δ：8.02(1H，s)，7.92-7.85(2H，m)，7.60-7.40(5H，m)，7.21(1H，dd，J＝1.8，8.4Hz)，6.62(1H，d，J＝3.6Hz).Step 2.6-chloro-2-benzoyl-1- (phenylsulfonyl) indole
To a solution of 6-chloro-1- (benzenesulfonyl) indole (step 1, 12.58g, 43.0mmol) in THF (270ml) cooled to-78 deg.C was added dropwise tert-butyllithium (32ml, 52.0mmol, 1.64M n-pentane) with stirring and the internal temperature was kept below-65 deg.C. After stirring for 30 minutes at-78 deg.C, the solution was transferred via cannula to a solution of benzoyl chloride (6.0ml, 52.0mmol) in THF (30ml) cooled to-78 deg.C. The mixture was stirred for 1.5 h and then quenched with a saturated solution of ammonium chloride (200ml) cooled to-78 ℃ and the mixture was warmed to room temperature. The aqueous layer was separated, neutralized with aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (50 ml. times.2). The combined organic extracts were washed with brine Washed (50ml), dried (magnesium sulfate) and concentrated. The residue was crystallized from ether/hexane (1: 3) to give the title compound as a white solid (14.4g, 85%).1H-NMR(CDCl3)δ：8.20-8.16(1H，m)，8.14-8.06(2H，m)，8.01-7.93(2H，m)，7.66-7.47(7H，m)，7.29(1H，dd，J＝1.7，8.5Hz)，6.89(1H，J＝0.7Hz).Step 3.2-benzoyl-6-chloroindole
2-benzoyl-6-chloro-1- (phenylsulfonyl) indole (step 2, 48g, 0.12mol) and potassium carbonate (80g, 0.58mol) in THF-MeOH-H2The mixture in O (4: 2: 1, 1100ml) was heated to reflux overnight. After removal of the solvent, the residue was extracted with ether (300ml × 2) and dried (magnesium sulfate). The solvent was removed to give the crude product as a light brown solid. After recrystallization from ethyl acetate, 20g (65%) of the title compound are obtained as a white solid. m.p.: 206- & lt207 & gt.1H-NMR(CDCl3)δ：9.31(1H，br s)，8.01-7.95(2H m)，7.68-7.47(5H，m)，7.17-7.12(2H，m).Step 4. alpha-acetoxy- (2-benzoyl-6-chloro-1H-indol-3-yl) malonic acid diethyl ester
A mixture of 2-benzoyl-6-chloroindole (step 3, 4.0g, 16mmol), manganese (III) acetate dihydrate (13g, 48mmol), diethyl malonate (14g, 80mmol) and sodium acetate (6.6g, 80mmol) in acetic acid (150ml) was heated and stirred at 80 ℃ for 2 hours. Manganese (III) acetate dihydrate (3g, 11mmol) was added and heating was continued for 2 hours. The mixture was cooled and brine (200ml) was added. The resulting mixture was extracted with diethyl ether (200ml × 2), and the combined organic extracts were dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 3) to give 5.2g (69%) of the title compound as a yellow solid. m.p.: 141 and 144 ℃. 1H-NMR(CDCl3)δ：8.84(1H，br s)，7.90-7.81(3H，m)，7.66-7.58(1H，m)，7.51-7.42(2H，m)，7.38(1H，d，J＝1.3Hz)，7.15(1H，dd，J＝2.0，8.7Hz)，4.30-4.06(4H，m)，1.70(3H，s)，1.30-1.58 (6H，m).Step 5 (2-benzoyl-6-chloro-1H-indol-3-yl) malonic acid diethyl ester
Alpha-acetoxy- (2-benzyl)A mixture of acyl-6-chloro-1H-indol-3-yl) malonic acid diethyl ester (step 4, 5.0g, 11mmol), trifluoroacetic acid (3.3ml, 44mmol) and triethylsilane (2.1ml, 13mmol) in dichloromethane (80ml) was heated under reflux for 12H, then cooled and concentrated. The resulting residue was partitioned between saturated aqueous sodium bicarbonate (50ml) and dichloromethane (80 ml). The aqueous layer was separated and extracted with dichloromethane (80 ml). The combined organic extracts were dried (magnesium sulfate) and the solvent was removed. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 4) to give 4.0g (87%) of the title compound as a white solid.1H-NMR(CDCl3)δ：8.93(1H，br s)，7.81-7.70(3H，m)，7.68-7.60(1H，m)，7.55-7.48(2H，m)，7.32(1H，s)，7.12(1H，dd，J＝1.8，8.8Hz)，5.29(1H，s)，4.26-4.09(4H，m)，1.21(6H，t，J＝7.1Hz).(2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid
A solution of diethyl (2-benzoyl-6-chloro-1H-indol-3-yl) malonate (step 5, 4.4g, 11mmol) in a mixture of ethanol (120ml) and 2N aqueous NaOH (15ml) was heated under reflux for 1 hour. The mixture was cooled and concentrated, the residue was carefully acidified with 2N aqueous HCl (30 ml). The mixture was extracted with ether (150 ml. times.3), and the combined extracts were dried (magnesium sulfate) and concentrated. The remaining solid was recrystallized from ethyl acetate/hexane to give 1.1g (30%) of the title compound as a pale yellow solid. m.p.: 183-186 ℃ IR (KBr) v: 1700, 1610, 1520, 1425, 1330, 1000cm -1.1H-NMR(DMSO-d6)δ：12.26(1H，br s)，11.76(1H，s)，7.77-7.66(4H，m)，7.62-7.54(2H，m)，7.48(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝1.8，8.7Hz)，3.80(2H，s).Example 3 (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, sodium salt
A solution of (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2, 480mg, 1.5mmol) in ethanol (10ml) was treated with 2N aqueous NaOH (0.7ml, 1.4mmol) at room temperature for 30 min and then concentrated. The residue was dissolved in water (10ml), washed with diethyl ether (15 ml. times.2), and the aqueous layer was concentrated to give 350mg (68%) of the title compound as a pale brown solid.m.p.：185-189℃.IR(KBr)ν：1523，1380，1230，1060，1004，918cm-1.1H-NMR(DMSO-d6)δ：11.46(1H，br s)，7.88-7.84(2H，m)，7.66(1H，d，J＝8.4Hz)，7.64-7.46(3H，m)，7.39(1H，d，J＝1.8Hz)，7.00(1H，dd，J＝1.8，8.4Hz)，3.32(2H，s).Example 4 [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (2-methylbenzoyl) -1- (benzenesulfonyl) indole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and o-methylbenzoyl chloride following the method described in step 2 of example 2 (method B). 0.3 part of tlc: Rf (1: 10 parts of ethyl acetate/hexane)Step 2.6-chloro-2- (2-methylbenzoyl) indole
The title compound was prepared from 6-chloro-2- (2-methylbenzoyl) -1- (benzenesulfonyl) indole (step 1) following the procedure described in step 3 of example 2 (method B).1H-NMR(CDCl3)δ：9.37(1H，br s)，7.58(2H，d，J＝8.91Hz)，7.48(1H，s)，7.42(1H，dd，J＝1.49，7.75Hz)，7.34-7.27(2H，m)，7.12(2H，dd，J＝1.81，8.56Hz)，2.44(3H，s).Step 3. alpha-acetoxy- [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl]Malonic acid Diethyl ester
The title compound was prepared from 6-chloro-2- (2-methylbenzoyl) indole (step 2) following the procedure described in step 4 of example 2 (method B). 1H-NMR(CDCl3)δ：8.52(1H，br s)，7.78(1H，d，J＝8.88Hz)，7.48-7.13(6H，m)，4.31-4.16(4H，m)，2.52(3H，s)，1.96(3H，s)，1.22(6H，t，7.26Hz).Step 4.[ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), from α -acetoxy- [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：9.0(1H，br s)，7.73(1H，d，J＝8.88Hz)，7.73-7.09(5H，m)，7.11(1H，dd，J＝1.97，8.75Hz)，4.89(1H，s)，4.20-4.08(4H，m)，2.35(3H，s)，1.19(6H，t，J＝7.1Hz).Step 5.[ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 150 ℃. IR (KBr) v: 3321, 1717, 1624, 1602, 1568, 1531, 1431, 1319, 1249, 1230cm-1.1H-NMR(DMSO-d6)δ：11.70(1H，s)，7.69(2H，d，8.72Hz)，7.51-7.31(3H，m)，7.10(2H，dd，J＝1.97，8.56Hz)，3.57(2H，s)，2.24(3H，s).Example 5 [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (3-methylbenzoyl) -1- (benzenesulfonyl) indole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and m-methylbenzoyl chloride following the method described in step 2 of example 2 (method B). 0.3 part of tlc: Rf (1: 10 parts of ethyl acetate/hexane)Step 2.6-chloro-2- (2-methylbenzoyl) indole
The title compound was prepared from 6-chloro-2- (3-methylbenzoyl) -1- (benzenesulfonyl) indole (step 1) following the procedure described in step 3 of example 2 (method B). 1H-NMR(CDCl3)δ：9.37(1H，s)，7.77(2H，br s)，7.64(1H，d，J＝8.56Hz)，7.47-7.12(5H，m)，2.47(3H，s).Step 3. alpha-acetoxy- [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Malonic acid Diethyl ester
The title compound was prepared from 6-chloro-2- (3-methylbenzoyl) indole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.80(1H，br s)，7.83(1H，d，J＝8.88Hz)，7.67-7.32(5H，m)，7.16(1H，dd，J＝1.81，8.88Hz)，4.27-4.15(4H，m)，2.39(3H，s)，1.72(3H，s)，1.29(6H，t，J＝7.26Hz).Step 4.[ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl) malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), from α -acetoxy- [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：9.21(1H，br s)，7.71(1H，d，J＝8.51Hz)，7.59-7.28(5H，m)，7.10(1H，dd，J＝1.97，8.72Hz)，5.27(1H，s)，4.23-4.07(4H，m)，2.40(3H，s)，1.21(6H，t，J＝7.1Hz).Step 5.[ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 182 ℃. 184. IR (KBr) v: 3313, 1699, 1616, 1568, 1533, 1408, 1325, 1265, 1203cm-1.1H-NMR(DMSO-d6)δ：11.75(1H，s)，7.70(1H，d，J＝8.75)，7.55-7.46(5H，m)，7.12(1H，dd，J＝1.97，8.72Hz)，3.75(2H，s)，2.39(3H，s).Example 6 [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (4-methylbenzoyl) -1- (benzenesulfonyl) indole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and p-methylbenzoyl chloride following the method described in step 2 of example 2 (method B). 0.3 part of tlc: Rf (1: 10 parts of ethyl acetate/hexane) Step 2.6-chloro-2- (4-methylbenzoyl) indole
The title compound was prepared from 6-chloro-2- (4-methylbenzoyl) -1- (benzenesulfonyl) indole (step 1) following the procedure described in step 3 of example 2 (method B).1H-NMR(CDCl3)δ：9.37(1H，br s)，7.90(2H，d，J＝8.6Hz)，7.63(1H，d，J＝8.9Hz)，7.48(1H，s)，7.34(2H，d，J＝8.6Hz)，7.16-7.10(2H，m)，2.47(3H，s).Step 3. alpha-acetoxy- [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl]Malonic acid Diethyl ester
As described in step 4 of example 2 (method B)The title compound was prepared from 6-chloro-2- (4-methylbenzoyl) indole (step 2).1H-NMR(CDCl3)δ：8.65(1H，br s)，7.84(1H，d，J＝8.9Hz)，7.76(2H，d，J＝8.2Hz)，7.39-7.37(1H，m)，7.27(2H，d，J＝8.2Hz)，7.16(1H，dd，J＝1.8，8.2Hz)，4.36-4.16(4H，m)，2.44(3H，s)，1.72(3H，s)，1.34-1.22(6H，m).Step 4.[ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), from α -acetoxy- [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.83(1H，br s)，7.76(1H，d，J＝8.7Hz)，7.71(2H，d，J＝8.2Hz)，7.39-7.36(1H，m)，7.32(2H，d，J＝8.2Hz)，7.14(1H，dd，J＝2.0，8.7Hz)，5.30(1H，s)，4.26-4.14(4H，m)，2.47(3H，s)，1.22(6H，t，J＝7.1Hz).Step 5.[ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 182 ℃. 184. IR (KBr) v: 3321, 1705, 1616, 1602, 1566, 1529, 1431, 1323, 1257, 1230cm-1.1H-NMR(DMSO-d6)δ：11.72(1H，s)，7.74-7.64(3H，m)，7.49-7.45(1H，m)，7.39(2H，d，J＝8.1Hz)，7.16-7.09(1H，m)，3.g1(2H，s)，2.43(3H，s).Example 7 [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ]Acetic acid Step 1.6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
To a suspension of 6-chloroindole-2-carboxylic acid (h.n.rydon and j.c.tweddle, j.chem.soc., 1955, 3499, 7.0g, 36mmol) in thionyl chloride (30ml) was added dropwise DMF (1ml) with stirring. After stirring for 30 min, the mixture was concentrated and the residue was dissolved in dichloromethane (100ml) and cooled to 0 ℃. To the mixture were added N, O-dimethylhydroxylamine hydrochloride (7.0g, 72mmol) and pyridine (15 ml). After stirring for 2 hoursThe mixture was quenched with water (100ml) and extracted with dichloromethane (150 ml. times.2). The combined organic extracts were washed with 2N aqueous HCl (100ml), saturated aqueous sodium bicarbonate (100ml), brine (100ml) and dried (magnesium sulfate). The solvent was removed to give 8.2g (96%) of the title compound as a yellow solid.1H-NMR(CDCl3)δ：9.48(1H，br s)，7.60(1H，d，J＝8.6Hz)，7.46-7.41(1H，m)，7.22-7.18(1H，m)，7.11(1H，dd，J＝8.6，1.8Hz)，3.85(3H，s)，3.44(3H，s).Step 2.6-chloro-2- (3-chlorobenzoyl) indole
To 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl ] at-78 deg.C with stirring]To a solution of indole (step 1, 610mg, 2.56mmol) and 3-bromochlorobenzene (1.47g, 7.67mmol) in THF (20ml) was added dropwise n-butyllithium (1.54M in hexane, 4.90ml, 7.67 mmol). After stirring for 1 hour, the mixture was quenched with a saturated ammonium chloride solution (20ml) and extracted with ethyl acetate (50 ml. times.2). The combined organic extracts were washed with 2N aqueous HCl (50ml), saturated aqueous sodium bicarbonate (50ml), brine (50ml) and dried (magnesium sulfate). The solvent was removed and the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 10) to give 565mg (76%) of the title compound as a pale brown solid. 1H-NMR(CDCl3)δ：9.31(1H，br s)，7.94(1H，t，J＝1.9Hz)，7.85(1H，dt，J＝1.9，7.6Hz)，7.65(1H，d，J＝8.4Hz)，7.63-7.58(1H，m)，7.52-7.45(2H，m)，7.18-7.12(2H，m).Step 3. alpha-acetoxy- [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 6-chloro-2- (3-chlorobenzoyl) indole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.88(1H，br s)，7.87-7.74(3H，m)，7.61-7.56(1H，m)，7.43(1H，d，J＝7.6Hz)，7.41-7.38(1H，m)，7.20-7.14(1H，m)，4.30-4.14(4H，m)，1.74(3H，s)，1.20(6H，t，J＝8.2Hz).Step 4.[ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
As described in step 5 of example 2 (method B)The process described is carried out from alpha-acetoxy- [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.87(1H，br s)，7.79-7.74(2H，m)，7.70-7.58(2H，m)，7.47(1H，t，J＝8.1Hz)，7.39-7.37(1H，m)，7.15(1H，dd，J＝1.8，8.7Hz)，5.19(1H，s)，4.27-4.10(4H，m)，1.22(6H，t，J＝7.1Hz).Step 5.[ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl) acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 199 ℃ and 201 ℃.1H-NMR(DMSO-d6)δ：12.25(1H，br s)，11.81(1H，s)，7.79-7.57(5H，m)，7.48(1H，d，J＝1.8Hz)，7.14(1H，dd，J＝1.8，8.7Hz)，3.81(2H，s).Example 8 [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid methyl esterMethod AStep 1, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester
To trans-2-amino-4-chlorocinnamic acid methyl ester (r.w.carling et al, j.med.chem., 1993,363397, 30.7g, 0.15mol) and pyridine (36ml, 0.45mol) in dichloromethane (500ml) was added benzenesulfonyl chloride (20ml, 0.16 mol). After stirring for 20 hours, methanol (50ml) was added and the mixture was concentrated. The remaining solid was dissolved in dichloromethane (700ml), washed with 2N aqueous HCl (150ml), brine (150ml) and dried (magnesium sulfate). After removal of the solvent, the remaining solid was recrystallized from ethanol to yield 40g (76%) of the title compound as a pale yellow solid. 1H-NMR(CDCl3)δ：7.77-7.71(2H，m)，7.59-7.52(1H，m)，7.48-7.35(5H，m)，7.20(1H，dd，J＝2.0，8.4Hz)，6.85(1H，br s)，6.15(1H，d，J＝15.8Hz)，3.78(3H，s).Step 2.[ 6-chloro-2- (4-chlorobenzoyl) -1- (benzenesulfonyl) indolin-3-yl]Acetic acid A Esters
Methyl trans-4-chloro-2- (benzenesulfonylamino) cinnamate (step 1, 1.1g, 3.1mmol), 4-chlorobenzoylmethyl bromide (1.1g, 4.6mmol) and potassium carbonate (2.6 mmol) were stirred at room temperature1g, 15.4mmol) in acetone (10ml) for 1.5 hours. The mixture was filtered and the filtrate was concentrated. The remaining solid was recrystallized from ethyl acetate/hexane to give 0.91g (59%) of the title compound as a pale yellow solid.1H-NMR(CDCl3)δ：7.97-7.94(2H，m)，7.86-7.81(2H，m)，7.65-7.58(1H，m)，7.55-7.46(5H，m)，7.02(1H，dd，J＝2.0，8.2Hz)，6.90(1H，d，J＝8.2Hz)，5.99(1H，d，J＝9.7Hz)，4.00-3.87(1H，m)，3.41(3H，s)，2.63(1H，dd，J＝6.3，17.6Hz)，2.51(1H，dd，J＝6.3，17.6Hz).Step 3.[ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid methyl ester
To [ 6-chloro-2- (4-chlorobenzoyl) -1- (benzenesulfonyl) indolin-3-yl under stirring]Methyl acetate (step 2, 50mg, 0.10mmol) d THF solution was added 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU, 30. mu.l, 0.20 mmol). After stirring for 15 hours, the mixture was quenched with water (30ml), and the mixture was extracted with ethyl acetate (50 ml). The extract was washed with 2N aqueous HCl (30ml), saturated aqueous sodium bicarbonate (30ml), brine (30ml) and dried (magnesium sulfate). After removal of the solvent, 34mg (93%) of the title compound are obtained as a yellow solid. MS (EI) m/z: 361 (M)+).1H-NMR(CDCl3) δ: 8.90(1H, br s), 7.74(2H, d, J ═ 8.6Hz), 7.56(1H, d, J ═ 8.6Hz), 7.49(2H, d, J ═ 8.6Hz), 7.36(1H, d, J ═ 1.6Hz), 7.16(1H, dd, J ═ 1.6, 8.6Hz), 3.81(2H, s), 3.66(3H, s)
A mixture of methyl trans-4-chloro-2- (benzenesulfonylamino) cinnamate (step 1 of method A, 0.70g, 2.0mmol), 4-chlorobenzoylmethyl bromide (0.51g, 2.2mmol) and potassium carbonate (0.83g, 6.0mmol) in acetone (10ml) was stirred at room temperature. After stirring for 2 hours, cesium carbonate (2.0g, 6.0mmol) was added and stirring was continued for an additional 4 hours. The mixture was concentrated, the residue diluted with water (100ml0, the aqueous mixture extracted with ethyl acetate (100 ml. times.2.) the combined organic extracts were washed with 2N HCl aqueous solution (100ml), saturated aqueous sodium bicarbonate solution (100ml), brine (100ml), dried (magnesium sulfate). after removal of the solvent, the solid was recrystallized in ethanol to yield 0.44g (61%) of the title compound MSAnd NMR spectrum the same as that of the compound prepared in step 3.Example 9 [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acidMethod AStep 1.6-chloro-2- (4-chlorobenzoyl) indole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 4-bromochlorobenzene.1H-NMR(DMSO-d6)δ：12.14(1H，br s)，7.97(2H，d，J＝8.4Hz)，7.76(1H，d，J＝8.6Hz)，7.66(2H，d，J＝8.4Hz)，7.54-7.50(1H，m)，7.20(1H，s)，7.14(1H，dd，J＝2.0，8.6Hz).Step 2. alpha-acetoxy- [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 6-chloro-2- (4-chlorobenzoyl) indole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.83(1H，br s)，7.87-7.77(3H，m)，7.48-7.36(3H，m)，7.17(1H，dd，J＝2.0，8.9Hz)，4.28-4.14(4H，m)，1.73(3H，s)，1.20(6H，t，J＝7.1Hz).Step 3.[ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：8.91(1H，br s)，7.75(2H，d，J＝8.6Hz)，7.75-7.69(1H，m)，7.50(2H，d，J＝8.6Hz)，7.29(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝1.8，8.7Hz)，5.23(1H，s)，4.28-4.07(4H，m)，1.23(6H，t，J＝7.2Hz).Step 4.[ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 189 ℃. IR (KBr) v: 3309, 1699, 1616, 1525, 1431, 1325, 1255, 1226, 1091cm-1.1H-NMR(DMSO-d6) δ: 11.78(1H, s), 7.80-7.72(3H, m), 7.65(2H, d, J ═ 8.6Hz), 7.47(1H, d, J ═ 1.8Hz), 7.13(1H, dd, J ═ 1.8, 8.7Hz), 3.83(2H, s). method B[ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Stirring [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl at 80 deg.C]A mixture of methyl acetate (example 8, 1.80g) and 2N aqueous NaOH (7.5ml) in MeOH-THF (10ml-10ml) was used for 1 hour. The mixture was cooled and concentrated. The residue was dissolved in water (150ml) and washed with diethyl ether (50 ml). The aqueous layer was acidified with 2N aqueous HCl (10ml) and extracted with ethyl acetate (100 ml. times.2). The combined organic extracts were washed with brine (50ml), dried (magnesium sulfate) and concentrated. The remaining solid was recrystallized from toluene to yield 1.58g (91%) of the title compound. The MS and NMR spectra are identical to those of the compound prepared in method a. Example 10 [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (3-fluorobenzoyl) -1H-indole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 3-bromofluorobenzene.1H-NMR(CDCl3)δ：9.28(1H，br s)，7.79-7.75(1H，m)，7.68-7.63(2H，m)，7.56-7.48(2H，m)，7.36-7.30(1H，m)，7.17-7.14(2H，m).Step 2. alpha-acetoxy- [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 6-chloro-2- (3-fluorobenzoyl) indole (step 1) according to the method described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：9.15(1H，br s)，8.83(1H，d，J＝8.72Hz)，7.66-7.27(5H，m)，7.17(1H，dd，J＝2.00，8.72Hz)，4.25-4.13(4H，m)，1.75(3H，s)，1.19(6H，t，J＝7.07Hz).Step 3.[ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), starting from α -acetoxy- [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：8.91(1H，br s)，7.77-7.12(7H，m)，5.21(1H，s)，4.25-4.11(4H，m)，1.22(6H，t，J＝7.07Hz).Step 4.[ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 278-: 3385, 1697, 1638, 1583, 1541, 1508, 1420, 1400, 1315, 1261, 1236cm -1.1H-NMR(DMSO-d6)δ：11.79(1H，s)，7.76-7.48(7H，m)，7.13(1H，dd，J＝1.97，8.56Hz)，3.80(2H，s).Example 11 [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (4-fluorobenzoyl) -1H-indole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 4-bromofluorobenzene.1H-NMR(CDCl3)δ：9.29(1H，br s)，8.05-8.00(2H，m)，7.64(1H，d，8.72Hz)，7.48-7.11(5H，m).Step 2. alpha-acetoxy- [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 6-chloro-2- (4-fluorobenzoyl) indole (step 1) according to the method described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：9.20(1H，br s)，7.92-7.11(7H，m)，4.25-4.14(4H，m)，1.73(3H，s)，1.20(6H，t，J＝7.10Hz).Step 3.[ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a-acetoxy- [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl group is prepared]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：9.01(1H，br s)，7.87-7.69(2H，m)，7.71(2H，d，J＝8.91Hz)，7.27-7.10(4H，m)，5.25(1H，s)，4.26-4.11(4H，m)，1.22(6H，t，J＝7.07Hz).Step 4.[ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 181 ℃. IR (KBr) v: 3309, 1701, 1616, 1601, 1566, 1527, 1508, 1419, 1323, 1257, 1229cm -1.1H-NMR(DMSO-d6)δ：11.75(1H，s)，7.87-7.82(2H，m)，7.73(1H，d，J＝8.72)，7.47-7.36(3H，m)，7.12(1H，dd，J＝1.84，8.72Hz)，3.78(2H，s).Example 12 [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl]Acetic acid Step 1.2- (3-bromobenzoyl) -6-chloroindole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 3-bromoiodobenzene.1H-NMR(CDCl3)δ：9.28(1H，br s)，8.11-8.08(1H，m)，7.93-7.87(1H，m)，7.79-7.73(1H，m)，7.65(1H，d，J＝8.6Hz)，7.50-7.38(2H，m)，7.19-7.01(2H，m).Step 2. alpha-acetoxy- [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 2- (3-bromobenzoyl) -6-chloroindole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.73(1H，br s)，7.93(1H，t，J＝1.8Hz)，7.85(1H，d，J＝8.6Hz)，7.82-7.72(2H，m)，7.42-7.32(2H，m)，7.18(1H，dd，J＝2.0，8.6Hz)，4.32-4.16(4H，m)，1.75(3H，s)，1.20(6H，t，J＝7.1Hz).Step 3.[2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), α -acetoxy- [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：8.88(1H，br s)，7.92-7.90(1H，m)，7.80-7.68(3H，m)，7.45-7.36(2H，m)，7.15(1H，dd，J＝1.8，8.7Hz).5.20(1H，s)，4.30-4.10(4H，m)，1.23(6H，t，J＝7.2Hz).Step 4.[2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 215 ℃. IR (KBr) v: 3369, 1710, 1604, 1558, 1533, 1423, 1319, 1253, 1228cm -1.1H-NMR(DMSO-d6)δ：11.81(1H，s)，7.92-7.83(2H，m)，7.78-7.70(2H，m)，7.54(1H，t，J＝7.8Hz)，7.48(1H，d，J＝2.0Hz)，7.13(1H，dd，J＝2.0，8.7Hz)，3.80(2H，s).Example 13 [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl]Acetic acid Step 1.2- (4-bromobenzoyl) -6-chloroindole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 3-bromoiodobenzene.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，7.88(2H，d，J＝8.7Hz)，7.80(2H，d，J＝8.7Hz).7.76(1H，d，J＝8.7Hz)，7.53-7.50(1H，m)，7.22-7.19(1H，m)，7.13(1H，dd，J＝2.0，8.7Hz).Step 2. alpha-acetoxy- [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 2- (4-bromobenzoyl) -6-chloroindole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.72(1H，br s)，7.84(1H，d，J＝8.7Hz)，7.73(2H，d，J＝8.4Hz)，7.62(2H，d，J＝8.4Hz)，7.38(1H，d，J＝1.8Hz)，7.18(1H，dd，J＝1.8，8.7Hz)，4.28-4.14(4H，m)，1.73(3H，s)，1.20(6H，t，J＝7.1Hz).Step 3.[2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), starting from α -acetoxy- [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：8.86(1H，br s)，7.75(1H，d，J＝8.4Hz)，7.67(4H，s)，7.37-7.32(1H，m)，7.18-7.12(1H，m)，5.22(1H，s)，4.26-4.10(4H，m)，1.23(6H，t，J＝7.1Hz).Step 4.[2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 199 ℃. IR (KBr) v: 3300, 1699, 1618, 1587, 1525, 1433, 1406, 1325, 1255, 1226cm -1.1H-NMR(DMSO-d6)δ：11.78(1H，s)，7.80(2H，d，J＝8.4Hz)，7.75(1H，d，J＝8.6Hz)，7.69(2H，d，J＝8.4Hz)，7.47(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝1.8，8.6Hz)，3.84(2H，s).Example 14 [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 3-bromophenyl trifluoromethane.1H-NMR(DMSO-d6)δ：12.23(1H，br s)，8.28-8.04(3H，m)，7.89-7.75(2H，m)，7.55-7.51(1H，m)，7.22-7.12(2H，m).Step 2. alpha-acetoxy- [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl]C3 Diacid diethyl ester
The title compound was prepared from 6-chloro-2- (3-trifluoromethylbenzoyl) indole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.82(1H，br s)，8.25-7.80(4H，m)，7.68-7.57(1H，m)，7.43-7.41(1H，m)，7.22-7.16(1H，m)，4.36-4.20(4H，m)，1.67(3H，s)，1.20(6H，t，J＝7.1Hz).Step 3.[ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
According to example 2 (method B)The process described in step 5, starting from α -acetoxy- [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：8.91(1H，br s)，8.08-8.03(1H，m)，8.02-7.87(2H，m)，7.76(1H，d，J＝9.0Hz)，7.73-7.64(1H，m)，7.39-7.36(1H，m)，7.15(1H，dd，J＝1.8，9.0Hz).5.15(1H，s)，4.26-4.10(4H，m)，1.22(6H，t，J＝7.2Hz).Step 4.[ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 194-196 ℃ IR (KBr) v: 3371, 1705, 1631, 1421, 1307, 1228, 1168, 1122, 1072cm -1.1H-NMR(DMSO-d6)δ：11.86(1H，s)，8.10-7.98(3H，m)，7.83(1H，t，J＝7.7Hz)，7.75(1H，d，J＝8.6Hz)，7.49(1H，d，J＝2.0Hz)，7.15(1H，dd，J＝2.0，8.6Hz)，3.80(2H，s).Example 15 [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-1- (benzenesulfonyl) -2- (3-trifluoromethylbenzoyl) indole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and 4-trifluoromethylbenzoyl chloride following the procedure described for step 2, example 2. Rf 0.2 (ethyl acetate/hexane 1: 4).
The title compound was prepared from 6-chloro-1-benzenesulfonyl-2- (4-trifluoromethylbenzoyl) indole (step 1) following the procedure described in step 3 of example 2 (method B).1H-NMR(CDCl3)δ：9.53(1H，br s)，7.94(4H，dd，J＝8.24，69.1Hz)，7.63(1H，d，J＝8.56Hz)，7.49-7.11(3H，m).Step 3. alpha-acetoxy- [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl]C3 Diacid diethyl ester
Following the procedure described in step 4 of example 2 (method B), from 6-chloro-2- (4-trifluoromethylbenzoyl) indole (step (u))Step 2) the title compound was prepared.1H-NMR(CDCl3)δ：8.66(1H，br s)，7.98(2H，d，J＝8.24Hz)，7.87(1H，d，J＝8.91Hz)，7.75(2H，d，J＝8.07Hz)，7.39(1H，d，J＝1.81Hz)，7.19(1H，dd，J＝1.81，7.10Hz)4.36-4.16(4H，m)，1.70(3H，s)，1.34-1.22(6H，m).Step 4.[ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：9.24(1H，br s)，7.84(4H，dd，J＝7.91，25.7Hz)，7.69-7.09(3H，m)，5.24(1H，s)，4.21-4.06(4H，m)，1.21(6H，t，J＝7.07Hz).Step 5.[ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound.1H-NMR(DMSO-d6)δ：11.78(1H，s)，7.94(4H，s)，7.76(1H，d，J＝8.72Hz)，7.47(1H，m)，7.14(1H，d，J＝1.81，8.72)，3.81(2H，s).Example 16 [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl) acetic acid Step 1.6-chloro-2- (3, 4-dichlorobenzoyl) indole
From 6-chloro-2- [ (N-methoxy-N-methylamino) carbonyl, following the procedure described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 7) and 1-bromo-3, 4-dichlorobenzene. tlc: Rf 0.7 (ethyl acetate/hexane 1: 3)Step 2. alpha-acetoxy- [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl]Third two Acid diethyl ester
The title compound was prepared from 6-chloro-2- (3, 4-dichlorobenzoyl) indole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.80(1H，br s)，7.90-7.79(2H，m)，7.71(1H，dd，J＝2.0，8.4Hz)，7.57(1H，d，J＝8.4Hz)，7.40-7.35(1H，m)，7.18(1H，dd，J＝1.8，8.8Hz)，4.30-4.14(4H，m)，1.77(3H，s)，1.20(6H，t，J＝7.1Hz).Step 3.[ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：8.95(1H，br s)，7.88(1H，d，J＝1.6Hz)，7.72(1H，d，J＝8.7Hz)，7.68-7.58(2H，m)，7.28(1H，d，J＝1.6Hz)，7.14(1H，dd，J＝1.6，8.7Hz).5.18(1H，s)，4.28-4.10(4H，m)，1.23(6H，t，J＝7.1Hz).Step 4.[ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. m.p.: 206 ℃. IR (KBr) v: 3435, 1708, 1620, 1583, 1525, 1423, 1384, 1301, 1263, 1228cm-1.1H-NMR(DMSO-d6)δ：11.62(1H，br s)，7.95-7.75(3H，m)，7.68(1H，d，J＝8.7Hz)，7.42(1H，d，J＝2.0Hz)，7.02(1H，dd，J＝2.0，8.7Hz)，3.50(2H，s).Example 17 [ 2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid Step 1.4-chloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
The title compound was prepared according to the procedure described in step 1 of example 7, using 4-chloroindole-2-carboxylic acid (f.c. uhle, j.amer.chem.soc., 1949,71，761)。1H-NMR(CDCl3)δ：9.56(1H，br s)，7.36-7.29(2H，m)，7.24-7.12(2H，m)，3.88(3H，s)，3.45(3H，s).step 2.2-benzoyl-4-chloroindole
To the cooled 4-chloro-2- [ (N-methoxy-N-methylamino) carbonyl group to-78 ℃]Indole (step 1, 3.4g, 0.014mol) in THF (60ml) was added dropwise to a solution of phenyllithium (1.8M in cyclohexane/diethyl ether (7: 3),30ml, 0.070 mol). After stirring for 1 hour, the mixture was poured into water (80ml), and extracted with ethyl acetate (80 ml. times.2). After drying and removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 10) to give 3.6g (100%) of the title compound as a white solid.1H-NMR(CDCl3)δ：9.46(1H，br s)，8.05-8.00(2H，m)，7.73-7.51(3H，m)，7.40(1H，dd，J＝1.0，8.3Hz)，7.33-7.24(2H，m)，7.18(1H，d，J＝7.6Hz).Step 3. alpha-acetoxy- (2-benzoyl-4-chloro-1H-indol-3-yl) ]Malonic acid diethyl ester
The title compound was prepared from 2-benzoyl-4-chloroindole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：9.49(1H，br s)，7.98-7.92(2H，m)，7.66-7.57(1H，m)，7.53-7.44(2H，m)，7.34(1H，dd，J＝2.0，7.1Hz)，7.21-7.15(2H，m)，4.30-3.90(4H，m)，2.08(3H，s)，1.15(6H，t，J＝7.3Hz).Step 4. (2-benzoyl-4-chloro-1H-indol-3-yl)]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), starting from α -acetoxy- (2-benzoyl-4-chloro-1H-indol-3-yl)]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.88(1H，br s)，7.83-7.77(2H，m)，7.64-7.58(1H，m)，7.55-7.46(2H，m)，7.25-7.05(3H，m)，5.86(1H，s)，4.25-4.08(4H，m)，1.23(6H，t，J＝7.3Hz).Step 5. (2-benzoyl-4-chloro-1H-indol-3-yl)]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from (2-benzoyl-4-chloro-1H-indol-3-yl)]Diethyl malonate (step 3) prepares the title compound. Melting point: 206 ℃ in 209 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 1700, 1575, 1245cm-1.1H-NMR(DMSO-d6)δ：12.20(1H，br s)，11.98(1H，s)，7.85-7.67(3H，m)，7.63-7.55(2H，m)，7.45(1H，d，J＝8.2Hz)，7.25(1H，t，J＝8.2Hz)，7.12(1H，d，J＝7.6Hz)，4.02(2H，s).Example 18 [ 5-chloro-2- (3-methylbenzoyl) -1H-Indol-3-yl) acetic acid Step 1.5-chloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
The title compound was prepared from 5-chloroindole-2-carboxylic acid following the procedure described in step 1 of example 7.1H-NMR(CDCl3)δ：9.68(1H，br s)，7.68-7.65(1H，m)，7.37(1H，d，J＝8.7Hz)，7.23(1H，d，J＝1.6Hz)，7.18-7.15(1H，m)，3.85(3H，s)，2.05(3H，s).Step 2.5-chloro-2- (3-methylbenzoyl) indole
From 5-chloro-2- [ (N-methoxy-N-methylamino) carbonyl as described in step 2 of example 17 ]Indole (step 1) and 3-methylphenyllithium the title compound was prepared. Melting point: 197.5-198 deg.C (recrystallization from ethyl acetate/hexane). Ir (kbr) v: 3310, 1626, 1603, 1583, 1516, 1406, 1377, 1337, 1269, 1178, 1134cm-1.1H-NMR(CDCl3)δ：9.39(1H，br s)，7.28-7.76(2H，m)，7.71-7.68(1H，m)，7.46-7.38(3H，m)，7.32(1H，dd，J＝8.7，2.0Hz)，7.08(1H，dd，J＝2.0，0.8Hz)，2.47(3H，s).Step 3. alpha-acetoxy- [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Diacid of diacid Diethyl ester
The title compound was prepared from 5-chloro-2- (3-methylbenzoyl) indole (step 2) following the procedure described in step 4 of example 2 (method B). Melting point: 173 ℃ and 174 ℃ for recrystallization in ethyl acetate/hexane.1H-NMR(CDCl3)δ：8.64(1H，br s)，7.91(1H，br s)，7.69-7.61(2H，m)，7.46-7.22(4H，m)，4.30-4.16(4H，m)，2.39(3H，s)，1.72(3H，s)，1.23(3H，t，J＝7.2Hz).Step 4.[ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), from α -acetoxy- [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. Melting point: 143 ℃ and 144 ℃ (recrystallization in ethyl acetate/hexane).1H-NMR(CDCl3)δ：8.88(1H，br s)，7.84-7.80(1H，m)，7.62-7.55(2H，m)，7.48-7.36(2H，m)，7.32-7.28(2H，m)，5.27(1H，s)，4.30-4.10(4H，m)，2.42(3H，s)，1.24(3H，t，J＝7.1Hz).Step 5.[ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate the title compound was prepared. Melting point: 241 ℃ and 242 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 3321, 1703, 1618, 1535, 1431, 1335, 1232, 1016, 808, 758cm -1.1H-NMR(DMSO-d6)δ：11.7(1H，br s)，7.62(1H，d，J＝1.8Hz)，7.45-7.30(6H，m)，7.19(1H，dd，J＝8.6，1.8Hz)，3.63(2H，s)，2.27(3H，s).Example 19 [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid Step 1.5-chloro-2- (4-chlorobenzoyl) indole
From 5-chloro-2- [ (N-methoxy-N-methylamino) carbonyl as described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 18) and 4-bromochlorobenzene.1H-NMR(CDCl3)δ：9.32(1H，br s)，7.94(2H，d，J＝8.4Hz)，7.70(1H，s)，7.53(2H，d，J＝8，4Hz)，7.42(1H，d，J＝8.9Hz)，7.34(1H，dd，J＝2.0，8.9Hz)，7.07(1H，s).Step 2. alpha-acetoxy- [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 5-chloro-2- (4-chlorobenzoyl) indole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：9.11(1H，br s)，7.87(1H，s)，7.76(2H，d，J＝8.6Hz)，7.41(2H，d，J＝8.6Hz)，7.27(1H，d，J＝8.7Hz)，7.22(1H，dd，J＝1.8，8.7Hz)，4.25-4.14(4H，m)，1.72(3H，s)，1.24-1.19(6H，m).Step 3.[ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester (step)2) The title compound was prepared.1H-NMR(CDCl3)δ：9.13(1H，br s)，7.73(2H，d，J＝8.4Hz)，7.68(1H，d，J＝2.0Hz)，7.48(2H，d，J＝8.4Hz)，7.11(1H，dd，J＝2.0，8.9Hz)，7.02(1H，d，J＝8.9Hz)，5.28(1H，s)，4.24-4.03(4H，m)，1.27-1.21(6H，m).Step 4.[ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. Melting point: 220 ℃ and 224 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 3321, 1618, 1535, 1379, 1339, 1263, 1130, 1090, 1057, 1007cm -1.1H-NMR(DMSO-d6)δ：11.83(1H，s)，7.80-7.75(3H，m)，7.67-7.62(2H，m)，7.48(1H，d，J＝8.7Hz)，7.31(1H，dd，J＝2.0，8.7Hz)，3.84(2H，s).Example 20 [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl) acetic acid Step 1.5-chloro-2- (3-chlorobenzoyl) indole
From 5-chloro-2- [ (N-methoxy-N-methylamino) carbonyl as described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 18) and 3-bromochlorobenzene.1H-NMR(CDCl3)δ：9.28(1H，br s)，7.95(1H，t，J＝1.7Hz)，7.88-7.84(1H，m)，7.71(1H，d，J＝2.0Hz)，7.63-7.59(1H，m)，7.49(1H，t，J＝7.7Hz)，7.42(1H，d，J＝8.7Hz)，7.34(1H，dd，J＝2.0，8.7Hz)，7.10-7.09(1H，m).Step 2. alpha-acetoxy- [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 5-chloro-2- (3-chlorobenzoyl) indole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.94(1H，br s)，7.91(1H，d，J＝1.8Hz)，7.79-7.76(1H，m)，7.74(1H，d，J＝7.7Hz)，7.60-7.56(1H，m)，7.42(1H，t，J＝7.7Hz)，7.33(1H，d，J＝8.7Hz)，7.27(1H，dd，J＝1.8，8.7Hz)，4.37-4.19(4H，m)，1.75(3H，s)，1.26-1.20(6H，m).Step 3.[ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：9.04(1H，br，s)，7.77-7.75(2H，m)，7.68-7.58(2H，m)，7.46(1H，t，J＝7.7Hz)，7.24-7.20(2H，m)，5.23(1H，s)，4.27-4.14(4H，m)，1.27-1.22(6H，m).Step 4.[ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound. Melting point: 243 ℃ and 247 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 3329, 1707, 1618, 1535, 1431, 1406, 1375, 1333, 1279, 1232, 1053cm -1.1H-NMR(DMSO-d6)δ：11.87(1H，s)，7.81-7.68(4H，m)，7.64-7.58(1H，m)，7.49(1H，d，J＝8.9Hz)，7.32(1H，dd，J＝2.0，8.9Hz)，3.82(2H，s).Example 21 [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl) acetic acid Step 1.5-fluoro-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
The title compound was prepared from 5-fluoroindole-2-carboxylic acid following the procedure described in step 1 of example 7.1H-NMR(CDCl3)δ：10.15(1H，br s)，7.41-7.36(1H，m)，7.32(1H，dd，J＝2.5，9.1Hz)，7.20-7.19(1H，m)，7.09-7.01(1H，m)，3.84(3H，s)，3.47(3H，s).Step 2.2- (4-chlorobenzoyl) -5-fluoro-indole
From 5-fluoro-2- [ (N-methoxy-N-methylamino) carbonyl according to the method described in step 2 of example 7]Indole (step 1) and 4-bromochlorobenzene prepared the title compound.1H-NMR(CDCl3)δ：9.27(1H，br s)，7.94(2H，d，J＝8.4Hz)，7.52(2H，d，J＝8.4Hz)，7.45-7.40(1H，m)，7.37-7.33(1H，m)，7.21-7.12(1H，m)，7.10-7.09(1H，m).Step 3. alpha-BAcyloxy- [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 2- (4-chlorobenzoyl) -5-fluoro-indole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：9.01(1H，br s)，7.80-7.77(2H，m)，7.58-7.54(1H，m)，7.45-7.41(2H，m)，7.36-7.27(1H，m)，7.12-7.01(1H，m)，4.29-4.15(4H，m)，1.74(3H，s)，1.28-1.17(6H，m).Step 4.[2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.98(1H，br s)，7.77-7.72(2H，m)，7.51-7.46(2H，m)，7.40(1H，dd，J＝2.5，9.7Hz)，7.18-7.13(1H，m)，7.04-6.96(1H，m)，5.28(1H，s)，4.26-4.07(4H，m)，1.30-1.18(6H，m).Step 5.[2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ]Diethyl malonate (step 4) prepares the title compound. Melting point: 233 ℃ and 238 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 3317, 1707, 1624, 1609, 1587, 1526, 1458, 1408, 1344, 1263, 1242cm-1.1H-NMR(DMSO-d6)δ：11.73(1H，s)，7.77(2H，d，J＝8.6Hz)，7.65(2H，d，J＝8.6Hz)，7.52-7.44(2H，m)，7.22-7.15(1H，m)，3.84(2H，s).Example 22 [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl) acetic acid Step 1.2- (3-chlorobenzoyl) -5-fluoroindole
From 5-fluoro-2- [ (N-methoxy-N-methylamino) carbonyl according to the method described in step 2 of example 7]The title compound was prepared from indole (step 1 of example 21) and 3-bromochlorobenzene.1H-NMR(CDCl3)δ：9.29(1H，m)，7.96-7.94(1H，m)，7.88-7.84(1H，m)，7.63-7,59(1H，m)，7.48(1H，t，J＝8.0Hz)，7.45-7.40(1H，m)，7.36(1H，dd，J＝2.6，8.6Hz)，7.20-7.11(2H，m).Step 2. alpha-acetoxy- [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Malonic acid di Ethyl ester
The title compound was prepared from 2- (3-chlorobenzoyl) -5-fluoroindole (step 1) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.73(1H，br s)，7.79-7.74(2H，m)，7.61-7.56(2H，m)，7.43(1H，t，J＝7.6Hz)，7.37-7.32(1H，m)，7.13-7.06(1H，m)，4.34-4.20(4 H，m)，1.76(3H，s)，1.33-1.20(6H，m).Step 3.[2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Diethyl malonate (step 2) prepares the title compound.1H-NMR(CDCl3)δ：9.05(1H，br s)，7.76-7.75(1H，m)，7.68-7.64(1H，m)，7.61-7.56(1H，m)，7.48-7.40(2H，m)，7.24-7.19(1H，m)，7.08-7.00(1H，m)，5.25(1H，s)，4.28-4.07(4H，m)，1.33-1.21(6H，m).Step 4.[2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ]Diethyl malonate (step 3) prepares the title compound. Melting point: 208 ℃ and 212 ℃ (recrystallized from ethyl acetate/hexane). Ir (kbr) v: 3337, 1709, 1618, 1560, 1529, 1477, 1458, 1427, 1408, 1335, 1304cm-1.1H-NMR(DMSO-d6)δ：11.78(1H，s)，7.77-7.58(4H，m)，7.52-7.46(2H，m)，7.24-7.16(1H，m)，3.82(2H，s).Example 23 [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl) acetic acid Step 1.5-methoxy-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
The title compound was prepared from 5-methoxyindole-2-carboxylic acid following the procedure described in step 1 of example 7.1H-NMR(CDCl3)δ：9.29-9.13(1H，br)，7.33(1H，d，J＝8.9Hz)，7.19-7.14(1H，m)，7.10(1H，d，J＝2.3Hz)，6.98(1H，dd，J＝8.9，2.3Hz)，3.86(3H，s)，3.84(3H，s)，3.42(3H，s).Step 2.5-methoxy-2- (3-methylbenzoyl) indole
From 5-methoxy-2- [ (N-methoxy-N-methylamino) carbonyl according to the procedure described in step 2 of example 17]Indole (step 1) and 3-methylphenyllithium the title compound was prepared.1H-NMR(CDCl3)δ：9.65-9.45(1H，br)，7.84-7.75(2H，m)，7.46-7.35(3H，m)，7.12-7.01(3H，m)，3.85(3H，s)，2.46(3H，s).Step 3. alpha-acetoxy- [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl]C3 Diacid diethyl ester
The title compound was prepared from 5-methoxy-2- (3-methylbenzoyl) indole (step 2) following the procedure described in step 4 of example 2 (method B). tlc: Rf 0.45 (ethyl acetate/hexane 1: 3)Step 4.[ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), from α -acetoxy- [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl ]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：9.52-9.13(0.5H，m)，8.81-8.71(0.5H，m)，7.80-7.72(1H，m)，7.63-7.55(1H，m)，7.47-7.00(5H，m)，5.41(0.5H，s)，5.37(0.5H，s)，4.27-4.15(4H，m)，3.89(1.5H，s)，3.84(1.5H，s)，2.45(1.5H，s)，2.43(1.5H，s)，1.29-1.19(6H，m).Step 5.[ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. Melting point: 230.4-232.0 deg.C (decomposed) (recrystallized in ethyl acetate). Ir (kbr) v: 3310, 1705, 1614, 1583cm-1.1H-NMR(DMSO-d6)δ：11.47(1H，br s)，7.60-7.34(5H，m)，7.16-7.09(1H，m)，6.98(1H，dd，J＝9.0，2.4Hz)，3.78(5H，s)，2.40(3H，s).13C-NMR(DMSO-d6)δ：188.1，172.1，153.8，138.9，137.9，132.7，132.3，132.0，129.2，128.5，128.0，125.8，117.0，115.6，113.6，100.7，55.3，30.6，20.8.Example 24 (2-benzoyl-7-chloro-1H-indol-3-yl) acetic acid Step 1.7-chloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
The title compound (h.n.rydon and j.c.tweddle, j.chem.soc., 1955, 3499) was prepared from 7-chloroindole-2-carboxylic acid following the procedure described in step 1 of example 7.1H-NMR(CDCl3)δ：9.40(1H，br s)，7.59(1H，d，J＝8.1Hz)，7.32-7.25(2H，m)，7.08(1H，t，J＝8.1Hz)，3.85(3H，s)，3.43(3H，s).Step 2.2-benzoyl-7-chloroindole
Following the procedure described in step 2 of example 17, from 7-chloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indole (step 1) and phenyllithium the title compound was prepared.1H-NMR(CDCl3)δ：9.40(1H，br s)，8.01-7.96(2H，m)，7.70-7.50(4H，m)，7.38(1H，d，J＝7.6Hz)，7.18(1H，d，J＝2.0Hz)，7.11(1H，t，J＝7.6Hz).Step 3. alpha-acetoxy- (2-benzoyl-7-chloro-1H-indol-3-yl) malonic acid diethyl ester
The title compound was prepared from 2-benzoyl-7-chloro-indole (step 2) following the procedure described in step 4 of example 2 (method B). 1H-NMR(CDCl3)δ：8.76(1H，br s)，7.92-7.81(3H，m)，7.68-7.60(1H，m)，7.53-7.45(2H，m)，7.33(1H，d，J＝7.6Hz)，7.1 5(1H，t，J＝8.2Hz)，4.60-4.20(4H，m)，1.71(3H，s)，1.98(6H，t，J＝7.1Hz).Step 4. (2-benzoyl-7-chloro-1H-indol-3-yl) malonic acid diethyl ester
The title compound was prepared from diethyl α -acetoxy- (2-benzoyl-7-chloro-1H-indol-3-yl) malonate (step 3) according to the method described in step 5 of example 2 (method B).1H-NMR(CDCl3)δ：8.94(1H，br s)，7.86-7.80(2H，m)，7.75(1H，d，J＝8.1Hz)，7.70-7.62(1H，m)，7.55-7.50(2H，m)，7.36(1H，d，J＝7.6Hz)，7.13(1H，t，J＝7.6Hz)，5.29(1H，s)，4.25-4.11(4H，m)，1.22(6H，t，J＝7.3Hz).Step 5. (2-benzoyl-7-chloro-1H-indol-3-yl) acetic acid
The title compound was prepared from diethyl (2-benzoyl-7-chloro-1H-indol-3-yl) malonate (step 4) according to the method described in step 6 of example 2 (method B). Melting point: 190 ℃ and 193 ℃ were added (recrystallized from ethyl acetate/hexane). Ir (kbr) v: 1691, 1627, 1598, 1323, 12601199, 1010cm-1.1H-NMR(DMSO-d6)δ：11.90(1H，br s)，7.82(2H，m)，7.74-7.65(2H，m)，7.62-7.38(2H，m)，7.40(1H，d，J＝7.6Hz)，7.13(1H，t，J＝7.6Hz)，3.75(2H，s).Example 25 (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid Step 1.4, 5-dichloro-indol-3-yl) acetic acid
To a solution of 4, 5-dichloroindole-2-carboxylic acid ethyl ester (Ishii et al, chem. pharm. Bull, 1974,221981, 1.8g, 7.0mmol) in ethanol (40ml) was added 2N aqueous NaOH (10ml) and the reaction mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature and concentrated. The remaining solid was acidified with 2N aqueous HCl (30ml) and extracted with diethyl ether (80 ml. times.2). The organic extracts were dried (magnesium sulfate) and concentrated to give 1.5g (94%) of the title compound as a yellow solid. 1H-NMR(DMSO-d6)δ：12.34(1H，br s)，7.47-7.39(2H，m)，7.08(1H，d，J＝1.8Hz).Step 2.4, 5-dichloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indoles
The title compound was prepared from 4, 5-dichloroindole-2-carboxylic acid (step 1) following the procedure described in step 1 of example 7.1H-NMR(CDCl3)δ：9.62(1H，br s)，7.40-7.05(3H，m)，3.88(3H，s)，3.45(3H，s).Step 3.2-benzoyl-4, 5-dichloroindole
Following the procedure described in step 2 of example 17, from 4, 5-dichloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indole (step 2) andphenyl lithium the title compound was prepared. Melting point: 206 ℃ C. (recrystallization from ethyl acetate/hexane).1H-NMR(CDCl3)δ：9.58(1H，br s)，8.05-7.98(2H，m)，7.71-7.53(3H，m)，7.42(1H，d，J＝8.9Hz)，7.35(1H，d，J＝8.9Hz)，7.22(1H，s).Step 4. alpha-acetoxy- (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) malonic acid diethyl ester Esters
The title compound was prepared from 2-benzoyl-4, 5-dichloro-indole (step 3) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.85(1H，br s)，7.91-7.86(2H，m)，7.66-7.58(1H，m)，7.52-7.44(2H，m)，7.36(1H，d，J＝8.7Hz)，7.21(1H，d，J＝8.7Hz)，4.20-3.98(4H，m)，2.07(3H，s)，1.15(6H，t，J＝7.3Hz).Step 5 (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) malonic acid diethyl ester
The title compound was prepared from diethyl α -acetoxy- (2-benzoyl-4, 5 dichloro-1H-indol-3-yl) malonate (step 4) according to the method described in step 5 of example 2 (method B).1H-NMR(CDCl3)δ：9.24(1H，br s)，7.82-7.76(2H，m)，7.65-7.58(1H，m)，7.55-7.44(2H，m)，7.20(1H，d，J＝8.7Hz)，7.03(1H，d，J＝8.7Hz)，5.89(1H，s)，4.16-4.02(4H，m)，1.20(6H，t，J＝7.3Hz).(2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid
The title compound was prepared from diethyl (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) malonate (step 5) according to the method described in step 6 of example 2 (method B). Melting point: 249-252 deg.C (recrystallization from ethyl acetate/hexane). Ir (kbr) v: 1701, 1625, 1523, 1450, 1330, 1257, 1012cm -1.1H-NMR(CDCl3)δ：9.92(1H，br s)，7.85-7.81(2H，m)，7.66-7.42(3H，m)，7.36(1H，d，J＝8.8Hz)，7.29(1H，d，J＝8.8Hz)，4.09(2H，s).Example 26 (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid Step 1.4, 6-dichloro-2- (N-methoxy-N-methylamino) carbonyl]Indoles
Following the procedure described in step 1 of example 7, a starting material was prepared from 4, 6-dichloroindole-2-carboxylic acid (Salituro, Francesco g. et al, j.med.chem., 1990,332944) the title compound was prepared.1H-NMR(DMSO-d6)δ：12.09(1H，br s)，7.48(1H，dd，J＝1.0，1.6Hz)，7.25(1H，d，J＝1.6Hz)，7.11(1H，s)，3.82(3H，s)，3.63(3H，s).Step 2.2-benzoyl-4, 6-dichloroindole
Following the procedure described in step 2 of example 17, from 4, 6-dichloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indole (step 1) and phenyllithium the title compound was prepared. Melting point: 214 ℃ and 218 ℃.1H-NMR(CDCl3)δ：9.45(1H，br s)，8.02-7.95(2H，m)，7.70-7.52(3H，m)，7.40(1H，d，J＝1.6Hz)，7.25(1H，s)，7.20(1H，d，J＝1.6Hz).Step 3. alpha-acetoxy- (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) malonic acid diethyl ester Esters
The title compound was prepared from 2-benzoyl-4, 6-dichloro-indole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.92(1H，br s)，7.95-7.86(2H，m)，7.68-7.43(3H，m)，7.29(1H，d，J＝1.8Hz)，7.23(1H，d，J＝1.8Hz)，4.60-4.00(4H，m)，2.04(3H，s)，1.30-1.10(6H，m)Step 4. (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) malonic acid diethyl ester
The title compound was prepared from diethyl α -acetoxy- (2-benzoyl-4, 6 dichloro-1H-indol-3-yl) malonate (step 3) according to the method described in step 5 of example 2 (method B). Melting point: 170 ℃ and 172 ℃.1H-NMR(CDCl3)δ：9.15(1H，br s)，7.84-7.75(2H，m)，7.66-7.45(3H，m)，7.26(1H，s)，7.12(1H，s)，5.79(1H，s)，4.20-4.00(4H，m)，1.20(6H，t，J＝7.3Hz).Step 5. (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from (2-benzoyl-4, 6-dichloro-1H-indole-3)-yl) malonic acid diethyl ester (step 4) the title compound was prepared. Melting point: 239 ℃ and 243 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 1725, 1555, 1525, 1330, 1287, 1250, 1005cm-1.1H-NMR(DMSO-d6)δ：12.40(1H，br s)，12.12(1H，br s)，7.80-7.67(3H，m)，7.64-7.54(2H，m)，7.48(1H，d，J＝1.8Hz)，7.23(1H，d，J＝1.8Hz)，3.99(2H，s).Example 27 (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid Step 1.5, 6-dichloro-indol-3-yl) acetic acid
The title compound was prepared from 5, 6-dichloroindole-2-carboxylic acid following the procedure described in step 1 of example 25 (Ishii et al, chem. pharm. ball., 1974,22，1981)。1H-NMR(DMSO-d6)δ：12.06(1H，br s)，7.95(1H，s)，7.62(1H，s)，7.09(1H，s).step 2.5, 6-dichloro-2- [ N-methoxy-N-methylamino) carbonyl]Indoles
The title compound was prepared from 5, 6-dichloroindole-2-carboxylic acid (step 1) following the procedure described in step 1 of example 7.1H-NMR(CDCl3)δ：11.86(1H，br s)，7.96(1H，s)，7.66(1H，s)，7.16(1H，s)，3.80(3H，s)，3.34(3H，s).Step 3.2-benzoyl-5, 6-dichloroindole
Following the procedure described in step 2 of example 17, starting from 5, 6-dichloro-2- [ (N-methoxy-N-methylamino) carbonyl]Indole (step 2) and phenyllithium the title compound was prepared. Melting point: 206 ℃ C. (recrystallization from ethyl acetate/hexane).1H-NMR(CDCl3)δ：9.35(1H，br s)，8.00-7.93(2H，m)，7.81(1H，s)，7.69-7.51(3H，m)，7.26(1H，s)，7.08(1H，s).Step 4. alpha-acetoxy- (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) malonic acid diethyl ester Esters
The title compound was prepared from 2-benzoyl-5, 6-dichloroindole (step 3) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.76(1H，br s)，8.05(1H，s)，7.90-7.82(2H，m)，7.67-7.59(1H，m)，7.54-7.44(3H，m)，4.30-4.10(4H，m)，1.69(3H，s)，1.35-1.20(6H，m).Step 5 (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) malonic acid diethyl ester
The title compound was prepared from diethyl α -acetoxy- (2-benzoyl-5, 6 dichloro-1H-indol-3-yl) malonate (step 4) according to the method described in step 5 of example 2 (method B).1H-NMR(CDCl3)δ：8.90(1H，br s)，7.95(1H，s)，7.82-7.76(2H，m)，7.70-7.61(1H，m)，7.58-7.46(3H，m)，5.26(1H，s)，4.30-4.05(4H，m)，1.24(6H，t，J＝7.1Hz).(2-benzoyl-5, 65-dichloro-1H-indol-3-yl) acetic acid
The title compound was prepared from diethyl (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) malonate (step 5) according to the method described in step 6 of example 2 (method B). Melting point: 208 ℃ and 210 ℃ (recrystallization in ethyl acetate/hexane).1H-NMR(DMSO-d6)δ：11.91(1H，br s)，8.04(1H，s)，7.77-7.50(6H，m)，3.81(2H，s).Example 28 dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid Step 1. alpha-methyl- (2-benzoyl-6-chloro-1H-indol-3-yl) malonic acid diethyl ester
The title compound was prepared from 2-benzoyl-6-chloroindole (step 3 of method B, example 2) and diethyl methylmalonate according to the method described in step 4 of example 2 (method B). m.p.: 193 ℃ and 196 ℃.1H-NMR(CDCl3)δ：8.42(1H，br s)，7.87(2H，m)，7.66-7.48(3H，m)，7.42(1H，d，J＝8.8Hz)，7.35(1H，d，J＝1.8Hz)，7.11(1H，dd，J＝1.8，8.8Hz)，4.30-4.02(4H，m)，1.98(3H，s)，1.15(6H，t，J＝7.1Hz).Step 2 dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid
The title compound was prepared from diethyl α -methyl- (2-benzoyl-6-chloro-1H-indol-3-yl) malonate (step 1) according to the method described in step 6 of example 2 (method B). Melting point: 204 ℃ and 208 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 1720, 1620, 1475, 1260, 1230cm-1.1H-NMR(DMSO-d6)δ：12.29(1H，br s)，11.72(1H，br s)，7.82-7.76(2H，m)，7.75-7.68(2H，m)，7.65-7.57(2H，m)，7.48(1H，d，J＝1.8Hz)，7.12(1H，dd，J＝1.8，8.4Hz)，4.15(1H，q，J＝7.1Hz)，1.44(3H，d，J＝7.1Hz).Examples 29 and 30 Less polar enantiomer 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid (example 29) And the more polar enantiomer 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid (example) 30)
Chiral separation of dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid with DAICEL CHIRALCEL OJ (4.6 × 250mm, eluent: hexane/isopropanol/trifluoroacetic acid 85: 15: 0.1, flow rate: 1.0 ml/min) gave the less polar compound (retention time: 17 min) and the more polar compound (retention time: 27 min).Example 31 [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid Step 1, trans-4-chloro-2- (ethoxycarbonylamino) cinnamic acid methyl ester
To trans-2-amino-4-chlorocinnamic acid methyl ester (r.w. carling et al, j.med. chem., 1993,36ethyl chloroformate (16.2ml, 0.17mol) was added dropwise to a solution of 32.6g, 0.15mol, pyridine (14.9ml, 0.17mol) and 4-dimethylaminopyridine (0.5g) in dichloromethane (500 ml). After stirring for 2 hours, the mixture was concentrated. The residue was diluted in ethyl acetate (1000ml) and washed with 10% aqueous citric acid (500 ml). The organic layer was washed successively with water (500ml), saturated sodium bicarbonate (500ml), water (500ml), brine (500 ml). After drying (magnesium sulfate) and removal of the solvent, the remaining solid was recrystallized from ethyl acetate/hexane to give 39.13g (92%) of the title compound. 1H-NMR(CDCl3)δ：7.95(1H，br s)，7.76(1H，d，J＝15.8Hz)，7.42(1H，d，J＝8.6Hz)，7.22(1H，dd，J＝2.1，8.5Hz)，6.69(1H，br)，6.37(1H，d，J＝15.7Hz)，4.26(2H，q，J＝7.3Hz)，3.82(3H，s)，1.34(3H，t，J＝7.25Hz).Step 2.[ 6-chloro-1-ethoxycarbonyl-2- (4-methylpyridine-2-carbonyl) indolin-3-yl] Acetic acid methyl ester
Heating to reflux trans-4-chloro-2- (ethoxycarbonylamino) cinnamic acid methyl ester (step 1, 1.5g, 5.3mmol), 2-bromoacetyl-4-methylpyridine hydrobromide*A mixture of potassium carbonate (7.3g, 53mmol) and acetonitrile (50ml) for 17 hours. The mixture was then cooled and concentrated. The residue was diluted in ethyl acetate (200ml) and washed with water (200ml) and brine (200 ml). After drying (magnesium sulfate) and removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 5) to give 433mg (20%) of the title compound. MS (EI) m/z: 416 (M)+)。*2-Bromoacetyl-4-methylpyridine hydrobromide was prepared according to the following method:
to 2-acetyl-4-methylpyridine (f.h.case et al, j.am.chem.soc., 1956,785842, 7.8g, 57.7mmol) in 25% HBr-AcOH (40ml) a solution of bromine (10.1g, 63.5mmol) in AcOH (10ml) was added dropwise. After stirring for 1 hour, diethyl ether (100ml) was added and the precipitate was collected by filtration to give 10.8g (63%) of the title compound.1H-NMR(DMSO-d6)d：8.71(1H，d，J＝5.1Hz)，8.14(1H，s)，7.75(1H，d，J＝5.1Hz)，5.07(2H，s)，2.52(3H，s).Step 3.[ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Heating and refluxing [ 6-chloro-1-ethoxycarbonyl-2- (4-methylpyridine-2-carbonyl) indol-3-yl group under stirring]A solution of methyl acetate (step 2, 930mg, 2.2mmol) in ethanol (20ml) and an aqueous solution of 2N NaOH (10ml) for 72 h. After cooling to room temperature, the resulting mixture was neutralized with 2N aqueous HCl (10ml) and concentrated. The residue was diluted in dichloromethane/methanol (10: 1, 300ml) and dried (magnesium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/methanol (20: 1) and then washed with isopropanol (approximately 20ml) to yield 120mg (17%) of the title compound as a yellow powder. Melting point: 223 deg.C (decomposition). Ir (kbr) v: 1707, 1647, 1595, 1533, 1487, 1429, 1276, 1289, 1196cm-1.1H-NMR(DMSO-d6)δ：12.30(1H，s)，8.70(1H，d，J＝4.9Hz)，7.96(1H.br s)，7.85-7.70(2H，m)，7.65-7.55(1H，m)，7.17-7.07(1H，m)，4.08(2H，s)，2.47(3H，s).Example 32 [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid Step 1.[ 6-chloro-1-ethoxycarbonyl-2- (5-methylpyridine-2-carbonyl) indolin-3-yl] Acetic acid methyl ester
Following the procedure described in step 2 of example 31, trans-4-chloro-2- (ethoxycarbonylamino) cinnamic acid methyl ester (step l of example 31) and 2-bromoacetyl-5-methylpyridine*Two diastereomers of the title compound were prepared. Less polar products: 0.30% of tlc, 0.30 (1/2% of ethyl acetate/hexane), MS (EI) M/z: 416 (M) +) (ii) a More polar products: rf 0.25 (ethyl acetate/hexane 1/2), ms (ei) m/z: 416 (M)+)。*2-Bromoacetyl-5-methylpyridine was prepared according to the following method:
a mixture of 2-bromo-5-methylpyridine (5.00g, 29.06mmol), tributyl (1-ethoxyvinyl) tin (10.49g, 29.07mmol) and tetrakis (triphenylphosphine) palladium (3.36g, 2.91mmol) in toluene (40ml) was heated at reflux for 18 h. The mixture was cooled, filtered through a pad of celite, and concentrated. The residue (ca. 10g) was dissolved in a mixture of THF (100ml) and water (20ml), cooled to 0 ℃ and N-bromosuccinimide (5.43g, 30.52mmol) was added over a period of 20 minutes. The resulting mixture was stirred at this temperature for 0.5 h and then concentrated to about 20 ml. The mixture was diluted in ethyl acetate (300ml), washed with water (200 ml. times.3) and dried (magnesium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 15-1: 10) to give 2.30g (37%) of the title compound as an oil.1H-NMR(CDCl3)δ：8.49(1H，br s)，8.01(1H，d，J＝8.1Hz)，7.68-7.64(1H，m)，4.84(2H，s)，2.44(3H，s).Step 2.[ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 3 of example 31, [ 6-chloro-1-ethoxycarbonyl-2- (5-methylpyridine-2-carbonyl) indolin-3-yl group was each reacted ]Two diastereomeric transformations of methyl acetate (step 2)Is the title compound. MS (EI) m/z: 328 (M)+) Melting point: 235 ℃ and 238 ℃ (recrystallization in ethyl acetate). Ir (kbr) v: 3281, 1699, 1638, 1529, 1310, 1150, 797, 702cm-1.1H-NMR(DMSO-d6) δ: 12.26(1H, br s), 8.68(1H, br s), 8.04(1H, d, J ═ 8.1Hz), 7.94(1H, br d, J ═ 9.1Hz), 7.79(1H, d, J ═ 8.7Hz), 7.74(1H, br s), 7.11(1H, br d, J ═ 8.6Hz), 4.10(2H, s), 2.47(3H, s), no NH or COOH signal was observed.Example 33 [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Methyl trans-4-chloro-2- (benzenesulfonylamino) cinnamate (step 1, 675mg, 1.92mmol of example 8, method A), 2-bromoacetyl-4-chloropyridine hydrobromide were heated under reflux*A mixture of (907mg, 2.88mol) and potassium carbonate (2.65g, 19.18mmol) in acetone (20ml) was left for 4 h. The mixture was cooled and concentrated. The residue was diluted in ethyl acetate (1500ml) and washed with water (70 ml. times.6). After drying (magnesium sulfate) and removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 6-1: 3) to give 195mg (28%) of the title compound (yellow solid) and 264mg (27%) [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1- (phenylsulfonyl) indolin-3-yl ]Methyl acetate (brown crystals). [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate: MS (EI) m/z: 362 (M)+)。1H-NMR(CDCl3) δ: 12.09(1H, br s), 8.62(1H, d, J ═ 5.3Hz), 8.28(1H, d, J ═ 2.1Hz), 7.57(1H, d, J ═ 8.6Hz), 7.52(1H, dd, J ═ 2.0 and 5.3Hz), 7.45(1H, d, J ═ 1.8Hz), 7.08(1H, dd, J ═ 1.8 and 8.7Hz), 4.27(2H, s), 3.75(3H, s) [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1- (benzenesulfonyl) indolin-3-yl]Methyl acetate: rf 0.35 (ethyl acetate/hexane 1: 2). MS (EI) m/z (intensity): 504 (M)+，0.1)，363(90)，335(30)，304(100)，275(10)，223(15)。*2-Bromoacetyl-4-chloropyridine hydrobromide was prepared according to the following procedure: 4-chloro-2-pyridinecarbonitrile: to a mixture of 4-chloropyridine-N-oxide (5.00g, 38.6mmol) cooled to 0 ℃ and trimethylsilicon cyanide (4.84g, 46.3mmol) in dichloromethane (60 ml)) To the mixture in (1) was added dropwise N, N-dimethylcarbamoyl chloride (3.8ml, 40.5 mmol). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. The mixture was cooled to 0 ℃ and a 30% aqueous solution of potassium carbonate (100ml) was added. The crude product was extracted with dichloromethane (100ml × 2), the organic extracts were dried (magnesium sulfate) and distilled to give 4-chloro-2-pyridinecarbonitrile (5.35g, 100%). 1H-NMR(CDCl3) δ: 8.63(1H, d, J ═ 4.8Hz), 7.72(1H, d, J ═ 2.6Hz), 7.55(1H, dd, J ═ 1.8, 5.1Hz), 2-acetyl-4-chloropyridine: to a solution of 4-chloro-2-pyridinecarbonitrile (5.35g, 38.6mmol) in benzene (50ml) and diethyl ether (50ml) cooled to 0 ℃ was added dropwise a 2M solution of MeMgI in diethyl ether (23ml, 46.3mmol) over 20 minutes. After 0.5 hours, the mixture was allowed to warm to ambient temperature and stirring was continued for 2 hours. The mixture was cooled to 0 ℃ and 2M aqueous HCl (100ml) was added. The mixture was made basic with saturated aqueous sodium bicarbonate (about 80ml), the organic layer was separated and dried (magnesium sulfate). After removal of the solvent, the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1: 5) to give 3.60g (60%) of 2-acetyl-4-chloropyridine.1H-NMR(DMSO-d6) δ: 8.59(1H, d, J ═ 5.1Hz), 8.04(1H, d, J ═ 1.8Hz), 7.47(1H, dd, J ═ 1.8, 5.1Hz), 2.72(3H, s), 2-bromoacetyl-4-chloropyridine hydrobromide: 2-bromoacetyl-4-chloropyridine hydrobromide the compound was prepared according to the procedure of h.mckennis, jr., l.b.turnbull, e.r.bowman, and e.tamaki et al (see j.org.chem., 1963,28383-387), from 2-acetyl-4-chloropyridine.1H-NMR(DMSO-d6)δ：8.74(1H，d，J＝5.5Hz)，8.05(1H，d，J＝1.8Hz)，7.88(1H，dd，J＝2.2 and 5.5Hz)，5.02(2H，s).Example 34 [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Heating [ 6-chloro-2- [ 4-chloropyridine-2-carbonyl) -1H-indol-3-yl at 50 deg.C]A suspension of methyl acetate (example 33, 195mg, 0.537mmol) in ethanol (20ml) and 2N aqueous NaOH (4ml) was left for 1 h. After cooling to room temperature, 2N HCl (4ml) was added and the mixture was concentrated. The residue was diluted in ethyl acetate (100ml), washed with water (50 ml. times.2) anddried (magnesium sulfate). After removal of the solvent, the crystalline residue was recrystallized from ethyl acetate to yield 175mg (94%) of the title compound. m.p.: 233 ℃. IR (KBr) v: 3306, 1709, 1641, 1531, 1254, 1236, 741cm-1.1H-NMR(DMSO-d6)δ：12.20(1H，br s)，12.16(1H，br s)，8.80(1H，d，J＝5.4Hz)，8.12(1H，d，J＝2.1Hz)，7.90(1H，dd，J＝2.1，5.3Hz)，7.81(1H，d，J＝8.7Hz)，7.70(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝2.0，8.7Hz)，4.07(2H.s).Example 35 [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid Step 1.[ 6-chloro-1-ethoxycarbonyl-2- (pyridine-2-carbonyl) indolin-3-yl] Acetic acid methyl ester
The title compound was prepared from methyl trans-4-chloro-2- (ethoxycarbonylamino) cinnamate (step 1 of example 31) and 2-bromoacetylpyridine hydrobromide (h.mckennis et al, j.org.chem., 1963, 387) following the procedure described in step 2 of example 31. Rf 0.3 (ethyl acetate/hexane 1: 3).Step 2.[ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in step 3 of example 31, from [ 6-chloro-1-ethoxycarbonyl-2- (pyridine-2-carbonyl) indolin-3-yl respectively]Methyl acetate (step 1) the title compound was prepared. Melting point: 210 deg.C (decomposition). Ir (kbr) v: 3280, 1697, 1643, 1531, 1234, 1150cm-1.1H-NMR(DMSO-d6)δ：12.22(1H，s)，8.84(1H，d，J＝4.9Hz)，8.15-8.05(2H，m)，7.85-7.65(3H，m)，7.11(1H，dd，J＝1.9，8.7Hz)，4.04(2H，s).Example 36 [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid Step 1 trans-5-chloro-2-nitrocinnamic acid methyl ester
A mixture of 5-chloro-2-nitrobenzaldehyde (9.68g, 52.16mmol) and methyl (triphenylphosphoranylidene) acetate (18.31g, 54.77mmol) in toluene (200ml) was heated under reflux for 2 hours, the mixture was concentrated, and the crystalline residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 5) to give crystals. Recrystallization from ethyl acetate/hexane gave 7.54g of (60%) title compound as a pale yellow solid.1H-NMR(CDCl3)δ：8.09(1H，d，J＝15.8Hz)，8.04(1H，d，J＝8.7Hz)，7.60(1H，d，J＝2.1Hz)，7.51(1H，dd，J＝2.1，8.7Hz)，6.36(1H，d，J＝15.8Hz)，3.84(3H，s).Step 2 trans-2-amino-5-chlorocinnamic acid methyl ester
A mixture of methyl trans-5-chloro-2-nitrocinnamate (step 1, 3.00g, 12.42mmol), iron powder (3.65g, 62.08mmol), ammonium chloride (332mg, 6.21mmol), ethanol (60ml) and water (10ml) was heated under reflux for 2 hours, the mixture was cooled, filtered through a celite pad, and the filtrate was concentrated. The residue was diluted with ethyl acetate (200ml) and washed with water (100 ml. times.2). After drying (magnesium sulfate), the solvent was removed to obtain 2.57g (98%) of the title compound as crystals. 1H-NMR(CDCl3)δ：7.73(1H，d，J＝15.8Hz)，7.34(1H，d，J＝2.5Hz)，7.12(1H，dd，J＝2.3，8.6Hz)，6.64(1H，d，J＝8.6Hz)，6.35(1H，d，J＝15.8Hz)，3.95(2H，br s)，3.81(3H，s).Step 3, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-5-chlorocinnamic acid methyl ester (step 2) following the procedure described for step 1 of example 8 (method a).1H-NMR(CDCl3) δ: 7.72-7.67(2H, m), 7.58-7.51(1H, m), 7.47-7.40(4H, m), 7.36(1H, d, J ═ 8.6Hz), 7.31(1H, dd, J ═ 2.1, 8.6Hz), 6.14(1H, d, J ═ 15.8Hz), 3.78(3H.s). no NH signal was observed.Step 4.[ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1- (benzenesulfonylamino) indoline-3- Base of]Acetic acid methyl ester
Following the procedure described in step 2 of example 8 (method a), from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (f.h.case et al, j.am.chem.soc., 1956,785842) the title compound is prepared. tlc: Rf 0.32 (ethyl acetate/hexane 1: 2)Step 5.[ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
According to example 31From [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1- (benzenesulfonylamino) indolin-3-yl]Methyl acetate (step 4) the title compound was prepared. MS (EI) m/z: 328 (M)+) Melting point: 230 ℃ and 231 ℃ (recrystallization in ethyl acetate). Ir (kbr) v: 3292, 1699, 1597, 1533, 1282, 1198, 1059, 802, 704cm -1.1H-NMR(DMSO-d6) δ: 12.26(1H, br s), 8.69(1H, d, J ═ 5.1Hz), 7.93(1H, br s), 7.82(1H, d, J ═ 2.0Hz), 7.66(1H, d, J ═ 8.7Hz), 7.56(1H, br d, J ═ 4.9Hz), 7.31(1H, dd, J ═ 2.0, 8.7Hz), 4.02(2H, s), 2.46(3H, s). no NH or COOH signal was observed.Example 37 [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.[ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1- (benzenesulfonylamino) indoline-3- Base of]Acetic acid methyl ester
Following the procedure described in step 2 of example 8 (method a), starting from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-6-methylpyridine hydrobromide (h.erlenmeyer, j.jenni and b.prijs, j.med.pharm.chem., 1961,3561-. tlc: Rf 0.39 (ethyl acetate/hexane 2: 3)Step 2.[ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in step 3 of example 8 (method A), starting from [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1- (benzenesulfonylamino) indolin-3-yl]Methyl acetate (step 1) the title compound was prepared.1H-NMR(CDCl3)δ：12.62(1H，br s)，8.15(1H，d，J＝7.9Hz)，7.84(1H，t，J＝7.7Hz)，7.67(1H，d，J＝1.8Hz)，7.43(1H，d，J＝8.9Hz)，7.40(1H，d，J＝7.7Hz)，7.32(1H，dd，J＝2.0，8.7Hz)，4.28(2H，s)，3.73(3H，s)，2.76(3H，s).Example 38 [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in example 34, from [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl]The title compound was prepared with acetic acid.MS(EI)m/z：328(M+) Melting point: 225 ℃ and 226 ℃ were added (recrystallized from ethyl acetate). Ir (kbr) v: 1705, 1636, 1529, 1333, 1236, 1180, 1061, 669cm-1.1H-NMR(DMSO-d6)δ：12.13(1H，br s)，12.09(1H，br s)，7.99(1H，t，J＝7.7Hz)，7.87(1H，d，J＝7.7Hz)，7.84(1H，d，J＝2.0Hz)，7.66(1H，d，J＝8.9Hz)，7.59(1H，d，J＝7.6Hz)，7.33(1h，dd，J＝2.0，8.9Hz)，4.03(2H，s)，2.69(3H，s).Example 39 [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid Step 1.[ 6-chloro-1-ethoxycarbonyl-2- (1-methylimidazole-2-carbonyl) indolin-3-yl] Acetic acid methyl ester
Following the procedure described in step 2 of example 31, from trans-4-chloro-2- (ethoxycarbonylamino) cinnamic acid methyl ester (step 1 of example 31) and 2-bromoacetyl-1-methylimidazole hydrobromide*The title compound was prepared. MS (EI) m/z: 405 (M)+)。*2-bromoacetyl-1-methylimidazole hydrobromide salt was prepared according to the following procedure:
to a suspension of 2-acetyl-1-methylimidazole (d.h.davis, j.hall and e.h.smith, j.chem.soc.perkin trans.1, 1991, 2691, 3.0g, 26.8mmol) in 25% HBr-AcOH was added dropwise a solution of bromine (4.7g, 29.5mmol) with ice-cooling and stirring. After stirring for 0.5 h, the mixture was warmed to room temperature and stirring was continued for an additional 1 h. Diethyl ether (150ml) was added to the mixture, and the mixture was cooled with an ice bath. The precipitate was collected by filtration to yield 5.2g (66%) of the title compound as a pale yellow powder. 1H-NMR(DMSO-d6)d：7.61(1H，s)，7.27(1H，s)，4.68(2H，s)，3.81(3H，s).Step 2.[ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 3 of example 31, from [ 6-chloro-1-ethoxycarbonyl-2- (1-methylimidazole-2-carbonyl) indolin-3-yl]Acetic acid (step 1) the title compound was prepared. Melting point: 236 deg.C (decomposition). MS (EI) m/z: 317 (M)+).IR(KBr)ν：3238，1695，1630，1537，1402，1229，1146cm-1.1H-NMR(CDCl3+DMSO-d6)δ：12.30(1H，s)，7.65(1H，d，J＝8.7Hz)，7.50(1H，d，J＝1.8Hz)，7.42(1H，s)，7.28-7.23(1H，m)，7.16(1H，s)，7.09(1H，dd，J＝1.8，8.6Hz)，4.25(2H，s)，4.13(3H，s).Example 40 [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.[ 5-chloro-1-benzenesulfonyl-2- (thiazole-2-carbonyl) indolin-3-yl]Acetic acid methyl ester
Following the procedure described in step 2 of example 8 (method a), starting from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl thiazole hydrobromide (a. dondondononi, a. marra and p. merino, j.am. chem. soc., 1994,1163324) preparation of the title compound. And (4) tlc: rf 0.07 (ethyl acetate/hexane 1: 2).Step 2.[ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in step 3 of example 8 (method A), starting from [ 5-chloro-1-benzenesulfonyl-2- (thiazole-2-carbonyl) indolin-3-yl]Methyl acetate (step 1) the title compound was prepared.1H-NMR(CDCl3)δ：11.78(1H，br s)，8.12(1H，d，J＝3.1Hz)，7.75(1H，d，J＝3.1Hz)，7.68(1H，d，J＝1.8Hz)，7.44(1H，d，J＝8.7Hz)，7.34(1H，dd，J＝2.0，8.9Hz)，4.29(2H，s)，3.74(3H，s).EXAMPLE 41 [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, starting from [ 5-chloro-1-benzenesulfonyl-2- (thiazole-2-carbonyl) indolin-3-yl ]Methyl acetate (step 2) the title compound was prepared. MS (EI) m/z: 320 (M)+) Melting point: 230 ℃ and 231 ℃ (recrystallization in ethyl acetate). Ir (kbr) v: 3302, 1703, 1636, 1541, 1387, 1335, 1267, 1232, 1186, 1003, 766cm-1.1H-NMR(DMSO-d6)δ：12.23(1H，br s)，12.10(1H，br s)，8.33(1H，d，J＝3.1Hz)，8.31(1H，d，J＝3.1Hz)，7.89(1H，d，J＝2.0Hz)，7.77(1H，d，J＝8.9Hz)，7.36(1H，dd，J＝2.0，8.7Hz)，4.17(2H，s).Example 42 (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester
A mixture of (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2, 50mg, 0.16mmol) and 10% HCl in methanol (3ml) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 5) to give 23mg (44%) of the title compound as a white solid. m.p.: 134 ℃. 137. deg.C, IR (KBr) v: 1735, 1620, 1529, 1434, 1325, 1147, 1013, 945cm-1.1H-NMR(CDCl3)δ：8.96(1H，br s)，7.85-7.74(2H，m)，7.66-7.47(4H，m)，7.38(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝1.8，8.6Hz)，3.18(2H，s)，3.65(3H，s).Example 43 (2-benzoyl-6-chloro-1H-indol-3-yl) -N, N-dimethylacetamide
To a solution of (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2, 140mg, 0.45mmol), dimethylamine hydrochloride (45mg, 0.54mmol) and triethylamine (0.1ml, 0.54mmol) in DMF (2ml) at 0 deg.C was added diethyl cyanophosphate (DEPC, 0.1ml, 0.54 mmol). The mixture was then stirred at room temperature for 1 hour, poured into water (20ml), and extracted with diethyl ether (50 ml. times.2). The organic extracts were washed with water (30ml × 2), dried (magnesium sulfate) and concentrated. The remaining solid was recrystallized from ethyl acetate/hexane to yield 50mg (33%) of the title compound. Melting point: 190 ℃ and 193 ℃ were added (recrystallized from ethyl acetate/hexane). Ir (kbr) v: 1631, 1232, 1007, 908cm -1.1H-NMR(CDCl3)δ：11.72(1H，br s)，7.72-7.64(4H，m)，7.60-7.52(2H，m)，7.45(1H，d，J＝1.2Hz)，7.08(1H，d，J＝8.6Hz)，3.32(2H，s)，2.80(3H，s)，2.76(3H，s).Example 44 (2-benzoyl-6-chloro-1H-indol-3-yl) -N-methylacetamide
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and methylamine hydrochloride according to the method described in example 43. Melting point: 242 ℃ and 246 ℃ (recrystallized from ethyl acetate/hexane). Ir (kbr) v: 1618, 1527, 1409 and 1325cm-1.1H-NMR(CDCl3)δ：11.71(1H，br s)，7.82-7.75(2H，m)，7.62-7.52(5H，m)，7.49-7.46(1H，m)，7.15-7.08(1H，m)，3.64(2H，s)，3.31(3H，s).Example 45 (2-benzoyl-6-chloro-1H-indol-3-yl) acetamide
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and ammonia in THF according to the method described in example 43. m.p.: 234 ℃. IR (KBr) v: 1665, 1618, 1566, 1523, 1325.1259, 943cm-1.1H-NMR(CDCl3)δ：11.66(1H，br s)，7.82-7.75(2H，m)，7.74-7.65(2H，m)，7.62-7.53(2H，m)，7.46(1H，d，J＝1.8Hz)，7.27(1H，br s)，7.12(1H，dd，J＝1.8，8.6Hz)，6.85(1H，br s)，3.63(2H，s).Example 46 (2-benzoyl-6-chloro-1H-indol-3-yl) -N-methoxy-N-methylacetamide
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and N, O-dimethylhydroxylamine hydrochloride according to the method described in example 43. Melting point: 109.9-112.2 deg.C (decomposition). Ir (kbr) v: 3179, 2970, 2937, 1634, 1599, 1570cm-1.1H-NMR(CDCl3)δ：9.20-8.90(1H，m)，7.84-7.75(2H，m)，7.66-7.45(4H，m)，7.33(1H，d，J＝1.3Hz)，7.12(1H，dd，J＝8.6，1.8Hz)，3.94(2H，s)，3.51(3H，s)，3.13(3H，s).Example 47 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1-piperidino-1-ethanone Step 1.7-chloro-1-phenyl-9H-pyrano [3, 4-b ] ]Indol-3-ones
A solution of (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2, 200mg, 0.64mmol), diethyl cyanophosphate (DEPC, 0.12ml, 0.76mmol) and triethylamine (0.11ml, 0.76mmol) in DMF (3.0ml) was stirred at room temperature for 5 min. The mixture was then poured into water (20ml) and the orange precipitate collected by filtration to give 20mg (11%) of the title compound as an orange solid.1H-NMR(CDCl3)δ：10.79(1H，br s)，8.10(1H，d，J＝8.4Hz)，7.93-7.84(2H，m)，7.67-7.50(3H，m)，7.29(1H，s)，7.13(1H，d，J＝8.4Hz)，6.87(1H，s).Step 2.2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1-piperidino-1-Ethanones
Heating and refluxing 7-chloro-1-phenyl-9H-pyrano [3, 4-b ]]Indol-3-one (step 1, 0.30g, 1.0mmol) and piperidine (1.0ml, 10mmol) in methanol (20ml) for 2 hours. After cooling to room temperature, the yellow mixture was concentrated and the remaining solid was recrystallized from methanol/hexane to yield 0.12g (32%) of the title compound. m.p.: 223 ℃. IR (KBr) v: 3310, 2928, 1655, 1570, 1533, 1447, 1323, 1256, 1225, 1059, 945, 858, 737, 700cm-1.1H-NMR(DMSO-d6)δ：11.7(1H，br s)，7.74-7.63(4H，m).7.55(2H，t，J＝8.7Hz).7.46(1H，d，J＝1.8Hz)，7.09(1H，dd，J＝8.7，1.8Hz)，3.80(2H，s)，3.45-3.20(4H，m)，1.55-1.20(6H，m)Example 48 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -N- (4-methyl-1-piperazinyl) -1-ethanone
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and 1-methylpiperazine according to the method described in example 43. Melting point: 184 ℃ and 185 ℃ (recrystallization in methanol/hexane). Ir (kbr) v: 2939, 2795, 1634, 1531, 1435, 1325, 1229, 1144, 1001, 737, 700cm -1 1H-NMR(CDCl3)δ：9.37(1H，br s)，7.78-7.75(1H，m)，7.73(1H，d，J＝1.5Hz)，7.62-7.52(2H，m)，7.52-7.43(2H，m)，7.18-7.10(1H，m)，7.10-7.02(1H，m)，3.81(2H，s)，3.54(2H，br s)，3.36(2H，t，J＝4.8Hz)，2.36-2.22(4H，m).2.28(3H，s).Example 49 (2-benzoyl-6-chloro-1H-indol-3-yl) -N- (2-cyanoethyl) acetamide
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and aminopropionitrile according to the method described for example 43. Melting point: 233-233.5 deg.C (recrystallization from methanol/hexane).1H-NMR(DMSO-d6)δ：11.7(1H，br s)，8.16(1H，t，J＝6.3Hz)，7.81-7.75(2H，m)，7.72-7.64(2H，m)，7.62-7.53(2H，m)，7.47(1H，d，J＝1.9Hz)，7.10(1H，dd，J＝8.7，1.9Hz)，3.67(2H，s)，3.23(2H，q，J＝6.3Hz)，2.58(2H，t，J＝6.3Hz)Example 50 (2-benzene)formyl-6-chloro-1H-indol-3-yl) -N- (2-hydroxyethyl) acetamide
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and 2-aminoethanol according to the method described in example 43. Melting point: 178-179.5 deg.C (recrystallization in methanol/hexane).1H-NMR(DMSO-d6)δ：11.7(1H，br s)，7.84-7.75(3H，m)，7.72-7.64(2H，m)，7.61-7.52(2H，m)，7.46(1H，d，J＝2.0Hz)，7.11(1H，dd，J＝8.6，2.0Hz)，3.64(2H，s)，3.38-3.30(3H，m)，3.06(2H，q，J＝5.9Hz).Example 51 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1-morpholino-1-ethanone
The title compound was prepared from (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid (example 2) and morpholine according to the method described for example 43. m.p.: 187.7-189.5 ℃ IR (KBr) v: 3339, 2964, 2849, 1653, 1612, 1568cm-1.1H-NMR(CDCl3)δ：9.08-8.92(1H，m)，7.81-7.72(2H，m)，7.69-7.58(2H，m)，7.56-7.47(2H，m)，7.29(1H，d，J＝1.8Hz)，7.12(1H，dd，J＝8.6，1.8Hz)，3.87(2H，s)，3.67-3.46(6H，m)，3.41-3.31(2H，m).Example 52 [2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid Step 1.2- (4-chlorobenzoyl) -1- (benzenesulfonyl) indole
To a solution of 1- (phenylsulfonyl) indole (500mg, 1.94mmol) in THF (5ml) was added tert-butyllithium (1.4ml, 2.33mmol) dropwise under a nitrogen atmosphere at-78 ℃. The yellow solution was poured directly into a solution of p-chlorobenzoyl chloride (0.3ml, 2.33mmol) in THF (3ml) cooled to-78 deg.C and the reaction mixture was stirred at-78 deg.C for 2 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50ml), brine (50ml) and dried (magnesium sulfate). After removal of the solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (10: 1) to give 339mg (44.1%) of the title compound as yellow amorphous. 1H-NMR(CDCl3)δ：8.13(1H，d，J＝8.4Hz)，8.04-8.00(2H，m)，7.93-7.90(2H，m)，7.58-7.44(7H，m)，7.30(1H，t，J＝7.4Hz)，6.95(1H，s).Step 2.2- (4-chlorobenzoyl) indole
A mixture of 2- (4-chlorobenzoyl) -1- (benzenesulfonyl) indole (step 1, 334mg, 0.84mmol) and 2N sodium hydroxide (1.5ml, 2.78mmol) in ethanol (5ml) was heated under reflux for 15 min. The mixture was concentrated and the residue was diluted with ethyl acetate (100 ml). The organic layer was washed with water, dried (magnesium sulfate), and concentrated to give 211mg (98.2%) of the title compound as a yellow solid.1H-NMR(CDCl3)δ：9.45(1H，br.s)，7.97-7.92(2H，m)，7.74-7.70(1H，m)，7.54-7.47(3H，m)，7.42-7.36(1H，m)，7.21-7.13(2H，m).Step 3. alpha-acetoxy- [2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
The title compound was prepared according to the procedure described in example 2 (method B), step 4, using 2- (4-chlorobenzoyl) indole (step 2).1H-NMR(CDCl3)δ：8.94(1H，br.s)，7.90(1H，d，J＝8.4Hz)，7.81-7.77(2H，m)，7.43-7.36(3H，m)，7.32-7.26(1H，m)，7.22-7.16(1H，m)，4.27-4.14(4H，m)，1.75(3H，s)，1.29-1.16(6H，m).Step 4.[2- (4-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
The procedure described in step 5 of example 2 (method B) was followed using α -acetoxy- [2- (4-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.73(1H，br.s)，7.85-7.82(1H，m)，7.79-7.76(2H，m)，7.52-7.46(2H，m)，7.39-7.37(1H，m)，7.26-7.19(2H，m)，5.27(1H，s)，4.26-4.16(4H，m)，1.26-1.21(6H，m)Step 5.[2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), using [2- (4-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. Melting point: 221 ℃ and 224 ℃ (recrystallization in ethyl acetate/hexane). Ir (kbr) v: 3321, 1697, 1607, 1576, 1529, 1433, 1408, 1339, 1263, 1223, 1202cm -1.1H-NMR(DMSO-d6)δ：11.62(1H，s)，7.79-7.75(2H，m)，7.71-7.63(3H，m)，7.46(1H，d，J＝8.2Hz)，7.35-7.29(1H，m)，7.14-7.08(1H，m)，3.84(2H，s)Example 53 [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (2-furylcarbonyl) -1- (phenylsulfonyl) indole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and 2-furoyl chloride according to the method described in step 2 of example 2 (method B).1H-NMR(CDCl3)δ：8.11-8.19(3H，m)，7.73-7.74(1H，m)，7.51-7.65(4H，m)，7.27-7.31(2H，m)，7.10(1H，s)，6.62-6.64(1H，m).Step 2.6-chloro-2- (2-furylcarbonyl) indole
The title compound was prepared from 6-chloro-2- (2-furylcarbonyl) -1- (benzenesulfonyl) indole (step 1) following the procedure described in step 3 of example 2 (method B).1H-NMR(CDCl3)δ：9.33(1H，br s)，7.65-7.73(3H，m)，7.46-7.48(2H，m)，7.12-7.16(1H，m)，6.64-6.66(1H，m).Step 3. alpha-acetoxy- [ 6-chloro-2- (2-furylcarbonyl) indol-3-yl]Malonic acid diethyl ester
The title compound was prepared from 6-chloro-2- (2-furylcarbonyl) indole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：9.60(1H，br s)，7.76(1H，d，J＝8.9Hz)，7.62-7.63(1H，m)，7.43(1H，d，J＝1.3Hz)，7.28-7.29(1H，m)，7.13(1H，dd，J＝1.8Hz，8.7Hz)，6.59(1H，dd，J＝1.6Hz，3.5Hz)，4.18-4.32(4H，m)，1.88(3H，s)，1.18-1.28(6H，m).Step 4.[ 6-chloro-2- (2-furylcarbonyl) indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), a starting material was prepared from α -acetoxy- [ 6-chloro-2- (2-furylcarbonyl) indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：9.83(1H，br s)，7.67(1H，t，J＝0.8Hz)，7.63(1H，d，J＝8.9Hz)，7.40(1H，d，J＝3.6Hz)，7.30(1H，d，J＝1.8Hz)，7.01(1H，dd，J＝1.8Hz，8.9Hz)，6.62(1H，dd，J＝1.6Hz，2.1Hz)，6.19(1H，s)，4.20-4.32(4H，m)，1.27(6H，t，J＝7.3Hz).Step 5.[ 6-chloro-2- (2-furylcarbonyl) indol-3-yl]Acetic acid
Following the procedure described in step 6 of example 2 (method B), from [ 6-chloro-2- (2-furylcarbonyl) indol-3-yl ]Diethyl malonate (step 4) prepares the title compound.1H-NMR(DMSO-d6)δ：12.22(1H，br s)，11.76(1H，br s)，8.13(1H，d，J＝1.0Hz)，7.75(1H，d，J＝8.6Hz)，7.56(1H，d，J＝1.8Hz)，7.48(1H，d，J＝3.6Hz)，7.14(1H，dd，J＝1.8Hz，8.6Hz)，6.85(1H，dd，J＝1.8Hz，3.6Hz)，4.02(2H，s).Example 54 [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2-cyclohexanecarbonyl-1- (phenylsulfonyl) indole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and cyclohexanecarbonyl chloride following the method described in step 2 of example 2 (method B). And (4) tlc: rf 0.4 (1: 4 ethyl acetate/hexane)Step 2.6-chloro-2- (cyclohexanecarbonyl) indole
The title compound was prepared from 6-chloro-2-cyclohexanecarbonyl-1- (benzenesulfonyl) indole (step 1) according to the method described in step 3 of example 2 (method B).1H-NMR(CDCl3)δ：10.08(1H，br s)，8.08-7.04(4H.m)，2.28-1.20(11H，m).Step 3. alpha-acetoxy- [ 6-chloro-2- (cyclohexanecarbonyl) indol-3-yl]Malonic acid diethyl ester
The title compound was prepared from 6-chloro-2- (cyclohexanecarbonyl) indole (step 2) following the procedure described in step 4 of example 2 (method B).1H-NMR(CDCl3)δ：8.94(1H，br s)，8.12-7.09(3H，m)，4.34-4.21(4H，m)，2.20(3H，s)，1.81-1.20(17H，m).Step 4.[ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of example 2 (method B), starting from α -acetoxy- [ 6-chloro-2- (cyclohexanecarbonyl) indol-3-yl]Malonic acid diethyl ester (Step 3) the title compound was prepared.1H-NMR(CDCl3)δ：8.90(1H，br s)，7.72(1H，d，J＝8.72Hz)，7.36-7.09(2H，m)，5.70(1H，s)，4.28-4.19(4H，m)，1.91-1.22(17H，m).Step 5.[ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in step 6 of example 2 (method B), starting from [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 206-209 ℃ IR (KBr) v: 3314, 2924, 2856, 1734, 1650, 1537, 1396, 1248, cm-1 1H-NMR(DMSO-d6)δ：11.78(1H，s)，7.71(1H，d，J＝8.64Hz)，7.46-7.07(2H，m)，4.01(2H，s)，1.78-1.16(11H).Example 55 [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8) and 4-methoxybenzoylmethyl bromide according to the method described for example 8.1H-NMR(CDCl3)δ：8.85(1H，s)，7.82(2H，d，J＝8.9Hz)，7.56(1H，d，J＝8.6Hz)，7.40(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝1.8，8.6Hz)，6.99(2H，d，J＝8.6Hz)，3.90(3H，s)，3.86(2H，s)，3.67(3H，s).Example 56 [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9 (method B), starting from [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl]Methyl acetate (step 1) the title compound was prepared. m.p.: 187 ℃ 190 ℃1H-NMR(DMSO-d6)δ：11.72(1H，s)，7.78(2H，d，J＝8.7Hz)，7.70(1H，d，J＝8.6Hz)，7.49-7.45(1H，m)，7.15-7.07(3H，m)，3.87(3H，s)，3.81(2H，s).Example 57 [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Methyl trans-4-chloro-2- (benzenesulfonylamino) cinnamate (example 8, step 1, 700mg, 1.99mmol of method A), 2-bromoacetyl-4-ethylpyridine were stirred at room temperature*(545mg，2.39mmol), potassium carbonate (1.37g, 13.9mmol) and acetone (20 ml). After stirring for 3 hours, 1, 8-diazabicyclo [5.4.0 ] was added ]Undec-7-ene (DBU, 0.6ml, 3.98 mmol). The resulting mixture was stirred for an additional 19 hours and then concentrated. The residue was diluted with dichloromethane (200ml) and washed with water (100 ml. times.2). The organic layer was dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane/dichloromethane (1: 4: 1) to give the title compound as an impurity. The crude product was washed with ethyl acetate to yield 297mg (42%) of the title compound as a yellow solid.1H-NMR(CDCl3)δ：12.52(1H，br s)，8.64(1H，d，J＝4.9Hz)，8.21(1H，br s)，7.62(1H，d，J＝8.7Hz)，7.52(1H，d，J＝1.8Hz)，7.39-7.35(1H，m)，7.13(1H，dd，J＝1.8，8.6Hz)，4.31(2H，s)，3.73(3H，s)，2.78(2H，q，J＝7.6Hz)，1.32(3H，t，J＝7.6Hz).*2-Bromoacetyl-4-ethylpyridine was prepared as follows:
to 2-acetyl-4-ethylpyridine (e.c. constable et al, j.am.chem.soc., 1997,1195606, 8.37g, 56.1mmol) in 25% hydrobromic acid-acetic acid (150ml) a solution of bromine (9.86g, 61.7mmol) in acetic acid (30ml) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. Diethyl ether (500ml) was added to the mixture, and the resulting mixture was cooled with an ice bath. The brown oil that precipitated from the solution was collected by decantation. The oil was treated with saturated aqueous sodium bicarbonate (50ml) and extracted with diethyl ether (300 ml). The organic layer was dried (magnesium sulfate) and concentrated to give 15.3g (88%) of the title compound. 1H-NMR(CDCl3)δ：8.56(1H，d，J＝5.1Hz)，7.95(1H，br s)，7.36-7.34(1H，m)，4.86(2H，s)，2.74(2H，q，J＝7.7Hz)，1.29(3H，t.J＝7.6Hz).Example 58 [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Heating and refluxing [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]A yellow suspension of methyl acetate (example 57, 297mg, 0.83mmol) in 2N aqueous sodium hydroxide (2.5ml) and ethanol (20ml) was suspended for 3 h. Cooling the mixtureAfter cooling to room temperature, the reaction mixture was neutralized with a 2N aqueous hydrochloric acid solution (2.5ml), and concentrated. The residue was diluted with THF (150ml), dried (magnesium sulfate) and concentrated. The remaining solid was recrystallized from ethyl acetate to yield 251mg (88%) of the title compound as a yellow solid. MS (EI) m/z: 342 (M)+). Melting point: 215 ℃ and 216 ℃ (decomposition). Ir (kbr) v: 3206, 1707, 1643, 1595, 1535, 1421, 1227, 1192, 1140, 912, 777cm-1.1H-NMR(DMSO-d6)δ：12.30(1H，br s)，12.18(1H，br s)，8.73(1H，d，J＝4.9Hz)，7.98(1H，br s)，7.79(1H，d，J＝8.7Hz)，7.74(1H，d，J＝1.8Hz)，7.62(1H，br d，J＝5.1Hz)，7.12(1H，dd，J＝1.8，8.6Hz)，4.08(2H，s)，2.78(2H.q，J＝7.7Hz)，1.26(3H，t，J＝7.7Hz).Example 59 [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-ethylpyridine (for preparation see example 57) by the method described in example 57.1H-NMR(CDCl3)δ：12.57(1H，br s)，8.65(1H，d，J＝5.1Hz)，8.21(1H，br s)，7.68(1H，br s)，7.45(1H，d，J＝8.9Hz)，7.40-7.36(1H，m)，7.31(1H，dd，J＝2.0，8.7Hz)，4.28(2H，s)，3.74(3H，s)，2.78(2H，q，J＝7.7Hz)，1.32(3H，t，J＝7.7Hz).Example 60 [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 57, from [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ]Methyl acetate (example 59) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p.：217-218℃IR(KBr)ν：3269，1705，1643，1595，1533，1418，1335，1225，1200，1059，779cm-1.1H-NMR(DMSO-d6)δ：12.33(1H，br s)，8.73(1H，d，J＝4.9Hz)，7.98(1H，br s)，7.86(1H，d，J＝2.0Hz)，7.69(1H，d，J＝8.9Hz)，7.61(1H，dd，J＝4.8，1.6Hz)，7.33(1H，dd，J＝2.0，8.7Hz)，4.07(2H，s)，2.78(2H，q，J＝7.6Hz)，1.26(3H，t，J＝7.6Hz).Example 61 [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method A) and 2-bromoacetyl-4-isopropylpyridine were prepared*The title compound was prepared.1H-NMR(CDCl3)δ：12.53(1H，br s)，8.65(1H，d，J＝4.9Hz)，8.24(1H，d，J＝1.6Hz)，7.62(1H，d，J＝8.7Hz)，7.52(1H，d，J＝1.6Hz)，7.40(1H，dd，J＝1.8，4.9Hz)，7.13(1H，dd，J＝1.8，8.7Hz)，4.30(2H，s)，3.73(3H，s)，2.97-3.07(1H，m)，1.32(6H，d，J＝6.9Hz).*2-Bromoacetyl-4-isopropylpyridine was prepared as described for 2-bromoacetyl-4-ethylpyridine in example 57 from 2-acetyl-4-isopropylpyridine (K. Ishihama et al, J. Agric. food chem., 1992,401647).1H-NMR(CDCl3)δ：8.57(1H，d，J＝5.8Hz)，7.97-7.98(1H，m)，7.36-7.38(1H，m)，4.86(2H，s)，2.94-3.04(1H，m)，1.27-1.32(6H，m).Example 62 [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 61) the title compound was prepared. m.p.: 194-196 ℃ IR (KBr) v: 3244, 2965, 1692, 1647, 1597, 1537, 1254, 1200, 1178, 1150, 764cm-1.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，8.74(1H，d，J＝5.3Hz)，8.01(1H，s)，7.80(1H，d，J＝8.9Hz)，7.74(1H，d，J＝1.6Hz)，7.64-7.66(1H，m)，7.12(1H，dd，J＝1.8，8.6Hz)，4.08(2H，s)，3.02-3.13(1H，m)，1.28(6H，d，J＝6.9Hz).Example 63 [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-isopropylpyridine (preparation method thereof) were prepared The title compound is prepared as described in example 61).1H-NMR(CDCl3)δ：12.57(1H，br s)，8.65(1H，d，J＝5.1Hz)，8.24(1H，d，J＝1.6Hz)，7.67(1H，d，J＝2.0Hz)，7.44(1H，d，J＝8.2Hz)，7.40(1H，dd，J＝1.8，4.9Hz)，7.31(1H，dd，J＝2.0，8.7Hz)，4.28(2H，s)，3.74(3H，s)，2.97-3.07(1H，m)，1.32(6H，d，J＝6.9Hz).Example 64 [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 63) the title compound was prepared. MS (EI) m/z: 356 (M)+).m.p.：227-228℃.IR(KBr)ν：2964，1703，1643，1595，1537，1202，1059，768cm-1.1H-NMR(DMSO-d6)δ：12.32(1H，br s)，12.15(1H，br s)，8.74(1H，d，J＝4.9Hz)，8.00(1H，s)，7.86(1H，s)，7.64-7.71(2H，m)，7.31-7.35(1H，m)，4.08(2H，s)，3.03-3.13(1H，m)，1.28(6H，d，J＝6.9Hz).Example 65 [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method A) and 2-bromoacetyl-4-propylpyridine hydrobromide*The title compound was prepared.1H-NMR(CDCl3)δ：12.53(1H，br s)，8.64(1H，d，J＝4.9Hz)，8.19(1H，s)，7.62(1H，d，J＝8.7Hz)，7.53(1H，d，J＝1.6Hz)，7.35-7.37(1H，m)，7.13(1H，dd，J＝1.8，8.7Hz)，4.31(2H，s)，3.73(3H，s)，2.71(2H，t，J＝7.3Hz)，1.69-1.77(2H，m)，0.98(3H，t，J＝7.3Hz).*2-Bromoacetyl-4-propylpyridine hydrobromide was prepared according to the following procedure: 4-propyl-2-pyridinecarbonitrile:
following the procedure described for the preparation of 4-chloro-2-pyridinecarbonitrile in example 33, a starting material was prepared from 4-propylpyridine-N-oxide (s.ghersetti et al, j.heterocyclic. chem., 1969,6859) the title compound is prepared.1H-NMR(CDCl3) δ: 8.59(1H, d, J ═ 5.1Hz), 7.53(1H, s), 7.32-7.34(1H, m), 2.66(2H, t, J ═ 7.3Hz), 1.62-1.76(2H, m), 0.97(3H, t, J ═ 7.3Hz), 2-acetyl-4-propylpyridine:
the title compound was prepared from 4-propyl-2-pyridinecarbonitrile following the procedure described for the preparation of 2-acetyl-4-chloropyridine in example 33. 1H-NMR(CDCl3) δ: 8.56(1H, d, J ═ 4.9Hz), 7.88(1H, s), 7.27-7.30(1H, m), 2.72(3H, s), 2.66(2H, t, J ═ 7.4Hz), 1.62-1.76(2H, m), 0.95(3H, t, J ═ 7.4Hz), 2-bromoacetyl-4-propylpyridine hydrobromide:
the title compound was prepared from 2-acetyl-4-propylpyridine following the procedure for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of example 31.1H-NMR(DMSO-d6)δ：8.64(1H，d，J＝4.9Hz)，7.90(1H，d，J＝1.0Hz)，7.59(1H，dd，J＝16，4.9Hz)，5.02(2H，s)，2.70(2H，t，J＝7.4Hz)，1.57-1.71(2H，m)，0.89(3H，t，J＝7.3Hz).Example 66 [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, starting from 2- [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl]The title compound was prepared from acetic acid (example 65). m.p.: 189-191 ℃ C.,. IR (KBr) v: 2964, 2928, 1711, 1645, 1595, 1533, 1281, 1225, 1192, 799cm-1.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，8.73(1H，d，J＝5.1Hz)，7.96(1H，s)，7.73-7.81(2H，m)，7.59(1H，d，J＝4.9Hz)，7.10-7.13(1H，m)，4.08(2H，s)，2.73(2H，t，J＝7.1Hz)，1.63-1.72(2H，m)，0.92(3H，t，J＝7.3Hz).Example 67 [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the procedure described for the preparation of example 57 from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-propylpyridine hydrobromide (preparation method thereof see example 65).1H-NMR(CDCl3)δ：12.56(1H，br s)，8.64(1H，d，J＝4.9Hz)，8.18(1H，s)，7.67(1H，d，J＝2.0Hz)，7.45(1H，d，J＝8.7Hz)，7.29-7.37(2H，m)，4.28(2H，s)，3.74(3H，s)，2.71(2H，t，J＝7.4Hz)，1.80-1.66(2H，m)，0.97(3H，t，J＝7.3Hz).Example 68 [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 67) the title compound was prepared. m.p.: 208 ℃. IR (KBr) v: 3296, 2957, 1705, 1645, 1595, 1535, 1329, 1273, 1204, 1057, 795cm-1 1H-NMR(DMSO-d6)δ：12.33(1H，br s)，12.15(1H，br s)，8.73(1H，d，J＝4.9Hz)，7.95(1H，s)，7.86(1H，s)，7.69(1H，d，J＝8.7Hz)，7.58-7.61(1H，m)，7.31-7.35(1H，m)，4.08(2H，s)，2.73(2H，t，J＝7.4Hz)，1.64-1.72(2H，m)，0.92(3H，t，J＝7.4Hz).Example 69 [2- (4-tert-butylpyridin-2-carbonyl) -6-chloro-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method A) and 2-bromoacetyl-4-tert-butylpyridine were synthesized*The title compound was prepared.1H-NMR(CDCl3)δ：12.55(1H，br s)，8.67(1H，d，J＝5.3Hz)，8.39(1H，d，J＝2.1Hz)，7.63(1H，d，J＝8.7Hz)，7.53-7.55(2H，m)，7.13(1H，dd，J＝1.8，8.7Hz)，4.31(2H，s)，3.73(3H，s)，1.38(9H，s).*2-Bromoacetyl-4-tert-butylpyridine was prepared according to the procedure described in example 57 for the preparation of 2-bromoacetyl-4-ethylpyridine from 2-acetyl-4-tert-butylpyridine (E.C. Constable et al, J.Am.chem.Soc., 1997,1195606).1H-NMR(CDCl3)δ：8.58(1H，d，J＝4.8Hz)，8.11(1H，d，J＝1.6Hz)，7.51(1H，dd，J＝1.8，5.1Hz)，4.86(2H，s)，1.35(9H，s).Example 70 [2- (4-tert-butylpyridin-2-carbonyl) -6-chloro-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl]Methyl acetate (example 69) the title compound was prepared. MS (EI) m/z: 370 (M)+).m.p.：203-205℃.IR(KBr)ν：2966，1699，1647，1591，1535，1229cm-1.1H-NMR(DMSO-d6)δ：12.29(1H，br s)，8.76(1H，d，J＝5.3Hz)，8.10(1H，d，J＝2.0Hz)，7.74-7.81(3H，m)，7.12(1H，dd，J＝1.8，8.6Hz)，4.08(2H，s)，1.36(9H，s).Example 71 [2- (4-tert-butylpyridin-2-carbonyl) -5-chloro-1H-indol-3-yl ]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-tert-butylpyridine (preparation method see example 69) according to the method described in example 57.1H-NMR(CDCl3)δ：12.59(1H，br s)，8.67(1H，d，J＝5.3Hz)，8.38(1H，d，J＝2.0Hz)，7.68(1H，d，J＝2.0Hz)，7.54(2H，dd，2.0，5.3Hz)，7.45(1H，d，J＝8.9Hz)，7.32(1H，dd，J＝2.0，8.9Hz)，4.29(2H，s)，3.74(3H，s)，1.38(9H，s).Example 72 [2- (4-tert-butylpyridin-2-carbonyl) -5-chloro-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl]Methyl acetate (example 71) the title compound was prepared. MS (EI) m/z: 370 (M)+).m.p：209-211℃.IR(KBr)ν：3269，2968，1746，1705，1589，1531，1236，1207，1177，1150，1059，737cm-1.1H-NMR(DMSO-d6)δ：12.33(1H，br s)，8.76(1H，d，J＝5.3Hz)，8.10(1H，d，J＝2.0Hz)，7.86(1H，d，J＝2.0Hz)，7.78(1H，dd，J＝2.0，5.1Hz)，7.69(1H，d，J＝8.7Hz)，7.33(1H，dd，J＝2.0，8.7Hz)，4.08(2H，s)，1.36(9H，s).Example 73 [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
From trans-4-chloro-2- (phenylsulfonylamino) cinnamic acid methyl ester (step of example 8, method A) according to the method described in example 57Step 1) and 2-bromoacetyl-3-methylpyridine hydrobromide*The title compound was prepared.1H-NMR(CDCl3)δ：11.19(1H，br s)，8.54(1H，d，J＝4.6Hz)，7.65(1H，d，J＝7.7Hz)，7.55(1H，d，J＝8.6Hz)，7.33-7.38(2H，m)，7.06(1H，dd，J＝1.8，8.7Hz)，4.15(2H，s)，3.69(3H，s)，2.59(3H，s).*2-Bromoacetyl-3-methylpyridine according to the procedure described in step 2 of example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide, starting from 2-acetyl-3-methylpyridine (T.A. Crabb et al, org.Magn.Reson., 1982,20242).1H-NMR(DMSO-d6)δ：8.56(1H，d，J＝3.6Hz)，7.84(1H，d，J＝7.7Hz)，7.56-7.60(1H，m)，5.01(2H，s)，4.01(3H，s).Example 74 [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 73) the title compound was prepared. MS (EI) m/z: 328 (M)+).m.p.：195-196℃.IR(KBr)ν：3314，1703，1636，1526，1418，1396，1231，1196，1150，1109cm-1.1H-NMR(DMSO-d6)δ：12.14(1H，br s)，11.76(1H，br s)，8.53(1H，d，J＝3.8Hz)，7.85(1H，d，J＝7.9Hz)，7.74(1H，d，J＝8.6Hz)，7.52-7.56(2H，m)，7.10(1H，dd，J＝1.8，8.6Hz)，3.66(2H，s)，2.33(3H，s).Example 75 [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the procedure described for the preparation of example 57 from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-3-methylpyridine hydrobromide (preparation thereof see example 73).1H-NMR(CDCl3)δ：11.28(1H，br s)，8.56(1H，d，J＝3.1Hz)，7.61-7.69(2H，m)，7.23-7.41(3H，m)，4.15(2H，s)，3.70(3H，s)，2.61(3H，s).Example 76 [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, starting from 2- [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 75) the title compound was prepared. Melting point: 209 ℃ and 211 ℃ (decomposition). Ir (kbr) v: 3379, 3271, 1728, 1649, 1638, 1528, 1231, 1195, 1182, 1165, 1015cm-1.1H-NMR(DMSO-d6)δ：11.81(1H，br s)，8.53(1H，d，J＝4.4Hz)，7.85(1H，d，J＝7.7Hz)，7.80(1H，d，J＝2.0Hz)，7.49-7.56(2H，m)，7.31(1H，dd，J＝2.1，8.7Hz)，3.66(2H，s).2.33(3H，s).Example 77 [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 13 of method a) and 2-bromoacetyl-6-methylpyridine hydrobromide (h. erlenmeyer, j. jenni and b. prijs, j.med.pharm chem., 1961, 3561-.1H-NMR(CDCl3)δ：12.58(1H，br s)，8.15(1H，d，J＝7.9Hz)，7.83(1H，t，J＝7.7Hz)，7.62(1H，d，J＝8.7Hz)，7.51(1H，d，J＝1.8Hz)，7.40(1H，d.J＝7.7Hz)，7.13(1H，dd，J＝1.8，8.7Hz)，4.31(2H，s)，3.72(3H，s)，2.76(3H，s).Example 78 [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 77) the title compound was prepared. MS (EI) m/z: 328 (M)+).m.p.：230-231℃.IR(KBr)ν：3273，1697，1643，1535，1308，1227，1183，1150，797，760，671cm-1.1H-NMR(DMSO-d6)δ：12.06(1H，br s)，7.99(1H，t，J＝7.7Hz)，7.87(1H，d，J＝7.6Hz)，7.78(1H，d，J＝8.9Hz)，7.74(1H，d，J＝2.0Hz)，7.59(1H，d，J＝7.6Hz)，7.13(1H，dd，J＝2.0，8.7Hz)，4.04(2H，s)，2.69(3H，s).Example 79 [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
As described in example 57The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-5-methylpyridine (for its preparation see step 1 of example 32).1H-NMR(CDCl3)δ：12.48(1H，br s)，8.59(1H，d，J＝2.1Hz)，8.24(1H，d，J＝8.1Hz)，7.75(1H，dd，J＝2.1，8.1Hz)，7.67(1H，d，J＝2.0Hz)，7.44(1H，d，J＝8.7Hz)，7.31(1H，dd，J＝2.0，8.9Hz)，4.29(2H，s)，3.74(3H，s)，2.48(3H，s).Example 80 [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, starting from [ 5-chloro-2- (5-methylpyridine-2-carbonyl) - -1H-indol-3-yl]Methyl acetate (example 79) the title compound was prepared. MS (EI) m/z: 328 (M)+).m.p.：247-248℃.IR(KBr)ν：3288，1699，1638，1531，1427，1329，1285，1246，1209，1177，1059，1016，800，700cm-1.1H-NMR(DMSO-d6)δ：12.30(1H，br s)，12.15(1H，br s)，8.68(1H，br s)，8.04(1H，d，J＝7.9Hz)，7.93(1H，br d，J＝8.9Hz)，7.84(1H，br s)，7.69(1H，d，J＝8.9Hz)，7.33(1H，dd，J＝2.0，8.9Hz)，4.09(2H，s)，2.46(3H，s).Example 81 [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method A) and 2-bromoacetyl-5- (trifluoromethyl) pyridine were prepared *The title compound was prepared.1H-NMR(CDCl3)δ：11.97(1H，br s)，9.07(1H，br s)，8.48(1H，d，J＝8.4Hz)，8.23(1H，dd，J＝2.1，8.4Hz)，7.63(1H，d，J＝8.6Hz)，7.52(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝1.8，8.6Hz)，4.31(2H，s)，3.74(3H，s).*2-Bromoacetyl-5- (trifluoromethyl) pyridine was prepared from 2-chloro-5- (trifluoromethyl) pyridine following the procedure described for the preparation of 2-bromoacetyl-5-methylpyridine in step 1 of example 32.1H-NMR(CDCl3)δ：8.96(1H，br s)，8.23(1H，br d.J＝8.2Hz)，8.13(1H，dd，J＝2.1，8.1Hz)，4.83(2H，s).Example 82 [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (5-trifluoromethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 81) the title compound was prepared. MS (EI) m/z: 382 (M)+).m.p.：228-229℃.IR(KBr)ν：3325，1707，1636，1529，1333，1310，1138，1078，1020cm-1.1H-NMR(DMSO-d6)δ：12.05(1H，br s)，9.17(1H，br s)，8.54(1H，dd，J＝2.0，8.4Hz)，8.24(1H，d，J＝8.2Hz)，7.82(1H，d，J＝8.6Hz)，7.64(1H，d，J＝1.8Hz)，7.14(1H，dd，J＝2.0，8.7Hz)，4.06(2H，s).Example 83 [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-5- (trifluoromethyl) pyridine (for its preparation see example 81) according to the method described for example 57.1H-NMR(CDCl3)δ：12.01(1H，br s)，9.05(1H，br s)，8.45(1H，d，J＝8.2Hz)，8.21(1H，dd，J＝2.3，8.4Hz)，7.65(1H，br s)，7.43(1H，d，J＝8.7Hz)，7.32(1H，dd，J＝2.0，8.7Hz)，4.27(2H，s)，3.76(3H，s).Example 84 [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (5-trifluoromethylpyridine-2-carbonyl)]-1H-indol-3-yl]Methyl acetate (example 83) the title compound was prepared. MS (EI) m/z: 382 (M)+).m.p.：230-231℃.IR(KBr)ν：3300，1720，1701，1641，1531，1327，1235，1163，1130，1078，1020，864cm-1.1H-NMR(DMSO-d6)δ：12.09(1H，br s)，9.17(1H，br s)，8.54(1H，dd，J＝2.0，8.2Hz)，8.23(1H，d，J＝8.2Hz)，7.89(1H，d，J＝1.8Hz)，7.62(1H，d，J＝8.9Hz)，7.36(1H，dd，J＝1.8，8.9Hz)，4.06(2H，s).Examples85 [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-5-chloropyridine were synthesized*The title compound was prepared.1H-NMR(CDCl3)δ：12.01(1H，br s)，8.72(1H，d，J＝2.5Hz)，8.29(1H，d，J＝8.6Hz)，7.93(1H，dd，J＝2.5，8.6Hz)，7.65(1H，d，J＝2.0Hz)，7.43(1H，d，J＝8.7Hz)，7.31(1H，dd，J＝2.0，8.7Hz)，4.27(2H，s)，3.75(3H，s).*2-Bromoacetyl-5-chloropyridine was prepared according to the procedure described in step 1 of example 32 for 2-bromoacetyl-5-methylpyridine, starting from 2-bromo-5-chloropyridine (Case, J.am.chem.Soc., 1946,682574).1H-NMR(CDCl3)δ：8.63(1H，dd，J＝0.6，2.5Hz)，8.06(1H，dd，J＝0.6，8.4Hz)，7.85(1H，dd，J＝2.3，8.4Hz)，4.79(2H，s).Example 86 [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 85) the title compound was prepared. MS (EI) m/z: 348 (M)+).m.p.：259-260℃.IR(KBr)ν：3314，1703，1632，1528，1331，1236，1178，1111，1059，1015，806，698cm-1.1H-NMR(DMSO-d6)δ：12.18(1H，br s)，12.08(1H，br s)，8.84(1H，d，J＝2.5Hz)，8.25(1H，dd，J＝2.5，8.4Hz)，8.10(1H，d，J＝8.6Hz)，7.87(1H，d，J＝2.0Hz)，7.63(1H，d，J＝8.7Hz)，7.34(1H，dd，J＝2.1，8.9Hz)，4.06(2H，s).Example 87 [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the procedure described for example 57 from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-bromoacetyl-5-chloropyridine (preparation thereof is described in example 85).1H-NMR(CDCl3)δ：11.98(1H，br s)，8.74(1H，dd，J＝0.7 and 2.3Hz)，8.31(1H，dd，J＝0.7，8.6Hz)，7.94(1H，dd，J＝2.3，8.4Hz)，7.63(1H，d，J＝8.7Hz)，7.52(1H，d，J＝1.6Hz)，7.14(1H，dd，J＝1.8，8.7Hz)，4.30(2H，s)，3.73(3H，s).Example 88 [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ]Methyl acetate (example 87) the title compound was prepared. MS (EI) m/z: 348 (M)+).m.p.：242-244℃.IR(KBr)ν：3306，1703，1636，1529，1308，1234，1151，1109，698cm-1.1H-NMR(DMSO-d6)δ：12.05(1H，br s)，8.84(1H，d，J＝2.3Hz)，8.26(1H，dd，J＝2.3，8.4Hz)，8.10(1H，d，J＝8.4Hz)，7.80(1H，d，J＝8.7Hz)，7.67(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝1.8，8.7Hz)，4.06(2H，s).Example 89 [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-chloropyridine (for preparation see example 33) by the method described in example 57.1H-NMR(CDCl3)δ：12.20(1H，br s)，8.67(1H，d，J＝5.3Hz)，8.33(1H，d，J＝2.1Hz)，7.66(1H，d，J＝2.0Hz)，7.56(1H，dd，J＝2.1，5.3Hz)，7.43(1H，d，J＝8.7Hz)，7.32(1H，dd，J＝2.0，8.9Hz)，4.27(2H，s)，3.75(3H，s).Example 90 [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 89) the title compound was prepared. MS (EI) m/z: 348 (M)+).m.p.：243-244℃.IR(KBr)ν：3000，1719，1643，1528，1242，1202，741cm-1.1H-NMR(DMSO-d6)δ：12.20(1H，br s)，8.80(1H，d，J＝5.3Hz)，8.12(1H，d，J＝2.1Hz)，7.90(1H，dd，J＝2.1，5.4Hz)，7.66(1H，d，J＝8.9Hz)，7.34(1H，dd，J＝2.0，8.7Hz)，4.06(2H，s).Example 91 [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (phenylsulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 3-bromoacetylpyridine hydrobromide (g.b. barlin, l.p. davies, s.j.ireland, m.m.l.ngu, aust.j.chem., 1989,421735) preparation of the title compound.1H-NMR(CDCl3)δ：9.26(1H，br s)，9.00(1H，dd，J＝0.8，2.1Hz)，8.80(1H，dd，J＝1.6，4.8Hz)，8.10(1H，dt，J＝2.0，2.0，7.9Hz)，7.58(1H，d，J＝8.7Hz)，7.47(1H，ddd，J＝0.8，4.9，7.9Hz)，7.37(1H，d，J＝1.8Hz)，7.16(1H，dd，J＝1.8，8.6Hz)，3.84(2H，s)，3.65(3H，s).Example 92 [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ]Methyl acetate (example 91) the title compound was prepared. MS (EI) m/z: 314 (M)+).m.p.：267-268℃.IR(KBr)ν：3346，1705，1609，1566，1528，1433，1418，1327，1267，1215，943，761cm-1.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，11.86(1H，br s)，8.90(1H，br s)，8.85(1H，brd，J＝4.9Hz)，8.12(1H，dt，J＝2.0，2.0，7.9Hz)，7.77(1H，t，J＝8.6Hz)，7.62(1H，dd，J＝4.9，8.0Hz)，7.49(1H，d，J＝2.0Hz)，7.15(1H，dd，J＝1.6，8.4Hz)，3.85(2H，s).Example 93 [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4-bromoacetylpyridine hydrobromide (l.w. deady, m.s.stanborough, aust.j.chem., 1981,341295) preparation of the title compound.1H-NMR(CDCl3)δ：9.21(1H，br s)，8.82-8.79(2H，m)，7.59-7.57(2H，m)，7.56(1H，d，J＝8.7Hz)，7.33(1H，d，J＝1.8Hz)，7.16(1H，dd，J＝1.8，8.7Hz)，3.80(2H，s)，3.65(3H，s).Example 94 [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl]Methyl acetate (example 93) the title compound was prepared. MS (EI) m/z: 314 (M)+).m.p.：256-257℃.IR(KBr)ν：3352，1709，1607，1528，1431，1329，1259，1202，772，687cm-1.1H-NMR(DMSO-d6)δ：11.82(1H，br s)，8.82(2H，d，J＝5.8Hz)，7.77(1H，d，J＝8.6Hz)，7.64-7.62(2H，m)，7.48(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝2.0，8.7Hz)，3.83(2H，s).Example 95 [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.[ 6-chloro-2- [4- (tert-butyldimethylsilyloxymethyl) pyridine-2-carbonyl]-1H- Indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method A) and 2-bromoacetyl-4- (tert-butyldimethylsiloxymethyl) pyridine were prepared*The title compound was prepared.1H-NMR(CDCl3)δ：12.47(1H，br s)，8.70(1H，d，J＝4.9Hz)，8.21-8.22(1H，m)，7.55-7.58(2H，m)，7.50-7.51(1H，m)，7.10(1H，dd，J＝1.8，8.7Hz)，4.83(2H，s)，4.31(2H，s)，3.72(3H，s)，0.98(9H，s)，0.15(6H，s).*2-Bromoacetyl-4- (tert-butyldimethylsiloxymethyl) pyridine was prepared according to the following method: 2-acetyl-4- (tert-butyldimethylsiloxymethyl) pyridine:
Following the procedure for the preparation of 2-acetyl-4-chloropyridine described in example 33, 4- (tert-butyldimethylsilyloxymethyl) pyridinecarbonitrile (a. hadri et al, j. heterocyclic. chem., 1993,30631) preparation of the title compound.1H-NMR(CDCl3)δ：8.64(1H，d，J＝4.8Hz)，7.96(1H，s)，7.50(1H，d，J＝4.8Hz)，4.80(2H，s)，2.73(3H，s)，0.96(9H，s)，0.12(6H, s). 2-bromoacetyl-4- (tert-butyldimethylsiloxymethyl) pyridine:
to a solution of 2-bromoacetyl-4- (tert-butyldimethylsilyloxymethyl) pyridine (1.84g, 6.932mmol) in THF (50ml) was added dropwise a solution of lithium bis (trimethylsilyl) amide (1M in THF, 8.3ml, 8.3mmol) at-78 ℃. After stirring for 1 hour, triethylchlorosilane (1.7ml, 10.4mmol) was added to the mixture at-78 deg.C, the mixture was stirred at that temperature for 1 hour and then warmed to 0 deg.C. After stirring for 1 hour, a saturated aqueous solution of ammonium chloride (50ml) was added. The mixture was extracted with ether (100ml) and the organic layer was washed with water (50ml), dried (magnesium sulphate) and concentrated. The residue was dissolved in THF (20ml), followed by addition of water (4ml) and NBS at 0 ℃. After stirring for 1 hour, the mixture was diluted with ether (200ml), washed with water (50ml) and dried (magnesium sulfate). After removal of the solvent, the crude product was obtained. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 20) to give 0.74g (31%) of the title compound as crystals. 1H-NMR(CDCl3)δ：8.63(1H，d，J＝4.8Hz)，8.02(1H，q，J＝0.8Hz)，7.53(1H，dt， J＝0.8，4.9Hz)，4.87(2H，s)，4.81(2H，s)，0.96(9H，s)，0.13(3H，s).Step 2.[ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid methyl ester
To [ 6-chloro-2- [4- (tert-butyldimethylsilyloxymethyl) pyridine-2-carbonyl at room temperature]-1H-indol-3-yl]To a solution of methyl acetate (step 1, 171.5mg, 0.3625mmol) in THF (5ml) was added a solution of tetrabutylammonium fluoride (1M in THF, 0.54ml, 0.54 mmol). After stirring for 1 hour, the mixture was concentrated. The residue was diluted with ethyl acetate (100ml), washed with water (20 ml. times.2) and dried (magnesium sulfate). After removal of the solvent, the crude product was obtained. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexane/dichloromethane (1: 1) to give 69.6mg (54%) of the title compound as crystals.1H-NMR(CDCl3)δ：12.43(1H，br s)，8.74(1H，d，J＝5.1Hz)，8.29(1H，s)，7.59-7.64(2H，m)，7.52(1H，d，J＝1.5Hz)，7.13(1H，dd，J＝1.6，8.6Hz)，4.86(2H，d，J＝5.1Hz)，4.31(2H，s)，3.73(3H，s).Example 96 [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Methyl acetate (example 95) the title compound was prepared. MS (EI) m/z: 344 (M)+).m.p：210-212℃.IR(KBr)ν：3304，1728，1713，1622，1583，1526，1194cm-1.1H-NMR(DMSO-d6)δ：12.3I(1H，br s)，8.78(1H，d，J＝4.8Hz)，8.08(1H，s)，7.80(1H，d，J＝8.6Hz)，7.74(1H，d，J＝1.8Hz)，7.67(1H，d，J＝4.9Hz)，7.12(1H，dd，J＝1.8，8.7Hz)，4.69(2H，s)，4.09(2H，s).Example 97 [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.[ 5-chloro-2- [4- (tert-butyldimethylsilyloxymethyl) pyridine-2-carbonyl]-1H- Indol-3-yl ]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4- (tert-butyldimethylsiloxymethyl) pyridine (preparation thereof see step 1 of example 95) according to the method described for example 57.1H-NMR(CDCl3)δ：12.47(1H，br s)，8.66(1H，d，J＝4.9Hz)，8.18(1H，s)，7.60-7.61(1H，m)，7.54-7.57(1H，m)，7.39(1H，d，J＝8.9Hz)，7.25(1H，dd，J＝2.0，8.9Hz)，4.82(2H，s)，4.27(2H，s)，3.74(3H，s)，0.98(9H，s)，0.14(6H，s).Step 2.[ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in step 2 of example 95, from [ 5-chloro-2- [4- (tert-butyldimethylsilyloxymethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Methyl acetate (step 1) the title compound was prepared.1H-NMR(CDCl3)δ：12.48(1H，br s)，8.75(1H，d，J＝4.9Hz)，8.31(1H，s)，7.68(1H，s)，7.60-7.62(1H，m)，7.45(1H，d，J＝8.91Hz)，7.32(1H，dd，J＝2.0，8.9Hz)，4.87(2H，d，J＝5.4Hz)，4.28(2H，s)，3.74(3H，s).Example 98 [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, starting from [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Methyl acetate (example 97) the title compound was prepared. MS (EI) m/z: 344 (M)+).m.p.：218-219℃.IR(KBr)ν：3263，1705，1641，1595，1528，1327，1198.1061cm-1.1H-NMR(DMSO-d6)δ：12.34(1H，br s)，8.77(1H，d，J＝4.9Hz)，8.08(1H，s)，7.85(1H，s)，7.66-7.71(2H，m)，7.33(1H，dd，J＝1.8，8.9Hz)，5.63(1H，br s)，4.68(2H，s)，4.09(2H，s).Example 99 [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-3, 4-dimethylpyridine hydrobromide*The title compound was prepared. 1H-NMR(CDCl3)δ：12.20(1H，br s)，8.67(1H，d，J＝5.3Hz)，8.33(1H，d，J＝2.1Hz)，7.66(1H，d，J＝2.0Hz)，7.56(1H，dd，J＝2.1，5.3Hz)，7.43(1H，d，J＝8.7Hz)，7.32(1H，dd，J＝2.0，8.9Hz)，4.27(2H，s)，3.75(3H，s).*2-Bromoacetyl-3, 4-dimethylpyridine hydrobromide was prepared according to the following procedure: 3, 4-dimethylpyridine-2-carbonitrile:
following the procedure for the preparation of 4-chloro-2-pyridinecarbonitrile as described in example 33, a starting material was prepared from 3, 4-dimethylpyridine-N-oxide (Abramovitch et al, j.org.chem., 1972,371690) to yield the title compound comprising 4, 5-lutidine-2-carbonitrile in a ratio of 5: 1. 2-acetyl-3, 4-lutidine:
the title compound and 2-acetyl-4, 5-lutidine were obtained from 3, 4-lutidine-2-carbonitrile containing 4, 5-lutidine-2-carbonitrile according to the procedure for preparing 2-acetyl-4-chloropyridine as described in example 33 in a ratio of 5.5: 1. 2-acetyl-3, 4-dimethylpyridine：1H-NMR(CDCl3) δ: 8.34(1H, d, J ═ 4.6Hz), 7.19(1H, d, J ═ 4.8Hz), 2.69(3H, s), 2.43(3H, s), 2.34(3H, s), 2-acetyl-4, 5-lutidine:1H-NMR(CDCl3) δ: 8.39(1H, s), 7.83(1H, s), 2.70(3H, s), 2.33(3H, s), 2.32(3H, s). 2-bromoacetyl-3, 4-dimethylpyridine hydrobromide:
according to h.mckennis, jr., l.b.turnbull, e.r.bowman and e.tamaki, j.org.chem., 1963,23the title compound was prepared from 2-acetyl-3, 4-lutidine by the method described in 383-387. 1H-NMR(DMSO-d6)δ：8.39(1H，d，J＝4.8Hz)，7.46(1H，d，J＝4.8Hz)，4.96(2H，s)，2.38(3H，s)，2.35(3H，s).Example 100 [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 99) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p.：236-237℃.IR(KBr)ν：3395，1710，1641，1526，1339，1281，1196，1053，1007cm-1.1H-NMR(DMSO-d6)δ：11.76(1H，br s)，8.37(1H，d，J＝4.9Hz)，7.79(1H，d，J＝2.0Hz)，7.48(1H，d，J＝8.7Hz)，7.41(1H，d，J＝4.9Hz)，7.31(1H，dd，J＝2.0，8.7Hz)，3.56(2H，s)，2.35(3H，s)，2.16(3H，s).Example 101 [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4, 5-dimethylpyridine were synthesized from*The title compound was prepared.1H-NMR(CDCl3)δ：12.59(1H，br s)，8.47(1H，s)，8.12(1H，s)，7.67(1H，d，J＝1.8Hz)，7.44(1H，d，J＝9.4Hz)，7.30(1H，dd，J＝2.0，8.7Hz)，4.28(2H，s)，3.73(3H，s)，2.38(6H，s).*2-Bromoacetyl-4, 5-dimethylpyridine was as in example 57The process described for the preparation of 2-bromoacetyl-4-ethylpyridine is prepared from 2-acetyl-4, 5-dimethylpyridine (see example 99 for its preparation).1H-NMR(CDCl3)δ：8.39(1H，s)，7.87(1H，s)，4.83(2H，s)，2.35(3H.s)，2.34(3H，s).Example 102 [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 101) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p：245-246℃.IR(KBr)ν：3281，1697，1638，1589，1535，1254，1232，1188，1060，802cm-1.1H-NMR(DMSO-d6)δ：12.34(1H，br s)，12.15(1H，br s)，8.57(1H，s)，7.93(1H，s)，7.84(1H，d，J＝1.8Hz)，7.69(1H，d，J＝8.7Hz)，7.32(1H，dd，J＝2.0，8.7Hz)，4.09(2H，s)，2.39(3H，s)，2.38(3H，s).Example 103 [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-bromoacetyl-4, 5-lutidine (preparation method see example 99) according to the method described for example 57.1H-NMR(CDCl3)δ：12.55(1H，br s)，8.47(1H，s)，8.12(1H，s)，7.62(1H，d，J＝8.6Hz)，7.52(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝1.8，8.6Hz)，4.31(2H，s)，3.72(3H，s)，2.39(6H，s).Example 104 [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 103) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p.226-228℃.IR(KBr)ν：3275，1697，1638，1537，1258，1188，799cm-1.1H-NMR(DMSO-d6)δ：12.30(1H，br s)，8.57(1H，s)，7.94(1H，s)，7.78(1H，d，J＝8.7Hz)，7.74(1H，d，J＝1.8Hz)，7.11(1H，dd，J＝2.0，8.6Hz)，4.09(2H，s)，2.39(3H，s)，2.38(3H，s).Example 105 [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method A) and 2-bromoacetyl-4-methoxypyridine hydrobromide*The title compound was prepared.1H-NMR(CDCl3)δ：12.61(1H，br s)，8.57(1H，d，J＝5.9Hz)，7.89(1H，d，J＝2.6Hz)，7.63(1H，d，J＝8.6Hz)，7.52(1H，d，J＝1.8Hz)，7.13(1H，dd，J＝1.8，8.7Hz)，7.04(1H，dd，J＝2.6，5.8Hz)，4.30(2H，s)，3.96(3H，s)，3.73(3H，s).*2-Bromoacetyl-4-methoxypyridine hydrobromide was prepared according to the procedure described in step 2 of example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide from 2-acetyl-4-methoxypyridine (B.Case et al, J.org.chem., 1961,264415).1H-NMR(DMSO-d6)δ：8.59-8.62(1H，m)，7.63-7.65(1H，m)，7.33-7.37(1H，m)，5.03(2H，s)，3.96(3H，s).Example 106 [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 105) the title compound was prepared. MS (EI) m/z: 344 (M)+) Melting point: 213 deg.C (decomposition). Ir (kbr) v: 3200, 1709, 1645, 1589, 1533, 1225, 1207cm-1.1H-NMR(DMSO-d6)δ：12.35(1H，br s)，12.18(1H，br s)，8.66(1H，d，J＝5.6Hz)，7.80(1H，d，J＝8.9Hz)，7.74(1H，d，J＝1.8Hz)，7.63(1H，d，J＝2.6Hz)，7.31(1H，dd，J＝2.9，5.1Hz)，7.12(1H，dd，J＝1.3，8.7Hz)，4.09(2H，s)，3.96(3H.s).Example 107 [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
From trans-5-chloro-2- (phenylsulfonylamino) according to the procedure described in example 57) Methyl cinnamate (step 3 of example 36) and 2-bromoacetyl-4-methoxypyridine hydrobromide (prepared by the method described in example 105) the title compound was prepared.1H-NMR(CDCl3)δ：12.65(1H，br s)，8.57(1H，d，J＝5.8Hz)，7.88(1H，d，J＝2.5Hz)，7.68(1H，d，J＝2.0Hz)，7.45(1H，dd，J＝0.5，8.7Hz)，7.32(1H，dd，J＝1.8，8.7Hz)，7.05(1H，dd，J＝2.8，5.8Hz)，4.28(2H，s)，3.96(3H，s)，3.74(3H，s).Example 108 [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 107) the title compound was prepared. Melting point: 228 deg.C (decomposition). Ir (kbr) v: 3230, 1707, 1647, 1595, 1566, 1533, 1477, 1331, 1300, 1219, 1180, 1038, 1013cm-1.1H-NMR(DMSO-d6)δ：12.39(1H，br s)，12.16(1H，br s)，8.66(1H，d，J＝5.8Hz)，7.86(1H，d，J＝1.5Hz)，7.70(1H，d，J＝8.7Hz)，7.63(1H，d，J＝2.5Hz)，7.29-7.35(2H，m)，4.09(2H，s)，3.96(3H，s).Example 109 [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method A) and 2-bromoacetyl-3, 5-dimethylpyridine hydrobromide *The title compound was prepared.1H-NMR(CDCl3)δ：11.43(1H，br s)，8.43(1H，s)，7.60(1H，d，J＝8.7Hz)，7.51(1H，s)，7.45(1H，d，J＝1.8Hz)，7.12(1H，dd，J＝1.8，8.7Hz)，4.22(2H，s)，3.69(3H，s)，2.62(3H，s)，2.43(3H，s).*2-Bromoacetyl-3, 5-dimethylpyridine hydrobromide was prepared according to the following procedure: 2-acetyl-3, 5-lutidine:
following the procedure for the preparation of 2-acetyl-4-chloropyridine described in example 33, starting from 3, 5-dimethylpyridine-carbonitrile (k.takahashi et al, j.heterocyclic. chem., 1978,15，893) the title compound was obtained.1H-NMR(CDCl3) δ: 8.32(1H, s), 7.37(1H, s), 2.69(3H, s), 2.56(3H, s), 2.36(3H, s). 2-bromoacetyl-3, 5-dimethylpyridine hydrobromide:
according to h.mckennis, jr., l.b.turnbull, e.r.bowman and e.tamaki, j.org.chem., 1963,23383-387, the title compound was prepared from 2-acetyl-3, 5-lutidine.1H-NMR(DMSO-d6)δ：8.43(1H，s)，7.69(1H，s)，5.00(2H，s)，2.52(3H，s)，2.39(3H，s).Example 110 [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 109) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p.：199-200℃.IR(KBr)ν：3279，1705，1639，1526，1238，1177，827，797cm-1.1H-NMR(DMSO-d6)δ：12.12(1H，br s)，11.72(1H，br s)，8.38(1H，s)，7.74(1H，d，J＝8.6Hz)，7.68(1H，s)，7.52(1H，d，J＝2.0Hz)，7.10(1H，dd，J＝1.8，8.6Hz)，3.72(2H，s)，2.38(3H，s)，2.33(3H，s).Example 111 [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-ethyl-3-fluoropyridine were synthesized *The title compound was prepared.1H-NMR(CDCl3)δ：11.29(1H，br s)，8.45(1H，d，J＝4.8Hz)，7.64(1H，d，J＝1.8Hz)，7.44(1H，t，J＝4.8Hz)，7.38(1H，d，J＝8.9Hz)，7.29(1H，dd，J＝2.0，8.7Hz)，4.21(2H，s)，3.72(3H，s)，2.81(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz).*2-Bromoacetyl-4-ethyl-3-fluoropyridine was prepared as follows: 4-ethyl-3-fluoropyridine-N-oxide:
the reaction product of 4-ethyl-3-fluoropyridine (R.P. Dikinso)n et al, bioorg.med.chem.lett., 1996,62031, 28.51g, 205.9mmol) and 30% hydrogen peroxide (30ml) in acetic acid (300ml) were heated under reflux for 3 hours. After cooling to room temperature, the resulting mixture was concentrated. The residue was diluted in dichloromethane (300ml) and dried (magnesium sulfate). After removal of the solvent, 32.30g (100%) of the title compound are obtained as an oil.1H-NMR(DMSO-d6) d: 8.43-8.46(1H, m), 8.08(1H, d, J ═ 6.1Hz), 7.38(1H, dd, J ═ 6.6, 9.7Hz), 2.61(2H, q, J ═ 7.6Hz), 1.17(3H, t, J ═ 7.6Hz), 4-ethyl-3-fluoro-2-pyridinecarbonitrile:
the title compound was prepared from 4-ethyl-3-fluoropyridine-N-oxide following the procedure for preparation of 4-chloro-2-pyridinecarbonitrile as described in example 33.1H-NMR(CDCl3) d: 8.42(1H, d, J ═ 4.8Hz), 7.43(1H, t, J ═ 5.1Hz), 2.78(2H, q, J ═ 7.6Hz), 1.30(3H, t, J ═ 7.6Hz), 2-acetyl-4-ethyl-3-fluoropyridine:
the title compound was prepared from 4-ethyl-3-fluoro-2-pyridinecarbonitrile following the procedure described for the preparation of 2-acetyl-4-chloropyridine in example 33. 1H-NMR(CDCl3) d: 8.376(1H, d, J ═ 4.6Hz), 7.36(1H, t, J ═ 4.8Hz), 2.76(2H, q, J ═ 7.6Hz), 2.71(3H, s), 1.28(3H, t, J ═ 7.6Hz), 2-bromoacetyl-4-ethyl-3-fluoropyridine:
the title compound was prepared from 2-acetyl-4-ethyl-3-fluoropyridine following the procedure described for the preparation of 2-bromoacetyl-4-ethylpyridine in example 57.1H-NMR(CDCl3)d：8.38(1H，d，J＝4.6Hz)，7.43(1H，d，J＝4.6Hz)，4.75(2H，s)，2.78(2H，q，J＝7.6Hz)，1.29(3H，t，J＝7.6Hz).Example 112 [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Heating to reflux [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl group under stirring]A solution of methyl acetate (example 111, 391.2mg, 1.044mmol) in acetic acid (12ml) and 2N HCl in water (4ml) was left for 24 h. After cooling to room temperature, the resulting mixture was concentrated. The residue is in THF (100 m)l), diluted, dried (magnesium sulfate) and concentrated. The crude product was purified by recrystallization to yield 349.2mg (93%) of the title compound. MS (EI) m/z: 361 (M)+).m.p.208℃.IR(KBr)ν：3217，1720，1632，1516，1429，1234，1180，1057cm-1.1H-NMR(DMSO-d6)δ：11.78(1H，br s)，8.35(1H，d，J＝4.8Hz)，7.73(1H，d，J＝2.0Hz)，7.56(1H，t，J＝5.1Hz)，7.39(1H，d，J＝8.9Hz)，7.22(1H，dd，J＝2.0，8.9Hz)，3.65(2H，s)，2.65(2H，q，J＝7.6Hz)，1.14(3H，t，J＝7.6Hz).Example 113 [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) by the method described for example 57.1H-NMR(CDCl3)δ：11.23(1H，br s)，8.46(1H，d，J＝4.8Hz)，7.60(1H，d，J＝9.2Hz)，7.42-7.46(2H，m)，7.10-7.14(1H，m)，4.23(2H，s)，3.71(3H，s)，2.81(2H，q，J＝7.7Hz)，1.31(3H，t，J＝7.7Hz).Example 114 [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 113) the title compound was prepared. m.p.: 165 ℃ IR (KBr) v: 3300, 2974, 705, 1645, 1529, 1339, 1178cm-1.1H-NMR(DMSO-d6)δ：11.65(1H，br s)，8.32(1H，d，J＝4.6Hz)，7.73(1H，d，J＝8.9Hz)，7.47-7.52(2H，m)，7.10(1H，dd，J＝1.8，8.6Hz)，3.89(2H，q，J＝6.9Hz)，3.70(2H，s)，2.72(2H，q，J＝7.6Hz)，1.13-1.26(6H，m).Example 115 [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method A) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide*The title compound was prepared.1H-NMR(CDCl3)δ：10.05(1H，br s)，8.47(1H，d，J＝4.9Hz)，7.53(1H，d，J＝8.7Hz)，7.32-7.34(2H，m)，7.05(1H，dd，J＝1.8，8.7Hz)，3.79(2H，s)，3.61(3H，s)，2.83(2H，q，J＝7.6Hz)，1.28(3H，t，J＝7.6Hz).*2-Bromoacetyl-3-chloro-4-ethylpyridine hydrobromide was prepared according to the following procedure: 3-chloro-4-ethylpyridine-N-oxide:
following the procedure described for the preparation of 4-ethyl-3-fluoropyridine-N-oxide in example 111, the synthesis of 3-chloro-4-ethylpyridine (f. marsaisi et al, j. organomet. chem, 1981,216139) to obtain the title compound.1H-NMR(DMSO-d6) δ: 8.46(1H, d, J ═ 1.8Hz), 8.16(1H, d, J ═ 6.6Hz), 7.40(1H, dd, J ═ 1.8, 6.6Hz), 2.67(2H, q, J ═ 7.6Hz), 1.14-1.19(3H, m), 3-chloro-4-ethyl-2-pyridinecarbonitrile:
The title compound was prepared from 3-chloro-4-ethylpyridine-N-oxide following the procedure for preparation of 4-chloro-2-pyridinecarbonitrile as described in example 33.1H-NMR(CDCl3) δ: 8.50(1H, d, J ═ 4.9Hz), 7.41(1H, t, J ═ 4.9Hz), 2.84(2H, q, J ═ 7.4Hz), 1.30(3H, t, J ═ 7.6Hz), 2-acetyl-3-chloro-4-ethylpyridine:
the title compound was prepared from 3-chloro-4-ethylpyridine-2-pyridinecarbonitrile following the procedure described for the preparation of 2-acetyl-4-chloropyridine in example 33.1H-NMR(CDCl3) δ: 8.41(1H, d, J ═ 4.8Hz), 7.29(1H, d, J ═ 4.8Hz), 2.83(2H, q, J ═ 7.6Hz), 2.67(3H, s), 1.27(3H, t, J ═ 7.6Hz), 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide:
the title compound was prepared from 2-acetyl-3-chloro-4-ethylpyridine following the procedure for the preparation of 2-bromo-4-methylpyridine described in step 2 of example 31.1H-NMR(DMSO-d6)δ：8.55(1H，d，J＝4.9Hz)，7.66(1H，d，J＝4.8Hz)，4.93(2H，s)，2.82(2H，q，J＝7.3Hz)，1.21(3H，t，J＝7.4Hz).Example 116 [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 115) the title compound was prepared. m.p.: 158 ℃ IR (KBr) v: 3335, 1730, 1630, 1529, 1325, 1200cm-1.1H-NMR(DMSO-d6)δ：11.83(1H，br s)，8.54(1H，d，J＝4.8Hz)，7.75(1H，d，J＝8.7Hz)，7.63(1H，d，J＝4.9Hz)，7.46(1H，s)，7.12(1H，dd，J＝1.8，8.7Hz)，3.57(2H，s)，2.82(2H，q，J＝7.4Hz)，1.25(3H，t，J＝7.4Hz).Example 117 [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide (preparation method see example 115) according to the method described in example 57.1H-NMR(CDCl3)δ：9.87(1H，br s)，8.50(1H，d，J＝4.9Hz)，7.64(1H，s)，7.29-7.40(3H，m)，3.86(2H，s)，3.63(3H，s)，2.88(2H，q，J＝7.6Hz)，1.32(3H，t，J＝7.6Hz).Example 118 [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 117) the title compound was prepared. m.p.: 220 ℃ IR (KBr) v: 3341, 1695, 1626, 1533, 1458, 1429, 1229cm-1.1H-NMR(DMSO-d6)δ：11.88(1H，br s)，8.54(1H，d，J＝4.9Hz)，7.82(1H，s)，7.63(1H，d，J＝4.9Hz)，7.46(1H，d，J＝8.9Hz)，7.34(1H，dd，J＝2.0，8.9Hz)，3.60(2H，s)，2.82(2H，q，J＝7.4Hz)，1.25(3H，t，J＝7.4Hz).Example 119 [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4, 6-dimethylpyridine were synthesized from*The title compound was prepared.1H-NMR(CDCl3)δ：12.73(1H，br s)，7.98(1H，s)，7.67(1H，br s)，7.42(1H，d，J＝8.9Hz)，7.30(1H，dd，J＝1.8 and 8.7Hz)，7.22(1H，s)，4.27(2H，s)，3.73(3H，s)，2.70(3H，s)，2.43(3H，s).*2-Bromoacetyl-4, 6-lutidine was prepared as described in example 57 from 2-acetyl-4, 6-lutidine (Sundberg et al, J.Am.chem.Soc., 1969, 91And 658) are prepared.1H-NMR(CDCl3)δ：7.72(1H，s)，7.19(1H，s)，5.13(2H，s)，2.55(3H，s)，2.38(3H，s).Example 120 [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 119) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p.：233-235℃.IR(KBr)ν：3288，2919，1742，1630，1599，1529，1333，1232，1180，1067，772cm-1.1H-NMR(DMSO-d6)δ：11.99(1H，br s)，7.69(1H，s)，7.57(1H，s)，7.52(1H，d，J＝8.9Hz)，7.28(1H，s)，7.18(1H，dd，J＝2.1，8.9Hz)，3.87(2H，s)，2.49(3H，s)，2.27(3H，s).Example 121 [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-bromoacetyl-4, 6-lutidine (preparation method see example 119) according to the method described in example 57.1H-NMR(CDCl3)δ：12.69(1H，br s)，7.98(1H，s)，7.62(1H，d，J＝8.7Hz)，7.50(1H，d，J＝0.7Hz)，7.22(1H，s)，7.12(1H，dd，J＝1.6，8.6Hz)，4.30(2H，s)，3.72(3H，s)，2.70(3H，s)，2.43(3H，s).Example 122 [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
As described in example 58The process described is from [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 121) the title compound was prepared. MS (EI) m/z: 342 (M)+).m.p.：219-220℃.IR(KBr)ν：3300，1701，1639，1603，1535，1225，1180cm-1.1H-NMR(DMSO-d6)δ：11.95(1H，br s)，7.62(1H，d，J＝8.7Hz)，7.58(1H，d，J＝1.3Hz)，7.56(1H，s)，7.27(1H，s)，6.96(1H，dd，J＝2.0，8.7Hz)，3.87(2H，s)，2.49(3H，s)，2.26(3H，s).Example 123 [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1, trans-4, 5-dichloro-2-nitrocinnamic acid methyl ester
Following the procedure described in step 1 of example 36, a compound was prepared from 4, 5-dichloro-2-nitrobenzaldehyde (j.kenneth et al, j.med.chem., 1968, 11946) preparation of the title compound.1H-NMR(CDCl3)δ：8.20(1H，s)，8.04(1H，d，J＝15.8Hz)，7.72(1H，s)，6.36(1H，d，J＝15.8Hz).Step 2, trans-2-amino-4, 5-dichlorocinnamic acid methyl ester
The title compound was prepared from trans-4, 5-dichloro-2-nitrocinnamic acid methyl ester (step 1) following the procedure described for step 2 of example 36.1H-NMR(CDCl3)δ：7.65(1H，d，J＝15.8Hz)，7.42(1H，s)，7.26(1H，s)，6.81(1H，s)，6.28(1H，d，J＝15.8Hz).Step 3, trans-4, 5-dichloro-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-4, 5-dichlorocinnamic acid methyl ester (step 2) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.80-7.70(2H，m)，7.60-7.40(6H，m)，7.02(1H，br s)，6.13(1H，d，J＝16.1Hz)，3.79(3H，s).Step 4 [ (5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl)]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4, 5-dichloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide(see step 2 of example 31) the title compound was prepared.1H-NMR(DMSO-d6)δ：12.45(1H，br s)，8.69(1H，d，J＝5.1Hz)，8.14(1H，s)，8.00-7.93(2H，m)，7.59(1H，d，J＝4.3Hz)，4.16(2H，s)，3.59(3H，s)，3.32(3H，s).Example 124 [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 123) the title compound was prepared. m.p.: 220 ℃ and 224 ℃.1H-NMR(DMSO-d6)δ：12.41(1H，s)，12.20(1H，br s)，8.69(1H，d，J＝5.1Hz)，8.11(1H，s)，7.96-7.58(2H，m)，7.58(1H，d，J＝4.8Hz)，4.08(2H，s)，2.47(3H，s).Example 125 [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester Step 1. trans-2-amino-5-methyl cinnamic acid methyl ester
Following the procedure described in step 2 of example 36, trans-5-methyl-2-nitrocinnamic acid methyl ester (c.venkatasubban, j.annamala univ., 1933,2227) the title compound was prepared.1H-NMR(CDCl3)δ：7.82(1H，d，J＝15.8Hz)，7.20-7.19(1H，m)，7.01-6.98(1H，m)，6.63(1H，d，J＝8.2Hz)，6.35(1H，d，J＝15.8Hz)，3.83(2H，m)，3.80(3H，s)，2.24(3H，s).Step 2, trans-5-methyl-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-5-methyl cinnamic acid methyl ester (step 1) following the procedure described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.70-7.67(2H，m)，7.55-7.38(4H，m)，7.26-7.14(3H，m)，6.55(1H，br s)，6.14(1H，d，J＝16.0Hz)，3.77(3H，s)，2.33(3H，s)Step 3.[ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-methyl-2- (phenylsulfonylamino) cinnamic acid methyl ester (step 2) and 2-bromoacetyl-4-methyl esterPhenylpyridine hydrobromide (see step 2 of example 31) the title compound was prepared.1H-NMR(CDCl3)δ：12.32(1H，br s)，8.61(1H，d，J＝5.0Hz)，8.17(1H，s)，7.46(1H，s)，7.40(1H，d，J＝8.6Hz)，7.33-7.32(1H，m)，7.22-7.19(1H，m)，4.31(2H，s)，3.72(3H，s)，2.46(6H.m)Example 126 [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 125) the title compound was prepared. m.p.: 220 ℃. IR (KBr) v: 3736, 3649, 1697, 1533, 1508, 1398, 1194, 802cm-1.1H-NMR(DMSO-d6)δ：12.08(1H，br s)，8.69(1H，d，J＝4.8Hz)，7.94(1H，s)，7.56-7.49(3H，m)，7.17(1H，dd，J＝8.4Hz)，4.05(2H，s)，2.46(3H，s)，2.40(3H，s).Example 127 [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1 trans-5-fluoro-2-nitrocinnamic acid methyl ester
The title compound was prepared from 5-fluoro-2-nitrobenzaldehyde following the procedure described in step 1 of example 36.1H-NMR(CDCl3)δ：8.17-8.10(2H，m)，7.32-7.19(2H，m)，6.36(1H，d，J＝15.8Hz)，3.84(3H，s).Step 2 trans-5-fluoro-2-aminocinnamic acid methyl ester
The title compound was prepared from trans-5-fluoro-2-nitrocinnamic acid methyl ester (step 1) following the procedure described for step 2 of example 36.1H-NMR(CDCl3)δ：7.77(1H，dd，J＝15.8，1.5Hz)，7.10-7.06(1H，m)，6.94-6.87(1H，m)，6.68-6.63(1H，m)，6.33(1H，d，J＝15.8Hz)，3.85(2H，m)，3.81(3H，s).Step 3, trans-5-fluoro-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-5-fluoro-2-aminocinnamic acid methyl ester (step 2) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.68-7.65(2H，m)，7.55-7.49(2H，m)，7.44-7.33(3H，m)，7.18-7.13(1H，m)，7.10-7.04(1H，m)，6.10(1H，d，J＝15.8Hz)，3.78(3H，s).Step 4.[ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-fluoro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3) according to the method described in example 57.1H-NMR(CDCl3)δ：12.46(1H，br s)，8.58-8.56(1H，m)，8.12(1H，s)，7.43-7.39(1H，m)，7.33-7.26(2H，m)，7.14-7.06(1H，m)，4.26(2H，s)，3.74(3H，s)，2.45(3H，s).Example 128 [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 127) the title compound was prepared. Melting point: 223 deg.C (decomposition). Ir (kbr) v: 1705, 1643, 1570, 1277, 1227, 1204, 1186cm -1.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，8.70(1H，d.J＝4.9Hz)，7.95(1H，s)，7.71-7.66(1H，m)，7.58-7.52(2H，m)，7.25-7.17(1H，m)，4.06(2H，s)，2.47(3H，s).Example 129 [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1. trans-5-methoxy-2-nitrocinnamic acid methyl ester
The title compound was prepared from 5-methoxy-2-nitrobenzaldehyde following the procedure described in step 1 of example 36.1H-NMR(CDCl3)δ：8.21(1H，d，J＝15.8Hz)，8.16-8.12(1H，m)，7.00-6.96(2H，m)，6.30(1H，d，J＝15.8Hz)，3.93(3H，s)，3.83(3H，s).Step 2 trans-5-methoxy-2-aminocinnamic acid methyl ester
The title compound was prepared from trans-5-methoxy-2-nitrocinnamic acid methyl ester (step 1) following the procedure described for step 2 of example 36.1H-NMR(CDCl3)δ：7.83(1H，d，J＝15.8Hz)，6.92-6.91(1H，m)，6.82(1H，dd，J＝8.7，2.8Hz)，6.66(1H，d，J＝8.7Hz)，6.35(1H，d，J＝15.8Hz)，3.80(3H，s)，3.76(3H，s).Step 3. reverseFormula-5-methoxy-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-5-methoxy-2-aminocinnamic acid methyl ester (step 2) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.67-7.64(2H，m)，7.54-7.37(4H，m)，7.24(1H，d，J＝8.7Hz)，6.95(1H，d，J＝2.8Hz)，6.89(1H，dd，J＝8.7，2.8Hz)，6.82(1H，br s)，6.10(1H，d，J＝15.8Hz)，3.81(3H，s)，3.77(3H，s).Step 4.[ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-methoxy-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3) according to the method described in example 57.1H-NMR(CDCl3)δ：12.38(1H，br s)，8.61(1H，d，J＝4.9Hz)，8.17(1H，s)，7.40(1H，d，J＝8.7Hz)，7.34-7.32(1H，m)，7.08-7.03(2H，m)，4.31(2H，s)，3.88(3H，s)，3.73(3H，s)，2.47(3H，s).Example 130 [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 129) the title compound was prepared. Melting point: 235 deg.C (decomposition). Ir (kbr) v: 1701, 1638, 1595, 1528, 1448, 1423, 1340, 1279, 1263, 1234, 1223, 1192, 1111cm -1.1H-NMR(DMSO-d6)δ：12.11(1H，br s)，8.69(1H，d，J＝4.9Hz)，7.95(1H，s)，7.58-7.55(2H，m)，7.18(1H，m)，7.02-6.98(1H，m)，4.07(2H，s)，3.79(3H，s)，2.46(3H，s).Example 131 [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1 trans- (4-methoxy-2-nitro) cinnamic acid methyl ester
A mixture of 4-bromo-3-nitrobenzyl ether (4.177g, 18.0mmol), methyl acrylate (3.24ml, 36.0mmol), palladium (II) acetate (606.1mg, 2.7mmol), triphenylphosphine (1.416g, 5.4mmol), triethylamine (3.76ml, 27.0mmol) in DMF (45.0ml) was stirred at 130 deg.CFor 4 hours. After cooling to room temperature, the mixture was concentrated. To the residue was added water (30ml), and the mixture was extracted with ethyl acetate-toluene (3: 1, 40 ml). The aqueous layer was further extracted with ethyl acetate (2 × 30ml), the combined organic layers were dried (magnesium sulfate), and concentrated to give 6.42g (quantitative) of the title compound as a brown oil.1H-NMR(CDCl3)δ：8.07-6.97(4H，m)，6.31(1Hd，15.8Hz)，3.90(3H，s)，3.82(3H，s).Step 2 trans-2-amino-4-methoxycinnamic acid methyl ester
The title compound was prepared from trans- (4-methoxy-2-nitro) cinnamic acid methyl ester (step 1) following the procedure described for step 2 of example 36.1H-NMR(CDCl3)δ：7.80-6.21(5H，m)，4.03(2H，brs)，3.79(6H，s).Step 3, trans-4-methoxy-2- (p-toluenesulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-4-methoxy-2-aminocinnamic acid methyl ester (step 2) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.62-6.73(9H，m)，6.07(1H，d，15.8Hz)，3.80(3H，s)，3.77(3H，s)，2.37(3H，s).Step 4.[ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from methyl trans-4-methoxy-2- (p-toluenesulfonylamino) cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (preparation thereof see step 2 of example 31) according to the method described in example 57.1H-NMR(CDCl3)δ：12.32(1H，br s)，8.61(1H，d，4.94Hz)，8.19-7.55(2H，m)，7.34-6.82(3H，m)，4.31(2H，s)，3.89(3H，s)，3.72(3H，s)，2.47(3H，s).Example 132 [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 131) the title compound was prepared. m.p.: 204_ c.ir (KBr) v: 3198, 1709, 1630, 1593, 1531, 1460, 1423, 1334，1275，1213，1161，1136，1039，1001cm-1.1H-NMR(DMSO-d6)δ：12.11(1H，br s)，8.68(1H，d，4.94Hz)，7.94(1H，m)，7.62(1H，d，8.88Hz)，7.56-7.52(1H，m)，7.14(1H，d，2.30Hz)，6.76(1H，dd， 8，88Hz，2.30Hz)，4.05(2H，s)，3.82(3H，s)，2.47(3H，s).Example 133 [ 5-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1. trans-5-ethyl-2-aminocinnamic acid methyl ester
A mixture of 2-bromo-4-ethylaniline (1.0g, 5.10mmol), methyl acrylate (1.15ml, 12.74mmol), palladium (II) acetate (137mg, 0.61mmol), tri-o-tolyl-phosphine (745mg, 2.45mmol) and triethylamine (2.5ml) in acetonitrile (10ml) was heated at 110 ℃. After 2 hours in toluene, methyl acrylate (0.6ml, 6.37mmol), palladium (II) acetate (68mg, 0.30mmol), tri (o-tolyl) phosphine (372mg, 1.22mmol) and triethylamine (1.3ml) were added, and the mixture was stirred at 110 ℃ for 7 hours. After removal of the solvent, the residue was diluted with ethyl acetate (100ml), washed with water (100ml), dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 5/1: 4) to give 793mg (75.8%) of the title compound as a yellow solid. 1H-NMR(CDCl3)δ：7.83(1H，d，J＝15.8Hz)，7.21(1H，m)，7.04-7.01(1H，m)，6.64(1H，d，J＝8.2Hz)，6.36(1H，d，J＝15.8Hz)，3.87(2H，m)，3.80(3H，s)，2.51(2H，q，J＝7.6Hz)，1.19(3H，t，J＝7.6Hz).Step 2, trans-5-ethyl-2- (benzotransacylamino) cinnamic acid methyl ester
The title compound was prepared from trans-5-ethyl-2-aminocinnamic acid methyl ester (step 1) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.70-7.48(4H，m)，7.42-7.36(2H，m)，7.29-7.26(2H，m)，7.20-7.17(2H，m)，6.14(1H，d，J＝15.8Hz)，3.76(3H，s)，2.62(2H，q，J＝7.6Hz)，1.21(3H，t，J＝7.6Hz).Step 3.[ 5-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, fromThe title compound was prepared from formula-5-ethyl-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2).1H-NMR(CDCl3)δ：12.32(1H，br s)，8.59-8.57(1H，m)，8.14(1H，m)，7.47-7.39(2H，m)，7.30-7.21(2H，m)，4.32(2H，s)，3.73(3H，s)，2.75(2H，q，J＝7.6Hz)，2.43(3H，s)，1.27(3H，t，J＝7.6Hz)Example 134 [ 5-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 133) the title compound was prepared. Melting point: 215 deg.C (decomposition). Ir (kbr) v: 1701, 1638, 1597, 1535, 1443, 1420, 1398, 1331, 1279, 1236, 1205cm-1.1H-NMR(DMSO)δ：12.09(1H，br s)，8.69(1H，d，J＝4.9Hz)，7.94(1H，m)，7.58-7.51(3H，m)，7.23-7.20(1H，m)，4.06(2H，s)，2.69(2H，q，J＝7.6Hz)，2.46(3H，s)，1.23(3H，t，J＝7.6Hz).Example 135 [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester)
The title compound was prepared from trans-5-ethyl-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 133, step 2) and 2-bromoacetyl-4-ethylpyridine (prepared as described in example 57) by the method described for example 57.1H-NMR(CDCl3)δ：12.35(1H，br s)，8.63(1H，d，J＝5.1Hz)，8.20(1H，m)，7.48(1H，s)，742(1H，d，J＝8.6Hz)，7.34(1H，dd，J＝5.1，1.8Hz)，7.26-7.22(1H，m)，4.32(2H，s)，3.73(3H，s)，2.76(4H，q，J＝7.6Hz)，1.30(6H，t，J＝7.6Hz)Example 136 [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, starting from [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 135) the title compound was prepared. m.p.: 206.2 ℃ IR (KBr) v: 1703, 1636, 1595, 1533, 1431, 1333, 1283, 1236, 1188, 1117cm-1.1H-NMR(DMSO-d6)δ：12.09(1H，br s)，8.73(1H，d，J＝4.9Hz)，7.97(1H，s)，7.60-7.52(3H，m)，7.22(1H，d，J＝8.6Hz)，4.06(2H，s)，2.82-2.65(4H，m)，1.28-1.21(6H，m).Example 137 [ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1 trans- (4-acetyl-2-nitro) cinnamic acid methyl ester
The title compound was prepared from 4-bromo-3-nitroacetophenone and methyl acrylate according to the method described in example 131.1H-NMR(CDCl3)δ：8.58-8.10(3H，m)，7.77-7.74(1H，m)，6.48-6.42(1H，m)，3.85(3H，s)，2.68(3H，s).Step 2 trans-4- (1-hydroxyethyl) -2-nitrocinnamic acid methyl ester
To a solution of methyl trans-4-acetyl-2-nitrocinnamate (462.2mg, 1.854mmol) in methanol (55ml) was added sodium borohydride (176.3mg, 4.66mol) at room temperature. After stirring for 10 min, the mixture was concentrated. The residue was diluted with dichloromethane (20ml) and washed with brine (20 ml). The aqueous layer was extracted with dichloromethane (20 ml. times.2). The combined organic layers were dried (magnesium sulfate) and concentrated to give 442mg (quantitative) of the title compound.1H-NMR(CDCl3)δ：8.12-6.33(5H，m)，5.0(1H，m)，3.83(3H，s)，1.54(3H，d，9.56Hz).Step 3 trans- (4-ethyl-2-nitro) cinnamic acid methyl ester
To a mixture of sodium iodide (1.668g, 11.1mmol) and acetonitrile (581. mu.l, 11.1mmol) was added chlorotrimethylsilane (1.41ml, 11.1mmol) at room temperature. After stirring for 10 minutes, a solution of methyl trans-4- (1-hydroxyethyl) -2-nitrocinnamate (563.6mg, step 1) in hexane-toluene-acetonitrile (1: 1, 6.0ml) was added and the mixture was stirred for an additional 48 hours. The reaction mixture was diluted with toluene-ethyl acetate (2: 3, 25ml) and poured into water (25 ml). The organic layer was separated, washed with 5% sodium thiosulfate solution (30ml), brine (30ml), and dried (magnesium sulfate). After removal of the solvent 460mg (quantitative) of the title compound are obtained as a brown oil.1H-NMR(CDCl3)δ：8.12-6.32(5H，m)，3.83(3H，s)，2.76(2H，q，7.59Hz)，1.29(3H，t，7.59Hz).Step 4 trans-2-amino-4-ethylcinnamic acid methyl ester
The title compound was prepared from trans-4-ethyl-2-nitrocinnamic acid methyl ester (step 3) following the procedure described for step 2 of example 36.1H-NMR(CDCl3)δ：7.84-6.29(5H，m)，3.80(3H，s)，2.57(2H，m)，1.21(3H，t，7.59Hz).Step 5 trans-4-ethyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-4-ethyl methyl cinnamate (step 4) following the procedure described in step 1, method a, example 8.1H-NMR(CDCl3)δ：7.57(2H，d，8.40Hz)，7.46(1H，d，15.8Hz)，7.39-7.08(5H，m)，6.43(1H，s)，6.43(1H，d，15.8Hz)，3.78(3H，s)，2.61(2H，m)，2.37(3H，s)，1.18(3H，t，7.75Hz).Step 6.[ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from methyl trans-4-ethyl-2- (p-toluenesulfonylamino) cinnamate (step 5) and 2-bromoacetyl-4-methylpyridine hydrobromide (preparation thereof was found in step 2 of example 31) according to the method described in example 57. 1H-NMR(CDCl3)δ：12.30(1H，br s)，8.62(1H，d，4.94Hz)，8.18-7.32(4H，m)，7.05-7.02(2H，m)，4.33(2H，s)，3.72(3H，s)，2.79(2H，q，7.59Hz)，2.48(3H，s)，1.31(3H，t，7.59Hz).Example 138 [ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, starting from [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 137) the title compound was prepared. m.p.: 204 ℃. IR (KBr) v: 3240, 1709, 1636, 1593, 1531, 1394, 1204, 1144, 1001cm-1.1H-NMR(CDCl3)δ：12.07(1H，br s)，8.69(1H，d，4.94Hz)，7.93(1H，m)，7.63(1H，d，8.40Hz)，7.55(1H，m)，7.45(1H，s)，7.00-6.96(1H，m)，4.05(2H，s)，2.73(2H，q，7.56Hz)，2.46(3H，s)，1.24(3H，t，7.56Hz).Example 139 [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1. trans-5-isopropyl-2-aminocinnamic acid methyl ester
The title compound was prepared from 2-bromo-4-isopropylaniline following the procedure described in step 1 of example 133.1H-NMR(CDCl3)δ：7.83(1H，d，J＝15.8Hz)，7.23(1H，m)，7.08-7.05(1H，m)，6.66(1H，d，J＝8.4Hz)，6.37(1H，d，J＝15.8Hz)，3.85(2H，m)，3.81(3H，s)，2.84-2.76(1H，m)，1.21(6H，m).Step 2, trans-5-isopropyl-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-5-isopropyl-2-aminocinnamic acid methyl ester (step 1) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.71-7.68(2H，m)，7.58(1H，d，J＝15.8Hz)，7.51-7.20(6H，m)，7.09(1H，br.s)，6.16(1H，d，J＝15.8Hz)，4.11(3H，s)，2.94-2.83(1H，m)，1.24-1.21(6H，m).Step 3.[ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-isopropyl-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2) according to the method described in example 57.1H-NMR(CDCl3)δ：12.33(1H，br s)，8.61(1H，d，J＝5.1Hz)，8.17-8.16(1H，m)，7.50-7.42(2H，m)，7.33-7.26(2H，m)，4.32(2H，s)，3.73(3H，s)，3.08-2.97(1H，m)，2.46(3H，s)，1.33-1.30(6H，m).Example 140 [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid
Following the procedure described in example 58, from [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 139) the title compound was prepared. Melting point: 213 deg.C (decomposition). Ir (kbr) v: 1717, 1641, 1597, 1537, 1327, 1273, 1196cm-1.1H-NMR(DMSO-d6)δ：12.10(1H，br s)，8.70(1H，d，J＝4.9Hz)，7.95-7.94(1H，m)，7.59-7.54(2H，m)，7.27(1H，dd，J＝8.6，1.7Hz)，4.07(2H，s)，3.03(1H，m)，2.46(3H，s)，1.27-1.25(6H，m).Example 141 [2- (4-methylpyridine-2-Carbonyl) -6-trifluoromethyl-1H-indol-3-yl]Acetic acid methyl ester Step 1 trans-2-amino-4- (trifluoromethyl) cinnamic acid methyl ester
The title compound was prepared from 2-bromo-5- (trifluoromethyl) aniline following the procedure described in step 1 of example 133.1H-NMR(CDCl3)δ：7.79(1H，d，J＝15.8Hz)，7.46-7.43(1H，m)，7.00-6.94(2H，m)，6.41(1H，d，J＝15.8Hz)，4.18(2H，m)，3.82(3H，m).Step 2, trans-2-benzenesulfonylamino-4- (trifluoromethyl) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-4- (trifluoromethyl) cinnamic acid methyl ester (step 1) following the procedure described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.77-7.68(2H，m)，7.65-7.53(4H，m)，7.47-7.41(3H，m)，6.24(1H，d，J＝15.8Hz)，3.80(3H，s).Step 3.[2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-2-benzenesulfonylamino-4- (trifluoromethyl) cinnamic acid methyl ester (step 2) according to the method described in example 57.1H-NMR(CDCl3)δ：12.74(1H，br s)，8.58(1H，d，J＝4.9Hz)，8.12(1H，s)，7.81-7.74(2H，m)，7.35-7.32(2H，m)，4.32(2H，s)，3.75(3H，s)，2.46(3H，s).Example 142 [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ]Methyl acetate (example 141) the title compound was prepared. m.p.: 210-220 ℃ IR (KBr) v: 1697, 1651, 1599, 1537, 1506, 1339, 1283, 1196, 1103, 1055cm-1.1H-NMR(DMSO)δ：12.62(1H，br s)，8.71(1H，d，J＝4.9Hz)，8.10(1H，s)，7.99-7.97(2H，m)，7.61-7.59(1H，m)，7.39-7.36(1H，m)，4.14(2H，s)，2.48(3H，s).Example 143 [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1 trans-5-tert-butyl-2-aminocinnamic acid methyl ester
The title compound was prepared from 2-bromo-4-tert-butylaniline following the procedure described in step 1 of example 133.1H-NMR(CDCl3)δ：7.85(1H，d，15.8Hz)，7.38(1H，d，2.30Hz)，7.23(1H，dd，8.56Hz，2.30Hz)，6.67(1H，d，8.56Hz)，6.37(1H，d，15.8Hz).3.87(2H，br s)，3.81(3H，s)，1.28(9H，s).Step 2, trans-5-tert-butyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-5-tert-butyl-2-aminocinnamic acid methyl ester and p-toluenesulfonyl chloride by the method described in example 8, method A, step 1.1H-NMR(CDCl3)δ：7.60-7.20(8H，m)，6.53(1H，s)，6.17(1H，d，15.8Hz)，3.79(3H，s)，2.46(3H，s)，1.29(s，9H).Step 3.[ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-tert-butyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (for preparation thereof see step 2 of example 31) according to the method described in example 57.1H-NMR(CDCl3)δ：12.33(1H，br s)，8.63(1H，d，4.94Hz)，8.18(1H，m)，7.62-7.32(4H，m)，4.43(2H，s)，3.74(3H，s)，2.47(3H，s)，1.40(s，9H).Example 144 [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ]Methyl acetate (example 143) the title compound was prepared. Melting point: 191 deg.C. Ir (kbr) v: 2963, 1717, 1645, 1597, 1533, 1437, 1281, 1211, 1080, 1032, 1003cm-1.1H-NMR(DMSO-d6)δ：12.10(1H，br s)，7.70(1H，d，5.1Hz)，7.95-7.44(6H，m)，4.09(2H，s)，2.46(3H，s)，1.35(9H，s).Example 145 [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl]Acetic acid methyl ester Step 1, trans-2-amino-5- (trifluoromethoxy) cinnamic acid methyl esterEsters
The title compound was prepared from 2-bromo-4- (trifluoromethoxy) aniline following the procedure described in step 1 of example 133.1H-NMR(CDCl3)δ：7.74(1H，d，15.8Hz)，7.23-7.02(2H，m)，6.68(1H，d，8.72Hz)，6.36(1H，d，15.8Hz)，4.00(2H，br s)，3.81(3H，s).Step 2 trans-2-p-toluenesulfonylamino-5- (trifluoromethoxy) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-4-trifluoromethoxy cinnamic acid methyl ester (step 1) and p-toluenesulfonyl chloride following the procedure described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.59-7.19(8H，m)，6.76(1H，s)，6.15(1H，d，15.8Hz)，3.80(3H，s)，2.39(3H，s).Step 3.[2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl]Acetic acid A Esters
The title compound was prepared from trans-2-p-toluenesulfonylamino-5- (trifluoromethoxy) cinnamic acid methyl ester (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (for preparation thereof see step 2 of example 31) according to the method described in example 57.1H-NMR(CDCl3)δ：12.7(1H，br s)，8.64(1H，d，5.10Hz)，8.19(1H，m)，7.55-7.23(4H，m)，4.30(2H，s)，3.74(3H，s)，2.49(3H，s).Example 146 [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxyphenyl-1H-indol-3-yl ]Acetic acid
Following the procedure described in example 9, method B, from [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl]Methyl acetate (example 145) the title compound was prepared. Melting point: 235 ℃ and 238 ℃. Ir (kbr) v: 3248, 1701, 1645, 1597, 1537, 1447, 1420, 1333, 1259, 1203, 1115, 1034, 1003cm-1.1H-NMR(DMSO-d6)δ：12.40(1H，br s)，8.71(1H，d，4.94Hz)，7.97-7.96(1H，m)，7.80-7.30(4H，m)，4.09(2H，s)，2.47(3H，s).Example 147 [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the procedure described for example 57 from methyl trans-2- (p-toluenesulfonylamino) -5- (trifluoromethoxy) cinnamate (step 2 of example 145) and 2-bromoacetyl-4-ethylpyridine (for preparation thereof see example 57).1H-NMR(CDCl3)δ：8.66(1H，d，4.97Hz)，8.22(1H，br s)，7.55-7.26(4H，m)，4.30(2H，s)，3.74(3H，s)，2.79(2H，q，7.59Hz)，1.32(3H，t，7.59Hz).Example 148 [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxyphenyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl]Methyl acetate (example 147) the title compound was prepared. Melting point: 223 ℃. R (kbr) v: 3271, 1697, 1645, 1597, 1539, 1423, 1400, 1337, 1258, 1198, 1117, 1028, 1003cm-1.1H-NMR(DMSO-d6)δ：12.41(1H，br s)，8.74(1H，d，4.94Hz)，7.99(1H，m)，7.80-7.75(2H，m)，7.63-7.30(2H，m)，4.10(2H，s)，2.78(2H，q，7.59Hz)，1.26(3H，t，7.59Hz).Example 149 [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester Step 1. trans-2-amino-4-methyl cinnamic acid methyl ester
The title compound was prepared from trans-4-methyl-2-nitrocinnamic acid methyl ester following the procedure described in step 2 of example 36.1H-NMR(CDCl3)δ：7.81(1H，d，J＝15.8Hz)，7.30-7.26(1H，m)，6.60-6.57(1H，m)，6.52(1H，m)，6.31(1H，d，J＝15.8Hz)，3.92(2H，br s)，3.79(3H，s)，2.26(2H，s).Step 2, trans-4-methyl-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-4-methyl cinnamic acid methyl ester (step 1) following the procedure described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.72-7.68(2H，m)，7.55-7.49(1H，m)，7.44-7.34(4H，m)，7.26-722(1H，m)，7.07-7.04(1H，m)，6.62(1H，br s)，6.12(1H，d，J＝15.8Hz)，3.76(3H，s)，2.34(3H，s).Step 3.[ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-methyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 2) according to the method described in example 57.1H-NMR(CDCl3)δ：12.26(1H，br s)，8.61(1H，d，J＝4.9Hz)，8.17(1H，m)，7.58(1H，d，J＝8.4Hz)，7.34-7.29(2H，m)，7.01-6.98(1H，m)，4.32(2H，s)，3.72(3H，s)，2.49(3H，s)，2.47(3H，s).Example 150 [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 149) the title compound was prepared. Melting point: 208 deg.C (decomposition). Ir (kbr) v: 1707, 1638, 1593, 1531, 1277, 1205, 1142cm-1.1H-NMR(DMSO-d6)δ：12.02(1H，br s)，8.68(1H，d，J＝4.9Hz)，7.93(1H，s)，7.61(1H，d，J＝8.2Hz)，7.56-7.54(1H，m)，7.42(1H，s)，6.96-6.93(1H，m)，4.04(2H，s)，2.46(3H，s)，2.43(3H，s).Example 151 [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid methyl ester Step 1 trans-2-amino-5- (trifluoromethyl) cinnamic acid methyl ester
The title compound was prepared from 2-bromo-4- (trifluoromethyl) aniline following the procedure described in step 1 of example 133.1H-NMR(CDCl3)δ：7.77(1H，d，J＝15.8Hz)，7.61(1H，s)，7.39(1H，d，J＝8.4Hz)，6.74(1H，d，J＝8.4Hz)，6.41(1H，dd，J＝15.8，1.5Hz)，4.29(2H，m)，3.82(3H，m).Step 2 trans-2-benzenesulfonylamino-5- (trifluoromethyl) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-5- (trifluoromethyl) cinnamic acid methyl ester (step 1) following the procedure described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.79-7.76(2H，m)，7.66(1H，m)，7.60-7.44(6H，m)，7.06(1H，brs)，6.26(1H，d，J＝15.8Hz)，3.81(3H，s).Step 3.[2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-2-benzenesulfonylamino-5- (trifluoromethyl) cinnamic acid methyl ester (step 2) according to the method described in example 57.1H-NMR(CDCl3)δ：12.70(1H，br s)，8.62(1H，d，J＝4.9Hz)，8.17(1H，s)，8.00(1H，s)，7.61-7.54(2H，m)，7.38-7.36(1H，m)，4.34(2H，s)，3.75(3H，s)，2.48(3H，s).Example 152 [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Methyl acetate (example 151) the title compound was prepared. m.p.: 218 ℃. IR (KBr) v: 1697, 1645, 1599, 1541, 1337, 1277, 1202, 1161, 1111, 1053cm-1.1H-NMR(DMSO-d6)δ：12.52(1H，br s)，8.71(1H，d，J＝4.9Hz)，8.23(1H，s)，7.97(1H，m)，7.85(1H，d，J＝8.9Hz)，7.62-7.58(2H，m)，4.16(2H，s)，2.48(3H，s).Example 153 [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the procedure described for the preparation of example 57 from trans-2-benzenesulfonylamino-5- (trifluoromethyl) cinnamic acid methyl ester (step 2 of example 151) and 2-bromoacetyl-4-ethylpyridine (for its preparation see example 57). 1H-NMR(CDCl3)δ：12.65(1H，br s)，8.64(1H，d，J＝5.1Hz)，8.21(1H，m)，8.01(1H，s)，7.61-7.52(2H，m)，7.40-7.37(1H，m)，4.34(2H，s)，3.76(3H，s)，2.78(2H，q，J＝7.6Hz)，1.31(3H，t，J＝7.6Hz).Example 154 [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl]Methyl acetate (example 153) the title compound was prepared. m.p.: 203.6 ℃ IR (KBr) v: 1703, 1647, 1599, 1537, 1340, 1202, 1105，1051cm-1.1H-NMR(DMSO-d6)δ：12.52(1H，br s)，8.74(1H，d，J＝5.1Hz)，8.24(1H，s)，8.00-7.99(1H，m)，7.86(1H，d，J＝8.7Hz)，7.64-7.58(2H，m)，4.16(2H，s)，2.79(2H，q，J＝7.6Hz)，1.26(3H，t，J＝7.6Hz).Example 155 (2-benzoyl-1H-indol-3-yl) acetic acid methyl ester Step 1 trans-2- (benzenesulfonylamino) -cinnamic acid methyl ester
The title compound was prepared from trans-2-aminocinnamic acid methyl ester by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.71-7.67(2H，m)，7.58(1H，d，J＝15.8Hz)，7.52-7.32(6H，m)，7.28-7.22(1H，m)，7.08(1H，br s)，6.15(1H，d，J＝15.8Hz)，3.78(3H，s).Step 2. (2-benzoyl-1H-indol-3-yl) acetic acid methyl ester
The title compound was prepared from trans-methyl 2- (benzenesulfonylamino) cinnamate (step 1) according to the method described for example 57.1H-NMR(CDCl3)δ：8.91(1H，br s)，7.80-7.77(2H，m)，7.67-7.58(2H，m)，7.53-7.48(2H，m)，7.43-7.34(2H，m)，7.21-7.15(1H，m)，3.86(2H，s)，3.65(3H，s).Example 156 (2-benzoyl-1H-indol-3-yl) acetic acid
The title compound was prepared from methyl (2-benzoyl-1H-indol-3-yl) acetate (example 155) according to the method described in example 9, method B. m.p.: 194-196 ℃ IR (KBr) v: 1713, 1597, 1541, 1450, 1402, 1267, 1180, 729cm-1.1H-NMR(DMSO-d6)δ：11.62(1H，br s)，7.77-7.74(2H，m)，7.69-7.66(2H，m)，7.60-7.55(2H，m)，7.48-7.45(1H，m)，7.34-7.28(1H，m)，7.13-7.08(1H，m)，3.80(2H，s).Example 157 [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ]Acetic acid methyl ester
The title compound was prepared from trans-4-methyl-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2 of example 149) and 4-chlorobenzoylmethyl bromide according to the method described in example 57.1H-NMR(CDCl3)δ：8.84(1H，br s)，7.74-7.71(2H，m)，7.53-7.45(3H，m)，7.14(1H，m)，7.03-7.00(1H，m)，3.81(2H，s)，3.65(3H，s)，2.46(3H，s).Example 158 [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl]Methyl acetate (example 157) the title compound was prepared. m.p.: 193-195 deg.C. IR (KBr) v: 3302, 1697, 1587, 1335, 1263, 1090, 999, 770cm-1.1H-NMR(DMSO-d6)δ：11.47(1H，br s)，7.76-7.73(2H，m)，7.65-7.61(2H，m)，7.57(1H，d，J＝8.4Hz)，7.23(1H，s)，6.96-6.93(1H，m)，3.79(2H，s)，2.42(3H，s).Example 159 [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl]Acetic acid methyl ester Step 1.[2- (4-chlorobenzoyl) -5-methyl-1- (benzenesulfonyl) indole
Following the procedure described in step 2 of method B, example 2, from 5-methyl-1- (benzenesulfonyl) indole (e.wenkert, p.moeller and s.piettre, j.am. chem.soc., 1988,1107188-7194) and 4-chlorobenzoyl chloride.1H-NMR(CDCl3)δ：8.02-7.96(3H，m)，7.96-7.88(2H，m)，7.57-7.43(5H，m)，7.33-7.25(2H，m)，6.88(1H，s)，2.41(3H，s).Step 2.2- (4-chlorobenzoyl) -5-methylindole
The title compound was prepared from 2- (4-chlorobenzoyl) -5-methyl-1- (benzenesulfonyl) indole (step 1) according to the procedure described in example 2, step 3 of method B.1H-NMR(CDCl3)δ：9.43(1H，br s)，7.94-7.91(2H，m)，7.51-7.47(3H，m)，7.37(1H，d，J＝8.4Hz)，7.21(1H，dd，J＝8.4，1.5Hz)，7.04-7.03(1H，m)，2.44(3H，s).Step 3. alpha-acetoxy- [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ]Malonic acid Diethyl ester
The title compound was prepared from 2- (4-chlorobenzoyl) -5-methylindole (step 3) according to the procedure described in step 4 of method B, example 2.1H-NMR(CDCl3)δ：8.74(1H，br s)，7.79(2H，d，J＝8.4Hz)，7.67(1H，s)，7.42(2H，d，J＝8.4Hz)，7.27-7.24(1H，m)，7.14-7.11(1H，m)，4.24-4.16(4H，m)，2，45(3H，s)，1.28-1.18(6H，m).Step 4.[2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in example 2, step 5 of method B, from α -acetoxy- [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.80(1H，br s)，7.73(2H，d，J＝8.4Hz)，7.54(1H，s)，7.47(2H，d，J＝8.4Hz)，7.21-7.18(1H，m)，7.13-7.10(1H，m)，4.25-4.13(4H，m)，2.42(3H，s)，1.28-1.21(6H，m).Step 5.[2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 2, step 6 of method B, from [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 194 ℃ 197. IR (KBr) v: 3308, 1695, 1609, 1529, 1402, 1263, 1223, 1088.1015cm-1.1H-NMR(DMSO-d6)δ：12.18(1H，br s)，11.49(1H，s)，7.77-7.73(2H，m)，7.66-7.62(2H，m)，7.45(1H，s)，7.35(1H，d，J＝8.6Hz)，7.15(1H，dd，J＝8.6，1.5Hz)，3.81(2H，s)，2.39(3H，s).Example 160 [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-methoxy-3- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 3 of example 131) and 4-chlorobenzoyl methyl bromide following the method described for example 57.1H-NMR(CDCl3)δ：8.89(1H，br s)，7.74-7.43(5H，m)，6.86-6.77(m，2H)，3.85(3H，s)，3.79(3H，s)，3.65(3H，s).Example 161 [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid
The title is prepared from [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid methyl ester (example 160) according to the method described in example 9, method BA compound is provided. m.p.: 193 ℃ IR (KBr) v: 3308, 1701, 1628, 1603, 1526, 1427, 1335, 1271, 1205, 1148, 1092, 1032, 999cm-1.1H-NMR(DMSO-d6)δ：11.43(1H，brs)，7.75-7.56(5H，m)，6.87(1H，d，2.13Hz)，7.76(1H，dd，8.88Hz，2.13Hz)，3.80(3H，s)，3.79(2H，s).Example 162 [2- (4-chlorobenzoyl) -6-trifluoromethyl-1H-indol-3-yl]Acetic acid Step 1.1-benzenesulfonyl-6- (trifluoromethyl) indole
To a mixture of 6- (trifluoromethyl) indole (500mg, 2.70mmol), 50% aqueous sodium hydroxide (5ml), water (7ml) and tetrabutylammonium bromide (87mg, 0,27mmol) was added a solution of benzenesulfonyl chloride (379. mu.l, 2.97mmol) in toluene (5ml) at room temperature with stirring. After stirring for 1 hour, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (30ml), water (30ml), brine (30ml), dried (magnesium sulfate) and concentrated to yield 835mg (95%) of the title compound.1H-NMR(CDCl3)δ：8.29(1H，s)，7.91-7.88(2H，m)，7.71(1H，d，J＝3.6Hz)，7.64-7.54(2H，m)，7.49-7.44(3H，m)，6.72(1H，d，J＝3.6Hz).Step 2.2- (4-chlorobenzoyl) -1-benzenesulfonyl-6- (trifluoromethyl) indole
The title compound was prepared from 1-benzenesulfonyl-6- (trifluoromethyl) indole (step 1) according to the procedure described in step 2 of method B, example 2.1H-NMR(CDCl3)δ：8.42(1H，s)，8.05-8.01(2H，m)，7.92-7.89(2H，m)，7.71-7.47(7H，m)，6.95(1H，s).Step 3.2- (4-chlorobenzoyl) -6- (trifluoromethyl) indole
The title compound was prepared from 2- (4-chlorobenzoyl) -1-benzenesulfonyl-6- (trifluoromethyl) indole (step 2) according to the procedure described in example 2, method B, step 3.1H-NMR(CDCl3)δ：9.53(1H，br s)，7.99-7.95(2H，m)，7.85-7.79(2H，m)，7.56-7.53(2H，m)，7.42-7.39(1H，m)，7.19-7.18(1H，m).Step 4. alpha-acetoxy- [2- (4-chlorobenzoyl) -6- (trifluoromethyl) -1H-indol-3-yl] Malonic acid diethyl ester
The title compound was prepared from 2- (4-chlorobenzoyl) -6- (trifluoromethyl) indole (step 3) according to the method described in example 2, method B, step 4.1H-NMR(CDCl3)δ：9.27(1H，br s)，8.00(1H，d，J＝8.7Hz)，7.78(2H，d，J＝8.6Hz)，7.68(1H，s)，7.45-7.39(3H，m)，4.24-4.12(4H，m)，1.74(3H，s)，1.21-1.14(6H，m).Step 5.[2- (4-chlorobenzoyl) -6- (trifluoromethyl) O-1H-indol-3-yl]Malonic acid di Ethyl ester
Following the procedure described in example 2, method B, step 5, from α -acetoxy- [2- (4-chlorobenzoyl) -6- (trifluoromethyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound.1H-NMR(CDCl3)δ：9.37(1H，br s)，7.83(1H，d，J＝8.6Hz)，7.77-7.73(2H，m)，7.51-7.48(3H，m)，7.33-7.30(1H，m)，5.27(1H，s)，4.25-4.06(4H，m)，1.31-1.15(6H，m).Step 6.[2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 2, method B, step 6, from [2- (4-chlorobenzoyl) -6- (trifluoromethyl) -1H-indol-3-yl]Diethyl malonate (step 5) prepares the title compound. m.p.: 155 ℃. IR (KBr) v: 3379, 1705, 1611, 1589, 1516, 1337, 1229, 1119, 1092, 1055cm -1 1H-NMR(DMSO-d6)δ：12.09(1H，br s)，7.96-7.93(1H，m)，7，82-7.78(3H，m)，7.68-7.64(2H，m)，7.41-7.37(1H，m)，3.86(2H，s).Example 163 [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-ethyl-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2 of example 133) according to the method described in example 57.1H-NMR(CDCl3)δ：8.86(1H，br s)，7.74-7.71(2H，m)，7.48-7.41(3H，m)，7.32-7.21(2H，m)，3.85(2H，s)，3.66(3H，s)，2.75(2H，q，J＝7.6Hz)，1.28(3H，t，J＝7.6Hz)Example 164 [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl]Methyl acetate (example 163) the title compound was prepared. m.p.: 165-168 ℃ IR (KBr): 3321, 1693, 1605, 1531, 1221, 1088, 1011cm-1.1H-NMR(DMSO-d6)δ：11.49(1H，br s)，7.76-7.72(2H，m)，7.65-7.61(2H，m)，7.46(1H，m)，7.36(1H，d，J＝8.6Hz)，7.18(1H，dd，J＝8.6，1.5Hz)，3.81(2H，s)，2.67(2H，q，J＝7.6Hz)，1.21(3H，t，J＝7.6Hz).Example 165 [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-methoxy-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 129) according to the method described in example 57.1H-NMR(CDCl3)δ：8.81(1H，br s)，7.75-7.72(2H，m)，7.49-7.46(2H，m)，7.29(1H，d，J＝8.9Hz)，7.04(1H，dd，J＝8.9，2.5Hz)，6.98(1H，d，J＝2.5Hz)，3.86(3H，s)，3.85(2H，s)，3.67(3H，s)Example 166 [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl]Methyl acetate (example 165) the title compound was prepared. m.p.: 200 ℃. IR (KBr) v: 3325, 1724, 1607, 1526, 1429, 1356, 1265, 1229, 1092, 1011cm -1.1H-NMR(DMSO-d6)δ：11.46(1H，br s)，7.74(2H，d，J＝8.6Hz)，7.63(2H，d，J＝8.6Hz)，7.35(1H，d，J＝8.9Hz)，7.13(1H，d，J＝2.5Hz)，6.96(1H，dd，J＝8.9，2.5Hz)，3.83(2H，s)，3.77(3H，s).Example 167 [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-isopropyl-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2 of example 139) according to the method described in example 57.1H-NMR(CDCl3)δ：8.87(1H，br s)，7.74-7.70(2H，m)，7.49-7.44(3H，m)，7.33-7.25(2H，m)，3.85(2H，s)，3.66(3H，s)，3.07-2.96(1H，m)，1.32-1.29(6H，m)Example 168 [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl]Methyl acetate (example 169) the title compound was prepared. m.p.: 197 ℃. IR (KBr) v: 1697, 1609, 1533, 1429, 1348, 1265, 1090, 1011cm-1.1H-NMR(DMSO-d6)δ：12.18(1H，br s)，11.50(1H，br s)，7.77-7.74(2H，m)，7.65-7.62(2H，m)，7.50(1H，m)，7.40-7.37(1H，m)，7.26-7.23(1H，m)，3.83(2H，s)，3.03-2.92(1H，m)，1.26-1.24(6H，m).Example 169 [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-2-benzenesulfonylamino-5- (trifluoromethyl) cinnamic acid methyl ester (step 2 of example 151) according to the method described in example 57.1H-NMR(CDCl3)δ：9.34(1H，br s)，7.90(1H，s)，7.77-7.70(2H，m)，7.51-7.43(3H，m)，7.33(1H，d，J＝8.7Hz)，3.85(2H，s)，3.66(3H，s)Example 170 [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl]Methyl acetate (example 169) the title compound was prepared. m.p.: 198 ℃. IR (KBr) v: 3317, 1697, 1611, 1333, 1271, 1113, 1051, 1007cm -1.1H-NMR(DMSO-d6)δ：12.08(1H，br s)，8.18(1H，s)，7.80-7.77(2H，m)，7.68-7.57(4H，m)，3.92(2H，s).Example 171 [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-3-P-benzenesulfonylamino-5- (trifluoromethoxy) cinnamic acid methyl ester (step 2 of example 145) and 4-chlorobenzoylmethyl bromide according to the method described in example 57.1H-NMR(CDCl3)δ：8.93(1H，br s)，7.76(2H，d，8.75Hz)，7.52-7.40(5H，m)，3.82(2H，s)，3.68(3H，s).Example 172 [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl]Methyl acetate (example 171) the title compound was prepared. m.p.: 195 ℃ IR (KBr) v: 3339, 1705, 1622, 1589, 1533, 1435, 1342, 1256, 1225, 1177, 1092, 1013cm-1.1H-NMR(DMSO-d6)δ：11.91(1H，br s)，7.80-7.64(5H，m)，7.55(1H，d，8.91Hz).7.32-7.24(m，IH)，3.87(2H，s).Example 173 [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.2- [ 6-chloro-2 (2-methoxybenzoyl) -1H-indol-3-yl (acetic acid) Methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-methoxybenzoylmethyl bromide according to the method described in example 57.1H-NMR(CDCl3)δ：9.02(1H，br s)，7.60-7.46(2H，m)，7.42-7.34(2H，m)，7.15-6.99(3H，m)，3.78(3H，s)，3.66(2H，s)，3.60(3H，m).Example 174 [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl ]Methyl acetate (example 172) the title compound was prepared. m.p.: 214 ℃. IR (KBr) v: 3398, 2939, 2642, 1711, 1680, 1624, 1537, 1461, 1315, 1230, 937cm-1.1H-NMR(DMSO-d6)δ：11.61(1H，s)，7.67(1H，d，J＝8.7Hz)，7.60-7.51(1H，m)，7.45(1H，d，J＝2.0Hz)，7.28(1H，dd，J＝7.4，1.6Hz)，7.18(1H，d，J＝8.2Hz)，7.12-7.04(2H，m)，3.70(3H，s)，3.60(2H，s).Example 175 [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-4-chloro-2- (phenylsulphon)Acylamino) methyl cinnamate (step 1 of method a, example 8) and 3-methoxybenzoylmethyl bromide the title compound was prepared.1H-NMR(CDCl3)δ：8.86(1H，s)，7.57(1H，d，J＝8.7Hz)，7.46-7.26(4H，m)，7.19-7.12(2H，m)，3.86(3H，s)，3.83(2H，s).3.67(3H，s).Example 176 [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 175) the title compound was prepared. m.p.: 227 ℃. IR (KBr) v: 3354, 2933, 2636, 1709, 1607, 1569, 1427, 1321, 1269, 1218, 1049cm-1.1H-NMR(DMSO-d6)δ：11.76(1H，s)，7.72(1H，d，J＝8.6Hz)，7.54-7.45(2H，m)，7.35-7.22(3H，m)，7.16-7.10(1H，m)，3.83(3H，s)，3.79(2H，s).Example 177 [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, a mixture of trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 3-benzyloxyphenacyl bromide (a. hernandez et al, j. org. chem., 1994,591058) preparing the title compound. 1H-NMR(CDCl3)δ：8.79(1H，s)，7.56(1H，d，J＝8.6Hz)，7.46-7.33(9H，m)，7.26-7.19(1H，m)，7.16(1H，dd，J＝8.6，1.8Hz)，5.12(2H，s)，3.82(2H，s)，3.64(3H，s).Example 178 [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 177) the title compound was prepared. m.p.: 174 ℃. 177. degree. IR (KBr) v: 3308, 3028, 2897, 1697, 1612, 1566, 1444, 1328, 1269, 1223, 732cm-1.1H-NMR(DMSO-d6)δ：11.76(1H，s)，7.71(1H，d，J＝8.6Hz)，7.54-7.30(10H，m)，7.13(1H，dd，J＝8.6，1.6Hz)，5.18(2H，s)，3.78(2H，s).Example 179 [ 6-chloro-2- (3)-hydroxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
Stirring [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] under an atmosphere of hydrogen]A mixture of methyl acetate (example 177, 0.37g, 0.85mmol) and 10% palladium on activated carbon (80mg) in ethyl acetate-methanol (5: 1, 30ml) was added for 2.5 h. The mixture was filtered through a celite pad and the filtrate was concentrated. The solid was washed with dichloromethane (10ml) to give 70mg (24%) of the title compound as a white solid.1H-NMR(CDCl3)δ：10.36(1H，br s)，9.06(1H，s)，7.55(1H，d，J＝8.7Hz)，7.50-7.46(1H，m)，7.36-7.22(3H，m)，7.15-7.05(2H，m)，3.89(2H，s)，3.65(3H，s).Example 180 [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, starting from [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 179) the title compound was prepared. m.p.: 213-215 ℃ IR (KBr) v: 3311, 3069, 1715, 1624, 1583, 1529, 1448, 1325, 1278, 1220, 761cm -1.1H-NMR(DMSO-d6)δ：11.71(1H，s)，9.86(1H，br s)，7.71(1H，d，J＝8.6Hz)，7.47(1H，d，J＝1.5Hz)，7.41-7.32(1H，m)，7.20-7.02(4H，m)，3.82(2H，s).Example 181 [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, a compound of formula (i) was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4-benzyloxybenzoylmethyl bromide (a.brossi et al, j.heterocyclic.2310) preparation of the title compound.1H-NMR(CDCl3)δ：8.87(1H，br s)，7.81(2H，d，J＝8.6Hz)，7.55(1H，d，J＝8.7Hz)，7.48-7.32(6H，m)，7.14(1H，dd，J＝8.7，1.8Hz)，7.06(2H，d，J＝8.6Hz)，5.16(2H，s)，3.86(2H，s)，3.65(3H，s).Example 182 [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B[ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 181) the title compound was prepared. m.p.: 220 ℃. 222. degree. IR (KBr) v: 3331, 3013, 2914, 1717, 1699, 1599, 1564, 1508, 1253, 1167, 941cm-1.1H-NMR(DMSO-d6)δ：11.72(1H，s)，7.76(2H，d，J＝8.9Hz)，7.69(1H，d，J＝8.4Hz)，7.52-7.32(6H，m)，7.17(2H，d，J＝8.9Hz)，7.11(1H，dd，J＝8.4，2.2Hz)，5.23(2H，s)，3.81(2H，s).Example 183 [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 179, from [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 181) the title compound was prepared.1H-NMR (acetone-d)6)δ：10.82(1H，br s)，9.21(1H，br s)，7.75(2H，d，J＝8.7Hz)，7.71(1H，d，J＝8.7Hz)，7.56(1H，d，J＝2.0Hz)，7.13(1H，dd，J＝8.7，2.0Hz)，6.97(2H，d，J＝8.7Hz)，3.95(2H，s)，3.59(3H，s).Example 184 [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, starting from [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl ]Methyl acetate (example 183) the title compound was prepared. m.p.: 231 ℃. IR (KBr) v: 3250, 3120, 2822, 1734, 1618, 1539, 1456, 1321, 1236, 1120, 1060cm-1.1H-NMR(DMSO-d6)δ：11.58(1H，br s)，7.63-7.53(3H，m)，7.35(1H，d，J＝1.9Hz)，7.00(1H，dd，J＝8.6，1.9Hz)，6.80(2H，d，J＝8.9Hz)，3.69(2H，s).Example 185 [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
To [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl under stirring at room temperature under a nitrogen atmosphere]To a solution of methyl acetate (example 183, 0.15g, 0.44mmol) in DMF (5ml) was added sodium hydride (15mg, 0.46 mmol). After 5 minutes, 2-iodopropane (78mg) was added to stir the mixture for 7 hours. The mixture was quenched with 2N aqueous HCl (20ml) and extracted with ethyl acetate (50 ml). Water for extract liquid (30ml) and brine (30ml), dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1: 2) to give 72mg (43%) of the title compound as a white solid.1H-NMR(CDCl3) δ: 8.81(1H, br s), 7.80(2H, d, J ═ 8.9Hz), 7.56(1H, d, J ═ 8.7Hz), 7.41(1H, d, J ═ 1.8Hz), 7.15(1H, dd, J ═ 8.7, 1.8Hz), 6.95(2H, d, J ═ 8.9Hz), 4.67(1H, heptad, J ═ 6.1Hz), 3.87(2H, s), 3.67(3H, s)1.39(6H, d, J ═ 6.1Hz).Example 186 [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 185) the title compound was prepared. m.p.: 216-218 ℃ IR (KBr) v: 3304, 2972, 2881, 1707, 1614, 1596, 1560, 1508, 1311, 1261, 1163cm-1.1H-NMR(DMSO-d6) δ: 11.71(1H, br s), 7.75(2H, d, J ═ 8.9Hz), 7.69(1H, d, J ═ 8.6Hz), 7.46(1H, d, J ═ 2.0Hz), 7.12(1H, dd, J ═ 8.6, 2.0Hz), 7.07(2H, d, J ═ 8.9Hz), 4.78(1H, heptad, J ═ 5.9Hz), 3.82(2H, s)1.32(6H, d, J ═ 5.9Hz).Example 187 [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4-phenylbenzoylmethyl bromide following the method described in example 57.1H-NMR(CDCl3)δ：8.91(1H，br s)，7.88(2H，d，J＝8.1Hz)，7.73(2H，d，J＝8.1Hz)，7.68-7.38(7H，m)，7.16(1H，dd，J＝8.1，1.8Hz)，3.89(2H，s)，3.66(3H，s).Example 188 [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl]Methyl acetate (example 187) the title compound was prepared. m.p.: 228 ℃. IR (KBr) v: 3317, 3030, 2868, 1707, 1620, 1600, 1527, 1431, 1323, 1256,1 194cm-1.1H-NMR(DMSO-d6)δ：11.81(1H，s)，7.89(2H，d，J＝8.6Hz)，7.87(2H，d，J＝8.6Hz)，7.82-7.72(3H，m)，7.58-7.40(4H，m)，7.14(1H，dd，J＝8.6，1.8Hz)，3.87(2H，s).Example 189 [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4- (trifluoromethoxy) phenacyl bromide according to the method described in example 57.1H-NMR(CDCl3) δ: 8.85(1H, br s), 7.85(2H, d, J ═ 8.9Hz), 7.57(1H, d, J ═ 8.6Hz), 7.40(1H, d, J ═ 1.8Hz), 7.35(2H, d, J ═ 8.9Hz), 7.16(1H, dd, J ═ 8.6, 1.8Hz), 3.80(2H, s), 3.65(3H, s.) 4- (trifluoromethoxy) phenacyl bromide, prepared according to the following method:
a mixture of 4- (trifluoromethoxy) acetophenone (0.52g, 2.55mmol) and tetrabutylammonium bromide (1.35g, 2.80mmol) in dichloromethane-methanol (1: 1, 8ml) was stirred for 18 h, then concentrated. The residue was diluted with ethyl acetate (50ml), washed with water (50ml), brine (50ml) and dried (magnesium sulfate). After removal of the solvent, 0.36g (50%) of the title compound are obtained as a yellow oil. And (4) tlc: rf 0.47 (hexane-ethyl acetate 10: 1).Example 190 [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ]Methyl acetate (example 189) the title compound was prepared. m.p.: 166-168 ℃ IR (KBr) v: 3315, 3219, 1719, 1699, 1616, 1527, 1508, 1254, 1221, 1167, 943cm-1.1H-NMR(DMSO-d6)δ：11.79(1H，s)，7.88(2H，d，J＝8.6Hz)，7.75(1H，d，J＝8.9Hz)，7.56(2H，d，J＝8.6Hz)，7.47(1H，d，J＝1.8Hz)，7.14(1H，dd，J＝8.9，1.8Hz)，3.85(2H，s).Example 191 [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the method described in example 8, method B from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 4- (trifluoromethoxy) phenacyl bromide (preparation of which was found in example 189).1H-NMR(CDCl3)δ：8.92(1H，br s)，7.85(2H，d，J＝8.7Hz)，7.61(1H，br s)，7.38-7.28(4H，m)，3.79(2H，s)，3.67(3H，s).Example 192 [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 191) the title compound was prepared. m.p.: 186.7 ℃ IR (KBr) v: 3332, 3086, 2925, 1697, 1610, 1408, 1259, 1217, 1161, 1007, 941cm-1.1H-NMR(DMSO-d6)δ：11.85(1H，br s)，7.89(2H，d，J＝8.7Hz)，7.81(1H，d，J＝2.1Hz)，7.60-7.53(2H，m)，7.48(1H，d，J＝8.7Hz)，7.32(1H，dd，J＝8.7，2.1Hz)，3.86(2H，s).Example 193 [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 4-methoxybenzoylmethyl bromide according to the method described in example 57. 1H-NMR(CDCl3)δ：8.86(1H，s)，7.82(2H，d，J＝8.9Hz)，7.63-7.60(1H，m)，7.37-7.26(2H，m)，6.99(2H，d，J＝8.9Hz)，3.90(3H，s)，3.84(2H，s)，3.69(3H，s).Example 194 [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl]Methyl acetate (example 193) the title compound was prepared. m.p.: 232 ℃. IR (KBr) v: 3312, 2833, 2621, 1701, 1599, 1510, 1454, 1263, 1167, 1001, 777cm-1.1H-NMR(DMSO-d6)δ：11.78(1H，s)，7.78(2H，d，J＝8.9Hz)，7.75(1H，d，J＝2.0Hz)，7.47(1H，d，J＝8.7Hz)，7.29(1H，dd，J＝8.7，2.0Hz)，7.11(2H，d，J＝8.9Hz)，3.88(3H，s)，3.82(2H，s).Example 195 [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the method described in example 57 from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4-nitrobenzoylmethyl bromide.1H-NMR(CDCl3)δ：8.92(1H，br s)，8.37(2H，d，J＝8.9Hz)，7.93(2H，d，J＝8.9Hz)，7.57(1H，d，J＝8.7Hz)，7.40(1H，d，J＝1.8Hz)，7.18(1H，dd，J＝8.7，1.8Hz)，3.73(2H，s)，3.65(3H，s).Example 196 [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl]Methyl acetate (example 195) prepared the title compound. Melting point: 218.9 deg.C (decomposition). Ir (kbr) v: 3365, 3101, 2846, 1718, 1699, 1647, 1537, 1348, 1255, 1227, 852m-1.1H-NMR(DMSO-d6)δ：11.84(1H，s)，8.38(2H，d，J＝8.9Hz)，7.97(2H，d，J＝8.9Hz)，7.78(1H，d，J＝8.6Hz)，7.48(1H，d，J＝2.0Hz)，7.15(1H，dd，J＝8.6，2.0Hz)，3.83(2H，s).Example 197 [ 6-chloro-2- [ (4-methanesulfonyl) benzoyl ] carbonyl]) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from 4- (methylsulfonyl) phenacyl bromide according to the method described for example 57. 1H-NMR(CDCl3)δ：9.10(1H，br s)，8.08(2H，d，J＝8.6Hz)，7.93(2H，d，J＝8.3Hz)，7.57(1H，d，J＝8.7Hz)，7.37(1H，br)，7.20-7.10m(1H，m)，3.78(2H，s)，3.64(3H，s)，3.12(3H，s).Example 198 [ 6-chloro-2- [ (4-methanesulfonyl) benzoyl ] carbonyl]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-methanesulfonyl) benzoyl]-1H-indol-3-yl]Methyl acetate (example 197) the title compound was prepared. Melting point: 241 deg.C (decomposition). IR(KBr)ν：3330，1713，1614，1524，1230，1150，941，781cm-1.1H-NMR(DMSO-d6)δ：11..83(IH，s)，8.12(2H.d，J＝8.3Hz)，7.96(2H，d，J＝8.3Hz)，7.78(1H，d，J＝8.7Hz)，7.48(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝1.8，8.7Hz)，3.85(2H，s)，3.33(3H，s).Example 199 [ 6-chloro-2- [4- (methylsulfonylamino) benzoyl group]-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method a) and 4- (methylsulfonylamino) phenacyl bromide following the procedure described in example 8, method B.1H-NMR(CDCl3) δ: 8.86(1H, br s), 7.82(2H, d, J ═ 8.72Hz), 7.58(1H, d, J ═ 8.72Hz), 7.42-7.15(4H, m), 6.80(1H, br s), 3.83(2H, s), 3.67(3H, s), 3.13(3H, s.) 4- (methylsulfonylamino) phenacyl bromide was prepared as described in example 189 from (4-acetylphenyl) methanesulfonamide (R.Lis et al, J.org.Chem., 1987,524377).1H-NMR(CDCl3)δ：8.01(2H，d，8.72Hz)，7.28(2H，d，8.72Hz)，4.40(2H，s)，3.13(2H，s)Example 200 [ 6-chloro-2- [4- (methylsulfonylamino) benzoyl group]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-methanesulfonylamino) benzoyl ]-1H-indol-3-yl]Methyl acetate (example 199) the title compound was prepared. m.p.: 207 ℃. IR (KBr) v: 3333, 3248, 1715, 1603, 1570, 1529, 1508, 1394, 1323, 1259, 1231, 1159, 1061cm-1.1H-NMR(DMSO-d6)δ：11.6(1H，br s)，7.76(2H，d，J＝8.88Hz)，7.71(1H，d，J＝8.56Hz)，7.46(1H，1.65Hz)，7.12(1H，dd，J＝8.56Hz，1.65Hz)，3.81(2H，s)，3.13(3H，s).Example 201 [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (2-chlorobenzoyl) -1- (benzenesulfonyl) indole
Pressing to realThe title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (example 1, step 1 of method B) and 2-chlorobenzoyl chloride by the method described in method B, step 2, example 1. The crude product was used directly in the next step without purification. And (4) tlc: rf 0.25 (hexane-ethyl acetate 4: 1).Step 2.6-chloro-2- (2-chlorobenzoyl) indole
The title compound was prepared from 6-chloro-2- (2-chlorobenzoyl) -1- (benzenesulfonyl) indole (step 1) according to the procedure described in example 1, step 3 of method B. The crude product was used in the next step without purification. And (4) tlc: rf 0.37 (hexane-ethyl acetate 4: 1).Step 3. alpha-acetoxy-2- [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl]Third two Acid diethyl ester
The title compound was prepared from 6-chloro-2- (2-chlorobenzoyl) indole (step 2) according to the procedure described in example 1, method B, step 4. 1H-NMR(CDCl3)δ：8.61(1H，br s)，7.79(1H，d，J＝8.88Hz)，7.52-7.33(5H，m)，7.15(1H，dd，J＝1.97Hz，8.88Hz)，4.26(4H，m)，2.02(3H，s)，1.22(6H，t，J＝7.07Hz).Step 4.[ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in example 1, step 5 of method B, from α -acetoxy- [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.95(1H，br s)，7.75(1H，d，J＝8.88Hz)，7.53-7.39(5H，m)，4.83(1H，s)，4.15(4H，m)，1.20(6H，t，J＝7.26Hz).Step 5.2- [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of method B, example 1, from [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. m.p.: 138-140_ C.IR (KBr) v: 3315, 1713, 1632, 1564, 1526, 1435, 1325, 1254, 1215, 1151, 1061cm-1.1H-NMR(DMSO-d6)δ：11.67(1H，s)，7.61(1H，d，J＝8.72)，7.51-7.34(5H，m)，7.50(1H，dd，J＝1.97，8.72Hz)，3.75(2H，s).Example 202 [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl]Acetic acid Step 1.6-chloro-2- (2, 4-dichlorobenzoyl) -1- (benzenesulfonyl) indole
The title compound was prepared according to the method described in example 1, method B, step 2, from 6-chloro-1- (benzenesulfonyl) indole (example 1, method B, step 1) and 2, 4-dichlorobenzoyl chloride. The crude product was used in the next step without purification. And (4) tlc: rf 0.34 (hexane-ethyl acetate 4: 1).Step 2.6-chloro-2- (2, 4-dichlorobenzoyl) indole
The title compound was prepared from 6-chloro-2- (2, 4-dichlorobenzoyl) -1- (benzenesulfonyl) indole (step 1) according to the method described in example 1, step 3 of method B. The crude product was used in the next step without purification. And (4) tlc: rf 0.45 (hexane-ethyl acetate 4: 1). Step 3. alpha-acetoxy- [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl]Third two Acid diethyl ester
The title compound was prepared from 6-chloro-2- (2, 4-dichlorobenzoyl) indole (step 2) according to the method described in step 4 of example 1.1H-NMR(CDCl3)δ：8.92(1H，br s)，7.79-7.11(6H，m)，4.24(4H，m)，2.02(3H，s)，1.22(6H，t，J＝7.10Hz).Step 4.[ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl]Malonic acid diethyl ester
Following the procedure described in step 5 of method B, example 1, from α -acetoxy- [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：8.92(1H，br s)，7.75(1H，d，J＝8.92Hz)，7.55-7.36(4H，m)，7.13(1H，dd，8.92Hz，1.81Hz)，4.85(1H，s)，4.17(4H，m)，1.21(6H，t，J＝7.10Hz).Step 5.[ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of method B, example 1, from 2- [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl]Preparation of diethyl malonate (step 4)The title compound. m.p.: 190 ℃. 192. deg.C, IR (KBr) v: 3304, 1709, 1630, 1589, 1526, 1427, 1321, 1231, 1150, 1061cm-1.1H-NMR(DMSO-d6)δ：11.66(1H，s)，7.72(1H，d，J＝2.00Hz)，7.64(1H，d，8.91Hz)，751-7.33(3H，m)，7.01(1H，dd，J＝2.00，8.91Hz)，3.61(2H，s).Example 203 [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4-chloro-3-fluorobenzoylmethyl bromide according to the method described in example 57. 1H-NMR(CDCl3) δ: 8.87(1H, br s), 7.65-7.36(4H, m), 7.17(1H, dd, J ═ 8.72Hz, 1.81Hz), 3.80(2H, s), 3.68(3H, s.) 4-chloro-3-fluorobenzoylmethyl bromide was prepared according to the following method: 4-acetyl-1-chloro-2-fluorobenzene:
to a solution of 1-bromo-4-chloro-3-fluorobenzene (2.09g, 10mmol) in dry diethyl ether (12.0ml) was added a solution of n-butyllithium (1.55M in hexane, 6.77ml, 10.5mmol) at-78 ℃ under a nitrogen atmosphere. The mixture was warmed to-20 ℃ and stirred for 45 minutes. A solution of N, N-dimethylacetamide (1.04ml, 11.2mmol) in diethyl ether (1.5ml) was added, and the mixture was stirred for 1 hour, after which the mixture was warmed to room temperature. After stirring for 3 hours, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (20ml), and extracted with diethyl ether (30 ml. times.3). The combined organic layers were washed with 2N aqueous HCl (20ml), saturated aqueous sodium bicarbonate (20ml), brine (20ml) and dried (magnesium sulfate). After removal of the solvent, the title compound was obtained as a yellow oil (quantitative).1H-NMR(CDCl3) δ: 7.75-7.09(3H, m), 2.59(3H, s). 4-chloro-3-fluorobenzoylmethyl bromide:
the title compound was prepared from 4-acetyl-1-chloro-2-fluorobenzene following the procedure for preparation of 4- (trifluoromethoxy) phenacyl bromide as described in example 189. 1H-NMR(CDCl3)δ：7.79-7.71(2H，m)，7.58-7.52(1H，m)，4.38(2H，s).Example 204 [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- (4-methanesulfonylaminobenzoylmethyl) -1H-indol-3-yl]Methyl acetate (example 203) the title compound was prepared. m.p.: 179-182 ℃ MS (EI) m/z: 365 (M)+).1H-NMR(DMSO-d6)δ：11.80(1H，br s)，7.85-7.48(5H，m)，7.14(1H，dd，J＝8.72Hz，1.97Hz)，3.84(2H，s).Example 205 [ 6-chloro-2- (4-cyanobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the method described in example 8, method B from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method a) and 4-cyanobenzoyl methyl bromide.1H-NMR(CDCl3)δ：8.88(1H，br s)，7.89-7.80(4H，m)，7.58(1H，d，J＝8.75Hz)，7.41(1H，d，1.65Hz)，7.18(1H，dd，8.75Hz，1.65Hz)，3.74(2H，s)，3.36(3H，s).Example 206 [ 6-chloro-2- (4- (bromo) benzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 4-bromobenzoylmethyl bromide following the method described for example 57.1H-NMR(CDCl3)δ：8.89(1H，br s)，7.66(4H，s)，7.55(1H，d，J＝8.6Hz)，7.36(1H，d，J＝1.6Hz)，7.15(1H，dd，J＝8.6，1.6Hz)，3.81(2H，s)，3.66(3H，s).Example 207 [ 6-chloro-2- [4- (2-thienyl) benzoyl group]-1H-indol-3-yl]Acetic acid methyl ester
Refluxing [ 6-chloro-2- (4-bromobenzoyl) -1H-indol-3-yl]A mixture of methyl acetate (example 206, 0.40g, 0.98mmol), thiophene-2-boronic acid (0.14g, 1.08mmol), saturated aqueous sodium bicarbonate (4ml) and bis (triphenylphosphine) palladium (II) dichloride (70mg, 0.098mmol) in DME (15ml) was used for 3 hours. The mixture was poured into water (30ml), which was subjected to extraction with ethyl acetate (50 ml. times.2). The combined extracts were washed with brine (50ml), dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1: 6) to give 0.33g of (C 83%) title compound as a yellow solid.1H-NMR(CDCl3)δ：8.88(1H，br s)，7.83(2H，d，J＝8.2Hz)，7.75(2H，d，J＝8.2Hz)，7.58(1H，d，J＝8.6Hz)，7.46(1H，dd，J＝3.6，1.2Hz)，7.42-7.38(2H，m)，7.19-7.12(2H，m)，3.87(2H，s)，3.67(3H，s).Example 208 [ 6-chloro-2- [4- (2-thienyl) benzoyl group]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- [4- (2-thienyl) benzoyl]-1H-indol-3-yl]Methyl acetate (example 207) the title compound was prepared. m.p.: 246-249 ℃ IR (KBr) v: 3319, 3068, 2628, 1705, 1610, 1593, 1427, 1323, 1257, 1186, 941cm-1.1H-NMR(DMSO-d6)δ：11.79(1H，s)，7.87(2H，d，J＝8.6Hz)，7.82(2H，d，J＝8.6Hz)，7.77-7.68(3H，m)，7.48(1H，d，J＝1.5Hz)，7.26-7.20(1H，m)，7.13(1H，dd，J＝8.6，2.0Hz)，3.86(2H，s).Example 209 [ 6-chloro-2- [4- (2-furyl) benzoyl group]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 207, from [ 6-chloro-2- (4-bromobenzoyl) -1H-indol-3-yl]Methyl acetate (example 206) and furan-2-boronic acid the title compound was prepared.1H-NMR(CDCl3)δ：8.90(1H，br s)，7.83(2H，d，J＝8.7Hz)，7.80(2H，d，J＝8.7Hz)，7.60-7.54(2H，m)，7.40(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝8.6，1.8Hz)，6.83(1H，d，J＝3.5Hz)，6.57-6.52(1H，m)，3.86(2H，s)，3.66(3H，s).Example 210 [ 6-chloro-2- [4- (2-furyl) benzoyl group]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- [4- (2-furyl) benzoyl]-1H-indol-3-yl]Methyl acetate (example 209) the title compound was prepared. m.p.: 230 ℃. 232 ℃ IR (KBr) v: 3315, 2873, 2630, 1709, 1616, 1597, 1527, 1431, 1321, 1257, 1232cm-1.1H-NMR(DMSO-d6)δ：11.80(1H，s)，7.93-7.79(3H，m)，7.83(2H，d，J＝8.1Hz)，7.73(1H，d，J＝8.6Hz)，7.48(1H，d，J＝1.8Hz)，7.21(1H，d，J＝3.5Hz)，7.14(1H，dd，J＝8.6，1.8Hz)，6.72-6.66(1H，m)，3.84(2H，s).Example 211 [ 6-chloro-2- [4- (3-pyridyl) benzoyl group]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 207, from [ 6-chloro-2- (4-bromobenzoyl) -1H-indol-3-yl]Methyl acetate (example 206) and pyridine-3-boronic acid the title compound was prepared.1H-NMR(CDC13)δ：8.95(1H，br s)，8.90(1H，d，J＝2.5Hz)，8.69-8.65(1H，m)，7.98-7.92(1H，m)，7.92(2H，d，J＝8.6Hz)，7.73(2H，d，J＝8.6Hz)，7.59(1H，d，J＝8.7Hz)，7.48-7.40(2H，m)，7.17(1H，dd，J＝8.7，1.8Hz)，3.88(2H，s)，3.67(3H，s).Example 212 [ 6-chloro-2- [4- (3-pyridyl) benzoyl group]-1H-indol-3-yl]Acetic acid
From [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] according to the method described in example 9, method B]-1H-indol-3-yl]Methyl acetate (example 211) the title compound was prepared. m.p.: 194.8 ℃ IR (KBr) v: 3224, 2960, 1604, 1568, 1527, 1382, 1321, 1259, 1004, 920cm-1.1H-NMR(CD3OD)δ：8.93-8.89(1H，m)，8.57(1H，dd，J＝4.8，1.5Hz)，8.24-8.17(1H，m)，7.98(2H，d，J＝8.6Hz)，7.85(2H，d，J＝8.6Hz)，7.68(1H，d，J＝8.6Hz)，7.60-7.53(1H，m)，7.46-7.42(1H，m)，7.04(1H，dd，J＝8.6，1.8Hz)，3.67(2H，s).Example 213 [ 6-chloro-2- [4- (2-thiazolyl) benzoyl group]-1H-indol-3-yl]Acetic acid methyl ester
To a solution of thiazole (0.11g, 1.23mmol) in diethyl ether (4ml) was added n-butyllithium (1.55M in hexane, 0.79ml) under stirring at-78 ℃. After stirring for 30 min, zinc chloride (1.0M in ether, 3.7ml, 3.7mmol) was added and the mixture was stirred at 0 ℃ for 30 min. To the resulting mixture was added a palladium catalyst prepared by treating bis (triphenylphosphine) palladium (II) dichloride (0.22g, 0.31mmol) with n-butyllithium (1.55M in hexane, 0.39ml) in THF (5 ml). To the mixture was added [ 6-chloro-2- (4-bromobenzoyl) -1H-indol-3-yl ]Methyl acetate (example 206, 0.25g, 0.61 mmol). The reaction mixture was heated under reflux for 4 hours, which was poured into water (50ml), followed by extraction with ethyl acetate (50 ml). The combined extracts were washed with brine (50ml), dried (magnesium sulfate) and concentrated. The crude product was purified by flash column chromatography eluting with ethyl acetate-hexane (1: 3) to give 0.18g (72%) of the title compound as a yellow solid.1H-NMR(DMSO-d6)δ：11.87(1H，br s)，8.16(2H，d，J＝8.4Hz)，8.04(1H，d，J＝3.1Hz)，7.93(1H，d，J＝3.1Hz)，7.86(2H，d，J＝8.4Hz)，7.77(1H，d，J＝8.6Hz)，7.49(1H，d，J＝1.6Hz)，7.15(1H，dd，J＝8.6，1.6Hz)，3.97(2H，s)，3.54(3H，s).Example 214 [ 6-chloro-2- [4- (2-thiazolyl) benzoyl group]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, starting from [ 6-chloro-2- [4- (2-thiazolyl) benzoyl]-1H-indol-3-yl]Methyl acetate (example 213) the title compound was prepared. m.p.: 230 ℃. IR (KBr) v: 3331, 3126, 2546, 1693, 1635, 1535, 1350, 1313, 1213, 1150, 912cm-1.1H-NMR(DMSO-d6)δ：11.82(1H，s)，8.15(2H，d，J＝8.6Hz)，8.04(1H，d，J＝3.3Hz)，7.93(1H，d，J＝3.3Hz)，7.88(2H，d，J＝8.6Hz)，7.75(1H，d，J＝8.7Hz)，7.49(1H，d，J＝2.0Hz)，7.14(1H，dd，J＝8.7，2.0Hz)，3.86(2H，s).Example 215 [ 6-chloro-2- (3-bromobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 3-bromobenzoylmethyl bromide following the method described for example 57.1H-NMR(CDCl3)δ：8.91(1H，br s)，7.93-7.87(1H，m)，7.77-7.67(2H，m)，7.57(1H，d，J＝8.7Hz)，7.43-7.35(2H，m)，7.19-7.13(1H，m)，3.78(2H，s)，3.69(3H，s).Example 216 [ 6-chloro-2- [3- (2-furyl) benzoyl group]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 207, from [ 6-chloro-2- (3-bromobenzoyl) -1H-indol-3-yl ]Methyl acetate (example 215) and furan-2-boronic acid the title compound was prepared.1H-NMR(CDCl3)δ：8.93(1H，br s)，8.05-8.01(1H，m)，7.94-7.88(1H，m)，7.68-7.62(1H，m)，7.60-7.47(3H，m)，7.45-7.41(1H，m)，7.16(1H，dd，J＝8.6，1.6Hz)，6.74(1H，d，J＝3.3Hz)，6.52-6.47(1H，m)，3.80(2H，s)，3.57(3H，s).Example 217 [ 6-chloro-2- [3- (2-furyl) benzoyl group]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 9, method B, from [ 6-chloro-2- [3- (2-furyl) benzoyl]-1H-indol-3-yl]Methyl acetate (example 216) the title compound was prepared. m.p.: 246-249 ℃ IR (KBr) v: 3310, 2984, 2632, 1695, 1624, 1568, 1327, 1227, 1062, 806, 739cm-1.1H-NMR(DMSO-d6)δ：11.81(1H，s)，8.05-7.96(2H，m)，7.82-7.77(1H，m)，7.74(1H，d，J＝8.7Hz)，7.68-7.61(2H，m)，7.49(1H，d，J＝2.0Hz)，7.14(1H，dd，J＝8.7，2.0Hz)，7.09(1H，d，J＝3.3Hz)，6.66-6.61(1H，m)，3.83(2H，s).Example 218 dl-2- [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Propionic acid methyl ester Step 1.[ 1-tert-Butoxycarbonyl-2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl]Second step Acid methyl ester
To [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl at room temperature with stirring]To a suspension of methyl acetate (example 8, method B, 2.0g, 5.5mmol) in dichloromethane (20ml) were added di-tert-butyl carbonate (2.4g, 11mmol) and 4-dimethylaminopyridine (670mg, 5.5 mmol). After stirring for 5 minutes, the mixture was poured into 10% citric acid (200ml) and extracted with dichloromethane (200 ml). The extract was washed with water (200ml), brine (200ml), dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1: 4) to give 2.3g (90%) of the title compound as a yellow solid. 1H-NMR(CDCl3)δ：8.26(1H，d，J＝2.2Hz)，7.74(2H，d，J＝8.6Hz)，7.53(1H，d，J＝8.6Hz)，7.44(2H，d，J＝8.6Hz)，7.32(1H，dd，J＝1.6，8.4Hz)，3.72(2H，s)，3.56(3H，s)，1.30(9H，s).Step 2 [ 1-tert-Butoxycarbonyl ]2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl]C3 Acid methyl ester
To [ 1-tert-butoxycarbonyl-2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl at-78 deg.C with stirring]To a solution of methyl acetate (step 1, 200mg, 0.43mmol) in THF (3ml) was added a solution of lithium bis (trimethylsilyl) amide in THF (1M, 0.5 ml). After stirring for 0.5 h, iodomethane (0.14ml, 2.2mmol) was added at the same temperature. The mixture was warmed to-10 ℃ and stirred for a further 0.5 h. The resulting mixture was poured into a saturated aqueous ammonium chloride solution (50ml), and extracted with diethyl ether (50 ml). The extract was washed with water (50ml), brine (50ml), dried (magnesium sulfate) and concentrated. The residue was purified by TLC and developed with ethyl acetate-hexane (1: 4) to give 146mg (71%) of the title compound as a colorless oil.1H-NMR(CDCl3)δ：8.28(1H，d，J＝1.9Hz)，7.75(2H.d，J＝8.4Hz)，7.59(1H，d，J＝8.4Hz)，7.44(2H，d，J＝8.6Hz)，7.28(1H，dd，J＝1.9，8.4Hz)，3.86(1H，q，J＝7.3Hz)，3.54(3H，s)，1.54(3H，d，J＝7.3Hz)，1.30(9H，s).Step 3 dl- [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl]Propionic acid methyl ester
[ 1-Boc-2- (4-chlorobenzoyl) -1H-indol-3-yl]Methyl propionate (step 2, 270mg, 0.72mmol) was dissolved in trifluoroacetic acid (5 ml). After stirring for 10 min, the mixture was concentrated. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate (30ml), and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water (50ml), brine (50ml), dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1: 3) to give 210mg (78%) of the title compound as a yellow solid. 1H-NMR(CDCl3)δ：8.89(1H，br)，7.78(2H，d，J＝8.7Hz)，7.67(1H，d，J＝8.7Hz)，7.50(2H，d，J＝8.6Hz)，7.40-7.37(1H，m)，7.11(1H，dd，J＝1.8，8.7Hz)，4.20(1H，q，J＝7.2Hz)，3.64(3H，s)，1.54(3H，d，J＝7.2Hz).Example 219 dl-2- [2- (4-chlorobenzoyl) -6-chloro-1H-indol-3-yl]Propionic acid
As described in example 9, method BThe process described is carried out from dl-2- [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl]Methyl propionate (example 218) the title compound was prepared.1H-NMR(CDCl3)δ：8.77(1H，br s)，7.82(2H，d，J＝8.6Hz)，7.75(1H，d，J＝8.7Hz)，7.53(2H，d，J＝8.6Hz)，7.40(1H，br)，7.13(1H，dd，J＝1.8，8.7Hz)，4.29(1H，q，J＝7.2Hz)，1.61(3H，d，J＝7.2Hz).Example 220 [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 3-bromoacetyl isoquinoline hydrobromide salt according to the method described in example 57.1H-NMR(CDCl3) δ: 12.72(1H, br s), 9.37(1H, s), 8.80(1H, s), 8.15-8.02(2H, m), 7.87-7.76(2H, m), 7.69(1H, d, J ═ 2.0Hz), 7.48(1H, d, J ═ 8.9Hz), 7.32(1H, dd, J ═ 2.0, 8.7Hz), 4.33(2H, s), 3.76(3H, s) · 3-bromoacetylisoquinoline hydrobromide is according to the methods of h.mckennis, jr., l.b.turnbull, e.r.bowman and e.tamaki (see j.g.chem, 1963,28383-387), from 3-acetylisoquinoline (D.L. Klayman et al, Arzneim. Forsch., 1986,36and 10) preparation.1H-NMR(DMSO-d6)δ：9.49(1H，s)，8.68(1H，s)，8.34-8.26(2H，m)，7.99-7.88(2H，m)，5.14(2H，s).Example 221 [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ]Methyl acetate (example 219) the title compound was prepared. MS (EI) m/z: 364 (M)+).m.p.：239-240℃.IR(KBr)ν：3277，1699，1641，1531，1329，1202，1059，961，787cm-1.1H-NMR(DMSO-d6)δ：12.46(1H，br s)，9.56(1H，s)，8.69(1H，s)，8.39-8.26(2H，m)，7.99-7.90(2H，m)，7.87(1H，d，J＝2.1Hz)，7.72(1H，d，J＝8.7Hz)，7.35(1H，dd，J＝2.1，8.9Hz)，4.13(2H，s)..Example 222 [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared according to the method described for example 57 from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 3-bromoacetylisoquinoline (preparation of which is described for example 220).1H-NMR(CDCl3)δ：12.69(1H，br s)，9.38(1H，s)，8.81(1H，s)，8.16-8.04(2H，m)，7.88-7.77(2H，m)，7.65(1H，d，J＝8.9Hz)，7.57(1H，d，J＝2.0Hz)，7.15(1H，dd，J＝2.0and 8.7Hz)，4.36(2H，s)，3.75(3H，s).Example 223 [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl]Methyl acetate (example 222) the title compound was prepared. MS (EI) m/z: 364 (M)+).m.p.：236-237℃.IR(KBr)ν：3229，1709，1641，1618，1531，1198，793cm-1.1H-NMR(DMSO-d6)δ：12.43(1H，br s)，9.56(1H，s)，8.70(1H，s)，8.41-8.26(2H，m)，7.99-7.87(2H，m)，7.82(1H，d，J＝8.7Hz)，7.77(1H，d，J＝1.5Hz)，7.14(1H，dd，J＝2.0，8.6Hz)，4.14(2H，s).Example 224 [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, a mixture of trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 3-bromoacetyl-5-methylisoxazole (m.d. amici et al, j.org.chem., 1989,542646) preparation of the title compound.1H-NMR(CDCl3)δ：10.75(1H，br s)，7.68(1H，br s)，7.42(1H，d，J＝8.2Hz)，7.34(1H，dd，J＝1.8，9.1Hz)，6.60(1H，s)，4.25(2H，s)，3.74(3H，s)，2.56(3H，s).Example 225 [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ]Methyl acetate (example 224) the title compound was prepared. MS (EI) m/z: 318 (M)+).m.p.：253-255℃.IR(KBr)ν：3379，1699，1639，1539，1425，1259，1207，1059，804cm-1.1H-NMR(DMSO-d6)δ：11.76(1H，br s)，7.81(1H，d，J＝2.0Hz)，7.59(1H，d，J＝8.9Hz)，7.29(1H，dd，J＝2.0，8.7Hz)，6.67(1H，s)，4.00(2H，s)，2.49(3H，s).Example 226 [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, a mixture of trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 3-bromoacetyl-5-methylisoxazole (m.d. amici et al, j.org.chem., 1989,542646) preparation of the title compound.1H-NMR(CDCl3)δ：10.70(1H，br s)，7.62(1H，d，J＝8.7Hz)，7.49(1H，d，J＝1.8Hz)，7.15(1H，dd，J＝1.8 and 8.7Hz)，6.60(1H，br s)，4.27(2H，s)，3.72(3H，s)，2.56(3H，s).Example 227 [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl]Methyl acetate (example 226) the title compound was prepared. MS (EI) m/z: 318 (M)+).m.p.：227-229℃.IR(KBr)ν：3331，1713，1645，1543，1404，1259，1202，891，804cm-1.1H-NMR(DMSO-d6)δ：11.70(1H，br s)，7.74(1H，d，J＝8.7Hz)，7.62(1H，d，J＝1.3Hz)，7.07(1H，dd，J＝1.8，8.6Hz)，6.67(1H，br s)，4.01(2H，s)，2.49(3H，s).Example 228 [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 5-bromoacetyl-4-methyl-1, 2, 3-thiadiazole hydrobromide according to the method described in example 57.1H-NMR(CDCl3)δ：9.00(1H，br s)，7.63(1H，br s)，7.34(1H，dd，J＝1.8，8.9Hz)，7.28(1H，d，J＝8.9Hz)，3.81(2H，s)，3.66(3H，s)，2.78(3H，s) 5-bromoacetyl-4-methyl-1, 2, 3-thiadiazole hydrobromide salt was prepared according to the following method: N-methoxy-N-methyl-4-methyl-1, 2, 3-thiadiazole-5-carboxamide:
To a solution of 1, 2, 3-thiadiazole-5-carbonyl chloride (10.00g, 61.5mmol) and N, O-dimethylhydroxylamine hydrochloride (7.20g, 73.8mmol) in dichloromethane (200ml0 was added triethylamine (20.6ml, 147.6mmol) at 0 deg.C, and after stirring the mixture at room temperature for 2 hours, the mixture was diluted with dichloromethane (300ml), washed with water (200 ml. times.2), dried (magnesium sulfate), and the solvent was removed to give 11.31g (98%) of the title compound as brown crystals.1H-NMR(CDCl3) δ: 3.75(3H, s), 3.40(3H, s), 3.01(3H, s), 5-acetyl-4-methyl-1, 2, 3-thiadiazole:
to a solution of N-methoxy-N-methyl-4-methyl-1, 2, 3-thiadiazole-5-carboxamide (11.31g, 60.4mmol) in THF (100ml) at 0 deg.C was added a 2M solution of methyl magnesium iodide in diethyl ether (45.3ml, 90.6mmol) over 0.5 hours. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was quenched with saturated aqueous ammonium chloride (100ml) and then extracted with diethyl ether (200 ml. times.2). The extracts were dried (magnesium sulfate) and concentrated to give 7.49g (87%) of the title compound as a light brown oil.1H-NMR(CDCl3) δ: 2.96(3H, s), 2.67(3H, s), 5-bromoacetyl-4-methyl-1, 2, 3-thiadiazole:
to a solution of 5-acetyl-4-methyl-1, 2, 3-thiadiazole (1.00g, 7.03mmol) in chloroform (20ml) was added dropwise a solution of bromine (1.24g, 7.73mmol) in chloroform (10ml) at room temperature over 0.5 hour. The mixture was heated to reflux for 2 hours. After cooling to room temperature, the mixture was made basic with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (100ml × 2). Drying (magnesium sulfate) and concentration of the extract gave 1.55g (100%) of the title compound as a brown oil. 1H-NMR(CDCl3)δ：4.28(2H，s)，2.98(3H，s).Example 229 [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl]Acetic acid
Heating and refluxing [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl]A mixture of methyl acetate (example 228, 190mg, 0.54mmol), 2N aqueous HCl (4ml) and acetic acid (20ml) was added for 2 hours. The mixture was cooled to room temperature and then concentrated. The crystalline residue was diluted with THF (100ml), dried (magnesium sulfate) and concentrated. The remaining solid was washed with ethyl acetate to give 145mg (79%) of the title compound as a yellow solid. MS (EI) m/z: 335 (M)+).m.p.：229-230℃.IR(KBr)ν：3300，1715，1622，1526，1329，1261，1204，1063，1009，822cm-1.1H-NMR(DMSO-d6)δ：11.92(1H，br s)，7.89(1H，d，J＝2.0Hz)，7.48(1H，d，J＝8.9Hz)，7.36(1H，dd，J＝2.0，8.9Hz)，3.95(2H，s)，2.63(3H，s).Example 230 [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 5-bromoacetyl-4-methyl-1, 2, 3-thiadiazole (prepared as described in example 228) according to the method described for example 57. And (4) tlc: rf 0.56 (ethyl acetate/hexane 1: 2).Example 231 [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 229, from [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ]The title compound was prepared from acetic acid (example 230). MS (EI) m/z: 335 (M)+).m.p.：215-216℃.IR(KBr)ν：3300，1709，1645，1531，1327，1211，1065，922，789cm-1.1H-NMR(DMSO-d6)δ：12.35(1H，br s)，11.86(1H，br s)，7.82(1H，d，J＝8.7Hz)，7.47(1H，d，J＝1.8Hz)，7.17(1H，dd，J＝1.8，8.6Hz)，3.93(2H，s)，2.63(3H，s).Example 232 [ 5-chloro-2- (5-methyl-thiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-5-methylthiazole hydrobromide salt according to the method described in example 57.1H-NMR(CDCl3) δ: 11.74(1H, br s), 7.76(1H, d, J ═ 1.1Hz), 7.67(1H, d, J ═ 1.8), 7.43(1H, d, J ═ 8.7Hz), 7.32(1H, dd, J ═ 2.0, 8.7Hz), 4.28(2H, s), 3.73(3H, s), 2.62(3H, d, J ═ 1.0Hz), 2-bromoacetyl-5-methylthiazole, according to the methods of h.mckennis, jr, l.b.turnbull, e.r.bowman and e.tamaki (see j.org.chem., 1963,28383-387), from 2-acetyl 5-methylthiazole (Metzger et al, Bu7.Soc. Chim. Fr, 1953,702) And (4) preparation.1H-NMR(DMSO-d6)δ：7.91(1H，d，J＝1.2Hz)，4.87(2H，s)，2.58(3H，d，J＝0.8Hz).Example 233 [ 5-chloro-2- (5-methyl-thiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (5-methyl-thiazole-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 232) the title compound was prepared. MS (EI) m/z: 334 (M)+).m.p.：231-233℃.IR(KBr)ν：3348，1699，1630，1541，1404，1333，1271，1057，1003，804cm-1.1H-NMR(DMSO-d6)δ：12.05(1H，br s)，8.04(1H，s)，7.88(1H，br s)，7.77(1H，d，J＝8.7Hz)，7.35(1H，brd，J＝8.9Hz)，4.15(2H，s)，2.63(3H，s).Example 234 [ 6-chloro-2- (5-methyl-thiazole-2-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester
The title compound was prepared according to the procedure described for example 57 from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-bromoacetyl-5-methyl-thiazole (preparation method see example 232).1H-NMR(CDCl3)δ：11.73(1H，br s)，7.77(1H，s)，7.62(1H，d，J＝8.2Hz)，7.51(1H，brs)，7.14(1H，br d，J＝8.7Hz)，4.31(2H，s)，3.72(3H，s)，2.62(3H，s).Example 235 [ 6-chloro-2- (5-methyl-thiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (5-methyl-thiazole-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 234) the title compound was prepared. MS (EI) m/z: 334 (M)+).m.p.：225-226℃.IR(KBr)ν：3277，1707，1630，1541，1398，1350，1231，1219，1138，878，800cm-1.1H-NMR(DMSO-d6)δ：12.25(1H，br s)，11.99(1H，br s)，8.04(1H，s)，7.82(1H，s)，7.81(1H，d，J＝9.0Hz)，7.13(1H，br d，J＝8.7Hz)，4.15(2H，s)，2.63(3H，s).Example 236 [ 6-chloro-2- (2-thienyl) carbonylindol-3-yl]Acetic acid Step 1.6-chloro-2- (2-thienylcarbonyl) -1-benzenesulfonylindole
The title compound was prepared from 6-chloro-1- (benzenesulfonyl) indole (step 1 of method B, example 2) and 2-thiophenecarbonyl chloride according to the method described in step 2 of method B, example 2.1H-NMR(CDCl3)δ：8.13-8.16(3H，m)，7.77-7.80(2H，m)，7.50-7.63(4H，m)，7.29(1H，dd，J＝1.8，8.4Hz)，7.19(1H，t，J＝5.4Hz)，7.03(1H，s).Step 2.6-chloro-2- (2-thiophenecarbonyl) indole
The title compound was prepared from 6-chloro-2- (2-thiophenecarbonyl) -1-benzenesulfonylindole (step 1) according to the procedure described in example 2, method B, step 3.1H-NMR(CDCl3)δ：10.96(1H，br s)，8.01(1H，dd，J＝1.2，3.8Hz)，7.73(1H，dd，J＝1.2，4.9Hz)，7.64(1H，d，J＝8.6Hz)，7.54-7.55(1H，m)，7.35-7.37(1H，m)，7.23(1H，dd，J＝3.8，4.9Hz)，7.10(1H，dd，J＝1.8，8.6Hz).Step 3. alpha-acetoxy- [ 6-chloro-2- (2-thiophenecarbonyl) -1H-indol-3-yl]Malonic acid diethyl ester Esters
The title compound was prepared from 6-chloro-2- (2-thiophenecarbonyl) indole (step 2) according to the method described in step 4 of method B, example 2.1H-NMR(CDCl3)δ：8.93(1H，br s)，7.82(1H，d，J＝8.9Hz)，7.76(1H，d，J＝4.9Hz)，7.55(1H，d，J＝3.8Hz)，7.39(1H，d，J＝1.8Hz)，7.11-7.18(2H，m)，4.16-4.31(4H，m)，1.87(3H，s)，1.17-1.32(6H，m).Step 4.[ 6-chloro-2- (2-thiophenecarbonyl) -1H-indol-3-yl]Malonic acid diethyl ester
From alpha-acetoxy according to the method described in step 5 of method B of example 2- [ 6-chloro-2- (2-thiophenecarbonyl) -1H-indol-3-yl]Diethyl malonate (step 3) prepares the title compound.1H-NMR(CDCl3)δ：9.27(1H，br s)，7.71-7.75(2H，m)，7.60-7.66(1H，m)，7.05-7.17(3H，m)，5.56(1H，s)，4.07-4.26(4H，m)，1.20-1.28(6H，m).Step 5.[ 6-chloro-2- (2-thiophenecarbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in step 6 of method B, example 2, from [ 6-chloro-2- (2-thiophenecarbonyl) -1H-indol-3-yl]Diethyl malonate (step 4) prepares the title compound. MS (EI) m/z: 319 (M)+).m.p.：177-178℃.IR(KBr)ν：3323，1701，1593，1568，1524，1435，1412，1323，1258，1229，920cm-1.1H-NMR(DMSO-d6)δ：12.25(1H，br s)，11.85(1H，br s)，8.13(1H，d，J＝4.9Hz)，7.89(1H，d，J＝3.6Hz)，7.74(1H，d，J＝8.7Hz)，7.51(1H，d，J＝1.8Hz)，7.34(1H，t，J＝4.8Hz)，7.15(1H，dd，J＝1.8，8.7Hz)，3.96(2H，s).Example 237 [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl]-1H-indol-3-yl]Acetic acid Methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-chloroacetyl-3- (1-hydroxy-1-methylethyl) furan by the method described in example 57.1H-NMR(CDCl3) δ: 9.89(1H, br s), 7.59(1H, d, J ═ 1.6Hz), 7.53(1H, d, J ═ 8.7Hz), 7.34(1H, d, J ═ 1.5Hz), 7.08(1H, dd, J ═ 1.6, 8.7Hz), 6.57(1H, d, J ═ 1.8Hz), 6.39(1H, br), 4.22(2H, s), 3.73(3H, s), 1.57(6H, s) · 2-chloroacetyl-3- (1-hydroxy-1-methylethyl) furan were prepared according to the following method:
To 2- (3-furyl) -2-propanol (t.m. bargar et al, j.med.chem., 1986,29315, 2.0g, 15.85mmol) in THF (100ml) was added a solution of n-butyllithium in hexane (1.55M, 30.7ml, 47.55 mmol). After stirring for 1 hour, 2-chloro-N-methoxy-N-methylacetamide (6.54g, 47.55mmol) was added at 0 ℃. Adding into the mixtureSaturated aqueous ammonium chloride (100ml) and the organic layer was separated. The organic layer was washed with water (100 ml. times.2) and brine (50ml) and dried (magnesium sulfate). After removal of the solvent, the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 4) to give 1.03g (32%) of the title compound as an oil.1H-NMR(CDCl3)δ：7.52(1H，d，J＝1.8Hz)，6.56(1H，d，J＝1.8Hz)，5.51(1H，s)，4.74(2H，s)，1.56(6H，s).Example 238 [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl]-1H-indol-3-yl]Methyl acetate (example 237) the title compound was prepared. MS (EI) m/z: 361 (M)+).m.p.：229-230℃.IR(KBr)ν：3270，2980，1270，1591，1564，1522，1398，1302，1263，1200，785cm-1.1H-NMR(DMSO-d6)δ：11.78(1H，br s)，7.97(1H，d，J＝1.6Hz)，7.77(1H，d，J＝8.6Hz)，7.56(1H，d，J＝1.5Hz)，7.13(1H，dd，J＝1.8，8.6Hz)，6.87(1H，d，J＝1.6Hz)，5.69(1H，brs)，3.96(2H，s)，1.53(6H，s).Example 239 [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl group]-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and 2-chloroacetyl-3- (methoxymethyl) furan by the method described in example 57. 1H-NMR(CDCl3) δ: 9.81(1H, br), 7.60(1H, d, J ═ 1.6Hz), 7.56(1H, d, J ═ 8.7Hz), 7.40(1H, d, J ═ 1.5Hz), 7.10(1H, dd, J ═ 1.8, 8.7Hz), 6.79(1H, d, J ═ 1.6Hz), 4.81(2H, s), 4.26(2H, s), 3.74(3H, s), 3.48(3H, s), 2-chloroacetyl-3- (methoxymethyl) furan were prepared as described in example 37, from 3- (methoxymethyl) furan (n.greens et al, Synthesis, 1993, 1109).1H-NMR(CDCl3)δ：7.52(1H，d，J＝1.8Hz)，6.74(1H，d，J＝1.8Hz).4.73(2H，s)，4.62(2H，s)，3.44(3H，s).Example 240 [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl group]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (3-methoxymethyl-2-furoyl) -1H-indol-3-yl]Methyl acetate (example 239) the title compound was prepared. MS (EI) m/z: 347 (M)+).m.p.：212-213℃.IR(KBr)ν：3373，3221，1720，1601，1576，1529，1205，1173，1115，1088cm-1.1H-NMR(DMSO-d6)δ：11.72(1H，br s)，8.04(1H，d，J＝1.6Hz)，7.76(1H，d，J＝8.7Hz)，7.59(1H，d，J＝1.5Hz)，7.12(1H，dd，J＝1.8，8.7Hz)，6.86(1H，d，J＝1.6Hz)，4.70(2H，s)，4.02(2H，s)，3.36(3H，s).Example 241 [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid Step 1.[ 6-chloro-1-ethoxycarbonyl-2- (1-methylimidazole-2-carbonyl) indolin-3-yl] Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (ethoxycarbonyl) cinnamic acid methyl ester (step 1 of example 31) and 2-bromoacetyl-1-methylimidazole hydrobromide salt following the procedure described in step 2 of example 31. MS (EI) m/z: 405 (M) +). 2-bromoacetyl-1-methylimidazole hydrobromide was prepared from 2-acetyl-1-methylimidazole according to the method for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of example 31.1H-NMR(DMSO-d6)δ：7.69(1H，s)，7.27(1H，s)，4.68(2H，s)，3.81(3H，s).Step 2.[ 6-chloro-1-ethoxycarbonyl-2- (1-methylimidazole-2-carbonyl) indol-3-yl]Acetic acid
Following the procedure described in step 3 of example 31, from [ 6-chloro-1-ethoxycarbonyl-2- (1-methylimidazole-2-carbonyl) indolin-3-yl]Methyl acetate (step 1) the title compound was prepared. m.p.: 235.5 ℃ IR (KBr) v: 3238, 1695, 1630, 1538, 1402, 1229, 1146cm-1.1H-NMR(CDCl3)δ：12.3(1H，br s)，7.64(1H，d，J＝8.7Hz)，7.50(1H，d，J＝1.8Hz)，7.41(1H，s)，7.16(1H，s)，7.09(1H，dd，J＝1.8，8.6Hz)，4.25(2H，s)，4.13(3H，s).Example 242 [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
To [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl group at room temperature with stirring]To a solution of acetic acid (example 241, 65mg, 0.21mmol) in methanol (10ml) was added (trimethylsilyl) diazomethane (1.0M in hexane, 1.05ml, 2.1 mmol). After stirring for 19 hours, the mixture was concentrated. The residue was purified by TLC and developed with ethyl acetate-hexane (1: 2) to give 20mg (23%) of the title compound as a yellow solid.1H-NMR(CDCl3)δ：12.35(1H，br s)，7.59(1H，d，J＝8.0Hz)，7.49(1H，d，J＝1.5Hz)，7.24(1H，s)，7.11(1H，dd，J＝1.7，8.1Hz)，7.08(1H，s)，4.30(2H，s)，4.12(3H，s)，3.71(3H，s).Example 243 [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester
The title compound was prepared according to the procedure described for the preparation of example 57 from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-1-methylimidazole hydrobromide (for preparation see example 241).1H-NMR(DMSO-d6)δ：12.28(1H，br s)，7.85(1H，s)，7.77(1H，d，J＝8.7Hz)，7.66(1H，s)，7.33-7.29(2H，m)，4.21(2H，s)，4.03(3H，s)，3.60(3H，s).Example 244 [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 243) the title compound was prepared. m.p.: 230 ℃ and 233 ℃.1H-NMR(DMSO-d6)d：12.50(1H，br s)，7.84(1H，s)，7.76(1H，d，J＝13.2Hz)，7.66(1H，s)，7.35-7.7.28(2H，m).4.15(2H，s)，4.06(3H，s).Example 245 [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl] Step 1.[ 5-chloro-2- [1- [2- (trimethylsilyl) ethoxymethyl group]Imidazole-2-carbonyl Base of]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-chloroacetyl-1- [2- (trimethylsilyl) ethoxymethyl]Imidazole the title compound was prepared.1H-NMR(CDCl3) d: 12.38(1H, br s), 7.66(1H, s), 7.46-7.38(2H, m), 7.34-7.29(2H, m), 5.95(2H, s), 4.29(2H, s), 3.73(3H, s), 3.66(2H, t, J ═ 8.0Hz), 0.98(2H, t, J ═ 8.0Hz), 0.03(9H, s.) 2-chloroacetyl-1- [2- (trimethylsilyl) ethoxymethyl ]Imidazole was prepared according to the following method:
to 1- [2- (trimethylsilyl) ethoxymethyl group at-78 ℃ with stirring]Imidazole (Jeffrey P.Whitten et al, J.org.chem., 51, 1891(1986), 3.0g, 15mmol) in THF (30ml) was added dropwise n-butyllithium (1.55M in hexane, 11.0ml, 17mmol) and the mixture was stirred for 1 hour. To the resulting mixture was added 2-chloro-N-methoxy-N-methylacetamide (2.4g, 17mol) at this temperature, and the mixture was warmed to 0 ℃ and stirred for 2 hours. The mixture was poured into water (50ml), which was extracted with ethyl acetate (80ml), dried (magnesium sulfate), and concentrated. The residual brown oil was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 4) to give 1.2g (32%) of the title compound as a yellow oil.1H-NMR(CDCl3)d：7.39(1H，s)，7.25(1H，s)，5.81(2H，s)，4.96(2H，s)，3.60(2H，t，J＝8.2Hz)，0.95(2H，t，J＝8.2Hz)，0.02(9H，s).Step 2.[ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
To [ 5-chloro-2- [1- [2- (trimethylsilyl) ethoxymethyl group]Imidazole-2-carbonyl]-1H-indol-3-yl]To a solution of methyl acetate (step 1, 300mg, 0.67mmol) in methanol (10ml) was added 2N aqueous HCl (7ml) and the mixture was refluxed for 1.5 hours. The mixture was cooled to room temperature and then concentrated. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate (10ml), and the mixture was concentrated. The remaining yellow solid was dissolved in THF (100ml) and dried (magnesium sulfate). After removal of the solvent, 220mg (100%) of the title compound are obtained as a yellow solid. 1H-NMR(CDCl3)d：12.16(1H，br s)，10.80(1H，br s)，7.68(1H，s)，7.50-7.28(5H，m)，4.29(2H，s)，3.70(3H，s).Example 246 [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 245) the title compound was prepared. m.p.: 253 and 254 ℃.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，7.84(1H，d，J＝2.0Hz)，7.80(1H，d，J＝9.1Hz)，7.32(1H，dd，J＝2.0，9.1Hz)，4.17(2H，s).Example 247 [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.[ 6-chloro-2- [1- [2- (trimethylsilyl) ethoxymethyl group]Imidazole-2-carbonyl Base of]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of method A, example 8) and 2-chloroacetyl-1- [2- (trimethylsilyl) ethoxymethyl]Imidazole (preparation of which is described in step 1 of example 245) the title compound was prepared.1H-NMR(CDCl3)δ：12.34，(1H，br s)，7.61(1H，d，J＝8.6Hz)，7.52(1H，d，J＝1.6Hz)，7.40(1H，d，J＝1.4Hz)，7.31(1H，d，J＝1.4Hz)，7.13(1H，dd，J＝1.6，8.6Hz)，5.95(2H，s)，4.32(2H，s)，3.72(3H，s)，3.67(2H，t，J＝8.0Hz)，1.00(2H，t，J＝8.0Hz)，0.02(9H，s).Step 2.[ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
From [ 6-chloro-2- [1- [2- (trimethylsilyl) ethoxymethyl ] according to the method described in step 2 of example 245]Imidazole-2-carbonyl]-1H-indol-3-yl]Methyl acetate (step 1) the title compound was prepared.1H-NMR(CDCl3)δ：12.50(1H，br s)，7.68-7.48(2H，m)，7.40-7.30(1H，m)，7.19-7.06(1H，m)，6.97-6.92(1H，m)，4.30(2H，s)，3.67(3H，s).Example 248 [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ]Acetic acidMethyl ester (example 247) the title compound was prepared. m.p.: 252 ℃ and 253 ℃.1H-NMR(DMSO-d6)δ：13.63(1H，br s)，12.40-12.15(2H，br)，7.88(1H，d，J＝1.8Hz)，7.78(1H，d，J＝8.6Hz)，7.59(1H，s)，7.40(1H，s)，7.11(1H dd，J＝1.8，8.6Hz)，4.18(2H，Example 249 [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William b. et al, aust.j.chem., 1985,381257) the title compound is prepared.1H-NMR(DMSO-d6)δ：12.02(1H，br s)，7.93-7.85(2H，m)，7.75(1H，d，J＝8.9Hz)，7.38(1H，dd，J＝2.0，8.9Hz)，4.23(2H，s)，3.60(3H，s)，2.61(3H，s).Example 250 [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 249) the title compound was prepared. m.p.: 218 ℃ and 220 ℃.1H-NMR(DMSO-d6)δ：11.97(1H，br s)，7.89(1H，d，J＝2.0Hz)，7.75(1H，d，J＝8.7Hz)，7.37(1H，dd，J＝2.0，8.7Hz)，4.13(2H，s)，2.62(3H，s).Example 251 [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 2-chloroacetyl-1-methylpyrrole (p.d. croce et al, Synthesis, 1990, 212) according to the method described in example 8, method B.1H-NMR(DMSO-d6)δ：11.8(1H，br s)，7.80(1H，br s)，7.55(1H，d，J＝8.6Hz)，7.40-7.32(2H，m)，6.95-6.90(1H，m)，6.35-6.26(1H，m)，4.00(2H，s)，3.43(3H，s)，2.50(3H，s).Example 252 [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Heating and refluxing [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ]A mixture of methyl acetate (example 251, 250mg, 0.79mmol) and potassium carbonate (900mg, 6.4mmol) in methanol-water (1: 1, 40ml) was stirred for 1 h. The mixture was cooled to room temperature and then concentrated. The residue was neutralized with 2N aqueous HCl and extracted with ethyl acetate (50 ml. times.2). The combined organic extracts were dried (magnesium sulfate) and concentrated. The solid of the residue was recrystallized from ethyl acetate/hexane to give 40mg (23%) of the title compound as a pale yellow solid. mp: 203-.1H-NMR(DMSO-d6)δ：11.56(1H，br s)，7.57(1H，s)，7.33(1H，d，J＝8.6Hz)，7.20-7.10(2H，m)，6.72(1H，s)，6.10(1H，s)，3.81(2H，s)，2.52(3H，s).Example 253 [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 8, method B, from trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 4-bromoacetyl-2-methylimidazole (Deady, Leslie w. et al, aust.j.chem., 1981,341295) preparation of the title compound.1H-NMR(DMSO-d6)δ：12.04(1H br s)，8.51(1H，s)，7.86(1H，d，J＝2.0Hz)，7.71(1H，d，J＝8.9Hz)，7.34(1H，dd，J＝2.0，8.9Hz)，4.17(2H，s)，3.59(3H，s)，2.71(3H，s).Example 254 [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl]Methyl acetate (example 253) the title compound was prepared. m.p.: 237 ℃ and 238 ℃.1H-NMR(DMSO-d6)δ：12.03(1H，br)，12.00(1H，s)，8.49(1H，s)，7.83(1H，d，J＝2.0Hz)，7.70(1H，d，J＝8.9Hz)，7.34(1H，dd，J＝2.0，8.9Hz)，4.09(2H，s)，2.87(3H，s).Example 255 [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl ]Acetic acid methyl ester
Following the procedure described in example 57, trans-5-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 3 of example 36) and 5-bromoacetylThiazole hydrobromide the title compound was prepared.1H-NMR(CDCl3) d: 12.05(1H, br s), 9.51(1H, s), 8.62(1H, s), 7.85(1H, d, J ═ 1.9Hz), 7.55(1H, d, J ═ 8.7Hz), 7.35(1H, dd, J ═ 1.9, 8.7Hz), 4.09(2H, s), 3.59(3H, s.) 5-bromoacetylthiazole hydrobromide was prepared from 5-acetylthiazole according to the method for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of example 31.1H-NMR(DMSO-d6)δ：9.49(1H，s)，8.34(1H，s)4.91(2H，s).Example 256 [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl]Methyl acetate (example 255) the title compound was prepared. m.p.: 175 ℃ and 180 ℃.1H-NMR(DMSO-d6)δ：11.80(1H，br s)，9.48(1H，s)，8.74(1H，s)，7.78(1H，s)，7.48(1H，d，J＝8.7Hz)，7.30(1H，d，J＝8.9Hz)，3.81(2H，s).Example 257 [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 8, method B, from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method a) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al, Aust, j.chem., 1985, 381257) the title compound is prepared.1H-NMR(DMSO-d6)δ：11.95(1H，br s)，7.90(1H，s)，7.84(1H，d，J＝8.7Hz)，7.84(1H，d，J＝2.0Hz)，7.15(1H，d，J＝2.0Hz)，4.24(2H，s)，3.60(3H，s)，2.62(3H，s).Example 258 [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 257) the title compound was prepared. m.p.: 239-.1H-NMR(DMSO-d6)δ：11.80(1H，br s)，7.75(1H，s)，7.68(1H，d，J＝8.4Hz)，7.67(1H，d，J＝2.0Hz)，7.02(1H，dd，J＝2.0，8.4Hz)，4.03(2H，s)，2.49(3H，s).Example 259 [ 5-chloro-2- [3- (ethoxycarbonyl) isoxazole-5-carbonyl]-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from methyl trans-5-chloro-2- (benzenesulfonylamino) cinnamate (step 3 of example 36) and ethyl 5- (bromoacetyl) isoxazole-3-carboxylate following the procedure described in example 8, method B.1H-NMR(DMSO-d6)δ：12.07(1H，br s)，7.93(1H，d，J＝1.9Hz)，7.70(1H，s)，7.39(1H，dd，J＝1.9，12.8Hz).7.62(1H，d.J＝12.8Hz)，4.44(2H，q，J＝7.1Hz)，4.15(2H，s)，3.60(3H，s)，1.37(3H，t，J＝7.1Hz).Example 260 [ 5-chloro-2- [3- (carboxy) isoxazole-5-carbonyl]) -1H-indol-3-yl]Acetic acid
To [ 5-chloro-2- [3- (ethoxycarbonyl) isoxazole-5-carbonyl]-1H-indol-3-yl]A solution of methyl acetate (example 259, 314mg, 0.80mmol) in acetic acid (20ml) was added 2N aqueous HCl (6.0ml), the mixture was heated at 110 ℃ for 5 hours, then the mixture was cooled to room temperature and concentrated. The remaining yellow solid was washed with ethyl acetate and recrystallized from ethyl acetate/hexane to give 120mg (43%) of the title compound as a pale yellow solid. m.p.: 200 ℃ and 205 ℃. 1H-NMR(DMSO-d6)δ：12.01(1H，s)，7.91(1H，s)，7.65-7.56(2H，m)，7.39(1H，d，J＝8.9Hz)，4.06(2H，s).Example 261 [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl group]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and bromomethylcyclopropyl ketone by the method described in example 57.1H-NMR(CDCl3) δ: 9.55(1H, br s), 7.58(1H, d, J ═ 8.56Hz), 7.26(1H, d, J ═ 1.97Hz)7.10(1H, dd, J ═ 8.56Hz, 1.97Hz), 4.17(2H, s), 3.73(3H, s), 2.58-2.49(1H, m), 1.30-1.25(2H, m), 1.09-1.02(2H, m.) bromomethylcyclopropyl ketone was prepared from cyclopropylmethyl ketone following the procedure described for the preparation of 4- (trifluoromethoxy) phenacyl bromide in example 189.1H-NMR(CDCl3)δ：3.91(2H，s)，2.65(1H，t，6.94Hz)，1.20-0.98(4H，m).Example 262 [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl group]Acetic acid
Following the procedure described in method B of example 9, starting from 2- (6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl)]Methyl acetate (example 261) the title compound was prepared. m.p.: 207-210_ C.IR (KBr) v: 3304, 3013, 1709, 1624, 1566, 1443, 1414, 1387, 1340, 1286, 1248, 1217, 1200, 1157, 1057, 1045, 1022cm-1.1H-NMR(DMSO-d6)δ：11.98(1H，br s)，7.75(1H，d，J＝8.75Hz)，7.48(1H，d，J＝1.81Hz)7.11(1H，dd，J＝8.75Hz，1.81Hz)，4.08(2H，s)，2.73(1H，quintet，6.24Hz)，1.07(4H，d，6.24Hz).Example 263 [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (example 8, step 1 of method a) and bromomethylcyclobutyl ketone by the method described in example 57. 1H-NMR(CDCl3) δ: 9.35(1H, br s), 7.53(1H, d, J ═ 8.72Hz), 7.18(1H, d, J ═ 1.65Hz)7.07(1H, dd, J ═ 8.72Hz, 1.65Hz), 4.10(2H, s), 3.77(3H, s), 3.72(1H, m), 2.44-1.86(6H, m.) bromomethylcyclobutyl ketone was prepared from cyclobutylmethyl ketone following the procedure described for the preparation of 4- (trifluoromethoxy) phenacyl bromide in example 189.1H-NMR(CDCl3)δ：3.88(2H，s)，3.60(1H，m)，2.33-1.80(6H，m)Example 264 [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]Acetic acid
Following the procedure described in method B of example 9, starting from 2- (6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl)]Methyl acetate (example 263) the title compound was prepared. m.p.: 225 ℃. IR (KBr) v: 3303, 2954, 1705, 1632, 1564, 1529, 1437, 1412, 1335, 1242, 1213, 1188, 1157, 1056, 1024cm-1.1H-NMR(DMSO-d6)δ：11.63(1H，br s)，7.71(1H，d，J＝8.72Hz)，7.46(1H，d，J＝1.81Hz)，7.09(1H，dd，J＝8.72Hz，1.81Hz)，4.04(2H，s)，2.30-1.78(7H，m).Practice ofExample 265 [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-tert-butyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 2 of example 143) and 4-chlorobenzoylmethyl bromide according to the method described for example 57.1H-NMR(CDCl3)δ：8.82(1H，br s)，7，8-7.31(7H，m)，3.87(2H，s)，3.67(3H，s)，1.38(9H，s).Example 266 [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in method B of example 9, starting from [ 5-tert-butyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ]Methyl acetate (example 265) the title compound was prepared. m.p.: ir (KBr) v: 3241, 2963, 1699, 1634, 1589/1541, 1394, 1331, 1222, 1091, 1011cm-1 1H-NMR(DMSO-d6)δ：11.48(1H，br s)，7.78-7.37(7H，m)，3.85(2H，s)，1.34(9H，s).Example 267 [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N, N-dimethylacetamide
Following the procedure described in example 43, from [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl](example 31) the title compound was prepared. Melting point: 208 deg.C (decomposition). IR (KBr): 3233, 1655, 1638, 1524, 1398, 1200, 1134cm-1.1H-NMR(CDCl3)δ：12.54(1H，br s)，8.62(1H，d，J＝5.0Hz)，8.15(1H，br)，7.79(1H，d，J＝8.7Hz)，7.49(1H，d，J＝1.8Hz)，7.40-7.30(1H，m)，7.09(1H，dd，J＝1.8，8.7Hz)，4.43(2H，s)，3.16(3H，s)，2.98(3H，s)，2.48(3H，s).Example 268 [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N-methylacetamide
Following the procedure described in example 43, from [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid (example 31) and methylamine hydrochloride the title compound was prepared. m.p.: 231 ℃ IR (KBr) v: 3306, 1643, 1595, 1560, 1526, 1277, 1202, 797cm-1.1H-NMR(CDCl3)δ：12.45(1H，br)，8.64(1H，d，J＝4.9Hz)，8.19(1H，br)，7.85(1H，d，J＝8.6Hz)，7.50(1H，br)，7.40(1H，br d，J＝4.6Hz)，7.15(1H，dd，J＝1.6，8.9Hz)，6.67(1H，br)，4.14(2H，s)，2.73(3H，d，J＝4.8Hz)，2.51(3H，s).Example 269 [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N- (2-hydroxyethyl) acetamide
Following the procedure described in example 43, from [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid (example 36) and 2-aminoethanol. MS (EI) m/z: 371 (M) +).m.p.：195.9℃.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，8.69(1H，d，J＝4.9Hz)，7.94(1H，br s)，7.78(2H，m)，7.66(1H，d，J＝8.7Hz)，7.56(1H，m)，7.31(1H，dd，J＝2.0Hz，8.7Hz)，3.94(2H，s)，3.09(2H，dd，J＝5.93Hz，11.86Hz)，2.47(3H，s).Example 270 [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N-methoxyacetamide
Following the procedure described in example 43, from [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid (example 36) and O-methyl hydroxylamine hydrochloride the title compound was prepared. MS (EI) m/z: 357 (M)+).1H-NMR(CDCl3)δ：12.53(1H，br s)，9.54(1H，br s)，8.65(1H，d，J＝5.1Hz)，8.19(1H，br s)，7.92(1H，br s)，7.42(2H，m)，7.34(1H，dd，J＝1.7Hz，8.9Hz)，4.01(2H，s)，3.74(3H，s)，2.52(3H，s).Example 271 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-1- (1-piperazinyl) -1-ethane Ketones Step 1.2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-1- (4-tert-butoxy) Alkylcarbonyl-1-piperazinyl) -1-ethanone
Following the procedure described in example 43, from [ 5-chloro-2- (4-methylpyridine) -1H-indol-3-yl]Acetic acid (example 36) and tert-butyl 1-piperazinecarboxylate.1H-NMR(CDCl3)δ：12.61(1H，br s)，8.62(1H，d，J＝5.1Hz)，8.14(1H，br s)，7.84(1H，s)，7.42(1H，d，J＝8.7Hz)，7.37(br d，1H，J＝4.9Hz)，7.30(1H，dd，J＝2.0Hz，8.9Hz)，4.42(2H，s)，3.66(4H，m)，2.50(3H，s)，1.64(4H，m)，1.46(9H，s).Step 2.2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-1- (1-piperazine) 1-ethanone
To [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl at 0 DEG C]Trifluoroacetic acid (2ml) was added dropwise to a solution of (E) -N- (4-tert-butoxycarbonyl-1-piperazinyl (piperadino)) acetamide (step 1, 152.6mg, 0.042mmol) in IHF (1 ml). The mixture was stirred at room temperature for 1.5 hours, then concentrated. The residue was diluted with dichloromethane (25ml) and washed with saturated aqueous sodium bicarbonate (25 ml). The aqueous layer was extracted with dichloromethane (25 ml. times.2). The combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by flash column chromatography eluting with methanol/dichloromethane (1: 10) to give 80.8mg of the title compound as yellow crystals. MS (EI) m/z: 396 (M) +).m.p.：.205.0C.IR(KBr)ν：3244，1647，1595，1525，1429，1205cm-1.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，8.68(1H，d，J＝4.9Hz)，7.90(1H，br s)，7.81(1H，br s)，7.65(1H，d，J＝8.9Hz)，7.56(br d，1H，J＝4.1Hz)，7.31(1H，dd，J＝1.8Hz，8.9Hz)，4.15(2H，br s)，3.50-3.15(4H，m)，2.70-2.55(4H，m)，2.46(3H，s).Example 272 [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N- (2-aminoethyl) acetamide Step 1.[ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N- (2-tert-butoxy) Carbonylaminoethyl) acetamide
Following the procedure described in example 43, from [ 5-chloro-2- (4-methylpyridine) -1H-indol-3-yl]Acetic acid (example 36) and tert-butyl N- (2-aminoethyl) carbamate.1H-NMR(CDCl3)δ：12.29(1H，br s)，8.68(1H，d，J＝4.9Hz)，7.94(1H，br s)，7.78(2H，m)，7.67(1H，d，J＝8.9Hz)，7.57(1H，br d，J＝4.9Hz)，7.32(dd，1H，J＝2.0Hz，8.7Hz)，6.73(1H，m)，3.94(2H，s)，3.05-2.95(4H，m)，2.47(3H，s)，1.35(9H，s).Step 2.[ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N- (2-aminoethyl) Acetamide
Following the procedure described in step 2 of example 273 from [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-N- (2-tert-butoxycarbonylaminoethyl) acetamide (step 1) the title compound was prepared. MS (EI) m/z: 370 (M)+).m.p.：165.7℃.IR(KBr)ν：3346，2927，1665，1627，1593，1515，1435，1267，1207cm-1.1H-NMR(DMSO-d6)δ：12.28(1H，br s)，8.69(1H，d，J＝4.9Hz)，7.93(1H，br s)，7.80-7.76(2H，m)，7.66(1H，d，J＝8.9Hz)，7.57(1H，m)，7.31(dd，1H，J＝2.0Hz，8.9Hz)，3.94(2H，s)，3.01(2H，q，J＝5.77Hz)，2.55-2.45(2H，m)，2.47(3H，s).Example 273 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-1- (3-amino-1-pyrrolidine 1-ethanone Step 1.2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-1- [3- (tert-butyl) benzene Oxycarbonylamino) -1-pyrrolidinyl]-1-ethanone
Following the procedure described in example 43, from [ 5-chloro-2- (4-methylpyridine) -1H-indol-3-yl]Acetic acid (example 36) and 3- (tert-butoxycarbonylamino) pyrrolidine.1H-NMR(CDCl3)δ：12.56(1H，br s)，8.62(1H，d，J＝4.9Hz)，8.18(1H，br s)，7.78(1H，br s)，7.42(1H，d，J＝8.9Hz)，7.35(1H，br d，J＝4.9Hz)，7.29(2H，m)，4.89(1H，br d，J＝25.05)，4.36-3.45(7H，m)，2.48(3H，s)，2.35-1.80(2H，m)，1.46(9H，s).Step 2.2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ]-1- (3-amino) -1-pyrrolidinyl) -1-ethanone
Following the procedure described in step 2 of example 271, 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]-1- [3- (tert-butoxycarbonylamino) -1-pyrrolidinyl]1-ethanone (step 1) the title compound was prepared. MS (EI) m/z: 396 (M)+).m.p.：179.2℃.IR(KBr)ν：3238，2876，1638，1595，1526，1423，1203cm-1.1H-NMR(DMSO-d6)δ：12.26(1H，br s)，8.68(1H，d，J＝4.9Hz)，7.89(1H，br s)，7.81(1H，d，J＝1.81Hz)，7.65(1H，d，J＝8.9Hz)，7.55(1H，br d，J＝5.1Hz)，7.31(dd，1H，J＝2.0Hz，8.7Hz)，4.07(1H，s).4.05(1H，s)，3.70-2.90(5H，m)，2.46(3H，s)，2.10-1.80(1H，m)，1.75-1.45(1H，m).Example 274 [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Acetic acid methyl ester Step 1 trans-2-amino-4-chloro-5-fluorocinnamic acid methyl ester
The title compound was prepared from 2-bromo-5-chloro-4-fluoroaniline (JP01311056 a2, Nippon Kayaku co., ltd., Japan) according to the method described in step 1 of example 133.1H-NMR(CDCl3)δ：7.69(1H，d，J＝15.8Hz)，7.15(1H，d，J＝9.7Hz)，6.74(1H，d，J＝6.4Hz)，6.31(1H，d，J＝15.8Hz)，3.81(3H，s).Step 2, trans-4-chloro-5-fluoro-2- (phenylsulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans-2-amino-4-chloro-5-fluorocinnamic acid methyl ester (step 1) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.71-7.68(1H，m)，7.57-7.40(6H，m)，7.23(1H，d，J＝9.4Hz)，6.09(1H，d，J＝15.8Hz)，3.77(3H，s).Step 3.[ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-5-fluoro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2) according to the method described for example 57.1H-NMR(CDCl3)δ：9.05(1H，br.s)，7.74(2H，d，J＝8.7Hz)，7.49(2H，d，J＝8.7Hz)，7.35-7.32(2H，m)，3.77(2H，s)，3.66(3H，s)Example 275 [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ]Methyl acetate the title compound was prepared. m.p.: 215 ℃. IR (KBr) v: 1709, 1626, 1585, 1529, 1456, 1439, 1279, 1250cm-1.1H-NMR(DMSO-d6)δ：11.85(1H，br.s)，7.79-7.75(3H，m)，7.67-7.63(2H，m)，7.60-7.58(1H，m)，3.83(2H，s).Example 276 [ 6-chloro-5 ]-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-chloro-5-fluoro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 2 of example 274) according to the method described in example 57.1H-NMR(CDCl3)δ：12.54(1H，br.s)，8.58(1H，d，J＝4.9Hz)，8.14(1H，m)，7.56-7.53(1H，m)，7.39-7.34(2H，m)，4.25(2H，s)，3.75(3H，s)，2.48(3H，s).Example 277 [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 276) the title compound was prepared. mp: 219.5 ℃ IR (KBr) v: 1732, 1709, 1647, 1597, 1529, 1279, 1252, 1204cm-1.1H-NMR(DMSO-d6)δ：12.35(1H，br.s)，8.70(1H，d，J＝5.1Hz)，7.96(1H，s)，7.87(1H，d，J＝6.6Hz)，7.81(1H，d，J＝10.1Hz)，7.59-7.58(1H，m)，4.05(2H，s)，2.47(3H，s).Example 278 [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid methyl ester Step 1.[ 6-chloro-2- [4- [1- (tert-butyldimethylsilyloxy) ethyl group]Pyridine-2-carbonyl Base of]-1H-indol-3-yl]Acetic acid methyl ester
Following the procedure described in example 57, trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid methyl ester (step 1 of example 8, method A) and 2-bromoacetyl-4- [1- (tert-butyldimethylsiloxy) ethyl ester ]Pyridine to prepare the title compound.1H-NMR(CDCl3) δ: 12.49(1H, br s), 8.71(1H, d, J ═ 4.9Hz), 8.24(1H, d, J ═ 1.5Hz), 7.61-7.63(2H, m), 7.53(1H, d, J ═ 1.8Hz), 7.13(1H, dd, J ═ 1.8, 8.7Hz), 4.96(1H, q, J ═ 6.4Hz), 4.32(2H, s), 3.73(3H, s), 1.45(3H, d, J ═ 6.4Hz), 0.93(9H, s), 0.10(3H, s), 0.03(3H, s) · 2-bromoacetyl-4- [1- (tert-butyldimethylsiloxy) ethyl, 8.24(1H, d, J ═ 1.5Hz), 7.61 (2H, m), 7.7 (1H, m), 7.3H, s)]Pyridine was prepared according to the following method: 4- [1- (trimethylsilyloxy) ethyl]-2-pyridinecarbonitrile:
following the procedure for the preparation of 4-chloro-2-pyridinecarbonitrile as described in example 33, a starting material was prepared from 4- (1-hydroxyethyl) pyridine-N-oxide (c.w.muth et al, j.heterocyclic. chem., 1972,91299) preparation of the title compound.1H-NMR(CDCl3) δ: 8.64(1H, d, J ═ 5.1Hz), 7.69-7.70(1H, m), 7.45-7.48(1H, m), 4.88(2H, q, J ═ 6.4Hz), 1.43(3H, d, J ═ 6.6Hz), 0.14(9H, s).4- [1- (tert-butyldimethylsilyloxy) ethyl]-2-pyridinecarbonitrile:
to 4- [1- (trimethylsiloxy) ethyl group at room temperature]-2-Pyridinecarbonitrile (39.04g, 0.1624mol) in THF (200ml) was added tetrabutylammonium fluoride in THF (1M, 178.6ml, 0.1786 mol). The mixture was stirred for 0.5 h and then concentrated. The residue was diluted with ethyl acetate (300ml) and washed with water (200 ml). The aqueous layer was then extracted with dichloromethane (200ml × 2). The combined organic layers were dried (magnesium sulfate) and concentrated. The residual oil was dissolved in DMF (200 ml). To the solution was added tert-butyldimethylsilyl chloride (36.72g, 0.2436mol) and imidazole (22.11g, 0.3248mol) at room temperature. After the mixture was stirred for 19 hours, diethyl ether (500ml) and water (200ml) were added to separate an organic layer. The organic layer was washed with water (100ml × 2), dried (magnesium sulfate), and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1: 20) to give 39.23g (92%) of the title compound as an oil. 1H-NMR(CDCl3) δ: 8.64(1H.d, J ═ 5.1Hz), 7.67-7.68(1H, m), 7.46-7.48(1H, m), 4.89(1H, q, J ═ 6.4Hz), 1.42(3H, d, J ═ 6.4Hz), 0.92(9H, s), 0.10(6H, s), 2-acetyl-4- [1- (tert-butyldimethylsilyloxy) ethyl]Pyridine:
following the procedure described for the preparation of 2-acetyl-4-chloropyridine in example 33, from 4- [1- (tert-butyldimethylsiloxy) ethyl]-2-pyridinecarbonitrile the title compound was prepared.1H-NMR(CDCl3) δ: 8.62(1H, d, J ═ 4.9Hz), 7.95-7.96(1H, m), 7.49-7.52(1H, m), 4.91(1H, q, J ═ 6.4Hz), 2.73(3H, s), 1.41(3H, d, J ═ 6.4Hz), 0.91(9H, s), 0.10(6H, s), 2-bromoacetyl-4- [1- (tert-butyldimethylsilane)Oxy) ethyl]Pyridine:
following the procedure described for the preparation of 2-bromoacetyl-4- (tert-butyldimethylsiloxymethyl) pyridine as in example 95, 2-acetyl-4- [1- (tert-butyldimethylsilyloxy) ethyl]Pyridine the title compound was prepared.Step 2.[ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid A Esters
Following the procedure described in step 2 of example 95, from [ 6-chloro-2- [4- [1- (tert-butyldimethylsiloxy) ethyl ]Pyridine-2-carbonyl]-1H-indol-3-yl]Methyl acetate (step 1) the title compound was prepared.1H-NMR(DMSO-d6)δ：12.34(1H，br s)，8.77(1H，d，J＝5.1Hz)，8.11(1H，s)，7.81(1H，d，J＝8.7Hz)，7.75(1H，d，J＝1.6Hz)，7.70(1H，dd，J＝1.2，4.9Hz)，7.13(1H，dd，J＝1.8，8.6Hz)，5.61(1H，d，J＝4.6Hz)，4.84-4.93(1H，m)，4.17(2H，s)，3.59(3H，s)，1.39(3H，d，J＝6.4Hz).Example 279 [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Acetic acid
Following the procedure described in example 58, from [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl]-1H-indol-3-yl]Methyl acetate (example 278) the title compound was prepared. m.p.: 193-194 ℃ IR (KBr) v: 3464, 1707, 1632, 1591, 1526, 1250, 1225, 1192, 1144, 914cm-1.1H-NMR(DMSO-d6)δ：12.30(1H，br s)，8.78(1H，d，J＝5.1Hz)，8.11(1H，s)，7.79(1H，d，J＝8.6Hz)，7.74(1H，d，J＝1.6Hz)，7.71(1H，d，J＝5.3Hz)，7.12(1H，dd，J＝1.8、8.7Hz)，5.60(1H，d，J＝4.4Hz)，4.84-4.93(1H，m)，4.09(2H，s)，1.39(3H，d，J＝6.6Hz).Example 280 [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in example 112, from [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 113) the title compound was prepared. m.p.; 193-194 ℃ IR (KBr) v: 3256, 1707, 1645, 1529, 1420, 1227, 1180, 1159, 1153cm-1.MS(EI)m/z：360(M+).1H-NMR(DMSO-d6)δ：11.84(1H，br s)，8.46(1H，d，J＝5.3Hz)，7.77(1H，d，J＝8.7Hz)，7.67(1H，t，J＝5.1Hz)，7.51(1H，d，J＝1.8Hz)，7.12(1H，dd，J＝1.8，8.6Hz)，3.74(2H，s)，2.76(2H，q，J＝7.6Hz)，1.25(3H，t，J＝7.6Hz).Example 281 [ 6-chloro-2- (2-nitrobenzoyl) -1H-indol-3-yl]Acetic acid Step 1. Trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid attached to Polymer
To a mixture of Melamine resin (200 mesh 400, 1.37g, ca. 0.89mmol) and trans-4-chloro-2- (phenylsulfonylamino) cinnamic acid (600mg, 1.77mmol) were added dichloromethane (10ml) and N, N-diisopropylethylamine (1.86ml, 10.7 mmol). The mixture was allowed to stand for 1 hour, then 4-dimethylaminopyridine (22mg, 0.18mmol) and WSC (339mg, 1.77mmol) were added. The mixture was stirred for 18 hours and filtered. The residue was washed with water (20 ml. times.3), methanol (20 ml. times.3), acetone (20 ml. times.3), methylene chloride (20 ml. times.3), and dried to give 1.65g of the title compound. Step 2.[ 6-chloro-2- (2-nitrobenzoyl) -1H-indol-3-yl]Acetic acid
To a mixture of trans-4-chloro-2- (benzenesulfonylamino) cinnamic acid (step 1, 100mg, 53mmol) and 2-nitrobenzoylmethyl bromide (39mg, 0.16mmol) attached to the polymer in acetone (3ml) was added potassium carbonate (37mg, 0.27 mmol). The mixture was stirred for 18 hours and filtered. The residual resin was washed with water (20 ml. times.3), acetone (20 ml. times.3), dichloromethane (20 ml. times.3) and THF (20 ml. times.2) and dried. The resin was diluted with THF (4ml) and DBU (40. mu.l, 0.27mmol) was added. After stirring for 16 hours, the resin was filtered off and washed with THF (20 ml. times.3), acetone (20 ml. times.3) and dichloromethane (20 ml. times.3). To the resin was added a solution of 95% trifluoroacetic acid in dichloromethane (5ml), and the mixture was stirred for 3 hours. The mixture was filtered and the residue was washed with dichloromethane (20ml × 5). The filtrate was concentrated and the residue was purified by HPLC (MeOH/AcONH)4Aqueous solution 60/40-90/10) to yield 3.2mg (17%) of the title compound. MS (ESI) m/z: 359 (MH)+)。Example 282 [ 6-chloro-2- (2, 4-dimethoxybenzoyl) -1H-indol-3-yl]Acetic acid
The title compound was prepared from 4-chloro-2- (benzenesulfonylamino) cinnamic acid according to the method described in example 281. MS (ESI) m/z: 374 (MH) +)。Example 283 [ 6-chloro-2- (4-difluoromethoxybenzoyl) -1H-indol-3-yl]Acetic acid
The title compound was prepared from 4-chloro-2- (benzenesulfonylamino) cinnamic acid according to the method described in example 289. MS (ESI) m/z: 380 (MH)+)。Example 284 [ 6-chloro-2- (2, 5-dimethoxybenzoyl) -1H-indol-3-yl]Acetic acid
The title compound was prepared from 4-chloro-2- (benzenesulfonylamino) cinnamic acid according to the method described in example 281. MS (ESI) m/z: 374 (MH)+)。Example 285 [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1.4-acetyl-2-bromoaniline
Hydrochloric acid (3ml) was added dropwise to a suspension of 4-acetamido-3-bromoacetophenone in ethanol (12ml) at 0 ℃ with stirring. The reaction mixture was stirred at reflux for 4.5 hours, cooled and the mixture was concentrated. The remaining solid was partitioned between saturated aqueous sodium bicarbonate (50ml) and diethyl ether (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml. times.2). The combined organic layers were dried (magnesium sulfate) and concentrated to give 1.79g (quantitative) of the title compound as a brown oil.1H-NMR(CDCl3)δ：8.06(1H，d，1.97Hz)，7.76-7.72(1H，m)，6.74(1H，d，8.40Hz)，4.60(1H，br s)，2.50(s，3H)Step 2 trans- (5-acetyl-2-amino) cinnamic acid methyl ester
The title compound was prepared from 4-acetyl-2-bromoaniline (step 1) and methyl acrylate following the procedure described for step 1 of example 133. 1H-NMR(CDCl3)δ：8.02(1H，d，2.13Hz)，7.81-7.75(2H，m)，6.70(1H，d，8.56Hz)，6.44(1H，d，15.8Hz)，4.55(2H，br s)，3.81(3H，s)，2.53(3H，s).Step 3, trans-5-acetyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester
Pressing to realThe title compound was prepared from trans- (5-acetyl-2-amino) cinnamic acid methyl ester (step 2) by the method described in example 8, method a, step 1.1H-NMR(CDCl3)δ：8.01(1H，d，2.00Hz)，7.89(1H，dd，8.59Hz，1.97Hz)，7.68-7.22(7H，m)，6.30(1H，s)，6.15(1H，d，15.8Hz)，3.81(3H，s)，2.57(3H，s)，2.38(3H，s).Step 4.[ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-5-acetyl-2- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 3) and 4-chlorobenzoylmethyl bromide according to the method described for example 57.1H-NMR(CDCl3)δ：9.2(1H，br s)，8.34-7.75(4H，m)，7.52-7.45(3H，m)，3.89(2H，s)，3.69(3H，s)，2.68(3H，s).Example 286 [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in method B of example 9, starting from [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl]Methyl acetate (example 285) the title compound was prepared. m.p.: 225 ℃ IR (KBr) v: 3281, 1703, 1666, 1643, 1614, 1574, 1539, 1452, 1425, 1402, 1364, 1263, 1240, 1178, 1092, 1011, 959cm-1 1H-NMR(DMSO-d6)δ：12.01(1H，br s)，8.49(1H，br s)，7.93-7.89(1H，m)，7.78(2H，d，8.56Hz)，7.65(d，2H，8.56Hz)，7.52(1H，d，8.72Hz)，3.93(2H，s)，2.63(3H，s).Example 287 [ 6-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester Step 1 trans- (4-fluoro-2-nitro) cinnamic acid methyl ester
The title compound was prepared from 3-fluoro-6-iodonitrobenzene and methyl acrylate following the method described in step 1 of example 133. 1H-NMR(CDCl3)δ：8.67(1H，d，15.8Hz)，7.78(1H，dd，8.07Hz，2.65Hz)，7.68-7.63(2H，m)，6.34(1H，d，15.8Hz)，3.84(3H，s).Step 2 trans- (2-amino-4-fluoro) cinnamic acid methyl ester
Following the procedure described in step 2 of example 36, from trans- (4-fluoro-2-nitro)) Methyl cinnamate (step 1) the title compound was prepared.1H-NMR(CDCl3)δ：7.75(1H，d，15.8Hz)，7.37-7.31(1H，m)，6.50-6.37(2H，m)，6.32-6.26(1H，m)，4.13(2H，br s)，3.80(3H，s).Step 3, trans-4-fluoro-2- (p-toluenesulfonylamino) cinnamic acid methyl ester
The title compound was prepared from trans- (2-amino-4-fluoro) cinnamic acid methyl ester (step 2) following the procedure described in example 8, method a, step 1.1H-NMR(CDCl3)δ：7.64(1H，d，8.40Hz)，7.46-7.19(4H，m)，6.94-6.87(1H，m)，6.77(1H，s)，6.16-6.10(1H，m)，3.79(3H，s)，2.38(3H，s).Step 4.[ 6-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-fluoro-2- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 3) according to the method described for example 57.1H-NMR(CDCl3)δ：12.49(1H，br s)，8.61(1H，d，4.94Hz)，8.17-7.61(2H，m)，7.36-7.14(2H，m)，6.98-6.90(1H，m)，4.31(2H，s)，3.73(3H，s)，2.47(3H，s).Example 288 [ 6-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in method B of example 9, starting from [ 6-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl]Methyl acetate (example 287) the title compound was prepared. m.p.: 208 ℃ IR (KBr) v: 3238, 1701, 1638, 1597, 1533, 1398, 1281, 1211, 1132, 1003cm-1.1H-NMR(CDCl3)δ：12.28(1H，br s)，8.70(1H，d，4.94Hz)，7.96(1H，s)，7.83-7.77(1H，m)，7.57(1H，d，4.94Hz)，7.42(1H，dd，10.2Hz，2.13Hz)，7.03-6.95(1H，m)，4.09(2H，s)，2.47(3H，s).Example 289 [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid methyl ester
The title compound was prepared from trans-4-fluoro-3- (p-toluenesulfonylamino) cinnamic acid methyl ester (step 3 of example 287) and 4-chlorobenzoylmethyl bromide according to the method described in example 57. 1H-NMR(CDCl3)δ：9.10(1H，br s)，7.76-7.71(2H，m)，7.60-7.54(2H，m)，7.50-7.45(2H，m)，7.04-6.90(2H，m)，3.81(2H，s)，3.66(3H，s).Example 290 [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Acetic acid
Following the procedure described in method B of example 9, starting from [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl]Methyl acetate (example 289) the title compound was prepared. m.p.: 214 ℃ IR (KBr) v: 3335, 1699, 1618, 1605, 1587, 1531, 1425, 1327, 1267, 1231, 1134, 1094, 1001cm-1.1H-NMR(DMSO-d6)δ：11.73(1H，br s)，7.78-7.63(5H，m)，7.17(1H，dd，9.72Hz，2.13Hz)，7.04-6.96(1H，m)，3.84(2H，s).Example 291 [2- (4-methylpyridine-2-carbonyl) -5-methylsulfanyl-1H-indol-3-yl]Acetic acid Step 1 trans- (2-amino-5-methylthio) cinnamic acid methyl ester
The title compound was prepared from 2-bromo-4-methylthiooxaniline (JP80-122756) and methyl acrylate following the procedure described in step 1 of example 133.1H-NMR(CDCl3)δ：7.77(1H，d，15.8Hz)，7.38(1H，d，2.13Hz)，7.19(1H，dd，8.40Hz，2.13Hz)，6.66(1H，d，8.40Hz)，6.36(1H，d，15.8Hz)，3.97(1H，br s)，3.80(3H，s)，2.43(3H，s).Step 2, trans-2-p-toluenesulfonylamino-5-methylthiocinnamic acid methyl ester
The title compound was prepared from methyl trans- (2-amino-4-methylthio) cinnamate (step 1) and p-toluenesulfonyl chloride following the procedure described for step 1 of example 8.1H-NMR(CDCl3)δ：7.81(2H，d，8.40Hz)，7.56-6.91(8H，m)，6.13(1H，d，156Hz)，3.79(3H，s)，2.46(3H，s)，2.39(3H，s).Step 3, trans- [2- (4-methylpyridine-2-carbonyl) -5-methylthio-1H-indol-3-yl]Acetic acid Methyl ester
The title compound was prepared from trans-2-p-toluenesulfonylamino-5-methylthiocinnamic acid methyl ester (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (for preparation thereof see step 2 of example 31) according to the method described in example 57. 1H-NMR(CDCl3)δ：12.47(1H，br s)，8.62(1H，d，4.78Hz)，8.19-8.17(1H，m)，7.65-7.62(1H，m)，7.47-7.30(3H，m)，4.31(2H，s)，3.73(3H，s)，2.48(3H，s).Example 292 [2- (4-methylpyridine-2-carbonyl) -5-methylsulfanyl-1H-indol-3-yl]Acetic acid
Following the procedure described in method B of example 9, starting from [2- (4-methylpyridine-2-carbonyl) -5-methylsulfanyl-1H-indol-3-yl]Methyl acetate (example) the title compound was prepared.1H-NMR(DMSO-d6)δ：12.22(1H，br s)，8.70(1H，d，4.62Hz)，7.95-7.17(4H，m)，4.08(2H，s)，2.47(3H，s)，2.35(3H，s).MS(EI)m/z：340(M+).Example 293 3- [ 4-chloro-2- (toluene-4-sulfonylamino) -phenyl]-acrylic acid ethyl ester
To a solution of ethyl 3- (2-amino-4-chloro-phenyl) acrylate (18.0g, 79.8mmol) in dichloromethane (144ml) was added pyridine (9.04ml, 112mmol) and p-toluenesulfonyl chloride (16.0g, 83.9 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then the mixture was poured into 1N hydrochloric acid (150 ml). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid was slurried in hexane and filtered to give 3- [ 4-chloro-2- (toluene-4-sulfonamido) -phenyl]-ethyl acrylate (28.3g, 93%). mp 124-.1H NMR(300MHz，CDCl3)d 1.35(t，3，J＝7.2)，2.40(s，3)，4.27(q，2，J＝7.2)，6.12(dd，1，J＝15.9，0.9)，7.20-7.39(m，4)，7.39(d，1，J＝8.6)，7.48-7.53(m，2)，7.62(d，2，J＝8.3).13C NMR(75MHz，CDCl3)d 15.50，22.79，62.24，122.48.127.98，128.49，129.34，129.50，131.05，136.82，137.00，137.73，138.93，145.55，167.59.IR 3214，1694，1631，1318，1167cm-1.C18H18ClNO4And (3) analysis of S:
calculated values: c, 56.91; h, 4.78; n, 3.69
Measurement value: c, 57.10; h, 5.08; n, 3.70Example 294 [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl]Acetic acid
To the 3- [ 4-chloro-2- (toluene-4-sulfonylamino) -phenyl group]To a solution of ethyl-acrylate (13.0g, 34.2mmol) in N, N-dimethylacetamide (120ml) were added potassium carbonate (9.45g, 68.4mmol) and 2-bromo-4' -chloroacetophenone (8.78g, 37.6mmol), and the reaction mixture was stirred at room temperature for 15 minutes. 1N sodium hydroxide (130ml) was added and the reaction mixture was heated at 100 ℃ for 8 hours. The reaction mixture was cooled to room temperature, poured into a separatory funnel and washed with methyl tert-butyl ether (2X 200 ml). The aqueous layer was acidified to pH1 with 6N hydrochloric acid and extracted with ethyl acetate (150 ml). The solvent was removed under reduced pressure, and to the resulting oil were added isopropanol (24ml) and water (48 ml). The precipitated solid and slurry were stirred for 12 hours. The precipitate was filtered off, washed with water and dried to give [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl ]Acetic acid (9.73g, 82%). mp 181-183 ℃.1H NMR(400MHz，d6-DMSO)d 3.79(s，2)，7.08(dd，1，J＝8.5，1.9)，7.42(d，1，J＝1.9)，7.60(d，2，J＝8.5)，7.62-7.73(m，3)，11.74(bs，1)，12.22(bs，1).13C NMR(75 MHz，d6-DMSO)d 31.74，113.25，118.00，121.93，123.96，127.69，130.10，131.30，132.02，133.59，138.02，138.37，138.58，173.20，188.29.IR 3314，1710，1700，1618，1522，1323，1227，1093，941cm-1.C17H11Cl2NO3Analysis of (2):
calculated values: c, 58.64; h, 3.18; n, 4.02
Measurement value: c, 58.58; h, 3.22; n, 3.93Example 295 3- { 4-chloro-2- [ [2- (4-chloro-phenyl) -2-oxo-ethyl]- (toluene-4-sulfonyl) -amino]- Phenyl } -acrylic acid ethyl ester
To the 3- [ 4-chloro-2- (toluene-4-sulfonylamino) -phenyl group]Ethyl (E) -acrylate (3.00g, 7.90mmol) in N, N-dimethylacetamide (15.0ml) was added potassium carbonate (2.18g, 15.8mmol) and 2-bromo-4' -chloroacetophenone (2.03g, 8.69mmol), and the reaction mixture was stirred for 30 minutes. Poured into 1N hydrochloric acid (30ml) and extracted with methyl tert-butyl ether (2X 30 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated to a small volume. Adding hexaneA solid precipitated out. The precipitate was filtered off to give 3- { 4-chloro-2- [ [2- (4-chloro-phenyl) -2-oxo-ethyl]- (toluene-4-sulfonyl) -amino]-phenyl } -acrylic acid ethyl ester (3.19g, 76%). mp 162-165 ℃.1H NMR(300MHz，CDCl3)d 1.38(t，3，J＝7.2)，2.47(s，3)，4.28(q，2，J＝7.2)，5.00(bs，2)，6.23(d，1，J＝16.0)，7.29-7.36(m，4)，7.47(d，2，J＝8.7)，7.54(d，1，J-8.4)，7.59(d，2，J＝8.3)，7.74(d，1，J＝16.0)，7.88(d，2，J＝8.7).13C NMR(75MHz，CDCl3)d 14.33，21.62，57.72，60.66，112.49，120.69，128.07，129.21，129.58，129.70，131.22，132.80，133.83，134.80，135.84，138.55，139.28，140.38，144.46，166.02，191.70.IR 1720，1698，1590，1338，1313，1179，1161，1089cm-1.C26H23Cl2NO5And (3) analysis of S:
calculated values: c, 58.65; h, 4.35; n, 2.63
Measurement value: c, 58.74; h, 4.56; n, 2.72Example 296 Cis-and trans- [ 6-chloro-2- (4-chloro-benzoyl) -1- (toluene-4-sulfonyl) -2, 3-dihydro -1H-indol-3-yl ]Ethyl acetate
To 3- { 4-chloro-2- [ [2- (4-chloro-phenyl) -2-oxo-ethyl]- (toluene-4-sulfonyl) -amino]To a solution of ethyl-phenyl } -acrylate (1.00g, 1.88mmol) in N, N-dimethylacetamide (5.0ml) was added potassium carbonate (0.520g, 3.76mmol), and the reaction mixture was stirred for 4 hours. Poured into 1N hydrochloric acid (30ml) and extracted with methyl tert-butyl ether (2X 30 ml). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The resulting solid was purified by silica gel chromatography (EtOAc/hexane 20/80) to give cis-and trans- [ 6-chloro-2- (4-chloro-benzoyl) -1- (toluene-4-sulfonyl) -2, 3-dihydro-1H-indol-3-yl]A 1-9 mixture of ethyl acetate isomers (0.488g, 49%). Some of importance1NMR(300MHz，CDCl3) The signals are: d 1.0)9(t, J ═ 7.2), 1.19(t, J ═ 7.2), 2.44(s), 5.40(d, J ═ 4.0), 5.99(d, J ═ 9.7), 6.92(dd, J ═ 8.1, 1.1), 7.04(dd, J ═ 8.1, 1.9), 7.52(d, J ═ 8.4), 757(d, J ═ 1.9), 7.73(d, J ═ 8.3), 7.99(d, J ═ 8.6) Lc-MS analysis of the diastereomer mixtures showed that these products had the same mass 531(M + H)+)。Example 297 [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl]Ethyl acetate
To the 3- [ 4-chloro-2- (toluene-4-sulfonylamino) -phenyl group ]Ethyl (E) -acrylate (3.00g, 7.90mmol) in N, N-dimethylacetamide (15.0ml) was added potassium carbonate (2.18g, 15.8mmol) and 2-bromo-4' -chloroacetophenone (2.03g, 8.69mmol), and the reaction mixture was stirred for 30 minutes. Adding 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (3.54ml, 23.7mmol), the reaction mixture was stirred for 1 hour, poured into 1N hydrochloric acid (30ml) and extracted with methyl tert-butyl ether (2X 30 ml). The organic extract was dried over magnesium sulfate, filtered, and concentrated to give a solid. Slurrying the solid in a mixture of methyl tert-butyl ether and hexane to give [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl]Ethyl acetate (2.42g, 81%). mp is 186-188 ℃.1H NMR(300MHz，CDCl3)d 1.27(t，2，J＝7.1)，3.80(s，2)，4.11(q，2，J＝7.1)，7.15(ddd，1，J＝8.5，1.7，0.5)，7.28-7.30(m，1)，7.48(d，J＝8.3)，7.54-7.57(m，1)，7.77(d，2，J＝8.3)，9.16(bs，1).13C NMR(75MHz，CDCl3)d 15.42，32.29，62.45，113.27，117.60，122.99，123.23，127.85，130.12，131.77，133.61，137.86，138.13，140.10，172.45，188.25.IR 3305，1732，1618，1323cm-1.C19H15Cl2NO3Analysis of (2):
calculated values: c, 60.65; h, 4.02; n, 3.72
Measurement value: c, 60.70; h, 3.97; n, 3.71Example 298 [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl]Acetic acid
To [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl]To a solution of ethyl acetate (200mg, 0.532mmol) in methanol (2ml) and water (0.8ml) was added sodium hydroxide (137mg, 3.43 mmol). The reaction mixture was stirred for 24 hours and concentrated to a small volume. Adding water (4)ml), the mixture was transferred to a separatory funnel and washed with dichloromethane (5 ml). The aqueous layer was acidified to pH1 with 1N hydrochloric acid and extracted with ethyl acetate (15 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give [ 6-chloro-2- (4-chloro-benzoyl) -1H-indol-3-yl ]Ethyl acetate (150mg, 81%).1The NMR spectrum was the same as the compound obtained according to the method described in example 2.
The chemical structures of the compounds prepared in examples 1-292 are summarized in the following table.
Watch (A)
Example number (X)n R1 Z Q
1 6-Cl H Ethoxy radical Phenyl radical
2 6-Cl H OH Phenyl radical
3 6-Cl H ONa Phenyl radical
4 6-Cl H OH 2-methylphenyl radical
5 6-Cl H OH 3-methylphenyl radical
6 6-Cl H OH 4-methylphenyl radical
7 6-Cl H OH 3-chlorophenyl group
8 6-Cl H Methoxy radical 4-chlorophenyl group
9 6-Cl H OH 4-chlorophenyl group
10 6-Cl H OH 3-fluorophenyl group
11 6-Cl H OH 4-fluorophenyl group
12 6-Cl H OH 3-bromophenyl radical
13 6-Cl H OH 4-bromophenyl radical
14 6-Cl H OH 3-CF3-phenyl radical
15 6-Cl H OH 4-CF3-phenyl radical
16 6-Cl H OH 3, 4-dichlorophenyl
17 4-Cl H OH Phenyl radical
18 5-Cl H OH 3-methylphenyl radical
19 5-Cl H OH 4-chlorophenyl group
20 5-Cl H OH 3-chlorophenyl group
21 5-F H OH 4-chlorophenyl group
22 5-F H OH 3-chlorophenyl group
23 5-methoxy radical H OH 3-methylphenyl radical
24 7-Cl H OH Phenyl radical
25 4, 5-dichloro-benzene H OH Phenyl radical
26 4, 6-dichloro-benzene H OH Phenyl radical
27 5, 6-dichloro-benzene H OH Phenyl radical
28 (racemic) 6-Cl Methyl radical OH Phenyl radical
29 (less polar enantiomer) 6-Cl Methyl radical OH Phenyl radical
30 (the more polar enantiomer) 6-Cl Methyl radical OH Phenyl radical
31 6-Cl H OH 4-methyl-2-pyridyl
32 6-Cl H OH 5-methyl-2-pyridyl
33 6-Cl H Methoxy radical 4-chloro-2-pyridinyl
34 6-Cl H OH 4-chloro-2-pyridinyl
35 6-Cl H OH 2-pyridyl group
36 5-Cl H OH 4-methyl-2-pyridyl
37 5-Cl H Methoxy radical 6-methyl-2-pyridyl
38 5-Cl H OH 6-methyl-2-pyridyl
39 6-Cl H OH 1-methyl-2-imidazolyl
40 5-Cl H Methoxy radical 2-thiazolyl group
41 5-Cl H OH 2-thiazolyl group
42 6-Cl H Methoxy radical Phenyl radical
43 6-Cl H Dimethylamino group Phenyl radical
44 6-Cl H Methylamino radical Phenyl radical
45 6-Cl H Amino group Phenyl radical
46 6-Cl H N-methoxy-N-methylamino Phenyl radical
47 6-Cl H Piperidino group Phenyl radical
48 6-Cl H 4-methyl-1-piperazinyl Phenyl radical
49 6-Cl H 2-cyanoethylamino Phenyl radical
50 6-Cl H 2-HO-ethylamino Phenyl radical
51 6-Cl H Morpholino group Phenyl radical
52 H H OH 4-chlorophenyl group
53 6-Cl H OH 2-furyl radical
54 6-Cl H OH Cyclohexyl radical
55 6-Cl H OH 4-methoxyphenyl radical
56 6-Cl H Methoxy radical 4-methoxyphenyl radical
57 6-Cl H Methoxy radical 4-Ethyl-2-pyridinyl
58 6-Cl H OH 4-Ethyl-2-pyridinyl
59 5-Cl H Methoxy radical 4-Ethyl-2-pyridinyl
60 5-Cl H OH 4-Ethyl-2-pyridinyl
61 6-Cl H Methoxy radical 4-isopropyl-2-pyridinyl
62 6-Cl H OH 4-isopropyl-2-pyridinyl
63 5-Cl H Methoxy radical 4-isopropyl-2-pyridinyl
64 5-Cl H OH 4-isopropyl-2-pyridinyl
65 6-Cl H Methoxy radical 4-n-propyl-2-pyridyl
66 6-Cl H OH 4-n-propyl-2-pyridyl
67 5-Cl H Methoxy radical 4-n-propyl-2-pyridyl
68 5-Cl H OH 4-positivePropyl-2-pyridyl
69 6-Cl H Methoxy radical 4-tert-butyl-2-pyridyl
70 6-Cl H OH 4-tert-butyl-2-pyridyl
71 5-Cl H Methoxy radical 4-tert-butyl-2-pyridyl
72 5-Cl H OH 4-tert-butyl-2-pyridyl
73 6-Cl H Methoxy radical 3-methyl-2-pyridyl
74 6-Cl H OH 3-methyl-2-pyridyl
75 5-Cl H Methoxy radical 3-methyl-2-pyridyl
76 5-Cl H OH 3-methyl-2-pyridyl
77 6-Cl H Methoxy radical 6-methyl-2-pyridyl
78 6-Cl H OH 6-methyl-2-pyridyl
79 5-Cl H Methoxy radical 5-methyl-2-pyridyl
80 5-Cl H OH 5-methyl-2-pyridyl
81 6-Cl H Methoxy radical 5-trifluoromethyl-2-pyridinyl
82 6-Cl H OH 5-trifluoromethyl-2-pyridinyl
83 5-Cl H Methoxy radical 5-trifluoromethyl-2-pyridinyl
84 5-Cl H OH 5-trifluoromethyl-2-pyridinyl
85 5-Cl H Methoxy radical 5-chloro-2-pyridinyl
86 5-Cl H OH 5-chloro-2-pyridinyl
87 6-Cl H Methoxy radical 5-chloro-2-pyridinyl
88 6-Cl H OH 5-chloro-2-pyridinyl
89 5-Cl H Methoxy radical 4-chloro-2-pyridinyl
90 5-Cl H OH 4-chloro-2-pyridinyl
91 6-Cl H Methoxy radical 3-pyridyl group
92 6-Cl H OH 3-pyridyl group
93 6-Cl H Methoxy radical 4-pyridyl group
94 6-Cl H OH 4-pyridyl group
95 6-Cl H Methoxy radical 4-hydroxymethyl-2-pyridinyl
96 6-Cl H OH 4-hydroxymethyl-2-pyridinyl
97 5-Cl H Methoxy radical 4-hydroxymethyl-2-pyridinyl
98 5-Cl H OH 4-hydroxymethyl-2-pyridinyl
99 5-Cl H Methoxy radical 3, 4-dimethyl-2-pyridinyl
100 5-Cl H OH 3, 4-dimethyl-2-pyridinyl
101 5-Cl H Methoxy radical 4, 5-dimethyl-2-pyridinyl
102 5-Cl H OH 4, 5-dimethyl-2-pyridinyl
103 6-Cl H Methoxy radical 4, 5-dimethyl-2-pyridinyl
104 6-Cl H OH 4, 5-dimethyl-2-pyridinyl
105 6-Cl H Methoxy radical 4-methoxy-2-pyridyl
106 6-Cl H OH 4-methoxy-2-pyridyl
107 5-Cl H Methoxy radical 4-methoxy-2-pyridyl
108 5-Cl H OH 4-methoxy-2-pyridyl
109 6-Cl H Methoxy radical 3, 5-dimethyl-2-pyridinyl
110 6-Cl H OH 3, 5-dimethyl-2-pyridinyl
111 5-Cl H Methoxy radical 3-fluoro-4-ethyl-2-pyridinyl
112 5-Cl H OH 3-fluoro-4-ethyl-2-pyridinyl
113 6-Cl H Methoxy radical 3-fluoro-4-ethyl-2-pyridinyl
114 6-Cl H OH 3-ethoxy-4-ethyl-2-pyridinyl
115 6-Cl H Methoxy radical 3-chloro-4-ethyl-2-pyridinyl
116 6-Cl H OH 3-chloro-4-ethyl-2-pyridinyl
117 5-Cl H Methoxy radical 3-chloro-4-ethyl-2-pyridinyl
118 5-Cl H OH 3-chloro-4-ethyl-2-pyridinyl
119 5-Cl H Methoxy radical 4, 6-dimethyl-2-pyridinyl
120 5-Cl H OH 4, 6-dimethyl-2-pyridinyl
121 6-Cl H Methoxy radical 4, 6-dimethyl-2-pyridinyl
122 6-Cl H OH 4, 6-dimethyl-2-pyridinyl
123 5, 6-dichloro-benzene H Methoxy radical 4-methyl-2-pyridyl
124 5, 6-dichloro-benzene H OH 4-methyl-2-pyridyl
125 5-methyl group H Methoxy radical 4-methyl-2-pyridyl
126 5-methyl group H OH 4-methyl-2-pyridyl
127 5-F H Methoxy radical 4-methyl-2-pyridyl
128 5-F H OH 4-methyl-2-pyridyl
129 5-methoxy radical H Methoxy radical 4-methyl-2-pyridyl
130 5-methoxy radical H OH 4-methyl-2-pyridyl
131 6-methoxy radical H Methoxy radical 4-methyl-2-pyridyl
132 6-methoxy radical H OH 4-methyl-2-pyridyl
133 5-Ethyl radical H Methoxy radical 4-methyl-2-pyridyl
134 5-Ethyl radical H OH 4-methyl-2-pyridyl
135 5-Ethyl radical H Methoxy radical 4-Ethyl-2-pyridinyl
136 5-Ethyl radical H OH 4-Ethyl-2-pyridinyl
137 6-Ethyl radical H Methoxy radical 4-methyl-2-pyridyl
138 6-Ethyl radical H OH 4-methyl-2-pyridyl
139 5-isopropyl group H Methoxy radical 4-Ethyl-2-pyridinyl
140 5-isopropyl group H OH 4-methyl-2-pyridyl
141 6-CF3 H Methoxy radical 4-methyl-2-pyridyl
142 6-CF3 H OH 4-methyl-2-pyridyl
143 5-tert-butyl H Methoxy radical 4-methyl-2-pyridyl
144 5-tert-butyl H OH 4-methyl-2-pyridyl
145 5-CF3O H Methoxy radical 4-methyl-2-pyridyl
146 5-CF3O H OH 4-methyl-2-pyridyl
147 5-CF3O H Methoxy radical 4-Ethyl-2-pyridinyl
148 5-CF3O H OH 4-Ethyl-2-pyridinyl
149 6-methyl group H Methoxy radical 4-methyl-2-pyridyl
150 6-methyl group H OH 4-methyl-2-pyridyl
151 5-CF3 H Methoxy radical 4-methyl-2-pyridyl
152 5-CF3 H OH 4-methyl-2-pyridyl
153 5-CF3 H Methoxy radical 4-Ethyl-2-pyridinyl
154 5-CF3 H OH 4-Ethyl-2-pyridinyl
155 H H Methoxy radical Phenyl radical
156 H H OH Phenyl radical
157 6-methyl group H Methoxy radical 4-chlorophenyl group
158 6-methyl group H OH 4-chlorophenyl group
159 5-methyl group H OH 4-chlorophenyl group
160 6-methoxy radical H Methoxy radical 4-chlorophenyl group
161 6-methoxy radical H OH 4-chlorophenyl group
162 6-CF3 H OH 4-chlorophenyl group
163 5-Ethyl radical H Methoxy radical 4-chlorophenyl group
164 5-Ethyl radical H OH 4-chlorophenyl group
165 5-methoxy radical H Methoxy radical 4-chlorophenyl group
166 5-methoxy radical H OH 4-chlorophenyl group
167 5-isopropyl group H Methoxy radical 4-chlorophenyl group
168 5-isopropyl group H OH 4-chlorophenyl group
169 5-CF3 H Methoxy radical 4-chloro groupPhenyl radical
170 5-CF3 H OH 4-chlorophenyl group
171 5-CF3O H Methoxy radical 4-chlorophenyl group
172 5-CF3O H OH 4-chlorophenyl group
173 6-Cl H Methoxy radical 2-methoxyphenyl radical
174 6-Cl H OH 2-methoxyphenyl radical
175 6-Cl H Methoxy radical 3-methoxyphenyl radical
176 6-Cl H OH 3-methoxyphenyl radical
177 6-Cl H Methoxy radical 3-benzyloxy-phenyl
178 6-Cl H OH 3-benzyloxy-phenyl
179 6-Cl H Methoxy radical 3-hydroxyphenyl group
180 6-Cl H OH 3-hydroxyphenyl group
181 6-Cl H Methoxy radical 4-benzyloxyphenyl
182 6-Cl H OH 4-benzyloxyphenyl
183 6-Cl H Methoxy radical 4-hydroxyphenyl group
184 6-Cl H OH 4-hydroxyphenyl group
185 6-Cl H Methoxy radical 4-Isopropoxyphenyl group
186 6-Cl H OH 4-Isopropoxyphenyl group
187 6-Cl H Methoxy radical 4-biphenylyl group
188 6-Cl H OH 4-biphenylyl group
189 6-Cl H Methoxy radical 4-CF3O-phenyl
190 6-Cl H OH 4-CF3O-phenyl
191 5-Cl H Methoxy radical 4-CF3O-phenyl
192 5-Cl H OH 4-CF3O-phenyl
193 5-Cl H Methoxy radical 4-methoxyphenyl radical
194 5-Cl H OH 4-methoxyphenyl radical
195 6-Cl H Methoxy radical 4-Nitrophenyl radical
196 6-Cl H OH 4-NitroPhenyl radical
197 6-Cl H Methoxy radical 4-methyl-S (O)2-phenyl radical
198 6-Cl H OH 4-methyl-S (O)2-phenyl radical
199 6-Cl H Methoxy radical 4-methyl-S (O)2-NH-phenyl
200 6-Cl H OH 4-methyl-S (O)2-NH-phenyl
201 6-Cl H OH 2-chlorophenyl group
202 6-Cl H OH 2, 4-dichlorophenyl
203 6-Cl H Methoxy radical 3-fluoro-4-chlorophenyl
204 6-Cl H OH 3-fluoro-4-chlorophenyl
205 6-Cl H Methoxy radical 4-cyanophenyl group
206 6-Cl H Methoxy radical 4-bromophenyl radical
207 6-Cl H Methoxy radical 4- (2-thienyl) benzeneBase of
208 6-Cl H OH 4- (2-thienyl) phenyl
209 6-Cl H Methoxy radical 4- (2-furyl) phenyl
210 6-Cl H OH 4- (2-furyl) phenyl
211 6-Cl H Methoxy radical 4- (3-pyridyl) phenyl
212 6-Cl H OH 4- (3-pyridyl) phenyl
213 6-Cl H Methoxy radical 4- (2-thiazolyl) phenyl
214 6-Cl H OH 4- (2-thiazolyl) phenyl
215 6-Cl H Methoxy radical 3-bromophenyl radical
216 6-Cl H Methoxy radical 3- (2-furyl) phenyl
217 6-Cl H OH 3- (2-furyl) phenyl
218 6-Cl Methyl radical Methoxy radical 4-chlorophenyl group
219 6-Cl Methyl radical OH 4-chlorophenyl group
220 5-Cl H Methoxy radical Isoquinolin-3-yl
221 5-Cl H OH Isoquinolin-3-yl
222 6-Cl H Methoxy radical Isoquinolin-3-yl
223 6-Cl H OH Isoquinolin-3-yl
224 5-Cl H Methoxy radical 5-methyl-3-isoxazolyl
225 5-Cl H OH 5-methyl-3-isoxazolyl
226 6-Cl H Methoxy radical 5-methyl-3-isoxazolyl
227 6-Cl H OH 5-methyl-3-isoxazolyl
228 5-Cl H Methoxy radical 4-methyl-5- (1, 2, 3-thiadiazolyl)
229 5-Cl H OH 4-methyl-5- (1, 2, 3-thiadiazolyl)
230 6-Cl H Methoxy radical 4-methyl-5- (1, 2, 3-thiadiazolyl)
231 6-Cl H OH 4-methyl-5- (1, 2, 3-thiadiazolyl)
232 5-Cl H Methoxy radical 5-methyl-2-thiazolyl
233 5-Cl H OH 5-methyl-2-thiazolyl
234 6-Cl H Methoxy radical 5-methyl-2-thiazolyl
235 6-Cl H OH 5-methyl-2-thiazolyl
236 6-Cl H OH 2-thienyl radical
237 6-Cl H Methoxy radical 3-(HO)(CH3)2C-2-furyl radical
238 6-Cl H OH 3-(HO)(CH3)2C-2-furyl radical
239 6-Cl H Methoxy radical 3-methoxymethyl-2-furyl group
240 6-Cl H OH 3-methoxymethyl-2-furyl group
241 6-Cl H OH 1-methyl-2-imidazolyl
242 6-Cl H Methoxy radical 1-methyl-2-imidazolyl
243 5-Cl H Methoxy radical 1-methyl-2-imidazolyl
244 5-Cl H OH 1-methyl-2-imidazolyl
245 5-Cl H Methoxy radical 2-imidazolyl
246 5-Cl H OH 2-imidazolyl
247 6-Cl H Methoxy radical 2-imidazolyl
248 6-Cl H OH 2-imidazolyl
249 5-Cl H Methoxy radical 4-methyl-2-thiazolyl
250 5-Cl H OH 4-methyl-2-thiazolyl
251 5-Cl H Methoxy radical 1-methyl-2-pyrrolyl
252 5-Cl H OH 1-methyl-2-pyrrolyl
253 5-Cl H Methoxy radical 2-methyl-4-thiazolyl
254 5-Cl H OH 2-methyl-4-thiazolyl
255 5-Cl H Methoxy radical 5-thiazolyl group
256 5-Cl H OH 5-thiazolyl group
257 6-Cl H Methoxy radical 4-methyl-2-thiazolyl
258 6-Cl H OH 4-methyl-2-thiazolyl
259 5-Cl H Methoxy radical 3-carboxy-5-isoxazolyl
260 5-Cl H OH 3-carboxy-5-isoxazolyl
261 6-Cl H Methoxy radical Cyclopropyl group
262 6-Cl H OH Cyclopropyl group
263 6-Cl H Methoxy radical Cyclobutyl radical
264 6-Cl H OH Cyclobutyl radical
265 5-tert-butyl H Methoxy radical 4-chlorophenyl group
266 5-tert-butyl H OH 4-chlorophenyl group
267 6-Cl H Dimethylamino group 4-methyl-2-pyridyl
268 6-Cl H Methylamino radical 4-methyl-2-pyridyl
269 5-Cl H HO-(CH2)2-NH- 4-methyl-2-pyridyl
270 5-Cl H Methoxy amino group 4-methyl-2-pyridyl
271 5-Cl H 1-piperazinyl 4-methyl-2-pyridyl
272 5-Cl H H2N-(CH2)2-NH- 4-methyl-2-pyridyl
273 5-Cl H 3-amino-1-pyrrolidinyl 4-methyl-2-pyridyl
274 5-F，6-Cl H Methoxy radical 4-chlorophenyl group
275 5-F，6-Cl H OH 4-chlorophenyl group
276 5-F，6-Cl H Methoxy radical 4-Methyl-2-pyridyl
277 5-F，6-Cl H OH 4-methyl-2-pyridyl
278 6-Cl H Methoxy radical 4-(HO)(H3C) CH-2-pyridinyl
279 6-Cl H OH 4-(HO)(H3C) CH-2-pyridinyl
280 6-Cl H OH 4-ethyl-3-fluoro-2-pyridinyl
281 6-Cl H OH 2-Nitrophenyl radical
282 6-Cl H OH 2, 4-Dimethoxyphenyl
283 6-Cl H OH 4-CHF2O-phenyl
284 6-Cl H OH 2, 5-Dimethoxyphenyl
285 5-acetyl group H Methoxy radical 4-chlorophenyl group
286 5-acetyl group H OH 4-chlorophenyl group
287 6-F H Methoxy radical 4-methyl-2-phenyl
288 6-F H OH 4-methyl-2-phenyl
289 6-F H Methoxy radical 4-chlorophenyl group
290 6-F H OH 4-chlorophenyl group
291 5-methylthio group H Methoxy radical 4-methyl-2-phenyl
292 5-methylthio group H OH 4-methyl-2-phenyl

Claims (81)

1. A compound of the formula:or pharmaceutically acceptable salts thereof, wherein Z is OH or C1-6Alkoxy, -NR2R3Or a group of formula (II) or (III):wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4And W is OH or-NR2R3(ii) a Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r 1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; r4Is H or C1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4.
2. The compound of claim 1 wherein Z is OH, C1-6Alkoxy, dimethylamino, methylamino, amino, N-methoxy-N-methylamino, 2-cyanoethylamino, 2-hydroxyethylamino, pyrrolidinyl, piperidino, piperazinyl, N-methylpiperazinyl, morpholino, methoxyamino, piperazinyl, aminopyrrolidinyl or aminoethylaminoAn amino group.
3. The compound of claim 2, wherein Z is OH or C1-6An alkoxy group; and Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) A 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) c selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl3-7Cycloalkyl, and said cycloalkyl is optionally substituted by 1 member selected from the group consisting of OH, methyl, ethyl, propyl, F, Cl and CF3Substituted with the substituent(s); and
(e) a benzo-fused heterocycle selected from the group consisting of quinolinyl, isoquinolinyl, 1, 2-naphthyridinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, and indolyl, said benzo-fused heterocycle being optionally substituted with 1, 2, or 3 substituents independently selected from the group of (a-1) above.
4. The compound of claim 3, wherein Q is selected from the group consisting of:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkyl sulfonic acidAcylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) A 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) selected from cyclopropyl, cyclobutyl and cyclohexyl; and
(e) quinolyl or isoquinolyl, and said quinolyl or isoquinolyl being optionally substituted by 1 member selected from halogen, C1-4Alkyl, NH2、OH、C1-4Alkoxy and C1-4Substituted with a halogenated alkyl group.
5. The compound of claim 4 wherein Z is OH, C1-5An alkoxy group; q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH 2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical,C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above; and
(e) An isoquinolinyl group; r1Is H, C1-4An alkyl group; r2And R3Independently is H or methyl; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOR4、C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2 or 3.
6. The compound of claim 5, wherein Z is OH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; q is selected from the following groups:
(a) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, HO- (C)1-4) Alkyl, aryl, heteroaryl, and heteroaryl,C1-4alkoxy-C1-4Alkyl, -COOH, C1-4Alkylsulfonylamino, nitro, C1-4An alkylsulfonyl group and a cyano group,
(a-2) phenyl or benzyloxy and the phenyl moiety of phenyl or benzyloxy is optionally substituted by 1 atom selected from C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy and NH2The substituent (b) of (a) is substituted,
(a-3) a 5-membered monocyclic aryl group selected from imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, and the 5-membered monocyclic aryl group is optionally substituted with 1 member selected from C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy and NH2The substituent (b) of (a) is substituted,
(a-4) a 6-membered monocyclic aryl group selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, and the 6-membered monocyclic aryl group is optionally substituted with 1 member selected from C1-4Alkyl, halogen substituted C1-4Alkyl, halogen, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy and NH2The substituent (b) of (a) is substituted,
(b) a 6-membered monocyclic aryl group selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, and said monocyclic aryl group is optionally substituted with 1 or 2 substituents independently selected from the group of (a-1), (a-2), (a-3) or (a-4) above,
(c) a 5-membered monocyclic aryl group selected from the group consisting of imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, and said monocyclic aryl group is optionally substituted with 1 or 2 substituents independently selected from the group of (a-1), (a-2), (a-3) or (a-4) above; r 1Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl and aminosulfonyl; and n is 0, 1, 2 or 3.
7. The compound of claim 6, wherein Z is OH, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; q is selected from the following groups:
(a) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
(a-1) fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, butyl, CH2F、CHF2、CF3Methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, CH2F-O-、CHF2-O-、CF3-O-, methylthio, ethylthio, hydroxymethyl, methoxymethyl, methoxyethyl, ethoxymethyl, OH, NO2Methanesulfonyl, CN, (HO) (H)3C)2C-, acetyl and methylsulfonylamino,
(a-2) phenyl or benzyloxy and the phenyl moiety of phenyl or benzyloxy is optionally substituted with 1 member selected from the group consisting of methyl, ethyl, propyl, CF 3F, Cl, OH, methoxy, ethoxy and NH2The substituent (b) of (a) is substituted,
(a-3) a 5-membered monocyclic aryl group selected from furyl, thienyl and pyrrolyl, and the 5-membered monocyclic aryl group is optionally substituted with 1 group selected from methyl, ethyl, propyl, CF3F, Cl, OH, methoxy, ethoxy and NH2The substituent (b) of (a) is substituted,
(a-4) is optionally substituted by 1 member selected from methyl, ethyl, propyl, CF3F, Cl, OH, methoxy, ethoxy and NH2A pyridyl group substituted with the substituent(s) of (a),
(b) pyridyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the above-mentioned (a-1), (a-2), (a-3) or (a-4),
(c) imidazolyl, thiazolyl, furylThienyl, isoxazolyl, 1, 2, 3-thiadiazolyl or pyrrolyl, and said imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1, 2, 3-thiadiazolyl or pyrrolyl is optionally substituted with 1 or 2 substituents independently selected from the group of (a-1), (a-2), (a-3) or (a-4) above; r1Is H, methyl, ethyl, n-propyl, isopropyl; x is independently selected from F, Cl, Br, methyl, ethyl, propyl, butyl, CH2F、CHF2、CF3Methoxy, CF3-O-or ethoxy; and n is 0, 1 or 2.
8. The compound of claim 7, wherein Z is OH, ethoxy, or methoxy; q is phenyl, chlorophenyl, fluorophenyl, bromophenyl, tolyl, methoxyphenyl, (furyl) phenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, dimethylpyridyl, chloropyridyl, fluoropyridyl, trifluoromethylpyridyl, methoxypyridyl, (ethyl) (ethoxy) pyridyl, (chloro) (ethyl) pyridyl, thiazolyl, methylthiazolyl, furyl, methoxymethylfuryl, isoquinolyl, cyclohexyl, methoxyphenyl, (fluoro) (ethyl) pyridyl, dimethylpyridyl, or (ethoxy) (ethyl) pyridyl; r 1Is H; x is F, Cl, methyl, ethyl, isopropyl, tert-butyl, CF3Or a methoxy group; and n is 1 or 2.
9. The compound of claim 8, wherein Z is OH, ethoxy, or methoxy; q is phenyl, chlorophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl or chloropyridyl; r1Is H; x is F, Cl, methyl or CF3(ii) a And n is 1 or 2.
10. The compound of claim 1 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, sodium salt, [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, and, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-7-chloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the less polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the more polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl acetate, ethyl acetate, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl (2-benzoyl-6-chloro-1H-indol-3-yl) acetate, methyl (2-benzoyl-6-chloro-1H-indol-3-yl) -N, N-dimethylacetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) -N-methylacetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) acetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) -N-methoxy-N-methylacetamide, methyl acetate, ethyl acetate, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1-piperidino-1-ethanone, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) -1- (4-methyl-1-piperazinyl) -1-ethanone, (2-benzoyl-6-chloro-1H-indol-3-yl) -N- (2-cyanoethyl) acetamide, (2-benzoyl-6-chloro-1H-indol-3-yl) -N- (2-hydroxyethyl) acetamide, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) ) -1-morpholino-1-ethanone, [2- (4-chlorobenzoyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol- 3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl ester, [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetate, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl ] acetate, methyl [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl, [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate -yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, Methyl [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl-2- (4-methylpyridine-, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid methyl ester [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate -yl ] acetic acid, methyl [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, methyl (2-benzoyl-1H-indol-3-yl ] acetate, methyl (I) indole-3-yl) acetate, methyl (I) indole-3-yl ] acetate, methyl (I) indole-2-yl ] acetate, methyl (I), (2-benzoyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetate, methyl [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, methyl [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, methyl [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl acetate, [2- (4-chlorobenzoyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl ] ethyl acetate Acid methyl ester, [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-methoxybenzoyl) -1H-indole-3-yl ] acetic acid Indole-3-yl acetic acid methyl ester, [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl ester, and salts thereof, [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, and [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester Methyl [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate, and ethyl [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indole- 3-yl acetic acid, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [ (4-methanesulfonyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [ (4-methanesulfonyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (methanesulfonylamino) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (methanesulfonylamino) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-cyanobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [ 4-bromobenzoyl ] -1H-indol-3-yl ] acetic acid methyl ester -3-yl methyl acetate, [ 6-chloro-2- [4- (2-thienyl) benzoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (2-thienyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] -1H-indol-3-yl ] acetate [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-thiazolyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (2-thiazolyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-bromobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- [3- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, methyl acetate, and mixtures thereof, [ 6-chloro-2- [3- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, dl-2- [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] propionic acid methyl ester, dl-2- [2- (4-chlorobenzoyl) -6-chloro-1H-indol-3-yl ] propionic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl ester, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, acetic acid, [ 6-chloro-2- (2-thienyl) carbonylindol-3-yl ] acetic acid, methyl [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indazol-3-yl ] acetate Indole-3-yl acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [3- (ethoxycarbonyl) isoxazole-5-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- [3- (carboxy) isoxazole-5-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl ] acetate, methyl [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl ] acetic acid, methyl [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, methyl [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N, n-dimethylacetamide, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N-methylacetamide, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N- (2-hydroxyethyl) acetamide, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N-methoxyacetamide, 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -1-piperazinyl-1-ethanone, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -N- (2-aminoethyl) acetamide, 2- [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] -1- (3-amino-1-pyrrolidinyl) -1-ethanone, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-nitrobenzoyl) -1H-indol-3- Yl ] acetic acid, [ 6-chloro-2- (2, 4-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-difluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 5-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluorobenzoyl) -5-indol-3-yl ] acetic acid -1H-indol-3-yl ] acetic acid methyl ester, [ 6-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-fluoro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-methylsulfanyl-1H-indol-3-yl ] acetic acid, methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-methylthio-1H-indol-3-yl ] acetic acid and salts thereof.
11. The compound of claim 10 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, sodium salt, [ 6-chloro-2- (2-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, and, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-7-chloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the less polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, the more polar enantiomer, 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl acetate, ethyl acetate, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl (2-benzoyl-6-chloro-1H-indol-3-yl) acetate, [2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl (I) and (II) methyl (III) acetate, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-tert-butylpyridine-2-carbonyl) -5-chloro-1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3, 4-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl acetic acid, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] ethylidene ] acetic acid Acids, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, (2-benzoyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-ethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methoxy-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-isopropyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] ethyl acetate Acids, [ 6-chloro-2- (2-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-benzyloxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-hydroxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-phenylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-nitrobenzoyl) -1H-indol-3-yl ] ethyl ] acetic acid Acids, [ 6-chloro-2- [ (4-methanesulfonylamino) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 4-dichlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloro-3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-cyanobenzoyl) -1H-indol-3-yl ] acetic acid Indole-3-yl methyl acetate, [ 6-chloro-2- [ 4-bromobenzoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (2-thienyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (3-pyridyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (2-thiazolyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-bromobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [3- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, dl-2- [2- (4-chlorobenzoyl) -6-chloro-1H-indol-3-yl ] propionic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methyl-1, 2, 3-thiadiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid -yl ] acetic acid, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-thienyl) carbonylindol-3-yl ] acetic acid, [ 6-chloro-2- [3- (1-hydroxy-1-methylethyl) -2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (imidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, and salts thereof, [ 5-chloro-2- (1-methylpyrrole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (thiazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [3- (carboxy) isoxazole-5-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl ] acetic acid, [5- (tert-butyl) -2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 4-ethyl-3-fluoropyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2-nitrobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (2, 4-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-difluoromethoxybenzoyl) -1H-indol-3-yl ] ethyl ] acetic acid Acids, [ 6-chloro-2- (2, 5-dimethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-acetyl-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid and salts thereof.
12. The compound of claim 10 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl (I) acetate, methyl (II) acetate, methyl (III) acetate, and mixtures thereof, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, less polar enantiomer 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, and salts thereof, The more polar enantiomers 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetate, methyl [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 5-dimethylpyridine-2, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, methyl, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester Esters, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, salts of these compounds, and their use as medicaments, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-Ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [2- (4-methylpyridine-2-carbonyl) -, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate Acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid methyl ester, acetic acid methyl ester, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid methyl ester -yl ] acetic acid, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, a salt thereof, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, salts thereof, solvates thereof, and pharmaceutical compositions comprising the same, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 4-ethyl-3-fluoropyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, and [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid methyl ester, and salts thereof.
13. The compound of claim 10 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid ethyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl (I) acetate, methyl (II) acetate, methyl (III) acetate, and mixtures thereof, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, (2-benzoyl-4-chloro-1H-indol-3-yl) acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, dl-2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, less polar enantiomer 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, and salts thereof, The more polar enantiomers 2- (2-benzoyl-6-chloro-1H-indol-3-yl) propionic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (2-furylcarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, methyl ester, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-tert-butylpyridine-2-carbonyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- [4- (hydroxymethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid -3-yl acetic acid, [ 5-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid 3-yl acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methoxy-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-Ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -6-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid An alkyl ] acetic acid, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylisoxazole-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier thereof, and a pharmaceutically acceptable carrier, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (1-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, 2- { 6-chloro-2- [ 4-ethyl-3-fluoro-2-pyridyl ] carbonyl } -1H-indol-3-yl ] acetic acid -3-yl } acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetate, and salts thereof.
14. The compound of claim 10 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] ethylidene Acids, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, salts thereof, and salts thereof, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 2-methyl-2- (2-carbonyl) -1H-indol-3-, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, [ 5-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate Esters, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, esters, salts of the corresponding compounds, and pharmaceutical compositions containing the same, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, and methyl [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) acetate 1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetate, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate Acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-methyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid methyl ester, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetate Indol-3-yl acetic acid, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (2-methylimidazole-4-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 2-methyl-2- (4-methylthiazole-2-carbonyl) -1, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid methyl ester and salts thereof.
15. The compound of claim 10 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-fluorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (3-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [2- (4-bromobenzoyl) -6-chloro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-methylbenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [2- (3-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-4, 5-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-4, 6-dichloro-1H-indol-3-yl) acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 5-chloro-2- (thiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, and mixtures thereof, (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid methyl ester, [ 6-chloro-2- (cyclohexanecarbonyl) -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] ethylidene Acids, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (6-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, salts thereof, solvates thereof, and pharmaceutical compositions containing the same, [ 6-chloro-2- [5- (trifluoromethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 5-chloro-2- (4, 5-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (3-ethoxy-4-ethylpyridine-2-carbonyl) -1H-indol-3- Yl ] acetic acid, [ 6-chloro-2- (3-chloro-4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4, 6-dimethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [5, 6-dichloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid Yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-ethyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-isopropyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -6-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 5-tert-butyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methyl-2-pyridine-2-carbonyl) -5-trifluoromethoxy-1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [2- (4-methylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-trifluoromethoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (2-furyl) benzoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid -3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetate, [ 6-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [ 3-methoxymethyl-2-furoyl ] -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (2-methylimidazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (5-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (2-methylimidazole-2-carbonyl) -, [ 6-chloro-2- (4-methylthiazole-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl ] -1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetate, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and salts thereof.
16. The compound of claim 1 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and pharmaceutically acceptable salts thereof, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetate, methyl [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, methyl acetate, ethyl acetate, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, and mixtures thereof, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid methyl [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetate, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid methyl ester, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl ] -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, methyl acetate, methyl-2- (4-methylpyridine-2-carbonyl) -1, Methyl [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetate, methyl [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetate (cj-020,099), [ 6-chloro-5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetate, and salts thereof.
17. The compound of claim 10 selected from: (2-benzoyl-6-chloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (3-chlorobenzoyl) -1H-indol-3-yl ] acetic acid, [2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, (2-benzoyl-5, 6-dichloro-1H-indol-3-yl) acetic acid, [ 6-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid -indol-3-yl acetic acid, [ 6-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-isopropylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-propylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, and, [2- (4-ethylpyridine-2-carbonyl) -5-trifluoromethyl-1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-methoxypyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-fluoro-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (4-methoxybenzoyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- [4- (1-hydroxyethyl) pyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-ethyl-3-fluoropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (5-chloropyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-methyl-2- (4-methylpyridine-2-carbonyl) -1H-indol-3-yl ] acetic acid, [ 5-chloro-2- (isoquinoline-3-carbonyl) -1H-indol-3-yl ] acetic acid, [ 6-chloro-2- (4-chlorobenzoyl) -5-fluoro-1H-indol-3-yl ] acetic acid, and salts thereof.
18. A pharmaceutical composition for the treatment of medical conditions associated with prostaglandins as pathogens comprising a compound of formula (I) according to claim 1 and a pharmaceutically inert carrier.
19. A pharmaceutical composition according to claim 18, wherein the compound of formula (I) is as defined in claim 2.
20. A pharmaceutical composition according to claim 19, wherein the compound of formula (I) is as defined in claim 3.
21. A pharmaceutical composition according to claim 20, wherein the compound of formula (I) is as defined in claim 4.
22. A pharmaceutical composition according to claim 21, wherein the compound of formula (I) is as defined in claim 5.
23. A pharmaceutical composition according to claim 22, wherein the compound of formula (I) is as defined in claim 6.
24. The pharmaceutical composition of claim 23, wherein the compound is as defined in claim 7.
25. The pharmaceutical composition of claim 24, wherein the compound is as defined in claim 8.
26. A pharmaceutical composition according to claim 25, wherein the compound is as defined in claim 9.
27. A pharmaceutical composition according to claim 26, wherein the compound is as defined in claim 10.
28. A pharmaceutical composition according to claim 27, wherein the compound is as defined in claim 11.
29. A pharmaceutical composition according to claim 28, wherein the compound is as defined in claim 12.
30. The pharmaceutical composition of claim 29, wherein the compound is as defined in claim 13.
31. A pharmaceutical composition according to claim 30, wherein the compound is as defined in claim 14.
32. The pharmaceutical composition of claim 31, wherein the compound is as defined in claim 15.
33. The pharmaceutical composition of claim 32, wherein the compound is as defined in claim 16.
34. The pharmaceutical composition of claim 33, wherein the compound is as defined in claim 17.
35. A method of treating a medical condition associated with prostaglandins as pathogens in a mammalian subject comprising administering the pharmaceutical composition of claim 1.
36. A compound of the formula:wherein B is a suitable protecting group: q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C 1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) Optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-C6An alkyl group; and n is 0, 1, 2, 3 or 4.
37. A compound of the formula:wherein B is a suitable protecting group: q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C) 1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) A 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-C6An alkyl group; and n is 0, 1, 2, 3 or 4.
38. A process for preparing a compound of the formula: Wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, the method comprising the steps of:
i) reacting a compound of the formula:
wherein B is a suitable protecting group, R5Is C1-6Alkyl, X and n are as defined above, with a compound of the formula:
wherein E is halogen and Q is as defined above;
ii) reacting the product of step i) with a second base;
iii) reacting the product of step ii) with an acid.
39. The process of claim 38, wherein said first base is potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or cesium carbonate.
40. The process of claim 38, wherein said first base is potassium carbonate.
41. The process of claim 38, wherein said second base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium pentoxide (then water), sodium methoxide (then water), or potassium tert-butoxide in water (then water).
42. The process of claim 38, wherein said second base is sodium hydroxide.
43. The method of claim 38, wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, or aqueous ammonium chloride.
44. The method of claim 38, wherein said acid is aqueous hydrochloric acid.
45. The process of claim 38 wherein said solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
46. The method of claim 38, wherein said solvent is N, N-dimethylacetamide.
47. A process for preparing a compound of the formula:wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C 1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 independentlySelected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) Optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of the formula:
wherein R is5Is C1-6Alkyl groups, Q, X and n are as previously defined, with a base in a suitable solvent.
48. The process of claim 47 wherein said base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-amylate, sodium methoxide, sodium ethoxide, or potassium tert-butoxide.
49. The method of claim 47, wherein said base is sodium hydroxide.
50. The method of claim 47, wherein said solvent is methanol, ethanol, isopropanol, or a mixture of tetrahydrofuran and water.
51. The method of claim 47, wherein said solvent is methanol containing water.
52. A process for preparing a compound of the formula:wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7CycloalkanesThe base group is a group of a compound,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) benzene optionally substituted with 1, 2 or 3 substituents independently selected from the group of (a-1) above And a fused heterocyclic ring; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of the formula:
wherein B, Q, X, n and R5As defined above, with a base in a suitable solvent.
53. The method of claim 52, wherein said base is 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 3, 3-tetramethylguanidine, sodium tert-amylate, sodium methoxide, or potassium tert-butoxide.
54. The method of claim 52, wherein said base is 1, 8-diazabicyclo [5.4.0] undec-7-ene or potassium tert-butoxide.
55. The process of claim 52 wherein said solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
56. The method of claim 52, wherein said solvent is N, N-dimethylacetamide.
57. A process for preparing a compound of the formula:wherein B is a suitable protecting group; q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C) 1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl radical、OH、C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C 1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of the formula:
wherein B, Q, X, n and R5As defined above, with a base in the presence of a solvent.
58. The process of claim 57 wherein the base is potassium carbonate, potassium bicarbonate, sodium carbonate, or cesium carbonate.
59. The process of claim 57 wherein said base is potassium carbonate.
60. The process of claim 57 wherein said solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran.
61. The method of claim 57 wherein said solvent is N, N-dimethylacetamide.
62. A process for preparing a compound of the formula:wherein B is a suitable protecting group; q is selected from the following groups:
(a) Phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C 1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r2And R3Independently H, OH,C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO 2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; r5Is C1-6An alkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of the formula:
wherein B, X, n and R5As previously defined, with a compound of the formula:
wherein E is halogen and Q is as defined above.
63. The method of claim 62, wherein said base is potassium carbonate, potassium bicarbonate, sodium carbonate, or cesium carbonate.
64. The method of claim 62, wherein said base is potassium carbonate.
65. The method of claim 62, wherein said solvent is N, N-dimethylacetamide, N-dimethylformamide, methyl ethyl ketone, acetone, or tetrahydrofuran.
66. The method of claim 62, wherein said solvent is N, N-dimethylacetamide.
67. A process for preparing a compound of the formula:wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) A 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 groups independently selected from (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 groups independently selected from (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; r5Is C1-6An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C 1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which comprises treating a compound of the formula (X):
wherein R is1、R5X, Q and n are as previously defined and B is a suitable protecting group to give a compound of formula (XII).
68. A process for preparing a compound of formula (XII):wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C) 1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C 1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; r5Is C1-6An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which comprises reacting a compound of formula (IX):
wherein R is1、R5X and n are as defined above and B is a suitable protecting group, with a compound (XI) of the formula:
wherein E is halogen and Q is as defined above, to give a compound of formula (XII).
69. The process of claim 68, wherein the reaction is carried out at a temperature of 0-100 ℃.
70. The process of claim 68 wherein the suitable base is potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride or potassium fluoride.
71. The process of claim 68, wherein the reaction is first carried out in the presence of a base for 2 minutes to 1 day, and then another base is added to the reaction mixture.
72. The method of claim 71, wherein the reaction is carried out for 30 minutes to 8 hours.
73. The method of claims 67-68, wherein a suitable protecting group is methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl, or trifluoromethanesulfonyl.
74. The method of claim 73, wherein a suitable protecting group is benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, or trifluoromethanesulfonyl.
75. The method of claim 71, wherein the first base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, and diethylisopropylamine, and the second base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, potassium hydride, and mixtures thereof, 1, 4-diazabicyclo [2.2.2] octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, and diethylisopropylamine.
76. The process of claim 75, wherein the first base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydride, and potassium fluoride, and the second base is selected from the group consisting of 1, 8-diazabicyclo [5.4.0] undec-7-ene, cesium carbonate, pyrrolidine, diisopropylamine, triethylamine, diethylisopropylamine, and diisopropylethylamine.
77. The method of claim 75, wherein the first base is potassium carbonate, cesium carbonate, or potassium fluoride and the second base is 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium tert-butoxide, or cesium carbonate.
78. The method of claim 77, wherein the combination of the first base and the second base (first base/second base) is selected from the group consisting of potassium carbonate/1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate/cesium carbonate, cesium carbonate/potassium tert-butoxide, cesium carbonate/1, 8-diazabicyclo [5.4.0] undec-7-ene and potassium fluoride/cesium carbonate.
79. The method of claim 78, wherein the combination of the first base and the second base (first base/second base) is selected from the group consisting of potassium carbonate/1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate/cesium carbonate, and cesium carbonate/potassium tert-butoxide.
80. A process for preparing a compound of formula (VIII): Wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) optionally substituted by 1,2 or 3 are independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C 1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is0. 1, 2, 3 or 4, which process comprises treating a compound of formula (X) below with a suitable base under hydrolysis conditions:
wherein R is1、R5X, Q and n are as defined above to give a compound of formula (VIII).
81. A process for preparing a compound of formula (VIII):wherein Q is selected from the following groups:
(a) phenyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:
(a-1) halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group,
(a-2) aryl or-O- (CH)2)n-aryl, and the aryl or aryl moiety is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Substituents of alkylamino and CN,
(a-3) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-45-membered monocyclic aryl substituted with substituents of alkylamino and CN,
(a-4) is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4A 6-membered monocyclic aryl group substituted with a substituent of alkylamino and CN,
(b) a 6-membered monocyclic aryl group containing 1, 2, 3 or 4N atoms, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(c) a 5-membered monocyclic aryl group containing one heteroatom selected from O, S and N and optionally containing 1, 2 or 3N atoms in addition to said heteroatom, and said monocyclic aryl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (a-1), (a-2), (a-3) or (a-4) above;
(d) Optionally substituted by 1 or 2 substituents independently selected from OH, C1-4Alkyl, halogen and halogen substituted C1-4C substituted by alkyl substituents3-7A cycloalkyl group; and
(e) a benzo-fused heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of the groups of (a-1) above; r1Is H, C1-4Alkyl or halogen; r2And R3Independently H, OH, C1-4Alkoxy radical, C1-4Alkyl or substituted by halogen, OH, C1-4Alkoxy, NH2Or C substituted by CN1-4An alkyl group; x is independently selected from halogen, C1-4Alkyl, halogen substituted C1-4Alkyl, OH, C1-4Alkoxy, halogen substituted C1-4Alkoxy radical, C1-C4Alkylthio, NO2、NH2Two (C)1-4Alkyl) amino, C1-4Alkylamino, CN, HO- (C)1-4) Alkyl radical, C1-4alkoxy-C1-4Alkyl radical, C1-4Alkylsulfonyl, aminosulfonyl, -NH2S(O)2NR2R3Acetyl, -COOH, -C (O) O-C1-4Alkyl radical, C1-4Alkylsulfonylamino and C3-7A cycloalkyl group; and n is 0, 1, 2, 3 or 4, which comprises hydrolyzing a compound of the formula (XII):
wherein R is5Is C1-6Alkyl radical, R1X, Q and n are as previously defined.
HK01104208.9A 1998-01-05 1998-12-18 2,3-substituted indole compounds as cox-2 inhibitors HK1033670A (en)

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