US20130338158A1 - 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity - Google Patents
6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity Download PDFInfo
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- US20130338158A1 US20130338158A1 US13/946,564 US201313946564A US2013338158A1 US 20130338158 A1 US20130338158 A1 US 20130338158A1 US 201313946564 A US201313946564 A US 201313946564A US 2013338158 A1 US2013338158 A1 US 2013338158A1
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- indole
- isopropyl
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- USNVSOZWZJIKFZ-MAQMNSDVSA-N [2H]C([2H])([2H])C([2H])(OC1=CC=C2C(=C1)N(CC1=CC=CC=N1)/C(C(C)C)=C\2C(=O)CCC1=CC(F)=C(F)C=C1)C([2H])([2H])[2H] Chemical compound [2H]C([2H])([2H])C([2H])(OC1=CC=C2C(=C1)N(CC1=CC=CC=N1)/C(C(C)C)=C\2C(=O)CCC1=CC(F)=C(F)C=C1)C([2H])([2H])[2H] USNVSOZWZJIKFZ-MAQMNSDVSA-N 0.000 description 1
- XVEUEBVMTCQRCS-UHFFFAOYSA-N [H]/C(CCCCCCCCCCCCC)=C(/[H])C(O)C(N)COC Chemical compound [H]/C(CCCCCCCCCCCCC)=C(/[H])C(O)C(N)COC XVEUEBVMTCQRCS-UHFFFAOYSA-N 0.000 description 1
- HELQQEYUYVMIOV-UHFFFAOYSA-N [H]C(=O)/C1=C(\C(=O)CCC2=CC=C(F)C(F)=C2)C2=CC=C(OC(C)C)C=C2N1CC1=CC=CC=N1 Chemical compound [H]C(=O)/C1=C(\C(=O)CCC2=CC=C(F)C(F)=C2)C2=CC=C(OC(C)C)C=C2N1CC1=CC=CC=N1 HELQQEYUYVMIOV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to derivatives and/or analogues of sphingosine and pharmaceutical compositions, including such derivatives and/or analogues, which are useful as drugs for the treatment of fungal infections, allergic diseases, immune disorders, etc.
- Sphingosine is a compound having the chemical structure shown in the general formula described below, in which Y 1 is hydrogen. It is known that various sphingolipids, having sphingosine as a constituent, are widely distributed in the living body including on the surface of cell membranes of cells in the nervous system.
- a sphingolipid is one of the lipids having important roles in the living body.
- a disease called lipidosis is caused by accumulation of a specified sphingolipid in the body.
- Sphingolipids present on cell membranes function to regulate cell growth; participate in the development and differentiation of cells; function in nerves; are involved in the infection and malignancy of cells; etc. Many of the physiological roles of sphingolipids remain to be solved.
- ceramide a derivative of sphingosine, has an important role in the mechanism of cell signal transduction has been indicated, and studies about its effect on apoptosis and cell cycle have been reported.
- Sphingosine-1-phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomeyeline cycle (in animals cells). It has also been found in insects, yeasts and plants.
- the enzyme, ceramidase acts upon ceramides to release sphingosine, which is phosphorylated by spingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate.
- the reverse reaction can occur also by the action of sphingosine phosphatases, and the enzymes act in concert to control the cellular concentrations of the metabolite, which concentrations are always low. In plasma, such concentration can reach 0.2 to 0.9 ⁇ M, and the metabolite is found in association with the lipoproteins, especially the HDL.
- sphingosine-1-phosphate formation is an essential step in the catabolism of sphingoid bases.
- sphingosine-1-phosphate is a potent messenger molecule that perhaps uniquely operates both intra- and inter-cellularly, but with very different functions from ceramides and sphingosine.
- the balance between these various sphingolipid metabolites may be important for health. For example, within the cell, sphingosine-1-phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits. Intracellularly, it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli. Current opinion appears to suggest that the balance between sphingosine-1-phosphate and ceramide and/or spingosine levels in cells is critical for their viability.
- sphingosine-1-phosphate exerts many of its extra-cellular effects through interaction with five specific G protein-coupled receptors on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development and immunity, and for directed cell movement.
- Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease.
- physiological stimuli such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease.
- the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis.
- sphingosine-1-phosphate together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium.
- lysophosphatidic acid it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers.
- Fungi and plants have sphingolipids and the major sphingosine contained in these organisms has the formula described below. It is known that these lipids have important roles in the cell growth of fungi and plants, but details of the roles remain to be solved.
- derivatives of sphingolipids and their related compounds exhibit a variety of biological activities through inhibition or stimulation of the metabolism pathways.
- These compounds include inhibitors of protein kinase C, inducers of apoptosis, immuno-suppressive compounds, antifungal compounds, and the like. Substances having these biological activities are expected to be useful compounds for various diseases.
- the present invention provides a derivative or analogue of sphingosine that is able to regulate the functions of sphingolipid, and pharmaceutical compositions comprising said derivative or analogue.
- the aryl group is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprise from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and preferably said aryl group is selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole, oxazole, oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalen, chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofur
- Said aryl groups can be bonded to the above moiety at any position.
- Said aryl group may itself be substituted with any common organic functional group including but not limited to C 1 to C 12 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halo, C 1 to C 12 haloalkyl, hydroxyl, C 1 to C 12 alkoxyl, C 1 to C 12 alkylcarbonyl, formyl, oxycarbonyl, carboxyl, C 1 to C 12 alkyl carboxylate, C 1 to C 12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl groups.
- Z is O.
- the carbocyclic aryl group will comprise from 6 to 14 carbon atoms, e.g. from 6 to 10 carbon atoms.
- the heterocyclic aryl group will comprise from 2 to 14 carbon atoms and one or more, e.g. from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- A is CH 2 .
- X is NH
- n is 0 or an integer of 1 or 2 and R 4 is fluoro.
- R 1 is i-propyl
- R 3 is selected from the group consisting of phenyl, which may be substituted with one or two fluoro groups, and pyridyl.
- p is 0.
- a 1 and A 2 are absent.
- B is OR 6 or COOR 7 .
- X is O, r is 1, A 1 is absent, A 2 is (CH 2 ) v , wherein v is 1 or 2, and B is OR 6 or NR 8 R 9
- R 6 , R 8 and R 9 are methyl.
- B is CR 10 ⁇ NOR 11 R 10 wherein R 10 is H and R 11 is methyl or i-butyl or B is CONR 8 R 9 wherein R 8 and R 9 are selected from the group consisting of H, methyl, ethyl and propyl, or R 8 and R 9 , together with N, form a 5-member ring.
- a 1 is absent, r is 0,
- a 2 is CH 2 and B is OR 6 , wherein R 6 is H, or X is O, r is 1 and B is COR 10 , wherein R 10 is methyl.
- methyl 6-methoxyindole-2-carboxylate is treated with an electrophilic compound (e.g. benzyl bromide) in the presence of an weak base (e.g. potassium carbonate) to produce an N-alkylated indole (e.g. methyl 1-benzyl-6-methoxyindole-2-carboxylate).
- an electrophilic compound e.g. benzyl bromide
- an electrophilic compound e.g. benzyl bromide
- an electrophilic compound e.g. potassium carbonate
- the resulting 2-alkyl indole is carboxylated in the 3-position by treatment with dimethylformamide and phosphorus oxychloride followed by sodium hypochlorite oxidation of the resulting aldehyde.
- the carboxylic acid may be further functionalized by treatment with an amine in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodimide (EDC) to produce a 6-methoxyindole-3-carboxamide derivative (e.g. 3,4-difluorophenylmethyl 6-methoxy-2-isopropyl-1-benzylindole-3-carboxamide).
- the carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively.
- the 6-methoxy group may then be deprotected using boron tribromide and the resulting hydroxide subjected to alkylating (e.g. cyclopentyl iodide/potassium carbonate) or acylating (e.g. pivaloyl chloride/pyridine) reagents to produce a large variety of 6-substituted indole homologs and derivatives within the scope of the invention.
- alkylating e.g. cyclopentyl iodide/potassium carbonate
- acylating e.g. pivaloyl chloride/pyridine
- ethyl 4-iodobenzoate may be nitrated in the 3-position with fuming nitric acid and the resulting nitro compound reduced under mild conditions (e.g. SnCl 2 -H 2 O) to produce ethyl 3-amino-4-iodobenzoate.
- This compound may be converted to the indole by treatment with a terminal alkyne (e.g. 3-methylbutyne) in the presence of a palladium catalyst and copper iodide followed by heating the aryl alkyne in the presence copper iodide.
- the resulting 2-alkyl indole may then be carbonylated in the 3-position by treatment with dimethylformamide and phosphorus oxychloride and N-alkylated as described above (benzyl bromide, potassium carbonate), followed by sodium hypochlorite oxidation to produce an N-alkylindole-3-carboxylic acid.
- the carboxylic acid may be further functionalized by treatment with an amine in the presence of EDC to
- 6-methoxyindole-3-carboxamide derivative e.g. 3-pyridylmethyl 1-benzyl-6-carboethoxy-2-isopropylindole-3-carboxamide.
- the carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively.
- the 6-carboethoxy group may be further functionalized to produce a large variety of 6-substituted indole homologs and derivatives within the scope of the invention.
- the 6-carboethoxy group be hydrolyzed with strong base and the resulting carboxylic acid converted to the carboxylic acid chloride, which could be reacted with various alcohols or amines in the presence of base to produce ester or amide derivatives, respectively, such as 3-pyridylmethyl1-benzyl-2-isopropyl-6-(1-pyrrolidinylcarbamoyl)indole-3-carboxamide.
- the 6-carboethoxy group could be reduced to an alcohol and re-oxidized to an aldehyde intermediate, which may then be treated with an amine under reducing conditions to give amine derivatives such as 3-pyridylmethyl 1-benzyl-2-isopropyl-6-(1-pyrrolidinylmethyl)-indole-3-carboxamide.
- the aldehyde may also be treated with oxime or hydrazine compounds to produce oxime and hydrazone derivatives, respectively.
- many compounds within the scope of the invention may be produced by the general route depicted in Scheme 2. Additional compounds within the scope of the invention are exemplified in Tables 1 and 1A.
- Me refers to methyl
- tBu refers to t-butyl
- iPr refers to i-propyl
- Ph refers to phenyl
- “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon.
- the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
- Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
- the alkyl group may be optionally substituted with one or more substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, ⁇ O, ⁇ S, NO 2 , halogen, dimethyl amino and SH.
- Alkenyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond.
- the alkenyl group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, most preferably 2 to 4 carbons.
- the alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO 2 , halogen, dimethyl amino and SH.
- Alkynyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond.
- the alkynyl group has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7 carbons, most preferably 2 to 4 carbons.
- the alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO 2 , halogen, dimethyl amino and SH.
- Alkoxy refers to an “O-alkyl” group.
- Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
- the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
- Alkaryl refers to an alkyl that is covalently joined to an aryl group.
- the alkyl is a lower alkyl.
- Aryloxy refers to an “O-aryl” group.
- Arylalkyloxy refers to an “O-alkaryl” group.
- Carbocyclic refers to cyclic saturated or unsaturated aliphatic hydrocarbon and aryl hydrocarbon groups wherein the ring atoms are exclusively carbons, and comprises from 6 to 20 carbon atoms, including said ring atoms.
- Carbocyclic aryl refers to an aryl group wherein the ring atoms are carbon.
- Heterocyclic refers to cyclic groups wherein the ring atoms comprise carbon atoms and at least one oxygen, nitrogen, and/or sulfur atom and may be saturated, unsaturated, i.e. have one or more double bonds, or aryl, and comprises up to 20 carbon atoms and from 1 to 5 of the above heteroatoms.
- Heterocyclic aryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen.
- Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
- the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
- “Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
- Amide refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
- “Ester” refers to —C(O)—O—R′, wherein R′ is alkyl, aryl or alkylaryl.
- Thioamide refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
- Thiol ester refers to —C(O)—S—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
- “Amine” refers to a—N(R′′)R′′′ group, wherein R′′ and R′′′ are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
- Thioether refers to —S—R′′, wherein R′′ is alkyl, aryl, or alkylaryl.
- “Sulfonyl” refers to —S(O) 2 —R′′′′, where R′′′′ is aryl, C(CN) ⁇ C-aryl, CH 2 CN, alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.
- substituent on the phenyl moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.
- substituent on the phenyl moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.
- the 5 substituent is also a m substituent and the 6 substituent is an o substituent.
- Specific compounds of the invention that are prepared according to Example 2 through 199 and/or Schemes 1 through 16, are able to inhibit the activity of sphingosine-1-phosphate receptors reported in Table I, below.
- Compounds were assessed for their ability to activate or block activation of the human S1P3 receptor in T24 cells stably expressing the human S1P3 receptor.
- Ten thousand cells/well were plated into 384-well poly-D-lysine coated plates one day prior to use.
- the growth media for the S1P3 receptor expressing cell line was McCoy's 5A medium supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1% antibiotic-antimycotic and 400 ⁇ g/ml geneticin.
- the cells were washed twice with Hank's Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer). The cells were then dye loaded with 2 uM Fluo-4 diluted in the HBSS/Hepes buffer with 1.25 mM Probenecid and incubated at 37° C. for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates.
- S1P Sphingosine-1-Phosphate
- HBSS/Hepes buffer 4 mg/ml fatty acid free bovine serum albumin.
- the FLIPR transferred 12.5 ⁇ l from the ligand microplate to the cell plate and took fluorescent measurements for 75 seconds, taking readings every second, and then for 2.5 minutes, taking readings every 10 seconds. Drugs were tested over the concentration range of 0.61 nM to 10,000 nM. Data for Ca +2 responses were obtained in arbitrary fluorescence units and not translated into Ca +2 concentrations. IC 50 values were determined through a linear regression analysis using the Levenburg Marquardt algorithm.
- the compounds of Table 1B are prepared according to procedures analogous to the procedures of Schemes 1 through 19 and/or Examples 2 through 226. These compounds are also tested for ability to inhibit the activity of the S1P3 receptor.
- CeCl 3 cerium chloride
- DIBAL diisobutylaluminium hydride
- KH 2 PO 4 potassium dihydrogen phosphate
- NaH 2 PO 4 sodium dihydrogen phosphate
- n-Bu 4 NI tetrabutylammonium iodide
- NMO N-methylmorpholine N-oxide
- PCC pyridinium chlorochromate
- Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)
- Tf 2 O trifluoromethanesulfonic (triflic) anhydride
- TPAP tetrapropylammonium perruthenate
- N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 27 mg, 0.058 mmol) in CH 2 Cl 2 (2 ml) was added 1,2-ethylene-diamine (5 l, 0.070 mmol). The reaction was stirred at room temperature for 1 h and NBS (13 mg, 0.070 mmol) was added. The reaction was stirred for 16 h and the solvent was removed in vacuo.
- N-(3,4-difluorobenzyl)-2-(1-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 108, 8.0 mg, 0.017 mmol) in CH 2 Cl 2 (1 ml) was added NMO (6.0 mg, 0.051 mmol) and TPAP (0.6 mg, 0.0017 mmol). The reaction was stirred at room temperature for 1 h and was purified directly by PTLC (75% EtOAc-hexanes) to yield the title compound.
- the title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137), 3-(bromomethyl)pyridine.HBr, and (5-fluoropyridin-3-yl) methanamine (Compound 145) by, in order, General Procedure J, General Procedure K, General Procedure C, and General Procedure L.
- the title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139), 3,4-difluorobenzylamine, and pyridin-4-ylboronic acid by, in order, General Procedure C, General Procedure L, General Procedure V, and General Procedure W.
- the title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137), 3-(bromomethyl)pyridine.HBr, 3,4-difluorobenzylamine, and cyclobutyl bromide by, in order, General Procedure J, General Procedure K, General Procedure C, General Procedure L, and General Procedure N.
Abstract
The invention provides compounds represented by the formula I, each of which compounds may have sphingosine-1-phosphate receptor agonist and or antagonist biological activity:
and wherein the variables Y, R4, n, o, A, A1, A2, X, Z, R1, R3, R2, p, q and r are as defined in the specification. These compounds are useful for treating a disease or condition selected from the group consisting of glaucoma, dry eye, angiogenesis, cardiovascular conditions and diseases, and wound healing
Description
- This application is a divisional application of United States Non-Provisional patent application Ser. No. 12/013,239, filed Jan. 11, 2008, which claims the benefit of U.S. Provisional Application Ser. No. 60/884,470, filed Jan. 11, 2007, all of which are incorporated here by reference in their entirety.
- 1. Field of the Invention
- The present invention relates to derivatives and/or analogues of sphingosine and pharmaceutical compositions, including such derivatives and/or analogues, which are useful as drugs for the treatment of fungal infections, allergic diseases, immune disorders, etc.
- 2. Summary of the Art
- Sphingosine is a compound having the chemical structure shown in the general formula described below, in which Y1 is hydrogen. It is known that various sphingolipids, having sphingosine as a constituent, are widely distributed in the living body including on the surface of cell membranes of cells in the nervous system.
- A sphingolipid is one of the lipids having important roles in the living body. A disease called lipidosis is caused by accumulation of a specified sphingolipid in the body. Sphingolipids present on cell membranes function to regulate cell growth; participate in the development and differentiation of cells; function in nerves; are involved in the infection and malignancy of cells; etc. Many of the physiological roles of sphingolipids remain to be solved. Recently the possibility that ceramide, a derivative of sphingosine, has an important role in the mechanism of cell signal transduction has been indicated, and studies about its effect on apoptosis and cell cycle have been reported.
- Sphingosine-1-phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomeyeline cycle (in animals cells). It has also been found in insects, yeasts and plants.
- The enzyme, ceramidase, acts upon ceramides to release sphingosine, which is phosphorylated by spingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate. The reverse reaction can occur also by the action of sphingosine phosphatases, and the enzymes act in concert to control the cellular concentrations of the metabolite, which concentrations are always low. In plasma, such concentration can reach 0.2 to 0.9 μM, and the metabolite is found in association with the lipoproteins, especially the HDL. It should also be noted that sphingosine-1-phosphate formation is an essential step in the catabolism of sphingoid bases.
- Like its precursors, sphingosine-1-phosphate is a potent messenger molecule that perhaps uniquely operates both intra- and inter-cellularly, but with very different functions from ceramides and sphingosine. The balance between these various sphingolipid metabolites may be important for health. For example, within the cell, sphingosine-1-phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits. Intracellularly, it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli. Current opinion appears to suggest that the balance between sphingosine-1-phosphate and ceramide and/or spingosine levels in cells is critical for their viability. In common with the lysophospholipids, especially lysophosphatidic acid, with which it has some structural similarities, sphingosine-1-phosphate exerts many of its extra-cellular effects through interaction with five specific G protein-coupled receptors on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development and immunity, and for directed cell movement.
- Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease. On the other hand the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1-phosphate metabolism is under active investigation.
- Fungi and plants have sphingolipids and the major sphingosine contained in these organisms has the formula described below. It is known that these lipids have important roles in the cell growth of fungi and plants, but details of the roles remain to be solved.
- Recently it has been known that derivatives of sphingolipids and their related compounds exhibit a variety of biological activities through inhibition or stimulation of the metabolism pathways. These compounds include inhibitors of protein kinase C, inducers of apoptosis, immuno-suppressive compounds, antifungal compounds, and the like. Substances having these biological activities are expected to be useful compounds for various diseases.
- Derivatives of sphingosine have been prepared in various patents. For example, see U.S. Pat. Nos. 4,952,683; 5,110,987; 6,235,912 B1 and 6,239,297 B1.
- Also, compounds which are similar to certain spingosine derivatives, but which are not reported as being ligands for the spingosine receptors are reported in various patents and published patent applications. See for example, U.S. Pat. Nos. 5,294,722; 5,102,901; 5,403,851 and 5,580,878. U.S. Patent Application Publication No. U.S. 2003/0125371 A2. While certain of the compounds reported in the above patents are indoles, it does not appear that indole compounds have been reported as being ligands for sphingosine receptor or having activity as sphingosine agonists or antagonists.
- The present invention provides a derivative or analogue of sphingosine that is able to regulate the functions of sphingolipid, and pharmaceutical compositions comprising said derivative or analogue.
-
- Compounds represented by the formula I having sphingosine-1-phosphate receptor agonist and or antagonist biological activity:
-
- wherein:
- R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, halo, C1 to C12 haloalkyl, hydroxyl, C1 to C12 alkoxy, C3 to C20 arylalkyloxy, C1 to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, C1 to C12 alkyl carboxylate, C1 to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, and sulfonyl groups;
- X and X1 are independently selected from the group consisting of NR5, O and S; R5 is hydrogen, an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons, phenyl or lower alkylphenyl; Y is a carbocyclic aryl or heterocyclic aryl group wherein said carbocyclic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said aryl may be bonded to A at any position;
- Z is O or S;
- n is 0 or an integer of from 1 to 5;
- o is 0 or an integer of from 1 to 3;
- p is 0 or an integer of from 1 to 3;
- q is 0 or 1;
- r is 0 or 1;
- A, A1 and A2 are independently selected from the group consisting of (CH2)v wherein v is 0 or an integer of from 1 to 12, branched chain alkyl having 3 to 12 carbons, cycloalkyl having 3 to 12 carbons, alkenyl having 2 to 10 carbons and 1-3 double bonds and alkynyl having 2 to 10 carbons and 1 to 3 triple bonds; B is selected from the group consisting of hydrogen, OR6, COOR7, NR8R9, CONR8R9, COR10, CH═NOR11, CH═NNR12R13 wherein R6, R7, R10 and R11 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, R8, R9, R12 and R13 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, or R8 and R9 and/or R12 and R13, together, can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen, wherein any of R6, R7, R8, R9, R10, R11, R12 or R13 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mercapto or thiol radical; provided however, when v is 0, and r is 0, B is not hydrogen; or B is a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, and wherein when said B is a carbocyclic or heterocyclic group B may be bonded to A2 at any position, or a pharmaceutically acceptable salt of said compound.
- The aryl group is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprise from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and preferably said aryl group is selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole, oxazole, oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalen, chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofuran, dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and coumarinone. Said aryl groups can be bonded to the above moiety at any position. Said aryl group may itself be substituted with any common organic functional group including but not limited to C1 to C12 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halo, C1 to C12 haloalkyl, hydroxyl, C1 to C12 alkoxyl, C1 to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxyl, C1 to C12 alkyl carboxylate, C1 to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl groups.
- Preferably Z is O.
- Preferably, the carbocyclic aryl group will comprise from 6 to 14 carbon atoms, e.g. from 6 to 10 carbon atoms. Preferably the heterocyclic aryl group will comprise from 2 to 14 carbon atoms and one or more, e.g. from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- Preferably, A is CH2.
- Preferably, X is NH.
- Preferably, n is 0 or an integer of 1 or 2 and R4 is fluoro.
- Preferably, R1 is i-propyl.
- Preferably, R3 is selected from the group consisting of phenyl, which may be substituted with one or two fluoro groups, and pyridyl.
- Preferably, p is 0.
- Preferably, A1 and A2 are absent.
- Preferably, B is OR6 or COOR7.
- Preferably, X is O, r is 1, A1 is absent, A2 is (CH2)v, wherein v is 1 or 2, and B is OR6 or NR8R9
- and R6, R8 and R9 are methyl.
- Preferably, B is CR10═NOR11R10 wherein R10 is H and R11 is methyl or i-butyl or B is CONR8R9 wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl, or R8 and R9, together with N, form a 5-member ring.
- Preferably, A1 is absent, r is 0, A2 is CH2 and B is OR6, wherein R6 is H, or X is O, r is 1 and B is COR10, wherein R10 is methyl.
- Specific Examples of the compounds of formula I include
- Some compounds within the scope of the invention may be prepared as depicted in Scheme 1. Thus, methyl 6-methoxyindole-2-carboxylate is treated with an electrophilic compound (e.g. benzyl bromide) in the presence of an weak base (e.g. potassium carbonate) to produce an N-alkylated indole (e.g. methyl 1-benzyl-6-methoxyindole-2-carboxylate). The 2-carboxylate group is converted to an alkyl group by a three-step process: Grignard reaction, elimination, and hydrogenation. The resulting 2-alkyl indole is carboxylated in the 3-position by treatment with dimethylformamide and phosphorus oxychloride followed by sodium hypochlorite oxidation of the resulting aldehyde. The carboxylic acid may be further functionalized by treatment with an amine in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodimide (EDC) to produce a 6-methoxyindole-3-carboxamide derivative (e.g. 3,4-difluorophenylmethyl 6-methoxy-2-isopropyl-1-benzylindole-3-carboxamide). The carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively. The 6-methoxy group may then be deprotected using boron tribromide and the resulting hydroxide subjected to alkylating (e.g. cyclopentyl iodide/potassium carbonate) or acylating (e.g. pivaloyl chloride/pyridine) reagents to produce a large variety of 6-substituted indole homologs and derivatives within the scope of the invention.
- Many other compounds within the scope of the invention may be prepared as depicted in Scheme 2. Thus, ethyl 4-iodobenzoate may be nitrated in the 3-position with fuming nitric acid and the resulting nitro compound reduced under mild conditions (e.g. SnCl2-H2O) to produce ethyl 3-amino-4-iodobenzoate. This compound may be converted to the indole by treatment with a terminal alkyne (e.g. 3-methylbutyne) in the presence of a palladium catalyst and copper iodide followed by heating the aryl alkyne in the presence copper iodide. The resulting 2-alkyl indole may then be carbonylated in the 3-position by treatment with dimethylformamide and phosphorus oxychloride and N-alkylated as described above (benzyl bromide, potassium carbonate), followed by sodium hypochlorite oxidation to produce an N-alkylindole-3-carboxylic acid. The carboxylic acid may be further functionalized by treatment with an amine in the presence of EDC to
- produce a 6-methoxyindole-3-carboxamide derivative (e.g. 3-pyridylmethyl 1-benzyl-6-carboethoxy-2-isopropylindole-3-carboxamide). The carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively. The 6-carboethoxy group may be further functionalized to produce a large variety of 6-substituted indole homologs and derivatives within the scope of the invention. For example, the 6-carboethoxy group be hydrolyzed with strong base and the resulting carboxylic acid converted to the carboxylic acid chloride, which could be reacted with various alcohols or amines in the presence of base to produce ester or amide derivatives, respectively, such as 3-pyridylmethyl1-benzyl-2-isopropyl-6-(1-pyrrolidinylcarbamoyl)indole-3-carboxamide. Alternatively, the 6-carboethoxy group could be reduced to an alcohol and re-oxidized to an aldehyde intermediate, which may then be treated with an amine under reducing conditions to give amine derivatives such as 3-pyridylmethyl 1-benzyl-2-isopropyl-6-(1-pyrrolidinylmethyl)-indole-3-carboxamide. The aldehyde may also be treated with oxime or hydrazine compounds to produce oxime and hydrazone derivatives, respectively. Thus, many compounds within the scope of the invention may be produced by the general route depicted in Scheme 2. Additional compounds within the scope of the invention are exemplified in Tables 1 and 1A.
- Unless otherwise indicated, the following terms as used throughout this specification have the following meanings:
- “Me” refers to methyl.
- “Et” refers to ethyl.
- “tBu” refers to t-butyl.
- “iPr” refers to i-propyl.
- “Ph” refers to phenyl.
- “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- “Alkyl” refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl group may be optionally substituted with one or more substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, ═O, ═S, NO2, halogen, dimethyl amino and SH.
- “Alkenyl” refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably, the alkenyl group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, most preferably 2 to 4 carbons. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO2, halogen, dimethyl amino and SH.
- “Alkynyl” refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Preferably, the alkynyl group has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7 carbons, most preferably 2 to 4 carbons. The alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO2, halogen, dimethyl amino and SH.
- “Alkoxy” refers to an “O-alkyl” group.
- “Aryl” refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO2, amine, thioether, cyano, alkoxy, alkyl, and amino.
- “Alkaryl” refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.
- “Aryloxy” refers to an “O-aryl” group.
- “Arylalkyloxy” refers to an “O-alkaryl” group.
- “Carbocyclic” refers to cyclic saturated or unsaturated aliphatic hydrocarbon and aryl hydrocarbon groups wherein the ring atoms are exclusively carbons, and comprises from 6 to 20 carbon atoms, including said ring atoms.
- “Carbocyclic aryl” refers to an aryl group wherein the ring atoms are carbon.
- “Heterocyclic” refers to cyclic groups wherein the ring atoms comprise carbon atoms and at least one oxygen, nitrogen, and/or sulfur atom and may be saturated, unsaturated, i.e. have one or more double bonds, or aryl, and comprises up to 20 carbon atoms and from 1 to 5 of the above heteroatoms.
- “Heterocyclic aryl” refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen.
- “Hydrocarbyl” refers to a hydrocarbon radical having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
- “Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
- “Amide” refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
- “Ester” refers to —C(O)—O—R′, wherein R′ is alkyl, aryl or alkylaryl.
- “Thioamide” refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
- “Thiol ester” refers to —C(O)—S—R′, wherein R′ is alkyl, aryl, alkylaryl or hydrogen.
- “Amine” refers to a—N(R″)R′″ group, wherein R″ and R′″ are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
- “Thioether” refers to —S—R″, wherein R″ is alkyl, aryl, or alkylaryl.
- “Sulfonyl” refers to —S(O)2—R″″, where R″″ is aryl, C(CN)═C-aryl, CH2CN, alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.
- Also, alternatively the substituent on the phenyl moiety, as shown below, is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively. (Obviously, the 5 substituent is also a m substituent and the 6 substituent is an o substituent.)
- Specific compounds of the invention, that are prepared according to Example 2 through 199 and/or Schemes 1 through 16, are able to inhibit the activity of sphingosine-1-phosphate receptors reported in Table I, below. Compounds were assessed for their ability to activate or block activation of the human S1P3 receptor in T24 cells stably expressing the human S1P3 receptor. Ten thousand cells/well were plated into 384-well poly-D-lysine coated plates one day prior to use. The growth media for the S1P3 receptor expressing cell line was McCoy's 5A medium supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1% antibiotic-antimycotic and 400 μg/ml geneticin. On the day of the experiment, the cells were washed twice with Hank's Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer). The cells were then dye loaded with 2 uM Fluo-4 diluted in the HBSS/Hepes buffer with 1.25 mM Probenecid and incubated at 37° C. for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates. The positive control, Sphingosine-1-Phosphate (S1P), was diluted in HBSS/Hepes buffer with 4 mg/ml fatty acid free bovine serum albumin. The FLIPR transferred 12.5 μl from the ligand microplate to the cell plate and took fluorescent measurements for 75 seconds, taking readings every second, and then for 2.5 minutes, taking readings every 10 seconds. Drugs were tested over the concentration range of 0.61 nM to 10,000 nM. Data for Ca+2 responses were obtained in arbitrary fluorescence units and not translated into Ca+2 concentrations. IC50 values were determined through a linear regression analysis using the Levenburg Marquardt algorithm.
-
TABLE 1 S1P3 IC50 Compound (% inh) Number Structure Kb 7 560 nM (98) 8 3.1 M (71) 9 19 nM (100) 10 5 nM (100) 2 nM 11 6 nM (100) 2 nM 12 3 nM (100) 13 1.2 nM (100) 1.6 nM 14 3.1 M (96) 15 260 nM (100) 16 3 nM (100) 1.2 nM 17 6.5 nM (99) 18 242 nM (94) 19 6 nM (100) 20 81 nM (100) 21 24 nM (99) 22 4 nM (99) 23 14 nM (100) 24 20 nM (100) 25 14 nM (100) 26 39 nM (100) 13 nM 27 6 nM (100) 11 nM 43 7 nM (100) 8 nM 44 24 nM (100) 45 NA 46 241 nM (100) 47 350 nM (100) 48 24 nM (100) 49 870 nM (100) 50 69 nM (100) 51 NA 52 2.0 M (85) 54 NA 55 234 nM (100) 69 5.0 M (98) 70 36 nM (100) 71 47 nM (97) 72 43 nM (99) 73 35 nM (100) 74 49 nM (99) 75 17 nM (97) 76 33 nM (99) 77 46 nM (96) 78 78 nM (100) 79 25 nM (96) 80 7 nM (99) 81 1.6 M (81) 82 44 nM (100) 83 280 nM (99) 84 40 nM (89) 85 18 nM (100) 86 48 nM (100) 87 115 nM (100) 89 59 nM (98) 93 NA 98 632 nM (100) 100 NA 103 NA 104 3.9 M (50) 105 485 nM (98) 106 689 nM (96) 107 NA 108 15 nM (98) 109 21 nM (99) 110 384 nM (100) 111 263 nM (100) 116 124 242 nM (90) 125 1.7 M (90) 126 177 nM (100) 127 890 nM (97) 128 502 nM (99) 130 44 nM (99) 131 890 nM (96) 132 16 nM (99) 133 36 nM (99) 140 NA 141 NA 142 48 nM (99) 143 36 nM (99) 146 NA 147 NA 148 13 nM (100) 149 29 nM (100) 150 5 nM (100) 151 65 nM (98) 152 17 nM (97) 153 5 nM (99) 154 15 nM (100) 156 NA 157 NA 158 NA 159 41 nM (96) 161 22 nM (100) 162 NA 163 55 nM (100) 164 42 nM (100) 165 7 nM (100) 171 NA 172 NA 173 NA 174 NA 175 1.1 M (100) 176 7.6 M (98) 177 NA 178 NA 180 NA 181 500 nM (100) 182 NA 183 152 nM (100) 184 >8.3 M (80) 186 NA 187 NA 188 120 nM (100) 189 87 nM (100) 190 13 nM (100) 191 38 nM (99) 192 70 nM (100) 193 163 nM (100) 194 20 nM (100) 195 51 nM (99) 196 70 nM (100) 197 67 nM (100) 198 10 nM (100) 199 51 nM (100) 203 580 nM (98) 204 1.6 M (97) 205 376 nM (97) 206 390 nM (99) 207 130 nM (97) 211 10 nM (100) 212 393 nM (100) 213 189 nM (100) 214 53 nM (100) 215 23 nM (99) 218 5.4 M (67) 219 38 nM (99) 221 21 nM (100) 222 10 nM (100) 223 24 nM (100) 224 NA 225 NA 226 87 nM (100) - The compounds of Table 1B are prepared according to procedures analogous to the procedures of Schemes 1 through 19 and/or Examples 2 through 226. These compounds are also tested for ability to inhibit the activity of the S1P3 receptor.
-
TABLE 1B S1P3 IC50 Compound (% inh) Number Structure Kb 12 nM (100) >10 M (40) 170 nM (100) 197 nM (100) 634 nM (100) 346 nM (99) 146 nM (99) 362 nM (93) 990 nM (98) 2.3 M (84) 2.5 M (87) 2.6 M (77) 12 nM (97) 4 nM (97) 9 nM (100) 0.9 nM (100) 21 nM (99) 88 nM (100) 86 nM (95) 9 nM (100) 9 nM (96) 187 nM (95) 145 nM (99) ND (98) 1.2 M (99) 124 nM (99) ND (54) 42 nM (99) 43 nM (99) 45 nM (99) 145 nM (99) 262 nM (98) 147 nM (100) NA 673 nM (100) 2.4 M (80) 174 nM (100) 58 nM (100) 19 nM (100) 21 nM 3 nM (100) 4 nM 288 nM (100) 324 nM (99) 5 nM (100) 9 nM 8 nM (100) 15 nM (100) 13 nM NA ND (65) 93 nM (100) 137 nM (100) -
- As a result of the above activity of the compounds utilized in the method of the present invention, it is clear that such compounds may be used in treating the following diseases and conditions for the following reasons.
- Glaucoma
-
- S1P3 subtypes are expressed in primary human trabecular meshwork cells and S1P decreases outflow facility>30% in perfused porcine eyes (See IOVS 45, 2263; 2004) by altering paracellular permeability.
- Dry Eye/Immunology
-
- Induces lymphocyte sequestration without affecting T cell proliferation.
- Angiogenesis disorders
-
- S1P3 receptor subtype is expressed in vascular endothelial cells and siRNA knockdown of S1P1 and S1P3 inhibits angiogenesis. S1P also promotes vascular endothelial cell migration and promotes barrier assembly and integrity.
- Cardiovascular (S1P3)
-
- S1P3 “knock out” mice lack S1P induced pulmonary edema.
- The invention is further illustrated by the following examples which are illustrative of a specific mode of practicing the invention and are not intended as limiting the scope of the claims.
- Unless otherwise indicated, the following Chemical Abbreviations are used in the examples:
- AlCl3; aluminum chloride
- BBr3: boron tribromide
- BOP:benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
- C3D7I: 2-iodopropane-d7
- CeCl3: cerium chloride
- Cs2CO3: cesium carbonate
- CH2Cl2:methylene chloride
- CH3CN: acetonitrile
- ClCH2CH2Cl: 1,2-dichloroethane
- (COCl)2: oxalyl chloride
- CuI: copper(I) iodide
- DIBAL: diisobutylaluminium hydride
- DMAP: 4-dimethylaminopyridine
- DMF: N,N-dimethylformamide
- DMSO: dimethyl sulfoxide
- Et2O: diethyl ether
- Et3N: triethylamine
- EtOAc: Ethyl acetate
- EtOH: ethanol
- EtSH: ethane thiol
- H2: hydrogen
- H2O: water
- H2SO4: sulfuric acid
- HBr: hydrogen bromide
- HCl: hydrogen chloride
- HOAc: acetic acid
- HONH2.HCl: hydroxylamine hydrochloride
- i-Pr2NEt: diisopropylethylamine
- i-PrCOCl: isobutyryl chloride
- K2CO3: potassium carbonate
- KH2PO4: potassium dihydrogen phosphate
- KOt-Bu: potassium tert-butoxide
- LiCl: lithium chloride
- MCPBA: meta-chloroperbenzoic acid
- MeI: methyl iodide
- MeLi: methyl lithium
- MeMgBr: methyl magnesiumbromide
- MeOH: methanol
- MeONH2.HCl: methoxylamine hydrochloride
- MgSO4: magnesium sulfate
- N2: nitrogen
- Na2CO3: sodium carbonate
- Na2SO4: sodium sulfate
- NaBH(OAc)3: sodium triacetoxyborohydride
- NaBH3CN: sodium cyanoborohydride
- NaBH4: sodium borohydride
- NaClO2: sodium chlorite
- NaH2PO4: sodium dihydrogen phosphate
- NaHCO3: sodium bicarbonate
- NaOH: sodium hydroxide
- NBS: N-bromosuccimide
- n-Bu4NI: tetrabutylammonium iodide
- NH3.H2O: ammonia
- NH4Cl: ammonium chloride
- NMO: N-methylmorpholine N-oxide
- NMP: N-methylpyrrolidone
- n-PrCOCl: butyryl chloride
- PCC: pyridinium chlorochromate
- Pd(PPh3)2Cl2: dichlorobis(triphenylphosphine)palladium (II)
- Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0)
- Pd—C: palladium on activated carbon
- POCl3: phosphorus(V) oxyxhloride
- PTLC: preparative thin layer chromatography
- t-BuOH: tert-butanol
- Tf2O: trifluoromethanesulfonic (triflic) anhydride
- THF: tetrahydrofuran
- TPAP: tetrapropylammonium perruthenate
- PTLC: preparative thin layer chromatography
- Acetyl chloride, benzyl bromide, 2-bromoethyl methyl ether, cyclopentyl iodide, diisopropylethylamine, 2-dimethylaminoethyl chloride hydrochloride, dimethylcarbamyl chloride, 1-iodobutane, 2-iodobutane, iodoethane, 1-iodohexane, 1-iodopropane, 2-iodopropane, 4-methylbenzene-1 sulfonyl chloride, pivaloyl chloride, pyridinium p-toluenesulfonate and tetrahydrofuran-3-ol were purchased from Aldrich Chemical Company.
- To a solution of methyl 6-methoxy-1H-indole-2-carboxylate (Compound 1, 1.0 g, 4.9 mmol) in DMF (10 ml) was added K2CO3 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol). The mixture was stirred at room temperature for 40 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from Et2O to yield the title compound as an off-white solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 3.81 (s, 3H), 3.85 (s, 3H), 5.81 (s, 2H), 6.73 (d, J=2.0 Hz, 1H), 6.84 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=6.8 Hz, 2H), 7.19-7.29 (m, 3H), 7.33 (s, 1H), 7.58 (d, J=8.8 Hz, 1H).
- To a solution of methyl 1-benzyl-6-methoxy-1H-indole-2-carboxylate (Compound 2, 4.33 g, 14.7 mmol) in THF (50 ml) at 0° C. under argon was added MeLi (3.0 M in diethoxymethane, 19.6 ml, 58.7 mmol) slowly. After 1 h, the ice-water bath was removed and the reaction was stirred at room temperature for 1 h, cooled to −78° C., quenched with dry ice, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo to yield the crude title compound as a yellow solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.69 (s, 6H), 3.73 (s, 3H), 5.76 (s, 2H), 6.42 (s, 1H), 6.55 (d, J=2.4 Hz, 1H), 6.75-6.81 (m, 1H), 6.96 (d, J=7.3 Hz, 2H), 7.22 (d, J=7.3 Hz, 1H), 7.25-7.30 (m, 2H), 7.49 (d, J=8.8 Hz, 1H).
- To a solution of 2-(1-benzyl-6-methoxy-1H-indol-2-yl)propan-2-ol (Compound 3, 1.05 g, 3.57 mmol) in EtOAc (35 ml) and EtOH (15 ml) was added 10% Pd—C (190 mg, 0.18 mmol) and HCl-Et2O (1.0 M, 1.25 ml, 1.25 mmol). The mixture was stirred under hydrogen gas (atmospheric pressure) for 1 h and was filtered. To the filtrate was added NaHCO3 (0.5 g) and H2O (0.5 ml), followed by Na2SO4 and MgSO4. This was then filtered and concentrated in vacuo to yield the crude title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.31 (d, J=6.7 Hz, 6H), 2.90-3.10 (m, 1H), 3.79 (s, 3H), 5.33 (s, 2H), 6.33 (s, 1H), 6.68 (d, J=2.1 Hz, 1H), 6.79 (dd, J=8.5, 2.3 Hz, 1H), 6.94-7.04 (m, 2H), 7.20-7.37 (m, 2H), 7.49 (d, J=8.5 Hz, 1H).
- POCl3 (0.48 ml, 5.23 mmol) was added dropwise to anhydrous DMF (2 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole (Compound 4, 583 mg, 2.09 mmol) in anhydrous DMF (8 ml) at 0° C. under argon. The reaction was stirred for 1 h at 0° C. and 30 min at room temperature, diluted with EtOAc, washed with aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a light yellow syrup.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.45 (d, J=7.3 Hz, 6H), 3.40-3.52 (m, 1H), 3.79 (s, 3H), 5.40 (s, 2H), 6.69 (d, J=2.4 Hz, 1H), 6.94 (dd, J=8.8, 2.0 Hz, 1H), 7.01 (d, J=7.3 Hz, 2H), 7.25-7.35 (m, 3H), 8.28 (d, J=8.8 Hz, 1H), 10.45 (s, 1H).
- To a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 5, 608 mg, 1.98 mmol) in t-BuOH (15 ml), CH3CN (15 ml), and 2-methyl-2-butene (10 ml) was added a solution of KH2PO4 (5.4 g, 39.6 mmol) and NaClO2 (80%, 4.5 g, 39.6 mmol) in H2O (50 ml). The mixture was stirred at room temperature and additional 2-methyl-2-butene, KH2PO4, and NaClO2 were added at the above ratio every 16-24 h until the starting material was consumed. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.39 (d, J=7.3 Hz, 6H), 3.75 (s, 3H), 3.99-4.17 (m, 1H), 5.45 (s, 2H), 6.62 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.8, 2.4 Hz, 1H), 6.99 (d, J=7.3 Hz, 2H), 7.22-7.34 (m, 3H), 8.18 (d, J=8.8 Hz, 1H).
- To a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 6, 226 mg, 0.70 mmol) in CH2Cl2 (7.0 ml) was added EDC (202 mg, 1.05 mmol) and DMAP (128 mg, 1.05 mmol) followed by 3,4-difluorobenzylamine (0.25 ml, 2.1 mmol). The reaction was stirred at room temperature for 18 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.3 Hz, 6H), 3.65-3.73 (m, 1H), 3.74 (s, 3H), 4.66 (d, J=5.9 Hz, 2H), 5.40 (s, 2H), 6.30 (t, J=6.3 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 6.82 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=6.8 Hz, 2H), 7.11-7.17 (m, 2H), 7.21-7.31 (m, 4H), 7.51 (d, J=8.3 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 7, 452 mg, 1.0 mmol) in CH2Cl2 (20 ml) at 0° C. was added BBr3 (1.0 M in CH2Cl2, 3.0 ml, 3.0 mmol) dropwise. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature, quenched with ice, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.3 Hz, 6H), 3.65-3.74 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 4.78 (s, 1H), 5.37 (s, 2H), 6.27 (t, J=5.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.71 (dd, J=8.5, 2.2 Hz, 1H), 6.95 (d, J=6.8 Hz, 2H), 7.11-7.17 (m, 2H), 7.21-7.32 (m, 4H), 7.46 (d, J=8.8 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (2.0 ml) was added K2CO3 (39 mg, 0.28 mmol) and iodoethane (22 l, 0.28 mmol). The reaction was stirred at room temperature for 48 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as an off-white solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.37 (t, J=7.0 Hz, 3H), 1.38 (d, J=7.3 Hz, 6H), 3.68-3.75 (m, 1H), 3.96 (q, J=7.0 Hz, 2H), 4.67 (d, J=6.3 Hz, 2H), 5.40 (s, 2H), 6.31 (t, J=5.4 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 6.82 (dd, J=8.8, 2.0 Hz, 1H), 6.97 (d, J=6.8 Hz, 2H), 7.13-7.17 (m, 2H), 7.23-7.31 (m, 4H), 7.52 (d, J=8.3 Hz, 1H)
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8.0 mg, 0.018 mmol) in DMF (1.0 ml) was reacted with K2CO3 (8.0 mg, 0.055 mmol) and 1-iodopropane (9.0 l, 0.092 mmol) to yield the title compound as a white solid.
- 1H NMR (500 MHz, METHANOL-d4) ppm 0.99 (t, J=7.6 Hz, 3H), 1.32 (d, J=7.3 Hz, 6H), 1.67-1.77 (m, 2H), 3.42-3.53 (m, 1H), 3.84 (t, J=6.6 Hz, 2H), 4.57 (s, 2H), 5.46 (s, 2H), 6.73 (d, J=2.0 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz, 1H), 6.95 (d, J=6.8 Hz, 2H), 7.19-7.29 (m, 5H), 7.30-7.36 (m, 1H), 7.49 (d, J=8.3 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8.0 mg, 0.018 mmol) in DMF (1.0 ml) was reacted with K2CO3 (8.0 mg, 0.055 mmol) and 2-iodopropane (9.0 l, 0.092 mmol) to yield the title compound as a white solid.
- 1H NMR (500 MHz, METHANOL-d4) ppm 1.21 (d, J=5.9 Hz, 6H), 1.33 (d, J=7.3 Hz, 6H), 3.45-3.55 (m, 1H), 4.41-4.50 (m, 1H), 4.57 (s, 2H), 5.46 (s, 2H), 6.72 (d, J=2.0 Hz, 1H), 6.74-6.79 (m, 1H), 6.96 (d, J=7.3 Hz, 2H), 7.18-7.29 (m, 5H), 7.30-7.37 (m, 1H), 7.49 (d, J=8.8 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodobutane (14.0 l, 0.12 mmol) to yield the title compound as a white solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 0.93 (t, J=7.3 Hz, 3H), 1.37 (d, J=7.3 Hz, 6H), 1.40-1.50 (m, 2H), 1.66-1.74 (m, 2H), 3.61-3.75 (m, 1H), 3.88 (t, J=6.6 Hz, 2H), 4.66 (d, J=6.3 Hz, 2H), 5.39 (s, 2H), 6.30 (t, J=5.9 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 6.81 (dd, J=8.5, 2.2 Hz, 1H), 6.96 (d, J=6.8 Hz, 2H), 7.10-7.17 (m, 2H), 7.21-7.32 (m, 4H), 7.50 (d, J=8.8 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 2-iodobutane (14.0 l, 0.12 mmol) to yield the title compound as a white solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 0.98 (d, J=6.8 Hz, 6H), 1.36 (d, J=7.3 Hz, 6H), 1.96-2.08 (m, 1H), 3.65 (d, J=6.8 Hz, 2H), 3.65-3.72 (m, 1H), 4.66 (d, J=6.3 Hz, 2H), 5.39 (s, 2H), 6.29 (t, J=5.6 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 6.82 (dd, J=8.8, 2.0 Hz, 1H), 6.96 (d, J=6.8 Hz, 2H), 7.11-7.16 (m, 2H), 7.21-7.31 (m, 4H), 7.50 (d, J=8.8 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodohexane (18.0 l, 0.12 mmol) to yield the title compound as a white solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 0.85-0.93 (m, 3H), 1.24-1.33 (m, 4H), 1.37 (d, J=6.8 Hz, 6H), 1.38-1.46 (m, 2H), 1.66-1.77 (m, 2H), 3.63-3.75 (m, 1H), 3.87 (t, J=6.6 Hz, 2H), 4.66 (d, J=5.9 Hz, 2H), 5.39 (s, 2H), 6.30 (t, J=5.6 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.81 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=6.8 Hz, 2H), 7.10-7.16 (m, 2H), 7.21-7.31 (m, 4H), 7.50 (d, J=8.8 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) and acetone (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol), benzyl bromide (14.0 l, 0.12 mmol), and catalytic amount of NaI to yield the title compound as an off-white solid.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.3 Hz, 6H), 3.65-3.75 (m, 1H), 4.66 (d, J=6.3 Hz, 2H), 4.99 (s, 2H), 5.37 (s, 2H), 6.28 (t, J=6.3 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.89 (dd, J=8.8, 2.0 Hz, 1H), 6.95 (d, J=6.8 Hz, 2H), 7.11-7.18 (m, 2H), 7.22-7.30 (m, 5H), 7.31-7.39 (m, 4H), 7.51 (d, J=8.8 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (1.0 ml) was reacted with K2CO3 (38 mg, 0.28 mmol), cyclopentyl iodide (53 l, 0.46 mmol) to yield the title compound as a white solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 1.48-1.60 (m, 2H), 1.66-1.86 (m, 6H), 3.62-3.83 (m, 1H), 4.56-4.77 (m, 3H), 5.38 (s, 2H), 6.32 (t, J=5.9 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H), 6.78 (dd, J=8.8, 2.1 Hz, 1H), 6.91-7.02 (m, 2H), 7.08-7.17 (m, 2H), 7.17-7.36 (m, 4H), 7.49 (d, J=8.5 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 17 mg, 0.039 mmol) in DMF (1.0 ml) was reacted with K2CO3 (28 mg, 0.20 mmol), 2-bromoethyl methyl ether (18 l, 0.20 mmol) to yield the title compound (9 mg, 49%).
- 1H NMR (300 MHz, CDCl3) ppm 1.37 (d, J=7.04 Hz, 6H), 3.40 (s, 3H), 3.60-3.78 (m, 3H), 4.04 (dd, J=5.42, 3.96 Hz, 2H), 4.66 (d, J=5.86 Hz, 2H), 5.39 (s, 2H), 6.30 (t, J=5.86 Hz, 1H), 6.68 (d, J=2.35 Hz, 1H), 6.85 (dd, J=8.65, 2.20 Hz, 1H), 6.89-7.01 (m, 2H), 7.10-7.18 (m, 2H), 7.17-7.35 (m, 4H), 7.51 (d, J=8.79 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 17 mg, 0.039 mmol) in DMF (1.0 ml) was reacted with K2CO3 (28 mg, 0.20 mmol), 2-dimethylamino ethyl chloride hydrochloride (20 mg, 0.20 mmol) to yield the title compound (10 mg, 53%).
- 1H NMR (300 MHz, CD3OD) ppm 1.32 (d, J=7.04 Hz, 6H), 2.30 (s, 6H), 2.71 (t, J=5.42 Hz, 2H), 3.37-3.59 (m, 1H), 4.02 (t, J=5.42 Hz, 2H), 4.57 (s, 2H), 5.48 (s, 2H), 6.73-6.88 (m, 2H), 6.89-7.02 (m, 2H), 7.12-7.40 (m, 6H), 7.50 (d, J=8.50 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 8 mg, 0.039 mmol) in DMF (1.0 ml) was added K2CO3 (13 mg, 0.092 mmol) and catalytic amount of NaOH, 3-iodotetrahydrofuran (Compound 29, 120 mg, crude). The reaction was stirred at room temperature for 2 days, and purified by a short silica gel column to yield the title compound (8 mg, 86%).
- 1H NMR (300 MHz, CDCl3) ppm 1.38 (d, J=7.04 Hz, 6H), 1.95-2.14 (m, 2H), 3.59-4.01 (m, 5H), 4.66 (d, J=6.16 Hz, 2H), 4.74-4.88 (m, 1H), 5.39 (s, 2H), 6.29 (t, J=4.40 Hz, 1H), 6.57 (d, J=2.05 Hz, 1H), 6.69-6.83 (m, 1H), 6.96 (d, J=7.62 Hz, 2H), 7.08-7.19 (m, 2H), 7.18-7.35 (m, 4H), 7.51 (d, J=8.79 Hz, 1H).
- Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 19 mg, 0.044 mol) in DMF (1.0 ml) was reacted with K2CO3 (30 g, 0.22 mmol), 3-bromodihydrofuran-2(3H)-one (20 mg, 0.22 mmol) to yield the title compound (16 mg, 71%).
- 1H NMR (300 MHz, acetone-d6) ppm 1.33 (d, J=5.57 Hz, 6H), 2.21-2.42 (m, 1H), 2.68-2.88 (m, 1H), 3.43-3.65 (m, 1H), 4.21-4.53 (m, 2H), 4.66 (d, J=6.16 Hz, 2H), 5.10-5.24 (m, 1H), 5.54 (s, 2H), 6.90 (dd, J=8.65, 2.20 Hz, 1H), 6.97-7.08 (m, 2H), 7.11 (d, J=2.35 Hz, 1H), 7.17-7.35 (m, 5H), 7.42 (dd, J=12.31, 8.50 Hz, 1H), 7.62 (d, J=8.79 Hz, 1H), 7.68-7.78 (m, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 18 mg, 0.041 mol) in pyridine (1 ml) was added dimethylcarbamyl chloride (40 l, 0.41 mmol) and stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid (17 mg, 82%).
- 1H NMR (300 MHz, CD3OD) ppm 1.32 (d, J=7.04 Hz, 6H), 2.96 (s, 3H), 3.09 (s, 3H), 3.37-3.55 (m, 1H), 4.58 (s, 2H), 5.48 (s, 2H), 6.87 (dd, J=8.65, 1.91 Hz, 1H), 6.91-6.99 (m, 2H), 7.02 (d, J=2.05 Hz, 1H), 7.16-7.39 (m, 6H), 7.58 (d, J=8.79 Hz, 1H).
- Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 18 mg, 0.041 mol) in pyridine (1 ml) was reacted with pivaloyl chloride (5.1 l, 0.41 mmol) to yield the title compound (16 mg, 74%).
- 1H NMR (300 MHz, CD3OD) ppm 1.25-1.40 (m, 15H), 3.34-3.55 (m, 1H), 4.58 (d, J=5.86 Hz, 2H), 5.49 (s, 2H), 6.73-6.88 (m, 1H), 6.89-6.99 (m, 2H), 7.00 (d, J=1.76 Hz, 1H), 7.14-7.41 (m, 6H), 7.60 (d, J=8.50 Hz, 1H).
- Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 7 mg, 0.016 mol) in pyridine (1 ml) was reacted with acetyl chloride (1.0 l, 0.16 mmol) to yield the title compound (8 mg, 100%).
- 1H NMR (300 MHz, CDCl3) ppm 1.37 (d, J=7.04 Hz, 6H), 2.26 (s, 3H), 3.54-3.76 (m, 1H), 4.66 (d, J=6.16 Hz, 2H), 5.41 (s, 2H), 6.28 (t, J=6.01 Hz, 1H), 6.81-7.01 (m, 4H), 7.06-7.19 (m, 2H), 7.18-7.35 (m, 4H), 7.61 (d, J=9.09 Hz, 1H).
- Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 7 mg, 0.016 mol) in pyridine (1 ml) was reacted with propionyl chloride (1.4 l, 0.16 mmol) to yield the title compound (8 mg, 100%).
- 1H NMR (300 MHz, CDCl3) ppm 1.23 (t, J=7.48 Hz, 3H), 1.37 (d, J=7.33 Hz, 6H), 2.55 (q, J=7.43 Hz, 2H), 3.53-3.73 (m, 1H), 4.66 (d, J=5.86 Hz, 2H), 5.41 (s, 2H), 6.30 (t, J=5.72 Hz, 1H), 6.83-7.00 (m, 4H), 7.06-7.18 (m, 2H), 7.18-7.35 (m, 4H), 7.60 (d, J=8.50 Hz, 1H).
- Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 9 mg, 0.021 mol) in pyridine (1 ml) was reacted with isobutyryl chloride (4.1 l, 0.21 mmol) to yield the title compound (8 mg, 80%).
- 1H NMR (300 MHz, CDCl3) ppm 1.13-1.42 (m, 12H), 2.47-2.85 (m, 1H), 3.50-3.74 (m, 1H), 4.66 (d, J=6.16 Hz, 2H), 5.41 (s, 2H), 6.20-6.44 (m, 1H), 6.74-7.00 (m, 4H), 7.07-7.18 (m, 2H), 7.17-7.35 (m, 4H), 7.60 (d, J=8.50 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added i-Pr2NEt (47 l, 0.27 mmol) and MOMCl (35 l, 0.45 mmol). The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 3.42 (s, 3H), 3.59-3.78 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 5.10 (s, 2H), 5.40 (s, 2H), 6.29 (t, J=5.7 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.89-7.01 (m, 3H), 7.10-7.17 (m, 2H), 7.20-7.34 (m, 4H), 7.52 (d, J=8.5 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added 2,3-dihydrofuran (68 l, 0.90 mmol) and catalytic amount of PPTS. The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.36 (d, J=7.3 Hz, 6H), 1.85-1.98 (m, 1H), 2.01-2.19 (m, 3H), 3.58-3.73 (m, 1H), 3.85-3.95 (m, 1H), 3.96-4.07 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 5.40 (s, 2H), 5.70 (d, J=4.7 Hz, 1H), 6.29 (t, J=5.7 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 6.89-6.99 (m, 3H), 7.11-7.17 (m, 2H), 7.19-7.32 (m, 4H), 7.51 (d, J=8.5 Hz, 1H).
- To a solution of tetrahydrofuran-3-ol (500 mg, 5.67 mmol) in pyridine (10 ml) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.08 g, 5.67 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated in vacuo to yield crude oil (1.2 g).
- 1H NMR (300 MHz, CDCl3) ppm 1.91-2.23 (m, 2H), 3.61-4.05 (m, 4H), 4.95-5.24 (m, 1H), 7.36 (d, J=7.92 Hz, 2H), 7.80 (d, J=8.50 Hz, 2H).
- To a solution of crude tetrahydrofuran-3-yl 4-methylbenzenesulfonate (Compound 28, 1.2 g, 4.96 mmol) in dry acetone (50 ml) was added NaI (1.1 g, 7.44 mmol). The reacted was heated at 60° C. for 2 days. The mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated in vacuo to yield crude oil which was used directly without purification.
- 1H NMR (300 MHz, CDCl3) ppm 2.23-2.55 (m, 2H), 3.81-4.08 (m, 3H), 4.08-4.43 (m, 2H).
- To a solution of ethyl-4-iodobenzoate (10.0 g, 36.2 mmol) in H2SO4 (20 ml) at 0° C. was added dropwise HNO3 (4.7 ml, 72.4 mmol). Reaction was stirred at room temperature for 1 h, cooled to 0° C., quenched with ice, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo to yield the crude title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.41 (t, J=7.09 Hz, 3H), 4.40 (q, J=7.09 Hz, 2H), 7.89 (dd, J=6.11, 1.96 Hz, 1H), 8.19 (d, J=7.62 Hz, 1H), 8.45 (s, 1H).
- To a solution of ethyl 4-iodo-3-nitrobenzoate (Compound 30, 9.45 g, 29.4 mmol) in ethyl acetate (200 ml) and tin(II) chloride dehydrate (33.1 g, 147 mmol). Reaction was heated to 85° C. for 1 h, cooled to 25° C., quenched with NaHCO3(S), filtered off white solid, and then organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.38 (t, J=7.09 Hz, 3H), 4.34 (q, J=7.18 Hz, 2H), 7.11 (dd, J=8.21, 2.05 Hz, 1H), 7.39 (d, J=2.05 Hz, 1H), 7.71 (d, J=8.06 Hz, 1H).
- To a solution of ethyl 3-amino-4-iodobenzoate (Compound 31, 6.87 g, 23.1 mmol) in triethylamine (50 ml) at 25° C. under argon then added CuI (22 mg, 1.16 mmol), Pd(PPh3)2Cl2 (82 mg, 1.16 mmol), and 3-methyl-1-butyne (3.18 g, 46.2 mmol). The reaction was stirred for 20 h at 25° C., filtered off brown solid, and then rinsed solid with EtOAc, organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (t, J=7.11 Hz, 3H), 2.86 (dt, J=13.67, 6.87 Hz, 1H), 4.25 (br. s., 2H), 4.34 (q, J=7.08 Hz, 2H), 7.29 (s, 1H), 7.32 (d, J=1.47 Hz, 1H), 7.33-7.38 (m, 1H).
- To a solution of ethyl 3-amino-4-(3-methylbut-1-ynyl)benzoate (Compound 32, 5.30 g, 22.9 mmol) in DMF (50 ml) at 25° C. under argon then added CuI (218 mg, 11.5 mmol). The reaction was heated for 2 h at 160° C., filtered off black solid, and then rinsed solid with EtOAc, organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (s, 3H), 1.39 (s, 3H), 1.40-1.44 (m, 3H), 1.42 (t, J=7.09 Hz, 3H), 3.11 (ddd, J=13.71, 6.74, 6.52 Hz, 1H), 4.39 (q, J=7.08 Hz, 2H), 6.30 (ddd, J=2.09, 0.99, 0.88 Hz, 1H), 7.53 (d, J=8.21 Hz, 1H), 7.78 (dd, J=8.36, 1.47 Hz, 1H), 8.08 (d, J=0.73 Hz, 1H), 8.17 (br. s., 1H).
- To a solution of ethyl 2-isopropyl-1H-indole-6-carboxylate (Compound 33, 2.00 g, 8.66 mmol) in DMF (12 ml) at 0° C. under argon then added dropwise POCl3 (1.58 ml, 17.3 mmol) was added dropwise. The reaction was stirred for 30 minutes at 25° C. then cooled to 0° C., quenched with saturated NaHCO3, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light tan solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.43 (t, J=7.18 Hz, 3H), 1.48 (s, 3H), 1.50 (s, 3H), 3.84 (dt, J=14.00, 6.93 Hz, 1H), 4.42 (q, J=7.18 Hz, 2H), 7.97 (dd, J=8.28, 1.39 Hz, 1H), 8.18 (d, J=0.73 Hz, 1H), 8.28 (d, J=8.21 Hz, 1H), 8.95 (br. s., 1H), 10.29 (s, 1H).
- To a solution of ethyl 3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 2.08 g, 8.04 mmol) in DMF (15 ml) was added K2CO3 (3.32 g, 24.1 mmol) and benzyl bromide (1.91 ml, 16.1 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.37 (t, J=7.11 Hz, 3H), 1.44 (s, 3H), 1.47 (s, 3H), 3.54-3.76 (m, 0H), 4.35 (q, J=7.18 Hz, 2H), 5.67 (s, 2H), 7.02 (d, J=7.18 Hz, 1H), 7.18-7.42 (m, 4H), 7.93 (d, J=8.36 Hz, 1H), 8.08 (s, 1H), 8.33 (d, J=8.65 Hz, 1H), 10.41 (s, 1H).
- Following General Procedure C, ethyl 3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 278 mg, 1.07 mmol) in DMF (15 ml) was added K2CO3 (590 mg, 4.28 mmol) and 2-(bromomethyl)pyridine (914 mg, 5.35 mmol). The reaction was stirred at 60° C. for 5 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.36 (t, J=7.17 Hz, 3H), 1.47 (s, 3H), 1.50 (s, 3H), 3.62-3.72 (m, 1H), 4.34 (d, J=7.18 Hz, 2H), 5.74 (s, 2H), 7.01 (d, J=7.77 Hz, 1H), 7.32 (d, J=7.48 Hz, 1H), 7.75 (td, J=7.70, 1.76 Hz, 1H), 7.93 (td, J=4.14, 1.39 Hz, 1H), 8.07 (d, J=0.73 Hz, 1H), 8.34 (t, J=4.18 Hz, 1H), 8.52 (ddd, J=4.87, 1.72, 0.88 Hz, 1H), 10.42 (s, 1H).
- To a solution of ethyl 3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 1.00 g, 3.86 mmol) in DMF (50 ml) was added NaH (463 mg, 19.3 mmol) and 3-(bromomethyl)pyridine (2.62 g, 15.4 mmol). The reaction was stirred at 60° C. for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.36 (t, J=7.11 Hz, 3H), 1.46 (s, 3H), 1.49 (s, 3H), 3.66 (dt, J=14.37, 7.18 Hz, 1H), 4.35 (q, J=7.08 Hz, 2H), 5.78 (s, 2H), 7.40 (qd, J=3.81, 3.66 Hz, 3H), 7.94 (dd, J=8.36, 1.47 Hz, 1H), 8.10 (d, J=0.73 Hz, 1H), 8.30-8.40 (m, 1H), 8.47 (dd, J=4.47, 1.98 Hz, 1H), 10.43 (s, 1H).
- To a solution of ethyl 3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 1.22 g, 4.72 mmol) in DMF (10 ml) was added NaH (170 mg, 7.08 mmol) and 2-(chloromethyl)oxazole (1.10 g, 9.44 mmol). The reaction was stirred at 25° C. for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.40 (t, J=7.11 Hz, 3H), 1.54 (s, 3H), 1.56 (s, 3H), 3.77 (dt, J=14.33, 7.13 Hz, 1H), 4.38 (q, J=7.04 Hz, 2H), 5.80 (s, 2H), 7.15 (d, J=0.73 Hz, 1H), 7.80-8.11 (m, 2H), 8.11-8.52 (m, 2H), 10.42 (s, 1H).
- General Procedure D. To a solution of ethyl 1-benzyl-3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 35, 220 mg, 0.63 mmol) in t-BuOH (6 ml), CH3CN (1 ml), and 2-methyl-2-butene (1.76 ml) was added a solution of NaH2PO4 (1.51 g, 12.6 mmol) and NaClO2 (80%, 1.13 g, 12.6 mmol) in H2O (6 ml). The mixture was stirred at room temperature fro 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.35 (t, J=7.11 Hz, 3H), 1.37 (s, 3H), 1.40 (s, 3H), 3.80-4.08 (m, 1H), 4.33 (q, J=7.13 Hz, 2H), 5.67 (s, 2H), 6.96 (d, J=9.23 Hz, 2H), 7.20-7.38 (m, 3H), 7.84 (dd, J=8.50, 1.47 Hz, 1H), 7.98 (s, 1H), 8.21 (dd, J=8.50, 0.59 Hz, 1H).
- Following General Procedure D, ethyl 3-formyl-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 36, 287 mg, 0.82 mmol) in t-BuOH (6 ml), 2-methyl-2-butene (2.29 ml) was added a solution of NaH2PO4 (1.97 g, 16.4 mmol) and NaClO2 (80%, 1.48 g, 16.4 mmol) in H2O (6 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30-1.47 (m, 9H), 3.94-4.13 (m, 1H), 4.33 (q, J=7.13 Hz, 2H), 5.74 (s, 2H), 6.76 (d, J=8.06 Hz, 1H), 7.26-7.37 (m, 1H), 7.65-7.77 (m, 1H), 7.85 (d, J=7.04 Hz, 1H), 7.98 (d, J=0.73 Hz, 1H), 8.21 (d, J=8.50 Hz, 1H), 8.55 (dd, J=6.23, 1.25 Hz, 1H).
- Following General Procedure D, ethyl 3-formyl-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (Compound 37, 754 mg, 1.54 mmol) in t-BuOH (30 ml), 2-methyl-2-butene (6.0 ml) was added a solution of NaH2PO4 (5.17 g, 30.8 mmol) and NaClO2 (80%, 3.88 g, 30.8 mmol) in H2O (12 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→60% EtOAc-hexanes) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.36 (t, J=7.11 Hz, 3H), 1.39 (s, 3H), 1.42 (s, 3H), 3.85-4.13 (m, 1H), 4.33 (q, J=7.08 Hz, 2H), 5.77 (s, 2H), 7.36 (t, J=2.05 Hz, 2H), 7.86 (dd, J=8.50, 1.47 Hz, 1H), 8.00 (d, J=0.88 Hz, 1H), 8.22 (dd, J=8.50, 0.73 Hz, 1H), 8.27 (d, J=1.76 Hz, 1H), 8.45 (dd, J=4.03, 2.42 Hz, 1H).
- Following General Procedure D, ethyl 3-formyl-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 38, 240 mg, 0.70 mmol) in t-BuOH (20 ml), 2-methyl-2-butene (2.0 ml) was added a solution of NaH2PO4 (1.69 g, 14.0 mmol) and NaClO2 (80%, 1.27 g, 14.0 mmol) in H2O (4 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a light tan solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.40 (t, J=7.11 Hz, 3H), 1.46 (s, 3H), 1.48 (s, 3H), 3.94-4.15 (m, 1H), 4.38 (q, J=7.18 Hz, 2H), 5.78 (s, 2H), 7.14 (d, J=0.73 Hz, 1H), 7.76-7.93 (m, 2H), 8.17 (d, J=2.05 Hz, 2H).
- To a solution of 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 1.00 g, 2.74 mmol) in CH2Cl2 (10 ml) was added EDC (1.04 g, 5.84 mmol) and DMAP (500 mg, 4.11 mmol), followed by 3,4-difluorobenzylamine (589 mg, 4.11 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31-1.39 (m, 9H), 3.47 (m, 1H), 4.33 (q, J=7.18 Hz, 2H), 4.59 (s, 2H), 5.60 (s, 2H), 6.96 (d, J=8.21 Hz, 1H), 7.22-7.40 (m, 6H), 7.67 (d, J=8.36 Hz, 1H), 7.82 (d, J=1.47 Hz, 1H), 8.00 (d, J=0.59 Hz, 1H).
- Following General Procedure E, 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 93 mg, 0.254 mmol) in CH2Cl2 (6 ml) was added EDC (97 mg, 0.508 mmol) and DMAP (46 mg, 0.381 mmol), followed by (5-fluoropyridin-3-yl)methanamine (81 mg, 0.63 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.27-1.43 (m, 9H), 3.40-3.59 (m, 1H), 4.33 (q, J=7.18 Hz, 2H), 4.69 (s, 2H), 5.61 (s, 2H), 6.95 (dd, J=7.48, 1.03 Hz, 2H), 7.19-7.34 (m, 3H), 7.65-7.76 (m, 2H), 7.82 (dd, J=8.36, 1.47 Hz, 1H), 8.00 (d, J=1.47 Hz, 1H), 8.39 (d, J=2.64 Hz, 1H), 8.52 (s, 1H).
- Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 150 mg, 0.409 mmol) in CH2Cl2 (6 ml) was added EDC (157 mg, 0.81 mmol) and DMAP (75 mg, 0.60 mmol), followed by (5-fluoropyridin-3-yl)methanamine (88 mg, 0.63 mmol). The crude material was purified by chromatography on silica gel (0-40% EtOAc-hexanes) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.25-1.45 (m, 9H), 3.40-3.59 (m, 1H), 4.33 (t, J=7.04 Hz, 2H), 4.60 (s, 2H), 5.68 (s, 2H), 6.74 (d, J=6.89 Hz, 1H), 7.18-7.43 (m, 4H), 7.61-7.76 (m, 2H), 7.82 (dd, J=8.50, 1.47 Hz, 1H), 8.00 (d, J=0.73 Hz, 1H), 8.54 (dt, J=5.42, 0.95 Hz, 1H).
- Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxylic acid (Compound 41, 365 mg, 0.997 mmol) in CH2Cl2 (12 ml) was added EDC (288 mg, 2.00 mmol) and DMAP (146 mg, 1.50 mmol), followed by 3,4-difluorobenzyl amine (171 mg, 1.50 mmol). The crude material was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.35 (dt, J=7.18, 3.59 Hz, 9H), 3.47 (m, 1H), 4.33 (q, J=7.18 Hz, 2H), 4.59 (s, 2H), 5.70 (s, 2H), 7.15-7.41 (m, 5H), 7.68 (dd, J=8.36, 0.59 Hz, 1H), 7.82 (dd, J=8.50, 1.47 Hz, 1H), 8.01 (d, J=0.73 Hz, 1H), 8.22 (d, J=1.91 Hz, 1H), 8.43 (dd, J=3.81, 2.64 Hz, 1H).
- Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 42, 244 mg, 0.685 mmol) in CH2Cl2 (12 ml) was added EDC (262 mg, 1.37 mmol) and DMAP (125 mg, 1.03 mmol), followed by 3,4-difluorobenzyl amine (197 mg, 1.03 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.33-1.52 (m, 9H), 3.59 (m, 1H), 4.37 (q, J=7.18 Hz, 2H), 4.57 (s, 2H), 5.70 (s, 2H), 7.12 (d, J=0.88 Hz, 1H), 7.18-7.42 (m, 3H), 7.63 (s, 1H), 7.81 (dd, J=8.43, 1.39 Hz, 2H), 7.85 (d, J=0.88 Hz, 1H), 8.18 (s, 1H).
- Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 80 mg, 0.22 mmol) in CH2Cl2 (5 ml) was added EDC (84 mg, 0.42 mmol) and DMAP (40 mg, 0.32 mmol), followed by 3,5-difluorobenzyl amine (47 mg, 0.32 mmol). The crude material was purified by chromatography on silica gel (0-40% EtOAc-hexanes) to yield the title compound as an off white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.28-1.41 (m, 9H), 3.51 (m, 1H), 4.32 (q, J=7.03 Hz, 2H), 4.62 (s, 2H), 5.68 (s, 2H), 6.74 (d, J=7.91 Hz, 1H), 6.85 (tt, J=9.08, 2.34 Hz, 1H), 7.04 (dd, J=8.50, 2.34 Hz, 2H), 7.30 (dd, J=6.74, 4.98 Hz, 1H), 7.59-7.75 (m, 2H), 7.74-7.88 (m, 1H), 8.00 (s, 1H), 8.53 (d, J=4.10 Hz, 1H).
- Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 150 mg, 0.41 mmol) in CH2Cl2 (25 ml) was added EDC (236 mg, 0.82 mmol) and DMAP (75 mg, 0.60 mmol), followed by (5-fluoropyridin-3-yl)methanamine (94 mg, 0.82 mmol). The crude material was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.25-1.45 (m, 9H), 3.42-3.62 (m, 1H), 4.33 (q, J=7.04 Hz, 2H), 4.69 (s, 2H), 5.68 (s, 2H), 6.69-6.80 (m, 1H), 7.26-7.36 (m, 1H), 7.63-7.76 (m, 3H), 7.79-7.86 (m, 1H), 8.00 (s, 1H), 8.39 (s, 1H), 8.52 (d, J=1.61 Hz, 2H).
- Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 80 mg, 0.22 mmol) in CH2Cl2 (5 ml) was added EDC (84 mg, 0.42 mmol) and DMAP (40 mg, 0.32 mmol), followed by 4-fluorobenzyl amine (47 mg, 0.32 mmol). The crude material was purified by chromatography on silica gel (0-45% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.27-1.44 (m, 9H), 3.48 (quin, J=7.25 Hz, 1H), 4.32 (q, J=7.13 Hz, 2H), 4.60 (s, 2H), 5.66 (s, 2H), 6.72 (d, J=7.91 Hz, 1H), 7.09 (dd, J=8.79, 4.40 Hz, 2H), 7.31 (d, J=5.86 Hz, 1H), 7.47 (dd, J=8.79, 5.27 Hz, 2H), 7.61-7.72 (m, 2H), 7.74-7.84 (m, 1H), 7.98 (s, 1H), 8.53 (d, J=4.10 Hz, 1H).
- Following General Procedure E, 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 39 mg, 0.11 mmol) in CH2Cl2 (4 ml) was added EDC (35 mg, 0.22 mmol) and DMAP (16 mg, 0.15 mmol), followed by 3,4-difluorobenzyl alcohol (20 mg, 0.15 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.21-1.44 (m, 9H), 3.74-4.03 (m, 1H), 4.32 (q, J=7.04 Hz, 2H), 5.39 (s, 2H), 5.66 (s, 2H), 6.96 (d, J=6.74 Hz, 2H), 7.21-7.37 (m, 5H), 7.38-7.56 (m, 1H), 7.83 (dd, J=8.50, 1.47 Hz, 1H), 8.01 (s, 1H), 8.12 (d, J=8.50 Hz, 1H).
- To a solution of ethyl 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 43, 200 mg, 0.408 mmol) in CH2Cl2 (10 ml) at −78° C. under argon was added Dibal-H (1.0 M in CH2Cl2, 1.6 ml, 1.63 mmol) slowly. The reaction was stirred for 3 h, quenched with methanol, celite, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (s, 3H), 1.33 (s, 3H), 3.41 (m, 1H), 4.58 (s, 2H), 4.62 (s, 2H), 5.53 (s, 2H), 5.66 (s, 2H), 6.96 (dd, J=6.16, 1.76 Hz, 2H), 7.14 (d, J=8.50 Hz, 1H), 7.30 (m, 6H), 7.39 (m, 1H), 7.60 (d, J=7.91 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-(hydroxymethyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 52, 340 mg, 0.759 mmol) in CH2Cl2 (10 ml) at 25° C. under argon was added molecular sieve powder (300 mg), NMO (267 mg, 2.28 mmol), TPAP (26 mg, 0.08 mmol). The reaction was stirred for 10 minutes, then concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.33 (s, 3H), 1.35 (s, 3H), 3.40-3.59 (m, 1H), 4.59 (s, 2H), 5.64 (s, 2H), 6.86-7.06 (m, 2H), 7.19-7.44 (m, 6H), 7.61-7.78 (m, 2H), 7.91 (d, J=0.73 Hz, 1H), 9.91 (s, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 18 mg, 0.040 mmol) in CH2Cl2 (1 ml) at 0° C. under argon was added ethylene diamine (2.5 mg, 0.042 mmol). The mixture was stirred at 0° C. for 30 minutes, and then added NBS (8 mg, 0.042 mmol). The reaction was stirred at 25° C. for 12 h, quenched with NaHCO3 (aqueous), diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (s, 3H), 1.33 (s, 3H), 3.38-3.52 (m, 1H), 3.73 (s, 4H), 4.58 (s, 2H), 5.57 (s, 2H), 6.94 (dd, J=7.77, 1.47 Hz, 2H), 7.15-7.41 (m, 6H), 7.56-7.60 (m, 1H), 7.64-7.67 (m, 1H), 7.82 (d, J=0.73 Hz, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 12 mg, 0.027 mmol) in MeOH (6 ml) was hydroxylamine hydrochloride (6.0 mg, 0.081 mmol) and pyridine (3 mg, 0.16 mmol). The mixture was stirred at 65° C. for 12 h, and then added concentrated in vacuo. The residue was purified by chromatography on silica gel (0-40% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (s, 3H), 1.33 (s, 3H), 3.36-3.52 (m, 1H), 4.58 (s, 2H), 5.54 (s, 2H), 6.95 (dd, J=7.99, 1.54 Hz, 2H), 7.17-7.38 (m, 5H), 7.42 (dd, J=8.36, 1.32 Hz, 1H), 7.49 (s, 1H), 7.61 (d, J=8.36 Hz, 1H), 8.10 (s, 1H).
- To a solution of ethyl 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 43, 609 mg, 1.24 mmol) in EtOH (15 ml) was added NaOH (248 mg, 6.21 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.38-3.59 (m, 1H), 4.59 (s, 2H), 5.59 (s, 2H), 6.96 (d, J=9.38 Hz, 2H), 7.18-7.44 (m, 6H), 7.63 (d, J=8.36 Hz, 1H), 7.80 (dd, J=8.36, 1.32 Hz, 1H), 8.00 (d, J=0.88 Hz, 1H).
- Following General Procedure F, ethyl 1-benzyl-3-((5-fluoropyridin-3-yl)methylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 44, 94 mg, 0.90 mmol) in EtOH (12 ml) was added NaOH (42 mg, 4.5 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.40-3.59 (m, 1H), 4.60 (s, 2H), 5.62 (s, 2H), 6.95 (dd, J=7.48, 1.03 Hz, 2H), 7.19-7.34 (m, 3H), 7.65-7.76 (m, 2H), 7.82 (dd, J=8.36, 1.47 Hz, 1H), 8.00 (d, J=1.47 Hz, 1H), 8.39 (d, J=2.64 Hz, 1H), 8.52 (s, 1H).
- Following General Procedure F, ethyl 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 45, 117 mg, 0.238 mmol) in EtOH (10 ml) was added NaOH (47 mg, 1.20 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.40-3.59 (m, 1H), 4.60 (s, 2H), 5.67 (s, 2H), 6.74 (d, J=6.89 Hz, 1H), 7.18-7.43 (m, 4H), 7.61-7.76 (m, 2H), 7.82 (dd, J=8.50, 1.47 Hz, 1H), 8.00 (d, J=0.73 Hz, 1H), 8.54 (dt, J=5.42, 0.95 Hz, 1H).
- Following General Procedure F, ethyl 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (Compound 46, 439 mg, 0.896 mmol)) in EtOH (12 ml) was added NaOH (179 mg, 4.48 mmol) and H2O (1 ml). The reaction was stirred at 25° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.40-3.59 (m, 1H), 4.59 (s, 2H), 5.70 (s, 2H), 7.15-7.41 (m, 5H), 7.68 (dd, J=8.36, 0.59 Hz, 1H), 7.82 (dd, J=8.50, 1.47 Hz, 1H), 8.01 (d, J=0.73 Hz, 1H), 8.22 (d, J=1.91 Hz, 1H), 8.43 (dd, J=3.81, 2.64 Hz, 1H).
- Following General Procedure F, ethyl 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 47, 197 mg, 0.414 mmol) in EtOH (12 ml) was added NaOH (82 mg, 2.07 mmol) and H2O (1 ml). The reaction was stirred at 25° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.59 (m, 1H), 4.57 (s, 2H), 5.70 (s, 2H), 7.12 (d, J=0.88 Hz, 1H), 7.18-7.42 (m, 3H), 7.63 (s, 1H), 7.81 (dd, J=8.43, 1.39 Hz, 2H), 7.85 (d, J=0.88 Hz, 1H), 8.18 (s, 1H).
- Following General Procedure F, ethyl 3-(3,5-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 48, 92 mg, 0.187 mmol) in EtOH (10 ml) was added NaOH (40 mg, 0.94 mmol) and H2O (1 ml). The reaction was stirred at 55° C. for 4 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.51 (m, 1H), 4.62 (s, 2H), 5.68 (s, 2H), 6.74 (d, J=7.91 Hz, 1H), 6.85 (tt, J=9.08, 2.34 Hz, 1H), 7.04 (dd, J=8.50, 2.34 Hz, 2H), 7.30 (dd, J=6.74, 4.98 Hz, 1H), 7.59-7.75 (m, 2H), 7.74-7.88 (m, 1H), 8.00 (s, 1H), 8.53 (d, J=4.10 Hz, 1H).
- Following General Procedure F, ethyl 3-(4-fluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 50, 90 mg, 0.18 mmol) in EtOH (6 ml) was added NaOH (39 mg, 0.90 mmol) and H2O (1 ml). The reaction was stirred at 55° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.48 (m, 1H), 4.60 (s, 2H), 5.66 (s, 2H), 6.72 (d, J=7.91 Hz, 1H), 7.09 (dd, J=8.79, 4.40 Hz, 2H), 7.31 (d, J=5.86 Hz, 1H), 7.47 (dd, J=8.79, 5.27 Hz, 2H), 7.61-7.72 (m, 2H), 7.74-7.84 (m, 1H), 7.98 (s, 1H), 8.53 (d, J=4.10 Hz, 1H).
- General Procedure G. To a solution of 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 30 mg, 0.065 mmol) in DMF (3 ml) was added BOP (35 mg, 0.090 mmol) and DIPEA (17 mg, 0.098 mmol), followed by ethanolamine (6 mg, 0.098 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (s, 3H), 1.34 (s, 3H), 3.37-3.46 (m, 1H), 3.49 (t, J=5.86 Hz, 2H), 3.65-3.74 (m, 2H), 4.59 (s, 2H), 5.60 (s, 2H), 6.94 (dd, J=7.92, 1.61 Hz, 2H), 7.17-7.42 (m, 6H), 7.65 (dd, J=2.35, 1.03 Hz, 2H), 7.91 (s, 1H).
- Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.076 mmol) in DMF (3 ml) was added BOP (40 mg, 0.091 mmol) and DIPEA (20 mg, 0.10 mmol), followed by 2-amino-2-methylpropan-1-ol (15 mg, 0.15 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (s, 3H), 1.34 (s, 3H), 1.39 (s, 6H), 3.43 (dt, J=14.18, 7.05 Hz, 1H), 3.66 (s, 2H), 4.58 (s, 2H), 5.59 (s, 2H), 6.96 (d, J=1.61 Hz, 2H), 7.16-7.49 (m, 5H), 7.52-7.60 (m, 1H), 7.60-7.68 (m, 1H), 7.84 (s, 1H), 7.97 (s, 1H).
- Following General Procedure G, 1-benzyl-3-(5-fluoropyridin-3-yl)methylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 57, 104 mg, 0.237 mmol) in DMF (6 ml) was added BOP (124 mg, 0.284 mmol) and DIPEA (61 mg, 0.355 mmol), followed by L-alanol (26 mg, 0.355 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.23 (s, 3H), 1.30 (s, 3H), 1.32 (s, 3H), 3.37-3.48 (m, 1H), 3.54-3.61 (m, 2H), 4.12-4.23 (m, 1H), 4.69 (s, 2H), 5.60 (s, 2H), 6.95 (dd, J=7.62, 1.03 Hz, 2H), 7.19-7.31 (m, 3H), 7.63-7.76 (m, 4H), 7.93 (s, 1H), 8.39 (d, J=2.35 Hz, 1H).
- Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 37 mg, 0.08 mmol) in DMF (3 ml) was added BOP (42 mg, 0.10 mmol) and DIPEA (16 mg, 0.10 mmol), followed by D-alanol (16 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.22 (d, J=6.89 Hz, 3H), 1.31 (s, 3H), 1.33 (s, 3H), 3.38-3.48 (m, 1H), 3.58 (d, J=5.57 Hz, 2H), 4.17 (q, J=6.89 Hz, 1H), 4.59 (s, 2H), 5.59 (s, 2H), 6.94 (dd, J=7.92, 1.61 Hz, 2H), 7.18-7.41 (m, 6H), 7.65 (s, 2H), 7.91 (s, 1H).
- Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 42 mg, 0.089 mmol) in DMF (4 ml) was added BOP (48 mg, 0.11 mmol) and DIPEA (23 mg, 0.10 mmol), followed by (S)-2-aminobutan-1-ol (16 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a light yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 0.97 (t, J=7.16 Hz 3H), 1.24 (t, J=7.11 Hz, 4H), 1.32 (s, 3H), 1.34 (s, 3H), 3.38-3.52 (m, 1H), 3.61-3.78 (m, 2H), 3.83-3.95 (m, 1H), 4.59 (s, 2H), 5.61 (s, 2H), 6.96 (d, J=8.21 Hz, 2H), 7.18-7.43 (m, 6H), 7.66 (s, 2H), 7.92 (d, J=1.03 Hz, 1H).
- Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.080 mmol) in DMF (4 ml) was added BOP (40 mg, 0.10 mmol) and DIPEA (20 mg, 0.11 mmol), followed by 1-amino-2-methylpropan-2-ol (10 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.21 (s, 6H), 1.31 (s, 3H), 1.34 (s, 3H), 3.39 (s, 2H), 3.40-3.51 (m, 1H), 4.59 (s, 2H), 5.59 (s, 2H), 6.96 (d, J=1.76 Hz, 2H), 7.16-7.40 (m, 6H), 7.66 (dd, J=3.30, 1.10 Hz, 2H), 7.91 (s, 1H).
- Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.080 mmol) in CH2Cl2 (3 ml) was added EDC (25 mg, 0.15 mmol) and DMAP (15 mg, 0.09 mmol), followed by propargyl amine (7 mg, 0.09 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as an oil.
- 1H NMR (500 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.33 (s, 3H), 2.55 (t, J=2.57 Hz, 1H), 3.44 (dt, J=14.27, 7.11 Hz, 1H), 4.13 (s, 2H), 4.58 (s, 2H), 5.58 (s, 2H), 6.94 (d, J=6.97 Hz, 2H), 7.18-7.30 (m, 5H), 7.31-7.41 (m, 1H), 7.59-7.70 (m, 2H), 7.89 (d, J=0.73 Hz, 1H).
- To a solution of 1-benzyl-N3-(3,4-difluorobenzyl)-N6-(2-hydroxyethyl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 63, 17 mg, 0.033 mmol) in CH2Cl2 (2 ml) at 0° C. under argon was added Et3N (0.03 ml, 0.2 mmol), and then added MsCl (7 mg, 0.066 mmol). The reaction was stirred at 25° C. for 3 h, quenched with H2O diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.35 (s, 3H), 3.41-3.56 (m, 1H), 3.98 (t, J=9.38 Hz, 2H), 4.45 (t, J=9.53 Hz, 2H), 4.59 (d, J=4.10 Hz, 2H), 5.57 (s, 2H), 6.94 (d, J=6.16 Hz, 2H), 7.13-7.43 (m, 6H), 7.55-7.79 (m, 2H), 7.87 (s, 1H), 8.71 (t, J=5.13 Hz, 1H).
- The title compound was prepared from 1-benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxy-2-methylpropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 64) by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.18-1.47 (m, 12H), 3.37-3.53 (m, 1H), 4.20-4.46 (m, 2H), 4.59 (d, J=5.57 Hz, 2H), 5.59 (s, 2H), 6.94 (d, J=3.96 Hz, 2H), 7.06-7.43 (m, 6H), 7.55-7.84 (m, 2H), 7.89-7.96 (m, 1H), 8.78 (d, J=1.17 Hz, 1H).
- The title compound was prepared from (S)-1-benzyl-N3-((5-fluoropyridin-3-yl)methyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 65) by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.26-1.36 (m, 9H), 3.39-3.53 (m, 1H), 4.04 (t, J=7.99 Hz, 1H), 4.27-4.46 (m, 1H), 4.61 (d, J=8.36 Hz, 1H), 4.69 (d, J=5.72 Hz, 2H), 5.59 (s, 2H), 6.89-7.03 (m, 2H), 7.12-7.35 (m, 3H), 7.56-7.78 (m, 3H), 7.91 (s, 1H), 8.39 (d, J=2.64 Hz, 1H), 8.51 (s, 1H), 8.82 (t, J=7.84 Hz, 1H).
- The title compound was prepared from (S)-1-benzyl-N3-((5-fluoropyridin-3-yl)methyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 65) by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 0.96 (t, J=7.40 Hz, 3H), 1.31 (s, 3H), 1.33 (s, 3H), 1.51-1.81 (m, 2H), 3.39-3.57 (m, 1H), 4.11 (dd, J=7.48, 6.45 Hz, 2H), 4.50 (dd, J=8.94, 7.92 Hz, 1H), 4.68 (s, 2H), 5.58 (s, 2H), 6.94 (dd, J=7.77, 1.47 Hz, 2H), 7.14-7.35 (m, 4H), 7.62-7.81 (m, 3H), 7.90 (s, 1H), 8.39 (d, J=2.64 Hz, 1H), 8.51 (s, 1H).
- The title compound was prepared from (R)-1-benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 66) by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.26 (s, 3H), 1.37 (s, 3H), 3.36-3.51 (m, 1H), 4.09 (t, J=7.11 Hz, 1H), 4.26-4.42 (m, 1H), 4.59 (s, 2H), 4.71 (m, 1H), 5.60 (s, 2H), 6.89-7.02 (m, 2H), 7.16-7.44 (m, 6H), 7.59-7.75 (m, 2H), 7.90 (s, 1H).
- The title compound was prepared from (S)-1-benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxybutan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 67) by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 0.96 (t, J=7.40 Hz, 3H), 1.32 (s, 3H), 1.34 (s, 3H), 1.52-1.81 (m, 2H), 3.38-3.52 (m, 1H), 4.12 (d, J=7.62 Hz, 1H), 4.15-4.29 (m, 1H), 4.51 (dd, J=8.94, 7.92 Hz, 1H), 4.57-4.62 (m, 2H), 5.58 (s, 2H), 6.95 (d, J=1.76 Hz, 2H), 7.08-7.45 (m, 6H), 7.51-7.82 (m, 2H), 7.89 (d, J=0.59 Hz, 1H), 8.72 (t, J=7.84 Hz, 1H).
- The title compound was prepared from (S)-1-benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.21-1.41 (m, 9H), 3.39-3.56 (m, 1H), 4.12 (t, J=8.21 Hz, 1H), 4.59 (s, 2H), 4.65 (d, J=8.50 Hz, 1H), 5.60 (s, 2H), 6.88-6.99 (m, 2H), 7.15-7.41 (m, 6H), 7.63-7.78 (m, 2H), 7.93 (s, 1H).
- The title compound was prepared from (R)-1-benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxy-3-methoxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 1.34 (s, 3H), 1.36 (s, 3H), 3.37 (s, 3H), 3.44-3.61 (m, 2H), 4.31-4.57 (m, 2H), 4.60 (d, J=5.57 Hz, 2H), 5.60 (s, 2H), 6.97 (d, J=1.76 Hz, 2H), 7.17-7.45 (m, 6H), 7.63-7.80 (m, 2H), 7.93 (s, 1H), 8.74 (s, 1H).
- The title compound was prepared from (R)—N3-(3,4-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 1.32 (m, 9H), 3.43-3.55 (m, 1H), 4.00 (t, J=8.06 Hz, 1H), 4.28-4.38 (m, 1H), 4.52-4.64 (m, 3H), 5.65 (s, 1H), 6.71 (d, J=7.62 Hz, 1H), 7.20-7.40 (m, 4H), 7.63-7.75 (m, 3H), 7.88 (s, 1H), 8.53 (d, J=4.10 Hz, 1H), 8.72 (t, 1H).
- The title compound was prepared from (S)—N3-(3,4-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 1.24-1.39 (m, 9H), 3.42-3.60 (m, 1H), 4.00 (t, J=8.06 Hz, 1H), 4.25 (m, 1H), 4.38 (m, 1H), 4.56 (s, 2H), 5.65 (s, 2H), 6.70 (d, J=7.62 Hz, 1H), 7.18-7.40 (m, 4H), 7.60-7.77 (m, 3H), 7.88 (d, J=0.73 Hz, 1H), 8.54 (d, J=5.57 Hz, 1H).
- The title compound was prepared from (S)—N3-(3,4-difluorobenzyl)-N6-(1-hydroxybutan-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4) ppm 0.96 (t, J=7.61 Hz, 3H), 1.32 (s, 3H), 1.35 (s, 3H), 1.49-1.85 (m, 2H), 3.40-3.59 (m, 1H), 4.02-4.11 (m, 1H), 4.49 (t, J=8.79 Hz, 1H), 4.56 (s, 2H), 5.65 (s, 2H), 6.70 (d, J=7.62 Hz, 1H), 7.18-7.40 (m, 4H), 7.60-7.77 (m, 3H), 7.88 (d, J=0.73 Hz, 1H), 8.54 (d, J=5.57 Hz, 1H).
- Following General Procedure H, (S)-6-(4-(benzyloxymethyl)-4,5-dihydrooxazol-2-yl)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide was prepared (10 mg, 0.015 mmol), was then reacted with BBr3 (1M in CH2Cl2, 0.05 ml, 0.05 mmol) in CH2Cl2 (2 ml) at −78° C. for 1 h, quenched with water, diluted with EtOAc, washed organic with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.34 (s, 3H), 3.41-3.57 (m, 1H), 3.59-3.76 (m, 2H), 4.27-4.43 (m, 1H), 4.50 (t, J=8.28 Hz, 1H), 4.59 (s, 2H), 5.65 (s, 2H), 6.70 (d, J=7.92 Hz, 1H), 7.18-7.42 (m, 4H), 7.61-7.79 (m, 3H), 7.91 (s, 1H), 8.53 (d, J=4.98 Hz, 1H).
- The title compound was prepared from (S)—N3-(3,4-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 1.22-1.42 (m, 9H), 3.41-3.62 (m, 1H), 3.99 (t, J=8.06 Hz, 1H), 4.31 (dd, J=9.52, 6.89 Hz, 1H), 4.54 (d, J=8.20 Hz, 1H), 4.59 (s, 2H), 5.67 (s, 2H), 7.08-7.31 (m, 2H), 7.29-7.49 (m, 3H), 7.56-7.80 (m, 2H), 7.89 (s, 1H), 8.21 (s, 1H), 8.43 (d, J=3.52 Hz, 1H).
- The title compound was prepared from (S)—N3-(3,4-difluorobenzyl)-N6-(1-hydroxybutan-2-yl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (500 MHz, METHANOL-d4) ppm 1.00 (t, J=7.46 Hz, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 1.55-1.87 (m, 2H), 3.57 (dt, J=14.18, 7.09 Hz, 1H), 4.17 (t, J=7.83 Hz, 1H), 4.25 (ddd, J=14.73, 7.27, 7.09 Hz, 1H), 4.57 (s, 2H), 5.67 (s, 2H), 7.11 (s, 1H), 7.19-7.28 (m, 2H), 7.34 (d, J=7.82 Hz, 1H), 7.61 (d, J=8.31 Hz, 1H), 7.73 (d, J=8.56 Hz, 1H), 7.84 (s, 1H), 8.05 (s, 1H), 8.71 (br. s., 1H).
- The title compound was prepared from (S)—N3-(3,5-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 1.23-1.42 (m, 9H), 3.41-3.58 (m, 1H), 3.98 (t, 1H), 4.23-4.38 (m, 1H), 4.47-4.58 (m, 1H), 4.62 (m, 1H), 5.65 (s, 2H), 6.76 (d, J=7.91, Hz, 1H), 6.76-6.91 (m, 1H), 7.00-7.11 (m, 1H), 7.21-7.36 (m, 1H), 7.61-7.79 (m, 4H), 7.88 (s, 1H), 8.44-8.58 (m, 1H).
- The title compound was prepared from (S)—N3-(3,5-difluorobenzyl)-N6-(1-hydroxybutan-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 0.96 (t, J=7.61 Hz, 3H), 1.32 (s, 3H), 1.35 (s, 3H), 1.49-1.85 (m, 2H), 3.40-3.59 (m, 1H), 4.12 (t, J=7.61 Hz, 2H), 4.14-4.30 (m, 1H), 4.49 (t, J=8.79 Hz, 1H), 4.63 (s, 2H), 5.65 (s, 2H), 6.71 (d, J=7.91 Hz, 1H), 6.79-6.90 (m, 1H), 6.99-7.10 (m, 1H), 7.25-7.33 (m, 1H), 7.62-7.78 (m, 4H), 7.89 (s, 1H), 8.52 (d, J=5.57 Hz, 1H).
- The title compound was prepared from (S)—N3-(4-fluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide by General Procedure H.
- 1H NMR (300 MHz, METHANOL-d4 ppm 1.34 (m, 9H), 3.41-3.61 (m, 1H), 3.95 (t, J=7.91 Hz, 1H), 4.25-4.43 (m, 1H), 4.54 (t, J=8.79 Hz, 1H), 4.63 (s, 2H), 5.65 (s, 2H), 6.63 (d, J=7.91 Hz, 1H), 7.01-7.14 (m, 2H), 7.23-7.33 (m, 1H), 7.40-7.54 (m, 2H), 7.61-7.76 (m, 3H), 7.90 (s, 1H), 8.53 (d, J=5.57 Hz, 1H).
- To a solution of N3-(4-fluorobenzyl)-N6-(2-hydroxy-2-methylpropyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide (Compound 68, 23 mg, 0.043 mmol) in benzene (6 ml) at 25° C. was added P2O5 (120 mg, 0.86 mmol). The mixture was stirred at 50° C. for 4 h, quenched with 6N NaOH (1 ml), extracted several times with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (s, 3H), 1.34 (s, 3H), 1.46 (s, 6H), 3.35-3.54 (m, 1H), 3.71 (s, 2H), 4.58 (s, 2H), 5.57 (s, 2H), 6.94 (d, J=6.16 Hz, 2H), 7.24 (dd, J=3.59, 1.39 Hz, 6H), 7.67 (dd, J=2.05, 1.03 Hz, 2H), 7.85 (s, 1H).
- Following General Procedure E, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 82 mg, 0.176 mmol) in CH2Cl2 (8 ml) was added EDC (51 mg, 0.264 mmol) and DMAP (26 mg, 0.256 mmol), followed by hydrazine (7 mg, 0.264 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.29-1.41 (m, 6H), 3.38-3.54 (m, 1H), 4.59 (s, 2H), 5.59 (s, 2H), 6.88-7.02 (m, 2H), 7.14-7.43 (m, 6H), 7.52-7.73 (m, 2H), 7.73-7.88 (m, 1H), 8.00 (br. s., 1H), 8.71 (d, J=2.93 Hz, 1H).
- 1-benzyl-N-(3,4-difluorobenzyl)-6-(hydrazinecarbonyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 88, 21 mg, 0.044 mmol) in triethyl orthoformate (5 ml) was heated to 145° C. for 5 h, then concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (s, 3H), 1.36 (s, 3H), 3.39-3.59 (m, 1H), 4.60 (s, 2H), 5.63 (s, 2H), 6.98 (d, J=8.06 Hz, 2H), 7.15-7.47 (m, 6H), 7.70-7.90 (m, 2H), 8.02 (d, J=0.59 Hz, 1H), 8.90 (s, 1H).
- POCl3 (2.94 ml, 32.2 mmol) was added dropwise to anhydrous DMF (10 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of methyl 6-methoxy-1H-indole-2-carboxylate (Aldrich, 2.2 g, 10.7 mmol) in anhydrous DMF (20 ml) at 0° C. under argon. The reaction was stirred for 20 h at room temperature, quenched with ice, diluted with EtOAc, a precipitate formed and was filtered and washed with H2O (×3) to give the title compound as an off-white solid.
- 1H NMR (300 MHz, DMSO-d6) ppm 3.81 (s, 3H), 3.97 (s, 3H), 6.79-7.09 (m, 2H), 8.09 (d, J=9.1 Hz, 1H), 10.57 (s, 1H), 12.66 (s, 1H).
- General Procedure J. 2-Bromomethylpyridine.HBr salt (7.0 g, 27.7 mmol) was treated with NaOH (4M, 6.9 ml, 27.6 mmol) in Et2O (20 ml). The ether layer was separated, washed with brine, and dried over MgSO4, filtered into a flask containing a suspension of methyl 3-formyl-6-methoxy-1H-indole-2-carboxylate (Compound 90, 1.29 g, 5.54 mmol) and K2CO3 (2.3 g, 16.6 mmol) in DMF (25 ml). The reaction was stirred at 60° C. for 3 h, cooled to room temperature, quenched with H2O and extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by washing with H2O (×3) and filtration to yield the title compound as a golden brown solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 3.80 (s, 3H), 3.99 (s, 3H), 5.89 (s, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 7.00 (dd, J=8.8, 2.3 Hz, 1H), 7.19 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 7.57 (td, J=7.7, 1.9 Hz, 1H), 8.40 (d, J=9.1 Hz, 1H), 8.59 (ddd, J=4.7, 1.8, 0.9 Hz, 1H), 10.65 (s, 1H).
- To a suspension of methyl 3-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 91, 1.64 g, 5.07 mmol) in t-BuOH (120 ml) and dioxane (20 ml) was added 2-methyl-2-butene (25 ml) and a solution of NaH2PO4 (7.3 g, 61 mmol) and NaClO2 (80%, 5.7 g, 50.7 mmol) in H2O (100 ml). The reaction was stirred at room temperature for 6 h, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as an off-white solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 3.82 (s, 3H), 3.92 (s, 3H), 5.76 (s, 2H), 6.66-6.79 (m, 2H), 7.02 (dd, J=9.1, 2.1 Hz, 1H), 7.22 (dd, J=7.3, 5.3 Hz, 1H), 7.59 (td, J=7.8, 1.8 Hz, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.62 (d, J=5.0 Hz, 1H).
- To a solution of 6-methoxy-2-(methoxycarbonyl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 92, 1.59 g, 4.7 mmol) in anhydrous CH2Cl2 (50 ml) was added DMF (3 drops, catalytic amount) and (COCl)2 (2M in CH2Cl2, 5.9 ml, 11.8 mmol). The resulting mixture was stirred at room temperature for 1 h, and was concentrated in vacuo. To a solution of the crude product in CH2Cl2 (50 ml) was added 3,4-difluorobenzylamine (0.84 ml, 7.05 mmol), followed by Et3N (2.0 ml, 14.1 mmol). The reaction was stirred at room temperature for 1 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 3.78 (s, 3H), 3.80 (s, 3H), 4.64 (d, J=5.9 Hz, 2H), 5.73 (s, 2H), 6.71 (d, J=2.1 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 6.93 (dd, J=8.9, 2.2 Hz, 1H), 7.09-7.22 (m, 3H), 7.22-7.32 (m, 1H), 7.55 (td, J=7.6, 1.8 Hz, 1H), 8.14 (d, J=9.1 Hz, 2H), 8.58 (d, J=4.1 Hz, 1H).
- To a solution of methyl 3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 515 mg, 1.11 mmol) in CH2Cl2 (20 ml) at −78° C. was added DIBAL (1 M in CH2Cl2, 4.4 ml, 4.44 mmol) slowly. The reaction was stirred at −78° C. for 2 h, quenched with H2O, diluted with EtOAc, washed with NaOH and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a beige solid.
- 1H NMR (500 MHz, METHANOL-d4) ppm 3.81 (s, 3H), 4.62 (s, 2H), 5.98 (s, 2H), 6.89-6.96 (m, 3H), 7.22-7.30 (m, 3H), 7.31-7.37 (m, 1H), 7.65-7.72 (m, 1H), 7.80 (d, J=9.8 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H), 10.15 (s, 1H).
- The title compound was also isolated in the synthesis of Compound 94.
- 1H NMR (500 MHz, METHANOL-d4) ppm 3.75 (s, 3H), 4.60 (s, 2H), 4.95 (s, 2H), 5.62 (s, 2H), 6.80-6.88 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 7.20-7.26 (m, 2H), 7.26-7.37 (m, 2H), 7.71 (td, J=7.8, 1.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 8.51 (d, J=4.6 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 94, 70 mg, 0.16 mmol) in ClCH2CH2Cl (10 ml) at room temperature was added dimethylamine (2 M in THF, 0.24 ml, 0.48 mmol), HOAc (14 l, 0.24 mmol), and NaBH(OAc)3 (102 mg, 0.48 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc, then 9:1 EtOAc-Et3N, then 7:2:1 CH2Cl2-MeOH-Et3N) to yield the title compound as an off-white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 2.07 (s, 6H), 3.70 (s, 2H), 3.76 (s, 3H), 4.54 (s, 2H), 5.61 (s, 2H), 6.76-6.93 (m, 3H), 7.15-7.37 (m, 4H), 7.66 (td, J=7.6, 1.8 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-((dimethylamino)methyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 96) by General Procedure M.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 2.06 (s, 6H), 3.56 (s, 2H), 4.57 (d, J=5.3 Hz, 2H), 5.41 (s, 2H), 6.50 (d, J=7.9 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 6.85 (dd, J=8.6, 2.2 Hz, 1H), 7.03-7.24 (m, 4H), 7.42-7.53 (m, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 9.96-10.14 (m, J=5.6 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-((dimethylamino)methyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 97) by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.30 (d, J=6.2 Hz, 6H), 2.09 (s, 6H), 3.57 (s, 2H), 4.42-4.63 (m, 3H), 5.49 (s, 2H), 6.51 (d, J=6.4 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.8, 2.1 Hz, 1H), 7.04-7.25 (m, 4H), 7.43-7.57 (m, 1H), 8.27 (d, J=9.4 Hz, 1H), 8.59 (d, J=4.4 Hz, 1H), 9.96 (s, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-(hydroxymethyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 95) by General Procedure M.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.09 (t, J=7.3 Hz, 3H), 2.41 (q, J=7.3 Hz, 2
- H), 4.24 (s, 2H), 4.58 (s, 2H), 5.54 (s, 2H), 6.62 (d, J=1.8 Hz, 1H), 6.69-6.83 (m, 2H), 7.17-7.40 (m, 4H), 7.61 (d, J=8.2 Hz, 1H), 7.63-7.72 (m, 1H), 8.52 (d, J=5.6 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-(ethylthiomethyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 99) by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.19 (t, J=7.5 Hz, 3H), 1.47-1.65 (m, 4H), 1.69-1.87 (m, 4H), 2.55 (q, J=7.3 Hz, 2H), 4.28 (s, 2H), 4.61-4.75 (m, 3H), 5.54 (s, 2H), 6.61-6.72 (m, 2H), 6.84 (dd, J=8.8, 2.1 Hz, 1H), 7.09-7.31 (m, 4H), 7.48-7.58 (m, 1H), 7.67 (d, J=9.4 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H).
- The title compound was prepared from methyl 3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93) by General Procedure M and General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.17 (d, J=6.4 Hz, 6H), 1.25 (d, J=6.2 Hz, 6H), 4.51-4.64 (m, 3H), 5.05-5.18 (m, 1H), 5.84 (s, 2H), 6.80-6.89 (m, 3H), 7.16-7.29 (m, 3H), 7.30-7.40 (m, 1H), 7.56-7.71 (m, 2H), 8.49 (d, J=5.0 Hz, 1H).
- A solution of isopropyl 3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 101, 551 mg, 1.06 mmol) in MeOH (15 ml) and NaOH (1 M, 5.3 ml, 5.3 mmol) was stirred at room temperature for 4 h. The reaction was quenched cautiously with 6 M HCl at 0° C., extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc, then 8:2 EtOAc-MeOH, then 7:2:1 EtOAc-MeOH-Et3N) to yield the title compound as its Et3N salt.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.22 (d, J=5.9 Hz, 6H), 4.43-4.55 (m, 1H), 4.57 (s, 2H), 5.86 (s, 2H), 6.72 (d, J=2.1 Hz, 1H), 6.79 (dd, J=8.8, 2.3 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 7.15-7.36 (m, 4H), 7.58-7.69 (m, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H).
- To a solution of 3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic acid (Compound 102, 73 mg, 0.12 mmol) in DMF (2 ml) was added 2-aminoethanol (11 l, 0.17 mmol), BOP (64 mg, 0.14 mmol), and i-Pr2NEt 30 l, 0.17 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow syrup.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.29 (d, J=5.9 Hz, 6H), 3.55-3.69 (m, 2H), 3.74-3.85 (m, 2H), 4.45-4.58 (m, 1H), 4.63 (d, J=5.9 Hz, 2H), 5.63 (s, 2H), 6.77 (d, J=2.1 Hz, 1H), 6.87 (dd, J=8.9, 2.2 Hz, 1H), 7.06-7.28 (m, 4H), 7.32 (d, J=7.9 Hz, 1H), 7.63-7.74 (m, 1H), 7.80-7.96 (m, 2H), 8.52 (d, J=4.1 Hz, 1H), 9.93-10.08 (m, 1H).
- To a solution of N3-(3,4-difluorobenzyl)-N2-(2-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dicarboxamide (Compound 103, 36 mg, 0.069 mmol) in CH2Cl2 (3 ml) at 0° C. was added Et3N (58 l, 0.41 mmol) and methanesulfonyl chloride (11 l, 0.14 mmol). The reaction was stirred at room temperature for 0.5 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow film.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.25 (d, J=6.2 Hz, 6H), 3.94 (t, J=10.0 Hz, 2H), 4.31 (t, J=9.8 Hz, 2H), 4.47-4.64 (m, 3H), 5.85 (s, 2H), 6.79-6.92 (m, 3H), 7.16-7.42 (m, 4H), 7.61-7.73 (m, 1H), 7.85 (d, J=9.4 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H).
- The title compound was prepared from methyl 3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 96) by General Procedure 0.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.27 (d, J=6.2 Hz, 6H), 4.51-4.70 (m, 3H), 5.96 (s, 2H), 6.86-7.00 (m, 3H), 7.19-7.41 (m, 4H), 7.63-7.74 (m, 1H), 7.78 (d, J=9.7 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 10.16 (s, 1H).
- The title compound was also isolated in the synthesis of Compound 105.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.32 (d, J=5.9 Hz, 6H), 4.47-4.60 (m, 1H), 4.64 (d, J=5.9 Hz, 2H), 4.95 (s, 2H), 5.38 (s, 2H), 6.02 (s, 1H), 6.79-6.91 (m, 3H), 7.07-7.32 (m, 4H), 7.68 (td, J=7.8, 1.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 8.48 (d, J=4.4 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 27 mg, 0.058 mmol) in CH2Cl2 (2 ml) was added 1,2-ethylene-diamine (5 l, 0.070 mmol). The reaction was stirred at room temperature for 1 h and NBS (13 mg, 0.070 mmol) was added. The reaction was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (9:1 EtOAc-Et3N, then 8:2:1 EtOAc-MeOH-Et3N) followed by PTLC eluted with EtOAc to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.30 (d, J=6.2 Hz, 6H), 3.78 (s, 4H), 4.43-4.58 (m, 1H), 4.62 (s, 2H), 5.51 (s, 2H), 6.66 (d, J=2.1 Hz, 1H), 6.87 (dd, J=8.9, 2.2 Hz, 1H), 7.06-7.32 (m, 4H), 7.38 (d, J=7.9 Hz, 1H), 7.68-7.82 (m, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 9.95 (s, 1H).
- To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 102 mg, 0.23 mmol) in 1,2-dimethoxy-ethane (15 ml) was added MeMgBr (1.4 M in toluene-THF, 0.5 ml, 0.70 mmol) at 0° C. The reaction was stirred at room temperature for 2 h and more MeMgBr (1.0 ml, 1.4 mmol) was added. The reaction was stirred at room temperature for another 2 h and was quenched with ice, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.23 (dd, J=6.0, 1.3 Hz, 6H), 1.44 (d, J=6.7 Hz, 3H), 4.41-4.67 (m, 3H), 5.43 (q, J=6.9 Hz, 1H), 5.56-5.76 (m, 2H), 6.75-6.91 (m, 3H), 7.15-7.39 (m, 4H), 7.61-7.74 (m, 1H), 7.79 (d, J=8.8 Hz, 1H), 8.52 (d, J=4.7 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-2-(1-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 108, 8.0 mg, 0.017 mmol) in CH2Cl2 (1 ml) was added NMO (6.0 mg, 0.051 mmol) and TPAP (0.6 mg, 0.0017 mmol). The reaction was stirred at room temperature for 1 h and was purified directly by PTLC (75% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.29 (dd, J=6.0, 0.7 Hz, 6H), 2.59 (s, 3H), 4.46-4.60 (m, 1H), 4.67 (d, J=5.9 Hz, 2H), 5.67 (s, 2H), 6.55 (t, J=6.3 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 6.83-6.89 (m, 1H), 6.94 (d, J=7.6 Hz, 1H), 7.07-7.35 (m, 4H), 7.48-7.63 (m, 2H), 8.54 (d, J=4.7 Hz, 1H).
- To a solution of 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109, 18 mg, 0.038 mmol) in MeOH (3 ml) was added HONH2.HCl (8.0 mg, 0.11 mmol) and pyridine (30 l, 0.38 mmol). The reaction was stirred at 65° C. for 20 h and the solvent was removed in vacuo. The residue was purified by PTLC (75% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.26 (d, J=5.9 Hz, 6H), 2.08 (s, 3H), 4.40-4.53 (m, 1H), 4.58 (d, J=5.9 Hz, 2H), 5.46 (s, 2H), 6.59-6.71 (m, 3H), 6.89 (dd, J=8.9, 2.2 Hz, 1H), 7.03-7.24 (m, 4H), 7.41-7.55 (m, 1H), 7.92 (d, J=8.8 Hz, 1H), 8.50 (d, J=4.1 Hz, 1H), 10.61 (s, 1H).
- The title compound was prepared from 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109) and MeONH2.HCl by General Procedure Q.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.27 (d, J=6.2 Hz, 6H), 2.12 (s, 3H), 3.82 (s, 3H), 4.42-4.56 (m, 1H), 4.61 (d, J=5.6 Hz, 2H), 5.40 (s, 2H), 6.69 (d, J=2.1 Hz, 1H), 6.73-6.85 (m, 2H), 6.89 (dd, J=8.8, 2.1 Hz, 1H), 7.03-7.25 (m, 4H), 7.49-7.59 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 8.58 (d, J=4.4 Hz, 1H).
- A solution of ethyl 4,4-dimethyl-3-oxopentanoate (Alfa Aesar, 2.4 g, 14 mmol) and 3,4-difluorobenzylamine (Aldrich, 2.0 g, 14 mmol) in toluene (15 ml) was refluxed for 24 h. The solvent was removed to yield the title compound as an off-white wax. Used without further purification.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.18 (s, 9H), 3.55 (s, 2H), 4.42 (d, J=6.2 Hz, 2H), 6.95-7.31 (m, 3H), 7.57 (s, 1H).
- A solution of 4-fluoro-3-nitrobenzoic acid (Alfa Aesar, 10.0 g, 54 mmol) and concentrated H2SO4 (0.2 ml, 4.1 mmol) in EtOH (200 ml) was refluxed for 40 h. The mixture was cooled to 0° C., solid NaHCO3 and MgSO4 was added, and the suspension was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as an off-white solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.43 (t, J=7.0 Hz, 3H), 4.44 (q, J=7.2 Hz, 2H), 7.39 (dd, J=10.3, 8.8 Hz, 1H), 8.33 (ddd, J=8.6, 4.2, 2.1 Hz, 1H), 8.74 (dd, J=7.2, 2.2 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-4,4-dimethyl-3-oxopentanamide (Compound 112, 126 mg, 0.47 mmol) and ethyl 4-fluoro-3-nitrobenzoate (Compound 113, 100 mg, 0.47 mmol) in DMSO (1 ml) was added K2CO3 (130 mg, 0.94 mmol). The mixture was stirred at room temperature for 16 h, diluted with EtOAc, washed with 1 M HCl, H2O, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.17 (s, 9H), 1.41 (t, J=7.2 Hz, 3H), 4.35 (dd, J=5.9, 1.8 Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 5.86 (s, 1H), 6.63 (t, J=5.9 Hz, 1H), 6.86-7.14 (m, 3H), 7.77 (d, J=8.2 Hz, 1H), 8.21 (dd, J=8.2, 1.8 Hz, 1H), 8.50 (d, J=1.8 Hz, 1H).
- General Procedure R. To a solution of ethyl 4-(1-(3,4-difluorobenzylamino)-4,4-dimethyl-1,3-dioxopentan-2-yl)-3-nitrobenzoate (Compound 114, 91 mg, 0.20 mmol) in MeOH (10 ml) and saturated aqueous NH4Cl (5 ml) was added zinc dust (320 mg, 4.9 mmol). The mixture was stirred at room temperature for 0.5 h, filtered and concentrated. The remaining aqueous suspension was extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.39 (t, J=7.2 Hz, 3H), 1.53 (s, 9H), 4.37 (q, J=7.1 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 6.39 (t, J=6.0 Hz, 1H), 7.07-7.29 (m, 3H), 7.53 (d, J=8.5 Hz, 1H), 7.79 (dd, J=8.5, 1.5 Hz, 1H), 8.12 (d, J=1.2 Hz, 1H), 8.89 (s, 1H).
- To a solution of ethyl 2-tert-butyl-3-(3,4-difluorobenzylcarbamoyl)-1H-indole-6-carboxylate (Compound 115, 33 mg, 0.080 mmol) in DMF (1 ml) was added benzyl bromide (47 l, 0.40 mmol) and K2CO3 (33 mg, 0.24 mmol). The mixture was stirred at room temperature for 24 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) followed by PTLC (5% MeOH—CH2Cl2) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.33 (t, J=7.2 Hz, 3H), 1.49 (s, 9H), 4.30 (q, J=7.0 Hz, 2H), 4.65 (d, J=5.9 Hz, 2H), 5.67 (s, 2H), 6.26 (t, J=6.0 Hz, 1H), 6.87 (dd, J=7.9, 1.8 Hz, 2H), 7.12-7.35 (m, 6H), 7.45 (d, J=9.1 Hz, 1H), 7.72-7.82 (m, 2H).
- To a solution of 2-amino-4-nitrophenol (Aldrich, 1.0 g, 6.5 mmol) in THF (25 ml) was added n-PrCOCl (694 mg, 6.5 mmol) and pyridine (2.6 ml, 32.4 mmol). The reaction was refluxed for 5 days, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a brown solid.
- 1H NMR (300 MHz, acetone) ppm 0.99 (t, J=7.5 Hz, 3H), 1.60-1.89 (m, 2H), 2.54 (t, J=7.5 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.92 (dd, J=8.9, 2.8 Hz, 1H), 8.83 (d, J=2.9 Hz, 1H), 9.10 (s, 1H), 10.68 (s, 1H).
- To a solution of N-(2-hydroxy-5-nitrophenyl)butyramide (Compound 117, 1.75 g, 7.8 mmol) in CH2Cl2 (40 ml) at 0° C. was added Et3N (1.4 ml, 10.1 mmol) and Tf2O (1.7 ml, 10.2 mmol). After 10 min, the reaction was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.05 (t, J=7.5 Hz, 3H), 1.73-1.89 (m, 2H), 2.46 (t, J=7.5 Hz, 2H), 7.44 (s, 1H), 7.49 (d, J=9.1 Hz, 1H), 8.05 (dd, J=9.1, 2.6 Hz, 1H), 9.34 (d, J=2.6 Hz, 1H).
- A mixture of 2-butyramido-4-nitrophenyl trifluoromethanesulfonate (Compound 118, 200 mg, 0.56 mmol), CuI (32 mg, 0.17 mmol), and n-Bu4NI (311 mg, 0.84 mmol) in CH3CN (5 ml) and Et3N (1 ml) was purged with N2 for 10 min and Pd(PPh3)4 (64 mg, 0.056 mmol) was added and the mixture was purged with N2 for another 5 min. The mixture was then cooled to 0° C. and 3-methyl-1-butyne (76 mg, 1.12 mmol) was added. After 5 min, the reaction was quenched with aqueous NaHCO3, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.06 (t, J=7.5 Hz, 3H), 1.36 (d, J=6.7 Hz, 6H), 1.72-1.92 (m, 2H), 2.44 (t, J=7.5 Hz, 2H), 2.85-3.01 (m, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.88 (dd, J=8.8, 2.3 Hz, 1H), 8.04 (s, 1H), 9.33 (d, J=2.3 Hz, 1H).
- To a solution of N-(2-(3-methylbut-1-ynyl)-5-nitrophenyl)butyramide (Compound 119, 900 mg, 3.29 mmol) in NMP (10 ml) was added KOt-Bu (552 mg, 4.94 mmol) and the mixture was stirred at 70° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.41 (d, J=7.0 Hz, 6H), 3.07-3.22 (m, 1H), 6.38 (d, J=2.3 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.8, 2.1 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H).
- POCl3 (0.12 ml, 1.4 mmol) was added dropwise to anhydrous DMF (1.5 ml) at 0° C. under argon. After stirred for 20 min, a solution of 2-isopropyl-6-nitro-1H-indole (Compound 120, 115 mg, 0.56 mmol) in anhydrous DMF (1.5 ml) was added slowly to the above reaction and stirred for 1 h at 0° C. and 2 h at room temperature. The reaction was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.44 (d, J=7.0 Hz, 6H), 3.65-3.84 (m, 1H), 7.38 (s, 1H), 8.04-8.12 (m, 1H), 8.18-8.32 (m, 2H), 10.13 (s, 1H).
- To a solution of 2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 121, 244 mg, 1.05 mmol) in DMF (10 ml) was added benzyl bromide (0.62 ml, 5.26 mmol) and K2CO3 (726 mg, 5.26 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.49 (d, J=7.0 Hz, 6H), 3.45-3.60 (m, 1H), 5.54 (s, 2H), 6.94-7.02 (m, 2H), 7.29-7.41 (m, 3H), 8.16-8.24 (m, 2H), 8.49 (d, J=8.5 Hz, 1H), 10.51 (s, 1H).
- The title compound was prepared from 1-benzyl-2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 122) by General Procedure K.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.40 (d, J=7.3 Hz, 6H), 3.87-4.10 (m, 1H), 5.72 (s, 2H), 6.98 (dd, J=7.3, 1.5 Hz, 2H), 7.22-7.41 (m, 3H), 8.07 (dd, J=8.9, 2.2 Hz, 1H), 8.22-8.35 (m, 2H).
- The title compound was prepared from 1-benzyl-2-isopropyl-6-nitro-1H-indole-3-carboxylic acid (Compound 123) by General Procedure C.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.42 (d, J=7.3 Hz, 6H), 3.51-3.67 (m, 1H), 4.70 (d, J=6.2 Hz, 2H), 5.53 (s, 2H), 6.28 (t, J=6.9 Hz, 1H), 6.94 (dd, J=7.2, 1.9 Hz, 2H), 7.12-7.19 (m, 2H), 7.19-7.37 (m, 4H), 7.69 (d, J=8.8 Hz, 1H), 8.08 (dd, J=8.8, 2.1 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H).
- A solution of 1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-nitro-1H-indole-3-carboxamide (Compound 124, 300 mg, 0.65 mmol) in EtOAc (5 ml) was treated with 10% Pd—C (6.8 mg, 0.065 mmol) and hydrogen gas under atmospheric pressure at room temperature for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.3 Hz, 6H), 3.38-3.58 (m, 1H), 4.56 (s, 2H), 5.41 (s, 2H), 6.58-6.73 (m, 2H), 6.89-7.01 (m, 2H), 7.16-7.37 (m, 6H), 7.39 (d, J=8.5 Hz, 1H).
- To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 15 mg, 0.035 mmol) in MeOH (1 ml) was added dihydrofuran-3(2H)-one (Compound 129, 6.0 mg, 0.069 mmol), NaBH3CN (2.2 mg, 0.035 mmol), and HOAc (1 drop). The reaction was stirred at room temperature for 3 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.38 (d, J=7.0 Hz, 6H), 1.69-1.83 (m, 1H), 2.08-2.23 (m, 1H), 3.61 (dd, J=9.4, 2.9 Hz, 1H), 3.70-3.94 (m, 4H), 3.96-4.05 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 5.38 (s, 2H), 6.23-6.34 (m, 2H), 6.53 (dd, J=8.5, 1.8 Hz, 1H), 7.00 (d, J=8.2 Hz, 2H), 7.11-7.19 (m, 2H), 7.20-7.34 (m, 4H), 7.43 (d, J=8.8 Hz, 1H).
- To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 18 mg, 0.042 mmol) in CH2Cl2 (1 ml) was added i-PrCOCl (8.7 l, 0.089 mmol) and DMAP (10 mg, 0.089 mmol). The reaction was stirred at room temperature for 2 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.21 (d, J=6.7 Hz, 6H), 1.34 (d, J=7.0 Hz, 6H), 2.38-2.56 (m, 1H), 3.48-3.65 (m, 1H), 4.65 (d, J=6.2 Hz, 2H), 5.39 (s, 2H), 6.31 (t, J=6.0 Hz, 1H), 6.88-6.95 (m, 2H), 6.99 (dd, J=8.5, 1.8 Hz, 1H), 7.09-7.17 (m, 2H), 7.19-7.29 (m, 4H), 7.32 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H).
- A solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 20 mg, 0.046 mmol) and ethyl 4-bromobutanoate (13 l, 0.092 mmol) in NMP (1 ml) was heated at 168° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 2.06-2.20 (m, 2H), 2.57 (t, J=8.1 Hz, 2H), 3.59-3.74 (m, 1H), 3.78-3.88 (m, 2H), 4.66 (d, J=5.9 Hz, 2H), 5.44 (s, 2H), 6.30 (t, J=6.4 Hz, 1H), 6.94 (dd, J=7.9, 1.8 Hz, 2H), 7.10-7.18 (m, J=8.8, 4.7 Hz, 2H), 7.20-7.33 (m, 5H), 7.56-7.63 (m, 2H).
- To a suspension of PCC (4.2 g, 19.3 mmol) and 4 Å molecular sieves (2.0 g) in CH2Cl2 (40 ml) was added a solution of tetrahydrofuran-3-ol (Aldrich, 0.92 ml, 11.4 mmol) in CH2Cl2 (20 ml) and the mixture was heated to reflux for 16 h, cooled to room temperature, filtered through Celite, diluted with Et2O, filtered again through Celite, washed successively with 2 M HCl, H2O, and brine, dried over Na2SO4, and concentrated in vacuo. The crude was used without further purification.
- The title compound was prepared from 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125) and cyclopentanone by General Procedure T.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.31-1.47 (m, 1H), 1.37 (d, J=7.3 Hz, 6H), 1.50-1.76 (m, 3H), 1.84-2.02 (m, 3H), 2.12-2.23 (m, 1H), 3.61-3.86 (m, 2H), 4.66 (d, J=6.2 Hz, 2H), 5.37 (s, 2H), 6.25-6.37 (m, 2H), 6.53 (dd, J=8.6, 1.9 Hz, 1H), 6.96-7.06 (m, 2H), 7.10-7.18 (m, 2H), 7.19-7.34 (m, 4H), 7.40 (d, J=8.5 Hz, 1H).
- The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8) and 2-(chloromethyl)oxazole by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.38 (d, J=7.3 Hz, 6H), 3.62-3.79 (m, 1H), 4.67 (d, J=5.9 Hz, 2H), 5.09 (s, 2H), 5.40 (s, 2H), 6.30 (t, J=6.0 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 6.88-7.00 (m, 3H), 7.07 (s, 1H), 7.11-7.19 (m, 2H), 7.19-7.34 (m, 4H), 7.54 (d, J=8.5 Hz, 1H), 7.61 (s, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 12 mg, 0.028 mmol) in DMF (1 ml) was added K2CO3 (19 mg, 0.14 mmol) and 2-bromothiazole (23 mg, 0.14 mmol). The mixture was stirred at room temperature overnight and a small amount of NaOH was added. The reaction was kept stirring for 72 h, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.39 (d, J=7.0 Hz, 6H), 3.61-3.76 (m, 1H), 4.67 (d, J=5.6 Hz, 2H), 5.42 (s, 2H), 6.24-6.32 (m, 1H), 6.74 (d, J=3.8 Hz, 1H), 6.94 (dd, J=8.1, 1.3 Hz, 3H), 7.06-7.32 (m, 8H), 7.65 (d, J=9.1 Hz, 1H).
- The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8) and 4-iodotetrahydro-2H-pyran (Maybridge) by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.38 (d, J=7.0 Hz, 6H), 1.62-1.78 (m, 2H), 1.83-1.96 (m, 2H), 3.42-3.56 (m, 2H), 3.65-3.80 (m, 1H), 3.87-3.99 (m, 2H), 4.28-4.41 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 5.39 (s, 2H), 6.28 (t, J=5.7 Hz, 1H), 6.66 (d, J=2.1 Hz, 1H), 6.83 (dd, J=8.6, 2.2 Hz, 1H), 6.93-7.01 (m, 2H), 7.10-7.18 (m, 2H), 7.18-7.34 (m, 4H), 7.51 (d, J=8.8 Hz, 1H).
- To a solution of 1-iodo-4-methoxy-2-nitrobenzene (Aldrich, 10 g, 35.8 mmol) in Et3N (60 ml) and DMF (6 ml) was added CuI (34 mg, 0.18 mmol), Pd(PPh3)2Cl2 (126 mg, 0.18 mmol), and 3-methyl-1-butyne (5.0 ml, 73.5 mmol). The mixture was stirred at room temperature for 16 h and was concentrated. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→15% EtOAc-hexanes) to yield the title compound as a brown oil.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.27 (d, J=6.4 Hz, 6H), 2.70-2.92 (m, 1H), 3.86 (s, 3H), 7.06 (dd, J=8.9, 2.8 Hz, 1H), 7.40-7.50 (m, 2H).
- To a solution of 4-methoxy-1-(3-methylbut-1-ynyl)-2-nitrobenzene (Compound 134, 2.97 g, 13.6 mmol) in THF (45 ml) and EtOH (15 ml) at 0° C. was added SnCl2 (12.9 g, 68 mmol), followed by NaBH4 (3.1 g, 81.6 mmol) in three equal portions with one hour between each addition. The reaction was stirred at 0° C. for a total of 3.5 h and was quenched with aqueous ammonia, filtered through a pad of Celite, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.27 (d, J=7.0 Hz, 6H), 2.73-2.90 (m, 1H), 3.75 (s, 3H), 4.16 (s, 2H), 6.16-6.34 (m, 2H), 7.15 (d, J=8.2 Hz, 1H).
- To a solution of 5-methoxy-2-(3-methylbut-1-ynyl)aniline (Compound 135, 1.8 g, 9.5 mmol) in DMF (20 ml) was added CuI (101 mg, 0.53 mmol). The reaction was stirred at 160° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a brownish red solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.34 (d, J=7.0 Hz, 6H), 2.97-3.10 (m, 1H), 3.83 (s, 3H), 6.13-6.19 (m, 1H), 6.74 (dd, J=8.5, 2.3 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.76 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole (Compound 136) by General Procedure I.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.44 (d, J=7.0 Hz, 6H), 3.70-3.82 (m, 1H), 3.84 (s, 3H), 6.86 (d, J=2.1 Hz, 1H), 6.91 (dd, J=8.8, 2.3 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.36 (s, 1H), 10.21 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 139) by General Procedure J.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.45 (d, J=7.0 Hz, 6H), 3.43-3.64 (m, 1H), 3.79 (s, 3H), 5.50 (s, 2H), 6.59-6.77 (m, 2H), 6.94 (dd, J=8.5, 2.1 Hz, 1H), 7.17-7.26 (m, 1H), 7.50-7.67 (m, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.62 (d, J=5.3 Hz, 1H), 10.44 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carbaldehyde (Compound 138) by General Procedure K.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.39 (d, J=7.0 Hz, 6H), 3.76 (s, 3H), 4.06-4.29 (m, 1H), 5.58 (s, 2H), 6.56 (d, J=7.9 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.8, 2.3 Hz, 1H), 7.16-7.24 (m, 1H), 7.49-7.60 (m, 1H), 8.15 (d, J=9.1 Hz, 1H), 8.64 (d, J=5.3 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) and (6-(trifluoromethyl)pyridin-3-yl)methanamine by General Procedure C.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 3.68-3.87 (m, 4H), 4.81 (d, J=6.2 Hz, 2H), 5.52 (s, 2H), 6.41 (t, J=5.9 Hz, 1H), 6.52 (d, J=7.9 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.85 (dd, J=8.6, 2.2 Hz, 1H), 7.19 (dd, J=7.5, 4.8 Hz, 1H), 7.47-7.58 (m, 2H), 7.69 (d, J=7.9 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 8.62 (d, J=4.7 Hz, 1H), 8.79 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 140) by General Procedure L.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.36 (d, J=7.3 Hz, 6H), 3.71-3.86 (m, 1H), 4.80 (d, J=6.2 Hz, 2H), 5.49 (s, 2H), 6.40 (t, J=6.2 Hz, 1H), 6.52-6.60 (m, 2H), 6.74 (dd, J=8.5, 2.1 Hz, 1H), 7.15-7.23 (m, 1H), 7.45-7.59 (m, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.98 (dd, J=7.3, 2.3 Hz, 1H), 8.56 (d, J=4.7 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H).
- The title compound was prepared from 6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 141) and cyclopentyl iodide by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.36 (d, J=7.0 Hz, 6H), 1.49-1.64 (m, 2H), 1.67-1.88 (m, 6H), 3.71-3.91 (m, 1H), 4.67 (s, 1H), 4.80 (d, J=5.9 Hz, 2H), 5.51 (s, 2H), 6.46 (t, J=5.9 Hz, 1H), 6.53 (d, J=7.9 Hz, 1H), 6.62 (d, J=2.1 Hz, 1H), 6.81 (dd, J=8.8, 2.1 Hz, 1H), 7.18 (dd, J=7.3, 5.0 Hz, 1H), 7.46-7.57 (m, 2H), 7.68 (d, J=8.2 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 8.61 (d, J=4.1 Hz, 1H), 8.78 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) by, in order, General Procedure C, General Procedure L, and General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.38 (d, J=7.0 Hz, 6H), 1.62-1.79 (m, 2H), 1.84-1.98 (m, 2H), 3.44-3.57 (m, 2H), 3.71-3.87 (m, 1H), 3.87-4.00 (m, 2H), 4.31-4.44 (m, 1H), 4.67 (d, J=6.2 Hz, 2H), 5.50 (s, 2H), 6.28 (t, J=5.4 Hz, 1H), 6.54 (d, J=7.9 Hz, 1H), 6.68 (d, J=2.1 Hz, 1H), 6.85 (dd, J=8.6, 2.2 Hz, 1H), 7.09-7.31 (m, 4H), 7.45-7.58 (m, 2H), 8.62 (d, J=4.7 Hz, 1H).
- To a Parr reaction bottle was added Pd—C (10%, 560 mg, 0.52 mmol), followed by 6 M HCl (50 ml) and a solution of 2,6-dichloro-5-fluoronicotinonitrile (Aldrich, 10.0 g, 52.4 mmol) in MeOH (100 ml). The mixture was placed under 50 psi H2 on a shaker type Parr apparatus for 21 h, filtered and concentrated. The crude was dissolved in EtOAc, basified with aqueous NaOH, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as crude light yellow oil. Used without further purification.
- 1H NMR (300 MHz, METHANOL-d4) ppm 4.31 (s, 2H), 8.06 (d, J=8.2 Hz, 1H).
- To a Parr reaction bottle was added Pd—C (10%, 560 mg, 0.52 mmol), followed by 28% NH3.H2O (50 ml) and a solution of (2,6-dichloro-5-fluoropyridin-3-yl)methanamine (Compound 144, 10.1 g, 52 mmol) in MeOH (100 ml). The mixture was placed under 51 psi H2 on a shaker type Parr apparatus for 16 h, filtered and concentrated. The resulting aqueous solution was basified with NaOH, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by distillation under vacuum to yield the title compound as colorless oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 3.87 (s, 2H), 7.61-7.73 (m, 1H), 8.25-8.44 (m, 2H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) and (5-fluoropyridin-3-yl)methanamine (Compound 145) by General Procedure C.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30 (d, J=7.0 Hz, 6H), 3.38-3.57 (m, 1H), 3.73 (s, 3H), 4.67 (s, 2H), 5.56 (s, 2H), 6.63 (d, J=7.9 Hz, 1H), 6.76-6.85 (m, 2H), 7.29 (dd, J=6.9, 5.1 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.62-7.75 (m, 2H), 8.38 (d, J=2.6 Hz, 1H), 8.50 (s, 1H), 8.54 (d, J=4.1 Hz, 1H).
- The title compound was prepared from N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 146) by General Procedure L.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30 (d, J=7.0 Hz, 6H), 3.44-3.57 (m, 1H), 4.67 (s, 2H), 5.48 (s, 2H), 6.57-6.65 (m, 2H), 6.70 (dd, J=8.4, 1.9 Hz, 1H), 7.29 (dd, J=7.2, 4.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.61-7.74 (m, 2H), 8.38 (d, J=2.6 Hz, 1H), 8.50 (s, 1H), 8.54 (d, J=5.0 Hz, 1H).
- The title compound was prepared from N-((5-fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 147) by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 1.50-1.61 (m, 2H), 1.67-1.84 (m, 6H), 3.73-3.88 (m, 1H), 4.62-4.71 (m, 1H), 4.75 (d, J=5.9 Hz, 2H), 5.50 (s, 2H), 6.37 (t, J=6.0 Hz, 1H), 6.53 (d, J=7.9 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H), 6.76-6.85 (m, 1H), 7.18 (dd, J=7.6, 5.0 Hz, 1H), 7.47-7.57 (m, 3H), 8.40 (d, J=2.3 Hz, 1H), 8.49 (s, 1H), 8.61 (d, J=3.8 Hz, 1H).
- The title compound was prepared from N-((5-fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 147) by General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 0.98 (d, J=6.4 Hz, 6H), 1.30 (d, J=7.3 Hz, 6H), 1.91-2.06 (m, 1H), 3.42-3.58 (m, 1H), 3.66 (d, J=6.4 Hz, 2H), 4.67 (s, 2H), 5.54 (s, 2H), 6.63 (d, J=7.9 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.81 (dd, J=8.6, 2.2 Hz, 1H), 7.29 (dd, J=7.3, 5.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.61-7.75 (m, 2H), 8.38 (d, J=2.6 Hz, 1H), 8.50 (s, 1H), 8.54 (d, J=5.0 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) by, in order, General Procedure C, General Procedure L, and General Procedure U.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.3 Hz, 6H), 3.65-3.79 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 5.50 (s, 2H), 6.31-6.41 (m, 1H), 6.56 (d, J=7.9 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H), 7.05-7.31 (m, 7H), 7.48-7.58 (m, 1H), 7.65 (d, J=9.1 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and 3-(bromomethyl)pyridine.HBr by, in order, General Procedure J, General Procedure K, General Procedure C, and General Procedure L.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 3.66-3.81 (m, 1H), 4.66 (d, J=6.2 Hz, 2H), 5.36 (s, 2H), 6.28-6.36 (m, 1H), 6.53 (d, J=1.2 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 7.08-7.31 (m, 6H), 7.46 (d, J=8.5 Hz, 1H), 8.41 (d, J=36.9 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 151) by General Procedure U.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.35 (d, J=7.3 Hz, 6H), 3.40-3.54 (m, 1H), 4.59 (s, 2H), 5.61 (s, 2H), 6.95 (d, J=3.8 Hz, 1H), 7.08 (dd, J=8.4, 2.2 Hz, 1H), 7.18 (d, J=4.1 Hz, 1H), 7.21-7.28 (m, 2H), 7.29-7.41 (m, 4H), 7.68 (d, J=8.5 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.41 (dd, J=4.4, 1.8 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 151) by General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (d, J=7.3 Hz, 6H), 1.52-1.63 (m, 2H), 1.64-1.87 (m, 6H), 3.43-3.57 (m, 1H), 4.57 (s, 2H), 4.67-4.77 (m, 1H), 5.55 (s, 2H), 6.70 (d, J=2.1 Hz, 1H), 6.76 (dd, J=8.6, 2.2 Hz, 1H), 7.19-7.27 (m, 2H), 7.28-7.40 (m, 3H), 7.49 (d, J=8.5 Hz, 1H), 8.22 (s, 1H), 8.41 (dd, J=4.4, 2.1 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 151) by General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.21 (d, J=6.2 Hz, 6H), 1.33 (d, J=7.3 Hz, 6H), 3.42-3.57 (m, 1H), 4.43-4.54 (m, 1H), 4.57 (s, 2H), 5.55 (s, 2H), 6.74-6.83 (m, 2H), 7.19-7.27 (m, 2H), 7.28-7.39 (m, 3H), 7.50 (d, J=9.1 Hz, 1H), 8.21 (s, 1H), 8.41 (dd, J=4.3, 2.2 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) by General Procedure K.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.30 (d, J=6.7 Hz, 6H), 2.51-2.74 (m, 1H), 3.89 (s, 3H), 6.63 (dd, J=8.9, 2.5 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 11.15 (s, 1H).
- To a solution of 2-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 155, 10 mg, 0.046 mmol) in CH2Cl2 (1 ml) was added i-Pr2NEt (17 l, 0.098 mmol) and 3,4-difluorobenzylamine (11 l, 0.092 mmol), followed by BOP. After completion, the reaction was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.27 (d, J=6.7 Hz, 6H), 2.53-2.68 (m, 1H), 3.86 (s, 3H), 4.56 (d, J=5.9 Hz, 2H), 6.47 (dd, 1H), 6.57 (dd, J=8.8, 2.6 Hz, 1H), 7.01-7.22 (m, 3H), 7.39 (d, J=8.8 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H), 11.57 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and 1-iodo-2-methylpropane by, in order, General Procedure J, General Procedure K, and General Procedure C.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 0.96 (d, J=6.7 Hz, 6H), 1.50 (d, J=7.0 Hz, 6H), 2.13-2.26 (m, 1H), 3.28-3.41 (m, 1H), 3.86 (s, 3H), 3.89 (d, J=7.6 Hz, 2H), 4.65 (d, J=6.2 Hz, 2H), 6.20-6.28 (m, 1H), 6.76-6.83 (m, 2H), 7.10-7.17 (m, 2H), 7.19-7.30 (m, 1H), 7.47 (d, J=8.5 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-1-isobutyl-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 157) by General Procedure L.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 0.95 (d, J=6.7 Hz, 6H), 1.49 (d, J=7.0 Hz, 6H), 2.11-2.27 (m, 1H), 3.26-3.40 (m, 1H), 3.86 (d, J=7.6 Hz, 2H), 4.65 (d, J=6.2 Hz, 2H), 4.79 (s, 1H), 6.23 (t, J=6.2 Hz, 1H), 6.68 (dd, J=8.5, 1.8 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 7.09-7.16 (m, 2H), 7.18-7.28 (m, 1H), 7.42 (d, J=8.5 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-1-isobutyl-2-isopropyl-1H-indole-3-carboxamide (Compound 158) by General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 0.96 (d, J=6.7 Hz, 6H), 1.49 (d, J=7.0 Hz, 6H), 1.59-1.70 (m, 2H), 1.73-1.97 (m, 6H), 2.12-2.26 (m, 1H), 3.27-3.40 (m, 1H), 3.88 (d, J=7.6 Hz, 2H), 4.65 (d, J=5.9 Hz, 2H), 4.76-4.84 (m, 1H), 6.24 (t, J=6.6 Hz, 1H), 6.74-6.81 (m, 2H), 7.09-7.16 (m, 2H), 7.18-7.28 (m, 1H), 7.42-7.48 (m, 1H).
- To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 48 mg, 0.11 mmol) in CH2Cl2 (2 ml) was added 2-[N,N-bis(trifluoromethylsulphonyl)amino]-5-chloropyridine (48 mg, 0.12 mmol) and DMAP (15 mg, 0.12 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.39 (d, J=7.3 Hz, 6H), 3.57-3.72 (m, 1H), 4.65 (d, J=5.9 Hz, 2H), 5.43 (s, 2H), 6.30 (t, J=5.7 Hz, 1H), 6.89-6.98 (m, 2H), 7.02-7.09 (m, 2H), 7.11-7.18 (m, 2H), 7.18-7.36 (m, 4H), 7.66 (d, J=9.4 Hz, 1H).
- A mixture of 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl trifluoromethanesulfonate (Compound 160, 50 mg, 0.088 mmol), pyridin-4-ylboronic acid (22 mg, 0.18 mmol), Pd(PPh3)4 (5.0 mg, 0.0043 mmol), K2CO3 (61 mg, 0.44 mmol), and LiCl (19 mg, 0.44 mmol) in toluene (3 ml), MeOH (1 ml), and H2O (0.5 ml) was heated at 90° C. for 16 h. The reaction was then cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.35 (d, J=7.0 Hz, 6H), 3.41-3.58 (m, 1H), 4.60 (s, 2H), 5.63 (s, 2H), 6.94-7.06 (m, 2H), 7.16-7.44 (m, 5H), 7.49-7.81 (m, 6H), 8.47 (dd, J=4.7, 1.8 Hz, 2H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137), 3-(bromomethyl)pyridine.HBr, and (5-fluoropyridin-3-yl) methanamine (Compound 145) by, in order, General Procedure J, General Procedure K, General Procedure C, and General Procedure L.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.0 Hz, 6H), 3.41-3.58 (m, 1H), 4.67 (d, J=6.2 Hz, 2H), 5.50 (s, 2H), 6.61 (d, J=2.1 Hz, 1H), 6.71 (dd, J=8.5, 2.1 Hz, 1H), 7.29-7.39 (m, 2H), 7.46 (d, J=8.5 Hz, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H), 8.35-8.44 (m, 2H), 8.50 (s, 1H), 8.60 (t, J=5.7 Hz, 1H).
- The title compound was prepared from N-((5-fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 162) and cyclopentyl iodide by General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.33 (d, J=7.3 Hz, 6H), 1.50-1.64 (m, 2H), 1.64-1.90 (m, 6H), 3.44-3.58 (m, 1H), 4.67 (s, 2H), 4.70-4.77 (m, 1H), 5.56 (s, 2H), 6.72 (d, J=2.1 Hz, 1H), 6.77 (dd, J=8.8, 2.1 Hz, 1H), 7.30-7.41 (m, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.65-7.75 (m, 1H), 8.22 (s, 1H), 8.35-8.45 (m, 2H), 8.50 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139), 3,4-difluorobenzylamine, and pyridin-4-ylboronic acid by, in order, General Procedure C, General Procedure L, General Procedure V, and General Procedure W.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.35 (d, J=7.0 Hz, 6H), 3.44-3.57 (m, 1H), 4.60 (s, 2H), 5.71 (s, 2H), 6.74 (d, J=7.9 Hz, 1H), 7.21-7.42 (m, 4H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.62-7.79 (m, 5H), 8.49 (d, J=6.2 Hz, 2H), 8.54 (d, J=4.1 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137), 3-(bromomethyl)pyridine.HBr, 3,4-difluorobenzylamine, and cyclobutyl bromide by, in order, General Procedure J, General Procedure K, General Procedure C, General Procedure L, and General Procedure N.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.39 (d, J=7.3 Hz, 6H), 1.60-1.74 (m, 2H), 2.04-2.15 (m, 2H), 2.27-2.39 (m, 2H), 3.70-3.81 (m, 1H), 4.50-4.60 (m, 1H), 4.66 (d, J=5.9 Hz, 2H), 5.41 (s, 2H), 6.29 (t, J=5.6 Hz, 1H), 6.49 (d, J=2.2 Hz, 1H), 6.75 (dd, J=8.7, 2.1 Hz, 1H), 7.11-7.18 (m, 3H), 7.18-7.28 (m, 2H), 7.50 (d, J=8.6 Hz, 1H), 8.43 (s, 1H), 8.52 (s, 1H).
- To a solution of 1,5-difluoro-2,4-dinitrobenzene (Aldrich, 10.6 g, 52.0 mmol) in THF (100 ml) was added ethyl isobutyryl acetate (8.4 ml, 52.0 mmol) and K2CO3 (8.6 g, 62.3 mmol). The mixture was stirred at room temperature for 2 h, diluted with EtOAc, washed with aqueous HCl and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.07 (d, J=6.7 Hz, 3H), 1.13 (t, J=7.0 Hz, 3H), 1.19 (d, J=6.7 Hz, 3H), 2.22-2.48 (m, 1H), 3.91-4.38 (m, 2H), 7.24 (d, J=10.3 Hz, 1H), 8.79 (d, J=7.0 Hz, 1H), 13.21 (d, J=1.5 Hz, 1H).
- The title compound was prepared from ethyl 2-(5-fluoro-2,4-dinitrophenyl)-4-methyl-3-oxopentanoate (Compound 166) by General Procedure R.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.34 (d, J=7.0 Hz, 6H), 1.44 (t, J=7.0 Hz, 3H), 3.70 (s, 2H), 3.99-4.15 (m, 1H), 4.37 (q, J=7.1 Hz, 2H), 6.71 (d, J=7.6 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 8.12 (s, 1H).
- To a solution of ethyl 6-amino-5-fluoro-2-isopropyl-1H-indole-3-5 carboxylate (Compound 167, 1.92 g, 7.3 mmol) in acetone (20 ml) and CH2Cl2 (20 ml) was added saturated aqueous NaHCO3 (10 ml) and MCPBA (6.3 g, 36.5 mmol). The resulting reddish brown solution was stirred at room temperature for 2 h, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.41 (d, J=7.0 Hz, 6H), 1.46 (t, J=7.0 Hz, 3H), 4.06-4.21 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 7.94 (d, J=12.3 Hz, 1H), 8.16 (d, J=6.2 Hz, 1H), 8.65 (s, 1H).
- The title compound was prepared from ethyl 5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 168) and benzyl bromide by General Procedure J.
- 1H NMR (500 MHz, CHLOROFORM-d) ppm 1.41 (d, J=7.3 Hz, 6H), 1.50 (t, J=7.2 Hz, 3H), 3.90-4.04 (m, 1H), 4.45 (q, J=7.1 Hz, 2H), 5.54 (s, 2H), 6.93 (d, J=6.4 Hz, 2H), 7.29-7.36 (m, 3H), 7.96 (d, J=6.1 Hz, 1H), 8.00 (d, J=12.7 Hz, 1H).
- To a solution of ethyl 1-benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 169, 546 mg, 1.54 mmol) in EtOH (10 ml) was added 5 M NaOH (3.1 ml, 15.5 mmol). The reaction was heated at 80° C. for 5 h, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a brown solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.46 (d, J=7.0 Hz, 6H), 3.94-4.16 (m, 1H), 5.57 (s, 2H), 6.91-7.01 (m, 2H), 7.32 (t, J=6.4 Hz, 3H), 7.92-8.01 (m, 1H), 8.16 (d, J=12.3 Hz, 1H).
- The title compound was prepared from 1-benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylic acid (Compound 170) and 3,4-difluorobenzylamine by General Procedure C.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.40 (d, J=7.0 Hz, 6H), 3.48-3.63 (m, 1H), 4.67 (d, J=5.9 Hz, 2H), 5.48 (s, 2H), 6.21 (t, J=6.0 Hz, 1H), 6.92 (dd, J=7.5, 2.2 Hz, 2H), 7.12-7.36 (m, 6H), 7.43 (d, J=12.0 Hz, 1H), 7.98 (d, J=5.9 Hz, 1H).
- The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxamide (Compound 171) by General Procedure S.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30 (d, J=7.3 Hz, 6H), 3.39-3.52 (m, 1H), 4.56 (s, 2H), 5.40 (s, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.93 (dd, J=7.9, 1.5 Hz, 2H), 7.16-7.38 (m, 7H).
- The title compound was prepared from 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172) and cyclopentanone by General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.33 (d, J=7.3 Hz, 6H), 1.36-2.10 (m, 8H), 3.46-3.59 (m, 1H), 3.58-3.70 (m, 1H), 4.56 (s, 2H), 5.43 (s, 2H), 6.46 (d, J=7.3 Hz, 1H), 6.93-7.03 (m, 2H), 7.13-7.41 (m, 7H), 8.40 (s, 1H).
- To a solution of 1-benzyl-6-(cyclopentylamino)-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 173, 12 mg, 0.023 mmol) in DMF (2 ml) was added MeI (15 l, 0.23 mmol) and K2CO3 (32 mg, 0.23 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase chromatography on C18 bonded silica gel (90% MeOH—H2O) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.33 (d, J=7.0 Hz, 6H), 1.57-1.89 (m, 8H), 3.36-3.54 (m, 1H), 3.65 (s, 6H), 4.58 (s, 2H), 4.74-4.83 (m, 1H), 5.69 (s, 2H), 6.92-7.01 (m, 2H), 7.19-7.40 (m, 7H), 7.60 (d, J=15.2 Hz, 1H), 7.75 (d, J=6.7 Hz, 1H), 8.77 (t, J=6.0 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 94) and pyrrolidine by, in order, General Procedure P, General Procedure M, and General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.30 (d, J=6.2 Hz, 6H), 1.55 (s, 4H), 2.34 (s, 4H), 3.76 (s, 2H), 4.45-4.62 (m, 3H), 5.50 (s, 2H), 6.51 (d, J=7.6 Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.92 (dd, J=8.5, 1.8 Hz, 1H), 7.05-7.30 (m, 4H), 7.45-7.56 (m, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H), 10.15 (t, J=4.5 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-2-(pyrrolidin-1-ylmethyl)-1H-indole-3-carboxamide (Compound 175, 17 mg, 0.033 mmol) in acetone (1 ml) was added MeI (0.1 ml, 1.6 mmol). The reaction was stirred at room temperature for 16 h and the solvent was removed in vacuo. The residue was purified by PTLC on silica gel (10% MeOH-EtOAc) to yield the title compound.
- 1H NMR (300 MHz, acetone) ppm 1.22 (d, J=5.9 Hz, 6H), 2.25 (s, 4H), 3.35 (s, 3H), 3.72-3.97 (m, 4H), 4.52-4.67 (m, 1H), 4.70 (t, J=5.3 Hz, 2H), 5.63 (s, 2H), 5.93 (s, 2H), 6.84 (dd, J=8.8, 2.1 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 7.20-7.54 (m, 5H), 7.70-7.79 (m, 1H), 7.88 (d, J=9.1 Hz, 1H), 8.19 (t, J=6.3 Hz, 1H), 8.44 (d, J=4.1 Hz, 1H).
- A mixture of 2-pyrrolidinone (47 mg, 0.55 mmol) and POCl3 (0.10 ml, 1.1 mmol) was stirred at 0° C. to room temperature for 2 h. To the above mixture was then added a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 50 mg, 0.11 mmol) in toluene (3 ml). The reaction was heated to 110° C. for 16 h and was cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase chromatography on C18 bonded silica gel (MeOH) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.26-1.37 (m, 8H), 2.53 (t, J=7.8 Hz, 2H), 3.37-3.57 (m, 3H), 4.57 (s, 2H), 5.47 (s, 2H), 6.90-7.02 (m, 3H), 7.15-7.41 (m, 7H).
- General Procedure AA. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 39 mg, 0.086 mmol) in CH2Cl2 (1 ml) was added 2-chloroethyl isothiocyanate (25 l, 0.26 mmol) and Et3N (1 drop). The reaction was stirred at room temperature for 16 h and was purified directly by chromatography on silica gel (0→60% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.36 (d, J=7.0 Hz, 6H), 3.28 (t, J=7.0 Hz, 2H), 3.58-3.70 (m, 1H), 3.79 (t, J=6.9 Hz, 2H), 4.65 (d, J=5.6 Hz, 2H), 5.38 (s, 2H), 6.17-6.25 (m, 1H), 6.96 (d, J=6.4 Hz, 2H), 7.10-7.18 (m, 2H), 7.20-7.35 (m, 6H).
- To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 96, 324 mg, 0.72 mmol) in MeOH (5 ml) at −10° C. was added 2 M H2SO4 (3 ml, 6.0 mmol) followed by sodium nitrite (50 mg, 0.72 mmol). The reaction was stirred at −10° C. for 0.5 h and a solution of potassium iodide (477 mg, 2.9 mmol) in H2O (3 ml) was added. The mixture was stirred for another 0.5 h and was extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.3 Hz, 6H), 3.37-3.52 (m, 1H), 4.57 (s, 2H), 5.47-5.53 (m, 2H), 6.82-6.97 (m, 2H), 7.17-7.39 (m, 8H).
- To a mixture of sodium methoxide (freshly prepared from 25 mg sodium and 1 ml MeOH) and CuI (30 mg, 0.16 mmol) was added a solution of 1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-6-iodo-2-isopropyl-1H-indole-3-carboxamide (Compound 179, 30 mg, 0.053 mmol) in DMF (0.5 ml). The reaction was heated to 110° C. for 16 h, and was filtered and concentrated. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.0 Hz, 6H), 3.37-3.51 (m, 1H), 3.76 (s, 3H), 4.56 (s, 2H), 5.50 (s, 2H), 6.88-6.98 (m, 3H), 7.17-7.38 (m, 7H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, and General Procedure C.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (d, J=7.3 Hz, 6H), 3.41-3.58 (m, 1H), 4.59 (s, 2H), 5.72 (s, 2H), 6.90 (d, J=7.9 Hz, 1H), 7.19-7.41 (m, 4H), 7.67-7.78 (m, 2H), 8.04 (dd, J=8.8, 2.1 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.51 (d, J=4.1 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-isopropyl-6-nitro-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 181) by General Procedure S.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30 (d, J=7.0 Hz, 6H), 3.41-3.58 (m, 1H), 4.56 (s, 2H), 5.48 (s, 2H), 6.54-6.62 (m, 2H), 6.66 (dd, J=8.5, 1.8 Hz, 1H), 7.17-7.37 (m, 4H), 7.39 (d, J=8.5 Hz, 1H), 7.58-7.70 (m, 1H), 8.53 (d, J=4.1 Hz, 1H).
- The title compound was prepared from 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182) by General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.3 Hz, 6H), 1.34-1.75 (m, 6H), 1.80-1.95 (m, 2H), 3.47-3.60 (m, 1H), 3.61-3.73 (m, 1H), 4.56 (s, 2H), 5.49 (s, 2H), 6.39 (d, J=1.8 Hz, 1H), 6.58-6.67 (m, 2H), 7.19-7.36 (m, 4H), 7.38 (d, J=8.8 Hz, 1H), 7.60-7.71 (m, 1H), 8.54 (d, J=5.0 Hz, 1H).
- The title compound was prepared from 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 106) by General Procedure AA.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.3 Hz, 6H), 3.24 (t, J=7.0 Hz, 2H), 3.43-3.58 (m, 1H), 3.79 (t, J=7.2 Hz, 2H), 4.57 (s, 2H), 5.54 (s, 2H), 6.65 (d, J=7.9 Hz, 1H), 6.93 (dd, J=8.5, 1.8 Hz, 1H), 7.14-7.39 (m, 5H), 7.51 (d, J=8.5 Hz, 1H), 7.61-7.69 (m, 1H), 8.53 (d, J=4.1 Hz, 1H).
- The title compound was also isolated in the synthesis of Compound 184.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.3 Hz, 6H), 3.41-3.54 (m, 1H), 3.58 (t, J=7.5 Hz, 2H), 3.99 (t, J=7.6 Hz, 2H), 4.59 (d, J=4.1 Hz, 2H), 5.61 (s, 2H), 6.81 (d, J=7.9 Hz, 1H), 7.04-7.12 (m, 1H), 7.19-7.41 (m, 5H), 7.64-7.77 (m, 2H), 8.51 (d, J=4.1 Hz, 1H), 8.67 (t, J=6.0 Hz, 1H).
- To a solution of 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182, 48 mg, 0.11 mmol) in CH2Cl2 (1 ml) was added chloroethyl isocyanate (10 l, 0.12 mmol). The reaction was stirred at room temperature for 16 h, and the solvent was removed. To the residue was added H2O and the mixture was heated at 80° C. for 3 h, diluted with EtOAc, washed with aqueous K2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30 (d, J=7.3 Hz, 6H), 3.40-3.53 (m, 1H), 3.72 (t, J=8.4 Hz, 2H), 4.34 (t, J=8.4 Hz, 2H), 4.57 (s, 2H), 5.55 (s, 2H), 6.65 (d, J=7.9 Hz, 1H), 7.01 (dd, J=8.5, 1.8 Hz, 1H), 7.19-7.38 (m, 5H), 7.52 (d, J=8.8 Hz, 1H), 7.60-7.68 (m, 1H), 8.52 (d, J=4.1 Hz, 1H).
- The title compound was also isolated in the synthesis of Compound 186.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.0 Hz, 6H), 3.42-3.54 (m, 3H), 3.55-3.67 (m, 2H), 4.57 (s, 2H), 5.54 (s, 2H), 6.65 (d, J=7.9 Hz, 1H), 6.99 (dd, J=8.5, 2.1 Hz, 1H), 7.17-7.38 (m, 4H), 7.46-7.56 (m, 2H), 7.61-7.72 (m, 1H), 8.53 (d, J=4.7 Hz, 1H).
- To a solution of 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182, 64 mg, 0.15 mmol) in toluene (2 ml) was added 1,4-dibromobutane (19 l, 0.16 mmol) and i-Pr2NEt (77 l, 0.44 mmol). The reaction was heated at 110° C. for 16 h, and was purified directly by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.0 Hz, 6H), 1.92-2.00 (m, 4H), 3.04-3.26 (m, 4H), 3.40-3.65 (m, 1H), 4.57 (s, 2H), 5.50 (s, 2H), 6.17-6.35 (m, 1H), 6.50-6.67 (m, J=8.4, 8.4 Hz, 2H), 7.19-7.38 (m, 4H), 7.45 (d, J=8.5 Hz, 1H), 7.58-7.70 (m, 1H), 8.54 (d, J=5.0 Hz, 1H).
- The title compound was prepared from 1-benzyl-6-(cyclopentylamino)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 130) by General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (d, J=7.0 Hz, 6H), 1.41-1.57 (m, 4H), 1.57-1.77 (m, 4H), 2.68 (s, 3H), 3.45-3.61 (m, 1H), 3.69-3.81 (m, 1H), 4.57 (s, 2H), 5.47 (s, 2H), 6.78 (d, J=1.8 Hz, 1H), 6.88-7.01 (m, 3H), 7.15-7.39 (m, 6H), 7.50 (d, J=8.8 Hz, 1H).
- The title compound was prepared from 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125) by General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.2 Hz, 6H), 1.66-1.86 (m, 4H), 2.18-2.32 (m, 2H), 3.44-3.60 (m, 1H), 3.73-3.88 (m, 1H), 4.56 (s, 2H), 5.41 (s, 2H), 6.36 (d, J=1.9 Hz, 1H), 6.57 (dd, J=8.6, 2.0 Hz, 1H), 6.94-7.01 (m, 2H), 7.18-7.35 (m, 6H), 7.38 (d, J=8.5 Hz, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.0 Hz, 6H), 1.35-1.47 (m, 2H), 1.47-1.59 (m, 2H), 1.60-1.73 (m, 2H), 1.79-1.93 (m, 2H), 3.46-3.59 (m, 1H), 3.61-3.73 (m, 1H), 4.55-4.64 (m, 2H), 5.41 (s, 2H), 6.45 (d, J=1.8 Hz, 1H), 6.62 (dd, J=8.5, 2.1 Hz, 1H), 6.76-6.88 (m, 1H), 6.93-7.08 (m, 4H), 7.13-7.29 (m, 3H), 7.41 (d, J=8.5 Hz, 1H), 8.38 (t, J=6.2 Hz, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.3 Hz, 6H), 1.35-1.45 (m, 2H), 1.50-1.59 (m, 2H), 1.62-1.75 (m, 2H), 1.79-1.93 (m, 2H), 3.44-3.58 (m, 1H), 3.61-3.73 (m, 1H), 4.58 (d, J=5.9 Hz, 2H), 5.41 (s, 2H), 6.44 (d, J=1.8 Hz, 1H), 6.60 (dd, J=8.5, 2.1 Hz, 1H), 6.95-6.99 (m, 2H), 7.03-7.12 (m, 2H), 7.17-7.29 (m, 3H), 7.36 (d, J=8.8 Hz, 1H), 7.40-7.50 (m, 2H), 8.30 (t, J=6.0 Hz, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.3 Hz, 6H), 1.34-1.45 (m, 2H), 1.47-1.60 (m, 2H), 1.61-1.75 (m, 2H), 1.80-1.94 (m, 2H), 3.46-3.58 (m, 1H), 3.60-3.72 (m, 1H), 4.65 (s, 2H), 5.40 (s, 2H), 6.44 (d, J=1.8 Hz, 1H), 6.62 (dd, J=8.6, 1.9 Hz, 1H), 6.94-7.00 (m, 2H), 7.15-7.30 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.68 (dd, J=9.4, 2.1 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H), 8.49 (s, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (d, J=7.3 Hz, 6H), 1.67-1.82 (m, 4H), 2.20-2.31 (m, 2H), 3.46-3.61 (m, 1H), 3.73-3.87 (m, 1H), 4.56-4.62 (m, 2H), 5.41 (s, 2H), 6.36 (d, J=2.1 Hz, 1H), 6.58 (dd, J=8.6, 1.9 Hz, 1H), 6.77-6.88 (m, 1H), 6.93-7.07 (m, 4H), 7.16-7.30 (m, 3H), 7.41 (d, J=8.5 Hz, 1H), 8.40 (t, J=6.0 Hz, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.3 Hz, 6H), 1.67-1.83 (m, 4H), 2.18-2.33 (m, 2H), 3.44-3.61 (m, 1H), 3.72-3.86 (m, 1H), 4.53-4.62 (m, 2H), 5.40 (s, 2H), 6.35 (d, J=2.1 Hz, 1H), 6.55 (dd, J=8.5, 2.1 Hz, 1H), 6.92-7.00 (m, 2H), 7.01-7.13 (m, 2H), 7.15-7.30 (m, 3H), 7.36 (d, J=8.5 Hz, 1H), 7.40-7.49 (m, 2H), 8.29 (t, J=6.3 Hz, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.30 (d, J=7.3 Hz, 6H), 1.64-1.86 (m, 4
- H), 2.18-2.32 (m, 2H), 3.44-3.60 (m, 1H), 3.72-3.86 (m, 1H), 4.64 (s, 2H), 5.40 (s, 2H), 6.36 (d, J=1.8 Hz, 1H), 6.58 (dd, J=8.6, 1.9 Hz, 1H), 6.91-7.01 (m, 2H), 7.15-7.31 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.63-7.73 (m, 1H), 8.36 (d, J=2.6 Hz, 1H), 8.48 (s, 1H).
- The title compound was prepared from 1-fluoro-2,4-dinitrobenzene and methyl isobutyryl acetate by, in order, General Procedure X, General Procedure R, General Procedure Y, General Procedure J, General Procedure Z, General Procedure C, General Procedure S, and General Procedure T.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.31 (d, J=7.3 Hz, 6H), 1.67-1.83 (m, 4H), 2.19-2.32 (m, 2H), 3.46-3.61 (m, 1H), 3.73-3.87 (m, 1H), 4.56 (s, 2H), 5.48 (s, 2H), 6.31 (d, J=1.8 Hz, 1H), 6.54-6.64 (m, 2H), 7.17-7.43 (m, 5H), 7.58-7.69 (m, 1H), 8.54 (d, J=4.1 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) by General Procedure C, General Procedure L, and General Procedure N.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.37 (d, J=7.0 Hz, 6H), 3.69-3.89 (m, 1H), 4.67 (d, J=5.9 Hz, 2H), 5.51 (s, 2H), 6.30 (t, J=6.0 Hz, 1H), 6.53 (d, J=7.9 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.6, 2.2 Hz, 1H), 7.09-7.32 (m, 4H), 7.45-7.57 (m, 2H), 8.62 (d, J=4.7 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-6-isopropoxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide-d7 (Compound 198, 71 mg, 0.15 mmol) in Et2O (5 ml) under air was added HCl (2 M in Et2O, 0.15 ml, 0.30 mmol). The solvent was removed and the residue was purified by PTLC (50% EtOAc-hexanes) to yield the title compound as a side product.
- 1H NMR (300 MHz, METHANOL-d4) ppm 2.00 (t, J=1.2 Hz, 3H), 4.55 (s, 2H), 5.18-5.25 (m, 1H), 5.44 (s, 2H), 5.57 (t, J=1.6 Hz, 1H), 6.71 (d, J=1.8 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.81 (dd, J=8.8, 2.3 Hz, 1H), 7.14-7.37 (m, 4H), 7.62-7.73 (m, 1H), 7.82 (d, J=8.8 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H).
- To a solution of 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139, 415 mg, 1.28 mmol) in CH2Cl2 (20 ml) at 0° C. was added (COCl)2 (2 M in CH2Cl2, 1.6 ml, 3.20 mmol) and a catalytic amount of DMF. The mixture was stirred at room temperature for 1 h, and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 ml), cooled to 0° C., and 3,4-difluorobenzylamine (0.23 ml, 1.92 mmol) was added, followed by Et3N (0.53 ml, 3.84 mmol). The reaction was stirred at room temperature for 4 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.36 (d, J=7.0 Hz, 6H), 3.74 (s, 3H), 3.74-3.83 (m, 1H), 4.65 (d, J=6.2 Hz, 2H), 5.51 (s, 2H), 6.37 (t, J=5.9 Hz, 1H), 6.52 (d, J=7.9 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.82 (dd, J=8.6, 2.2 Hz, 1H), 7.08-7.30 (m, 4H), 7.46-7.57 (m, 2H), 8.61 (d, J=4.1 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 200, 735 mg, 1.64 mmol) in CH2Cl2 (25 ml) at 0° C. was added BBr3 (1.0 M in CH2Cl2, 6.6 ml, 6.56 mmol) dropwise. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature, quenched with ice, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→85% EtOAc-hexanes) to yield the title compound as a yellow oil.
- 1H NMR (500 MHz, METHANOL-d4) ppm 1.30 (s, 3H), 1.32 (s, 3H), 3.43-3.57 (m, 1H), 4.57 (s, 2H), 5.48 (s, 2H), 6.54-6.64 (m, 2H), 6.68 (dd, J=8.56, 2.20 Hz, 1H), 7.19-7.37 (m, 4H), 7.43 (d, J=8.56 Hz, 1H), 7.66 (td, J=7.76, 1.59 Hz, 1H), 8.54 (d, J=4.89 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 201, 1.20 g, 2.76 mmol) in CH2Cl2 (50 ml) at 0° C. was added 2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (1.20 g, 3.04 mmol) and DMAP (370 mg, 3.04 mmol). The reaction was stirred at room temperature for 12 h, quenched with water, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-40% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (500 MHz, METHANOL-d4) ppm 1.33 (s, 3H), 1.34 (s, 3H), 3.42-3.54 (m, 1H), 4.58 (s, 2H), 5.62 (s, 2H), 6.78 (d, J=7.83 Hz, 1H), 7.11 (dd, J=8.68, 1.83 Hz, 1H), 7.21-7.39 (m, 5H), 7.68 (d, J=8.80 Hz, 2H), 8.52 (d, J=4.89 Hz, 1H), 8.73 (br. s., 1H).
- General Procedure BB. To a solution of 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 33 mg, 0.06 mmol) in toluene (8 ml) and MeOH (1 ml) at 25° C., bubbled with argon then added LiCl (8 mg, 0.18 mmol), Na2CO3 (aqueous) (2M, 0.1 ml), Pd(PPh3)4 (3.4 mg, 0.003 mmol), and 5-pyrimidine boronic acid (11 mg, 0.09 mmol). The reaction was stirred for 12 h at 80° C., diluted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (s, 3H), 1.36 (s, 3H), 3.50 (ddd, J=14.54, 7.14, 6.89 Hz, 1H), 4.61 (s, 2H), 5.71 (s, 2H), 6.76 (d, J=7.62 Hz, 1H), 7.18-7.42 (m, 4H), 7.46-7.63 (m, 1H), 7.62-7.74 (m, 2H), 7.78 (d, J=8.35 Hz, 1H), 8.53 (dd, J=4.98, 0.88 Hz, 1H), 9.00-9.09 (m, 3H).
- Following General Procedure BB, 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 29 mg, 0.05 mmol), was reacted with 1H-pyrazole boronic acid (9 mg, 0.08 mmol), LiCl (7 mg, 0.18 mmol), Na2CO3 (aqueous) (2M, 0.1 ml), Pd(PPh3)4 (3 mg, 0.003 mmol) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.34 (s, 3H), 3.49 (m, 1H), 4.60 (s, 2H), 5.65 (s, 2H), 6.61 (d, J=2.05 Hz, 1H), 6.69 (d, J=8.06 Hz, 1H), 7.19-7.42 (m, 4H), 7.52-7.77 (m, 5H), 8.54 (d, J=4.83 Hz, 1H).
- Following General Procedure BB, 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 39 mg, 0.07 mmol), was reacted with 1-methyl-1H-pyrazole-5-boronic acid pinocol ester (21 mg, 0.09 mmol), LiCl (9 mg, 0.18 mmol), Na2CO3 (aqueous) (2M, 0.1 ml), Pd(PPh3)4 (4 mg, 0.003 mmol) to yield the title compound as a white solid
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.32 (s, 3H), 1.34 (s, 3H), 3.49 (m, 1H), 3.75 (s, 3H), 4.60 (s, 2H), 5.65 (s, 2H), 6.35 (d, J=2.05 Hz, 1H), 6.69 (d, J=8.06 Hz, 1H), 7.19-7.42 (m, 4H), 7.52-7.77 (m, 5H), 8.54 (d, J=4.83 Hz, 1H).
- Following General Procedure BB, 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 57 mg, 0.10 mmol), was reacted with 3,5-dimethylisoxazol-4-ylboronic acid (21 mg, 0.15 mmol), LiCl (13 mg, 0.30 mmol), Na2CO3 (aqueous) (2M, 0.2 ml), Pd(PPh3)4 (6 mg, 0.006 mmol) to yield the title compound as a yellow solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.36 (s, 3H), 1.39 (s, 3H), 2.12 (s, 3H), 2.29 (s, 3H), 3.50-3.65 (m, 1H), 4.60 (s, 2H), 5.64 (s, 2H), 6.74 (d, J=7.91 Hz, 1H), 7.09 (dd, J=8.28, 1.39 Hz, 1H), 7.17 (d, J=0.88 Hz, 1H), 7.22-7.41 (m, 5H), 7.70 (dd, J=8.20, 0.59 Hz, 2H), 8.53 (ddd, J=4.91, 1.76, 0.81 Hz, 1H).
- To a solution of 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yltrifluoromethanesulfonate (Compound 202, 100 mg, 0.18 mmol) in toluene (10 ml) at 25° C., bubbled with argon then added morpholine (22 mg, 0.25 mmol), LiN(TMS)2 (1M in THF, 0.37 ml, 0.40 mmol), Pd2 (dba)3 (3.2 mg, 0.0035 mmol), and X-Phos (4 mg, 0.011 mmol). The reaction was stirred for 12 h at 110° C., diluted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a light brown solid.
- 1H NMR (300 MHz, <cd3od>) ppm 1.30 (s, 3H), 1.32 (s, 3H), 3.05 (t, J=4.98, 4H), 3.49 (m, 1H), 3.78 (t, J=4.98, 4H), 4.57 (s, 2H), 5.55 (s, 2H), 6.62 (d, J=8.20 Hz, 1H), 6.77 (d, J=1.76 Hz, 1H), 6.93 (dd, J=8.79, 2.05 Hz, 1H), 7.20-7.38 (m, 4H), 7.52 (d, J=8.79 Hz, 1H), 7.65 (td, J=7.76, 1.76 Hz, 2H), 8.54 (d, J=4.40 Hz, 2H).
- 2-Isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137, 0.54 g, 2.49 mmol) and 2-(chloromethyl)oxazole (0.58 g, 4.4 mmol) were reacted as described in General Procedure J to give the title compound as an oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.52 (d, J=7.0 Hz, 6H), 3.71 (p, J=7.0 Hz, 1H), 3.82 (s, 3H), 5.66 (s, 2H), 6.87 (dd, J=8.8, 2.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.15 (s, 1H), 7.88 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 10.32 (s, 1H).
- 2-Isopropyl-6-methoxy-1-(oxazol-2-ylmethyl)-1H-indole-3-carbaldehyde (Compound 208, 0.40 g, 1.34 mmol) was oxidized to the title compound by General Procedure K.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.42 (d, J=7.0 Hz, 6H), 3.80 (s, 3H), 4.04 (p, J=7.0 Hz, 1H), 5.62 (s, 2H), 6.81 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 7.15 (s, 1H), 7.83 (s, 1H), 7.96 (d, J=8.5 Hz, 1H).
- 2-Isopropyl-6-methoxy-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 209, 0.83 g, 2.64 mmol) was converted to the title compound by utilizing, in order, General Procedure C and General Procedure L.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.41 (d, J=7.0 Hz, 6H), 3.59 (p, J=7.0 Hz, 1H), 4.58 (s, 2H), 5.52 (s, 2H), 6.70 (dd, J=8.5, 2.2 Hz, 1H), 6.82 (d, J=2.2 Hz, 1H), 7.15 (s, 1H), 7.19-7.36 (m, 3H), 7.40 (d, J=8.5 Hz, 1H), 7.86 (s, 1H).
- N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210, 68 mg, 0.16 mmol) was reacted according to General Procedure N to give the title compound as an oil.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.41 (d, J=7.0 Hz, 6H), 1.60-2.00 (m, 8H), 3.50 (p, J=7.0 Hz, 1H), 4.58 (s, 2H), 5.54 (s, 2H), 6.74 (dd, J=8.5, 2.2 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 7.13 (s, 1H), 7.20-7.38 (m, 3H), 7.42 (d, J=8.5 Hz, 1H), 7.83 (s, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210) and n-propyl iodide by General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.04 (t, J=7.5 Hz, 3H), 1.39 (d, J=7.0 Hz, 6H), 1.78 (m, 2H), 3.57 (p, J=7.0 Hz, 1H), 3.94 (t, J=6.5 Hz, 2H), 4.55 (s, 2H), 5.55 (s, 2H), 6.78 (dd, J=8.8, 2.1 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 7.11-7.36 (m, 4H), 7.43 (d, J=8.8 Hz, 1H), 7.83 (d, J=0.88 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210) and isopropyl iodide by General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.29 (d, J=6.0 Hz, 6H), 1.39 (d, J=7.0 Hz, 6
- H), 3.59 (p, J=7.0 Hz, 1H), 4.55 (s, 2H), 4.57 (p, J=6.0 Hz, 1H), 5.54 (s, 2H), 6.74 (dd, J=8.5, 2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 7.12 (s, 1H), 7.20-7.38 (m, 3H), 7.40 (d, J=8.5 Hz, 1H), 7.83 (s, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210), 2-bromothiazole and DMSO with heating following General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.40 (d, J=7.0 Hz, 6H), 3.57 (p, J=7.0 Hz, 0H), 4.57 (s, 2H), 5.61 (s, 2H), 6.99 (d, J=3.81 Hz, 1H), 7.07 (dd, J=8.5, 1.8 Hz, 1H), 7.11 (d, J=0.88 Hz, 1H), 7.19-7.39 (m, 4H), 7.48 (d, J=1.8 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.83 (d, J=0.88 Hz, 1H).
- The title compound was also isolated in the synthesis of Compound 214.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.40 (d, J=7.3 Hz, 6H), 3.58 (p, J=7.3 Hz, 0H), 4.56 (s, 2H), 5.62 (s, 2H), 7.08 (dd, J=8.8, 2.1 Hz, 1H), 7.11 (d, J=0.88 Hz, 1H), 7.20-7.39 (m, 4H), 7.50 (d, J=1.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.83 (d, J=0.88 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and 3-(bromomethyl)-5-methylisoxazole by General Procedure J.
- 1H NMR (300 MHZ, METHANOL-D4) ppm 1.50 (d, J=7.3 Hz, 6H), 2.35 (s, 3H), 3.65 (p, J=7.3 Hz), 3.82 (s, 3H), 5.53 (s, 2H), 5.89 (s, 1H), 6.88 (dd, J=2.3, 8.7 Hz, 1H), 7.00 (d, J=2.3 Hz, 1H), 8.10 (d, J=8.7 Hz, 1H), 10.23 (s, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carbaldehyde (Compound 213) by General Procedure K.
- 1H NMR (300 MHZ, METHANOL-D4) ppm 1.42 (d, J=7.0 Hz, 6H), 2.31 (s, 3H), 3.55 (p, J=7.0 Hz), 3.80 (s, 3H), 5.55 (s, 2H), 5.78 (s, 1H), 6.82 (dd, J=2.0, 8.5 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carboxylic acid (Compound 217) by utilizing, in order, General Procedure C and General Procedure L.
- 1H NMR (300 MHZ, METHANOL-D4) ppm 1.36 (d, J=7.0 Hz, 6H), 2.32 (s, 3H), 3.54 (p, J=7.0 Hz), 4.55 (s, 2H), 5.38 (s, 2H), 5.74 (s, 1H), 6.67 (dd, J=2.2, 8.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 7.20-7.35 (m, 3H), 7.38 (d, J=8.5 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carboxamide (Compound 218) by General Procedure N.
- 1H NMR (300 MHZ, METHANOL-D4) ppm 1.38 (d, J=7.0 Hz, 6H), 1.60-1.95 (m, 8H), 2.31 (s, 3H), 3.55 (p, J=7.0 Hz), 4.55 (s, 2H), 5.43 (s, 2H), 5.75 (s, 1H), 6.74 (dd, J=2.0, 8.8 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 7.20-7.35 (m, 3H), 7.43 (d, J=8.8 Hz, 1H).
- The title compound was prepared from N-(3,4-difluorobenzyl)-2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 200) by General Procedure L.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.23 (t, J=7.0 Hz, 1H), 1.31 (d, J=7.0 Hz, 7H), 3.46 (p, J=7.18 Hz, 1H), 4.09 (q, 1H), 4.57 (s, 2H), 5.63 (s, 2H), 6.58 (d, J=1.8 Hz, 1H), 6.71 (dd, J=8.6, 2.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 7.19-7.38 (m, 3H), 7.44 (d, J=8.5 Hz, 1H), 7.60 (d, J=5.57 Hz, 1H), 8.01 (td, J=7.8, 1.6 Hz, 1H), 8.68 (d, J=4.4 Hz, 1H).
- To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 26 mg, 0.060 mmol) in dimethylformamide (1 ml) stirring at room temperature, was added cesium carbonate (83 mg, 0.25 mmol) and the reaction stirred for 5 minutes. 2-iodopyridine (0.05 mL, 0.09 g, 0.47 mmol) and then copper powder (7.0 mg, 0.11 mmol) was then directly added and the resulting mixture heated at 100° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100% EtOAc) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (d, J=7.2 Hz, 6H), 3.51 (p, J=7.2 Hz, 1H), 4.60 (d, J=5.9 Hz, 2H), 5.55 (s, 2H), 6.73 (d, J=7.9 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.91 (dd, J=8.5, 2.2 Hz, 1H), 7.01-7.10 (m, 2H), 7.20-7.42 (m, 4H), 7.65 (d, J=8.5 Hz, 1H), 7.69 (dd, J=7.9, 1.8 Hz, 1H), 7.74 (ddd, J=8.2, 7.2, 2.0 Hz, 1H), 8.07 (dt, J=5.7, 1.9 Hz, 1H), 8.50 (dt, J=4.8, 1.3 Hz, 1H), 8.67 (t, J=5.9 Hz, 1H).
- General Procedure G. To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 30 mg, 0.069 mmol) in N,N-dimethylacetamide (1.50 ml) stirring at room temperature, was added potassium hydroxide (80 mg, 1.43 mmol) and the reaction stirred for 5 minutes. 3-bromopyridine (0.05 mL, 0.08 g, 0.51 mmol) and then Copper powder (9.0 mg, 0.14 mmol) was then directly added and the resulting mixture heated at 120-140° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100% EtOAc) to yield N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide (Compound 222) as a yellow solid (2.3 mg). 1H NMR (300 MHz, METHANOL-d4) ppm 1.34 (d, J=7.0 Hz, 6H), 4.59 (s, 2H), 5.55 (s, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.92 (dd, J=8.6, 2.2 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.19-7.42 (m, 6H), 7.62-7.74 (m, 2H), 8.14-8.24 (m, 2H), 8.49 (d, J=5.0 Hz, 1H).
- The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and ethyl 2-bromoacetate by following, in order, General Procedure J, General Procedure K, General Procedure C, General Procedure L, and General Procedure N.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.25 (t, J=7.0 Hz, 3H), 1.39 (d, J=7.3 Hz, 6H), 1.60-2.00 (m, 8H), 3.48 (p, J=7.3 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 4.56 (s, 2H), 5.02 (s, 2H), 6.76 (dd, J=9.0, 2.1 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 7.20-7.36 (m, 3H), 7.45 (d, J=9.0 Hz, 1H).
- General Procedure L. To a solution of methyl 3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 149 mg, 0.32 mmol) in CH2Cl2 (10 ml) was added BBr3 (1 M in CH2Cl2, 1.6 ml, 1.6 mmol) slowly at 0° C. The mixture was stirred at room temperature for 2 h, and was quenched with ice, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by PTLC on silica gel (10% MeOH—CH2Cl2) to yield the title compound.
- 1H NMR (300 MHz, METHANOL-d4) ppm 3.74 (s, 3H), 4.57 (s, 2H), 5.91 (s, 2H), 6.77 (d, J=2.3 Hz, 1H), 6.80-6.92 (m, J=8.9, 2.2 Hz, 2H), 7.12-7.37 (m, 4H), 7.56-7.69 (m, 1H), 8.18 (d, J=8.2 Hz, 1H), 8.48 (s, 1H).
- General Procedure M. To a solution of AlCl3 (1.8 g, 13.5 mmol) in EtSH (25 ml) at room temperature was added a solution of methyl 3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 1.26 g, 2.7 mmol) in CH2Cl2 (75 ml). The reaction was stirred for 2 h and was quenched with ice. The mixture was concentrated in vacuo, and the resulting white suspension in aqueous solution was acidified with 1M HCl and filtered. The cake was washed with H2O (×3), taken in MeOH, dried over MgSO4, and concentrated in vacuo to yield the title compound as a crude yellowish white solid contaminated with unknown inorganic product. The crude was used without further purification.
- 1H NMR (300 MHz, METHANOL-d4) ppm 4.63 (s, 2H), 5.92 (s, 2H), 6.73 (d, J=1.5 Hz, 1H), 6.82 (dd, J=8.8, 2.1 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 7.17-7.30 (m, 2H), 7.30-7.44 (m, 2H), 7.65-7.84 (m, 2H), 8.47-8.57 (m, 1H).
- A solution of 3-(3,4-difluorobenzylcarbamoyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic acid (Compound 225, crude 6.5 g) and concentrated H2SO4 (0.1 ml, catalytic amount) in MeOH (100 ml) was heated to 90° C. for 16 h. The mixture was cooled and the suspension was filtered. The filtrate was concentrated, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo to give a pale brown solid as the crude product. General Procedure N. To a solution of the crude product in DMF (10 ml) was added 2-iodopropane (2.2 ml, 22 mmol) and K2CO3 (1.8 g, 13.2 mmol). The reaction was stirred at room temperature for 16 h and was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a white solid.
- 1H NMR (300 MHz, METHANOL-d4) ppm 1.26 (d, J=6.2 Hz, 6H), 3.69 (s, 3H), 4.50-4.66 (m, 3H), 5.87 (s, 2H), 6.79-6.93 (m, 3H), 7.20-7.31 (m, 3H), 7.33-7.44 (m, 1
- H), 7.59 (dd, J=8.5, 0.9 Hz, 1H), 7.67 (td, J=7.8, 1.8 Hz, 1H), 8.48 (ddd, J=5.0, 1.8, 0.9 Hz, 1H).
- The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention was to be governed only by the lawful construction of the appended claims. In particular, the present invention includes a 6-substituted indole-3-carboxylic acid-N-arylmethyl amide having sphingosine-1-phosphate antagonist activity wherein the 6-substituent is represented by the formula
-
-A1-(X1)rA2-B - wherein X1 is O;
r is 0 or 1;
A2 is absent or is (CH2)v, wherein v is 1 or 2;
B is OR6 or NR8R9, wherein R6, R8 and R9 are methyl; or
B is CR10═NO R11R19 wherein R19 is H and
R11 is methyl or i-butyl; or B is CONR8R9, wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl or R8 and R9, together with N, form a 5-membered ring; or B is OR6, wherein R6 is H; or
B is COR10, wherein R10 is methyl.
Claims (15)
1. A method of treating a disease or condition selected from the group consisting of: glaucoma, dry eye, angiogenesis, cardiovascular conditions, cardiovascular diseases, and wound healing, which comprises administering to a patient in need thereof a compound having sphingosine-1-phosphate receptor biological activity represented by the general Formula I:
wherein:
R1 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, halo, C1 to C12 haloalkyl, hydroxyl, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl, formyl, C1 to C12 alkyl carboxylate, C1 to C12 alkyl amide, aminocarbonyl, amino, cyano, nitro and sulfonyl groups;
R2 is selected from the group consisting of hydrogen and halo;
R3 is selected from the group consisting of straight or branched chain alkyl having 3 to 12 carbons, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl and C1 to C12 alkyl carboxylate;
R4 is selected from the group consisting of hydrogen, halo and C1 to C12 haloalkyl;
X is NR5;
X1 is selected from the group consisting of NR5, O and S;
R5 is hydrogen;
Y is a phenyl or a pyridyl group and wherein said phenyl or pyridyl group may be bonded to A at any position;
Z is O;
n is 0 or an integer of from 1 to 5;
o is an integer of from 1 to 3;
p is 1;
q is 1;
r is 0 or 1;
A is selected from the group consisting of (CH2)v wherein v is an integer of from 1 to 12;
A1 and A2 are independently selected from the group consisting of (CH2)v wherein v is 0 or an integer of from 1 to 12, and branched chain alkyl having 3 to 12 carbons;
B is selected from the group consisting of hydrogen, OR6, COOR7, NR8R9, CONR8R9, COR10, CH═NOR11, and CH═NNR12R13; and
wherein R6, R7, R10 and R11 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, R8, R9, R12 and R13 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, or R8 and R9 and/or R12 and R13, together, can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen, wherein any of R6, R7, R8, R9, R10, R11, R12 or R13 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mercapto or thiol radical; provided however, when v is 0, and r is 0, B is not hydrogen; or B is a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, and wherein when said B is a carbocyclic or heterocyclic group B may be bonded to A2 at any position, or a pharmaceutically acceptable salt of said compound.
2. The method according to claim 1 , wherein A is CH2.
3. The method according to claim 1 , wherein n is 0 or an integer of 1 or 2 and R4 is fluoro.
4. The method according to claim 1 , wherein R1 is i-propyl.
5. The method according to claim 1 , wherein A1 and A2 are absent.
6. The method according to claim 1 , wherein B is OR6.
7. The method according to claim 1 , wherein B is COOR7.
8. The method according to claim 1 , wherein B is CH═NOR11.
9. The method according to claim 1 , wherein
X1 is O;
r is 0 or 1;
A2 is absent or is (CH2)v, wherein v is 1 or 2;
B is OR6 or NR8R9, and R6, R8 and R9 are methyl; or
B is CH═NOR11 and R11 is methyl or i-butyl; or
B is CONR8R9 and R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl or R8 and R9, together with N, form a 5-membered ring; or
B is OR6 and R6 is H; or
B is COR10, and R10 is methyl.
10. A method of treating a disease or condition selected from the group consisting of: glaucoma, dry eye, angiogenesis, cardiovascular conditions, cardiovascular diseases, and wound healing, which comprises administering to a patient in need thereof a compound having sphingosine-1-phosphate receptor biological activity represented by the general Formula I:
wherein:
R1 is isopropyl;
R2 is selected from the group consisting of hydrogen and halo;
R3 is selected from the group consisting of straight or branched chain alkyl having 3 to 12 carbons, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl and C1 to C12 alkyl carboxylate;
R4 is selected from the group consisting of hydrogen, halo and C1 to C12 haloalkyl;
X is NR5;
X1 is O;
R5 is hydrogen;
Y is a phenyl or a pyridyl group and wherein said phenyl or pyridyl group may be bonded to A at any position;
Z is O;
n is 0 or an integer of from 1 to 5;
o is an integer of from 1 to 3;
p is 1;
q is 1;
r is 1;
A is selected from the group consisting of (CH2)v wherein v is an integer of from 1 to 12;
A1 is absent;
A2 is (CH2)v, wherein v is 1 or 2;
B is OR6 or NR8R9;
R6 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring;
R8 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring;
R9 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring;
or R8 and R9, together, can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen;
any of R6, R8 and R9 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mercapto or thiol moiety.
11. The method according to claim 10 , wherein R6, R8 and R9 are methyl.
12. The method according to claim 10 , wherein B is CH═NOR11 wherein R11 is methyl or i-butyl.
13. The method according to claim 10 , wherein B is CONR8R9 wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl, or R8 and R9, together with N, form a 5-member ring.
12. The method according to claim 10 , wherein A1 is absent, r is 0, A2 is CH2 and B is OR6, wherein R6 is H.
13. The method according to claim 10 , wherein A1 is absent, r is 1 and B is COR10 wherein R10 is methyl.
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US13/946,564 US20130338158A1 (en) | 2007-01-11 | 2013-07-19 | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity |
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US10450269B1 (en) | 2013-11-18 | 2019-10-22 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US11053195B2 (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
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KR102244719B1 (en) * | 2013-03-15 | 2021-04-26 | 플렉시콘 인코퍼레이티드 | Heterocyclic compounds and uses thereof |
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WO2018014862A1 (en) * | 2016-07-22 | 2018-01-25 | 南京明德新药研发股份有限公司 | S1p1 agonist and application thereof |
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US11053195B2 (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10450269B1 (en) | 2013-11-18 | 2019-10-22 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
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CA2711815A1 (en) | 2009-07-16 |
AU2008347006B2 (en) | 2013-11-14 |
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