# Patent

## Title
6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity

## 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.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is based on, and claims priority under 35 U.S.C. §120 to U.S. Provisional Application No. 60/884,470, filed on Jan. 11, 2007, and which is incorporated herein by reference.


BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
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 flouro 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-difluorophenylmethyl6-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, ethyl4-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-pyridylmethyl1-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.



DETAILED DESCRIPTION OF THE INVENTION
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, CH2 CN, 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 μM  (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 μM  (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 μM  (85)


 


54




NA


 


55




234 nM (100)


 


69




 5.0 μM  (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 μM  (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 μM  (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 μM  (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 μM (100)


 


176




 7.6 μM  (98)


 


177




NA


 


178




NA


 


180




NA


 


181




500 nM (100)


 


182




NA


 


183




152 nM (100)


 


184




>8.3 μM   (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 μM  (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 μM  (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 μM  (40)


 







170 nM (100)


 







197 nM (100)


 







634 nM (100)


 







346 nM  (99)


 







146 nM  (99)


 







362 nM  (93)


 







990 nM  (98)


 







 2.3 μM  (84)


 







 2.5 μM  (87)


 







 2.6 μM  (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 μM  (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 μM  (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-1sulfonyl chloride, pivaloyl chloride, pyridinium p-toluenesufonate and tetrahydrofuran-3-ol were purchased from Aldrich Chemical Company.







EXAMPLE 2
Methyl 1-Benzyl-6-methoxy-1H-indole-2-carboxylate (Compound 2). To a solution of methyl6-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) δ ppm 3.81 (s, 3 H), 3.85 (s, 3 H), 5.81 (s, 2 H), 6.73 (d, J=2.0 Hz, 1 H), 6.84 (dd, J=8.8, 2.0 Hz, 1 H), 7.07 (d, J=6.8 Hz, 2 H), 7.19-7.29 (m, 3 H), 7.33 (s, 1 H), 7.58 (d, J=8.8 Hz, 1 H).
EXAMPLE 3
2-(1-Benzyl-6-methoxy-1H-indol-2-yl)propan-2-ol (Compound 3). To a solution of methyl1-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) δ ppm 1.69 (s, 6 H), 3.73 (s, 3 H), 5.76 (s, 2 H), 6.42 (s, 1 H), 6.55 (d, J=2.4 Hz, 1 H), 6.75-6.81 (m, 1 H), 6.96 (d, J=7.3 Hz, 2 H), 7.22 (d, J=7.3 Hz, 1 H), 7.25-7.30 (m, 2 H), 7.49 (d, J=8.8 Hz, 1 H).
EXAMPLE 4
1-Benzyl-2-isopropyl-6-methoxy-1H-indole (Compound 4). 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) δ ppm 1.31 (d, J=6.7 Hz, 6 H), 2.90-3.10 (m, 1 H), 3.79 (s, 3 H), 5.33 (s, 2 H), 6.33 (s, 1 H), 6.68 (d, J=2.1 Hz, 1 H), 6.79 (dd, J=8.5, 2.3 Hz, 1 H), 6.94-7.04 (m, 2 H), 7.20-7.37 (m, 2 H), 7.49 (d, J=8.5 Hz, 1 H).
EXAMPLE 5
1-Benzyl-2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 5). 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) δ ppm 1.45 (d, J=7.3 Hz, 6 H), 3.40-3.52 (m, 1 H), 3.79 (s, 3 H), 5.40 (s, 2 H), 6.69 (d, J=2.4 Hz, 1 H), 6.94 (dd, J=8.8, 2.0 Hz, 1 H), 7.01 (d, J=7.3 Hz, 2 H), 7.25-7.35 (m, 3 H), 8.28 (d, J=8.8 Hz, 1 H), 10.45 (s, 1 H).
EXAMPLE 6
1-Benzyl-2-isopropyl-6-methoxy-1H-indole-3-carboxylic Acid (Compound 6). 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) δ ppm 1.39 (d, J=7.3 Hz, 6 H), 3.75 (s, 3 H), 3.99-4.17 (m, 1 H), 5.45 (s, 2 H), 6.62 (d, J=2.4 Hz, 1 H), 6.90 (dd, J=8.8, 2.4 Hz, 1 H), 6.99 (d, J =7.3 Hz, 2 H), 7.22-7.34 (m, 3 H), 8.18 (d, J=8.8 Hz, 1 H).
EXAMPLE 7
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 7). 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) δ ppm 1.37 (d, J=7.3 Hz, 6 H), 3.65-3.73 (m, 1 H), 3.74 (s, 3 H), 4.66 (d, J=5.9 Hz, 2 H), 5.40 (s, 2 H), 6.30 (t, J=6.3 Hz, 1 H), 6.63 (d, J=2.0 Hz, 1 H), 6.82 (dd, J=8.8, 2.4 Hz, 1 H), 6.96 (d, J=6.8 Hz, 2 H), 7.11-7.17 (m, 2 H), 7.21-7.31 (m, 4 H), 7.51 (d, J=8.3 Hz, 1 H).
EXAMPLE 8
1-Benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8). 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) δ ppm 1.37 (d, J=7.3 Hz, 6 H), 3.65-3.74 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 4.78 (s, 1 H), 5.37 (s, 2 H), 6.27 (t, J=5.6 Hz, 1 H), 6.60 (d, J=2.4 Hz, 1 H), 6.71 (dd, J=8.5, 2.2 Hz, 1 H), 6.95 (d, J=6.8 Hz, 2 H), 7.11-7.17 (m, 2 H), 7.21-7.32 (m, 4 H), 7.46 (d, J=8.8 Hz, 1 H).
EXAMPLE 9
1-benzyl-N-(3,4-difluorobenzyl)-6-ethoxy-2-isopropyl-1H-indole-3-carboxamide (Compound 9). General Procedure A. 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 μl, 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) δ ppm 1.37 (t, J=7.0 Hz, 3 H), 1.38 (d, J=7.3 Hz, 6 H), 3.68-3.75 (m, 1 H), 3.96 (q, J=7.0 Hz, 2 H), 4.67 (d, J=6.3 Hz, 2 H), 5.40 (s, 2 H), 6.31 (t, J=5.4 Hz, 1 H), 6.64 (d, J=2.4 Hz, 1 H), 6.82 (dd, J=8.8, 2.0 Hz, 1 H), 6.97 (d, J=6.8 Hz, 2 H), 7.13-7.17 (m, 2 H), 7.23-7.31 (m, 4 H), 7.52 (d, J=8.3 Hz, 1 H)
EXAMPLE 10
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-propoxy-1H-indole-3-carboxamide (Compound 10). 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 μl, 0.092 mmol) to yield the title compound as a white solid.
1H NMR (500 MHz, METHANOL-d4) δ ppm 0.99 (t, J=7.6 Hz, 3 H), 1.32 (d, J=7.3 Hz, 6 H), 1.67-1.77 (m, 2 H), 3.42-3.53 (m, 1 H), 3.84 (t, J=6.6 Hz, 2 H), 4.57 (s, 2 H), 5.46 (s, 2 H), 6.73 (d, J=2.0 Hz, 1 H), 6.78 (dd, J=8.8, 2.4 Hz, 1 H), 6.95 (d, J=6.8 Hz, 2 H), 7.19-7.29 (m, 5 H), 7.30-7.36 (m, 1 H), 7.49 (d, J=8.3 Hz, 1 H).
EXAMPLE 11
1-Benzyl-N-(3,4-difluorobenzyl)-6-isopropoxy-2-isopropyl-1H-indole-3-carboxamide (Compound 11). 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 μl, 0.092 mmol) to yield the title compound as a white solid.
1H NMR (500 MHz, METHANOL-d4) δ ppm 1.21 (d, J=5.9 Hz, 6 H), 1.33 (d, J=7.3 Hz, 6 H), 3.45-3.55 (m, 1 H), 4.41-4.50 (m, 1 H), 4.57 (s, 2 H), 5.46 (s, 2 H), 6.72 (d, J=2.0 Hz, 1 H), 6.74-6.79 (m, 1 H), 6.96 (d, J=7.3 Hz, 2 H), 7.18-7.29 (m, 5 H), 7.30-7.37 (m, 1 H), 7.49 (d, J=8.8 Hz, 1 H).
EXAMPLE 12
1-Benzyl-6-butoxy-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 12). 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 μl, 0.12 mmol) to yield the title compound as a white solid.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.37 (d, J=7.3 Hz, 6 H), 1.40-1.50 (m, 2 H), 1.66-1.74 (m, 2 H), 3.61-3.75 (m, 1 H), 3.88 (t, J=6.6 Hz, 2 H), 4.66 (d, J=6.3 Hz, 2 H), 5.39 (s, 2 H), 6.30 (t, J=5.9 Hz, 1 H), 6.63 (d, J=2.0 Hz, 1 H), 6.81 (dd, J=8.5, 2.2 Hz, 1 H), 6.96 (d, J=6.8 Hz, 2 H), 7.10-7.17 (m, 2 H), 7.21-7.32 (m, 4 H), 7.50 (d, J=8.8 Hz, 1 H).
EXAMPLE 13
1-Benzyl-N-(3,4-difluorobenzyl)-6-isobutoxy-2-isopropyl-1H-indole-3-carboxamide (Compound 13). 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 μl, 0.12 mmol) to yield the title compound as a white solid.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.98 (d, J=6.8 Hz, 6 H), 1.36 (d, J=7.3 Hz, 6 H), 1.96-2.08 (m, 1 H), 3.65 (d, J=6.8 Hz, 2 H), 3.65-3.72 (m, 1 H), 4.66 (d, J=6.3 Hz, 2 H), 5.39 (s, 2 H), 6.29 (t, J=5.6 Hz, 1 H), 6.63 (d, J=2.0 Hz, 1 H), 6.82 (dd, J=8.8, 2.0 Hz, 1 H), 6.96 (d, J=6.8 Hz, 2H), 7.11-7.16 (m, 2H), 7.21-7.31 (m, 4 H), 7.50 (d, J=8.8 Hz, 1 H).
EXAMPLE 14
1-Benzyl-N-(3,4-difluorobenzyl)-6-(hexoxy)-2-isopropyl-1H-indole-3-carboxamide (Compound 14). 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 μl, 0.12 mmol) to yield the title compound as a white solid.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.85-0.93 (m, 3 H), 1.24-1.33 (m, 4 H), 1.37 (d, J=6.8 Hz, 6 H), 1.38-1.46 (m, 2 H), 1.66-1.77 (m, 2 H), 3.63-3.75 (m, 1 H), 3.87 (t, J=6.6 Hz, 2 H), 4.66 (d, J=5.9 Hz, 2 H), 5.39 (s, 2 H), 6.30 (t, J=5.6 Hz, 1 H), 6.63 (d, J=2.4 Hz, 1 H), 6.81 (dd, J=8.8, 2.4 Hz, 1 H), 6.96 (d, J=6.8 Hz, 2 H), 7.10-7.16 (m, 2 H), 7.21-7.31 (m, 4 H), 7.50 (d, J=8.8 Hz, 1 H).
EXAMPLE 15
1-Benzyl-6-(benzyloxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 15). 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 μl, 0.12 mmol), and catalytic amount of NaI to yield the title compound as an off-white solid.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.37 (d, J=7.3 Hz, 6 H), 3.65-3.75 (m, 1 H), 4.66 (d, J=6.3 Hz, 2 H), 4.99 (s, 2 H), 5.37 (s, 2 H), 6.28 (t, J=6.3 Hz, 1 H), 6.71 (d, J=2.0 Hz, 1 H), 6.89 (dd, J=8.8, 2.0 Hz, 1 H), 6.95 (d, J=6.8 Hz, 2 H), 7.11-7.18 (m, 2 H), 7.22-7.30 (m, 5 H), 7.31-7.39 (m, 4 H), 7.51 (d, J=8.8 Hz, 1 H).
EXAMPLE 16
1-Benzyl-6-(cyclopentoxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 16). 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 μl, 0.46 mmol) to yield the title compound as a white solid.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 1.48-1.60 (m, 2 H), 1.66-1.86 (m, 6 H), 3.62-3.83 (m, 1 H), 4.56-4.77 (m, 3 H), 5.38 (s, 2 H), 6.32 (t, J=5.9 Hz, 1 H), 6.61 (d, J=2.1 Hz, 1 H), 6.78 (dd, J=8.8, 2.1 Hz, 1 H), 6.91-7.02 (m, 2 H), 7.08-7.17 (m, 2 H), 7.17-7.36 (m, 4 H), 7.49 (d, J=8.5 Hz, 1 H).
EXAMPLE 17
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(2-methoxyethoxy)-1H-indole-3-carboxamide (Compound 17). 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 μl, 0.20 mmol) to yield the title compound (9 mg, 49%).
1H NMR (300 MHz, CDCl3) δ ppm 1.37 (d, J=7.04 Hz, 6 H), 3.40 (s, 3 H), 3.60-3.78 (m, 3 H), 4.04 (dd, J=5.42, 3.96 Hz, 2 H), 4.66 (d, J=5.86 Hz, 2 H), 5.39 (s, 2 H), 6.30 (t, J=5.86 Hz, 1 H), 6.68 (d, J=2.35 Hz, 1 H), 6.85 (dd, J=8.65, 2.20 Hz, 1 H), 6.89-7.01 (m, 2 H), 7.10-7.18 (m, 2 H), 7.17-7.35 (m, 4 H), 7.51 (d, J=8.79 Hz, 1 H).
EXAMPLE 18
1-Benzyl-N-(3,4-difluorobenzyl)-6-(2-(dimethylamino)ethoxy)-2-isopropyl-1H-indole-3-carboxamide (Compound 18). 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) δ ppm 1.32 (d, J=7.04 Hz, 6 H), 2.30 (s, 6 H), 2.71 (t, J=5.42 Hz, 2 H), 3.37-3.59 (m, 1 H), 4.02 (t, J=5.42 Hz, 2 H), 4.57 (s, 2 H), 5.48 (s, 2 H), 6.73-6.88 (m, 2 H), 6.89-7.02 (m, 2 H), 7.12-7.40 (m, 6 H), 7.50 (d, J=8.50 Hz, 1 H).
EXAMPLE 19
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(tetrahydrofuran-3-yloxy)-1H-indole-3-carboxamide (Compound 19). 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) δ ppm 1.38 (d, J=7.04 Hz, 6 H), 1.95-2.14 (m, 2 H), 3.59-4.01 (m, 5 H), 4.66 (d, J=6.16 Hz, 2 H), 4.74-4.88 (m, 1 H), 5.39 (s, 2 H), 6.29 (t, J=4.40 Hz, 1 H), 6.57 (d, J=2.05 Hz, 1 H), 6.69-6.83 (m, 1 H), 6.96 (d, J=7.62 Hz, 2 H), 7.08-7.19 (m, 2 H), 7.18-7.35 (m, 4 H), 7.51 (d, J=8.79 Hz, 1 H).
EXAMPLE 20
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(2-oxotetrahydrofuran-3-yloxy)-1H-indole-3-carboxamide (Compound 20). Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1 H-indole-3-carboxamide (Compound 8, 19mg, 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 (16mg, 71%).
1H NMR (300 MHz, acetone-d6) δ ppm 1.33 (d, J=5.57 Hz, 6 H), 2.21-2.42 (m, 1 H), 2.68-2.88 (m, 1 H), 3.43-3.65 (m, 1 H), 4.21-4.53 (m, 2 H), 4.66 (d, J=6.16 Hz, 2 H), 5.10-5.24 (m, 1 H), 5.54 (s, 2 H), 6.90 (dd, J=8.65, 2.20 Hz, 1 H), 6.97-7.08 (m, 2 H), 7.11 (d, J=2.35 Hz, 1 H), 7.17-7.35 (m, 5 H), 7.42 (dd, J=12.31, 8.50 Hz, 1 H), 7.62 (d, J=8.79 Hz, 1 H), 7.68-7.78 (m, 1 H).
EXAMPLE 21
1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl Dimethylcarbamate (Compound 21). General Procedure B. To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 18mg, 0.041mol) in pyridine (1 ml) was added dimethylcarbamyl chloride (40 μl, 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) δ ppm 1.32 (d, J=7.04 Hz, 6 H), 2.96 (s, 3 H), 3.09 (s, 3 H), 3.37-3.55 (m, 1 H), 4.58 (s, 2 H), 5.48 (s, 2 H), 6.87 (dd, J=8.65, 1.91 Hz, 1 H), 6.91-6.99 (m, 2 H), 7.02 (d, J=2.05 Hz, 1 H), 7.16-7.39 (m, 6 H), 7.58 (d, J=8.79 Hz, 1 H).
EXAMPLE 22
1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl Pivalate (Compound 22). 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 μl, 0.41 mmol) to yield the title compound (16 mg, 74%).
1H NMR (300 MHz, CD3OD) δ ppm 1.25-1.40 (m, 15 H), 3.34-3.55 (m, 1 H), 4.58 (d, J=5.86 Hz, 2 H), 5.49 (s, 2 H), 6.73-6.88 (m, 1 H), 6.89-6.99 (m, 2 H), 7.00 (d, J=1.76 Hz, 1 H), 7.14-7.41 (m, 6 H), 7.60 (d, J=8.50 Hz, 1 H).
EXAMPLE 23
1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl Acetate (Compound 23). 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 μl, 0. 16 mmol) to yield the title compound (8 mg, 100%).
1H NMR (300 MHz, CDCl3) δ ppm 1.37 (d, J=7.04 Hz, 6 H), 2.26 (s, 3 H), 3.54-3.76 (m, 1 H), 4.66 (d, J=6.16 Hz, 2 H), 5.41 (s, 2 H), 6.28 (t, J=6.01 Hz, 1 H), 6.81-7.01 (m, 4 H), 7.06-7.19 (m, 2 H), 7.18-7.35 (m, 4 H), 7.61 (d, J=9.09 Hz, 1 H).
EXAMPLE 24
1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl Propionate (Compound 24). 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 μl, 0.16 mmol) to yield the title compound (8 mg, 100%).
1H NMR (300 MHz, CDCl3) δ ppm 1.23 (t, J=7.48 Hz, 3 H), 1.37 (d, J=7.33 Hz, 6 H), 2.55 (q, J=7.43 Hz, 2 H), 3.53-3.73 (m, 1 H), 4.66 (d, J=5.86 Hz, 2 H), 5.41 (s, 2 H), 6.30 (t, J=5.72 Hz, 1 H), 6.83-7.00 (m, 4 H), 7.06-7.18 (m, 2 H), 7.18-7.35 (m, 4 H), 7.60 (d, J=8.50 Hz, 1 H).
EXAMPLE 25
1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl Isobutyrate (Compound 25). 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 μl, 0.21 mmol) to yield the title compound (8 mg, 80%).
1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.42 (m, 12 H), 2.47-2.85 (m, 1 H), 3.50-3.74 (m, 1 H), 4.66 (d, J=6.16 Hz, 2 H), 5.41 (s, 2 H), 6.20-6.44 (m, 1 H), 6.74-7.00 (m, 4 H), 7.07-7.18 (m, 2 H), 7.17-7.35 (m, 4 H), 7.60 (d, J=8.50 Hz, 1H).
EXAMPLE 26
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(methoxymethoxy)-1H-indole-3-carboxamide (Compound 26). 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 μl, 0.27 mmol) and MOMCl (35 μl, 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) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 3.42 (s, 3 H), 3.59-3.78 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 5.10 (s, 2 H), 5.40 (s, 2 H), 6.29 (t, J=5.7 Hz, 1 H), 6.85 (d, J=2.1 Hz, 1 H), 6.89-7.01 (m, 3 H), 7.10-7.17 (m, 2 H), 7.20- 7.34 (m, 4 H), 7.52 (d, J=8.5 Hz, 1 H).
EXAMPLE 27
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(tetrahydrofuran-2-yloxy)-1H-indole-3-carboxamide (Compound 27). 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 μl, 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) δ ppm 1.36 (d, J=7.3 Hz, 6 H), 1.85-1.98 (m, 1 H), 2.01-2.19 (m, 3 H), 3.58-3.73 (m, 1 H), 3.85-3.95 (m, 1 H), 3.96-4.07 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 5.40 (s, 2 H), 5.70 (d, J=4.7 Hz, 1 H), 6.29 (t, J=5.7 Hz, 1 H), 6.86 (d, J=2.1 Hz, 1 H), 6.89-6.99 (m, 3 H), 7.11-7.17 (m, 2 H), 7.19-7.32 (m, 4 H), 7.51 (d, J=8.5 Hz, 1 H).




EXAMPLE 28
Tetrahydrofuran-3-yl4-methylbenzenesulfonate (Compound 28). 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) δ ppm 1.91-2.23 (m, 2 H), 3.61-4.05 (m, 4 H), 4.95-5.24 (m, 1 H), 7.36 (d, J=7.92 Hz, 2 H), 7.80 (d, J=8.50 Hz, 2 H).
EXAMPLE 29
3-Iodotetrahydrofuran (Compound 29). To a solution of crude tetrahydrofuran-3-yl4-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) δ ppm 2.23-2.55 (m, 2 H), 3.81-4.08 (m, 3 H), 4.08-4.43 (m, 2 H).







EXAMPLE 30
Ethyl 4-Iodo-3-nitrobenzoate (Compound 30). 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) δ ppm 1.41 (t, J=7.09 Hz, 3 H), 4.40 (q, J=7.09 Hz, 2 H), 7.89 (dd, J=6.11, 1.96 Hz, 1 H), 8.19 (d, J=7.62 Hz, 1 H), 8.45 (s, 1 H).
EXAMPLE 31
Ethyl 3-Amino-4-iodobenzoate (Compound 31). To a solution of ethyl4-iodo-3nitrobenzoate (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) δ ppm 1.38 (t, J=7.09 Hz, 3 H), 4.34 (q, J=7.18 Hz, 2 H), 7.11 (dd, J=8.21, 2.05 Hz, 1 H), 7.39 (d, J=2.05 Hz, 1 H), 7.71 (d, J=8.06 Hz, 1H).
EXAMPLE 32
Ethyl 3-Amino-4-(3-methylbut-1-ynyl)benzoate (Compound 32). To a solution of ethyl3-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) δ ppm 1.29 (s, 3 H), 1.31 (s, 3 H), 1.38 (t, J=7.11 Hz, 3 H), 2.86 (dt, J=13.67, 6.87 Hz, 1 H), 4.25 (br. s., 2 H), 4.34 (q, J=7.08 Hz, 2 H), 7.29 (s, 1 H), 7.32 (d, J=1.47 Hz, 1 H), 7.33-7.38 (m, 1 H).
EXAMPLE 33
Ethyl 2-Isopropyl-1H-indole-6-carboxylate (Compound 33). To a solution of ethyl3-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) 6 ppm 1.37 (s, 3 H), 1.39 (s, 3 H), 1.40-1.44 (m, 3 H), 1.42 (t, J=7.09 Hz, 3 H), 3.11 (ddd, J=13.71, 6.74, 6.52 Hz, 1 H), 4.39 (q, J=7.08 Hz, 2 H), 6.30 (ddd, J=2.09, 0.99, 0.88 Hz, 1 H), 7.53 (d, J=8.21 Hz, 1 H), 7.78 (dd, J=8.36, 1.47 Hz, 1 H), 8.08 (d, J=0.73 Hz, 1 H), 8.17 (br. s., 1 H).
EXAMPLE 34
Ethyl 3-Formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34). 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) δ ppm 1.43 (t, J=7.18 Hz, 3 H), 1.48 (s, 3 H), 1.50 (s, 3 H), 3.84 (dt, J=14.00, 6.93 Hz, 1 H), 4.42 (q, J=7.18 Hz, 2 H), 7.97 (dd, J=8.28, 1.39 Hz, 1 H), 8.18 (d, J=0.73 Hz, 1 H), 8.28 (d, J=8.21 Hz, 1 H), 8.95 (br. s., 1 H), 10.29 (s, 1 H).
EXAMPLE 35
Ethyl 1-Benzyl-3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 35). General Procedure C. To a solution of ethyl3-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) δ ppm 1.37 (t, J=7.11 Hz, 3 H), 1.44 (s, 3 H), 1.47 (s, 3 H), 3.54-3.76 (m, 0 H), 4.35 (q, J=7.18 Hz, 2 H), 5.67 (s, 2 H), 7.02 (d, J=7.18 Hz, 1 H), 7.18-7.42 (m, 4 H), 7.93 (d, J=8.36 Hz, 1 H), 8.08 (s, 1 H), 8.33 (d, J=8.65 Hz, 1 H), 10.41 (s, 1 H).
EXAMPLE 36
Ethyl 3-Formyl-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 36). Following General Procedure C, ethyl3-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) δ ppm 1.36 (t, J=7.17 Hz, 3 H), 1.47 (s, 3 H), 1.50 (s, 3 H), 3.62-3.72 (m, 1 H), 4.34 (d, J=7.18 Hz, 2 H), 5.74 (s, 2 H), 7.01 (d, J=7.77 Hz, 1 H), 7.32 (d, J=7.48 Hz, 1 H), 7.75 (td, J=7.70, 1.76 Hz, 1 H), 7.93 (td, J=4.14, 1.39 Hz, 1 H), 8.07 (d, J=0.73 Hz, 1 H), 8.34 (t, J=4.18 Hz, 1 H), 8.52 (ddd, J=4.87, 1.72, 0.88 Hz, 1 H), 10.42 (s, 1 H).
EXAMPLE 37
Ethyl 3-Formyl-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (Compound 37). To a solution of ethyl3-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 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) δ ppm 1.36 (t, J=7.11 Hz, 3 H), 1.46 (s, 3 H), 1.49 (s, 3 H), 3.66 (dt, J=14.37, 7.18 Hz, 1 H), 4.35 (q, J=7.08 Hz, 2 H), 5.78 (s, 2 H), 7.40 (qd, J=3.81, 3.66 Hz, 3 H), 7.94 (dd, J=8.36, 1.47 Hz, 1 H), 8.10 (d, J=0.73 Hz, 1 H), 8.30-8.40 (m, 1 H), 8.47 (dd, J=4.47, 1.98 Hz, 1 H), 10.43 (s, 1 H).
EXAMPLE 38
Ethyl 3-Formyl-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 38). To a solution of ethyl3-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) δ ppm 1.40 (t, J=7.11 Hz, 3 H), 1.54 (s, 3 H), 1.56 (s, 3 H), 3.77 (dt, J=14.33, 7.13 Hz, 1 H), 4.38 (q, J=7.04 Hz, 2 H), 5.80 (s, 2 H), 7.15 (d, J=0.73 Hz, 1 H), 7.80-8.11 (m, 2 H), 8.11-8.52 (m, 2 H), 10.42 (s, 1 H).
EXAMPLE 39
1-Benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic Acid (Compound 39). General Procedure D. To a solution of ethyl1-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) δ ppm 1.35 (t, J=7.11 Hz, 3 H), 1.37 (s, 3 H), 1.40 (s, 3 H), 3.80-4.08 (m, 1 H), 4.33 (q, J=7.13 Hz, 2 H), 5.67 (s, 2 H), 6.96 (d, J=9.23 Hz, 2 H), 7.20-7.38 (m, 3 H), 7.84 (dd, J=8.50, 1.47 Hz, 1 H), 7.98 (s, 1 H), 8.21 (dd, J=8.50, 0.59 Hz, 1 H).
EXAMPLE 40
6-(Ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic Acid (Compound 40). Following General Procedure D, ethyl3-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, 16.4mmol) 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) δ ppm 1.30-1.47 (m, 9 H), 3.94-4.13 (m, 1 H), 4.33 (q, J=7.13 Hz, 2 H), 5.74 (s, 2 H), 6.76 (d, J=8.06 Hz, 1 H), 7.26-7.37 (m, 1 H), 7.65-7.77 (m, 1 H), 7.85 (d, J=7.04 Hz, 1 H), 7.98 (d, J=0.73 Hz, 1 H), 8.21 (d, J=8.50 Hz, 1 H), 8.55 (dd, J=6.23, 1.25 Hz, 1 H).
EXAMPLE 41
6-(Ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic Acid (Compound 41). Following General Procedure D, ethyl3-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) δ ppm 1.36 (t, J=7.11 Hz, 3 H), 1.39 (s, 3 H), 1.42 (s, 3 H), 3.85-4.13 (m, 1 H), 4.33 (q, J=7.08 Hz, 2 H), 5.77 (s, 2 H), 7.36 (t, J=2.05 Hz, 2 H), 7.86 (dd, J=8.50, 1.47 Hz, 1 H), 8.00 (d, J=0.88 Hz, 1 H), 8.22 (dd, J=8.50, 0.73 Hz, 1 H), 8.27 (d, J=1.76 Hz, 1 H), 8.45 (dd, J=4.03, 2.42 Hz, 1 H).
EXAMPLE 42
6-(Ethoxycarbonyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic Acid (Compound 42). Following General Procedure D, ethyl3-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) δ ppm 1.40 (t, J=7.11 Hz, 3 H), 1.46 (s, 3 H), 1.48 (s, 3 H), 3.94-4.15 (m, 1 H), 4.38 (q, J=7.18 Hz, 2 H), 5.78 (s, 2 H), 7.14 (d, J=0.73 Hz, 1 H), 7.76-7.93 (m, 2 H), 8.17 (d, J=2.05 Hz, 2 H).
EXAMPLE 43
Ethyl 1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 43). General Procedure E. 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) δ ppm 1.31-1.39 (m, 9 H), 3.47 (m, 1 H), 4.33 (q, J=7.18 Hz, 2 H), 4.59 (s, 2 H), 5.60 (s, 2 H), 6.96 (d, J=8.21 Hz, 1 H), 7.22-7.40 (m, 6 H), 7.67 (d, J=8.36 Hz, 1 H), 7.82 (d, J=1.47 Hz, 1 H), 8.00 (d, J=0.59 Hz, 1 H).
EXAMPLE 44
Ethyl 1-Benzyl-3-((5-fluoropyridin-3-yl)methylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 44). 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, 0.381mmol), 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) δ ppm 1.27-1.43 (m, 9 H), 3.40-3.59 (m, 1 H), 4.33 (q, J=7.18 Hz, 2 H), 4.69 (s, 2 H), 5.61 (s, 2 H), 6.95 (dd, J=7.48, 1.03 Hz, 2 H), 7.19-7.34 (m, 3 H), 7.65-7.76 (m, 2 H), 7.82 (dd, J=8.36, 1.47 Hz, 1 H), 8.00 (d, J=1.47 Hz, 1 H), 8.39 (d, J=2.64 Hz, 1 H), 8.52 (s, 1 H).
EXAMPLE 45
Ethyl 3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 45). 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) δ ppm 1.25-1.45 (m, 9 H), 3.40-3.59 (m, 1 H), 4.33 (t, J=7.04 Hz, 2 H), 4.60 (s, 2 H), 5.68 (s, 2 H), 6.74 (d, J=6.89 Hz, 1 H), 7.18-7.43 (m, 4 H), 7.61-7.76 (m, 2 H), 7.82 (dd, J=8.50, 1.47 Hz, 1 H), 8.00 (d, J=0.73 Hz, 1 H), 8.54 (dt, J=5.42, 0.95 Hz, 1 H).
EXAMPLE 46
Ethyl 3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (Compound 46). 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) δ ppm 1.35 (dt, J=7.18, 3.59 Hz, 9 H), 3.47 (m, 1 H), 4.33 (q, J=7.18 Hz, 2 H), 4.59 (s, 2 H), 5.70 (s, 2 H), 7.15-7.41 (m, 5 H), 7.68 (dd, J=8.36, 0.59 Hz, 1 H), 7.82 (dd, J=8.50, 1.47 Hz, 1 H), 8.01 (d, J=0.73 Hz, 1 H), 8.22 (d, J=1.91 Hz, 1 H), 8.43 (dd, J=3.81, 2.64 Hz, 1 H).
EXAMPLE 47
Ethyl 3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 47). 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) δ ppm 1.33-1.52 (m, 9 H), 3.59 (m, 1 H), 4.37 (q, J=7.18 Hz, 2 H), 4.57 (s, 2 H), 5.70 (s, 2 H), 7.12 (d, J=0.88 Hz, 1 H), 7.18-7.42 (m, 3 H), 7.63 (s, 1 H), 7.81 (dd, J=8.43, 1.39 Hz, 2 H), 7.85 (d, J=0.88 Hz, 1 H), 8.18 (s, 1 H).
EXAMPLE 48
Ethyl 3-(3,5-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 48). 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, 0.32mmol). 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) δ ppm 1.28-1.41 (m, 9 H), 3.51 (m, 1 H), 4.32 (q, J=7.03 Hz, 2 H), 4.62 (s, 2 H), 5.68 (s, 2 H), 6.74 (d, J=7.91 Hz, 1 H), 6.85 (tt, J=9.08, 2.34 Hz, 1 H), 7.04 (dd, J=8.50, 2.34 Hz, 2 H), 7.30 (dd, J=6.74, 4.98 Hz, 1 H), 7.59-7.75 (m, 2 H), 7.74-7.88 (m, 1 H), 8.00 (s, 1 H), 8.53 (d, J=4.10 Hz, 1 H).
EXAMPLE 49
Ethyl 3-((5-Fluoropyridin-3-yl)methylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 49). 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) δ ppm 1.25-1.45 (m, 9 H), 3.42-3.62 (m, 1 H), 4.33 (q, J=7.04 Hz, 2 H), 4.69 (s, 2 H), 5.68 (s, 2 H), 6.69-6.80 (m, 1 H), 7.26-7.36 (m, 1 H), 7.63-7.76 (m, 3 H), 7.79-7.86 (m, 1 H), 8.00 (s, 1 H), 8.39 (s, 1 H), 8.52 (d, J=1.61 Hz, 2 H).
EXAMPLE 50
Ethyl 3-(4-Fluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 50). 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) δ ppm 1.27-1.44 (m, 9 H), 3.48 (quin, J=7.25 Hz, 1 H), 4.32 (q, J=7.13 Hz, 2 H), 4.60 (s, 2 H), 5.66 (s, 2 H), 6.72 (d, J=7.91 Hz, 1 H), 7.09 (dd, J=8.79, 4.40 Hz, 2 H), 7.31 (d, J=5.86 Hz, 1 H), 7.47 (dd, J=8.79, 5.27 Hz, 2 H), 7.61-7.72 (m, 2 H), 7.74-7.84 (m, 1 H), 7.98 (s, 1 H), 8.53 (d, J=4.10 Hz, 1 H).
EXAMPLE 51
3,4-Difluorobenzyl 1-Benzyl-6-(ethoxycarbonyl)--2-isopropyl-1H-indole-3-carboxylate (Compound 51). Following General Procedure E,1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 39 mg, 0.1 1 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) δ ppm 1.21-1.44 (m, 9 H), 3.74-4.03 (m, 1 H), 4.32 (q, J=7.04 Hz, 2 H), 5.39 (s, 2 H), 5.66 (s, 2 H), 6.96 (d, J=6.74 Hz, 2 H), 7.21-7.37 (m, 5 H), 7.38-7.56 (m, 1 H), 7.83 (dd, J=8.50, 1.47 Hz, 1 H), 8.01 (s, 1 H), 8.12 (d, J=8.50 Hz, 1 H).
EXAMPLE 52
1-Benzyl-N-(3,4-difluorobenzyl)-6-(hydroxymethyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 52). To a solution of ethyl1-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) δ ppm 1.31 (s, 3 H), 1.33 (s, 3 H), 3.41 (m, 1 H), 4.58 (s, 2 H), 4.62 (s, 2 H), 5.53 (s, 2 H), 5.66 (s, 2 H), 6.96 (dd, J=6.16, 1.76 Hz, 2 H), 7.14 (d, J=8.50 Hz, 1 H), 7.30 (m, 6 H), 7.39 (m, 1 H), 7.60 (d, J=7.91 Hz, 1 H).
EXAMPLE 53
1-Benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53). 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) δ ppm 1.33 (s, 3 H), 1.35 (s, 3 H), 3.40-3.59 (m, 1 H), 4.59 (s, 2 H), 5.64 (s, 2 H), 6.86-7.06 (m, 2 H), 7.19-7.44 (m, 6 H), 7.61-7.78 (m, 2 H), 7.91 (d, J=0.73 Hz, 1 H), 9.91 (s, 1 H).
EXAMPLE 54
1-Benzyl-N-(3,4-difluorobenzyl)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-isopropyl-1H-indole-3-carboxamide (Compound 54). 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) δ ppm 1.31 (s, 3 H), 1.33 (s, 3 H), 3.38-3.52 (m, 1 H), 3.73 (s, 4 H), 4.58 (s, 2 H), 5.57 (s, 2 H), 6.94 (dd, J=7.77, 1.47 Hz, 2 H), 7.15-7.41 (m, 6 H), 7.56-7.60 (m, 1 H), 7.64-7.67 (m, 1 H), 7.82 (d, J=0.73 Hz, 1 H).
EXAMPLE 55
(E)-1-Benzyl-N-(3,4-difluorobenzyl)-6-((hydroxyimino)methyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 55). 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) δ ppm 1.31 (s, 3 H), 1.33 (s, 3 H), 3.36-3.52 (m, 1 H), 4.58 (s, 2 H), 5.54 (s, 2 H), 6.95 (dd, J=7.99, 1.54 Hz, 2 H), 7.17-7.38 (m, 5 H), 7.42 (dd, J=8.36, 1.32 Hz, 1 H), 7.49 (s, 1 H), 7.61 (d, J=8.36 Hz, 1 H), 8.10 (s, 1 H).




EXAMPLE 56
1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic Acid (Compound 56). General Procedure F. To a solution of ethyl1-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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.38-3.59 (m, 1 H), 4.59 (s, 2 H), 5.59 (s, 2 H), 6.96 (d, J=9.38 Hz, 2 H), 7.18-7.44 (m, 6 H), 7.63 (d, J=8.36 Hz, 1 H), 7.80 (dd, J=8.36, 1.32 Hz, 1 H), 8.00 (d, J=0.88 Hz, 1 H).
EXAMPLE 57
1-Benzyl-3-(5-Fluoropyridin-3-yl)methylcarbamoyl)-2-isopropyl-1-indole-6-carboxylic Acid (Compound 57). Following General Procedure F, ethyl1-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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.40-3.59 (m, 1 H), 4.60 (s, 2 H), 5.62 (s, 2 H), 6.95 (dd, J=7.48, 1.03 Hz, 2 H), 7.19-7.34 (m, 3 H), 7.65-7.76 (m, 2 H), 7.82 (dd, J=8.36, 1.47 Hz, 1 H), 8.00 (d, J=1.47 Hz, 1 H), 8.39 (d, J=2.64 Hz, 1 H), 8.52 (s, 1 H).
EXAMPLE 58
3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylic Acid (Compound 58). Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1 H-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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.40-3.59 (m, 1 H), 4.60 (s, 2 H), 5.67 (s, 2 H), 6.74 (d, J=6.89 Hz, 1 H), 7.18-7.43 (m, 4 H), 7.61-7.76 (m, 2 H), 7.82 (dd, J=8.50, 1.47 Hz, 1 H), 8.00 (d, J=0.73 Hz, 1 H), 8.54 (dt, J=5.42, 0.95 Hz, 1 H).
EXAMPLE 59
3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylic Acid (Compound 59). Following General Procedure F, ethyl3-(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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.40-3.59 (m, 1 H), 4.59 (s, 2 H), 5.70 (s, 2 H), 7.15-7.41 (m, 5 H), 7.68 (dd, J=8.36, 0.59 Hz, 1 H), 7.82 (dd, J=8.50, 1.47 Hz, 1 H), 8.01 (d, J=0.73 Hz, 1 H), 8.22 (d, J=1.91 Hz, 1 H), 8.43 (dd, J=3.81, 2.64 Hz, 1 H).
EXAMPLE 60
3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylic Acid (Compound 60). Following General Procedure F, ethyl3-(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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.59 (m, 1 H), 4.57 (s, 2 H), 5.70 (s, 2 H), 7.12 (d, J=0.88 Hz, 1 H), 7.18-7.42 (m, 3 H), 7.63 (s, 1 H), 7.81 (dd, J=8.43, 1.39 Hz, 2 H), 7.85 (d, J=0.88 Hz, 1 H), 8.18 (s, 1 H).
EXAMPLE 61
3-(3,5-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylic Acid (Compound 61). Following General Procedure F, ethyl3-(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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.51 (m, 1 H), 4.62 (s, 2 H), 5.68 (s, 2 H), 6.74 (d, J=7.91 Hz, 1 H), 6.85 (tt, J=9.08, 2.34 Hz, 1 H), 7.04 (dd, J=8.50, 2.34 Hz, 2 H), 7.30 (dd, J=6.74, 4.98 Hz, 1 H), 7.59-7.75 (m, 2 H), 7.74-7.88 (m, 1 H), 8.00 (s, 1 H), 8.53 (d, J=4.10 Hz, 1 H).
EXAMPLE 62
3-(4-Fluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylic Acid (Compound 62). Following General Procedure F, ethyl3-(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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.48 (m, 1 H), 4.60 (s, 2 H), 5.66 (s, 2 H), 6.72 (d, J=7.91 Hz, 1 H), 7.09 (dd, J=8.79, 4.40 Hz, 2 H), 7.31 (d, J=5.86 Hz, 1 H), 7.47 (dd, J=8.79, 5.27 Hz, 2 H), 7.61-7.72 (m, 2 H), 7.74-7.84 (m, 1 H), 7.98 (s, 1 H), 8.53 (d, J=4.10 Hz, 1 H).
EXAMPLE 63
1-Benzyl-N3-(3,4-difluorobenzyl)-N6-(2-hydroxyethyl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 63). 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) δ ppm 1.31 (s, 3 H), 1.34 (s, 3 H), 3.37-3.46 (m, 1 H), 3.49 (t, J=5.86 Hz, 2 H), 3.65-3.74 (m, 2 H), 4.59 (s, 2 H), 5.60 (s, 2 H), 6.94 (dd, J=7.92, 1.61 Hz, 2 H), 7.17-7.42 (m, 6 H), 7.65 (dd, J=2.35, 1.03 Hz, 2 H), 7.91 (s, 1 H).
EXAMPLE 64
1-Benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxy-2-methylpropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 64). 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) δ ppm 1.31 (s, 3 H), 1.34 (s, 3 H), 1.39 (s, 6 H), 3.43 (dt, J=14.18, 7.05 Hz, 1 H), 3.66 (s, 2 H), 4.58 (s, 2 H), 5.59 (s, 2 H), 6.96 (d, J=1.61 Hz, 2 H), 7.16-7.49 (m, 5 H), 7.52-7.60 (m, 1 H), 7.60-7.68 (m, 1 H), 7.84 (s, 1 H), 7.97 (s, 1 H).
EXAMPLE 65
(S)-1-Benzyl-N3-((5-fluoropyridin-3-yl)methyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 65). 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) δ ppm 1.23 (s, 3 H), 1.30 (s, 3 H), 1.32 (s, 3 H), 3.37-3.48 (m, 1 H), 3.54-3.61 (m, 2 H), 4.12-4.23 (m, 1 H), 4.69 (s, 2 H), 5.60 (s, 2 H), 6.95 (dd, J=7.62, 1.03 Hz, 2 H), 7.19-7.31 (m, 3 H), 7.63-7.76 (m, 4 H), 7.93 (s, 1 H), 8.39 (d, J=2.35 Hz, 1 H).
EXAMPLE 66
(R)-1-Benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxypropan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 66). 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) δ ppm 1.22 (d, J=6.89 Hz, 3 H), 1.31 (s, 3 H), 1.33 (s, 3 H), 3.38-3.48 (m, 1 H), 3.58 (d, J=5.57 Hz, 2 H), 4.17 (q, J=6.89 Hz, 1 H), 4.59 (s, 2 H), 5.59 (s, 2 H), 6.94 (dd, J=7.92, 1.61 Hz, 2 H), 7.18-7.41 (m, 6 H), 7.65 (s, 2 H), 7.91 (s, 1 H).
EXAMPLE 67
(S)-1-Benzyl-N3-(3,4-difluorobenzyl)-N6-(1-hydroxybutan-2-yl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 67). 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) δ ppm 0.97 (t, J=7.16 Hz 3 H), 1.24 (t, J=7.11 Hz, 4 H), 1.32 (s, 3 H), 1.34 (s, 3 H), 3.38-3.52 (m, 1 H), 3.61-3.78 (m, 2 H), 3.83-3.95 (m, 1 H), 4.59 (s, 2 H), 5.61 (s, 2 H), 6.96 (d, J=8.21 Hz, 2 H), 7.18-7.43 (m, 6 H), 7.66 (s, 2 H), 7.92 (d, J=1.03 Hz, 1 H).
EXAMPLE 68
1-Benzyl-N3-(3,4-difluorobenzyl)-N6-(2-hydroxy-2-methylpropyl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 68). 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) δ ppm 1.21 (s, 6 H), 1.31 (s, 3 H), 1.34 (s, 3 H), 3.39 (s, 2 H), 3.40-3.51 (m, 1 H), 4.59 (s, 2 H), 5.59 (s, 2 H), 6.96 (d, J=1.76 Hz, 2 H), 7.16-7.40 (m, 6 H), 7.66 (dd, J=3.30, 1.10 Hz, 2 H), 7.91 (s, 1 H).
EXAMPLE 69
1-Benzyl-N3-(3,4-difluorobenzyl)-2-isopropyl-N6-(prop-2-ynyl)-1H-indole-3,6-dicarboxamide (Compound 69). 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 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) δ ppm 1.32 (s, 3 H), 1.33 (s, 3 H), 2.55 (t, J=2.57 Hz, 1 H), 3.44 (dt, J=14.27, 7.11 Hz, 1 H), 4.13 (s, 2 H), 4.58 (s, 2 H), 5.58 (s, 2 H), 6.94 (d, J=6.97 Hz, 2 H), 7.18-7.30 (m, 5 H), 7.31-7.41 (m, 1 H), 7.59-7.70 (m, 2 H), 7.89 (d, J=0.73 Hz, 1 H).
EXAMPLE 70
1-Benzyl-N-(3,4-difluorobenzyl)-6-(4,5-dihydrooxazol-2-yl)-2-isopropyl-1H-indole-3-carboxamide (Compound 70). General Procedure H. 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) δ ppm 1.32 (s, 3 H), 1.35 (s, 3 H), 3.41-3.56 (m, 1 H), 3.98 (t, J=9.38 Hz, 2 H), 4.45 (t, J=9.53 Hz, 2 H), 4.59 (d, J=4.10 Hz, 2 H), 5.57 (s, 2 H), 6.94 (d, J=6.16 Hz, 2 H), 7.13-7.43 (m, 6 H), 7.55-7.79 (m, 2 H), 7.87 (s, 1 H), 8.71 (t, J=5.13 Hz, 1 H).
EXAMPLE 71
1-Benzyl-N-(3,4-difluorobenzyl)-6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-isopropyl-1H-indole-3-carboxamide (Compound 71). 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) δ ppm 1.18-1.47 (m, 12 H), 3.37-3.53 (m, 1 H), 4.20-4.46 (m, 2 H), 4.59 (d, J=5.57 Hz, 2 H), 5.59 (s, 2 H), 6.94 (d, J=3.96 Hz, 2 H), 7.06-7.43 (m, 6 H), 7.55-7.84 (m, 2 H), 7.89-7.96 (m, 1 H), 8.78 (d, J=1.17 Hz, 1 H).
EXAMPLE 72
(S)-1-Benzyl-N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1H-indole-3-carboxamide (Compound 72). 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) δ ppm 1.26-1.36 (m, 9 H), 3.39-3.53 (m, 1 H), 4.04 (t, J=7.99 Hz, 1 H), 4.27-4.46 (m, 1 H), 4.61 (d, J=8.36 Hz, 1 H), 4.69 (d, J=5.72 Hz, 2 H), 5.59 (s, 2 H), 6.89-7.03 (m, 2 H), 7.12-7.35 (m, 3 H), 7.56-7.78 (m, 3 H), 7.91 (s, 1 H), 8.39 (d, J=2.64 Hz, 1 H), 8.51 (s, 1 H), 8.82 (t, J=7.84 Hz, 1 H).
EXAMPLE 73
(S)-1-Benzyl-6-(4-ethyl-4,5-dihydrooxazol-2-yl)-N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 73). 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) δ ppm 0.96 (t, J=7.40 Hz, 3 H), 1.31 (s, 3 H), 1.33 (s, 3 H), 1.51-1.81 (m, 2 H), 3.39-3.57 (m, 1 H), 4.11 (dd, J=7.48, 6.45 Hz, 2 H), 4.50 (dd, J=8.94, 7.92 Hz, 1 H), 4.68 (s, 2 H), 5.58 (s, 2 H), 6.94 (dd, J=7.77, 1.47 Hz, 2 H), 7.14-7.35 (m, 4 H), 7.62-7.81 (m, 3 H), 7.90 (s, 1 H), 8.39 (d, J=2.64 Hz, 1 H), 8.51 (s, 1 H).
EXAMPLE 74
(R)-1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1H-indole-3-carboxamide (Compound 74). 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) δ ppm 1.26 (s, 3 H), 1.37 (s, 3 H), 3.36-3.51 (m, 1 H), 4.09 (t, J=7.11 Hz, 1 H), 4.26-4.42 (m, 1 H), 4.59 (s, 2 H), 4.71 (m, 1H), 5.60 (s, 2 H), 6.89-7.02 (m, 2 H), 7.16-7.44 (m, 6 H), 7.59-7.75 (m, 2 H), 7.90 (s, 1 H).
EXAMPLE 75
(S)-1-Benzyl-N-(3,4-difluorobenzyl)-6-(4-ethyl-4,5-dihydrooxazol-2-yl)-2-isopropyl-1H-indole-3-carboxamide (Compound 75). 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) δ ppm 0.96 (t, J=7.40 Hz, 3 H), 1.32 (s, 3 H), 1.34 (s, 3 H), 1.52-1.81 (m, 2 H), 3.38-3.52 (m, 1H), 4.12 (d, J=7.62 Hz, 1H), 4.15-4.29 (m, 1 H), 4.51 (dd, J=8.94, 7.92 Hz, 1H), 4.57-4.62 (m, 2 H), 5.58 (s, 2 H), 6.95 (d, J=1.76 Hz, 2 H), 7.08-7.45 (m, 6 H), 7.51-7.82 (m, 2 H), 7.89 (d, J=0.59 Hz, 1H), 8.72 (t, J=7.84 Hz, 1H).
EXAMPLE 76
(S)-1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1H-indole-3-carboxamide (Compound 76). 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) δ ppm 1.21-1.41 (m, 9 H), 3.39-3.56 (m, 1H), 4.12 (t, J=8.21 Hz, 1H), 4.59 (s, 2 H), 4.65 (d, J=8.50 Hz, 1H), 5.60 (s, 2 H), 6.88-6.99 (m, 2 H), 7.15-7.41 (m, 6 H), 7.63-7.78 (m, 2 H), 7.93 (s, 1H).
EXAMPLE 77
(S)-1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(4-(methoxymethyl)-4,5-dihydrooxazol-2-yl)-1H-indole-3-carboxamide (Compound 77). 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) δ ppm 1.34 (s, 3 H), 1.36 (s, 3 H), 3.37 (s, 3 H), 3.44-3.61 (m, 2 H), 4.31-4.57 (m, 2 H), 4.60 (d, J=5.57 Hz, 2 H), 5.60 (s, 2 H), 6.97 (d, J=1.76 Hz, 2 H), 7.17-7.45 (m, 6 H), 7.63-7.80 (m, 2 H), 7.93 (s, 1H), 8.74 (s, 1H).
EXAMPLE 78
(R)—N-(3,4-Difluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 78). 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) δ ppm 1.32 (m, 9 H), 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, 3 H), 5.65 (s, 1H), 6.71 (d, J=7.62 Hz, 1 H), 7.20-7.40 (m, 4 H), 7.63-7.75 (m, 3 H), 7.88 (s, 1H), 8.53 (d, J=4.10 Hz, 1H), 8.72 (t, 1 H).
EXAMPLE 79
(S)—N-(3,4-Difluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 79). 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) δ ppm 1.24-1.39 (m, 9 H), 3.42-3.60 (m, 1H), 4.00 (t, J=8.06 Hz, 1 H), 4.25 (m, 1 H), 4.38 (m, 1 H), 4.56 (s, 2 H), 5.65 (s, 2 H), 6.70 (d, J=7.62 Hz, 1 H), 7.18-7.40 (m, 4 H), 7.60-7.77 (m, 3 H), 7.88 (d, J=0.73 Hz, 1 H), 8.54 (d, J=5.57 Hz, 1 H).
EXAMPLE 80
(S)—N-(3,4-Difluorobenzyl)-6-(4-ethyl-4,5-dihydrooxazol-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 80). 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) δ ppm 0.96 (t, J=7.61 Hz, 3 H), 1.32 (s, 3 H), 1.35 (s, 3 H), 1.49-1.85 (m, 2 H), 3.40-3.59 (m, 1 H), 4.02-4.11 (m, 1 H), 4.49 (t, J=8.79 Hz, 1 H), 4.56 (s, 2 H), 5.65 (s, 2 H), 6.70 (d, J=7.62 Hz, 1 H), 7.18-7.40 (m, 4 H), 7.60-7.77 (m, 3 H), 7.88 (d, J=0.73 Hz, 1 H), 8.54 (d, J=5.57 Hz, 1 H).
EXAMPLE 81
(S)—N-(3,4-Difluorobenzyl)-6-(4-(hydroxymethyl)-4,5-dihydrooxazol-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 81)
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) δ ppm 1.32 (s, 3 H), 1.34 (s, 3 H), 3.41-3.57 (m, 1 H), 3.59-3.76 (m, 2 H), 4.27-4.43 (m, 1 H), 4.50 (t, J=8.28 Hz, 1 H), 4.59 (s, 2 H), 5.65 (s, 2 H), 6.70 (d, J=7.92 Hz, 1 H), 7.18-7.42 (m, 4 H), 7.61-7.79 (m, 3 H), 7.91 (s, 1 H), 8.53 (d, J=4.98 Hz, 1 H).
EXAMPLE 82
(S)—N-(3,4-Difluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 82). 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) δ ppm 1.22-1.42 (m, 9 H), 3.41-3.62 (m, 1 H), 3.99 (t, J=8.06 Hz, 1 H), 4.31 (dd, J=9.52, 6.89 Hz, 1 H), 4.54 (d, J=8.20 Hz, 1 H), 4.59 (s, 2 H), 5.67 (s, 2 H), 7.08-7.31 (m, 2 H), 7.29-7.49 (m, 3 H), 7.56-7.80 (m, 2 H), 7.89 (s, 1H), 8.21 (s, 1 H), 8.43 (d, J=3.52 Hz, 1 H).
EXAMPLE 83
(S)—N-(3,4-Difluorobenzyl)-6-(4-ethyl-4,5-dihydrooxazol-2-yl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 83). 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) δ ppm 1.00 (t, J=7.46 Hz, 3 H), 1.38 (s, 3 H), 1.40 (s, 3 H), 1.55-1.87 (m, 2 H), 3.57 (dt, J=14.18, 7.09 Hz, 1 H), 4.17 (t, J=7.83 Hz, 1H), 4.25 (ddd, J=14.73, 7.27, 7.09 Hz, 1 H), 4.57 (s, 2 H), 5.67 (s, 2 H), 7.11 (s, 1 H), 7.19-7.28 (m, 2 H), 7.34 (d, J=7.82 Hz, 1 H), 7.61 (d, J=8.31 Hz, 1 H), 7.73 (d, J=8.56 Hz, 1 H), 7.84 (s, 1 H), 8.05 (s, 1 H), 8.71 (br. s., 1 H).
EXAMPLE 84
(S)—N-(3,5-Difluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 84). 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) δ ppm 1.23-1.42 (m, 9 H), 3.41-3.58 (m, 1 H), 3.98 (t, 1 H), 4.23-4.38 (m, 1 H), 4.47-4.58 (m, 1 H), 4.62 (m, 1 H), 5.65 (s, 2 H), 6.76 (d, J=7.91, Hz, 1 H), 6.76-6.91 (m, 1 H), 7.00-7.11 (m, 1 H), 7.21-7.36 (m, 1 H), 7.61-7.79 (m, 4 H), 7.88 (s, 1 H), 8.44-8.58 (m, 1 H).
EXAMPLE 85
(S)—N-(3,5-Difluorobenzyl)-6-(4-ethyl-4,5-dihydrooxazol-2-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 85). 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) δ ppm 0.96 (t, J=7.61 Hz, 3 H), 1.32 (s, 3 H), 1.35 (s, 3 H), 1.49-1.85 (m, 2 H), 3.40-3.59 (m, 1 H), 4.12 (t, J=7.61 Hz, 2 H), 4.14-4.30 (m, 1 H), 4.49 (t, J=8.79 Hz, 1 H), 4.63 (s, 2 H), 5.65 (s, 2 H), 6.71 (d, J=7.91 Hz, 1 H), 6.79-6.90 (m, 1 H), 6.99-7.10 (m, 1 H), 7.25-7.33 (m, 1 H), 7.62-7.78 (m, 4 H), 7.89 (s, 1 H), 8.52 (d, J=5.57 Hz, 1 H).
EXAMPLE 86
(S)—N-(4-Fluorobenzyl)-2-isopropyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 86). 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) δ ppm 1.34 (m, 9 H), 3.41-3.61 (m, 1 H), 3.95 (t, J=7.91 Hz, 1 H), 4.25-4.43 (m, 1 H), 4.54 (t, J=8.79 Hz, 1 H), 4.63 (s, 2 H), 5.65 (s, 2 H), 6.63 (d, J=7.91 Hz, 1 H), 7.01-7.14 (m, 2 H), 7.23-7.33 (m, 1 H), 7.40-7.54 (m, 2 H), 7.61-7.76 (m, 3 H), 7.90 (s, 1 H), 8.53 (d, J=5.57 Hz, 1 H).
EXAMPLE 87
6-(5,5-Dimethyl-4,5-dihydrooxazol-2-yl)-N-(4-fluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 87). 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) δ ppm 1.31 (s, 3 H), 1.34 (s, 3 H), 1.46 (s, 6 H), 3.35-3.54 (m, 1 H), 3.71 (s, 2 H), 4.58 (s, 2 H), 5.57 (s, 2 H), 6.94 (d, J=6.16 Hz, 2 H), 7.24 (dd, J=3.59, 1.39 Hz, 6 H), 7.67 (dd, J=2.05, 1.03 Hz, 2 H), 7.85 (s, 1 H).
EXAMPLE 88
1-Benzyl-N-(3,4-difluorobenzyl)-6-(hydrazinecarbonyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 88). 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) δ ppm 1.29-1.41 (m, 6 H), 3.38-3.54 (m, 1 H), 4.59 (s, 2 H), 5.59 (s, 2 H), 6.88-7.02 (m, 2 H), 7.14-7.43 (m, 6 H), 7.52-7.73 (m, 2 H), 7.73-7.88 (m, 1 H), 8.00 (br. s., 1 H), 8.71 (d, J=2.93 Hz, 1 H).
EXAMPLE 89
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(1,3,4-oxadiazol-2-yl)-1H-indole-3-carboxamide (Compound 89). 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) δ ppm 1.34 (s, 3 H), 1.36 (s, 3 H), 3.39-3.59 (m, 1 H), 4.60 (s, 2 H), 5.63 (s, 2 H), 6.98 (d, J=8.06 Hz, 2 H), 7.15-7.47 (m, 6 H), 7.70-7.90 (m, 2 H), 8.02 (d, J=0.59 Hz, 1 H), 8.90 (s, 1 H).




EXAMPLE 90
Methyl 3-Formyl-6-methoxy-1H-indole-2-carboxylate (Compound 90). General Procedure I. 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 methyl6-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) δ ppm 3.81 (s, 3 H), 3.97 (s, 3 H), 6.79-7.09 (m, 2 H), 8.09 (d, J=9.1 Hz, 1 H), 10.57 (s, 1 H), 12.66 (s, 1 H).
EXAMPLE 91
Methyl 3-Formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 91). 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 methyl3-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) δ ppm 3.80 (s, 3 H), 3.99 (s, 3 H), 5.89 (s, 2 H), 6.82 (d, J=2.3 Hz, 1 H), 6.86 (d, J=7.9 Hz, 1 H), 7.00 (dd, J=8.8, 2.3 Hz, 1 H), 7.19 (ddd, J=7.5, 4.8, 1.2 Hz, 1 H), 7.57 (td, J=7.7, 1.9 Hz, 1 H), 8.40 (d, J=9.1 Hz, 1 H), 8.59 (ddd, J=4.7, 1.8, 0.9 Hz, 1 H), 10.65 (s, 1 H).
EXAMPLE 92
6-Methoxy-2-(methoxycarbonyl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic Acid (Compound 92). General Procedure K. To a suspension of methyl3-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) δ ppm 3.82 (s, 3 H), 3.92 (s, 3 H), 5.76 (s, 2 H), 6.66-6.79 (m, 2 H), 7.02 (dd, J=9.1, 2.1 Hz, 1 H), 7.22 (dd, J=7.3, 5.3 Hz, 1 H), 7.59 (td, J=7.8, 1.8 Hz, 1 H), 8.52 (d, J=8.8 Hz, 1 H), 8.62 (d, J=5.0 Hz, 1 H).
EXAMPLE 93
Methyl 3-(3,4-Difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93). 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) δ ppm 3.78 (s, 3 H), 3.80 (s, 3 H), 4.64 (d, J=5.9 Hz, 2 H), 5.73 (s, 2 H), 6.71 (d, J=2.1 Hz, 1 H), 6.77 (d, J=7.9 Hz, 1 H), 6.93 (dd, J=8.9, 2.2 Hz, 1 H), 7.09-7.22 (m, 3 H), 7.22-7.32 (m, 1 H), 7.55 (td, J=7.6, 1.8 Hz, 1 H), 8.14 (d, J=9.1 Hz, 2 H), 8.58 (d, J=4.1 Hz, 1 H).




EXAMPLE 94
N-(3,4-Difluorobenzyl)-2-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 94). General Procedure O. To a solution of methyl3-(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) δ ppm 3.81 (s, 3 H), 4.62 (s, 2 H), 5.98 (s, 2 H), 6.89-6.96 (m, 3 H), 7.22-7.30 (m, 3 H), 7.31-7.37 (m, 1 H), 7.65-7.72 (m, 1 H), 7.80 (d, J=9.8 Hz, 1 H), 8.48 (d, J=5.1 Hz, 1 H), 10.15 (s, 1 H).
EXAMPLE 95
N-(3,4-Difluorobenzyl)-2-(hydroxymethyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 95). The title compound was also isolated in the synthesis of Compound 94.
1H NMR (500 MHz, METHANOL-d4) δ ppm 3.75 (s, 3 H), 4.60 (s, 2 H), 4.95 (s, 2 H), 5.62 (s, 2 H), 6.80-6.88 (m, 2 H), 7.01 (d, J=8.3 Hz, 1 H), 7.20-7.26 (m, 2 H), 7.26- 7.37 (m, 2 H), 7.71 (td, J=7.8, 1.6 Hz, 1 H), 7.75 (d, J=8.8 Hz, 1 H), 8.51 (d, J=4.6 Hz, 1 H).
EXAMPLE 96
N-(3,4-Difluorobenzyl)-2-((dimethylamino)methyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 96). General Procedure P. 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 μl, 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) δ ppm 2.07 (s, 6 H), 3.70 (s, 2 H), 3.76 (s, 3 H), 4.54 (s, 2 H), 5.61 (s, 2 H), 6.76-6.93 (m, 3 H), 7.15-7.37 (m, 4 H), 7.66 (td, J=7.6, 1.8 Hz, 1 H), 8.01 (d, J=8.8 Hz, 1 H), 8.51 (d, J=5.0 Hz, 1 H).
EXAMPLE 97
N-(3,4-Difluorobenzyl)-2-((dimethylamino)methyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 97). 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) δ ppm 2.06 (s, 6 H), 3.56 (s, 2 H), 4.57 (d, J=5.3 Hz, 2 H), 5.41 (s, 2 H), 6.50 (d, J=7.9 Hz, 1 H), 6.70 (d, J=2.1 Hz, 1 H), 6.85 (dd, J=8.6, 2.2 Hz, 1 H), 7.03-7.24 (m, 4 H), 7.42-7.53 (m, 1 H), 8.20 (d, J=8.5 Hz, 1 H), 8.53 (d, J=5.0 Hz, 1 H), 9.96-10.14 (m, J=5.6 Hz, 1 H).
EXAMPLE 98
N-(3,4-Difluorobenzyl)-2-((dimethylamino)methyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 98). 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) δ ppm 1.30 (d, J=6.2 Hz, 6 H), 2.09 (s, 6 H), 3.57 (s, 2 H), 4.42-4.63 (m, 3 H), 5.49 (s, 2 H), 6.51 (d, J=6.4 Hz, 1 H), 6.75 (d, J=2.1 Hz, 1 H), 6.92 (dd, J=8.8, 2.1 Hz, 1 H), 7.04-7.25 (m, 4 H), 7.43-7.57 (m, 1 H), 8.27 (d, J=9.4 Hz, 1 H), 8.59 (d, J=4.4 Hz, 1 H), 9.96 (s, 1 H).
EXAMPLE 99
N-(3,4-Difluorobenzyl)-2-(ethylthiomethyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 99). 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) δ ppm 1.09 (t, J=7.3 Hz, 3 H), 2.41 (q, J=7.3 Hz, 2 H), 4.24 (s, 2 H), 4.58 (s, 2 H), 5.54 (s, 2 H), 6.62 (d, J=1.8 Hz, 1 H), 6.69-6.83 (m, 2 H), 7.17-7.40 (m, 4 H), 7.61 (d, J=8.2 Hz, 1 H), 7.63-7.72 (m, 1 H), 8.52 (d, J=5.6 Hz, 1 H).
EXAMPLE 100
6-(Cyclopentyloxy)-N-(3,4-difluorobenzyl)-2-(ethylthiomethyl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 100). 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) δ ppm 1.19 (t, J=7.5 Hz, 3 H), 1.47-1.65 (m, 4 H), 1.69-1.87 (m, 4 H), 2.55 (q, J=7.3 Hz, 2 H), 4.28 (s, 2 H), 4.61-4.75 (m, 3 H), 5.54 (s, 2 H), 6.61-6.72 (m, 2 H), 6.84 (dd, J=8.8, 2.1 Hz, 1 H), 7.09-7.31 (m, 4 H), 7.48-7.58 (m, 1 H), 7.67 (d, J=9.4 Hz, 1 H), 8.60 (d, J=5.0 Hz, 1 H).
EXAMPLE 101
Isopropyl3-(3,4-Difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 101). The title compound was prepared from methyl3-(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) δ ppm 1.17 (d, J=6.4 Hz, 6 H), 1.25 (d, J=6.2 Hz, 6 H), 4.51-4.64 (m, 3 H), 5.05-5.18 (m, 1 H), 5.84 (s, 2 H), 6.80-6.89 (m, 3 H), 7.16-7.29 (m, 3 H), 7.30-7.40 (m, 1 H), 7.56-7.71 (m, 2 H), 8.49 (d, J=5.0 Hz, 1 H).
EXAMPLE 102
3-(3,4-Difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic Acid (Compound 102). 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) δ ppm 1.22 (d, J=5.9 Hz, 6 H), 4.43-4.55 (m, 1 H), 4.57 (s, 2 H), 5.86 (s, 2 H), 6.72 (d, J=2.1 Hz, 1 H), 6.79 (dd, J=8.8, 2.3 Hz, 1 H), 6.88 (d, J=7.9 Hz, 1 H), 7.15-7.36 (m, 4 H), 7.58-7.69 (m, 1 H), 8.23 (d, J=8.8 Hz, 1 H), 8.49 (d, J=5.0 Hz, 1 H).
EXAMPLE 103
N3-(3,4-Difluorobenzyl)-N2-(2-hydroxyethyl)-6-isopropoxy-l-(pyridin-2-ylmethyl)-1H-indole-2,3-dicarboxamide (Compound 103). 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 μl, 0.17 mmol), BOP (64 mg, 0.14 mmol), and i-Pr2NEt 30 μl, 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) δ ppm 1.29 (d, J=5.9 Hz, 6 H), 3.55-3.69 (m, 2 H), 3.74-3.85 (m, 2 H), 4.45-4.58 (m, 1 H), 4.63 (d, J=5.9 Hz, 2 H), 5.63 (s, 2 H), 6.77 (d, J=2.1 Hz, 1 H), 6.87 (dd, J=8.9, 2.2 Hz, 1 H), 7.06-7.28 (m, 4 H), 7.32 (d, J=7.9 Hz, 1 H), 7.63-7.74 (m, 1 H), 7.80-7.96 (m, 2 H), 8.52 (d, J=4.1 Hz, 1 H), 9.93-10.08 (m, 1 H).
EXAMPLE 104
N-(3,4-Difluorobenzyl)-2-(4,5-dihydrooxazol-2-yl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 104). 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 μl, 0.41 mmol) and methanesulfonyl chloride (11 μl, 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) δ ppm 1.25 (d, J=6.2 Hz, 6 H), 3.94 (t, J=10.0 Hz, 2 H), 4.31 (t, J=9.8 Hz, 2 H), 4.47-4.64 (m, 3 H), 5.85 (s, 2 H), 6.79-6.92 (m, 3 H), 7.16-7.42 (m, 4 H), 7.61-7.73 (m, 1 H), 7.85 (d, J=9.4 Hz, 1 H), 8.49 (d, J=5.0 Hz, 1 H).




EXAMPLE 105
N-(3,4-Difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105). The title compound was prepared from methyl3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 96) by General Procedure O.
1H NMR (300 MHz, METHANOL-d4) δ ppm 1.27 (d, J=6.2 Hz, 6 H), 4.51-4.70 (m, 3 H), 5.96 (s, 2 H), 6.86-7.00 (m, 3 H), 7.19-7.41 (m, 4 H), 7.63-7.74 (m, 1 H), 7.78 (d, J=9.7 Hz, 1 H), 8.48 (d, J=5.0 Hz, 1 H), 10.16 (s, 1 H).
EXAMPLE 106
N-(3,4-Difluorobenzyl)-2-(hydroxymethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 106). The title compound was also isolated in the synthesis of Compound 105.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32 (d, J=5.9 Hz, 6 H), 4.47-4.60 (m, 1 H), 4.64 (d, J=5.9 Hz, 2 H), 4.95 (s, 2 H), 5.38 (s, 2 H), 6.02 (s, 1 H), 6.79-6.91 (m, 3 H), 7.07-7.32 (m, 4 H), 7.68 (td, J=7.8, 1.8 Hz, 1 H), 7.85 (d, J=8.5 Hz, 1 H), 8.48 (d, J=4.4 Hz, 1 H).
EXAMPLE 107
N-(3,4-Difluorobenzyl)-2-(4,5-dihydro-1H-imidazol-2-yl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 107). 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 μl, 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) δ ppm 1.30 (d, J=6.2 Hz, 6 H), 3.78 (s, 4 H), 4.43-4.58 (m, 1 H), 4.62 (s, 2 H), 5.51 (s, 2 H), 6.66 (d, J=2.1 Hz, 1 H), 6.87 (dd, J=8.9, 2.2 Hz, 1 H), 7.06-7.32 (m, 4 H), 7.38 (d, J=7.9 Hz, 1 H), 7.68-7.82 (m, 1 H), 8.24 (d, J=8.8 Hz, 1 H), 8.53 (d, J=5.0 Hz, 1 H), 9.95 (s, 1 H).
EXAMPLE 108
N-(3,4-Difluorobenzyl)-2-(1-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 108). 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) δ ppm 1.23 (dd, J=6.0, 1.3 Hz, 6 H), 1.44 (d, J=6.7 Hz, 3 H), 4.41-4.67 (m, 3 H), 5.43 (q, J=6.9 Hz, 1 H), 5.56-5.76 (m, 2 H), 6.75-6.91 (m, 3 H), 7.15-7.39 (m, 4 H), 7.61-7.74 (m, 1 H), 7.79 (d, J=8.8 Hz, 1 H), 8.52 (d, J=4.7 Hz, 1 H).
EXAMPLE 109
2-Acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109). 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) δ ppm 1.29 (dd, J=6.0, 0.7 Hz, 6 H), 2.59 (s, 3 H), 4.46-4.60 (m, 1 H), 4.67 (d, J=5.9 Hz, 2 H), 5.67 (s, 2 H), 6.55 (t, J=6.3 Hz, 1 H), 6.79 (d, J=2.1 Hz, 1 H), 6.83-6.89 (m, 1 H), 6.94 (d, J=7.6 Hz, 1 H), 7.07-7.35 (m, 4 H), 7.48-7.63 (m, 2 H), 8.54 (d, J=4.7 Hz, 1 H).
EXAMPLE 110
(E)-N-(3,4-Difluorobenzyl)-2-(1-(hydroxyimino)ethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 110). General Procedure Q. 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 μl, 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) δ ppm 1.26 (d, J=5.9 Hz, 6 H), 2.08 (s, 3 H), 4.40-4.53 (m, 1 H), 4.58 (d, J=5.9 Hz, 2 H), 5.46 (s, 2 H), 6.59-6.71 (m, 3 H), 6.89 (dd, J=8.8, 2.2 Hz, 1 H), 7.03-7.24 (m, 4 H), 7.41-7.55 (m, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 8.50 (d, J=4.1 Hz, 1 H), 10.61 (s, 1 H).
EXAMPLE 111
(E)-N-(3,4-Difluorobenzyl)-6-isopropoxy-2-(1-(methoxyimino)ethyl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 111). 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) δ ppm 1.27 (d, J=6.2 Hz, 6 H), 2.12 (s, 3 H), 3.82 (s, 3 H), 4.42-4.56 (m, 1 H), 4.61 (d, J=5.6 Hz, 2 H), 5.40 (s, 2 H), 6.69 (d, J=2.1 Hz, 1 H), 6.37-6.85 (m, 2 H), 6.89 (dd, J=8.8, 2.1 Hz, 1 H), 7.03-7.25 (m, 4 H), 7.49-7.59 (m, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 8.58 (d, J=4.4 Hz, 1 H).




EXAMPLE 112
N-(3,4-Difluorobenzyl)-4,4-dimethyl-3-oxopentanamide (Compound 112). A solution of ethyl4,4-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) δ ppm 1.18 (s, 9 H), 3.55 (s, 2 H), 4.42 (d, J=6.2 Hz, 2 H), 6.95-7.31 (m, 3 H), 7.57 (s, 1 H).
EXAMPLE 113
Ethyl 4-Fluoro-3-nitrobenzoate (Compound 113). 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) δ ppm 1.43 (t, J=7.0 Hz, 3 H), 4.44 (q, J=7.2 Hz, 2 H), 7.39 (dd, J=10.3, 8.8 Hz, 1 H), 8.33 (ddd, J=8.6, 4.2, 2.1 Hz, 1 H), 8.74 (dd, J=7.2, 2.2 Hz, 1 H).
EXAMPLE 114
Ethyl 4-(1-(3,4-Difluorobenzylamino)-4,4-dimethyl-1,3-dioxopentan-2-yl)-3-nitrobenzoate (Compound 114). To a solution of N-(3,4-difluorobenzyl)-4,4-dimethyl-3-oxopentanamide (Compound 112, 126 mg, 0.47 mmol) and ethyl4-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) δ ppm 1.17 (s, 9 H), 1.41 (t, J=7.2 Hz, 3 H), 4.35 (dd, J=5.9, 1.8 Hz, 2 H), 4.42 (q, J=7.0 Hz, 2 H), 5.86 (s, 1 H), 6.63 (t, J=5.9 Hz, 1 H), 6.86-7.14 (m, 3 H), 7.77 (d, J=8.2 Hz, 1 H), 8.21 (dd, J=8.2, 1.8 Hz, 1 H), 8.50 (d, J=1.8 Hz, 1 H).
Example 115
Ethyl 2-tert-Butyl-3-(3,4-difluorobenzylcarbamoyl)-1H-indole-6-carboxylate (Compound 115). General Procedure R. To a solution of ethyl4-(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) δ ppm 1.39 (t, J=7.2 Hz, 3 H), 1.53 (s, 9 H), 4.37 (q, J=7.1 Hz, 2 H), 4.64 (d, J=6.2 Hz, 2 H), 6.39 (t, J=6.0 Hz, 1 H), 7.07-7.29 (m, 3 H), 7.53 (d, J=8.5 Hz, 1 H), 7.79 (dd, J=8.5, 1.5 Hz, 1 H), 8.12 (d, J=1.2 Hz, 1 H), 8.89 (s, 1 H).
EXAMPLE 116
Ethyl 1-Benzyl-2-tert-butyl-3-(3,4-difluorobenzylcarbamoyl)-1H-indole-6-carboxylate (Compound 116). To a solution of ethyl2-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 μl, 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) δ ppm 1.33 (t, J=7.2 Hz, 3 H), 1.49 (s, 9 H), 4.30 (q, J=7.0 Hz, 2 H), 4.65 (d, J=5.9 Hz, 2 H), 5.67 (s, 2 H), 6.26 (t, J=6.0 Hz, 1 H), 6.87 (dd, J=7.9, 1.8 Hz, 2 H), 7.12-7.35 (m, 6 H), 7.45 (d, J=9.1 Hz, 1 H), 7.72-7.82 (m, 2 H).







EXAMPLE 117
N-(2-Hydroxy-5-nitrophenyl)butyramide (Compound 117). 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) δ ppm 0.99 (t, J=7.5 Hz, 3 H), 1.60-1.89 (m, 2 H), 2.54 (t, J=7.5 Hz, 2 H), 7.07 (d, J=8.8 Hz, 1 H), 7.92 (dd, J=8.9, 2.8 Hz, 1 H), 8.83 (d, J=2.9 Hz, 1 H), 9.10 (s, 1 H), 10.68 (s, 1 H).
EXAMPLE 118
2-Butyramido-4-nitrophenyl trifluoromethanesulfonate (Compound 118). 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) δ ppm 1.05 (t, J=7.5 Hz, 3 H), 1.73-1.89 (m, 2 H), 2.46 (t, J=7.5 Hz, 2 H), 7.44 (s, 1 H), 7.49 (d, J=9.1 Hz, 1 H), 8.05 (dd, J=9.1, 2.6 Hz, 1 H), 9.34 (d, J=2.6 Hz, 1 H).
EXAMPLE 119
N-(2-(3-Methylbut-1-ynyl)-5-nitrophenyl)butyramide (Compound 119). 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) δ ppm 1.06 (t, J=7.5 Hz, 3 H), 1.36 (d, J=6.7 Hz, 6 H), 1.72-1.92 (m, 2 H), 2.44 (t, J=7.5 Hz, 2 H), 2.85-3.01 (m, 1 H), 7.49 (d, J=8.5 Hz, 1 H), 7.88 (dd, J=8.8, 2.3 Hz, 1 H), 8.04 (s, 1 H), 9.33 (d, J=2.3 Hz, 1 H).
EXAMPLE 120
2-Isopropyl-6-nitro-1H-indole (Compound 120). 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) δ ppm 1.41 (d, J=7.0 Hz, 6 H), 3.07-3.22 (m, 1 H), 6.38 (d, J=2.3 Hz, 1 H), 7.56 (d, J=8.8 Hz, 1 H), 8.00 (dd, J=8.8, 2.1 Hz, 1 H), 8.28 (d, J=2.1 Hz, 1 H).
EXAMPLE 121
2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 121). 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) δ ppm 1.44 (d, J=7.0 Hz, 6 H), 3.65-3.84 (m, 1 H), 7.38 (s, 1 H), 8.04-8.12 (m, 1 H), 8.18-8.32 (m, 2 H), 10.13 (s, 1 H).
EXAMPLE 122
1-Benzyl-2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 122). 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) δ ppm 1.49 (d, J=7.0 Hz, 6 H), 3.45-3.60 (m, 1 H), 5.54 (s, 2 H), 6.94-7.02 (m, 2 H), 7.29-7.41 (m, 3 H), 8.16-8.24 (m, 2 H), 8.49 (d, J=8.5 Hz, 1 H), 10.51 (s, 1 H).
EXAMPLE 123
1-Benzyl-2-isopropyl-6-nitro-1H-indole-3-carboxylic acid (Compound 123). 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) δ ppm 1.40 (d, J=7.3 Hz, 6 H), 3.87-4.10 (m, 1 H), 5.72 (s, 2 H), 6.98 (dd, J=7.3, 1.5 Hz, 2 H), 7.22-7.41 (m, 3 H), 8.07 (dd, J=8.9, 2.2 Hz, 1 H), 8.22-8.35 (m, 2 H).
EXAMPLE 124
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-nitro-1H-indole-3-carboxamide (Compound 124). 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) δ ppm 1.42 (d, J=7.3 Hz, 6 H), 3.51-3.67 (m, 1 H), 4.70 (d, J=6.2 Hz, 2 H), 5.53 (s, 2 H), 6.28 (t, J=6.9 Hz, 1 H), 6.94 (dd, J=7.2, 1.9 Hz, 2 H), 7.12-7.19 (m, 2 H), 7.19-7.37 (m, 4 H), 7.69 (d, J=8.8 Hz, 1 H), 8.08 (dd, J=8.8, 2.1 Hz, 1 H), 8.18 (d, J=1.8 Hz, 1 H).
EXAMPLE 125
6-Amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125). General Procedure S. 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) δ ppm 1.31 (d, J=7.3 Hz, 6 H), 3.38-3.58 (m, 1 H), 4.56 (s, 2 H), 5.41 (s, 2 H), 6.58-6.73 (m, 2 H), 6.89-7.01 (m, 2 H), 7.16-7.37 (m, 6 H), 7.39 (d, J=8.5 Hz, 1 H).
EXAMPLE 126
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(tetrahydrofuran-3-ylamino)-1H-indole-3-carboxamide (Compound 126). General Procedure T. 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) δ ppm 1.38 (d, J=7.0 Hz, 6 H), 1.69-1.83 (m, 1 H), 2.08-2.23 (m, 1 H), 3.61 (dd, J=9.4, 2.9 Hz, 1 H), 3.70-3.94 (m, 4 H), 3.96-4.05 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 5.38 (s, 2 H), 6.23-6.34 (m, 2 H), 6.53 (dd, J=8.5, 1.8 Hz, 1 H), 7.00 (d, J=8.2 Hz, 2 H), 7.11-7.19 (m, 2 H), 7.20-7.34 (m, 4 H), 7.43 (d, J=8.8 Hz, 1 H).
EXAMPLE 127
1-Benzyl-N-(3,4-difluorobenzyl)-6-isobutyramido-2-isopropyl-1H-indole-3-carboxamide (Compound 127). 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 μl, 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) δ ppm 1.21 (d, J=6.7 Hz, 6 H), 1.34 (d, J=7.0 Hz, 6 H), 2.38-2.56 (m, 1 H), 3.48-3.65 (m, 1 H), 4.65 (d, J=6.2 Hz, 2 H), 5.39 (s, 2 H), 6.31 (t, J=6.0 Hz, 1 H), 6.88-6.95 (m, 2 H), 6.99 (dd, J=8.5, 1.8 Hz, 1 H), 7.09-7.17 (m, 2 H), 7.19-7.29 (m, 4 H), 7.32 (s, 1 H), 7.51 (d, J=8.5 Hz, 1 H), 7.84 (d, J=1.5 Hz, 1 H).
EXAMPLE 128
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(2-oxopyrrolidin-1-yl)-1H-indole-3-carboxamide (Compound 128). 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 ethyl4-bromobutanoate (13 μl, 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) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 2.06-2.20 (m, 2 H), 2.57 (t, J=8.1 Hz, 2 H), 3.59-3.74 (m, 1 H), 3.78-3.88 (m, 2 H), 4.66 (d, J=5.9 Hz, 2 H), 5.44 (s, 2 H), 6.30 (t, J=6.4 Hz, 1 H), 6.94 (dd, J=7.9, 1.8 Hz, 2 H), 7.10-7.18 (m, J=8.8, 4.7 Hz, 2 H), 7.20-7.33 (m, 5 H), 7.56-7.63 (m, 2 H).
EXAMPLE 129
Dihydrofuran-3(2H)-one (Compound 129). 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.
EXAMPLE 130
1-Benzyl-6-(cyclopentylamino)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 130). 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) δ ppm 1.31-1.47 (m, 1 H), 1.37 (d, J=7.3 Hz, 6 H), 1.50-1.76 (m, 3 H), 1.84-2.02 (m, 3 H), 2.12-2.23 (m, 1 H), 3.61-3.86 (m, 2 H), 4.66 (d, J=6.2 Hz, 2 H), 5.37 (s, 2 H), 6.25-6.37 (m, 2 H), 6.53 (dd, J=8.6, 1.9 Hz, 1 H), 6.96-7.06 (m, 2 H), 7.10-7.18 (m, 2 H), 7.19-7.34 (m, 4 H), 7.40 (d, J=8.5 Hz, 1 H).
EXAMPLE 131
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(1,3-oxazol-2-ylmethoxy)-1H-indole-3-carboxamide (Compound 131). 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) δ ppm 1.38 (d, J=7.3 Hz, 6 H), 3.62-3.79 (m, 1 H), 4.67 (d, J=5.9 Hz, 2 H), 5.09 (s, 2 H), 5.40 (s, 2 H), 6.30 (t, J=6.0 Hz, 1H), 6.79 (d, J=2.1 Hz, 1 H), 6.88-7.00 (m, 3 H), 7.07 (s, 1 H), 7.11-7.19 (m, 2 H), 7.19-7.34 (m, 4 H), 7.54 (d, J=8.5 Hz, 1 H), 7.61 (s, 1 H).
EXAMPLE 132
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(1,3-thiazol-2-yloxy)-1H-indole-3-carboxamide (Compound 132). General Procedure U. 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) δ ppm 1.39 (d, J=7.0 Hz, 6 H), 3.61-3.76 (m, 1 H), 4.67 (d, J=5.6 Hz, 2 H), 5.42 (s, 2 H), 6.24-6.32 (m, 1 H), 6.74 (d, J=3.8 Hz, 1 H), 6.94 (dd, J=8.1, 1.3 Hz, 3 H), 7.06-7.32 (m, 8 H), 7.65 (d, J=9.1 Hz, 1 H).
EXAMPLE 133
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-3-carboxamide (Compound 133). 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) δ ppm 1.38 (d, J=7.0 Hz, 6 H), 1.62-1.78 (m, 2 H), 1.83-1.96 (m, 2 H), 3.42-3.56 (m, 2 H), 3.65-3.80 (m, 1 H), 3.87-3.99 (m, 2 H), 4.28-4.41 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 5.39 (s, 2 H), 6.28 (t, J=5.7 Hz, 1 H), 6.66 (d, J=2.1 Hz, 1 H), 6.83 (dd, J=8.6, 2.2 Hz, 1 H), 6.93-7.01 (m, 2 H), 7.10-7.18 (m, 2 H), 7.18-7.34 (m, 4 H), 7.51 (d, J=8.8 Hz, 1 H).







EXAMPLE 134
4-Methoxy-1-(3-methylbut-1-ynyl)-2-nitrobenzene (Compound 134). 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) δ ppm 1.27 (d, J=6.4 Hz, 6 H), 2.70-2.92 (m, 1 H), 3.86 (s, 3 H), 7.06 (dd, J=8.9, 2.8 Hz, 1 H), 7.40-7.50 (m, 2 H).
EXAMPLE 135
5-Methoxy-2-(3-methylbut-1-ynyl)aniline (Compound 135). 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) δ ppm 1.27 (d, J=7.0 Hz, 6 H), 2.73-2.90 (m, 1 H), 3.75 (s, 3 H), 4.16 (s, 2 H), 6.16-6.34 (m, 2 H), 7.15 (d, J=8.2 Hz, 1 H).
EXAMPLE 136
2-Isopropyl-6-methoxy-1H-indole (Compound 136). 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) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 2.97-3.10 (m, 1 H), 3.83 (s, 3 H), 6.13-6.19 (m, 1 H), 6.74 (dd, J=8.5, 2.3 Hz, 1 H), 6.83 (d, J=2.3 Hz, 1 H), 7.39 (d,J=8.8 Hz, 1 H), 7.76 (s, 1 H).
EXAMPLE 137
2-Isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137). The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole (Compound 136) by General Procedure I.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (d, J=7.0 Hz, 6 H), 3.70-3.82 (m, 1 H), 3.84 (s, 3 H), 6.86 (d, J=2.1 Hz, 1 H), 6.91 (dd, J=8.8, 2.3 Hz, 1 H), 8.14 (d, J=8.8 Hz, 1 H), 8.36 (s, 1 H), 10.21 (s, 1 H).
EXAMPLE 138
2-Isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carbaldehyde (Compound 138). 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) δ ppm 1.45 (d, J=7.0 Hz, 6 H), 3.43-3.64 (m, 1 H), 3.79 (s, 3 H), 5.50 (s, 2 H), 6.59-6.77 (m, 2 H), 6.94 (dd, J=8.5, 2.1 Hz, 1 H), 7.17-7.26 (m, 1 H), 7.50-7.67 (m, 1 H), 8.28 (d, J=8.8 Hz, 1 H), 8.62 (d, J=5.3 Hz, 1 H), 10.44 (s, 1 H).
EXAMPLE 139
2-Isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139). 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) δ ppm 1.39 (d, J=7.0 Hz, 6 H), 3.76 (s, 3 H), 4.06-4.29 (m, 1 H), 5.58 (s, 2 H), 6.56 (d, J=7.9 Hz, 1 H), 6.62 (d, J=2.3 Hz, 1 H), 6.92 (dd, J=8.8, 2.3 Hz, 1 H), 7.16-7.24 (m, 1 H), 7.49-7.60 (m, 1 H), 8.15 (d, J=9.1 Hz, 1 H), 8.64 (d, J=5.3 Hz, 1 H).
EXAMPLE 140
2-Isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 140). 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) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 3.68-3.87 (m, 4 H), 4.81 (d, J=6.2 Hz, 2 H), 5.52 (s, 2 H), 6.41 (t, J=5.9 Hz, 1 H), 6.52 (d, J=7.9 Hz, 1 H), 6.64 (d, J=2.1 Hz, 1 H), 6.85 (dd, J=8.6, 2.2 Hz, 1 H), 7.19 (dd, J=7.5, 4.8 Hz, 1 H), 7.47-7.58 (m, 2 H), 7.69 (d, J=7.9 Hz, 1 H), 7.98 (d, J=8.5 Hz, 1 H), 8.62 (d, J=4.7 Hz, 1 H), 8.79 (s, 1 H).
EXAMPLE 141
6-Hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 141). 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) δ ppm 1.36 (d, J=7.3 Hz, 6 H), 3.71-3.86 (m, 1 H), 4.80 (d, J=6.2 Hz, 2 H), 5.49 (s, 2 H), 6.40 (t, J=6.2 Hz, 1 H), 6.52-6.60 (m, 2 H), 6.74 (dd, J=8.5, 2.1 Hz, 1 H), 7.15-7.23 (m, 1 H), 7.45-7.59 (m, 2 H), 7.69 (d, J=8.2 Hz, 1 H), 7.98 (dd, J=7.3, 2.3 Hz, 1 H), 8.56 (d, J=4.7 Hz, 1 H), 8.79 (d, J=2.3 Hz, 1 H).
EXAMPLE 142
6-(Cyclopentyloxy)-2-isopropyl-1-(pyridin-2-ylmethyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 142). 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) δ ppm 1.36 (d, J=7.0 Hz, 6 H), 1.49-1.64 (m, 2 H), 1.67-1.88 (m, 6 H), 3.71-3.91 (m, 1 H), 4.67 (s, 1 H), 4.80 (d, J=5.9 Hz, 2 H), 5.51 (s, 2 H), 6.46 (t, J=5.9 Hz, 1 H), 6.53 (d, J=7.9 Hz, 1 H), 6.62 (d, J=2.1 Hz, 1 H), 6.81 (dd, J=8.8, 2.1 Hz, 1 H), 7.18 (dd, J=7.3, 5.0 Hz, 1 H), 7.46-7.57 (m, 2 H), 7.68 (d, J=8.2 Hz, 1 H), 7.97 (d, J=7.9 Hz, 1 H), 8.61 (d, J=4.1 Hz, 1 H), 8.78 (s, 1 H).
EXAMPLE 143
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-3-carboxamide (Compound 143). 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) δ ppm 1.38 (d, J=7.0 Hz, 6 H), 1.62-1.79 (m, 2 H), 1.84-1.98 (m, 2 H), 3.44-3.57 (m, 2 H), 3.71-3.87 (m, 1 H), 3.87-4.00 (m, 2 H), 4.31-4.44 (m, 1 H), 4.67 (d, J=6.2 Hz, 2 H), 5.50 (s, 2 H), 6.28 (t, J=5.4 Hz, 1 H), 6.54 (d, J=7.9 Hz, 1 H), 6.68 (d, J=2.1 Hz, 1 H), 6.85 (dd, J=8.6, 2.2 Hz, 1 H), 7.09-7.31 (m, 4 H), 7.45-7.58 (m, 2 H), 8.62 (d, J=4.7 Hz, 1 H).




EXAMPLE 144
(2,6-Dichloro-5-fluoropyridin-3-yl)methanamine (Compound 144). 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) δ ppm 4.31 (s, 2 H), 8.06 (d, J=8.2 Hz, 1 H).
EXAMPLE 145
(5-Fluoropyridin-3-yl)methanamine (Compound 145). 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) δ ppm 3.87 (s, 2 H), 7.61-7.73 (m, 1 H), 8.25-8.44 (m, 2 H).
EXAMPLE 146
N-((5-Fluoropyridin-3-yl)methyl)-2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 146). 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) δ ppm 1.30 (d, J=7.0 Hz, 6 H), 3.38-3.57 (m, 1 H), 3.73 (s, 3 H), 4.67 (s, 2 H), 5.56 (s, 2 H), 6.63 (d, J=7.9 Hz, 1 H), 6.76-6.85 (m, 2 H), 7.29 (dd, J=6.9, 5.1 Hz, 1 H), 7.52 (d, J=9.1 Hz, 1 H), 7.62-7.75 (m, 2 H), 8.38 (d, J=2.6 Hz, 1 H), 8.50 (s, 1 H), 8.54 (d, J=4.1 Hz, 1 H).
EXAMPLE 147
N-((5-Fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 147). 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) δ ppm 1.30 (d, J=7.0 Hz, 6 H), 3.44-3.57 (m, 1 H), 4.67 (s, 2 H), 5.48 (s, 2 H), 6.57-6.65 (m, 2 H), 6.70 (dd, J=8.4, 1.9 Hz, 1 H), 7.29 (dd, J=7.2, 4.8 Hz, 1 H), 7.46 (d, J=8.8 Hz, 1 H), 7.61-7.74 (m, 2 H), 8.38 (d, J=2.6 Hz, 1 H), 8.50 (s, 1 H), 8.54 (d, J=5.0 Hz, 1 H).
EXAMPLE 148
6-(Cyclopentyloxy)-N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 148). 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) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 1.50-1.61 (m, 2 H), 1.67-1.84 (m, 6 H), 3.73-3.88 (m, 1 H), 4.62-4.71 (m, 1 H), 4.75 (d, J=5.9 Hz, 2 H), 5.50 (s, 2 H), 6.37 (t, J=6.0 Hz, 1 H), 6.53 (d, J=7.9 Hz, 1 H), 6.61 (d, J=2.1 Hz, 1 H), 6.76-6.85 (m, 1 H), 7.18 (dd, J=7.6, 5.0 Hz, 1 H), 7.47-7.57 (m, 3 H), 8.40 (d, J=2.3 Hz, 1 H), 8.49 (s, 1 H), 8.61 (d, J=3.8 Hz, 1 H).
EXAMPLE 149
N-((5-Fluoropyridin-3-yl)methyl)-6-isobutoxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 149). 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) δ ppm 0.98 (d, J=6.4 Hz, 6 H), 1.30 (d, J=7.3 Hz, 6 H), 1.91-2.06 (m, 1 H), 3.42-3.58 (m, 1 H), 3.66 (d, J=6.4 Hz, 2 H), 4.67 (s, 2 H), 5.54 (s, 2 H), 6.63 (d, J=7.9 Hz, 1 H), 6.75 (d, J=2.1 Hz, 1 H), 6.81 (dd, J=8.6, 2.2 Hz, 1 H), 7.29 (dd, J=7.3, 5.0 Hz, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.61-7.75 (m, 2 H), 8.38 (d, J=2.6 Hz, 1 H), 8.50 (s, 1 H), 8.54 (d, J=5.0 Hz, 1 H).
EXAMPLE 150
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(thiazol-2-yloxy)-1H-indole-3-carboxamide (Compound 150). 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) δ ppm 1.37 (d, J=7.3 Hz, 6 H), 3.65-3.79 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 5.50 (s, 2 H), 6.31-6.41 (m, 1 H), 6.56 (d, J=7.9 Hz, 1 H), 6.74 (d, J=3.8 Hz, 1 H), 7.05-7.31 (m, 7 H), 7.48-7.58 (m, 1 H), 7.65 (d, J=9.1 Hz, 1 H), 8.58 (d, J=5.0 Hz, 1 H).
EXAMPLE 151
N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 151). 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) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 3.66-3.81 (m, 1 H), 4.66 (d, J=6.2 Hz, 2 H), 5.36 (s, 2 H), 6.28-6.36 (m, 1 H), 6.53 (d, J=1.2 Hz, 1 H), 6.73 (d, J=7.0 Hz, 1 H), 7.08-7.31 (m, 6 H), 7.46 (d, J=8.5 Hz, 1 H), 8.41 (d, J=36.9 Hz, 1 H).
EXAMPLE 152
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-6-(thiazol-2-yloxy)-1H-indole-3-carboxamide (Compound 152). 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) δ ppm 1.35 (d, J=7.3 Hz, 6 H), 3.40-3.54 (m, 1 H), 4.59 (s, 2 H), 5.61 (s, 2 H), 6.95 (d, J=3.8 Hz, 1 H), 7.08 (dd, J=8.4, 2.2 Hz, 1 H), 7.18 (d, J=4.1 Hz, 1 H), 7.21-7.28 (m, 2 H), 7.29-7.41 (m, 4 H), 7.68 (d, J=8.5 Hz, 1 H), 8.20 (d, J=1.2 Hz, 1 H), 8.41 (dd, J=4.4, 1.8 Hz, 1 H).
EXAMPLE 153
6-(Cyclopentyloxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 153). 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) δ ppm 1.34 (d, J=7.3 Hz, 6 H), 1.52-1.63 (m, 2 H), 1.64-1.87 (m, 6 H), 3.43-3.57 (m, 1 H), 4.57 (s, 2 H), 4.67-4.77 (m, 1 H), 5.55 (s, 2 H), 6.70 (d, J=2.1 Hz, 1 H), 6.76 (dd, J=8.6, 2.2 Hz, 1 H), 7.19-7.27 (m, 2 H), 7.28-7.40 (m, 3 H), 7.49 (d, J=8.5 Hz, 1 H), 8.22 (s, 1 H), 8.41 (dd, J=4.4, 2.1 Hz, 1 H).
EXAMPLE 154
N-(3,4-Difluorobenzyl)-6-isopropoxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 154). 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) δ ppm 1.21 (d, J=6.2 Hz, 6 H), 1.33 (d, J=7.3 Hz, 6 H), 3.42-3.57 (m, 1 H), 4.43-4.54 (m, 1 H), 4.57 (s, 2 H), 5.55 (s, 2 H), 6.74-6.83 (m, 2 H), 7.19-7.27 (m, 2 H), 7.28-7.39 (m, 3 H), 7.50 (d, J=9.1 Hz, 1 H), 8.21 (s, 1 H), 8.41 (dd, J=4.3, 2.2 Hz, 1 H).
EXAMPLE 155
2-Isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 155). 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) δ ppm 1.30 (d, J=6.7 Hz, 6 H), 2.51-2.74 (m, 1 H), 3.89 (s, 3 H), 6.63 (dd, J=8.9, 2.5 Hz, 1 H), 8.03 (d, J=9.1 Hz, 1 H), 8.48 (d, J=2.3 Hz, 1 H), 11.15 (s, 1 H).
EXAMPLE 156
N-(3,4-Difluorobenzyl)-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 156). 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 μl, 0.098 mmol) and 3,4-difluorobenzylamine (11 μl, 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) δ ppm 1.27 (d, J=6.7 Hz, 6 H), 2.53-2.68 (m, 1 H), 3.86 (s, 3 H), 4.56 (d, J=5.9 Hz, 2 H), 6.47 (dd, 1 H), 6.57 (dd, J=8.8, 2.6 Hz, 1 H), 7.01-7.22 (m, 3 H), 7.39 (d, J=8.8 Hz, 1 H), 8.41 (d, J=2.6 Hz, 1 H), 11.57 (s, 1 H).
EXAMPLE 157
N-(3,4-Difluorobenzyl)-1-isobutyl-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 157). 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) δ ppm 0.96 (d, J=6.7 Hz, 6 H), 1.50 (d, J=7.0 Hz, 6 H), 2.13-2.26 (m, 1 H), 3.28-3.41 (m, 1 H), 3.86 (s, 3 H), 3.89 (d, J=7.6 Hz, 2 H), 4.65 (d, J=6.2 Hz, 2 H), 6.20-6.28 (m, 1 H), 6.76-6.83 (m, 2 H), 7.10-7.17 (m, 2 H), 7.19-7.30 (m, 1 H), 7.47 (d, J=8.5 Hz, 1 H).
EXAMPLE 158
N-(3,4-Difluorobenzyl)-6-hydroxy-1-isobutyl-2-isopropyl-1H-indole-3-carboxamide (Compound 158). 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) δ ppm 0.95 (d, J=6.7 Hz, 6 H), 1.49 (d, J=7.0 Hz, 6 H), 2.11-2.27 (m, 1 H), 3.26-3.40 (m, 1 H), 3.86 (d, J=7.6 Hz, 2 H), 4.65 (d, J=6.2 Hz, 2 H), 4.79 (s, 1 H), 6.23 (t, J=6.2 Hz, 1 H), 6.68 (dd, J=8.5, 1.8 Hz, 1 H), 6.77 (d, J=2.3 Hz, 1 H), 7.09-7.16 (m, 2 H), 7.18-7.28 (m, 1 H), 7.42 (d, J=8.5 Hz, 1 H).
EXAMPLE 159
6-(Cyclopentyloxy)-N-(3,4-difluorobenzyl)-1-isobutyl-2-isopropyl-1H-indole-3-carboxamide (Compound 159). 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) δ ppm 0.96 (d, J=6.7 Hz, 6 H), 1.49 (d, J=7.0 Hz, 6 H), 1.59-1.70 (m, 2 H), 1.73-1.97 (m, 6 H), 2.12-2.26 (m, 1 H), 3.27-3.40 (m, 1 H), 3.88 (d, J=7.6 Hz, 2 H), 4.65 (d, J=5.9 Hz, 2 H), 4.76-4.84 (m, 1 H), 6.24 (t, J=6.6 Hz, 1 H), 6.74-6.81 (m, 2 H), 7.09-7.16 (m, 2 H), 7.18-7.28 (m, 1 H), 7.42-7.48 (m, 1 H).




EXAMPLE 160
1-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl trifluoromethanesulfonate (Compound 160). General Procedure V. 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) δ ppm 1.39 (d, J=7.3 Hz, 6 H), 3.57-3.72 (m, 1 H), 4.65 (d, J=5.9 Hz, 2 H), 5.43 (s, 2 H), 6.30 (t, J=5.7 Hz, 1 H), 6.89-6.98 (m, 2 H), 7.02-7.09 (m, 2 H), 7.11-7.18 (m, 2 H), 7.18-7.36 (m, 4 H), 7.66 (d, J=9.4 Hz, 1 H).
EXAMPLE 161
1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(pyridin-4-yl)-1H-indole-3-carboxamide (Compound 161). General Procedure W. 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) δ ppm 1.35 (d, J=7.0 Hz, 6 H), 3.41-3.58 (m, 1 H), 4.60 (s, 2 H), 5.63 (s, 2 H), 6.94-7.06 (m, 2 H), 7.16-7.44 (m, 5 H), 7.49-7.81 (m, 6 H), 8.47 (dd, J=4.7, 1.8 Hz, 2 H).
EXAMPLE 162
N-((5-Fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 162). 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) δ ppm 1.32 (d, J=7.0 Hz, 6 H), 3.41-3.58 (m, 1 H), 4.67 (d, J=6.2 Hz, 2 H), 5.50 (s, 2 H), 6.61 (d, J=2.1 Hz, 1 H), 6.71 (dd, J=8.5, 2.1 Hz, 1 H), 7.29-7.39 (m, 2 H), 7.46 (d, J=8.5 Hz, 1 H), 7.69 (d, J=9.1 Hz, 1 H), 7.90 (s, 1 H), 8.21 (s, 1 H), 8.35-8.44 (m, 2 H), 8.50 (s, 1 H), 8.60 (t, J=5.7 Hz, 1 H).
EXAMPLE 163
6-(Cyclopentyloxy)-N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 163). 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) δ ppm 1.33 (d, J=7.3 Hz, 6 H), 1.50-1.64 (m, 2 H), 1.64-1.90 (m, 6 H), 3.44-3.58 (m, 1 H), 4.67 (s, 2 H), 4.70-4.77 (m, 1 H), 5.56 (s, 2 H), 6.72 (d, J=2.1 Hz, 1 H), 6.77 (dd, J=8.8, 2.1 Hz, 1 H), 7.30-7.41 (m, 2 H), 7.51 (d, J=8.8 Hz, 1 H), 7.65-7.75 (m, 1 H), 8.22 (s, 1 H), 8.35-8.45 (m, 2 H), 8.50 (s, 1 H).
EXAMPLE 164
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-4-yl)-1H-indole-3-carboxamide (Compound 164). 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) δ ppm 1.35 (d, J=7.0 Hz, 6 H), 3.44-3.57 (m, 1 H), 4.60 (s, 2 H), 5.71 (s, 2 H), 6.74 (d, J=7.9 Hz, 1 H), 7.21-7.42 (m, 4 H), 7.56 (dd, J=8.2, 1.8 Hz, 1 H), 7.62-7.79 (m, 5 H), 8.49 (d, J=6.2 Hz, 2 H), 8.54 (d, J=4.1 Hz, 1 H).
EXAMPLE 165
6-Cyclobutoxy-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 165). 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) δ ppm 1.39 (d, J=7.3 Hz, 6 H), 1.60-1.74 (m, 2 H), 2.04-2.15 (m, 2 H), 2.27-2.39 (m, 2 H), 3.70-3.81 (m, 1 H), 4.50-4.60 (m, 1 H), 4.66 (d, J=5.9 Hz, 2 H), 5.41 (s, 2 H), 6.29 (t, J=5.6 Hz, 1 H), 6.49 (d, J=2.2 Hz, 1 H), 6.75 (dd, J=8.7, 2.1 Hz, 1 H), 7.11-7.18 (m, 3 H), 7.18-7.28 (m, 2 H), 7.50 (d, J=8.6 Hz, 1 H), 8.43 (s, 1 H), 8.52 (s, 1 H).







EXAMPLE 166
Ethyl 2-(5-Fluoro-2,4-dinitrophenyl)-4-methyl-3-oxopentanoate (Compound 166). General Procedure X. 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) δ ppm 1.07 (d, J=6.7 Hz, 3 H), 1.13 (t, J=7.0 Hz, 3 H), 1.19 (d, J=6.7 Hz, 3 H), 2.22-2.48 (m, 1 H), 3.91-4.38 (m, 2 H), 7.24 (d, J=10.3 Hz, 1 H), 8.79 (d, J=7.0 Hz, 1 H), 13.21 (d, J=1.5 Hz, 1 H).
EXAMPLE 167
Ethyl 6-Amino-5-fluoro-2-isopropyl-1H-indole-3-carboxylate (Compound 167). The title compound was prepared from ethyl2-(5-fluoro-2,4-dinitrophenyl)-4-methyl-3-oxopentanoate (Compound 166) by General Procedure R.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 1.44 (t, J=7.0 Hz, 3 H), 3.70 (s, 2 H), 3.99-4.15 (m, 1 H), 4.37 (q, J=7.1 Hz, 2 H), 6.71 (d, J=7.6 Hz, 1 H), 7.69 (d, J=12.0 Hz, 1 H), 8.12 (s, 1 H).
EXAMPLE 168
Ethyl 5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 92). General Procedure Y. To a solution of ethyl6-amino-5-fluoro-2-isopropyl-1H-indole-3-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) δ ppm 1.41 (d, J=7.0 Hz, 6 H), 1.46 (t, J=7.0 Hz, 3 H), 4.06-4.21 (m, 1 H), 4.42 (q, J=7.1 Hz, 2 H), 7.94 (d, J=12.3 Hz, 1 H), 8.16 (d, J=6.2 Hz, 1 H), 8.65 (s, 1 H).
EXAMPLE 169
Ethyl 1-Benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 169). The title compound was prepared from ethyl5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 168) and benzyl bromide by General Procedure J.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J=7.3 Hz, 6 H), 1.50 (t, J=7.2 Hz, 3 H), 3.90-4.04 (m, 1 H), 4.45 (q, J=7.1 Hz, 2 H), 5.54 (s, 2 H), 6.93 (d, J=6.4 Hz, 2 H), 7.29-7.36 (m, 3 H), 7.96 (d, J=6.1 Hz, 1 H), 8.00 (d, J=12.7 Hz, 1 H).
EXAMPLE 170
1-Benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylic acid (Compound 170). General Procedure Z. To a solution of ethyl1-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) δ ppm 1.46 (d, J=7.0 Hz, 6 H), 3.94-4.16 (m, 1 H), 5.57 (s, 2 H), 6.91-7.01 (m, 2 H), 7.32 (t, J=6.4 Hz, 3 H), 7.92-8.01 (m, 1 H), 8.16 (d, J=12.3 Hz, 1 H).
EXAMPLE 171
1-Benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxamide (Compound 171). 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) δ ppm 1.40 (d, J=7.0 Hz, 6 H), 3.48-3.63 (m, 1 H), 4.67 (d, J=5.9 Hz, 2 H), 5.48 (s, 2 H), 6.21 (t, J=6.0 Hz, 1 H), 6.92 (dd, J=7.5, 2.2 Hz, 2 H), 7.12-7.36 (m, 6 H), 7.43 (d, J=12.0 Hz, 1 H), 7.98 (d, J=5.9 Hz, 1 H).
EXAMPLE 172
6-Amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172). 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) δ ppm 1.30 (d, J=7.3 Hz, 6 H), 3.39-3.52 (m, 1 H), 4.56 (s, 2 H), 5.40 (s, 2 H), 6.70 (d, J=7.3 Hz, 1 H), 6.93 (dd, J=7.9, 1.5 Hz, 2 H), 7.16-7.38 (m, 7 H).
EXAMPLE 173
1-Benzyl-6-(cyclopentylamino)-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 173). 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) δ ppm 1.33 (d, J=7.3 Hz, 6 H), 1.36-2.10 (m, 8 H), 3.46-3.59 (m, 1 H), 3.58-3.70 (m, 1 H), 4.56 (s, 2 H), 5.43 (s, 2 H), 6.46 (d, J=7.3 Hz, 1 H), 6.93-7.03 (m, 2 H), 7.13-7.41 (m, 7 H), 8.40 (s, 1 H).
EXAMPLE 174
1-Benzyl-N-cyclopentyl-3-(3,4-difluorobenzylcarbamoyl)-5-fluoro-2-isopropyl-N,N-dimethyl-1H-indol-6-aminium chloride (Compound 174). 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 μl, 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) δ ppm 1.33 (d, J=7.0 Hz, 6 H), 1.57-1.89 (m, 8 H), 3.36-3.54 (m, 1 H), 3.65 (s, 6 H), 4.58 (s, 2 H), 4.74-4.83 (m, 1 H), 5.69 (s, 2 H), 6.92-7.01 (m, 2 H), 7.19-7.40 (m, 7 H), 7.60 (d, J=15.2 Hz, 1 H), 7.75 (d, J=6.7 Hz, 1 H), 8.77 (t, J=6.0 Hz, 1 H).
EXAMPLE 175
N-(3,4-Difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-2-(pyrrolidin-1-ylmethyl)-1H-indole-3-carboxamide (Compound 175). 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) δ ppm 1.30 (d, J=6.2 Hz, 6 H), 1.55 (s, 4 H), 2.34 (s, 4 H), 3.76 (s, 2 H), 4.45-4.62 (m, 3 H), 5.50 (s, 2 H), 6.51 (d, J=7.6 Hz, 1 H), 6.75 (d, J=1.8 Hz, 1 H), 6.92 (dd, J=8.5, 1.8 Hz, 1 H), 7.05-7.30 (m, 4 H), 7.45-7.56 (m, 1 H), 8.29 (d, J=8.8 Hz, 1 H), 8.58 (d, J=4.7 Hz, 1 H), 10.15 (t, J=4.5 Hz, 1 H).
EXAMPLE 176
1-((3-(3,4-Difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indol-2-yl)methyl)-1-methylpyrrolidinium iodide (Compound 176). 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) δ ppm 1.22 (d, J=5.9 Hz, 6 H), 2.25 (s, 4 H), 3.35 (s, 3 H), 3.72-3.97 (m, 4 H), 4.52-4.67 (m, 1 H), 4.70 (t, J=5.3 Hz, 2 H), 5.63 (s, 2 H), 6.84 (dd, J=8.8, 2.1 Hz, 1 H), 7.01 (d, J=2.1 Hz, 1 H), 7.20-7.54 (m, 5 H), 7.70-7.79 (m, 1 H), 7.88 (d, J=9.1 Hz, 1 H), 8.19 (t, J=6.3 Hz, 1 H), 8.44 (d, J=4.1 Hz, 1 H).
EXAMPLE 177
1-Benzyl-N-(3,4-difluorobenzyl)-6-(3,4-dihydro-2H-pyrrol-5-ylamino)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 177). 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 2h. 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) δ ppm 1.26-1.37 (m, 8 H), 2.53 (t, J=7.8 Hz, 2 H), 3.37-3.57 (m, 3 H), 4.57 (s, 2 H), 5.47 (s, 2 H), 6.90-7.02 (m, 3 H), 7.15-7.41 (m, 7 H).
EXAMPLE 178
1-Benzyl-N-(3,4-difluorobenzyl)-6-(4,5-dihydrothiazol-2-ylamino)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 178). 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 μl, 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) δ ppm 1.36 (d, J=7.0 Hz, 6 H), 3.28 (t, J=7.0 Hz, 2 H), 3.58-3.70 (m, 1 H), 3.79 (t, J=6.9 Hz, 2 H), 4.65 (d, J=5.6 Hz, 2 H), 5.38 (s, 2 H), 6.17-6.25 (m, 1 H), 6.96 (d, J=6.4 Hz, 2 H), 7.10-7.18 (m, 2 H), 7.20-7.35 (m, 6 H).
EXAMPLE 179
1-Benzyl-N-(3,4-difluorobenzyl)-5-fluoro-6-iodo-2-isopropyl-1H-indole-3-carboxamide (Compound 179). 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) δ ppm 1.32 (d, J=7.3 Hz, 6 H), 3.37-3.52 (m, 1 H), 4.57 (s, 2 H), 5.47-5.53 (m, 2 H), 6.82-6.97 (m, 2 H), 7.17-7.39 (m, 8 H).
EXAMPLE 180
1-Benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 180). 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) δ ppm 1.31 (d, J=7.0 Hz, 6 H), 3.37-3.51 (m, 1 H), 3.76 (s, 3 H), 4.56 (s, 2 H), 5.50 (s, 2 H), 6.88-6.98 (m, 3 H), 7.17-7.38 (m, 7 H).
EXAMPLE 181
N-(3,4-Difluorobenzyl)-2-isopropyl-6-nitro-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 181). 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) δ ppm 1.34 (d, J=7.3 Hz, 6 H), 3.41-3.58 (m, 1 H), 4.59 (s, 2 H), 5.72 (s, 2 H), 6.90 (d, J=7.9 Hz, 1 H), 7.19-7.41 (m, 4 H), 7.67-7.78 (m, 2 H), 8.04 (dd, J=8.8, 2.1 Hz, 1 H), 8.33 (d, J=2.1 Hz, 1 H), 8.51 (d, J=4.1 Hz, 1 H).
EXAMPLE 182
6-Amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182). 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) δ ppm 1.30 (d, J=7.0 Hz, 6 H), 3.41-3.58 (m, 1 H), 4.56 (s, 2 H), 5.48 (s, 2 H), 6.54-6.62 (m, 2 H), 6.66 (dd, J=8.5, 1.8 Hz, 1 H), 7.17-7.37 (m, 4 H), 7.39 (d, J=8.5 Hz, 1 H), 7.58-7.70 (m, 1 H), 8.53 (d, J=4.1 Hz, 1 H).
EXAMPLE 183
6-(Cyclopentylamino)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 183). 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) δ ppm 1.32 (d, J=7.3 Hz, 6 H), 1.34-1.75 (m, 6 H), 1.80-1.95 (m, 2 H), 3.47-3.60 (m, 1 H), 3.61-3.73 (m, 1 H), 4.56 (s, 2 H), 5.49 (s, 2 H), 6.39 (d, J=1.8 Hz, 1 H), 6.58-6.67 (m, 2 H), 7.19-7.36 (m, 4 H), 7.38 (d, J=8.8 Hz, 1 H), 7.60-7.71 (m, 1 H), 8.54 (d, J=5.0 Hz, 1 H).
EXAMPLE 184
N-(3,4-Difluorobenzyl)-6-(4,5-dihydrothiazol-2-ylamino)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 184). 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) δ ppm 1.32 (d, J=7.3 Hz, 6 H), 3.24 (t, J=7.0 Hz, 2 H), 3.43-3.58 (m, 1 H), 3.79 (t, J=7.2 Hz, 2 H), 4.57 (s, 2 H), 5.54 (s, 2 H), 6.65 (d, J=7.9 Hz, 1 H), 6.93 (dd, J=8.5, 1.8 Hz, 1 H), 7.14-7.39 (m, 5 H), 7.51 (d, J=8.5 Hz, 1 H), 7.61-7.69 (m, 1 H), 8.53 (d, J=4.1 Hz, 1 H).
EXAMPLE 185
N-(3,4-Difluorobenzyl)-6-(4,5-dihydrothiazol-2-ylamino)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide, hydrogen chloride salt (Compound 185). The title compound was also isolated in the synthesis of Compound 184.
1H NMR (300 MHz, METHANOL-d4) δ ppm 1.32 (d, J=7.3 Hz, 6 H), 3.41-3.54 (m, 1 H), 3.58 (t, J=7.5 Hz, 2 H), 3.99 (t, J=7.6 Hz, 2 H), 4.59 (d, J=4.1 Hz, 2 H), 5.61 (s, 2 H), 6.81 (d, J=7.9 Hz, 1 H), 7.04-7.12 (m, 1 H), 7.19-7.41 (m, 5 H), 7.64-7.77 (m, 2 H), 8.51 (d, J=4.1 Hz, 1 H), 8.67 (t, J=6.0 Hz, 1 H).
EXAMPLE 186
N-(3,4-Difluorobenzyl)-6-(4,5-dihydrooxazol-2-ylamino)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 186). 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 μl, 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) δ ppm 1.30 (d, J=7.3 Hz, 6 H), 3.40-3.53 (m, 1 H), 3.72 (t, J=8.4 Hz, 2 H), 4.34 (t, J=8.4 Hz, 2 H), 4.57 (s, 2 H), 5.55 (s, 2 H), 6.65 (d, J=7.9 Hz, 1 H), 7.01 (dd, J=8.5, 1.8 Hz, 1 H), 7.19-7.38 (m, 5 H), 7.52 (d, J=8.8 Hz, 1 H), 7.60-7.68 (m, 1 H), 8.52 (d, J=4.1 Hz, 1 H).
EXAMPLE 187
6-(3-(2-Chloroethyl)ureido)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 187). The title compound was also isolated in the synthesis of Compound 186.
1H NMR (300 MHz, METHANOL-d4) δ ppm 1.31 (d, J=7.0 Hz, 6 H), 3.42-3.54 (m, 3 H), 3.55-3.67 (m, 2 H), 4.57 (s, 2 H), 5.54 (s, 2 H), 6.65 (d, J=7.9 Hz, 1 H), 6.99 (dd, J=8.5, 2.1 Hz, 1 H), 7.17-7.38 (m, 4 H), 7.46-7.56 (m, 2 H), 7.61-7.72 (m, 1 H), 8.53 (d, J=4.7 Hz, 1 H).
EXAMPLE 188
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyrrolidin-1-yl)-1H-indole-3-carboxamide (Compound 188). 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 μl, 0.16 mmol) and i-Pr2NEt (77 μl, 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) δ ppm 1.31 (d, J=7.0 Hz, 6 H), 1.92-2.00 (m, 4 H), 3.04-3.26 (m, 4 H), 3.40-3.65 (m, 1 H), 4.57 (s, 2 H), 5.50 (s, 2 H), 6.17-6.35 (m, 1 H), 6.50-6.67 (m, J=8.4, 8.4 Hz, 2 H), 7.19-7.38 (m, 4 H), 7.45 (d, J=8.5 Hz, 1 H), 7.58-7.70 (m, 1 H), 8.54 (d, J=5.0 Hz, 1 H).
EXAMPLE 189
1-Benzyl-6-(cyclopentyl(methyl)amino)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 189). 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) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 1.41-1.57 (m, 4 H), 1.57-1.77 (m, 4 H), 2.68 (s, 3 H), 3.45-3.61 (m, 1 H), 3.69-3.81 (m, 1 H), 4.57 (s, 2 H), 5.47 (s, 2 H), 6.78 (d, J=1.8 Hz, 1 H), 6.88-7.01 (m, 3 H), 7.15-7.39 (m, 6 H), 7.50 (d, J=8.8 Hz, 1 H).
EXAMPLE 190
1-Benzyl-6-(cyclobutylamino)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 190). 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) δ ppm 1.32 (d, J=7.2 Hz, 6 H), 1.66-1.86 (m, 4 H), 2.18-2.32 (m, 2 H), 3.44-3.60 (m, 1 H), 3.73-3.88 (m, 1 H), 4.56 (s, 2 H), 5.41 (s, 2 H), 6.36 (d, J=1.9 Hz, 1 H), 6.57 (dd, J=8.6, 2.0 Hz, 1 H), 6.94-7.01 (m, 2 H), 7.18-7.35 (m, 6 H), 7.38 (d, J=8.5 Hz, 1 H).
EXAMPLE 191
1-Benzyl-6-(cyclopentylamino)-N-(3,5-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 191). 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) δ ppm 1.32 (d, J=7.0 Hz, 6 H), 1.35-1.47 (m, 2 H), 1.47-1.59 (m, 2 H), 1.60-1.73 (m, 2 H), 1.79-1.93 (m, 2 H), 3.46-3.59 (m, 1 H), 3.61-3.73 (m, 1 H), 4.55-4.64 (m, 2 H), 5.41 (s, 2 H), 6.45 (d, J=1.8 Hz, 1 H), 6.62 (dd, J=8.5, 2.1 Hz, 1 H), 6.76-6.88 (m, 1 H), 6.93-7.08 (m, 4 H), 7.13-7.29 (m, 3 H), 7.41 (d, J=8.5 Hz, 1 H), 8.38 (t, J=6.2 Hz, 1 H).
EXAMPLE 192
1-Benzyl-6-(cyclopentylamino)-N-(4-fluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 192). 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) δ ppm 1.32 (d, J=7.3 Hz, 6 H), 1.35-1.45 (m, 2 H), 1.50-1.59 (m, 2 H), 1.62-1.75 (m, 2 H), 1.79-1.93 (m, 2 H), 3.44-3.58 (m, 1 H), 3.61-3.73 (m, 1 H), 4.58 (d, J=5.9 Hz, 2 H), 5.41 (s, 2 H), 6.44 (d, J=1.8 Hz, 1 H), 6.60 (dd, J=8.5, 2.1 Hz, 1 H), 6.95-6.99 (m, 2 H), 7.03-7.12 (m, 2 H), 7.17-7.29 (m, 3 H), 7.36 (d, J=8.8 Hz, 1 H), 7.40-7.50 (m, 2 H), 8.30 (t, J=6.0 Hz, 1 H).
EXAMPLE 193
1-Benzyl-6-(cyclopentylamino)-N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 193). 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) δ ppm 1.31 (d, J=7.3 Hz, 6 H), 1.34-1.45 (m, 2 H), 1.47-1.60 (m, 2 H), 1.61-1.75 (m, 2 H), 1.80-1.94 (m, 2 H), 3.46-3.58 (m, 1 H), 3.60-3.72 (m, 1 H), 4.65 (s, 2 H), 5.40 (s, 2 H), 6.44 (d, J=1.8 Hz, 1 H), 6.62 (dd, J=8.6, 1.9 Hz, 1 H), 6.94-7.00 (m, 2 H), 7.15-7.30 (m, 3 H), 7.40 (d, J=8.8 Hz, 1 H), 7.68 (dd, J=9.4, 2.1 Hz, 1 H), 8.36 (d, J=2.6 Hz, 1 H), 8.49 (s, 1 H).
EXAMPLE 194
1-Benzyl-6-(cyclobutylamino)-N-(3,5-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 194). 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) δ ppm 1.32 (d, J=7.3 Hz, 6 H), 1.67-1.82 (m, 4 H), 2.20-2.31 (m, 2 H), 3.46-3.61 (m, 1 H), 3.73-3.87 (m, 1 H), 4.56-4.62 (m, 2 H), 5.41 (s, 2 H), 6.36 (d, J=2.1 Hz, 1 H), 6.58 (dd, J=8.6, 1.9 Hz, 1 H), 6.77-6.88 (m, 1 H), 6.93-7.07 (m, 4 H), 7.16-7.30 (m, 3 H), 7.41 (d, J=8.5 Hz, 1 H), 8.40 (t, J=6.0 Hz, 1 H).
EXAMPLE 195
1-Benzyl-6-(cyclobutylamino)-N-(4-fluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 195). 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) δ ppm 1.31 (d, J=7.3 Hz, 6 H), 1.67-1.83 (m, 4 H), 2.18-2.33 (m, 2 H), 3.44-3.61 (m, 1 H), 3.72-3.86 (m, 1 H), 4.53-4.62 (m, 2 H), 5.40 (s, 2 H), 6.35 (d, J=2.1 Hz, 1 H), 6.55 (dd, J=8.5, 2.1 Hz, 1 H), 6.92-7.00 (m, 2 H), 7.01-7.13 (m, 2 H), 7.15-7.30 (m, 3 H), 7.36 (d, J=8.5 Hz, 1 H), 7.40-7.49 (m, 2 H), 8.29 (t, J=6.3 Hz, 1 H).
EXAMPLE 196
1-Benzyl-6-(cyclobutylamino)-N-((5-fluoropyridin-3-yl)methyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 196). 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) δ ppm 1.30 (d, J=7.3 Hz, 6 H), 1.64-1.86 (m, 4 H), 2.18-2.32 (m, 2 H), 3.44-3.60 (m, 1 H), 3.72-3.86 (m, 1 H), 4.64 (s, 2 H), 5.40 (s, 2 H), 6.36 (d, J=1.8 Hz, 1 H), 6.58 (dd, J=8.6, 1.9 Hz, 1 H), 6.91-7.01 (m, 2 H), 7.15-7.31 (m, 3 H), 7.40 (d, J=8.8 Hz, 1 H), 7.63-7.73 (m, 1 H), 8.36 (d, J=2.6 Hz, 1 H), 8.48 (s, 1 H).
EXAMPLE 197
6-(Cyclobutylamino)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 197). 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) δ ppm 1.31 (d, J=7.3 Hz, 6 H), 1.67-1.83 (m, 4 H), 2.19-2.32 (m, 2 H), 3.46-3.61 (m, 1 H), 3.73-3.87 (m, 1 H), 4.56 (s, 2 H), 5.48 (s, 2 H), 6.31 (d, J=1.8 Hz, 1 H), 6.54-6.64 (m, 2 H), 7.17-7.43 (m, 5 H), 7.58-7.69 (m, 1 H), 8.54 (d, J=4.1 Hz, 1 H).




EXAMPLE 198
N-(3,4-Difluorobenzyl)-6-isopropoxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide-d7 (Compound 198). 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) δ ppm 1.37 (d, J=7.0 Hz, 6 H), 3.69-3.89 (m, 1 H), 4.67 (d, J=5.9 Hz, 2 H), 5.51 (s, 2 H), 6.30 (t, J=6.0 Hz, 1 H), 6.53 (d, J=7.9 Hz, 1 H), 6.65 (d, J=1.8 Hz, 1 H), 6.82 (dd, J=8.6, 2.2 Hz, 1 H), 7.09-7.32 (m, 4 H), 7.45-7.57 (m, 2 H), 8.62 (d, J=4.7 Hz, 1 H).
EXAMPLE 199
N-(3,4-Difluorobenzyl)-2-isopropenyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide-d7 (Compound 199). 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) δ ppm 2.00 (t, J=1.2 Hz, 3 H), 4.55 (s, 2 H), 5.18-5.25 (m, 1 H), 5.44 (s, 2 H), 5.57 (t, J=1.6 Hz, 1 H), 6.71 (d, J=1.8 Hz, 1 H), 6.76 (d, J=7.9 Hz, 1 H), 6.81 (dd, J=8.8, 2.3 Hz, 1 H), 7.14-7.37 (m, 4 H), 7.62-7.73 (m, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 8.50 (d, J=5.0 Hz, 1 H).




EXAMPLE 200
N-(3,4-Difluorobenzyl)-2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 200). 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) δ ppm 1.36 (d, J=7.0 Hz, 6 H), 3.74 (s, 3 H), 3.74-3.83 (m, 1 H), 4.65 (d, J=6.2 Hz, 2 H), 5.51 (s, 2 H), 6.37 (t, J=5.9 Hz, 1 H), 6.52 (d, J=7.9 Hz, 1 H), 6.62 (d, J=2.3 Hz, 1 H), 6.82 (dd, J=8.6, 2.2 Hz, 1 H), 7.08-7.30 (m, 4 H), 7.46-7.57 (m, 2 H), 8.61 (d, J=4.1 Hz, 1 H).
EXAMPLE 201
N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 201). 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) δ ppm 1.30 (s, 3 H), 1.32 (s, 3 H), 3.43-3.57 (m, 1 H), 4.57 (s, 2 H), 5.48 (s, 2 H), 6.54-6.64 (m, 2 H), 6.68 (dd, J=8.56, 2.20 Hz, 1 H), 7.19-7.37 (m, 4 H), 7.43 (d, J=8.56 Hz, 1 H), 7.66 (td, J=7.76, 1.59 Hz, 1 H), 8.54 (d, J=4.89 Hz, 1 H).
EXAMPLE 202
3-(3,4-Difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202). 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) δ ppm 1.33 (s, 3 H), 1.34 (s, 3 H), 3.42-3.54 (m, 1 H), 4.58 (s, 2 H), 5.62 (s, 2 H), 6.78 (d, J=7.83 Hz, 1 H), 7.11 (dd, J=8.68, 1.83 Hz, 1 H), 7.21-7.39 (m, 5 H), 7.68 (d, J=8.80 Hz, 2 H), 8.52 (d, J=4.89 Hz, 1 H), 8.73 (br. s., 1 H).
EXAMPLE 203
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyrimidin-5-yl)-1H-indole-3-carboxamide (Compound 203). 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) δ ppm 1.34 (s, 3 H), 1.36 (s, 3 H), 3.50 (ddd, J=14.54, 7.14, 6.89 Hz, 1 H), 4.61 (s, 2 H), 5.71 (s, 2 H), 6.76 (d, J=7.62 Hz, 1 H), 7.18-7.42 (m, 4 H), 7.46-7.63 (m, 1 H), 7.62-7.74 (m, 2 H), 7.78 (d, J=8.35 Hz, 1 H), 8.53 (dd, J=4.98, 0.88 Hz, 1 H), 9.00-9.09 (m, 3 H).
EXAMPLE 204
N-(3,4-Difluorobenzyl)-2-isopropyl-6-(1H-pyrazol-5-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 204). 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) δ ppm 1.32 (s, 3 H), 1.34 (s, 3 H), 3.49 (m, 1 H), 4.60 (s, 2 H), 5.65 (s, 2 H), 6.61 (d, J=2.05 Hz, 1 H), 6.69 (d, J=8.06 Hz, 1 H), 7.19-7.42 (m, 4 H), 7.52-7.77 (m, 5 H), 8.54 (d, J=4.83 Hz, 1 H).
EXAMPLE 205
N-(3,4-Difluorobenzyl)-2-isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 205). 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) δ ppm 1.32 (s, 3 H), 1.34 (s, 3 H), 3.49 (m, 1 H), 3.75 (s, 3H), 4.60 (s, 2 H), 5.65 (s, 2 H), 6.35 (d, J=2.05 Hz, 1 H), 6.69 (d, J=8.06 Hz, 1 H), 7.19-7.42 (m, 4 H), 7.52-7.77 (m, 5 H), 8.54 (d, J=4.83 Hz, 1 H).
EXAMPLE 206
N-(3,4-Difluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 206). 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) δ ppm 1.36 (s, 3 H), 1.39 (s, 3 H), 2.12 (s, 3 H), 2.29 (s, 3 H), 3.50-3.65 (m, 1 H), 4.60 (s, 2 H), 5.64 (s, 2 H), 6.74 (d, J=7.91 Hz, 1 H), 7.09 (dd, J=8.28, 1.39 Hz, 1 H), 7.17 (d, J=0.88 Hz, 1 H), 7.22-7.41 (m, 5 H), 7.70 (dd, J=8.20, 0.59 Hz, 2 H), 8.53 (ddd, J=4.91, 1.76, 0.81 Hz, 1 H).
EXAMPLE 207
N-(3,4-Difluorobenzyl)-2-isopropyl-6-morpholino-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 207). To a solution of 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (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>) δ ppm 1.30 (s, 3 H), 1.32 (s, 3 H), 3.05 (t, J=4.98, 4 H), 3.49 (m, 1 H), 3.78 (t, J=4.98, 4 H), 4.57 (s, 2 H), 5.55 (s, 2 H), 6.62 (d, J=8.20 Hz, 1 H), 6.77 (d, J=1.76 Hz, 1 H), 6.93 (dd, J=8.79, 2.05 Hz, 1 H), 7.20-7.38 (m, 4 H), 7.52 (d, J=8.79 Hz, 1 H), 7.65 (td, J=7.76, 1.76 Hz, 2 H), 8.54 (d, J=4.40 Hz, 2 H).




EXAMPLE 208
2-Isopropyl-6-methoxy-1-(oxazol-2-ylmethyl)-1H-indole-3-carbaldehyde (Compound 208). 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) δ ppm 1.52 (d, J=7.0 Hz, 6 H), 3.71 (p, J=7.0 Hz,1 H), 3.82 (s, 3 H), 5.66 (s, 2 H), 6.87 (dd, J=8.8, 2.2 Hz, 1 H), 7.04 (d, J=2.2 Hz, 1 H), 7.15 (s, 1 H), 7.88 (s, 1 H), 8.08 (d, J=8.8 Hz, 1 H), 10.32 (s, 1 H).
EXAMPLE 209
2-Isopropyl-6-methoxy-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic Acid (Compound 209). 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) δ ppm 1.42 (d, J=7.0 Hz, 6 H), 3.80 (s, 3 H), 4.04 (p, J=7.0 Hz,1 H), 5.62 (s, 2 H), 6.81 (dd, J=8.5, 2.0 Hz, 1 H), 6.95 (d, J=2.0 Hz, 1 H), 7.15 (s, 1 H), 7.83 (s, 1 H), 7.96 (d, J=8.5 Hz, 1 H).
EXAMPLE 210
N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210). 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) δ ppm 1.41 (d, J=7.0 Hz, 6 H), 3.59 (p, J=7.0 Hz,1 H), 4.58 (s, 2 H), 5.52 (s, 2 H), 6.70 (dd, J=8.5, 2.2 Hz, 1 H), 6.82 (d, J=2.2 Hz, 1 H), 7.15 (s, 1 H), 7.19-7.36 (m, 3 H), 7.40 (d, J=8.5 Hz, 1 H), 7.86 (s, 1 H).
EXAMPLE 211
6-(Cyclopentyloxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 211). 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) δ ppm 1.41 (d, J=7.0 Hz, 6 H), 1.60-2.00 (m, 8 H), 3.50 (p, J=7.0 Hz, 1 H), 4.58 (s, 2 H), 5.54 (s, 2 H), 6.74 (dd, J=8.5, 2.2 Hz, 1 H), 6.83 (d, J=2.2 Hz, 1 H), 7.13 (s, 1 H), 7.20-7.38 (m, 3 H), 7.42 (d, J=8.5 Hz, 1 H), 7.83 (s, 1 H).
EXAMPLE 212
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-6-propoxy-1H-indole-3-carboxamide (Compound 212). 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) δ ppm 1.04 (t, J=7.5 Hz, 3 H), 1.39 (d, J=7.0 Hz, 6 H), 1.78 (m, 2 H), 3.57 (p, J=7.0 Hz, 1 H), 3.94 (t, J=6.5 Hz, 2 H), 4.55 (s, 2 H), 5.55 (s, 2 H), 6.78 (dd, J=8.8, 2.1 Hz, 1 H), 6.95 (d, J=2.1 Hz, 1 H), 7.11-7.36 (m, 4 H), 7.43 (d, J=8.8 Hz, 1 H), 7.83 (d, J=0.88 Hz, 1 H).
EXAMPLE 213
N-(3,4-Difluorobenzyl)-6-isopropoxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 213). 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) δ ppm 1.29 (d, J=6.0 Hz, 6 H), 1.39 (d, J=7.0 Hz, 6 H), 3.59 (p, J=7.0 Hz, 1 H), 4.55 (s, 2 H), 4.57 (p, J=6.0 Hz, 1 H), 5.54 (s, 2 H), 6.74 (dd, J=8.5, 2.4 Hz, 1 H), 6.78 (d, J=2.4 Hz, 1 H), 7.12 (s, 1 H), 7.20-7.38 (m, 3 H), 7.40 (d, J=8.5 Hz, 1 H), 7.83 (s, 1 H).
EXAMPLE 214
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-6-(thiazol-2-yloxy)-1H-indole-3-carboxamide (Compound 214). 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) δ ppm 1.40 (d, J=7.0 Hz, 6 H), 3.57 (p, J=7.0 Hz, 0 H), 4.57 (s, 2 H), 5.61 (s, 2 H), 6.99 (d, J=3.81 Hz, 1 H), 7.07 (dd, J=8.5, 1.8 Hz, 1 H), 7.11 (d, J=0.88 Hz, 1 H), 7.19-7.39 (m, 4 H), 7.48 (d, J=1.8 Hz, 1 H), 7.62 (d, J=8.5 Hz, 1 H), 7.83 (d, J=0.88 Hz, 1 H).
EXAMPLE 215
6-(5-Bromothiazol-2-yloxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 215). The title compound was also isolated in the synthesis of Compound 214.
1H NMR (300 MHz, METHANOL-d4) δ ppm 1.40 (d, J=7.3 Hz, 6 H), 3.58 (p, J=7.3 Hz, 0 H), 4.56 (s, 2 H), 5.62 (s, 2 H), 7.08 (dd, J=8.8, 2.1 Hz, 1 H), 7.11 (d, J=0.88 Hz, 1 H), 7.20-7.39 (m, 4 H), 7.50 (d, J=1.8 Hz, 1 H), 7.63 (d, J=8.8 Hz, 1 H), 7.83 (d, J=0.88 Hz, 1 H).
EXAMPLE 216
2-Isopropyl-6-methoxy-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carbaldehyde (Compound 216). 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) δ ppm 1.50 (d, J=7.3 Hz, 6 H), 2.35 (s, 3 H), 3.65 (p, J=7.3 Hz), 3.82 (s, 3 H), 5.53 (s, 2 H), 5.89 (s, 1 H), 6.88 (dd, J=2.3, 8.7 Hz, 1 H), 7.00 (d, J=2.3 Hz, 1 H), 8.10 (d, J=8.7 Hz, 1 H), 10.23 (s, 1 H).
EXAMPLE 217
2-Isopropyl-6-methoxy-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carboxylic Acid (Compound 217). 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) δ ppm 1.42 (d, J=7.0 Hz, 6 H), 2.31 (s, 3 H), 3.55 (p, J=7.0 Hz), 3.80 (s, 3 H), 5.55 (s, 2 H), 5.78 (s, 1 H), 6.82 (dd, J=2.0, 8.5 Hz, 1 H), 6.93 (d, J=2.0 Hz, 1 H), 7.90 (d, J=8.5 Hz, 1 H).
EXAMPLE 218
N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carboxamide (Compound 218). 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) δ ppm 1.36 (d, J=7.0 Hz, 6 H), 2.32 (s, 3 H), 3.54 (p, J=7.0 Hz),4.55 (s, 2 H), 5.38 (s, 2 H), 5.74 (s, 1 H), 6.67 (dd, J=2.2, 8.5 Hz, 1 H), 6.74 (d, J=2.2 Hz, 1 H), 7.20-7.35 (m, 3 H), 7.38 (d, J=8.5 Hz, 1 H).
EXAMPLE 219
6-(Cyclopentyloxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carboxamide (Compound 219). 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) δ ppm 1.38 (d, J=7.0 Hz, 6 H), 1.60-1.95 (m, 8 H), 2.31 (s, 3 H), 3.55 (p, J=7.0 Hz), 4.55 (s, 2 H), 5.43 (s, 2 H), 5.75 (s, 1 H), 6.74 (dd, J=2.0, 8.8 Hz, 1 H), 6.85 (d, J=2.0 Hz, 1 H), 7.20-7.35 (m, 3 H), 7.43 (d, J=8.8 Hz, 1 H).




EXAMPLE 220
N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220). 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) δ ppm 1.23 (t, J=7.0 Hz, 1 H), 1.31 (d, J=7.0 Hz, 7 H), 3.46 (p, J=7.18 Hz, 1 H), 4.09 (q, 1 H), 4.57 (s, 2 H), 5.63 (s, 2 H), 6.58 (d, J=1.8 Hz, 1 H), 6.71 (dd, J=8.6, 2.2 Hz, 1 H), 6.88 (d, J=8.2 Hz, 1 H), 7.19-7.38 (m, 3 H), 7.44 (d, J=8.5 Hz, 1 H), 7.60 (d, J=5.57 Hz, 1 H), 8.01 (td, J=7.8, 1.6 Hz, 1 H), 8.68 (d, J=4.4 Hz, 1 H).
EXAMPLE 221
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-2-yloxy)-1H-indole-3-carboxamide (Compound 221). 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) δ ppm 1.34 (d, J=7.2 Hz, 6 H), 3.51 (p, J=7.2 Hz, 1 H), 4.60 (d, J=5.9 Hz, 2 H), 5.55 (s, 2 H), 6.73 (d, J=7.9 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.91 (dd, J=8.5, 2.2 Hz, 1 H), 7.01-7.10 (m, 2 H), 7.20-7.42 (m, 4 H), 7.65 (d, J=8.5 Hz, 1 H), 7.69 (dd, J=7.9, 1.8 Hz, 1 H), 7.74 (ddd, J=8.2, 7.2, 2.0 Hz, 1 H), 8.07 (dt, J=5.7, 1.9 Hz, 1H), 8.50 (dt, J=4.8, 1.3 Hz, 1 H), 8.67 (t, J=5.9 Hz, 1 H).
EXAMPLE 222
N-(3,4-Difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide (Compound 222). 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) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 4.59 (s, 2 H), 5.55 (s, 2 H), 6.72 (d, J=8.2 Hz, 1 H), 6.92 (dd, J=8.6, 2.2 Hz, 1 H), 7.02 (d, J=2.0 Hz, 1 H), 7.19-7.42 (m, 6 H), 7.62-7.74 (m, 2 H), 8.14-8.24 (m, 2 H), 8.49 (d, J=5.0 Hz, 1 H).
EXAMPLE 223
Ethyl 2-(6-(Cyclopentyloxy)-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-1-yl)acetate (Compound 223). The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and ethyl2-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) δ ppm 1.25 (t, J=7.0 Hz, 3 H), 1.39 (d, J=7.3 Hz, 6 H), 1.60-2.00 (m, 8 H), 3.48 (p, J=7.3 Hz, 1 H), 4.21 (q, J=7.0 Hz, 2 H), 4.56 (s, 2 H), 5.02 (s, 2 H), 6.76 (dd, J=9.0, 2.1 Hz, 1 H), 6.77 (d, J=2.1 Hz, 1 H), 7.20-7.36 (m, 3 H), 7.45 (d, J=9.0 Hz, 1 H).
EXAMPLE 224
3-(3,4-Difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic Acid (Compound 224). General Procedure L. To a solution of methyl3-(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 (1M 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) δ ppm 3.74 (s, 3 H), 4.57 (s, 2 H), 5.91 (s, 2 H), 6.77 (d, J=2.3 Hz, 1 H), 6.80-6.92 (m, J=8.9, 2.2 Hz, 2 H), 7.12-7.37 (m, 4 H), 7.56-7.69 (m, 1 H), 8.18 (d, J=8.2 Hz, 1 H), 8.48 (s, 1 H).
EXAMPLE 225
3-(3,4-Difluorobenzylcarbamoyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic Acid (Compound 225). 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 methyl3-(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) δ ppm 4.63 (s, 2 H), 5.92 (s, 2 H), 6.73 (d, J=1.5 Hz, 1 H), 6.82 (dd, J=8.8, 2.1 Hz, 1 H), 6.94 (d, J=7.9 Hz, 1 H), 7.17-7.30 (m, 2 H), 7.30-7.44 (m, 2 H), 7.65-7.84 (m, 2 H), 8.47-8.57 (m, 1 H).
EXAMPLE 226
Methyl 3-(3,4-Difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 226). 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) δ ppm 1.26 (d, J=6.2 Hz, 6 H), 3.69 (s, 3 H), 4.50-4.66 (m, 3 H), 5.87 (s, 2 H), 6.79-6.93 (m, 3 H), 7.20-7.31 (m, 3 H), 7.33-7.44 (m, 1 H), 7.59 (dd, J=8.5, 0.9 Hz, 1 H), 7.67 (td, J=7.8, 1.8 Hz, 1 H), 8.48 (ddd, J=5.0, 1.8, 0.9 Hz, 1 H).
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)r-A2-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 R11R10 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-membered ring; or B is OR6, wherein R6 is H; or
    B is COR10, wherein R10 is methyl.

## Claims

1. A compound represented by the formula I having sphingosine-1-phosphate receptor agonist and or antagonist biological activity:




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 (CN2)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, R10and 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 compound of claim 1 wherein A is CH2.

3. The compound of claim 2 wherein n is 0 or an integer of 1 or 2 and R4 is fluoro.

4. The compound of claim 3 wherein R1 is i-propyl.

5. The compound of claim 4 wherein A1 and A2 are absent.

6. The compound of claim 5 wherein B is OR6.

7. The compound of claim 5 wherein B is COOR7.

8. A compound represented by the formula I having sphingosine-1-phosphate receptor agonist and or antagonist biological activity:




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 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 OR6or 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.

9. The compound of claim 8 wherein R6, R8 and R9 are methyl.

10. The compound of claim 5 wherein B is CH═NOR11 wherein R11 is methyl or i-butyl.

11. The compound of claim 5 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 compound of claim 4 wherein A1 is absent, r is 0, A2 is CH2 and B is OR6, wherein R6 is H.

13. The compound of claim 5 wherein A1 is absent, r is 1 and B is COR10 wherein R10 is methyl.

14. The compound of claim 1 having sphingosine-1-phosphate antagonist activity, 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 CH═NOR1l;
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.