The present invention relates to a pyrrolidineaniline that is useful as a progesterone receptor modulator.
Endometriosis is a disease characterized by the growth of endometrial tissue (called lesions) at extrauterine sites. This lesion attachment can result in pain, dysmenorrhea, dyspareunia, and infertility. It is estimated that greater than 80% of patients presenting with chronic pelvic pain are eventually diagnosed with endometriosis. The prevalence of the disease is about 7-10% of women of reproductive years with a familial association risk increase of 10-fold. Definitive diagnosis is only reached by laparoscopy, but typically there is about a ten year delay from disease onset to conclusive diagnosis. Consistent with their uterine origins, it is believed that the endometriotic lesions are hormonally dependent upon estrogen; consequently, therapies that functionally antagonize estrogen production or action, such as drugs containing progesterone receptor (PR) modulators, are efficacious in alleviating symptoms. Current therapeutic goals include reducing pain with anti-inflammatory agents and suspending the ovarian cycle using hormonal modulation drugs.
Another disease believed to be hormonally responsive to estrogen is uterine leiomyomas (fibroids), which appear as benign uterine smooth muscle tumors occurring primarily in women of reproductive age. Fibroids occur at rates of 20-25% and are the leading indication for hysterectomies. The most common symptoms are menorrhagia, pelvic pain/discomfort, bladder and bowel compression symptoms, and possibly infertility. Medical treatments for leiomyomas consist of those commonly prescribed for endometriosis, with treatments containing progesterone receptor modulators being most common due to safety, tolerability, ease of use and cost.
Most drug development has focused on modulation by full agonism or antagonism of progesterone receptors. For example, progestins are molecules that interact with progesterone receptor to activate or repress gene expression in target cells in a manner presumed to be progesterone-like. Though progestins are used in oral contraception, hormone therapy, and treatment of reproductive disorders, such as endometriosis and leiomyomas, these agents cause a number of adverse effects, including breakthrough bleeding, mood altering, acne, weight gain, and breast tenderness. Paradoxically, progesterone receptor antagonists such as mifepristone have been suggested as potential therapies, but the data are limited with few patients and no placebo-controlled randomized trials.
D. DeManno et al. (Steroids 68 (2003) 1019-1032), report that asoprisnil is a progesterone receptor modulator with mixed agonist/antagonistic activities. While the efficacy of the agent in treatment of endometriosis or fibroids is uncertain, early data from healthy female subjects indicate that the agent induces endometrial atrophy and amenorrhea, which suggests a predominantly progesterone receptor antagonist action in humans. Unfortunately, PR antagonists such as RU-486 tend to be abortifacient.
Accordingly, it would be desirable to discover a way to suppress estrogen-dependent endometriotic growth while reducing the systemic effects associated with current progesterone receptor modulating therapy.
In a first aspect, the present invention provides a compound represented by the following formula:
or a pharmaceutically acceptable salt thereof;
wherein Z is Cl, NO2, OCH3, or CN;
R1 is H, C1-C6-alkyl, CF3, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, heterocycloalkyl, C1-C6-alkyl-heterocycloalkyl, heteroaryl-(R3)n, phenyl-(R3′)n, or —CH2R4;
y is 0 or 1, with the proviso that when R1 is H, y is 0; and
R2 is C1-C5-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C5-alkyl, C1-C6-alkyloxy-C1-C5-alkyl, C3-C6-cycloalkyl, heterocycloalkyl, C1-C6-alkyl-heterocycloalkyl, C2-C4-alkenyl, naphthyl, heteroaryl-(R3)n, or phenyl-(R3′)n, where n is 0, 1, 2, or 3;
each R3 is independently CH3, F, Cl, Br, CF3, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, dimethylamino, C2-C4-alkenyl, or CN, or where 2 of the R3 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring;
each R3 is independently C1-C6-alkyl, F, Cl, Br, CF3, C1-C6-alkoxy, dimethylamino, amido, C2-C4-alkenyl, nitro, —COO—C1-C6-alkyl, OH, COOH, or CN, or where 2 of the R3′ groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
R4 is F, Cl, Br, C1-C6-alkyloxy-C1-C6-alkyl, CF3, CH2CF3, COOH, CH2CN, CN, C1-C6-alkylcarbonyl, heterocycloalkyl, C1-C6-alkyl-heterocycloalkyl, heterocycloalkyl-CH2—, aminocarbonyl, aminocarbonyl-CH2—, di-C1-C6-alkylaminocarbonyl, C2-C4-alkenyl, hydroxy-C1-C6-alkyl, naphthyl, heteroaryl-(R3)n, phenyl-(R3′)n, or CH2— phenyl-(R3′)n.
Compounds of the present invention are useful as progesterone receptor modulators.
The present invention is a compound represented by the following formula:
or a pharmaceutically acceptable salt thereof;
wherein Z is Cl, NO2, OCH3, or CN;
R1 is H, C1-C6-alkyl, CF3, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-cycloalkyl, heterocycloalkyl, C1-C6-alkyl-heterocycloalkyl, heteroaryl-(R3)n, phenyl-(R3′)n, or —CH2R4;
y is 0 or 1, with the proviso that when R1 is H, y is 0; and
R2 is C1-C5-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C5-alkyl, C1-C6-alkyloxy-C1-C5-alkyl, C3-C6-cycloalkyl, heterocycloalkyl, C1-C6-alkyl-heterocycloalkyl, C2-C4-alkenyl, naphthyl, heteroaryl-(R3)n, or phenyl-(R3′)n, where n is 0, 1, 2, or 3;
each R3 is independently CH3, F, Cl, Br, CF3, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, dimethylamino, C2-C4-alkenyl, or CN, or where 2 of the R3 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring;
each R3 is independently C1-C6-alkyl, F, Cl, Br, CF3, C1-C6-alkoxy, dimethylamino, amido, C2-C4-alkenyl, nitro, —COO—C1-C6-alkyl, OH, COOH, or CN, or where 2 of the R3′ groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
R4 is F, Cl, Br, C1-C6-alkyloxy-C1-C6-alkyl, CF3, CH2CF3, COOH, CH2CN, CN, C1-C6-alkylcarbonyl, heterocycloalkyl, C1-C6-alkyl-heterocycloalkyl, heterocycloalkyl-CH2—, aminocarbonyl, aminocarbonyl-CH2—, di-C1-C6-alkylaminocarbonyl, C2-C4-alkenyl, hydroxy-C1-C6-alkyl, naphthyl, heteroaryl-(R3)n, phenyl-(R3′)n, or CH2— phenyl-(R3′)n.
As used herein, “C1-6-alkyl” refers to a straight or branched chain monovalent radical of 1 to 6 carbon atoms, including, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl and isomers thereof.
Examples of suitable C1-C6-alkoxy groups include methoxy and ethoxy groups; examples of suitable C1-C6-alkoxycarbonyl-C1-C6-alkyl groups include —C(CH3)2C(O)OCH2CH3 and —CH2CH2C(O)O— t-butyl groups; an example of a suitable C1-C6-alkoxy-C1-C6-alkyl group is CH3OCH2— (methoxymethyl); examples of suitable C1-C6-alkoxycarbonyl groups include —CO2CH2CH3 and —CO2-t-butyl groups; examples of suitable C3-C6-cycloalkyl groups include cyclopentyl and cyclohexyl groups.
As used herein, “heterocycloalkyl” refers to a 3-6-membered ring that contains at least one heteroatom selected from N, O, and S. Examples of suitable heterocycloalkyl groups include piperidinyl, pyrrolidinyl, pyrazinyl, morpholino, and 1,3-dioxolan-2-yl groups. Similarly, “C1-C6-alkyl-heterocycloalkyl” refers to a heterocycloalkyl group substituted with a C1-C6-alkyl group. An example of a C1-C6-alkyl-heterocycloalkyl group is N-methylpiperidinyl.
The term “heteroaryl” is used herein to describe an aromatic group that contains at least one heteroatom selected from N, O, and S. Examples of suitable heteroaryl groups include pyridinyl, oxidopyridinyl, furyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyrimidinyl, and benzothiadiazolyl groups. The heteroaryl and phenyl groups may also be substituted as described herein. Heteroaryl also includes more than one heteroaryl groups, for example, pyridinylthienyl and methoxypyridinylthienyl groups.
Examples of C2-4-alkenyl groups include vinyl, allyl, and isopropenyl groups.
When R2 is heteroaryl-(R3)n or phenyl-(R3′)n and n is 2 or 3, two of the R3 or R3′ groups can, together with the heteroaryl or phenyl groups respectively to which they are attached, form a fused bicyclic group. Examples of such fused bicyclic groups include benzodioxinyl and benzodioxolyl groups.
The term “IC50” is used herein to refer to the molar concentration of a compound required to inhibit binding of 50% of Fluormone PL Red to the progesterone receptor. Furthermore, pIC50 is the negative log of the molar IC50.
The terms “a compound of the present invention” and “the compound of the present invention” are used herein to refer to one or more compounds of the present invention. The present invention includes compounds as well as their pharmaceutically acceptable salts alternatively or collectively. Accordingly, the word “or” in the context of a compound or a pharmaceutically acceptable salt thereof, is understood to include the alternative (either a compound or a pharmaceutically acceptable salt) as well as the collective (both the compound and its pharmaceutically acceptable salt).
Pharmaceutically acceptable salts of the compounds of the present invention include salts formed by the addition of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or by the addition of an organic acid such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, or tartaric acid.
A skilled artisan will appreciate that the compound and/or pharmaceutically acceptable salt of the present invention includes all of its manifestations including amorphous and one or more crystalline forms or any combinations thereof. Crystalline forms include anhydrous forms as well as aqueous and non-aqueous solvate forms.
The compounds of the present invention may exist as optical isomers including diastereoisomers and enantiomers, and mixtures of isomers in all ratios including racemic mixtures. Indeed, another aspect of the present invention is a compound of the formula:
or a pharmaceutically acceptable salt thereof; where X, Z, R1, R2, and y are as previously defined.
The present invention also relates to a pharmaceutical composition comprising the compound of the formula of the present invention or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable earner therefor. The composition may be formulated for administration by any route, such as oral, topical or parenteral. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The present invention also relates to a method comprising administering to a patient in need thereof an effective amount of the compound of the formula of the present invention or a pharmaceutically-acceptable salt thereof to treat endometreosis or uterine fibroids. In addition the compound of the present invention can be combined with one or more exogenous estrogens prescribed for hormone therapy to reduce the risk of estrogen-dependent cancers such as endometrial cancer.
Acquest/Biosystems is a multi-mode reader (FP reader); CHAPS refers to 3-cholamidopropyl-dimethylammonio 1-propanesulfonate; DTT refers to dithiothreitol.
PR Binding Assay—The assay was performed according to the manufacturers protocol (PR Competitor Assay Kit, Red—(Invitrogen—Product No. P2962)) with minor amendments. Briefly, 40 nM PR-Ligand Binding Domain, 2 nM Fluormone PL Red and 1 mM DTT were dissolved and mixed in Complete PR RED Buffer supplemented with 2 mM CHAPS. 10 μL of the mix was dispensed to each well of Greiner low volume plates, containing compounds at the required concentration. The plates were spun for 1 min at 200 g, covered to protect the reagents from light, and then incubated at room temperature for approximately 2 hours. Plates were read on an Acquest using a 530-25 nm excitation and 580-10 nm emission interference filter and a 561 nm Dichroic mirror.
All data was normalized to the mean of 16 high and 16 low control wells on each plate. A four parameter curve fit of the following form was then applied
Where a is the minimum, b is the Hill slope, c is the XC50 and d is the maximum. Data is presented as the mean pIC50 with the standard deviation of the mean of n experiments.
The compounds of the present invention are useful as modulators of progesterone receptors and may be useful in the treatment of disease associated with endometreosis and uterine fibroids. Thus, the present invention further relates to a method of treating a patient comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically-acceptable salt thereof or combination thereof to treat endometreosis or uterine fibroids.
Compounds of the present invention can be prepared, for example, in accordance with the following schemes. As used herein, Boc refers to t-butoxycarbonyl; DMSO refers to dimethyl sulfoxide; DMF refers to dimethylformamide; TFA refers to trifluoroacetic acid; DCE refers to dichloroethane; and Et2O refers to diethyl ether.
In a first step, illustrated in Scheme 1, nucleophilic addition of pyrrolidine 1a to a phenyl fluoride forms aniline 1b or 1f. In the case where X=Cl, aniline 1b can be hydrogenated to form aniline 1c. Alternatively, reductive amination of aniline 1 h with ketone 1i yields secondary aniline 1j. Compounds 1b, 1c, 1f, or 1j can be further modified by treatment with strong base and electrophile to form the respective tertiary anilines and subsequent removal of the Boc protecting group under acidic conditions forms compounds 1e, 1g, and 1k.
Compounds 1e, 1g, and 1k can be further functionalized in accordance with Scheme 2:
Treatment of the pyrrolidine 1e with alkyl or benzyl bromides or t-butyl acrylate (Scheme 3) under basic conditions can afford the desired pyrrolidines 3a and 3b (Method E or F) while reaction of 1e with McSO2Cl and pyridine yields the desired sulfonamide 3c (Method G).
Pyrrolidine 1b can be deprotected under acidic conditions to form 4a and the pyrrolidine nitrogen can be selectively functionalized to form 4b-4e (Scheme 4).
The aniline nitrogen can then be modified, for example, as shown in Scheme 5.
Scheme 6 illustrates the synthesis of various electrophiles that can be used to make compounds of the present invention:
It may be desirable to further derivatize a compound of the present invention. For example, thiophene bromide 7a can undergo a Suzuki reaction to yield 7b or the methyl ester 7c can be hydrolyzed to the acid 7d (Scheme 7). Moreover, as illustrated in Scheme 8, the ethyl ester 8a can be hydrolyzed under basic conditions to the acid 8b, which then can be reacted with LiAlH4 to yield the primary alcohol 8c.
Treatment of pyrrolidine 9a with PtO2 and H2 forms the desired compound 9b (Scheme 9). Moreover, as shown in Scheme 10, reaction of 10a or 10b under similar conditions yields the desired functionalized pyrrolidines 10c or 10d, respectively.
The following Examples are for illustrative purposes only and are not intended to limit the scope of the invention. The compounds from these Examples exhibit a pIC50 of greater than 5 (i.e., an IC50 of less than 10 μM). The phrase “IC50 of less than 10 μM” refers to an IC50 of less than 10 μM as measured using the PR binding assay described herein.
RT=room temperature
EtOAc=Ethyl acetate
Et2O=Diethyl ether
DMSO=Dimethyl sulfoxide
TFA=Trifluoroacctic acid
NaBH(OAc)3=Sodium triacetoxyborohydride
KOAc=Potassium acetate
AcOH=Acetic acid
KCN=Potassium cyanide
NaOMe=Sodium methoxide
AIBN=2,2′-Azobis(2-methylpropionitrile)
Pd(dppf)Cl2=[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 400 MHz, and chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured in Hertz. CDCl3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD3OD or d4-CH3OH is tetradeuteriomethanol. Mass spectra were obtained using electrospray (ES) or atmospheric pressure chemical ionization (APCI) techniques. E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel or on an ISCO Combi-flash purification system using pre-filled silica gel cartridges. Preparative HPLC was performed using Gilson chromatography systems using a 30×100 mm Xterra Prep RP column at a flow rate of 40 mL/min. The solvent system used was a variable gradient of 18% to 90% acetonitrile/water using either 0.1% TFA or ammonium hydroxide to adjust the pH to 10. Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colo.
A mixture of 2-chloro-4-fluorobenzonitrile (4.26 g, 27.5 mmol), 1,1-dimethylethyl (3S)-3-amino-1-pyrrolidinecarboxylate (5.11 g, 27.5 mmol) and NaHCO3 (4.62 g, 55 mmol) in 45 mL of DMSO and 5 mL of H2O was heated with stirring at 96° C. for 6 h and 86° C. for 16 h. The reaction was diluted with 200 mL of H2O and extracted with Et2O (3×). The extracts were washed with H2O (2×), dried over Na2SO4, filtered, and concentrated. The residue was crystallized from Et2O hexane to yield the titled compound (6.88 g, 78%). LC-MS (ES) m/e 322 [M+H]+.
NaH (60% dispersion in mineral oil, 1.95 g, 48.7 mmol) was washed free of mineral oil with hexane, suspended in 100 mL of DMF stirred, and cooled in an ice bath. A solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-1-pyrrolidinecarboxylate (10.43 g, 32.5 mmol) in 40 mL of DMF was added dropwise over 20 min. The reaction was stirred an additional 40 min, and a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (11.65 g, 48.7 mmol) in 25 mL of DMF was rapidly added. The reaction mixture was stirred for 30 min at 0° C. and 30 min at RT. The mixture was poured into 200 mL of cold aqueous NH4Cl, and extracted with Et2O (3×). The extracts were washed with H2O (2×), dried over NaSO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with 25% EtOAc/hexane) to yield the titled compound (14.28 g, 92%). LC-MS (ES) m/e 480 [M+H]+.
A solution of 1,1-dimethylethyl (3S)-3-((3-chloro-4-cyanophenyl){[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinecarboxylate (14.0 g, 29 mmol) in 16 mL of CH2Cl2 was treated with TFA (15 mL) and stirred for 1.5 h. The reaction mixture was concentrated. The residue was triturated with Et2O and 0.1 mL of MeOH to yield the trifluoroacetate salt as a white solid. The heterogeneous mixture was filtered, washed with Et2O, and dried. The trifluoroacetate salt was dissolved in 20 mL of MeOH and added to a stirred mixture of aqueous K2CO3 and Et2O. The Et2O was separated and the aqueous phase was extracted with Et2O (2×). The combined Et2O extracts were washed with H2O and saturated NaCl, dried over Na2SO4, filtered, and concentrated to yield the titled compound (10.74 g, 98%). LC-MS (ES) m/e 380 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-2-chlorobenzene. LC-MS (ES) m/e 346 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from benzyl bromide. LC-MS (ES) m/e 312 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-2-methylbenzene. LC-MS (ES) m/e 326 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-2-fluorobenzene. LC-MS (ES) m/e 330 [M+H]+.
This compound was made according to general procedure of example 1 (part a) from 4-fluoro-2-trifluoromethylbenzonitrile. LC-MS (ES) m/e 356 [M+H]+.
This compound was made according to general procedure of example 1 (part b) from 1,1-dimethylethyl (3S)-3-[(3-trifluoromethyl-4-cyanophenyl)amino]-1-pyrrolidinecarboxylate. LC-MS (ES) m/e 514 [M+H]+.
This compound was made according to general procedure of example 1 (part c) from 1,1-dimethylethyl (3S)-3-([4-cyano-3-(trifluoromethyl)phenyl]{[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinecarboxylate LC-MS (ES) m/e 414 [M+H]+.
This compound was made according to general procedure of example 1 (part b) from 1-(bromomethyl)-2-chlorobenzene and 1,1-dimethylethyl (3S)-3-([4-cyano-3-(trifluoromethyl)phenyl]{[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinecarboxylate.
LC-MS (ES) m/e 380 [M+H]+.
A solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-1-pyrrolidinecarboxylate (400 mg, 1.25 mmol) and KOAc (400 mg) in 25 mL of MeOH was treated with 5% Pd/C (40 mg) and the mixture was hydrogenated at 1 atmosphere H2 pressure for 25 min. The reaction mixture was filtered through Celite (to remove the catalyst) and the filtrate was concentrated. The residue was dissolved in Et2O, washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was crystallized from a mixture of CH2Cl2 and hexane to yield the titled compound (320 mg, 89%). LC-MS (ES) m/e 288 [M+H]+.
This compound was made according to general procedure of example 1 (part b) from 1,1-dimethylethyl (3S)-3-[4-cyanophenyl)amino]-1-pyrrolidinecarboxylate and 2-trifluoromethylbenzyl bromide. LC-MS (ES) m/e 446 [M+H]+.
This compound was made according to general procedure of example 1 (part c) from 1,1-dimethylethyl (3S)-3-((4-cyanophenyl){[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinecarboxylate. LC-MS (ES) m/c 346 [M+H]+.
A solution of 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile (9.0 g, 24 mmol) in 125 mL of McOH was treated with formaldehyde (10.9 mL of a 37% aqueous solution, 142 mmol). After 30 min, the solution was cooled in an ice bath. NaBH4 (2.0 g, 52 mmol) was slowly added and the reaction stirred for 30 min. Successively added were 200 mL of cold H2O and aqueous NH4Cl until the excess NaBH4 was decomposed. The mixture was extracted with Et2O. The combined extracts were washed with H2O and concentrated. The residue was purified on a short Al2O3 (neutral, Brockman 2.8) column (eluted with Et2O) to yield the titled compound (8.31 g, 88%). LC-MS (ES) m/e 394 [M+H]+.
This compound was made according to general procedure of example 9 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 360 [M+H]+.
This compound was made according to general procedure of example 9 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)-2-(trifluoromethyl)benzonitrile. LC-MS (ES) m/e 428 [M+H]+.
This compound was made according to general procedure of example 9 from 4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}-2-(trifluoromethyl)benzonitrile. LC-MS (ES) m/e 394 [M+H]+.
This compound was made according to general procedures of example 9 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 326 [M+H]+.
This compound was made according to general procedures of example 9 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 340 [M+H]+.
This compound was made according to general procedures of example 9 from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 344 [M+H]+.
This compound was made according to general procedures of example 9 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile. LC-MS (ES) m/e 360 [M+H]+.
A solution of 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile (169 mg, 0.45 mmol) and 2-cyanobenzaldehyde (59 mg, 0.45 mmol) in 10 mL of 1,2-dichloroethane and 1 drop of AcOH was treated with NaBH(OAc)3 (143 mg, 0.68 mmol), and the reaction was stirred 2 h. The reaction mixture was concentrated and the residue was dissolved in a mixture of H2O and Et2O. The organic solution was separated, washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on an Al2O3 column (neutral, Brockman 2.8) (eluted with Et2O) to yield the titled compound (196 mg, 88%). LC-MS (ES) m/e 495 [M+H]+.
This compound was made according to general procedure of example 17 from 4-fluorobenzaldehyde. LC-MS (ES) m/e 488 [M+H]+.
This compound was made according to general procedure of example 17 from 2,3,5-trifluorobenzaldehyde. LC-MS (ES) m/e 524 [M+H]+.
This compound was made according to general procedure of example 17 from 2,5-difluorobenzaldehyde. LC-MS (ES) m/e 506 [M+H]+.
This compound was made according to general procedure of example 17 from pyridine-4-carboxaldehyde-N-oxide. LC-MS (ES) m/e 487 [M+H]+.
This compound was made according to general procedure of example 17 from 2,3-dihydro-1,4-benzodioxin-6-carboxaldehyde. LC-MS (ES) m/e 528 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-methyl-2-thiophenecarbaldehyde. LC-MS (ES) m/e 436.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-thiophenecarbaldehyde. LC-MS (ES) m/e 422.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-methyl-2-thiophenecarbaldehyde. LC-MS (ES) m/e 436.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-pyridinecarbaldehyde. LC-MS (ES) m/e 417.6 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-furancarbaldehyde. LC-MS (ES) m/e 406.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-methyl-2-furancarbaldehyde.
LC-MS (ES) m/e 420.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-(methyloxy)benzaldehyde.
LC-MS (ES) m/e 445.8 [M+H]+.
A solution of 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (180 mg, 0.52 mmol) and 1-methylimidazole-2-carboxaldehyde (58 mg, 0.52 mmol) in 5 mL of EtOH was treated with a solution of KCN (34 mg, 0.52 mmol) in 0.3 mL of H2O and 1.0 N HCl (0.52 mL), and stirred for 16 h. NaBH4 (200 mg) was added and the reaction heated to 50° C. for 15 min. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried over Na2SO4, and concentrated to yield the titled compound (225 mg, 100%). LC-MS (ES) m/e 440 [M+H]+.
This compound was made according to general procedure of example 30 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and imidazole-2-carboxaldehyde. LC-MS (ES) m/c 460 [M+H]+.
This compound was made according to general procedure of example 30 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 2-fluorobenzaldehyde.
LC-MS (ES) m/e 488 [M+H]+.
This compound was made according to general procedure of example 30 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and p-anisaldehyde. LC-MS (ES) m/e 500 [M+H]+.
This compound was made according to general procedure of example 30 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and p-dimethylaminobenzaldehyde. LC-MS (ES) m/e 513 [M+H]+.
This compound was made according to general procedure of example 30 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and cyclopentanone. LC-MS (ES) m/e 448 [M+H]+.
This compound was made according to general procedure of example 30 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and cyclopentanone. LC-MS (ES) m/e 414 [M+H]+.
To a solution of 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (128 mg, 0.37 mmol) and acetone cyanohydrin (32 mg, 0.37 mmol) in 5 mL of EtOH was added 4 Å molecular sieves (crushed, activated, 500 mg). The mixture was stirred at 22° C. for 3 h and 60° C. for 2 h. The reaction mixture was cooled to 22° C. and NaBH4 (100 mg) was added. The reaction mixture was stirred 16 h. The reaction mixture was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on an Al2O3 column (neutral, Brockman 2.8) (eluted with EtOAc) to yield the titled compound (140 mg, 99%). This product was converted to the HCl salt and crystallized from EtOAc, 100 mg. LC-MS (ES) m/e 388 [M+H]+.
This compound was made according to general procedure of example 37 from 4-hydroxy-1-methyl-4-piperidinecarbonitrile. LC-MS (ES) m/e 443 [M+H]+.
This compound was made according to general procedure of example 37 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and acetone cyanohydrin. LC-MS (ES) m/e 422 [M+H]+.
This compound was made according to general procedure of example 37 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and acetone cyanohydrin. LC-MS (ES) m/e 388 [M+H]+.
A solution of 2-chloro-4-{[(2-trifluoromethylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (138 mg, 0.36 mmol) and 3-(bromomethyl)-5-methylisoxazole (64 mg, 0.36 mmol) in 5 mL of acetonitrile was treated with K2CO3 (100 mg, 0.72 mmol), and the stirred mixture was heated to 75° C. for 15 min. The reaction mixture was concentrated, diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried over Na2SO4, and concentrated. The residue was purified on a small Al2O3 (neutral, Brockman 2.8) column (eluted with Et2O) to yield the titled compound (114 mg, 67%). 1H NMR (400 MHz, CDCl3) 7.74 (d, 1H), 7.36-7.48 (m, 3H), 7.18 (d, 1H), 6.76 (d, 1H), 6.46 (m, 1H), 5.92 (s, 1H), 5.14 (d, 1H), 4.74 (d, 1H), 4.56 (m, 1H), 3.67 (d, 1H), 3.55 (d, 1H), 3.02 (m, 1H), 2.79 (m, 1H), 2.57 (m, 1H), 2.48 (m, 1H), 2.38 (m, 1H), 2.33 (s, 3H), 1.82 (m, 1H).
This product was converted to the HCl salt which crystallized from EtOAc/Et2O and to afford 2-chloro-4-({(3S)-1-[(5-methyl-3-isoxazolyl)methyl]-3-pyrrolidinyl}{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile hydrochloride, 90 mg. LC-MS (ES) m/c 475 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-trifluoromethylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-bromomethyl pyridine in 57% yield. LC-MS (ES) m/e 471 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-trifluoromethylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,6-difluorobenzyl bromide. LC-MS (ES) m/e 506 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-trifluoromethylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-(bromomethyl)-1,3-dioxolane. LC-MS (ES) m/e 466 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and benzyl bromide. LC-MS (ES) m/e 436 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-chloromethylpyridine. LC-MS (ES) m/e 437 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-chloromethylpyridine in 21% yield. LC-MS (ES) m/e 437 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-bromomethylpyridine in 39% yield. LC-MS (ES) m/e 437 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-iodo-3,3,3-trifluoropropane in 76% yield. LC-MS (ES) m/e 442 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-bromo-2-methoxyethane in 80% yield. LC-MS (ES) m/e 404 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and bromoacetonitrile in 95% yield.
LC-MS (ES) m/e 385 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and ethyl bromoacetate in 91% yield.
LC-MS (ES) m/e 432 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and ethyl 2-bromo-2-methyl propionate in 15% yield. LC-MS (ES) m/e 460 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-bromoacetamide in 30% yield.
LC-MS (ES) m/e 403 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and α-chloro-N,N-dimethylacetamide in 52% yield. LC-MS (ES) m/e 431 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and chloroacetone. LC-MS (ES) m/e 402 [M+H]+.
This compound was made according to general procedure of example 41 from 4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}-2-(trifluoromethyl)benzonitrile and benzyl bromide in 89% yield. LC-MS (ES) m/e 470 [M+H]+.
This compound was made according to general procedure of example 41 from 4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}-2-(trifluoromethyl)benzonitrile and 3-bromo-2-methyl-1-propene in 74% yield. LC-MS (ES) m/e 434 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)-2-(trifluoromethyl)benzonitrile and ethylbromoacetate in 83% yield. LC-MS (ES) m/e 500 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)-2-(trifluoromethyl)benzonitrile and t-butyl bromoacetate in 77% yield. LC-MS (ES) m/e 528 [M+H]+.
To a mixture of 1,1-dimethylethyl [(3S)-3-([4-cyano-3-(trifluoromethyl)phenyl]{[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinyl]acetate (90 mg, 0.17 mmol) and CH2Cl2 (1 mL), TFA (1 mL) was added. The reaction was stirred for 40 minutes and then concentrated. TFA (1 mL) was then added to the residue and the reaction was stirred for 30 minutes. After concentration the residue was triturated with Et2O to yield the titled compound as a white solid (65 mg, 65%). LC-MS (ES) m/e 472.2 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)-2-(trifluoromethyl)benzonitrile and 1-bromo-2-methoxyethane in 39% yield. LC-MS (ES) m/e 472 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 2-bromomethylpyridine in 65% yield. LC-MS (ES) m/e 437 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 3-bromomethylpyridine in 43% yield. LC-MS (ES) m/e 437 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 4-bromomethylpyridine in 64% yield. LC-MS (ES) m/e 437 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and bromoacetonitrile in 75% yield. LC-MS (ES) m/e 385 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 1-iodo-3,3,3-trifluoroethane in 92% yield. LC-MS (ES) m/e 442 [M+H]+.
This compound was made according to general procedure of example 41 from 4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and ethyl 2-bromo-2-methyl propionate in 28% yield. LC-MS (ES) m/e 460 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and bromoacetonitrile in 92% yield.
LC-MS (ES) m/e 365.4 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-(bromomethyl)-2-methylbenzene in 92% yield. LC-MS (ES) m/e 430.2 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-(bromomethyl)-2-chlorobenzene in 92% yield. LC-MS (ES) m/e 450.4 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-(bromomethyl)-3-chlorobenzene. LC-MS (ES) m/e 450.6 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-(bromomethyl)-3-(methyloxy)benzene. LC-MS (ES) m/e 446.6 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-(bromomethyl)-4-chlorobenzene. LC-MS (ES) m/e 450.4 [M+H]+.
A solution of 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile (270 mg, 0.71 mmol) and t-butyl acrylate (91 mg, 0.71 mmol) in 5 mL of MeOH was treated with 1 drop of 3.87 M NaOMc in MeOH, and the reaction was stirred 72 h. The reaction mixture was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with 15% EtOAc/hexane) to yield the titled compound (200 mg, 56%).
LC-MS (ES) m/e 508 [M+H]+.
A solution of ethyl [(3S)-3-([4-cyano-3-(trifluoromethyl)phenyl]{[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinyl]acetate (170 mg, 0.34 mmol) in 5 mL of Et2O was added to a suspension of LiAlH4 (200 mg) in 20 mL of Et2O at −20° C. After 5 min, the reaction was quenched by the consecutive addition of 0.2 mL of H2O, 0.2 mL of 15% NaOH and 0.6 mL of H2O. After stirring at 22° C. for 15 min, the mixture was filtered and the filtrate concentrated. The residue was purified by column chromatography on a Florisil® column (eluted with 2% MeOH/CH2Cl2) to yield the titled compound (90 mg, 56%). LC-MS (ES) m/e 458 [M+H]1.
A solution of 4-{[(2-chlorophenyl)methyl][(3S)-1-(2-methyl-2-propen-1-yl)-3-pyrrolidinyl]amino}-2-(trifluoromethyl)benzonitrile hydrochloride (105 mg, 0.22 mmol) in 2 mL of EtOH and 2 mL of MeOH was treated with PtO2 and hydrogenated at 1 atmosphere H2 pressure for 15 min. The reaction mixture was filtered (to remove the catalyst) and concentrated. The residue was converted to the free base and purified by column chromatography (eluted with 25% EtOAc/hexane) on an Al2O3 column (neutral, activity 1) to yield the titled compound (43 mg, 41%). LC-MS (ES) m/e 436 [M+H]+.
To a solution of 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (1.8 g, 5.5 mmol) in anhydrous CH2Cl2 was added pyridine (0.90 mL, 11.0 mmol) followed by methanesulfonyl chloride (0.47 mL, 6.0 mmol). The reaction mixture stirred at RT for 2 h. The crude, dark brown mixture was diluted with CH2Cl2 and washed with 1N HCl (3×50 mL). The organic phase was concentrated, and the residue was purified by column chromatography (silica gel 60, EMD Chemicals) (using a gradient of 30-60% EtOAc:hexanes) to yield the titled compound (1.4 g, 61%) as a white solid. LC-MS (ESI) 404.2 [M+H]+.
To a solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-1-pyrrolidinecarboxylate (6.0 g, 18.7 mmol) in CH2Cl2 (40 mL) was added TFA (9.2 mL, 148 mmol). The reaction mixture was stirred for 5 h. Toluene (20 mL) was added to reaction mixture and then the mixture was concentrated. Saturated NaHCO3 (50 mL) was added to the residue and the mixture was extracted with EtOAc (5×100 mL). The organic extracts were dried over MgSO4, filtered, and concentrated to yield the crude product as a red-brown solid (6.8 g). LC-MS (ES) m/e 222.0 [M+H]+.
To a solution of 2-chloro-4-[(3S)-3-pyrrolidinylamino]benzonitrile (2.0 g, 9 mmol) in MeOH (100 mL) was added formaldehyde (0.7 mL, 9 mmol). After reaction mixture was stirred for 1 h, NaBH4 (1.02 g, 27 mmol) was added. After reaction was stirred overnight, it was quenched with H2O (15 mL). The mixture was concentrated to aqueous solution and extracted with CH2Cl2 (4×100 mL). The organic extracts were dried over MgSO4, filtered, concentrated, and purified via column chromatography to yield the titled compound (2.02 g, 75%) as a brown oil. LC-MS (ES) m/e 236.0[M+H]+.
To a solution of 2-chloro-4-{[(3S)-1-methyl-3-pyrrolidinyl]amino}benzonitrile (120 mg, 0.5 mmol) in DMF (2 mL) was added NaH (60% in mineral oil, 93 mg, 1.75 mmol). Reaction was stirred for 1 h and then 4-fluoro-2-(trifluoromethyl)benzyl bromide (129 mg, 0.5 mmol) in DMF (0.5 mL) was added dropwise. Reaction was stirred for 2 h and extracted with EtOAc (12 mL) and H2O (4 mL). The organic layer was washed with saturated NaHCO3 (4×5 mL). The organic layer was then dried with MgSO4, filtered, and concentrated. The residue was purified via column chromatography (eluted with EtOAc and hexane, 1:1) to yield the titled compound (87 mg, 45%) as a brown oil. LC-MS (ES) m/e 413.0 [M+H]+.
This compound was made according to general procedure of example 78 from 3-fluorobenzyl bromide. LC-MS (ES) m/e 344.2 [M+H]+.
This compound was made according to general procedure of example 78 from 3-chlorobenzyl bromide. LC-MS (ES) m/e 360.0 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-2-fluoro-3-methylbenzene. LC-MS (ES) m/e 358.4 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-3-methylbenzene. LC-MS (ES) m/c 341.4 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 412.4 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 428.0 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-4-(trifluoromethyl)benzene. LC-MS (ES) m/e 394.4 [M+H]+.
This compound was made according to general procedure of example 78 from 5-(bromomethyl)-2,1,3-benzothiadiazole. LC-MS (ES) m/c 384 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 413.0 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 394.0 [M+H]+.
This compound was made according to general procedure of example 78 from iodoethane. LC-MS (ES) m/e 264.0 [M+H]+.
This compound was made according to general procedure of example 78 from 3-(bromomethyl)benzonitrile. LC-MS (ES) m/e 351.6 [M+H]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-4-chlorobenzene. LC-MS (ES) m/e 360 [M+H]+.
This compound was made according to general procedure of example 78 from 5-bromo-6-(bromomethyl)-1,3-benzodioxole. LC-MS (ES) m/e 450.0 [M+H]+.
This compound was made according to general procedure of example 78 from 3-bromo-2-methyl-1-propene. LC-MS (ES) m/e 290.0 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)-1-chloro-4-fluorobenzene. LC-MS (ES) m/e 379 [M+H]+.
This compound was made according to general procedure of example 78 from 3-(bromomethyl)-5-methylisoxazole. LC-MS (ES) m/e 331 [M+H]+.
This compound was made according to general procedure of example 78 from 1-bromo-2-(bromomethyl)benzene. LC-MS (ES) m/e 404 [M]+.
This compound was made according to general procedure of example 78 from 4-(bromomethyl)-2-(trifluoromethyl)furan. LC-MS (ES) m/c 384 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)-1-chloro-3-fluorobenzene. LC-MS (ES) m/e 378 [M+H]+.
This compound was made according to general procedure of example 78 from (bromomethyl)cyclohexane. LC-MS (ES) m/e 331.6 [M]+.
This compound was made according to general procedure of example 78 from 1-bromo-3-(bromomethyl)benzene. LC-MS (ES) m/e 404.2 [M]+.
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-2-chloro-3,4-bis(methyloxy)benzene. LC-MS (ES) m/e 422 [M+H]+.
This compound was made according to general procedure of example 78 from 3-bromo-1-propene.
LC-MS (ES) m/e 276 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)naphthalene. LC-MS (ES) m/e 376 [M+H]+.
This compound was made according to general procedure of example 78 from 1-bromobutane.
LC-MS (ES) m/e 292 [M+H]+.
Methanesulfonyl chloride (0.52 g, 4.57 mmol) was added to a solution of 2-chloro-4-[(3S)-3-pyrrolidinylamino]benzonitrile (1.15 g, 3.81 mmol) and TEA (1.53 g, 15.24 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction mixture was stirred at RT for 2 h and then partitioned between H2O and CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with 0% EtOAc in CH2Cl2 grading to 17% EtOAc in CH2Cl2) to yield the titled compound (0.93 g, 81%) as a white foam. LC-MS (ES) m/e 300.4 [M+H]1.
NaH (60% in mineral oil, 0.035 g, 0.875 mmol) was added to a solution of 2-chloro-4-{[(3S)-1-(methylsulfonyl)-3-pyrrolidinyl]amino}benzonitrile (0.068 g, 0.226 mmol) in DMF (3 mL) at 0° C. under a N2 atmosphere. After stirring for 30 min, 1-(bromomethyl)-2-chlorobenzene (0.049 g, 0.238 mmol) was added and the reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with H2O and then partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography (with 0% EtOAc in hexane grading to 45% EtOAc in hexane) to yield the titled compound (0.074 g, 77%) as a light brown solid. LC-MS (ES) m/c 424.4 [M+H]1.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 458.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-bromo-2-(bromomethyl)benzene. LC-MS (ES) m/e 467.4 [M]+.
This compound was made according to general procedure of example 105 from 3-bromo-2-methyl-1-propene. LC-MS (ES) m/e 354.4 [M+H]+.
This compound was made according to general procedure of example 105 from iodoethane. LC-MS (ES) m/e 328.2 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2-fluorobenzene. LC-MS (ES) m/e 408.6 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)thiophene. LC-MS (ES) m/e 396.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)furan. LC-MS (ES) m/e 380.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 458.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-3-methylthiophene. LC-MS (ES) m/e 410.2 [M+H]+.
This compound was made according to general procedure of example 105 from 3-(bromomethyl)furan. LC-MS (ES) m/e 380.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-1-chloro-4-fluorobenzene. LC-MS (ES) m/e 441.6 [M]+.
LiAlH4 (1M in THF, 5.6 mL) was added dropwise to a solution of 5-methyl-2-thiophenecarboxylic acid (0.4 g, 2.8 mmol) in THF (10 mL) at 0° C. under a N2 atmosphere. After stirring for 4 h, saturated K2CO3 was added slowly, and the mixture was filtered through a pad of Celite. The filtrate was partitioned between EtOAc and H2O, and the organic layer was dried over Na2SO4, filtered, concentrated to yield the titled compound (0.165 g, 46%) as a clear oil. 1H-NMR (CDCl3) δ: 2.495 (s, 3H,), 4.761 (s, 2H), 6.636 (m, 1H), 6.818 (d, 1H, J=3.2 Hz).
Methanesulfonyl chloride (0.192 g, 1.68 mmol) was added to a solution of (5-methyl-2-thienyl)methanol (0.165 g, 1.29 mmol) and TEA (0.39 g, 3.86 mmol) in CH2Cl2 (6 mL) at 0° C. The reaction mixture was stirred at RT for 2 h, and then partitioned between H2O and CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to yield the titled compound (0.150 g, 56%) as a brown oil. 1H-NMR (CDCl3) δ: 2.490 (s, 3H), 3.166 (s, 3H), 4.767 (s, 2H), 6.611 (m, 1H), 6.887 (d, 1H, J=1.6 Hz).
The title compound was prepared from (5-methyl-2-thienyl)methyl methanesulfonate using the procedure described in example 105 (part b). LC-MS (ES) m/e 410.2 [M+H]+.
This compound was made according to general procedure of example 117 part b and c from (3-methyl-2-furanyl)methanol. LC-MS (ES) m/e 394.2 [M+H]+.
N-bromosuccinimide (1.11 g, 6.2 mmol) was added to a solution of 2-bromo-5-methylthiophene (1 g, 5.6 mmol) in CCl4 (35 mL), and the reaction mixture was refluxed for 16 h. After cooled down to RT, the mixture was filtered through a pad of Celite, and the filtrate was concentrated to yield the titled compound (1.3 g, 100%) as a light yellow oil. 1H-NMR (CDCl3) δ: 4.664 (s, 2H), 6.898 (m, 2H).
This compound was made according to general procedure of example 78 (part c) from 2-bromo-5-(bromomethyl)thiophene and 2-chloro-4-{[(3S)-1-methyl-3-pyrrolidinyl]amino}benzonitrile using the procedure described in example 78 (part c). LC-MS (ES) m/e 410.4 [M]+.
Pd(dppf)Cl2 with CH2Cl2 (0.01 g, 0.0097 mmol) was added to a suspension of 4-{[(5-bromo-2-thienyl)methyl][(3S)-1-methyl-3-pyrrolidinyl]amino}-2-chlorobenzonitrile) (0.04 g, 0.097 mmol), [6-(methyloxy)-3-pyridinyl]boronic acid (0.015 g, 0.125 mmol, and K2CO3 (0.046 g, 0.33 mmol) in 3:1 dioxane/H2O (2 mL). The reaction mixture was heated in the microwave at 100° C. for 10 min, and then filtered through a pad of Celite. The filtrate was partitioned between H2O and EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (with 0% MeOH in CH2Cl2 grading to 4% MeOH in CH2Cl2) to yield the titled compound (7 mg, 16%) as a brown oil. LC-MS (ES) m/e 439.4 [M+H]+.
PtO2 (83% on carbon, 10 mg) was added to a degassed solution of 2-chloro-4-{(2-methyl-2-propen-1-yl)[(3S)-1-methyl-3-pyrrolidinyl]amino}benzonitrile (0.022 g, 0.076 mmol) and 2 drops of 1M HCl in 1:1 ethanol/MeOH (3 mL). The reaction mixture was stirred at RT for 1 h under a H2 atmosphere (1 atm), and then filtered through a pad of Celite. The filtrate was concentrated, and the residue was partitioned between EtOAc and saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography (with 0% MeOH in CH2Cl2 grading to 8% MeOH in CH2Cl2) to yield the titled compound (0.022 g, 99%) as a yellow oil. LC-MS (ES) m/e 292.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-4-fluoro-1-methylbenzene. LC-MS (ES) m/e 422.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-bromo-2-(bromomethyl)-4,5-bis(methyloxy)benzene. LC-MS (ES) m/e 528.4 [M]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 475.0 [M]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-1,4-dichlorobenzene. LC-MS (ES) m/e 458.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)benzonitrile. LC-MS (ES) m/e 415.6 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 476.2 [M+H]+.
This compound was made according to general procedure of example 105 from (bromomethyl)cyclohexane. LC-MS (ES) m/e 396.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-bromo-3-methylbutane. LC-MS (ES) m/e 370.2 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-1-chloro-3-fluorobenzene. LC-MS (ES) m/e 442.6 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,3-difluorobenzene. LC-MS (ES) m/e 426.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-1-methyl-4-(trifluoromethyl)benzene. LC-MS (ES) m/e 472.6 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-1,4-difluorobenzene. LC-MS (ES) m/e 426.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,4,5-trifluorobenzene. LC-MS (ES) m/e 444.6 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,4-difluorobenzene. LC-MS (ES) m/e 426.2 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-4-chloro-1-(trifluoromethyl)benzene. LC-MS (ES) m/e 492.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-4-fluoro-1-(trifluoromethyl)benzene. LC-MS (ES) m/e 476.4 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 476.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and ethanesulfonyl chloride.
LC-MS (ES) m/e 472.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 2-propanesulfonyl chloride. LC-MS (ES) m/e 486.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride. LC-MS (ES) m/e 518.6 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and benzenesulfonyl chloride. LC-MS (ES) m/e 486.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-methyl-2-thiophenesulfonyl
chloride. LC-MS (ES) m/e 506.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-chlorobenzenesulfonyl chloride. LC-MS (ES) m/e 520.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-chlorobenzenesulfonyl chloride. LC-MS (ES) m/e 520.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-(2-pyridinyl)-2-thiophenesulfonyl chloride. LC-MS (ES) m/e 569.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-propanesulfonyl chloride.
LC-MS (ES) m/e 452.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4,5-dichloro-2-thiophenesulfonyl chloride. LC-MS (ES) m/e 560.0 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-(methyloxy)benzenesulfonyl chloride. LC-MS (ES) m/e 516.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-bromo-2-thiophenesulfonyl chloride. LC-MS (ES) m/e 570.2 [M]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-(methyloxy)benzenesulfonyl chloride. LC-MS (ES) m/e 516.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and trifluoromethanesulfonyl chloride. LC-MS (ES) m/e 478.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-bromo-6-chloro-3-pyridinesulfonyl chloride. LC-MS (ES) m/e 599.2 [M]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and ethanesulfonyl chloride. LC-MS (ES) m/e 438.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride. LC-MS (ES) m/e 504.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-cyanobenzenesulfonyl chloride. LC-MS (ES) m/e 513.6 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and cyclopropanesulfonyl chloride.
LC-MS (ES) m/e 450.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-thiophenesulfonyl chloride.
LC-MS (ES) m/e 492.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-chlorobenzenesulfonyl chloride. LC-MS (ES) m/e 520.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-fluorobenzenesulfonyl chloride. LC-MS (ES) m/e 504.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-fluorobenzenesulfonyl chloride. LC-MS (ES) m/e 504.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-fluorobenzenesulfonyl chloride. LC-MS (ES) m/e 504.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and phenylmethanesulfonyl chloride.
LC-MS (ES) m/e 500.2 [M+H]+.
This compound was made according to general procedure of example 77 from 4-chlorobenzenesulfonyl chloride. LC-MS (ES) m/e 500.6 [M+H]+.
This compound was made according to general procedure of example 77 from 3-fluorobenzenesulfonyl chloride. LC-MS (ES) m/e 484.4 [M+H]+.
This compound was made according to general procedure of example 77 from 5-methyl-2-thiophenesulfonyl chloride. LC-MS (ES) m/e 486.4 [M+H]+.
This compound was made according to general procedure of example 77 from 4-(methyloxy)benzenesulfonyl chloride. LC-MS (ES) m/e 496.4 [M+H]+.
This compound was made according to general procedure of example 77 from phenylmethanesulfonyl chloride. LC-MS (ES) m/e 480.6 [M+H]+.
This compound was made according to general procedure of example 77 from 2-propanesulfonyl chloride. LC-MS (ES) m/e 432.6 [M+H]+.
This compound was made according to general procedure of example 77 from ethanesulfonyl chloride. LC-MS (ES) m/e 418.6 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chlorobenzenesulfonyl chloride. LC-MS (ES) m/e 500.4 [M+H]+.
This compound was made according to general procedure of example 77 from 4-fluorobenzenesulfonyl chloride. LC-MS (ES) m/e 484.2 [M+H]+.
This compound was made according to general procedure of example 77 from 3-(methyloxy)benzenesulfonyl chloride. LC-MS (ES) m/e 496.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-fluorobenzenesulfonyl chloride. LC-MS (ES) m/e 484.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-thiophenesulfonyl chloride. LC-MS (ES) m/e 472.4 [M+H]+.
This compound was made according to general procedure of example 77 from 3-chlorobenzenesulfonyl chloride. LC-MS (ES) m/e 500.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and (3,5-dichlorophenyl)methanesulfonyl chloride. LC-MS (ES) m/e 568.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-(acetylamino)-2-methylbenzenesulfonyl chloride. LC-MS (ES) m/e 557.0 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and (4-methylphenyl)methanesulfonyl chloride. LC-MS (ES) m/e 514.6 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and [3-(trifluoromethyl)phenyl]methanesulfonyl chloride. LC-MS (ES) m/e 568.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate. LC-MS (ES) m/e 550.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and (4-chlorophenyl)methanesulfonyl chloride. LC-MS (ES) m/e 534.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-(4-chlorophenyl)ethanesulfonyl chloride. LC-MS (ES) m/e 548.4 [M+H]+.
This compound was made according to general procedure of example 77 from 1-butanesulfonyl chloride. LC-MS (ES) m/e 446.2 [M+H]+.
This compound was made according to general procedure of example 77 from 1-pentanesulfonyl chloride. LC-MS (ES) m/e 460.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2,2,2-trifluoroethanesulfonyl chloride. LC-MS (ES) m/e 472.4 [M+H]+.
This compound was made according to general procedure of example 77 from 1-propanesulfonyl chloride. LC-MS (ES) m/e 432.6 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and ethanesulfonyl chloride. LC-MS (ES) m/e 422.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-propanesulfonyl chloride. LC-MS (ES) m/e 436.1 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-2,3-difluorobenzene. LC-MS (ES) m/e 348.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2,3-difluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-propanesulfonyl chloride.
LC-MS (ES) m/e 454.2 [M+H]+.
This compound was made according to general procedure of example 190 from ethanesulfonyl chloride. LC-MS (ES) m/e 440.4 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 2-(bromomethyl)-1-chloro-4-fluorobenzene. LC-MS (ES) m/e 364.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2-chloro-5-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and ethanesulfonyl chloride.
LC-MS (ES) m/e 456.4 [M+H]+.
This compound was made according to general procedure of example 192 from 2-propanesulfonyl chloride. LC-MS (ES) m/e 470.2 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 2-(bromomethyl)-4-fluoro-1-methylbenzene. LC-MS (ES) m/e 344.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-propanesulfonyl
chloride. LC-MS (ES) m/e 450.4 [M+H]+.
This compound was made according to general procedure of example 194 from ethanesulfonyl chloride. LC-MS (ES) m/e 436.4 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 2-(bromomethyl)-1,4-dichlorobenzene. LC-MS (ES) m/e 380.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and ethanesulfonyl chloride. LC-MS (ES) m/e 472.2 [M+H]+.
This compound was made according to general procedure of example 196 from 2-propanesulfonyl chloride. LC-MS (ES) m/e 488.0 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-bromo-2-(bromomethyl)benzene. LC-MS (ES) m/e 390.2 [M+H]+.
This compound was made according to general procedure of example 77 from 4-{[(2-bromophenyl)methyl][(3S)-3-pyrrolidinyl]amino}-2-chlorobenzonitrile and 2-propanesulfonyl chloride. LC-MS (ES) m/e 496.4 [M]+.
This compound was made according to general procedure of example 198 from ethanesulfonyl chloride. LC-MS (ES) m/e 482.0 [M]+.
This compound was made according to general procedures of example 1 (part b and c) from 2-(bromomethyl)-1,4-difluorobenzene. LC-MS (ES) m/e 348.2 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-{[(2,5-difluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-propanesulfonyl chloride.
LC-MS (ES) m/e 454.4 [M+H]+.
This compound was made according to general procedure of example 200 from ethanesulfonyl chloride. LC-MS (ES) m/e 440.4 [M+H]+.
To a solution of methyl 4-chloro-3-methylbenzoate (2.22 g, 12 mmol) in CCl4 (16 mL) was added NBS (2.35 g, 13.2 mmol) and AIBN (0.031 g, 0.19 mmol) and the reaction was refluxed for 3 h. After cooled down, the reaction was filtered and the filtrate was washed with H2O, dried over Na2SO4, and concentrated. The solid residue was recrystallized with EtOAc and hexane (1:4) to yield the titled product (0.95 g, 30%) as clear crystals. 1H-NMR (CDCl3) δ: 3.949 (s, 3H), 4.628 (s, 2H,), 7.494 (d, 1H, J=8.4 Hz), 7.942 (d, 1H, J=8.4 Hz), 8.143 (s, 1H).
This compound was made according to general procedure of example 105 from methyl 3-(bromomethyl)-4-chlorobenzoate with the following exception: after working up the reaction mixture was acidified with 1N HCl, extracted with EtOAc, and concentrated. MeOH (10 mL) and concentrated H2SO4 (2 drops) were added to the residue and the reaction was stirred at 65° C. until the esterification completed. Solvent was removed; saturated NaHCO3 was added and the reaction was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated, and purified via column chromatography (cluted with 5% EtOAc in hexane grading to 55% EtOAc in hexane) to yield the titled compound as a white solid. LC-MS (ES) m/e 483.0 [M+H]+.
A mixture of methyl 4-chloro-3-({(3-chloro-4-cyanophenyl)[(3S)-1-(methylsulfonyl)-3-pyrrolidinyl]amino}methyl)benzoate (0.038 g, 0.078 mmol), 2N NaOH (0.5 mL) and THF (3 mL) was stirred at RT for 3 days. Solvent was removed and the reaction was acidified with 1N HCl, extracted with EtOAc, and concentrated. The residue was purified by HPLC to give the product (0.02 g, 54%) as a white solid. LC-MS (ES) m/e 468.4 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)-1,4-dichlorobenzene. LC-MS (ES) m/e 394 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)-1,3-dichlorobenzene. LC-MS (ES) m/e 394.4 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)pyridine. LC-MS (ES) m/e 327.0 [M+H]+.
This compound was made according to general procedure of example 78 from 2-(bromomethyl)-4-fluoro-1-methylbenzene. LC-MS (ES) m/e 358.4 [M+H]+.
This compound was made according to general procedure of example 78 from ethyl bromoacetate.
LC-MS (ES) m/e 322.4 [M+H]+.
PBr3 (0.13 g, 0.5 mmol) was added dropwise to a solution of [2-chloro-3,4-bis(methyloxy)phenyl]methanol (0.404 g, 2 mmol) in Et2O (10 mL) and the reaction was stirred at RT for 2 h. NaHCO3 was added and the reaction was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated to yield the crude product (0.5 g, 94%). 1H-NMR (CDCl3) δ: 3.903 (d, 6H, J=2.8 Hz), 4.619 (s, 2H), 6.831 (d, 1H, J=8.4 Hz), 7.189 (d, 1H, J=8.8 Hz).
This compound was made according to general procedure of example 78 from 1-(bromomethyl)-2-chloro-3,4-bis(methyloxy)benzene. LC-MS (ES) m/e 422.0 [M+H]+.
A mixture of [3,4-bis(methyloxy)phenyl]methanol (0.84 g, 5 mmol), Br2 (0.4 mL) and AcOH (4 mL) was stirred at RT for 1 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and sat. NaHCO3 (5 mL). Layers were separated and the organic layer was dried over MgSO4 and concentrated to yield the product (1.66 g, 100%) as a clear oil. 1H-NMR (CDCl3) δ: 3.891 (d, 6H, J=3.2 Hz), 4.601 (s, 2H), 6.941 (s, 1H), 7.029 (s, 1H).
This compound was made according to general procedure of example 78 from 1-bromo-2-(bromomethyl)-4,5-bis(methyloxy)benzene. LC-MS (ES) m/e 464.2 [M]+.
This compound was prepared using procedure of example 209 (part a) from (6-chloro-1,3-benzodioxol-5-yl)methanol. 1H-NMR (CDCl3) δ: 4.562 (s, 2H), 6.016 (s, 2H), 6.869 (s, 1H), 6.898 (s, 1H).
This compound was made according to general procedure of example 78 from 5-(bromomethyl)-6-chloro-1,3-benzodioxole. LC-MS (ES) m/e 405 [M+H]+.
NaBH(OAc)3 (1.34 g, 6.3 mmol) was added to an ice cold solution of 2-chloro-4-[(3S)-3-pyrrolidinylamino]benzonitrile (1 g, 4.5 mmol), 2-thiophenecarbaldehyde (0.45 mL, 4.95 mmol) and acetic acid (0.308 mL, 5.4 mmol) in CH2Cl2 (30 mL). The reaction was stirred at RT for 3.5 h. Saturated NaHCO3 was added and the reaction was extracted with EtOAc (4×100 mL). The organic extracts were dried over MgSO4 and concentrated. The residue was purified by column chromatography (eluted with EtOAc/hexane) to give the titled product (0.9 g, 63%). LC-MS (ES) m/e 318.2 [M+H]+.
This compound was made according to procedure of example 78 (part c) from 2-chloro-4-{[(3S)-1-(2-thienylmethyl)-3-pyrrolidinyl]amino}benzonitrile and 1-(bromomethyl)-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 476.2 [M+H]+.
This compound was made according to general procedure of example 212 from 1-(bromomethyl)-2-fluorobenzene. LC-MS (ES) m/e 426.4 [M+H]+.
This compound was made according to general procedure of example 212 from 1-bromo-2-(bromomethyl)benzene. LC-MS (ES) m/e 486.4 [M]+.
This compound was made according to general procedure of example 212 from 1-(bromomethyl)-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 476.4 [M+H]+.
This compound was made according to general procedure of example 212 from iodoethane. LC-MS (ES) m/e 346.4 [M+H]+.
This compound was made according to general procedure of example 212 from 3-bromo-2-methyl-1-propene. LC-MS (ES) m/e 372.4 [M+H]+.
This compound was made according to general procedure of example 212 from 1-bromo-2-methylpropane. LC-MS (ES) m/e 374.2 [M+H]+.
This compound was made according to general procedure of example 212 from 1-(bromomethyl)-2-chlorobenzene. LC-MS (ES) m/e 442.4 [M+H]+.
This compound was made according to general procedure of example 212 from (bromomethyl)benzene. LC-MS (ES) m/e 408.4 [M+H]+.
TEA (excess) was added to a solution of [3-(dimethylamino)phenyl]methanol (0.048 g, 0.32 mmol) in benzene (3 mL) with stirring. The reaction was cooled in an ice bath and methanesulfonyl chloride (0.036 g, 0.31 mmol) was added and the reaction solution was stirred at this temperature for 20 min (reaction 1). In reaction flask 2:2-chloro-4-{[(3S)-1-(2-thienylmethyl)-3-pyrrolidinyl]amino}benzonitrile (0.063 g, 0.2 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.035 g, 0.88 mmol) was added and the reaction mixture was stirred for 30 min. To this mixture, the reaction 1 was added to reaction flask 2 and the reaction mixture was stirred at RT for 18 h. Saturated NH4Cl was added and the reaction was extracted with EtOAc, dried over Na2SO4, and concentrated. The residue was purified via column chromatography (eluted with 0% EtOAc in hexane grading to 35% EtOAc in hexane) to give the titled product (0.069 g, 76%) as white foam. LC-MS (ES) m/e 452.6 [M+H]+.
This compound was made according to procedure of example 212 (part a) from 5-methyl-2-furancarbaldehyde. LC-MS (ES) m/e 316.2 [M+H]+.
This compound was made according to procedure of example 78 (part c) from 2-chloro-4-({(3S)-1-[(5-methyl-2-furanyl)methyl]-3-pyrrolidinyl}amino)benzonitrile and 1-(bromomethyl)-2-chlorobenzene. LC-MS (ES) m/e 440.4 [M+H]+.
This compound was made according to general procedure of example 222 from (bromomethyl)benzene. LC-MS (ES) m/e 406.6 [M+H]+.
This compound was made according to general procedure of example 222 from 1-(bromomethyl)-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 474.6 [M+H]+.
This compound was made according to general procedure of example 222 from iodoethane. LC-MS (ES) m/e 344.2 [M+H]+.
This compound was made according to general procedure of example 222 from 3-bromo-2-methyl-1-propene. LC-MS (ES) m/e 370.2 [M+H]+.
This compound was made according to general procedure of example 222 from 1-(bromomethyl)-3-(trifluoromethyl)benzene. LC-MS (ES) m/e 374.4 [M+H]+.
This compound was made according to general procedure of example 222 from 1-bromo-2-(bromomethyl)benzene. LC-MS (ES) m/e 484.2 [M]+.
This compound was made according to general procedure of example 222 from 1-(bromomethyl)-2-fluorobenzene. LC-MS (ES) m/e 424.4 [M+H]+.
This compound was made according to general procedure of example 222 from 5-(bromomethyl)-6-chloro-1,3-benzodioxole. LC-MS (ES) m/e 484.2 [M+H]+.
This compound was made according to procedure of example 212 (part a) from 5-methyl-2-thiophenecarbaldehyde. LC-MS (ES) m/e 332.2 [M+H]+.
This compound was made according to procedure of example 78 (part c) from 2-chloro-4-({(3S)-1-[(5-methyl-2-thienyl)methyl]-3-pyrrolidinyl}amino)benzonitrile and 1-(bromomethyl)-2-chlorobenzene. LC-MS (ES) m/e 456.4 [M+H]+.
This compound was made according to general procedure of example 231 from 1-(bromomethyl)-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 490.6 [M+H]+.
This compound was made according to general procedure of example 231 from 1-bromo-2-methylpropane. LC-MS (ES) m/e 388.4 [M+H]+.
This compound was made according to general procedure of example 231 from 1-bromo-2-(bromomethyl)-4,5-bis(methyloxy)benzene. LC-MS (ES) m/e 560.0 [M]+.
This compound was made according to general procedure of example 231 from 2-(bromomethyl)-1,3-dichlorobenzene. LC-MS (ES) m/e 490.0 [M+H]+.
This compound was made according to general procedure of example 231 from 2-(bromomethyl)-1-chloro-3-fluorobenzene. LC-MS (ES) m/e 474.4 [M+H]+.
This compound was made according to procedure of example 212 (part a) from 3-methyl-2-thiophenecarbaldehyde. LC-MS (ES) m/e 332.2 [M+H]+.
This compound was made according to procedure of example 78 (part c) from 2-chloro-4-({(3S)-1-[(3-methyl-2-thienyl)methyl]-3-pyrrolidinyl}amino)benzonitrile and 1-(bromomethyl)-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 490.6 [M+H]+.
This compound was made according to general procedure of example 237 from 1-(bromomethyl)-2-chlorobenzene. LC-MS (ES) m/e 456.4 [M+H]+.
This compound was made according to general procedure of example 237 from (bromomethyl)benzene. LC-MS (ES) m/e 422.4 [M+H]+.
This compound was made according to general procedure of example 237 from 1-bromo-2-methylpropane. LC-MS (ES) m/c 387.8 [M+H]+.
This compound was made according to general procedure of example 237 from 1-bromo-2-(bromomethyl)-4,5-bis(methyloxy)benzene. LC-MS (ES) m/e 560.4 [M]+.
This compound was made according to general procedure of example 237 from 5-(bromomethyl)-6-chloro-1,3-benzodioxole. LC-MS (ES) m/e 501 [M+H]+.
K2CO3 (1.313 g, 9.50 mmol) was added to a solution of 2-chloro-4-[(3S)-3-pyrrolidinylamino]benzonitrile (0.7 g, 3.17 mmol) in MeCN (20 mL) and the reaction was heated to 55° C. 1,1,1-Trifluoro-3-iodopropane (2.84 g, 12.67 mmol) was added dropwise and the reaction mixture was stirred for 24 h. After cooling, saturated NaHCO3 was added and the reaction was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to yield the product (0.72 g, 72%). LC-MS (ES) m/e 318.2 [M+H]+.
This compound was made according to procedure of example 78 (part c) from 2-chloro-4-{[(3S)-1-(3,3,3-trifluoropropyl)-3-pyrrolidinyl]amino}benzonitrile and 2-(bromomethyl)-1-chloro-3-fluorobenzene. LC-MS (ES) m/e 460.6 [M+H]+.
This compound was made according to general procedure of example 243 from (bromomethyl)benzene. LC-MS (ES) m/e 408.4 [M+H]+.
This compound was made according to general procedure of example 243 from 1-(bromomethyl)-2-methylbenzene. LC-MS (ES) m/e 422.0 [M+H]+.
This compound was made according to general procedure of example 243 from 2-(bromomethyl)-4-fluoro-1-methylbenzene. LC-MS (ES) m/e 440.4 [M+H]+.
This compound was made according to general procedure of example 243 from 1-(bromomethyl)-2-(trifluoromethyl)benzene. LC-MS (ES) m/e 476.4 [M+H]+.
This compound was made according to general procedure of example 243 from 1-bromo-2-(bromomethyl)benzene. LC-MS (ES) m/e 486.0 [M]+.
This compound was made according to general procedure of example 243 from iodoethane. LC-MS (ES) m/e 346.0 [M+H]+.
This compound was made according to general procedure of example 243 from 1-bromo-2-methylpropane. LC-MS (ES) m/c 374.2 [M+H]+.
This compound was made according to general procedure of example 243 from 1-(bromomethyl)-2-fluorobenzene. LC-MS (ES) m/e 426.2 [M+H]+.
This compound was made according to general procedure of example 243 from 1-bromo-2-(bromomethyl)-4,5-bis(methyloxy)benzene. LC-MS (ES) m/e 548.0 [M+H]+.
This compound was made according to general procedure of example 243 from 5-(bromomethyl)-6-chloro-1,3-benzodioxole. LC-MS (ES) m/e 486.4 [M+H]+.
This compound was prepared according to procedure of example 8 (part a) from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-1-methyl-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/c 306.4 [M+H]+.
This compound was prepared according to procedure of example 8 (part a) from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-1-methyl-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 310.0 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-formylbenzoic acid. LC-MS (ES) m/e 460.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-formylbenzoic acid. LC-MS (ES) m/e 460.6 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and tetrahydro-3-furancarbaldehyde.
LC-MS (ES) m/e 410.6 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarbaldehyde. LC-MS (ES) m/e 450.6 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and hydroxyacetaldehyde. LC-MS (ES) m/e 370.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-hydroxybutanal. LC-MS (ES) m/e 398.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and acetaldehyde. LC-MS (ES) m/e 354.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,4-dimethyl-1,3-thiazole-5-carbaldehyde. LC-MS (ES) m/e 452.0 [M+H]+.
This compound was made according to general procedure of example 17 from 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarbaldehyde. LC-MS (ES) m/e 504.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 4-formyl-3-hydroxybenzoic acid. LC-MS (ES) m/e 476.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde. LC-MS (ES) m/e 435.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1,3-dimethyl-1H-pyrazole-5-carbaldehyde. LC-MS (ES) m/e 434.0 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarbaldehyde. LC-MS (ES) m/e 470.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1H-imidazole-4-carbaldehyde.
LC-MS (ES) m/e 406.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarbaldehyde. LC-MS (ES) m/e 453.8 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-formylbenzoic acid. LC-MS (ES) m/e 460.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1H-pyrazole-4-carbaldehyde.
LC-MS (ES) m/e 406.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 5-formyl-2-hydroxybenzoic acid. LC-MS (ES) m/c 476.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and methyl 3-formyl-4-nitrobenzoate. LC-MS (ES) m/e 519.2 [M+H]+.
This compound was made according to general procedure of example 17 from 1-methyl-1H-pyrazole-5-carbaldehyde. LC-MS (ES) m/e 474.6 [M+H]+.
This compound was made according to general procedure of example 17 from 2-pyrazinecarbaldehyde. LC-MS (ES) m/e 472.4 [M+H]+.
This compound was made according to general procedure of example 17 from 5-pyrimidinecarbaldehyde. LC-MS (ES) m/e 472.6 [M+H]+.
This compound was made according to general procedure of example 17 from 1-methyl-1H-pyrazole-4-carbaldehyde. LC-MS (ES) m/e 474.2 [M+H]+.
This compound was made according to general procedure of example 17 from 2,2-dimethylpropanal. LC-MS (ES) m/e 450.4 [M+H]+.
This compound was made according to general procedure of example 17 from methyl 3-formylbenzoate. LC-MS (ES) m/e 528.4 [M+H]+.
This compound was made according to general procedure of example 17 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and methyl 3-formylbenzoate. LC-MS (ES) m/e 416.2 [M+H]+.
This compound was made according to general procedure of example 41 from 2-bromo-1,1,1-trifluoroethane. LC-MS (ES) m/e 462.4 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-chlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1,1-dimethylethyl bromoacetate.
LC-MS (ES) m/e 460.4 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-bromo-1-propanol. LC-MS (ES) m/e 384.2 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-bromopropanenitrile. LC-MS (ES) m/e 379.2 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-(2-bromoethyl)-1,3-dioxolane.
LC-MS (ES) m/e 426.4 [M+H]+.
This compound was made according to general procedure of example 41 from 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3-bromopropanamide. LC-MS (ES) m/e 397 [M+H]+.
A mixture of methyl 3-{[(3S)-3-((3-chloro-4-cyanophenyl){[2-(trifluoromethyl)phenyl]methyl}amino)-1-pyrrolidinyl]methyl}benzoate (0.04 g, 0.08 mmol), EtOH (2 mL), H2O (0.5 mL) and 1N NaOH (0.25 mL) was heated with stirring at 55° C. for 2 h. The reaction was cooled and diluted with H2O (5 mL) and acidified to pH˜5 with 1N HCl. The white solid precipitate was filtered, washed with H2O, and dried to give the product (0.033 g, 85%).
LC-MS (ES) m/e 514.6 [M+H]+.
A mixture of 3,4-dichloroaniline (0.175 g, 1.1 mmol), 1,1-dimethylethyl 3-oxo-1-pyrrolidinecarboxylate (0.1 g, 0.54 mmol) and NaBH3CN (0.134 g, 2.16 mmol) in DMF was stirred in a microwave synthesizer at 70° C. for 30 min. The reaction was partitioned between H2O and EtOAc and the organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography to give the product. LC-MS (ES) m/e 275.2 [M−56]+.
This compound was prepared according to procedure of example 1 part b and c from 1,1-dimethylethyl 3-[(3,4-dichlorophenyl)amino]-1-pyrrolidinecarboxylate and 1-(bromomethyl)-2-methylbenzene. LC-MS (ES) m/e 335.2 [M+H]+.
This compound was made according to general procedure of example 9 from N-(3,4-dichlorophenyl)-N-[(2-methylphenyl)methyl]-3-pyrrolidinamine. LC-MS (ES) m/e 349 [M+H]+.
This compound was made according to procedure of example 77 from N-(3,4-dichlorophenyl)-N-[(2-methylphenyl)methyl]-3-pyrrolidinamine. LC-MS (ES) m/e 413.0 [M+H]+.
This compound was made according to procedure of example 289 part a from 3-chloro-4-(methyloxy)aniline. LC-MS (ES) m/c 326.4 [M+H]+.
This compound was made according to procedure of example 1 (part b and c) from 1,1-dimethylethyl 3-{[3-chloro-4-(methyloxy)phenyl]amino}-1-pyrrolidinecarboxylate and 1-(bromomethyl)-2-methylbenzene. LC-MS (ES) m/c 331.4 [M+H]+.
This compound was made according to procedure of example 77 from N-[3-chloro-4-(methyloxy)phenyl]-N-[(2-methylphenyl)methyl]-3-pyrrolidinamine. LC-MS (ES) m/e 409.6 [M+H]+.
1,1-Dimethylethyl (3S)-3-amino-1-pyrrolidinecarboxylate (0.534 g, 2.87 mmol) was added to an ice cold suspension of NaH (60% in mineral oil, 0.384 g, 9.6 mmol) in DMF. After stirring for 10 min, 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (0.5 g, 2.4 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with H2O and then partitioned between H2O and EtOAc. The organic layer was dried over MgSO4, concentrated, and purified via HPLC to give the product. LC-MS (ES) m/e 376.6 [M+H]+.
This compound was made according to procedure of example 1 (part b and c) from 1,1-dimethylethyl (3S)-3-{[4-nitro-3-(trifluoromethyl)phenyl]amino}-1-pyrrolidinecarboxylate and 1-(bromomethyl)-2-methylbenzene. LC-MS (ES) m/e 380.6 [M+H]+.
This compound was made according to procedure of example 77 from N-[3-chloro-4-(methyloxy)phenyl]-N-[(2-methylphenyl)methyl]-3-pyrrolidinamine. LC-MS (ES) m/e 458.2 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-4-chloro-1-fluorobenzene. LC-MS (ES) m/e 442.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,4-dichloro-5-fluorobenzene. LC-MS (ES) m/e 476.0 [M+H]+.
This compound was made according to general procedure of example 105 from 2-(bromomethyl)-3-chloro-1,4-difluorobenzene. LC-MS (ES) m/e 460.1 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,3-difluoro-4-methylbenzene. LC-MS (ES) m/e 440.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,3-difluorobenzene. LC-MS (ES) m/e 426.2 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-3-chloro-2-fluorobenzene. LC-MS (ES) m/e 442.0 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzene. LC-MS (ES) m/e 510.4 [M+H]+.
This compound was made according to general procedure of example 105 from 1-(bromomethyl)-2,4-dichlorobenzene. LC-MS (ES) m/e 458.0 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-4-chloro-2-methylbenzene and used directly in the next step.
This compound was made according to general procedures of example 77 from 2-chloro-4-{[(4-chloro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 438.4 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-2,3,4-trifluorobenzene and used directly in the next step.
This compound was made according to general procedures of example 77 from 2-chloro-4-{(3S)-3-pyrrolidinyl[(2,3,4-trifluorophenyl)methyl]amino}benzonitrile. LC-MS (ES) m/e 444.4 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 2-(bromomethyl)-1,3,5-trichlorobenzene and used directly in the next step.
This compound was made according to general procedures of example 77 from 2-chloro-4-{(3S)-3-pyrrolidinyl[(2,4,6-trichlorophenyl)methyl]amino}benzonitrile. LC-MS (ES) m/e 492.2 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from 1-(bromomethyl)-2,3,5-trifluorobenzene and used directly in the next step.
This compound was made according to general procedures of example 77 from 2-chloro-4-{(3S)-3-pyrrolidinyl[(2,3,5-trifluorophenyl)methyl]amino}benzonitrile. LC-MS (ES) m/e 444.2 [M+H]+.
2-chloro-4-{[(2-chloro-5-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (0.081 g, 0.22 mmol), phenylmethanesulfonyl chloride (0.106 g, 0.56 mmol), DIEA (0.086 g, 0.67 mmol) in CH2Cl2 (3 mL) were stirred at RT for 18 h. The reaction was concentrated and purified via column chromatography (eluted with 0% EtOAc in hexane grading to 80% EtOAc in hexane) to give the product (0.048 g, 42%) as a white powder. LC-MS (ES) m/e 518.3 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from (bromomethyl)cyclohexane. LC-MS (ES) m/e 318.4 [M+H]+.
This compound was made according to general procedures of example 305 from 2-chloro-4-{(cyclohexylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-propanesulfonyl chloride. LC-MS (ES) m/e 424.3 [M+H]+.
This compound was made according to general procedures of example 306 from 2-propanesulfonyl chloride. LC-MS (ES) m/e 424.3 [M+H]+.
This compound was made according to general procedures of example 306 from ethanesulfonyl chloride. LC-MS (ES) m/e 390.4 [M+H]+.
This compound was made according to general procedures of example 1 (part b and c) from (bromomethyl)cyclobutane. LC-MS (ES) m/e 290.0 [M+H]+.
A solution of 2-chloro-4-{(cyclobutylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile (0.039 g, 0.135 mmol) and DIEA (0.052 g, 0.405 mmol) in DMF (1 mL) was added to cyclohexylmethanesulfonyl chloride (0.053 g, 0.27 mmol) and the reaction was stirred at RT for 18 h. MeOH (1 mL) was added and the reaction was diluted with H2O, and extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by HPLC (40 mL/min, A: acetonitrile, B: water, A: 15 to 100% over 25 min) to give the product (0.033 g, 54%) as a brown solid. LC-MS (ES) m/e 450.3 [M+H]+.
This compound was made according to general procedure of example 309 from 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/e 450.4 [M+H]+.
This compound was made according to general procedure of example 309 (part b) from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and chloromethanesulfonyl chloride. LC-MS (ES) m/e 442.4 [M+H]+.
This compound was made according to general procedure of example 309 (part b) from 2-chloro-4-{[(2-fluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,2,2-trifluoroethanesulfonyl chloride except: after adding MeOH, the reaction was filtered and purified.
LC-MS (ES) m/e 476.1 [M+H]+.
This compound was made according to general procedure of example 312 from phenylmethanesulfonyl chloride. LC-MS (ES) m/e 484.1 [M+H]+.
This compound was made according to general procedure of example 312 from cyclopropanesulfonyl chloride. LC-MS (ES) m/e 434.0 [M+H]+.
This compound was made according to general procedure of example 312 from 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/e 490.1 [M+H]+.
This compound was made according to general procedure of example 312 from 1-butanesulfonyl chloride. LC-MS (ES) m/e 450.1 [M+H]+.
This compound was made according to general procedure of example 312 from 1-propanesulfonyl chloride. LC-MS (ES) m/e 436.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(cyclohexylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and phenylmethanesulfonyl chloride.
LC-MS (ES) m/e 472.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(cyclohexylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and cyclopropanesulfonyl chloride.
LC-MS (ES) m/e 422.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(cyclohexylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,2,2-trifluoroethanesulfonyl chloride. LC-MS (ES) m/e 464.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(cyclohexylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/c 478.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(cyclohexylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-butanesulfonyl chloride. LC-MS (ES) m/e 438.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and phenylmethanesulfonyl chloride. LC-MS (ES) m/e 534.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/e 540.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 2,2,2-trifluoroethanesulfonyl chloride. LC-MS (ES) m/e 526.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and cyclopropanesulfonyl chloride. LC-MS (ES) m/e 484.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 1-propanesulfonyl chloride. LC-MS (ES) m/e 484.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 1-butanesulfonyl chloride.
LC-MS (ES) m/e 500.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-butanesulfonyl chloride. LC-MS (ES) m/e 432.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and ethanesulfonyl chloride. LC-MS (ES) m/e 404.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and cyclopropanesulfonyl chloride. LC-MS (ES) m/e 416.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/e 472.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and phenylmethanesulfonyl chloride. LC-MS (ES) m/c 466.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 2-propanesulfonyl chloride. LC-MS (ES) m/e 418.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,2,2-trifluoroethanesulfonyl chloride.
LC-MS (ES) m/e 458.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{(phenylmethyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-propanesulfonyl chloride. LC-MS (ES) m/e 418.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and cyclopropanesulfonyl chloride.
LC-MS (ES) m/e 486.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-propanesulfonyl chloride.
LC-MS (ES) m/e 486.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and phenylmethanesulfonyl chloride. LC-MS (ES) m/e 534.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-butanesulfonyl chloride.
LC-MS (ES) m/e 500.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,2,2-trifluoroethanesulfonyl chloride. LC-MS (ES) m/e 526.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/e 540.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-difluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and cyclopropanesulfonyl chloride.
LC-MS (ES) m/e 452.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-difluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-butanesulfonyl chloride.
LC-MS (ES) m/e 468.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(2,5-difluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-propanesulfonyl chloride.
LC-MS (ES) m/e 454.0 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 2,2,2-trifluoroethanesulfonyl chloride. LC-MS (ES) m/e 490.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 3,3,3-trifluoro-1-propanesulfonyl chloride. LC-MS (ES) m/e 504.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and cyclopropanesulfonyl chloride. LC-MS (ES) m/e 448.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and 1-propanesulfonyl chloride. LC-MS (ES) m/e 450.1 [M+H]+.
This compound was made according to general procedure of example 312 from 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile and phenylmethanesulfonyl chloride. LC-MS (ES) m/e 498.1 [M+H]+.
This compound was made according to general procedure of example 77 from 2-pyridinesulfonyl chloride. LC-MS (ES) m/e 467.4 [M+H]+.
This compound was made according to general procedure of example 77 from 2-chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile and 2-pyridinesulfonyl chloride. LC-MS (ES) m/e 521.4 [M+H]+.
This compound was made according to procedure of example 121 from 2-chloro-4-{(2-methyl-2-propen-1-yl)[(3S)-1-(methylsulfonyl)-3-pyrrolidinyl]amino}benzonitrile. LC-MS (ES) m/e 356.4[M+H]+.
Filing Document | Filing Date | Country | Kind | 371c Date |
---|---|---|---|---|
PCT/US06/61317 | 11/29/2006 | WO | 00 | 5/30/2008 |
Number | Date | Country | |
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60740965 | Nov 2005 | US |