WO2004082682A1 - Amino cyclobutylamide modulators of chemokine receptor activity - Google Patents

Amino cyclobutylamide modulators of chemokine receptor activity Download PDF

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Publication number
WO2004082682A1
WO2004082682A1 PCT/US2004/007792 US2004007792W WO2004082682A1 WO 2004082682 A1 WO2004082682 A1 WO 2004082682A1 US 2004007792 W US2004007792 W US 2004007792W WO 2004082682 A1 WO2004082682 A1 WO 2004082682A1
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hydroxy
6alkyl
3alkyl
substituents
fluoro
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PCT/US2004/007792
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French (fr)
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Richard Jiao
Lihu Yang
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Merck & Co. Inc.
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Priority to EP04720791A priority Critical patent/EP1617841A4/en
Priority to US10/549,739 priority patent/US7553841B2/en
Priority to JP2006507176A priority patent/JP2006520783A/en
Priority to CA002519220A priority patent/CA2519220A1/en
Priority to AU2004222336A priority patent/AU2004222336B2/en
Publication of WO2004082682A1 publication Critical patent/WO2004082682A1/en

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    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • chemokines are a family of small (70-120 amino acids), proinflammatory cytokines, with potent chemotactic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and
  • ⁇ -chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils
  • ⁇ -chemokines such as RANTES, MIP- 1 , MIP- 1 ⁇ , monocyte chemotactic protein- 1 (MCP- 1 ), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, monocytes, T-cells, eosinophils and basophils (Deng, et al., Nature. 381, 661-666 (1996)).
  • the chemokines are secreted by a wide variety of cell types and bind to specific G-protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. Sci, 15, 159-165 (1994)) present on leukocytes and other cells. These chemokine receptors form a sub-family of GPCRs, which, at present, consists of fifteen characterized members and a number of orphans. Unlike receptors for promiscuous chemoattractants such as C5a, fMLP, PAF, and LTB4, chemokine receptors are more selectively expressed on subsets of leukocytes. Thus, generation of specific chemokines provides a mechanism for recruitment of particular leukocyte subsets.
  • GPCRs G-protein coupled receptors
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • CCR-1 or "CKR-1" or "CC-CKR-1” [M-P-l ⁇ , MEP-l ⁇ , MCP-3, RANTES] (Ben-Barruch, et al., J. Biol.
  • the ⁇ - chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted”) among other chemokines.
  • Chemokine receptors such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • Humans who are homozygous for the 32- basepair deletion in the CCR-5 gene appear to have less susceptibility to rheumatoid arthritis (Gomez, et al. Arthritis & Rheumatism, 42, 989-992 (1999)).
  • chemokines are potent chemoattractants for monocytes and macrophages.
  • MCP-1 monocyte chemoattractant protein- 1
  • CCR2 primary receptor 2
  • MCP-1 is produced in a variety of cell types in response to inflammatory stimuli in various species, including rodents and humans, and stimulates chemotaxis in monocytes and a subset of lymphocytes. In particular, MCP-1 production correlates with monocyte and macrophage infiltration at inflammatory sites.
  • agents which modulate chemokine receptors such as the CCR-2 receptor would be useful in such disorders and diseases.
  • the recruitment of monocytes to inflammatory lesions in the vascular wall is a major component of the pathogenesis of atherogenic plaque formation.
  • MCP-1 is produced and secreted by endothelial cells and intimal smooth muscle cells after injury to the vascular wall in hypercholesterolemic conditions.
  • Monocytes recruited to the site of injury infiltrate the vascular wall and differentiate to foam cells in response to the released MCP-1.
  • CCR2 antagonists may inhibit atherosclerotic lesion formation and pathological progression by impairing monocyte recruitment and differentiation in the arterial wall.
  • the present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
  • the present invention is directed to compounds of formula I and of formula II:
  • X is selected from O, N, S, SO2, or C.
  • Y is selected from:
  • Rl 1 is independently selected from: hydroxy, hydrogen,
  • Rl2 is selected from: hydrogen, C ⁇ _ alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, Ci-3alkyl, Ci-3alkoxy, -CO2H, -CO2-C1-6 alkyl, and triflu
  • Z is independently selected from C or N, where at most two of the Z are N.
  • R 1 is selected from: hydrogen, -C ⁇ _6alkyl, -Crj-6alkyl-0-Ci-6alkyl, -C()-6alkyl-S-Ci-6alkyl, -(C ⁇ -6alkyl) ⁇ (C3-7cycloalkyl)-(C ⁇ -6alkyl), hydroxy, heterocycle, -CN, -NR 12 Rl2 -NR12C0R 13 , -NRl2S02R 14 , -COR 11 , -CONR12R12, and phenyl; the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
  • R2 is selected from:
  • R3 is selected from:
  • R 4 is selected from:
  • R5 is selected from: (a) Ci- ⁇ alkyl, where alkyl may be unsubstituted or substituted with
  • (k) phenyl which may be unsubstituted or substituted with one or more substituents selected from: halo, trifluoromethyl, Ci-
  • R6 is selected from:
  • R7 is selected from: hydrogen, (C()-6alkyl)-phenyl, (C ⁇ -6alkyl)-heterocycle, (C ⁇ -6alkyl)-C3_
  • R7 and R ⁇ may be joined together to form a ring which is selected from:
  • R ⁇ and R ⁇ or R ⁇ and RtO may be joined together to form a ring which is phenyl or heterocycle, wherein the ring is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
  • R9 and R 1 ⁇ are independently selected from: (a) hydrogen,
  • R 1 ⁇ is selected from:
  • Ci- ⁇ alkyl which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, -CO2H, -C ⁇ 2Ci-6alkyl, and -O-C1- 3alkyl;
  • R 1 ⁇ is selected from:
  • Ci-6alkyl where alkyl may be unsubstituted or substituted with
  • substituents where the substituents are selected from: fluoro, Ci-3alkoxy, hydroxy, -COR 11 ,
  • R 1 ⁇ is selected from:
  • substituents where the substituents are selected from: fluoro, C ⁇ _3alkoxy, hydroxy, -COR 11 ,
  • alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are selected from: fluoro, C ⁇ _3alkoxy, hydroxy, -COR 11 , or R 1 ⁇ and R 1 ⁇ may be joined together by a Ci-4alkyl chain or a C ⁇ -3alkyl-0-C ⁇ -3alkyl chain to form a 3-6 membered ring;
  • R 1 ⁇ is selected from:
  • Ci-6alkyl where alkyl may be unsubstituted or substituted with
  • alkyl may be unsubstituted or substituted with 1-6 fluoro, or R 1 ⁇ and R 1 ⁇ may be joined together by a C2-3alkyl chain to form a 5-6 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, -COR 11 , Ci_3alkyl, and Ci-3alkoxy, or R ⁇ and R 1 ⁇ may be joined together by a Ci-2alkyl-0-Ci-2alkyl chain to form a 6-8 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, -COR 11 , Ci-3alkyl, and Ci-3alkoxy, or R 1 ⁇ and R ⁇ may be joined together by a -0-C ⁇
  • R ⁇ is selected from:
  • Ci- ⁇ alkyl which may be substituted or unsubstituted with 1-6 of the following substituents: -COR 1 1, hydroxy, fluoro, chloro, -0-Ci-3alkyl; or
  • R2 and R!9 can also be joined together to form a heterocycle ring with a linker selected from the following list (with the left side of the linker being bonded to the amide nitrogen at R!9):
  • R28 is selected from selected from:
  • R28 is connected to the ring via a double bond (in which case the other R28 at the same position is nothing, and where R29 is selected from: (a) hydrogen,
  • C ⁇ _6alkyl which may be substituted or unsubstituted with 1-6 of the following substituents: -COR 1 1, hydroxy, fluoro, chloro, -0-Ci-3alkyl;
  • n is selected from 1 or 2;
  • the dashed line represents a single or a double bond
  • a further embodiment of the present invention includes compounds of formula la.
  • a further embodiment of the present invention includes compounds of formula Hb.
  • Rl, R3, R5, R10 J and Z are described above, and R23 and R24 are independently selected from: (a) hydrogen,
  • Rl, R3, R5, R10 ? R23, and R24 are described above, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • X is C, O or N.
  • X is C.
  • Y is -CH2- or -O-
  • Z is C.
  • R 1 is selected from: hydrogen, phenyl, heterocycle, -Ci-6alkyl, -C ⁇ -6alkyl-0-Ci-6alkyl, and -(Co-6alkyl)-(C3-7cycloalkyl)-(Co-6alkyl), where the alkyl, phenyl, heterocycle, and the cycloalkyl are unsubsti toted or substituted with 1-7 substituents where the substituents are independently selected from:
  • R is selected from:
  • R 1 is selected from: (a) hydrogen, (b) Ci-6alkyl, which may be unsubstituted or substituted with 1-6 substituents independently selected from: fluoro and hydroxy
  • R 1 is selected from:
  • R2 is hydrogen
  • R3 is nothing.
  • R is selected from:
  • R3 is selected from:
  • R 4 is hydrogen
  • R5 is selected from: (a) C ⁇ _6alkyl substituted with 1-6 fluoro, (b) -0-Ci-6alkyl substituted with 1-6 fluoro,
  • R ⁇ is selected from:
  • R ⁇ is trifluoromethyl
  • R ⁇ is hydrogen
  • R7 is phenyl, heterocycle, C3-7cycloalkyl
  • phenyl, heterocycle, C3_7cycloalkyl, and Ci-6alkyl is unsubstituted or substituted with 1-5 substitoents where the substituents are independently selected from:
  • R ⁇ is phenyl, heterocycle, Ci-4alkyl, -COR 1 1, and -CONH-V-COR 1 1;
  • V is selected from Ci ⁇ 6alkyl or phenyl; and the phenyl, heterocycle, and C ⁇ _4alkyl is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: (a) halo,
  • X is C, R ⁇ is hydrogen
  • R9 is hydrogem
  • R 1 ⁇ is selected from: (a) hydrogen, (b) hydroxy,
  • R ⁇ is hydrogen or methyl.
  • R 1 ⁇ is selected from:
  • Ci-3alkyl which is unsubstituted or substituted with 1-6 fluoro
  • R ⁇ is selected from:
  • R 1 is hydrogen
  • R 1 ⁇ is selected from:
  • R 1 ⁇ is hydrogen
  • R 1 ⁇ and R 1 ⁇ are joined together by a -CH2CH2- chain or a -CH2CH2CH2- chain to form a cyclopentyl ring or a cyclohexyl ring.
  • R 5 is hydrogen.
  • R26 is oxygen and connected via a double bond.
  • n 1.
  • Representative compounds of the present invention include those presented in the Examples and pharmaceutically acceptable salts and individual diastereomers thereof.
  • the compounds of the instant invention have at least two asymmetric centers at the 1- and 3-positions of the cyclobutyl ring. Additional asymmetiic centers may be present depending upon the natore of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention.
  • the absolute configurations of selected compounds of this orientation, with substituents on the cyclopentyl ring (amide and amine units), are as depicted below:
  • Keto-acid 1-1 (the preparation of which is described in Scheme 2) can first be protected as the corresponding ester, where R27 represents an alkyl such as methyl, ethyl, tert-butyl or benzyl which serves as a protecting group (Greene, T; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991).
  • Reductive amination of 1-2 with an amine preferably of the from 1-3 (a preparation of which is depicted in Scheme 3) in the presence of a reducing agent such as sodium cyanoborhydride or sodium triacetoxyborohydride gives amino-ester 1-4.
  • ester 1-4 Conversion of ester 1-4 to the carboxylic acid 1-5 can be achieved by a number of conditions depending on the nature of the ester.
  • methyl or ethyl esters can be readily saponified with sodium hydroxide, or lithium hydroxide; tert- butyl ester can be removed by treatment with TFA.
  • Coupling of the acid 1-5 with amine 1-6 (a preparation of which is described in Scheme 4), to give chemokine modulators of the form 1-7, can be accomplished by the standard amide bond formation conditions using a coupling reagent such as DCC, EDC and a catalyst such as DMAP, HOBT or HO AT.
  • Alternativly 1-1 can be directly coupled to amine 1-6 to give the keto-amide 1-8.
  • Reductive amination with amine 1-3 in the presence of a borohydride such as sodium triacetoxyborohydride or sodium cyanoborohydride then provides the chemokine modulator 1-7.
  • Scheme 1A depicts the preparation of chemokine modulators of the form 1-14.
  • Intermediate 2-2a (described in Scheme 2) is first reduced to the primary amine 1-9 by catalytic hydrogenation using Raney nickel. Protection of the amine with the appropriate protecting group, such as a tert-butylcarbamate, by treatment with di-tert- butyl dicarbonate followed by reductive amination with amine 1-3 gives intermediate 1-11. Removal of the protecting group, with for example HCl in dioxane or TFA for the boc protected amine gives the free amine 1-12. Acylation of the amine with an acid chloride (1-13) gives the chemokine modulator 1-14. Alternatively the amine can be coupled (as described in Scheme 1) to an appropriate benzoic acid (not shown) to give similar amides 1-14.
  • SCHEME 2 Scheme 2
  • the keto cyclobutanoic acid (1-1) can be readily synthesized from commercially available materials.
  • the initial protected intermediates of the form 2-2 can be made by a double alkylation reaction of an active ester (2- lb) or nitrile (2- la) with 1,3-dibromo 2,2-dimethoxypropane, using a base such as sodium hydride. Removal of the dimethyl acetal and the hydrolysis of the ester or nitrile can be accomplished under acidic conditions in one reaction step to give intermediate 1-1.
  • Amines 1-3 were obtained from various sources. Some were commercially available, some were known from the literature and could be prepared according to published procedures, and some were prepared as described herein. Since their structures and the methods for their preparation are diverse, only one Scheme will be outlined in this section; individual syntheses of amines 1-3 can be found in the Experimental Section.
  • Scheme 3 shows one method for the synthesis of 4-aryl substitoted piperidines as well as 4-aryl-3-alkyl-piperidines.
  • Enol triflate 3-1 (prepared according to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995.) could be coupled to boronic acids 3-2 as described by Wustrow and Wise.
  • Hydrogenation of the olefin in 4-3 could be achieved using hydrogen in the presence of a catalyst such as Pd(OH)2/C.
  • Oxidation of 3-4 using Ru(IV)oxide hydrate and sodium periodate leads to Boc-lactam 3-5.
  • Alkylation with an alkyl halide in the presence of a base such as LDA gives 3-6, with the trans product being predominant.
  • Removal of the Boc protecting group could be achieved using standard acidic conditions, such as HCl in dioxane or TFA/DCM.
  • Reduction of the lactam 3-7 with, for example borane provides 1-3.2.
  • intermediate 3-4 can itself be deprotected under acidic conditions to afford piperidine 1-3.1.
  • Amines of the form 1-6 are synthesized in a variety of ways.
  • An example of such a synthesis is depicted in Scheme 4.
  • the reduction of the nitrile in the presence of an aromatic halide to the corresponding amine can be successfully accomplished e.g. with borane in THF.
  • Step B To a cooled (0 °C) solution of ethanolamine (41.8 g, 0.685 mol) in water (90 mL) was added neat (R)-propylene oxide (4.97 g, 85.6 mmol), dropwise. After 1 h at 0 °C the reaction was allowed to rise to room temperature and stirred overnight. " The reaction mixture was concentrated at -80 °C in vacuo to remove the water and most of the ethanolamine, to give 11.79 g of crude product, containing some residual ethanolamine. This material was used without further purification in Step B. Step B
  • Step B (860mg, 3.13 mmol) in THF (5mL) was added slowly. The reaction mixture was stirred at -78°C for 30 minutes before Mel (584/ ⁇ L, 9.38 mmol) was added. The reaction was warmed up to room temperatore slowly and stirred overnight. Saturated NH4CI was added and the solution was extracted with EtOAc (3x). Combined organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The crude product was purified by MPLC (20:80, EtOAc :Hexanes) to yield 3-C (383mg, 42.4%).
  • reaction mixture was washed with 5% citric acid solution (100 mL), water (2 x 100 mL), saturated NaCl (50 mL), dried over MgS04, filtered and concentrated in vacuo to give 13.5 g crude product, which was used without further purification in step B.
  • Step B To a mixture of the amide (Step B) (73 g, 256 mmol) and paraformaldehyde (11.5 g, 385 mmol) was added 200 mL of acetic acid. The reaction mixture was stirred at room temperature for 5 min before concentrated sulfuric acid (200 mL). An exothermic reaction was observed. After 30 min, TLC showed a complete conversion. The mixtore was cooled to RT before poured onto ice water (2000 mL) and extracted with EtOAc (3 x 500 mL). Combined organic layers were washed with water (2x), saturated NaHC03, and brine, dried over MgS04, filtered, evaporated and dried in vacuum.
  • EtOAc 3 x 500 mL
  • Cis and ttans isomers were also separated (cis 90mg, trans 23mg, 73.4%) Cis was the less polar and more active isomer.
  • Cis isomer NMR (500 MHz, CDCI3) ⁇ 7.81 (s, IH), 7.78
  • Example 16 A solution of Example 16 (40 mg, 0.08 mmol), 37% formaldehyde (20 ⁇ L, 0.24 mmol), DIEA (25 ⁇ L, 0.12 mmol), TFA (5/iL), NaCNBH (25 mg, 0.40 mmol), and MeOH (1.5 mL) was stirred at room temperature and the reaction was monitored by TLC. The crude reaction was purified by preparative TLC (5:0.5:94.5, MeOH:NH4 ⁇ H:DCM). Cis and ttans isomers were separated with the more polar isomer being the cis and more active isomer. LC-MS for C26H28F6N2O2 MW calculated 514.21, found 515.35.
  • Example 42 was synthesized from Example 21 using the procedure detailed in
  • Example 41 Cis and trans isomers were synthesized separately from the cis and trans isomers of Example 41, with the ttans being the more polar and active isomer.
  • Step D the product from Step D (400 mg, 0.873 mmol) was stirred in a solution of 95% TFA in water (5 mL). The reaction was monitored by HPLC. Upon completion of reaction, the mixture was concenttated in vacuo, redissolved in a minimum amount of DCM, and washed with saturated NaHC03 (4x) to get rid of TFA. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to yield the desired product (208 mg, 66.5%). The crude product was used on next step.
  • Example 57 (15 mg, 0.028 mmol) and Pd/C (5 mg) were stirred in EtOH (7mL) under hydrogen overnight. The reaction was filtered through celite and concenttated in vacuo to yield Example 65 (13.6 mg, 90.7%). LC-MS for C29H32F6N2O MW calculated 538.24, found 5.39.2. EXAMPLE 66
  • Example 58 (15 mg, 0.028 mmol) and Pd/C (5 mg) were stirred in EtOH (7mL) under hydrogen overnight. The reaction was filtered through celite and concenttated in vacuo to yield Example 66 (15 mg, 100%). LC-MS for C28H32F4N2O MW calculated 488.25, found 489.25.
  • Example 75 A solution of Example 75 (10 mg, 0.025 mmol), formaldehyde (6 ⁇ L, 0.08 mmol), DIEA (7 ⁇ L, 0.04 mmol), TFA (2.5 ⁇ L), NaCNBH (9 mg, 0.1 mmol), and MeOH (l/2mL) was stirred at room temperature. The reaction was monitored by TLC. Upon completion of reaction, the reaction mixture was purified by preparative TLC (3:0.3:96.7, MeOH:NH4 ⁇ H:DCM) to yield Example 77 (6.2mg, 60.2%). LC-MS for C21H28F4N2O2 MW calculated 416.21, found 417.25.
  • Example 78 was synthesized from Example 76 according to the procedure detailed in Example 77. The crude product was purified by preparative TLC (5:0.5:94.5, MeOH:NH4 ⁇ H:DCM). LC-MS for C26H30F4N2O2 MW calculated 478.22, found
  • Example 79 was synthesized according to the procedure detailed in Example 67, Step F. LC-MS for C30H34F4N2O3 MW calculated 578.22, found 579.25.
  • Example 80 (36mg, 46.4%).
  • R2 was derivatized by using either 2-iodoprotane or acetone as the alkylating agent in Step C.
  • Rl was derivatized by using different benzylamine in Step E. 1.5 equivalent of DIEA was added for hydrochloride benzylamine.
  • R3 was derivatized by incorporating different amines in Step F. All of the components are either commercially available or are described in the Intermediates section. Isomers for some of these compounds were separated by preparative TLC. A few most active ones were resolved using chiral chromatography. A summary of these compounds is listed in the table below.
  • Example 83 A solution of Example 83 (40 mg, 0.10 mmol), 37% formaldehyde (25 ⁇ -L, 0.30 mmol), DIEA (23 ⁇ L, 0.15 mmol), TFA (10 ⁇ L), NaCNBH (28 mg, 0.50 mmol), and MeOH (3 mL) was stirred at room temperature and the reaction was monitored by TLC. The crude reaction was purified by preparative TLC (5:0.5:94.5, MeOH:NH4 ⁇ H:DCM). LC-MS for C22H30F4N2O2 MW calculated 430, found
  • Example 118 was synthesized from Example 91 using the procedure detailed in Example 117. LC-MS for C23H30F4N2O2 MW calculated 480, found 481.
  • Example 85 (15 mg, 0.029 mmol) was stirred in 4 M HCl in dioxane (5 mL). The reaction was monitored by HPLC. Upon completion of reaction, the mixtore was concentrated in vacuo to yield Example 119. LC-MS for C21H29F4N3O2 MW calculated 415, found 416.
  • Example 120 was synthesized from Example 92 using the procedure detailed in Example 119. LC-MS for C22H29F6N3O MW calculated 465, found 466.
  • the cis isomer was the less polar peak and the more active isomer.
  • the cis isomer was further separated by chiral HPLC (AD, 10% EtOH/heptane) to give two enantiomers.
  • a variety of compounds were synthesized according to the procedure detailed in Example 122.
  • Rl was derivatized by using either 2-iodopropane or acetone as the alkylating agent in Step A.
  • R2 was derivatized by using a different amine in Step C.
  • R3 was derivatized by incorporating different amines.

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Abstract

The present invention is directed to compounds of the formulas I and II : wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, R17, R18, R19, R25, R26, Y, Z, l, m, n and the broken lines are as defined herein which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.

Description

TITLE OF THE INVENTION
AMINO CYCLOBUTYLAMIDE MODULATORS OF CHEMOKINE RECEPTOR ACΠVΠΎ
BACKGROUND OF THE INVENTION
The chemokines are a family of small (70-120 amino acids), proinflammatory cytokines, with potent chemotactic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and
Murphy, Rev. Imrnun., 12, 593-633 (1994)). These molecules were originally defined by four conserved cysteines and divided into two subfamilies based on the arrangement of the first cysteine pair. In the CXC-chemokine family, which includes IL-8, GRO , NAP-2 and IP-10, these two cysteines are separated by a single amino acid, while in the CC-chemokine family, which includes RANTES, MCP-1, MCP-2, MCP-3, MlP-l , MIP-lβ and eotaxin, these two residues are adjacent.
The α-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas β-chemokines, such as RANTES, MIP- 1 , MIP- 1 β, monocyte chemotactic protein- 1 (MCP- 1 ), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, monocytes, T-cells, eosinophils and basophils (Deng, et al., Nature. 381, 661-666 (1996)).
The chemokines are secreted by a wide variety of cell types and bind to specific G-protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. Sci, 15, 159-165 (1994)) present on leukocytes and other cells. These chemokine receptors form a sub-family of GPCRs, which, at present, consists of fifteen characterized members and a number of orphans. Unlike receptors for promiscuous chemoattractants such as C5a, fMLP, PAF, and LTB4, chemokine receptors are more selectively expressed on subsets of leukocytes. Thus, generation of specific chemokines provides a mechanism for recruitment of particular leukocyte subsets. On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1") [M-P-lα, MEP-lβ, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or "CKR-2A'7"CKR- 2A" or "CC-CKR-2A'7"CC-CKR-2A") [MCP-1, MCP-2, MCP-3, MCP-4]; CCR-3 (or "CKR-3" or "CC-CKR-3") [Eotaxin, Eotaxin 2, RANTES, MCP-2, MCP-3] (Rollins, et al., Blood, 90, 908-928 (1997)); CCR-4 (or "CKR-4" or "CC-CKR-4") [M-P-lα, RANTES, MCP-1] (Rollins, et al, Blood, 90, 908-928 (1997)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MlP-lα, RANTES, MlP-lβ] (Sanson, et al. Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, et al, J. Biol. Chem., 269, 7835-7838 (1994)). The β- chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein") and RANTES ("regulation-upon-activation, normal T expressed and secreted") among other chemokines.
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Humans who are homozygous for the 32- basepair deletion in the CCR-5 gene appear to have less susceptibility to rheumatoid arthritis (Gomez, et al. Arthritis & Rheumatism, 42, 989-992 (1999)). A review of the role of eosinophils in allergic inflammation is provided by Kita, H, et al, J. Exp. Med. 183, 2421-2426 (1996). A general review of the role of chemokines in allergic inflammation is provided by Lustger, A.D, New England J. Med., 338(7), 426-445 (1998).
A subset of chemokines are potent chemoattractants for monocytes and macrophages. The best characterized of these is MCP-1 (monocyte chemoattractant protein- 1), whose primary receptor is CCR2. MCP-1 is produced in a variety of cell types in response to inflammatory stimuli in various species, including rodents and humans, and stimulates chemotaxis in monocytes and a subset of lymphocytes. In particular, MCP-1 production correlates with monocyte and macrophage infiltration at inflammatory sites. Deletion of either MCP-1 or CCR2 by homologous recombination in mice results in marked attenuation of monocyte recruitment in response to thioglycollate injection and Listeria monocytogenes infection (Lu et al, J. Exp. Med.. 187, 601-608 (1998); Kurihara et al. J. Exp. Med., 186, 1757-1762 (1997); Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Kuziel et al. Proc. Natl. Acad. Sci., 94, 12053-12058 (1997)). Furthermore, these animals show reduced monocyte infiltration into granulomatous lesions induced by the injection of schistosomal or mycobacterial antigens (Boring et al. J. Clin. Invest.. 100, 2552-2561 (1997); Warmington et al. Am J. Path.. 154, 1407-1416 (1999)). These data suggest that MCP-1 -induced CCR2 activation plays a major role in monocyte recruitment to inflammatory sites, and that antagonism of this activity will produce a sufficient suppression of the immune response to produce therapeutic benefits in immunoinflammatory and autoimmune diseases.
Accordingly, agents which modulate chemokine receptors such as the CCR-2 receptor would be useful in such disorders and diseases. In addition, the recruitment of monocytes to inflammatory lesions in the vascular wall is a major component of the pathogenesis of atherogenic plaque formation. MCP-1 is produced and secreted by endothelial cells and intimal smooth muscle cells after injury to the vascular wall in hypercholesterolemic conditions. Monocytes recruited to the site of injury infiltrate the vascular wall and differentiate to foam cells in response to the released MCP-1. Several groups have now demonstrated that aortic lesion size, macrophage content and necrosis are attenuated in MCP-1 -/- or CCR2 -/- mice backcrossed to APO-E -/-, LDL-R -/- or Apo B transgenic mice maintained on high fat diets (Boring et al. Nature. 394, 894-897 (1998); Gosling et al. J. Clin. Invest., 103, 773-778 (1999)). Thus, CCR2 antagonists may inhibit atherosclerotic lesion formation and pathological progression by impairing monocyte recruitment and differentiation in the arterial wall.
SUMMARY OF THE INVENTION
The present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of formula I and of formula II:
Figure imgf000005_0001
Figure imgf000005_0002
π
wherein:
X is selected from O, N, S, SO2, or C.
Y is selected from:
-0-, -NR12-, -S-, -SO-, -SO2-, and -CRl2Rl2., -NSO2R14-,
-NCOR^-, -CR12CORll-, -CR12OCOR13-, -CO-,
Rl 1 is independently selected from: hydroxy, hydrogen,
Cι_6 alkyl, -0-Cι_6alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, Cl-3alkyl, Ci-3alkoxy, - CO2H, -CO2-C1-6 alkyl, and trifluoromethyl; Rl2 is selected from: hydrogen, Cι_ alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, Ci-3alkyl, Ci-3alkoxy, -CO2H, -CO2-C1-6 alkyl, and trifluoromethyl; Rl3 is selected from: hydrogen, Cχ- alkyl, -0-Cι_6alkyl, benzyl, phenyl, C3.6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, Cι_ 3alkyl, Cι_3alkoxy, -CO2H, -CO2-C1-6 alkyl, and trifluoromethyl; Rl4 is selected from: hydroxy, Cχ-6 alkyl, -O-Ci-βalkyl, benzyl, phenyl, C3.6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, Ci- 3alkyl, Cι_3alkoxy, -CO2H, -CO2-CI-6 alkyl, and trifluoromethyl;
Z is independently selected from C or N, where at most two of the Z are N.
R1 is selected from: hydrogen, -Cι_6alkyl, -Crj-6alkyl-0-Ci-6alkyl, -C()-6alkyl-S-Ci-6alkyl, -(Cθ-6alkyl)~(C3-7cycloalkyl)-(Cθ-6alkyl), hydroxy, heterocycle, -CN, -NR12Rl2 -NR12C0R13, -NRl2S02R14, -COR11, -CONR12R12, and phenyl; the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo, (b) hydroxy,
(c) -0-Ci-3alkyl,
(d) trifluoromethyl,
(f) Ci_3alkyl,
(g) -0-Ci-3alkyl, (h) -CΌRH,
(i) -SO2R14. (j) -NHCOCH3,
(k) -NHS02CH3, (1) -heterocycle, (m) =0,
(n) -CN, and where the phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, -COR11, Ci-3alkyl, Cι_3alkoxy and trifluoromethyl;
R2 is selected from:
(a) hydrogen,
' (b) Cι_3alkyl, optionally substituted with 1-3 fluoro,
(c) -0-Ci-3alkyl, optionally substituted with 1-3 fluoro,
(d) hydroxy,
(e) chloro,
(f) fluoro,
(g) bromo,
( ) phenyl,
(g) heterocycle, and
(h) nothing or O (when the Z bonded to R2 is N);
R3 is selected from:
(a) hydrogen,
(b) Cι_3alkyl, optionally substituted with 1-3 fluoro,
(c) -0-Ci_3alkyl, optionally substituted with 1-3 fluoro,
(d) hydroxy,
(e) chloro,
(f) fluoro,
(g) bromo,
(h) phenyl,
(g) heterocycle, and
( ) nothing or O (when the Z bonded to R3 is N);
R4 is selected from:
(a) hydrogen,
(b) Ci-3alkyl, optionally substituted with 1-3 fluoro,
(c) -0-Ci-3alkyl, optionally substituted with 1-3 fluoro,
(d) hydroxy, (e) chloro,
(f) fluoro,
(g) bromo,
(h) phenyl,
(g) heterocycle, and
(h) nothing or 0 (when the Z bonded to R4 is N):
R5 is selected from: (a) Ci-βalkyl, where alkyl may be unsubstituted or substituted with
1-6 fluoro and optionally substituted with hydroxyl,
(b) -0-Ci-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(c) -CO-Ci-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(d) -S-Cι_6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(e) -pyridyl, which may be unsubstituted or substituted with one or more substituents selected from: halo, trifluoromethyl, C . 4alkyl, and COR ,
(f) fluoro,
(g) chloro, (h) bromo,
(i) -C4_6cycloalkyl, (j) -0-C4~6cycloalkyl,
(k) phenyl, which may be unsubstituted or substituted with one or more substituents selected from: halo, trifluoromethyl, Ci-
4alkyl, and COR11,
(1) -O-phenyl, which may be unsubstituted or substituted with one or more substituents selected from: halo, trifluoromethyl, Ci_
4alkyl, and COR11, (m) -C3-6cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro, (n) -0-C3-6cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(o) -heterocycle,
(P) -CN, and
(q) -COR11;
R6 is selected from:
(a) hydrogen,
(b) Ci-3alkyl, optionally substituted with 1-3 fluoro,
(c) -0-Ci-3alkyl, optionally substituted with 1-3 fluoro,
(d) hydroxy,
(e) chloro,
( ) fluoro,
(g) bromo,
( ) phenyl,
(g) heterocycle, and
(h) nothing or 0 (when the Z bonded to R6 is N);
R7 is selected from: hydrogen, (C()-6alkyl)-phenyl, (Cθ-6alkyl)-heterocycle, (Cθ-6alkyl)-C3_
7cycloalkyl , (Co-δalky^-COR11, (Cθ-6alkyl)-(alkene)-COR11, (Crj- 6alkyl)-S0 H, (Cθ-6alkyl)-W-C0-4alkyl,
Figure imgf000009_0001
phenyl, (Cθ-6alkyl)-CONR20-V-COR11, and nothing (when X is O, S, or Sθ2), where W is selected from: a single bond, -0-, -S-, -SO-, - SO2-, -CO-, -C02-, -CONR!2- and - R12-, and where V is selected from Ci-βalkyl or phenyl, and where the R20 can be hydrogen, Ci_4alkyl, or where R20 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring, and where the Cfj-6alkyl is unsubstituted or substituted with 1-5 substituents, where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -Co-6alkyl
(d) -0-Ci-3alkyl, (e) trifluoromethyl, and
(f) -Co-2alkyl-phenyl,
and where the phenyl, heterocycle, cycloalkyl, and Cθ-4alkyl is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy, (d) Ci-3alkyl,
(e) -0-Ci-3alkyl,
Figure imgf000010_0001
(g) -CN,
(h) -NR^Rl^ (i) -CONR^Rl^ and
(j) -Co-3-heterocycle, or where the phenyl and heterocycle may be fused to another heterocycle, which itself may be unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR11, and -C1_3alkylj and where alkene is unsubstituted or substituted with 1-3 substituents which are independently selected from: (a) halo,
(b) trifluoromethyl,
(c) Cl-3alkyl,
(d) phenyl, and
(e) heterocycle;
lected from:
(a) hydrogen,
(b) nothing when X is either O, S, S02 or N or when a double bond joins the carbons to which R7 and R!0 are attached,
(c) hydroxy,
(d) Ci-6alkyl,
(e) C l -6alkyl-hydroxy , ( ) -0-Cl-3alkyl,
(g) -COR11,
(h) -CONR^R^, and
(i) -CN;
or where R7 and R^ may be joined together to form a ring which is selected from:
(a) lH-indene,
(b) 2,3 -dihydro- 1 H-indene,
(c) 2,3-dihydro-benzofuran,
(d) 1 ,3-dihydro-isobenzofuran,
(e) 2,3-dihydro-benzothiofuran,
(f) 1,3-dihydro-isobenzothiofuran,
(g) 6H-cyclopenta[-i] isoxazol-3 -ol
(h) cyclopentane, and
(i) cyclohexane, where the ring formed may be unsubstituted or substituted with 1-5 substituents independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) Ci-3alkyl,
(e) -0-Ci-3alkyl,
(f) -Co-3-COR11,
(g) -CN,
(h) -NR12R12
(i) -CONRi2Rl2, and
(j) -Cθ-3-heterocycle,
or where R^ and R^ or R^ and RtO may be joined together to form a ring which is phenyl or heterocycle, wherein the ring is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl, (c) hydroxy,
(d) Ci-3alkyl,
(e) -0-Cι_3alkyl,
(f) -COR11,
(g) -CN,
(h) -NR12R12, and
(i) -CONR12R12;
R9 and R1^ are independently selected from: (a) hydrogen,
(b) hydroxy,
(c) Cι_6alkyl,
(d) Ci-βalkyl-COR11,
(e) C i _6alkyl-hydroxy,
(f) -0-Ci_3alkyl,
(g) =0, when R9 or R ^ is connected to the ring via a double bond
(h) halo;
R1^ is selected from:
(a) hydrogen, and
(b) Ci-βalkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, -CO2H, -Cθ2Ci-6alkyl, and -O-C1- 3alkyl;
R1^ is selected from:
(a) hydrogen,
(b) Ci-6alkyl, where alkyl may be unsubstituted or substituted with
1-6 substituents where the substituents are selected from: fluoro, Ci-3alkoxy, hydroxy, -COR11,
(c) fluoro,
(d) -0-Ci-3alkyl, where alkyl may be unsubstituted or substituted with 1-3 fluoro, and
(e) C3-6 cycloalkyl, (f) -0-C3-6cycloalkyl,
(g) hydroxy, (h) -COR11, (i) -OCOR13, or R ^ and R1^ may be joined together via a C2-4alkyl or a
C0-2alkyl-O-Ci-3alkyl chain to form a 5-7 membered ring;
R1^ is selected from:
(a) hydrogen, (b) Cχ-6alkyl, where alkyl may be unsubstituted or substituted with
1-6 substituents where the substituents are selected from: fluoro, Cι_3alkoxy, hydroxy, -COR11,
(c) COR11,
(d) hydroxy, and (e) -0-Ci-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are selected from: fluoro, Cι_3alkoxy, hydroxy, -COR11, or R1^ and R1^ may be joined together by a Ci-4alkyl chain or a Cθ-3alkyl-0-Cθ-3alkyl chain to form a 3-6 membered ring;
R1^ is selected from:
(a) hydrogen, and
(b) Ci-6alkyl, where alkyl may be unsubstituted or substituted with
1-6 fluoro, (c) fluoro,
(d) -0-C3-6cycloalkyl, and
(e) -0-Ci-3alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro, or R1^ and R1^ may be joined together by a C2-3alkyl chain to form a 5-6 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, -COR11, Ci_3alkyl, and Ci-3alkoxy, or R ^ and R1^ may be joined together by a Ci-2alkyl-0-Ci-2alkyl chain to form a 6-8 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, -COR11, Ci-3alkyl, and Ci-3alkoxy, or R1^ and R ^ may be joined together by a -0-Cι_2alkyl-0-chain to form a 6-7 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, -COR 1, Ci-3alkyl, and Ci-3alkoxy;
R^ is selected from:
(a) hydrogen,
(b) phenyl,
(c) Ci-βalkyl which may be substituted or unsubstituted with 1-6 of the following substituents: -COR11, hydroxy, fluoro, chloro, -0-Ci-3alkyl; or
R2 and R!9 can also be joined together to form a heterocycle ring with a linker selected from the following list (with the left side of the linker being bonded to the amide nitrogen at R!9):
(a) -CH2(CR28R28)1_3-,
Figure imgf000014_0001
(c) -NR29CR28R28.,
(d) -CH20-,
(e) -CH2SO2-,
(f) -CH2SO-,
(g) -CH2S-,
(h) -CR28R28., where R28 is selected from selected from:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) Ci-3alkyl, where the alkyl is unsubstituted or substituted wii
1-6 substituents independently selected from: fluoro, and hydroxy, (e) -NR12R12
(f) -COR11,
(g) -CONRi2Rl2, (h) -NR12COR13, (i) -OCONR12R12,
0) -NR12CONR12R12,
(k) -heterocycle,
(1) -CN,
(m) -NR12-S02-NR12Rl2 (n) -NR12-S02-R14,
(o) -S02-NR12R12, and
(p) =0, where R28 is connected to the ring via a double bond (in which case the other R28 at the same position is nothing, and where R29 is selected from: (a) hydrogen,
(b) Ci-3alkyl, where the alkyl is unsubstituted or substituted with
1-6 substituents independently selected from: fluoro, and hydroxy,
(c) COR13, (d) SO2R14 and
(e) Sθ2NRi2Rl2;
R25 and R26 are independently selected from: (a) =0, where R25 and/or R26 is oxygen and is connected via a double bond.
(b) hydrogen,
(c) phenyl,
(d) Cι_6alkyl which may be substituted or unsubstituted with 1-6 of the following substituents: -COR11, hydroxy, fluoro, chloro, -0-Ci-3alkyl;
m is selected from 0, 1, or 2; n is selected from 1 or 2;
the dashed line represents a single or a double bond;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
A further embodiment of the present invention includes compounds of formula la.
Figure imgf000016_0001
la wherein R1, R3, R5, R16, RH γ; and z are defined above,
and pharmaceutically acceptable salts and individual diastereomers thereof.
A still further embodiment of the present invention include compounds of formula Ha:
Figure imgf000016_0002
Ha Wherein Rl, R5, R7, R8, R9, R10 X and Z are described above.
A further embodiment of the present invention includes compounds of formula Hb.
Figure imgf000017_0001
πb wherein R1, R3, R5, R7; R8; R9, RIO, X, and z are defined above,
and pharmaceutically acceptable salts and individual diastereomers thereof.
A still further embodiment of the present invention includes compounds of formula He:
Figure imgf000017_0002
He
Wherein Rl, R3, R5, R10J and Z are described above, and R23 and R24 are independently selected from: (a) hydrogen,
(b) halo,
(c) trifluoromethyl,
(d) hydroxy,
(e) Ci-3alkyl, (f) -0-Ci-3alkyl,
Figure imgf000017_0003
(h) -Cθ-3-Cθ2Ci_3alkyl,
(i) -CN, and
(j) -Cfj-3 -heterocycle, or where the R23 and R24 are joined together to form a heterocycle which is fused to the phenyl ring, and which itself may be unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR11, and -C^alkyl;
and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embodiment of the present invention includes compounds of formula Ud:
Figure imgf000018_0001
nd wherein R1, R3, R ^9, R23; R24, ar i z are defined above and the dashed line represents a single or a double bond,
and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embodiment of the present invention includes compounds of formula He:
Figure imgf000018_0002
He Wherein Rl, R3, R5, R10? R23, and R24 are described above, and pharmaceutically acceptable salts and individual diastereomers thereof.
A still further embodiment of the present invention includes those of formula Hf :
Figure imgf000019_0001
πf wherein R1, R3, R ,R9, R23, and R24 are defined above,
and pharmaceutically acceptable salts and individual diastereomers thereof.
In a still further aspect of the present invention X is C, O or N.
In a still further aspect of the present invention X is C.
In a still further aspect of the present invention Y is -CH2- or -O-
In a further aspect of the present invention Z is C.
In another aspect of the present invention R1 is selected from: hydrogen, phenyl, heterocycle, -Ci-6alkyl, -Cθ-6alkyl-0-Ci-6alkyl, and -(Co-6alkyl)-(C3-7cycloalkyl)-(Co-6alkyl), where the alkyl, phenyl, heterocycle, and the cycloalkyl are unsubsti toted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -0-Ci- alkyl,
(d) trifluoromethyl,
(f) Ci-3alkyl,
(g) -0-Ci_3alkyl,
(h) -COR11, (i) -CN,
(j) -NRΪ2R12, and
(k) -CONR12R12.
In a still further aspect of the present invention R is selected from:
(1) -Cι_6alkyl, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy, (c) -0-Cι_3alkyl,
(d) trifluoromethyl, and
(e) -COR11,
(2) -Cθ-6alkyl-0-Ci-6alkyl-, which is unsubstituted or substituted with 1-
6 substituents where the substituents are independently selected from: (a) halo,
(b) trifluoromethyl, and
(c) -COR11,
(3) -(C3-5cycloalkyl)-(Cθ-6alkyl), which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -0-Ci-3alkyl,
(d) trifluoromethyl, and (e) -COR11,
(4) phenyl or heterocycle which is unsubstituted or substituted with 1-3 substitoents where the substituents are independently selected from:
(a) halo,
(b) hydroxy, (c) -0-Cι_3alkyl,
(d) trifluoromethyl, and
(e) -COR11,
In a further aspect of the present invention R1 is selected from: (a) hydrogen, (b) Ci-6alkyl, which may be unsubstituted or substituted with 1-6 substituents independently selected from: fluoro and hydroxy
(c) phenyl, and
(d) pyridyl.
In a still further aspect of the present invention that R1 is selected from:
(a) hydrogen
(b) -CH(CH3)2,
(c) -C(OH)(CH3)2- (b) -CH(OH)CH3,
(c) -CH2CF3,
(d) -CH3, and
(e) phenyl,
In another aspect of the present invention R2 is hydrogen.
In still another aspect of the present invention when Z is N, R3 is nothing.
In a still further aspect of the present invention when Z is C, R is selected from:
(a) hydrogen
(b) halo
(c) hydroxy (d) Ci-3alkyl, where the alkyl is unsubstituted or substituted with
1-6 substituents independently selected from: fluoro, and hydroxy,
(e) -COR11,
(f) -CONR^RΠ
(g) -heterocycle, (h) _NRl2-S02-NR12Rl2)
(i) -NR12-S02-R14,
Figure imgf000021_0001
(k) -nitro, and
(1) -NR12R12; In another aspect of the present invention, when Z is C, R3 is selected from:
(a) fluoro,
(b) trifluoromethyl,
(c) hydrogen;
In a still further aspect of the present invention R4 is hydrogen.
In another aspect of the present invention R5 is selected from: (a) Cι_6alkyl substituted with 1-6 fluoro, (b) -0-Ci-6alkyl substituted with 1-6 fluoro,
(c) chloro,
(d) bromo, and
(e) phenyl.
In a still further aspect of the present invention R^ is selected from:
(a) trifluoromethyl,
(b) trifluoromethoxy,
(c) chloro,
(d) bromo, and (e) phenyl.
In a still further aspect of the present invention R^ is trifluoromethyl.
In another aspect of the present invention R^ is hydrogen.
In another aspect of the present invention R7 is phenyl, heterocycle, C3-7cycloalkyl,
Ci_6alkyl, -COR11, and -CONH-V-CORll, where V is selected from Ci-βalkyl or phenyl, and
where the phenyl, heterocycle, C3_7cycloalkyl, and Ci-6alkyl is unsubstituted or substituted with 1-5 substitoents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl, (c) hydroxy,
(d) Ci-3alkyl,
(e) -0-Ci- alkyl,
(f) -COR11,
(g) -CN,
(h) -heterocycle, and
(i) -CONR^R
In an additional aspect of the present invention (when X is not O) R^ is phenyl, heterocycle, Ci-4alkyl, -COR11, and -CONH-V-COR11;
V is selected from Ci~6alkyl or phenyl; and the phenyl, heterocycle, and Cι_4alkyl is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: (a) halo,
(b) hydroxy,
(c) Ci-3alkyl,
(d) -0-Ci.3alkyl,
(e) -COR11, and (f) -heterocycle.
In another aspect of the present invention when X is O, R^ is nothing;
In another aspect of the present invention X is C, R^ is hydrogen;
In another aspect of the present invention R9 is hydrogem
In another aspect of the present invention R1^ is selected from: (a) hydrogen, (b) hydroxy,
(c) -CH3,
(d) -O-CH3, and
(e) =0 (where R9 is joined to the ring via a double bond).
In still another aspect of the present invention R ^ is hydrogen or methyl. In another aspect of the present invention R1^ is selected from:
(a) hydrogen,
(b) Ci-3alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(c) -0-Ci-3alkyl, and
(d) fluoro, and
(e) hydroxy.
In yet another aspect of the present invention R ^ is selected from:
(a) hydrogen,
(d) trifluoromethyl,
(c) methyl,
(d) methoxy,
(e) ethoxy,
(f) ethyl,
(g) fluoro, and
(h) hydroxy.
In another aspect of the present invention R1 is hydrogen.
In another aspect of the present invention R1^ is selected from:
(a) hydrogen,
(b) methyl, and (c) methoxy.
In still another aspect of the present invention R1^ is hydrogen.
In yet another aspect of the present invention R1^ and R1^ are joined together by a -CH2CH2- chain or a -CH2CH2CH2- chain to form a cyclopentyl ring or a cyclohexyl ring.
In still another aspect of the present invention R 5 is hydrogen. In another aspect of the present invention R26 is oxygen and connected via a double bond.
In still another aspect of the present invention 1 = 1.
In still another aspect of the present invention m = 1.
In yet another aspect of the present invention n = 1.
Representative compounds of the present invention include those presented in the Examples and pharmaceutically acceptable salts and individual diastereomers thereof.
The compounds of the instant invention have at least two asymmetric centers at the 1- and 3-positions of the cyclobutyl ring. Additional asymmetiic centers may be present depending upon the natore of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The absolute configurations of selected compounds of this orientation, with substituents on the cyclopentyl ring (amide and amine units), are as depicted below:
Figure imgf000025_0001
Figure imgf000026_0001
The independent syntheses of diastereomers and enantiomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made by known procedures or as illustrated.
Figure imgf000028_0001
The preparation of compounds within the scope of the instant invention which bear a 1,1,3-trisubstituted cyclobutane framework is detailed in
Scheme 1. Keto-acid 1-1 (the preparation of which is described in Scheme 2) can first be protected as the corresponding ester, where R27 represents an alkyl such as methyl, ethyl, tert-butyl or benzyl which serves as a protecting group (Greene, T; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991). Reductive amination of 1-2 with an amine preferably of the from 1-3 (a preparation of which is depicted in Scheme 3) in the presence of a reducing agent such as sodium cyanoborhydride or sodium triacetoxyborohydride gives amino-ester 1-4. Conversion of ester 1-4 to the carboxylic acid 1-5 can be achieved by a number of conditions depending on the nature of the ester. For example, methyl or ethyl esters can be readily saponified with sodium hydroxide, or lithium hydroxide; tert- butyl ester can be removed by treatment with TFA. Coupling of the acid 1-5 with amine 1-6 (a preparation of which is described in Scheme 4), to give chemokine modulators of the form 1-7, can be accomplished by the standard amide bond formation conditions using a coupling reagent such as DCC, EDC and a catalyst such as DMAP, HOBT or HO AT. Alternativly 1-1 can be directly coupled to amine 1-6 to give the keto-amide 1-8. Reductive amination with amine 1-3 in the presence of a borohydride such as sodium triacetoxyborohydride or sodium cyanoborohydride then provides the chemokine modulator 1-7.
SCHEME 1A
Figure imgf000030_0001
2-2a 1-9 1-10
Figure imgf000030_0002
Scheme 1A depicts the preparation of chemokine modulators of the form 1-14. Intermediate 2-2a (described in Scheme 2) is first reduced to the primary amine 1-9 by catalytic hydrogenation using Raney nickel. Protection of the amine with the appropriate protecting group, such as a tert-butylcarbamate, by treatment with di-tert- butyl dicarbonate followed by reductive amination with amine 1-3 gives intermediate 1-11. Removal of the protecting group, with for example HCl in dioxane or TFA for the boc protected amine gives the free amine 1-12. Acylation of the amine with an acid chloride (1-13) gives the chemokine modulator 1-14. Alternatively the amine can be coupled (as described in Scheme 1) to an appropriate benzoic acid (not shown) to give similar amides 1-14. SCHEME 2
Figure imgf000031_0001
Figure imgf000031_0002
1 -1 c 2-4
Figure imgf000031_0003
As depicted in Scheme 2, the keto cyclobutanoic acid (1-1) can be readily synthesized from commercially available materials. The initial protected intermediates of the form 2-2 can be made by a double alkylation reaction of an active ester (2- lb) or nitrile (2- la) with 1,3-dibromo 2,2-dimethoxypropane, using a base such as sodium hydride. Removal of the dimethyl acetal and the hydrolysis of the ester or nitrile can be accomplished under acidic conditions in one reaction step to give intermediate 1-1. In the case where R1 is an ester functionality (2-lc) this ■ hydrolysis is accompanied by decarboxylation to give the simple (R1 = H) keto- cyclobutane (1-lc). The ketone (1-lc) can be reprotected as the dimethyl acetal using trimethyl orthoformate with an acid catalyst in an appropriate solvent. When this solvent is methanol, the reaction is accompanied by esterification of the carboxylic acid to give 2-4 (where R27 is a methyl group). Alkylation of 2-4 with an alkyl halide or an aldehyde or ketone (to give an appropriate aldol product) gives intermediates 2- 5. The deprotection of the ketone and hydrolysis of the ester can again be achieved in one step under acidic conditions to give 1-1.
Amines 1-3 were obtained from various sources. Some were commercially available, some were known from the literature and could be prepared according to published procedures, and some were prepared as described herein. Since their structures and the methods for their preparation are diverse, only one Scheme will be outlined in this section; individual syntheses of amines 1-3 can be found in the Experimental Section. Scheme 3 shows one method for the synthesis of 4-aryl substitoted piperidines as well as 4-aryl-3-alkyl-piperidines. Enol triflate 3-1 (prepared according to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995.) could be coupled to boronic acids 3-2 as described by Wustrow and Wise. Hydrogenation of the olefin in 4-3 could be achieved using hydrogen in the presence of a catalyst such as Pd(OH)2/C. Oxidation of 3-4 using Ru(IV)oxide hydrate and sodium periodate leads to Boc-lactam 3-5. Alkylation with an alkyl halide in the presence of a base such as LDA gives 3-6, with the trans product being predominant. Removal of the Boc protecting group could be achieved using standard acidic conditions, such as HCl in dioxane or TFA/DCM. Reduction of the lactam 3-7 with, for example borane provides 1-3.2. Alternatively, intermediate 3-4 can itself be deprotected under acidic conditions to afford piperidine 1-3.1. SCHEME 3
Figure imgf000033_0001
1 -3.1 1-3.2 3-7
Amines of the form 1-6 are synthesized in a variety of ways. An example of such a synthesis is depicted in Scheme 4. According to this, the commercially available 3- trifluoromethyl-5-amino bromobenzene (4-1) is converted to the corresponding nitrile using zinc cyanide in the presence of palladium, and a Sandmeyer reaction is then used to produce the respective halide 6-3, R = CI, I. The reduction of the nitrile in the presence of an aromatic halide to the corresponding amine can be successfully accomplished e.g. with borane in THF. SCHEME 4
Figure imgf000034_0001
4-3 4-4
Another example, which describes a synthesis of a pyridylmetliylamine is detailed in Scheme 5. According to this, the commercially available 5- trifluoromethyl-2-pyridinal (5-1) is brominated in acetic acid and the aromatic bromide is converted to the respective aldehyde 5-3 by transmetalation and quench with dimethyl formamide. Dehydration of the corresponding oxime yields the required nitrile (5-4) and then phosphoryl chloride is used to produce the respective aromatic chloride. The simultaneous reduction of the nitrile and chloride to yield 5-6 can be accomplished with catalytic hydrogenation, preferably with Raney nickel and elevated pressure.
SCHEME 5
Figure imgf000035_0001
Additional examples of benzyl amines incorporated into the amide portion of compounds within the scope of the instant invention, as well as their syntheses are further described in the Experimental section.
In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
Concentration of solutions was generally carried out on a rotary evaporator under reduced pressure. Flash chromatography was carried out on silica gel (230-400 mesh). NMR spectra were obtained in CDCI3 solution unless otherwise noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether (ether), trietliylamine (TEA), N,N-diisopropylethylamine (DIEA) saturated aqueous (sat'd), room temperature (rt), hour(s) (h), minute(s) (min).
The following are representative Procedures for the preparation of the compounds used in the following Examples or which can be substituted for the compounds used in the following Examples which may not be commercially available.
INTERMEDIATE 1
Figure imgf000036_0001
Step A
MeO. X02iPr
MeO^^^ OgiPr
To a flame-dried three-necked round-bottomed flask equipped with a stir-bar, addition funnel, thermometer, and reflux condenser, was suspended 60% NaH (8.4g, 210 mmol) in dry DMF under nitrogen. Diisopropylmalonate (36.3 ml, 191 mmol) was added dropwise while keeping temperature under 70°C. On cessation of gas evolution, l,3-dibromo-2,2-dimethoxypropane (25g, 95 mmol) was added. The reaction mixture was stirred at 140OC for 48 h before being cooled to room temperature and poured into an aqueous solution of NH4CI (25 g in 400 mL) to prevent emulsion formation. The aqueous layer was extracted with hexanes (3x). The combined organic layers were washed with water and a saturated NaHC03 solution, dried over anhydrous MgSθ4, and concentrated in vacuo. The crude product was purified by vacuum distillation (0.1 mm, 92-100°C) to yield pure product (12.0g, 43.6%). 1H NMR (400 MHz, CDC13) δ 5.07 (p, J=12.5 Hz, 6.25 Hz, 2H), 3.17 (s, 6H), 2.71 (s, 4H), 1.25 (d, J=6.2 Hz, 12H).
Step B
Figure imgf000036_0002
Product from Step A (4.8g, 17 mmol) was stirred with 20% HCl (20 ml) at reflux for 60 h before being cooled to room temperature. Ether was added and the solution was vigorously stirred for 24 hours. The ether layer was removed and the aqueous layer was extracted with ether (3x). The combined organic layers were dried over anhydrous MgS04 and concentrated in vacuo to yield Intermediate 1 (1.84g, 96.8%).
The crude product was used on next step. NMR (400 MHz, CDC13) δ 3.52-3.26 (m, 5H).
INTERMEDIATE 2
Figure imgf000037_0001
Step A
H T
To a cooled (0 °C) solution of ethanolamine (41.8 g, 0.685 mol) in water (90 mL) was added neat (R)-propylene oxide (4.97 g, 85.6 mmol), dropwise. After 1 h at 0 °C the reaction was allowed to rise to room temperature and stirred overnight." The reaction mixture was concentrated at -80 °C in vacuo to remove the water and most of the ethanolamine, to give 11.79 g of crude product, containing some residual ethanolamine. This material was used without further purification in Step B. Step B
30C f
HO' OH The diol prepared in Step A (11.8 g crude [~86% pure], ca. 83 mmol) was dissolved in DCM (150 mL) and treated with di-tert-butyl dicarbonate (23.4 g, 107 mmol) in DCM (75 mL) over 15 min. The reaction mixture was stirred over the weekend, concentrated, and purified by MPLC, eluting with 5% MeOH/EtOAc to provide 14.8 g (81%) of product. Step C
BOC T
MsO OMs To a solution of the Boc-protected diol prepared in Step B (13.2 g, 60.3 mmol) and triethylamine (21.0 mL, 15.3 g, 151 mmol) in DCM (150 mL) at 0 °C was added dropwise methanesulfonyl chloride (9.56 mL, 14.1 g, 125 mmol). The reaction mixture was then stirred for 1.5 h, diluted with more DCM (100 mL) and washed with 3N HCl (250 mL). The aqueous layer was extracted again with DCM (200 mL), and the organic layers were combined and washed with IN HCl (250 mL), saturated NaHCθ3 solution (250 mL), and brine (250 mL). The organic layer was dried over MgSθ4, filtered, and concentrated to give 22.8 g of crude bis-mesylate, which was used immediately. If not used immediately the bis-mesylate underwent decomposition. Step D
Figure imgf000038_0001
Indene (7.03 mL, 7.00 g, 60.3 mmol) was added dropwise over 4 min to a 1.0 M THF solution of LHMDS (127 mL, 127 mmol) at 0 °C. After stirring for an additional 30 min., this solution was transferred via cannula to a solution of bis- mesylate (22.6 g, 60.3 mmol), prepared as described in Step C above, in THF (75 mL) at 0 °C. The mixture was stirred for 2 h, warmed to rt and stirred overnight. The reaction mixture was partially concentrated and then partitioned between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the organic layers were combined. The organic phase was then washed with brine, dried over MgSθ4, filtered and concentrated to give 17.3 g of crude product. Purification by
MPLC, eluting with 15% ethyl acetate/hexane, afforded 9.51 g (53%) of piperidine as a ~3: 1 mixture of trans to cis (determined by H NMR). The mixture was crystallized from hot hexane to give 6 g (33%) of pure trans isomer (>20:1 by H NMR). H NMR (CDCI3, 400 MHz): □ 7.29 (dt, J = 6.4, 1.6 Hz, IH), 7.20 (m, 3H), 6.83 (d, J = 6.0
Hz, IH), 6.67 (d, J = 5.6 Hz, IH), 4.20 (br s, 2H), 2.97 (br t, J = 3.2 Hz, IH), 2.69 (br t, J = 2.4 Hz, IH), 2.16 (m, IH), 2.07 (dt, J = 4.4, 13.2 Hz, IH), 1.49 (s, 9H), 1.25 (m, lH), 0.31 (d, J = 6.8 Hz, 3H). Step E
Figure imgf000038_0002
The Boc-piperidine prepared in Step D (4.35 g, 14.5 mmol) was dissolved in an anhydrous 4 N HCl solution in dioxane and stirred at rt for 1 h. The reaction mixture was then concentrated to afford 3.81 g of product. EI-MS calc. for C14H17N: 199; Found: 200 (M)+.
INTERMEDIATE 3
Figure imgf000039_0001
Intermediate 1 (3.5g, 30.7 mmol), benzyl alcohol (3.17 ml, 30.7 mmol), DMAP (375mg, 3.07 mmol), EDC (8.8g, 46.0 mmol) and DCM (100 ml) were mixed together and stirred at room temperature for 18 hours. The reaction mixture was washed with water (3x). The combined aqueous layer was extracted witli DCM. The combined organic layer was washed with brine, dried over anhydrous MgS04, and concentrated in vacuo. Crude product was purified by MPLC (30:70, ethyl acetate:hexanes) to yield Intermediate 3 (5.25g, 84.0%). NMR (400 MHz, CDC13) δ 7.39 (m, 4H), 5.21 (s, 2H), 3.49-3.41 (m, 2H), 3.36-3.28 (m, 3H).
INTERMEDIATE 4
Figure imgf000039_0002
Step A
Figure imgf000039_0003
A solution of 4-phenylpiρeridine hydrochloride (7.00 g, 35.8 mmol), di-tert-butyl dicarbonate (11.7 g, 53.6 mmol), DIEA (6.2 mL, 35.8 mmol) and DCM (125mL) was stirred at room temperatore and the reaction was monitored by HPLC. Upon completion of reaction, the reaction mixture was concentrated in vacuo and redissolved in EtOAc. Insoluble DIEA hydrochloride was filtered out. The filtrate was concentrated to dryness and redissolved in DCM, washed with 15% citric acid, saturated NaHC03 and brine, dried over anhydrous MgS04, and concentrated in vacuo. The crude product was purified by flash chromatography (10:90, EtOAc:hexanes) to yield 3-A (8.48g, 90.6%). IH NMR (400 MHz, CDC13) δ 7.35- 7.30 (m, 2H), 7.25-7.21 (m, 3H), 4.26 (s, 2H), 2.82 (t, J=12 Hz, 2H), 2.66 (tt, J=12.1 Hz, 3.5 Hz, IH), 1.84 (d, J=13.2 Hz, 2H), 1.63 (dq, J=12.7 Hz, 4.1 Hz, 2H), 1.52 (d, J=17.4 Hz, 9H). Step B
Figure imgf000040_0001
The product from Step A (2.10g, 8.0 mmol) and Ruθ2 (0.30g) were suspended in CHCI3 (150mL) which had been de-alcoholed by washing with water (3x) (Solution A). In a separate flask, NaI04 (6.8g, 32 mmol) was suspended in water (150mL) (Solution B). Solution B was added to Solution A and the combined mixture was vigorously stirred at room temperature for 2 days. The organic layer was separated and the aqueous layer was extracted with CHCI3 (3x) and DCM (3x). MeOH (20mL) was added to the combined organic layer to destroy excess oxidant. The mixture was filtered through celite. The filtrate was washed with 10% aqueous sodium thiosulfate (20mL), dried over anhydrous MgS04, and concentrated in vacuo. The crude product was purified by MPLC (20:80, EtOAc: hexanes) to yield pure 3-B (867mg, 39.4%). IH NMR (500 MHz, CDC13) 87.36 (app t, J=7.5 Hz, 2H), 7.29-7.27 (m, IH), 7.23 (app d, J=7.3 Hz, 2H), 3.89 (dt, J=13.0 Hz, 4.5Hz, IH), 3.64 (ddd, J=19.7 Hz, 11 Hz, 4.1 Hz, IH), 3.14 (ddd, J=15.8 Hz, 11.2 Hz, 4.8 Hz, IH), 2.86 (ddd, J=17.1 Hz, 5.5 Hz, 2.0 Hz, IH ), 2.65 (dd, J= 17.2 Hz, 11.3 Hz, IH), 2.24-2.18 (m, IH), 2.00 (dddd, 1=24.1 Ηz, 16.0 Hz, 11.0 Hz, 5.0 Hz , IH), 1.56 (s, 9H). Step C
Figure imgf000041_0001
KΗMDS (686mg, 3.44mmol) was dissolved in THF (10 ml) in a flamed dried flask under N2- The mixture was cooled to -78°C before a solution of the product from
Step B (860mg, 3.13 mmol) in THF (5mL) was added slowly. The reaction mixture was stirred at -78°C for 30 minutes before Mel (584/ιL, 9.38 mmol) was added. The reaction was warmed up to room temperatore slowly and stirred overnight. Saturated NH4CI was added and the solution was extracted with EtOAc (3x). Combined organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The crude product was purified by MPLC (20:80, EtOAc :Hexanes) to yield 3-C (383mg, 42.4%). IH NMR (500 MHz, CDC13) δ 7.35 (app t, J=7.4 Hz, 2H), 3.27 (m, IH), 7.20 (app d, J=7.1 Hz, 2H), 3.86 (dt, J=12.8 Hz, 5.0 Hz, IH), 3.74 (ddd, J=13.1 Hz, 10.1 Hz, 4.6 Hz, IH), 2.69 (m, 2H), 2.14 (m, IH), 2.05 (m, IH), 1.57 (s, 9H), 1.10 (d, J=6.4 Hz, 3H). Step D
Figure imgf000041_0002
The product from Step C (1.34 g, 4.63 mmol) was stirred in 4 M HCl in dioxane (30 mL) for 2 hours before concentrated in vacuo to yield the desired HCl salt (871mg, 99.4%). IH NMR (400 MHz, CDCI3) δ 8.94 (s, IH), 7.87 (s, IH), 7.38 (m, 2H), 7.30
(m, IH), 7.20 (m, 2H), 3.57 (m, 2H), 2.76-2.71 (m, 2H), 2.70-2.06 (m, 2H). Step E
Figure imgf000041_0003
To a flamed-dried flask was added one pellet of LAH (1 g). Ether (20 mL) was added slowly to dissolve the LAH before the product from Step D (870mg, 4.6mmol) was added. The reaction mixture was stirred at room temperature overnight before cooled to 0OC. Water (ImL) was added dropwise followed by a 15% NaOH solution (ImL), and water (3mL). The mixture was vigorously stirred for 3 hours before filtered and concentrated in vacuo. The product was redissolved in DCM and added 4N HCl to form a HCl salt of 3-E (805mg, 82.7%). IH NMR (400 MHz, CD30D) δ 7.33 (m, 2H), 7.23 (m, 3H), 3.45 (m, 2H), 3.10 (m, IH), 2.79 (t, J=6.8 Hz, IH), 2.46 (m, IH), 2.16-2.07 (m, IH), 2.00-1.95 (m, 2H), 0.74 (d, J=6.4 Hz, 3H).
INTERMEDIATE 5
Figure imgf000042_0001
80% 20%
Intermediate 5 was synthesized from 4-fluoro-4-phenylpiperidine using the reaction scheme detailed in the synthesis of Intermediate 4. A mixture of methyl and dimethyl compounds were synthesized.
INTERMEDIATE 6
Figure imgf000042_0002
Figure imgf000042_0003
A solution of 3-fluoro-5-trifluoromethylbenzylamine (2 g, 10 mmol), di-tert-butyl- dicarbonate (3.4 g, 15 mmol), and DMAP (tare) in DCM (50 mL) was stirred at room temperatore overnight. The reaction mixture was concentrated in vacuo, redissolved in EtOAc, washed with saturated N-1HCO3 and brine, dried over anhydrous MgSθ4.
The crude product was purified by MPLC (15:85, EtOAc: hexanes) to yield 5-A (l.Og,
33.3%).
Step B
Figure imgf000043_0001
60% NaH (205 mg, 5.12 mmol) was suspended in DMF (25 mL) under nitrogen. The mixture was cooled to -78°C before the product from Step A (1.0 g, 3.4mmol) and Mel (640 μL, 10.2 mmol) were added. The solution was stirred at -78°C for another 30 minutes before being raised to room temperature. The reaction was diluted with ether, washed with water (3x), dried over anhydrous MgSθ4, and concentrated in vacuo. The crude product was purified by MPLC (10:90, EtOAc :hexanes) to yield the product (823mg, 78.5%). IH NMR (500 MHz, CDC13) δ 7.30 (s, IH), 7.25 (d, J=8.0 Hz, IH), 7.14 (d, J=8 Hz, IH), 4.47 (s, 2H), 2.88 (d, J=14.5 Hz, 3H), 1.49 (d, J=10.3 Hz, 9H). Step C
Figure imgf000043_0002
The product from Step B (823mg, 2.68mmol) was dissolved in 4 M HCl in dioxane (10 mL). Upon on completion of reaction, the solution was concentrated down to yield the desired product (614 mg, 94.3%). IH NMR (400 MHz, CD30D) δ 7.72 (s, IH), 7.60 (t, J=4.5 Hz, 2H), 4.31 (s, 2H), 2.76 (s, 3H). INTERMEDIATE 7
Figure imgf000044_0001
Step A
Figure imgf000044_0002
To a suspension of 4-(4-fluorophenyl)-l,2,3,6-tetrahydropyridine hydrochloride (10 g, 47 mmol) in dichloromethane (150 mL) was added diisopropylethylamine (8.97 mL, 51.5 mmol), followed by di-tert-butyl dicarbonate (12.27 g, 56.2 mmol), and the resulting mixture stirred at room temperature for 2 hours. N,N-dimethylethylenediamine (1 mL, 9 mmol) was added and stirring continued for a further 30 mins. The reaction mixture was washed with 5% citric acid solution (100 mL), water (2 x 100 mL), saturated NaCl (50 mL), dried over MgS04, filtered and concentrated in vacuo to give 13.5 g crude product, which was used without further purification in step B.
Step B
Figure imgf000044_0003
To a cooled (0°C) solution of borane-methyl sulfide complex (5.9 mL, 59 mmol) in anhydrous tetrahydrofuran (100 mL) under an atmosphere of nitrogen, was added using a canula, a solution of the BOC tetrahydropyridine prepared in Step A (13.5 g, 49 mmol) in tetrahydrofuran (100 mL). The resulting mixtore was stirred at room temperature for 17 hours, then cooled in an ice bath and sodium hydroxide (18 mL of a 3N solution, 53.8 mmol) added in a dropwise manner, followed by hydrogen peroxide (20 mL of a 30% solution). The resulting mixture was stirred at 450C for 1 hour, then poured into water (500 mL) and extracted with diethyl ether (3 x 100 mL). The combined diethyl ether layers were washed with water (500 mL), saturated NaHC03 (200 mL), saturated NaCl (150 mL), dried over MgS04, filtered and concentrated in vacuo to give 12.1 g (84%) of product. This material was used in Step C without further purification. H NMR (CDCI3, 500 MHz): δ 7.26 (dd, J = 5.5, 8.7
Hz, 2H), 7.03 (t, J = 8.7 Hz, 2H), 4.40 (br m, IH), 4.20 (br m, IH), 3.64 (m, IH), 2.76 (br m, IH), 2.63 (br m, IH), 2.53 (m, IH), 1.86-1.64 (m, 3H), 1.48 (s, 9H). Step C
Figure imgf000045_0001
A solution of the BOC piperidine prepared in Step B (500 mg, 1.7 mmol) in methanol (20 mL) was saturated with anhydrous hydrogen chloride gas, and the resulting mixture left standing at room temperature for 7 hours. The mixtore was concentrated in vacuo, and the residue partitioned between saturated NaHC03 (30 mL) and dichloromethane (20 mL). The organic layer was separated, and the aqueous layer extracted with further portions of dichloromethane (2 x 20 mL). The combined dichloromethane layers were dried over MgS04, filtered and concentrated in vacuo to give 260 mg (78%). ESI-MS calc. for C11H14FNO: 195; Found: 196 (M+H).
INTERMEDIATE 8
Figure imgf000045_0002
Step A
Figure imgf000045_0003
To a solution of 4- trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2 N NH3/MeOH (400 mL) was added Raney Ni (-4.0 g). The reaction mixture was placed in a Parr Apparatus and hydrogentated under 50 lb pressure of H2 overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95%). ESI-MS calc. For C9H10F3N: 189; Found: 190
(M+H).
Step B
Figure imgf000046_0001
The above amine (Step A) (38 g, 200 mmol) and DIEA (52 mL, 300 mmol) were dissolved in DCM (300 mL). The solution was cooled to 0 °C before TFAA (36 mL, 250 mmol) was added slowly. The reaction mixture was stirred in the ice bath for another 10 minutes before being warmed up to room temperatore. The reaction was completed in 30 minutes and was poured into water and exttacted with DCM (2x). The organic layer was washed with 1 N HCl and saturated NaCl solution, dried over MgSθ4, and concentrated in vacuo to yield the desired amide (56 g, 98%). ESI-MS calc. For C11H9F6NO: 285; Found: 286 (M+H). Step C
Figure imgf000046_0002
To a mixture of the amide (Step B) (73 g, 256 mmol) and paraformaldehyde (11.5 g, 385 mmol) was added 200 mL of acetic acid. The reaction mixture was stirred at room temperature for 5 min before concentrated sulfuric acid (200 mL). An exothermic reaction was observed. After 30 min, TLC showed a complete conversion. The mixtore was cooled to RT before poured onto ice water (2000 mL) and extracted with EtOAc (3 x 500 mL). Combined organic layers were washed with water (2x), saturated NaHC03, and brine, dried over MgS04, filtered, evaporated and dried in vacuum. The desired amide (72.7 g, 96%) was obtained as a light-yellow solid. IH NMR (400MHz, CDC13) δ 7.22 (q, J=11.67 Hz, 8.46 Hz, IH), 7.11 (t, J=10.53 Hz, IH), 7.03 (d, J=11.67 Hz, IH), 4.79 (d, J=23.57 Hz, 2H), 3.91 (t, J=6.18Hz, IH), 3.87 (t, J=5.72 Hz, IH), 2.97 (m, 2H). ESI-MS calc. For C12H9F6NO: 297; Found: 298 (M+H). Step D
HcσcFs The amide (Step C) (50 g, 168 mmol) was dissolved in EtOH (200 mL) before solid K2CO3 (50 g, 360 mmol) and H2O (50 mL) were added. The reaction mixture was refluxed for 15 hours before concentrated in vacuo. The concentrate was diluted with H2O (100 mL) and exttacted with DCM (5x). Combined organic layers were dried over MgS04, filtered, concentrated and purified on FC (10% [aq. NH40H/MeOH l/9]/DCM) to yield the amine (Step D)(30 g, 89%). IH NMR (400MHz, CDC13) δ 7.11 (d, J=8.4 Hz, IH), 7.01 (bd, J=8.4 Hz, IH), 6.89 (s, IH), 4.03 (s, 2H), 3.15 (t, J=6.1 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 1.80 (s, IH). ESI-MS calc. For C10H10F3N:
201; Found: 202 (M+H).
INTERMEDIATE 9
Figure imgf000047_0001
To a solution of tettahydro-4H-ρyran-4-one (5 g, 50 mmol) and benzhydryl amine (8.41 mL, 50 mmol) in DCM (250 mL) was added molecular sieves (4 A, powder) followed by NaBH(OAc)3 (32 g, 150 mmol). The reaction mixture was stirred at room temperature overnight before filtered through celite, washed with saturated NaHCθ3 (4x), dried over MgS04, filtered, and concentrated in vacuo to yield a crude product of the amine which was used on next step (13.25 g, 99.9%). IH NMR
(400MHz, CDCI3) δ 7.42 (bd, J=7.0 Hz, 4H), 7.32 (bt, J=7.2 Hz, 4H), 7.24 (bt, J=7.3 Hz, 2H), 5.07 (s, IH), 3.96 (dt, J=ll.l Hz, 3.5 Hz, 2H), 3.33 (td, J=11.5 Hz, 2.1 Hz,
2H), 2.66 (m, IH), 1.93 (m, 2H), 1.54 (bs, IH), 1.44 (m, 2H).
Figure imgf000048_0001
A mixtore of the amine (Step A) (13.2 g, 49.4 mmol), 4 N HCl/dioxane (12.5 mL, 49.4 mmol), Pd/C 10% (1.1 g), dioxane (30 mL), and EtOH (120 mL) was placed on a Parr Apparatus and hydrogenated at 35 lb pressure of H2 overnight. The reaction mixture was filtered through celite and concentrated to dryness. The concentrate was stirred in DCM. The precipitate was filtered and dried to yield Intermediate 3 (4.9 lg, 72.2%). IH NMR (400MHz, CD3OD) δ 3.99 (dd, J=12.1 Hz, 5.1 Hz, 2H), 1.89 (td,
J=11.9 Hz, 2.1 Hz, 2H), 3.38-3.32 (m, IH), 1.96-1.92 (m, 2H), 1.70-1.59 (m, 2H).
INTERMEDIATE 10
Figure imgf000048_0002
Intermediate 10 was prepared according to the procedure described in /. Am. Chem. Soc, 1991, 113, 2079-2089.
INTERMEDIATE 11
Figure imgf000048_0003
To a solution of 5-trifluoromethyl-2-pyridinal (51 g, 310 mmol) and sodium acetate (26.2g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80 °C for 2.5 h. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHC03 solution and extracted with ethyl acetate (3 x 200 mL). The organics were combined, dried over MgS04j filtered, and evaporated in vacuo to yield 74.45 g (98%) of the crude product. IH NMR (400 MHz, CDCI3) δ 8.04 (d, J=2.6 Hz, IH), 7.89 (m, IH).
Step B
Figure imgf000049_0001
Under nitrogen, the substituted pyridine described in Step A (48.8g,
202 mmol) was added in small portions to a suspension of NaH (8.9 g, 220 mmol) in anhydrous tetrahydrofuran (500 mL). After complete addition of the intermediate, the reaction mixture was cooled to -78 °C and treated with tert-butyllithium (260 mL, 444 mmol) added dropwise via syringe. After stirring for 5 min, N,N- dimethylformamide (50 mL, 707 mmol) was added slowly to maintain the temperature below -50 °C. The resulting mixture was then stirred for 10 h allowing it to warm to room temperature. The mixture was quenched with 2 N HCl and then diluted with ethyl acetate (1000 mL). The organic layer was separated, washed with brine, dried over MgS04, and evaporated in vacuo. The desired product was precipitated out of ethyl acetate and hexanes and filtered to yield a light brown solid (28.55 g, 74%). lH NMR (500 MHz, CD3OD) δ 10.13 (s, IH), 8.21 (s, 2H).
Figure imgf000049_0002
A mixture of the intermediate from Step B (18 g, 95 mmol), sodium formate (7.1 g, 110 mmol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and formic acid (150 mL) was stirred at room temperatore for 2 h and then heated to reflux overnight. The reaction mixture was cooled and allowed to stand at room temperatore for 7 days. The reaction was poured into water and extracted with ethyl acetate (3 x). The combined organic layers were washed with water (2 x), saturated NaHCθ3 and brine, dried over Na2S04, filtered, and concentrated in vacuo to yield the desired product as a brown powder (17.84 g, 90%). lH NMR (400 MHz, CD3OD) 6 8.37 (d, J=2.7 Hz, IH), 8.19 (q, J=0.7 Hz, 0.3 Hz, IH).
Figure imgf000050_0001
To a mixture of phosphorous oxychloride (13.4 mL, 144 mmol) and quinoline (8.7 mL, 73 mmol) was added the product from Step C (24.6 g, 131 mmol) and the resulting mixture was heated to reflux for 3 h. The reaction was cooled to 100 °C before water (70 mL) was slowly added. The mixture was further cooled to room temperature and neutralized carefully with saturated NaHC03 solution. The aqueous layer was extracted with ethyl acetate (3 x) and the organic layers were combined, dried over MgS04, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography to afford (23.5 g, 87%) of the desired compound. lH NMR (500 MHz, CDCI3) δ 8.88 (d, J=2.0 Hz, IH), 8.26 (d, J=2.5
Hz, IH).
Figure imgf000050_0002
To a suspension of NaH (7.8 g, 200 mmol) in tetrahydrofuran (100 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (20 mL, 120 mmol) in anhydrous tetrahydrofuran (100 mL) via syringe. The reaction mixture was stirred for 0.5 h before a solution of the intermediate prepared in Step D (20.1 g, 97.6 mmol) in tetrahydrofuran (200 mL) was added slowly via syringe. The reaction was stirred at room temperature overnight, then quenched with a saturated solution of NH4CI. The organic layer was separated and the aqueous layer was exttacted with ethyl acetate (3 x). The combined organic layers were washed with water (3 x), dried over Na2S04, filtered, and evaporated in vacuo. Flash chromatography afforded 31.76 g (95%) of the pure desired product. lH NMR (500 MHz, CDCI3) δ 9.03 (d, J=1.5 Hz, IH), 8.25 (d, J=2.0 Hz, IH), 5.25 (s, IH), 3.86 (s,
3H), 1.52 (s, 9H)
Figure imgf000051_0001
A suspension of Raney Ni (1 g) and the product from Step E (18.2 g, 52.9 mmol) in ethanol (130 mL) was placed on a Parr apparatus and hydrogenated at 40 psi H2 overnight. The suspension was filtered through celite and the filtrate was evaporated in vacuo to afford 16.35 g (98%) of the crude product. lH NMR (500 MHz, CDCI3) δ 8.83 (s, IH), 7.89 (s, IH), 7.82 (s, IH), 4.83 (d, J=16 Hz, IH), 4.72
(s, IH), 4.49 (d, J=16 Hz, IH), 1.45 (s, 9H).
Step G O"'
To the mixtore of the product from Step F (16 g, 51 mmol) in dichloromethane (60 mL) was added TFA (30 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The mixture was neuttalized by the slow addition of a solution of saturated sodium bicarbonate and the organic layer was removed. The aqueous layer was extracted with dichloromethane (4 x) and the combined organic layers were dried over Na2S04, filtered, and evaporated in vacuo to afford 10.42 g (95%) of the desired product. lH NMR (400 MHz, CDCI3) δ 8.81 (s, IH), 7.78 (s, IH), 7.30 (s, IH), 4.63 (s, 2H), 3.90 (s, 2H).
Step H
Figure imgf000052_0001
To a solution of the product from Step G (18.0 g, 83.3 mmol) in tetrahydrofuran (50 mL) was added 1.0 M borane in tetrahydrofuran (417 mL, 420 mmol) and the resulting solution was stirred at room temperature overnight. The solution was evaporated under reduced pressure and the residue was treated with 1% HCl/ methanol solution. The resutling mixture was heated at 50 °C overnight to breakdown the borane complex. Treatment with acidic methanol was repeated twice to insure that the borane complex was removed. A solution of this crude product (83.3 mmol, assuming 100% conversion) and diisopropylethylamine (43 mL, 250 mmol) in dichloromethane was treated with di-tert-butyl dicarbonate (36.4 g, 167 mmol) and the resulting mixtore was stirred at room temperatore overnight. The solution was washed with saturated sodium bicarbonate solution, water, and brine. The aqueous layers were combined and back-washed with dichloromethane (2 x). The combined organic layers were then dried over Na2S04, filtered, and evaporated to dryness. The crude product was purified by flash chromatography and MPLC to afford (11.89 g, 47%) as a yellow solid. lH NMR (500 MHz, CDCI3) δ 8.69 (s, IH),
7.66 (s, IH), 4.67 (s, 2H), 3.79 (t, J=6.0 Hz, 2H), 3.08 (t, J=5.5 Hz, 2H), 1.51 (s, 9H).
Figure imgf000052_0002
The product described in Step H (11.89 g) was treated with a solution of 4 N HCl in dioxane. The solution was stirred at room temperature for 2 h and then evaporated in vacuo to afford Intermediate 10 (10.85 g, 99%) as a yellow powder. LC-MS for C9H10F3N2 calculated 202.07, found [M+H] + 203.0.
INTERMEDIATE 12
Figure imgf000053_0001
Step A
Figure imgf000053_0002
To a stirred solution of 4-hydroxypiperidine (60.8 g) in dichloromethane (500 mL) was added a solution of di-tert-butyl dicarbonate (19 g, 0.55 mol) in dichloromethane (500 mL) very slowly. After the addition, which took 1 h, the resulted mixture was stirred at ambient temperature for 5 h. The mixture was then washed with saturated NaHCθ3, 3 N HCl, brine, dried and evaporated to give tert-butyl 4- hydroxypiperidine-1-carboxylate as a thick oil (90 g). Step B:
Figure imgf000053_0003
To a stirred solution of tert-butyl 4-hydroxypiperidine- 1-carboxylate (21.1 g, 100 mmol) and ttiethyl amine (22 mL) in dichloromethane (250 mL) at 0 °C was slowly added methanesulfonyl chloride (9.0 mL, 1.1 equiv.). The resulting mixture was stirred for an additional 1 h and during this time white solid was formed. The mixture was then washed with 3 N HCl, dried over Na2S04 and evaporated to give: tert-butyl
4-[(methylsulfonyl)oxy]piperidine-l-carboxylate as a white solid (29.2 g). lH NMR (400 MHz, CDCI3): δ 4.92-4.87 (m, IH), 3.75-3.69 (m, 2H), 3.34-3.28 (m, 2H), 3.05
(s, 3H), 2.01-1.94 (m, 2H), 1.87-1.78 (m, 2H). Step C:
Figure imgf000054_0001
To a stirred solution of : tert-butyl 4-[(methylsulfonyl)oxy]piperidine-l-carboxylate (5.9 g, 21 mmol) and 1,2,4-ttiazole (1.8 g, 25 mmol equiv.) in DMF at ambient temperatore was added sodium hydride (60 % in mineral oil, 1.0 g, 25 mmol). The mixture was stirred at 60 °C for 5 days, and the TLC showed no starting mesylate left. The mixture was poured into ice water and exttacted with ethyl acetate (3 x). The organic layer was dried, evaporated and purified by silica flash column eluting with 0- 10 % methanol in ethyl acetate to give tert-butyl 4-(lH-l,2,4-triazol-l-yl)piperidine- 1-carboxylate as a white solid. The solid was then treated with hydrogen chloride in dioxane (4 N, 10 mL) for 2 h. The mixture was then evaporated to remove most of the dioxane to give a white solid, which was washed with ethyl acetate to give the desired 4-(lH-l,2,4-ttiazol-l-yl)piperidine hydrochloride salt (5.55 g). lΗ NMR (300 MHz, CD3OD): δ 10.00 (s, IH), 8.97 (s, IH), 5.10-5.00 (m, IH), 3.63-3.58 (br. d,
2H), 3.33-3.26 (br. d, 2H), 2.50-2.30 (m, 4H).
The following intermediates 13-17 were prepared in a similar fashion to Intermediate 12 using : tert-butyl 4-[(methylsulfonyl)oxy]piperidine-l-carboxylate and the appropriate heterocycles.
INTERMEDIATE 13
Figure imgf000054_0002
Prepared from 1,2,3-triazole according to the procedure for Intermediate 12. 4-(lH-l,2,3-triazol-l-yl)piρeridine hydrochloride: lH NMR (400 MHz, CD3OD): δ
8.77 (s, IH), 8.54 (s, IH), 5.26-5.19 (m, IH), 3.65-3.59 (m, 2H), 3.37-3.29 (m, 2H), 2.60-2.54 (m, 2H), 2.50-2.39 (m, 2H). INTERMEDIATE 14
Figure imgf000055_0001
Prepared from 1,2,3-ttiazole according to the procedure for Intermediate 12. 4-(2H-l,2,3-ttiazol-2-yl)piperidine hydrochloride: lH NMR (400 MHz, CD3OD): δ
7.72 (s, 2H), 4.94-4.87 (m, IH), 3.54-3.48 (m, 2H), 3.28-3.22 (m, 2H), 2.46-2.32 (m, 4H).
INTERMEDIATE 15
Figure imgf000055_0002
Prepared from tetrazole according to the procedure for Intermediate 12. 4-(lH-tetraazol-l-yl)ρiρeridine hydrochloride: lH NMR (400 MHz, CD3OD): δ 8.77 (s, IH), 5.30-5.23 (m, IH), 3.58-3.53 (m, 2H), 3.35-3.29 (m, 2H), 2.58-2.2.52 (m, 2H), 2.48-2.38 (m, 2H).
INTERMEDIATE 16
Figure imgf000055_0003
Prepared from tetrazole according to the procedure for Intermediate 12. 4-(2H-tetraazol-2-yl)piρeridine hydrochloride: lΗ NMR (400 MHz, CD3OD): δ 9.32 (s, IH), 5.08-5.00 (m, IH), 3.61-3.57 (m, 2H), 3.33-3.28 (m, 2H), 2.52-2.47 (m, 2H), 2.42-2.32 (m, 2H).
INTERMEDIATE 17
Figure imgf000056_0001
Prepared from 5-methyltetrazole according to the procedure for Intermediate 12. lH NMR (400 MHz, CD3OD): δ 5.08-5.00 (m, IH), 3.61-3.57 (m, 2H), 3.33-3.28
(m, 2H), 2.52-2.47 (m, 2H), 2.42-2.32 (m, 2H), 1.68 (s, 3H).
EXAMPLE 1
Figure imgf000056_0002
Intermediate 1 (200mg, 1.75 mmol), tώ-trifluoromethylbenzylamine (490mg, 1.75 mmol), DBA (306 μL, 1.75 mmol), HO AT (240 mg, 1.75 mmol), EDC (504mg, 2.63 mmol) and DCM (15 ml) were mixed and stirred at room temperatore for 18 hours. The reaction mixtore was diluted with DCM, washed with IN HCl, saturated NaHCθ3 solution, water and brine, dried over anhydrous MgS04, and concentrated in vacuo to yield the product (529mg, 89%). NMR (300 MHz, CDCI3) δ 7.81 (s, IH), 7.74 (s, 2H), 6.13 (s, IH), 4.62 (d, J=6.04 Hz, 2H), 3.56-3.47 (m, 2H), 3.29-3.20 (m,
2H), 3.07 (m, IH).
Figure imgf000057_0001
Product from Step A (lOOmg, 0.295 mmol), Intermediate 2 (70mg, 0.295 mmol), DIEA (103 μL, 0.590 mmol), molecular sieves, NaBH(OAc)3 (313, 1.474 mmol), and
DCE (10 ml) were mixed and stirred at room temperature for 18 hours. The reaction was purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM). Cis and ttans isomers were also separated (cis 90mg, trans 23mg, 73.4%) Cis was the less polar and more active isomer. Cis isomer : NMR (500 MHz, CDCI3) δ 7.81 (s, IH), 7.78
(s, 2H), 7.30 (d, J= 7.1 Hz, IH), 7.24 (dt, J= 7.2 Hz, 1.6 Hz, IH), 7.18 (m, 2H), 6.96 (s, IH), 6.81 (d, J=5.8 Hz, IH), 6.64 (d, J=6.0 Hz, IH), 4.61 (d, J=5.9 Hz, 2H), 3.01 (s, IH), 2.95-2.84 (m, 3H), 2.50 (t, J=5.6 Hz, 2H), 2.25-2.13 (m, 5H), 1.90 (m, IH), 1.33 (m, IH), 0.32 (d, J=6.9 Hz, 3H). LC-MS for C28H28F6N2O MW calculated
522.21, found 523.2.
A variety of amine substitution on the R position of cyclobutane ring was prepared using the same reaction procedure illustrated in Example 1. The table below summarizes these compounds.
Figure imgf000057_0002
Figure imgf000058_0002
EXAMPLE 11
Figure imgf000058_0001
Step A
Figure imgf000059_0001
Intermediate 3 (100 mg, 0.49 mmol), Intermediate 2 (116mg, 0.49 mmol), DIEA (171 μL, 0.98 mmol), molecular sieves, NaBH(OAc)3 (520mg, 2.45 mmol), and DCM (10 ml) were mixed together and stirred at room temperature for 60 hours. The reaction was purified by preparative TLC (2:0.2:97.8, MeOH:NH4θH:DCM) to yield the product (95mg, 50%). LC-MS for C26H29NO2 MW calculated 387.22, found 388.15.
Figure imgf000059_0002
The product from Step A (90mg, 0.232mmol), 5N NaOH solution (325 μL, 1.63 mmol), EtOH (3 ml) and water (2.65 mL) were mixed together and stirred at room temperature. Upon disappearance of starting material, reaction mixture was concentrated in vacuo and redissolved in water. The aqueous layer was neutralized to pH7.0 with 2N HCl solution before extracted with DCM (7x). The organic layer contained mostly benzyl alcohol. The aqueous layer was concentrated down and redissolved in DCM. The organic layer was filtered and concentrated in vacuo to yield the product (60mg, 87.0%).
Figure imgf000059_0003
The product from Step B (60mg, 0.202mmol), 3-fluoro-5-trifluoromethylbenzylamine (30 μL, 0.202mmol), HOAT (28mg, 0.202mmol), and EDC (60mg, 0.303mmol) were mixed together and stirred at room temperatore for 18 hours. The reaction mixture was purified by preparative TLC (3 :0.3 :96.7, MeOH:NH-iOH:DCM). Cis and trans isomers were separated (cis 12mg, ttans lmg, 13.7%). LC-MS for C27H28F4N2O MW calculated 472.21, found 473.2.
EXAMPLE 12
Figure imgf000060_0001
A solution of 60% NaH (lOg, 250 mmol) suspended in DMF (100 ml) was cooled to 0
°C before benzylcyanide (11.7g, 100 mmol) was added slowly. The solution was stirred at 0°C for another 10 minutes before dimethoxy-dibromomethane (13.1g,
50mmol) was added. The reaction mixture was stirred at 6O0C for 18 hours before cooled to room temperatore, poured into water, and exttacted with ether. The combined organic layer was concenttated in vacuo. The crude product was purified by flash chromatography (20:80, ethylacetate:hexanes) to yield the desired product
(6.4g, 59%). NMR (300 MHz, CDC13) δ 7.50-7.32 (m, 5H), 3.23 (d, J=30.6 Hz, 6H),
3.11 (dm, J=13.6 Hz, 2H), 2.73 (dm, J=11.7 Hz, 2H).
Figure imgf000060_0002
A solution of The product from Step A (4.4 g, 20 mmol), 5 M NaOH (20 mL), EtOH (50 mL), and water (50 mL) were heated at reflux overnight before concentrated to dryness. The concentrated was redissolved in water (20 mL), dioxane (30 mL), and 12 M HCl (10 mL). The reaction mixtore was stirred at room temperature for 3 hours before concenttated in vacuo. The reaction was redissolved in IN HCl and exttacted with EtOAc (2x). Combined organic layer was dried over anhydrous MgSθ4 and concentrated in vacuo to yield a white solid of 12-B. The crude product was used on next step. NMR (500 MHz, CDCI3) δ 7.43-7.36 (m, 5H), 3.95 (dm, J=20.1 Hz, 2H),
3.62 (dm, J=20.4 Hz, 2H).
Figure imgf000061_0001
A solution of the product from Step B (500mg, 2.63mmol), 3,5- bisttifluoromethylbenzylamine (735 mg, 2.63 mmol), DIEA (686 μL, 3.94 mmol), HO AT (358 mg, 2.63 mmol), EDC (755 mg, 3.94 mmol), and DCM (20mL) were stirred at room temperature overnight. The reaction mixtore was washed with 1 M HCl (2x), saturated NaHCθ3 and water (3x), dried over anhydrous MgSθ4, and concenttated in vacuo to yield the desired product as a white powder (630 mg, 57.8%). The crude product was used in next step. NMR (500 MHz, CDC13) δ 7.76 (s, IH), 7.53 (s, 2H), 7.50 (m, 2H), 7.42 (m, 3H), 5.75 (s, IH), 4.51 (d, J=6.2 Hz, 2H), 4.00-3.96 (dm, J=19.2 Hz, 2H), 3.56-3.52 (dm, J=19.2 Hz, 2H).
Figure imgf000061_0002
A solution of the product from Step C (200 mg, 0.482 mmol), Intermediate 2 (115mg, 0.482 mmol), DIEA (126μL, 0.723mmol), 4 A powdered molecular sieves, NaBH(OAc)3 (515 mg, 2.41 mmol), and DCM (20 ml) was stirred at room temperature overnight before being filtered through celite and purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM). The cis and trans isomers were also separated (less polar isomer 82.4 mg, more polar isomer 128 mg, 74.9%). More polar isomer: IH NMR (500 MHz, CDC13) δ 7.75 (s, IH), 7.55 (s, 2H), 7.46 (m, 2H), 7.38- 7.32 (m, IH), 7.32-7.27 (m, IH), 7.27-7.2 (m, 2H), 6.80 (d, J=5.7 Hz, IH), 6.61 (d, J=5.7 Hz, IH), 4.51 (d, J=6.2 Hz, 2H), 3.08-2.77 (m, 7H), 2.31-2.18 (m, 3H), 1.93 (t, J=10.9 Hz, IH), 1.34 (d, J=12.8 Hz, IH), 0.33 (d, J=7.1Hz, 3H). LC-MS for C34H32F6N2O MW calculated 598.24, found 599.25.
A variation of compounds with phenyl substitution at Rl position, amine substitution at R2 position, and fluorine substitution at R3 position were prepared using the reaction scheme detailed in Example 12. Phenyl derivatives were synthesized from different substituted phenylniteiles using the procedure detailed in Step A. 3-fluoro-5- ttifluoromethylbenzylamine was substituted in Step C. Amine SAR was followed the same procedure detailed in Step D. All of the components are either commercially available or are described in the Intermediates section. These compounds are summarized in the table below.
Figure imgf000062_0001
X 1 X 2 X 4 X5 X 6 X7
Figure imgf000062_0002
Figure imgf000062_0003
Figure imgf000063_0001
EXAMPLE 41
Figure imgf000064_0001
A solution of Example 16 (40 mg, 0.08 mmol), 37% formaldehyde (20 μL, 0.24 mmol), DIEA (25 μL, 0.12 mmol), TFA (5/iL), NaCNBH (25 mg, 0.40 mmol), and MeOH (1.5 mL) was stirred at room temperature and the reaction was monitored by TLC. The crude reaction was purified by preparative TLC (5:0.5:94.5, MeOH:NH4θH:DCM). Cis and ttans isomers were separated with the more polar isomer being the cis and more active isomer. LC-MS for C26H28F6N2O2 MW calculated 514.21, found 515.35.
EXAMPLE 42
Figure imgf000064_0002
Example 42 was synthesized from Example 21 using the procedure detailed in
Example 41. Cis and trans isomers were synthesized separately from the cis and trans isomers of Example 41, with the ttans being the more polar and active isomer. LC-MS for C25H28F4N2O2 MW calculated 464.21, found 465.25.
EXAMPLE 43
Figure imgf000064_0003
Step A
Figure imgf000065_0001
A solution of the product from Step A, Example 12 (2.0g, 9.2 mmol), Raney Ni (200 mg), NH4OH (lOmL) and EtOH (50 ml) was shaken on a Parr-Apparatus at 40 psi for
24 hours. Upon disappearance of starting material on HPLC, the reaction mixture was filtered through celite and concenttated in vacuo. The crude product was used on next step.
Figure imgf000065_0002
The product from Step A (2.0 g, 9.2 mmol) was dissolved in DCM before di-tert- butyl dicarbonate (2.4 g, 11 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours before concentrated in vacuo to yield the product, which was used directly in the next step.
Figure imgf000065_0003
The product from Step C (2.96g, 9.2mmol) was dissolved in dioxane (20 ml) and water (20πιL) before 1 M HCl (2 mL) was added. The reaction mixtore was stirred at room temperatore for 18 hours before being extracted with EtOAc. The organic layer was washed with saturated NaHC03 solution and concenttated in vacuo to yield the product. The crude product was used on next step.
Figure imgf000065_0004
A solution of the product from Step C (500 mg, 1.82 mmol), Intermediate 2 (430 mg, 1.82 mmol), DIEA (475 μL, 2.73 mmol), 4 A molecular sieves, NaBH(OAc)3 (1.90 g,
9.10 mmol), and DCM (40 mL) was stirred at room temperatore overnight before being filtered through celite and purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM) to yield the desired product (696mg, 83.6%). LC-MS for C30H38N2O2 MW calculated 458.29, found 459.
Figure imgf000066_0001
the product from Step D (400 mg, 0.873 mmol) was stirred in a solution of 95% TFA in water (5 mL). The reaction was monitored by HPLC. Upon completion of reaction, the mixture was concenttated in vacuo, redissolved in a minimum amount of DCM, and washed with saturated NaHC03 (4x) to get rid of TFA. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to yield the desired product (208 mg, 66.5%). The crude product was used on next step.
Figure imgf000066_0002
A solution of the product from Step E (10 mg, 0.028 mmol), 3,5- bisttifluoromethylbenzoic acid (7.2 mg, 0.028 mmol), HOAT (3.8 mg, 0.028 mmol), EDC (8.0 mg, 0.028 mmol), and DCM (0.75 mL) was stirred at room temperature overnight. The crude reaction mixture was purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM) to yield Example 43. Cis and ttans isomers were separated with cis being the more polar and active isomer. LC-MS for C33H32 F6N2O1 MW calculated 598.24, found 599.35. A variety of compounds with different benzoic amide was prepared using the reaction scheme detailed in Example 43 using different benzoic acids, that were commercially available. These compounds are summarized in the table below.
Figure imgf000068_0001
Figure imgf000068_0002
EXAMPLE 54
Step A
Figure imgf000069_0001
Intermediate 3 (4.93 g, 24.2 mmol) was dissolved in DCM (50 mL) and MeOH (50 mL) first before TMOF (26.5 mL, 242 mmol) was added. TsOH (460 mg, 2.42 mmol) was added last. The reaction mixture was stirred for 2.5 hours before being concenttated in vacuo. The concentrate was diluted with EtOAc, quenched with saturated NaHC03 solution, washed with brine, dried over anhydrous MgS04, and concenttated in vacuo. The crude product was purified by MPLC (20:80, EtOAc:hexanes) to yield the desired product (5.71g, 94.5%). IH NMR (500 MHz, CDCI3) δ 7.37 (m, 5H), 5.16 (s, 2H), 3.17 (d, J=11.6 Hz, 6H), 2.95 (m, IH), 2.44 (m,
4H). Step B
Figure imgf000069_0002
To a flamed dried round-bottomed flask were added the product from Step A (300mg, 1.20mmol), Mel (150μL, 2.40mmol), and THF (7mL) at -78 oc under N2. 0.5 M KHMDS in THF (4.8 mL, 2.40 mmol) was added last. The reaction mixtore was stirred at -78°C for 6 hours before being warmed to room temperature and stirred overnight. The reaction mixture was poured into saturated NH4CI solution and exttacted with ether (4x). Combined organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The crude product was purified by preparative TLC (20:80, EtOAc:hexanes) to yield the desired product (228mg, 71.9%). IH NMR (400 MHz, CDC13) δ 7.37 (m, 5H), 5.16 (s, 2H), 3.15 (d, J=18.4 Hz, 6H), 2.68 (dm, J=13.3 Hz, 2H), 2.08 (dm, J=13.1 Hz, 2H), 1.47 (s, 3H).
Figure imgf000070_0001
The product from Step B (220 mg, 0.83 mmol) was stirred in a solution of 90% TFA in water (10 mL). Upon completion of reaction, the mixtore was concenttated to dryness and redissolved in ether. The organic layer was washed with saturated NaHCθ3 (4x) and water, dried over anhydrous MgSθ4, and concentrated in vacuo to yield the desired product (150 mg, 82.4%). IH NMR (500 MHz, CDCI3) δ 7.37 (m,
5H), 5.22 (s, 2H), 3.61 (dm, J=19.9 Hz, 2H), 2.93 (dm, J=19.9 Hz, 2H), 1.62 (s, 3H).
Figure imgf000070_0002
A solution of the product from Step C (150 mg, 0.688 mmol), Intermediate 2 (165 mg, 0.688 mmol), DIEA (180μL, 1.03mmol), molecular sieves, NaBH(OAc)3 (730 mg, 3.44 mmol) in DCM (15mL) was stirred at room temperature overnight. The reaction mixtore was filter through celite, concenttated in vacuo, and purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM) to yield the desired product as a mixture of cis and ttans isomers (267mg, 96.7%). LC-MS for C27H31NO2 MW calculated 401.24, found 402.2.
Figure imgf000070_0003
The product from Step D (260 mg, 0.648 mmol), 5 M NaOH solution (650 μL, 324 mmol), EtOH (5 mL) and water (1 mL) were mixed together and stirred at room temperatore. Upon disappearance of starting material, the reaction mixture was concenttated in vacuo and redissolved in water. The aqueous layer was first washed with ether to get rid of the benzyl alcohol before being neuttalized to pH 7.0 with 2 M HCl solution. The aqueous layer was extracted with DCM (5x). The combined organic layer was dried over anhydrous MgS04, filtered, and concenttated in vacuo to yield the desired product (112mg, 55.6%).
Figure imgf000071_0001
The product from Step E (30 mg, 0.096 mmol), bis-trifluoromethylbenzylamine hydrochloride (30 mg, 0.096 mmol), DIEA (25 μL, 0.15 mmol), HOAT (15 mg, 0.096 mmol), and EDC (28 g, 0.15 mmol) were mixed together in DCM and stirred at room temperatore overnight. The reaction mixtore was purified by preparative TLC
(3:0.3:96.7, MeOH:NH4θH:DCM). Cis and trans isomers were separated with cis being the less polar and more active isomer (cis 43mg, trans 3.5mg, 89.0%). LC-MS for C29H30F6N2O MW calculated 536.23, found 537.25.
A variety of compounds with different alkyl substitution at the Rl and R2 position were prepared using the reaction procedures detailed in Example 57. Alkylating used were Etl, Prl, and methyl disulfide (MeS). The stereoisomers of the propyl and thiomethyl compounds were separated on a chiral OD column. The table below summarizes these compounds.
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000072_0003
EXAMPLE 64
Figure imgf000072_0001
The product from Example 54, Step E (25 mg, 0.080 mmol), Intermediate 6 (20 mg, 0.080 mmol), DIEA (21 μL, 0.12 mmol), HOAT (12 mg, 0.080 mmol), and EDC (25 mg, 0.12 mmol) were mixed together in DCM (2 mL) and stirred at room temperature overnight. The reaction mixture was purified by preparative TLC (50:50, EtOAc:hexanes) to yield Example 64 (12.5mg, 31.3%). LC-MS for C29H32F4N2O
MW calculated 500.25, found 501.25.
EXAMPLE 65
Figure imgf000072_0002
Example 57 (15 mg, 0.028 mmol) and Pd/C (5 mg) were stirred in EtOH (7mL) under hydrogen overnight. The reaction was filtered through celite and concenttated in vacuo to yield Example 65 (13.6 mg, 90.7%). LC-MS for C29H32F6N2O MW calculated 538.24, found 5.39.2. EXAMPLE 66
Figure imgf000073_0001
Example 58 (15 mg, 0.028 mmol) and Pd/C (5 mg) were stirred in EtOH (7mL) under hydrogen overnight. The reaction was filtered through celite and concenttated in vacuo to yield Example 66 (15 mg, 100%). LC-MS for C28H32F4N2O MW calculated 488.25, found 489.25.
EXAMPLE 67
Figure imgf000073_0002
Step A
O
0: OMe
A solution of Intermediate 1 (2.0 g, 18 mmol), MeOH (710 μL, 17.5 mmol), DMAP (215 mg, 1.75 mmol), EDC (5.04 g, 26.3 mmol) and DCM (100 mL) were mixed and stirred at room temperature overnight. The reaction mixture was washed with water (3x). Combined aqueous layer was exttacted with DCM. Combined organic layer was washed with brine, dried over anhydrous MgSθ4, and concenttated in vacuo to yield the desired product.. IH NMR (400 MHz, CDCI3) δ 3.79 (s, 3H), 3.48-3.25 (m, 5H).
Step B
O
MeO.
OMe MeO The product from Step A (2.25 g, 17.6 mmol) was dissolved in MeOH (25 mL) and DCM (25 mL) first before ttimethyl orthoformate (19 mL, 180 mmol) was added. TsOH (335 mg, 1.76 mmol) was added last. The mixture was stirred at room temperatore for 2 hours before concentrated in vacuo. The concentrate was redissolved in EtOAc, quenched with saturated NaHCθ3, washed with brine, dried over anhydrous MgS04, and concenttated in vacuo. The crude product was purified by MPLC (20:80, EtOAc:hexanes) to yield the desired product (1.72 g, 56.2% for last two steps). IH NMR (400 MHz, CDCI3) δ 3.71 (s, 3H), 3.17 (d, J=8.2 Hz, 6H), 2.90
(p, J=8.7 Hz, IH), 2.49-2.36 (m, 4H).
Figure imgf000074_0001
To a flame-dried flask was dissolved KHMDS (690 mg, 3.44 mmol) in THF (10 mL) under nitrogen. The mixture was cooled to -78°C before The product from Step B (300 mg, 1.72 mmol) and BnBr (615μL, 5.17 mmol) were added. The mixture was stirred at - 78 °C for 15 minutes before raised to room temperature. The reaction was monitored by TLC. Upon completion of reaction, the mixtore was dumped in saturated NH4CI solution and extracted with ether (3x). Combined organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The crude product was purified by preparative TLC (20:80, EtOAc:hexanes) to yield the desired product (261 mg, 57.4%). IH NMR (500 MHz, CDCI3) δ 7.33-7.2 (m, 3H), 7.10 (d, 2H), 3.67 (s,
3H), 3.17 (d, J=25.4 Hz, 6H), 2.60 (app d, J=13.3 Hz, 2H), 3.14 (s, 2H), 2.26 (app d,
J=13.5 Hz, 2H).
Figure imgf000074_0002
A solution of The product form Step C (261 mg, 0.988 mmol), 5 M NaOH (1 mL, 5 mmol) and EtOH (7 mL) was heated to reflux for 30 minutes before being concenttated to dryness. The concentrate was redissolved in 2 M HCl and dioxane. The solution was stirred at room temperature and the reaction was monitored by HPLC. Upon completion of the reaction, the mixtore was concentrated in vacuo to yield the crude product (157 mg, 77.7%). The crude product was used in next step without purification. IH NMR (500 MHz, CDCI3) δ 7.35-7.28 (m, 3H), 7.23 (app d,
J=7.1, 2H), 3.54 (app d, J=19.9 Hz, 2H), 3.30 (s, 2H), 3.16 (app d, J=20.1 Hz, 2H).
Figure imgf000075_0001
A solution of the product form Step D (150 mg, 0.735 mmol), 3-fluoro-5- ttifluoromethylbenzylamine (110 μL, 0.735 mmol), HOAT (100 mg, 0.735 mmol), EDC (215 mg, 1.10 mmol) and DCM (10 mL) were mixed together and stirred at room temperatore overnight. The crude reaction was purified by preparative TLC (30:70, EtOAc:hexanes) to yield the desired product (177 mg, 63.7%). IH NMR (500 MHz, CDCI3) δ 7.27 (app q, J=3.4 Hz, 1.8 Hz, 2H), 7.14 (s, IH), 7.22 (s, 2H), 7.11
(m, 2H), 7.01 (d, J=8.9 Hz, IH), 5.74 (s, IH), 4.42 (d, J=5.9 Hz, 2H), 3.53 (app d,
J=19.9 Hz, 2H), 3.23 (s, 2H), 3.15 (app d, J=19.9 Hz, 2H).
Step F
Figure imgf000075_0002
A solution of the product form Step E (40 mg, 0.11 mmol), Intermediate 2 (25 mg, 0.11 mmol), DIEA (28 μL, 0.16 mmol), 4 A molecular sieves, NaBH(OAc)3 (115 mg,
0.530 mmol) and DCM (5 mL) was stirred at room temperature overnight. The crude reaction was purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM) to yield the final product (57 mg, 96.1%). LC-MS for C34H34F4N2O MW calculated 562.26, found 563.35.
A variety of compounds with different amine and alkyl substitution were prepared according to the procedures detailed in Example 67 utilizing different amines and alkyl halides. All of the components are either commercially available or are described in the Intermediates section. Cis and trans isomers for some of these compounds were separated by preparative TLC. These compounds are summarized in the table below.
Figure imgf000076_0001
X1 X2 X3 X4
Figure imgf000076_0002
Y1 Y2 Y3 Y4 Y5
Figure imgf000076_0003
Figure imgf000077_0003
EXAMPLE 77
Figure imgf000077_0001
A solution of Example 75 (10 mg, 0.025 mmol), formaldehyde (6 μL, 0.08 mmol), DIEA (7 μL, 0.04 mmol), TFA (2.5 μL), NaCNBH (9 mg, 0.1 mmol), and MeOH (l/2mL) was stirred at room temperature. The reaction was monitored by TLC. Upon completion of reaction, the reaction mixture was purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM) to yield Example 77 (6.2mg, 60.2%). LC-MS for C21H28F4N2O2 MW calculated 416.21, found 417.25.
EXAMPLE 78
Figure imgf000077_0002
Example 78 was synthesized from Example 76 according to the procedure detailed in Example 77. The crude product was purified by preparative TLC (5:0.5:94.5, MeOH:NH4θH:DCM). LC-MS for C26H30F4N2O2 MW calculated 478.22, found
479.35.
EXAMPLE 79
Figure imgf000078_0001
Step A
Figure imgf000078_0002
This intermediate was synthesized according to the procedure detailed in Example 67, Step A-E. Diisopropylsulfide was used as the alkylating agent in Step C. IH NMR (500 MHz, CDCI3) δ 7.53 (s, IH), 7.37 (s, IH), 3.28 (m, IH), 7.23 (d, J=9.7 Hz, IH),
4.56 (d, J=6.2 Hz, 2H), 3.93 (app d, J=19.7 Hz, 2H), 3.19 (app d, J=19.7 Hz, 2H),
2.96 (h J=6.8 Hz, IH), 1.23 (d, J=6.6 Hz, 6H).
Step B
Figure imgf000078_0003
A solution of the product from Step A (120 mg, 0.331mmol), iPrOH (5 mL), oxone (406 mg, 0.662mmol) and water (5 mL) were stirred at room temperature. The reaction was monitored by HPLC. The mixture was concentrated in vacuo. The concentrate was redissolved in ether, washed with water (3x), dried over anhydrous MgSθ4, and concenttated to yield the crude product (100 mg, 76.3%). The crude product was used on next step. Step C
Figure imgf000079_0001
Example 79 was synthesized according to the procedure detailed in Example 67, Step F. LC-MS for C30H34F4N2O3 MW calculated 578.22, found 579.25.
EXAMPLE 80
Figure imgf000079_0002
Step A
Figure imgf000079_0003
Concentrated sulfuric acid (5 mL, 90 mmol) was added to a vigorously stirred suspension of anhydrous MgS04 (42 g, 350 mmol) in DCM (250 mL). The mixture was stirred for 15 minutes before Intermediate 1 (10 g, 88 mmol) was added followed by tert-butanol (42.5 mL, 438 mmol). The reaction flask was stoppered tightly and stirred at room temperatore for 60 hours. Satorated NaHC03 solution was added and the resulting mixture was stirred until the reaction mixture became clear as all MgS04 dissolved. The organic layer was separated and washed with brine, dried over anhydrous MgS04, and concenttated in vacuo. The crude product was used in next step.
Figure imgf000079_0004
The product from Step A (15 g, 88 mmol) was dissolved in DCM (100 mL) and MeOH (100 mL) first before trimethyl orthoformate (96 mL, 880 mmol) was added. TsOH (1.7 g, 8.8 mmol) was added last. The reaction mixture was stirred at room temperatore for 1 hour before being concenttated in vacuo. The concentrate was diluted with ether, quenched with saturated NaHC03, washed with brine, dried over anhydrous MgS04, and concentrated to dryness. The crude product was purified by
MPLC (10:90, EtOAc :hexanes) to yield the desired product (12.21g, 64.3% for last two steps). IH NMR (400 MHz, CDCI3) δ 3.17 (d, J=6.4 Hz, 6H), 2.80 (p, J=8.8 Hz, IH), 2.43-2.31 (m, 4H), 1.47 (s, 9H).
Step C
Figure imgf000080_0001
To a flamed-dried flask under nittogen, iPr2N (5.2 mL, 37 mmol) was added to THF (100 mL) at -78oC followed by nBuLi (14.9 mL, 37.2 mmol) and the product from Step B (7.0 g, 32 mmol). The mixture was stirred for 30 minutes before 2- iodopropane (9.7 mL, 97 mmol) was added. The reaction was stirred at -78°C for 1 hour before being placed in a freezer (-15°C) for 18 hours. The solution was quenched with 10% citric acid (50 mL) and exttacted with ether (3x). Combined organic layer was washed with water and brine, dried over anhydrous MgS04, and concentrated in vacuo. The crude product was purified by MPLC (7.5:92.5, EtOAc:hexanes) to yield the desired product (5.16g, 61.7%). IH NMR (500 MHz, CDCI3) δ 3.13 (s, 6H), 2.57 (app d, J=13.5 Hz, 2H), 2.01 (app d, J=13.3 Hz, 2H), 1.90 (h, J=6.9 Hz, IH), 1.47 (s, 9 H), 0.91 (d, J=6.8 Hz, 6H).
Figure imgf000080_0002
The product from Step C (5.2 g, 20 mmol) was dissolved in 20% HCl (30 mL). The reaction mixture was heated to reflux for 60 hours before being cooled to room temperature. Ether was added and the solution was vigorously stirred for 24 hours. The ether layer was separated and the aqueous layer was further exttacted with ether (3x). The combined organic layers were dried over anhydrous MgSθ4 and concenttated in vacuo to yield the desired white solid product (2.46 g, 78.8%). IH NMR (500 MHz, CDC13) δ 3.52 (app d, J=20.9 Hz, 2H), 3.15 (app d, J=20.8 Hz, 2H), 2.29 (p, J=6.9 Hz, IH), 1.08 (d, J=6.9 Hz, 6H).
Figure imgf000081_0001
A solution of the product from Step D (300 mg, 1.92 mmol), 3-fluoro-5- trifluoromethylbenzylamine (280 μL, 1.92 mmol), HOAT (260 mg, 1.92 mmol), EDC (550 mg, 2.89 mmol), and DCM (20 mL) was stirred at room temperature overnight. The reaction was diluted with DCM, washed with 1 M HCl solution, saturated NaHC03, water (2x) and brine, dried over anhydrous MgS04, and concenttated in vacuo. The crude product was purified by preparative TLC (20:80, EtOAc: hexanes) to yield the desired product (444 mg, 69.8%). IH NMR (400 MHz, CDCI3) δ 7.36
(s, IH), 7.29-7.22 (m, 2H), 5.99 (s, IH), 4.57 (d, J=6.0 Hz, 2H), 3.44 (app d, J=20.1 Hz, 2H), 3.05 (app d, J=20.3 Hz, 2H), 2.14 (h, J=6.8 Hz, IH), 1.03 (d, J=6.8 Hz, 6H).
Figure imgf000081_0002
A solution of the product from Step E (50 mg, 0.13 mmol), Intermediate 2 (32mg, 0.13 mmol), DIEA (25 μL, 0.13 mmol), 4 A molecular sieves, NaBH(OAc)3 (110 mg,
0.52 mmol) and DCM (7 mL) was stirred at room temperature overnight. The crude reaction was purified by preparative TLC (3:0.3:96.7, MeOH:NH4θH:DCM) to yield Example 80 (36mg, 46.4%). LC-MS for C30H34F4N2O MW calculated 514, found 515. A variety of compounds were synthesized according to the procedure detailed in Example 80. R2 was derivatized by using either 2-iodoprotane or acetone as the alkylating agent in Step C. Rl was derivatized by using different benzylamine in Step E. 1.5 equivalent of DIEA was added for hydrochloride benzylamine. R3 was derivatized by incorporating different amines in Step F. All of the components are either commercially available or are described in the Intermediates section. Isomers for some of these compounds were separated by preparative TLC. A few most active ones were resolved using chiral chromatography. A summary of these compounds is listed in the table below.
Figure imgf000082_0001
Y9 Y12 Y13 Y1 Y15 Y16 Y17
Figure imgf000082_0002
Figure imgf000083_0001
EXAMPLE 117
Figure imgf000084_0001
A solution of Example 83 (40 mg, 0.10 mmol), 37% formaldehyde (25 μ-L, 0.30 mmol), DIEA (23 μL, 0.15 mmol), TFA (10 μL), NaCNBH (28 mg, 0.50 mmol), and MeOH (3 mL) was stirred at room temperature and the reaction was monitored by TLC. The crude reaction was purified by preparative TLC (5:0.5:94.5, MeOH:NH4θH:DCM). LC-MS for C22H30F4N2O2 MW calculated 430, found
431.
EXAMPLE 118
Figure imgf000084_0002
Example 118 was synthesized from Example 91 using the procedure detailed in Example 117. LC-MS for C23H30F4N2O2 MW calculated 480, found 481.
EXAMPLE 119
Figure imgf000084_0003
Example 85 (15 mg, 0.029 mmol) was stirred in 4 M HCl in dioxane (5 mL). The reaction was monitored by HPLC. Upon completion of reaction, the mixtore was concentrated in vacuo to yield Example 119. LC-MS for C21H29F4N3O2 MW calculated 415, found 416.
EXAMPLE 120
Figure imgf000085_0001
Example 120 was synthesized from Example 92 using the procedure detailed in Example 119. LC-MS for C22H29F6N3O MW calculated 465, found 466.
EXAMPLE 121
Figure imgf000085_0002
Concenttated sulfuric acid (2mL) was cooled to 0°C before a solution of Example 98 (55 mg, 0.098 mmol) in acetonitrile (700 μL) was added. The mixtore was stirred at room temperature overnight. The reaction was poured onto ice slowly, made basic with 5 M NaOH, and exttacted with ether (3x). Combined organic layer was dried over anhydrous MgS04 and concenttated in vacuo. The crude product was purified by preparative TLC (1:0.1 :98.9, MeOH:NH40H:EtOAc) to yield Examplel21. Cis and trans isomers were also separated (total yield 30 mg, 54.2%). LC-MS for C30H34F7N3O2 MW calculated 601.25, found 602. EXAMPLE 122
Figure imgf000086_0001
Figure imgf000086_0002
To a solution of diisopropylamine (1.1 mL, 7.7 mmol) in THF (20 mL) was added BuLi (1.6 M in hexane, 4.2 mL) at -15°C. After 15 minutes, the reaction was cooled to -78°C and the product from Example 80, Step B was added dropwise. The solution was stirred at -78°C for another 30 minutes before a solution of acetaldehyde (437 μL, 7.74 mmol) in THF (5 mL) was added. The reaction was further stirred at - 78 °C for 10 minutes before being quenched by pouring into a satorated NaHC03 aqueous solution (120 mL). The aqueous layer was extracted with ether three times and the organic layers were combined, washed with brine, dried over Na2S04, concenttated and purified by flash chromatography (20% EtOAc/hexane) to give the product as a colorless oil. IH NMR (500 MHz, CDCI3) δ 3.92-3.87 (m, IH), 3.15 (s,
6H, OMe), 2.79 (d, J = 8.0 Hz, IH), 2.62 (d, J = 9.0 Hz, IH), 2.10-2.00 (m, 2H), 1.50 (s, 9H), 1.12 (d, J = 6.4 Hz, 3H, CH3), LC-MS for Cχ3H24θ5Na [M+Na+]: calculated 283.16, found 283.1. Step B
Figure imgf000086_0003
To the product from Step A was added 20%TFA/CH2Cl2 (15 mL) at room temperature. The reaction was stirred for 3 hours before acetone (1 mL) and water (500 μL) was added. The reaction was further stirred for 1 hour before being concenttated in vacuo to afford the desired ketone acid (457 mg, 94%) as foaming solid. IH NMR (500 MHz, CDCI3) δ 4.25 (q, J = 6.4 Hz, IH), 3.60-3.42 (m, 2H),
3.35-3.25 (m, IH), 3.22-3.15 (m, IH), 1.40 (d, J = 6.4 Hz, 3H). Step C
Figure imgf000087_0001
To a mixture of The product from Step B (171 mg, 1.08 mmol), 2-ttifluoro-4- aminomethyl-pyridine (230 mg, 1.08 mmol), EDC (311 mg, 1.62 mmol) and.HOBT (220 mg, 1.62 mmol) was added anhydrous CH2CI2 (5 mL) followed by DIEA (377 μL, 2.16 mmol). The reaction was stirred at room temperature overnight and then concenttated in vacuo. The resulted oil was purified by flash chromatography (85% EtOAc/hexane) to give the desired product (195 mg, 57%) as white solid. LC-MS for C 4H 6F3N2O3 [M+H+]: calculated 317.10, found 317.1.
Step D
Figure imgf000087_0002
To a solution of the product from Step C (23 mg, 0.072 mmol) and Intermediate 2 (25 mg, 0.11 mmol) in CH2CI2 (1 mL) was added DIEA (14 μL, 0.080 mmol) followed by NaBH(OAc)3 (25 mg, 0.12 mmol). The reaction was stirred at room temperature overnight before being concenttated to a crude oil. This oil was purified by reverse phase HPLC (MetaChem Polaris C18-A 5 micron, 15% to 80%
CH3CN/H2θ/0.1%TFA) to give a cis racemate (20 mg) and a trans racemate (15 mg).
The cis isomer was the less polar peak and the more active isomer. The cis isomer was further separated by chiral HPLC (AD, 10% EtOH/heptane) to give two enantiomers. LC-MS for C28H33F3N3O2 [M+Na+]: calculated 500.24, found 500.25. A variety of compounds were synthesized according to the procedure detailed in Example 122. Rl was derivatized by using either 2-iodopropane or acetone as the alkylating agent in Step A. R2 was derivatized by using a different amine in Step C. R3 was derivatized by incorporating different amines. All of the components are either commercially available or are described in the Intermediates section. Isomers for some of these compounds were separated by reverse-phase HPLC. Some of these compounds were resolved into their individual stereoisomers using chiral chromatography. A summary of these compounds is listed in the table below.
Figure imgf000088_0001
Figure imgf000088_0002
Y1 Y2
Y3
Figure imgf000088_0003
Figure imgf000089_0001

Claims

WHAT IS CLAIMED IS:
Figure imgf000090_0001
Figure imgf000090_0002
π
wherein:
X is O, N, S, S02 or C;
Y is selected from: -0-, -NR12-, -S-, -SO-, -Sθ2-, and -CR12R12-, -NSO2R14-, -NCOR!3-, -CR12CORl 1-, -CR12OCOR13- and -CO-;
RU is selected from: hydroxy, hydrogen, Cχ-6alkyl, -0-Cχ-6alkyl, benzyl, phenyl and C3_6cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substitoted with 1-3 substituents, and where said substitoents are independently selected from: halo, hydroxy, Ci-3alkyl, Ci_3alkoxy, -CO2H, -Cθ2-Ci_6alkyl and trifluoromethyl; Rl is selected from: hydrogen, Cχ-6 alkyl, benzyl, phenyl and
C3-6cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents, and where said substituents are independently selected from: halo, hydroxy, Ci-3alkyl, Cχ_3alkoxy, -CO2H, -Cθ2-Ci-6alkyl, and trifluoromethyl;
Rl3 is selected from: hydrogen, Cχ-6alkyl, -0-Cχ-6alkyl, benzyl, phenyl and C3_6cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents, and where said substituents are independently selected from: halo, hydroxy, Ci-3alkyl,
Cχ_3alkoxy, -CO2H, -Cθ2-Cι_6alkyl and trifluoromethyl;
Rl4 is selected from: hydroxy, Cχ-6 alkyl, -0-Ci-6alkyl, benzyl, phenyl, C3- 6cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substitoents, and where said substituents are independently selected from: halo, hydroxy, Cχ-3alkyl, Cχ-3alkoxy, -CO2H, -CO2-C1-6 alkyl and trifluoromethyl; each Z is independently selected from C or N, where at most two of the Z are N;
Rl is selected from:
(a) hydrogen,
(b) -C -6alkyl,
(c) -Cθ-6alkyl-0-Ci_6alkyl, (d) -Co-6alkyl-S-Ci-6alkyl,
(e) -(Co-6alkyl)-(C3-7cycloalkyl)-(Co-6alkyl),
(f) hydroxy,
(g) heterocycle, (h) -CN, (i) -NR12Rl2
(j) -NR12COR13, (k) -NR12S02R14,
(l) -CORll, (m) -CONR12R12 and (n) phenyl; where said alkyl and cycloalkyl are unsubstituted or substituted with 1-7 substituents, and where said substituents are independently selected from: halo, hydroxy, -0-Cχ-3alkyl, trifluoromethyl, Cχ.3alkyl, -0-Cχ_3alkyl, - CORl 1, -SO2RH -NHCOCH3, -NHS02CH3, -heterocycle, =o, -CN, and where said phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents where the substitoents are independently selected from: halo, hydroxy, -CORH, Ci_3alkyl, Cι_3alkoxy and trifluoromethyl;
R2 is selected from:
(a) hydrogen,
(b) Cχ-3alkyl, optionally substitoted with 1-3 fluoro,
(c) -0-Cι_3alkyl, optionally substituted with 1-3 fluoro,
(d) hydroxy,
(e) chloro,
(f) fluoro,
(g) bromo,
GO phenyl,
(i) heterocycle, and
G) nothing or O (when the Z bonded to R is N);
R3 is selected from:
(a) hydrogen,
(b) C 1-3 alkyl, optionally substitoted with 1-3 fluoro,
(c) -0-Ci-3alkyl, optionally substituted with 1-3 fluoro,
(d) hydroxy,
(e) chloro,
(f) fluoro,
(g) bromo,
(h) phenyl, (i) heterocycle, and
(j) nothing or O (when the Z bonded to R3 is N);
R4 is selected from:
(a) hydrogen,
(b) C ι_3 alkyl, optionally substituted with 1-3 fluoro,
(c) -0-Cχ-3alkyl, optionally substitoted with 1-3 fluoro,
(d) hydroxy,
(e) chloro,
(f) fluoro,
(g) bromo,
(h) phenyl, (i) heterocycle, and
CD nothing or O (when the Z bonded to R4 is N); R5 is selected from:
(a) Ci-6alkyl, where alkyl is unsubstituted or substituted with 1-6 fluoro and optionally substituted with hydroxyl,
(b) -O-Ci-6alkyl, where alkyl is unsubstitoted or substitoted with 1-6 fluoro,
(c) -CO-Ci-6alkyl, where alkyl is unsubstitoted or substitoted with 1-6 fluoro, (d) -S-Cι_6alkyl, where alkyl is unsubstituted or substitoted with 1-6 fluoro, (e) -pyridyl, which is unsubstituted or substituted with one or more substituents selected from: halo, trifluoromethyl, Ci-4alkyl, and COR11, (f) fluoro,
(g) chloro, (h) bromo, (i) -C4_6cycloalkyl, (j) -0-C4-6cycloalkyl, (k) phenyl, which is unsubstitoted or substituted with one or more substituents selected from: halo, trifluoromethyl, Ci-4alkyl, and COR11, (1) -O-phenyl, which is unsubstitoted or substitoted with one or more substituents selected from: halo, trifluoromethyl, Ci-4alkyl, and COR11,
(m) -C3-6cycloalkyl, where alkyl is unsubstitoted or substituted with 1-6 fluoro, (n) -0-C3-6cycloalkyl, where alkyl is unsubstituted or substituted with 1-6 fluoro, (o) -heterocycle,
(p) -CN, and
(q) -COR11;
R6 is selected from:
(a) hydrogen,
(b) C 1-3 alkyl, optionally substitoted with 1-3 fluoro,
(c) -0-Cl-3alkyl, optionally substitoted with 1-3 fluoro,
(d) hydroxy, (e) chloro,
(f) fluoro,
(g) bromo, (h) phenyl,
(g) heterocycle, and
(h) nothing, when the Z bonded to R6 is N;
R is selected from: (a) hydrogen, (b) (Co-6alkyl)-phenyl, '
(c) (Cθ-6alkyl)-heterocycle,
(d) (Co-6alkyl)-C3-7cycloalkyl , (e) (Co-6al yl)-COR11,
(f) (Co-6alkyl)-(alkene)-COR11,
(g) (C0-6alkyl)-SO3H,
(h) (Co-6alkyl)-W-C0-4alkyl,
Figure imgf000094_0001
G)(Cθ-6alkyl)-CONR20-V-COR11, and
(k) nothing, when X is O, S, or SO2), where W is selected from: a single bond, -O-, -S-, -SO-, -SO2-, -CO-, -CO2-, - CONRi - and -NRl-2-, where V is selected from Cι_6alkyl or phenyl,
where R20 is hydrogen, Ci-4alkyl or is joined via a 1-5 carbon tether to one of the carbons of V to form a ring, where the Cθ-6alkyl is unsubstituted or substituted with 1-5 substituents, where said substituents are independently selected from: halo, hydroxy, - )- βalkyl, -0-Ci-3alkyl, trifluoromethyl, and -Cθ-2alkyl-phenyl, where the phenyl, heterocycle, cycloalkyl, and Cθ-4alkyl is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from: halo, trifluoromethyl, hydroxy, Ci-3alkyl, -0-Ci-3alkyl,
Co-3-COR11, -CN, -NR^Rl^ -CONR12R12 and -Cθ-3-heterocycle, or where the phenyl and heterocycle are fused to another heterocycle, which itself is unsubstitoted or substitoted with 1-2 substitoents independently selected from hydroxy, halo, -COR11, and -C 1-3 alkyl, and where alkene is unsubstitoted or substituted with 1-3 substituents which are independently selected from: halo, trifluoromethyl, Ci-3alkyl, phenyl, and heterocycle;
R8 is selected from: (a) hydrogen,
(b) nothing when X is either O, S, SO2 or N or when a double bond joins the carbons to which R7 and R!0 are attached,
(c) hydroxy, (d) Ci-6alkyl,
(e) Ci_6alkyl-hydroxy,
(f) -0-Ci- alkyl,
(g) -COR11,
(h) -CONRi2Rl2 and (i) -CN;
or where R^ and R§ are be joined together to form a ring which is selected from:
(a) lH-indene, (b) 2,3-dihydro-lH-indene,
(c) 2,3-dihydro-benzofuran,
(d) 1,3-dihydro-isobenzofuran,
(e) 2,3-dihydro-benzothiofuran,
(f) 1,3-dihydro-isobenzothiofuran, (g) 6H-cyclopenta[-φsoxazol-3-ol
(h) cyclopentane, and (i) cyclohexane, where the ring formed is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, Cι_3alkyl, -O-
Ci-3alkyl, -Cθ-3-COR11, -CN, -NRi2Rl2 -CONR^RΗ and - )-3- heterocycle,
or where R^ and R" or R° and Rl-0 are joined together to form a ring which is phenyl or heterocycle, where said ring is unsubstituted or substituted with 1-7 substituents, where said substituents are independently selected from: halo, trifluoromethyl, hydroxy, Ci_3alkyl, -0-Cι_3alkyl, -COR11, -CN, -NRi2Rl2 and -CONRI2R12;
R9 and R1^ are independently selected from:
(a) hydrogen,
(b) hydroxy,
(c) Ci_6alkyl,
(d) Ci-όalkyl-COR11, (e) Cι_6alkyl-hydroxy,
(f) -0-Ci-3alkyl,
(g) =0, when R9 or R1^ is connected to the ring via a double bond, and (h) halo;
R ^ is hydrogen or Ci-βalkyl, which is unsubstitoted or substitoted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, -CO2H, -Cθ2Ci-6alkyl, and -0-Ci-3alkyl;
R1^ is selected from:
(a) hydrogen,
(b) Ci-βalkyl, where alkyl is unsubstituted or substituted with 1-6 substitoents where the substituents are selected from: fluoro,
Ci-3alkoxy, hydroxy, -COR11,
(c) fluoro,
(d) -0-Cι_3alkyl, where alkyl is unsubstitoted or substitoted with 1-3 fluoro, and
(e) C3-6 cycloalkyl,
(f) -0-C3-6cycloalkyl,
(g) hydroxy,
(h) -COR11,
0) -OCOR13,
or R1^ and R1^ are joined together via a C2-4alkyl or a Cθ-2alkyl-0-Ci-3alkyl chain to form a 5-7 membered ring;
R1^ is selected from:
(a) hydrogen,
(b) Ci-βalkyl, where alkyl is unsubstitoted or substitoted with 1-6 substituents, where said substituents are selected from: fluoro, Ci- 3alkoxy, hydroxy, -COR11 ,
(c) COR11,
(d) hydroxy, and
(e) -0-Cχ-6alkyl, where alkyl is unsubstitoted or substituted with 1-6 substitoents, where said substituents are selected from: fluoro, Ci- 3alkoxy, hydroxy, -COR11,
or R1^ and R ^ are joined together by a Cl-4alkyl chain or a Cθ-3alkyl-0-Cθ-3alkyl chain to form a 3-6 membered ring;
R18 is selected from: (a) hydrogen, and
(b) Ci-6alkyl, where alkyl is unsubstituted or substitoted with 1-6 fluoro,
(c) fluoro, (d) -0-C3_6cycloalkyl, and
(e) -O-C 1-3 alkyl, where alkyl is unsubstituted or substitoted with 1-6 fluoro,
or R1^ and R1^ are joined together by a C2-3alkyl chain to form a 5-6 membered ring, where the alkyl are unsubstitoted or substituted with 1-3 substitoents where the substiuents are independently selected from: halo, hydroxy, -COR11, Ci-3alkyl, and C 1-3 alkoxy,
or R1^ and R1^ are joined together by a Ci-2alkyl-0-Ci_2alkyl chain to form a 6-8 membered ring, where the alkyl are unsubstituted or substitoted with 1-3 substitoents where the substiuents are independently selected from: halo, hydroxy, -COR11, Ci- 3alkyl, and C 1-3 alkoxy,
or R1^ and R1^ are joined together by a -0-Cι_2alkyl-0-chain to form a 6-7 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, -COR11, Cι_ 3alkyl, and Cι_3alkoxy;
Rl9 is selected from:
(a) hydrogen,
(b) phenyl,
(c) Ci_6alkyl which is substituted or unsubstituted with 1-6 of the following substituents: -COR11, hydroxy, fluoro, chloro, -0-Ci-3alkyl;
or R2 and R!9 are joined together to form a heterocycle ring with a linker selected from:
(a) -CH2(CR28R28)1_3-,
Figure imgf000097_0001
(c) -NR29CR28R28-;
(d) -CH20-,
(e) -CH2SO2-,
(f) -CH2SO-, (g) -CH2S-, (h) -CR28R28-,
R28 is i selected from selected from:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) Ci-3alkyl, where the alkyl is unsubstitoted or substitoted with
1-6 substituents independently selected from: fluoro, and hydroxy,
(e) -NR12R12
(f) -COR11,
(g) -CONRi2Rl2
GO -NR^COR13,
G) -OCONRi2Rl2
(i) -NR^CONR^RΠ
(k) -heterocycle,
0) -CN,
Figure imgf000098_0001
(o) -S02-NRi2Rl2) and
(P) =0, where R28 is connected to the ring via a double bond and the other R28 at the same position is nothing, and where R29 is selected from: hydrogen, Cι_3alkyl, where the alkyl is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, hydroxy, COR13, SO2R14, and Sθ2NRi2Rl2;
R25 and R are independently selected from:
(a) =0, where R25 and or R26 is oxygen and is connected via a double bond,
(b) hydrogen,
(c) phenyl,
(d) Cι_6alkyl which is substituted or unsubstitoted with 1-6 of the following substitoents: -COR 1, hydroxy, fluoro, chloro, -O-Ci- 3alkyl; m is selected from 0, 1, or 2; n is selected from 1 or 2; the dashed line represents a single or a double bond; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
2. A compound of Claim 1 of formula la:
Figure imgf000099_0001
la wherein R1, R3, R5, R!6, R17; γ? ar-d Z are defined in Claim 1, and pharmaceutically acceptable salts and individual diastereomers thereof.
3. A compound of Claim 1 of formula Ha:
Figure imgf000099_0002
Ha wherein Rl, R5, R7, R8, R9, RIO X and Z are described in Claim 1, and pharmaceutically acceptable salts and individual diastereomers thereof.
4. A compound of Claim 1 of formula Hb:
Figure imgf000099_0003
Hb wherein R1, R3, R5, R7, R8, R9, RiO, x, and Z are defined in Claim 1, and pharmaceutically acceptable salts and individual diastereomers thereof.
5. A compound of Claim 1 of formula He:
Figure imgf000100_0001
Ac wherein Rl, R3, R5, Rl0; and Z are described in Claim 1, and R23 and R24 are independently selected from: (a) hydrogen,
(b) halo,
(c) trifluoromethyl,
(d) hydroxy,
(e) Ci-3alkyl, (f) -0-Ci.3alkyl,
(g) -Co-3-C02H, (h) -Co-3-C02Ci-3alkyl, (i) -CN, and (j) -Cθ-3-heterocycle, or where the R23 and R24 are joined together to form a heterocycle which is fused to the phenyl ring, and which itself is unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR11, and -C _3alkyl;
and pharmaceutically acceptable salts and individual diastereomers thereof.
6. A compound of Claim 1 of formula ud:
Figure imgf000100_0002
wherein R1, R3, R5 ,R9, R23, R24; and Z are defined in Claim 1 and the dashed line represents a single or a double bond, and pharmaceutically acceptable salts and individual diastereomers thereof.
7. A compound of Claim 1 of formula He:
Figure imgf000101_0001
He wherein R1, R3, R5, Rl0; R23; and R24 are described in Claim 1, and pharmaceutically acceptable salts and individual diastereomers thereof.
8. A compound of Claim 1 of formula H :
Figure imgf000101_0002
πf wherein R1, R3, R5 ,R9, R23, and R24 are defined in Claim 1, and pharmaceutically acceptable salts and individual diastereomers thereof.
9. A compound of Claim 8 wherein R is selected from: hydrogen, phenyl, heterocycle, -Ci-βalkyl, -Cθ-6alkyl-0-Ci-6alkyl, and
-(Co-6alkyl)-(C3-7cycloalkyl)-(Co-6alkyl), where said alkyl, phenyl, heterocycle, and cycloalkyl are unsubstituted or substituted with 1-7 substitoents, where said substitoents are independently selected from: (a) halo, (b) hydroxy,
(c) -0-Cι_3alkyl,
(d) trifluoromethyl,
(f) Ci-3alkyl,
(g) -0-Ci-3alkyl, (h) -COR11,
G) -CN,
(j) -NR12R12 and
(k) -CONRi2Rl2.
10. A compound of Claim 9 wherein R1 is selected from:
(1) -Cι_6alkyl, which is unsubstituted or substitoted with 1-6 substituents where said substituents are independently selected from:
(a) halo,
(b) hydroxy, (c) -0-Ci-3alkyl,
(d) trifluoromethyl, and
(e) -COR11,
(2) -Cθ-6alkyl-0-Cl-6alkyl-, which is unsubstituted or substitoted with 1- 6 substituents where said substitoents are independently selected from: (a) halo,
(b) trifluoromethyl, and
(c) -COR11,
(3) -(C3_5cycloalkyl)-(Cθ-6alkyl), which is unsubstitoted or substitoted with 1-7 substituents where said substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) -0-Cι_3alkyl,
(d) trifluoromethyl, and (e) -COR11,
(4) phenyl or heterocycle which is unsubstituted or substituted with 1-3 substituents where said substituents are independently selected from:
(a) halo,
(b) hydroxy, (c) -0-Ci-3alkyl,
(d) trifluoromethyl, and
(e) -COR11-
11. A compound of Claim 10 wherein R1 is selected from:
(a) hydrogen,
(b) Ci-6alkyl, which is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro and hydroxy
(c) phenyl, and
(d) pyridyl.
12. A ce >mpound of Claim 6 wherein Z is C and R3 is selected from:
(a) hydrogen
(b) halo
(c) hydroxy
(d) Ci-3alkyl, where the alkyl is unsubstituted or substituted with 1-6 substitoents independently selected from: fluoro, and hydroxy,
(e) -COR11, ω -CONRi2Rl2
(g) -heterocycle,
GO -NR12-Sθ2-NRi2Rl2
G) -NRi2-S02-R14,
(j) -S02-NRi2Rl2,
(k) -nitro, and
G) -NR12R12.
13. A compound of Claim 12 wherein Z is C, R3 is selected from:
(a) fluoro,
(b) trifluoromethyl,
(c) hydrogen.
14. A compound of Claim 8 wherein R^ is selected from:
(a) Ci-6alkyl substituted with 1-6 fluoro,
(b) -0-Ci_6alkyl substitoted with 1-6 fluoro,
(c) chloro,
(d) bromo, and
(e) phenyl.
15. A col mpound of Claim 4 wherein R7 is phenyl, heterc
7cycloalkyl, Cι_6alkyl, -COR11, and -CONH-V-COR11, where V is selected from Ci-βalkyl or phenyl, and where the phenyl, heterocycle, C3-7cycloalkyl, and Ci-6alkyl is unsubstituted or substituted with 1-5 substituents, where said substitoents are independently selected from: (a) halo, (b) trifluoromethyl,
(c) hydroxy,
(d) Ci.3alkyl,
(e) -0-Ci-3alkyl,
(f) -COR11, (g) -CN,
(h) -heterocycle, and (i) -CONR12R12.
16. A compound of Claim 15 wherein, when X is not O, R7 is phenyl, heterocycle, Cι_4alkyl, -COR11 or -CONH-V-COR11 ;
V is selected from Ci-6alkyl or phenyl; and the phenyl, heterocycle, and Ci_4alkyl is unsubstituted or substituted with 1-3 substitoents, where said substitoents are independently selected from: (a) halo,
(b) hydroxy,
(c) Cl-3alkyl,
(d) -0-Cι_3alkyl,
(e) -COR11, and
(f) -heterocycle.
17. A ce impound of Claim 7 wherein R1^ is selected from:
(a) hydrogen,
(b) hydroxy,
(c) -CH3,
(d) -O-CH3, and
(e) =0 (where R9 is joined to the ring via a double bond).
18. A compound of Claim 2 wherein R1" is selected from:
(a) hydrogen,
(b) Ci_3alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(c) -0-Ci_3alkyl,
(d) fluoro, and
(e) hydroxy.
19. A ce impound of Claim 18 wherein R!6 is selected from:
(a) hydrogen,
(d) trifluoromethyl,
(c) methyl,
(d) methoxy,
(e) ethoxy,
( ) ethyl,
(g) fluoro, and
GO hydroxy.
20. A pharmaceutical composition which comprises an inert carrier and a compound of Claim 1.
21. A method for modulation of chemokine receptor activity in a mammal which comprises the administtation of an effective amount of a compound of Claim 1.
22. A method for treating, ameliorating, controlling or reducing the risk of an inflammatory and immunoregulatory disorder or disease which comprises the administtation to a patient of an effective amount of a compound of Claim 1.
23. A method for treating, ameliorating, controlling or reducing the risk of rheumatoid arthritis which comprises the administtation to a patient of an effective amount of a compound of Claim 1.
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