1h-benzo(f)indazol-5-yl derivatives as selective glucocorticoid receptor modulators

Intracellular receptors (IR) are a class of structurally related proteins involved in the regulation of gene expression. Steroid hormone receptors are a subgroup of this superfamily, and their natural ligands are usually composed of endogenous steroids such as estradiol, progesterone, and cortisol. Artificial ligands for these receptors play important roles in human health, and among these receptors, the glucocorticoid receptor has an essential role in the regulation of human physiology and immune response. Steroids that interact with glucocorticoid receptors have been shown to be potent anti-inflammatory agents.

<p> The present invention is a selective glucocorticoid receptor modulator having potent anti-inflammatory and immunosuppressive activity and having advantages over steroidal glucocorticoid ligands in terms of side effects, efficacy, toxicity and / or metabolism. Orients to a novel class of compounds that are.</p>

<p> The present invention is useful as a selective glucocorticoid receptor ligand for treating various autoimmune and inflammatory diseases or conditions, formula I</p><p><chemistry num="8"><img file="JP4570878B2_D0001.tif" /></chemistry>Includes compounds of or pharmaceutically compatible salts or hydrates thereof. Pharmaceutical compositions and methods of use are also included.</p><p> The present invention is in formula I</p><p><chemistry num="9"><img file="JP4570878B2_D0002.tif" /></chemistry>Includes compounds represented by or pharmaceutically compatible salts or hydrates thereof. here n is 0, 1 or 2; J is NR¹Or C (R¹) (R²) To be selected; K is NR³Or C (R³) (R⁴) To be selected; L is NR⁵Or C (R⁵) (R⁶) To be selected; X is a bond, -C (O), -N (R)¹⁴)-, -N (R)¹⁴) -C (O)-or</p><p><chemistry num="10"><img file="JP4570878B2_D0003.tif" /></chemistry>Is; R¹, R⁸And R¹⁰Is (1) C_1-6Alkyl, (2) C_2-6Alkenyl, (3) C_3-6Alkenyl, (4) C_3-6Cycloalkyl, (5) C_1-6Alkoxy, (6) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (7) Aryl, (8) Aralkill, (9) HET, (10) -C_1-6Alkyl-HET, (11) Aryloxy, (12) Aloyloxy, (13) Alarkenil, (14) Alarkinil, (15) Hydrogen, (16) Hydroxy and (17) C_1-6Alkyl-N (R)¹⁴)-S (O)_k-(Where k is 0, 1 or 2) Each is independently selected from the group consisting of The alkyl moieties of items (1) to (6) above, items (8), (10) and (17) above, the alkenyl moiety of item (13) above and the alkynyl moiety of item (14) above are halos. , OR¹³, N (R)¹⁴)₂, C_3-6Cycloalkyl, C_1-6Alkyl-S (O)_k-And aryl-S (O)_k-(Where k is 0, 1 or 2) is optionally substituted from 1 to the maximum number of replaceable positions by a substituent independently selected from the group. The aryl portion of the above items (7), (9), (11) and (12) and the above items (8), (13) and (14) and the HET portion of the above item (10) are (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl, (f) C_3-6Alkyne, (g) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (h) Aryl, (i) Aryl-S (O)_k-(Where k is 0, 1 or 2), (j) HET, (k) Aralkill, (l) Aroyl, (m) aryloxy, (n) Aralkoxy and (o) CN In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. The alkyl moieties of items (d) to (g) above and item (k) above are halo, OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, and Items (h), (i), (j), (l) and (m) above and the aryl moieties of items (k) and (n) above are halo, OR¹³And C_1-4It is optionally substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of alkyl, or R if X is a bond.⁸And R¹⁰Connect together, O, S and NR¹⁴A 4- to 8-membered monocyclic ring may be formed that contains 1 to 3 heteroatoms, optionally selected from, and optionally contains 1 or 2 double bonds. ; R², R³, R⁴, R⁵And R⁶Is (1) Hydrogen, (2) Haro, (3) C_1-6Alkyl, (4) C_2-6Alkenyl, (5) C_3-6Alkyne, (6) C_3-6Cycloalkyl, (7) C_1-6Alkoxy, (8) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (9) Aryl, (10) Aralkill, (11) HET and (12) -C_1-6Alkyl-HET, Each is independently selected from the group consisting of The alkyl moieties of items (3) to (8) above and items (10) and (12) above are halo, OR¹³, N (R)¹⁴)₂And C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2) is optionally substituted from 1 to the maximum number of replaceable positions by a substituent selected independently from the group; The aryl portion of items (9) and (11) and (10) and the HET portion of item (12) above (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl, (f) C_3-6Alkyne and (g) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2) In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. Items (d) to (g) above are halo and OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, or R¹And R³Or R³And R⁵May be linked together to form a double bond; R⁷Is (1) Hydrogen, (2) OR¹³, (3) C_1-4Alkyl, (4) Aryl and (5) Aralkill It is selected independently from the group consisting of The alkyl portion of item (3) and item (5) above is halo, OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, and The aryl portion of item (4) above and item (5) above (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl and (f) C_3-6Alkyne In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. Items (d) to (f) above are halo, OR¹³And N (R¹⁴)₂In some cases, it is substituted from 1 to the maximum number of substitutable positions by a substituent independently selected from the group consisting of; Y is (1) Hydrogen, (2)-OR⁹, (3)-S (O)_k-R⁹(Where k is 0, 1 or 2), (4)-CWR⁹(Where W is O or S (O)_kIs), (5)-N (R)¹⁵)₂, (6)-S (O)_k-N (R)¹⁵)₂, (7)-N (R)¹⁵)-S (O)_k-N (R)¹⁵)₂, (8) NO₂, (9) -C (O) -R¹⁵, (10)-C (O) OR¹⁵, (11)-CN, (12) Halo and (13)-OS (O)_k-R¹⁵It is selected independently from the group consisting of R⁹Is hydrogen, C_1-12Alkyl and aryl (where C_1-12Alkyl and aryl are selected from the group consisting of (possibly substituted from 1 to the maximum number of substitutable positions by halo), or Y is OR.⁹If, then R⁸And R⁹May be linked together to form a carbonyl group; Each R¹¹And R¹²Is (1) Haro, (2) C_1-6Alkyl, (3) C_2-6Alkenyl, (4) C_1-6Alkoxy and (5) Hydroxy It is selected independently from the group consisting of Items (2) to (4) above are halo, OR¹², N (R)¹³)₂And C_1-6Alkyl-S (O)_k-In some cases, a substituent selected independently from the group consisting of (where k is 0, 1 or 2) substitutes from 1 to the maximum number of replaceable positions; Each R¹³And R¹⁴Is hydrogen, C_1-4Alkyl and C_2-4It is independently selected from the group consisting of alkenyl and is described in C._1-4Alkyl and C_2-4Each of the alkenyl is halo, C_1-4Alkoxy, aryl, C_3-6Cycloalkyl, CN and C_1-4Alkyl-S (O)_kIt is optionally substituted from 1 to the maximum number of replaceable positions by a substituent independently selected from the group consisting of (where k is 0, 1 or 2); Each R¹⁵Is hydrogen, C_1-6Alkyl, aryl and C_1-12It is independently selected from the group consisting of alkoxycarbonyl, and is C._1-6Alkyl and C_1-12Alkoxycarbonyls are optionally substituted from 1 to the maximum number of substitutable positions by halos; and the aryls are halos and C (sometimes substituted by 1 to 3 halo groups)._1-4It is optionally substituted by alkyl from 1 to the maximum number of substitutable positions; and HETs contain 1 to 4 heteroatoms selected from O, S and N, and are optionally substituted with 1 to 2 oxo groups, 5- to 10-membered aromatics, partially It is an aromatic or non-aromatic monocyclic or bicyclic ring.</p><p> Embodiments of the present invention are formulated in Formula I.</p><p><chemistry num="11"><img file="JP4570878B2_D0004.tif" /></chemistry>Includes compounds represented by or pharmaceutically compatible salts or hydrates thereof. here n is 0, 1 or 2; J is NR¹Or C (R¹) (R²) To be selected; K is NR³Or C (R³) (R⁴) To be selected; L is NR⁵Or C (R⁵) (R⁶) To be selected; X is a bond, -C (O), -N (R)¹⁴)-, -N (R)¹⁴) -C (O)-or</p><p><chemistry num="12"><img file="JP4570878B2_D0005.tif" /></chemistry>Is; R¹, R⁸And R¹⁰Is (1) C_1-6Alkyl, (2) C_2-6Alkenyl, (3) C_3-6Alkenyl, (4) C_3-6Cycloalkyl, (5) C_1-6Alkoxy, (6) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (7) Aryl, (8) Aralkill, (9) HET, (10) -C_1-6Alkyl-HET, (11) Aryloxy, (12) Aloyloxy, (13) Alarkenil, (14) Alarkinil, (15) Hydrogen, (16) Hydroxy Each is independently selected from the group consisting of The alkyl moieties of items (1) to (6) and items (8) and (10) above, the alkenyl moiety of item (13) above, and the alkynyl moiety of item (14) above are halo, OR.¹³, N (R)¹⁴)₂, C_3-6Cycloalkyl and C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2) is optionally substituted from 1 to the maximum number of replaceable positions by a substituent independently selected from the group. The aryl portion of the above items (7), (9), (11) and (12) and the above items (8), (13) and (14) and the HET portion of the above item (10) are (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl, (f) C_3-6Alkyne, (g) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (h) Aryl, (i) Aryl-S (O)_k-(Where k is 0, 1 or 2), (j) HET, (k) Aralkill, (l) Aroyl, (m) aryloxy, (n) Aralkoxy and (o) CN In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. The alkyl moieties of items (d) to (g) above and item (k) above are halo, OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, and Items (h), (i), (j), (l) and (m) above and the aryl moieties of items (k) and (n) above are halo, OR¹³And C_1-4It is optionally substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of alkyl. If X is a bond, then R⁸And R¹⁰Connect together, O, S and NR¹⁴A 4- to 8-membered monocyclic ring may be formed that contains 1 to 3 heteroatoms, optionally selected from, and optionally contains 1 or 2 double bonds. ; R², R³, R⁴, R⁵And R⁶Is (1) Hydrogen, (2) Haro, (3) C_1-6Alkyl, (4) C_2-6Alkenyl, (5) C_3-6Alkyne, (6) C_3-6Cycloalkyl, (7) C_1-6Alkoxy, (8) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (9) Aryl, (10) Aralkill, (11) HET and (12) -C_1-6Alkyl-HET, Each is independently selected from the group consisting of The alkyl moieties of items (3) to (8) above and items (10) and (12) above are halo, OR¹³, N (R)¹⁴)₂And C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2) is optionally substituted from 1 to the maximum number of replaceable positions by a substituent selected independently from the group; The aryl portion of items (9) and (11) and (10) and the HET portion of item (12) above (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl, (f) C_3-6Alkyne and (g) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2) In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. Items (d) to (g) above are halo and OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, or R¹And R³Or R³And R⁵May be linked together to form a double bond; R⁷Is (1) Hydrogen, (2) OR¹³, (3) C_1-4Alkyl, (4) Aryl and (5) Aralkill, It is selected independently from the group consisting of The alkyl portion of item (3) and item (5) above is halo, OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, and The aryl portion of item (4) above and item (5) above (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl and (f) C_3-6Alkyne In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. Items (d) to (f) above are halo, OR¹³And N (R¹⁴)₂In some cases, it is substituted from 1 to the maximum number of substitutable positions by a substituent independently selected from the group consisting of; Y is (1) Hydrogen, (2)-OR⁹, (3)-S (O) kR⁹(Where k is 0, 1 or 2), (4)-CWR⁹(Where W is O or S (O) k), (5)-N (R)¹⁵)₂, (6)-S (O)_k-N (R)¹⁵)₂, (7)-N (R)¹⁵)-S (O)_k-N (R)¹⁵)₂, (8) NO₂, (9) -C (O) -R¹⁵, (10)-C (O) OR¹⁵, (11)-CN, (12) Halo and (13)-OS (O)_k-R¹⁵It is selected independently from the group consisting of R⁹Is hydrogen, C_1-12Alkyl and aryl (where C_1-12Alkyl and aryl are selected from the group consisting of (possibly substituted from 1 to the maximum number of substitutable positions by halo), or Y is OR.⁹If, then R⁸And R⁹May be linked together to form a carbonyl group; Each R¹¹And R¹²Is (1) Haro, (2) C_1-6Alkyl, (3) C_2-6Alkenyl, (4) C_1-6Alkoxy and (5) Hydroxy It is selected independently from the group consisting of Items (2) to (4) above are halo, OR¹², N (R)¹³)₂And C_1-6Alkyl-S (O)_k-In some cases, a substituent selected independently from the group consisting of (where k is 0, 1 or 2) substitutes from 1 to the maximum number of replaceable positions; Each R¹³And R¹⁴Is hydrogen and C (possibly substituted from 1 to the maximum number of substitutable positions by halo)_1-4It is independently selected from the group consisting of alkyl; Each R¹⁵Is hydrogen, C_1-6Alkyl, aryl and C_1-12It is independently selected from the group consisting of alkoxycarbonyl, and is C._1-6Alkyl and C_1-12Alkoxycarbonyl is optionally substituted from 1 to the maximum number of substitutable positions by the halo, and The aryl is halo and (possibly substituted with 1 to 3 halo groups) C_1-4It is optionally substituted from 1 to the maximum number of substitutable positions by alkyl.</p><p> The double bond, which may or may not be shown in the ring A of the compound of formula I, is indicated by the dotted line, and this double bond may or may not be present as shown below. Means.</p><p><chemistry num="13"><img file="JP4570878B2_D0006.tif" /></chemistry> Substituent R in Formula I¹²May or may not exist. One or two Rs, if present¹²The group may occupy the following positions.</p><p><chemistry num="14"><img file="JP4570878B2_D0007.tif" /></chemistry>Two R¹²The groups may be on the same carbon atom.</p><p> Substituent R in Formula I¹¹May or may not exist. One, two or three Rs, if present¹¹The group may occupy the following positions.</p><p><chemistry num="15"><img file="JP4570878B2_D0008.tif" /></chemistry>Two R¹¹The groups may be on the same carbon atom.</p><p> The double bond, which may or may not be shown in ring B of the compound of formula I, may occupy the following position:</p><p><chemistry num="16"><img file="JP4570878B2_D0009.tif" /></chemistry><img file="JP4570878B2_D0010.tif" />J, K and L defined in Equation I mean, for example, the following structure.</p><p><chemistry num="17"><img file="JP4570878B2_D0011.tif" /></chemistry><img file="JP4570878B2_D0012.tif" /> If X is a bond, then R⁸And R¹⁰Connect together, O, S and NR¹⁴A 4- to 8-membered monocyclic ring may be formed, optionally containing 1 to 3 heteroatoms selected from, and optionally containing 1 or 2 double bonds. , This means, for example:</p><p><chemistry num="18"><img file="JP4570878B2_D0013.tif" /></chemistry>These compounds are incorporated herein by reference, eg, J.Am.Chem.Soc., Vol.118,100-110,1996 and J.Am.Chem.Soc.,vol.115,p.9856-9924. It can be manufactured by following the procedure outlined in 1993.</p><p> Y is OR⁹If, then R⁸And R¹⁰May be linked together to form a carbonyl group, which means, for example:</p><p><chemistry num="19"><img file="JP4570878B2_D0014.tif" /></chemistry></p><p> X is -N (R¹⁴) -C (O)-, this group binds as follows.</p><p><chemistry num="20"><img file="JP4570878B2_D0015.tif" /></chemistry></p><p> Another embodiment of the invention includes a compound of formula I. here, J is NR¹Is; K is NR³Is; L is C (R⁵) (R⁶) And; R³And R⁵Are linked together to form a double bond.</p><p> Another embodiment of the present invention includes a compound of formula I in which a double bond may or may not be present in the ring A of the compound of formula I.</p><p> Another embodiment of the present invention is R.¹Is an aryl or HET, and the aryl or HET is (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl, (f) C_3-6Alkyne, (g) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (h) Aryl, (i) Aryl-S (O)_k-(Where k is 0, 1 or 2), (j) HET, (k) Aralkill, (l) Aroyl, (m) aryloxy, (n) Aralkoxy and (o) CN In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. The alkyl moieties of items (d) to (g) above and item (k) above are halo, OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, and Items (h), (i), (j), (l) and (m) above and the aryl moieties of items (k) and (n) above are halo, OR¹³And C_1-4A compound of formula I that is optionally substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of alkyl. Including.</p><p> Within this embodiment of the invention, R¹Included are compounds of formula I, where is a phenyl that is optionally substituted with 1 to 3 halo groups.</p><p> In another embodiment of the invention, Y is OR⁹Includes compounds of formula I: R within this embodiment of the invention⁹Included are compounds of formula I where is hydrogen.</p><p> Another embodiment of the present invention is R.⁷Includes compounds of formula I where is methyl.</p><p> Another embodiment of the present invention is R.⁸Includes compounds of formula I where is hydrogen or methyl.</p><p> Another embodiment of the invention includes a compound of formula I in which X is attached.</p><p> Another embodiment of the present invention is R.¹⁰But (1) C_1-6Alkyl, (2) C_2-6Alkenyl, (3) C_3-6Alkyne, (4) C_3-6Cycloalkyl, (5) C_1-6Alkoxy, (6) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), It is selected from the group consisting of Items (1) to (6) above are halo, OR¹³, N (R)¹⁴)₂, C_3-6Cycloalkyl and C_1-6Alkyl-S (O)_k-A compound of formula I that is optionally substituted from 1 to the maximum number of substituents that can be substituted by a substituent independently selected from the group consisting of (where k is 0, 1 or 2). Include.</p><p> Another embodiment of the present invention is R.¹⁰But (1) Phenyl, (2) Naftil, (3) Benzyl, (4) Funetil, (5) Phenoxy, (6) Benzoyl and (7) Benzoyloxy It is selected from the group consisting of The aryl portion of items (1) to (7) above is (a) Haro, (b) OR¹³, (c) N (R)¹⁴)₂, (d) C_1-6Alkyl, (e) C_2-6Alkenyl, (f) C_3-6Alkyne, (g) C_1-6Alkyl-S (O)_k-(Where k is 0, 1 or 2), (h) Aryl, (i) Aryl-S (O)_k-(Where k is 0, 1 or 2), (j) HET, (k) Aralkill, (l) Aroyl, (m) aryloxy, (n) Aralkoxy and (o) CN In some cases, it is substituted from 1 to the maximum number of substituent positions by a substituent independently selected from the group consisting of. The alkyl moieties of items (d) to (g) above and item (k) above are halo, OR¹³And N (R¹⁴)₂Substituents independently selected from the group consisting of 1 to the maximum number of substituent positions are optionally substituted, and Items (h), (i), (j), (l) and (m) above and the aryl moieties of items (k) and (n) above are halo, OR¹³And C_1-4It is optionally substituted from 1 to the maximum number of substitutable positions by a substituent independently selected from the group consisting of alkyl. Includes compounds of formula I.</p><p> Another embodiment of the present invention is R.¹⁰Is HET or -C_1-4Alkyl-HET, HET (1) Pyridine, (2) Thiophene and (3) Franc, Or the benzo fusion analogs of (1) to (3) above Includes compounds of formula I selected from the group consisting of.</p><p> Another embodiment of the present invention is Formula II.</p><p><chemistry num="21"><img file="JP4570878B2_D0016.tif" /></chemistry>Includes compounds of or pharmaceutically compatible salts or hydrates thereof. here, X is a bond; R⁸And R¹⁰Is (1) C which is sometimes replaced by hydroxy_1-6Alkyl, (2) C_2-6Alkenyl, (3) C_3-6Alkyne, (4) C_3-6Cycloalkyl, (5) Phenyl (6) Naftil, (7) Benzyl, (8) Funetil and (9) Pyridine, thiophene or furan, or benzo fusion analogs thereof Each is independently selected from the group consisting of, and R⁸Is further selected from hydrogen, The aryl moieties of items (5), (6) and (9) above and items (7) and (8) above (a) Haro, (b) Hydroxy, (c) Methoxy, (d) C_1-4Alkyl, (e) Trifluoromethyl, (f) Phenoxy, (g) Benzyloxy, which is optionally substituted with methoxy, and (h) CN In some cases, it is substituted from 1 to the maximum number of substitutable positions by a substituent independently selected from the group consisting of; Each R¹¹Is (1) Haro, (2) Methyl and (3) Hydroxy It is independently selected from the group consisting of; and R¹⁴Is hydrogen and C_1-4It is independently selected from the group consisting of alkyl.</p><p> Another embodiment of the present invention is R.⁸Is hydrogen or C_1-4Includes compounds of formula II selected from the group consisting of alkyl.</p><p> Another embodiment of the present invention is Formula III</p><p><chemistry num="22"><img file="JP4570878B2_D0017.tif" /></chemistry>Includes compounds of or pharmaceutically compatible salts or hydrates thereof. here, n is 0 or 1 R⁸Is hydrogen or methyl, R⁹Is hydrogen or methyl, or R⁸And R⁹May be linked together with the oxygen atom represented by Formula III to form a carbonyl group; R¹⁰Is (1) Phenyl, (2) Naftil, (3) Pyridil, (4) Frills or benzofrills, (5) Thienyl or benzothienyl, or their S, S-dioxides, (6) Benzyl, (7) Kinolin, (8) Thiazolyl or benzothiazolyl, and (9) Phenylsulfonylmethyl or phenylsulfonylethyl It is selected from the group consisting of Basics (1) to (9) (a) Haro, (b) Trifluoromethyl, (c) Trifluoromethoxy, (d)-N (R)¹⁴) (Here, each R¹⁴Is independently hydrogen or C_1-4Alkyl), (e) Piloryl, (f) methoxy, ethoxy or isopropoxy, which are optionally substituted with substituents selected from methoxy, benzyl, cyclopropylmethyl, cyano, methylthio, methylsulfinyl and methylsulfonyl, respectively. (g) Methyl, (h) Vinyl and (i) Hydroxy It is optionally substituted by 1 to 3 substituents independently selected from the group consisting of, and R¹¹Is hydrogen or halo.</p><p> Another embodiment of the present invention is Formula IV.</p><p><chemistry num="23"><img file="JP4570878B2_D0018.tif" /></chemistry>Includes compounds of or pharmaceutically compatible salts or hydrates thereof. here, n is 0 or 1 R¹⁰Is (1)-CH (OR)¹³)-Aryl (where aryl is phenyl or naphthyl), (2)-CH (OR)¹³)-HET, and (3) In some cases substituted with phenylsulfonyl-CH (OR)¹³)-C_1-4Alkyl or -CH (OR¹³)-C_2-4Alkenyl It is selected independently from the group consisting of R¹³Is hydrogen or methyl, HET (1) Pyridil, (2) Frills or benzofrills, (3) Thienyl or benzothienyl, or their S, S-dioxides, (4) Benzyl, (5) Quinoline, (6) Thiazolyl or benzothiazolyl It is selected from the group consisting of The aryl or HET (a) Haro, (b) Trifluoromethyl, (c) Trifluoromethoxy, (d)-N (R)¹⁴) (Here, each R¹⁴Is independently hydrogen or C_1-4Alkyl), (e) Piloryl, (f) methoxy, ethoxy or isopropoxy, which are optionally substituted with substituents selected from methoxy, benzyl, cyclopropylmethyl, cyano, methylthio, methylsulfinyl and methylsulfonyl, respectively. (g) Methyl, (h) Vinyl and (i) Hydroxy, It is optionally substituted by 1 to 3 substituents independently selected from the group consisting of R¹¹Is hydrogen or halo.</p><p> Another embodiment of the invention includes a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically compatible carrier.</p><p> Another embodiment of the invention requires such treatment, comprising administering to the patient a compound of formula I in an amount effective for the treatment of a glucocorticoid receptor-mediated disease or condition. Includes methods of treating glucocorticoid receptor-mediated diseases or conditions in mammalian patients.</p><p> Among these embodiments are tissue rejection, leukemia, lymphoma, Cushing syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, multiple nodular arteritis, granulomatous polymorphism, myeloid cell lines. Inhibition, immune proliferation / apoptosis, suppression and regulation of HPA axis, hypercorticoid disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital Adrenal cortex hyperplasia, cerebral edema, thrombocytopenia, Little syndrome, obesity, metabolic syndrome, inflammatory bowel disease, systemic erythema erythema, multiple nodular arteritis, Wegener granulomatosis, Giant cell atopic dermatitis, Ryumachi-like arteritis, Juvenile Ryumachi-like arteritis, Glucocorticoiditis, Bacterial fever, Allergic rhinitis, urticaria, Vascular neuroedema, Chronic obstructive lung disease, Asthma, Adrenal inflammation Flames, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, liver cirrhosis, inflammatory scalp alopecia, subcutaneous adipose tissue inflammation, psoriasis, discoid erythroidodes, inflammatory cyst, atopy Atopic dermatitis, necrotizing pyoderma, pyoderma vulgaris, glucocorticoid vulgaris, systemic erythema, dermatitis, gestational herpes, eosinophilic myocarditis, recurrent polychondritis, inflammatory Vascular inflammation, sarcomatosis, Sweet disease, type I reactive Hansen's disease, capillary hemangiomas, contact dermatitis, atopic dermatitis, squamous dermatitis, shedding dermatitis, nodular erythema, acne, Hairiness, toxic epidermal necrosis, polymorphic erythema, cutaneous T-cell lymphoma, human immunodeficiency Beers (HIV), cell apoptosis, cancer, Kaposi sarcoma, retinal pigment degeneration, cognitive function, memory and learning enhancement, Included above are methods of selecting this glucocorticoid receptor-mediated disease or condition from the group consisting of depression, indulgence, mood disorders, chronic fatigue syndrome, schizophrenia, sleep disorders, and anxiety.</p><p> Another embodiment of the invention comprises administering to a patient a compound of formula I in an amount effective for the treatment of a glucocorticoid receptor-mediated disease or condition, a glucocorticoid receptor in mammals. Includes methods of selectively modulating the effects of activation, suppression, promotion and antagonism of.</p><p> The present invention is illustrated by the following compounds.</p><p> Unless otherwise specified, the present invention is described using the following definitions.</p><p> The term "halogen" or "halo" includes F, Cl, Br, and I.</p><p> The term "alkyl" means a linear or branched structure having the indicated number of carbon atoms and a combination thereof. Thus, for example, C_1-6Alkyls include methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.</p><p> The term "alkoxy" means a linear, branched or cyclic conformational alkoxy group having the indicated number of carbon atoms. C_1-6Alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy and the like.</p><p> The term "alkylthio" means a linear, branched or cyclic alkylthio group having the indicated number of carbon atoms. C_1-6Alkylthio includes, for example, methylthio, propylthio, isopropylthio and the like.</p><p> The term "alkenyl" has at least one carbon-carbon double bond in which hydrogen may be replaced by an additional carbon-carbon double bond, linear or indicated carbon atom number. It means a branched structure and a combination thereof. C_2-6Alkenyl includes, for example, ethenyl, propenyl, 1-methylethenyl, butenyl and the like.</p><p> The term "alkynyl" means a linear or branched structure having at least one carbon-carbon triple bond with the indicated number of carbon atoms and a combination thereof. C_3-6Alkynes include, for example, propenyl, 1-methylethenyl, butenyl and the like.</p><p> The term "cycloalkyl" means a monocyclic, bicyclic, or tricyclic structure that is optionally combined with a linear or branched structure with the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo [4.4.0] decyl and the like.</p><p> The term "aryl" is defined as a monocyclic or bicyclic aromatic ring system and includes, for example, phenyl, naphthyl.</p><p> The term "aralkyl" means the above-defined alkyl group of 1 to 6 carbon atoms, including the above-defined aryl group substituted for one of the alkyl hydrogen atoms, such as benzyl.</p><p> The term "aryloxy" means the aryl group defined above that is attached to a molecule by an oxygen atom (aryl-O) and includes, for example, phenoxy, naphthoxy.</p><p> The term "ararcoxy" means the aralkyl group defined above that is attached to a molecule by an oxygen atom (aryl-O) and includes, for example, benzyloxy.</p><p> The term "arylthio" means an aryl group as defined above that is attached to a molecule by a sulfur atom (aryl-S) and includes, for example, thiophenoxy, thionaphthoxy.</p><p> The term "aroyl" means the aryl group defined above that is attached to the molecule by a carbonyl group (aryl-C (O)-) and includes, for example, benzoyl, naphthoyl.</p><p> The term "aroyloxy" means the aryl group defined above that is attached to a molecule by an oxygen atom (aloyl-O) and includes, for example, benzoyloxy or benzoxy, naphthoyloxy.</p><p> The term "HET" is an aromatic, moiety of a 5- to 10-membered ring selected from O, S and N and containing 1 to 4 heteroatoms optionally substituted with 1 to 2 oxo groups. It is defined as an aromatic or non-aromatic monocyclic or bicyclic ring. Preferably, "HET" is a 5- or 6-membered aromatic or non-aromatic monocyclic ring containing 1 to 3 heteroatoms selected from O, S and N, such as pyridine, pyrimidine, etc. Aromatic or partial 9- or 10-membered rings containing 1 to 3 heteroatoms, such as pyridazine, furan, thiophene, thiazole, oxazole, isooxazole, or selected from O, S and N. Aromatic bicyclic rings such as benzofuran, benzothiophene, indol, pyranopyrrole, benzopyran, quinoline, benzocyclohexyl, naphthylidine and the like. "HET" also refers to benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carborinyl, quinolinyl, furanyl, imidazolyl, indolinyl, indrill, indrazinyl, indazolyl, isobenzofla Nil, Isoindrill, Isoquinolyl, Isothiazolyl, Isoxazolyl, Naftyridinyl, Oxaziazolyl, Oxazolyl, Pyrazinyl, Pyrazolyl, Pyridopyridinyl, Pyridadinyl, Pyridyl, Pyrimidyl, Pyrrolyl, Kinazolinyl, Kinolyl, Kinoxalinyl, Thiasiazolyl, Thiazolyl, Thienyl, Triazolyl 4-Dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindrill , Dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolill, dihydroquinolinyl, dihydrotetrazoli Also included are dihydrothiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl. For all of the above definitions, each reference to a group is independent of all other references to the same group, as referred to herein. For example, R¹And R²If both are HETs, then the definitions of HETs are independent of each other, and R¹And R²May be different HET groups, such as furan and thiophene.</p><p> The term "treat" not only treats a patient to remove signs and symptoms of the disease or condition from the patient, but also prophylactically treats an asymptomatic patient to prevent the onset of the disease or condition. Alternatively, it also includes the prevention, delay or reversal of the progression of the disease or condition. The term "effective amount to treat" is a drug or drug that produces a biological or medical response pursued by researchers, veterinarians, doctors or other clinicians in tissues, systems, animals or humans. It is intended to mean the amount of medicinal agent. The term also prevents or reduces the risk of biological or medical events pursued for prevention by researchers, veterinarians, physicians or other clinicians in tissues, systems, animals or humans. It also includes the amount of medicinal drug to cause.</p><p> The following abbreviations have the indicated meanings. AIBN = 2,2'-azobisisobutyronitrile BP = benzoyl peroxide Bn = benzyl CCl₄= Carbon tetrachloride D = -O (CH)₂)₃O- DAST = Diethylamine Sulfur Trifluoride DCC = dicyclohexylcarbodiimide DCI = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide DEAD = diethyl azodicarboxylate DIBAL = diisobutylaluminum hydride DME = ethylene glycol dimethyl ether DMAP = 4- (dimethylamino) pyridine DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide Et₃N = triethylamine LDA = lithium diisopropylamide m-CPBA = meta-chloroperbenzoic acid NBS = N-Bromosuccinimide NSAID = non-steroidal anti-inflammatory drug PCC = pyridinium chlorochromate PDC = pyridinium dichromate Ph = phenyl 1,2-Ph = 1,2-benzenediyl Pyr = Pyridine Diyl Qn = 7-chloroquinoline-2-yl Rs = CH₂SCH₂CH₂Ph rt = room temperature rac. = Racemic THF = tetrahydrofuran THP = tetrahydropyran-2-yl Alkyl group abbreviation Me = methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = Normal Butyl i-Bu = Isobutyl s-Butyl = Secondary Butyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl Some of the compounds described herein contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. The present invention is intended to include such diastereomers as well as their racemates and split, enantiomeric pure forms and salts of these pharmaceutically compatible.</p><p> Some of the compounds described herein contain olefin-type double bonds and are intended to contain E and Z geometric isomers unless otherwise noted.</p><p> The pharmaceutical composition of the present invention comprises a compound of formula I or a pharmaceutically compatible salt thereof as an active ingredient, and may also contain a pharmaceutically compatible carrier and optionally other therapeutic ingredients. The term "pharmaceutical compatible salt" refers to a salt made from a drug compatible non-toxic base, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese salts, divalent manganese, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically compatible organic, non-toxic bases are primary, secondary, and tertiary amines, substituted amines containing naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine. , Betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholin, N-ethylpiperidine, glucamine, glucosamine, Includes salts such as histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, prokine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.</p><p> If the compounds of the invention are basic, salts may be made from non-toxic, pharmaceutically compatible acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloride, isetionic acid, lactic acid, maleic acid. , Apple acid, mandelic acid, methanesulfonic acid, mucilage acid, nitrate, pamonic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloride, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.</p><p> In the therapeutic method discussions that follow, it is understood that references to compounds of formula I are meant to also include pharmaceutically compatible salts.</p><p> The extent of the prophylactic or therapeutic dose of a compound of formula I will, of course, depend on the nature and severity of the condition being treated and on the particular compound of formula I and the route of administration. It also depends on a variety of factors, including the age, weight, general health, sex, diet, dosing time, excretion rate, drug combination and response of the individual patient. Generally, a daily dose of about 0.001 mg to about 100 mg, preferably 0.01 mg to about 10 mg / kg of mammal body weight. On the other hand, in some cases it may be necessary to use doses outside these limits.</p><p> The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, formulations intended for oral administration to humans contain from about 0.5 mg to about 5 g of activator mixed with an appropriate and convenient amount of carrier material that varies from 5 to about 95 percent of the total composition. You may. The dose unit form generally contains about 1 mg to about 2 g of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.</p><p> For the treatment of glucocorticoid receptor-mediated disorders, the compounds of formula I are oral, topical, non-oral as dose-based formulations containing conventional non-toxic drug-compatible carriers, adjuvants and vehicles. It may be administered orally, by inhalation spray, or rectally. The term "parenteral" includes, as used herein, subcutaneous, intravenous, intramuscular, intrathoracic injection or infusion. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cows, sheep, dogs, cats, the compounds of the present invention are effective in the treatment of humans.</p><p> Pharmaceutical compositions containing this active ingredient are suitable for oral use, for example as tablets, troches, rhombic tablets, solutions, aqueous or oily suspensions, dispersed powders or granules, emulsions, hard or soft capsules, syrups or elixirs. It may be of any shape. Compositions intended for oral use may be produced by any method known in the art for the production of pharmaceutical compositions, and such compositions may be a pharmaceutically sophisticated and palatable formulation. It may contain one or more agents selected from the group consisting of sweeteners, flavors, colorants and preservatives to provide. The tablets contain the active ingredient when mixed with non-toxic, pharmaceutically compatible excipients suitable for the manufacture of tablets. These excipients are inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulators and disintegrants such as corn den powder or alginic acid; binders such as den powder, It may be gelatin or acacia; and a lubricant such as magnesium stearate, stearic acid or talc. The tablet may be uncoated or coated by a known method that delays disintegration and absorption in the gastrointestinal tract, thereby providing a long lasting effect. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by the methods described in US Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.</p><p> Formulations for oral use may be as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient may be in a water-miscible solvent such as propylene glycol, PEG and ethanol. , Or as a soft gelatin capsule mixed with an oil medium, such as peanut oil, liquid paraffin, or olive oil.</p><p> The aqueous suspension contains an excipient suitable for producing the aqueous suspension and an active material in a mixed manner. Such excipients are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacant gum and acacia gum; dispersants or wetting agents are naturally occurring phosphatides such as lecithin. , A condensation product of alkylene oxide and fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide and long-chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a moiety derived from ethylene oxide, fatty acid and hexitol. It may be a condensation product with an ester, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol hydride, such as polyethylene sorbitan monooleate. This aqueous suspension also contains one or more preservatives such as ethyl- or n-propyl-p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners. For example, sucrose, saccharin or aspartame may also be contained.</p><p> Oily suspensions may be formulated by suspending the active ingredient in vegetable oils such as lacquer oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin. The oily suspension may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those described above and flavoring agents may be added to provide a palatable oral formulation. These compositions may be preserved by adding antioxidants such as ascorbic acid.</p><p> Dispersed powders and granules suitable for making aqueous suspensions by adding water are mixed with dispersants or wetting agents, suspending agents and one or more preservatives to provide the active ingredient. Suitable dispersants or wetting agents and suspending agents are exemplified by those already listed above. Additional excipients such as sweeteners, flavors and colorants may also be present.</p><p> The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or lacquer oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers are naturally occurring phosphatides, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol hydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as poly. It may be an oxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.</p><p> Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain palliatives, preservatives and flavors and colorants. The pharmaceutical composition may be in the form of a sterile aqueous or oily injectable suspension. The suspension may be formulated by known methods using the suitable dispersants or wetting and suspending agents listed above. This sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, eg, as a solution in 1,3-butanediol. .. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol or polyethylene glycol may also be used. In addition, sterile non-volatile oil is commonly used as a solvent or suspension medium. Any sterile non-volatile oil containing synthetic mono- or diglycerides may be used for this purpose. In addition, fatty acids such as oleic acid are used in the production of injection solutions.</p><p> The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions are prepared by mixing the drug with a suitable non-irritating excipient that is solid at ambient temperature but liquid at rectal temperature and melts in the rectum to release the drug. Can be manufactured. Such materials are cocoa butter and polyethylene glycol.</p><p> For topical use, creams, ointments, gels, solutions or suspensions containing compounds of formula I are used (for the purposes of this application, topical application shall include mouthwash and gargle). Topical formulations may generally consist of pharmaceutical carriers, co-solvents, emulsifiers, penetration enhancers, preservatives, and emollients.</p><p> The ability of compounds of formula I to selectively modulate glucocorticoid receptors makes them useful in treating, preventing or reversing the progression of various inflammatory and autoimmune diseases and pathologies. Thus, the compounds of the invention are useful in treating, preventing or ameliorating the following diseases or conditions: inflammation, tissue rejection, autoimmunity, various malignant diseases such as leukemia and lymphoma, Cushing syndrome, acute. Adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, multiple nodular arteritis, granulomatous polyplasia, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of HPA axis, hypercorticoid disease, Stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little syndrome, obesity and metabolic syndrome ..</p><p> The compounds of the present invention also include systemic inflammation such as inflammatory bowel disease, systemic erythema, polyarteritis nodosa, Wegener granulomatosis, giant cell arteritis, rheumatoid arthritis, juvenile rheumatism. Rheumatoid arteritis, vegetative inflammation, hay fever, allergic rhinitis, urticaria, vasoneuropathy, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune It is useful for treating, preventing or reversing the progression of disease states associated with chronic active hepatitis, organ transplantation, hepatitis, and liver cirrhosis.</p><p> The compounds of the present invention can be used in a variety of local disorders such as inflammatory scalp alopecia, subcutaneous adipose tissue inflammation, psoriasis, discoid erythroidosis, inflammatory cysts, atopic dermatitis, necrotizing pyoderma, pyoderma vulgaris, Bufros psoriasis, systemic erythema, dermatitis, gestational herpes, eosinophilia myelitis, recurrent polychondritis, inflammatory vasculitis, sarcomatosis, Sweet disease, type I reactive Progression of Hansen's disease, capillary hemangiomas, contact dermatitis, atopic dermatitis, squamous lichen, shedding dermatitis, nodular erythema, acne, hirsutism, toxic epidermal necrosis, polymorphic erythema, and cutaneous T-cell lymphoma It is useful for treating, preventing or reversing.</p><p> The compounds of the present invention also include human immunodeficiency virus (HIV), cell apoptosis, and, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IIL-I expression, It is useful in treating, preventing or reversing the development of natural killer cells, the progression of cancer-related disease states, including lymphocytic leukemia, and in the treatment of retinal pigment degeneration. Cognitive and behavioral processes are also potentially useful in the treatment of processes such as cognitive function, memory and learning enhancement, depression, indulgence, mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep disorders, and anxiety. It is susceptible to the effects of sugar corticoid treatment.</p><p> The present invention also treats glucocorticoid receptor-mediated disorders, including the accompanying administration of a compound of formula I and one or more agents to a patient in need of such treatment. Also includes methods for. For the treatment or prevention of asthma or chronic obstructive pulmonary disease, the compounds of formula I are formulated with β-agonists (eg salmeterol), theophylline, anticholinergic agents (eg atripin and ipratropium bromide), chromolin, nedocromil and leukotriene modifications. It may be combined with one or more agents selected from the group consisting of yer (eg, montelukast). For the treatment or prevention of inflammation, compounds of formula I may be combined with one or the following: salicylate with acetylsalicylic acid, indomethacin, slindac, mephenamic, meclophenamic, tolfenamic, tolmethin. , Ketoprofen, dicophenac, ibuprofen, naproxen, phenoprofen, ketoprofen, non-steroidal anti-inflammatory drugs including flurbiprofen and oxaprozin, TNF inhibitors including etanercept and infliximab, IL-1 receptor antagonists, methotrexate, leflonamide, Cytotoxic or immunosuppressive agents, including azathiopurine and cyclosporine, gold compounds, hydroxychlorokin or sulfasalazine, penicillamine, dalbferon, and ρ38 kinase inhibitors. Compounds of formula I may also be used in combination with bisphosphonates such as alendronate to treat glucocorticoid-mediated disorders and simultaneously inhibit osteoclast-mediated bone reabsorption.</p><p> Synthesis method In general, the compounds of the present invention are synthesized according to the following synthetic schemes.</p><p><chemistry num="24"><img file="JP4570878B2_D0019.tif" /></chemistry> An acid such as p-toluenesulfonic acid is added to the solution of Wieland-Miescher ketone i in ethylene glycol to give the ketal ii. Ethyl formate and sodium hydride are added to the ketal ii in an organic solvent such as anhydrous benzene to give the hydroxyketone iii. Hydroxyketone iii is dissolved in a suitable acid such as glacial acetic acid and the appropriate hydrazine such as p-fluorophenylhydrazine hydrochloride and the appropriate base such as sodium acetate are added to give pyrazole ketal iv. Pyrazole ketal iv is dissolved in an aprotic solvent such as THF and an acid aqueous solution such as 6N HCl aqueous solution is added to obtain ketone v.</p><p> Potassium bis (trimethylsilylamide) is added to (methoxymethyl) triphenylphosphonium chloride in an aprotic solvent such as THF. Ketone v is added to give compound vi. R¹⁰-Li is added at low temperature in an aprotic solvent such as THF to give the final product vii.</p><p> In view of the methods and examples described below, those skilled in the art will be able to readily discern how to prepare compounds of formula I outside the scope of formula vii. For example, Syth.Commun., 1994, vol.24, pp.279-292; Org.Syth., 1985, vol.63, pp.37-43; Org.Syth., 1985, vol.63, pp.26 See -36; and Setroids, 1963, vol.2, p.399.</p><p> The present invention will be illustrated by the following non-limiting examples. In this embodiment, unless otherwise specified, it is as follows. (i) All operations were performed at room temperature or ambient temperature, ie temperatures in the range 18-25 ° C. (ii) The solvent was evaporated using a rotary evaporator under reduced pressure (600-4000 Pascal: 4.5-30 mmHg) at a bath temperature of up to 60 ° C. (iii) The reaction pathway was followed by thin layer chromatography (TLC) and reaction times are shown for illustration only. (iv) Melting point is uncorrected, and "d" indicates decomposition; given melting point is obtained for the material produced as stated; polymorphism occurs during material isolation and is The melting points of the formulations may differ. (v) The structure and purity of all final products was confirmed by at least one of TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy or microanalytical data techniques. (vi) Yields are shown for illustration purposes only. (vii) When displayed, the NMR data is the delta (δ) value for the main proton to be measured, determined at 500 MHz or 600 MHz using the displayed solvent, and is the internal standard tetramethylsilane (TMS). Indicated by parts per million parts per million (ppm) for; the idiomatic abbreviations used for the shape of the signal are: s. singlet; d. doublet; t. triplet; m. multiplet; br. Broad etc. Yes; in addition, "Ar" means aromatic signal. (viii) The chemical symbols have their usual meanings and also used the following abbreviations: v (volume), w (weight), bp (boiling point), mp (melting point), L (liter), mL (milliliter). ), G (gram), mg (milligram), mol (mol), mmol (mmol), eq (equal volume).</p><p>Synthesis example</p><p><chemistry num="25"><img file="JP4570878B2_D0020.tif" /></chemistry> Step 1: 4 Å molecular sieves (~ 5 g) and p-toluenesulfonic acid (5.34 g, 28.05 mmol) were added to a solution of Wieland-Miescher ketone (5 g, 28.05 mmol) in ethylene glycol (140 mL). After stirring at room temperature for 23 minutes, the reaction is iced water / saturated LVDS.₃It was poured slowly into a 2: 1 mixture of (150 mL) aqueous solution. The reaction was extracted with EtOAc (4 x 100 mL) and the combined organic layers were washed with brine (100 mL) and EDTA.₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-40% EtOAc / Hexanes) to give 5.77 g (93%) of this ketal as a white solid. LCMS = 223; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ5.83 (br d, J = 1.8Hz, 1H), 4.43-3.94 (m, 4H), 2.49-2.40 (m, 3H), 2.39-2.27 (m, 2H), 1.95-1.88 ( m, 1H), 1.84-1.78 (m, 1H), 1.76-1.64 (m, 3H), 1.37 (s, 3H).</p><p> Stage 2: Ethyl formate (7.36 mL, 86.48 mmol) and sodium hydride (60% suspension of mineral oil; 3.46 g, 86.48 mmol) were added to a cooled solution (-40 ° C) of this ketal anhydrous benzene (200 mL). did. MeOH (450 μL) was added dropwise over 15 minutes and the reaction was warmed to room temperature. After stirring at room temperature for 3 hours, the reaction is cooled to 0 ° C and 50 mL H₂O was added. Shake this two-phase system, and H the organic layer₂Washed with O (3 x 50 mL). This combined aqueous layer was washed with diethyl ether (100 mL) and then saturated KH.₂PO₄It was acidified to pH 5.5-6 with an aqueous solution. The aqueous layer was extracted with EtOAc (5 x 200 mL). This combined extract is Na₂SO₄It was dried on top and concentrated in vacuo to give 5.04 g (93%) of hydroxyketone product as an orange oil. LCMS = 251; (M + 1)⁺。 </p><p> Stage 3: This hydroxyketone (4.1 g, 16.4 mmol) was dissolved in glacial acetic acid (40 mL), and p-fluorophenylhydrazine hydrochloride (2.8 g, 17.22 mmol) and sodium acetate (1.41 g, 17.22 mmol) were added. After stirring at room temperature for 2 hours, the reaction is 10% LVDS.₃It was poured slowly into (1 L) and extracted with EtOAc (6 x 500 mL). This combined extract was washed with brine (500 mL) and EDTA₄It was dried on top and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (10% EtOAc / Hexanes) to give 2.26 g (41%) of this pyrazole ketal as an orange solid. LCMS = 421; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.47-7.44 (m, 2H), 7.43 (s, 1H), 7.18-7.16 (d, J = 8.5Hz, 1H), 7.16-7.14 (d, J = 8.7Hz, 1H), 6.22 (br d, J = 2.2Hz, 1H), 4.11-4.01 (m, 4H), 3.20-3.16 (d, J = 15.7Hz, 1H), 2.54-2.51 (d, J = 16Hz, 1H), 2.51 -2.40 (m, 1H), 2.34-2.28 (m, 1H), 1.88-1.64 (m, 4H), 1.23 (s, 3H).</p><p> Stage 4: This pyrazole ketal (2.26 g; 6.65 mmol) was dissolved in THF (65 mL) and 6N HCl (4.43 mL, 26.6 mL) was added. The reaction was heated at 65 ° C for 3.5 hours, then 10% LVDS.₃Pour slowly into (150 mL). The mixture is extracted with EtOAc (4 x 250 mL) and the combined extracts are washed with brine (2 x 200 mL) and deli₄It was dried on top and concentrated in vacuo to give 1.97 g (100%) of Ketone A as a brown oil. LCMS = 297; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.50 (s, 1H), 7.49-7.45 (m, 2H), 7.20-7.16 (m, 2H), 6.31 (br d, J = 2Hz, 1H), 2.96-2.88 (m, 2H) ), 2.72-2.62 (m, 2H), 2.59-2.53 (m, 2H), 2.14-2.08 (m, 1H), 1.75-1,64 (qt, J = 13.1Hz, J = 4.3Hz, 1H), 1.27 (s, 3H).</p><p><chemistry num="26"><img file="JP4570878B2_D0021.tif" /></chemistry> Step 1: Production of Aldehyde B</p><p><chemistry num="27"><img file="JP4570878B2_D0022.tif" /></chemistry> A THF suspension (40 mL) of (methoxymethyl) triphenylphosphonium chloride (4.17 g, 12.16 mmol) was cooled to -40 ° C. Potassium bis (trimethylsilylamide) (20.3 mL 0.5 M toluene solution, 10.15 mmol) was added dropwise by syringe and the reaction was warmed to 0 ° C and kept at that temperature for 15 minutes. A THF solution (12 mL) of ketone A (1.2 g, 4.05 mmol) was added and the reaction was warmed to room temperature. After stirring at room temperature for 24 hours, 10 mL of a 1: 1 solution of THF / MeOH was added to the reaction, followed by 10 mL of 4N HCl. The reaction became biphasic and stirring was continued at room temperature. After 36 hours, the reaction is diluted with EtOAc (300 mL) and H₂O, saturated LVDS₃, And brine (50 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-25% EtOAc / hexane) on silica gel to give 939.7 mg (75%) of Product B as a yellowish brown solid. An 8: 1 (β: α) mixture of aldehyde diastereomers. R_f= 0.19 (25% EtOAc / Hexanes). LCMS = 311; (M + 1)⁺。¹H NMR (major isomer) (CDCl₃, 500MHz) δ9.91 (d, J = 1.8Hz, 1H), 7.43-7.46 (m, 3H), 7.16 (t, J = 8.6Hz, 2H), 6.17 (d, J = 1.9Hz, 1H), 3.11 (d, J = 15.6Hz, 1H), 2.91 (d, J = 15.6Hz, 1H), 2.32-2.45 (m, 3H), 1.87-1.98 (m, 2H), 1.75 (m, 1H), 1.43 (m, 1H), 1.12 (s, 3H).</p><p> Ketone C was produced in the same manner as Ketone A.</p><p><chemistry num="28"><img file="JP4570878B2_D0023.tif" /></chemistry> Step 1:</p><p><chemistry num="29"><img file="JP4570878B2_D0024.tif" /></chemistry> A THF suspension (25 mL) of methyltriphenylphosphonium bromide (2.05 g, 5.75 mmol) was cooled to -40 ° C. Potassium bis (trimethylsilylamide) (9.2 mL 0.5 M toluene solution, 4.6 mmol) was added dropwise by syringe and the reaction was warmed to 0 ° C and kept at that temperature for 15 minutes. Next, a solution of ketone C (323.7 mg, 1.15 mmol) in THF (5 mL) was added by cannula. The reaction was warmed to room temperature. After stirring at room temperature for 2 hours, the reaction was filtered through the silica gel filler with 50% EtOAc / Hexanes. The filtrate was concentrated and the residue was purified by flash chromatography with 15% EtOAc / hexanes to give 265.2 mg (83%) D. R_f= 0.39 (25% EtOAc / Hexanes). LCMS = 281; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.46-7.49 (m, 2H), 7.44 (s, 1H), 7.13-7.17 (m, 2H), 6.19 (s, 1H), 4.95 (s, 1H), 4.86 (s, 1H) , 2.81 (d, J = 15.3Hz, 1H), 2.73 (m, 1H), 2.69 (d, J = 15.6Hz, 1H), 2.54-2.67 (m, 2H), 2.48 (m, 1H), 1.17 ( s, 3H).</p><p> Stage 2:</p><p><chemistry num="30"><img file="JP4570878B2_D0025.tif" /></chemistry> 9-BBN (5.7 mL 0.5 MTHF solution, 2.84 mmol) was added to a THF solution (17 mL) of D (265.2 mg, 0.947 mmol). The reaction was stirred at room temperature for 1.5 hours and then cooled to 0 ° C. EtOH (6.8 mL), 6NNaOH (2.25 mL) and 30% H₂O₂(1.2 mL) was added, the ice bath was removed, and the reaction was heated at 50 ° C. for 1 hour. The reaction is then cooled to room temperature, diluted with EtOAc (100 mL), and H₂Washed with O and brine (50 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography with 60% EtOAc / Hexanes to give 282.2 mg (100%) of E. R_f= 0.19 (55% EtOAc / Hexanes). LCMS = 299; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.46-7.48 (m, 2H), 7.41 (s, 1H), 7.13-7.16 (m, 2H), 6.14 (s, 1H), 3.81 (dd, J = 10.6, 7.1Hz, 1H) , 3.75 (dd, J = 10.8, 7.0Hz, 1H), 2.92 (d, J = 15.3Hz, 1H), 2.66 (d, J = 15.3Hz, 1H), 2.63 (m, 1H), 2.47 (m, 1H), 2.10 (m, 1H), 2.03 (m, 1H), 1.58 (m, 1H), 0.97 (s, 3H).</p><p> Stage 3:</p><p><chemistry num="31"><img file="JP4570878B2_D0026.tif" /></chemistry> CH of oxalyl chloride (46 μL, 0.524 mmol)₂Cl₂CH in solution (2 mL) at -78 ° C₂Cl₂DMSO (75 μL, 1.05 mmol) in (1 mL) was added. The reaction is stirred at -78 ° C for 5 minutes, then CH.₂Cl₂Alcohol E (52.1 mg, 0.175 mmol) in (2 mL) was added. The reaction is stirred for 15 minutes and then Et.₃N (295 μL, 2.1 mmol) was added. The reaction was warmed to room temperature, stirred for 20 minutes and diluted with EtOAc (50 mL). H this organic solution₂O, saturated LVDS₃, Brine, 1NHCl, saturated LVDS₃, And brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40% EtOAc / Hexanes) to give 41.5 mg (80%) of F as a clear, colorless oil. R_f= 0.27 (40% EtOAc / Hexanes). LCMS = 297; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ9.89 (d, J = 1.6Hz, 1H), 7.43-7.46 (m, 2H), 7.42 (s, 1H), 7.13-7.16 (m, 2H), 6.17 (s, 1H), 3.01 (d, J = 15.4Hz, 1H), 2.88 (d, J = 15.4Hz, 1H), 2.67-2.75 (m, 2H), 2.51 (m, 1H), 2.56 (m, 1H), 2.06 (m, 1H), 1.06 (s, 3H).</p>

(Example 1)

<chemistry num="32"><img file="JP4570878B2_D0027.tif" /></chemistry> Step 1: Add aryl Grignard reagent to aldehyde B

<chemistry num="33"><img file="JP4570878B2_D0028.tif" /></chemistry> Aldehyde B (42.7 mg, 0.138 mmol) was dissolved in THF (4 mL) and cooled to 0 ° C. 4-Fluorobenzylmagnesium chloride (5.5 mL 0.25 MEt)₂Solution O, 1.38 mmol) was added dropwise with a syringe. The reaction is stirred at 0 ° C for 1 hour and then saturated NH₄Quenched with Cl (25 mL). The mixture is extracted with EtOAc (100 mL) and the organic layer is H₂Wash with O and brine (25 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The main product was isolated by flash chromatography (5-25% EtOAc / Hexanes) to give 40.6 mg (70%) of Example 1 as a single diastereomer. R_f= 0.11 (25% EtOAc / Hexanes). LCMS = 421; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.42-7.44 (m, 2H), 7.38 (s, 1H), 7.13-7.20 (m, 4H), 7.02 (t, J = 8.6Hz, 2H), 6.09 (d, J = 2.3) Hz, 1H), 4.16 (br s, 1H), 2.85-2.90 (m, 2H), 2.68 (dd, J = 13.5, 5.7Hz, 1H), 2.41 (m, 1H), 2.26-2.32 (m, 2H) ), 1.95 (m, 1H), 1.80 (m, 1H), 1.71 (qd, J = 13.0, 3.3Hz, 1H), 1.56 (dd, J = 12.5, 3.5Hz, 1H), 1.40 (m, 1H) , 1.12 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described for Example 1.

<tables num="3"><img file="JP4570878B2_D0029.tif" /></tables><img file="JP4570878B2_D0030.tif" /><img file="JP4570878B2_D0031.tif" /><img file="JP4570878B2_D0032.tif" /><img file="JP4570878B2_D0033.tif" /><img file="JP4570878B2_D0034.tif" /><img file="JP4570878B2_D0035.tif" />

(Example 32)

<chemistry num="34"><img file="JP4570878B2_D0036.tif" /></chemistry> Step 1: Add aryl or vinyl lithium reagent to aldehyde B

<chemistry num="35"><img file="JP4570878B2_D0037.tif" /></chemistry> Et of 1-bromo-4-fluorobenzene (176 μL, 1.6 mmol)₂Solution O (16 mL) was cooled to -78 ° C and t-BuLi (1.9 mL 1.7 M pentane solution, 3.2 mmol) was added dropwise by syringe. The reaction was stirred at 78 ° C. for 20 minutes, then aldehyde B (49.6 mg, 0.16 mmol) in THF (4 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol is added at -78 ° C and the reaction is saturated with NH.₄I poured it into Cl. The mixture is extracted with EtOAc (100 mL) and the organic layer is H₂Washed with O and brine (25 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-20% EtOAc / Hexanes) gave 52.8 mg of Example 32 contaminated with a small amount of diastereomers. Further purification by chiral HPLC (AD column, 20% isopropyl alcohol / heptane) gave 35.6 mg (55%) of pure Example 32. R_f= 0.16 (25% EtOAc / Hexanes). LCMS = 407; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.45 (m, 4H), 7.32 (dd, J = 9.5,5.0Hz, 2H), 7.15 (t, J = 8.5Hz, 2H), 7.04 (t, J = 8.8Hz, 2H) , 6.12 (d, J = 2.1Hz, 1H), 5.18 (s, 1H), 3.18 (d, J = 15.1Hz, 1H), 2.75 (d, J = 15.1Hz, 1H), 2.41 (m, 1H) , 2.28 (bd, J = 15.1Hz, 1H), 1.82 (m, 1H), 1.66-1.71 (m, 2H), 1.58 (m, 1H), 1.26 (s, 3H), 1.20 (m, 1H).

The following compounds were synthesized according to a procedure similar to that described for Example 32.

<tables num="4"><img file="JP4570878B2_D0038.tif" /></tables><img file="JP4570878B2_D0039.tif" /><img file="JP4570878B2_D0040.tif" /><img file="JP4570878B2_D0041.tif" /><img file="JP4570878B2_D0042.tif" /><img file="JP4570878B2_D0043.tif" /><img file="JP4570878B2_D0044.tif" /><img file="JP4570878B2_D0045.tif" /><img file="JP4570878B2_D0046.tif" />

(Example 64)

<chemistry num="36"><img file="JP4570878B2_D0047.tif" /></chemistry> Step 1: Oxidation to ketones

<chemistry num="37"><img file="JP4570878B2_D0048.tif" /></chemistry> CH of Example 32 (23.0 mg, 0.057 mmol)₂Cl₂The solution (2 mL) was cooled to 0 ° C. and NMO (10 mg, 0.085 mmol) was added. After 5 minutes, TPAP (2 mg, 0.0057 mmol) was added to the reaction. The reaction was stirred at 0 ° C. for 3 hours and then loaded directly onto the silica gel column. 100% CH₂Cl₂And subsequent elution with 25% EtOAc / Hexanes resulted in 19.2 mg (84%) of Product G. R_f= 0.32 (25% EtOAc / hexane). LCMS = 405; (M + 1)⁺。

Step 2: Ketone reduction

<chemistry num="38"><img file="JP4570878B2_D0049.tif" /></chemistry> Compound G (19.2 mg, 0.048 mmol) was dissolved in MeOH (2 mL) and cooled to 0 ° C. NaBH₄(10 mg, 0.238 mmol) was added. The reaction is stirred at 0 ° C for 15 minutes and then saturated NH.₄Quenched with Cl (5 mL). The mixture was extracted with EtOAc (30 mL). This organic layer is H₂Wash with O and brine (10 mL each) and remove this organic layer with Na.₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40% EtOAc / Hexanes) followed by chiral HPLC to remove small amounts of impurities (AD column, 12% IPA / hexanes) to remove 12.6 mg (65%) of pure Example 64. Got R_f= 0.16 (25% EtOAc / heptane). LCMS = 407; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.45 (dd, J = 9.0,4.8Hz, 2H), 7.40 (s, 1H), 7.32 (dd, J = 8.4,5.4Hz, 2H), 7.14 (t, J = 8.4Hz, 2H), 7.04 (t, J = 8.4Hz, 2H), 6.15 (s, 1H), 4.64 (d, J = 9.0Hz, 1H), 3.63 (d, J = 16.2Hz, 1H), 2.78 (d, J = 16.2Hz, 1H), 2.27-2.29 (m, 2H), 2.07 (bs, 1H), 1.89 (m, 1H), 1.68 (m, 1H), 1.05-1.25 (m, 2H), 1.13 (s , 3H).

The following compounds were synthesized according to a procedure similar to that described for Example 64.

<tables num="5"><img file="JP4570878B2_D0050.tif" /></tables><img file="JP4570878B2_D0051.tif" />

(Example 69)

<chemistry num="39"><img file="JP4570878B2_D0052.tif" /></chemistry> Step 1: Add aryllithium to aldehyde B

<chemistry num="40"><img file="JP4570878B2_D0053.tif" /></chemistry> Et of O-triisopropylsilyloxy-3-bromobenzyl alcohol (230 mg, 0.67 mmol)₂Solution O (6.5 mL) was cooled to -78 ° C and t-BuLi (785 μL 1.7 M pentane solution, 1.34 mmol) was added. The reaction was stirred at -78 ° C for 15 minutes. Aldehyde B (20.7 mg, 0.067 mmol) was added as a solution in THF (2 mL) by cannulation. The reaction was stirred at 78 ° C. for 30 minutes. Add 1 mL of isopropyl alcohol and saturate this reaction NH₄Pour into Cl (15 mL). The mixture was extracted with EtOAc (50 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 5-15% EtOAc / Hexanes) to give 32.4 mg of product containing one major diastereomer and two secondary diastereomers. Further purification by chiral HPLC (AD column, 15% IPA / heptane) resulted in 19.4 mg (51%) of pure H (main diastereomers). R_f= 0.22 (25% EtOAc / Hexanes). LCMS = 575; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.45-7.48 (m, 3H), 7.36 (s, 1H), 7.33 (t, J = 7.6Hz, 1H), 7.24 (t, J = 6.8Hz, 2H), 7.13-7.17 ( m, 2H), 6.11 (d, J = 2.0Hz, 1H), 5.19 (s, 1H), 4.86 (s, 2H), 3.19 (d, J = 15.1Hz, 1H), 2.76 (d, J = 15.1 Hz, 1H), 2.41 (m, 1H), 2.27 (br d, J = 15.1Hz, 1H), 1.63-1.82 (m, 5H), 1.27 (s, 3H), 1.15-1.22 (m, 3H), 1.10 (d, J = 6.9Hz, 18H).

Step 2: Desilylation of protected alcohol or phenol

<chemistry num="41"><img file="JP4570878B2_D0054.tif" /></chemistry> Compound H (19.4 mg, 0.034 mmol) was dissolved in THF (3 mL) and cooled to 0 ° C. TBAF (169 μL of 1 MTHF solution, 0.169 mmol) was added. The reaction is stirred at 0 ° C for 20 minutes and then saturated NH.₄Quenched with Cl (5 mL). The mixture was extracted with EtOAc (30 mL). This organic layer is H₂Wash with O and brine (10 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (75% EtOAc / Hexanes) to give 12.9 mg (91%) of pure Example 69. R_f= 0.28 (75% EtOAc / Hexanes). LCMS = 419; (M + 1)⁺。¹H NMR (DMSO, 500MHz): δ7.50-7.53 (m, 3H), 7.34 (t, J = 8.8Hz, 2H), 7.29 (s, 1H), 7.25 (t, J = 7.4Hz, 1H), 7.21 (d, J = 7.6Hz, 1H), 7.12 (d, J = 7.3Hz, 1H), 6.17 (s, 1H), 5.12 (t, J = 5.8Hz, 1H), 4.99-5.03 (m, 2H) ), 4.48 (d, J = 5.7Hz, 2H), 3.19 (d, J = 15.3Hz, 1H), 2.73 (d, J = 15.3Hz, 1H), 2.26-2.36 (m, 2H), 1.63-1.71 (m, 2H), 1.53 (d, J = 11.2Hz, 1H), 1.38 (d, J = 12.8Hz, 1H), 1.17 (s, 3H), 1.03 (m, 1H).

The following compounds were synthesized according to a procedure similar to that described for Example 69.

<tables num="6"><img file="JP4570878B2_D0055.tif" /></tables><img file="JP4570878B2_D0056.tif" />

(Example 74)

<chemistry num="42"><img file="JP4570878B2_D0057.tif" /></chemistry> Step 1: Alkylation of Example 73

<chemistry num="43"><img file="JP4570878B2_D0058.tif" /></chemistry> Example 73 (10.5 mg, 0.025 mmol) and Cs₂CO₃(32.4 mg, 0.100 mmol) were combined in a 10 mL flask and DMF (1 mL) was added. Allyl iodide (5 μL, 0.055 mmol) was added and the reaction was stirred at room temperature for 1 hour. Next, this reactant is H₂It was poured into O (5 mL) and the aqueous solution was extracted with EtOAc (25 mL). Wash this organic layer with brine (5 mL) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification of this residue by flash chromatography (40% EtOAc / Hexanes) resulted in 11.4 mg (99%) of Example 74. Rf 0.25 (40% EtOAc / Hexanes). LCMS = 463; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.44-7.47 (m, 3H), 7.16 (t, J = 8.5Hz, 2H), 7.05 (dd, J = 11.0,8.0Hz, 1H), 6.99 (dd, J = 8.5,2.0) Hz, 1H), 6.85 (m, 1H), 6.11 (d, J = 1.5Hz, 1H), 6.07 (m, 1H), 5.43 (dd, J = 17.5, 1.5Hz, 1H), 5.31 (dd, J = 10.5,1.0Hz, 1H), 5.13 (s, 1H), 4.63 (d, J = 4.5Hz, 1H), 3.17 (d, J = 15.0Hz, 1H), 2.73 (d, J = 15.0Hz, 1H ), 2.40 (m, 1H), 2.28 (d, J = 15.0Hz, 1H), 1.58-1.83 (m, 4H), 1.25 (s, 3H), 1.21 (m, 1H).

The following compounds were synthesized according to a procedure similar to that described for Example 74.

<tables num="7"><img file="JP4570878B2_D0059.tif" /></tables><img file="JP4570878B2_D0060.tif" />

(Example 82)

<chemistry num="44"><img file="JP4570878B2_D0061.tif" /></chemistry> Step 1:

<chemistry num="45"><img file="JP4570878B2_D0062.tif" /></chemistry> CH Aldehyde B (105.5 mg, 0.34 mmol)₂Cl₂It was dissolved in (8 mL), and N, N-diisopropylethylamine (1.42 mL, 8.16 mmol) followed by TESOTf (1.08 mL, 4.08 mmol) was added. The reaction was stirred at room temperature for 6 hours, quenched with 1 mL of isopropyl alcohol and diluted with EtOAc (50 mL). Saturate this organic layer LVDS₃And brine (10 mL each), wash with Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (15% EtOAc / Hexanes) to give I, which was used directly in the next reaction without further characterization.

Stage 2:

<chemistry num="46"><img file="JP4570878B2_D0063.tif" /></chemistry> CH I₂Cl₂It was dissolved in (5 mL) and N-fluorobenzenesulfonimide (536 mg, 1.7 mmol) was added. The reaction was stirred at room temperature for 15 hours and then concentrated. The residue was purified by flash chromatography (5 to 15% EtOAc / Hexanes) with 52.1 mg (47%) of two separable diastereomers, ie 19.5 mg (18%) of low polar diastereomers J and 32.6 mg (29%) of highly polar diastereomer K was obtained.

Low Polar Diastereomer J: R_f= 0.24 (50/42/8 Hexane / CH₂Cl₂/ TBME). LCMS = 329; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ9.88 (d, J = 7.1Hz, 1H), 7.42-7.45 (m, 2H), 7.37 (s, 1H), 7.14-7.18 (m, 2H), 6.25 (s, 1H), 2.89 (d, J = 16Hz, 1H), 2.78 (d, J = 16Hz, 1H), 2.53 (m, 1H), 2.33 (br d, J = 14Hz, 1H), 2.06 (m, 1H), 1.97 ( m, 1H), 1.83 (m, 1H), 1.69 (m, 1H), 1.32 (d, J = 1.4Hz, 3H).

High Polar Diastereomer K: R_f= 0.21 (50/42/8 Hexane / CH₂Cl₂/ TBME). LCMS = 329; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ9.91 (d, J = 5.7Hz, 1H), 7.42-7.45 (m, 3H), 7.16 (t, J = 8.6Hz, 2H), 6.27 (d, J = 2.1Hz, 1H) , 3.51 (d, J = 15.3Hz, 1H), 2.44-2.52 (m, 2H), 2.39 (br d, J = 15.8Hz, 1H), 2.10 (m, 1H), 1.76-1.90 (m, 2H) , 1.30 (m, 1H), 1.18 (s, 3H).

Stage 3:

<chemistry num="47"><img file="JP4570878B2_D0064.tif" /></chemistry> Fluoraldehyde diastereomer J (17.6 mg, 0.054 mmol) was dissolved in THF (2 mL) and cooled to -78 ° C. BnMgCl (536 μL 1MEt₂Solution O, 0.536 mmol) was added dropwise with a syringe . The reaction was warmed to 0 ° C for 10 minutes, then quenched with isopropyl alcohol (500 μL) and saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (50 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5 to 15% EtOAc / Hexanes) to produce 5.3 mg (24%) of low-polarity diastereomers of Example 82 and 3.8 mg (17%) of high-polarity diastereomers of Example 82. I got a stereomer.

Low Polarity Diastereomer of Example 82: R_f= 0.40 (25% EtOAc / Hexanes, 2 elutions). LCMS = 421; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.41-7.44 (m, 2H), 7.38 (s, 1H), 7.31-7.34 (m, 2H), 7.24-7.26 (m, 3H), 7.12-7.16 (m, 2H), 6.14 ( s, 1H), 4.21 (t, J = 9.5Hz, 1H), 3.19 (d, J = 16.0Hz, 1H), 3.11 (d, J = 13.3Hz, 1H), 7.75 (dd, J = 13.5,10.5) Hz, 1H), 2.67 (d, J = 16.0Hz, 1H), 2.61 (m, 1H), 2.30 (m, 1H), 2.16 (m, 1H), 1.97-2.12 (m, 2H), 1.81 (m) , 1H), 1.26 (d, J = 2.5Hz, 3H).

High Polarity Diastereomer of Example 82: R_f= 0.37 (25% EtOAc / Hexanes, 2 elutions). LCMS = 421; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.45 (dd, J = 8.5,4.8Hz, 2H), 7.42 (s, 3H), 7.33 (t, J = 7.4Hz, 2H), 7.14-7.18 (m, 3H), 6.18 (s , 1H), 4.05 (dd, J = 21,10.5Hz, 1H), 3.12 (d, J = 13.5Hz, 1H), 2.97 (s, 2H), 2.78 (dd, J = 13.5, 10.4Hz, 1H) , 2.69 (m, 1H), 2.24 (m, 1H), 1.89-2.05 (m, 3H), 1.79 (br s, 1H), 1.67 (m, 1H), 1.35 (d, J = 3Hz, 1H).

These two other possible diastereomers of Example 82 were prepared from the highly polar fluoroaldehyde diastereomers K in a similar manner.

(Examples 83 and 84)

<chemistry num="48"><img file="JP4570878B2_D0065.tif" /></chemistry> Step 1: Add Grignard reagent to fluoroaldehyde K

<chemistry num="49"><img file="JP4570878B2_D0066.tif" /></chemistry> Fluoroaldehyde K (28.7 mg, 0.0875 mmol) was dissolved in THF (6 mL) and cooled to 0 ° C. 4-Fluorobenzylmagnesium bromide (218 μL 2.0 M diethyl ether solution, 0.438 mmol) was added dropwise by syringe. The reaction is stirred at 0 ° C for 1 hour and then saturated NH₄Quenched with Cl (10 mL). The mixture is extracted with EtOAc (40 mL) and the organic layer is H₂Wash with O and brine (10 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-80% EtOAc / Hexanes) produced a mixture of the two diastereomers. PTLC (40/40/20 Hexane / CH₂Cl₂/ Et₂Further purification with O) resulted in 18.4 mg (50%) of this low-polarity diastereomer and 11.1 mg (30%) of this highly polar diastereomer.

Low Polar Diastereomer: R_f= 0.20 (25% ETOAC / hexane). LCMS = 425; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.43 (m, 2H), 7.40 (s, 1H), 7.36 (t, J = 6Hz, 2H), 7.13 (t, J = 8.4Hz, 2H), 7.05 (t, J = 9Hz) , 2H), 6.17 (s, 1H), 5.20 (s, 1H), 3.36 (d, J = 15Hz, 1H), 2.81 (s, 1H), 2.77 (d, J = 15Hz, 1H), 2.47 (m , 1H), 2.29 (m, 1H), 2.15 (m, 1H), 1.82 (m, 1H), 1.57 (m, 2H), 1.33 (s, 3H).

High Polar Diastereomer: R_f= 0.20 (25% EtOAc / Hexanes). LCMS = 425; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.43-7.36 (m, 5H), 7.13 (t, J = 8.4Hz, 2H), 7.05 (t, J = 9Hz, 2H), 6.18 (s, 1H), 4.93 (d, J) = 15.5Hz, 1H), 3.42 (d, J = 16Hz, 1H), 3.12 (d, J = 16Hz, 1H), 2.52 (m, 1H), 2.36 (m, 1H), 1.90 (m, 1H), 1.66 (m, 1H), 1.03 (s, 3H).

(Examples 84 and 85)

<chemistry num="50"><img file="JP4570878B2_D0067.tif" /></chemistry> Step 1: Addition of aryllithium reagent to fluoroaldehyde K

<chemistry num="51"><img file="JP4570878B2_D0068.tif" /></chemistry> 4-Bromopyridine HCl (257.9 mg, 1.33 mmol) in 5% Na₂CO₃Dissolved in (8 mL). Then this solution is Et₂Extracted by O (12 mL), and this Et₂The O layer was dried over Mg2SO4, filtered and concentrated to dryness. This residue is azeotropically boiled with benzene (1 mL) and then Et.₂Dissolved in O (11.2 mL) and cooled to -78 ° C. t-BuLi (527 μL 1.7 M pentane solution, 0.973 mmol) was added dropwise by syringe. The reaction was stirred at 78 ° C. for 20 minutes, then fluoroaldehyde K (29.0 mg, 0.088 mmol) in THF (3 mL) was added dropwise by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (10 mL). The mixture is extracted with EtOAc (50 mL) and the organic layer is H₂Washed with O and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (20-100% EtOAc / Hexanes) produced a mixture of the two diastereomers. Further purification with an AD chiral column (25% IPA / heptane) resulted in a peak 1 of 19.1 mg (53%) and a peak 2 of 4.8 mg (13%).

Peak 1: R_f= 0.50 (100% EtOAc). LCMS = 408; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ8.42 (s, 2H), 7.40 (m, 2H), 7.36 (s, 1H), 7.34 (m, 2H), 7.12 (t, J = 8.4Hz, 2H), 6.16 (s, 1H), 3.37 (d, J = 16Hz, 1H), 2.77 (d, J = 16Hz, 1H), 2.46 (m, 1H), 2.20 (m, 2H), 1.52 (m, 3H), 1.18 (s, 3H).

Peak 2: R_f= 0.50 (100% EtOAc). LCMS = 408; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ8.63 (s, 2H), 7.42 (m, 2H), 7.36 (m, 2H), 7.26 (s, 1H), 7.15 (t, J = 8.4Hz, 2H), 6.29 (s, 1H), 4.92 (d, J = 18.6Hz, 1H), 3.43 (d, J = 16Hz, 1H), 3.13 (d, J = 15.6Hz, 1H), 2.36 (m, 2H), 1.69 (m, 1H) ), 1.65 (m, 2H), 1.12 (s, 3H).

The following compounds were synthesized starting from aldehyde F, following a procedure similar to that described for fluoroaldehyde K.

<tables num="8"><img file="JP4570878B2_D0069.tif" /></tables>

(Example 86)

<chemistry num="52"><img file="JP4570878B2_D0070.tif" /></chemistry> Step 1: Add aryllithium to fluoroaldehyde 1

<chemistry num="53"><img file="JP4570878B2_D0071.tif" /></chemistry> 3-Bromothianaphthenic acid (113.3 μL, 0.866 mmol) Et₂Solution O (8 mL) was cooled to -78 ° C and t-BuLi (1.01 mL 1.7 M pentane solution, 1.73 mmol) was added dropwise by syringe. The reaction was stirred at 78 ° C. for 20 minutes, then fluoroaldehyde L (27.2 mg, 0.0866 mmol) in THF (2 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Flash chromatography (5 to 20% EtOAc / Hexanes) followed by PTLC (20/40/40 Hexanes / CH)₂Cl₂/ Et₂Purification with O) and AD chiral column (25% IPA / heptane) resulted in 1.6 mg (4%) of Example 86. R_f= 0.43 (60% EtOAc / Hexanes). LCMS = 449; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.95 (d, J = 7.8Hz, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.65 (s, 1H), 7.42 (m, 4H), 7.15 (t, J = 8.4Hz, 2H), 6.27 (s, 1H), 5.38 (dd, J = 5.4Hz, 22.2Hz, 1H), 3.38 (d, J = 16.2Hz, 1H), 3.06 (d, J = 16.2Hz, 1H) ), 2.58 (m, 2H), 2.04 (m, 1H), 1.73 (m, 1H), 1.36 (s, 3H).

(Example 87)

<chemistry num="54"><img file="JP4570878B2_D0072.tif" /></chemistry> Step 1:

<chemistry num="55"><img file="JP4570878B2_D0073.tif" /></chemistry> Aldehyde B (19.7 mg, 0.0635 mmol) was dissolved in MeOH (2 mL) and the solution was cooled to 0 ° C. NaBH₄(12 mg, 0.317 mmol) was added and the reaction was stirred at 0 ° C. for 30 minutes. 1 mL saturated NH₄Cl was added, the reaction was quenched and the mixture was extracted with EtOAc (25 mL). This organic layer is H₂Wash with O and brine (10 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-30% EtOAc / Hexanes) to give 13.2 mg (67%) of Example 87 as a white solid (9: 1 ratio diastereomers). R_f= 0.13 (25% EtOAc / Hexanes). LCMS = 313; (M + 1)⁺。¹1 H NMR (Main Diastereomer) (CDCl₃, 500MHz) δ7.43-7.47 (m, 2H), 7.40 (s, 1H), 7.15 (t, J = 8.5Hz, 1H), 6.12 (d, J = 1.9Hz, 1H), 3.91 (dd, J = 10.5,3.9Hz, 1H), 3.51 (dd, J = 10.0, 8.9Hz, 1H), 2.96 (d, J = 15.5Hz, 1H), 2.66 (d, J = 15.5Hz, 1H), 2.30-2.42 (m, 2H), 2.02 (m, 1H), 1.89 (m, 1H), 1.66 (m, 1H), 1.34-1.45 (m, 2H), 0.95 (s, 3H).

(Example 88)

<chemistry num="56"><img file="JP4570878B2_D0074.tif" /></chemistry> Stage 1

<chemistry num="57"><img file="JP4570878B2_D0075.tif" /></chemistry> CH Example 22 (9.5 mg, 0.0236 mmol)₂Cl₂It was dissolved in (1 mL) and PCC (15.2 mg, 0.0708 mmol) was added. The reaction was stirred at room temperature for 1 hour, then diluted with hexane (2 mL) and filtered from the silica gel filling with 40% EtOAc / Hexane. The filtrate was concentrated and the residue was purified by synthetic thin layer chromatography (25% EtOAc / Hexanes) to give 5.0 mg (53%) of Example 88 as a white solid. R_f= 0.27 (25% EtOAc / Hexanes).

LCMS = 401; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.42-7.45 (m, 1H), 7.37 (s, 1H), 7.35 (t, J = 7.4Hz, 1H), 7.28 (d, J = 7.3Hz, 1H), 7.22 (d, J) = 7.1Hz, 1H), 7.13-7.22 (m, 1H), 6.11 (d, J = 2.3Hz, 1H), 3.81 (d, J = 15.3Hz, 1H), 3.77 (d, J = 15.3Hz, 1H) ), 2.83 (dd, J = 12.5, 3.1Hz, 1H), 2.76 (d, J = 15.2Hz, 1H), 2.67 (d, J = 15.2Hz, 1H), 2.42 (m, 1H), 2.29 (m) , 1H), 1.77-1.89 (m, 2H), 1.67 (m, 1H), 1.35 (m, 1H), 1.20 (s, 3H).

(Example 89)

<chemistry num="58"><img file="JP4570878B2_D0076.tif" /></chemistry> Step 1:

<chemistry num="59"><img file="JP4570878B2_D0077.tif" /></chemistry> CH Example 22 (165.9 mg, 0.412 mmol)₂Cl₂It was dissolved in (20 mL) and the solution was cooled to 0 ° C. 2,6-Lutidine (265 μL, 2.27 mmol) and TBDMSOTf (142 μL, 0.618 mmol) were added and the reaction was warmed to room temperature. After stirring for 16 hours, additional 2,6-lutidine (300 μL, 2.58 mmol) and TBDMSOTf (300 μL, 1.31 mmol) were added to the reaction. The reaction was stirred for an additional 3 hours and then quenched with isopropyl alcohol (1 mL). The reaction is diluted with EtOAc (100 mL) and the organic solution is saturated with LVDS.₃, Brine, 1NHCl, saturated LVDS₃, And brine (25 mL each) were washed. This organic layer is Na₂SO₄It was dried on, filtered, and concentrated. Purification by flash chromatography (15% TBME / hexane) gave 207.1 mg (97%) of Compound M. R_f= 0.38 (15% ETOAC / hexane).¹1 H NMR (CDCl₃, 500MHz) δ7.37-7.39 (m, 2H), 7.26-7.30 (m, 3H), 7.18 (t, J = 7.5Hz, 1H), 7.10-7.14 (m, 4H), 5.98 (d, J = 2.1Hz, 1H), 4.24 (dd, J = 10.5,4.0Hz, 1H), 2.96 (dd, J = 13.0, 4.0Hz, 1H), 2.72 (dd, J = 13.0, 10.5Hz, 1H), 2.55 ( d, J = 15.3Hz, 1H), 2.35 (m, 1H), 2.22 (bd, J = 15.3Hz, 1H), 1.88 (m, 1H), 1.80 (m, 1H), 1.64-1.73 (m, 2H) ), 1.44 (dd, J = 10.5,3.0Hz, 1H), 1.28 (m, 1H), 1.02 (s, 3H), 0.94 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H) ..

Stage 2:

<chemistry num="60"><img file="JP4570878B2_D0078.tif" /></chemistry> CrO₃Place (550 mg, 5.5 mmol) in a 50 mL round bottom flask equipped with a stir bar, and 15 mL dry CH₂Cl₂Was added. The suspension was cooled to -20 ° C and 3,5-dimethylpyrrole (793 mg, 8.25 mmol) was added. The reaction is stirred at -20 ° C for 15 minutes and compound M (142 mg, 0.275 mmol) is channeled to CH.₂Cl₂Added in (6 mL). The reaction was stirred for 1.5 hours, keeping the temperature between -20 and -15 ° C. The reaction is then added to 100 mL of 3: 1 hexane / Et.₂Diluted with O and filtered from silica gel filling. The filtrate was concentrated and the residue was purified by flash chromatography with 15% EtOAc / Hexanes and then with 2% TBME / toluene to give 20.8 mg (14%) of Compound N. R_f= 0.29 (15% ETOAC / hexane). LCMS = 531; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.44 (s, 1H), 7.39-7.41 (m, 2H), 7.29-7.32 (m, 2H), 7.22 (s, 1H), 7.13-7.21 (m, 5H), 4.33 (dd, dd, J = 10.5,4.0Hz, 1H), 3.04 (dd, J = 13.0, 4.0Hz, 1H), 2.70-2.79 (m, 3H), 2.32 (m, 1H), 2.01-2.07 (m, 1H), 1.85 (d, J = 16.1Hz, 1H), 1.75 (m, 1H), 1.11 (s, 3H), 0.93 (s, 9H), 0.24 (s, 3H), 0.20 (s, 3H).

Stage 3:

<chemistry num="61"><img file="JP4570878B2_D0079.tif" /></chemistry> Compound N (15.8 mg, 0.0298 mmol) was dissolved in THF (4.5 mL), and the solution was cooled to -78 ° C, and MeLi (42 μL 1.4 MEt).₂Solution O (0.0596 mmol)) was added dropwise with a syringe. The reaction was stirred at 78 ° C. for 15 minutes and then quenched with isopropyl alcohol (100 μL). Saturate this cold solution NH₄It was poured into Cl (10 mL) and the mixture was extracted with EtOAc (50 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. This crude residue (17.0 mg) was dissolved in toluene (2 mL) and p-toluenesulfonic acid monohydrate (5 mg, 0.0263 mmol) was added. The reaction was stirred at room temperature for 15 minutes and then diluted with EtOAc (40 mL). This organic layer is saturated LVDS₃And brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (15% EtOAc / Hexanes) to give 5.7 mg (36%) of compound O. R_f= 0.30 (15% EtOAc / Hexanes). LCMS = 529; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.40-7.43 (m, 3H), 7.25-7.28 (m, 2H), 7.12-7.18 (m, 5H), 6.10 (s, 1H), 5.88 (d, J = 5.5Hz, 1H) , 4.40 (dd, J = 10.3,4.1Hz, 1H), 2.95 (dd, J = 13.0, 4.1Hz, 1H), 2.70-2.75 (m, 2H), 2.61 (m, 1H), 2.25 (dt, J) = 19.0,5.0Hz, 1H), 1.96 (d, J = 15.4Hz, 1H), 1.76 (s, 3H), 1.73 (dd, J = 12.5, 4.3Hz, 1H), 1.04 (s, 3H), 0.94 (s, 9H), 0.20 (s, 6H).

Stage 4:

<chemistry num="62"><img file="JP4570878B2_D0080.tif" /></chemistry> Compound O (5.7 mg, 0.0108 mmol) was dissolved in THF (3 mL) and TBAF (150 μL 1 MTHF solution, 0.15 mmol) was added. The reaction is stirred at room temperature for 3 hours and then saturated NH₄Pour into Cl (10 mL). The mixture is extracted with EtOAc (50 mL) and the organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by synthetic thin layer chromatography (30% EtOAc / Hexanes) to give 3.5 mg (78%) of Example 89. R_f= 0.39 (40% EtOAc / Hexanes). LCMS = 415; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.46-7.48 (m, 2H), 7.43 (s, 1H), 7.41 (t, J = 7.5Hz, 2H), 7.23-7.27 (m, 3H), 7.15-7.18 (m, 2H) , 6.22 (s, 1H), 5.92 (d, J = 5.5Hz, 1H), 4.31 (m, 1H), 2.97 (d, J = 15.4Hz, 1H), 2.86 (dd, J = 13.0, 9.0Hz, 1H), 2.70 (dd, J = 13.0, 5.0Hz, 1H), 2.63 (m, 1H), 2.48 (d, J = 15.1Hz, 1H), 2.31 (dt, J = 18.7, 5.0Hz, 1H), 1.89 (dd, J = 12.3, 4.3Hz, 1H), 1.83 (s, 3H), 1.14 (s, 3H).

(Example 90)

<chemistry num="63"><img file="JP4570878B2_D0081.tif" /></chemistry> Step 1:

<chemistry num="64"><img file="JP4570878B2_D0082.tif" /></chemistry> Ketone A (18.6 mg, 0.063 mmol) was dissolved in THF and cooled to 0 ° C. BnMgCl (314 μL of 1 MTHF solution, 0.314 mmol) was added and the reaction was stirred at 0 ° C. for 1 hour. Saturated NH₄Cl (1 mL) was added to quench the reaction and the mixture was extracted with EtOAc (40 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-20% EtOAc / Hexanes) to give 14.0 mg (57%) of Example 90. R_f= 0.21 (25% EtOAc / Hexanes). LCMS = 389; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.45-7.48 (m, 2H), 7.38 (s, 3H), 7.15-7.30 (m, 7H), 6.26 (s, 1H), 3.52 (d, J = 17.1Hz, 1H), 2.98 (d, J = 14.0Hz, 1H), 2.86 (d, J = 14.0Hz, 1H), 2.68 (d, J = 17.1Hz, 1H), 2.61 (m, 1H), 2.20 (dd, J = 9.0, 4.4Hz, 1H), 1.61-1.75 (m, 3H), 1.46 (m, 1H), 1.37 (s, 3H).

(Example 91)

<chemistry num="65"><img file="JP4570878B2_D0083.tif" /></chemistry> Step 1:

<chemistry num="66"><img file="JP4570878B2_D0084.tif" /></chemistry> Et of t-BuLi (150 μL 1.7 M pentane solution, 0.258 mmol)₂Solution O (5 mL) was cooled to -78 ° C and aldehyde B (16.0 mg, 0.0516 mmol) was added as a solution in THF (2 mL). The reaction was slowly warmed to -20 ° C and then returned to -78 ° C. The reaction was quenched by the addition of isopropyl alcohol (1 mL) and then saturated NH.₄Pour into Cl (10 mL). The mixture is extracted with EtOAc (40 mL) and the organic layer is H₂Wash with O and brine (15 mL each) and remove this organic layer with Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-20% EtOAc / Hexanes) to give 8.0 mg (42%) of Example 91. R_f= 0.24 (25% EtOAc / Hexanes). LCMS = 369; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.43-7.46 (m, 2H), 7.41 (s, 1H), 7.14 (t, J = 8.5Hz, 1H), 6.11 (d, J = 1.6Hz, 1H), 3.49 (s, 1H) ), 2.83 (d, J = 15.1Hz, 1H), 2.45 (d, J = 15.1Hz, 1H), 2.39 (m, 1H), 2.32 (br d, J = 14.6Hz, 1H), 1.59-1.86 ( m, 3H), 1.41 (m, 1H), 1.07 (s, 3H), 0.96 (s, 9H).

(Example 92)

<chemistry num="67"><img file="JP4570878B2_D0085.tif" /></chemistry> Step 1:

<chemistry num="68"><img file="JP4570878B2_D0086.tif" /></chemistry> 2-Phenyl-1,3-dithiane (408 mg, 2.08 mmol) was dissolved in THF (8 mL) and cooled to -78 ° C. n-BuLi (865 μ 1.6 M hexane solution, 1.38 mmol) was added and the reaction was warmed to 0 ° C. The reaction was stirred at 0 ° C for 30 minutes and then returned to -78 ° C. A solution of aldehyde B (53.7 mg, 0.173 mmol) was added by cannula in THF (2 mL). The reaction was stirred at 78 ° C. for 10 minutes, then warmed to 0 ° C. and then stirred at that temperature for 1 hour. The reaction was quenched with isopropyl alcohol (1 mL) and saturated NH₄Pour into Cl (20 mL). The mixture is extracted with EtOAc (50 mL) and the organic layer is H₂Wash with O and brine (20 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5 to 15% EtOAc / Hexanes) to give 54.0 mg (62%) of P. R_f= 0.23 (25% EtOAc / Hexanes). LCMS = 507; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ8.04 (d, J = 7.6Hz, 2H), 7.41-7.45 (m, 4H), 7.38 (s, 1H), 7.32 (t, J = 7.3Hz, 1H), 7.13 (m, 2H) ), 6.04 (d, J = 2.1Hz, 1H), 4.12 (m, 1H), 2.64-2.75 (m, 5H), 2.17-2.30 (m, 3H), 1.92-1.96 (m, 2H), 1.58 ( m, 1H), 1.37 (qd, J = 13.5, 2.0Hz, 1H), 1.18 (m, 1H), 1.00 (s, 3H), 0.90 (m, 1H).

Stage 2:

<chemistry num="69"><img file="JP4570878B2_D0087.tif" /></chemistry> CH to Dithiane P (10.3 mg, 0.020 mmol)₃CN (900 μL), toluene (200 μL), and H₂O (100 μL) was added. The two-phase solution was vigorously stirred and [bis (trifluoroacetoxy) iodo] benzene (17.5 mg, 0.041 mmol) was added. After 15 minutes, an additional portion of [bis (trifluoroacetoxy) iodo] benzene (25 mg, 0.058 mmol) was added. The reaction is stirred for an additional 10 minutes and then saturated LVDS.₃Quenched with (5 mL). The mixture is extracted with EtOAc (40 mL) and the organic layer is washed with brine (10 mL) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by synthetic thin layer chromatography to give 4.4 mg (52%) of Example 92. R_f= 0.33 (25% ETOAC / hexane, 2 elution). LCMS = 417; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.90 (d, J = 7.1Hz, 2H), 7.62 (t, J = 7.4Hz, 1H), 7.49-7.63 (m, 3H), 7.42-7.45 (m, 2H), 7.13-7.17 (m, 2H), 6.08 (d, J = 2Hz, 1H), 5.44 (d, J = 6.2Hz, 1H), 3.79 (d, J = 6.2Hz, 1H), 3.30 (d, J = 14.6Hz, 1H), 2.85 (d, J = 14.7Hz, 1H), 2.36 (m, 1H), 2.22 (m, 1H), 1.90 (dd, J = 12.5, 2.0Hz, 1H), 1.76 (m, 1H), 1.70 (dd, J = 12.5, 2.0Hz, 1H), 1.29 (s, 3H), 1.10-1.18 (m, 2H).

<chemistry num="70"><img file="JP4570878B2_D0088.tif" /></chemistry> CH Example 42 (50 mg, 0.13 mmol)₂Cl₂It was dissolved in (8 mL) and NMO (22.8 mg, 0.195 mmol) was added. The reaction was stirred at 0 ° C. for 5 minutes and TPAP (4.5 mg, 0.013 mmol) was added. Stirring was continued at 0 ° C for another hour. The reaction was diluted with hexane (2 mL) and filtered through the silica gel filler with 10% EtOAc / Hexanes to give 40 mg (80%) of Example 93 as a yellow oil. R_f= 0.35 (25% EtOAc / Hexanes). LCMS = 393; (M + 1)⁺。

<chemistry num="71"><img file="JP4570878B2_D0089.tif" /></chemistry> Example 93 (20 mg, 0.051 mmol) was dissolved in diethyl ether (5 mL) and the solution was cooled to -78 ° C. Phenyllithium (300 μL 1.8 MEt₂O solution (0.53 mmol)) was added dropwise with a syringe. The reaction was stirred at 78 ° C. for 1 hour and then quenched with isopropyl alcohol (500 μL). Saturate this cold solution NH₄It was poured into Cl (10 mL) and the mixture was extracted with EtOAc (50 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. This residue is subjected to reverse phase HPLC (20% AcCN / H).₂Purification by O) gave 16 mg (67%) of Example 94 as a single diastereomer. R_f= 0.20 (30% EtOAc / Hexanes). LCMS = 471; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.61-7.59 (m, 1H), 7.49-7.45 (m, 1H), 7.35-7.27 (m, 1H), 7.32-7.11 (m, 9H), 7.03-7.02 (dd, J = 3.5) , 4.8Hz, 1H), 6.13 (br s, 1H), 2.76 (dd, J = 3.4,11.0Hz, 1H), 2.58 (d, J = 16Hz, 1H), 2.45-2.39 (m, 3H), 2.23 (d, J 16.0Hz, 1H), 1.04 (s, 3H).

<chemistry num="72"><img file="JP4570878B2_D0090.tif" /></chemistry> Example 93 (20 mg, 0.051 mmol) was dissolved in diethyl ether (5 mL) and the solution was cooled to -78 ° C. Methyllithium (760 μL 1.4 MEt₂O solution) was added dropwise with a syringe. The reaction was stirred at 78 ° C. for 3 hours and then quenched with isopropyl alcohol (1 mL). Saturate this cold solution NH₄It was poured into Cl (10 mL) and the mixture was extracted with EtOAc (50 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc / Hexanes) to give 8.8 mg (42%) of Example 95. R_f= 0.60 (30% EtOAc / Hexanes). LCMS = 409, (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) 8 7.48-7.45 (m, 2H), 7.31-7.27 (m, 2H), 7.29-7.14 (m, 1H), 6.13 (br s, 1H), 3.29 (d, J = 16Hz, 1H), 2.70 (d, J = 16Hz, 1H), 2.39-2.28 (m, 2H), 2.08-2.05 (m, 2H), 1.71 (s, 3H), 1.66-1.57 (m, 4H), 1.28 (s, 3H) ).

<chemistry num="73"><img file="JP4570878B2_D0091.tif" /></chemistry> Example 95 (6.2 mg, 0.015 mmol) was dissolved in dichloromethane (7 mL) and the solution was cooled to 0 ° C. Boron trifluoride diethyl etherate (191, 0.15 mmol) and triethylsilane (24 μL, 0.15 mmol) were added dropwise by syringe. The reaction is stirred at 0 ° C for 1 hour and then saturated LVDS.₃Quenched with (2 mL). H₂It was poured into O (10 mL) and the mixture was extracted with EtOAc (75 mL). This organic layer is H₂Wash with O and brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc / Hexanes) to give 3.5 mg (59%) of Example 96. R_f= 0.60 (15% EtOAc / Hexanes). LCMS = 393; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.47-7.46 (m, 3H), 7.24 (dd, J = 4.9,3.0Hz, 1H), 7.17-7.14 (m, 3H), 6.13 (br s, 1H), 3.41-3.39 (dq) , J = 7.3Hz, 2.3Hz, 1H), 3.11 (d, J = 15.4Hz, 1H), 2.75 (d, J = 15.4Hz, 1H), 2.32-2.23 (m, 2H), 1.89-1.84 (m) , 2H), 1.71 (dt, J = 5.4,2.8Hz, 1H), 1.41-1.38 (m, 1H), (d, J = 7.3Hz, 3H), 1.33-1.24 (m, 2H), 0.84 (s) , 3H).

<chemistry num="74"><img file="JP4570878B2_D0092.tif" /></chemistry> Example 35, TPAP and NMO were treated as in Example 93 to obtain the desired compound. R_f= 0.40 (25% EtOAc / Hexanes). LCMS = 393; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.99-7.97 (m, 2H), 7.61-7.59 (m, lH), 7.52 (t, J = 8.5Hz, 1H), 7.47-7.43 (m, 4H), 7.19 (t, J = 8.5Hz, 1H), 6.19 (br s, 1H), 3.73-3.70 (dd, J = 9.6Hz, 2.7Hz, 1H), 2.73 (d, J = 15.6Hz, 1H), 2.51-2.40 (m, 2H) ), 2.38-2.35 (m, 1H), 2.07-1.99 (m, 2H), 1.81-1.77 (m, 1H), 1.27 (s, 3H).

<chemistry num="75"><img file="JP4570878B2_D0093.tif" /></chemistry> Examples 97 and MeLi were treated as in Example 95 to give the desired compound. R_f= 0.30 (25% EtOAc / Hexanes). LCMS = 403; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.53-7.30 (m, 8H), 7.17-7.13 (m, 2H), 6.11 (br s, 1H), 3.16-3.13 (d, J = 16Hz, 1H), 2.65-2.61 (d, J = 16Hz, 1H), 2.47-2.30 (m, 2H), 1.70 (s, 3H), 1.63-1.52 (m, 2H), 1.29 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described for Examples 93 and 95.

<tables num="9"><img file="JP4570878B2_D0094.tif" /></tables><img file="JP4570878B2_D0095.tif" />

(Examples 105 and 106)

<chemistry num="76"><img file="JP4570878B2_D0096.tif" /></chemistry> Step 1: Add Grignard reagent to aldehyde F

<chemistry num="77"><img file="JP4570878B2_D0097.tif" /></chemistry> Aldehyde F (16.7 mg, 0.0564 mmol) was dissolved in THF (3 mL) and cooled to 0 ° C. 3-Butenyl magnesium chloride (1.1 mL 0.5 MTHF solution, 0.564 mmol) was added dropwise by syringe. The reaction is stirred at 0 ° C for 1 hour and then saturated NH₄Quenched with Cl (10 mL). The mixture is extracted with EtOAc (40 mL) and the organic layer is H₂Wash with O and brine (10 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The two diastereomeric products were isolated by flash chromatography (5-20% EtOAc / Hexanes) and 9.6 mg (48%) low polar diastereomers and 5.0 mg (25%) high polar diastereomers. Got

Low Polar Diastereomer: R_f= 0.17 (25% EtOAc / Hexanes). LCMS = 353; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.44-7.47 (m, 2H), 7.40 (s, 1H), 7.14 (t, J = 8.5Hz, 2H), 6.13 (s, 1H), 5.88 (m, 1H), 5.10 ( dd, J = 17,1.4Hz, 1H), 5.02 (d, J = 10.3Hz, 1H), 3.77 (m, 1H), 2.85 (d, J = 15.3Hz, 1H), 2.61 (m, 1H), 2.57 (d, J = 15.3Hz, 1H), 2.42 (m, 1H), 2.29 (m, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 1.81-1.91 (m, 2H), 1.72 (m, 1H), 1.60 (m, 1H), 1.00 (s, 3H).

High Polar Diastereomer: R_f= 0.12 (25% EtOAc / Hexanes). LCMS = 353; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.45-7.48 (m, 2H), 7.39 (s, 1H), 7.14 (t, J = 9.0Hz, 2H), 6.13 (s, 1H), 5.88 (m, 1H), 5.09 ( dd, J = 17,1.4Hz, 1H), 5.01 (d, J = 10.0Hz, 1H), 3.71 (m, 1H), 3.13 (d, J = 15.3Hz, 1H), 2.65 (d, J = 15.3 Hz, 1H), 2.60 (m, 1H), 2.45 (m, 1H), 2.29 (m, 1H), 2.19 (m, 1H), 1.83-1.91 (m, 2H), 1.72 (m, 1H), 1.45 -1.56 (m, 2H), 1.04 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described for Implementations 105 and 106.

<tables num="10"><img file="JP4570878B2_D0098.tif" /></tables><img file="JP4570878B2_D0099.tif" /><img file="JP4570878B2_D0100.tif" />

(Examples 115 and 116)

<chemistry num="78"><img file="JP4570878B2_D0101.tif" /></chemistry> Step 1: Addition of aryllithium reagent to aldehyde F

<chemistry num="79"><img file="JP4570878B2_D0102.tif" /></chemistry> Et of 1-bromo-4-fluorobenzene (85 μL, 0.777 mmol)₂Solution O (8 mL) was cooled to -78 ° C and t-BuLi (914 μL 1.7 M pentane solution, 1.55 mmol) was added dropwise by syringe. The reaction was stirred at 78 ° C. for 20 minutes, then aldehyde F (23.0 mg, 0.0777 mmol) in THF (2 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on, filtered, and concentrated. Purification by flash chromatography (5-20% EtOAc / Hexanes) produced a mixture of the two diastereomers. PTLC (20/60/20 Hexane / CH₂Cl₂/ Et₂Further purification with O) resulted in 13.8 mg (45%) of low-polarity diastereomers and 9.0 mg (30%) of high-polarity diastereomers.

Low Polar Diastereomer (115): R_f= 0.42 (20/60/20 Hexane / CH₂Cl₂/ Et₂O). LCMS = 393; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.36-7.43 (m, 4H), 7.19 (s, 1H), 7.08-7.14 (m, 4H), 6.11 (s, 1H), 4.66 (d, J = 8.5Hz, 1H), 2.63 (m, 1H), 2.45 (m, 1H), 2.22-2.32 (m, 2H), 2.09 (d, J = 15.6Hz, 1H), 1.95 (m, 1H), 1.71 (d, J = 15.6Hz) , 1H), 1.00 (s, 3H).

High Polar Diastereomer (116): R_f= 0.20 (20/60/20 Hexane / CH₂Cl₂/ Et₂O). LCMS = 393; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.45-7.48 (m, 2H), 7.41 (s, 1H), 7.33-7.36 (m, 2H), 7.12-7.15 (m, 2H), 7.03-7.06 (m, 2H), 6.14 (s, 1H), 4.64 (d, J = 10.1Hz, 1H), 3.25 (d, J = 15.8Hz, 1H), 2.78 (d, J = 15.8Hz, 1H), 2.53 (m, 1H), 2.33 (m, 1H), 2.17 (m, 1H), 1.93 (br s, 1H), 1.46 (m, 1H), 1.23 (m, 1H), 1.17 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described for Examples 115 and 116.

<tables num="11"><img file="JP4570878B2_D0103.tif" /></tables><img file="JP4570878B2_D0104.tif" /><img file="JP4570878B2_D0105.tif" /><img file="JP4570878B2_D0106.tif" /><img file="JP4570878B2_D0107.tif" /><img file="JP4570878B2_D0108.tif" />

(Example 137 + 138)

<chemistry num="80"><img file="JP4570878B2_D0109.tif" /></chemistry> Step 1: Addition of lithium reagent to aldehyde F resulting from deprotonation with BuLi

<chemistry num="81"><img file="JP4570878B2_D0110.tif" /></chemistry> A THF solution (16 mL) of benzothiophene (403 μL, 3.45 mmol) was cooled to -78 ° C and n-BuLi (1.73 mL 1.6 M hexane solution, 2.76 mmol) was added dropwise by syringe. The reaction was warmed to 0 ° C for 15 minutes and then returned to -78 ° C. Aldehyde F (68.1 mg, 0.230 mmol) in THF (4 mL) was added by cannula and the reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification of this residue by flash chromatography (5-25% EtOAc / Hexanes) gave the product as a mixture of diastereomers. 40/40 / 20CH of these two diastereomers₂Cl₂/ Hexane / Et₂TLC for synthesis in O subsequently results in 50/50/3 hexane / CH₂Cl₂Separated by TLC for synthesis with / MeOH. 22.6 mg Example 137 (23%) and 28.4 mg Example 138 (29%) were isolated. Characterization for 137: R_f= 0.18 (25% EtOAc / Hexanes). LCMS = 431; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.87 (d, J = 7.5Hz, 1H), 7.79 (d, J = 7.0Hz, 1H), 7.35-7.44 (m, 4H), 7.30 (s, 1H), 7.17 (s, 1H) ), 7.12 (m, 2H), 6.14 (t, J = 2Hz, 1H), 5.07 (dd, J = 8.5,3Hz, 1H), 2.66 (dd, J = 19,10.5Hz, 1H), 2.48 (m) , 1H), 2.32-2.41 (m, 3H), 2.07-2.10 (m, 2H), 1.98 (m, 1H), 1.08 (s, 3H).

Characterization for 138: R_f= 0.18 (25% EtOAc / Hexanes). LCMS = 431; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.84 (d, J = 7.5Hz, 1H), 7.73 (d, J = 7.0Hz, 1H), 7.47 (m, 2H), 7.42 (s, 1H), 7.33 (m, 2H), 7.23 (s, 1H), 7.14 (m, 2H), 6.16 (t, J = 2.0Hz, 1H) 5.02 (dd, J = 10.0,3.0Hz, 1H), 3.25 (d, J = 15.5Hz, 1H) , 2.81 (d, J = 15.5Hz, 1H), 2.58 (m, 1H), 2.34-2.44 (m, 2H), 2.11 (d, J = 3Hz, 1H), 1.55 (m, 1H), 1.19 (s) , 3H).

The following compounds were synthesized according to a procedure similar to that described for Examples 137 and 138.

<tables num="12"><img file="JP4570878B2_D0111.tif" /></tables>

(Example 143)

<chemistry num="82"><img file="JP4570878B2_D0112.tif" /></chemistry> Step 1: Addition of lithium reagent to aldehyde B resulting from deprotonation with BuLi

<chemistry num="83"><img file="JP4570878B2_D0113.tif" /></chemistry> A solution of thiophene (82 μL, 1.021 mmol) in THF (8 mL) was cooled to 78 ° C. and n-BuLi (510 μL of 1.6 M hexane solution, 0.816 mmol) was added dropwise by syringe. The reaction was warmed to 0 ° C for 15 minutes and then returned to -78 ° C. Aldehyde B (21.1 mg, 0.068 mmol) in THF (2 mL) was added by cannula and the reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification of this residue by flash chromatography (5 to 15% EtOAc / Hexanes) resulted in 20.5 mg (76%) of Example 143. R_f= 0.18 (25% EtOAc / Hexanes). LCMS = 395; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.44-7.46 (m, 2H), 7.43 (s, 1H), 7.22 (dd, J = 5.0,1.0Hz, 1H), 7.14-7.17 (m, 2H), 6.99 (dd, J = 5.0,3.5Hz, 1H), 6.95 (d, J = 3.5Hz, 1H), 6.12 (d, J = 2.2Hz, 1H), 5.38 (s, 1H), 3.10 (d, J = 15.1Hz, 1H) , 2.70 (d, J = 15.1Hz, 1H), 2.42 (m, 1H), 2.31 (m, 1H), 2.2 (br s, 1H), 1.91 (dd, J = 12.3,3.4Hz, 1H), 1.88 (m, 1H), 1.70-1.79 (m, 2H), 1.33 (m, 1H), 1.23 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described for Example 143.

<tables num="13"><img file="JP4570878B2_D0114.tif" /></tables><img file="JP4570878B2_D0115.tif" />

The following compounds were synthesized according to a procedure similar to that described for Examples 93 and 95, and starting from Examples 115/116.

<tables num="14"><img file="JP4570878B2_D0116.tif" /></tables><img file="JP4570878B2_D0117.tif" />

(Example 150)

<chemistry num="84"><img file="JP4570878B2_D0118.tif" /></chemistry> Step 1. Reduction of ketones

<chemistry num="85"><img file="JP4570878B2_D0119.tif" /></chemistry> Example 88 (10.0 mg, 0.025 mmol) was dissolved in THF (1 mL) and MeOH (1 mL) was added. Cool this solution to 0 ° C and NaBH₄(15 mg, 0.125 mmol) was added. The reaction is stirred at 0 ° C for 2 hours and then saturated NH.₄Quenched with Cl (1 mL). The mixture is extracted with EtOAc (25 mL) and the organic layer is H₂Washed with O and brine (5 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by PTLC to give 7.9 mg (79%) alcohol as a 3: 1 mixture of diastereomers in which Example 150 predominates over Example 22. Further purification by chiral HPLC (OD column, 35% IPA / heptane) gave 4.7 mg (47%) of pure Example 150 (slowly eluted isomers). R_f= 0.23 (25% EtOAc / Hexanes). LCMS = 403; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.45-7.47 (m, 2H), 7.40 (s, 1H), 7.36 (t, J = 7.4Hz, 2H), 7.28 (t, J = 7.7Hz, 3H), 7.14-7.17 (m) , 2H), 6.14 (s, 1H), 4.02 (m, 1H), 3.22 (d, J = 15.5Hz, 1H), 3.03 (d, J = 12.5Hz, 1H), 2.71 (d, J = 15.5Hz) , 1H), 2.60 (dd, J = 13.1,10.6Hz, 1H), 2.36 (m, 2H), 2.02 (m, 1H), 1.93 (m, 1H), 1.86 (dt, J = 12.4, 3.6Hz, 1H), 1.39-1.55 (m, 2H), 1.14 (s, 3H).

(Examples 151 and 152)

<chemistry num="86"><img file="JP4570878B2_D0120.tif" /></chemistry> Stage 1.

<chemistry num="87"><img file="JP4570878B2_D0121.tif" /></chemistry> Example 22 (21.3 mg, 0.053 mmol) was dissolved in THF (3 mL) and PtO₂(6 mg) was added. H₂Placed down and stirred at room temperature. After 3 hours, the catalyst was filtered off and the filtrate was concentrated. Purification by flash chromatography (5-20% EtOAc / Hexanes) resulted in 7.7 mg (36%) of Example 151 as a white solid and 9.2 mg (43%) of Example 152 as a white solid.

151 (Low Polar Diastereomer): R_f= 0.28 (25% ETOAC / hexane). LCMS = 405; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.44-7.46 (m, 2H), 7.38 (s, 1H), 7.27 (t, J = 7.4Hz, 2H), 7.19 (t, J = 7.4Hz, 1H), 7.13 (m, 4H), 4.22 (m, 1H), 2.92 (d, J = 16.0Hz, 1H), 2.81 (dd, J = 13.3,8.9Hz, 1H), 2.72 (dd, J = 16.8, 6.2Hz, 1H), 2.62 (dd, J = 13.3,4.5Hz, 1H), 2.54 (dd, J = 16.9, 6.1Hz, 1H), 2.15 (d, J = 16.0Hz, 1H), 2.08 (br s, 1H), 1.86 ( m, 1H), 1.79 (m, 1H), 1.67-1.72 (m, 2H), 1.59 (m, 1H), 1.28-1.37 (m, 2H), 1.15 (s, 3H).

152 (High Polar Diastereomer): R_f= 0.21 (25% EtOAc / Hexanes). LCMS = 405; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.46-7.48 (m, 2H), 7.42 (s, 1H), 7.35 (t, J = 7.6Hz, 2H), 7.26 (t, J = 7.9Hz, 3H), 7.12-7.15 ( m, 2H), 4.26 (m, 1H), 2.90 (dd, J = 13.3,8.6Hz, 1H), 2.74 (d, J = 15.4Hz, 1H), 2.72 (dd, J = 13.3,5.5Hz, 1H) ), 2.53 (dd, J = 16.3,4.8Hz, 1H), 2.38 (dd, J = 16,12Hz, 1H), 2.01 (d, J = 15.1Hz, 1H), 1.91 (m, 1H), 1.73 ( m, 1H), 1.64 (m, 1H), 1.57 (m, 1H), 1.51 (m, 1H), 1.34-1.43 (m, 2H), 1.29 (m, 1H), 0.95 (s, 3H).

(Example 153)

<chemistry num="88"><img file="JP4570878B2_D0122.tif" /></chemistry> Step 1. Cyclopropaneation of this alkene

<chemistry num="89"><img file="JP4570878B2_D0123.tif" /></chemistry> The solution in Et2Zn (410 μL 1M hexane solution, 0.41 mmol) in dichloroethane (1 mL) was cooled to 0 ° C and CH.₂I₂(66 μL, 0.821 mmol) was added. The reaction was stirred for 5 minutes and the formation of a white precipitate was observed. A solution of Example 43 (17.0 mg, 0.041 mmol) in dichloroethane (1 mL) was added by cannula. The reaction was warmed to room temperature and stirred for 1 hour. After this time, the reaction was quenched with 1N HCl (1 mL). The mixture was extracted with EtOAc (50 mL). This organic layer is H₂O, NaHSO₃Aqueous solution, saturated LVDS₃, And brine (15 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-20% EtOAc / Hexanes) resulted in 10.2 mg (58%) of Example 153. R_f= 0.14 (25% EtOAc / Hexanes). LCMS = 429; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.37-7.44 (m, 5H), 7.30 (t, J = 7.4Hz, 2H), 7.23 (t, J = 7.4Hz, 1H), 7.12-7.16 (m, 2H), 6.05 (d , J = 2.1Hz, 1H), 3.59 (s, 1H), 2.79 (d, J = 15.1Hz, 1H), 2.19-2.31 (m, 3H), 1.83 (dd, J = 12.7,3.0Hz, 1H) , 1.63 (m, 1H), 1.11-1.34 (m, 1H), 1.04 (s, 3H) 1.00 (m, 1H), 0.89 (m, 1H), 0.83 (m, 1H), 0.78 (m, 1H) ..

Example 154 was synthesized according to a procedure similar to that described for Example 153.

<tables num="15"><img file="JP4570878B2_D0124.tif" /></tables>

(Example 156)

<chemistry num="90"><img file="JP4570878B2_D0125.tif" /></chemistry> Stage 1.

<chemistry num="91"><img file="JP4570878B2_D0126.tif" /></chemistry> T-BuOH (200 μL), 2-methyl-2-butene (200 μL), and NaC in a solution of aldehyde B (35.5 mg, 0.1145 mmol) in THF (200 μL)₁O₂(23 mg, 0.252 mmol) and NaH₂PO₄(35 mg, 0.252 mmol) H₂O solution (250 μL) was added. The reaction is stirred at room temperature for 2 hours, then EtOAc and H₂Distributed between O (25 mL each). The aqueous layer was acidified with 1N HCl and extracted with EtOAc (3 x 25 mL). All of this organic extract was combined and washed with brine (25 mL). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40/60/1 EtOAc / Hexanes / HOAc) to give 33.3 mg (89%) of Example 155 acid. R_f= 0.22 (40/60/1 EtOAc / Hexane / HOAc). LCMS = 327; (M + 1)⁺。

Step 2. Coupling of carboxylic acid to amine

<chemistry num="92"><img file="JP4570878B2_D0127.tif" /></chemistry> CH of Example 155 (10.5 mg, 0.0322 mmol)₃DIPEA (23 μL, 0.129 mmol) and HATU (15 mg, 0.0387 mmol) were added to the CN solution (0.5 mL). The reaction was stirred at room temperature for 5 minutes, then benzylamine (6 μL, 0.0483 mmol) was added. After 30 minutes, the reaction was washed with EtOAc (40 mL) and saturated LVDS.₃, Brine, 1NHCl, saturated LVDS₃, And brine (10 mL each). This organic layer is Na₂SO₄It was dried on, filtered, and concentrated. Purification by flash chromatography (20-60% EtOAc / Hexanes) resulted in 9.4 mg (70%) of Example 156. R_f= 0.22 (40% EtOAc / Hexanes). LCMS = 416; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.41-7.44 (m, 2H), 7.29-7.38 (m, 6H), 7.12-7.16 (m, 2H), 6.11 (d, J = 1.8Hz, 1H), 5.87 (t, J = 5.4Hz, 1H), 4.47 (m, 2H), 2.81 (d, J = 15.3Hz, 1H), 2.68 (d, J = 15.3Hz, 1H), 2.43 (m, 1H), 2.29 (m, 1H) , 2.25 (dd, J = 12.7, 3.3Hz, 1H), 1.97 (qd, J = 13,3.4Hz, 1H) 1.89 (m, 1H), 1.79 (m, 1H), 1.37 (m, 1H), 1.19 (s, 3H).

Example 157 was synthesized according to a procedure similar to that described for Example 156.

<tables num="16"><img file="JP4570878B2_D0128.tif" /></tables>

(Example 159)

<chemistry num="93"><img file="JP4570878B2_D0129.tif" /></chemistry> Stage 1.

<chemistry num="94"><img file="JP4570878B2_D0130.tif" /></chemistry> Example 87 (35.4 mg, 0.113 mmol) CH at 0 ° C.₂Cl₂In solution (270 μL, 2.72 mmol) and MsC₁(105 μL, 1.36 mmol) was added. The reaction was stirred at 0 ° C. for 1 hour and then diluted with EtOAc (50 mL). Saturate this organic solution LVDS₃, H₂Washed with O, 1N HCl, and brine (10 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. This crude residue was dissolved in DMPU (4 mL) and NaN3 (37 mg, 0.565 mmol) was added. The reaction was stirred at room temperature for 3 days and then heated to 50 ° C. for 6 hours. The reaction is cooled to room temperature, diluted with EtOAc (50 mL), and H₂Washed with O and brine (10 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (20% EtOAc / Hexanes) resulted in 32.2 mg (84%) of Example 158. R_f= 0.38 (25% EtOAc / Hexanes). LCMS = 338; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.43-7.46 (m, 2H), 7.41 (s, 1H), 7.13-7.17 (m, 2H), 6.14 (d, J = 1.9Hz, 1H), 3.61 (dd, J = 12.1, 3.7Hz, 1H), 3.11 (dd, J = 12.0, 9.7Hz, 1H), 2.91 (d, J = 15.4Hz, 1H), 2.63 (d, J = 15.4Hz, 1H), 2.29-2.40 (m, 2H), 1.97 (m, 1H), 1.87 (m, 1H), 1.71 (m, 1H), 1.31-1.43 (m, 2H), 0.96 (s, 3H).

Stage 2.

<chemistry num="95"><img file="JP4570878B2_D0131.tif" /></chemistry> Triphenylphosphine (10 mg, 0.0381 mmol) and water (20 μL) were added to a solution of Example 158 (3.8 mg, 0.0113 mmol) in THF (300 μL). The reaction was stirred at room temperature overnight, then DIPEA (50 μL) was added. CH this reactant₂Cl₂Dilute with (30 mL) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. CH this residue₂Cl₂It was dissolved in (1 mL) and DIPEA (100 μL, 0.574 mmol) and benzoyl chloride (20 μL, 0.172 mmol) were added. The reaction is stirred at room temperature for 10 minutes, diluted with EtOAc (25 mL) and saturated with acrylamide.₃, Brine, 1NHCl, and brine (5 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (60% EtOAc / Hexanes) resulted in 4.1 mg (88%) of Example 159. R_f= 0.35 (60% EtOAc / Hexanes). LCMS = 416; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.78 (d, J = 7.4Hz, 2H), 7.43-7.52 (m, 6H), 7.15 (t, J = 8.5Hz, 2H), 6.20 (s, 1H), 6.13 (d, J) = 1.6Hz, 1H), 3.75 (m, 1H), 3.32 (m, 1H), 3.07 (d, J = 15.3Hz, 1H), 2.78 (d, J = 15.3Hz, 1H) 2.40 (m, 1H) , 2.32 (m, 1H), 1.88 (m, 2H), 1.76 (m, 1H), 1.32-1.50 (m, 2H), 1.05 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described in Example 159.

<tables num="17"><img file="JP4570878B2_D0132.tif" /></tables>

(Example 164)

<chemistry num="96"><img file="JP4570878B2_D0133.tif" /></chemistry> Stage 1.

<chemistry num="97"><img file="JP4570878B2_D0134.tif" /></chemistry> Example 145 (7.4 mg, 0.018 mmol) in THF solution (1 mL) with 1 AH (144 μL, 1 MEt)₂O solution, 0.144 mmol) was added. The reaction is stirred at room temperature for 24 hours, then Et.₂It was added slowly to a mixture of O / 1N HCl (10/1, 20 mL). H this mixture₂Wash with O and brine (5 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification of this residue by flash chromatography (5-20% EtOAc / Hexanes) resulted in 4.5 mg (61%) of Example 164. R_f= 0.17 (25% EtOAc / Hexanes). LCMS = 415; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.45-7.47 (m, 2H), 7.43 (s, 1H), 7.40 (d, J = 7.4Hz, 2H), 7.33 (t, J = 7.7Hz, 2H), 7.25 (t, J) = 7.3Hz, 1H), 7.15 (t, J = 8.5Hz, 2H), 6.62 (d, J = 15.9Hz, 1H), 6.31 (dd, J = 16.0, 5.4Hz, 1H), 6.12 (d, J = 1.8Hz, 1H), 4.73 (d, J = 5.0Hz, 1H), 3.09 (d, J = 15.1Hz, 1H), 2.62 (d, J = 15.1Hz, 1H), 2.42 (m, 1H), 2.32 (m, 1H), 1.91 (m, 1H), 1.79 (m, 1H), 1.67-1.72 (m, 2H), 1.38 (m, 1H), 1.22 (s, 3H).

(Example 165)

<chemistry num="98"><img file="JP4570878B2_D0135.tif" /></chemistry> Stage 1.

<chemistry num="99"><img file="JP4570878B2_D0136.tif" /></chemistry> Pd on CaCO3 poisoned with lead (4 mg) and quinoline (15 μL) was added to Example 145 (12.9 mg, 0.031 mmol) in hexane / THF (3/1) solution (1.6 mL). The reaction is stirred at room temperature for 15 minutes, then H₂I put it down. The reaction was stirred at room temperature for 2 hours and then the catalyst was removed by filtration. The filtrate is diluted with EtOAc (35 mL), washed with 1N HCl and brine (10 mL each) and Na.₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (5-20% EtOAc / Hexanes) resulted in 7.3 mg (56%) of Example 165. R_f= 0.17 (25% EtOAc / Hexanes). LCMS = 415; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.38-7.44 (m, 4H), 7.32-7.35 (m, 4H), 7.14 (t, J = 8.6Hz, 2H), 6.56 (d, J = 11.7Hz, 1H), 6.08 (d , J = 1.8Hz, 1H), 5.90 (dd, J = 11.7, 9.0Hz, 1H), 4.91 (d, J = 8.9Hz, 1H), 2.76 (d, J = 15.2Hz, 1H), 2.29-2.42 (m, 3H), 1.88-1.96 (m, 2H), 1.77 (qd, J = 9.6, 3.3Hz, 1H), 1.62 (dd, J = 12.5, 2.4Hz, 1H), 1.41 (m, 1H), 1.10 (s, 3H).

(Example 166 + 167)

<chemistry num="100"><img file="JP4570878B2_D0137.tif" /></chemistry> Step 1: Addition of lithium phenyl sulfone reagent to aldehyde F

<chemistry num="101"><img file="JP4570878B2_D0138.tif" /></chemistry> A solution of methylphenyl sulfone (285 mg, 1.83 mmol) in THF (16 mL) was cooled to 0 ° C. and n-BuLi (950 μL of 1.6 M hexane solution, 1.52 mmol) was added via syringe. The reaction was stirred at 0 ° C for 1 hour and then further cooled to -78 ° C. Aldehyde F (45.1 mg, 0.152 mmol) in THF (4 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (25 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (10-50% EtOAc / Hexanes) produced a mixture of the two diastereomers. PTLC (20/40/40 Hexane / CH₂Cl₂/ Et₂Further purification with O) resulted in 24.4 mg (35%) of low-polarity diastereomers and 11.3 mg (16%) of high-polarity diastereomers. Low Polar Diastereomer: R_f= 0.32 (50% EtOAc / Hexanes). LCMS = 453; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.98 (d, J = 7.8Hz, 2H), 7.70 (t, J = 7.5Hz, 1H), 7.61 (t, J = 7.8Hz, 2H), 7.42 (m, 2H), 7.36 (s, 1H), 6.08 (s, 1H), 4.32 (m, 1H), 3.48 (s, 1H), 3.32 (m, 2H), 2.67 (d, J = 15Hz, 1H), 2.57 (m, 1H) ), 2.51 (d, J = 15Hz, 1H), 2.15 (s, 1H), 1.99 (m, 1H), 1.91 (m, 1H), 1.83 (m, 1H), 0.89 (s, 3H).

High Polar Diastereomer: R_f= 0.32 (50% EtOAc / Hexanes). LCMS = 453; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.95 (d, J = 8.4Hz, 2H), 7.68 (m, 1H), 7.61 (t, J = 9Hz, 2H), 7.45 (m, 2H), 7.38 (s, 1H), 7.13 (t, J = 9Hz, 2H), 6.11 (s, 1H), 4.26 (m, 1H), 3.27 (s, 2H), 3.15 (d, J = 19.2Hz, 2H), 2.63 (d, J = 19.2Hz, 1H), 2.57 (m, 1H), 2.42 (m, 1H), 2.15 (s, 1H), 1.98 (m, 1H), 1.71 (m, 2H), 1.42 (m, 1H), 1.03 ( s, 3H).

Starting from the appropriate aldehyde, the following compounds were synthesized according to a procedure similar to that described for Examples 166 and 167.

<tables num="18"><img file="JP4570878B2_D0139.tif" /></tables><img file="JP4570878B2_D0140.tif" />

<chemistry num="102"><img file="JP4570878B2_D0141.tif" /></chemistry> Step 1:

<chemistry num="103"><img file="JP4570878B2_D0142.tif" /></chemistry> Trimethylsulfooxonium iodide (240 mg, 1.09 mmol) was added as a solid to a suspension of sodium hydride (36.5 mg, 60% dispersion of 0.91 mmol mineral oil) in DMSO (2 mL). The reaction was stirred at room temperature for 10 minutes. Aldehyde F (54.0 mg, 0.18 mmol) in THF (4 mL) was added by cannula. The reaction was stirred at room temperature for 2 hours. Add 1 mL of water and then saturate the reaction LVDS₃Pour into (25 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-40% EtOAc / Hexanes) produced 8.8 mg (16%) of low-polarity diastereomers and 11.2 mg (20%) of high-polarity diastereomers. Low Polar Diastereomer: R_f= 0.56 (50% EtOAc / Hexanes). LCMS = 311; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.15 (m, 2H), 6.91 (s, 1H), 6.80 (t, J = 8.7Hz, 2H), 5.85 (s, 1H), 2.56 (m, 1H), 2.44 (d, J = 15.6Hz, 1H), 2.32 (m, 1H), 2.24 (m, 1H), 2.18 (d, J = 15.6Hz, 1H), 2.12 (m, 1H), 2.02 (m, 1H), 1.45 ( m, 2H), 1.31 (m, 1H), 0.63 (s, 3H).

High Polar Diastereomer: R_f= 0.52 (50% EtOAc / Hexanes). LCMS = 311; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.12 (m, 2H), 6.94 (s, 1H), 6.84 (t, J = 8.7Hz, 2H), 5.82 (s, 1H), 2.50 (m, 1H), 2.47 (s, 1H), 2.79 (m, 1H), 2.17 (m, 2H), 2.07 (m, 2H), 1.44 (m, 2H), 1.19 (m, 1H), 0.67 (s, 3H).

Starting from the appropriate aldehyde, the following compounds were synthesized according to a procedure similar to that described for Q / R.

<tables num="19"><img file="JP4570878B2_D0143.tif" /></tables><img file="JP4570878B2_D0144.tif" />

(Examples 170 and 171)

<chemistry num="104"><img file="JP4570878B2_D0145.tif" /></chemistry> Step 1: Addition of lithium phenyl sulfone reagent to epoxide R

<chemistry num="105"><img file="JP4570878B2_D0146.tif" /></chemistry> A solution of methylphenyl sulfone (305 mg, 1.92 mmol) in THF (12 mL) was cooled to 0 ° C. and n-BuLi (1 mL of 1.6 M hexane solution, 1.6 mmol) was added dropwise by syringe. The reaction was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. Epoxide R (10 mg, 0.032 mmol) in THF (2 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. The reaction was warmed to room temperature and allowed to stand overnight at room temperature. After stirring overnight at room temperature, 1 mL of isopropyl alcohol is added and the reaction is saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (25 mL) and the organic layer was washed with water and brine (10 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-100% EtOAc / Hexanes) produced a mixture of the desired product and a small amount of impurities. PTLC (20/40/40 Hexane / CH₂Cl₂/ Et₂Further purification with O) resulted in 4.9 mg (33%) of Example 170. R_f= 0.17 (50% EtOAc / Hexanes). LCMS = 467; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.94 (d, J = 7.8Hz, 2H), 7.68 (t, J = 7.5Hz, 1H), 7.59 (t, J = 7.8Hz, 2H), 7.45 (m, 2H), 7.37 (s, 1H), 7.13 (t, J = 8.1Hz, 2H), 6.13 (s, 1H), 3.82 (t, J = 7.8Hz, 1H), 3.29 (m, 2H), 3.05 (d, J = 15.6Hz, 1H), 2.61 (m, 1H), 2.45 (m, 1H), 2.12 (m, 1H), 1.83 (m, 4H), 1.64 (m, 1H), 1.53 (m, 1H), 1.01 ( s, 3H).

<chemistry num="106"><img file="JP4570878B2_D0147.tif" /></chemistry> A solution of methylphenyl sulfone (305 mg, 1.92 mmol) in THF (12 mL) was cooled to 0 ° C. and n-BuLi (1 mL of 1.6 M hexane solution, 1.6 mmol) was added dropwise by syringe. The reaction was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. Epoxide Q (10 mg, 0.032 mmol) in THF (2 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. The reaction was warmed to room temperature and allowed to stand overnight at room temperature. After stirring overnight at room temperature, 1 mL of isopropyl alcohol is added and the reaction is saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (25 mL) and the organic layer was washed with water and brine (10 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-100% EtOAc / Hexanes) produced a mixture of the desired product and some small amounts of impurities. PTLC (20/40/40 Hexane / CH₂Cl₂/ Et₂Further purification by O) resulted in 3.2 mg of Example 171 (21%). R_f= 0.17 (50% EtOAc / Hexanes). LCMS = 467; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.96 (d, J = 7.8Hz, 2H), 7.69 (m, 1H), 7.61 (m, 2H), 7.45 (m, 2H), 7.38 (s, 1H), 7.14 (t, J = 7.8Hz, 2H), 6.12 (s, 1H), 3.87 (m, 1H), 3.34 (m, 2H), 2.75 (d, J = 15.5Hz, 1H), 2.60 (m, 1H), 2.53 ( d, J = 15.5Hz, 1H), 2.43 (m, 1H), 2.14 (m, 1H), 1.89 (m, 1H), 1.81 (m, 3H), 0.96 (s, 3H).

Starting from the appropriate epoxide, the following compounds were synthesized according to a procedure similar to that described for Examples 170 and 171.

<tables num="20"><img file="JP4570878B2_D0148.tif" /></tables><img file="JP4570878B2_D0149.tif" />

(Example 174)

<chemistry num="107"><img file="JP4570878B2_D0150.tif" /></chemistry> Steps 1: 1,2 Addition of phenylenediamine to aldehyde B

<chemistry num="108"><img file="JP4570878B2_D0151.tif" /></chemistry> 1,2 phenylenediamine (10.5 mg, 0.097 mmol) and aldehyde B (15.0 mg, 0.05 mmol) were placed in a flask under nitrogen. Nitrobenzene (500 μL) was added and the reaction was heated to 150 ° C. The reaction was stirred at 150 ° C. for 4 hours. After cooling to room temperature, the reaction was loaded directly onto silica gel, and the column was eluted with 100% hexane to remove nitrobenzene and subsequently eluted with 40-80% EtOAc / Hexanes as desired. A mixture of the product and some small amounts of impurities was produced. PTLC (2/98 MeOH / CH₂Cl₂Further purification by) gave Example 174 of 16.0 mg (84%). LCMS = 399; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.55 (s, 1H), 7.39 (m, 2H), 7.26 (s, 1H), 7.20 (m, 2H), 7.11 (t, J = 8.5Hz, 3H), 6.14 (s, 1H), 3.19 (m, 1H), 2.88 (d, J = 15.5Hz, 1H), 2.63 (d, J = 15.5Hz, 1H), 2.40 (m, 2H), 2.21 (m, 2H), 1.94 ( m, 2H), 1.44 (m, 1H), 1.21 (s, 3H).

Starting from the appropriate aldehyde, the following compounds were synthesized according to a procedure similar to that described for benzimidazole in Example 174.

<tables num="21"><img file="JP4570878B2_D0152.tif" /></tables>

(Examples 177 and 178)

<chemistry num="109"><img file="JP4570878B2_D0153.tif" /></chemistry> Stage 1. Addition of DAST to Example 119

<chemistry num="110"><img file="JP4570878B2_D0154.tif" /></chemistry> CH of Example 119 (38.2 mg, 0.089 mmol) in a plastic vial₂Cl₂The solution (500 μL) was cooled to 0 ° C. and sulfur diethylaminotrifluoride (23.6 μL, 0.178 mmol) was added dropwise by syringe. The reaction was stirred at 0 ° C. for 10 minutes and then warmed to room temperature. The reaction was stirred at room temperature for 2 hours. Saturate this reactant LVDS₃Pour into (10 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with brine (15 mL). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-20% EtOAc / Hexanes) produces a mixture of the two diastereomers, separated using an OD chiral column (15% IPA / heptane), 4.6 mg (12%). Peak 1 and peak 2 of 6.9 mg (18%) were obtained.

Peak 1: R_f= 0.39 (40% EtOAc / Hexanes). LCMS = 433; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ8.00 (d, J = 7.8Hz, 1H), 7.89 (d, J = 7.8Hz, 1H), 7.48 (m, 2H), 7.46 (s, 1H), 7.15 (t, J = 8.4Hz, 2H), 6.17 (s, 1H), 5.81 (dd, J = 47.4Hz, 10.8Hz, 1H), 3.21 (dd, J = 15.9Hz, 3.9Hz, 1H), 2.88 (d, J = 16.2 Hz, 1H), 2.80 (m, 1H), 2.59 (m, 1H), 2.40 (m, 1H), 1.59 (m, 1H), 1.48 (m, 1H), 1.26 (s, 3H).

Peak 2: R_f= 0.44 (40% EtOAc / Hexanes). LCMS = 433; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.92 (d, J = 1.8Hz, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.49 (d, J = 1.8Hz, 1H), 7.41 (m, 4H), 7.14 (t, J = 9Hz, 2H), 6.14 (t, J = 1.8Hz, 1H), 5.91 (dd, J = 46.8Hz, 6.6Hz, 1H), 2.69 (m, 2H), 2.47 (m, 1H) , 2.88 (dd, J = 38.7Hz, 15Hz, 2H), 2.17 (m, 1H), 1.21 (d, J = 6Hz, 1H), 1.15 (s, 3H).

<chemistry num="111"><img file="JP4570878B2_D0155.tif" /></chemistry> Step 1:

<chemistry num="112"><img file="JP4570878B2_D0156.tif" /></chemistry> Trimethylsulfooxonium iodide (334 mg, 1.52 mmol) was added as a solid to a suspension of sodium hydride (54 mg, 60% dispersion of 1.35 mmol mineral oil) in DMSO (4 mL). The reaction was stirred at room temperature for 10 minutes. Ketone A (100 mg, 0.338 mmol) in THF (0.5 mL) was added by cannula. The reaction was stirred at room temperature overnight. Add 1 mL of water and then saturate the reaction LVDS₃Pour into (25 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-40% EtOAc / Hexanes) resulted in 101.6 mg (97%) U. R_f= 0.56 (40% EtOAc / Hexanes). LCMS = 311; (M + 1)⁺。

Stage 2:

<chemistry num="113"><img file="JP4570878B2_D0157.tif" /></chemistry> Trifluoroacetic acid (1.5 mL) was added to epoxide U (101.6 mg, 0.322 mmol). The reaction was stirred at room temperature for 20 minutes. Then ice / H this reactant₂Pour into O, and 10% K₂CO₃Neutralized by. The mixture was extracted with EtOAc (20 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-40% EtOAc / Hexanes) resulted in 59.1 mg (58%) V. R_f= 0.42 (50% EtOAc / Hexanes). LCMS = 311; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ7.29 (s, 1H), 7.64 (s, 1H), 7.51 (m, 2H), 7.16 (s, 1H), 7.12 (t, J = 8.4Hz, 2H), 3.69 (d, J = 10.8Hz, 1H), 3.45 (d, J = 10.8Hz, 1H), 2.82 (m, 2H), 1.96 (m, 1H), 1.75 (m, 2H), 1.52 (m, 1H), 1.24 ( m, 3H).

Stage 3:

<chemistry num="114"><img file="JP4570878B2_D0158.tif" /></chemistry> CH of oxalyl chloride (75.4 μL, 0.86 mmol)₂Cl₂The solution in (4 mL) was cooled to -78 ° C. DMSO (122.7 μL, 1.73 mmol) was added. The reaction was stirred at room temperature for 10 minutes. CH Alcohol V (53.6 mg, 0.173 mmol)₂Cl₂It was dissolved in (1 mL) and added to the reaction by cannula. This was stirred at 78 ° C. for 20 minutes. Triethylamine (482.0 μL, 3.46 mmol) was cooled at 78 ° C. and then the reaction was warmed to room temperature. The mixture is extracted with EtOAc (20 mL) and the organic layer is water, 1NHCl, LVDS.₃, And brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-50% EtOAc / Hexanes) resulted in 39.8 mg (75%) W. R_f= 0.69 (50% ETOAC / hexane). LCMS = 309; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz): δ9.55 (s, 1H), 8.11 (s, 1H), 7.66 (m, 2H), 7.53 (s, 1H), 7.44 (s, 1H), 7.23 (t, J = 8.4Hz, 2H), 2.97 (m, 2H), 2.19 (m, 1H), 1.91 (m, 2H), 1.74 (m, 1H), 1.54 (m, 3H).

The following compounds were synthesized starting from Ketone A and following a procedure similar to that described for Aldehyde W.

<tables num="22"><img file="JP4570878B2_D0159.tif" /></tables>

(Examples 179 and 180)

<chemistry num="115"><img file="JP4570878B2_D0160.tif" /></chemistry> Step 1: Add Grignard reagent to aldehyde W

<chemistry num="116"><img file="JP4570878B2_D0161.tif" /></chemistry> Aldehyde W (38.2 mg, 0.121 mmol) was dissolved in THF (6 mL) and cooled to 0 ° C. 4-Fluorobenzylmagnesium bromide (310 μL 2.0 M diethyl ether solution, 0.620 mmol) was added dropwise by syringe. The reaction is stirred at 0 ° C for 1 hour and then saturated NH₄Quenched with Cl (10 mL). The mixture is extracted with EtOAc (40 mL) and the organic layer is H₂Wash with O and brine (10 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-80% EtOAc / Hexanes) produced a mixture of the two diastereomers, separated using an AD chiral column (30% IPA / heptane), 24.4 mg (49%). Peak 1 and peak 2 of 17.2 mg (34%) were obtained. Peak 1: R_f= 0.11 (25% EtOAc / Hexanes). LCMS = 405; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ8.03 (s, 1H), 7.83 (s, 1H), 7.56 (m, 2H), 7.15 (t, J = 8.5Hz, 2H), 7.09 (m, 2H), 7.16 (s, 1H), 6.86 (t, J = 8.8Hz, 2H), 4.76 (s, 1H), 2.72 (m, 2H), 2.43 (s, 1H), 1.97 (s, 1H), 1.74 (m, 2H), 1.46 (m, 1H), 1.35 (s, 3H).

Peak 2: R_f= 0.11 (25% EtOAc / Hexanes). LCMS = 405; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.95 (s, 1H), 7.69 (s, 1H), 7.51 (m, 2H), 7.16 (s, 1H), 7.17 (m, 2H), 7.09 (m, 2H), 6.86 ( t, J = 8.8Hz, 2H), 4.95 (s, 1H), 2.78 (m, 2H), 2.03 (m, 1H), 1.97 (s, 1H), 1.72 (s, 1H), 1.52 (m, 2H) ), 1.11 (s, 3H).

The following compounds were synthesized starting from aldehyde X, following a procedure similar to that described for Examples 179 and 180.

<tables num="23"><img file="JP4570878B2_D0162.tif" /></tables>

(Examples 183 and 184)

<chemistry num="117"><img file="JP4570878B2_D0163.tif" /></chemistry> Step 1: Add aryllithium to aldehyde W

<chemistry num="118"><img file="JP4570878B2_D0164.tif" /></chemistry> 3-Bromothianaphthenic acid (162.2 μL, 1.24 mmol) Et₂The solution in O (16 mL) was cooled to -78 ° C and t-BuLi (1.45 mL 1.7 M pentane solution, 2.48 mmol) was added dropwise by syringe. The reaction was stirred at 78 ° C. for 20 minutes, then aldehyde W (38.2 mg, 0.124 mmol) in THF (2 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol is added at -78 ° C and the reaction is saturated with NH.₄Pour into Cl (10 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-20% EtOAc / Hexanes) produced a mixture of the two diastereomers, separated using an AD chiral column (25% PA / heptane), 3.8 mg (6.9%). Peak 1 and peak 2 of 6.7 mg (12%) were obtained.

Peak 1: R_f= 0.74 (40% EtOAc / Hexanes). LCMS = 443; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ8.01 (s, 1H), 7.90 (s, 1H), 7.83 (m, 1H), 7.73 (m, 1H), 7.55 (m, 1H), 7.16 (s, 1H), 7.19 ( m, 2H), 5.23 (s, 1H), 2.72 (m, 2H), 2.09 (s, 1H), 1.93 (s, 1H), 1.83 (m, 1H), 1.61 (m, 1H), 1.45 (s , 3H).

Peak 2: R_f= 0.74 (40% EtOAc / Hexanes). LCMS = 443; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.90 (s, 1H), 7.78 (s, 1H), 7.69 (m, 1H), 7.64 (m, 1H), 7.51 (m, 1H), 7.20 (s, 1H), 7.14 ( m, 2H), 7.08 (s, 1H), 7.07 (t, J = 9.0Hz, 2H), 5.47 (s, 1H), 2.73 (t, J = 6.3Hz, 1H), 2.17 (m, 1H), 1.93 (s, 1H), 1.79 (m, 1H), 1.57 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.21 (s, 3H).

The following compounds were synthesized starting from aldehyde X, following a procedure similar to that described for Examples 183 and 184.

<tables num="24"><img file="JP4570878B2_D0165.tif" /></tables>

<chemistry num="119"><img file="JP4570878B2_D0166.tif" /></chemistry> Step 1:

<chemistry num="120"><img file="JP4570878B2_D0167.tif" /></chemistry> A THF suspension (8 mL) of (methoxymethyl) triphenylphosphonium chloride (763 mg, 2.2 mmol) was cooled to 0 ° C. Potassium bis (trimethylsilylamide) (3.6 mL 0.5 M toluene solution, 1.78 mmol) was added dropwise by syringe and the reaction turned bright orange / red. Next, a solution of aldehyde F (132 mg, 0.44 mmol) in THF (4 mL) was added by cannula. The reaction was warmed to room temperature. After stirring at room temperature for 2 hours, 4N HCl was added slowly and the reaction was left to stir for an additional hour. The reaction is then diluted with EtOAc (50 mL) and LVDS.₃Quench with (50 mL), and H₂Washed with O and brine (25 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5 to 35% EtOAc / Hexanes) to give 95.1 mg (69%) Y. R_f= 0.29 (25% EtOAc / Hexanes). LCMS = 311; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz) δ9.86 (t, J = 2.1Hz, 1H), 7.44-7.47 (m, 2H), 7.39 (s, 1H), 7.13-7.16 (m, 1H), 6.17 (s, 1H), 2.68 (d, J = 15.0Hz, 1H), 2.60 (m, 2H), 2.55 (d, J = 15.0Hz, 1H), 2.46 (m, 2H), 2.34 (m, 1H), 2.10 (m, 1H) , 1.58 (m, 2H), 0.93 (s, 3H).

<chemistry num="121"><img file="JP4570878B2_D0168.tif" /></chemistry> Aldehyde Z was synthesized from aldehyde B using the same procedure used to synthesize aldehyde Y.

(Examples 187 and 188)

<chemistry num="122"><img file="JP4570878B2_D0169.tif" /></chemistry> Step 1: Add Grignard reagent to aldehyde Y

<chemistry num="123"><img file="JP4570878B2_D0170.tif" /></chemistry> Aldehyde Y (53.0 mg, 0.17 mmol) was dissolved in THF (6 mL) and cooled to 0 ° C. 3-Butenyl magnesium chloride (1.7 mL 0.5 MTHF solution, 0.85 mmol) was added dropwise by syringe. The reaction was stirred at 0 ° C. for 1 hour, then 1 mL of isopropyl alcohol was added. This reactant is then saturated with NH₄It was poured into Cl (25 mL) and extracted with EtOAc (40 mL). This organic layer is H₂Wash with O and brine (25 mL each) and Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. The two diastereomeric products were isolated by flash chromatography (5-20% EtOAc / Hexanes) and 17.3 mg (28%) low polar diastereomers and 19.9 mg (32%) high polar diastereomers. Got Low Polar Diastereomer: R_f= 0.15 (25% EtOAc / Hexanes). LCMS = 366; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.44-7.47 (m, 2H), 7.33 (m, 2H), 7.30 (s, 1H), 7.01 (m, 1H), 5.73 (m, 1H), 4.95 (m, 1H), 4.87 (dd, J = 8.5,1.8Hz, 1H), 4.86 (d, J = 10.3Hz, 2H), 3.63 (m, 1H), 2.62 (d, J = 15.5Hz, 1H), 2.47 (m, 1H) ), 2.42 (d, J = 7.5Hz, 1H), 2.07 (m, 2H), 1.92 (m, 1H), 1.74 (m, 1H), 1.38-1.56 (m, 6H), 0.80 (s, 3H) ..

High Polar Diastereomer: R_f= 0.14 (25% EtOAc / Hexanes). LCMS = 366; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.45 (m, 2H), 7.38 (m, 2H), 7.30 (s, 1H), 7.12 (m, 2H), 6.12 (m, 1H), 5.85 (m, 2H), 5.07 ( m, 1H), 4.99 (dd, J = 8.5,1.8Hz, 1H), 3.69 (m, 1H), 2.72 (d, J = 15.5Hz, 1H), 2.57 (m, 1H), 2.51 (d, J = 15.5Hz, 1H), 2.51 (m, 1H), 2.41 (m, 1H), 2.19 (m, 2H), 2.07 (m, 2H), 1.61-1.39 (m, 6H), 0.90 (s, 3H) ..

The following compounds were synthesized according to a procedure similar to that described for Examples 187 and 188.

<tables num="25"><img file="JP4570878B2_D0171.tif" /></tables><img file="JP4570878B2_D0172.tif" />

The following compounds were synthesized starting from aldehyde Z, following a procedure similar to that described for Examples 183 and 188.

<tables num="26"><img file="JP4570878B2_D0173.tif" /></tables><img file="JP4570878B2_D0174.tif" /><img file="JP4570878B2_D0175.tif" />

(Examples 199 and 200)

<chemistry num="124"><img file="JP4570878B2_D0176.tif" /></chemistry> Step 1: Addition of aryllithium reagent to aldehyde Y

<chemistry num="125"><img file="JP4570878B2_D0177.tif" /></chemistry> Et of 1-bromothianaphthenic acid (259 μL, 1.98 mmol)₂Solution O (8 mL) was cooled to -78 ° C and t-BuLi (2.3 mL 1.7 M pentane solution, 3.95 mmol) was added dropwise by syringe. The reaction was stirred at 78 ° C. for 20 minutes, then aldehyde Y (61.3 mg, 0.20 mmol) in THF (2 mL) was added by cannula. The reaction was stirred at -78 ° C for 45 minutes. 1 mL of isopropyl alcohol was added at -78 ° C, then the reaction was saturated with NH.₄Pour into Cl (25 mL). The mixture is extracted with EtOAc (50 mL) and the organic layer is H₂Washed with O and brine (15 mL each). This organic layer is Na₂SO₄It was dried on top, filtered, and concentrated in vacuo. Purification by flash chromatography (5-20% EtOAc / Hexanes) produced a mixture of the two diastereomers. PTLC (40/40/20 Hexane / CH₂Cl₂/ Et₂Further purification with O) resulted in 34.7 mg of low polar diastereomers and 28.2 mg (32%) of high polar diastereomers containing small amounts of impurities. Final purification of low-polarity diastereomers using an AD chiral column (35% isopropyl alcohol / heptane) resulted in 22.3 mg (25%) of low-polarity diastereomers.

Low Polar Diastereomer: R_f= 0.21 (25% EtOAc / Hexanes). LCMS = 445; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.86 (d, J = 8Hz, 1H), 7.80 (d, J = 7.5Hz, 1H), 7.33 (m, 3H), 7.29 (s, 1H), 7.20 (s, 1H), 7.02 (m, 2H), 6.00 (s, 1H), 5.09 (t, J = 6.5Hz, 1H), 2.64 (d, J = 15Hz, 1H), 2.48 (m, 1H), 2.33 (d, J = 15Hz, 1H), 2.70 (m, 1H), 2.13 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.73 (m, 1H), 1.52 (m, 1H), 1.18 (m) , 1H), 0.86 (s, 3H).

High Polar Diastereomer: R_f= 0.21 (25% EtOAc / Hexanes). LCMS = 445; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz): δ7.88 (t, J = 6Hz, 2H), 7.34-7.45 (m, 6H), 7.13 (t, J = 6.25Hz, 2H), 6.13 (s, 1H), 5.16 (d, J) = 6.5Hz, 1H), 2.73 (d, J = 12.5Hz, 1H), 2.59 (m, 1H), 2.54 (d, J = 12.5Hz, 1H), 2.46 (m, 1H), 2.17 (m, 2H) ), 2.05 (m, 1H), 1.86 (m, 1H), 1.59 (m, 1H), 1.25 (m, 1H), 0.90 (s, 3H).

The following compounds were synthesized according to a procedure similar to that described for Examples 199 and 200.

<tables num="27"><img file="JP4570878B2_D0178.tif" /></tables>

Starting from Aldehyde Z, the following compounds were synthesized according to a procedure similar to that described for Examples 199 and 200.

<tables num="28"><img file="JP4570878B2_D0179.tif" /></tables><img file="JP4570878B2_D0180.tif" />

(Example 207)

<chemistry num="126"><img file="JP4570878B2_D0181.tif" /></chemistry> Stage 1

<chemistry num="127"><img file="JP4570878B2_D0182.tif" /></chemistry> Example 61 (4.3 mg, 0.01 mmol) was dissolved in EtOAc (0.5 mL) and activated carbon with 10% Pd (1.0 mg) was added. This reactant is H₂It was placed down and stirred at room temperature for 45 minutes. This catalyst was removed by filtration. The filtrate was concentrated and the residue was purified by synthetic thin layer chromatography (25% EtOAc / Hexanes) to give 2.8 mg (65%) of Example 207. R_f= 0.15 (25% EtOAc / Hexanes). LCMS = 435; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz) δ7.45-7.47 (m, 3H), 7.12-7.17 (m, 4H), 6.98 (t, J = 8.4Hz, 1H), 6.12 (s, 1H), 5.16 (s, 1H), 3.18 (d, J = 15Hz, 1H), 2.75 (d, J = 15Hz, 1H), 2.65-2.70 (m, 2H), 2.41 (m, 1H), 2.28 (d, J = 15Hz, 1H), 1.59- 1.83 (m, 5H), 1.26 (s, 3H), 1.24 (t, J = 7.8Hz, 3H).

(Example 208)

<chemistry num="128"><img file="JP4570878B2_D0183.tif" /></chemistry> Stage 1

<chemistry num="129"><img file="JP4570878B2_D0184.tif" /></chemistry> Example 38 (11.6 mg, 0.03 mmol) was dissolved in EtOAc (2 mL) and NaH (10 mg, 0.42 mmol) was added. The reaction was stirred at room temperature for 5 minutes, then MeI (3 μL, 0.05 mmol) was added. After 15 minutes, the reaction was poured into water (10 mL) and extracted with EtOAc (25 mL). This organic layer is washed with brine and Na₂SO₄It was dried on, filtered, and concentrated. This residue is subjected to synthetic thin layer chromatography (5% MeOH / CH).₂Cl₂) To give 10.0 mg (83%) of Example 208. R_f= 0.18 (5% MEOH / CH)₂Cl₂). LCMS = 404; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ8.59 (bs, 2H), 7.44-7.47 (m, 3H), 7.21 (d, J = 4.0Hz, 2H), 7.15 (t, J = 8.5Hz, 2H), 6.11 (d, J = 1.5Hz, 1H), 4.48 (s, 1H), 3.28 (s, 3H), 3.17 (d, J = 15Hz, 1H), 2.75 (d, J = 15Hz, 1H), 2.38 (m, 1H), 2.25 (d, J = 14.5Hz, 1H), 1.68-1.79 (m, 2H), 1.48-1.57 (m, 2H), 1.18 (s, 3H), 1.10 (m, 1H).

Starting from Example 32, the following compounds were synthesized according to a procedure similar to that described for Example 208.

<tables num="28"><img file="JP4570878B2_D0185.tif" /></tables>

(Example 210)

<chemistry num="130"><img file="JP4570878B2_D0186.tif" /></chemistry> Stage 1

<chemistry num="131"><img file="JP4570878B2_D0187.tif" /></chemistry> CH Example 81 (9.0 mg, 0.019 mmol)₂Cl₂It was dissolved in (1 mL) and the solution was cooled to -40 ° C. m-CPBA (6.4 mg, 0.037 mmol) was added and the reaction was stirred at -40 ° C for 20 minutes. The reaction is then diluted with EtOAc (25 mL) to saturate NaHSO.₃Aqueous solution, saturated LVDS₃, And brine (10 mL each). This organic layer is Na₂SO₄It was dried on, filtered, and concentrated. The residue was purified by flash chromatography (100% EtOAc to 5% MeOH / EtOAc) to give 7.2 mg (78%) of Example 210._f= 0.19 (EtOAc). LCMS = 499; (M + 1)⁺。¹1 H NMR (CDCl₃, 600MHz) δ7.43-7.46 (m, 3H), 7.26 (m, 1H), 7.14-7.16 (m, 2H), 7.08 (dd, J = 8.4, 10.0Hz, 1H), 6.97 (m, 1H) , 6.11 (d, J = 2.4Hz, 1H), 5.12 (s, 1H), 5.05 (dd, J = 10.2,3.0Hz, 1H), 4.97 (dd, J = 10.2,8.4Hz, 1H), 3.16 ( d, J = 15Hz, 1H), 2.73 (d, J = 15Hz, 1H), 2.72 (s, 3H), 2.26-2.42 (m, 2H), 1.64-1.83 (m, 3H), 1.51 (m, 1H) ), 1.24 (s, 3H), 1.18 (m, 1H).

(Example 211)

<chemistry num="132"><img file="JP4570878B2_D0188.tif" /></chemistry> Stage 1

<chemistry num="133"><img file="JP4570878B2_D0189.tif" /></chemistry> Example 81 (6.0 mg, 0.012 mmol) was dissolved in THF (100 μL) and MeOH (400 μL) was added. The solution was cooled to 0 ° C. Oxone (14 mg, 0.024 mmol) H₂It was dissolved in O (400 μL) and this solution was added to the solution of Example 81. The reaction was warmed to room temperature and stirred for 4 hours. The reaction is then diluted with EtOAc (25 mL) and then water, saturated NaHSO.₃Aqueous solution, saturated LVDS₃, And brine (10 mL each). This organic layer is Na₂SO₄It was dried on, filtered, and concentrated. The residue was purified by synthetic thin layer chromatography (60% EtOAc / Hexanes) to give 1.6 mg (25%) of Example 211. R_f= 0.54 (75% EtOAc / Hexanes). LCMS = 515; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.45-7.48 (m, 3H), 7.01-7.26 (m, 4H), 7.02 (m, 1H), 6.12 (d, J = 2.0Hz, 1H), 5.16 (s, 1H), 5.02 (s, 3H), 3.18 (d, J = 15.5Hz, 1H), 3.07 (s, 3H), 2.74 (d, J = 15Hz, 1H), 2.40 (m, 1H), 2.28 (m, 1H), 1.52-1.89 (m, 4H), 1.25 (s, 3H), 1.19 (m, 1H).

(Example 212)

<chemistry num="134"><img file="JP4570878B2_D0190.tif" /></chemistry> Stage 1

<chemistry num="135"><img file="JP4570878B2_D0191.tif" /></chemistry> Example 119 (11.0 mg, 0.026 mmol) was dissolved in THF (200 μL) and MeOH (200 μL) was added. The solution was cooled to 0 ° C. Oxone (32 mg, 0.051 mmol) H₂It was dissolved in O (800 μL) and this solution was added to the solution of Example 119. The reaction was warmed to room temperature and stirred for 4 hours. At this point, additional oxone (32 mg, 0.051 mmol) was added as a solid. The reaction is stirred at room temperature for an additional 24 hours, then diluted with EtOAc (25 mL) and water, saturated acrylamide.₃, And brine (10 mL each). This organic layer is Na₂SO₄It was dried on, filtered, and concentrated. The residue was purified by synthetic thin layer chromatography (60% EtOAc / Hexanes) to give 2.5 mg (21%) of Example 212. R_f= 0.13 (40% ETOAC / hexane). LCMS = 463; (M + 1)⁺。¹1 H NMR (CDCl₃, 500MHz) δ7.76 (d, J = 7.5Hz, 1H), 7.52-7.60 (m, 3H), 7.40-7.45 (m, 3H), 7.14 (t, J = 8.5Hz, 2H), 6.72 (s , 1H), 6.14 (s, 1H), 5.02 (d, J = 2.0Hz, 1H), 2.89 (d, J = 14.5Hz, 1H), 2.65 (m, 1H), 2.55 (d, J = 15Hz, 1H), 2.37-2.45 (m, 2H), 2.28 (m, 1H), 1.96-2.14 (m, 3H), 1.14 (s, 3H).

(Example 213)

<chemistry num="136"><img file="JP4570878B2_D0192.tif" /></chemistry> Example 213 was manufactured in the same manner as in Example 212, starting from Example 120.

Biological assay The following assay can be used to assess the activity of the compounds of the invention as modulators of this glucocorticoid receptor.

Ligand binding assay Cytosols were prepared from recombinant baculovirus expression receptors for the hGRα ligand binding assay. Frozen cell pellet ice-cooled KPO₄Buffer solution (10m MKPO)₄, 20 mM sodium molybdate, 1 mM EDTA, 5 mM DTT and (complete protease inhibitor tablets from Boehringer (Mannheim)) were downshomogenized with a "B" plunger. The homogenate was centrifuged in a JA-20 rotor at 35,000 xg at 4 ° C for 1 hour. 2.5 nM [1,2,4,6,7- in the presence of increasing concentrations (10-11 to 10-6) of cold dexamethasone or this ligand³H] IC by incubating the cytosol at the final concentration of dexamethasone at 4 ° C for 24 hours.₅₀Asked. Bounds and frees were separated by gel filtration assay (Geissler et al., Personal communication). KPO containing 1 mg / mL BSA⁴Half of this reaction was added to a gel filtration plate (MIllIPORE) containing Sephadex G-25 beads pre-equilibrium with buffer and centrifuged at 1000 xg for 5 minutes. The reaction plate was centrifuged at 1000 xg for 5 minutes, and the reaction was collected in a second 96-well plate, and a scintillation cocktail was added, and counted in a (Wallac) double-matched beta counter. did. IC using a 4-parameter fit program₅₀Was calculated.

The compounds of the present invention exhibited activity in the range of 0.1 nM to 1 μM in the assay procedure described above.