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MODULATORS OF THE INTEGRATED STRESS PATHWAY

20250145594 ยท 2025-05-08

    Inventors

    Cpc classification

    International classification

    Abstract

    Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (I SR) and for treating related diseases, disorders, and conditions.

    Claims

    1.-92. (canceled)

    93. A compound of Formula (I): ##STR00764## or a pharmaceutically acceptable salt thereof, wherein: D is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4-6-membered monocyclic cycloalkyl, a 4-6-membered monocyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4-6-membered monocyclic cycloalkyl, 4-6-membered monocyclic heterocyclyl, or cubanyl is optionally substituted on one or more available carbons with 1-4 R.sup.X; and wherein if the 4-6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N1; U is NR.sup.1C(O), C(O)NR.sup.1 or 5-6-membered heteroaryl; E is absent or is a bond, NR.sup.2C(O), C(O)NR.sup.2, 5-6-membered heteroaryl or 5-6-membered heterocyclyl; wherein 5-6-membered heteroaryl or 5-6-membered heterocyclyl is optionally substituted on one or more available carbons with 1-5 R.sup.G; and wherein if the 5-6-membered heteroaryl or 5-6-membered heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N2; or E is ##STR00765## wherein Y is a 4-9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclyl, wherein the 4-9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclyl is optionally substituted on one or more available carbons with 1-5 R.sup.G; and wherein if the 4-9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N2, L.sup.1 is a bond, C.sub.1-C.sub.6 alkylene, 2-7 membered heteroalkylene, NR.sup.N3, or O, wherein C.sub.1-C.sub.6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R.sup.L1; L.sup.2 is absent or is a bond, C.sub.1-C.sub.6 alkylene, 2-7 membered heteroalkylene, or O, wherein C.sub.1-C.sub.6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R.sup.L2; wherein E and L.sup.2 both cannot be either a bond or absent simultaneously; R.sup.1 is hydrogen or C.sub.1-C.sub.6 alkyl; R.sup.2 is hydrogen or C.sub.1-C.sub.6 alkyl; W is a 8-10 membered, partially unsaturated, fused bicyclic ring moiety comprising a 5-6 membered heterocyclyl fused to a phenyl or 5-6-membered heteroaryl; wherein the heterocyclyl may be optionally substituted on one or more available carbons with 1-4 R.sup.W1; wherein the phenyl or heteroaryl may optionally be substituted on one or more available unsaturated carbons with 1-4 R.sup.W2; wherein if the heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may optionally be substituted with R.sup.N4; and wherein W is attached to L.sup.2 through an available saturated carbon or nitrogen atom within the heterocyclyl; A is C.sub.3-C.sub.6 cycloalkyl, phenyl, 4-6-membered heterocyclyl, 5-6-membered heteroaryl, or 8-10-membered bicyclic heteroaryl, wherein C.sub.3-C.sub.6 cycloalkyl, phenyl, 4-6-membered heterocyclyl, 5-6-membered heteroaryl, or 8-10-membered bicyclic heteroaryl is optionally substituted on one or more available carbons or silicons with 1-5 R.sup.Y; and wherein if the 5-6-membered heteroaryl or 8-10-membered bicyclic heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N5; each R.sup.L1 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, SR.sup.E, S(O)R.sup.D, and S(O).sub.2R.sup.D; each R.sup.L2 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, thioxo, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, SR.sup.E, S(O)R.sup.D, and S(O).sub.2R.sup.D; R.sup.N1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OR.sup.D, and S(O).sub.2R.sup.D; R.sup.N2 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OR.sup.D, and S(O).sub.2R.sup.D; R.sup.N3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OR.sup.D, and S(O).sub.2R.sup.D; R.sup.N4 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkenyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl-CO.sub.2H, C.sub.1-C.sub.6 alkyl-CO.sub.2-C.sub.1-C.sub.6 alkyl, C(O)C.sub.1-C.sub.3 alkyl-OC.sub.1-C.sub.3 alkyl-OC.sub.1-C.sub.3 alkyl, C(O)-phenyl, C(O)-heteroaryl, C(O)-heterocyclyl, S(O).sub.2-C.sub.1-C.sub.6 alkyl, S(O).sub.2-phenyl, S(O).sub.2-heteroaryl, C(O)NR.sup.BR.sup.Cand C(O)OR.sup.D; wherein C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkenyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl-CO.sub.2H, C.sub.1-C.sub.6 alkyl-CO.sub.2-C.sub.1-C.sub.6 alkyl, C(O)-heterocyclyl, and S(O).sub.2-C.sub.1-C.sub.6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of fluoro, hydroxyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl (optionally substituted by one, two or three fluorine atoms) and S(O).sub.WC.sub.1-6 alkyl (wherein w is 0, 1 or 2); and C(O)-phenyl, C(O)-heteroaryl, S(O).sub.2-phenyl and S(O).sub.2-heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C.sub.1-C.sub.6 alkyl (optionally substituted by one, two or three fluorine atoms), C.sub.1-C.sub.6 alkoxy (optionally substituted by one, two or three fluorine atoms), and S(O).sub.2NR.sup.BR.sup.C; R.sup.N5 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OR.sup.D, and S(O).sub.2R.sup.D; each R.sup.W1 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl (optionally substituted by CO.sub.2H), hydroxy-C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl-O, halo-C.sub.1-C.sub.6 alkyl, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, CNOH, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BR.sup.CC, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, SR.sup.E, S(O)R.sup.D, and S(O).sub.2R.sup.D; each R.sup.W2 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl-O, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, S(R.sup.F).sub.m, S(O)R.sup.D, and S(O).sub.2R.sup.D; or 2 R.sup.W2 groups on adjacent atoms, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R.sup.x; each R.sup.X is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, SR.sup.E, S(O)R.sup.D, and S(O).sub.2R.sup.D; each R.sup.Y is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, halo, cyano, oxo, C.sub.1-C.sub.6 alkylene-OR.sup.A, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BR.sup.CC, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, S(R.sup.F).sub.m, S(O)R.sup.D, S(O).sub.2R.sup.D, and G.sup.1; or 2 R.sup.Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R.sup.X; each G.sup.1 is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 R.sup.Z; each R.sup.Z is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, and S(O).sub.2R.sup.D; R.sup.A is, at each occurrence, independently hydrogen, C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, or C(O)OR.sup.D; each of R.sup.B and R.sup.C is independently hydrogen or C.sub.1-C.sub.6 alkyl; or R.sup.B and R.sup.C together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R.sup.Z; each R.sup.CC is independently selected from the group consisting of hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 alkyl-CO.sub.2H, C.sub.1-C.sub.6 alkyl-CO.sub.2-C.sub.1-C.sub.6 alkyl, C(O) C.sub.1-C.sub.6 alkyl, S(O).sub.2 C.sub.1-C.sub.6 alkyl and 3-6-membered cycloalkyl and 4-6-membered heterocyclyl; wherein 3-6-membered cycloalkyl and 4-6-membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, hydroxyl, halo and C(O)OH; each R.sup.D is independently C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, or halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene; each R.sup.E is independently hydrogen, C.sub.1-C.sub.6 alkyl, or halo-C.sub.1-C.sub.6 alkyl; each R.sup.F is independently hydrogen, C.sub.1-C.sub.6 alkyl, or halo; each R.sup.G is independently hydrogen, C.sub.1-C.sub.6 alkyl, halo or oxo; and m is 1 when R.sup.F is hydrogen or C.sub.1-C.sub.6 alkyl, 3 when R.sup.F is C.sub.1-C.sub.6 alkyl, or 5 when R.sup.F is halo.

    94. The compound of claim 93, wherein D is selected from the group consisting of ##STR00766##

    95. The compound of claim 93, wherein U is selected from the group consisting of *NHC(O), *C(O)NH, and ##STR00767## wherein * indicates the attachment point to D.

    96. The compound of claim 93, wherein L.sup.1 is a bond or C.sub.1-C.sub.6 alkylene, wherein C.sub.1-C.sub.6 alkylene is substituted with 0-5 R.sup.L1.

    97. The compound of claim 93, wherein W is represented by Formula (W-a): ##STR00768## wherein: X is O, NR.sup.N4, or C(R.sup.X1)(R.sup.X2); R.sup.N4 is hydrogen or C.sub.1-C.sub.6 alkyl; R.sup.X1 is hydrogen or hydroxyl; R.sup.X2 is hydrogen or hydroxyl; or R.sup.X1 and R.sup.X2 taken together to form an oxo moiety.

    98. The compound of claim 93, wherein each R.sup.W2 is independently bromo, chloro, fluoro, or CF.sub.3.

    99. The compound of claim 93, wherein E is selected from the group consisting of a bond, *NR.sup.2C(O), *C(O)NR.sup.2, ##STR00769## ##STR00770## wherein * indicates the attachment point to D, and R.sup.2 is hydrogen.

    100. The compound of claim 93, wherein E is absent.

    101. The compound of claim 93, wherein L.sup.2 is a bond, CH.sub.2, CH.sub.2O*, C(O), C(S), OCH.sub.2C(O)*, C(O)NH*, OCH.sub.2*, OCH.sub.2C(O)NH*, or O, wherein * indicates the attachment point to A.

    102. The compound of claim 93, wherein L.sup.2 is absent.

    103. The compound of claim 93, wherein A is selected from the group consisting of ##STR00771## ##STR00772## ##STR00773## wherein R.sup.X is CH.sub.2CH.sub.2OCF.sub.3, and each R.sup.N5 is independently C(O)CH.sub.3, CF.sub.3, or CH.sub.2CF.sub.3.

    104. The compound of claim 93, wherein each R.sup.Y is independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxyl, phenyl, oxo, CHF.sub.2, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, OCH.sub.3, OCHF.sub.2, OCF.sub.3, OCH.sub.2CF.sub.3, OCH(CH.sub.3).sub.2, CH.sub.2OCF.sub.3, CH.sub.2OCH.sub.2CF.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2OCF.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2OCF.sub.3, CN, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.2CF.sub.3, OCH.sub.2CH.sub.2CH.sub.2C(CH.sub.3)F.sub.2, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CH.sub.2CF.sub.3, NHCH.sub.2CH.sub.2OCF.sub.3, NHCH.sub.2CH.sub.2CH.sub.2OCF.sub.3, N(CH.sub.3)CH.sub.2CH.sub.2OCF.sub.3, N(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2OCF.sub.3, N(CH.sub.3)CH(CH.sub.3)CH.sub.2OCF.sub.3, OCH.sub.2CH.sub.2OCF.sub.3, OCH.sub.2CH.sub.2OCHF.sub.2, OCH.sub.2CH.sub.2OCH.sub.3, OCH.sub.2CH.sub.2CH.sub.2OCF.sub.3, OCH.sub.2CH.sub.2OCH.sub.2CF.sub.3, OCH(CH.sub.3)CH.sub.2OCF.sub.3, OCH.sub.2CH(CH.sub.3)OCF.sub.3, CH.sub.2OCH.sub.2CH.sub.2OCF.sub.3, C(O)CH.sub.2OCF.sub.3, CH.sub.2OC(O)OCH.sub.2CH.sub.3, and cyclopropyl.

    105. The compound of claim 93, wherein R.sup.Y is OC.sub.1-C.sub.6 alkylene-C.sub.1-C.sub.6 alkoxy optionally substituted with 1-6 halogen.

    106. A compound of Formula (I-b): ##STR00774## or a pharmaceutically acceptable salt thereof, wherein: D is selected from the group consisting of ##STR00775## R.sup.1 is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.W2 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl-O, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, S(R.sup.F).sub.m, S(O)R.sup.D, and S(O).sub.2R.sup.D; or 2 R.sup.W2 groups on adjacent atoms, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R.sup.X; each R.sup.X is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, SR.sup.E, S(O)R.sup.D, and S(O).sub.2R.sup.D; each R.sup.Z is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo, cyano, OR.sup.A, NR.sup.BR.sup.C, NR.sup.BC(O)R.sup.D, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, C(O)OH, C(O)OR.sup.D, and S(O).sub.2R.sup.D; R.sup.A is, at each occurrence, independently hydrogen, C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, C(O)NR.sup.BR.sup.C, C(O)R.sup.D, or C(O)OR.sup.D; each of R.sup.B and R.sup.C is independently hydrogen or C.sub.1-C.sub.6 alkyl; or R.sup.B and R.sup.C together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R.sup.Z; each R.sup.D is independently C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, or halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene; each R.sup.E is independently hydrogen, C.sub.1-C.sub.6 alkyl, or halo-C.sub.1-C.sub.6 alkyl; each R.sup.F is independently hydrogen, C.sub.1-C.sub.6 alkyl, or halo; and m is 1 when R.sup.F is hydrogen or C.sub.1-C.sub.6 alkyl, 3 when R.sup.F is C.sub.1-C.sub.6 alkyl, or 5 when R.sup.F is halo.

    107. The compound of claim 106, wherein D is ##STR00776##

    108. A compound of Formula (II): ##STR00777## or a pharmaceutically acceptable salt thereof, wherein: D.sup.II is a bridged bicyclic cycloalkyl, a bridged bicyclic heterocyclyl, a 4-6-membered monocyclic cycloalkyl, a 4-6-membered monocyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, 4-6-membered monocyclic cycloalkyl, 4-6-membered monocyclic heterocyclyl, or cubanyl is optionally substituted on one or more available carbons with 1-4 R.sup.X-II; and wherein if the 4-6-membered monocyclic heterocyclyl or bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N1-II; U.sup.II is NR.sup.1-II C(O) or C(O)NR.sup.1-II; E.sup.II is absent or is a bond, NR.sup.2-IIC(O), C(O)NR.sup.2-II, 5-6-membered heteroaryl or 5-6-membered heterocyclyl; wherein 5-6-membered heteroaryl or 5-6-membered heterocyclyl is optionally substituted on one or more available carbons with 1-5 R.sup.G-II; and wherein if the 5-6-membered heteroaryl or 5-6-membered heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N2-II; or E.sup.II is ##STR00778## Y.sup.II is a 4-9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclyl, wherein the 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclyl is optionally substituted on one or more available carbons with 1-5 R.sup.G-II; and wherein if the 4-9-membered nitrogen-containing monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N2-II; L.sup.1-II is a bond, C.sub.1-C.sub.6 alkylene, 2-7 membered heteroalkylene, NR.sup.N3-II, or O, wherein C.sub.1-C.sub.6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R.sup.L1-II; L.sup.2-II is absent or is a bond, C.sub.1-C.sub.6 alkylene, 2-7 membered heteroalkylene, C(O), or O, wherein C.sub.1-C.sub.6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R.sup.L2-II; wherein E.sup.II and L.sup.2-II both cannot be either a bond or absent simultaneously; R.sup.1-II is hydrogen or C.sub.1-C.sub.6 alkyl; R.sup.2-II is hydrogen or C.sub.1-C.sub.6 alkyl; W.sup.II is phenyl or 5-6-membered heteroaryl; wherein phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 R.sup.W-II; and wherein if the 5-6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N4-II; A.sup.II is C.sub.3-C.sub.6 cycloalkyl, 4-6-membered heterocyclyl, phenyl, or 5-6-membered heteroaryl, wherein C.sub.3-C.sub.6 cycloalkyl, phenyl, or 5-6-membered heteroaryl is optionally substituted on one or more available carbons with 1-5 R.sup.Y-II; and wherein if the 5-6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R.sup.N5-II; each R.sup.L1-II is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, halo, cyano, OR.sup.A-II, NR.sup.B-IIR.sup.C-II, NR.sup.B-IIC(O)R.sup.D-II, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OH, C(O)OR.sup.D-II, SR.sup.E-II, S(O)R.sup.D-II, and S(O).sub.2R.sup.D-II; each R.sup.L2-II is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, halo, cyano, OR.sup.A-II, NR.sup.B-IIR.sup.C-II, NR.sup.B-IIC(O)R.sup.D-II, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OH, C(O)OR.sup.D-II, SR.sup.E-II, S(O)R.sup.D-II, and S(O).sub.2R.sup.D-II; R.sup.N1-II is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OR.sup.D-II, and S(O).sub.2R.sup.D-II; R.sup.N2-II is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OR.sup.D-II, and S(O).sub.2R.sup.D-II; R.sup.N3-II is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OR.sup.D-II, and S(O).sub.2R.sup.D-II; R.sup.N4-II is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkenyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl-CO.sub.2H, C.sub.1-C.sub.6 alkyl-CO.sub.2-C.sub.1-C.sub.6 alkyl, C(O)C.sub.1-C.sub.3 alkyl-OC.sub.1-C.sub.3 alkyl-OC.sub.1-C.sub.3 alkyl, C(O)-phenyl, C(O)-heteroaryl, C(O)-heterocyclyl, S(O).sub.2-C.sub.1-C.sub.6 alkyl, S(O).sub.2-phenyl, S(O).sub.2-heteroaryl, C(O)NR.sup.B-IIR.sup.C-II and C(O)OR.sup.D; wherein C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkenyl, C(O)C.sub.1-C.sub.6 alkyl, C(O)C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl-CO.sub.2H, C.sub.1-C.sub.6 alkyl-CO.sub.2-C.sub.1-C.sub.6 alkyl, C(O)-heterocyclyl, and S(O).sub.2-C.sub.1-C.sub.6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of fluoro, hydroxyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl (optionally substituted by one, two or three fluorine atoms) and S(O).sub.w-IIC.sub.1-6 alkyl (wherein w-II is 0, 1 or 2); and C(O)-phenyl, C(O)-heteroaryl, S(O).sub.2-phenyl and S(O).sub.2-heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C.sub.1-C.sub.6 alkyl (optionally substituted by one, two or three fluorine atoms), C.sub.1-C.sub.6 alkoxy (optionally substituted by one, two or three fluorine atoms), and S(O.sub.2)NR.sup.B-IIR.sup.C-II; R.sup.N5-II is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl, halo-C.sub.2-C.sub.6 alkyl, amino-C.sub.2-C.sub.6 alkyl, cyano-C.sub.2-C.sub.6 alkyl, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OR.sup.D-II, and S(O).sub.2R.sup.D-II; each R.sup.W-II is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.2-C.sub.6 alkyl-O, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, CNOH, halo, cyano, OR.sup.A-II, NR.sup.B-IIR.sup.C-II, NR.sup.B-IIR.sup.CC-II, NR.sup.B-II C(O)R.sup.D-II, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OH, C(O)OR.sup.D-II, SR.sup.E-II, S(O)R.sup.D-II, and S(O).sub.2R.sup.D-II; or 2 R.sup.W-II groups on adjacent atoms, together with the atoms to which they are attached, form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R.sup.X-II; each R.sup.X-II is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, oxo, halo, cyano, OR.sup.A-II, NR.sup.B-IIR.sup.C-II, NR.sup.B-IIC(O)R.sup.D-II, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OH, C(O)OR.sup.D-II, SR.sup.E-II, S(O)R.sup.D-II, and S(O).sub.2R.sup.D-II; each R.sup.Y-II is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, amino-C.sub.1-C.sub.6 alkyl, cyano-C.sub.1-C.sub.6 alkyl, halo, cyano, OR.sup.A-II, NR.sup.B-IIR.sup.C-II, NR.sup.B-IIC(O)R.sup.D-II, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OH, C(O)OR.sup.D-II, S(R.sup.F-II).sub.m-II, S(O)R.sup.D-II, S(O).sub.2R.sup.D-II, and G.sup.1-II; or 2 R.sup.Y-II groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R.sup.X-II; each G.sup.1-II is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 R.sup.Z-II; each R.sup.Z-II is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo, cyano, OR.sup.A-II, NR.sup.B-IIR.sup.C-II, NR.sup.B-IIC(O)R.sup.D-II, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, C(O)OH, C(O)OR.sup.D-II, and S(O).sub.2R.sup.D-II; R.sup.A-II is, at each occurrence, independently hydrogen, C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkylene, C(O)NR.sup.B-IIR.sup.C-II, C(O)R.sup.D-II, or C(O)OR.sup.D-II; each of R.sup.B-II and R.sup.C-II is independently hydrogen or C.sub.1-C.sub.6 alkyl; or R.sup.B-II and R.sup.C-II together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R.sup.Z-II; each R.sup.CC-II is independently selected from the group consisting of hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-CO.sub.2H, C.sub.1-C.sub.6 alkyl-CO.sub.2-C.sub.1-C.sub.6 alkyl, C(O) C.sub.1-C.sub.6 alkyl, S(O).sub.2 C.sub.1-C.sub.6 alkyl and 3-6-membered cycloalkyl and 4-6-membered heterocyclyl; wherein 3-6-membered cycloalkyl and 4-6-membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, hydroxyl, halo and C(O)OH; each R.sup.D-II is independently C.sub.1-C.sub.6 alkyl or halo-C.sub.1-C.sub.6 alkyl; each R.sup.E-II is independently hydrogen, C.sub.1-C.sub.6 alkyl, or halo-C.sub.1-C.sub.6 alkyl; each R.sup.F-II is independently hydrogen, C.sub.1-C.sub.6 alkyl, or halo; and each R.sup.G-II is independently hydrogen, C.sub.1-C.sub.6 alkyl, halo or oxo; provided that when D.sup.II is a bridged bicyclic 5-membered cycloalkyl, E.sup.II is NR.sup.2-IIC(O).

    109. A compound selected from the group consisting of: ##STR00779## ##STR00780## ##STR00781## ##STR00782## ##STR00783## ##STR00784## ##STR00785## ##STR00786## ##STR00787## ##STR00788## ##STR00789## ##STR00790## ##STR00791## ##STR00792## ##STR00793## ##STR00794## ##STR00795## ##STR00796## ##STR00797## ##STR00798## ##STR00799## ##STR00800## ##STR00801## ##STR00802## ##STR00803## ##STR00804## ##STR00805## ##STR00806## ##STR00807## ##STR00808## ##STR00809## ##STR00810## ##STR00811## ##STR00812## ##STR00813## ##STR00814## ##STR00815## ##STR00816## ##STR00817## ##STR00818## ##STR00819## ##STR00820## ##STR00821## ##STR00822## ##STR00823## ##STR00824## ##STR00825## ##STR00826## ##STR00827## ##STR00828## ##STR00829## ##STR00830## ##STR00831## ##STR00832## ##STR00833## ##STR00834## ##STR00835## ##STR00836## ##STR00837## ##STR00838## ##STR00839## ##STR00840## ##STR00841## ##STR00842## ##STR00843## ##STR00844## and a pharmaceutically acceptable salt thereof.

    110. A compound, wherein the compound is ##STR00845## or a pharmaceutically acceptable salt thereof.

    111. A method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway in a subject in need thereof, the method comprising administering to the subject a compound of claim 93.

    112. A method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway in a subject in need thereof, the method comprising administering to the subject a compound of claim 106.

    113. A method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway in a subject in need thereof, the method comprising administering to the subject a compound of claim 108.

    114. A method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway in a subject in need thereof, the method comprising administering to the subject a compound of claim 109.

    115. A method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease or a disease or disorder associated with impaired function of eIF2B or components in the ISR pathway in a subject in need thereof, the method comprising administering to the subject a compound of claim 110.

    Description

    EXAMPLES

    [1118] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

    Synthetic Protocols

    [1119] The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. General scheme relating to methods of making exemplary compounds of the invention are additionally described in the section entitled Methods of Making Compounds.

    [1120] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

    Abbreviations

    [1121] APCI for atmospheric pressure chemical ionization; BTMG for 2-tert-butyl-1,1,3,3-tetramethylguanidine; CDI for N,N-carbonyldiimidazole; CPhos for 2-dicyclohexylphosphino-2,6-bis(N,N-dimethylamino)biphenyl; CPhos Pd G4 for [2-(dicyclohexylphosphanyl-P)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl[1,1-biphenyl]-2,6-diamine](methanesulfonatato-O)[2-(methylamino-N)[1,1-biphenyl]-2-yl-C.sup.2]palladium; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCI for desorption chemical ionization; DIPEA for N,N-diisopropylethylamine; DMSO for dimethyl sulfoxide; ELS for evaporative light scattering; ESI for electrospray ionization; HATU for 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HPLC for high performance liquid chromatography; LED for light-emitting diode; MS for mass spectrum; NMR for nuclear magnetic resonance; PDA for photodiode array; psi for pounds per square inch; P(t-Bu).sub.3 Pd G4 for [2-(methylamino)[1,1-biphenyl]-2-yl](tri-tert-butyl-.sup.5-phosphanyl)palladium(1+) methanesulfonate, PyAOP for tri(pyrrolidin-1-yl)[(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy]phosphanium hexafluoridophosphate, SCX for strong cation exchange; SFC for supercritical fluid chromatography; T3P for 1-propanephosphonic anhydride; TBAI for tetrabutylammonium iodide; tBuBrettPhos for 2-(di-tert-butylphosphino)-2,4,6-triisopropyl-3,6-dimethoxy-1,1-biphenyl; tBuBrettPhos Pd G3 for [(2-di-tert-butylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate; TLC for thin-layer chromatography; UV for ultraviolet; w/w for weight/weight; XPhos for 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; and XPhos-Pd-G3 for (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate.

    Example 1: (2R)-6-chloro-N-(3-{5-[(3,5-dimethylphenoxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 100)

    Example 1A: tert-butyl (3-(5-((3,5-dimethylphenoxy)methyl)-2-oxooxazolidin-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1122] A 30 mL vial was charged with iodomesitylene diacetate (127 mg, 0.35 mmol), 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (Enamine, 157 mg, 0.691 mmol) and toluene (5 mL), and the mixture was stirred at 55 C. for 30 minutes. Toluene was then removed under high vacuum. Iridium(III) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C.sub.20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate (14 mg, 0.014 mmol), copper(I) thiophene-2-carboxylate (31.6 mg, 0.166 mmol), 4,7-diphenyl-1,10-phenanthroline (83 mg, 0.249 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.29 mL, 1.45 mmol) and metaxalone (153 mg, 0.691 mmol) were added sequentially followed by dioxane (5.0 mL). The vial was degassed by sparging with nitrogen for 3 minutes before sealing with a polytetrafluoroethylene-lined cap. The vial was then put inside a 250 mL glass Dewar filled with water and clamped at a 45 angle to increase exposure to the light-emitting diode (LED). (The glass Dewar was used to focus the blue LED to the vial, and the water bath was used to keep a constant temperature). The reaction was stirred and irradiated using 40W Kessil PR160 390 nm Photoredox lamp just 5 cm above the vial. The bath temperature was measured as 22 C. when setting up the reaction and rose to 38 C. after an hour, and the temperature was stabilized at 38 C. for the remainder of the reaction time. After 48 hours, the reaction mixture was quenched by exposing to air and partitioned between water (50 mL) and dichloromethane (250 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 2-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (12.6 mg, 0.031 mmol, 4.5% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm 6.59 (s, 1H), 6.53 (s, 2H), 4.69-4.44 (m, 1H), 4.16-4.01 (m, 2H), 3.75 (t, J=9.0 Hz, 1H), 3.53 (dd, J=8.8, 6.1 Hz, 1H), 2.29 (s, 6H), 2.24 (s, 6H), 1.42 (s, 9H); MS (APCI.sup.+) m/z 403 (M+H).sup.+.

    Example 1B: (R)-6-chloro-4-oxochroman-2-carboxylic acid

    [1123] 6-Chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Princeton) was purified by preparative chiral supercritical fluid chromatography (SFC) [performed on a Thar 200 preparative SFC (SFC-5) system using a Daicel CHIRALPAK AD-H, 30250 mm I.D., 5 m column. The column was heated at 38 C., and the backpressure regulator was set to maintain 100 bar. The mobile phase was 40% methanol in carbon dioxide at a flow rate of 80 g/minute] to give the title compound as the earlier eluting fraction. MS (ESI.sup.) m/z 225 (MH).sup..

    Example 1C: (2R)-6-chloro-N-(3-{5-[(3,5-dimethylphenoxy)methyl-2-oxo-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1124] The product of Example 1A (7 mg, 0.031 mmol) was combined with trifluoroacetic acid (0.1 mL) and stirred at ambient temperature for 30 minutes, and then the mixture was concentrated under reduced pressure. The product of Example 1B (7 mg, 0.031 mmol), triethylamine (0.017 mL), N,N-dimethylformamide (1.0 mL) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 15.3 mg, 0.04 mmol) were added sequentially, and the resulting reaction mixture was stirred at ambient temperature for 3 hours. Water (0.1 mL) was added and the resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (13 mg, 0.025 mmol, 82% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 7.65 (d, J=2.7 Hz, 1H), 7.58 (dd, J=8.8, 2.7 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 6.60 (s, 1H), 6.56 (s, 2H), 5.05 (t, J=7.1 Hz, 1H), 4.83-4.72 (m, 1H), 4.09 (qd, J=11.1, 4.4 Hz, 2H), 3.68 (t, J=8.8 Hz, 1H), 3.39 (dd, J=8.8, 6.3 Hz, 1H), 2.94 (d, J=7.1 Hz, 2H), 2.29 (s, 6H), 2.23 (s, 6H); MS (APCI.sup.+) m/z 511 (M+H).sup.+.

    Example 2: (2R)-6-chloro-N-{(1R,3r,5S)-8-[3-(4-chlorophenoxy)propyl]-8-azabicyclo[3.2.1]octan-3-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 101)

    Example 2A: (1R,3r,5S)-8-(3-(4-chlorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-amine

    [1125] rac-tert-Butyl ((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (Combi-Blocks, 155 mg, 0.685 mmol), 1-(3-bromopropoxy)-4-chlorobenzene (Enamine, 188 mg, 0.75 mmol) and N,N-diisopropylethylamine (0.5 mL) were combined with dimethyl sulfoxide (1 mL) and stirred at 90 C. for 18 hours. The reaction mixture was cooled to ambient temperature and partitioned between water (50 mL) and dichloromethane (230 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was taken up in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. After stirring at ambient temperature for 1 hour, the solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 50100 mm, flow rate 90 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.13 g, 0.44 mmol, 64% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6-D.sub.2O) ppm 7.32-7.26 (m, 2H), 6.96-6.90 (m, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.09-2.99 (m, 3H), 2.37 (t, J=7.3 Hz, 2H), 1.98-1.85 (m, 4H), 1.84-1.73 (m, 4H), 1.36-1.23 (m, 2H); MS (APCI.sup.+) m/z 295 (M+H).sup.+.

    Example 2B: (2R)-6-chloro-N-{(1R,3r,5S)-8-[3-(4-chlorophenoxy)propyl]-8-azabicyclo[3.2.1]octan-3-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1126] The product of Example 1B (15 mg, 0.068 mmol), the product of Example 2A (20 mg, 0.068 mmol) and triethylamine (0.019 mL) were combined with N,N-dimethylformamide (1 mL) and stirred at ambient temperature. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 28 mg, 0.075 mmol) was added in one portion. After stirring at ambient temperature for 30 minutes, water (0.2 mL) was added to the reaction mixture. The resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (25 mg, 0.050 mmol, 73% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.78 (d, J=5.5 Hz, 1H), 7.68-7.59 (m, 2H), 7.34-7.26 (m, 2H), 7.17 (d, J=8.6 Hz, 1H), 6.98-6.90 (m, 2H), 5.21 (dd, J=7.5, 5.1 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H), 3.77-3.71 (m, 1H), 3.11-2.91 (m, 4H), 2.36 (t, J=7.0 Hz, 2H), 2.00-1.69 (m, 7H), 1.62-1.43 (m, 3H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 3: (2R,4R)-6-chloro-N-[(1r,4R)-4-{[(4-chloro-3-fluorophenoxy)acetyl](methyl)amino}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 102)

    Example 3A: tert-butyl ((1r,4r)-4-(2-(4-chloro-3-fluorophenoxy)-N-methylacetamido)cyclohexyl)carbamate

    [1127] The reaction and purification conditions described in Example 2B substituting 2-(4-chloro-3-fluorophenoxy)acetic acid for the product of Example 1B, and tert-butyl (trans-4-(methylamino)cyclohexyl)carbamate for the product of Example 2A gave the title compound.

    [1128] MS (APCI.sup.+) m/z 415 (M+H).sup.+.

    Example 3B: (2R,4R)-6-chloro-4-hydroxychroman-2-carboxylic acid

    [1129] The product of Example 1B (250 mg, 1.1 mmol) was dissolved in methanol (2 mL) and stirred at ambient temperature. Sodium borohydride (167 mg, 4.41 mmol) was added. After stirring for 5 minutes, saturated ammonium chloride solution (1 mL) was added. After stirring for another 10 minutes, the resulting mixture was combined with diatomaceous earth (10 g) and concentrated under reduced pressure to give a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 30 m 175 g column, flow rate 100 mL/minute, 5-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (0.24 g, 1.05 mmol, 95% yield). MS (APCI.sup.) m/z 227 (MH).sup..

    Example 3C: (2R,4R)-6-chloro-N-[(1r,4R)-4-{[(4-chloro-3-fluorophenoxy)acetyl](methyl)amino}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1130] The product of Example 3A (34 mg, 0.082 mmol) and trifluoroacetic acid (0.5 mL) were combined and stirred at 25 C. for 30 minutes and then concentrated under reduced pressure. To the residue was added N,N-dimethylformamide (2 mL), the product of Example 3B (20.6 mg, 0.090 mmol) and N,N-diisopropylethylamine (0.114 mL). While stirring, 1-propanephosphonic anhydride (T3P, 50 weight % solution in N,N-dimethylformamide, 0.057 mL) was added dropwise over 2 minutes, and the resulting mixture was stirred for 1 hour and then partitioned between dichloromethane (225 mL) and aqueous sodium carbonate (1.0 M, 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (26 mg, 0.049 mmol, 60% yield). .sup.1H NMR (120 C., 400 MHz, DMSO-d.sub.6) ppm 7.45-7.37 (m, 2H), 7.34 (d, J=8.1 Hz, 1H), 7.15 (dd, J=8.8, 2.7 Hz, 1H), 6.97 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.82 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 5.23 (d, J=5.9 Hz, 1H), 4.87-4.77 (m, 3H), 4.60 (dd, J=11.3, 2.8 Hz, 1H), 3.96 (br s, 1H), 3.70-3.57 (m, 1H), 2.84 (s, 3H), 2.42 (ddd, J=13.2, 5.9, 2.9 Hz, 1H), 1.98-1.88 (m, 2H), 1.83 (dt, J=13.1, 10.5 Hz, 1H), 1.74-1.61 (m, 4H), 1.54-1.37 (m, 2H); MS (APCI.sup.+) m/z 507 (MH.sub.2O+H).sup.+.

    Example 4: 3-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[(6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide (Compound 103)

    [1131] Modifying a reported benzylic oxidation procedure (U.S. Pat. Appl. Publ. (2004), US 20040224994 A1), to a mixture of Example 30 (0.019 g, 0.038 mmol) in CH.sub.3CN (0.15 mL) and H.sub.2O (0.15 mL) was added potassium persulfate (0.026 g, 0.095 mmol) and copper(II) sulfate pentahydrate (0.010 g, 0.038 mmol). The reaction mixture was heated to 80 C. for 20 minutes and then to 50 C. overnight. Then the reaction mixture was cooled to ambient temperature, diluted with H.sub.2O (1 mL), and extracted with dichloromethane (35 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated. The crude material was diluted with N,N-dimethylformamide, filtered, and purified by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) to give the title compound (0.013 g, 0.026 mmol, 67% yield).

    [1132] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 8.06 (t, J=5.9 Hz, 1H), 7.69-7.57 (m, 2H), 7.49 (t, J=8.9 Hz, 1H), 7.12-7.03 (m, 2H), 6.85 (ddd, J=9.0, 2.8, 1.2 Hz, 1H), 4.67-4.56 (m, 1H), 4.47 (s, 2H), 3.51 (dt, J=13.9, 6.1 Hz, 1H), 3.43-3.37 (m, 1H), 2.79 (dd, J=17.1, 12.1 Hz, 1H), 2.67 (dd, J=17.1, 3.5 Hz, 1H), 2.20 (s, 6H); MS (APCI.sup.+) m/z 507 (M+H).sup.+.

    Example 5: 3-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-{[rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]methyl}bicyclo[1.1.1]pentane-1-carboxamide (Compound 104)

    [1133] To a mixture of Example 4 (0.0076 g, 0.015 mmol) in methanol (0.27 mL) was added sodium borohydride (0.006 g, 0.26 mmol). This reaction mixture was allowed to stir at ambient temperature for 3 hours, was quenched with ammonium chloride (saturated aqueous solution, 1 mL) and extracted with ethyl acetate (35 mL). The combined organic layers were concentrated under heated N.sub.2, diluted with N,N-dimethylformamide, and purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.003 g, 0.006 mmol, 39% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.4, dr 17:1) ppm 8.73 (s, 1H), 8.03 (t, J=6.0 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.37 (dd, J=2.7, 1.0 Hz, 1H), 7.29 (d, J=2.6 Hz, 0.6H), 7.20 (dd, J=8.7, 2.7 Hz, 0.6H), 7.14 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.81 (d, J=8.7 Hz, 0.6H), 6.74 (d, J=8.7 Hz, 1H), 5.66-5.59 (m, 1H), 4.74 (dd, J=10.7, 6.0 Hz, 1H), 4.47 (s, 2H), 4.19 (dtd, J=11.5, 5.8, 1.9 Hz, 1H), 3.44-3.38 (m, 1H), 3.27 (dt, J=13.6, 5.7 Hz, 1H), 2.20 (s, 0.36H), 2.20 (s, 6H), 2.15 (ddd, J=13.0, 6.1, 1.9 Hz, 1H), 1.53 (dt, J=13.0, 11.2 Hz, 1H); MS (APCI.sup.+) m/z 491 (MH.sub.2O+H).sup.+.

    Example 6: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 105)

    Example 6A: tert-butyl ((1r,4r)-4-(((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclohexyl)carbamate

    [1134] The reaction and purification conditions described in Example 2B substituting trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (ArkPharm) for the product of Example 1B, and (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (PharmaBlock) for the product of Example 2A gave the title compound. MS (APCI.sup.+) m/z 402 (M+H).sup.+.

    Example 6B: (R)-6-chloro-4-oxo-N-((1r,4R)-4-(((5-(triflioromethyl)pyridin-2-yl)methyl)carbamoyl)cyclohexyl)chroman-2-carboxamide

    [1135] The reaction and purification conditions described in Example 1C substituting the product of Example 6A for the product of Example 1A gave the title compound. MS (APCI.sup.+) m/z 510 (M+H).sup.+.

    Example 6C: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1136] The product of Example 6B (24 mg, 0.047 mmol) was combined with methanol (1 mL), and the mixture was stirred at ambient temperature. Sodium borohydride (7.1 mg, 0.188 mmol) was added. After stirring for 30 minutes, saturated ammonium chloride solution (0.2 mL) was added, the resulting mixture was stirred for 10 minutes and then partitioned between dichloromethane (25 mL) and aqueous sodium carbonate solution (1M, 5 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was taken up in methanol (I mL) and filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (16 mg, 0.031 mmol, 66% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.91-8.86 (m, 1H), 8.49 (t, J=6.0 Hz, 1H), 8.17 (dd, J=8.3, 2.4 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.61 (dd, J=11.9, 2.2 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 3.64-3.56 (m, 1H), 2.35 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 2.20 (tt, J=11.9, 3.2 Hz, 1H), 1.88-1.78 (m, 4H), 1.72 (td, J=12.3, 10.7 Hz, 1H), 1.54-1.24 (m, 4H); MS (APCI.sup.+) m/z 512 (M+H).sup.+.

    Example 7: (2R)-6-chloro-4-oxo-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 106)

    Example 7A: (2R)-4-amino-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)bicyclo[2.2.2]octane-1-carboxamide, trifluoroacetic acid

    [1137] (5-(Trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Pharma Block 53 mg, 0.25 mmol), 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (Ark Pharm, 67 mg, 0.25 mmol), and triethylamine (0.104 mL) were combined with N,N-dimethylformamide (5 mL) and stirred at ambient temperature. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 104 mg, 0.274 mmol) was added. After stirring at ambient temperature for 2 hours, the reaction mixture was partitioned between dichloromethane (325 mL) and aqueous sodium carbonate (1.0 M, 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was taken up in dichloromethane (2 mL) and trifluoroacetic acid (0.019 mL, 0.25 mmol) was added in one portion. After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by preparative HPLC [YMC TriArt Hybrid C18 5 m ODS column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (78 mg, 0.18 mmol, 71% yield). MS (APCI.sup.+) m/z 328 (M+H).sup.+.

    Example 7B: (2R)-6-chloro-4-oxo-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1138] The reaction and purification conditions described in Example 2B substituting the product of Example 7A for the product of Example 2A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.88-8.85 (m, 1H), 8.20-8.13 (m, 2H), 7.71 (s, 1H), 7.66-7.58 (m, 2H), 7.37 (d, J=8.3 Hz, 1H), 7.15 (dd, J=8.7, 0.6 Hz, 1H), 5.06 (dd, J=8.3, 4.9 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 3.04-2.83 (m, 2H), 1.87-1.72 (m, 12H); MS (APCI.sup.+) m/z 536 (M+H).sup.+.

    Example 8: (2R,4R)-6-chloro-4-hydroxy-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 107)

    [1139] The reaction and purification conditions described in Example 6C substituting the product of Example 7 for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.91-8.86 (m, 1H), 8.49 (t, J=6.0 Hz, 1H), 8.17 (dd, J=8.3, 2.4 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.61 (dd, J=11.9, 2.2 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 3.64-3.56 (m, 1H), 2.35 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 2.20 (tt, J=11.9, 3.2 Hz, 1H), 1.88-1.78 (m, 4H), 1.72 (td, J=12.3, 10.7 Hz, 1H), 1.54-1.24 (m, 4H); MS (APCI.sup.+) m/z 538 (M+H).sup.+.

    Example 9: (2R)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 108)

    [1140] The reaction and purification conditions described in Example 2B substituting 3-(5-((4-chloro-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (prepared as described in International Patent Publication WO2017/193030 A1) for the product of Example 2A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.15 (s, 1H), 7.69-7.61 (m, 2H), 7.53 (t, J=8.8 Hz, 1H), 7.25 (dd, J=11.3, 2.9 Hz, 1H), 7.21-7.14 (m, 1H), 6.97 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 5.43 (s, 2H), 5.13 (dd, J=7.7, 6.6 Hz, 1H), 3.00-2.94 (m, 2H), 2.49 (s, 6H); MS (APCI.sup.+) m/z 518 (M+H).sup.+.

    Example 10: (2S)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 109)

    Example 10A: (S)-6-chloro-4-oxochroman-2-carboxylic acid

    [1141] Chiral SFC purification as described in Example 1B also gave this title compound as the later eluting fraction. MS (ESI.sup.) m/z 225 (MH).sup..

    Example 10B: (2S)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1142] The reaction and purification conditions described in Example 2B substituting 3-(5-((4-chloro-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine for the product of Example 2A, and the product of Example 10A for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.15 (s, 1H), 7.68-7.62 (m, 2H), 7.53 (t, J=8.8 Hz, 1H), 7.24 (dd, J=11.2, 2.9 Hz, 1H), 7.20-7.15 (m, 1H), 6.97 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 5.43 (s, 2H), 5.13 (dd, J=7.7, 6.6 Hz, 1H), 3.02-2.94 (m, 2H), 2.49 (s, 6H); MS (APCI.sup.+) m/z 518 (M+H).sup.+.

    Example 11: (2R,4R)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 110)

    [1143] The reaction and purification conditions described in Example 6C substituting the product of Example 9 for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.53 (t, J=8.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.25 (dd, J=11.2, 3.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.97 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.2 Hz, 1H), 5.43 (s, 2H), 4.82 (dt, J=11.4, 6.0 Hz, 1H), 4.63 (dd, J=11.9, 2.3 Hz, 1H), 2.51 (s, 6H), 2.37 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.78-1.65 (m, 1H); MS (APCI.sup.+) m/z 502 (MH.sub.2O+H).sup.+.

    Example 12: (2S,4S)-6-chloro-N-(3-{5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 111)

    [1144] The reaction and purification conditions described in Example 6C substituting the product of Example 10 for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 7.53 (t, J=8.9 Hz, 1H), 7.39 (dd, J=2.6, 1.0 Hz, 1H), 7.25 (dd, J=11.3, 2.9 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.97 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.2 Hz, 1H), 5.43 (s, 2H), 4.82 (dt, J=11.4, 6.0 Hz, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.51 (s, 6H), 2.37 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 1.76-1.66 (m, 1H); MS (APCI.sup.+) m/z 502 (MH.sub.2O+H).sup.+.

    Example 13: 2-(4-chloro-3-fluorophenoxy)-N-[(2S)-2-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide (Compound 112)

    Example 13A: ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

    [1145] A mixture of ethyl 4-oxocyclohexanecarboxylate (11.70 mL, 73.4 mmol), ethane-1,2-diol (12.29 mL, 220 mmol), and p-toluenesulfonic acid monohydrate (1.397 g, 7.34 mmol) in toluene (200 mL) was stirred at reflux with a Dean-Stark trap apparatus for 180 minutes. The reaction mixture was neutralized with N-ethyl-N-isopropylpropan-2-amine and then concentrated. The residue was purified on silica gel (0-30% ethyl acetate in heptane) to give 12.77 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.01 (q, J=7.1 Hz, 2H), 3.81 (s, 4H), 2.32 (tt, J=10.4, 3.8 Hz, 1H), 1.83-1.71 (m, 2H), 1.66-1.57 (m, 1H), 1.62-1.38 (m, 5H), 1.13 (t, J=7.1 Hz, 3H).

    Example 13B: ethyl 8-acetyl-1,4-dioxaspiro[4.5]decane-8-carboxylate

    [1146] To a solution of diisopropylamine (5.19 mL, 36.4 mmol) in tetrahydrofuran (25 mL) at 0 C. was added n-butyllithium slowly below 5 C. After stirring for 30 minutes, the solution was cooled to 78 C. under nitrogen, and a solution of Example 13A (6.0 g, 28.0 mmol) in tetrahydrofuran (3 mL) was added slowly, and the resultant mixture was stirred for 30 minutes at the same temperature. Then acetyl chloride (2.59 mL, 36.4 mmol) was added slowly to maintain the temperature below 60 C., and the mixture was stirred at 70 C. for 2 hours. The reaction was quenched with saturated NH.sub.4Cl solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-70% ethyl acetate in heptane) to give 6.78 g of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.19-4.11 (m, 2H), 3.85 (s, 4H), 2.13 (s, 3H), 2.10-2.01 (m, 2H), 1.90 (ddd, J=13.9, 9.6, 4.6 Hz, 2H), 1.54 (th, J=13.6, 4.7 Hz, 4H), 1.18 (dd, J=7.6, 6.5 Hz, 3H).

    Example 13C: ethyl 1-acetyl-4-oxocyclohexane-1-carboxylate

    [1147] A mixture of Example 13B (6.5 g, 25.4 mmol) and HCl (21.13 mL, 127 mmol) in acetone (60 mL) was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give 5.46 g of the title compound which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.16 (q, J=7.1 Hz, 2H), 2.17 (s, 3H), 2.35 2.07 (m, 8H), 1.17 (t, J=7.1 Hz, 3H).

    Example 13D: ethyl 4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylate, hydrochloric acid

    [1148] A mixture of Example 13C (9.7 g, 45.7 mmol), benzylamine (14.98 mL, 137 mmol), and p-toluenesulfonic acid monohydrate (0.087 g, 0.457 mmol) in toluene (100 mL) was stirred at reflux with a Dean-Stark trap apparatus overnight. The mixture was concentrated, and the residue was stirred with a mixture of ethyl acetate (50 mL) and 3 N HCl (100 mL) for 30 minutes. The precipitate was collected by filtration, washed with mixture of ethyl acetate/heptane, and air-dried to give 11.3 g of the title compound as an HCl salt. The filtrate was neutralized with 6 N NaOH and extracted with ethyl acetate (100 mL2). The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue was purified on silica gel (0-70% ethyl acetate in heptane) to give another 0.77 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.73 (t, J=6.2 Hz, 2H), 7.87-7.12 (m, 5H), 4.09 (m, 4H), 2.88 (s, 2H), 2.08 (dt, J=20.7, 13.4 Hz, 6H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI.sup.+) m/z 302.1 (M+H).sup.+.

    Example 13E: 4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylic acid hydrochloride

    [1149] A mixture of Example 13D (20.7 g, 61.3 mmol) and 25% aqueous sodium hydroxide (49.0 mL, 306 mmol) in methanol (200 mL) and water (200 mL) was stirred for 24 hours at ambient temperature. The mixture was concentrated, and the residue was acidified with 1 N HCl. The precipitate was collected by filtration, washed with water, and air dried to give 16.4 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.70 (s, 1H), 9.67 (s, 2H), 7.62 (dd, J=7.5, 2.0 Hz, 2H), 7.43 (d, J=6.6 Hz, 3H), 4.13 (s, 2H), 2.87 (s, 2H), 2.08 (tdq, J=14.4, 10.8, 5.8, 5.0 Hz, 8H).

    Example 13F: 1-amino-4-(benzylamino)bicyclo[2.2.2]octan-2-one, trifluoroacetic acid

    [1150] To a mixture of Example 13E (5.0 g, 16.14 mmol) and oxalyl chloride (24.21 mL, 48.4 mmol) in dichloromethane (100 mL) was added N,N-dimethylformamide (0.250 mL, 3.23 mmol), and the suspension was stirred at ambient temperature for 14 hours. The mixture was concentrated, and the residue was triturated with ether/heptane. The precipitate was collected by filtration and dried to give 4.99 g of 4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carbonyl chloride which was used in next step without further purification. To a mixture of sodium azide (0.832 g, 12.80 mmol) in dioxane (10 mL) and water (10 mL) at 0 C. was added a suspension of the crude 4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carbonyl chloride (0.934 g, 3.2 mmol) in dioxane (30 mL), and the solution was stirred at ambient temperature for 30 minutes. Volatiles were removed to give the crude corresponding acyl azide which was suspended with 50 mL of toluene and heated at 65 C. for 2 hours to convert to the isocyanate, 4-(benzylamino)-1-isocyanatobicyclo[2.2.2]octan-2-one. Then 3 N HCl (40 mL) was added carefully, and the mixture was stirred at 100 C. for 3 hours. Volatiles were removed under vacuum, and the residue was stirred with methanol, and the inorganic salts were removed by filtration. The filtrate was concentrated, and the residue was purified by HPLC (060% acetonitrile in 0.1% trifluoroacetic acid/water on Phenomenex C18 10 m (250 mm50 mm) column at a flow rate of 50 mL/minute) to give 550 mg of the title compound as a trifluoroacetate salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.47 (s, 2H), 8.59 (s, 3H), 7.55-7.39 (m, 5H), 4.18 (s, 2H), 3.01 (s, 2H), 2.28-2.09 (m, 6H), 1.96 (td, J=12.6, 12.0, 7.0 Hz, 2H), MS (ESI.sup.+) m/z 245.1 (M+H).sup.+.

    Example 13G: (S)-tert-butyl (4-(benzylamino)-2-hydroxybicyclo[2.2.2]octan-1-yl)carbamate, hydrochloric acid

    [1151] Magnesium sulfate (0.196 g) and nicotinamide adenine dinucleotide phosphate (NADPH, 0.200 g) were mixed in 360 mL of potassium phosphate buffer (125 mM, pH=7.0) and 0.04 L of isopropanol. A portion of this solution (60 mL) was reserved and used to dissolve Codexis KRED-P2-C02 enzyme (400 mg). Example 13F (20.0 g) was added to the 340 mL of remaining buffered solution and the pH was adjusted to 7.5 with 50% (weight/weight) NaOH. The reaction was initiated by addition of the enzyme in the 60 mL of buffered solution. The reaction mixture was stirred overnight at 40 C. The cloudy, aqueous solution was adjusted to pH>11 with 50% weight/weight aqueous sodium hydroxide. Diatomaceous earth (20 g) was added to the reaction mixture and then stirred for 10 minutes. The mixture was filtered to remove all insoluble material. The aqueous layer was charged back to the reaction vessel and di-tert-butyl dicarbonate (16 g, 1.2 equivalent) in 400 mL of ethyl acetate was charged to the same vessel. The biphasic solution was stirred for two hours. The aqueous layer was routinely checked to maintain pH>10. At 2 hours, the two layers were separated, and the aqueous layer was charged back to the reaction vessel. The amount of amino alcohol intermediate remaining in the aqueous layer was determined by high performance liquid chromatography (HPLC: Supelco Acentis Express C18 column, 4.6150 mm, 2.7 micron. Mobile A=0.1% H.sub.3PO.sub.4 in water: Mobile B=85% acetonitrile-15% methanol. Wavelength=218 nm. Flow rate=1.25 mL/minute, 25 C. column temperature.) and 1.2 equivalents of di-tert-butyl dicarbonate were added to the reaction vessel dissolved in ethyl acetate (200 mL). The pH was maintained >10. This reaction proceeded for 2 hours and the two layers were separated. The organic layers were combined, washed with brine containing 2.5% sodium hydroxide (60 mL), filtered through magnesium sulfate, and concentrated in vacuo. The residual material was taken up in 200 mL methyl tert-butyl ether. The mixture was cooled to 5 C. and 4 N HCl in dioxane (14.0 mL) was slowly added. The precipitated material was collected by filtration and dried in vacuo to provide the title compound. (18.1 g, 75%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.28 (t, J=6.3 Hz, 2H), 7.69-7.55 (m, 2H), 7.48-7.30 (m, 31H), 6.23 (s, 1H), 5.18 (s, 1H), 4.03-3.98 (m, 3H), 2.40-2.26 (m, 1H), 2.11-1.64 (m, 9H), 1.37 (s, 9H); MS (APCI.sup.+) m/z 347.4 (M+H).sup.+.

    Example 13H: (S)-tert-butyl (4-amino-2-hydroxybicyclo[2.2.2]octan-1-yl)carbamate, hydrochloric acid

    [1152] To a mixture of Example 13G (29.75 g, 78 mmol) in methanol (96 mL) was added to 10% Pd(OH).sub.2/C wet, (3.15 g, 9.42 mmol) in a 600 mL stainless steel reactor. The reactor was purged with nitrogen, and then was stirred at 900 RPM under 50 psi of hydrogen at 50 C. for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.09 (brs, 3H), 6.16 (s, 1H), 5.12 (d, J=4.2 Hz, 1H), 3.95 (dt, J=9.3, 3.2 Hz, 1H), 2.14 (ddd, J=12.7, 9.4, 3.0 Hz, 1H), 2.09 1.97 (m, 1H), 1.92-1.52 (m, 8H), 1.36 (s, 9H); MS (+ESI) m/z 257.1 (M+H).sup.+.

    Example 131: (S)-allyl (4-amino-3-hydroxybicyclo[2.2.2]octan-1-yl)carbamate, hydrochloric acid

    [1153] To a suspension of Example 13H (15.00 g, 51.2 mmol) and sodium carbonate (16.29 g, 154 mmol) in tetrahydrofuran (150 mL) and water (75 mL) at 0 C. was added allyl chloroformate (6.56 mL, 61.5 mmol). The mixture was stirred at 0 C. for 10 minutes and then warmed to ambient temperature and stirred for an additional 1.5 hours. The reaction was diluted with ethyl acetate (200 mL) and washed with water (150 mL), 1 N HCl (75 mL), water (75 mL), and brine (75 mL). The organic layer was dried over MgSO.sub.4, filtered, concentrated, and triturated with heptane to give the crude (S)-allyl tert-butyl (2-hydroxybicyclo[2.2.2]octane-1,4-diyl)dicarbamate which was used in the next step without further purifications. This crude material was dissolved in methanol (110 mL), a 4 N dioxane solution of HCl (21.15 mL, 85 mmol) was added, and the mixture was stirred at 50 C. for 1 hour. Volatiles were removed under vacuum. The residue was triturated in tert-butyl methyl ether (50 mL), filtered, and vacuum oven-dried to provide the title compound, which was used in the next step without further purifications. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.01 (s, 3H), 7.03 (s, 1H), 5.88 (ddt, J=17.2, 10.6, 5.4 Hz, 1H), 5.57 (d, J=4.7 Hz, 1H), 5.26 (dq, J=17.2, 1.8 Hz, 1H), 5.16 (dq, J=10.4, 1.6 Hz, 1H), 4.40 (d, J=5.3 Hz, 2H), 3.84 (ddt, J=9.4, 4.9, 2.7 Hz, 1H), 2.22 (ddd, J=13.0, 9.5, 3.0 Hz, 1H), 2.05-1.95 (m, 1H), 1.93-1.53 (m, 8H); MS (DCI.sup.+) m/z 241.2 (M+H).sup.+.

    Example 13J: (S)-allyl (4-(2-(4-chloro-3-fluorophenoxy)acetamido)-3-hydroxybicyclo[2.2.2]octan-1-yl)carbamate

    [1154] To a suspension of Example 131 (11 g, 39.7 mmol) and 2-(4-chloro-3-fluorophenoxy)acetic acid (9.76 g, 47.7 mmol) in dimethylformamide (100 mL) was added triethylamine (16.62 mL, 119 mmol) followed by HATU (18.14 g, 47.7 mmol). The mixture was stirred for 90 minutes, diluted with water (300 mL), and extracted with ethyl acetate (300, 150 mL). The combined organic layers were washed with brine and concentrated. The concentrate was dissolved in methanol (30 mL) and tetrahydrofuran (60 mL) and treated with a solution of lithium hydroxide (1.428 g, 59.6 mmol) in water (20 mL). The mixture was stirred for 2 hours and then concentrated. The residue was dissolved in ethyl acetate (120 mL), washed with water (60 mL) and brine (100 mL), dried over MgSO.sub.4, and filtered. The filtrate was concentrated and flushed through a silica plug eluting with ethyl acetate/heptanes (9:1) to provide the title compound as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.48 (t, J=8.9 Hz, 1H), 7.25 (s, 1H), 7.05 (dd, J=11.4, 2.8 Hz, 1H), 6.94 (s, 1H), 6.83 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 5.88 (ddt, J=17.2, 10.6, 5.3 Hz, 1H), 5.26 (dq, J=17.2, 1.7 Hz, 1H), 5.16 (dq, J=10.5, 1.5 Hz, 1H), 5.05 (d, J=4.4 Hz, 1H), 4.46 (s, 2H), 4.40 (d, J=5.4 Hz, 2H), 4.06-3.98 (m, 1H), 2.18 (ddd, J=12.8, 9.5, 2.9 Hz, 1H), 2.10-1.97 (m, 1H), 1.95-1.64 (m, 8H); MS (+ESI) m/z 427.2 (M+H).

    Example 13K: (S)N-(4-amino-2-hydroxybicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide

    [1155] To a solution of Example 13J (15.43 g, 36.1 mmol) and diethylamine (37.8 mL, 361 mmol) in dichloromethane (100 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.835 g, 0.723 mmol). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture concentrated, and the residue was purified on a 330 g column using the Biotage Isolera One flash system eluting with dichloromethane/methanol/30% ammonium hydroxide (10:1:0.1). The desired fractions were concentrated; the residue was dissolved in ethyl acetate with 2% methanol and concentrated until most of the solvents were removed. To the warm remaining solution was added heptane. The resulting solution was cooled to room temperature, and a precipitate formed. The solids were collected by filtration and washed with ethyl acetate/heptanes (1:9). The precipitation process was repeated two more times. The solids were dried in a vacuum oven to provide 9.7 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.48 (t, J=8.9 Hz, 1H), 7.18 (s, 1H), 7.05 (dd, J=11.4, 2.9 Hz, 1H), 6.82 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.95 (d, J=4.3 Hz, 1H), 4.45 (s, 2H), 3.97 (dd, J=8.0, 3.5 Hz, 1H), 2.04 (ddd, J=13.1, 11.2, 4.8 Hz, 1H), 1.94-1.69 (m, 4H), 1.54-1.22 (m, 5H); MS (+ESI) m/z 343.3 (M+H).

    Example 13L: (cis)-3-(benzyloxy)cyclobutanol

    [1156] To a solution of 3-(benzyloxy)cyclobutanone (1.0 g, 5.67 mmol) in methanol (10 mL), sodium tetrahydroborate (0.215 g, 5.67 mmol) was added portionwise at 30 C. over 10 minutes, and then the mixture was stirred at the same temperature for one hour. The reaction mixture was cooled with an ice bath, and saturated ammonium chloride solution was added carefully to quench the reaction. The volatiles were removed under vacuum. The residue was extracted with ethyl acetate. The organic layer was dried over magnesium sulfated and filtered. The filtrate was concentrated, and the residue was purified on silica gel (070% ethyl acetate in heptane) to give 0.75 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.38-7.23 (m, 5H), 4.33 (s, 2H), 3.68 (ddt, J=14.5, 7.9, 6.7 Hz, 1H), 3.60-3.48 (m, 1H), 2.59-2.49 (m, 2H), 1.73 (dtd, J=8.9, 7.8, 2.9 Hz, 2H).

    Example 13M: tert-butyl 2-((cis)-3-(benzyloxy)cyclobutoxy)acetate

    [1157] To a solution of Example 13L (0.63 g, 3.53 mmol), tert-butyl 2-bromoacetate (0.783 mL, 5.30 mmol) and tetrabutylammonium hydrogen sulfate (0.060 g, 0.177 mmol) in toluene (10 mL) and water (0.3 mL), sodium hydroxide (2.121 g, 53.0 mmol) in 3 mL of water was added. The two-phase mixture was stirred at ambient temperature for 2 hours. The organic layer was diluted with more ethyl acetate, washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified on silica gel (060% ethyl acetate in heptane) to give 0.95 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.39-7.23 (m, 5H), 4.35 (s, 2H), 3.86 (s, 2H), 3.71-3.58 (m, 2H), 2.56 (dtd, J=9.4, 6.6, 2.9 Hz, 2H), 1.79 (dtd, J=9.2, 7.6, 2.9 Hz, 2H), 1.41 (s, 9H).

    Example 13N: tert-butyl, 2-((cis)-3-hydroxycyclobutoxy)acetate

    [1158] To a solution of Example 13M (0.94 g, 3.22 mmol) in tetrahydrofuran (8 mL) in a 20 mL Barnstead Hast C reactor was added 5% Pd/C, wet (0.1 g, 0.470 mmol), and the reaction mixture was stirred at 50 C. and 78 psi of hydrogen for 4 hours. The suspension was filtered, and the filtrate was concentrated under vacuum to give 0.67 g of the title compound which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.99 (d, J=6.6 Hz, 1H), 3.83 (s, 2H), 3.64 (ddt, J=14.5, 7.9, 6.6 Hz, 1H), 3.53 (tt, J=7.9, 6.5 Hz, 1H), 2.51-2.44 (m, 2H), 1.78-1.65 (m, 2H), 1.41 (s, 9H).

    Example 13O: tert-butyl 2-((cis)-3-(trifluoromethoxy)cyclobutoxy)acetate

    [1159] To a mixture of silver(I) trifluoromethanesulfonate (2.52 g, 9.79 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.734 g, 4.89 mmol), and potassium fluoride (0.758 g, 13.05 mmol) in a flask wrapped with aluminum foil and cooled with a water bath, Example 13N (0.66 g, 3.26 mmol) in ethyl acetate (25 mL) was added, followed by 2-fluoropyridine (0.841 mL, 9.79 mmol) and trimethyl(trifluoromethyl)silane (4.89 mL, 9.79 mmol) dropwise to keep the internal temperature lower than 30 C. The reaction mixture was stirred at ambient temperature overnight. The suspension was filtered through a diatomaceous earth cartridge and washed with more ethyl acetate. The organic filtrate was dried over magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (070% ethyl acetate in heptane) to give 0.46 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.46 (p, J=7.1 Hz, 1H), 3.92 (s, 2H), 3.79-3.67 (m, 1H), 2.74 (dtt, J=9.2, 5.7, 2.8 Hz, 2H), 2.15-2.03 (m, 2H), 1.42 (s, 9H).

    Example 13P: 2-((cis)-3-(trifluoromethoxy)cyclobutoxy)acetic acid

    [1160] A mixture of Example 13O (0.46 g, 1.702 mmol) and 2,2,2-trifluoroacetic acid (3.93 mL, 51.1 mmol) in dichloromethane (5.0 mL) was stirred at ambient temperature for 3 hours. Solvent and excess trifluoroacetic acid were removed under high vacuum to give 0.36 g of the title compound which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.63 (s, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.95 (s, 2H), 3.81-3.70 (m, 1H), 2.75 (tdt, J=9.0, 5.7, 2.4 Hz, 2H), 2.15-2.03 (m, 2H).

    Example 13Q: 2-(4-chloro-3-fluorophenoxy)-N-[(2S)-2-hydroxy-4-(2-{[(s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide

    [1161] To a mixture of Example 13K (52 mg, 0.152 mmol), Example 13P (34.1 mg, 0.159 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.106 mL, 0.607 mmol) in N,N-dimethylformamide (2.0 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (72.1 mg, 0.190 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under high vacuum, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100A AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 67 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.48 (t, J=8.9 Hz, 1H), 7.25 (s, 1H), 7.09-6.97 (m, 2H), 6.83 (dd, J=9.0, 2.7 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 4.46 (s, 2H), 4.03 (dd, J=9.7, 3.1 Hz, 1H), 3.69 (p, J=6.9 Hz, 1H), 3.68 (s, 2H), 2.72 (dtt, J=9.2, 5.8, 2.9 Hz, 2H), 2.26 (ddd, J=12.5, 9.5, 2.4 Hz, 1H), 2.12 (dp, J=9.6, 3.6 Hz, 2H), 2.11 2.00 (m, 1H), 1.97-1.72 (m, 8H); MS (APCI+) m/z 539.1 (M+H).

    Example 14: 6-chloro-4-oxo-N-[3-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 113)

    Example 14A: tert-butyl (3-(6-chloro-4-oxochroman-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1162] The reaction and purification conditions described in Example 2B substituting 6-chloro-4-oxochroman-2-carboxylic acid (Princeton Bio) for the product of Example 1B, and tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock) for the product of Example 2A gave the title compound. MS (ESI.sup.) m/z 405 (MH).sup..

    Example 14B: N-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-4-oxochroman-2-carboxamide, trifluoroacetic acid

    [1163] The product of Example 14A (600 mg, 1.48 mmol) was stirred in dichloromethane (2 mL) at ambient temperature. Trifluoroacetic acid (1 mL) was added in one portion. After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure to give the title compound (0.63 g, 1.50 mmol, 102% yield). MS (ESI.sup.+) m/z 307 (M+H).sup.+.

    Example 14C: 6-chloro-4-oxo-N-[3-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1164] The reaction and purification conditions described in Example 2B substituting the product of Example 14B for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.36 (s, 1H), 7.68-7.60 (m, 2H), 7.20-7.12 (m, 1H), 5.08 (t, J=7.1 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.72 (s, 2H), 3.75-3.63 (m, 1H), 2.94 (d, J=7.1 Hz, 2H), 2.79-2.67 (m, 2H), 2.23 (s, 6H), 2.19-2.08 (m, 2H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 15: rac-(2R,4R)-6-chloro-4-hydroxy-N-[3-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 114)

    [1165] The reaction and purification conditions described in Example 6C substituting the product of Example 14C for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.66 (s, 1H), 8.36 (s, 1H), 7.37 (dd, J=2.7, 1.0 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.84-5.57 (m, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.58 (dd, J=12.1, 2.3 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.72 (s, 2H), 3.74-3.64 (m, 1H), 2.79-2.68 (m, 2H), 2.36-2.30 (m, 1H), 2.25 (s, 6H), 2.20-2.09 (m, 2H), 1.75-1.60 (m, 1H); MS (APCI.sup.+) m/z 487 (MH.sub.2O+H).sup.+.

    Example 16: (2R)-6-chloro-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 115)

    Example 16A: tert-butyl ((S)-4-((R)-6-chloro-4-oxochroman-2-carboxamido)-2-hydroxybicyclo[2.2.2]octan-1-yl)carbamate

    [1166] The reaction and purification conditions described in Example 2B substituting the product of Example 13H for the product of Example 2A gave the title compound. MS (ESI.sup.+) m/z 409 (MC(CH.sub.3).sub.3+H).sup.+.

    Example 16B: (2R)-6-chloro-N-[(3S)-3-hvdroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1167] The reaction and purification conditions described in Example 1C substituting the product of Example 16A for the product of Example 1A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 7.66-7.57 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.92 (s, 1H), 5.19 (d, J=4.6 Hz, 1H), 5.04 (dd, J=8.2, 5.0 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.95-3.88 (m, 1H), 3.77-3.64 (m, 3H), 2.99-2.85 (m, 2H), 2.74 (dtd, J=9.9, 6.7, 3.3 Hz, 2H), 2.28-2.16 (m, 2H), 2.11 (d, J=9.6 Hz, 2H), 1.95-1.81 (m, 3H), 1.78-1.66 (m, 5H); MS (APCI.sup.+) m/z 561 (M+H).sup.+.

    Example 17: 2-(4-chlorophenoxy)-N-[4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide (Compound 116)

    Example 17A: N-(4-aminobicyclo[2.2.2]octan-1-yl)-2-(4-chlorophenoxy))acetamide, 2 trifluoroacetic acid

    [1168] The reaction and purification conditions described in Examples 14A through 14B substituting 2-(4-chlorophenoxy)acetic acid for 6-chloro-4-oxochroman-2-carboxylic acid, and tert-butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate for tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate gave the title compound. MS (ESI.sup.) m/z 407 (MH).sup..

    Example 17B: 2-(4-chlorophenoxy)-N-[4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide

    [1169] The reaction and purification conditions described in Example 2B substituting the product of Example 17A for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.43 (s, 1H), 7.36-7.29 (m, 2H), 6.98 (s, 1H), 6.96-6.89 (m, 2H), 4.47 (p, J=7.1 Hz, 1H), 4.38 (s, 2H), 3.68 (p, J=6.9 Hz, 1H), 3.68 (s, 2H), 2.77-2.68 (m, 2H), 2.16-2.07 (m, 2H), 1.89 (s, 12H); MS (APCI.sup.+) m/z 505 (M+H).sup.+.

    Example 18: (2R,4R)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 117)

    [1170] The reaction and purification conditions described in Example 6C substituting the product of Example 16B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.37 (dd, J=2.7, 0.9 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.66 (br s, 1H), 5.22 (br s, 1H), 4.77 (dd, J=10.6, 5.9 Hz, 1H), 4.55 (dd, J=11.8, 2.2 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.94 (dd, J=9.5, 3.3 Hz, 1H), 3.78-3.65 (m, 3H), 2.81-2.69 (m, 2H), 2.36-2.19 (m, 3H), 2.18-2.07 (m, 2H), 2.02-1.65 (m, 9H); MS (APCI.sup.+) m/z 545 (MH.sub.2O+H).sup.+.

    Example 19: (1s,3s)-N-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-3-(trifluoromethoxy)cyclobutane-1-carboxamide (Compound 118)

    [1171] The reaction and purification conditions described in Example 2B substituting N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide (prepared as described in International Patent Publication WO2017/193034 A1) for the product of Example 2A, and the product of Example 25O for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.69 (s, 1H), 8.52 (s, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.73 (p, J=7.5 Hz, 1H), 4.47 (s, 2H), 2.60-2.51 (m, 1H), 2.43 (dtd, J=10.2, 7.2, 2.9 Hz, 2H), 2.29-2.17 (m, 2H), 2.22 (s, 6H); MS (APCI.sup.+) m/z 451 (M+H).sup.+.

    Example 20: (2R,4R)-6-chloro-4-hydroxy-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 119)

    [1172] The reaction and purification conditions described in Example 6C substituting the product of Example 33B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92-8.87 (m, 1H), 8.70 (s, 1H), 8.54 (t, J=6.0 Hz, 1H), 8.19 (dd, J=8.3, 2.4 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.38 (dd, J=2.7, 0.9 Hz, 1H), 7.20 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (s, 1H), 4.85-4.76 (m, 1H), 4.60 (dd, J=12.0, 2.3 Hz, 1H), 4.43 (d, J=6.0 Hz, 2H), 2.36 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.25 (s, 6H), 1.77-1.63 (m, 1H); MS (APCI.sup.+) m/z 496 (M+H).sup.+.

    Example 21: 2-(4-chloro-3-fluorophenoxy)-N-{(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}acetamide (Compound 120)

    Example 21A: tert-butyl ((3R,6S)-6-(3-(4-chlorophenoxy)azetidine-1-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate

    [1173] The methodologies described in Example 30D substituting (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (purchased from Astatech) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting 3-(4-chlorophenoxy)azetidine (purchased from PharmaBlock) for Example 30C gave the title compound. MS (APCI.sup.+) m/z 411 (M+H).sup.+.

    Example 21B: ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)(3-(4-chlorophenoxy)azetidin-1-yl)methanone

    [1174] To a solution of Example 21A (0.045 g, 0.110 mmol) in dichloromethane (0.11 mL) was added trifluoroacetic acid (0.06 mL, 0.77 mmol). The reaction mixture stirred for 1 hour and was concentrated to afford the title compound which was carried forward without further purification. MS (APCI.sup.+) m/z 311 (M+H).sup.+.

    Example 21C: 2-(4-chloro-3-fluorophenoxy)-N-{(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}acetamide

    [1175] The methodologies described in Example 30D substituting 2-(4-chloro-3-fluorophenoxy)acetic acid for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 21B for Example 30C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.99 (dd, J=7.9, 5.2 Hz, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.06 (dd, J=11.4, 2.8 Hz, 1H), 6.92-6.85 (m, 2H), 6.88-6.80 (m, 1H), 5.03 (dtt, J=8.5, 6.2, 2.8 Hz, 1H), 4.75-4.65 (m, 1H), 4.52 (s, 2H), 4.32 (ddt, J=10.4, 6.4, 1.7 Hz, 1H), 4.22-4.13 (m, 1H), 3.92-3.85 (m, 1H), 3.81 (dddd, J=10.1, 8.1, 4.3, 1.5 Hz, 2H), 3.75 (m, 1H), 3.12 (td, J=10.3, 1.4 Hz, 1H), 1.92-1.78 (m, 2H), 1.66-1.46 (m, 2H); MS (APCI.sup.+) m/z 497 (M+H).sup.+.

    Example 22: (2R,4R)-6-chloro-4-hydroxy-N-[(3R,6S)-6-({[4-(trifluoromethyl)phenyl]methyl}carbamoyl)oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide and (2S,4S)-6-chloro-4-hydroxy-N-[(3R,6S)-6-({[4-(trifluoromethyl)phenyl]methyl}carbamoyl)oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 121)

    [1176] The methodologies described in Example 5 substituting Example 38 for Example 4 and purifying by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title compounds. .sup.1H NMR (400 MHz, DMSO-d.sub.6, dr 20:1) ppm 8.41 (td, J=6.3, 1.7 Hz, 1H), 8.04 (t, J=8.3 Hz, 0.03H), 7.96 (dd, J=8.1, 2.3 Hz, 1H), 7.90 (d, J=8.4 Hz, 0.03H), 7.68 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.39 (dd, J=2.7, 0.9 Hz, 1H), 7.33-7.22 (m, 0.08H), 7.22-7.16 (m, 1H), 6.98 (dd, J=43.5, 8.9 Hz, 0.05H), 6.88 (d, J=8.7 Hz, 1H), 6.12 (s, 0.01H), 4.81 (dd, J=10.6, 5.9 Hz, 1H), 4.64 (dd, J=11.8, 2.3 Hz, 1H), 4.59 (t, J=3.6 Hz, 0.05H), 4.35 (d, J=6.3 Hz, 2H), 3.92 (dddd, J=8.0, 6.3, 4.6, 1.9 Hz, 1H), 3.88-3.73 (m, 2H), 3.30-3.18 (m, 1H), 2.35 (ddt, J=13.0, 5.7, 2.5 Hz, 1H), 2.08-1.99 (m, 1H), 1.96-1.89 (m, 1H), 1.80-1.68 (m, 1H), 1.71-1.58 (m, 1H), 1.55-1.40 (m, 1H); MS (APCI.sup.+) m/z 513 (M+H).sup.+.

    Example 23: (2R,4R)-6-chloro-N-{(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide and (2S,4S)-6-chloro-N-{(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 122)

    [1177] The methodologies described in Example 5 substituting Example 40 for Example 4 and purifying by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title compounds. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.92 (t, J=7.0 Hz, 1H), 7.41-7.29 (m, 3H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.96-6.84 (m, 3H), 5.03 (dq, J=6.6, 3.3 Hz, 1H), 4.81 (dd, J=10.6, 5.9 Hz, 1H), 4.76-4.65 (m, 1H), 4.64 (dd, J=11.8, 2.3 Hz, 1H), 4.37-4.27 (m, 1H), 4.18 (dt, J=10.2, 3.7 Hz, 1H), 3.92-3.71 (m, 3H), 3.23-3.11 (m, 1H), 2.39-2.29 (m, 1H), 1.90 (s, 1H), 1.86 (dt, J=9.2, 2.8 Hz, 1H), 1.72 (dtd, J=12.6, 11.0, 2.7 Hz, 1H), 1.69-1.52 (m, 2H); MS (APCI.sup.+) m/z 521 (M+H).sup.+.

    Example 24: rac-(2R,4R)-6-chloro-4-hydroxy-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 123)

    [1178] The reaction and purification conditions described in Example 6C substituting the product of Example 35 for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92-8.87 (m, 1H), 8.70 (s, 1H), 8.54 (t, J=6.0 Hz, 1H), 8.19 (dd, J=8.3, 2.4 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.38 (dd, J=2.7, 0.9 Hz, 1H), 7.20 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (s, 1H), 4.85-4.76 (m, 1H), 4.60 (dd, J=12.0, 2.3 Hz, 1H), 4.43 (d, J=6.0 Hz, 2H), 2.36 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.25 (s, 6H), 1.77-1.63 (m, 1H); MS (ESI.sup.+) m/z 496 (M+H).sup.+.

    Example 25: 2-(4-chloro-3-fluorophenoxy)-N-(2-hydroxy-4-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)acetamide (Compound 124)

    Example 25A: dimethyl 2-oxobicyclo[2.2.2]octane-1,4-dicarboxylate

    [1179] To a mixture of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (3.89 g, 17.19 mmol, Enamine) in acetic acid (40 mL) was added chromium trioxide (3.44 g, 34.4 mmol) at 20 C., and then the mixture was stirred at 90 C. for 18 hours. The reaction mixture was diluted with ethyl acetate (200 mL), poured into water (100 mL), and adjusted to pH=9 with solid NaHCO.sub.3. The aqueous layer was extracted with ethyl acetate (3200 mL). The organic phase was washed with brine (300 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=20:1-10:1) to give crude title compound which was treated with petroleum ether (50 mL). The solid was collected by filtration and dried under high vacuum to give 0.8 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6), ppm 1.68-2.16 (m, 8H), 2.25-2.35 (m, 2H), 2.58 (s, 2H), 3.64 (s, 1H), 3.70 (s, 3H), 3.74 (s, 3H).

    Example 25B: 4-(methoxycarbonyl)-2-oxobicyclo[2.2.2]octane-1-carboxylic acid

    [1180] To a solution of Example 25A (8.4 g, 33.2 mmol) in tetrahydrofuran (80 mL) and methanol (20 mL) was added a solution of lithium hydroxide monohydrate (1.116 g, 26.6 mmol) in water (20 mL) at 0 C., and the resulting mixture was stirred for 48 hours at 25 C. The mixture was concentrated under reduced pressure at 25 C., and the residue was diluted with water (40 mL) and extracted with 2-methoxy-2-methylpropane (280 mL). The aqueous layer was adjusted to pH=2 with aqueous 0.5 N HCl, and the precipitate was collected by filtration and dried under high vacuum to give the title compound (4 g, yield 50.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.88-2.12 (m, 7H), 2.27-2.39 (m, 2H), 2.60 (s, 2H), 3.72 (s, 1H), 3.75 (s, 3H).

    Example 25C: 4-tert-butyl 1-methyl 2-oxobicyclo[2.2.2]octane-1,4-dicarboxylate

    [1181] To a solution of Example 25B (4 g, 16.80 mmol) in t-butanol (60 mL) was added pyridine (9.57 g, 121 mmol) and N,N-dimethylpyridin-4-amine (2.052 g, 16.80 mmol). Then di-tert-butyl dicarbonate (18.33 g, 84 mmol) was added slowly at 20 C., and the mixture was stirred at 35 C. for 24 hours. The resulting solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with water (2100 mL), dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure to give the title compound (5.5 g) which was used in the subsequent step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.37 (s, 9H), 1.79 (br d, J=12.35 Hz, 2H), 1.83-2.00 (m, 4H), 2.21 (br d, J=13.33 Hz, 2H), 2.46 (s, 2H), 3.68 (s, 3H).

    Example 25D: 4-(tert-butoxycarbonyl)-2-oxobicyclo[2.2.2]octane-1-carboxylic acid

    [1182] To a solution of Example 25C (5.5 g, 19.48 mmol) in tetrahydrofuran (80 mL) and methanol (20 mL) was added a solution of NaOH (0.779 g, 19.48 mmol) in water (20 mL) at 0 C., and the mixture was stirred at 0 C. to 25 C. for 12 hours. The mixture was concentrated under reduced pressure at 25 C. The residue was diluted with water (30 mL) and washed with 2-methoxy-2-methylpropane (250 mL). The aqueous layer was acidified to pH=1 with aqueous 1 N HCl, and the precipitate was collected by filtration and dried under high vacuum to give the title compound (2.4 g, yield 41%). .sup.1H NMR (400 MHz, CDCl.sub.3), ppm 1.22 (s, 1H), 1.41-1.53 (m, 9H), 1.78-1.98 (m, 2H), 2.03-2.27 (m, 6H), 2.57-2.69 (m, 2H).

    Example 25E: tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-oxobicyclo[2.2.2]octane-1-carboxylate

    [1183] To a solution of Example 25D (1 g, 3.73 mmol) in toluene (100 mL) was added triethylamine (1.558 mL, 11.18 mmol) and diphenyl phosphorazidate (2.051 g, 7.45 mmol) sequentially at 20 C., and the mixture was stirred for 2 hours at 120 C. under N.sub.2. Then benzyl alcohol (1.163 mL, 11.18 mmol) was added at 120 C., and the mixture was stirred at 120 C. for 12 hours. The reaction mixture was cooled to 25 C. and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2100 mL). The organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluted with petroleum ether and ethyl acetate (100:1 to 30:1 to 10:1) to give the title compound (0.95 g, yield 62.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.37 (s, 9H), 1.50-1.56 (m, 2H), 1.70-1.88 (m, 3H), 1.97-2.12 (m, 3H), 2.55 (s, 2H), 2.72-2.90 (m, 2H), 4.99 (s, 2H), 5.92 (br s, 1H), 7.25-7.31 (m, 5H).

    Example 25F: tert-butyl 4-amino-3-oxobicyclo[2.2.2]octane-1-carboxylate

    [1184] To a mixture of Pd(OH).sub.2 (600 mg, 4.27 mmol) in tetrahydrofuran (60 mL) was added a solution of Example 25E (2 g, 4.82 mmol) in tetrahydrofuran (60 mL) at 20 C. under argon, and the resulting mixture was stirred for 2 hours under H.sub.2 at 15 psi. The resulting mixture was filtered through a pad of diatomaceous earth, and the cake was washed with ethyl acetate (30 mL). Water (20 mL) was added, and the resulting mixture was adjusted to pH=1 with aqueous 1.2 M HCl. The two phases were separated, and the aqueous layer was washed with ethyl acetate (220 mL). The aqueous layer was lyophilized to give the title compound (1.2 g, yield 88%). .sup.1H NMR (400 MHz, CD30D) ppm 1.46-1.49 (m, 9H), 1.94-2.07 (m, 4H), 2.13-2.25 (m, 4H), 2.74 (s, 2H).

    Example 25G: tert-butyl 4-(2-(4-chloro-3-fluorophenoxy)acetamido)-3-oxobicyclo[2.2.2]octane-1-carboxylate

    [1185] A mixture of Example 25F (0.51 g, 1.849 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (0.435 g, 2.127 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.969 mL, 5.55 mmol) in N,N-dimethylformamide (10.0 mL) was treated with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.703 g, 1.849 mmol), and the reaction mixture was stirred at ambient temperature overnight. Water (100 mL) was added dropwise, and stirring was continued for 15 minutes. The precipitate was collected by filtration, washed with water and heptane, and dried under vacuum to give 0.74 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.67 (s, 1H), 7.45 (t, J=8.9 Hz, 1H), 7.04 (dd, J=11.3, 2.9 Hz, 1H), 6.81 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.52 (s, 2H), 2.53 (d, J=1.3 Hz, 2H), 2.46-2.29 (m, 2H), 1.94 (t, J=9.9 Hz, 2H), 1.87-1.79 (m, 1H), 1.78 (d, J=10.5 Hz, 3H), 1.36 (s, 9H); MS (ESI.sup.+) m/z 426.1 (M+H).sup.+.

    Example 25H: 4-(2-(4-chloro-3-fluorophenoxy)acetamido)-3-oxobicyclo[2.2.2]octane-1-carboxylic acid

    [1186] To a solution of Example 25G (0.73 g, 1.714 mmol) in dichloromethane (10.0 mL) was added 2,2,2-trifluoroacetic acid (1.321 mL, 17.14 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours and 50 C. for 1 hour. Volatiles were removed under high vacuum. The residue was triturated with dichloromethane/heptane to give 0.63 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.53 (s, 1H), 7.71 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.85 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.57 (s, 2H), 2.59 (d, J=1.3 Hz, 2H), 2.42 (dd, J=11.5, 8.5 Hz, 2H), 2.09-1.93 (m, 2H), 1.84 (d, J=8.3 Hz, 4H); MS (ESI.sup.+) m/z 370.2 (M+H).sup.+.

    Example 251: methyl 4-(2-(4-chloro-3-fluorophenoxy)acetamido)-3-oxobicyclo[2.2.2]octane-1-carboxylate

    [1187] To a solution of Example 25H (4.5 g, 10.95 mmol) in methanol (100 mL) was added H.sub.2SO.sub.4 (5 mL, 92 mmol) at 20 C., and the reaction mixture was stirred for 12 hours at 80 C. The mixture was concentrated under reduced pressure, and the residue was diluted with water (100 mL), and the mixture was extracted with ethyl acetate (2200 mL). The organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was treated with methanol, the solid was collected by filtration, and dried by high vacuum to give the title compound (2.66 g, yield 55.7%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.81-1.92 (m, 4H), 1.96-2.08 (m, 2H), 2.42 (br dd, J=11.19, 8.74 Hz, 2H), 2.64 (s, 2H), 3.63 (s, 4H), 4.58 (s, 2H), 6.86 (dt, J=8.93, 1.41 Hz, 1H), 7.09 (dd, J=11.43, 2.87 Hz, 1H), 7.50 (t, J=8.86 Hz, 1H), 7.73 (s, 1H).

    Example 25J: methyl 4-(2-(4-chloro-3-fluorophenoxy)acetamido)-3-hydroxybicyclo[2.2.2]octane-1-carboxylate

    [1188] To a solution of Example 251 (2 g, 4.69 mmol) in methanol (50 mL) was added NaBH.sub.4 (0.124 g, 3.28 mmol) at 0 C., and the reaction mixture was stirred for 3 hours at the same temperature. The reaction was quenched with saturated NH.sub.4Cl solution, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2-50 mL). The organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (2.1 g, yield 89%) which was used in the next step directly. MS (ESI+) m/z 386.0 (M+H).sup.+.

    Example 25K: methyl 3-((tert-butyldimethylsilyl)oxy)-4-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.2.2]octane-1-carboxylate

    [1189] To a solution of Example 25J (2 g, 4.15 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added 2,6-dimethylpyridine (1.777 g, 16.59 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.74 g, 10.37 mmol) in order at 0 C., and the reaction mixture was stirred for 3 hours at 0 C. Saturated aqueous NH.sub.4Cl (100 mL) was added, the two phases were separated, and the organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by reverse phase MPLC (Stationary phase: SNAP C18 120 g, 2535 m, 100 , Mobile phase: A: trifluoroacetic acid/H.sub.2O=0.05% volume/volume; B: acetonitrile, flow rate: 50 mL/minute; gradient (the percent of B): 5%-10% 5 minutes; 10%-30% 10 minutes; 30%-40% 15 minutes 40%-100% 20 minutes; 100% 6 minutes), and the desired fractions were concentrated under reduced pressure. The residue was basified by adding water and 2 g of NaHCO.sub.3. The mixture was extracted with ethyl acetate (2100 mL). The organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (2.8 g, yield 99%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.00 (s, 3H), 0.06 (s, 3H), 0.84 (s, 10H), 1.62-1.76 (m, 2H), 1.77-1.98 (m, 7H), 2.24 (br dd, J=13.14, 9.60 Hz, 1H), 2.34-2.45 (m, 1H), 3.62 (s, 3H), 4.04-4.13 (m, 1H), 4.29 (d, J=0.98 Hz, 2H), 6.41 (br s, 1H), 6.61 (br d, J=8.93 Hz, 1H), 6.68 (dd, J=10.39, 2.69 Hz, 1H), 7.20-7.33 (m, 1H).

    Example 25L: N-(2-((tert-butyldimethylsilyl)oxy)-4-(hydrazinecarbonyl)bicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide

    [1190] A mixture of Example 25K (1.0 g, 2.000 mmol) and hydrazine monohydrate (1.471 mL, 30.0 mmol) was stirred at 120 C. for 16 hours. The resulting solution was cooled to ambient temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) to give 110 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.12 (s, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.16-6.97 (m, 2H), 6.82-6.75 (m, 1H), 4.46-4.25 (m, 3H), 2.23-2.10 (m, 2H), 1.80-1.57 (m, 7H), 1.51 (dt, J=13.5, 2.4 Hz, 1H), 0.84 (s, 9H), 0.02 (s, 3H), 0.03 (s, 3H).

    Example 25M: (cis)-benzyl 3-hydroxycyclobutanecarboxylate

    [1191] To a solution of benzyl 3-oxocyclobutanecarboxylate (5.0 g, 24.48 mmol) in methanol (50 mL), sodium tetrahydroborate (0.926 g, 24.48 mmol) was added portionwise at 30 C. over 10 minutes followed by stirring at the same temperature for 3 hours. The mixture was cooled with an ice bath, saturated ammonium chloride was added carefully, and volatiles were removed under vacuum. The residue was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified on silica gel (060% ethyl acetate in heptane) to give 2.55 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.42-7.28 (m, 5H), 5.21 (d, J=7.0 Hz, 1H), 5.08 (s, 2H), 3.97 (tq, J=8.3, 6.9 Hz, 1H), 2.68-2.54 (m, 1H), 2.40 (dddt, J=10.2, 6.8, 5.2, 2.5 Hz, 2H), 2.04 1.90 (m, 2H).

    Example 25N: (cis)-benzyl 3-(trifluoromethoxy)cyclobutanecarboxylate

    [1192] The title compound was synthesized using the same procedure as described in Example 130 substituting Example 13N with Example 25M. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.43-7.29 (m, 4H), 5.11 (s, 2H), 4.77 (p, J=7.5 Hz, 1H), 2.94-2.81 (m, 1H), 2.63 (dtt, J=9.7, 7.2, 2.3 Hz, 2H), 2.40-2.26 (m, 2H).

    Example 25O: (cis)-3-(trifluoromethoxy)cyclobutanecarboxylic acid

    [1193] A mixture of Example 25N (0.1 g, 0.365 mmol) and sodium hydroxide (0.912 mL, 1.823 mmol) in tetrahydrofuran (0.7 mL) was stirred at ambient temperature overnight. Solvent was removed under vacuum, and the residue was partitioned between dichloromethane and 1 N HCl. The organic layer was dried over magnesium sulfate and concentrated to give 0.047 g of the title compound which was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.40 (brs, 1H), 5.75 (s, 1H), 4.74 (p, J=7.4 Hz, 1H), 2.77-2.52 (m, 3H), 2.34-2.21 (m, 2H).

    Example 25P: N-(2-((tert-butyldimethylsilyl)oxy)-4-(2-((cis)-3-(trifluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide

    [1194] To a mixture of Example 25L, Example 25O (0.040 g, 0.220 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.123 mL, 0.704 mmol) in N,N-dimethylformamide (2.5 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.084 g, 0.220 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. Volatiles were removed under high vacuum, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 65 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.62 (d, J=1.5 Hz, 1H), 9.30 (d, J=1.6 Hz, 1H), 7.46 (t, J=8.8 Hz, 1H), 7.10 (d, J=11.7 Hz, 1H), 7.01 (dd, J=11.4, 2.8 Hz, 1H), 6.79 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.75 (p, J=7.6 Hz, 1H), 4.46-4.31 (m, 3H), 2.63 (qd, J=9.5, 7.4 Hz, 1H), 2.51-2.40 (m, 2H), 2.29-2.07 (m, 4H), 1.84 (ddd, J=10.9, 8.3, 4.6 Hz, 1H), 1.80-1.68 (m, 3H), 1.64 (qd, J=12.8, 10.9, 5.5 Hz, 3H), 1.50 (dt, J=13.6, 2.4 Hz, 1H), 0.81 (s, 9H), 0.00 (s, 3H), 0.06 (s, 3H).

    Example 25Q: N-(2-((tert-butyldimethylsilyl)oxy)-4-(5-((cis)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide

    [1195] To a suspension of Example 25P (0.065 g, 0.098 mmol) in acetonitrile (2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.051 mL, 0.293 mmol), followed by 4-methylbenzene-1-sulfonyl chloride (0.037 g, 0.195 mmol). The reaction mixture was stirred at ambient temperature overnight. Volatiles were removed, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 45-100% gradient of acetonitrile (A) and 0.10% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 44 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.45 (t, J=8.9 Hz, 1H), 7.20 (s, 1H), 7.07 6.96 (m, 1H), 6.79 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.84 (p, J=7.4 Hz, 1H), 4.47 (ddd, J=9.4, 5.4, 2.9 Hz, 1H), 4.42-4.34 (m, 2H), 2.78 (dtt, J=9.6, 7.4, 2.6 Hz, 2H), 2.46-2.22 (m, 4H), 1.98-1.76 (m, 4H), 1.78-1.62 (m, 3H), 0.81 (s, 9H), 0.00 (s, 3H), 0.05 (s, 3H).

    Example 25R: 2-(4-chloro-3-fluorophenoxy)-N-(2-hydroxy-4-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)acetamide

    [1196] A solution of Example 25N (0.043 g, 0.066 mmol) in tetrahydrofuran (1.0 mL) was treated with tetrabutylammonium fluoride (0.166 mL, 0.166 mmol), and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm 50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 23 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.47 (t, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.05 (dd, J=11.4, 2.8 Hz, 1H), 6.83 (ddd, J=9.0, 2.8, 1.2 Hz, 1H), 5.19 (s, 1H), 4.87 (p, J=7.5 Hz, 1H), 4.48 (s, 2H), 4.12 (dd, J=7.0, 4.3 Hz, 1H), 4.04-3.95 (m, 1H), 2.80 (dddt, J=9.7, 7.4, 5.2, 2.5 Hz, 2H), 2.48-2.40 (m, 1H), 2.35-2.25 (m, 1H), 2.14-2.02 (m, 2H), 2.02-1.76 (m, 5H), 1.76-1.55 (m, 2H); MS (APCI.sup.+) m/z 534.1 (M+H).sup.+.

    Example 26: (2R,4R)-6-chloro-N-{(1R,3r,5S)-8-[3-(4-chlorophenoxy)propyl]-8-azabicyclo[3.2.1]octan-3-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 125)

    [1197] The reaction and purification conditions described in Example 6C substituting the product of Example 2B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.47 (d, J=6.3 Hz, 1H), 7.38 (dd, J=2.7, 0.9 Hz, 1H), 7.36-7.26 (m, 2H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.99-6.92 (m, 2H), 6.88 (d, J=8.7 Hz, 1H), 5.67 (d, J=6.1 Hz, 1H), 4.80 (dt, J=11.0, 5.8 Hz, 1H), 4.69 (dd, J=11.2, 2.6 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.83 (q, J=6.6 Hz, 1H), 3.15-3.10 (m, 2H), 2.39 (t, J=6.9 Hz, 2H), 2.32 (ddd, J=12.9, 5.8, 2.7 Hz, 1H), 2.10-1.92 (m, 2H), 1.91-1.68 (m, 7H), 1.60 (dd, J=13.8, 8.1 Hz, 2H); MS (ESI.sup.+) m/z 505 (M+H).sup.+.

    Example 27: rac-(2R,4R)-6-chloro-N-[(1r,4R)-4-{[(6-chloro-1H-benzimidazol-2-yl)methyl]carbamoyl}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 126)

    [1198] The reaction and purification conditions described in Example 6C substituting the product of Example 39B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.38 (t, J=5.6 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.41-7.36 (m, 2H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 7.12 (dd, J=8.5, 2.1 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.81 (dd, J=10.7, 6.0 Hz, 1H), 4.61 (dd, J=11.9, 2.2 Hz, 1H), 4.45 (d, J=5.5 Hz, 2H), 3.71-3.52 (m, 2H), 2.35 (ddd, J=13.1, 6.0, 2.4 Hz, 1H), 2.24-2.13 (m, 1H), 1.88-1.77 (m, 3H), 1.71 (q, J=12.0 Hz, 1H), 1.51-1.29 (m, 3H); MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 28: (2R,4R)-6-chloro-N-(3-{[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 127)

    [1199] The reaction and purification conditions described in Example 6C substituting the product of Example 36 for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.69 (s, 1H), 8.48 (t, J=5.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.59 (dd, J=12.0, 2.2 Hz, 1H), 4.43 (d, J=5.7 Hz, 2H), 2.35 (ddd, J=13.0, 5.9, 2.4 Hz, 1H), 2.24 (s, 6H), 2.07 (s, 1H), 1.69 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 29: (2R,4R)-6-chloro-4-hydroxy-N-(3-{[(1s,3S)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 128)

    [1200] The reaction and purification conditions described in Example 6C substituting the product of Example 34 for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.66 (s, 1H), 8.52 (s, 1H), 7.37 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.69 (br s, 1H), 4.80 (dd, J=10.9, 6.0 Hz, 1H), 4.78-4.68 (m, 1H), 4.58 (dd, J=12.0, 2.3 Hz, 1H), 2.61-2.52 (m, 2H), 2.49-2.39 (m, 2H), 2.39-2.29 (m, 1H), 2.29-2.18 (m, 1H), 2.23 (s, 6H), 1.75-1.62 (m, 1H); MS (APCI.sup.+) m/z 456 (MH.sub.2O+H).sup.+.

    Example 30: N-[(6-chloro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentane-1-carboxamide (Compound 129)

    Example 30A: 6-chlorochroman-2-carbaldehyde

    [1201] To a cooled (0 C.) solution of 6-chlorochroman-2-carboxylic acid (0.45 g, 2.1 mmol) in methanol (3.5 mL) was added thionyl chloride (0.39 mL, 5.3 mmol), and the mixture was then heated to 65 C. for 3 hours. The reaction mixture was then cooled to ambient temperature, concentrated, and diluted with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (310 mL), and the combined organic layers were washed with water (10 mL) and brine (10 mL), dried (Na.sub.2SO.sub.4), and concentrated to provide methyl 6-chlorochroman-2-carboxylate.

    [1202] To a cooled (78 C.) suspension of methyl 6-chlorochroman-2-carboxylate (0.47 g, 2.1 mmol) in dichloromethane (0.77 mL) and toluene (3.1 mL) was added DIBAL-H (diisobutylaluminum hydride) (2.2 mL, 2.2 mmol, 1 M in toluene) dropwise. The reaction mixture stirred for 1.5 hours while remaining cold. This reaction mixture was then quenched with methanol (1 mL) and allowed to warm to ambient temperature. A saturated Rochelle salt aqueous solution (1 mL) was then added to the reaction which was stirred rapidly for 10 minutes. The reaction mixture was extracted with diethyl ether (35 mL), and the combined organic phases were concentrated under heated N.sub.2 to provide the title compound as a mixture with remaining methyl 6-chlorochroman-2-carboxylate and (6-chlorochroman-2-yl)methanol. The residue was carried forward without further purification.

    Example 30B: N-benzyl-1-(6-chlorochroman-2-yl)methanamine

    [1203] To a solution of the product of Example 30A (0.30 g, 1.5 mmol) in 2.4 weight % sodium acetate trihydrate and 3.6 weight % acetic acid in methanol (15 mL) was added benzylamine (0.17 mL, 1.5 mmol). To this reaction mixture was added sodium cyanoborohydride (0.24 g, 3.8 mmol) at ambient temperature, and the mixture was stirred for 2 hours, was concentrated, and purified by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give the title compound (0.18 g, 0.62 mmol, 41% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.33 (s, 2H), 7.58-7.48 (m, 2H), 7.51-7.37 (m, 3H), 7.21-7.11 (m, 2H), 6.84 (d, J=8.6 Hz, 1H), 4.38 (ddt, J=10.9, 8.7, 2.8 Hz, 1H), 4.32-4.20 (m, 2H), 3.27 (dd, J=13.2, 3.4 Hz, 1H), 3.19 (dd, J=13.2, 8.7 Hz, 1H), 2.79 (qdd, J=13.5, 8.4, 4.2 Hz, 2H), 2.03 (ddq, J=15.9, 5.9, 3.1, 2.6 Hz, 1H), 1.68 (dtd, J=13.6, 10.6, 5.9 Hz, 1H); MS (APCI.sup.+) m/z 288 (M+H).sup.+.

    Example 30C: (6-chlorochroman-2-yl)methanamine

    [1204] Example 30B (0.178 g, 0.621 mmol) in tetrahydrofuran (2.0 mL) was added to 10% Pd(OH).sub.2/C wet (0.0386 g, 0.115 mmol) in a 20 mL RS10 with a glass liner. 4M HCl in dioxane (0.50 mL, 2.0 mmol) was added. The reactor was purged with argon. The mixture was stirred at 1200 rpm under 55 psi of hydrogen at 25 C. After 20.4 hours, no reaction occurred, so ethanol (2.0 mL) and 10% Pd(OH).sub.2/C wet (0.208 g, 0.621 mmol) was added to the reaction mixture, and the solution was placed back under hydrogen pressure and allowed to stir for 4 days. Although there was incomplete conversion, some dehalogenation occurred, so then the mixture was filtered and purified by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) to give the title compound (0.028 g, 0.14 mmol, 23% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.00 (s, 3H), 7.25-7.17 (m, 1H), 7.14 (dd, J=8.7, 2.7 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 4.22 (ddt, J=10.5, 8.2, 2.8 Hz, 1H), 3.18 (s, 1H), 3.12-3.04 (m, 1H), 2.80 (qdd, J=13.7, 8.5, 4.2 Hz, 2H), 2.09-1.98 (m, 1H), 1.68 (dtd, J=13.6, 10.7, 5.9 Hz, 1H).

    Example 30D: N-[(6-chloro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentane-1-carboxamide

    [1205] To a mixture of 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid (0.050 g, 0.16 mmol, CALICO Life Sciences; AbbVie Inc.; Sidrauski, Carmela; et al. WO2017/193030, 2017, A1) and the product of Example 30C (0.033 g, 0.17 mmol) in N,N-dimethylformamide (0.91 mL) was added triethylamine (0.09 mL, 0.64 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 0.067 g, 0.18 mmol). This reaction mixture was allowed to stir at ambient temperature for 5 hours. Then the reaction mixture was diluted with water (0.5 mL) and filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give the title compound (0.028 g, 0.057 mmol, 36% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 8.00 (t, J=5.9 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.11 (d, J=14.8 Hz, 1H), 7.07 (dd, J=5.5, 2.8 Hz, 1H), 6.85 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.47 (s, 2H), 4.05 (dtd, J=9.8, 6.0, 2.3 Hz, 1H), 3.45-3.33 (m, 1H), 3.26 (dt, J=13.6, 6.0 Hz, 1H), 2.80-2.68 (m, 2H), 2.20 (s, 6H), 2.02-1.89 (m, 1H), 1.56 (dtd, J=13.6, 9.8, 6.6 Hz, 1H); MS (APCI.sup.+) mi 493 (M+H).sup.+.

    Example 31: 6-chloro-N-{(1r,4r)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]cyclohexyl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 130)

    Example 31A: tert-butyl ((1r,4r)-4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)carbamate

    [1206] To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (15 g, 69 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 39.5 g, 104 mmol) in tetrahydrofuran (600 mL) was added N-ethyl-N-isopropylpropan-2-amine (24.2 mL, 138 mmol). Then the mixture was stirred at 15 C. for 15 minutes, followed by the addition of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (14.8 g, 69.2 mmol). The reaction mixture was stirred at 15 C. for 12 hours, was filtered, and the filter cake was washed with tetrahydrofuran (10 mL) to give the title compound (26.0 g, 64.7 mmol, 93% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.91 (d, J=7.6 Hz, 1H), 7.46 (t, J=8.80 Hz, 1H), 7.04 (d, J=8.20 Hz, 1H), 6.82 (d, J=10.4 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 4.45 (s, 2H), 3.51 (s, 1H), 3.15 (s, 1H), 1.69-1.76 (m, 4H), 1.15-1.34 (m, 14H).

    Example 31B: N-((1r,4r)-4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamide, hydrochloric acid

    [1207] To a solution of Example 31A (25.9 g, 64.3 mmol) in methanol (250 mL) was added a solution of hydrogen chloride (250 mL, 4 M in methanol) dropwise at 0 C., and the resulting mixture was allowed to warm to ambient temperature for 12 hours. Then methyl tert-butyl ether (1 L) was added, the mixture was cooled to 0 C., and a precipitate was generated. The resulting mixture stirred for 1 hour. The precipitate was collected by filtration was filtered and dried under high vacuum to give the title compound. .sup.1H NMR (400 MHz, D.sub.2O) ppm 7.28 (t, J=8.80 Hz, 1H), 6.74-6.77 (m, 1H), 6.63-6.66 (m, 1H), 4.34 (s, 2H), 3.57-3.62 (m, 1H), 3.03-3.09 (m, 1H), 1.94 (d, J=12.4 Hz, 2H), 1.82 (d, J=12.0 Hz, 2H), 1.37-1.44 (m, 2H), 1.25-1.32 (m, 2H).

    Example 31C: 6-chloro-N-{(1r,4r)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]cyclohexyl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1208] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 31B for Example 30C gave the title compound. .sup.1H NMR (501 MHz, DMSO-d.sub.6) ppm 8.16 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.72-7.57 (m, 2H), 7.48 (t, J=8.9 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.05 (dd, J=11.4, 2.9 Hz, 1H), 6.83 (ddd, J=9.0, 3.0, 1.1 Hz, 1H), 5.11 (dd, J=8.2, 5.2 Hz, 1H), 4.48 (s, 2H), 3.54 (d, J=33.1 Hz, 2H), 3.03-2.82 (m, 2H), 1.73 (d, J=37.6 Hz, 4H), 1.31 (q, J=12.3, 11.0 Hz, 4H); MS (APCI.sup.+) m/z 509 (M+H).sup.+.

    Example 32: (2S,4S)-6-chloro-N-[(3R,6S)-6-{[(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl]carbamoyl}oxan-3-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide and (2R,4R)-6-chloro-N-[(3R,6S)-6-{[(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl]carbamoyl}oxan-3-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 131)

    [1209] The methodologies described in Example 5 substituting Example 41 for Example 4 and purifying by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) gave the title compounds. .sup.1H NMR (501 MHz, DMSO-dc, dr 5.6:1) d ppm 8.78 (s, 1H), 8.77 (s, 1H), 8.42-8.36 (m, 1H), 8.03 (d, J=4.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.92 (dd, J=8.1, 3.8 Hz, 0.18H), 7.50 (t, J=2.1 Hz, 0.18H), 7.44-7.36 (m, 3H), 7.24-7.17 (m, 1H), 7.07-7.01 (m, 0.18H), 6.93 (d, J=8.8 Hz, 0.18H), 6.88 (d, J=8.7 Hz, 1H), 6.11 (t, J=5.4 Hz, 0.18H), 4.91 (t, J=5.4 Hz, 0.18H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 4.59 (d, J=3.1 Hz, 0.18H), 4.48 (d, J=6.0 Hz, 3H), 3.97-3.89 (m, 1H), 3.81 (dt, J=11.5, 2.5 Hz, 2H), 3.24 (dt, J=11.9, 10.6 Hz, 1H), 2.39-2.31 (m, 1H), 2.08-2.01 (m, 1H), 1.93 (s, 1H), 1.79-1.61 (m, 2H), 1.56-1.45 (m, 1H); MS (APCI.sup.+) m/z 520 (M+H).sup.+.

    Example 33: (2R)-6-chloro-4-oxo-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 132)

    Example 33A: 3-amino-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide, 2 trifluoroacetic acid

    [1210] The reaction and purification conditions described in Examples 14A through 14B substituting 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (Enamine) for 6-chloro-4-oxochroman-2-carboxylic acid, and (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Apollo) for tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock) gave the title compound. MS (ESI.sup.+) m/z 286 (M+H).sup.+.

    Example 33B: (2R)-6-chloro-4-oxo-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1211] The reaction and purification conditions described in Example 2B substituting the product of Example 33A for the product of Example 2A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.91-8.86 (m, 1H), 8.53 (t, J=6.1 Hz, 1H), 8.18 (dd, J=8.2, 2.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.44 (d, J=8.2 Hz, 1H), 7.21-7.13 (m, 1H), 5.09 (dd, J=8.3, 6.0 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H), 3.03-2.88 (m, 2H), 2.23 (s, 6H); MS (APCI.sup.+) m/z 494 (M+H).sup.+.

    Example 34: (2R)-6-chloro-4-oxo-N-(3-{[(1s,3S)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 133)

    [1212] The reaction and purification conditions described in Examples 14A through 14C substituting the product of Example 25O for the product of Example 13P, and the product of Example 1B for 6-chloro-4-oxochroman-2-carboxylic acid gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.52 (s, 1H), 7.67-7.59 (m, 2H), 7.20-7.12 (m, 1H), 5.07 (t, J=7.1 Hz, 1H), 4.73 (p, J=7.5 Hz, 1H), 2.94 (d, J=7.1 Hz, 2H), 2.57-2.52 (m, 1H), 2.48-2.37 (m, 2H), 2.28-2.20 (m, 2H), 2.20 (s, 6H); MS (APCI.sup.+) m/z 473 (M+H).sup.+.

    Example 35: 6-chloro-4-oxo-N-[3-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 134)

    [1213] The reaction and purification conditions described in Example 33B substituting the racemic 6-chloro-4-oxochroman-2-carboxylic acid for (R)-6-chloro-4-oxochroman-2-carboxylic acid gave the title compound. .sup.1H NMR (501 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.90-8.87 (m, 1H), 8.54 (t, J=6.0 Hz, 1H), 8.18 (dd, J=8.4, 2.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.44 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.5, 0.7 Hz, 1H), 5.08 (dd, J=8.4, 5.9 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H), 2.96 (d, J=3.6 Hz, 1H), 2.94 (s, 1H), 2.23 (s, 6H); MS (ESI.sup.+) m/z 494 (M+H).sup.+.

    Example 36: (2R)-6-chloro-N-(3-{[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 135)

    [1214] The title compound was prepared using the methodologies described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.34 (s, 1H), 8.94 (s, 1H), 8.48 (t, J=5.8 Hz, 1H), 7.68-7.60 (m, 2H), 7.54 (br s, 2H), 7.21-7.13 (m, 1H), 5.08 (dd, J=8.2, 6.2 Hz, JH), 4.43 (d, J=5.8 Hz, 2H), 3.01-2.91 (m, 2H), 2.22 (s, 6H); MS (ESI) m/z 501 (M+H).sup.+.

    Example 37: rac-(2R,4R)-6-chloro-N-[(1r,4R)-4-{3-[5-(difluoromethyl)pyrazin-2-yl]-2-oxoimidazolidin-1-yl}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 136)

    Example 37A: tert-butyl (2-(((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)amino)ethyl)carbamate

    [1215] To a mixture of benzyl ((1r,4r)-4-aminocyclohexyl)carbamate (2.5 g, 10.1 mmol) and tert-butyl (2-oxoethyl)carbamate (2.48 g, 15.6 mmol) in methanol (67 mL) stirred at ambient temperature was added acetic acid (4 mL) followed by sodium cyanoborohydride (1.39 g, 22.2 mmol) and trifluoroacetic acid (0.776 mL). After 18 hours, the resulting solution was concentrated under reduced pressure to less than 20 mL, filtered through a glass microfiber frit and directly purified by preparative HPLC [YMC TriArt C-18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (1.0 g, 2.55 mmol, 25% yield). MS (APCI.sup.+) m/z 392 (M+H).sup.+.

    Example 37B: benzyl ((1r,4r)-4-((2-aminoethyl)amino)cyclohexyl)carbamate

    [1216] Trifluoroacetic acid (1 mL) was added to a dichloromethane (1.0 mL) solution of the product of Example 37A (1 g, 2.55 mmol) stirred at 0 C. The reaction mixture was slowly warmed up to ambient temperature over 30 minutes and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 mL) and aqueous NaOH (2.5 M, 20 mL). The organic layers were combined and concentrated under reduced pressure. The resulting residue was taken up in methanol (20 mL) and filtered through a glass microfiber frit. The filtrate was concentrated under reduced pressure to give the title compound (0.72 g, 2.47 mmol, 97% yield). MS (ESI.sup.+) m/z 292 (M+H).sup.+.

    Example 37C: benzyl ((1r,4r)-4-(2-oxoimidazolidin-1-yl)cyclohexyl)carbamate

    [1217] To a mixture of the product of Example 37B (0.715 g, 2.45 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.055 mL, 0.368 mmol) in tetrahydrofuran (24 mL) was added N,N-carbonyldiimidazole (458 mg, 2.82 mmol). The resulting mixture was stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. The residue was directly purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 0-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (267 mg, 0.84 mmol, 34% yield). MS (ESI.sup.+) m/z 318 (M+H).sup.+.

    Example 37D: benzyl ((1r,4r)-4-(3-(5-(difluoromethyl)pyrazin-2-yl)-2-oxoimidazolidin-1-yl)cyclohexylcarbamate

    [1218] 2-Bromo-5-(difluoromethyl)pyrazine (Matrix, 44.5 mg, 0.213 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (XPhos, 11.7 mg, 0.025 mmol) tris(dibenzylideneacetone)dipalladium(0) (11.3 mg, 0.012 mmol), the product of Example 37C (52 mg, 0.164 mmol) and cesium carbonate (160 mg, 0.492 mmol) were added to a sealed tubed followed by dioxane (2 mL). The tube was degassed three times with a nitrogen back flush each time and then sealed. The reaction mixture was warmed to 55 C. and stirred for 3 hours and then at 100 C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between dichloromethane (225 mL) and aqueous sodium carbonate (1.0 M, 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt M C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (65 mg, 0.146 mmol, 89% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.52 (d, J=1.5 Hz, 1H), 8.62-8.59 (m, 1H), 7.40-7.28 (m, 5H), 7.22 (d, J=7.8 Hz, 1H), 7.03 (t, J=54.6 Hz, 1H), 5.01 (s, 2H), 3.93 (dd, J=9.0, 6.9 Hz, 2H), 3.64 (ddt, J=11.8, 7.7, 4.0 Hz, 1H), 3.52 (t, J=8.0 Hz, 2H), 3.33-3.24 (m, 1H), 1.95-1.85 (m, 2H), 1.74-1.52 (m, 4H), 1.31 (qd, J=12.8, 3.8 Hz, 2H); MS (ESI.sup.+) m/z 446 (M+H).sup.+.

    Example 37E. 1-((1r,4r)-4-aminocyclohexyl)-3-(5-(difluoromethyl)pyrazin-2-yl)imidazolidin-2-one

    [1219] The product of Example 37D (60 mg, 0.135 mmol) was combined with trifluoroacetic acid (3 mL) in a sealed tube and stirred at 70 C. for 1 hour. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (34 mg, 0.11 mmol, 81% yield).

    [1220] MS (APCI+) m/z 312 (M+H).sup.+.

    Example 37F: 6-chloro-N-((1r,4r)-4-(3-(5-(difluoromethyl)pyrazin-2-yl)-2-oxoimidazolidin-1-yl)cyclohexyl)-4-oxochroman-2-carboxamide

    [1221] The reaction and purification conditions described in Example 2B substituting the product of Example 37E for the product of Example 2A, and 6-chloro-4-oxochroman-2-carboxylic acid (Princeton Bio) for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 520 (M+H).sup.+.

    Example 37G: rac-(2R4R)-6-chloro-N-[(1r,4R)-4-{3-[5-(difluoromethyl)pyrazin-2-yl]-2-oxoimidazolidin-1-yl}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1222] The reaction and purification conditions described in Example 6C substituting the product of Example 37F for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.64 (d, J=1.5 Hz, 1H), 8.51 (s, 1H), 7.45 (dd, J=2.6, 0.8 Hz, 1H), 7.19 (dd, J=8.7, 2.6 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.68 (t, J=55.2 Hz, 1H), 6.40 (d, J=8.3 Hz, 1H), 4.91 (q, J=7.0 Hz, 1H), 4.65 (dd, J=9.2, 3.2 Hz, 1H), 4.06-4.00 (m, 2H), 3.91 (tt, J=12.1, 3.9 Hz, 1H), 3.80 (dtd, J=11.9, 8.0, 4.1 Hz, 1H), 3.57-3.50 (m, 2H), 2.68 (ddd, J=13.7, 5.7, 3.3 Hz, 1H), 2.26 (d, J=7.1 Hz, 1H), 2.21-2.12 (m, 2H), 2.08-1.98 (m, 1H), 1.96-1.83 (m, 2H), 1.70-1.57 (m, 2H), 1.48-1.27 (m, 2H); MS (APCI.sup.+) m/z 522 (M+H).sup.+.

    Example 38: 6-chloro-4-oxo-N-[(3R,6S)-6-({[4-(trifluoromethyl)phenyl]methyl}carbamoyl)oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 137)

    Example 38A: tert-butyl ((3R,6S)-6-((4-(trifluoromethyl)benzyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamate

    [1223] The methodologies described in Example 30D substituting (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (purchased from Astatech) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting (4-(trifluoromethyl)phenyl)methanamine hydrochloride for Example 30C gave the title compound. MS (APCI.sup.+) m/z 303 (MC(O)OC(CH.sub.3).sub.3+H).sup.+.

    Example 38B: (2S,5R)-5-amino-N-(4-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide

    [1224] The methodologies described in 21B substituting Example 38A for Example 21A gave the title compound. MS (APCI.sup.+) m/z 303 (M+H).sup.+.

    Example 38C: 6-chloro-4-oxo-N-[(3R,6S)-6-({[4-(trifluoromethyl)phenyl]methyl}carbamoyl)oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1225] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 38B for Example 30C gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.41 (td, J=6.3, 4.0 Hz, 1H), 8.25 (dd, J=7.9, 3.1 Hz, 1H), 7.70-7.61 (m, 4H), 7.45 (d, J=8.1 Hz, 2H), 7.17 (dt, J=8.6, 0.8 Hz, 1H), 5.14 (td, J=6.6, 1.6 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H), 3.94-3.80 (m, 1H), 3.82-3.78 (m, 1H), 3.78-3.68 (m, 1H), 3.17 (dt, J=25.9, 10.6 Hz, 1H), 3.00-2.95 (m, 2H), 2.02 (ddd, J=13.0, 8.2, 3.0 Hz, 1H), 1.89 (dd, J=43.0, 12.6 Hz, 1H), 1.60 (pd, J=12.8, 3.9 Hz, 1H), 1.47 (tdd, J=11.4, 6.4, 3.8 Hz, 1H); MS (APCI.sup.+) m/z 511 (M+H).sup.+.

    Example 39: 6-chloro-N-[(1r,4r)-4-{[(6-chloro-1H-benzimidazol-2-yl)methyl]carbamoyl}cyclohexyl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 138)

    Example 39A: tert-butyl (trans-4-(((6-chloro-1H-benzo[d]imidazol-2-yl)methyl)carbamoyl)cyclohexyl)carbamate

    [1226] The reaction and purification conditions described in Example 2B substituting (6-chloro-1H-benzo[d]imidazol-2-yl)methanamine for the product of Example 2A, and trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid for the product of Example 1B gave the title compound. MS (ESI.sup.+) m/z 407 (M+H).sup.+.

    Example 39B: 6-chloro-N-[(1r,4r)-4-{[(6-chloro-1H-benzimidazol-2-yl)methyl]carbamoyl}cyclohexyl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1227] The reaction and purification conditions described in Example 1C substituting the product of Example 39A for the product of Example 1A, and 6-chloro-4-oxochroman-2-carboxylic acid for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.55 (t, J=5.5 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.36 (dd, J=8.6, 2.0 Hz, 1H), 7.24-7.13 (m, 1H), 5.11 (dd, J=8.1, 5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 3.04-2.88 (m, 2H), 2.23-2.12 (m, 1H), 1.89-1.79 (m, 3H), 1.78-1.70 (m, 1H), 1.48-1.33 (m, 2H), 1.37-1.17 (m, 2H), MS (APCI.sup.+) m/z 515 (M+H).sup.+.

    Example 40: 6-chloro-N-{(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 139)

    Example 40A: tert-butyl ((3R,6S)-6-(3-(4-chlorophenoxy)azetidine-1-carbonyl)tetrahydro-2H-pyran-3-yl)carbamate

    [1228] The methodologies described in Example 30D substituting (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (purchased from Astatech) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting 3-(4-chlorophenoxy)azetidine (purchased from PharmaBlock) for Example 30C gave the title compound. MS (APCI.sup.+) m/z 411 (M+H).sup.+.

    Example 40B: ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)(3-(4-chlorophenoxy)azetidin-1-yl)methanone

    [1229] The methodologies described in 21B substituting Example 40A for Example 21A gave the title compound. MS (APCI.sup.+) m/z 303 (M+H).sup.+.

    Example 40C: 6-chloro-N-{(3R,6S)-6-[3-(4-chlorophenoxy)azetidine-1-carbonyl]oxan-3-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1230] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 40B for Example 30C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.20 (dt, J=7.8, 5.0 Hz, 1H), 7.68-7.59 (m, 2H), 7.39-7.30 (m, 2H), 7.16 (ddd, J=8.6, 1.4, 0.7 Hz, 1H), 6.92-6.83 (m, 2H), 5.14 (dd, J=7.6, 5.9 Hz, 1H), 5.02 (dp, J=7.6, 3.2, 2.5 Hz, 1H), 4.74-4.64 (m, 1H), 4.31 (dd, J=10.9, 6.5 Hz, 1H), 4.16 (dd, J=10.5, 3.3 Hz, 1H), 3.92-3.85 (m, 1H), 3.85-3.78 (m, 1H), 3.81-3.70 (m, 1H), 3.68 (s, 1H), 3.18-3.03 (m, 1H), 3.03-2.89 (m, 2H), 1.97-1.79 (m, 2H), 1.56 (s, 1H), 1.61-1.45 (m, 1H); MS (APCI.sup.+) m/z 520 (M+H).sup.+.

    Example 41: 6-chloro-N-[(3R,6S)-6-{[(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl]carbamoyl}oxan-3-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 140)

    Example 41A: tert-butyl ((3R,6S)-6-(((7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamate

    [1231] The methodologies described in Example 30D substituting (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (purchased from Astatech) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid, substituting (7-chloroimidazo[1,2-a]pyridin-2-yl)methanamine hydrochloride (purchased from Anichem) for Example 30C, and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] gave the title compound. MS (APCI.sup.+) m/z 409 (M+H).sup.+.

    Example 41B: (2S,5R)-5-amino-N-((7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)tetrahydro-2H-pyran-2-carboxamide

    [1232] The methodologies described in 21B substituting Example 41A for Example 21A gave the title compound. MS (APCI.sup.+) m/z 309 (M+H).sup.+.

    Example 41C: 6-chloro-N-[(3R,6S)-6-{[(7-chloroimidazo[1,2-a]pyridin-2-yl)methyl]carbamoyl}oxan-3-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1233] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid, substituting Example 41B for Example 30C, and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.54 (dd, J=7.2, 0.8 Hz, 1H), 8.23 (dd, J=7.9, 3.3 Hz, 1H), 8.11 (td, J=6.0, 2.3 Hz, 1H), 7.74 (s, 1H), 7.69-7.60 (m, 3H), 7.21-7.13 (m, 1H), 6.94 (dd, J=7.2, 2.1 Hz, 1H), 5.14 (td, J=6.7, 1.0 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 3.87 (dddd, J=33.3, 10.6, 4.8, 1.9 Hz, 1H), 3.76 (ddd, J=19.9, 11.3, 3.3 Hz, 2H), 3.17 (dt, J=21.0, 10.5 Hz, 1H), 3.01-2.94 (m, 2H), 2.03 (ddt, J=13.5, 8.0, 2.6 Hz, 1H), 1.97-1.80 (m, 1H), 1.69-1.40 (m, 2H); MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 42: 6-chloro-N-{(1r,4r)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 141)

    [1234] To a solution of Example 31 (0.012 g, 0.024 mmol) in acetonitrile (0.16 mL) was added zinc chloride (0.010 g, 0.071 mmol). After stirring at 50 C. for 5 minutes, sodium cyanoborohydride (0.005 g, 0.071 mmol) was added, and this mixture was allowed to stir at 50 C. for 3 days. Then the reaction mixture was cooled to ambient temperature, diluted with N,N-dimethylformamide/water (1.2 mL, 3:1) and purified by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) to give the title compound (0.006 g, 0.012 mmol, 50% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6, dr 2.5:1) ppm 8.17 (d, J=7.9 Hz, 1H), 7.96 (t, J=7.1 Hz, 2H), 7.89 (d, J=8.1 Hz, 0.2H), 7.67-7.59 (m, 2H), 7.49 (td, J=8.9, 2.2 Hz, 1H), 7.40-7.35 (m, 0.2H), 7.23-7.14 (m, 1H), 7.06 (dt, J=11.5, 2.9 Hz, 2H), 6.92-6.81 (m, 2H), 6.51 (s, 0.2H), 5.69 (d, J=6.4 Hz, 0.2H), 5.11 (dd, J=8.1, 5.4 Hz, 1H), 4.81 (m, 0.4H), 4.66-4.57 (m, 0.4H), 4.49 (d, J=3.7 Hz, 3H), 3.59 (s, 5H), 2.96 (dd, J=6.7, 3.9 Hz, 2H), 1.78 (s, 7H), 1.70 (s, 2H), 1.37-1.28 (m, 8H); MS (ESI.sup.+) m/z 493 (MH.sub.2O+H).sup.+.

    Example 43: (2R,4R)-6-chloro-N-(3-{5-[(3,5-dimethylphenoxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 142)

    [1235] The reaction and purification conditions described in Example 6C substituting the product of Example 1C for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.60 (br s, 1H), 6.57 (br s, J=1.5 Hz, 2H), 5.72 (d, J=6.3 Hz, 1H), 4.88-4.76 (m, 2H), 4.62 (dd, J=12.0, 2.2 Hz, 1H), 4.13 (dd, J=11.0, 3.3 Hz, 1H), 4.06 (dd, J=11.0, 5.5 Hz, 1H), 3.70 (t, J=8.9 Hz, 1H), 3.44-3.37 (m, 1H), 2.36 (ddd, J=13.0, 6.0, 2.5 Hz, 1H), 2.32 (s, 6H), 2.23 (s, 6H), 1.77-1.63 (m, 1H); MS (APCI.sup.+) m/z 495 (MH.sub.2O+H).sup.+.

    Example 44: (2R,4R)-6-chloro-N-{2-[(4-chloro-3-fluorophenoxy)acetyl]-2-azaspiro[3.3]heptan-6-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 143)

    Example 44A: tert-butyl (2-(2-(4-chloro-3-fluorophenoxy)acetyl)-2-azaspiro[3.3]heptan-6-yl)carbamate

    [1236] The reaction and purification conditions described in Example 2B substituting 2-(4-chloro-3-fluorophenoxy)acetic acid (CombiBlocks) for the product of Example 1B, and tert-butyl 2-azaspiro[3.3]heptan-6-ylcarbamate (Enamine) for the product of Example 2A gave the title compound. MS (APCI.sup.+) m/z 399 (M+H).sup.+.

    Example 44B: (2R,4R)-6-chloro-N-{2-[(4-chloro-3-fluorophenoxy)acetyl]-2-azaspiro[3.3]heptan-6-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1237] The reaction and purification conditions described in Example 3C substituting the product of Example 44A for the product of Example 1A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.26 (t, J=8.4 Hz, 1H), 7.47 (td, J=8.9, 1.5 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.24-7.17 (m, 1H), 7.06 (ddd, J=11.3, 5.3, 2.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.86-6.77 (m, 1H), 5.69 (d, J=5.3 Hz, 1H), 4.81 (dt, J=10.9, 5.5 Hz, 1H), 4.66-4.56 (m, 3H), 4.31-4.10 (m, 3H), 3.97 (s, 1H), 3.86 (s, 1H), 2.50-2.43 (m, 2H), 2.34 (ddd, J=12.3, 6.0, 3.2 Hz, 1H), 2.29-2.21 (m, 2H), 1.76-1.62 (m, 1H); MS (APCI.sup.) m/z 507 (MH).sup..

    Example 45: 2-(4-chloro-3-fluorophenoxy)-N-[2-(6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]acetamide (Compound 144)

    Example 45A: tert-butyl 6-(2-(4-chloro-3-fluorophenoxy)acetamido)-2-azaspiro[3.3]heptane-2-carboxylate

    [1238] The reaction and purification conditions described in Example 2B substituting 2-(4-chloro-3-fluorophenoxy)acetic acid (Pharmablock) for the product of Example 1B, and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (Synnovator) for the product of Example 2A gave the title compound. MS (ESI.sup.+) m/z 343 (MC(CH.sub.3).sub.3+H).sup.+.

    Example 45B: 2-(4-chloro-3-fluorophenoxy)-N-(2-azaspiro[3.3]heptan-6-yl)acetamide, 3 trifluoroacetic acid

    [1239] The product of Example 45A (1.55 g, 3.89 mmol) was dissolved in dichloromethane (20 mL) and stirred at 0 C. Trifluoroacetic acid (5 mL) was added in one portion. The reaction mixture was slowly warmed up to ambient temperature over 20 minutes and stirred for one hour. The mixture was then concentrated under reduced pressure to give the title compound (2.5 g, 3.90 mmol, 100% yield). MS (APCI.sup.+) m/z 299 (M+H).sup.+.

    Example 45C: 2-(4-chloro-3-fluorophenoxy)-N-[2-(6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]acetamide

    [1240] The reaction and purification conditions described in Example 2B substituting the product of Example 45B for the product of Example 2A, and 6-chloro-4-oxochroman-2-carboxylic acid for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d.sub.6) ppm 7.86 (t, J=2.2 Hz, 1H), 7.45 (td, J=8.5, 2.6 Hz, 1H), 7.33 (t, J=8.6 Hz, 1H), 6.97 (dd, J=10.3, 8.8 Hz, 1H), 6.75 (dd, J=10.2, 2.9 Hz, 1H), 6.71-6.63 (m, 1H), 6.56 (dd, J=12.3, 7.7 Hz, 1H), 5.00 (td, J=10.7, 4.0 Hz, 1H), 4.43 (s, 2H), 4.52-4.29 (m, 3H), 4.17-4.13 (m, 1H), 4.06-3.98 (m, 1H), 3.08 (ddd, J=17.2, 10.8, 1.5 Hz, 1H), 2.93 (ddd, J=17.3, 6.7, 4.0 Hz, 1H), 2.75-2.65 (m, 2H), 2.30-2.17 (m, 2H); MS (APCI.sup.+) m/z 507 (M+H).sup.+.

    Example 46: 2-(4-chloro-3-fluorophenoxy)-N-{2-[rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl]-2-azaspiro[3.3]heptan-6-yl}acetamide (Compound 145)

    [1241] The reaction and purification conditions described in Example 6C substituting the product of Example 45C for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d.sub.6) ppm 7.43 (d, J=2.6 Hz, 1H), 7.33 (td, J=8.6, 1.9 Hz, 1H), 7.16 (td, J=8.4, 2.6 Hz, 1H), 6.83-6.71 (m, 2H), 6.70-6.63 (m, 1H), 6.53 (t, J=9.3 Hz, 1H), 4.91-4.81 (m, 1H), 4.74-4.65 (m, 1H), 4.42 (s, 2H), 4.46-4.30 (m, 3H), 4.09 (q, J=10.4 Hz, 1H), 4.03-3.90 (m, 2H), 2.74-2.60 (m, 2H), 2.45 (q, J=4.7 Hz, 2H), 2.28-2.12 (m, 2H); MS (APCI.sup.+) m/z 491 (MH.sub.2O+H).sup.+.

    Example 47: 6-chloro-N-[(3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl]-4-oxo-4H-1-benzopyran-2-carboxamide (Compound 146)

    Example 47A: (S)-tert-butyl (4-(6-chloro-4-oxo-4H-chromene-2-carboxamido)-2-hydroxybicyclo[2.2.2]octan-1-yl)carbamate

    [1242] The methodologies described in Example 30D substituting 6-chloro-4-oxo-4H-chromene-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid, substituting (S)-tert-butyl (4-amino-2-hydroxybicyclo[2.2.2]octan-1-yl)carbamate hydrochloric acid (CALICO Life Sciences; AbbVie Inc.; Sidrauski, Carmela; et al. WO2017/193030, 2017, A1) for Example 30C, and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] gave the title compound. MS (APCI.sup.+) m/z 463 (M+H).sup.+.

    Example 47B: (S)N-(4-amino-3-hydroxybicyclo[2.2.2]octan-1-yl)-6-chloro-4-oxo-4H-chromene-2-carboxamide

    [1243] The methodologies described in Example 21B substituting Example 47A for Example 21A gave the title compound. MS (APCI.sup.+) m/z 363 (M+H).sup.+.

    Example 47C: 6-chloro-N-[(3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl]-4-oxo-4H-1-benzopyran-2-carboxamide

    [1244] To a solution of Example 25N (0.040 g, 0.15 mmol) in methanol (2.2 mL) was added sodium hydroxide (0.23 mL, 0.58 mmol, 2.5M aqueous). After stirring at 50 C. for 10 minutes, the reaction mixture was concentrated in vacuo, diluted with a drop of acetonitrile and concentrated HCl, and concentrated again. The residue was taken up in N,N-dimethylformamide (2.2 mL) and triethylamine (0.16 mL, 1.2 mmol). This suspension was then added to Example 47B (0.053 g, 0.15 mmol), followed by the addition of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 0.072 g, 0.19 mmol). The reaction mixture was stirred for 24 hours, was diluted with water (0.3 mL), and then was concentrated in vacuo. The residue was taken up in N,N-dimethylformamide (3 mL), and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (1% TFA)] to give the title compound (0.093 g, 0.176 mmol, 121% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.24 (s, 1H), 7.99-7.91 (m, 2H), 7.86 (d, J=9.0 Hz, 1H), 7.33 (s, 1H), 6.81 (s, 1H), 6.54 (s, 1H), 5.19 (d, J=3.8 Hz, 1H), 4.73 (p, J=7.6 Hz, 1H), 4.12 (d, J=9.3 Hz, 1H), 3.33 (s, 4H), 2.70-2.59 (m, 1H), 2.42 (q, J=6.4 Hz, 2H), 2.38-2.17 (m, 3H), 2.09-1.92 (m, 2H), 1.90-1.84 (m, 3H), 1.73 (dt, J=13.0, 6.6 Hz, 1H); MS (APCI.sup.+) m/z 529 (M+H).sup.+.

    Example 48: (2S,4S)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide and (2R,4R)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 147)

    [1245] The methodologies described in Example 5 substituting Example 47 for Example 4 and purifying by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title compounds. .sup.1H NMR (400 MHz, Chloroform-d, dr 10:1) ppm 7.42 (d, J=2.6 Hz, 1H), 7.32 (d, J=2.6 Hz, OH), 7.21 (dd, J=8.8, 2.6 Hz, OH), 7.17 (dd, J=8.7, 2.6 Hz, 1H), 6.86 (dd, J=8.7, 1.8 Hz, OH), 6.81 (dd, J=8.7, 2.4 Hz, 1H), 6.35 (s, OH), 6.27 (s, 1H), 5.27 (s, 1H), 4.87 (t, J=6.2 Hz, 1H), 4.77 (s, OH), 4.61 (s, OH), 4.54 (tt, J=8.1, 4.7 Hz, 2H), 4.08 (d, J=8.6 Hz, 1H), 2.66-2.50 (m, 2H), 2.54-2.39 (m, 3H), 2.23-2.00 (m, 1H), 1.99-1.79 (m, 2H), 1.79-1.68 (m, 2H), 1.56 (dq, J=11.8, 6.0 Hz, 1H); MS (APCI.sup.+) m/z 515 (MH.sub.2O+H).sup.+.

    Example 49: 6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 148)

    Example 49A: tert-butyl (3-(4-(3,4-difluorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1246] Modifying a reported preparation of imidazoles (Sumitomo Dainippon Pharma Co, Ltd, etc. EP2905279, 2015, A 1), to a solution of 3,4-difluorobenzaldehyde (0.78 mL, 7.0 mmol) in ethanol (30 mL) and tetrahydrofuran (9 mL) was added toluene-4-sulfonylmethyl isocyanide (TOSMIC, 1.51 g, 7.74 mmol), followed by a solution of sodium cyanide (0.038 g, 0.77 mmol) in a few drops of water. This reaction mixture was allowed to stir at ambient temperature for 4 hours, was concentrated, diluted with ethyl acetate, and concentrated again to provide an impure residue containing 5-(3,4-difluorophenyl)-4-tosyl-4,5-dihydrooxazole.

    [1247] To a solution of 5-(3,4-difluorophenyl)-4-tosyl-4,5-dihydrooxazole (2.00 g, 5.93 mmol) in xylene (12 mL) was added tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (1.93 g, 9.72 mmol). This reaction mixture was allowed to stir at 135 C. for 4.5 hours, was cooled to ambient temperature, and concentrated in vacuo. The residue was diluted with N,N-dimethylformamide (6 mL), and purified by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) to give the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.90-7.78 (m, 2H), 7.75-7.51 (m, 2H), 2.47 (s, 6H), 1.41 (s, 9H); MS (APCI.sup.+) m/z 362 (M+H).sup.+.

    Example 49B: 3-(4-(3,4-difluorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1248] The methodologies described in Example 21B substituting Example 49A for Example 21A gave the title compound as a trifluoroacetic acid salt. MS (APCI.sup.+) m/z 262 (M+H).sup.+.

    Example 49C: 6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1249] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 49B for Example 30C gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.22 (s, 1H), 8.50-8.46 (m, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.85-7.75 (m, 1H), 7.69-7.67 (m, 1H), 7.66-7.60 (m, 2H), 7.52 (dt, J=10.7, 8.5 Hz, 1H), 7.19 (dd, J=8.4, 0.9 Hz, 1H), 5.17 (dd, J=8.7, 5.7 Hz, 1H), 3.03-2.97 (m, 2H), 2.58 (s, 6H); MS (APCI.sup.+) m/z 470 (M+H).sup.+.

    Example 50: rac-(2R,4R)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 149)

    [1250] The methodologies described in Example 5 substituting Example 49 for Example 4 and purifying by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6, dr 25:1) ppm 8.99 (s, 1H), 8.71 (d, J=1.4 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 7.85 (ddd, J=11.9, 7.7, 2.2 Hz, 1H), 7.68-7.61 (m, 1H), 7.55 (dt, J=10.6, 8.5 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.34 (d, J=2.6 Hz, 0.04H), 7.27 (dd, J=8.7, 2.7 Hz, 0.05H), 7.22 (ddd, J=8.8, 2.7, 0.7 Hz, J H), 6.91 (d, J=8.7 Hz, 1H), 4.88-4.81 (m, 1H), 4.68 (dd, J=S1.9, 2.4 Hz, 1H), 4.64-4.59 (m, 0.12H), 2.63 (s, 6H), 2.40 (ddd, J=12.9, 6.0, 2.4 Hz, 1H), 1.75 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 472 (M+H).sup.+.

    Example 51: 6-chloro-4-oxo-N-(4-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 150)

    Example 51A: (1s,3s)-3-(trifluoromethoxy)cyclobutanecarbohydrazide

    [1251] To a suspension of Example 25N (0.10 g, 0.37 mmol) in ethanol (1.5 mL) was added hydrazine hydrate (0.18 mL, 1.8 mmol, 50 weight %), and the reaction mixture was heated at 90 C. overnight. Then the reaction mixture was cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (0-100% ethyl acetate/heptanes) and visualized by KMnO.sub.4 thin-layer chromatography stain to give the title compound (0.067 g, 0.34 mmol, 93% yield). .sup.1H NMR (400 MHz, Chloroform-d) ppm 6.67 (s, 1H), 4.56 (p, J=7.6 Hz, 1H), 3.92-3.89 (m, 2H), 2.60-2.54 (m, 4H), 2.54-2.42 (m, 1H); MS (APCI.sup.+) m/z 199 (M+H).sup.+.

    Example 51B: tert-butyl (4-(2-((1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[2.1.1]hexane-1-yl)carbamate

    [1252] The methodologies described in Example 25P substituting Example 51A for Example 25L and substituting 4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid for

    Example 25O gave the title compound. .SUP.1.H NMR (400 MHz, Chloroform-d) ppm 8.72 (s, 1H), 8.36 (d, J=6.2 Hz, 1H), 4.99 (s, 1H), 4.59 (p, J=7.5 Hz, 1H), 2.71-2.62 (m, 1H), 2.58 (t, J=7.9 Hz, 4H), 1.96-1.87 (m, 3H), 1.73 (dd, J=3.9, 1.9 Hz, 2H), 1.58 (s, 3H), 1.45 (s, 9H); MS (APCI.SUP.+.) m/z 422 (M+H).SUP.+

    Example 51C: tert-butyl (4-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[2.1.1]hexan-1-yl)carbamate

    [1253] The methodologies described in Example 25Q substituting Example 51B for Example 25P gave the title compound. MS (APCI.sup.+) m/z 404 (M+H).sup.+.

    Example 51D: 4-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[2.1.1]hexan-1-amine

    [1254] The methodologies described in Example 21B substituting Example 51C for Example 21A gave the title compound. MS (APCI.sup.+) m/z 304 (M+H).sup.+.

    Example 51E: 6-chloro-4-oxo-N-(4-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1255] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 51D for Example 30C gave the title compound. .sup.1H NMR (400 MHz, Chloroform-A) ppm 7.90 (d, J=2.7 Hz, 1H), 7.50 (dd, J=8.8, 2.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.01 (s, 1H), 4.88 (dd, J=13.4, 3.3 Hz, 1H), 4.77-4.65 (m, 1H), 3.33 (tt, J=10.1, 7.7 Hz, 1H), 3.20 (dd, J=17.3, 3.3 Hz, 1H), 2.95-2.79 (m, 3H), 2.75-2.63 (m, 2H), 2.63-2.55 (m, 2H), 2.30-2.17 (m, 2H), 2.20-2.06 (m, 2H), 2.10-1.90 (m, 2H); MS (APCI.sup.+) m/z 512 (M+H).sup.+.

    Example 52: 6-chloro-4-oxo-N-(3-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 151)

    Example 52A: methyl 3-(6-chlorochroman-2-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate

    [1256] The methodologies described in Example 30D substituting 6-chlorochroman-2-carboxylic acid (purchased from Anichem) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride for Example 30C gave the title compound. MS (APCI.sup.+) m/z 336 (M+H).sup.+.

    Example 52B: 6-chloro-N-(3-(hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)chroman-2-carboxamide

    [1257] The methodologies described in Example 51A substituting 52A for Example 25N gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.04 (s, 1H), 8.62 (s, 1H), 7.17-7.10 (m, 2H), 6.91-6.82 (m, 1H), 4.45 (dd, J=9.2, 3.1 Hz, 1H), 4.19 (s, 2H), 2.79 (ddd, J=15.9, 9.8, 5.6 Hz, 1H), 2.66 (dt, J=16.7, 5.1 Hz, 1H), 2.16 (s, 6H), 2.11 (dt, J=8.5, 5.3 Hz, 1H), 1.89-1.75 (m, 1H);); MS (APCI.sup.+) m/z 336 (M+H).sup.+.

    Example 52C: 6-chloro-N-(3-(2-((1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)chroman-2-carboxamide

    [1258] The methodologies described in Example 47C substituting Example 52B for Example 47B gave the title compound. .sup.1H NMR (600 MHz, Chloroform-d) ppm 8.13 (d, J=6.1 Hz, 1H), 8.07 (s, 1H), 7.11-7.05 (m, 2H), 6.97 (s, 1H), 6.82 (d, J=8.6 Hz, 1H), 4.61-4.55 (m, 1H), 4.42 (dd, J=10.1, 2.8 Hz, 1H), 2.86 (ddd, J=16.6, 10.7, 5.8 Hz, 1H), 2.75 (dt, J=16.5, 4.6 Hz, 1H), 2.60 (d, J=6.3 Hz, 5H), 2.46 (s, 6H), 2.45-2.37 (m, 1H), 2.00-1.90 (m, 1H); MS (APCI.sup.+) m/z 502 (M+H).sup.+.

    Example 52D: 6-chloro-N-(3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)chroman-2-carboxamide

    [1259] The methodologies described in Example 25Q substituting Example 52C for Example 25P gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d) ppm 7.14-7.04 (m, 3H), 6.83 (d, J=8.5 Hz, 1H), 4.71 (p, J=7.6 Hz, 1H), 4.45 (dd, J=10.1, 2.8 Hz, 1H), 3.34 (tt, J=10.1, 7.7 Hz, 1H), 2.95-2.76 (m, 4H), 2.76-2.66 (m, 3H), 2.65 (s, 5H), 2.49-2.37 (m, 1H), 2.04-1.90 (m, 1H); MS (APCI.sup.+) m/z 484 (M+H).sup.+.

    Example 2E. 6-chloro-4-oxo-N-(3-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1260] The methodologies described in Example 4 substituting Example 52D for Example 30 gave the title compound and Example 60. .sup.1H NMR (500 MHz, Chloroform-d) ppm 7.90 (d, J=2.6 Hz, 1H), 7.50 (dd, J=8.8, 2.7 Hz, 1H), 7.10-7.03 (m, 2H), 4.87 (dd, J=13.6, 3.3 Hz, 1H), 4.71 (p, J=7.6 Hz, 1H), 3.33 (tt, J=10.2, 7.7 Hz, 1H), 3.20 (dd, J=17.3, 3.3 Hz, 1H), 2.93-2.82 (m, 3H), 2.76-2.64 (m, 2H), 2.67 (s, 6H); MS (APCI.sup.+) m/z 498 (M+H).sup.+.

    Example 53: 6-chloro-4-oxo-N-[(3R,6S)-6-{5-[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 152)

    Example 53A: tert-butyl ((3R,6S)-6-(2-((1s,3R)-3-(trfluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)tetrahydro-2H-pyran-3-yl)carbamate

    [1261] The methodologies described in Example 25P substituting Example 51A for Example 25L and substituting (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (purchased from Astatech) for Example 25O gave the title compound. MS (APCI.sup.+) m/z 425 (M+H).sup.+.

    Example 53B: tert-butyl ((3R,6S)-6-(5-((1s,3R)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)carbamate

    [1262] The methodologies described in Example 25Q substituting Example 53A for Example 25P gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d) ppm 4.70 (p, J=7.6 Hz, 1H), 4.62 (dd, J=9.9, 3.2 Hz, 1H), 4.43 (s, 1H), 4.16 (dd, J=11.0, 4.2 Hz, 1H), 3.75 (s, 1H), 3.41-3.21 (m, 2H), 2.87 (dtd, J=10.1, 7.4, 2.9 Hz, 1H), 2.72 (t, J=9.5 Hz, 2H), 2.29-2.01 (m, 3H), 1.45 (s, 9H); MS (APCI.sup.+) m/z 408 (M+H).sup.+.

    Example 53C: (3R,6S)-6-(5-((1s,3R)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)tetrahydro-2H-pyran-3-amine

    [1263] The methodologies described in Example 21B substituting Example 53B for Example 21A gave the title intermediate. MS (APCI.sup.+) m/z 308 (M+H).sup.+.

    Example 53D: 6-chloro-4-oxo-N-[(3R,6S)-6-{5-[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1264] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (purchased from Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 53C for Example 30C gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d) ppm 7.89 (dd, J=2.7, 1.1 Hz, 1H), 7.50 (ddd, J=8.9, 2.7, 0.9 Hz, 1H), 7.06 (dd, J=8.8, 1.7 Hz, 1H), 6.58 (dd, J=7.9, 2.9 Hz, 1H), 4.92 (dd, J=13.0, 3.4 Hz, 1H), 4.78-4.66 (m, 2H), 4.24-4.14 (m, 1H), 4.18-4.10 (m, 1H), 3.50-3.30 (m, 2H), 3.20 (dd, J=17.3, 3.4 Hz, 1H), 2.89 (tdd, J=13.0, 9.4, 6.1 Hz, 3H), 2.78-2.64 (m, 2H), 2.38-2.07 (m, 2H), 1.73 (dddd, J=20.6, 18.0, 10.1, 4.8 Hz, 1H), 1.41 (s, 1H); MS (APCI.sup.+) m/z 516 (M+H).sup.+.

    Example 54: 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]acetamide (Compound 153)

    [1265] The methodologies described in Example 30 substituting 2-(4-chloro-3-fluorophenoxy)acetic acid for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 53C for Example 30C gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d) ppm 7.34 (t, J=8.6 Hz, 1H), 6.77 (dd, J=10.2, 2.8 Hz, 1H), 6.69 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 4.77-4.65 (m, 2H), 4.47 (s, 2H), 4.22-4.12 (m, 2H), 3.43-3.28 (m, 2H), 2.93-2.82 (m, 2H), 2.78-2.64 (m, 1H), 2.27 (dd, J=13.5, 4.5 Hz, 1H), 2.22-2.06 (m, 2H), 1.77-1.58 (m, 1H); MS (APCI.sup.+) m/z 494 (M+H).sup.+.

    Example 55: (2R,4R)-6-chloro-N-(3-{3-[(4-chloro-3-fluorophenoxy)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 154)

    [1266] The purification conditions of Example 57 also afforded this title compound (as an earlier eluting fraction). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.37 (dd, J=2.8, 1.0 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 7.14 (dd, J=11.3, 2.9 Hz, 1H), 6.93-6.89 (m, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.74 (s, 1H), 5.75-5.70 (m, 1H), 5.53 (d, J=1.3 Hz, 1H), 4.82-4.71 (m, 2H), 4.57 (dd, J=12.0, 2.2 Hz, 1H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 1.90 (s, 6H), 1.67 (td, J=12.5, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 504 (MH.sub.2O+H).sup.+.

    Example 56: (2R)-6-chloro-N-(3-{3-[(4-chloro-3-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 155)

    [1267] The reaction and purification conditions described in Example 2B substituting 3-(3-((4-chloro-3-fluorophenoxy)methyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-amine (prepared as described in International Patent Publication WO2017/193030 A1) for the product of Example 2A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.18 (s, 1H), 7.69-7.61 (m, 2H), 7.52 (t, J=8.9 Hz, 1H), 7.22 (dd, J=11.4, 2.9 Hz, 1H), 7.20-7.16 (m, 1H), 6.94 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 5.31 (s, 2H), 5.13 (dd, J=7.7, 6.6 Hz, 1H), 2.98 (d, J=1.3 Hz, 1H), 2.97 (s, 1H), 2.53 (s, 6H); MS (APCI.sup.+) m/z 518 (M+H).sup.+.

    Example 57: (2R,4R)-6-chloro-N-(3-{3-[(4-chloro-3-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 156)

    [1268] The product of Example 56 (24 mg, 0.046 mmol) was combined with methanol (1 mL) and stirred at ambient temperature. Sodium borohydride (10.5 mg, 0.28 mmol) was added. After stirring at ambient temperature for 20 minutes, saturated ammonium chloride solution (0.1 mL) was added. After stirring for another 10 minutes, the resulting mixture was combined with diatomaceous earth (5 g) and concentrated under reduced pressure to a free flowing powder and the powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 15 m 120 g column, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (12 mg, 0.023 mmol, 50% yield) as a later eluting fraction relative to Example 55. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (dd, J=4.5, 2.8 Hz, 1H), 7.21-7.18 (m, 1H), 6.94 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.75 (br s, 1H), 5.30 (s, 2H), 4.81 (dd, J=10.6, 5.9 Hz, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.55 (s, 6H), 2.37 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.77-1.64 (m, 1H); MS (APCI.sup.+) m/z 502 (MH.sub.2O+H).sup.+.

    Example 58: 4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}bicyclo[2.2.2]octane-1-carboxamide (Compound 157)

    Example 58A: tert-butyl (4-(((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)carbamate

    [1269] The reaction and purification conditions described in Example 2B substituting (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Chem-Impex) for the product of Example 2A, and 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (Combi-Blocks) for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 428 (M+H).sup.+.

    Example 58B: 4-(2-((1s,3s)-3-(trifluoromethoxy)cyclobutoxy)acetamido)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)bicyclo[2.2.2]octane-1-carboxamide

    [1270] The reaction and purification conditions described in Example 1C substituting the product of Example 58A for the product of Example 1A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.89-8.84 (m, 1H), 8.22-8.12 (m, 2H), 7.37 (d, J=8.3 Hz, 1H), 7.02 (s, 1H), 4.48 (p, J=7.1 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 3.70 (p, J=6.9 Hz, 1H), 3.69 (s, 2H), 2.79-2.68 (m, 2H), 2.18-2.07 (m, 2H), 1.89-1.75 (m, 12H); MS (APCI.sup.+) m/z 524 (M+H).sup.+.

    Example 59: (1r,4r)-4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclohexane-1-carboxamide (Compound 158)

    Example 59A: tert-butyl ((1r,4r)-4-(((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclohexyl)carbamate

    [1271] The reaction and purification conditions described in Example 2B substituting (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Chem-Impex) for the product of Example 2A, and (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (Enamine) for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 402 (M+H).sup.+.

    Example 59B: (1r,4r)-4-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclohexane-1-carboxamide

    [1272] The reaction and purification conditions described in Example 1C substituting the product of Example 59A for the product of Example 1A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.55 (t, J=5.5 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.36 (dd, J=8.6, 2.0 Hz, 1H), 7.24-7.13 (m, 1H), 5.11 (dd, J=8.1, 5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 3.04-2.88 (m, 2H), 2.23-2.12 (m, 1H), 1.89-1.79 (m, 3H), 1.78-1.70 (m, 1H), 1.48-1.33 (m, 2H), 1.37-1.17 (m, 2H); MS (APCI.sup.+) m/z 515 (M+H).sup.+.

    Example 60: rac-(2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 159)

    [1273] The methodologies described in Example 4 substituting Example 52D for Example 30 gave the title compound and Example 52. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.99 (s, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.26 (dd, J=8.8, 2.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 4.90 (p, J=7.5 Hz, 1H), 4.61 (t, J=3.7 Hz, 1H), 4.57 (dd, J=11.1, 2.7 Hz, 1H), 3.44-3.33 (m, 2H), 2.92-2.78 (m, 3H), 2.49 (s, 6H), 2.17-2.08 (m, 1H), 1.91 (ddd, J=14.2, 10.8, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 500 (M+H).sup.+.

    Example 61: rac-(2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 160)

    [1274] The methodologies described in Example 5 substituting Example 51 for Example 4 and purifying by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) gave the title compound. .sup.1H NMR (400 MHz, Chloroform-d, dr 33:1) d ppm 7.44 (d, J=2.6 Hz, 1H), 7.40 (t, J=3.1 Hz, 0.03H), 7.21 (dd, J=8.8, 2.6 Hz, 0.03H), 7.16 (dd, J=8.8, 2.6 Hz, 1H), 7.08 (s, 1H), 7.04 (d, J=5.4 Hz, 0.03H), 6.90 (d, J=8.8 Hz, 0.03H), 6.83 (d, J=8.7 Hz, 1H), 4.94 (dd, J=8.6, 5.4 Hz, 1H), 4.81 (d, J=3.2 Hz, 0.03H), 4.70 (p, J=7.5 Hz, 1H), 4.64 (dd, J=9.6, 3.2 Hz, 1H), 3.34 (tt, J=10.1, 7.7 Hz, 1H), 2.86 (dtt, J=9.9, 7.5, 2.5 Hz, 2H), 2.66 (dddq, J=13.8, 8.8, 5.6, 3.0 Hz, 3H), 2.58-2.48 (m, 2H), 2.22-1.94 (m, 8H); MS (APCI.sup.+) m/z 514 (M+H).sup.+.

    Example 62: (2RS,4RS)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 161)

    [1275] To a suspension of Example 53 (0.070 g, 0.14 mmol) in methanol (2.4 mL) was added sodium borohydride (0.026 g, 0.68 mmol). This mixture was allowed to stir at ambient temperature for 1 hour and then was quenched with a drop of water and concentrated under heated N.sub.2. The residue was diluted with N,N-dimethylformamide (2 mL) and water (0.5 mL), filtered, and purified by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) to give the title compound (0.070 g, 0.14 mmol, quantitative yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.45 (td, J=2.4, 0.9 Hz, 1H), 7.19 (dddd, J=8.7, 2.6, 1.3, 0.6 Hz, 1H), 6.86 (dd, J=8.7, 4.2 Hz, 1H), 6.52 (dd, J=14.3, 8.0 Hz, 1H), 4.93 (dd, J=8.1, 5.4 Hz, 1H), 4.77-4.65 (m, 3H), 4.20-4.05 (m, 2H), 3.45-3.26 (m, 2H), 2.93-2.83 (m, 2H), 2.76-2.60 (m, 2H), 2.34-2.06 (m, 4H), 1.74-1.57 (m, 1H); MS (APCI.sup.+) m/z 500 (MH.sub.2O+H).sup.+. Example 63: (2R)-6-chloro-4-oxo-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 162)

    Example 63A: (R)-tert-butyl (3-(6-chloro-4-oxochroman-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1276] The reaction and purification conditions described in Example 2B substituting tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock) for the product of Example 2A gave the title compound. MS (ESI.sup.+) m/z 407 (M+H).sup.+.

    Example 63B: (2R)-6-chloro-4-oxo-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1277] The reaction and purification conditions described in Example 1C substituting the product of Example 63A for the product of Example 1A and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.38 (s, 1H), 7.68-7.60 (m, 2H), 7.21-7.13 (m, 1H), 5.08 (t, J=7.1 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.72 (s, 2H), 3.76-3.63 (m, 1H), 2.95 (d, J=7.1 Hz, 2H), 2.79-2.67 (m, 2H), 2.23 (s, 6H), 2.20-2.08 (m, 2H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 64: 6-chloro-4-oxo-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 163)

    Example 64A: tert-butyl (1-vinyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamate

    [1278] To a solution of 1-vinyl-2-oxabicyclo[2.2.2]octane-4-carboxylic acid (4.3 g, 23.60 mmol) in toluene (150 mL) was added 4A molecular sieves (6 g, 23.60 mmol), diphenylphosphoryl azide (7.14 g, 26.0 mmol) and triethylamine (3.62 mL, 26.0 mmol) in order at 20 C., and the mixture was stirred under N.sub.2 at 20 C. for 2 hours and then at 120 C. for 2 hours. After insoluble materials were filtered off, the filtrate was concentrated in vacuo. To a solution of the residue in anhydrous tetrahydrofuran (120 mL) was added potassium tert-butoxide (5.83 g, 51.9 mmol) under cooling with ice, the mixture was stirred at 20 C. for 12 hours. After quenching the reaction by addition of 10% aqueous citric acid solution, the mixture was concentrated in vacuo. After dilution of the residue with ethyl acetate, the mixture was washed with saturated sodium hydrogen carbonate solution, water, and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with petroleum ether and ethyl acetate from 100:1 to 10:1 to give the title compound (5.2 g, yield 85%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 5.81 (dd, J=17.54, 10.96 Hz, 1H), 5.15 (d, J=17.54 Hz, 1H), 5.03 (d, J=10.96 Hz, 1H), 4.29 (br s, 1H), 3.99 (s, 2H), 2.05-2.16 (m, 2H), 1.91-2.02 (m, 2H), 1.74-1.91 (m, 4H), 1.42 (s, 9H).

    Example 64B: tert-butyl (1-formyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamate

    [1279] To a solution of the product of Example 64A (2.6 g, 9.75 mmol) in tetrahydrofuran (90 mL) and water (60 mL) was added sodium periodate (6.26 g, 29.2 mmol) and osmium tetroxide (1.239 g, 4.87 mmol) in order at 0 C. and the mixture was stirred for 12 hours at 20 C. One additional reaction on 2.6 g scale was set up as described above. And these two reactions were combined, diluted with water (200 mL), and extracted with ethyl acetate (2250 mL). The combined organic fractions were dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate (100:1 to 4:1) to give the title compound (3.7 g, yield 70.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.57 (s, 1H), 7.26 (s, 1H), 4.33 (br s, 1H), 4.06 (s, 2H), 2.08-2.20 (m, 2H), 1.94-2.05 (m, 2H), 1.81-1.92 (m, 4H), 1.42 (s, 9H).

    Example 64C: tert-butyl (1-formyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamate

    [1280] To a solution of the product of Example 64B (1.9 g, 7.07 mmol) in tetrahydrofuran (60 mL), 2-methylpropan-2-ol (60 mL, 656 mmol) and water (20 mL) was added sodium dihydrogen phosphate (3.39 g, 28.3 mmol) and 2-methyl-2-butene (7.49 mL, 70.7 mmol) and sodium chlorite (1.279 g, 14.14 mmol) in order at 20 C. and the mixture was stirred at 20 C. for 12 hours. One additional reaction on 0.3 g scale and two additional reactions on 0.5 g scale were set up as described above. These four reactions were combined and concentrated under reduced pressure to remove most of volatiles, and the remaining mixture was diluted with water (50 mL), adjusted to pH=12 by aqueous NaOH (1 M), and extracted with methyl tert-butyl ether (50 mL) and ethyl acetate (50 mL) in order. The aqueous layer was adjusted to pH=1 by aqueous HCl (1 M) and extracted with ethyl acetate (2100 mL). The organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (3.1 g, yield 91%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.42 (br s, 1H), 6.68 (br s, 1H), 3.80 (s, 2H), 1.85-1.99 (m, 5H), 1.85-1.99 (m, 1H), 1.73-1.84 (m, 2H), 1.35 (s, 9H).

    Example 64D: cis-3-(trifluoromethoxy)cyclobutanecarbohydrazide

    [1281] A mixture of the product of Example 25N (0.8 g, 2.92 mmol) and hydrazine hydrate (1.419 mL, 14.59 mmol) in ethanol (12.0 mL) was heated at reflux for 16 hours. Solvent and excess hydrazine were removed under the high vacuum to give 0.56 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.08 (s, 1H), 4.76 (p, J=7.6 Hz, 1H), 4.22 (s, 2H), 2.60-2.50 (m, 11H), 2.44 (dtd, J=10.1, 7.1, 2.8 Hz, 2H), 2.34-2.18 (m, 2H).

    Example 64E: tert-butyl (1-(2-(cis-3-(trifluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate

    [1282] To a mixture of the product of Example 64C (0.2 g, 0.737 mmol), the product of Example 64D (0.153 g, 0.774 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.386 mL, 2.211 mmol) in N,N-dimethylformamide (5.0 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.350 g, 0.921 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. Solvent was removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 5-80% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 292 mg of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.77 (s, 1H), 9.37 (s, 1H), 6.72 (s, 1H), 4.78 (p, J=7.6 Hz, 1H), 3.89 (s, 2H), 2.66 (tt, J=9.4, 7.5 Hz, 1H), 2.47 (dp, J=7.0, 2.4 Hz, 1H), 2.28 (dd, J=8.8, 2.9 Hz, 1H), 2.28-2.17 (m, 1H), 1.99-1.90 (m, 4H), 1.84 (ddt, J=19.0, 14.2, 6.0 Hz, 4H), 1.37 (s, 8H).

    Example 64F: tert-butyl (1-(5-(cis-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate

    [1283] The title compound was synthesized using the same procedure as described in Example 25Q substituting the product of Example 25P with the product of Example 64E. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 6.80 (s, 1H), 4.90 (p, J=7.5 Hz, 1H), 3.92 (s, 2H), 3.50-3.38 (m, 1H), 2.84 (dtt, J=9.6, 7.4, 2.5 Hz, 2H), 2.50-2.43 (m, 1H), 2.36-2.23 (m, 2H), 2.12-2.00 (m, 2H), 1.93-1.82 (m, 2H), 1.37 (s, 9H); MS (APCI.sup.+) m/z 433.98 (M+H).sup.+.

    Example 64G: 1-(5-(cis-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-amine, trifluoroacetic acid

    [1284] A solution of the product of Example 64F (0.15 g, 0.346 mmol) in dichloromethane (5.0 mL) was treated with 2,2,2-trifluoroacetic acid (1.333 mL, 17.30 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. Solvent and excess 2,2,2-trifluoroacetic acid were removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 5-80% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 162 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.27 (s, 3H), 4.91 (p, J=7.4 Hz, 1H), 3.89 (s, 2H), 3.45 (tt, J=9.8, 7.8 Hz, 1H), 2.84 (dtt, J=9.6, 7.4, 2.5 Hz, 2H), 2.50-2.33 (m, 3H), 2.23-2.10 (m, 2H), 1.99 (tq, J=11.0, 6.8, 6.2 Hz, 4H); MS (APCI.sup.+) m/z 334.1 (M+H).sup.+.

    Example 64H: 6-chloro-4-oxo-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1285] The product of Example 64G (0.06 g, 0.134 mmol), 6-chloro-4-oxochroman-2-carboxylic acid (0.033 g, 0.148 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.094 mL, 0.537 mmol) were combined in N,N-dimethylformamide (1.5 mL). 2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.064 g, 0.168 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. Solvent was removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 57 mg of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.04 (s, 1H), 7.67 7.60 (m, 2H), 7.17 (d, J=8.7 Hz, 1H), 5.10 (dd, J=8.5, 4.9 Hz, 1H), 4.90 (p, J=7.5 Hz, 1H), 3.99 (t, J=1.3 Hz, 2H), 3.43 (tt, J=9.9, 7.8 Hz, 1H), 3.03-2.79 (m, 5H), 2.73 (s, 1H), 2.50-2.43 (m, 1H), 2.33 (ddt, J=13.1, 11.2, 3.6 Hz, 2H), 2.17-2.11 (m, 1H), 2.09 (ddd, J=15.8, 12.7, 4.0 Hz, 3H), 1.98 (dd, J=10.3, 6.8 Hz, 2H); MS (APCI.sup.+) m/z 541.67 (M+H).sup.+.

    Example 65: (2R,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 164)

    [1286] The reaction and purification conditions described in Example 6C substituting the product of Example 63B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 8.35 (s, 1H), 7.37 (dd, J=2.8, 1.0 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.59 (dd, J=12.0, 2.2 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.72-3.66 (m, 1H), 2.79-2.68 (m, 2H), 2.39-2.30 (m, 1H), 2.26 (s, 6H), 2.20-2.09 (m, 2H), 1.75-1.62 (m, 1H); MS (APCI.sup.+) m/z 487 (MH.sub.2O+H).sup.+.

    Example 66: 6-chloro-4-hydroxy-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 165)

    [1287] To a suspension of the product of Example 64 (0.043 g, 0.079 mmol) in methanol (2.0 mL), sodium tetrahydroborate (6.00 mg, 0.159 mmol) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. Solvent was removed under vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 32 mg of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.66 (s, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.90 (p, J=7.5 Hz, 1H), 4.79 (dd, J=10.6, 5.9 Hz, 1H), 4.60 (dd, J=11.7, 2.3 Hz, 1H), 4.10-4.00 (m, 2H), 3.44 (dd, J=17.7, 2.1 Hz, 1H), 2.85 (dtt, J=9.7, 7.3, 2.4 Hz, 2H), 2.55 (d, J=13.7 Hz, 1H), 2.51-2.44 (m, 1H), 2.41-1.98 (m, 10H); MS (APCI.sup.+) m/z 544.15 (M+H).sup.+.

    Example 67: 2-(4-chloro-3-fluorophenoxy)-N-(3-{5-[rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 166)

    Example 67A: methyl rac-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-chloro-3,4-dihydro-2H-1-benzopyran-2-carboxylate

    [1288] To a solution of methyl 6-chloro-4-hydroxychroman-2-carboxylate (Princeton, 1.49 g, 6.12 mmol) in tetrahydrofuran (24 mL) at 0 C. and was added tert-butyldimethylchlorosilane (TBS-Cl, 2.03 G, 13.5 mmol) followed by imidazole (1.00 g, 14.7 mmol). The cooling bath was removed and the flask was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with water (80 mL), extracted with diethyl ether (325 mL), and concentrated in vacuo. A portion of the residue was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.25 (dd, J=8.7, 2.6 Hz, 1H), 7.16 (dd, J=2.7, 0.7 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 5.07 (dd, J=6.5, 4.6 Hz, 1H), 4.97-4.92 (m, 1H), 3.66 (s, 3H), 2.35 (dt, J=13.9, 4.6 Hz, 1H), 2.15 (dt, J=13.9, 6.2 Hz, 1H), 0.87 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H).

    Example 67B: rac-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-chloro-3,4-dihydro-2H-1-benzopyran-2-carbohydrazide

    [1289] The methodologies described in Example 51A substituting Example 67A for Example 25N and purifying by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) gave the title intermediate. MS (APCI.sup.+) m/z 357 (M+H).sup.+.

    Example 67C: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl]hydrazinecarbonyl}bicyclo[1.1.1]pentan-1-yl)acetamide

    [1290] The methodologies described in Example 30D substituting Example 67B for Example 30C and substituting Hunig's base (1.7 equivalents) for triethylamine gave the title intermediate.

    [1291] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 10.00 (d, J=1.3 Hz, 1H), 9.81 (d, J=1.2 Hz, 1H), 8.76 (s, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.23-7.15 (m, 1H), 7.11-7.05 (m, 1H), 6.88-6.84 (m, 2H), 4.84 (dd, J=10.7, 5.8 Hz, 1H), 4.79 (dd, J=12.1, 2.3 Hz, 1H), 4.48 (s, 2H), 2.41-2.34 (m, 1H), 2.25 (s, 6H), 2.22 (dd, J=13.6, 5.5 Hz, 1H), 1.75 (td, J=12.5, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 521 (MH.sub.2O+H).sup.+.

    Example 67D: 2-(4-chloro-3-fluorophenoxy)-N-{3-[5-(6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-1-yl}acetamide

    [1292] The methodologies described in Example 25Q substituting Example 67C for Example 25 P gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6, dr 25:1) ppm 8.95 (s, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.43 (dd, J=2.7, 1.0 Hz, 1H), 7.39 (t, J=3.2 Hz, 0.07H), 7.27 (dd, J=8.8, 2.7 Hz, 0.05H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 7.09 (dd, J=11.3, 2.8 Hz, 1H), 7.03 (s, 0.06H), 6.93 (d, J=8.8 Hz, 0.06H), 6.87 (ddd, J=9.0, 2.8, 1.2 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.81 (s, 1H), 5.69 (dd, J=11.5, 2.3 Hz, 1H), 5.58-5.53 (m, 0.04H), 4.91 (dd, J=10.3, 5.9 Hz, 1H), 4.75 (s, 0.03H), 4.51 (s, 2H), 2.56-2.51 (m, 1H), 2.51 (s, 6H), 2.32-2.30 (m, 0.09H), 2.15 (ddd, J=13.1, 11.6, 10.4 Hz, 1H); MS (APCI.sup.+) m/z 502 (MH.sub.2O+H).sup.+.

    Example 68: 6-chloro-4-oxo-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 167)

    Example 68A: tert-butyl (4-(2-(cis-3-(trifluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-yl)carbamate

    [1293] The methodologies described in Example 25P substituting Example 51A for Example 25L and substituting 4-(tert-butoxycarbonyl)amino)bicycle[2.2.2]octane-1-carboxyl acid (purchased from AChemBlock) for Example 25O gave the title intermediate. MS (APCI.sup.+) m/z 450 (M+H).sup.+.

    Example 68B: tert-butyl (4-(5-((cis)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

    [1294] The methodologies described in Example 25Q substituting Example 68A for Example 25P gave the title intermediate. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.73-4.62 (m, 1H), 4.40-4.35 (m, 1H), 2.87-2.78 (m, 2H), 2.64 (q, J=10.0 Hz, 2H), 2.09-2.01 (m, 6H), 2.00-1.92 (m, 6H), 1.43 (s, 9H); MS (APCI.sup.+) m/z 432 (M+H).sup.+.

    Example 68C: 4-(5-((cis)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine

    [1295] The methodologies described in Example 21B substituting Example 68B for Example 21A gave the title intermediate. MS (APCI.sup.+) m/z 332 (M+H).sup.+.

    Example 68D: 6-chloro-4-oxo-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1296] The methodologies described in Example 30D substituting 6-chloro-4-oxochroman-2-carboxylic acid (Princeton Bio) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 68C for Example 30C gave the title compound. .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.89 (d, J=2.7 Hz, 1H), 7.48 (dd, J=8.8, 2.7 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.31 (s, 1H), 4.80 (dd, J=13.0, 3.4 Hz, 1H), 4.75-4.65 (m, 1H), 3.32 (tt, J=10.1, 7.7 Hz, 1H), 3.17 (dd, J=17.3, 3.4 Hz, 1H), 2.90-2.80 (m, 3H), 2.65 (tdd, J=10.1, 7.8, 2.9 Hz, 2H), 2.10 (s, 12H); MS (APCI.sup.+) m/z 540 (M+H).sup.+.

    Example 69: 2-(4-chloro-3-fluorophenoxy)-N-[rac-(1R,2S,4R,5S)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]acetamide (Compound 168)

    Example 69A: furan-3-ylmethanol

    [1297] To a solution of furan-3-carboxylic acid (50 g, 446 mmol) in tetrahydrofuran (500 mL) was added a solution of borane in tetrahydrofuran (669 mL, 669 mmol) at 0 C., and the mixture was stirred at 20 C. for 1 hour. One additional vial on 25 g scale and six additional vials on 50 g scale were set up as described above. The reactions conducted in parallel were combined for work up. After cooling to 0 C., the reaction mixture was quenched with water until gas evolution had ceased. After bulk solvent removal, the resulting crude residue was then partitioned between saturated aqueous NaHCO.sub.3 and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate (21000 mL). The combined organic phases were washed with brine (1000 mL), dried Na.sub.2SO.sub.4, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether:ethyl acetate=3:1 to give the title compound (230 g, yield 63.1%) as a yellow oil. .sup.1HNMR (400 MHz, DMSO-d.sub.6) ppm 7.46-7.61 (m, 2H), 4.34 (d, J=5.50 Hz, 2H), 4.97 (t, J=5.50 Hz, 1H), 6.44 (d, J=0.63 Hz, 1H).

    Example 69B: 3-((benzyloxy)methyl)furan

    [1298] To a solution of the product of Example 69A (20 g, 183 mmol) in N,N-dimethylformamide (200 mL) was added NaH (8.81 g, 220 mmol) at 0 C. and the mixture was stirred at 0 C. for 0.5 hour. (Bromomethyl)benzene (37.7 g, 220 mmol) was added at 0 C. and the reaction mixture was stirred at 20 C. for 12 hours. One additional vial on 5 g scale and nine additional vials on 20 g scale were set up as described above. The reactions conducted in parallel were combined for work up. After cooling to 0 C., the reaction was quenched with water until gas evolution ceased. The mixture was extracted with ethyl acetate (33000 mL). The combined organic fractions were washed with brine (21000 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate=100:1 to 50:1 to give the title compound (480 g, yield 91%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.27 (s, 7H), 6.37 (s, 1 H), 4.45 (s, 2H), 4.35 (s, 2H).

    Example 69C: rac-(1R,2R,4R)-5-((benzyloxy)methyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile

    [1299] Acrylonitrile (33.8 g, 638 mmol) was treated portion-wise with zinc chloride (20.85 g, 153 mmol), and the mixture was stirred at 20 C. for 10 minutes. Then the product of Example 69B (30 g, 128 mmol) was added to the mixture and the mixture was stirred at 20 C. for 12 hours. Fifteen additional vials on 30 g scale were set up as described above. The reactions conducted in parallel were combined for work up. The combined reaction mixtures were diluted with ethyl acetate (1000 mL) and purified by column chromatography on silica gel eluted with ethyl acetate: petroleum ether (1:3) to give the title compound (129 g, yield 20.96%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.20-7.41 (m, 5H), 6.01-6.33 (m, 1H), 5.17-5.23 (m, 1H), 5.01-5.08 (m, 1H), 4.40-4.52 (m, 2H), 4.08-4.23 (m, 2H), 3.97-4.07 (m, 1H), 2.72 (dd, J=8.57, 3.81 Hz, 1H), 1.98 (s, 2H), 1.85-1.94 (m, 1H), 1.71-1.82 (m, 1H), 1.17 (t, J=7.13 Hz, 2H).

    Example 69D: rac-(1R,2R,4R)-5-((benzyloxy)methyl)-7-oxabicyclo[2.2.1]heptane-2-carbonitrile

    [1300] To a solution of the product of Example 69C (15 g, 49.7 mmol) in methanol (150 mL) was added Pd/C (5.29 g, 2.487 mmol) under argon, and the mixture was stirred at 20 C. under hydrogen (15 psi) for 2 hours. One additional vial on 1 g scale and two additional vials on 15 g scale were set up as described above. The reactions conducted in parallel were combined for work up. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with methanol (5200 mL). The combined filtrates were concentrated to dryness and the residue was purified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate (3:1) to give the title compound (38 g, yield 64.5%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.25-7.45 (m, 5H), 4.74-4.88 (m, 1H), 4.56-4.71 (m, 1H), 4.37-4.52 (m, 1H), 3.45-3.64 (m, 1H), 2.89-3.23 (m, 1H), 2.09-2.36 (m, 2H), 1.85-2.04 (m, 1H), 1.62-1.84 (m, 1H), 1.05 (dd, J=12.51, 5.50 Hz, 1H).

    Example 69E: rac-(1R,2S,4R)-5-((benzyloxy)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

    [1301] To a solution of the product of Example 69D (27 g, 89 mmol) in ethanol (270 mL) was added and aqueous solution of 3 N KOH (237 mL, 710 mmol) at 20 C., and the mixture was stirred at 100 C. for 16 hours. One additional vial on 1 g scale and one additional vial on 10 g scale were set up as described above. The reactions conducted in parallel were combined for work up. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3500 mL). The aqueous phase was adjusted to pH=1 with 1 N HCl. The mixture was extracted with ethyl acetate (3500 mL), and the combined organic fractions were concentrated under reduced pressure to give the title compound (35 g, yield 85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.03-12.41 (m, 1H), 7.23-7.49 (m, 5H), 4.55-4.67 (m, 1H), 4.33-4.54 (m, 3H), 3.52 (dd, J=9.66, 6.36 Hz, 1H), 2.19-2.38 (m, 1H), 1.70-1.90 (m, 2H), 1.02 (dd, J=12.04, 5.20 Hz, 1H).

    Example 69F: 2-(trimethylsilyl)ethyl (rac-(1S,2R,4S)-5-((benzyloxy)methyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1302] To a mixture of the product of Example 69E (6.0 g, 22.87 mmol), N,N-diisopropylethylamine (11.99 mL, 68.6 mmol) and 2-(trimethylsilyl)ethanol (21.0 g, 178 mmol) in toluene (60 mL) stirred at ambient temperature was added diphenylphosphoryl azide (7.9 mL, 0.00 mmol). The resulting solution was heated at 80 C. for 16 hours and cooled down to ambient temperature. The reaction mixture was diluted with toluene (30 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and then brine (50 mL). The organic phase was dried with magnesium sulfate, filtered and concentrated. The residue was purified on silica gel using a gradient of 0-40% ethyl acetate in heptane to give 5.72 g of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.38-7.23 (m, 5H), 7.03 (d, J=6.3 Hz, 1H), 4.50-4.35 (m, 3H), 4.14 (d, J=5.9 Hz, 1H), 4.06-3.97 (m, 2H), 3.52-3.41 (m, 2H), 3.31-3.25 (m, 2H), 2.19 (tdd, J=11.4, 7.6, 4.7 Hz, 1H), 2.04-1.96 (m, 1H), 1.82-1.65 (m, 1H), 0.90-0.81 (m, 3H), 0.00 (s, 9H).

    Example 69G: 2-(trimethylsilyl)ethyl (rac-(1R2S,4R)-5-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1303] To a solution of the product of Example 69F (5.72 g, 15.15 mmol) in tetrahydrofuran (69 mL) was added 10% Pd(OH).sub.2/C (2.8 g, 9.97 mmol) in a 160 mL stainless steel reactor. The suspension was stirred under 60 psi of hydrogen at ambient temperature for 18 hours. The mixture was filtered and the filtrate was concentrated to give 4.08 g of the title compound, used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 6.99 (d, J=6.3 Hz, 1H), 4.51 (t, J=4.9 Hz, 1H), 4.35 (t, J=5.1 Hz, 1H), 4.12 (d, J=5.9 Hz, 1H), 4.10-3.93 (m, 2H), 3.51-3.37 (m, 1H), 3.24 (td, J=10.4, 4.9 Hz, 1H), 2.06 (td, J=12.0, 11.1, 6.7 Hz, 2H), 1.82-1.72 (m, 1H), 1.65 (dt, J=11.8, 5.9 Hz, 1H), 1.38 (d, J=13.4 Hz, 1H), 0.99-0.76 (m, 3H), 0.00 (s, 9H).

    Example 69H: 2-(trimethylsilyl)ethyl (rac-(1R,2S,4R)-5-cyano-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1304] To a solution of the product of Example 69G (4.08 g, 14.19 mmol) in acetonitrile/water (9:1, 50 mL) were successively added TEMPO (0.222 g, 1.419 mmol) and ammonium acetate (4.38 g, 56.8 mmol) and (diacetoxyiodo)benzene (10.06 g, 31.2 mmol). The mixture was stirred at ambient temperature for 3 hours. Solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0-70% ethyl acetate in heptane to give 3.7 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.20-7.08 (m, 1H), 4.79-4.68 (m, 1H), 4.36 (d, J=5.6 Hz, 1H), 4.06-3.96 (m, 2H), 3.64 (ddd, J=8.1, 6.2, 3.4 Hz, 1H), 3.30 (s, 1H), 3.09-2.88 (m, 1H), 2.18 (dd, J=13.5, 8.1 Hz, 1H), 2.11-1.82 (m, 1H), 1.60 (dt, J=12.1, 4.6 Hz, 2H), 0.94-0.85 (m, 2H), 0.00 (s, 9H).

    Example 69I: rac-(1R,2S,4R,5S)S-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

    [1305] A solution of the product of Example 69H (3.7 g, 13.10 mmol) and potassium hydroxide (43.7 mL, 131 mmol) in ethanol (40 mL) was heated at 80 C. for 5 hours. Solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous phase was then acidified with cold 0.5 N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 0.56 g of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.18 (s, 1H), 7.03 (d, J=6.4 Hz, 1H), 4.62 (d, J=5.5 Hz, 1H), 4.25 (d, J=5.7 Hz, 1H), 4.08-3.91 (m, 2H), 3.52 (dd, J=8.4, 6.1 Hz, 1H), 2.54 (dd, J=9.1, 4.5 Hz, 1H), 1.93-1.72 (m, 2H), 1.59 (dd, J=12.4, 9.1 Hz, 1H), 1.49 (dt, J=12.6, 4.2 Hz, 1H), 0.98-0.81 (m, 2H), 0.00 (s, 9H).

    Example 69J: 2-(trimethylsilyl)ethyl [rac-(1R,2S,4R,5S)-5-{2-[cis-3-(trifluoromethoxy)cyclobutane-1-carbonyl]hydrazinecarbonyl}-7-oxabicyclo[2.2.1]heptan-2-yl]carbamate

    [1306] The title compound was synthesized using the procedure described in Example 64E substituting the product of Example 64C with the product of Example 69I. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.75 (s, 2H), 7.02 (d, J=6.4 Hz, 1H), 4.77 (p, J=7.4 Hz, 1H), 4.53 (d, J=5.4 Hz, 1H), 4.23 (d, J=5.6 Hz, 1H), 4.01 (t, J=8.8 Hz, 2H), 3.64-3.46 (m, 2H), 3.32 (s, 6H), 2.73-2.60 (m, 1H), 2.48-2.42 (m, 1H), 2.25 (q, J=9.6 Hz, 2H), 1.94-1.81 (m, 2H), 1.60-1.44 (m, 2H), 0.89 (t, J=8.4 Hz, 2H), 0.00 (d, J=1.0 Hz, 9H).

    Example 69K: 2-(4-chloro-3-fluorophenoxy)-N-[rac-(1R,2S,4R,5S)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]acetamide

    [1307] A suspension of the product of Example 69J (0.105 g, 0.218 mmol) in acetonitrile (5.0 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.114 mL, 0.654 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.083 g, 0.436 mmol). The reaction mixture was stirred at 50 C. overnight. The mixture was concentrated and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 8 mg of 2-(trimethylsilyl)ethyl [rac-(1R,2S,4R,5S)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]carbamate. This intermediate was dissolved in dichloromethane (1.0 mL) and treated with 2,2,2-trifluoroacetic acid (0.5 mL, 6.49 mmol) at ambient temperature for 45 minutes. Solvent and excess 2,2,2-trifluoroacetic acid were removed under high vacuum to give rac-(1R,2S,4R,5S)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-amine that was used without further purification. To a mixture of the crude amine, 2-(4-chloro-3-fluorophenoxy)acetic acid (4.41 mg, 0.022 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.173 mmol) in N,N-dimethylformamide (1 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (9.84 mg, 0.026 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. Solvent was removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 5 mg of the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.33 (t, J=8.6 Hz, 1H), 6.75 (dd, J=10.3, 2.8 Hz, 1H), 6.75-6.60 (m, 2H), 4.91 (d, J=5.6 Hz, 1H), 4.69 (td, J=14.3, 13.5, 6.7 Hz, 1H), 4.59 (d, J=5.8 Hz, 1H), 4.45 (d, J=1.6 Hz, 2H), 4.42-4.30 (m, 1H), 3.39-3.25 (m, 1H), 3.21 (dd, J=9.0, 4.3 Hz, 1H), 2.85 (tdd, J=12.1, 5.9, 1.6 Hz, 2H), 2.67 (td, J=12.5, 11.5, 8.8 Hz, 2H), 2.36 (dt, J=13.2, 5.0 Hz, 1H), 2.30-2.16 (m, 1H), 2.14-1.97 (m, 1H), 1.67 (ddd, J=13.3, 5.8, 3.2 Hz, 2H); MS (APCI.sup.+) m/z 506.02 (M+H).sup.+.

    Example 70: (2R,4R)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 169)

    [1308] Example 62 was purified by chiral SFC (supercritical fluid chromatography) using a (S,S) Whelk-O1 column (20250 mm, 5 micron) eluted with 40% CH.sub.3OH in CO.sub.2 at 34 C. with a CO.sub.2 flow rate of 36 mL/minute, CH.sub.3OH flow rate of 24 mL/minute, front pressure of 171 bar, and back pressure of 100 bar to give the title compound (first isomer eluted out of the column, 0.0093 g, 0.018 mmol, 20% yield). The absolute stereochemistry of this title compound was arbitrarily assigned. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.45 (d, J=2.5 Hz, 1H), 7.20 (dd, J=8.7, 2.5 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.52-6.46 (m, 1H), 5.00-4.87 (m, 2H), 4.75-4.64 (m, 2H), 4.24-4.01 (m, 1H), 3.47-3.28 (m, 1H), 2.91-2.82 (m, 3H), 2.70 (dt, J=20.5, 9.2 Hz, 3H), 2.18 (dd, J=18.4, 6.1 Hz, 3H), 2.10 (d, J=5.1 Hz, 1H); MS (APCI.sup.+) ml; 500 (MH.sub.2O+H).sup.+.

    Example 71: (2S,4S)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 170)

    [1309] Example 62 was purified by chiral SFC (supercritical fluid chromatography) using a (S,S) Whelk-O1 column (20250 mm, 5 micron) eluted with 40% CH.sub.3OH in CO.sub.2 at 34 C. with a CO.sub.2 flow rate of 36 mL/minute, CH.sub.3OH flow rate of 24 mL/minute, front pressure of 171 bar, and back pressure of 100 bar to give the title compound (second isomer eluted out of the column, 0.014 g, 0.028 mmol, 31% yield). The absolute stereochemistry of this title compound was arbitrarily assigned. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.45 (d, J=2.7 Hz, 1H), 7.20 (dd, J=8.7, 2.6 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.45 (d, J=8.0 Hz, 1H), 4.96-4.89 (m, 1H), 4.73-4.65 (m, 2H), 4.13-4.05 (m, 3H), 3.38-3.27 (m, 1H), 2.86 (dd, J=11.7, 7.1 Hz, 2H), 2.74-2.63 (m, 2H), 2.37-2.25 (m, 1H), 2.24-2.14 (m, 1H), 2.11 (d, J=6.6 Hz, 1H), 1.74-1.64 (m, 1H); MS (APCI.sup.+) m t 500 (MH.sub.2O+H).sup.+.

    Example 72: rac-(2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 171)

    [1310] The methodologies described in Example 5 substituting Example 68 for Example 4 gave the title compound. .sup.1H NMR (500 MHz, CDCl.sub.3, dr 33:1) ppm 7.44 (dd, J=2.7, 0.8 Hz, 1H), 7.33 (s, 0.01H), 7.18 (dd, J=8.7, 2.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 0.03H), 6.83 (d, J=8.7 Hz, 1H), 6.39 (s, 0.03H), 6.30 (s, 1H), 4.90 (dd, J=7.9, 5.5 Hz, 1H), 4.79 (d, J=3.5 Hz, 0.02H), 4.69 (p, J=7.7 Hz, 1H), 4.58 (dd, J=8.8, 3.4 Hz, 1H), 3.31 (tt, J=10.1, 7.7 Hz, 1H), 2.84 (dtt, J=9.9, 7.3, 2.6 Hz, 2H), 2.69-2.63 (m, 1H), 2.66-2.57 (m, 2H), 2.18 (ddd, J=13.7, 8.8, 7.9 Hz, 1H), 2.12-2.00 (m, 12H); MS (APCI.sup.+) m/z 542 (M+H).sup.+.

    Example 73: (2S,4R)-6-chloro-4-hydroxy-N-[trans-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 172)

    Example 73A: (2S,4S)-6-chloro-4-hydroxychroman-2-carboxylic acid

    [1311] The reaction and purification conditions described in Example 3B substituting the product of Example 10A for the product of Example 1B gave the title compound. MS (APCI.sup.) m/z 227 (MH).sup..

    Example 73B: (2S,4R)-6-chloro-4-hydroxychromane-2-carboxylic acid

    [1312] The product of Example 73A (140 mg, 0.612 mmol) was combined with trifluoroacetic acid (1.0 mL) and stirred at 30 C. for 2 hours. The reaction mixture was concentrated under high vacuum. The residue was taken up in acetonitrile (3.0 mL), and aqueous ammonium hydroxide (3 M, 3 mL) was added. The resulting mixture was stirred at ambient temperature for 18 hours and then concentrated under high vacuum. The residue was taken up in methanol, filtered through a glass microfiber frit and purified by preparative HPLC [Waters SunFire C18 5 m OBD column, 30150 mm, flow rate 30 mL/minute, 3-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (80 mg, 0.35 mmol, 57% yield).

    [1313] MS (ESI.sup.) m/z 227 (MH).sup..

    Example 73C: (2S,4R)-6-chloro-4-hydroxy-N-[trans-4-({5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1314] The reaction and purification conditions described in Example 3C substituting the product of Example 59A for the product of Example 3A, and the product of Example 73B for the product of Example 3B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90-8.85 (m, 1H), 8.48 (t, J=5.9 Hz, 1H), 8.17 (dd, J=8.3, 2.4 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.24 (dd, J=8.7, 2.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 5.62 (br s, 1H), 4.62-4.53 (m, 2H), 4.43 (d, J=5.2 Hz, 2H), 3.58 (s, 1H), 2.19 (tt, J=11.8, 3.2 Hz, 1H), 2.09 (dt, J=13.9, 3.4 Hz, 1H), 1.97-1.76 (m, 5H), 1.52-1.25 (m, 4H); MS (APCI.sup.+) m/z 512 (M+H).sup.+.

    Example 74: (2R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 173)

    Example 74A: tert-butyl (trans-4-(3-(4-chlorophenyl)azetidine-1-carbonyl)cyclohexyl)carbamate

    [1315] The reaction and purification conditions described in Example 2B substituting 3-(4-chlorophenyl)azetidine (Enamine) for the product of Example 2A, and trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (Ark Pharm) for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 393 (M+H).sup.+.

    Example 74B: (2R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1316] The reaction and purification conditions described in Example 1C substituting the product of Example 74A for the product of Example 1A give the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.14 (d, J=7.9 Hz, 1H), 7.67-7.59 (m, 2H), 7.45-7.35 (m, 4H), 7.16 (d, J=8.7 Hz, 1H), 5.11 (dd, J=7.8, 5.5 Hz, 1H), 4.55 (t, J=8.5 Hz, 1H), 4.22 (t, J=8.9 Hz, 1H), 4.14 (dd, J=8.5, 5.9 Hz, 1H), 3.90-3.79 (m, 1H), 3.77 (dd, J=9.2, 6.2 Hz, 1H), 3.54-3.46 (m, 1H), 3.04-2.88 (m, 2H), 2.22-2.11 (m, 1H), 1.86-1.65 (m, 4H), 1.43-1.16 (m, 4H); MS (APCI.sup.+) m/z 501 (M+H).sup.+.

    Example 75: (2R,4R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 174)

    [1317] The reaction and purification conditions described in Example 6C substituting the product of Example 74B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.87 (d, J=8.1 Hz, 1H), 7.46-7.35 (m, 5H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.69 (br s, 1H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.61 (dd, J=11.9, 2.2 Hz, 1H), 4.56 (t, J=8.5 Hz, 1H), 4.23 (t, J=8.9 Hz, 1H), 4.15 (dd, J=8.5, 5.9 Hz, 1H), 3.91-3.79 (m, 1H), 3.78 (dd, J=9.3, 6.1 Hz, 1H), 3.64-3.50 (m, 1H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.22-2.12 (m, 1H), 1.87-1.66 (m, 5H), 1.48-1.27 (m, 4H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 76: (2S)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 175)

    [1318] The methodologies described in Example 30D substituting the product of Example 10A for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 49B for Example 30C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.19 (s, 1H), 8.47-8.42 (m, 1H), 8.07 (d, J=1.4 Hz, 1H), 7.80 (ddd, J=12.0, 7.7, 2.2 Hz, 1H), 7.70-7.61 (m, 2H), 7.65-7.57 (m, 1H), 7.52 (dt, J=10.7, 8.5 Hz, 1H), 7.23 7.15 (m, 1H), 5.17 (dd, J=8.3, 6.0 Hz, 1H), 3.07-2.92 (m, 2H), 2.57 (s, 6H); MS (APCI.sup.+) m/z 470 (M+H).sup.+.

    Example 77: (2R)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 176)

    [1319] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 49B for Example 30C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.19 (s, 1H), 8.40 (s, 1H), 8.06 (d, J=1.4 Hz, 1H), 7.80 (ddd, J=12.1, 7.8, 2.2 Hz, 1H), 7.70-7.61 (m, 2H), 7.61 (ddd, J=6.0, 4.5, 2.1 Hz, 1H), 7.51 (dt, J=10.7, 8.5 Hz, 1H), 7.24-7.15 (m, 1H), 5.17 (dd, J=8.2, 6.0 Hz, 1H), 3.03-2.96 (m, 2H), 2.57 (s, 6H); MS (APCI.sup.+): 470 (M+H).sup.+.

    Example 78: (2S)-6-chloro-4-oxo-N-[(3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 177)

    [1320] The methodologies described in Example 30D substituting the product of Example 10A for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 53C for Example 30C gave the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.89 (d, J=2.6 Hz, 1H), 7.50 (dd, J=8.8, 2.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.57 (d, J=7.8 Hz, 1H), 4.92 (dd, J=13.2, 3.4 Hz, 1H), 4.78-4.66 (m, 2H), 4.26-4.09 (m, 2H), 3.47-3.29 (m, 2H), 3.20 (dd, J=17.3, 3.4 Hz, 1H), 2.88 (dddd, J=13.2, 11.1, 5.4, 3.0 Hz, 3H), 2.71 (tdd, J=9.2, 7.0, 4.0 Hz, 2H), 2.33 (dtt, J=13.2, 4.6, 2.3 Hz, 1H), 2.32-2.19 (m, 1H), 2.22-2.10 (m, 1H), 1.82-1.70 (m, 1H); MS (APCI.sup.+) m/z 516 (M+H).sup.+.

    Example 79: (2S,4R)-6-chloro-N-{trans-4-[3-(4-chlorophenyl)azetidine-1-carbonyl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 178)

    [1321] The reaction and purification conditions described in Example 3C substituting the product of Example 74A for the product of Example 3A, and the product of Example 73B for the product of Example 3B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.87 (d, J=8.1 Hz, 1H), 7.39-7.29 (m, 4H), 7.24 (d, J=2.6 Hz, 1H), 7.17 (dd, J=8.8, 2.7 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.55 (br s, 1H), 4.55-4.45 (m, 3H), 4.16 (t, J=8.9 Hz, 1H), 4.08 (dd, J=8.5, 6.0 Hz, 1H), 3.84-3.72 (m, 1H), 3.71 (dd, J=9.2, 6.1 Hz, 1H), 3.56-3.45 (m, 1H), 2.15-2.04 (m, 1H), 2.05-1.96 (m, 1H), 1.85 (ddd, J=14.1, 10.7, 3.8 Hz, 1H), 1.79-1.64 (m, 4H), 1.39-1.10 (m, 4H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 80: (2R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl]bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 179)

    Example 80A: tert-butyl{3-[3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1322] The reaction and purification conditions described in Example 1A substituting 1-(4-chlorophenyl)imidazolidin-2-one (Enamine) for metaxalone gave the title compound. MS (APCI.sup.+) m/z 378 (M+H).sup.+.

    Example 80B: (2R)-6-chloro-N-(3-[3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1323] The reaction and purification conditions described in Example 1C substituting the product of Example 80A for the product of Example 1A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 7.68-7.60 (m, 2H), 7.60-7.52 (m, 2H), 7.39-7.30 (m, 2H), 7.22-7.14 (m, 1H), 5.10 (dd, J=7.8, 6.4 Hz, 1H), 3.81-3.72 (m, 2H), 3.48-3.41 (m, 2H), 2.99-2.92 (m, 2H), 2.30 (s, 6H); MS (APCI.sup.+) m/z 486 (M+H).sup.+.

    Example 81: (2S,4S)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 180)

    [1324] The methodologies described in Example 5 substituting Example 76 for Example 4 and purifying by preparative HPLC (Phenomenex Luna C8(2) 5 pm AXIA column (150 mm30 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.51 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.84-7.72 (m, 1H), 7.64-7.56 (m, 1H), 7.50 (dt, J=10.7, 8.5 Hz, 1H), 7.36 (dd, J=2.7, 0.9 Hz, 1H), 7.18 (dd, J=8.7, 2.7 Hz, 1H), 6.90-6.77 (m, 1H), 4.80 (dd, J=10.6, 5.9 Hz, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 2.57 (s, 6H), 2.44-2.26 (m, 2H), 1.77-1.60 (m, 1H); MS (APCI.sup.+) m/z 472 (M+H).sup.+.

    Example 82: (2R,4R)-6-chloro-N-{3-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 181)

    [1325] The methodologies described in Example 5 substituting Example 77 for Example 4 and purifying by preparative HPLC (Phenomenex Luna C8(2) 5 m AXIA column (150 mm30 mm) using a 30-100% gradient of acetonitrile (A) and 0.10% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 7.81 (ddd, J=12.0, 7.8, 2.1 Hz, 1H), 7.62 (ddd, J=8.0, 3.8, 2.0 Hz, 1H), 7.52 (dt, J=10.7, 8.6 Hz, 1H), 7.40 (d, J=2.7 Hz, J H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 4.83 (dd, J=10.7, 5.8 Hz, 1H), 4.67 (dd, J=11.9, 2.3 Hz, 1H), 2.59 (s, 6H), 2.43-2.35 (m, 1H), 1.73 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 472 (M+H).sup.+.

    Example 83: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-(3-phenylazetidine-1-carbonyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 182)

    Example 83A: tert-butyl ((trans)-4-(3-phenylazetidine-1-carbonyl)cyclohexyl)carbamate

    [1326] Palladium hydroxide on carbon (moistened, 10-20% dry basis, 1.5 mg) was added to a solution of the product of Example 74A (15.4 mg, 0.039 mmol) in methanol (2 mL) in a 4 mL-vial followed by addition of sodium borohydride (5.9 mg, 0.157 mmol). After stirring at ambient temperature for 10 minutes, more sodium borohydride (5.9 mg, 0.157 mmol) was added. The vial was flushed with nitrogen, sealed, and stirred for another 2 hours. Water (0.2 mL) was added. The resulting mixture was stirred for 10 minutes, filtered through a syringe filter and purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (13 mg, 0.036 mmol, 93% yield). MS (APCI.sup.+) m/z 359 (M+H).sup.+.

    Example 83B: (2R)-6-chloro-4-oxo-N-[trans-4-(3-phenylazetidine-1-carbonyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1327] The reaction and purification conditions described in Example 1C substituting the product of Example 83A for the product of Example 1A gave the title compound. MS (APCI.sup.+) m/z 467 (M+H).sup.+.

    Example 83C: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-(3-phenylazetidine-1-carbonyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1328] The reaction and purification conditions described in Example 6C substituting the product of Example 83B for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.88 (d, J=8.1 Hz, 1H), 7.41-7.32 (m, 5H), 7.32-7.22 (m, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.80 (dd, J=10.7, 6.0 Hz, 1H), 4.64-4.53 (m, 2H), 4.29-4.19 (m, 1H), 4.19-4.12 (m, 1H), 3.90-3.76 (m, 2H), 3.64-3.53 (m, 1H), 2.34 (ddd, J=13.0, 6.0, 2.3 Hz, 1H), 2.24-2.13 (m, 1H), 1.85-1.64 (m, 5H), 1.47-1.26 (m, 4H); MS (APCI.sup.+) m/z 469 (M+H).sup.+.

    Example 84: (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxoimidazolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 183)

    [1329] The reaction and purification conditions described in Example 6C substituting the product of Example 80 for the product of Example 6B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.75 (s, 1H), 7.61-7.52 (m, 2H), 7.40-7.28 (m, 3H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.66 (br s, 1H), 4.81 (dd, J=10.6, 5.9 Hz, 1H), 4.60 (dd, J=12.0, 2.3 Hz, 1H), 3.77 (dd, J=9.3, 6.6 Hz, 2H), 3.48-3.42 (m, 2H), 2.41-2.33 (m, 1H), 2.32 (s, 6H), 1.70 (td, J=12.3, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 488 (M+H).sup.+.

    Example 85: (2R)-6-chloro-4-oxo-N-[(3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 184)

    [1330] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 53C for Example 30C gave the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.89 (d, J=2.6 Hz, 1H), 7.50 (ddd, J=8.8, 2.7, 0.6 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.61 (d, J=7.9 Hz, 1H), 4.92 (dd, J=12.9, 3.4 Hz, 1H), 4.78-4.66 (m, 2H), 4.17 (dddd, J=14.2, 12.6, 6.5, 2.9 Hz, 2H), 3.50-3.38 (m, 1H), 3.41-3.29 (m, 1H), 3.24-3.14 (m, 1H), 2.96-2.82 (m, 3H), 2.76-2.65 (m, 3H), 2.26 (s, 1H), 2.16 (qd, J=10.0, 9.5, 4.6 Hz, 2H), 1.75-1.64 (m, 1H); MS (APCI.sup.+) m/z 516 (M+H).sup.+.

    Example 86: (2S,4R)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 185)

    Example 86A: tert-butyl (rac-(1R,2S,4R)-5-((benzyloxy)methyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1331] The title compound was synthesized using the same procedure as described in Example 69E substituting 2-(trimethylsilyl)ethanol with tert-butanol. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.29-7.39 (m, 5H), 4.71 (br d, J=6.50 Hz, 1H), 4.42-4.61 (m, 3H), 4.24-4.36 (m, 1H), 3.60-3.72 (m, 1H), 3.60-3.72 (m, 1H), 3.47-3.58 (m, 1H), 3.15-3.33 (m, 1H), 2.40 (tq, J=10.43, 5.14 Hz, 1H), 2.23 (br dd, J=13.45, 8.07 Hz, 1H), 1.89 (td, J=11.94, 6.00 Hz, 1H), 1.35-1.53 (m, 9H), 1.29-1.33 (m, 1H), 0.81-0.98 (m, 1H).

    Example 86B: tert-butyl (rac-(1R,2S,4R)-5-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1332] The title compound was synthesized using the same procedure as described in Example 69F substituting the product of Example 69E with the product of Example 86A. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.77 (br d, J=7.38 Hz, 1H), 4.58 (t, J=5.07 Hz, 1H), 4.32 (br d, J=5.88 Hz, 1H), 3.65-3.84 (m, 3H), 3.48 (t, J=10.01 Hz, 1H), 2.19-2.40 (m, 2H), 1.83-1.95 (m, 3H), 1.44 (s, 9H), 1.34 (dt, J=13.45, 4.35 Hz, 1H), 0.87-1.00 (m, 1H).

    Example 86C: tert-butyl (rac-(1R,2S,4R)-5-cyano-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1333] The title compound was synthesized using the same procedure as described in Example 69G substituting the product of Example 69F with the product of Example 86B. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.75 (t, J=5.07 Hz, 1H), 4.65 (br s, 1H), 4.51 (br d, J=5.63 Hz, 1H), 3.94 (br s, 1H), 2.77-2.87 (m, 1H), 2.62 (dd, J=14.01, 8.13 Hz, 1H), 2.22 (td, J=12.35, 5.82 Hz, 1 H), 1.74 (br dd, J=12.82, 5.32 Hz, 1H), 0.83-0.92 (m, 2H) 0.94-1.01 (m, 1H) 1.23-1.33 (m, 1H) 1.41-1.48 (m, 9H) 1.49-1.52 (m, 1H).

    Example 86D: rac-(1R,2S,4R,5S)-5-((tert-butoxycarbonyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

    [1334] The title compound was synthesized using the same procedure as described in Example 69H substituting the product of Example 69G with the product of Example 86C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.14 (br s, 2H), 7.21-7.43 (m, 6H), 4.60 (d, J=5.63 Hz, 1H), 4.39-4.52 (m, 4H), 3.47-3.56 (m, 1H), 2.51-2.57 (m, 2H), 2.16-2.34 (m, 2H), 1.70-1.89 (m, 3 H), 1.02 (dd, J=11.94, 5.19 Hz, 1H).

    Example 86E: tert-butyl (rac-(1R,2S,4R,5S)-5-(2-(cis-3-(trifluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1335] The title compound was synthesized using the same procedure as described in Example 64E substituting the product of Example 64C with the product of Example 86D. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.77 (d, J=1.8 Hz, 1H), 9.65 (d, J=1.7 Hz, 1H), 6.76 (d, J=6.4 Hz, 1H), 4.74 (p, J=7.5 Hz, 1H), 4.58-4.41 (m, 1H), 4.20 (d, J=5.5 Hz, 1H), 2.65 (tt, J=9.3, 7.8 Hz, 1H), 2.43 (dd, J=9.0, 4.5 Hz, 1H), 2.24 (dd, J=11.1, 8.3 Hz, 2H), 1.94-1.77 (m, 2H), 1.58-1.40 (m, 2H), 1.34 (s, 9H).

    Example 86F: tert-butyl (rac-(1R,2S,4R,5S)-5-(5-(cis-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)-7-oxabicyclo[2.2.1]heptan-2-yl)carbamate

    [1336] The title compound was synthesized using the same procedures described in Example 25Q substituting the product of Example 25P with the product of Example 86E. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 6.89 (d, J=6.2 Hz, 1H), 4.89 (p, J=7.5 Hz, 1H), 4.71 (d, J=5.5 Hz, 1H), 4.38 (d, J=5.5 Hz, 1H), 3.59 (t, J=4.4 Hz, 1H), 3.46-3.35 (m, 1H), 3.24 (dd, J=8.9, 4.5 Hz, 1H), 2.83 (tdt, J=9.7, 7.4, 2.4 Hz, 2H), 2.51-2.35 (m, 1H), 2.09-1.96 (m, 2H), 1.91 (dd, J=12.6, 8.9 Hz, 1H), 1.63-1.52 (m, 1H), 1.39 (s, 9H); MS (DCI.sup.+) m/z 420.3 (M+H).sup.+.

    Example 86G: (rac-(1R,2S,4R,5S)-5-(5-(cis-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)-7-oxabicyclo[2.2.1]heptan-2-amine trifluoroacetic acid

    [1337] To a solution of the product of Example 86F (0.22 g, 0.525 mmol) in dichloromethane (5.0 mL) was added 2,2,2-trifluoroacetic acid (2.5 mL, 32.4 mmol). The reaction mixture was stirred at ambient temperature for one hour. Solvent and excess 2,2,2-trifluoroacetic acid were removed under high vacuum to give 0.24 g of the title compound, which was used without further purification. MS (DCI.sup.+) m/z 320.2 (M+H).sup.+.

    Example 86H: (2S,4R)-6-chloro-4-hydroxy-N-[(1S,2SR,4RS,5S)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1338] To a solution of the product of Example 86G (27 mg, 0.044 mmol), the product of Example 73B (12.47 mg, 0.055 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.174 mmol) in N,N-dimethylformamide (1 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (24.88 mg, 0.065 mmol) and the mixture was stirred at ambient temperature for 30 minutes. Solvent was removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 13 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.10 (dd, J=6.7, 3.9 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.24 (dt, J=8.8, 2.1 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 4.90 (p, J=7.4 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.62 (ddd, J=14.2, 7.1, 3.5 Hz, 2H), 4.47 (dd, J=10.0, 5.4 Hz, 1H), 3.95 (dq, J=11.3, 4.1 Hz, 1H), 3.31 (dd, J=8.8, 4.7 Hz, 1H), 2.83 (dtd, J=10.2, 7.4, 3.0 Hz, 2H), 2.19-1.89 (m, 5H), 1.72 (ddq, J=12.9, 8.8, 5.5, 4.4 Hz, 1H).

    Example 87: (2S,4S)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 186)

    Example 87A: (2S)-6-chloro-4-oxo-N-[(1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1339] To the mixture of the product of Example 86G (75.0 mg, 0.121 mmol), the product of Example 10A (34.3 mg, 0.151 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.085 mL, 0.485 mmol) in N,N-dimethylformamide (1 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (69.1 mg, 0.182 mmol) and the mixture was stirred at ambient temperature for 30 minutes. Solvent was removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 44 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.37 (d, J=6.8 Hz, 1H), 7.67-7.58 (m, 2H), 7.16 (dd, J=8.6, 1.1 Hz, 1H), 5.13 (ddd, J=8.2, 5.7, 3.5 Hz, 1H), 4.90 (p, J=7.6 Hz, 1H), 4.81 (d, J=5.5 Hz, 1H), 4.45 (d, J=5.5 Hz, OH), 4.36 (d, J=5.5 Hz, 1H), 3.90 (td, J=7.6, 3.4 Hz, 1H), 3.32-3.25 (m, 1H), 3.05-2.91 (m, 2H), 2.93-2.77 (m, 2H), 2.22-2.01 (m, 2H), 1.98 (ddd, J=12.3, 8.9, 2.9 Hz, 1H), 1.63 (ddt, J=17.8, 13.1, 4.5 Hz, 1H).

    Example 87B: (2S,4S)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1340] The title compound was synthesized using the same procedure as described in Example 6C substituting the product of Example 6B with the product of Example 87A. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.02 (t, J=7.5 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.19 (dt, J=8.7, 2.4 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.63 (s, 1H), 4.90 (p, 1=7.5 Hz, 1H), 4.80 (q, J=6.6, 5.7 Hz, 2H), 4.66 (dt, J=11.7, 2.5 Hz, 1H), 4.48 (t, J=5.8 Hz, 1H), 3.95 (ddq, J=8.2, 5.6, 2.8 Hz, 1H), 3.30 (d, J=4.7 Hz, 1H), 2.89-2.78 (m, 2H), 2.54 (t, J=3.7 Hz, OH), 2.38-2.27 (m, 1H), 2.19-1.96 (m, 3H), 1.84-1.73 (m, 1H), 1.71 (dq, J=13.1, 5.1, 4.5 Hz, 1H); MS (APCI.sup.+) m/z 530.64 (M+H).sup.+.

    Example 88: (2R,4R)-6-chloro-4-hydroxy-N-[1RS,2SR,4RS,5SR)-5-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 187)

    [1341] The title compound was synthesized using the same procedures described in Example 87A through Example 87B substituting the product of Example 10A with the product of Example 1B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.02 (dd, J=8.2, 6.8 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.19 (dt, J=8.7, 2.4 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.69 (s, 1H), 4.90 (p, J=7.5 Hz, 1H), 4.80 (q, J=6.8, 5.7 Hz, 2H), 4.66 (dt, J=11.8, 2.5 Hz, 1H), 4.48 (t, J=5.7 Hz, 1H), 3.95 (ddt, J=8.2, 5.8, 2.7 Hz, 1H), 3.47-3.34 (m, 11H), 3.31 (dd, J=8.8, 4.7 Hz, 1H), 2.83 (dtd, J=10.1, 7.4, 2.9 Hz, 2H), 2.38-2.27 (m, 1H), 2.19-1.93 (m, 3H), 1.84-1.73 (m, 1H), 1.76-1.66 (m, 1H); MS (APCI.sup.) m/z 530.64 (M+H).sup.+.

    Example 89: (2R)-6-chloro-4-oxo-N-[(1r,4R)-4-{2-oxo-3-[3-(trifluoromethoxy)cyclobutyl]imidazolidin-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 188)

    Example 89A: benzyl ((1r,4r)-4-(2-oxo-3-(3-(trifluoromethoxy)cyclobutyl)imidazolidin-1-yl)cyclohexyl)carbamate

    [1342] The reaction and purification conditions described in Example 1A substituting the product of Example 25O for 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid, and the product of Example 37C for metaxalone gave the title compound. MS (APCI.sup.+) m/z 456 (M+H).sup.+.

    Example 89B: (2R)-6-chloro-4-oxo-N-[(1r,4R)-4-{2-oxo-3-[3-(trifluoromethoxy)cyclobutyl]imidazolidin-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1343] The reaction and purification conditions described in Example 1C substituting the product of Example 89A for the product of Example 1A, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.16 (dd, J=8.0, 1.4 Hz, 1H), 7.67-7.61 (m, 2H), 7.17 (dd, J=8.7, 0.6 Hz, 1H), 5.11 (dd, J=7.9, 5.7 Hz, 1H), 4.89 (tt, J=7.1, 3.6 Hz, 0.4H, trans cyclobutane), 4.59 (p, J=7.2 Hz, 0.6H, cis cyclobutane), 4.47-4.39 (m, 0.4H, trans cyclobutane), 4.08-3.88 (m, 0.6H, cis cyclobutane), 3.56-3.42 (m, 2H), 3.31 (d, J=1.9 Hz, 2H), 3.25-3.19 (m, 2H), 3.03-2.91 (m, 2H), 2.50-2.43 (m, 2H), 2.38-2.32 (m, 2H), 1.84-1.78 (m, 1H), 1.74-1.69 (m, 1H), 1.60-1.43 (m, 4H), 1.39-1.25 (m, 2H); MS (APCI.sup.+) m/z 530 (M+H).sup.+.

    Example 90: (2R)-6,7-difluoro-4-oxo-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 189)

    Example 90A: tert-butyl [4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]carbamate

    [1344] The reaction and purification conditions described in Example 2B substituting tert-butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 437 (M+H).sup.+.

    Example 90B: (E)-4-(4,5-difluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid

    [1345] Maleic anhydride (1.90 g, 19.37 mmol) and aluminum chloride (5.17 g, 38.7 mmol) were combined with dichloroethane (20 mL) and stirred at 50 C. for 2 minutes. 3,4-Difluoroanisole (2.0 mL, 16.85 mmol) was added dropwise over a period of 2 minutes. The resulting reaction mixture was stirred at 50 C. for 5 hours and then at ambient temperature for 18 hours before being poured into a mixture of concentrated aqueous HCl (11.6 M, 20 mL) and ice (about 100 grams). After all ice was melted and while the mixture was still cold, the precipitate was collected by filtration through filter paper, and dried in a 40 C. vacuum oven overnight to give the title compound (1.54 g, 6.75 mmol, 40% yield). .sup.1H NMR (DMSO-d.sub.6) ppm 13.00 (br s, 1H), 11.67 (s, 1H), 7.90 (d, J=15.5 Hz, 1H), 7.83 (dd, J=11.4, 9.4 Hz, 1H), 7.11-7.05 (m, 1H), 6.65 (d, J=15.4 Hz, 1H); MS (ESI.sup.) m/z 227 (MH).sup..

    Example 90C: 6,7-difluoro-4-oxochroman-2-carboxylic acid

    [1346] The product of Example 90B (340 mg, 1.49 mmol) was suspended in water (7.45 mL) and stirred at ambient temperature. Aqueous NaOH (1.0 M, 1.64 mL) was added dropwise over a period of 2 minutes. The reaction mixture was heated to 100 C. and stirred at that temperature for 2 minutes and then cooled to ambient temperature over a period of 15 minutes. Aqueous HCl (6.0 M) was added dropwise to adjust the pH to about 1. The resulting milky solution was partitioned between dichloromethane (230 mL) and water (10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 0-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (0.2 g, 0.88 mmol, 59% yield). MS (ESI.sup.) m/z 227 (MH).sup..

    Example 90D: (R)-6,7-difluoro-4-oxochroman-2-carboxylic acid

    [1347] The product of Example 90C was purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 6 mL/minute, 80% ethanol and 0.1% trifluoroacetic acid in heptane (isocratic gradient)] to give the title compound as the earlier eluting fraction. MS (ESI.sup.) m/z 227 (MH).sup..

    Example 90E: (2R)-6,7-difluoro-4-oxo-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1348] The reaction and purification conditions described in Example 1C substituting the product of Example 90A for the product of Example 1A, and the product of Example 90D for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.69 (s, 1H), 7.66 (dd, J=10.3, 9.2 Hz, 1H), 7.30 (dd, J=11.5, 6.5 Hz, 1H), 6.99 (s, 1H), 5.06 (dd, J=8.4, 5.0 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.73-3.63 (m, 1H), 3.67 (s, 2H), 2.98-2.84 (m, 2H), 2.77-2.68 (m, 2H), 2.16-2.07 (m, 2H), 1.90-1.83 (m, 12H); MS (APCI.sup.+) m/z 547 (M+H).sup.+.

    Example 91: (2S,4S)-6-chloro-4-hydroxy-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 190)

    [1349] The title compound was synthesized using the same procedures as described in Example 87A through Example 87B substituting the product of Example 86G with product of Example 64G. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.67 (s, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.68 (s, 1H), 4.90 (p, J=7.5 Hz, 1H), 4.79 (dd, J=10.6, 5.9 Hz, 1H), 4.60 (dd, J=11.7, 2.3 Hz, 1H), 4.05 (t, J=1.9 Hz, 2H), 3.49-3.40 (m, 1H), 2.85 (tdt, J=9.7, 7.4, 2.3 Hz, 2H), 2.51-2.44 (m, 1H), 2.41-2.13 (m, 6H), 2.13-1.98 (m, 4H), 1.77 (dt, J=12.8, 10.9 Hz, 1H); MS (APCI.sup.+) m/z 519.06 (M+H).sup.+.

    Example 92: (2R,4R)-6-chloro-4-hydroxy-N-(1-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 191)

    [1350] The title compound was synthesized using the same procedures as described in Example 87A through Example 87B substituting the product of Example 86G with the product of Example 64G and the product of Example 10A with the product of Example 1B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.66 (s, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.19 (dd, J=8.8, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.90 (p, J=7.4 Hz, 1H), 4.79 (dd, J=10.5, 5.9 Hz, 1H), 4.60 (dd, J=11.7, 2.3 Hz, 1H), 4.10-4.00 (m, 2H), 2.85 (dtd, J=9.9, 7.4, 2.8 Hz, 2H), 2.50-2.43 (m, 1H), 2.41-2.27 (m, 3H), 2.31-2.20 (m, 1H), 2.23-2.16 (m, 1H), 2.16 (d, J=8.0 Hz, 1H), 2.13-1.99 (m, 2H), 2.06 (s, 2H), 1.77 (dt, J=12.7, 10.9 Hz, 1H); MS (APCI.sup.+) m/z 519.06 (M+H).sup.+.

    Example 93: (2R)-6-chloro-4-oxo-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 192)

    [1351] The reaction and purification conditions described in Example 1C substituting the product of Example 90A for the product of Example 1A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 1 7.68 (s, 1H), 7.65-7.58 (m, 2H), 7.15 (dd, J=8.8, 0.5 Hz, 1H), 6.98 (s, 1H), 5.04 (dd, J=8.5, 4.8 Hz, 1H), 4.47 (p, J=7.2 Hz, 1H), 3.72-3.64 (m, 1H), 3.67 (s, 2H), 2.98-2.85 (m, 2H), 2.76-2.68 (m, 2H), 2.15-2.06 (m, 2H), 1.92-1.82 (m, 12H); MS (APCI.sup.+) m/z 545 (M+H).sup.+.

    Example 94: (2S,4R)-6-chloro-4-hydroxy-N-[4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 193)

    [1352] The reaction and purification conditions described in Example 3C substituting the product of Example 58A for the product of Example 3A, and the product of Example 73B for the product of Example 3B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89-8.85 (m, 1H), 8.20 (t, J=6.0 Hz, 1H), 8.16 (dd, J=8.4, 2.4 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.23 (dd, J=8.8, 2.7 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 5.61 (s, 1H), 4.61-4.53 (m, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.09-1.99 (m, 1H), 2.02-1.92 (m, 1H), 1.95-1.77 (m, 12H); MS (APCI.sup.+) m/z 538 (M+H).sup.+.

    Example 95: (2R,4R)-6,7-difluoro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 194)

    [1353] The reaction and purification conditions described in Example 6C substituting the product of Example 90 for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.32 (s, 1H), 7.36-7.28 (m, 1H), 7.00 (s, 1H), 6.96 (dd, J=11.9, 7.0 Hz, 1H), 5.70 (s, 1H), 4.74 (dd, J=10.7, 6.0 Hz, 1H), 4.56 (dd, J=11.8, 2.3 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.73-3.64 (m, 3H), 2.78-2.68 (m, 2H), 2.26 (ddd, J=12.9, 5 9, 2.3 Hz, 1H), 2.17-2.07 (m, 2H), 1.94-1.87 (m, 12H), 1.72 (ddd, J=13.0, 11.9, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 549 (M+H).sup.+.

    Example 96: (2R,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 195)

    [1354] The reaction and purification conditions described in Example 6C substituting the product of Example 93 for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.37 (dd, J=2.7, 1.0 Hz, 1H), 7.31 (s, 1H), 7.18 (dd, J=8.6, 2.7 Hz, 1H), 7.00 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.69 (s, 1H), 4.77 (dd, J=10.7, 5.9 Hz, 1H), 4.55 (dd, J=11.8, 2.2 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.73-3.64 (m, 1H), 3.68 (s, 2H), 2.78-2.68 (m, 2H), 2.26 (ddd, J=12.9, 6.0, 2.3 Hz, 1H), 2.16-2.06 (m, 2H), 1.96-1.87 (m, 12H), 1.72 (ddd, J=13.0, 11.9, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 547 (M+H).sup.+.

    Example 97: (2R,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.1.1]hexan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 196)

    Example 97A: (R)-tert-butyl (4-(6-chloro-4-oxochroman-2-carboxamido)bicyclo[2.1.1]hexan-1-yl)carbamate

    [1355] The reaction and purification conditions described in Example 2B substituting tert-butyl (4-aminobicyclo[2.1.1]hexan-1-yl)carbamate (Matrix) for the product of Example 2A gave the title compound. MS (APCI.sup.+) m/z 365 (MC(CH.sub.3).sub.3+H).sup.+.

    Example 97B: (2R)-6-chloro-4-oxo-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.1.1]hexan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1356] The reaction and purification conditions described in Example 1C substituting the product of Example 97A for the product of Example 1A, and the product of Example 13P for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 97C: (2R,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.1.1]hexan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1357] The reaction and purification conditions described in Example 6C substituting the product of Example 97B for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.41 (s, 1H), 8.11 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.19 (ddd, J=8.6, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (s, 1H), 4.83-4.77 (m, 1H), 4.59 (dd, J=12.0, 2.2 Hz, 1H), 4.49 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.73-3.68 (m, 1H), 2.78-2.70 (m, 2H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.20-2.11 (m, 2H), 2.08-2.04 (m, 2H), 1.85-1.77 (m, 6H), 1.72 (ddd, J=12.8, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 501 (MH.sub.2O+H).sup.+.

    Example 98: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{2-oxo-3-[3-(trifluoromethoxy)cyclobutyl]imidazolidin-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 197)

    [1358] The reaction and purification conditions described in Example 6C substituting the product of Example 89 for the product of Example 6B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.93-7.88 (m, 2H), 7.38 (d, J=2.7 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.90 (tt, J=7.1, 3.7 Hz, 0.4H, trans cyclobutane), 4.81 (dd, J=10.7, 6.0 Hz, 1H), 4.64-4.55 (m, 1.6H), 4.03-3.94 (m, 0.6H, cis cyclobutane), 3.62-3.57 (m, 1H), 3.51-3.30 (m, 3H), 3.27-3.21 (m, 2H), 2.67-2.61 (m, 1H), 2.47 (ddd, J=9.8, 5.9, 2.8 Hz, 2H), 2.41-2.31 (m, 3H), 1.85-1.77 (m, 2H), 1.76-1.67 (m, 1H), 1.61-1.55 (m, 2H), 1.58-1.46 (m, 2H), 1.45-1.34 (m, 2H); MS (APCI.sup.+) m/z 514 (MH.sub.2O+H).sup.+.

    Example 99: (2R,4S)-6-chloro-4-hydroxy-N-[trans-4-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 198)

    [1359] The product of Example 6C (12 mg, 0.023 mmol) was dissolved in trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred at ambient temperature for 1 hour. The solution was concentrated under reduced pressure. The resulting residue was taken up in acetonitrile (2 mL) and aqueous ammonium hydroxide (1.7 M, 5 mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in methanol (2 mL) and filtered through a glass microfiber frit. The residue was purified by reversed-phase chiral HPLC [Phenomenex Lux i-Cellulose-5 5 m column, 21.2150 mm, flow rate 25 mL/minute, 30-60% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, pH 8.2)] to give the title compound (6 mg, 0.012 mmol, 50% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91-8.86 (m, 1H), 8.50 (t, J=6.0 Hz, 1H), 8.18 (dd, J=8.3, 2.4 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.25 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 5.63 (s, 1H), 4.62-4.54 (m, 2H), 4.43 (d, J=5.9 Hz, 2H), 3.63-3.57 (m, 1H), 2.19 (tt, J=12.1, 3.3 Hz, 1H), 2.09 (dt, J=13.8, 3.3 Hz, 1H), 1.91 (ddd, J=14.2, 10.9, 3.8 Hz, 1H), 1.87-1.77 (m, 4H), 1.51-1.40 (m, 2H), 1.40-1.26 (m, 2H); MS (APCI.sup.+) m/z 512 (M+H).sup.+.

    Example 100: (2S,4S)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 199)

    Example 100A: rac-(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1360] The reaction and purification conditions described in Example 3B substituting 6-chloro-4-oxochroman-2-carboxylic acid (Princeton Bio) for the product of Example 1B gave the title compound. MS (ESI.sup.) m/z 227 (MH).

    Example 100B: (2S,4S)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1361] The title compound was prepared using the procedures described for the synthesis of Example 131D, substituting the product from Example 100A for the product from Example 73B. The crude product was purified by chiral SFC separation [Column: CHIRALPAK IG, 10250 mm, 5 m, gradient: 40% methanol in CO.sub.2 (isocratic), flow rate: 15 g/minute; column temperature: 40 C.; automatic back-pressure regulator setting: 1700 psi] to give the title compound as the later eluting fraction. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 7.95 (dd, J=9.5, 2.0 Hz, 1H), 7.87 (dd, J=8.5, 2.0 Hz, 1H), 7.84-7.78 (m, 1H), 7.41-7.37 (m, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.74-5.70 (m, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=12.0, 2.5 Hz, 1H), 2.60 (s, 6H), 2.41-2.34 (m, 1H), 1.77-1.67 (m, 1H); MS (ESI) m/z 488 (MH).

    Example 101: (2S,4S)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 200)

    Example 101A: 6-chloro-4-oxo-N-(3-{4-[6-(triiodomethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1362] To a solution of the product from Example 132A (240 mg, 0.609 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL, 64.9 mmol) and the resulting solution was stirred at room temperature for 16 hours. The volatiles were removed in vacuo. The residue was combined with 6-chloro-4-oxochroman-2-carboxylic acid (134 mg, 0.593 mmol) and N,N-diisopropylethylamine (0.311 mL, 1.780 mmol) in N,N-dimethylformamide (5 mL). (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 271 mg, 0.712 mmol) was added, and the reaction mixture stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (50 mL) and washed with brine (350 mL), and the combined organic extract were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to give the title compound (186 mg, 0.289 mmol, 48.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.19 (s, 1H), 9.14 (d, J=2.1 Hz, 1H), 8.36 (dd, J=8.4, 2.1 Hz, 1H), 8.12 (d, J=1.3 Hz, 1H), 7.93-7.88 (m, 2H), 7.70-7.64 (m, 2H), 7.20 (dd, J=8.5, 0.8 Hz, 1H), 5.17 (dd, J=8.9, 5.4 Hz, 1H), 3.02-2.97 (m, 2H), 2.56 (s, 6H).

    Example 101B: (2S,4S)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1363] The product from Example 101A (163 mg, 0.324 mmol) was suspended in methanol (7 mL) and cooled to 0 C. Sodium borohydride (16 mg, 0.42 mmol) was added slowly portionwise. The reaction mixture was stirred at 0 C. for 1 hour and was quenched with 1 M HCl (25 mL) and extracted with ethyl acetate (40 mL3). The combined organic extract was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to afford 6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (105 mg), which was subjected to chiral SFC separation [Column: Chiralpak IG, 10250 mm, 5 m, gradient: 35% methanol in CO.sub.2 (isocratic), flow rate: 15 g/minute; column temperature: 40 C.; automatic back-pressure regulator setting: 1700 psi] to give the title compound as the later eluting fraction. (15 mg, 9%).

    [1364] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.14 (d, J=2.0 Hz, 1H), 8.93 (s, 1H), 8.36 (dd, J=8.0, 2.0 Hz, 1H), 8.13 (d, J=1.5 Hz, 1H), 7.94-7.87 (m, 2H), 7.41-7.38 (m, 1H), 7.24-7.18 (m, 1H), 6.90 (d, J=8.5 Hz, 1H), 5.73 (s, 1H), 4.83 (dd, J=10.5, 6.0 Hz, 1H), 4.67 (dd, J=12.0, 2.5 Hz, 1H), 2.58 (s, 6H), 2.42-2.34 (m, 1H), 1.78-1.69 (m, 1H); MS (ESI) m/z 505 (M+H).sup.+.

    Example 102: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 201)

    [1365] The title compound was prepared using the method described for the synthesis of Example 101B. It was the first of two stereoisomers to elute during the SFC purification step (18 mg, 10%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.14 (d, J=2.0 Hz, 1H), 8.93 (s, 1H), 8.36 (dd, J=8.0, 2.0 Hz, 1H), 8.13 (d, J=1.5 Hz, 1H), 7.95-7.88 (m, 2H), 7.42-7.38 (m, 1H), 7.22 (dd, J=8.5, 2.5 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 5.78-5.69 (m, 1H), 4.86-4.80 (m, 1H), 4.67 (dd, J=12.0, 2.5 Hz, 1H), 2.58 (s, 6H), 2.42-2.34 (m, 1H), 1.78-1.69 (m, 1H); MS (ESI) ma 505 (M+H).sup.+.

    Example 103: (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 202)

    [1366] The title compound was prepared using the procedures described for the synthesis of Example 131D, substituting the product from Example 100A for the product from Example 73B. The crude product was purified by chiral SFC separation [Column: Chiralpak IG, 10250 mm, 5 m, gradient: 40% methanol in CO.sub.2 (isocratic), flow rate: 15 g/minute; column temperature: 40 C.; automatic back-pressure regulator setting. 1700 psi] to give the title compound as the earlier eluting fraction. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.93-7.85 (m, 2H), 7.69-7.62 (m, 1H), 7.45-7.41 (m, 1H), 7.16 (dd, J=8.5, 2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.96-4.89 (m, 1H), 4.64 (dd, J=11.5, 2.5 Hz, 1H), 2.68 (s, 6H), 2.59-2.51 (m, 1H), 1.95-1.85 (m, 1H); MS (ESI) m/z 488 (MH).sup..

    Example 104: (2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 203)

    Example 104A: (2R)-6-chloro-4-oxo-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1367] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 68C for Example 30C gave the title intermediate. MS (APCI.sup.+) m/z 540 (M+H).sup.+.

    Example 104B: (2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1368] The methodologies described in Example 5 substituting Example 104A for Example 4 gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.43 (s, 1H), 7.38 (dd, J=2.8, 1.0 Hz, 1H), 7.18 (dd, J=8.8, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.89 (p, J=7.5 Hz, 1H), 4.78 (dd, J=10.7, 6.0 Hz, 1H), 4.58 (dd, J=11.8, 2.2 Hz, 1H), 2.82 (tdt, J=9.7, 7.4, 2.3 Hz, 2H), 2.47 (ddd, J=9.9, 7.5, 2.6 Hz, 2H), 2.28 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 1.96 (s, 12H), 1.80-1.70 (m, 1H); MS (APCI.sup.+) m/z 542 (M+H).sup.+.

    Example 105: (2S,4S)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 204)

    Example 105A: (2S)-6-chloro-4-oxo-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1369] The methodologies described in Example 30D substituting the product of Example 10A for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 68C for Example 30C gave the title intermediate. MS (APCI.sup.+) m/z 540 (M+H).sup.+.

    Example 105B: (2S,4S)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1370] The methodologies described in Example 5 substituting Example 105A for Example 4 gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.41 (s, 1H), 7.40-7.35 (m, 1H), 7.18 (dd, J=8.7, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.67 (s, 1H), 4.89 (p, J=7.5 Hz, 1H), 4.78 (dd, J=10.5, 6.0 Hz, 1H), 4.58 (dd, J=11.8, 2.3 Hz, 1H), 2.82 (dtt, J=9.7, 7.4, 2.5 Hz, 2H), 2.54-2.42 (m, 2H), 2.28 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 1.96 (s, 12H), 1.75 (dt, J=12.7, 11.0 Hz, 1H); MS (APCI.sup.+) m/z 542 (M+H).sup.+.

    Example 106: (2R,4R)-6-chloro-4-hydroxy-N-(1-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 205)

    Example 106A: cis-3-(trifluoromethoxy)cyclobutanamine

    [1371] A mixture of the product of Example 25O (1.25 g, 6.79 mmol), N,N-diisopropylethylamine (3.56 mL, 20.37 mmol) and 2-(trimethylsilyl)ethanol (9.73 mL, 67.9 mmol) in toluene (20 mL) was stirred at ambient temperature and diphenylphosphoryl azide (2.80 g, 10.18 mmol) was added. The mixture was heated to 80 C. overnight, then cooled to ambient temperature. The solution was diluted with toluene (30 mL) and washed with water (5 0 mL), saturated NaHCO.sub.3 (50 mL) and brine (50 mL). The organic fraction was dried with magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel using a gradient of 0-30% ethyl acetate in heptane to give 1.57 g of tert-butyl (cis-3-(trifluoromethoxy)cyclobutyl)carbamate. This compound was dissolved in dichloromethane (20 mL) and treated with 13 mL of trifluoroacetic acid for 3 hours. Solvent and excess trifluoroacetic acid were removed under high vacuum to give 1.8 g of the title compound, which was used without further purification. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.13 (s, 3H), 4.65 (p, J=7.2 Hz, 1H), 3.37 (s, 1H), 2.71 (tdt, J=9.5, 7.0, 2.4 Hz, 2H), 2.38-2.29 (m, 2H).

    Example 106B: tert-butyl (1-((cis-3-(trifluoromethoxy)cyclobutyl)carbamoyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate

    [1372] A mixture of the product of Example 64C (0.1 g, 0.369 mmol), the product of Example 106A (0.150 g, 0.461 mmol), N-ethyl-N-isopropylpropan-2-amine (0.322 mL, 1.843 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.210 g, 0.553 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at ambient temperature for 16 hours. Solvent was removed under high vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 35-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 118 mg of the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.96 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 4.52 (p, J=7.3 Hz, 1H), 3.94-3.84 (m, 1H), 3.89 (s, 2H), 2.57 (tdt, J=9.7, 6.9, 2.6 Hz, 2H), 2.31 (ddd, J=11.7, 10.1, 5.9 Hz, 2H), 1.96-1.88 (m, 4H), 1.80-1.71 (m, 4H), 1.36 (s, 9H).

    Example 106C: 4-amino-N-((cis)-3-(trifluoromethoxy)cyclobutyl)-2-oxabicyclo[2.2.2]octane-1-carboxamide trifluoroacetic acid

    [1373] A mixture of the product of Example 106B (0.12 g, 0.294 mmol) and 2,2,2-trifluoroacetic acid (0.023 mL, 0.294 mmol) in dichloromethane (5 mL) was stirred at ambient temperature for 16 hours. Solvent and excess 2,2,2-trifluoroacetic acid were removed under high vacuum to give 118 mg of the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.20 (s, 3H), 8.03 (d, J=8.3 Hz, 1H), 4.53 (p, J=7.3 Hz, 1H), 3.98-3.85 (m, 1H), 3.85 (s, 2H), 2.59 (dtd, J=9.7, 7.0, 3.1 Hz, 2H), 2.30 (dt, J=11.9, 8.8 Hz, 2H), 2.00 (td, J=12.6, 12.1, 8.7 Hz, 2H), 1.86 (tt, J=11.5, 7.3 Hz, 6H).

    Example 106D: (2R,4R)-6-chloro-4-hydroxy-N-(1-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1374] The title compound was synthesized using the same procedures as described in Example 87A through Example 87B substituting the product of Example 86G with the product of Example 106C and the product of Example 10A with the product of Example 1B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.00 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.18 (dd, J=8.7, 2.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.54 (s, 1H), 4.78 (dd, J=10.6, 5.9 Hz, 1H), 4.62-4.47 (m, 2H), 4.08-3.98 (m, 2H), 3.96-3.81 (m, 1H), 2.59 (dh, J=11.8, 3.1 Hz, 2H), 2.38-2.23 (m, 3H), 2.06 (dddd, J=17.4, 10.6, 6.0, 3.4 Hz, 2H), 1.94 (ddd, J=18.5, 11.4, 3.1 Hz, 3H), 1.91-1.77 (m, 2H), 1.80-1.69 (m, 1H); MS (APCI.sup.+) m/z 519.06 (M+H).sup.+.

    Example 107: (2S,4S)-6-chloro-4-hydroxy-N-(1-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-2-oxabicyclo[2.2.2]octan-4-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 206)

    [1375] The title compound was synthesized using the same procedures as described in Example 87A through Example 87B substituting the product of Example 86G with Example 106C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.02 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.37 (dd, J=2.8, 0.9 Hz, 11H), 7.18 (dd, J=8.6, 2.6 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.67 (s, 1H), 4.78 (dd, J=10.6, 5.9 Hz, 1H), 4.62-4.48 (m, 2H), 4.03 (qd, J=7.9, 2.5 Hz, 2H), 3.91 (dtd, J=16.2, 9.1, 7.3 Hz, 1H), 2.58 (tdd, J=12.0, 8.7, 5.2 Hz, 2H), 2.37-2.23 (m, 3H), 2.12-1.86 (m, 6H), 1.89-1.77 (m, 2H), 1.75 (ddd, J=12.9, 10.8, 9.7 Hz, 1H); MS (APCI.sup.+) mi 519.06 (M+H).sup.+.

    Example 108: (2R,4R)-6-chloro-N-{trans-4-[3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 207)

    Example 108A: benzyl ((trans)-4-(3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl)cyclohexyl)carbamate

    [1376] 4-Chloro-3-fluoroiodobenzene (161 mg, 0.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (24.0 mg, 0.026 mmol), 2-(dicyclohexylphosphino)-2, 4, 6-triisopropylbiphenyl (24.9 mg, 0.052 mmol, XPhos), the product of Example 37C (166 mg, 0.52 mmol) and cesium carbonate (426 mg, 1.31 mmol) were suspended in dioxane (5 mL). The reactor was degassed three times with a nitrogen back flush each time and then sealed. The reaction mixture was warmed to 100 C. and stirred for 2 hours. The resulting mixture was cooled to ambient temperature and combined with diatomaceous earth (about 5 grams) and concentrated under reduced pressure to a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (180 mg, 0.41 mmol, 77% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.73 (dd, J=12.7, 2.5 Hz, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.40-7.27 (m, 5H), 7.21 (d, J=7.9 Hz, 1H), 5.01 (s, 2H), 3.77 (dd, J=9.4, 6.7 Hz, 2H), 3.63-3.53 (m, 1H), 3.43 (dd, J=9.3, 6.7 Hz, 2H), 3.32-3.23 (m, 2H), 1.92-1.84 (m, 2H), 1.69-1.61 (m, 2H), 1.60-1.50 (m, 2H), 1.30 (qd, J=12.6, 3.8 Hz, 2H); MS (APCI.sup.+) m/z 466 (M+H).sup.+.

    Example 108B: (2R,4R)-6-chloro-N-{trans-4-[3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-1-yl]cyclohexyl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1377] The reaction and purification conditions described in Example 3C substituting the product of Example 108A for the product of Example 3A, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 65 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.91 (d, J=8.2 Hz, 1H), 7.74 (dd, J=12.7, 2.6 Hz, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.33 (ddd, J=9.0, 2.6, 1.0 Hz, 1H), 7.20 (dd, J=8.8, 2.6 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (d, J=6.4 Hz, 1H), 4.82 (dt, J=11.4, 5.9 Hz, 1H), 4.62 (dd, J=11.9, 2.2 Hz, 1H), 3.78 (dd, J=9.4, 6.6 Hz, 2H), 3.69-3.57 (m, 2H), 3.50-3.41 (m, 2H), 2.35 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 1.89-1.81 (m, 2H), 1.78-1.53 (m, 5H), 1.53-1.40 (m, 2H); MS (APCI.sup.+) m/z 504 (MH.sub.2O+H).sup.+.

    Example 109: (2S,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 208)

    Example 109A: tert-butyl [3-(2-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1378] The reaction and purification conditions described in Example 2B substituting tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock) for the product of Example 2A and the product of Example 25O for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.31 (s, 1H), 7.51 (s, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.73-3.64 (m, 3H), 2.77-2.68 (m, 2H), 2.18-2.11 (m, 2H), 2.11 (s, 6H), 1.37 (s, 9H); MS (APCI.sup.+) m/z 395 (M+H).sup.+.

    Example 109B: (2S,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1379] Trifluoroacetic acid (0.5 mL) was added to the product of Example 109A (32.6 mg, 0.083 mmol), and the reaction was stirred at ambient temperature for 15 minutes. The resulting solution was concentrated under reduced pressure to a residue. Triethylamine (0.058 mL), N,N-dimethylformamide (1 mL), the product of Example 73B (20.8 mg, 0.091 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (33.3 mg, 0.088 mmol, HATU) were added in sequential order. The resulting reaction mixture was stirred at ambient temperature for 1 hour. Water (0.2 mL) was then added. The resulting solution was filtered through a glass microfiber frit and directly purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (32 mg, 0.063 mmol, 77% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 8.37 (s, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.25 (dd, J=8.7, 2.7 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.64-5.60 (m, 1H), 4.60-4.56 (m, 1H), 4.54 (dd, J=10.9, 2.7 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.72-3.65 (m, 1H), 2.78-2.69 (m, 2H), 2.27-2.23 (m, 6H), 2.18-2.11 (m, 2H), 2.08 (ddd, J=13.9, 3.8, 2.8 Hz, 1H), 1.94-1.84 (m, 1H); MS (APCI.sup.+) m/z 505 (MH.sub.2O+H).sup.+.

    Example 110: (2R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 209)

    Example 110A: methyl 3-(4-(4-chlorophenyl)-1H-pyrmaol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1380] A 30 mL vial was charged with iodomesitylene diacetate (243 mg, 0.667 mmol), 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (227 mg, 1.33 mmol, Synthonix) and toluene (5 mL). The mixture was stirred at 60 C. for 45 minutes. Toluene was then removed under high vacuum. Iridium(III) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C.sub.20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate (25 mg, 0.025 mmol), 4-(4-chlorophenyl)-1H-pyrazole (240 mg, 1.34 mmol, Matrix), 4,7-diphenyl-1,10-phenanthroline (120 mg, 0.361 mmol), copper(II) acetate (121 mg, 0.666 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.48 mL, 2.38 mmol) were added sequentially followed by dioxane (5.0 mL). The vial was degassed by sparging with nitrogen for 3 minutes before sealing with a polytetrafluoroethylene-lined cap. The vial was then put inside a 250 mL glass Dewar filled with water and clamped at a 450 angle to increase exposure to the light-emitting diode (LED). (The glass Dewar was used to focus the blue LED to the vial, and the water bath was used to keep a constant temperature). The reaction was stirred and irradiated using an 18W 450 nm HepatoChem blue LED photoredox lamp just 5 cm above the vial. The bath temperature was measured as 22 C. when setting up the reaction and rose to 30 C. after an hour, and the temperature was stabilized at 30 C. for the remainder of the reaction time. After 18 hours, the reaction mixture was quenched by exposing to air and partitioned between water (50 mL) and dichloromethane (250 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (40 mg, 0.13 mmol, 9.8% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.34 (d, J=0.9 Hz, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.67-7.60 (m, 2H), 7.45-7.35 (m, 2H), 3.68 (s, 3H), 2.52 (s, 6H); MS (APCI.sup.+) m/z 303 (M+H).sup.+.

    Example 110B: 3-(4-(4-chlorophenyl)-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1381] The product of Example 110A (35 mg, 0.116 mmol) was combined with methanol (5 mL) and stirred at ambient temperature. Aqueous NaOH (0.185 mL, 2.5 M) was added. After stirring for 30 minutes, more NaOH (0.23 mL, 2.5 M) was added and the resulting solution was stirred at 45 C. for 2 hours and then at ambient temperature for 18 hours. The reaction mixture was combined with diatomaceous earth (about 5 grams) and concentrated under reduced pressure to a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (32 mg, 0.11 mmol, 96% yield). MS (APCI.sup.+) m/z 289 (M+H).sup.+.

    Example 110C: 3-(4-(4-chlorophenyl)-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1382] A mixture of the product of Example 110B (35 mg, 0.12 mmol), N,N-diisopropylethylamine (0.064 mL, 0.36 mmol), and 2-(trimethylsilyl)ethanol (0.26 mL, 1.82 mmol) in toluene (2 mL) was stirred at ambient temperature and diphenylphosphoryl azide (0.039 mL, 0.182 mmol) was added. The mixture was heated at 55 C. for 18 hours, cooled to ambient temperature, and then concentrated under reduced pressure. Trifluoroacetic acid (1.0 mL) was added to the residue. The mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was taken up in methanol (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (20 mg, 0.062 mmol, 51% yield). MS (APCI.sup.+) m/z 260 (M+H).sup.+.

    Example 110D: (2R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1383] The reaction and purification conditions described in Example 2B substituting the product of Example 110C for the product of Example 2A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.18 (s, 1H), 8.30 (d, J=0.8 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.68-7.60 (m, 4H), 7.42-7.38 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 5.15 (dd, J=8.2, 6.1 Hz, 1H), 3.01-2.93 (m, 2H), 2.51 (s, 6H); MS (APCI.sup.+) m/z 468 (M+H).sup.+.

    Example 111: (2R,4R)-6-chloro-4-hydroxy-N-[(1R*,2S*,4R*,5S*)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 210)

    Example 111A: rac-(1R,4R)-2,5-diisothiocyanatobicyclo[2.2.1]heptane

    [1384] To a solution of 2,5-norbornadiene (5.0 g, 54.3 mmol) in toluene (50 mL) was added ammonium thiocyanate (12.4 g, 163 mmol) and a solution of concentrated sulfuric acid (4.63 mL, 87 mmol) in water (3 mL). The resulting reaction mixture was stirred at 75 C. for 36 hours, cooled to ambient temperature, and then diluted with tetrahydrofuran (50 mL). The pH of the mixture was adjusted to around 8 with saturated aqueous ammonium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9-33% ethyl acetate in petroleum ether) to give the title compound (1.8 g, 8.56 mmol, 16% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.54 (dd, J=3.1, 7.1 Hz, 2H), 2.60 (br d, J=4.4 Hz, 2H), 1.80-1.66 (m, 6H).

    Example 111B: di-tert-butyl rac-(1R,2S,4R,5S)-bicyclo[2.2.1]heptane-2,5diyldicarbamate

    [1385] The product of Example 111A (16.0 g, 76 mmol) was combined with dioxane (160 mL) and aqueous HCl (12 M, 160 mL). The reaction was stirred at 100 C. for 12 hours, cooled to ambient temperature, and concentrated under reduced pressure. To the residue was added dichloromethane (300 mL), and the mixture was stirred at 0 C. Di-tert-butyl dicarbonate (88 ml, 380 mmol) was slowly added. The ice bath was then removed, and the resulting reaction mixture was allowed to stir at ambient temperature for 13 hours. The resulting organic mixture was washed with 0.5 M aqueous HCl (8100 mL), dried over sodium sulfate and triturated with petroleum ether (200 mL) to give the title compound (6 g, 17.46 mmol, 23% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.73 (br d, J=6.5 Hz, 2H), 3.25-3.08 (m, 2H), 1.96 (br s, 2H), 1.50-1.42 (m, 2H), 1.37 (s, 18H), 1.29 (br s, 2H), 1.20 (br d, J=12.5 Hz, 2H).

    Example 111C: rac-(1R2S,4R,5S)-bicyclo[2.2.1]heptane-2,5-diamine, 2 hydrochloric acid

    [1386] To a solution of the product of Example 111B (2 g, 6.13 mmol) in dichloromethane (50 mL) stirred at 0 C. was added HCl (4.0 M HCl in methanol, 20 mL). The ice bath was removed and the reaction solution was allowed to stir at 25 C. for 13 hours and then concentrated under reduced pressure to give the title compound (1.1 g, 5.52 mmol, 90% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm =3.22 (br dd, J=3.5, 7.7 Hz, 2H), 2.56 (br d, J=4.2 Hz, 2H), 1.98-1.88 (m, 2H), 1.79 (s, 2H), 1.60 (td, J=4.4, 14.0 Hz, 2H); MS (ESI.sup.+) m/z 127 (M+H).sup.+.

    Example 111D: benzyl [rac-(1R,2S,4R,5S)-5-aminobicyclo[2.2.1]heptan-2-yl]carbamaie

    [1387] To a solution of the product of Example 111C (37.5 g, 188 mmol) in a solvent mixture of dichloromethane (1200 mL) and methanol (400 mL) stirred at 0 C. was added N,N-diisopropylethylamine (132 mL, 753 mmol). The reaction solution was stirred at 0 C. for 1 hour. Then a solution of benzyl chloroformate (12.85 g, 75 mmol) in dichloromethane (400 mL) was added dropwise at 0 C. The reaction mixture was allowed to warm to 25 C. and stirred at 25 C. for 13 hours. Hydrochloric acid (4.0 M in methanol) was added to the reaction to adjust the pH to 3. The reaction mixture was then concentrated under reduced pressure, taken up in water (1.0 L) and then extracted with ethyl acetate (4400 mL). The pH of the aqueous phase was adjusted to 9 with potassium carbonate and then extracted with dichloromethane (4400 mL). The organic layers were combined and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol 50:1 to 10:1, 0.5% NH.sub.3) to give the title compound (35.3 g, 136 mmol, 18% yield). MS (ESI) m, 261 (M+H).sup.+.

    Example 111E: benzyl ((1RS,2SR,4RS,5SR)-5-((R)-6-chloro-4-oxochroman-2-carboxamido)bicyclo[2.2.1]heptan-2-yl)carbamate

    [1388] The reaction and purification conditions described in Example 2B substituting the product of Example 111D for the product of Example 2A gave the title compound. MS (APCI.sup.+) m/z 469 (M+H).sup.+.

    Example 111F: benzyl [(1R*, 2S*,4R*, 5S*)-5-{[(2R)-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[2.2.1]heptan-2-yl]carbamate

    [1389] The product of Example 111E was purified by preparative chiral HPLC [CHIRALCEL OJ 20 m column, 20250 mm, flow rate 7.5 mL/minute, 40% ethanol and 5% 2-propanol in heptane (isocratic gradient)]. The earlier eluting fraction was collected and concentrated to give the title compound. MS (APCI.sup.+) m/z 469 (M+H).sup.+.

    Example 111G: (2R)-6-chloro-4-oxo-N-[(1R*, 2S*,4R*, 5S*)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1390] The reaction and purification conditions described in Example 1C substituting the product of Example 111F for the product of Example 1A, the product of Example 13P for the product of Example 1B, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. MS (APCI.sup.+) m/z 469 (M+H).sup.+.

    Example 111H: (2R,4R)-6-chloro-4-hydroxy-N-[(1R*,2S*,4R*,5S*)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1391] The reaction and purification conditions described in Example 6C substituting the product of Example 111G for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.84 (d, J=6.9 Hz, 1H), 7.57 (d, J=7.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.79 (dd, J=10.7, 6.0 Hz, 1H), 4.59 (dd, J=11.9, 2.3 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 3.74 (s, 2H), 3.69 (p, J=6.9 Hz, 1H), 3.55-3.48 (m, 2H), 2.77-2.68 (m, 2H), 2.29 (ddd, J=12.9, 6.0, 2.4 Hz, 1H), 2.18-2.05 (m, 4H), 1.80-1.69 (m, 1H), 1.65-1.54 (m, 2H), 1.44-1.32 (m, 4H); MS (APCI.sup.+) m/z 515 (MH.sub.2O+H).sup.+.

    Example 112: (2R,4R)-6-chloro-4-hydroxy-N-[(1S*,2R*,4S*,5R*)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 211)

    Example 112A: benzyl [(1S*,2R*,4S*,5R*)-5-{[(2R)-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[2.2.1]heptan-2-yl]carbamate

    [1392] The product of Example 111E was purified by preparative chiral HPLC [CHIRALCEL OJ 20 m column, 20250 mm, flow rate 7.5 mL/minute, 40% ethanol and 5% 2-propanol in heptane (isocratic gradient)]. The later eluting fraction was collected and concentrated to give the title compound. MS (APCI.sup.+) m/z 469 (M+H).sup.+.

    Example 112B: (2R)-6-chloro-4-oxo-N-[(1S*,2R*,4S*,5R*)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1393] The reaction and purification conditions described in Example 1C substituting the product of Example 112A for the product of Example 1A, the product of Example 13P for the product of Example 1B, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. MS (APCI.sup.+) m/z 469 (M+H).sup.+.

    Example 112C: (2R,4R)-6-chloro-4 hydroxy-N-[(1S*,2R*,4S*,5R*)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1394] The reaction and purification conditions described in Example 6C substituting the product of Example 112B for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.84 (d, J=7.0 Hz, 1H), 7.57 (d, J=7.0 Hz, 1H), 7.37 (dd, J=2.8, 1.0 Hz, 1H), 7.18 (dd, J=8.7, 2.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 5.72 (br s, 1H), 4.79 (dd, J=10.7, 5.9 Hz, 1H), 4.60 (dd, J=11.8, 2.2 Hz, 1H), 4.47 (p, J=7.2 Hz, J H), 3.74 (s, 2H), 3.70 (t, J=6.8 Hz, 1H), 3.56-3.48 (m, 2H), 2.78-2.68 (m, 2H), 2.30 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.19-2.05 (m, 4H), 1.79-1.69 (m, 1H), 1.64-1.55 (m, 2H), 1.45-1.31 (m, 4H); MS (APCI.sup.+) m/z 515 (MH.sub.2O+H).sup.+.

    Example 113: (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 212)

    [1395] The reaction and purification conditions described in Example 6C substituting the product of Example 110 for the product of Example 6B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.31 (d, J=0.8 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.65-7.60 (m, 2H), 7.42-7.36 (m, 3H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.76 (br s, 1H), 4.83 (dd, J=10.7, 5.9 Hz, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 2.54 (s, 6H), 2.39 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 1.77-1.68 (m, 1H); MS (APCI.sup.+) m/z 470 (M+H).sup.+.

    Example 114: (2R)-6-chloro-4-oxo-N-[trans-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 213)

    Example 114A: (2R)N-(trans-4-aminocyclohexyl)-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1396] Benzyl (trans-4-aminocyclohexyl)carbamate (30 mg, 0.12 mmol) was combined with the product of Example 1B (27.4 mg, 0.12 mmol), triethylamine (0.084 mL) and N,N-dimethylformamide (2 mL). The mixture was stirred at ambient temperature and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (55 mg, 0.145 mmol, HATU) was added. The resulting suspension was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. Trifluoroacetic acid (0.5 mL) was added. The resulting solution was stirred at 65 C. for 30 minutes, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was taken up in methanol (3 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (26 mg, 0.081 mmol, 67% yield). MS (ESI.sup.+) m/z 323 (M+H).sup.+.

    Example 114B: (2R)-6-chloro-4-oxo-N-[trans-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1397] The reaction and purification conditions described in Example 2B substituting the product of Example 114A for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.17 (d, J=8.0 Hz, 1H), 7.67-7.61 (m, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.7, 0.5 Hz, 1H), 5.11 (dd, J=8.4, 5.1 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.75 (s, 2H), 3.70 (tt, J=7.3, 6.4 Hz, 1H), 3.59-3.47 (m, 2H), 3.01-2.90 (m, 2H), 2.77-2.69 (m, 2H), 2.19-2.11 (m, 2H), 1.80-1.65 (m, 4H), 1.39-1.22 (m, 4H); MS (APCI.sup.+) m/z 519 (M+H).sup.+.

    Example 115: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 214)

    [1398] The reaction and purification conditions described in Example 6C substituting the product of Example 114B for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.89 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.85-4.77 (m, 1H), 4.61 (dd, J=11.9, 2.2 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.75 (s, 2H), 3.76-3.66 (m, 1H), 3.63-3.51 (m, 2H), 2.78-2.69 (m, 2H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.21-2.11 (m, 2H), 1.80-1.66 (m, 5H), 1.40-1.30 (m, 4H); MS (APCI.sup.+) m/z 503 (MH.sub.2O+H).sup.+.

    Example 116: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 215)

    Example 116A: tert-butyl [trans-4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}cyclohexyl]carbamate

    [1399] The reaction and purification conditions described in Example 2B substituting the product of Example 106A for the product of Example 2A, and trans-4-[(tert-butoxycarbonyl)amino]cyclohexane-1-carboxylic acid for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 325 (MC(CH.sub.3).sub.3+H).sup.+.

    Example 116B: (2R)-6-chloro-4-oxo-N-[trans-4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1400] The reaction and purification conditions described in Example 1C substituting the product of Example 116A for the product of Example 1A gave the title compound. MS (APCI.sup.+) m/z 489 (M+H).sup.+.

    Example 116C: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1401] The reaction and purification conditions described in Example 6C substituting the product of Example 116B for the product of Example 6B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.06 (d, J=7.9 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.19 (ddd, J=8.7, 2.7, 0.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.60 (dd, J=12.0, 2.2 Hz, 1H), 4.56 (p, J=7.4 Hz, 1H), 3.93-3.83 (m, 1H), 3.61-3.52 (m, 1H), 2.71-2.62 (m, 2H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.14-2.05 (m, 2H), 1.99 (tt, J=11.9, 3.5 Hz, 1H), 1.83-1.67 (m, 5H), 1.43-1.23 (m, 4H), MS (APCI.sup.+) m/z 491 (M+H).sup.+.

    Example 117: (2R)-6-chloro-4-oxo-N-(3-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 216)

    Example 117A: (R)-methyl 3-(6-chloro-4-oxochroman-2-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate

    [1402] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (Princeton) for Example 30C gave the title intermediate. MS (APCI.sup.+) m/z 350 (M+H).sup.+.

    Example 117B: (R)-3-(6-chloro-4-oxochroman-2-carboxamido)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1403] To a solution of Example 117A (0.22 g, 0.64 mmol) in tetrahydrofuran (1.2 mL) was added lithium hydroxide (1 N aqueous, 1.2 mL, 1.2 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, was concentrated, and was neutralized with 1 N HCl. A precipitate formed upon neutralization that was collected by filtration and dried. The title intermediate was impure but carried forward without purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.66-7.60 (m, 3H), 7.19-7.12 (m, 4H), 6.89 (d, J=8.6 Hz, 2H), 5.06 (t, J=7.1 Hz, 1H), 2.94 (d, J=7.2 Hz, 2H), 2.06 (s, 6H); MS (APCI.sup.+) m/z 336 (M+H).sup.+.

    Example 117C: (2R)-6-chloro-4-oxo-N-(3-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1404] The methodologies described in Example 30D substituting Example 117B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting the product of Example 106A for Example 30C gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.68-7.61 (m, 2H), 7.17 (dd, J=8.3, 0.9 Hz, 1H), 5.08 (dd, J=8.9, 5.4 Hz, 1H), 4.56 (t, J=7.2 Hz, 1H), 3.90 (s, 1H), 2.97-2.93 (m, 2H), 2.20 (d, J=9.6 Hz, 2H), 2.15 (s, 6H); MS (APCI.sup.+) m/z 473 (M+H).sup.+.

    Example 118: (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 217)

    [1405] A solution of the product from Example 119G (62 mg, 0.124 mmol) in trifluoroacetic acid (2 mL, 26.0 mmol) was stirred at 0 C. for 5 minutes, and then at room temperature for 3 hours. The solution was concentrated in vacuo, and the residue was dissolved in toluene (3 mL) and concentrated in vacuo (3). The residue was dissolved in acetonitrile (2 mL), ammonium hydroxide (0.047 mL, 0.124 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give a mixture of hydroxychromane diastereomers that favored the desired (S,R)-isomer by 3:1 by .sup.1H NMR analysis. The mixture was separated by chiral SFC purification [Column: Chiralpak IG, 10250 mm, 5 m, gradient: 15% methanol in CO.sub.2 (isocratic), flow rate: 15 g/minute; column temperature: 40 C.; automatic back-pressure regulator setting: 1700 psi] to give the title compound (19 mg, 30%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.8, 2.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.65 (s, 1H), 4.91 (p, J=7.6 Hz, 1H), 4.64-4.54 (m, 2H), 3.31 (s, 1H), 2.83-2.72 (m, 2H), 2.54 (s, 6H), 2.43 (dt, J=12.4, 9.6 Hz, 2H), 2.12 (dt, J=13.9, 3.3 Hz, 1H), 1.92 (ddd, J=14.2, 11.0, 3.7 Hz, 1H); MS (ESI) m/z 500 (M+H).sup.+.

    Example 119: (2S,4S)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 218)

    Example 119A: cis-3-hydroxycyclobutanecarbonitrile

    [1406] 3-Oxocyclobutanecarbonitrile (2.0 g, 21.03 mmol) was dissolved in anhydrous tetrahydrofuran (60.0 mL) under a nitrogen atmosphere. The solution was cooled to 78 C. and lithium tri-sec-butylhydroborate (L-Selectride, 1.0 M in tetrahydrofuran, 21.03 mL) was added slowly via syringe. The reaction mixture was stirred at 78 C. for 3 hours. The reaction mixture was quenched with saturated NH.sub.4Cl (250 mL). The mixture was warmed to room temperature and extracted with ethyl acetate (250 mL3). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (1.579 g, 15.45 mmol, 73.4% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 5.41 (d, J=7.2 Hz, 1H), 4.05-3.96 (m, 1H), 2.78-2.70 (m, 1H), 2.65-2.51 (m, 2H), 2.14-2.01 (m, 2H).

    Example 119B: cis-3-((tert-butyldiphenylsilyl)oxy)-N-hydroxycyclobutanecarboximidamide

    [1407] To the product from Example 119A (0.5 g, 4.89 mmol) and imidazole (0.733 g, 10.76 mmol) in N,N-dimethylformamide (25 mL) at 0 C. was added tert-butyldiphenylchlorosilane (1.382 mL, 5.38 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and dissolved in ethyl acetate (50 mL), washed with water (250 mL) and brine (50 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. To a solution of the oil in ethanol (10 mL) was added hydroxylamine (0.790 mL, 12.89 mmol), and the resulting solution was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo to give the title compound (1.911 g, 4.93 mmol, 96% yield).

    Example 119C: tert-butyl (3-(((cis-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)(hydroxyimino)methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1408] 3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (200 mg, 0.880 mmol) and the product from Example 119B (389 mg, 1.056 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under a nitrogen atmosphere. The solution was cooled to 0 C., N,N-diisopropylethylamine (0.461 mL, 2.64 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 402 mg, 1.056 mmol) were added, and the reaction mixture was stirred at 0 C. for 10 minutes and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 1 M HCl (30 mL), saturated aqueous NaHCO.sub.3 (30 mL) and brine (30 mL3). The organic phase was dried via hydrophobic frit and concentrated in vacuo. The residue was taken up in ethyl acetate (35 mL) and washed with brine (50 mL3), and the organic phase was dried via hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-10% methanol in dichloromethane to afford the title compound (436 mg, 0.709 mmol, 81% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.64-7.57 (m, 4H), 7.49-7.41 (m, 6H), 6.25-6.03 (m, 2H), 4.15-4.06 (m, 1H), 2.35-2.25 (m, 3H), 2.22-2.10 (m, 8H), 1.38 (s, 9H), 0.98 (s, 9H).

    Example 119D: tert-butyl (3-(3-(cis-3-hydroxycyclobutyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1409] The product from Example 119C (432 mg, 0.748 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL) under a nitrogen atmosphere and the solution was cooled to 0 C. Tetra-n-butyl ammonium fluoride (1 M in tetrahydrofuran) (2.62 mL, 2.62 mmol) was added slowly via syringe. The reaction mixture was stirred at 0 C. for 15 minutes and then at 60 C. for 6 hours. The reaction mixture was adsorbed onto silica (2 g) and purified by chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane to afford the title compound (172 mg, 0.508 mmol, 68.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.78 (s, 1H), 5.27 (d, J=7.0 Hz, 1H), 4.13-4.03 (m, 1H), 3.06-2.97 (m, 1H), 2.56-2.51 (m, 2H), 2.37 (s, 6H), 2.11-2.01 (m, 2H), 1.39 (s, 9H).

    Example 119E: tert-butyl (3-(3-(cis-3-(trifluoromethoxy)cyclobutyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1410] A mixture of silver(I) trifluoromethanesulfonate (371 mg, 1.445 mmol), potassium fluoride (124 mg, 2.141 mmol) and Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (284 mg, 0.803 mmol) was stirred under a nitrogen atmosphere in a flask wrapped with aluminum foil. The flask was cooled in a water bath. The product from Example 119D (172 mg, 0.535 mmol) was dissolved in a mixed solvent of ethyl acetate (3 mL) and tetrahydrofuran (2 mL), and the resulting solution was added slowly to the previously described mixture. 2-Fluoropyridine (0.138 mL, 1.606 mmol) and trimethyl(trifluoromethyl)silane (0.238 mL, 1.606 mmol) were slowly added to the reaction mixture via syringe. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of diatomaceous earth, and washed with ethyl acetate (100 mL). The filtrate was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0-10% methanol in dichloromethane to afford the title compound (55 mg, 0.099 mmol, 18.47% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.76 (s, 1H), 4.89 (p, J=7.5 Hz, 1H), 3.36-3.24 (m, 1H), 2.81-2.71 (m, 2H), 2.46-2.33 (m, 8H), 1.39 (s, 9H).

    Example 119F: 3-(3-(cis-3-(trifluoromethoxy)cyclobutyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-amine

    [1411] The product from Example 119E (51 mg, 0.131 mmol) was dissolved in dichloromethane (1 mL) at 0 C. under a nitrogen atmosphere. Trifluoroacetic acid (0.124 mL, 1.611 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was taken up in methanol (3 mL) and adsorbed onto SCX (0.5 g). An SCX cartridge (3 g) was made and the pre-adsorbed suspension was added on top of the cartridge. The SCX pad was washed with methanol (60 mL), and the product was eluted with 0.7 M NH.sub.3 in methanol (60 mL). The filtrate was concentrated in vacuo to give the title compound (43 mg, 0.107 mmol, 82% yield).

    Example 119G: (2S,4S)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1412] The product from Example 119F (155 mg, 0.385 mmol) was dissolved in anhydrous dichloromethane (3 mL), the product from Example 73A (80 mg, 0.350 mmol) and N,N-diisopropylethylamine (0.244 mL, 1.400 mmol) were added, and the resulting suspension was cooled in an ice bath. A 50% solution of propanephosphonic acid anhydride (T3P) in N,N-dimethylformamide (0.409 mL, 0.700 mmol) was added, and the resulting yellow solution was stirred at 0 C. for 30 minutes, and then at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (10 mL) and washed with 1 M HCl (10 mL). The aqueous phase was extracted with dichloromethane (10 mL2), and the organic extracts were combined, dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (63 mg, 0.117 mmol, 33.5% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.78 (br, 1H), 4.91 (p, J=7.5 Hz, 1H), 4.82 (dd, J=10.6, 5.8 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.29 (s, 1H), 2.84-2.74 (m, 2H), 2.53 (d, J=10.0 Hz, 6H), 2.46-2.35 (m, 3H), 1.72 (q, J=11.8 Hz, 1H); MS (ESI) m/z 500 (M+H).sup.+.

    Example 120: (2R,4R)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 219)

    Example 120A: rac-(1S,2R,4S,5R)-5-amino-N-((cis)-3-(trifluoromethoxy)cyclobutyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide trifluoroacetic acid

    [1413] The title compound was synthesized using the same procedures as described in Example 106B through Example 106C substituting Example 86D with Example 64C. MS (APCI.sup.+) m/z 294.99 (M+H).sup.+.

    Example 120B: (2R,4R)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1414] The title compound was synthesized using the same procedures as described in Example 87A through Example 87B substituting Example 86G with Example 120A and Example 10A with Example 1B. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.09 (dd, J=7.8, 2.0 Hz, 1H), 7.93 (dd, J=10.1, 6.8 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.19 (dt, J=8.7, 2.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.68 (s, 1H), 4.79 (dd, J=10.5, 6.0 Hz, 1H), 4.68-4.58 (m, 2H), 4.56 (q, J=7.2 Hz, 1H), 4.30 (t, J=5.9 Hz, 1H), 3.96-3.84 (m, 1H), 3.84 (dd, J=7.5, 3.3 Hz, 1H), 2.75-2.62 (m, 2H), 2.41 (dd, J=9.0, 4.6 Hz, 1H), 2.31 (ddd, J=13.2, 5.9, 2.4 Hz, 1H), 2.20-2.05 (m, 2H), 1.99-1.86 (m, 2H), 1.82-1.68 (m, 1H), 1.62 (dd, J=7.9, 3.6 Hz, 1H), 1.61-1.53 (m, 1H); MS (APCI.sup.+) m/z 505.05 (M+H).sup.+.

    Example 121: (2R,4R)-6-chloro-4-hydroxy-N-[(2S)-2-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 220)

    [1415] The reaction and purification conditions described in Example 6C substituting the product of Example 124C for the product of Example 6B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.37 (dd, J=2.7, 0.9 Hz, 1H), 7.23-7.17 (m, 2H), 7.04 (s, 1H), 6.85 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.3 Hz, 1H), 5.13 (d, J=4.7 Hz, 1H), 4.78 (dt, J=11.3, 6.0 Hz, 1H), 4.60 (dd, J=11.5, 2.4 Hz, 1H), 4.47 (p, J=7.1 Hz, 1H), 4.05-3.99 (m, 1H), 3.72-3.65 (m, 1H), 3.68 (s, 2H), 2.76-2.69 (m, 2H), 2.35 (ddd, J=13.1, 5.9, 2.5 Hz, 1H), 2.28 (ddd, J=12.5, 9.3, 2.8 Hz, 1H), 2.21-2.15 (m, 1H), 2.15-2.08 (m, 2H), 1.97-1.75 (m, 8H), 1.75-1.67 (m, 1H); MS (APCI.sup.+) m/z 563 (M+H).sup.+.

    Example 122: (2R)-6-chloro-4-oxo-N-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 221)

    Example 122A: tert-butyl (4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[2.2.2]octan-1-yl)carbamate

    [1416] The reaction and purification conditions described in Example 2B substituting the product of Example 106A for the product of Example 2A, and 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (Ark Pharm) for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 407 (M+H).sup.+.

    Example 122B: (2R)-6-chloro-4-oxo-N-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1417] The reaction and purification conditions described in Example 1C substituting the product of Example 122A for the product of Example 1A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.69 (s, 1H), 7.65-7.58 (m, 31H), 7.15 (dd, J=8.7, 0.6 Hz, 1H), 5.05 (dd, J=8.4, 4.9 Hz, 1H), 4.54 (p, J=7.4 Hz, 1H), 3.94-3.83 (m, 1H), 2.99-2.92 (m, 1H), 2.92-2.84 (m, 1H), 2.65-2.56 (m, 2H), 2.23-2.14 (m, 2H), 1.81-1.65 (m, 12H); MS (APCI.sup.+) m/z 515 (M+H).sup.+.

    Example 123: (2R,4R)-6-chloro-4-hydroxy-N-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 222)

    [1418] The reaction and purification conditions described in Example 6C substituting the product of Example 122B for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.63 (d, J=7.9 Hz, 1H), 7.37 (dd, J=2.7, 1.0 Hz, 1H), 7.31 (s, 1H), 7.18 (ddd, J=8.7, 2.8, 0.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.68 (s, 1H), 4.77 (dd, J=10.6, 5.9 Hz, 1H), 4.59-4.50 (m, 2H), 3.95-3.84 (m, 1H), 3.48-3.21 (m, 1H), 2.66-2.57 (m, 2H), 2.27 (ddd, J=13.0, 5.9, 2.3 Hz, 1H), 2.24-2.15 (m, 2H), 1.88-1.67 (m, 12H); MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 124: (2R)-6-chloro-N-[(2S)-2-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 223)

    Example 124A: tert-butyl [(2S)-2-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]carbamate

    [1419] The reaction and purification conditions described in Example 2B substituting the product of Example 13H for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 453 (M+H).sup.+.

    Example 124B: N-[(3S)-4-amino-3-hydroxybicyclo[2.2.2]octan-1-yl]-2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamide

    [1420] Trifluoroacetic acid (1 mL) was added to the product of Example 124A (41 mg, 0.091 mmol) and stirred at ambient temperature for 20 minutes. The mixture was concentrated under reduced pressure to give the title compound (72 mg, 0.089 mmol, 98% yield) as a trifluoroacetic acid salt with excipient trifluoroacetic acid (3 equivalents). MS (APCI.sup.+) m/z 453 (M+H).sup.+.

    Example 124C: (2R)-6-chloro-N-[(2S)-2-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1421] The reaction and purification conditions described in Example 2B substituting the product of Example 124B for the product of Example 2A gave the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88 (d, J=2.6 Hz, 1H), 7.48 (dd, J=8.8, 2.7 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H), 6.53 (s, 1H), 6.19 (s, 1H), 4.84 (dd, J=12.9, 3.4 Hz, 1H), 4.35 (s, 1H), 4.31 (p, J=7.3 Hz, 1H), 4.19 (d, J=8.9 Hz, 1H), 3.74 (s, 2H), 3.68 (p, J=6.9 Hz, 1H), 3.17 (dd, J=17.3, 3.4 Hz, 1H), 2.92-2.75 (m, 3H), 2.55 (ddd, J=13.5, 8.9, 3.0 Hz, 1H), 2.41 (m, J=11.8 Hz, 1H), 2.30-2.19 (m, 2H), 2.15-2.03 (m, 3H), 2.02-1.90 (m, 3H), 1.83 (dt, J=13.3, 2.5 Hz, 1H), 1.73 (td, J=11.7, 6.0 Hz, 1H); MS (APCI.sup.+) m/z 561 (M+H).sup.+.

    Example 125: (2R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 224)

    Example 125A: ethyl 3-(3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1422] A 30 mL vial was charged with iodomesitylene diacetate (289 mg, 0.79 mmol), 3-(ethoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (292 mg, 1.59 mmol, Combi-Blocks) and toluene (5 mL). The mixture was stirred at 55 C. for 30 minutes. Toluene was then removed under high vacuum. Iridium(III) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C.sub.20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate (24 mg, 0.024 mmol), copper(I) thiophene-2-carboxylate (54 mg, 0.28 mmol), 4,7-diphenyl-1,10-phenanthroline (141 mg, 0.42 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.50 mL, 2.47 mmol) and 3-(4-chlorophenyl)pyrrolidin-2-one (230 mg, 1.18 mmol, ChemSpace) were added sequentially followed by dioxane (5.0 mL). The vial was degassed by sparging with nitrogen for 3 minutes before sealing with a polytetrafluoroethylene-lined cap. The reaction was stirred and irradiated using 2 lamps: a 40W Kessil PR160 390 nm Photoredox lamp, and an 18W 450 nm HepatoChem blue LED photoredox lamp, with forced air cooling via an electric fan blowing directly at the vial. After 18 hours, the reaction mixture was quenched by exposing to air and partitioned between water (50 mL) and dichloromethane (250 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (5 mL), filtered through a glass microfiber frit and purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 15 m 120 g column, flow rate 60 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (40 mg, 0.12 mmol, 10% yield). MS (APCI.sup.+) m/z 334 (M+H).sup.+.

    Example 125B: 3-(3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1423] The reaction and purification conditions described in Example 110B substituting the product of Example 125A for the product of Example 110A, and ethanol for methanol gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.52 (br s, 1H), 7.41-7.35 (m, 2H), 7.28-7.22 (m, 2H), 3.68 (t, J=9.2 Hz, 1H), 3.35 (d, J=7.6 Hz, 2H), 2.45-2.35 (m, 1H), 2.30-2.26 (m, 6H), 1.99 (ddt, J=12.6, 9.9, 8.5 Hz, 1H); MS (APCI.sup.+) m/z 306 (M+H).sup.+.

    Example 125C: 2-(trimethylsilyl)ethyl (3-(3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1424] The product of Example 125B (37 mg, 0.12 mmol) was azeotroped with dry toluene 3 times. Diisopropylethylamine (0.095 mL, 0.55 mmol), 2-(trimethylsilyl)ethanol (0.35 mL, 2.42 mmol), toluene (5 mL) and diphenylphosphoryl azide (0.039 mL, 0.18 mmol) were added sequentially. Dry nitrogen was bubbled through the reaction mixture for two to three minutes. The reaction mixture was then stirred at 60 C. for 10 hours, cooled to ambient temperature, and concentrated under reduced pressure. The resulting mixture was taken up in N,N-dimethylformamide (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt M C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (26 mg, 0.062 mmol, 51% yield).

    [1425] MS (APCI.sup.+) m/z 421 (M+H).sup.+.

    Example 125D: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)-3-(4-chlorophenyl)pyrrolidin-2-one

    [1426] The product of Example 125C (26 mg, 0.062 mmol) was dissolved in dichloromethane (0.5 mL) and stirred at ambient temperature. Trifluoroacetic acid (0.5 mL) was added. After stirring for 20 minutes, the reaction mixture was concentrated under reduced pressure, taken up in N,N-dimethylformamide (1 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (16 mg, 0.058 mmol, 94% yield). MS (APCI.sup.+) m/z 277 (M+H).sup.+.

    Example 125E: (2R)-6-chloro-N-{3-[3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1427] The reaction and purification conditions described in Example 2B substituting the product of Example 125D for the product of Example 2A gave the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88 (d, J=2.7 Hz, 1H), 7.48 (dd, J=8.8, 2.7 Hz, 1H), 7.35-7.27 (m, 2H), 7.24-7.16 (m, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.02 (s, 1H), 4.85 (dd, J=13.5, 3.3 Hz, 1H), 3.63 (t, J=9.2 Hz, 1H), 3.51-3.37 (m, 2H), 3.18 (dd, J=17.3, 3.3 Hz, 1H), 2.86 (dd, J=17.3, 13.5 Hz, 1H), 2.55 (s, 6H), 2.54-2.44 (m, 1H), 2.21-2.07 (m, 1H); MS (APCI.sup.+) m/z 485 (M+H).sup.+.

    Example 126: (2R,4R)-6-chloro-N-{3-[(3R*)-3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 225)

    [1428] The product of Example 125E was purified by preparative chiral HPLC [CHIRALCEL OZ-H 5 m column, 20250 mm, flow rate 20 mL/minute, 60% ethanol in heptane (isocratic gradient)] to give the title compound as the earlier eluting fraction wherein the stereochemistry on the lactam ring is arbitrarily assigned. .sup.1H NMR (90 C., 400 MHz, DMSO-d.sub.6) ppm 8.36 (s, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.30-7.22 (m, 2H), 7.16 (dd, J=8.6, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.41 (br s, 1H), 4.81 (dd, J=10.5, 5.9 Hz, 1H), 4.58 (dd, J=11.7, 2.6 Hz, 1H), 3.65 (t, J=9.0 Hz, 1H), 3.50-3.31 (m, 2H), 2.50-2.36 (m, 2H), 2.37 (s, 6H), 2.09-1.95 (m, 1H), 1.78 (ddd, J=13.0, 11.7, 10.4 Hz, 1H); MS (APCI.sup.+) m/z 487 (M+H).sup.+.

    Example 127: (2R,4R)-6-chloro-N-{3-[(3S*)-3-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 226)

    [1429] The product of Example 125E was purified by preparative chiral HPLC [CHIRALCEL OZ-H 5 m column, 20250 mm, flow rate 20 mL/minute, 60% ethanol in heptane (isocratic gradient)] to give the title compound as the later eluting fraction wherein the stereochemistry on the lactam ring is arbitrarily assigned. .sup.1H NMR (90 C., 400 MHz, DMSO-d.sub.6) ppm 8.37 (s, 1H), 7.41-7.39 (m, 1H), 7.38-7.33 (m, 2H), 7.30-7.22 (m, 2H), 7.16 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 4.81 (dd, J=10.4, 5.8 Hz, 1H), 4.59 (dd, J=11.6, 2.6 Hz, 1H), 3.66 (t, J=9.0 Hz, 1H), 3.51-3.35 (m, 2H), 2.48-2.32 (m, 2H), 2.37 (s, 6H), 2.09-1.95 (m, 1H), 1.85-1.71 (m, 1H); MS (APCI.sup.+) m/z 487 (M+H).sup.+.

    Example 128: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-hydroxycyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 227)

    Example 128A: tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1430] To a solution of 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (1.00 g, 4.43 mmol) in anhydrous tetrahydrofuran (25 mL) at 0 C. under a nitrogen atmosphere was added a 1.0 M solution of borane tetrahydrofuran complex in tetrahydrofuran (8.85 mL, 8.85 mmol) dropwise, and the reaction mixture was stirred at 0 C. for 1 hour and then at room temperature for 16 hours. The reaction mixture was quenched by the careful addition of methanol (50 mL) and stirred for 10 minutes before being concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO.sub.3 (40 mL) and ethyl acetate (75 mL3), and the combined organic extract was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane to give the title compound (0.64 g, 2.79 mmol, 63% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.40 (br. s, 1H), 4.45 (t, J=5.5 Hz, 1H), 3.42 (d, J=5.5 Hz, 2H), 1.73 (s, 6H), 1.37 (s, 9H).

    Example 128B: tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate

    [1431] A solution of oxalyl chloride (0.544 mL, 6.22 mmol) in anhydrous dichloromethane (12 mL) was cooled to 78 C. under a nitrogen atmosphere. A solution of dimethyl sulfoxide (0.882 mL, 12.43 mmol) in anhydrous dichloromethane (2.5 mL) was added slowly, and the reaction mixture was stirred at 78 C. for 30 minutes. A solution of the product from Example 128A (1.02 g, 4.78 mmol) in anhydrous dichloromethane (20 mL) was slowly added, and the reaction mixture was stirred at 78 C. for 30 minutes. Triethylamine (4.00 mL, 28.7 mmol) was added slowly and the reaction mixture was stirred at 78 C. for 30 minutes. The dry ice bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and quenched with water (40 mL). The phases were stirred for 5 minutes. The phases were separated, and the aqueous phase was extracted with dichloromethane (75 mL2). The organic phases were combined, dried via hydrophobic frit, and concentrated in vacuo to give the title compound (1.04 g, 4.48 mmol, 94% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.59 (s, 1H), 7.65 (br. s, 1H), 2.12 (s, 6H), 1.38 (s, 9H).

    Example 128C: tert-butyl (3-((hydroxyimino)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1432] To a solution of the product from Example 128B (950 mg, 4.50 mmol) in ethanol (23 mL) and water (2.56 mL) was added sodium acetate (1.50 g, 18.0 mmol) and hydroxylamine hydrochloride (1.88 g, 27.0 mmol), and the resulting mixture was stirred at 80 C. for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and extracted with water (50 mL). The aqueous phase was extracted with ethyl acetate (2100 mL) and dichloromethane (2-50 mL), and the combined organic extract was dried via hydrophobic frit and concentrated under reduced pressure to give the title compound (1.32 g, 4.49 mmol, 100% yield).

    Example 128D: cis-benzyl 3-((tert-butyldiphenylsilyl)oxy)cyclobutanecarboxylate

    [1433] A solution of benzyl 3-oxocyclobutanecarboxylate (8.8 g, 43.1 mmol) in anhydrous tetrahydrofuran (250 mL) under a nitrogen atmosphere was cooled to 78 C., and lithium tri-sec-butylhydroborate (1.0 M in tetrahydrofuran, 108 mL) was added slowly via syringe. The reaction mixture was stirred at 78 C. for 3 hours, and was then quenched with saturated NH.sub.4Cl (300 mL). The mixture was warmed to room temperature and extracted with ethyl acetate (3200 mL). The combined organic extract was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexanes to afford cis-benzyl 3-hydroxycyclobutanecarboxylate (3.85 g, 17.92 mmol, 41.6% yield). A portion of the cis-benzyl 3-hydroxycyclobutanecarboxylate (2.00 g, 9.70 mmol) and imidazole (1.452 g, 21.33 mmol) were dissolved in N,N-dimethylformamide (50 mL) and cooled in an ice-water bath. tert-Butyldiphenylchlorosilane (2.74 mL, 10.67 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 3 days. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (50 mL) and water (250 mL). The organic phase was washed with brine (50 mL) and dried over MgSO.sub.4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound (4.72 g, 8.49 mmol, 88% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.61-7.58 (m, 3H), 7.50-7.31 (m, 12H), 5.09 (s, 2H), 4.17 (tt, J=8.0, 6.8 Hz, 1H), 2.61 (tt, J=9.8, 7.7 Hz, 1H), 2.43-2.34 (m, 2H), 2.16 (dddd, J=11.5, 10.1, 6.7, 2.7 Hz, 2H), 0.98 (s, 9H).

    Example 128E: cis-3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylcyclobutanecarboxamide

    [1434] A solution of the product from Example 128D (4.70 g, 10.57 mmol) in tetrahydrofuran (30 mL) was cooled in an ice-water bath, and 1.0 M NaOH (26.4 mL, 26.43 mmol) was added slowly. The reaction mixture was stirred at 50 C. for 16 hours. The mixture was concentrated in vacuo and the basic aqueous mixture was extracted with ethyl acetate (40 mL). The organic layer was dried over MgSO.sub.4, filtered, and concentrated in vacuo to give cis-3-((tert-butyldiphenylsilyl)oxy)cyclobutanecarboxylic acid (1.54 g, 2.259 mmol, 21.37% yield) as a colorless oil. The oil (1.52 g, 4.29 mmol) was combined with N,O-dimethylhydroylamine hydrochloride (0.502 g, 5.15 mmol) in anhydrous dichloromethane (30 mL) and cooled in an ice-water bath. Hunig's base (3.00 mL, 17.15 mmol) was added, followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (2.445 g, 6.43 mmol), and the reaction mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (75 mL) and washed with 1 M HCl (30 mL), saturated aqueous NaHCO.sub.3 (30 mL) and brine (40 mL3). The organic phase was dried over MgSO.sub.4 and concentrated in vacuo to give the title compound (1.16 g, 1.751 mmol, 40.8% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.63-7.58 (m, 4H), 7.49-7.41 (m, 6H), 4.19 (p, J=7.4 Hz, 1H), 3.58 (s, 3H), 3.07 (s, 3H), 2.84 (s, 1H), 2.28 (dtt, J=9.9, 7.1, 2.6 Hz, 2H), 2.17-2.08 (m, 2H), 0.98 (s, 9H).

    Example 128F: cis-3-((tert-Butyldiphenylsilyl)oxy)cyclobutanecarbaldehyde

    [1435] A solution of the product from Example 128E (6.24 g, 15.69 mmol) in anhydrous tetrahydrofuran (150 mL) under a nitrogen atmosphere was cooled to 78 C., and diisobutylaluminum hydride (1.0 M in toluene) (34.5 mL, 34.5 mmol) was slowly added via syringe. The reaction mixture was stirred at 78 C. for 2 hours. Methanol (1 mL) was added and the reaction mixture was stirred at 78 C. for 10 minutes. Saturated Rochelle salt solution (150 mL) and ethyl acetate (150 mL) were added and the dry-ice bath was removed. The mixture was stirred vigorously while warming to room temperature. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2100 mL). The combined organic extract was dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-50% tert-butyl methyl ether in isohexanes to afford the title compound (4.82 g, 13.53 mmol, 86% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.66 (s, 0.15H), 9.56 (s, 0.85H), 7.65-7.55 (m, 4H), 7.52-7.40 (m, 6H), 4.30-4.20 (m, 1H), 2.70-2.57 (m, 1H), 2.34-2.22 (m, 2H), 2.19-2.08 (m, 2H), 0.99 (s, 9H).

    Example 128G: tert-butyldiphenyl(cis-3-vinylcyclobutoxy)silane

    [1436] A 2.5 M solution of n-butyllithium in hexanes (2.481 mL, 6.20 mmol) was added slowly to a suspension of methyltriphenylphosphonium bromide (2.216 g, 6.20 mmol) in anhydrous tetrahydrofuran (50 mL) at room temperature under a nitrogen atmosphere. The suspension was stirred at room temperature for 1 hour and then cooled to 78 C. A solution of the product from Example 128F (2.00 g, 5.91 mmol) in anhydrous tetrahydrofuran (50 mL) was added slowly, and the reaction mixture was stirred at 78 C. for 1 hour. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography on silica gel using a solvent gradient of 0-100% tert-butyl methyl ether in isohexane) to yield the title compound (1.23 g, 3.47 mmol, 58.8% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.62-7.58 (m, 4H), 7.46-7.41 (m, 6H), 5.95-5.73 (m, 1H), 5.09-4.70 (m, 2H), 4.14-4.04 (m, 1H), 2.33-2.17 (m, 3H), 1.85-1.67 (m, 2H), 0.97 (s, 9H).

    Example 128H: tert-butyl (3-{5-[cis-3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1437] A solution of the product from Example 128C (1.32 g, 5.83 mmol) in anhydrous N,N-dimethylformamide (12.5 mL) was cooled in an ice-water bath while a solution of N-chlorosuccinimide (0.857 g, 6.42 mmol) in anhydrous N,N-dimethylformamide (12.5 mL) was slowly added. The reaction mixture was stirred at 0 C. for 30 minutes and at room temperature for 3 hours. A solution of the product from Example 128G (1.189 g, 3.53 mmol) in anhydrous N,N-dimethylformamide (6 mL) was added, followed by triethylamine (0.739 mL, 5.30 mmol), and the reaction mixture was stirred at 60 C. for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with 1 M HCl (50 mL). The aqueous phase was extracted with ethyl acetate (75 mL2), and the combined organic extract was washed with brine (3100 mL), dried via hydrophobic frit, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate in isohexane to afford the title compound (1.27 g, 2.129 mmol, 60.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.63-7.57 (m, 4H), 7.49-7.40 (m, 6H), 4.48-4.41 (m, 1H), 4.10-4.04 (m, 1H), 2.93 (dd, J=17.5, 10.5 Hz, 1H), 2.42 (dd, J=17.5, 7.5 Hz, 1H), 2.18-2.01 (m, 8H), 1.83-1.73 (m, 2H), 1.73-1.62 (m, 1H), 1.38 (s, 9H), 0.98 (s, 9H).

    Example 128I: tert-butyl (3-{5-[cis-3-hydroxycyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1438] A solution of the product from Example 128H (1.27 g, 2.265 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled in an ice-water bath, and a 1.0 M solution of tetra-N-butylammonium fluoride in tetrahydrofuran (3.40 mL, 3.40 mmol) was added. The reaction mixture was stirred at 0 C. for 90 minutes, and then was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (660 mg, 1.945 mmol, 86% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.60 (br. s, 1H), 4.96 (d, J=6.5 Hz, 1H), 4.45-4.38 (m, 1H), 3.92-3.82 (m, 1H), 2.94 (dd, J=17.0, 10.5 Hz, 1H), 2.48-2.41 (m, 1H), 2.06 (s, 8H), 1.84-1.72 (m, 1H), 1.60-1.43 (m, 2H), 1.37 (s, 9H).

    Example 128J: (2R,4R)-6-chloro-4-hydroxy-N-(3-{S-[cis-3-hydroxycyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1439] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 128I for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.74 (br. s, 1H), 7.38 (dd, J=2.5, 1.0 Hz, 1H), 7.20 (dd, J=8.5, 2.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 5.75-5.61 (m, 1H), 4.97 (d, J=6.5 Hz, 1H), 4.85-4.75 (m, 1H), 4.59 (dd, J=12.0, 2.5 Hz, 1H), 4.47-4.38 (m, 1H), 3.96-3.82 (m, 1H), 2.97 (dd, J=17.0, 10.5 Hz, 1H), 2.49-2.46 (m, 1H), 2.39-2.30 (m, 1H), 2.25-2.09 (m, 8H), 1.85-1.75 (m, 1H), 1.75-1.63 (m, 1H), 1.62-1.44 (m, 2H); MS (ESI) m/z 433 (M+H).sup.+.

    Example 129: (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-hydroxycyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 228)

    [1440] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 128I for the product from Example 131C.

    [1441] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.80 (br. s, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.25 (dd, J=8.5, 2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 5.72-5.50 (m, 1H), 5.08-4.88 (m, 1H), 4.58 (t, J=3.5 Hz, 1H), 4.54 (dd, J=11.0, 2.5 Hz, 1H), 4.48-4.37 (m, 1H), 3.94-3.83 (m, 1H), 2.97 (dd, J=17.0, 10.5 Hz, 1H), 2.47-2.43 (m, 1H), 2.23-2.05 (m, 9H), 1.93-1.85 (m, 1H), 1.83-1.76 (m, 1H), 1.60-1.45 (m, 2H); MS (ESI) m/z 433 (M+H).sup.+.

    Example 130: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 229)

    [1442] The title compound was prepared using the method described for the synthesis of Example 119G, substituting the product from Example 3B for the product from Example 73A.

    [1443] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 7.39 (d, J=2.8 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.73 (br s, 1H), 4.91 (p, J=7.6 Hz, 1H), 4.82 (dd, J=10.7, 5.8 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.30 (s, 1H), 2.83-2.74 (m, 2H), 2.54 (s, 6H), 2.47-2.34 (m, 3H), 1.76-1.67 (m, 1H); MS (ESI) m/z 498 (MH).sup..

    Example 131: (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 230)

    Example 131A (Z)-4-chloro-3-fluoro-N-hydroxybenzimidamide

    [1444] To a solution of 4-chloro-3-fluorobenzonitrile (2.5 g, 16.07 mmol) in ethanol (20 mL) was added hydroxylamine (2.5 mL, 40.8 mmol) and the resulting solution heated at reflux for 16 hours. After this time, the reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting solid was triturated with dichloromethane/isohexane (3:1, 50 mL) to give the title compound (2.82 g, 14.21 mmol, 87% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.87 (s, 1H), 7.65 (dd, J=11.0, 1.9 Hz, 1H), 7.62-7.53 (m, 2H), 5.95 (s, 2H).

    Example 131B (E)-tert-butyl (3-(((4-chloro-3-fluorophenyl)(hydroxyimino)methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1445] The product from Example 131A (190 mg, 1.01 mmol) and 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (191 mg, 0.840 mmol) were dissolved in anhydrous N,N-dimethylformamide (11 mL) at 0 C. under a nitrogen atmosphere. N,N-Diisopropylethylamine (0.440 mL, 2.52 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 383 mg, 1.009 mmol) were added and the reaction mixture was stirred at 0 C. for 10 minutes and then at ambient temperature for 16 hours. The reaction mixture was poured into HCl (0.5 M, 50 mL) and extracted with dichloromethane (350 mL). The organic extracts were combined, passed through a phase separator, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane to afford the title compound (295 mg, 0.704 mmol, 84% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.76-7.68 (m, 2H), 7.67 (m, 1H), 7.60 (dd, J=8.4, 2.0 Hz, 1H), 6.90 (s, 2H), 2.25 (s, 6H), 1.39 (s, 9H).

    Example 131C: tert-butyl (3-(3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1446] The product from Example 131B (583 mg, 0.733 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere. The solution was cooled to 0 C. and tetra-n-butylammonium fluoride (1 M in tetrahydrofuran) (1.832 mL, 1.832 mmol) was added slowly via syringe. The reaction mixture was stirred at room temperature for 15 minutes and then at 60 C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (120 mg, 0.215 mmol, 29.3% yield).

    Example 131D: (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1447] To a solution of the product from Example 131C (120 mg, 0.316 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.024 mL, 0.316 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give 3-(3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid (134 mg, 0.317 mmol, 100% yield). A portion of the 3-(3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid (38.7 mg, 0.098 mmol) was combined with the product from Example 73B (15 mg, 0.066 mmol) and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol) in anhydrous N,N-dimethylformamide (1 mL) under a nitrogen atmosphere. The resulting mixture was cooled in an ice-water bath, and a 50% solution of propanephosphonic acid anhydride (T3P) in N,N-dimethylformamide (0.046 mL, 0.079 mmol) was added. The resulting solution was allowed to warm to room temperature and was stirred for 3 hours. The reaction mixture was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 1950 mm, 10-40% gradient of acetonitrile in buffer (0.1% aqueous ammonium bicarbonate)] to afford the title compound (5.3 mg, 16% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 7.95 (dd, J=9.7, 1.9 Hz, 1H), 7.90-7.85 (m, 1H), 7.82 (dd, J=8.3, 7.4 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.65 (s, 1H), 4.63-4.56 (m, 2H), 2.60 (s, 6H), 2.13 (dt, J=13.8, 3.4 Hz, 1H), 1.93 (ddd, J=14.1, 10.9, 3.7 Hz, 1H); MS (ESI) m/z 488 (MH).sup..

    Example 132: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 231)

    Example 132A: tert-butyl (3-(4-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1448] To a solution of 6-(trifluoromethyl)nicotinaldehyde (2.5 g, 14.28 mmol) in a 2:1 mixture of ethanol and tetrahydrofuran (100 mL) was added 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (3.27 g, 16.75 mmol) and sodium cyanide (0.105 g, 2.143 mmol) dissolved in a small amount of water. The mixture was stirred at room temperature for 3 hours and was concentrated under reduced pressure. Ethyl acetate (100 mL) was added, and the solution was dried over MgSO.sub.4, filtered, and concentrated in vacuo to give 4-tosyl-5-(6 -(trifluoromethyl)pyridin-3-yl)-4,5-dihydrooxazole (5.25 g, 12.76 mmol, 89% yield). A portion of this solid (1.04 g, 2.81 mmol) was combined with tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (1.00 g, 5.04 mmol) and xylene (50 mL), and the mixture was heated at 135 C. while stirring for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (243 mg, 0.561 mmol, 19.97% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.17-9.12 (m, 1H), 8.35 (dd, J=8.1, 2.1 Hz, 1H), 8.11-8.06 (m, 1H), 7.92-7.84 (m, 2H), 7.75 (s, 1H), 2.43 (s, 6H), 1.41 (s, 9H).

    Example 132B: (2S,4R)-6-Chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1449] The title compound was prepared using the procedures described for the synthesis of Example 131D, substituting the product from Example 132A for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.14 (d, J=2.1 Hz, 1H), 8.99 (s, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.28 (dd, J=8.7, 2.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.65 (d, J=4.7 Hz, 1H), 4.64-4.58 (m, 2H), 2.58 (s, 6H), 2.14 (dt, J=13.9, 3.3 Hz, 1H), 1.94 (ddd, J=14.2, 11.0, 3.6 Hz, 1H); MS (ESI) m/z 505 (M+H).sup.+.

    Example 133: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 232)

    [1450] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 134A for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.45 (d, J=2.5 Hz, 1H), 7.18 (dd, J=8.5, 2.5 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.96-4.89 (m, 1H), 4.62-4.55 (m, 2H), 4.55-4.47 (m, 1H), 2.96 (dd, J=17.0, 10.5 Hz, 1H), 2.66 (ddd, J=13.5, 5.5, 3.0 Hz, 1H), 2.51-2.31 (m, 9H), 2.19-2.00 (m, 4H); MS (ESI) m/z 501 (M+H).sup.+.

    Example 134: (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 233)

    Example 134A: tert-butyl (3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1451] The title compound was prepared using the method described for the synthesis of Example 119e, substituting the product from Example 128I for the product from Example 119D.

    [1452] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.61 (br. s, 1H), 4.71-4.63 (m, 1H), 4.54-4.48 (m, 1H), 2.99 (dd, J=17.5, 10.5 Hz, 1H), 2.49-2.44 (m, 1H), 2.38-2.30 (m, 2H), 2.09-1.94 (m, 8H), 1.90-1.80 (m, 1H), 1.37 (s, 9H).

    Example 134B: (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-4,5-dihydro-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1453] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 134A for the product from Example 131C. .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.32 (d, J=2.5 Hz, 1H), 7.22 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 4.83-4.78 (m, 1H), 4.68 (dd, J=12.0, 2.5 Hz, 1H), 4.63-4.56 (m, 1H), 4.56-4.46 (m, 1H), 2.98 (dd, J=17.0, 10.5 Hz, 1H), 2.57-2.33 (m, 10H), 2.18-2.03 (m, 3H), 2.03-1.92 (m, 2H); MS (ESI) m/z 501 (M+H).sup.+.

    Example 135: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 234)

    Example 135A: tert-butyl(cis-3-ethynylcyclobutoxy)diphenylsilane

    [1454] To a solution of the product from Example 128F (2.00 g, 5.91 mmol) in methanol (50 mL) was added K.sub.2CO.sub.3 (1.960 g, 14.18 mmol), and the resulting mixture was stirred at room temperature for 10 minutes. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.703 mL, 7.09 mmol) was added slowly via syringe, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated onto silica gel, and the crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-50% tert-butyl methyl ether in isohexanes to afford the title compound (1.54 g, 4.14 mmol, 70.1% yield).

    [1455] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.62-7.57 (m, 4H), 7.50-7.41 (m, 6H), 4.12-4.08 (m, 1H), 2.95 (d, J=2.2 Hz, 1H), 2.49-2.27 (m, 3H), 2.03-1.97 (m, 2H), 0.98 (s, 9H).

    Example 135B: tert-butyl (3-(5-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1456] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting the product from Example 135A for the product from Example 128G. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.65 (br s, 1H), 7.64-7.58 (m, 4H), 7.46 (dddd, J=14.1, 8.6, 5.7, 2.5 Hz, 6H), 6.25 (s, 1H), 4.25 (p, J=7.2 Hz, 1H), 3.00 (ddd, J=17.7, 10.1, 7.6 Hz, 1H), 2.57-2.52 (m, 2H), 2.19 (s, 6H), 2.16-2.12 (m, 2H), 1.39 (s, 9H), 0.99 (s, 9H).

    Example 135C: tert-butyl (3-(5-(cis-3-(trifluoromethoxy)cyclobutyl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1457] To a stirred solution of the product from Example 135B (402 mg, 0.719 mmol) in tetrahydrofuran (7.5 mL) was added a 1.0 M solution of tetra-N-butylammonium fluoride in tetrahydrofuran (1.08 mL, 1.08 mmol), and the resulting solution was stirred at room temperature for 48 hours. The reaction mixture was absorbed onto silica and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford tert-butyl (3-(5-(cis-3-hydroxycyclobutyl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (148 mg, 61% yield). A mixture of silver(I) trifluoromethanesulfonate (356 mg, 1.386 mmol), potassium fluoride (107 mg, 1.848 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (245 mg, 0.693 mmol, Selectfluor) was stirred under a nitrogen atmosphere in a flask wrapped with aluminum foil. The flask was cooled in a water bath, and a solution of tert-butyl (3-(5-(cis-3-hydroxycyclobutyl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (148 mg, 0.462 mmol) in 4:1 ethyl acetate:tetrahydrofuran (10 mL) was added slowly to the reaction mixture. 2-Fluoropyridine (0.12 mL, 1.39 mmol) and trimethyl(trifluoromethyl)silane (0.205 mL, 1.386 mmol) were slowly added to the reaction mixture via syringe. The reaction mixture was stirred at room temperature for 3 days. The mixture was adsorbed onto silica and the crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (82 mg, 37%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) b ppm 7.65 (s, 1H), 6.38 (s, 1H), 4.85 (p, J=7.4 Hz, 1H), 2.82-2.72 (m, 2H), 2.41-2.29 (m, 3H), 2.23-2.11 (m, 6H), 1.38 (s, 9H).

    Example 135D: (2R4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1458] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 135C for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.43 (s, 1H), 5.71 (d, J=6.5 Hz, 1H), 4.90-4.77 (m, 2H), 4.61 (dd, J=12.0, 2.0 Hz, 1H), 2.83-2.74 (m, 2H), 2.41-2.29 (m, 1H), 1.76-1.65 (m, 1H); MS (ESI) m/z 497 (MH).sup..

    Example 136: (2R,4R)-6-chloro-N-[3-(5-chloro-1H-indazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 235)

    Example 136A: methyl 3-(5-chloro-1H-indazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1459] A 30 mL vial was charged with iodomesitylene diacetate (0.57 g, 1.6 mmol), 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (0.58 g, 3.2 mmol, Synthonix) and toluene (7 mL). The mixture was stirred at 60 C. for 30 minutes. Toluene was then removed under high vacuum. Tris(2-phenylpyridine)iridium (10.3 mg, 0.016 mmol), copper(II) acetylacetonate (103 mg, 0.39 mmol), and 5-chloro-1H-indazole (0.12 g, 0.79 mmol) were added followed by dioxane (2.0 mL). The vial was degassed by sparging with nitrogen for 3 minutes before sealing with a polytetrafluoroethylene-lined cap. The reaction was stirred and irradiated using 2 lamps: a 40W Kessil PR160 390 nm Photoredox lamp, and a 18W 450 nm HepatoChem blue LED photoredox lamp. Both lamps were placed 3 cm away from the reaction vial set inside a continuously running tap water bath. The reaction temperature was measured to be 18 C. and maintained at that temperature for the duration of the reaction. After 4 hours, the reaction mixture was quenched by exposing to air and partitioned between water (100 mL) and dichloromethane (250 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (10 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt M C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 20-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (189 mg, 0.68 mmol, 87% yield). MS (ESI.sup.+) m/z 277 (M+H).sup.+.

    Example 136B: 3-(5-chloro-1H-indazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1460] The reaction and purification conditions described in Example 110B substituting the product of Example 136A for the product of Example 110A gave the title compound. MS (APCI.sup.+) m/z 263 (M+H).sup.+.

    Example 136C: 3-(5-chloro-1H-indazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1461] The reaction and purification conditions described in Examples 125C and 125D substituting the product of Example 136B for the product of Example 125B gave the title compound. MS (APCI.sup.+) m/z 234 (M+H).sup.+.

    Example 136D: (2R,4R)-6-chloro-N-[3-(5-chloro-1H-indazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-1-2H-1-benzopyran-2-carboxamide

    [1462] The product of Example 1B (26 mg, 0.12 mmol), the product of Example 136C (27 mg, 0.12 mmol) and triethylamine (0.081 mL, 0.58 mmol) were combined with N,N-dimethylformamide (2 mL) and stirred at ambient temperature. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (57 mg, 0.15 mmol, HATU) was added. The resulting suspension was stirred for 1 hour, and then partitioned between dichloromethane (225 mL) and aqueous sodium carbonate (1.0 M, 20 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (2 mL). To the resulting solution stirring at ambient temperature, sodium borohydride (53 mg, 1.4 mmol) was added in one portion. After stirring for 10 minutes, saturated aqueous ammonium chloride solution (0.1 mL) was added. The resulting mixture was combined with diatomaceous earth (about 2 grams) and concentrated under reduced pressure to a free flowing powder, and the powder was directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (39 mg, 0.09 mmol, 76% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.89 (dd, J=2.0, 0.7 Hz, 1H), 7.77 (dt, J=9.1, 0.9 Hz, 1H), 7.42 (dd, J=8.9, 2.0 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.74 (s, 1H), 4.87-4.81 (m, 1H), 4.68 (dd, J=12.0, 2.3 Hz, 1H), 2.72 (s, 6H), 2.39 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 1.74 (ddd, J=12.9, 12.1, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 555 (M+H).sup.+.

    Example 137: (2S,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 236)

    [1463] The reaction and purification conditions described in Example 2B substituting the product of Example 110C for the product of Example 2A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.32 (d, J=0.8 Hz, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.66-7.61 (m, 2H), 7.43-7.39 (m, 2H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.75-5.60 (m, 1H), 4.62-4.58 (m, 2H), 2.54 (s, 6H), 2.13 (ddd, J=13.9, 3.7, 2.7 Hz, 1H), 1.93 (ddd, J=13.8, 11.1, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 471 (M+H).sup.+.

    Example 138: (2R,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 237)

    Example 138A: tert-butyl 2-((4-chloro-3-fluorophenyl)amino)acetate

    [1464] To a solution of 4-chloro-3-fluoroaniline (4.00 g, 27.5 mmol) and tert-butyl 2-bromoacetate (4.46 mL, 30.2 mmol) in N,N-dimethylformamide (30 mL) were added sodium iodide (0.824 g, 5.50 mmol) and N,N-diisopropylethylamine (7.20 mL, 41.2 mmol). The resulting mixture was heated and stirred at 80 C. for 16 hours. The mixture was poured into water (200 mL) and was extracted with ethyl acetate (2100 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (0-50% ethyl acetate/isohexane) to afford the title compound (6.65 g, 88% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.20 (t, J=8.7 Hz, 1H), 6.52 (dd, J=12.5, 2.7 Hz, 1H), 6.45-6.36 (m, 2H), 3.80 (d, J=6.3 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z 204 (M+HC(CH.sub.3).sub.3).sup.+.

    Example 138B: 2-((4-chloro-3-fluorophenyl)amino)acetic acid

    [1465] To a stirred solution of the product of Example 138A (6.64 g, 25.6 mmol) in dioxane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was heated and stirred at 80 C. for 48 hours. The volatiles were evaporated under reduced pressure azeotroping with toluene (220 mL). The solid was triturated with isohexane-ethyl acetate (1:1, 50 mL), filtered and dried under vacuum to give the title compound (1.90 g, 33% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.65 (s, 1H), 7.20 (t, J=8.8 Hz, 1H), 6.54 (dd, J=12.5, 2.7 Hz, 1H), 6.43 (dd, J=8.8, 2.6 Hz, JH), 6.38 (s, 1H), 3.83 (s, 2H); MS (ESI) m/z 205 (M+H).sup.+.

    Example 138C: 2-((4-chloro-3-fluorophenyl)(nitroso)amino)acetic acid

    [1466] To a solution of the product of Example 138B (1.90 g, 9.33 mmol) in water (20 mL) and acetonitrile (10 mL) was added sodium nitrite (0.644 g, 9.33 mmol) and the resulting mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated under reduced pressure to give the title compound (2.24 g, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.75-7.59 (m, 2H), 7.47 (ddd, J=8.8, 2.5, 1.1 Hz, 1H), 4.35 (s, 2H), one exchangeable proton not observed; MS (ESI) m/z 231 (MH).sup..

    Example 138D: 3-(4-chloro-3-fluorophenyl)-2,3-dihydro-1,2,3-oxadiazol-5-ol

    [1467] A solution of the product of Example 138C (2.23 g, 9.59 mmol) in acetic anhydride (0.905 mL, 9.59 mmol) was stirred and heated at 100 C. for 2 hours. Then the reaction was concentrated under reduced pressure. The residue was suspended in water and the solid was recovered by filtration. The solid was washed with water (210 mL) and dried under vacuum at ambient temperature to give the title compound (1.92 g, 84% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.20 (dd, J=9.6, 2.5 Hz, 1H), 8.05-7.97 (m, 1H), 7.92-7.86 (m, 1H), 7.85 (s, 1H), 2 exchangeable protons not observed; MS (ESI) m/z 215 (M+H).sup.+.

    Example 138E: tert-butyl (3-(1-(4-chloro-3-fluorophenyl)-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1468] A mixture of the product of Example 138D (51 mg, 0.246 mmol), 4,7-diphenyl-1,10-phenanthroline (16.36 mg, 0.049 mmol), the product of Example 151A (53.3 mg, 0.246 mmol), copper (II) sulfate (7.85 mg, 0.049 mmol) and triethylamine (137 l, 0.984 mmol) in tert-butanol and water (1:1, 2 mL) was stirred and heated at 60 C. for 2 hours. The mixture was absorbed on silica and purified by chromatography on silica gel (0-30% MTBE/isohexane) to afford the title product (82 mg, 78% yield) as a yellow solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.43 (s, 1H), 7.90 (dd, J=11.0, 2.2 Hz, 1H), 7.75-7.67 (m, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 2.14 (d, J=7.8 Hz, 6H), 1.40 (s, 9H); MS (ESI) m/z 378 (M+H).sup.+.

    Example 138F: (2R,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1469] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 131C with the product from Example 138E and substituting the product from Example 73B with the product from Example 3B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 8.48 (s, 1H), 7.92 (dd, J=10.8, 2.3 Hz, 1H), 7.75-7.68 (m, 3H), 7.42-7.37 (m, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 4.87-4.78 (m, 1H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 2.42-2.35 (m, 1H), 2.30 (s, 6H), 1.77-1.67 (m, 1H); MS (ESI) m/z 488 (M+H).sup.+.

    Example 139: (2S,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 238)

    [1470] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 131C with the product from Example 138E. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.78 (s, 1H), 8.48 (s, 1H), 7.92 (dd, J=11.0, 2.3 Hz, 1H), 7.76-7.66 (m, 3H), 7.33 (d, J=2.6 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.63 (s, 1H), 4.63-4.54 (m, 2H), 2.30 (s, 6H), 2.16-2.08 (m, 1H), 1.97-1.88 (m, 1H); MS (ESI) m/z 488 (M+H).sup.+.

    Example 140: (2S,4R)-6-chloro-4-hydroxy-N-[4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 239)

    [1471] The reaction and purification conditions described in Example 1C substituting the product of Example 90A for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.38 (s, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.8, 2.7 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.59 (d, J=4.2 Hz, 1H), 4.60-4.51 (m, 2H), 4.47 (p, J=7.1 Hz, 1H), 3.69 (p, J=6.9 Hz, 1H), 3.68 (s, 2H), 2.78-2.67 (m, 2H), 2.17-2.06 (m, 2H), 2.05-1.97 (m, 1H), 1.97-1.90 (m, 1H), 1.93-1.88 (m, 12H); MS (APCI.sup.+) m/z 547 (M+H).sup.+.

    Example 141: (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 240)

    Example 141A: tert-butyl (3-(1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1472] tert-Butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (2 g, 10.09 mmol), 2,5-dimethoxytetrahydrofuran (2.2 mL, 17.15 mmol) in a mixture of acetic acid (4 mL) and water (4 mL) was heated to 100 C. for 10 minutes. The reaction mixture was cooled down to ambient temperature and 2 M aqueous NaOH (10 mL) and ethyl acetate (10 mL) were added. The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaHCO.sub.3 (10 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50/o ethyl acetate/isohexane) to afford the title compound (2.0 g, 78% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 6.75 (t, J=2.1 Hz, 2H), 6.02 (t, J=2.1 Hz, 2H), 2.30 (s, 6H), 1.40 (s, 9H), one exchangeable not observed; MS (ESI) m/z 249 (M+H).sup.+.

    Example 141B: tert-butyl (3-(3-bromo-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1473] To the product of Example 141A (1 g, 4.03 mmol) in dichloromethane (10 mL) at 78 C. was added N-bromosuccinimide (NBS, 0.717 g, 4.03 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at 78 C. for 1 hour then at ambient temperature for 30 minutes. The solvent was removed under vacuum. The crude product was purified by chromatography on silica gel (0-60% ethyl acetate/isohexane) to afford the title compound (1.1 g, 67% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 6.71-6.65 (m, 1H), 6.60-6.54 (m, 1H), 6.22-6.15 (m, 1H), 5.03 (s, JH), 2.43 (s, 6H), 1.48 (s, 9H); MS (ESI) m/z 327 (M+H).sup.+.

    Example 141C: tert-butyl (3-(3-(4-chlorophenyl)-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1474] A suspension of the product of Example 141B (350 mg, 1.070 mmol), (4-chlorophenyl)boronic acid (251 mg, 1.604 mmol), and sodium carbonate (227 mg, 2.139 mmol) in a mixture of dioxane (5 mL) and water (2 mL) was degassed under vacuum followed by a nitrogen back flush. Bis(1,2-bis(diphenylphosphino)ethane)palladium (19.32 mg, 0.021 mmol) was added and the reaction mixture was further degassed under vacuum and followed by a nitrogen back flush. The reaction mixture was heated to 80 C. for 50 minutes. Water (15 mL) and ethyl acetate (15 mL) were added, and the layers were separated. The organic layer was washed with water (5 mL). The organic layer was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-30% ethyl acetate/isohexane) to afford the title compound (105 mg, 26% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.73 (s, 1H), 7.57-7.50 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.28 (m, 1H), 6.82 (dd, J=2.8, 2.2 Hz, 1H), 6.46 (dd, J=2.9, 1.8 Hz, 1H), 2.34 (s, 6H), 1.41 (s, 9H); MS (ESI) m/z 359 (M+H).sup.+.

    Example 141D: 3-(3-(4-chlorophenyl)-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid

    [1475] To the product of Example 141C (102 mg, 0.284 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.328 mL, 4.26 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and coevaporated with toluene (35 mL) to afford the title compound (115 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.77 (s, 3H), 7.58-7.52 (m, 2H), 7.41-7.32 (m, 3H), 6.90 (t, J=2.5 Hz, 1H), 6.51 (dd, J=2.9, 1.8 Hz, 1H), 2.46 (s, 6H); MS (ESI) m/z 259 (M+H).sup.+.

    Example 141E. (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1476] The product of Example 3B (25 mg, 0.109 mmol) and the product from Example 141D (52 mg, 0.139 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL) at room temperature. N,N-Diisopropylethylamine (0.134 mL, 0.765 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in N,N-dimethylformamide (50%) (0.076 mL, 0.131 mmol) were added and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 1950 mm, 50-80% gradient of acetonitrile in buffer (0.1% aqueous ammonium bicarbonate)] to afford the title compound (19 mg, 36% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.59-7.53 (m, 2H), 7.42-7.38 (m, 1H), 7.37-7.30 (m, 3H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.87 (t, J=2.5 Hz, 1H), 6.48 (dd, J=2.9, 1.8 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.88-4.79 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.49 (s, 6H), 2.43-2.36 (m, 1H), 1.79-1.68 (m, 1H); MS (ESI) m/z 469 (M+H).sup.+.

    Example 142: (2S,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 241)

    [1477] The title compound was prepared using the method described for the synthesis of Example 141E, substituting the product of Example 73B for the product of Example 3B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.59-7.52 (m, 2H), 7.36-7.32 (m, 4H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.86 (t, J=2.5 Hz, 1H), 6.48 (dd, J=2.9, 1.8 Hz, 1H), 5.64 (d, J=4.7 Hz, 1H), 4.64-4.57 (m, 2H), 2.48 (s, 6H), 2.13 (dt, J=13.9, 3.4 Hz, 1H), 1.93 (ddd, J=14.3, 10.9, 3.7 Hz, 1H); MS (ESI) m/z 469 (M+H).sup.+.

    Example 143: (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 242)

    Example 143A: tert-butyl (3-(3-(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1478] The title compound was prepared using the method described for the synthesis of Example 141C, substituting (4-chloro-3-fluorophenyl)boronic acid for (4-chlorophenyl)boronic acid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 7.57 (dd, J=11.3, 2.0 Hz, 1H), 7.50-7.43 (m, 1H), 7.43-7.36 (m, 2H), 6.84 (dd, J=2.9, 2.2 Hz, 1H), 6.53 (dd, J=2.9, 1.8 Hz, 1H), 2.34 (s, 6H), 1.41 (s, 9H); MS (ESI) m/z 377 (M+H).sup.+.

    Example 143B: 3-(3-(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid

    [1479] The title compound was prepared using the method described for the synthesis of Example 141D, substituting product of Example 141C with the product of Example 143A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.77 (s, 3H), 7.58 (dd, J=11.3, 2.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 6.92 (t, J=2.5 Hz, 1H), 6.57 (dd, J=2.9, 1.8 Hz, 1H), 2.46 (s, 6H); MS (ESI) m/z 277 (M+H).sup.+.

    Example 143C: (2R,4R)-6-chloro-N-{3-[3(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1480] The title compound was prepared using the method described for the synthesis of Example 141E, substituting product of Example 141D with the product of Example 143B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.59 (dd, J=11.3, 2.0 Hz, 1H), 7.51-7.44 (m, 2H), 7.44-7.38 (m, 2H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.88 (t, J=2.5 Hz, 1H), 6.55 (dd, J=2.9, 1.8 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.87-4.79 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.49 (s, 6H), 2.42-2.35 (m, 1H), 1.74 (td, J=12.6, 10.9 Hz, 1H); MS (ESI) m/z 487 (M+H).sup.+.

    Example 144: (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1H-pyrrol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 243)

    [1481] The title compound was prepared using the methods described for the synthesis of Example 141E, substituting the product of Example 141D with the product of Example 143B, and substituting the product of Example 3B with the product of Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 7.59 (dd, J=11.3, 2.0 Hz, 1H), 7.51-7.43 (m, 2H), 7.41 (dd, J=8.4, 2.0 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.88 (t, 1H), 6.54 (dd, J=2.9, 1.8 Hz, 1H), 5.64 (d, J=4.7 Hz, 1H), 4.64-4.57 (m, 2H), 2.48 (s, 6H), 2.13 (dt, J=13.8, 3.3 Hz, 1H), 1.93 (ddd, J=14.2, 11.0, 3.7 Hz, 1H); MS (ESI) m/z 487 (M+H).sup.+.

    Example 145: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 244)

    Example 145A: tert-butyl (3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1482] The title compound was prepared using the method described for the synthesis of Example 141C, substituting (4-chlorophenyl)boronic acid with (6-(trifluoromethyl)pyridin-3-yl)boronic acid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.2, 2.2 Hz, 1H), 7.82-7.77 (m, 1H), 7.75 (s, 1H), 7.59 (t, J=2.0 Hz, 1H), 6.93 (dd, J=2.9, 2.1 Hz, 1H), 6.67 (dd, J=2.9, 1.8 Hz, 1H), 2.37 (s, 6H), 1.41 (s, 9H); MS (ESI) m/z 394 (M+H).sup.+.

    Example 145B: 3-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrrol-1-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid

    [1483] The title compound was prepared using the method described for the synthesis of Example 141D, substituting product of Example 141C with the product of Example 145A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (d, J=2.2 Hz, 1H), 8.85 (s, 3H), 8.16 (dd, J=8.2, 2.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.67 (t, J=2.0 Hz, 1H), 7.01 (dd, J=2.9, 2.1 Hz, 1H), 6.71 (dd, J=2.9, 1.8 Hz, 1H), 2.49 (s, 6H); MS (ESI) m/z 294 (M+H).sup.+.

    Example 145C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1484] The title compound was prepared using the method described for the synthesis of Example 141E, substituting product of Example 141D with the product of Example 145B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.98 (d, J=2.2 Hz, 1H), 8.89 (s, 1H), 8.17 (dd, J=8.0, 2.2 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.64 (t, J=2.0 Hz, 1H), 7.42-7.38 (m, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 7.00-6.95 (m, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.69 (dd, J=2.9, 1.8 Hz, 1H), 5.73 (d, J=6.3 Hz, 1H), 4.88-4.80 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.52 (s, 6H), 2.43-2.35 (m, 1H), 1.79-1.69 (m, 1H); MS (ESI) m/z 504 (M+H).sup.+.

    Example 146: (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 245)

    [1485] The title compound was prepared using the methods described for the synthesis of Example 141E, substituting the product from Example 141D with the product of Example 145B, and substituting the product of Example 3B with the product of Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.98 (d, J=2.2 Hz, 1H), 8.95 (s, 1H), 8.17 (dd, J=8.1, 2.2 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.64 (t, J=2.0 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 7.00-6.94 (m, 2H), 6.69 (dd, J=2.9, 1.8 Hz, 1H), 5.64 (d, J=4.5 Hz, 1H), 4.64-4.58 (m, 2H), 2.51 (s, 6H), 2.17-2.07 (m, 1H), 1.98-1.89 (m, 1H); MS (ESI) m/z 504 (M+H).sup.+.

    Example 147: (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 246)

    Example 147A: 4-chlorobenzaldehyde oxime

    [1486] The title compound was prepared using the method described for synthesis of Example 151B, substituting 4-chlorobenzaldehyde for 6-(trifluoromethyl)nicotinaldehyde. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 11.35 (s, 1H), 8.15 (s, 1H), 7.64-7.58 (m, 2H), 7.49-7.42 (m, 2H).

    Example 147B: tert-butyl (3-(3-(4-chlorophenyl)isoxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1487] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting the product from Example 147A for the product of Example 128C, and substituting the product from Example 151A for the product from Example 128G. MS (ESI) m/z 361 (M+H).sup.+.

    Example 147C: (2R,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1, 2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1488] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 147B for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.89-7.86 (m, 2H), 7.60-7.56 (m, 2H), 7.39 (dd, J=3.0, 1.0 Hz, 1H), 7.21 (ddd, J=8.5, 3.0, 1.0 Hz, 1H), 6.98 (s, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.71 (d, J=6.5 Hz, 1H), 4.86-4.77 (m, 1H), 4.63 (dd, J=12.0, 2.5 Hz, 1H), 2.47 (s, 6H), 2.41-2.34 (m, 1H), 1.77-1.67 (m, 1H); MS (ESI) m/z 469 (MH).sup..

    Example 148: (2S,4R)-6-chloro-N-{3-[3-(4-chlorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 247)

    [1489] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 147B for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.90-7.85 (m, 2H), 7.60-7.55 (m, 2H), 7.32 (d, J=2.5 Hz, 1H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.63 (d, J=4.5 Hz, 1H), 4.62-4.55 (m, 2H), 2.46 (s, 6H), 2.15-2.09 (m, 1H), 1.96-1.88 (m, 1H); MS (ESI) m/z 469 (MH).sup..

    Example 149: (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 248)

    Example 149A: 4-chloro-3-fluorobenzaldehyde oxime

    [1490] The title compound was prepared using the method described for synthesis of Example 151B, substituting 4-chloro-3-fluorobenzaldehyde for 6-(trifluoromethyl)nicotinaldehyde. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 11.55 (s, 1H), 8.16 (s, 1H), 7.65-7.55 (m, 2H), 7.46 (dd, J=8.0, 2.0 Hz, 1H).

    Example 149B: tert-butyl (3-(3-(4-chloro-3-fluorophenyl)isoxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1491] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting the product from Example 149A for the product of Example 128C, and substituting the product from Example 151A for the product from Example 128G. MS (ESI) m/z 379 (M+H).sup.+.

    Example 149C: (2R,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1492] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 149B for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.93-7.87 (m, 1H), 7.78-7.72 (m, 2H), 7.39 (dd, J=2.5, 1.0 Hz, 1H), 7.21 (ddd, J=8.5, 2.5, 1.0 Hz, 1H), 7.04 (s, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.72 (d, J=5.5 Hz, 1H), 4.87-4.77 (m, 1H), 4.63 (dd, J=12.0, 2.5 Hz, 1H), 2.47 (s, 6H), 2.41-2.35 (m, 1H), 1.76-1.67 (m, 1H); MS (ESI) m/z 487 (MH).sup..

    Example 150: (2S,4R)-6-chloro-N-{3-[3-(4-chloro-3-fluorophenyl)-1,2-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 249)

    [1493] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 149B for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.92-7.88 (m, 1H), 7.77-7.72 (m, 2H), 7.32 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.5, 2.5 Hz, 1H), 7.04 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.63 (d, J=4.5 Hz, 1H), 4.62-4.55 (m, 2H), 2.47 (s, 6H), 2.16-2.08 (m, 1H), 1.97-1.87 (m, 1H); MS (ESI) m/z 487 (MH).sup..

    Example 151: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 250)

    Example 151A: tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate

    [1494] The title compound (0.70 g, 74%) was prepared using the method described for the synthesis of Example 135A, substituting the product from Example 128B (1.29 g, 4.52 mmol) for the product from Example 128F. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.61 (s, 1H), 3.10 (s, 1H), 2.14 (s, 6H), 1.37 (s, 9H).

    Example 151B: 6-(trifluoromethyl)nicotinaldehyde oxime

    [1495] To a solution of 6-(trifluoromethyl)nicotinaldehyde (1.00 g, 5.71 mmol) in a mixed solvent of ethanol (25 mL) and water (2.78 mL) was added hydroxylamine hydrochloride (2.381 g, 34.3 mmol) and sodium acetate (2.81 g, 34.3 mmol), and the resulting mixture was stirred at 80 C. for 16 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL), and the aqueous phase was extracted with ethyl acetate (75 mL2). The combined organic extract was dried via hydrophobic frit and concentrated in vacuo to give the title compound (1.54 g, 5.67 mmol, 99% yield).

    Example 151C: tert-butyl (3-{3-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1496] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting the product from Example 151B for the product of Example 128C, and substituting the product from Example 151A for the product from Example 128G. MS (ESI) m/z 396 (M+H).sup.+.

    Example 151D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1497] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 151C for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.24 (d, J=2.0 Hz, 1H), 8.88 (s, 1H), 8.54 (dd, J=8.0, 2.0 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.39 (dd, J=3.0, 1.0 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 7.19 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 5.72 (d, J=5.5 Hz, 1H), 4.87-4.78 (m, 1H), 4.63 (dd, J=12.0, 2.5 Hz, 1H), 2.50 (s, 6H), 2.42-2.34 (m, 1H), 1.77-1.67 (m, 1H); MS (ESI) m/z 504 (MH).sup..

    Example 152: (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 251)

    [1498] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 151C for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.23 (d, J=2.0 Hz, 1H), 8.94 (s, 1H), 8.55-8.51 (m, 1H), 8.08 (dd, J=8.0, 1.0 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.5, 2.5 Hz, 1H), 7.18 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 5.64 (s, 1H), 4.62-4.56 (m, 2H), 2.49 (s, 6H), 2.15-2.09 (m, 1H), 1.96-1.88 (m, 1H); MS (ESI) m/z 504 (MH).sup..

    Example 153: 2-(4-chloro-3-fluorophenoxy)-N-(3-{5-[(2R*,4R*)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 252)

    [1499] Example 67 was purified by chiral SFC (supercritical fluid chromatography) using a Chiralcel OD-H, 25021 mm I.D., 5 m column eluting with 100% CH.sub.3OH in CO.sub.2 with a flow rate of 80 g/minute and back pressure of 100 bar to give the title compound (second isomer eluted out of the column). The stereochemistry of this title compound was arbitrarily assigned (This compound is the enantiomer of Example 154). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.43 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.09 (dd, J=11.3, 2.8 Hz, 1H), 6.90-6.84 (m, 2H), 5.80 (d, J=6.3 Hz, 1H), 5.69 (dd, J=11.5, 2.3 Hz, 1H), 4.91 (dt, J=11.2, 5.9 Hz, 1H), 4.51 (s, 2H), 2.54 (ddd, J=13.2, 6.0, 2.4 Hz, 1H), 2.51 (s, 6H), 2.15 (ddd, J=13.1, 11.6, 10.4 Hz, 1H); MS (APCI.sup.+) m/z 521 (M+H).sup.+.

    Example 154: 2-(4-chloro-3-fluorophenoxy)-N-(3-{5-[(2S*,4S*)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 253)

    [1500] Example 67 was purified by chiral SFC (supercritical fluid chromatography) using a Chiralcel OD-H, 25021 mm I.D., 5 m column eluting with 20% CH.sub.3OH in CO.sub.2 with a flow rate of 80 g/minute and back pressure of 100 bar to give the impure title compound (first isomer eluted out of the column). This impure residue was further purified by preparative HPLC (Phenomenex Luna C8(2) 5 m AXIA column (150 mm30 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) to isolate the title compound. The stereochemistry of this title compound was arbitrarily assigned (This compound is the enantiomer of Example 153). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 7.50 (td, J=8.9, 2.8 Hz, 1H), 7.42 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.08 (dd, J=11.3, 2.9 Hz, 1H), 6.89-6.82 (m, 2H), 5.68 (dd, J=11.5, 2.4 Hz, 1H), 4.91 (dd, J=10.3, 5.9 Hz, 1H), 4.51 (s, 2H), 2.57-2.52 (m, 1H), 2.51 (s, 6H), 2.25 (d, J=4.4 Hz, 1H), 2.14 (ddd, J=13.1, 11.5, 10.3 Hz, 1H); MS (APCI.sup.+) m/z 521 (M+H).sup.+.

    Example 155: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 254)

    Example 155A: tert-butyl (3-((2-(4-chlorophenyl)-2-oxoethyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1501] To a solution of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride (Fluorochem, 0.250 g, 1.21 mmol) in N,N-dimethylformamide (10 mL) was added 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (PharmaBlock, 0.331 g, 1.46 mmol), N,N-diisopropylethylamine (DIPEA, 0.64 mL, 3.6 mmol) and 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 0.692 g, 1.82 mmol). The reaction mixture was then stirred at ambient temperature for 19 hours. After this time, the solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate (10 mL), washed with HCl (1 M, 310 mL), sodium bicarbonate solution (saturated aqueous, 310 mL) and brine (310 mL). The organic layer was then concentrated in vacuo to give the title intermediate (0.864 g, 1.21 mmol, quantitative yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 8.10 (t, J=5.7 Hz, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 4.52 (d, J=5.7 Hz, 2H), 2.08 (s, 6H), 1.38 (s, 9H); MS (ESI.sup.+) m/z 379 (M+H).sup.+.

    Example 155B: 3-(5-(4-chlorophenyl)oxazol-2-yl)bicyclo[1.1.1]pentan-1-amine

    [1502] To the product of Example 155A (200 mg, 0.528 mmol) was added sulfuric acid (500 L, 9.38 mmol). The reaction mixture was heated at 80 C. for 30 minutes. The reaction mixture was then poured into an ice solution (10 mL) and basified with aqueous ammonia to basic pH. The aqueous layer was extracted with dichloromethane (35 mL). The combined organic layers were concentrated in vacuo to afford the title intermediate (72.0 mg, 0.257 mmol, 44% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.72-7.66 (m, 2H), 7.61 (s, 1H), 7.56-7.49 (m, 2H), 2.13 (s, 6H), MS (ESI.sup.+) m/z 261 (M+H).sup.+.

    Example 155C: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1503] The product of Example 3B (20 mg, 0.087 mmol) and Example 155B (30 mg, 0.12 mmol) were dissolved in N, N-dimethyl formamide (0.7 mL) at ambient temperature. To this solution were added N, N-diisopropylethylamine (0.11 mL, 0.61 mmol) and 1-propanephosphonic anhydride (T3P, 50 weight % solution in N,N-dimethylformamide, 0.062 mL, 0.11 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was purified by preparative HPLC [Waters XBridge C18 5 m, 1950 mm column, 20-65% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (13 mg, 0.028 mmol, 32% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.66 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.40 (d, J=2.8 Hz, 1H), 7.22 (dd, J=8.7, 2.8 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.84-4.81 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 2.49 (s, 6H), 2.38-2.36 (m, 1H), 1.74-1.71 (m, 1H); MS (ESI.sup.+) m/z 471/473 (.sup.35Cl/.sup.37Cl, M+H).sup.+.

    Example 156: (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 255)

    [1504] The methodologies described in Example 155C substituting the product of Example 73B for Example 3B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.77-7.69 (m, 2H), 7.66 (s, 1H), 7.59-7.51 (m, 2H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (d, J=4.7 Hz, 1H), 4.63-4.56 (m, 2H), 2.49 (s, 6H), 2.12 (dt, J=14.0, 3.4 Hz, 1H), 1.95-1.90 (m, 1H); MS (ESI+) m/z 471/473 (.sup.35Cl/.sup.37Cl, M+H).sup.+.

    Example 157: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 256)

    Example 157A: tert-butyl (3-(5-(4-chlorophenyl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1505] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting 1-chloro-4-ethynylbenzene for the product from Example 128G. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.88-7.82 (m, 2H), 7.69 (s, 1H), 7.63-7.57 (m, 2H), 7.04 (s, 1H), 2.26 (s, 6H), 1.40 (s, 9H).

    Example 157B: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1506] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 157A for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.82 (s, 1H), 7.89-7.82 (m, 2H), 7.64-7.57 (m, 2H), 7.39 (dd, J=2.5, 1.0 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 7.08 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 5.71 (d, J=6.5 Hz, 1H), 4.82 (dt, J=11.5, 6.0 Hz, 1H), 4.63 (dd, J=12.0, 2.0 Hz, 1H), 2.43-2.34 (m, 7H), 1.77-1.67 (m, 1H); MS (ESI) m/z 469 (MH).sup..

    Example 158: (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 257)

    [1507] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 157A for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.88-7.83 (m, 2H), 7.63-7.58 (m, 2H), 7.32 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.5, 2.5 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 5.63 (d, J=4.5 Hz, 1H), 4.62-4.54 (m, 2H), 2.40 (s, 6H), 2.12 (dt, J=14.0, 3.5 Hz, 1H), 1.96-1.88 (m, 1H); MS (ESI) m/z 469 (MH).sup..

    Example 159: (2R,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 258)

    Example 159A: 1-chloro-4-ethynyl-2-fluorobenzene

    [1508] The title compound was prepared using the method described for the synthesis of Example 135A, substituting 4-chloro-3-fluorobenzaldehyde (0.30 g, 1.89 mmol) for the product from Example 128F (0.29 g, 100%).

    Example 159B: tert-butyl (3-(5-(4-chloro-3fluorophenyl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1509] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting the product from Example 159A for the product from Example 128G. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.91 (dd, J=10.0, 2.0 Hz, 1H), 7.80-7.74 (m, 1H), 7.70 (dd, J=8.5, 2.0 Hz, 1H), 7.12 (s, 1H), 2.26 (s, 6H), 1.40 (s, 9H).

    Example 159C: (2R,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1510] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 159B for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.83 (s, 1H), 7.92 (dd, J=10.0, 2.0 Hz, 1H), 7.78 (app. t, J=8.0 Hz, 1H), 7.71 (dd, J=8.5, 2.0 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 7.17 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 5.71 (d, J=6.5 Hz, 1H), 4.86-4.79 (m, 1H), 4.63 (dd, J=12.0, 2.5 Hz, 1H), 2.43-2.34 (m, 7H), 1.77-1.66 (m, 1H); MS (ESI) m/z 487 (MH).sup..

    Example 160: (2S,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,2-oxazol-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 259)

    [1511] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 159B for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.92 (dd, J=10.0, 2.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.71 (dd, J=8.5, 2.0 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.5, 2.5 Hz, 1H), 7.16 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 5.63 (d, J=4.5 Hz, 1H), 4.62-4.55 (m, 2H), 2.41 (s, 6H), 2.12 (dt, J=14.0, 3.5 Hz, 1H), 1.96-1.87 (m, 1H); MS (ESI) m/z 487 (MH).sup..

    Example 161: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 260)

    Example 161A: 5-ethynyl-2-(trifluoromethyl)pyridine

    [1512] The title compound (0.29 g, 100%) was prepared using the method described for the synthesis of Example 135A, substituting 6-(trifluoromethyl)nicotinaldehyde (0.30 g, 1.71 mmol) for the product from Example 128F.

    Example 161B: tert-butyl (3-(5-(6-(trifluoromethyl)pyridin-3-yl)isoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1513] The title compound was prepared using the methods described for the synthesis of Example 128H, substituting the product from Example 161A for the product from Example 128G. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.24 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.34 (s, 1H), 2.29 (s, 6H), 1.40 (s, 9H).

    Example 161C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1514] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 161B for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.25 (d, J=2.0 Hz, 1H), 8.85 (s, 1H), 8.51 (dd, J=8.5, 2.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.71 (d, J=6.0 Hz, 1H), 4.86-4.79 (m, 1H), 4.63 (dd, J=12.0, 2.5 Hz, 1H), 2.44 (s, 6H), 2.40-2.35 (m, 1H), 1.78-1.67 (m, 1H); MS (ESI) m/z 504 (MH).sup..

    Example 162: (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 261)

    [1515] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 161B for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.24 (d, J=2.0 Hz, 1H), 8.90 (s, 1H), 8.51 (dd, J=8.5, 2.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.33 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.5, 2.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 5.63 (d, J=4.5 Hz, 1H), 4.63-4.55 (m, 2H), 2.43 (s, 6H), 2.15-2.09 (m, 1H), 1.96-1.88 (m, 1H); MS (ESI) m/z 504 (MH).sup..

    Example 163: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 262)

    Example 163A: 2-((6-(trifluoromethyl)pyridin-3-yl)amino)acetic acid

    [1516] At room temperature, sodium iodide (148 mg, 0.986 mmol) was added to a solution of N-ethyl-N-isopropylpropan-2-amine (1288 l, 7.39 mmol), 6-(trifluoromethyl)pyridin-3-amine (799 mg, 4.93 mmol), and tert-butyl 2-bromoacetate (801 L, 5.42 mmol) in N,N-dimethylformamide (5.0 mL). The suspension was stirred at 80 C. for 17 hours. Water (50 mL) was added, and the suspension was extracted with ethyl acetate (230 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO.sub.4, filtered and concentrated. The residue was purified by C18 reversed-phase flash chromatography (120 g cartridge, 5-40% acetonitrile/10 mM ammonium bicarbonate) to afford the title compound (457 mg, 1.829 mmol, 37.1% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.07 (d, J=2.8 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.98 (dd, J=8.7 Hz, 2.8 Hz, 1H), 6.79 (br t, 1H), 3.85 (d, J=5.4 Hz, 2H).

    Example 163B: 2-(nitroso(6-(trifluoromethyl)pyridin-3-yl)amino)acetic acid

    [1517] At room temperature, sodium nitrite (0.143 g, 2.076 mmol) was added to a suspension of the product of Example 163A (0.457 g, 2.076 mmol) in acetonitrile (2.3 mL) and water (4.6 mL) and the mixture was stirred for 3 hours. Then additional sodium nitrite (0.019 g, 0.415 mmol) was added, and the reaction mixture was stirred for another 30 minutes. The reaction mixture was concentrated to give the title compound (0.573 g, 1.460 mmol, 71% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.00 (d, J=2.5 Hz, 1H), 8.22 (dd, J=8.6 Hz, 2.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 4.42 (s, 2H).

    Example 163C: 3-(6-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro-1,2,3-oxadiazol-5-ol

    [1518] The suspension of acetic anhydride (5 mL, 53.0 mmol) and Example 163B (573 mg, 2.300 mmol) was stirred at 100 C. for 2 hours, and the reaction mixture was concentrated. Water (50 mL) was added and the suspension was extracted with ethyl acetate (350 mL). The combined organic extracts were washed with saturated aqueous NaHCO.sub.3 (50 mL) and brine (50 mL), dried over MgSO.sub.4, filtered, and concentrated to give the title compound (366 mg, 1.334 mmol, 58% yield) as an orange/brown solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.35 (d, J=2.5 Hz, 1H), 8.69 (dd, J=8.5 Hz, 2.5 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 7.98 (s, 1H).

    Example 163D: tert-butyl (3-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1519] The title compound was synthesized using the same procedure as described in Example 138E substituting the product of Example 138D with the product of Example 163C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.24 (d, J=2.5 Hz, 1H), 8.58 (s, 1H), 8.44 (dd, J=8.6, 2.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.76 (s, 1H), 7.57 (br s, 1H), 2.16 (s, 6H), 1.38 (s, 9H).

    Example 163E: 3-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-amine trifluoroacetic acid

    [1520] At room temperature, trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to the product of Example 163D (150 mg, 0.380 mmol). The solution was stirred at room temperature for 90 minutes. Toluene (5 mL) was added and the mixture was concentrated. Toluene (5 mL) was added again and the mixture was concentrated to give the title compound (146 mg, 0.325 mmol, 86% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.24 (d, J=2.5 Hz, 1H), 8.70 (br s, 3H), 8.68 (s, 1H), 8.44 (dd, J=8.5, 2.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.84 (s, 1H), 2.26 (s, 6H).

    Example 163F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1521] At room temperature, N,N-diisopropylethylamine (0.107 mL, 0.612 mmol), followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.061 mL, 0.105 mmol), were added to a solution of the product of Example 3B (20 mg, 0.087 mmol) and the product of Example 163E (41.7 mg, 0.102 mmol) in N,N-dimethylformamide (1.00 mL). The mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC (Waters XSelect Prep-C18, 5 m column (19 mm50 mm). A 35-65% gradient of 0.1% formic acid in acetonitrile (A) and 0.1% formic acid in water (B) was used over 7.5 minutes, at a flow rate of 30 mL/minute) to give the title compound (18.0 mg, 0.034 mmol, 38.7% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm: 9.25 (d, J=2.6 Hz, 1H), 8.72 (s, 1H), 8.62 (s, 1H), 8.45 (dd, J=8.5, 2.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.80 (s, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.83-4.78 (br m, 1H), 4.61 (dd, J=12.0, 2.3 Hz, 1H), 2.39-2.34 (m, 1H), 2.31 (s, 6H), 1.74-1.67 (m, 1H).

    Example 164: (2S,4R)-6-chloro-4-hydroxy-N-(3-{1-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 263)

    [1522] The title compound was synthesized using the same procedure as described in Example 163F substituting the product of Example 3B with the product of Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.25 (d, J=2.5 Hz, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.45 (dd, J=8.5, 2.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.80 (s, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.25 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.61 (br s, 1H), 4.59 (br t, J=3.7 Hz, 1H), 4.56 (dd, J=11.0, 2.7 Hz, 1H), 2.31 (s, 6H), 2.10 (dt, J=13.9, 3.4 Hz, 1H), 1.91 (ddd, J=14.2, 11.0, 3.7 Hz, 1H).

    Example 165: (2R,4R)-6-chloro-N-{3-[1-(4-chlorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 264)

    Example 165A: 3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-amine

    [1523] The title compound was synthesized using the same procedure as described in Example 163A through Example 163E substituting 6-(trifluoromethyl)pyridin-3-amine with 4-chloroaniline. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.60 (br s, 3H), 8.45 (s, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.68 (s, 1H), 7.54 (d, J=8.9 Hz, 2H), 2.24 (s, 6H).

    Example 165B: (2R,4R)-6-chloro-N-{3-[1-(4-chlorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1524] The title compound was synthesized using the same procedure as described in Example 163D substituting the product of Example 163C with the product of Example 165A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.70 (s, 1H), 8.39 (s, 1H), 7.83 (d, J=8.9 Hz, 2H), 7.64 (s, 1H), 7.52 (d, J=8.9 Hz, 2H), 7.38 (dd, J=2.7, 0.9 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (br s, 1H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.60 (dd, J=12.0, 2.2 Hz, 1H), 2.38-2.34 (m, 1H), 2.28 (s, 6H), 1.74-1.67 (m, 1H).

    Example 166: (2S,4R)-6-chloro-N-{3-[1-(4-chlorophenyl)-1H-pyrazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 265)

    [1525] The title compound was synthesized using the same procedure as described in Example 163D substituting the product of Example 163C with the product of Example 165A and the product of Example 3B with the product of Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.75 (s, 1H), 8.39 (s, 1H), 7.83 (d, J=8.9 Hz, 2H), 7.63 (s, 1H), 7.52 (d, J=8.9 Hz, 2H), 7.31 (d, J=2.7 Hz, 1H), 7.25 (dd, J=8.7, 2.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 5.61 (d, J=4.5 Hz, 1H), 4.60-4.57 (br m, 1H), 4.55 (dd, J=10.9, 2.8 Hz, 1H), 2.28 (s, 6H), 2.10 (dt, J=13.9, 3.3 Hz, 1H), 1.91 (ddd, J=14.2, 11.0, 3.7 Hz, 1H).

    Example 167: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 266)

    Example 167A: cis-N-methoxy-N-methyl-3-(trifluoromethoxy)cyclobutanecarboxamide

    [1526] To a stirred solution of the product of Example 25N (1.00 g, 5.43 mmol), N,N-diisopropylethylamine (3.78 mL, 21.73 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.636 g, 6.52 mmol) in N,N-dimethylformamide (20 mL), at 0 C. under an atmosphere of nitrogen, was added HATU (1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate) (3.10 g, 8.15 mmol) and the reaction mixture was stirred at this temperature for 1 hour, then warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO.sub.3(aqueous) (25 mL) followed by 1 M HCl (aqueous) (25 mL) then 1:1 brine:water (350 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, dichloromethane loading, 0-100% ethyl acetate/isohexane) to afford the title compound. This material was further purified by chromatography on silica gel (12 g cartridge, dichloromethane loading, 0-50% ethyl acetate/isohexane) to afford the title compound (976 mg, 3.87 mmol, 71.2% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 4.61 (p, J=7.6 Hz, 1H), 3.67 (s, 3H), 3.20 (s, 3H), 3.12-2.99 (m, 1H), 2.60-2.52 (m, 4H).

    Example 167B: cis-3-(trifluoromethoxy)cyclobutanecarbaldehyde

    [1527] The product of Example 167A (978 mg, 4.30 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) under a nitrogen atmosphere. The solution was cooled to 78 C. and diisobutylaluminum hydride (1.0 M in hexanes) (9.47 mL, 9.47 mmol) was slowly added via syringe. The reaction mixture was stirred at 78 C. for 1 hour. Methanol (0.3 mL) was added and the reaction mixture was stirred at 78 C. for 10 minutes. Hydrochloric acid (1 M aqueous, 55 mL) and dichloromethane (55 mL) were added and the dry ice bath was removed. The mixture was stirred vigorously whilst warming to room temperature and stirring was continued for 2.5 hours. The phases were separated and the aqueous phase was extracted with dichloromethane (50 mL2). The organic phases were combined, filtered through a hydrophobic phase separator, and concentrated under reduced pressure (250 mbar at 40 C.) to afford the crude title compound (723 mg, 4.30 mmol, 100% yield) which was used directly in the subsequent step (assumed quantitative).

    Example 167C: 3-(trifluoromethoxy)cyclobutanecarbaldehyde oxime

    [1528] The product of Example 167B (0.778 g, 4.63 mmol) was dissolved in a mixed solvent of ethanol (36 mL) and water (4 mL) at room temperature. Hydroxylamine hydrochloride (1.930 g, 27.8 mmol) and sodium acetate (2.279 g, 27.8 mmol) were added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The two layers were separated and the aqueous layer was re-extracted with dichloromethane (20 mL). The combined organic layers were passed through a hydrophobic cartridge and concentrated in vacuo to afford the crude title compound (0.848 g, 4.63 mmol, 100% yield).

    Example 167D: cis-N-hydroxy-3-(trifluoromethoxy)cyclobutanecarbimidoyl chloride

    [1529] The product of Example 167C (0.133 g, 0.724 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL). A solution of N-chlorosuccinimide (0.106 g, 0.796 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added slowly to the reaction mixture at 0 C. The reaction mixture was stirred at 0 C. for 1 hour and at room temperature for 4 hours. The reaction mixture was used directly, without analysis, in the subsequent step (assumed quantitative).

    Example 167E: tert-butyl (3-(3-(cis-3-(trifluoromethoxy)cyclobutyl)isoxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1530] To a stirred solution of the product of Example 151A (300 mg, 1.447 mmol) and triethylamine (0.202 mL, 1.447 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added the product of Example 167D (0.362 M in N,N-dimethylformamide) (1.999 mL, 0.724 mmol) and the reaction mixture was heated to 60 C. and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1 M HCl (aqueous) (20 mL) then 1:1 brine:water (325 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-50% ethyl acetate/isohexane) to afford the title compound (170 mg, 0.438 mmol, 30.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.69 (s, 1H), 6.43 (s, 1H), 4.84 (p, J=7.5 Hz, 1H), 3.21-3.10 (m, 1H), 2.80-2.69 (m, 2H), 2.40-2.28 (m, 2H), 2.25 (s, 6H), 1.39 (s, 9H).

    Example 167F: 3-(3-(cis-3-(trifluoromethoxy)cyclobutyl)isoxazol-5-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid

    [1531] To the product of Example 167E (170 mg, 0.438 mmol) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (0.506 mL, 6.57 mmol). The reaction mixture was stirred at room temperature for 5 hours. The volatiles were removed under vacuum and co-evaporated with toluene (320 mL) to afford the title compound which was used without further purification. MS (ESI.sup.+) m/z 289.3 (M+H).sup.+.

    Example 167G: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1532] The product of Example 3B (20 mg, 0.087 mmol) and the product of Example 167F (90 mg, 0.224 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL) at room temperature. N,N-Diisopropylethylamine (0.107 mL, 0.612 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in N,N-dimethylformamide (50%) (0.061 mL, 0.105 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (Waters XBridge Prep-C18, 5 m column (19 mm50 mm). A 40-70% gradient of acetonitrile (A) and 0.1% ammonium bicarbonate in water (B) was used over 7.5 minutes at a flow rate of 30 mL/minute) to afford the title compound (24 mg, 0.047 mmol, 53.9% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.82 (s, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.47 (s, 1H), 5.71 (d, J=6.2 Hz, 1H), 4.89-4.78 (m, 2H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 3.21-3.13 (m, 1H), 2.78-2.70 (m, 2H), 2.40 (s, 6H), 2.37-2.29 (m, 3H), 1.74-1.66 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm57.77.

    Example 168: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 267)

    Example 168A: tert-butyl(cis-3-(oxiran-2-yl)cyclobutoxy)diphenylsilane

    [1533] To a stirred suspension of the product of Example 128G (289 mg, 0.859 mmol) and sodium bicarbonate (72.1 mg, 0.859 mmol) in anhydrous dichloromethane at 0 C. under an atmosphere of nitrogen, was added 3-chlorobenzoperoxoic acid (183 mg, 0.816 mmol) dropwise as a solution in anhydrous dichloromethane (5 mL) and the reaction mixture stirred at this temperature for 1 hour then warmed to room temperature and stirred for 18 hours. The reaction mixture was partitioned between dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate (50 mL). The two layers were separated and the aqueous layer was re-extracted with dichloromethane (50 mL). The combined organic layers were passed through a hydrophobic cartridge and concentrated in vacuo to afford a crude colorless solid. The crude product was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-10% tert-butyl methyl ether/isohexane) to afford the title compound (191 mg, 0.515 mmol, 59.9% yield) as a colorless solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.59 (ddq, J=7.2, 3.1, 1.4 Hz, 4H), 7.47-7.40 (m, 6H), 4.12-4.06 (m, 1H), 2.92 (td, J=3.9, 2.6 Hz, 1H), 2.64 (dd, J=5.0, 4.0 Hz, 1H), 2.36 (dd, J=5.0, 2.7 Hz, 1H), 2.22-2.14 (m, 1H), 2.08-1.97 (m, 1H), 1.85-1.74 (m, 2H), 1.72-1.63 (m, 1H), 0.97 (s, 9H).

    Example 168B: tert-butyl (3-((2-((cis)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-hydroxyethyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1534] A mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.215 g, 1.084 mmol) and Example 168A (0.191 g, 0.542 mmol) were combined in ethanol (3 mL) and the reaction mixture stirred at 60 C., under an atmosphere for nitrogen, for 18 hours. The reaction mixture was concentrated in vacuo and the crude oil was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-100% ethyl acetate/isohexane, then 10% methanol/dichloromethane) to afford the title compound (0.257 g, 0.466 mmol, 86% yield) that was used without additional purification. MS (ESI.sup.+) m/z 551.3 (M+H).sup.+.

    Example 168C: tert-butyl (3-(5-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-oxooxazolidin-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1535] To a stirred solution of the product of Example 168B (133. mg, 0.241 mmol) in tetrahydrofuran (1 mL), at room temperature under an atmosphere of nitrogen, was added 1,1-carbonyldiimidazole (86 mg, 0.531 mmol) and the reaction mixture was stirred for 3 hours. After removal of solvent, the residue was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-100% ethyl acetate/isohexane) to afford the title compound (103 mg, 0.167 mmol, 69.3% yield). MS (ESI.sup.+) m/z 599.2 (M+Na).sup.+.

    Example 168D: tert-butyl (3-(5-(cis-3-hydroxycyclobutyl)-2-oxooxazolidin-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1536] To a solution of the product of Example 168C (119 mg, 0.206 mmol) in tetrahydrofuran (2. mL), at 0 C. under an atmosphere of nitrogen, was added tetrabutylammonium fluoride (0.413 mL, 0.413 mmol) (1 M in tetrahydrofuran) and the reaction mixture warmed to room temperature and stirred for 22 hours. Additional tetrabutylammonium fluoride (0.206 mL, 0.206 mmol) was added and the reaction mixture was stirred for an additional 3 hours. The reaction mixture was quenched with saturated NH.sub.4Cl (aqueous) (10 mL) and extracted with dichloromethane (210 mL). The combined organic layers were passed through a hydrophobic phase separator and concentrated in vacuo. The residue was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-100% ethyl acetate/isohexane followed by 10% methanol/dichloromethane) to afford the title compound (127 mg, 0.270 mmol, 131% yield). MS (EST.sup.+) m/z 339.1 (M+H).sup.+.

    Example 168E: tert-butyl (3-(2-oxo-5-(cis-3-(trifluoromethoxy)cyclobutyl)oxazolidin-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1537] The title compound was synthesized using the same procedure as described in Example 130 substituting the product of Example 13N with the product of Example 168D. .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.68.

    Example 168F: 3-(3-aminobicyclo[1.1.1]pentan-1-yl)-5-(cis-3-(trifluoromethoxy)cyclobutyl)oxazolidin-2-one trifluoroacetic acid

    [1538] To the product of Example 168E (123 mg, 0.303 mmol) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (0.350 mL, 4.54 mmol). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed under vacuum and co-evaporated with toluene (320 mL) to afford the title compound (126 mg, 0.270 mmol, 89% yield). The product was carried forward for the next step without further purification.

    Example 168G: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1539] To a mixture of the product of Example 3B (20 mg, 0.087 mmol) and the product of Example 168F (60 mg, 0.143 mmol) in N,N-dimethylformamide (1 mL) at room temperature, N,N-diisopropylethylamine (0.107 mL, 0.612 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in N,N-dimethylformamide (50%) (0.061 mL, 0.105 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (Waters X-Bridge Prep-C18, 5 m column (19 mm50 mm). A 40-70% gradient of acetonitrile (A) and 0.1% ammonium bicarbonate in water (B) was used over 7.5 minutes at a flow rate of 30 mL/minute) to afford the title compound (12 mg, 0.023 mmol, 26.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.74 (s, 1H), 7.38 (d, J=2.7 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.84-4.78 (m, 1H), 4.77-4.71 (m, 1H), 4.61 (dd, J=12.0, 2.3 Hz, 1H), 4.53 (q, J=6.6 Hz, 1H), 3.61 (t, J=8.7 Hz, 1H), 3.10 (dd, J=8.9, 6.7 Hz, 1H), 2.46-2.30 (m, 2H), 2.28 (s, 6H), 2.26-2.11 (m, 2H), 2.05-1.94 (m, 2H), 1.70 (q, J=11.9 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.68.

    Example 169: (2S,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 268)

    [1540] The title compound was synthesized using the same procedure as described in Example 167G substituting the product of Example 3B with the product of Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.47 (s, 1H), 5.62 (d, J=4.7 Hz, 1H), 4.85 (p, J=7.5 Hz, 1H), 4.61-4.54 (m, 2H), 3.22-3.12 (m, 1H), 2.78-2.70 (m, 2H), 2.39 (s, 6H), 2.37-2.28 (m, 2H), 2.13-2.07 (m, 1H), 1.95-1.87 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm57.77.

    Example 170: (2S,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazolidin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 269)

    [1541] The title compound was synthesized using the same procedure as described in Example 168G substituting the product of Example 3B with the product of Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.80 (s, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 5.61 (d, J=4.7 Hz, 1H), 4.74 (p, J=7.6 Hz, 1H), 4.60-4.50 (m, 3H), 3.61 (t, J=8.7 Hz, 1H), 3.10 (dd, J=8.9, 6.7 Hz, 1H), 2.47-2.36 (m, 1H), 2.28 (s, 6H), 2.24-2.15 (m, 1H), 2.13-1.86 (m, 5H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm57.68.

    Example 171: (2R,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 270)

    Example 171A: 2-bromo-1-(4-chloro-3-fluorophenyl)ethanone

    [1542] To a solution of 1-(4-chloro-3-fluorophenyl)ethanone (1.00 g, 5.79 mmol) in dichloromethane (10 mL) and methanol (30 mL) was added tetrabutylammonium tribromide (2.79 g, 5.79 mmol) portionwise. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was then concentrated under reduced pressure. The resulting residue was then dissolved in ethyl acetate (20 mL) and washed with water (320 mL). The organic layer was concentrated under reduced pressure to give the title intermediate (1.30 g, 4.65 mmol, 80% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.01 (dd, J=10.0, 2.0 Hz, 1H), 7.87-7.80 (m, 2H), 4.96 (s, 2H).

    Example 171B: 2-amino-1-(4-chloro-3-fluorophenyl)ethanone hydrochloride

    [1543] The methodologies described in Example 193D substituting Example 171A for Example 193C gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.39 (s, 3H), 8.07 (dd, J=9.9, 1.8 Hz, 1H), 7.91-7.85 (m, 2H), 4.61 (s, 2H).

    Example 171C: tert-butyl (3-((2-(4-chloro-3-fluorophenyl)-2-oxoethyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1544] The methodologies described in Example 193E substituting 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (PharmaBlock) for (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid, substituting Example 171B for 193D, and including a trituration of the crude intermediate, washing with tert-butyl methyl ether (310 mL) gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.14 (t, J=5.7 Hz, 1H), 7.98 (dd, J=9.9, 1.8 Hz, 1H), 7.83-7.80 (m, 1H), 7.21 (s, 1H), 6.91 (s, 1H), 4.52 (d, J=5.7 Hz, 2H), 2.01 (s, 6H), 1.37 (s, 9H); MS (ESI+) m/z 397 (M+H).sup.+.

    Example 171D: 3-(5-(4-chloro-3-fluorophenyl)oxazol-2-yl)bicyclo[1.1.1]pentan-1-amine

    [1545] The methodologies described in Example 155B substituting Example 171C for Example 155A gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.75 (dd, J=10.4, 2.0 Hz, 1H), 7.71-7.66 (m, 2H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 2.13 (s, 6H); MS (ESI.sup.+) m/z 262 (MNH.sub.2+H).sup.+.

    Example 171E: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1.]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1546] The methodologies described in Example 155C substituting Example 171D for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.78 (dd, J=10.4, 2.0 Hz, 1H), 7.75 (s, 1H), 7.70 (t, J=8.1 Hz, 1H), 7.57 (dd, J=8.6, 1.9 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.85-4.81 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 2.50 (s, 6H), 2.42-2.37 (m, 1H), 1.72 (q, J=11.7 Hz, 1H); MS (ESI+) m/z 489/491 (.sup.35Cl/.sup.17Cl, M+H).sup.+.

    Example 172: (2S,4R)-6-chloro-N-{3-[5-(4-chloro-3-fluorophenyl)-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 271)

    [1547] The methodologies described in Example 155C substituting the product of Example 73B for Example 3B and 171D for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.78 (dd, J=10.3, 2.0 Hz, 1H), 7.75 (s, 1H), 7.70 (t, J=8.1 Hz, 1H), 7.56 (dd, J=8.2, 2.0 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (d, J=4.7 Hz, 1H), 4.63-4.56 (m, 2H), 2.49 (s, 6H), 2.14-2.10 (m, 1H), 1.95-1.90 (m, 1H); MS (ESI+) m/z 489/491 (.sup.3SCl/.sup.37CI, M+H).sup.+.

    Example 173: (2R,4R)-6-chloro-N-{3-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 272)

    Example 173A: 3-(2-(4-chlorophenyl)thiazol-4-yl)bicyclo[1.1.1]pentan-1-amine

    [1548] To a solution of the product of Example 181B (50 mg, 0.164 mmol) in ethanol (2 mL) was added 4-chlorobenzothioamide (31.0 mg, 0.181 mmol). The resulting solution was stirred at 80 C. for 2 hours. The reaction mixture was then concentrated under reduced pressure. To the crude mixture, dichloromethane (4 mL) and trifluoroacetic acid (0.307 mL, 3.98 mmol) were added. The resulting solution was stirred at ambient temperature for 2 hours. To the reaction mixture was added SCX resin (1 g) and the suspension was stirred for 30 minutes, the SCX was collected by filtration and washed with methanol (20 mL). The product was then eluted with ammonia in methanol (3.5 M), and the filtrate was concentrated in vacuo to afford the title compound (80 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.96-7.89 (m, 2H), 7.59-7.52 (m, 2H), 7.38 (s, 1H), 2.31 (s, 2H), 2.03 (s, 6H); MS (ESI) m/z 277 (M+H).sup.+.

    Example 173B: (2R,4R)-6-chloro-N-{3-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1549] The title compound was prepared using the method described for the synthesis of Example 141E, substituting the product from Example 141D with the product of Example 173A.

    [1550] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 7.98-7.91 (m, 2H), 7.60-7.53 (m, 2H), 7.50 (s, 1H), 7.42-7.38 (m, 1H), 7.25-7.19 (m, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.2 Hz, 1H), 4.87-4.79 (m, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.42-2.32 (m, 7H), 1.78-1.68 (m, 1H); MS (ESI) m/z 487 (M+H).sup.+.

    Example 174: (2S,4R)-6-chloro-N-{3-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 273)

    [1551] The title compound was prepared using the methods described for the synthesis of Example 141E, substituting the product of Example 141D with the product from Example 173A, and substituting the product of Example 3B with the product of example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.83 (s, 1H), 7.99-7.89 (m, 2H), 7.61-7.53 (m, 2H), 7.50 (s, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.63 (d, J=4.7 Hz, 1H), 4.64-4.55 (m, 2H), 2.38 (s, 6H), 2.16-2.10 (m, 1H), 1.98-1.89 (m, 1H); MS (ESI) m/z 487 (M+H).sup.+.

    Example 175: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-4-methyl-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 274)

    Example 175A: 2-amino-1-(4-chlorophenyl)propan-1-one hydrochloride

    [1552] The methodologies described in Example 193D substituting 2-bromo-1-(4-chlorophenyl)propan-1-one (Apollo) for Example 193C and modifying each of the reaction times to 16 hours gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.13-8.06 (m, 2H), 7.71-7.67 (m, 2H), 7.40 (br, s, 3H), 5.11 (q, J=7.2 Hz, 1H), 1.41 (d, J=7.2 Hz, 3H); MS (ESI+) m/z 184 (M+H).sup.+.

    Example 175B: tert-butyl (3-((1-(4-chlorophenyl)-1-oxopropan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1553] The methodologies described in Example 155A substituting Example 175A for 2-amino-1-(4-chlorophenyl)ethanone hydrochloride gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.95-7.91 (m, 2H), 7.61-7.57 (m, 2H), 7.20 (s, 1H), 6.91 (s, 1H), 5.19-5.17 (m, 1H), 2.01 (s, 6H), 1.37 (s, 9H), 1.26 (d, J=7.1 Hz, 3H); MS (ESI.sup.+) m/z 393 (M+H).sup.+.

    Example 175C: 3-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)bicyclo[1.1.1]pentan-1-amine

    [1554] The methodologies described in Example 155B substituting Example 175B for Example 155A gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.60-7.56 (m, 2H), 7.55-7.50 (m, 2H), 2.29 (s, 3H), 2.09 (s, 6H); MS (ESI.sup.+) m/z 275 (M+H).sup.+.

    Example 175D: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-4-methyl-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1555] The methodologies described in Example 155C substituting Example 175C for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.63-7.59 (m, 2H), 7.57-7.53 (m, 2H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.84-4.81 (m, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.47 (s, 6H), 2.42-2.38 (m, 1H), 2.32 (s, 3H), 2.09 (d, J=5.9 Hz, 1H); MS (ESI.sup.+) m/z 486 (M+H).sup.+.

    Example 176: (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-4-methyl-1,3-oxazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 275)

    [1556] The methodologies described in Example 155C substituting Example 175C for Example 155B and substituting the product of Example 73B for Example 3B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 7.64-7.58 (m, 2H), 7.57-7.52 (m, 2H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.63 (d, J=4.6 Hz, 1H), 4.61-4.56 (m, 2H), 2.46 (s, 6H), 2.32 (s, 3H), 2.14-2.10 (m, 1H), 1.94-1.90 (m, 1H); MS (ESI+) m/z 486 (M+H).sup.+.

    Example 177: (2S,4S)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 276)

    Example 177A: tert-butyl [(2S)-4-{[(2S)-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-2-hydroxybicyclo[2.2.2]octan-1-yl]carbamate

    [1557] The reaction and purification conditions described in Example 2B substituting the product of Example 13H for the product of Example 2A, and the product of Example 10A for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 465 (M+H).sup.+.

    Example 177B: (2S)N-[(3S)-4-amino-3-hydroxybicyclo[2.2.2]octan-1-yl]-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1558] Trifluoroacetic acid (1 mL) was added to a solution the product of Example 177A (0.28 g, 0.60 mmol) in dichloromethane (2 mL) and the resulting mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was taken up in methanol (5 mL) and directly purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.2 g, 0.55 mmol, 91% yield). MS (APCI.sup.+) m/z 365 (M+H).sup.+.

    Example 177C: (2S,4S)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1559] The reaction and purification conditions described in Example 136D substituting the product of Example 177B for the product of Example 136C, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.37 (dd, J=2.8, 1.0 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.17 (dd, J=8.6, 2.7 Hz, 1H), 6.93 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.66 (s, 1H), 5.21 (s, 1H), 4.77 (dd, J=10.4, 6.0 Hz, 1H), 4.54 (dd, J=11.7, 2.2 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.94 (d, J=9.1 Hz, 1H), 3.78-3.65 (m, 3H), 2.80-2.69 (m, 2H), 2.35-2.18 (m, 3H), 2.17-2.06 (m, 2H), 2.02-1.66 (m, 9H); MS (APCI.sup.+) m/z 563 (M+H).sup.+.

    Example 178: (2R,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 277)

    [1560] The title compound was synthesized using the same procedures as described in Example 168A through Example 168C and Example F through Example G substituting Example 128G with 1-chloro-4-vinylbenzene. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.75 (s, 1H), 7.52-7.48 (m, 2H), 7.45-7.41 (m, 2H), 7.39-7.37 (m, 1H), 7.20 (dd, J=8.7, 2.6 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.69 (d, J=6.0 Hz, 1H), 5.59 (t, J=8.0 Hz, 1H), 4.81 (dd, J=10.8, 5.7 Hz, 1H), 4.61 (dd, J=12.0, 2.2 Hz, 1H), 3.98 (t, J=8.8 Hz, 1H), 3.42 (dd, J=9.0, 7.4 Hz, 1H), 2.38-2.27 (m, 7H), 1.73-1.65 (m, 1H).

    Example 179: (2S,4R)-6-chloro-N-{3-[5-(4-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 278)

    [1561] The title compound was synthesized using the same procedure as described in Example 178 substituting Example 3B with Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.81 (s, 1H), 7.52-7.48 (m, 2H), 7.45-7.42 (m, 2H), 7.31 (d, J=2.7 Hz, 1H), 7.25 (dd, J=8.8, 2.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 5.63-5.56 (m, 2H), 4.59-4.54 (m, 2H), 3.97 (t, J=8.8 Hz, 1H), 3.42 (dd, J=9.0, 7.3 Hz, 1H), 2.31 (s, 6H), 2.09 (dt, J=14.0, 3.4 Hz, 1H), 1.93-1.86 (m, 1H).

    Example 180: (2S,4R)-6-chloro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 279)

    [1562] The reaction conditions described in Example 99, substituting the product of Example 177C for the product of Example 6C, and purification by chiral preparative HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 10 mL/minute, 100% ethanol (isocratic gradient)] gave the title compound as the later eluting fraction. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.42 (s, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.59 (s, 1H), 5.21 (s, 1H), 4.60-4.50 (m, 2H), 4.47 (p, J=7.1 Hz, 1H), 3.93 (dd, J=9.5, 3.3 Hz, 1H), 3.77-3.65 (m, 3H), 2.80-2.69 (m, 2H), 2.35-2.18 (m, 2H), 2.16-2.06 (m, 2H), 2.04-1.66 (m, 10H); MS (APCI.sup.+) m/z 563 (M+H).sup.+.

    Example 181: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 280)

    Example 181A: tert-butyl (3-(methoxy(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1563] To an ice-cooled solution of N,O-dimethylhydroxylamine, hydrochloric acid (1.931 g, 19.80 mmol) and 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (3.00 g, 13.20 mmol) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (9.22 mL, 52.8 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 7.53 g, 19.80 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (75 mL) and washed with 1 M aqueous HCl (100 mL), saturated aqueous NaHCO.sub.3 (2100 mL) and brine (100 mL). The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate in isohexane to afford the title compound (3.18 g, 11.18 mmol, 85% yield).

    [1564] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.59 (s, 1H), 3.63 (s, 3H), 3.08 (s, 3H), 2.15 (s, 6H), 1.38 (s, 9H).

    Example 181B: tert-butyl (3-(2-bromoacetyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1565] To an ice-cooled solution of the product from Example 181A (3.18 g, 11.76 mmol) in anhydrous tetrahydrofuran (100 mL) was added methylmagnesium bromide (3.0 M in diethyl ether, 11.76 mL, 35.3 mmol) dropwise. The resulting solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with 1 M aqueous HCl (100 mL) and extracted with dichloromethane (100 mL). The organic layer was collected and the volatiles were removed in vacuo to give tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate (2.62 g, 10.47 mmol, 89% yield). A portion of the tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate (1.00 g, 4.44 mmol) was dissolved in tetrahydrofuran (10 mL), and phenyltrimethylammonium tribromide (1.669 g, 4.44 mmol) was added portionwise. The resulting solution was stirred at room temperature for 2 hours. The mixture was filtered, washing with tetrahydrofuran (5 mL), and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-50% ethyl acetate in isohexane to afford the title compound (244 mg, 0.762 mmol, 17% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.63 (s, 1H), 4.46 (s, 2H), 2.19 (s, 6H), 1.38 (s, 9H).

    Example 181C: cis-3-(trifluoromethoxy)cyclobutanecarbothioamide

    [1566] To a solution of the product from Example 25N (600 mg, 3.26 mmol) in dichloromethane (5 mL) was added ammonium chloride (1.74 g, 32.6 mmol), N,N-diisopropylethylamine (7.40 mL, 42.4 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.24 g, 3.26 mmol), and the resulting mixture was stirred at ambient temperature overnight. The mixture was partitioned between dichloromethane (30 mL) and 1 M aqueous HCl solution (30 mL), the aqueous layer was extracted with dichloromethane (30 mL), and the combined organic layers were passed through a hydrophobic cartridge and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-100% ethyl acetate in isohexane to afford cis-3-(trifluoromethoxy)cyclobutanecarboxamide (691 mg, 1.170 mmol, 35.9% yield). To a solution of cis-3-(trifluoromethoxy)cyclobutanecarboxamide (691 mg, 3.77 mmol) in tetrahydrofuran (20 mL) was added Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) (916 mg, 2.264 mmol), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated onto silica, and the crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (125 mg, 0.615 mmol, 16.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.52 (s, 1H), 9.20 (s, 1H), 4.77 (p, J=7.5 Hz, 1H), 2.99-2.89 (m, 1H), 2.61-2.52 (m, 2H), 2.49-2.41 (m, 2H).

    Example 181D: tert-butyl (3-(2-(cis-3-(trifluoromethoxy)cyclobutyl)thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1567] To a solution of the product from Example 181B (100 mg, 0.329 mmol) in ethanol (2 mL) was added the product from Example 181C (65.5 mg, 0.329 mmol). The resulting solution was stirred at 80 C. for 1 hour and concentrated in vacuo to afford the title compound. MS (ESI) m/z 405 (M+H).sup.+.

    Example 181E: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1568] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 181D for the product from Example 131C, and substituting the product from Example 3B for the product from Example 73B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.73 (s, 1H), 7.38 (dd, J=3.0, 1.0 Hz, 11H), 7.29 (s, 1H), 7.20 (dd, J=8.5, 2.5 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 5.70 (d, J=6.5 Hz, 1H), 4.89-4.77 (m, 2H), 4.61 (dd, J=12.0, 2.5 Hz, 1H), 3.51-3.42 (m, 1H), 2.91-2.80 (m, 2H), 2.44-2.33 (m, 3H), 2.32 (s, 6H), 1.78-1.64 (m, 1H); MS (ESI) m/z 515 (M+H).sup.+.

    Example 182: (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 281)

    Example 182A: tert-butyl (3-(4-(4-chlorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1569] The methodologies described in Example 49A substituting 4-chlorobenzaldehyde for 3,4-difluorobenzaldehyde and purifying by column chromatography on silica gel (0-100% ethyl acetate in isohexane) gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-do) 6 ppm 7.79-7.76 (m, 3H), 7.74 (d, J=1.3 Hz, 1H), 7.42-7.39 (m, 2H), 2.40 (s, 6H), 1.41 (s, 9H); MS (ESI+) m/z 360 (M+H).sup.+.

    Example 182B: 3-(4-(4-chlorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid

    [1570] The methodologies described in Example 21B substituting Example 182A for Example 21A gave the title intermediate as a trifluoroacetic acid salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 2H), 8.58 (s, 1H), 8.14 (s, 1H), 7.82-7.75 (m, 2H), 7.56-7.51 (m, 2H), 2.58 (s, 6H); MS (ESI+) m/z 260 (M+H).sup.+.

    Example 182C: (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1571] The methodologies described in Example 155C substituting Example 182B for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 7.83 (d, J=1.3 Hz, 1H), 7.81-7.71 (m, 3H), 7.46-7.36 (m, 3H), 7.22 (dd, J=8.7, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.85-4.81 (m, 1H), 4.67 (dd, J=12.0, 2.3 Hz, 1H), 2.54 (s, 6H), 2.42-2.39 (m, 1H), 1.74 (q, J=11.3 Hz, 1H); MS (ESI+) m/z 470/472 (.sup.35Cl/.sup.37Cl, M+H).sup.+.

    Example 183: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-3-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 282)

    Example 183A: tert-butyl (3-(4-(4-chloro-3-fluorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1572] The methodologies described in Example 49A substituting 4-chloro-3-fluorobenzaldehyde for 3,4-difluorobenzaldehyde and purifying by column chromatography on silica gel (0-100% ethyl acetate in isohexane) gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.89 (s, 1H), 7.78 (d, J=1.3 Hz, 1H), 7.72 (dd, J=11.0, 1.9 Hz, 1H), 7.63 (dd, J=8.4, 1.9 Hz, 1H), 7.56 (t, J=8.1 Hz, 1H), 2.41 (s, 6H), 1.41 (s, 9H); MS (ESI+) m/z 378 (M+H).sup.+.

    Example 183B: 3-(4-(4-chloro-3-fluorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-amine, trifluoroacetic acid

    [1573] The methodologies described in Example 21B substituting Example 183A for Example 21A gave the title intermediate as a trifluoroacetic acid salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.85 (s, 2H), 8.09 (s, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.75-7.72 (m, 1H), 7.64-7.59 (m, 2H), 2.54 (s, 6H); MS (ESI+) m/z 278 (M+H).sup.+.

    Example 183C: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-3-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1574] The methodologies described in Example 155C substituting Example 183B for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.82 (d, J=1.3 Hz, 1H), 7.76-7.71 (m, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.9, 2.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (d, J=6.3 Hz, 1H), 4.86-4.81 (m, 1H), 4.69-4.65 (m, 1H), 2.54 (s, 6H), 2.42-2.38 (m, 1H), 1.74 (q, J=11.7 Hz, 1H); MS (ESI+) m/z 488/490 (.sup.3SCl/.sup.37Cl, M+H).sup.+.

    Example 184: (2S,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 283)

    [1575] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 135C for the product from Example 131C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.25 (dd, J=9.0, 2.5 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 6.42 (s, 1H), 5.68 (br. s, 1H), 4.85 (p, J=7.5 Hz, 1H), 4.61-4.53 (m, 2H), 2.83-2.75 (m, 2H), 2.41-2.29 (m, 9H), 2.14-2.07 (m, 1H), 1.95-1.86 (m, 1H); MS (ESI) m/z 497 (MH).sup..

    Example 185: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[trans-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 284)

    Example 185A: cis-benzyl 3-hydroxycyclobutanecarboxylate

    [1576] To a stirred solution of benzyl 3-oxocyclobutanecarboxylate (5 g, 24.48 mmol), at 78 C. under an atmosphere of nitrogen, was added 1.0M lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (26.9 mL, 26.9 mmol) dropwise over 30 minutes and the resultant reaction mixture was stirred for 3 hour at this temperature. The reaction mixture was quenched with saturated NH.sub.4Cl(aqueous) (50 mL) and extracted with ethyl acetate (250 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, dichloromethane loading, 0-100% ethyl acetate/isohexane) to afford the title compound (4.3 g, 20.43 mmol, 83% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.42-7.30 (m, 5H), 5.20 (d, J=6.9 Hz, 1H), 5.09 (s, 2H), 4.06-3.92 (m, 1H), 2.62 (tt, J=10.0, 7.7 Hz, 1H), 2.41 (dddd, J=10.3, 9.4, 5.2, 2.5 Hz, 2H), 2.03-1.92 (m, 2H).

    Example 185B: trans-benzyl 3-(formyloxy)cyclobutanecarboxylate

    [1577] To a solution of the product of Example 185A (100 mg, 0.485 mmol) and formic acid (0.022 mL, 0.582 mmol) in tetrahydrofuran (2 mL), at room temperature under nitrogen, was added triphenylphosphine (153 mg, 0.582 mmol) followed by diisopropyl azodicarboxylate (0.104 mL, 0.533 mmol) and the subsequent reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-100% ethyl acetate/isohexane) to afford the title compound (38 mg, 0.159 mmol, 32.8% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.14 (s, 1H), 7.42-7.30 (m, 5H), 5.18-5.10 (m, 3H), 3.24-3.17 (m, 1H), 2.60-2.53 (m, 2H), 2.42-2.34 (m, 2H).

    Example 185C: trans-benzyl 3-hydroxycyclobutanecarboxylate

    [1578] A solution of the product of Example 185B (378 mg, 1.62 mmol) in dimethylamine (2 M in tetrahydrofuran) (2.5 mL, 5.0 mmol) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to afford the crude product which was purified by chromatography on silica gel (4 g cartridge, dichloromethane loading, 0-100/a ethyl acetate/isohexane) to afford the title compound (312 mg, 1.483 mmol, 92% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.42-7.30 (m, 5H), 5.18 (d, J=6.3 Hz, 1H), 5.10 (s, 2H), 4.33-4.19 (m, 1H), 3.04-2.94 (m, 1H), 2.44-2.33 (m, 2H), 2.15-2.04 (m, 2H).

    Example 185D: trans-3-(trifluoromethoxy)cyclobutanecarboxylic acid

    [1579] The title compound was synthesized using the same procedure as described in Example 25N through Example 250 substituting the product of Example 25M with the product of Example 185C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.43-7.30 (m, 5H), 5.13 (s, 2H), 4.92 (p, J=7.0 Hz, 1H), 3.25-3.17 (m, 1H), 2.64-2.51 (m, 4H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm57.80.

    Example 185E: 3-(3-(trans-3-(trifluoromethoxy)cyclobutyl)isoxazol-5-yl)bicyclo[1.1.1]pentan-1-amine trifluoroacetic acid

    [1580] The title compound was synthesized using the same procedures as described in Example 167A through Example 167F substituting the product of Example 25N with the product of Example 185D. MS (ESI.sup.+) m/z 289.1 (M+H).sup.+.

    Example 185F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[trans-3-(trifluoromethoxy)cyclobutyl]-1,2-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1581] The title compound was synthesized using the same procedure as described in Example 167G substituting the product of Example 167F with the product of Example 185E. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.83 (s, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.48 (s, 1H), 5.71 (d, J=3.6 Hz, 1H), 5.05 (p, J=6.9 Hz, 1H), 4.81 (dd, J=16.1, 1.6 Hz, 1H), 4.62 (dd, J=12.0, 2.2 Hz, 1H), 3.61-3.55 (m, 1H), 2.72-2.64 (m, 2H), 2.55 (ddt, J=10.7, 7.0, 3.7 Hz, 1H), 2.41 (s, 7H), 2.40-2.34 (m, 1H), 1.71 (q, J=11.9 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm57.54.

    Example 186: N-(3-{[(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-2-phenyl-1,3-oxazole-5-carboxamide (Compound 285)

    Example 186A: tert-butyl (3-(2-phenyloxazole-5-carboxamido)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1582] The reaction and purification conditions described in Example 2B substituting tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate for the product of Example 2A, and 2-phenyloxazole-5-carboxylic acid (Ark Pharm) for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 370 (M+H).sup.+.

    Example 186B: N-(3-{[(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-2-phenyl-1,3-oxazole-5-carboxamide (Compound 285)

    [1583] The product of Example 186A (40 mg, 0.108 mmol) was combined with trifluoroacetic acid (1.0 mL) and stirred at ambient temperature for 30 minutes. The mixture was concentrated under reduced pressure. Triethylamine (0.075 mL, 0.54 mmol), N,N-dimethylformamide (1 mL), the product of Example 1B (24.5 mg, 0.108 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (49.4 mg, 0.130 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for 1 hour and then partitioned between dichloromethane (230 mL) and saturated aqueous sodium bicarbonate (30 mL). The organic fractions were combined, dried over sodium sulfated, and concentrated under reduced pressure. The residue was taken up in methanol (5 mL) and sodium borohydride (49 mg, 1.3 mmol) was added in 3 portions over a period of 3 minutes. After stirring for another 20 minutes, saturated aqueous ammonium chloride (0.2 mL) was added and the resulting mixture was partitioned between dichloromethane (230 mL) and saturated aqueous sodium bicarbonate (30 mL). The organic layers were combined, dried over sodium sulfated, concentrated under reduced pressure, taken up in N,N-dimethylformamide (3 mL), and directly purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (26 mg, 0.054 mmol, 50% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.28 (s, 1H), 8.74 (s, 1H), 8.17-8.09 (m, 2H), 7.86 (s, 1H), 7.64-7.54 (m, 3H), 7.39 (dd, J=2.7, 0.9 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=4.4 Hz, 1H), 4.85-4.79 (m, 1H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 2.39 (s, 6H), 2.40-2.33 (m, 1H), 1.77-1.66 (m, 1H); MS (ESI.sup.+) m/z 480 (M+H).sup.+.

    Example 187: (2R,4R)-6-chloro-N-[3-(2-{[cis-3-cyanocyclobutyl]oxy}-1,3-thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 286)

    Example 187A: O-(cis-3-cyanocyclobutyl) carbamothioate

    [1584] At 0 C., under atmosphere of nitrogen, sodium hydride (49.4 mg, 1.236 mmol) (60 weight % dispersion in mineral oil) was added to a solution of the product of Example 119A (100 mg, 1.030 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred at 0 C. for 90 minutes before the addition of carbon disulfide (0.074 mL, 1.236 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 23 hours. Iodomethane (0.077 mL, 1.236 mmol) was then added and the mixture was stirred at room temperature for 5 hours. Ammonium hydroxide (0.139 mL, 2.059 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water (10 mL) was added and the suspension was extracted with dichloromethane (310 mL). The combined extracts were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% ethyl acetate/isohexane) to give the title compound (50 mg, 0.314 mmol, 30.5% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.82 (s, 1H), 8.49 (s, 1H), 5.18 (p, J=7.4 Hz, 1H), 3.10-3.02 (m, 1H), 2.85-2.73 (m, 2H), 2.37-2.22 (m, 2H).

    Example 187B: cis-3-((4-(3-aminobicyclo[1.1.1]pentan-1-yl)thiazol-2-yl)oxy)cyclobutanecarbonitrile

    [1585] At room temperature, the product of Example 187A (25.7 mg, 0.164 mmol) was added to a solution of the product of Example 181B (50 mg, 0.164 mmol) in ethanol (2 mL). The reaction mixture was stirred at 80 C. for 3 hour, and then was concentrated to give the crude tert-butyl (3-(2-(cis-3-cyanocyclobutoxy)thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (59 mg, 0.226 mmol, 137% yield). The material was used in the next step without further purification. This crude tert-butyl (3-(2-(cis-3-cyanocyclobutoxy)thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (120 mg, 0.332 mmol) was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (0.384 mL, 4.98 mmol). The reaction mixture was allowed to stir at room temperature overnight. Methanol (2.0 mL) was added followed by SCX resin (1.22 g), and the suspension was stirred for 1 hour. The solid was collected by filtration, washed with methanol (210 mL). The solid was washed with NH.sub.3 (3.5 M in methanol, 10 mL), and this filtrate was concentrated to give the title compound (59 mg, 0.196 mmol, 59.2% yield) (83% over 2 steps). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 6.61 (s, 1H), 5.05 (p, J=7.3 Hz, 1H), 3.14-3.06 (m, 1H), 2.87-2.80 (m, 2H), 2.46-2.39 (m, 2H), 1.89 (s, 6H).

    Example 187C: (2R,4R)-6-chloro-N-[3-(2-{[cis-3-cyanocyclobutyl]oxy}-1,3-thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1586] At room temperature, the product of Example 3B (18 mg, 0.079 mmol) was added to a solution of the product of Example 187B (26.7 mg, 0.102 mmol) in N,N-dimethylformamide (1 mL). Additional N,N-dimethylformamide (0.5 mL) was used to transfer the remaining acid into the reaction mixture. N,N-Diisopropylethylamine (0.107 mL, 0.611 mmol) was then added, followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.061 mL, 0.105 mmol) (50 weight % in N,N-dimethylformamide). The reaction mixture was stirred at room temperature over 3 nights. The reaction mixture was directly purified by preparative HPLC (Waters XBridge Prep-C18, 5 m column (19 mm50 mm). A 40-70% gradient of acetonitrile (A) and 0.1% ammonium bicarbonate in water (B) was used over 7.5 minutes at a flow rate of 30 mL/minute) to give the title compound (15.5 mg, 0.031 mmol, 39.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 7.37 (d, J=2.7 Hz, 1H), 7.19 (dd, J=8.8, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.73 (s, 1H), 5.71 (d, J=6.3 Hz, 1H), 5.07 (p, J=7.2 Hz, 1H), 4.80 (dt, J=10.6, 6.2 Hz, 1H), 4.59 (dd, J=11.9, 2.2 Hz, 1H), 3.11 (p, J=8.9 Hz, 1H), 2.89-2.78 (m, 2H), 2.47-2.40 (m, 2H), 2.23 (s, 6H), 1.68 (q, J=12.0 Hz, 1H).

    Example 188: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 287)

    Example 188A: cis-N-methoxy-N-methyl-3-(trifluoromethoxy)cyclobutanecarboxamide

    [1587] The title compound was prepared using the methods described for the synthesis of Example 181A, substituting the product from Example 250 for 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.80 (p, J=7.5 Hz, 1H), 3.64 (s, 3H), 3.19-3.03 (m, 4H), 2.58-2.52 (m, 2H), 2.34-2.24 (m, 2H).

    Example 188B: cis-3-(trifluoromethoxy)cyclobutanecarbaldehyde

    [1588] The title compound was prepared using the methods described for the synthesis of Example 128f, substituting the product from Example 188A for the product of Example 128e. The crude product was used without any analysis (assumed quantitative yield).

    Example 188C: tert-butyl (3-(4-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1589] To a solution of the product of Example 188B (510 mg, 3.03 mmol) in ethanol/tetrahydrofuran (2:1, 20 mL) was added dropwise 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (592 mg, 3.03 mmol) and sodium cyanide (28 mg, 0.57 mmol) dissolved in a small amount of water. The mixture was then stirred at ambient temperature for 3 hours. After this time, the reaction mixture was concentrated under reduced pressure and to the resulting residue was added dichloromethane (10 mL). The solution was then dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. To the crude intermediate (1 g, 2.75 mmol) was added tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (500 mg, 2.52 mmol) and xylene (10 mL). The reaction mixture was then heated at 135 C. for 16 hours and was then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (66 mg, 6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.81-7.64 (m, 1H), 7.56 (s, 1H), 7.03 (s, 1H), 4.77 (p, J=7.6 Hz, 1H), 3.00-2.90 (m, 1H), 2.64-2.57 (m, 2H), 2.42-2.23 (m, 8H), 1.40 (s, 9H); MS (ESI) m/z 388 (M+H).sup.+.

    Example 188D: 3-(4-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1590] The title compound was prepared using the methods described for the synthesis of Example 119F, substituting the product of Example 119E with the product of Example 188C.

    [1591] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.51 (s, 1H), 6.99 (s, 1H), 4.76 (p, J=7.6 Hz, 1H), 2.99-2.90 (m, 1H), 2.65-2.56 (m, 2H), 2.41 (s, 2H), 2.34-2.25 (m, 2H), 2.11 (s, 6H); MS (ESI) m/z 288 (M+H).sup.+.

    Example 188E. (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1592] The title compound was prepared using the methods described for the synthesis of Example 141E, substituting the product of Example 141E with the product of Example 188D.

    [1593] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 7.60 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.6, 2.7 Hz, 1H), 7.09 (s, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.74 (d, J=6.3 Hz, 1H), 4.86-4.74 (m, 2H), 4.68-4.62 (m, 1H), 3.00-2.92 (m, 1H), 2.65-2.58 (m, 2H), 2.47 (s, 6H), 2.41-2.35 (m, 1H), 2.35-2.27 (m, 2H), 1.72 (q, J=11.9 Hz, 1H); MS (ESI) m/z 498 (M+H).sup.+.

    Example 189: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 288)

    Example 189A: tert-butyl (3-((2-oxo-2-((cis)-3-(trifluoromethoxy)cyclobutyl)ethyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1594] The methodologies described in Example 193E substituting 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (PharmaBlock) for (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid gave the title intermediate.

    [1595] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.09 (t, J=5.9 Hz, 1H), 7.55 (s, 1H), 4.81 (p, J=7.5 Hz, 1H), 3.85 (d, J=5.8 Hz, 2H), 3.02-2.92 (m, 1H), 2.49-2.36 (m, 2H), 2.31-2.17 (m, 2H), 2.10 (s, 6H), 1.37 (s, 9H).

    Example 189B: 3-(4-(cis-3-(trifluoromethoxy)cyclobutyl)oxazol-2-yl)bicyclo[1.1.1]pentan-1-amine

    [1596] The methodologies described in Example 193F substituting Example 189A for Example 193E gave the title intermediate. .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 6.68 (d, J=7.9 Hz, 1H), 4.61 (p, J=7.6 Hz, 1H), 3.06 (tt, J=10.1, 7.4 Hz, 1H), 2.79-2.69 (m, 2H), 2.45 (t, J=8.7 Hz, 2H), 2.24 (s, 6H); MS (ESI+) m/z 289 (M+H).sup.+.

    Example 189C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1597] The methodologies described in Example 155C substituting Example 189B for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.83 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=0.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.82 (p, J=7.3 Hz, 2H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 3.22-3.16 (m, 1H), 2.81-2.68 (m, 2H), 2.41 (s, 6H), 2.37-2.30 (m, 3H), 1.71 (d, J=11.9 Hz, 1H); MS (ESI+) m/z 499 (M+H).sup.+.

    Example 190: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 289)

    Example 190A: tert-butyl (3-((2-oxo-2-((cis)-3-(trifluoromethoxy)cyclobutyl)ethyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1598] The methodologies described in Example 193E substituting 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (PharmaBlock) for (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid and decreasing the reaction time from 3 days to 16 hours gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.14-8.07 (m, 1H), 7.60-7.51 (m, 1H), 4.82 (p, J=7.4 Hz, 1H), 3.85 (d, J=5.3 Hz, 2H), 3.01-2.95 (m, 1H), 2.29-2.16 (m, 2H), 2.16-1.88 (s, 6H), 1.38 (s, 9H).

    Example 190B: tert-butyl (3-(5-((cis)-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1599] To a stirred solution of Example 190A (0.250 g, 0.440 mmol) in xylene (2.5 mL) was added ammonium acetate (0.678 g, 8.80 mmol) at ambient temperature, and the reaction mixture was heated at 140 C. for 2 hours. Then the reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% 0.7 N NH.sub.3 in methanol/dichloromethane) to afford the title intermediate (41 mg, 0.095 mmol, 22% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 11.60 (s, 1H), 7.21 (s, 1H), 6.87 (m, 1H), 4.79-4.67 (m, 1H), 2.98-2.82 (m, 1H), 2.60-2.55 (m, 2H), 2.34-2.19 (m, 2H), 2.16 (s, 6H), 1.39 (s, 9H).

    Example 190C: 3-(5-((cis)-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-2-yl)bicyclo[1.1.1]pentan-1-amine

    [1600] To a solution of Example 190B (41 mg, 0.11 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol) and the reaction mixture stirred at ambient temperature for 16 hours and then was diluted with methanol (15 mL). SCX resin (1 g) was added and the reaction mixture was stirred for 30 minutes. The mixture was loaded onto SCX resin (2 g), washed with methanol (310 mL), and eluted with 0.7 M NH.sub.3 in methanol (310 mL) to afford the title intermediate (18 mg, 0.056 mmol, 53% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 6.70 (s, 1H), 4.64-4.54 (m, 1H), 3.18-2.96 (m, 1H), 2.81-2.70 (m, 2H), 2.35-2.28 (m, 2H), 2.07 (s, 6H); MS (ESI+) m/z 288 (M+H).sup.+.

    Example 190D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1601] The methodologies described in Example 155C substituting Example 190C for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 11.72 (d, J=64.0 Hz, 1H), 8.73 (s, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.8 Hz, 1H), 6.98-6.76 (m, 2H), 5.71 (s, 1H), 4.91-4.69 (m, 2H), 4.61 (dd, J=12.0, 2.2 Hz, 1H), 3.03-2.84 (m, 1H), 2.62-2.57 (m, 2H), 2.40-2.35 (m, 2H), 2.34-2.30 (m, 7H), 1.71 (d, J=11.9 Hz, 1H); MS (ESI.sup.+) m/z 498 (M+H).sup.+.

    Example 191: (2R,4R)-6-chloro-N-[3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 290)

    Example 191A: methyl 3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1602] The reaction and purification conditions described in Example 136A substituting 4-cyclobutyl-1H-pyrazole (Combi-Blocks) for 5-chloro-1H-indazole gave the title compound. MS (APCI.sup.+) m/z 265 (M+H).sup.+.

    Example 191B: 3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1603] The product of Example 191A (96 mg, 0.39 mmol) was combined with methanol (2 mL) and aqueous sodium hydroxide (2.5 M, 1.0 mL) was added. After stirring at ambient temperature for 1 hour, the reaction mixture was partitioned between dichloromethane (250 mL) and aqueous citric acid (10 w/w %, 50 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure to give the title compound (91 mg, 0.39 mmol, 100% yield). MS (APCI.sup.+) m/z 233 (M+H).sup.+.

    Example 191C: 2-(trimethylsilyl)ethyl (3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1604] The reaction and purification conditions described in Example 125C substituting the product of Example 191B for the product of Example 125B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.91 (s, 1H), 7.57 (d, J=0.7 Hz, 1H), 7.34 (d, J=0.8 Hz, 1H), 4.08-3.98 (m, 2H), 3.32-3.26 (m, 1H), 2.42 (d, J=62.4 Hz, 6H), 2.28-2.17 (m, 2H), 2.03-1.75 (m, 4H), 0.99-0.85 (m, 2H), 0.02 (s, 9H); MS (APCI.sup.+) m/z 348 (M+H).sup.+.

    Example 191D: (2R,4R)-6-chloro-N-[3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1605] The reaction and purification conditions described in Example 1C substituting the product of Example 191C for the product of Example 1A, and the product of Example 3B for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.60 (s, 1H), 7.41-7.33 (m, 2H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.84-4.80 (m, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 3.37-3.26 (m, 1H), 2.47 (s, 6H), 2.37 (ddd, J=12.7, 5.9, 2.5 Hz, 1H), 2.28-2.17 (m, 2H), 2.04-1.77 (m, 4H), 1.77-1.66 (m, 1H); MS (APCI.sup.+) m/z 414 (M+H).sup.+.

    Example 192: (2S,4R)-6-chloro-N-[3-(4-cyclobutyl-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 291)

    [1606] The reaction and purification conditions described in Example 1C substituting the product of Example 191C for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.60 (t, J=0.7 Hz, 1H), 7.36-7.35 (m, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 5.63 (s, 1H), 4.63-4.55 (m, 2H), 3.39-3.25 (m, 1H), 2.47 (s, 6H), 2.27-2.18 (m, 2H), 2.15-2.08 (m, 1H), 2.03-1.75 (m, 5H); MS (APCI.sup.+) m/z 414 (M+H).sup.+.

    Example 193: (2R,4R)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 292)

    Example 193A: (cis)-N-methoxy-N-methyl-3-(trifluoromethoxy)cyclobutanecarboxamide

    [1607] To a cooled (0 C.) solution of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.42 g, 3.72 mmol), N-ethyl-N-isopropylpropan-2-amine (1.7 mL, 9.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.291 g, 2.98 mmol) in dichloromethane (12 mL) and N,N-dimethylformamide (5 mL) was added Example 25N (0.457 g, 2.48 mmol) and the reaction mixture was stirred at 0 C. for 1 hour. Then N,N-dimethylformamide (2 mL) was added until the mixture was a homogeneous solution. The reaction mixture was then stirred at ambient temperature for 24 hours. After this time, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with hydrogen chloride (1 M, 75 mL), saturated aqueous sodium bicarbonate (75 mL) and brine (100 mL3). The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo to give the title intermediate (0.643 g, 2.49 mmol, quantitative yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.79 (p, J=7.5 Hz, 1H), 3.63 (s, 3H), 3.22-2.93 (m, 4H), 2.56-2.51 (m, 2H), 2.32-2.24 (m, 2H).

    Example 193B: 1-((cis)-3-(trifluoromethoxy)cyclobutyl)ethanone

    [1608] To a cooled (0 C.) solution of Example 193A (1.00 g, 4.40 mmol) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (3 M in diethyl ether, 4.4 mL, 13 mmol) dropwise. The reaction mixture was stirred at ambient temperature overnight. Then the reaction mixture was quenched with HCl (0.5 M, aqueous, 50 mL) and extracted with dichloromethane (350 mL). The organic layers were combined and concentrated in vacuo without fully evaporating the solvent due to compound volatility to give the title intermediate (0.85 g, 2.0 mmol, 45% yield).

    [1609] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.77 (p, J=7.5 Hz, 1H), 2.97-2.89 (m, 1H), 2.56-2.50 (m, 2H), 2.25-2.17 (m, 2H), 2.07 (s, 3H).

    Example 193C: 2-bromo-1-((cis)-3-(trifluoromethoxy)cyclobutyl)ethanone

    [1610] To a solution of Example 193B (0.500 g, 1.15 mmol) in methanol (9 mL) was added a solution of HBr (48% aqueous solution, 0.07 mL, 1.3 mmol) in methanol (2 mL), followed by a solution of Br.sub.2 (0.07 mL, 1.3 mmol) in methanol (9 mL) dropwise. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then poured into ice water (50 mL) and extracted with dichloromethane (350 mL). The combined organic fractions were then washed with brine (350 mL), concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in isohexane) to give the title intermediate (0.32 g, 0.91 mmol, 79% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.81 (p, J=7.5 Hz, 1H), 4.38 (s, 2H), 3.18-3.11 (m, 1H), 2.63-2.52 (m, 2H), 2.35-2.23 (m, 2H).

    Example 1931): 2-amino-1-((cis)-3-(trifluoromethoxy)cyclobutyl)ethanone hydrochloride

    [1611] To a solution of Example 193C (1.8 g, 6.9 mmol) in acetonitrile (43 mL) was added N-formylformamide (sodium salt, 0.76 g, 7.9 mmol) and the reaction mixture was stirred at ambient temperature for 1.5 days. Then the volatiles were removed and the residue was dissolved in ethanol (85 mL) and hydrogen chloride (4 N in dioxane, 17 mL, 68 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. Then the volatiles were removed. The crude residue was then triturated with tert-butyl methyl ether (315 mL) to give the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.21 (s, 3H), 4.85 (p, J=7.5 Hz, 1H), 3.94 (s, 2H), 3.13-3.04 (m, 1H), 2.65-2.57 (m, 2H), 2.37-2.23 (m, 2H); MS (ESI.sup.+) m/z 198 (M+H).sup.+.

    Example 193E: tert-butyl ((3R,6S)-6-((2-oxo-2-((cis)-3-(trifluoromethoxy)cyclobutyl)ethyl)carbamoyl)tetrahydro-2H-pyran-3-yl)carbamate

    [1612] To a mixture of (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (Astatech, 0.50 g, 2.1 mmol) and Example 193D (0.40 g, 1.7 mmol) in N,N-dimethylformamide (9.7 mL) was added Hunig's Base (N,N-diisopropylethylamine) (0.89 mL, 5.1 mmol) followed by HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (0.98 g, 2.6 mmol). This reaction mixture was allowed to stir at ambient temperature for three days, and then the mixture was diluted with ethyl acetate (10 mL), washed with HCl (1 M, 5 mL), then sodium bicarbonate (saturated aqueous, 5 mL), and then brine (5 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford the title intermediate. MS (APCI.sup.+) m/z 369 (MtBu+H).sup.+.

    Example 193F: (3R,6S)-6-(5-(cis-3-(trifluoromethoxy)cyclobutyl)oxazol-2-yl)tetrahydro-2H-pyran-3-amine

    [1613] To Example 193E (0.72 g, 1.7 mmol) was added POCl.sub.3 (6.9 mL, 74 mmol). This reaction mixture was allowed to stir at 40 C. for 2 hours. After this time, the reaction mixture was cooled to ambient temperature and concentrated. The resulting solid was then dissolved in methanol (10 mL) and filtered through an SCX-2 (strong cation exchange) resin, washing with methanol (310 mL). The product was then eluted with 1 N NH.sub.3 in methanol (310 mL) and the volatiles were removed. The residue was diluted with N,N-dimethylformamide (2 mL) and water (0.5 mL), filtered, and purified by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) to give the title intermediate (0.50 g, 1.7 mmol, 97% yield). MS (ESI.sup.+) 307 (M+H).sup.+.

    Example 193G: (2R)-6-chloro-4-oxo-N-[(3R,6S)-6-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1614] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 193F for Example 30C gave the title intermediate. MS (APCI.sup.+) m/z 515 (M+H).sup.+.

    Example 193H: (2R,4R)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1615] The methodologies described in Example 5 substituting Example 193G for Example 4 and purifying by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.98 (d, J=8.0 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.99 (d, J=0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (d, J=6.3 Hz, 1H), 4.88-4.81 (m, 1H), 4.84-4.78 (m, 1H), 4.65 (dd, J=11.8, 2.3 Hz, 1H), 4.46 (dd, J=11.1, 2.4 Hz, 1H), 3.91-3.84 (m, 1H), 3.86-3.81 (m, 1H), 2.79-2.71 (m, 2H), 2.39-2.28 (m, 3H), 2.03-1.95 (m, 2H), 1.95-1.87 (m, 1H), 1.79-1.66 (m, 2H); MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 194: (2R,4S)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 293)

    [1616] The product of Example 65 was processed as described in Example 73B substituting for the product of Example 73A. The crude product was further purified by preparative chiral HPLC [CHIRALPAK IC 5 m column, 20250 mm, flow rate 20 mL/minute, 7% 2-propanol and 30% ethanol in heptane (isocratic gradient)] to give the title compound as the earlier eluting fraction. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 8.36 (s, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.24 (dd, J=8.8, 2.7 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.62 (s, 1H), 4.57 (t, J=3.8 Hz, 1H), 4.54 (dd, J=10.9, 2.7 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.72 (s, 2H), 3.72-3.66 (m, 1H), 2.78-2.69 (m, 2H), 2.25 (s, 6H), 2.18-2.11 (m, 2H), 2.08 (ddd, J=13.9, 3.8, 2.7 Hz, 1H), 1.89 (ddd, J=13.9, 10.9, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 505 (M+H).sup.+.

    Example 195: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 294)

    Example 195A: tert-butyl (3-(4-tosyl-4,5-dihydrooxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1617] To a solution of the product of Example 128B (130 mg, 0.615 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (120 mg, 0.615 mmol) in acetonitrile (1.25 mL) was added 1,8-diazabicycloundec-7-ene (9.28 L, 0.062 mmol) and the reaction mixture stirred at room temperature for 45 minutes. The reaction mixture was then concentrated in vacuo to afford the crude title compound (298 mg, 0.615 mmol, 100% yield) that was used directly in the next step (assumed quantitative). MS (ESI.sup.+) m/z 407.2 (M+H).sup.+.

    Example 195B: tert-butyl (3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1618] The product of Example 106A (177 mg, 0.923 mmol) was partitioned between xylene (2.5 mL) and saturated aqueous potassium carbonate (2.0 mL). The phases were separated, and the aqueous was further extracted with xylene (2.5 mL). The combined xylene fractions were dried over Na.sub.2SO.sub.4, decanted, and then used as the reaction media. To the xylene solution was added the product of Example 195A (250 mg, 0.615 mmol) and the reaction mixture was heated via microwave irradiation using a silicon carbide heating element at 140 C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, dichloromethane loading, 0-10% methanol in dichloromethane) to afford the title compound (72 mg, 0.167 mmol, 27.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.62 (d, J=1.4 Hz, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 4.69 (p, J=7.3 Hz, 1H), 4.39-4.28 (m, 1H), 2.90 (td, J=9.9, 7.0 Hz, 2H), 2.60-2.52 (m, 2H), 2.05 (s, 6H), 1.38 (s, 9H).

    Example 195C: 3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-4-yl)bicyclo[1.1.1]pentan-1-amine trifluoroacetic acid

    [1619] To the product of Example 195B (72 mg, 0.186 mmol) in dichloromethane (2.0 mL) at room temperature was added trifluoroacetic acid (0.215 mL, 2.79 mmol) and the reaction mixture was stirred for 2 hours. The volatiles were removed under vacuum and co-evaporated with toluene (310 mL) followed by co-evaporation with dichloromethane (minimum amount) and hexane (5 mL) to afford the title compound (100 mg, 0.204 mmol, 110% yield). MS (ESI.sup.+) m/z 288.1 (M+H).sup.+.

    Example 195D: (2R,4R)-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1620] The title compound was synthesized using the same procedure as described in Example 167G substituting the product of Example 167F with the product of Example 195C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 7.63 (d, J=1.4 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.22-7.18 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (d, J=5.1 Hz, 1H), 4.84-4.77 (m, 1H), 4.73-4.66 (m, 1H), 4.59 (dd, J=12.0, 2.2 Hz, 1H), 4.39-4.31 (m, 1H), 2.94-2.87 (m, 2H), 2.60-2.52 (m, 2H), 2.39-2.33 (m, 1H), 2.20 (s, 6H), 1.75-1.66 (m, 1H).

    Example 196: (2S,4S)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 295)

    [1621] The reaction and purification conditions described in Example 186B substituting the product of Example 109A for the product of Example 186A, and the product of Example 10A for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 8.35 (s, 1H), 7.38 (dd, J=2.8, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.68 (s, 1H), 4.83-4.77 (m, 1H), 4.59 (dd, J=12.0, 2.3 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.73 (s, 2H), 3.72-3.66 (m, 1H), 2.78-2.70 (m, 2H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.26 (s, 6H), 2.18-2.12 (m, 2H), 1.69 (ddd, J=12.9, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 487 (MH.sub.2O+H).sup.+.

    Example 197: (2R)-6-chloro-4-oxo-N-[3-({(1RS,2SR)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carbonyl}amino)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 296)

    Example 197A: 2-((benzyloxy)carbonyl)cyclopropanecarboxylic acid

    [1622] To a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (25 g, 223 mmol) in tetrahydrofuran (250 mL) was added benzyl alcohol (72.4 g, 669 mmol) and triethylamine (67.7 g, 669 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. Seven additional reactions were set up and run as described above. The reaction batches were combined and concentrated in vacuo. To the residue was added water (2 L), sodium carbonate solution to adjust the pH of the mixture to 8, and ethyl acetate (81 L). After separation, to the aqueous phase was added HCl (1 mol/L in water) to adjust the pH to 3. The aqueous phase was then extracted with ethyl acetate (3-2 L) and the combined organic phases were concentrated under reduced pressure to give the title intermediate (300 g, 1.23 mol, 69% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.37 (td, J=8.50, 5.08 Hz, 1H) 1.74 (td, J=6.84, 5.14 Hz, 1H) 2.05-2.29 (m, 2H) 5.15 (d, J=0.75 Hz, 2H) 7.30-7.44 (m, 5H).

    Example 197B: benzyl 2-(hydroxymethyl)cyclopropanecarboxylate

    [1623] To a solution of Example 197A (30 g, 123 mmol) in tetrahydrofuran (300 mL) at 0 C. under nitrogen was added borane dimethyl sulfide (24.5 mL, 245 mmol), and the reaction mixture was stirred at ambient temperature for 12 hours. Then the reaction mixture was cooled to 0 C., and the reaction mixture was quenched with methanol dropwise until gas evolution had ceased. Nine additional reactions were set up and run as described above and then combined. After bulk solvent removal, the resulting residue was concentrated under reduced pressure to give the title intermediate (230 g, 892 mmol, 73% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.07-1.23 (m, 2H) 1.53-1.72 (m, 1H) 1.84 (td, J=8.25, 5.75 Hz, 1H) 2.64 (br s, 1H) 3.75 (dd, J=11.82, 8.19 Hz, 1H) 3.94 (dd, J=11.88, 5.25 Hz, 1H) 5.15 (s, 2H) 7.29-7.45 (m, 5 H).

    Example 197C: benzyl 2-((trifluoromethoxy)methyl)cyclopropanecarboxylate

    [1624] A mixture of silver trifluoromethanesulfonate (20 g, 78 mmol), (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (Selectfluor, 10 g, 29 mmol), and potassium fluoride (4.5 g, 78 mmol) in a flask wrapped with aluminum foil was cooled in a water bath. To this reaction mixture was added a solution of Example 197B (5 g, 19 mmol) in ethyl acetate (100 mL), followed by 2-fluoropyridine (5.0 mL, 58 mmol) and (trifluoromethyl)trimethylsilane (8.6 mL, 58 mmol) dropwise to keep the internal temperature lower than 10 C. The mixture was stirred at ambient temperature for 48 hours. Then the suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (330 mL). The combined filtrates were concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 20:1) to give the title intermediate (2 g, 5.8 mmol, 30% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.14-1.25 (m, 2H) 1.64-1.76 (m, 1H) 1.92-2.00 (m, 1H) 4.10-4.16 (m, 1H) 4.33 (dd, J=10.96, 6.14 Hz, 1 H) 5.08-5.30 (m, 2H) 7.30-7.42 (m, 5H).

    Example 197D: rac-(1R,2S)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carboxylic acid

    [1625] To a solution of Example 197C (10 g, 29 mmol) in tetrahydrofuran (90 mL) was added palladium hydroxide on carbon (4.1 g, 2.9 mmol, 20% weight, 50% water) at ambient temperature, and the reaction mixture was stirred under hydrogen (15 psi) for 12 hours. Then the reaction mixture was diatomaceous earth and the filter cake was washed with ethyl acetate (20 mL3). The combined filtrates were concentrated to give a crude residue, which was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=40:1) to give the title intermediate. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.89-0.95 (m, 1H) 1.16 (td, J=8.25, 4.50 Hz, 1H) 1.64-1.75 (m, 1H) 1.76-1.84 (m, 1H) 4.14 (t, J=9.82 Hz, 1H) 4.40 (dd, J=10.44, 5.94 Hz, 1H) 12.40 (br s, 1H).

    Example 197E: tert-butyl [3-({rac-(1R,2S)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carbonyl}amino)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1626] The methodologies described in Example 30D substituting Example 197D for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid, substituting tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock) for Example 30C, and removing the HPLC purification gave the title intermediate, which was carried forward without purification. MS (APCI.sup.+) m/z 365 (M+H).sup.+.

    Example 197F: rac-(1R,2S)N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carboxamide

    [1627] The methodologies described in Example 21B substituting Example 197E for Example 21A gave the title intermediate. MS (APCI.sup.+) m/z 265 (M+H).sup.+.

    Example 197G: (2R)-6-chloro-4-oxo-N-[3-({(1RS,2SR)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carbonyl}amino)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1628] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 197F for Example 30C with extended reaction time to 3 days gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.79 (s, 1H), 7.67-7.61 (m, 2H), 7.16 (dd, J=8.6, 0.6 Hz, 1H), 5.08 (t, J=7.1 Hz, 1H), 4.35 (dd, J=10.2, 6.3 Hz, 1H), 4.15 (dd, J=10.2, 8.8 Hz, 1H), 2.94 (d, J=7.1 Hz, 2H), 2.20 (q, J=0.9 Hz, 6H), 1.73 (td, J=8.1, 5.7 Hz, 1H), 1.57-1.50 (m, 1H), 1.03-0.96 (m, 1H), 0.87 (ddd, J=6.5, 5.7, 4.2 Hz, 1H); MS (APCI.sup.+) m/z 473 (M+H).sup.+.

    Example 198: (2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 297)

    Example 198A: tert-butyl (4-((2-oxo-2-((cis)-3-(trifluoromethoxy)cyclobutyl)ethyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)carbamate

    [1629] The methodologies described in Example 193E substituting 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (AChemBlock) for (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid, decreasing the reaction time from 3 days to 2 hours, and including purification by preparative HPLC (Phenomenex Luna C8(2) 5 m AXIA column (150 mm30 mm) using a 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 25 minutes, at a flow rate of 50 mL/minute) gave the title intermediate. MS (APCI.sup.+) m/z 449 (M+H).sup.+.

    Example 198B: 4-(S-(3-(trifluoromethoxy)cyclobutyl)oxazol-2-yl)bicyclo[2.2.2]octan-1-amine

    [1630] The methodologies described in Example 193F substituting Example 198A for Example 193E and removing the resin work-up and HPLC purification gave the title intermediate, which was carried forward without purification. MS (ESI.sup.+) m/z 331 (M+H).sup.+.

    Example 198C: (2R,4R)-6-chloro-4-hydroxy-N-(4-{5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-2-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1631] To a mixture of Example 198B (0.010 g, 0.030 mmol) and the product of Example 3B (0.010 g, 0.045 mmol) in N,N-dimethylformamide (0.31 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.04 mL, 0.2 mmol) followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T.sub.3P, 50% in N,N-dimethylformamide, 0.02 mL, 0.04 mmol). This reaction mixture was allowed to stir at ambient temperature for 7 hours, was diluted with N,N-dimethylformamide (2 mL) and water (0.5 mL), filtered, and purified by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) to give the title compound (0.0014 g, 0.0026 mmol, 9% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.14 (s, 1H), 7.40-7.35 (m, 2H), 7.21-7.15 (m, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.83 (d, J=0.7 Hz, 1H), 4.85-4.78 (m, 1H), 4.79 (s, 1H), 4.57 (dd, J=11.8, 2.3 Hz, 1H), 2.73-2.69 (m, 2H), 2.33-2.27 (m, 1H), 1.93 (m, 12H), 1.93-1.89 (m, 2H), 1.80-1.69 (m, 1H), 1.25 (d, J=10.9 Hz, 1H), 1.15 (s, 1H); MS (ESI.sup.30) m/z 541 (M+H).sup.+.

    Example 199: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 298)

    Example 199A: (E)-tert-butyl (3-(3-(dimethylamino)acryloyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1632] To a solution tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate (500 mg, 2.219 mmol), the intermediate product of Example 181B, in N,N-dimethylformamide (8 mL) was added dimethylformamide dimethyl acetal (0.737 mL, 5.55 mmol) in a sealed vial. The reaction mixture was then stirred at 100 C. overnight. The reaction mixture was then cooled to ambient temperature and the volatiles were removed under reduced pressure to afford the title compound (589 mg, 76% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.51 (s, 1H), 7.45 (d, J=12.6 Hz, 1H), 5.06 (d, J=12.6 Hz, 1H), 3.06 (s, 3H), 2.77 (s, 3H), 2.01 (s, 6H), 1.38 (s, 9H).

    Example 199B: (cis-3-(benzyloxy)cyclobutyl)hydrazine

    [1633] A mixture of 3-(benzyloxy)cyclobutanone (3 g, 17.02 mmol) and tert-butyl hydrazinecarboxylate (2.250 g, 17.02 mmol) in isohexane (50 mL) was heated under reflux overnight. The reaction mixture was concentrated in vacuo to afford tert-butyl 2-(3-(benzyloxy)cyclobutylidene)hydrazinecarboxylate (4.5 g, 91% yield). tert-Butyl 2-(3-(benzyloxy)cyclobutylidene)hydrazinecarboxylate (1 g, 3.44 mmol) was dissolved in tetrahydrofuran (10 mL) at ambient temperature. Borane dimethyl sulfide complex (1.044 mL, 10.33 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with 6 M aqueous HCl (10 mL). The solid was collected by filtration and discarded. The filtrate was concentrated in vacuo. 1 M aqueous HCl (10 mL) was added to the residue and the solid was filtered off. The filtrate was once more concentrated in vacuo to afford the title compound as the hydrochloric acid salt (0.788 g, 3.44 mmol, 100% yield).

    Example 199C: tert-butyl (3-(1-(cis-3-(benzyloxy)cyclobutyl)-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1634] To a solution of the product of Example 199B (732 mg, 3.20 mmol) in ethanol (10 mL) was added the product of Example 199A (459 mg, 1.637 mmol) and the reaction mixture stirred at 85 C. overnight and then left standing for 24 hours at ambient temperature. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (59 mg, 8% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.45 (d, J=2.3 Hz, 1H), 7.39-7.31 (m, 5H), 6.12 (d, J=2.3 Hz, 1H), 4.99 (s, 1H), 4.49 (s, 2H), 4.48-4.37 (m, 1H), 3.97-3.86 (m, 1H), 2.95-2.86 (m, 2H), 2.44 (dddd, J=7.7, 6.5, 4.9, 2.6 Hz, 2H), 2.33 (s, 6H), 1.48 (s, 9H); MS (ESI) m/z 410 (M+H).sup.+.

    Example 199D: tert-butyl (3-(1-((cis-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl)-carbamate

    [1635] To a solution of the product of Example 199C (59 mg, 0.144 mmol) in ethanol (2 mL) was added 10% Pd-C(25 mg, 0.012 mmol) and the reaction mixture was stirred at ambient temperature for 3 days under 5 bar of hydrogen atmosphere. The reaction mixture was filtered through a microfiber filter and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (29 mg, 50% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.64 (d, J=2.2 Hz, 1H), 7.54 (s, 1H), 6.05 (d, J=2.2 Hz, 1H), 5.24 (d, J=6.7 Hz, JH), 4.30-4.20 (m, 1H), 3.96-3.85 (m, 1H), 2.72-2.62 (m, 2H), 2.29-2.20 (m, 2H), 2.11 (s, 6H), 1.39 (s, 9H); MS (ESI) m/z 320 (M+H).sup.+.

    Example 199E: tert-butyl (3-(1-((cis-3-(trifluoromethoxy)cyclobutyl)-1H-pyrazol-3-yl)bicyclo[1.1.1]-pentan-1-yl)carbamate

    [1636] A mixture of silver(I) trifluoromethanesulfonate (63.0 mg, 0.245 mmol), potassium fluoride (21.10 mg, 0.363 mmol), and Selectfluor (48.2 mg, 0.136 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of the product of Example 199D (29 mg, 0.091 mmol) in ethyl acetate (1 mL) followed by slow addition of 2-fluoropyridine (0.023 mL, 0.272 mmol) and then trimethyl(trifluoromethyl)silane (0.040 mL, 0.272 mmol). The reaction mixture then stirred at ambient temperature overnight. The reaction mixture was filtered through a pad of diatomaceous earth washed with ethyl acetate (5 mL) and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% ethyl acetate/isohexane) to afford the title compound (10 mg, 28% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.41 (d, J=2.2 Hz, 1H), 6.13 (d, J=2.3 Hz, 1H), 5.02 (s, 1H), 4.54 (p, J=7.3 Hz, 1H), 4.50-4.39 (m, 1H), 3.06-2.97 (m, 2H), 2.83-2.73 (m, 2H), 2.33 (s, 6H), 1.48 (s, 9H); MS (ESI) m/z 388 (M+H).sup.+.

    Example 199F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1637] The title compound was prepared using the methods described for the synthesis of Example 131D, substituting the product from Example 131C with the product of Example 199E and substituting the product of Example 73B with the product of Example 3B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.41-7.37 (m, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.12 (d, J=2.2 Hz, 1H), 5.73 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.73 (p, J=7.2 Hz, 1H), 4.61 (dd, J=12.0, 2.2 Hz, 1H), 4.55-4.45 (m, 1H), 2.94-2.85 (m, 2H), 2.68 (dd, J=10.9, 8.1 Hz, 2H), 2.41-2.33 (m, 1H), 2.28 (s, 6H), 1.77-1.66 (m, 1H); MS (ESI) m/z 498 (M+H).sup.+.

    Example 200: (2R,4R)-6-chloro-4-hydroxy-N-[3-({(1RS,2SR)-2-[(trifluoromethoxy)methyl]cyclopropane-1-carbonyl}amino)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 299)

    [1638] The methodologies described in Example 5 substituting Example 197 for Example 4 and purifying by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.64 (s, 1H), 7.37 (s, 1H), 7.23-7.16 (m, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.27 (s, 1H), 5.68 (d, J=6.3 Hz, 1H), 4.84-4.74 (m, 1H), 4.58 (d, J=10.2 Hz, 1H), 4.35 (dd, J=10.3, 5.9 Hz, 1H), 4.21-4.12 (m, 1H), 2.22 (s, 6H), 1.77-1.68 (m, 1H), 1.15 (s, 1H), 1.07-0.94 (m, 1H), 0.88 (d, J=5.0 Hz, 1H); MS (APCI.sup.+) m/z 456 (MH.sub.2O+H).sup.+.

    Example 201: (2R,4R)-6-chloro-4-hydroxy-N-[3-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1,3-thiazol-4-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 300)

    Example 201A: cis-3-(benzyloxy)cyclobutanol

    [1639] To a solution of 3-(benzyloxy)cyclobutanone (20 g, 113 mmol) in methanol (200 mL) was added sodium borohydride (4.29 g, 113 mmol) portionwise at 30 C. over 10 minutes. The reaction mixture was stirred at 30 C. for 1 hour, was quenched with ammonium chloride (saturated aqueous, 100 mL) at 20 C., and concentrated in vacuo. The residue was extracted with ethyl acetate (31000 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was combined with another batch and purified by column chromatography on silica gel (10:1 petroleum ether, ethyl acetate) to give the title intermediate (56 g, 283 mmol, 83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.22-7.39 (m, 5H), 5.00 (d, J=6.63 Hz, 1H), 4.33 (s, 1H), 4.30-4.36 (m, 1H), 3.68 (sxt, J=7.10 Hz, 1 H), 3.54 (quin, J=7.07 Hz, 1H), 2.51-2.60 (m, 2H), 1.73 (qd, J=8.09, 2.88 Hz, 2H).

    Example 201B: ((cis-3-(trifluoromethoxy)cyclobutoxy)methyl)benzene

    [1640] The title compound was synthesized using the same procedure as described in Example 130 substituting the product of Example 13N with the product of Example 201A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.24-7.40 (m, 2H), 4.46-4.57 (m, 1H), 4.39 (s, 1H), 3.65-3.79 (m, 1H), 2.69-2.80 (m, 1H), 2.08 (td, J=9.60, 7.57 Hz, 1H).

    Example 201C: cis-3-(trifluoromethoxy)cyclobutanol

    [1641] To a solution of the product of Example 201B (3.00 g, 11.0 mmol) in methanol (45 mL) was added palladium on carbon (1.17 g, 0.548 mmol) under argon. The reaction mixture was stirred at 50 C. under hydrogen (50 psi) for 12 hours. Then the suspension was filtered through a pad of diatomaceous earth and the pad was washed with methanol (3200 mL). The combined filtrates were concentrated and purified by column chromatography on silica gel (10:1 petroleum ether:ethyl acetate) to give the title intermediate (0.800 g, 4.61 mmol, 42% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 5.31 (d, J=6.75 Hz, 1H), 5.31 (d, J=6.75 Hz, 1H), 4.36 (quin, J=7.19 Hz, 1H), 3.75 (sxt, J=7.05 Hz, 1H), 1.92-2.08 (m, 2H).

    Example 201D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1642] The title compound was synthesized using the same procedures as described in Example 187A through Example 187C substituting the product of Example 119A with the product of Example 201C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.73 (s, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.87-4.77 (m, 2H), 4.69-4.57 (m, 2H), 3.03-2.96 (m, 2H), 2.40-2.33 (m, 3H), 2.24 (s, 6H), 1.74-1.66 (m, 1H).

    Example 202: (2R,4R)-6-chloro-4-hydroxy-N-[3-({4-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-thiazol-2-yl}oxy)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 301)

    Example 202A: tert-butyl (3-(carbamothioyloxy)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1643] To a solution of tert-butyl (3-hydroxybicyclo[1.1.1]pentan-1-yl)carbamate (PharmaBlock, 50 mg, 0.25 mmol) and N,N-dimethylpyridin-4-amine (3.1 mg, 0.025 mmol) in tetrahydrofuran (1 mL) at ambient temperature under nitrogen was added di(1H-imidazol-1-yl)methanethione (49 mg, 0.28 mmol) and the reaction mixture stirred for 2 hours. To the reaction mixture was added tetrahydrofuran (1 mL), followed by ammonium hydroxide (0.034 mL, 0.50 mmol) and the reaction mixture stirred at ambient temperature for 3 days. Then water (10 mL) was added and the suspension was extracted with ethyl acetate (3 10 mL). The combined extracts were washed with brine (5 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate in isohexane) to afford the title intermediate (15 mg, 0.057 mmol, 23% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.74 (s, 1H), 8.46 (s, 1H), 7.62 (s, 1H), 2.39 (s, 6H), 1.38 (s, 9H).

    Example 202B: tert-butyl (3-((4-((cis)-3-(trifluoromethoxy)cyclobutyl)thiazol-2-yl)oxy)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1644] A solution of Example 193C (14 mg, 0.053 mmol) in ethanol (0.8 mL) was added to a solution of Example 202A (14 mg, 0.053 mmol) and triethylamine (0.011 mL, 0.080 mmol) in ethanol (0.2 mL). The reaction mixture was stirred at 80 C. for 4 days and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in heptane) to afford the title intermediate (38 mg, 0.053 mmol, quantitative yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 6.81 (s, 1H), 4.78 (p, J=7.5 Hz, 1H), 3.09-2.97 (m, 1H), 2.70-2.60 (m, 2H), 2.38 (s, 6H), 2.36-2.27 (m, 2H), 1.39 (s, 9H); MS (ESI+) m/z 443 (M+Na).sup.+.

    Example 202C: 3-((4-((cis)-3-(trifluoromethoxy)cyclobutyl)thiazol-2-yl)oxy)bicyclo[1.1.1]pentan-1-amine

    [1645] The methodologies described in Example 21B substituting Example 202B for Example 21A gave the title compound. MS (ESI+) m/z 321 (M+H).sup.+.

    Example 202D: (2),4R)-6-chloro-4-hydroxy-N-[3-({4-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-thiazol-2-yl}oxy)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1646] The methodologies described in Example 155C substituting Example 202C for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.21 (dd, J=8.8, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 5.73-5.69 (m, 1H), 4.84-4.78 (m, 2H), 4.67-4.63 (m, 1H), 3.07-3.03 (m, JH), 2.70-2.64 (m, 2H), 2.53 (s, 6H), 2.39-2.35 (m, 2H), 1.72 (q, J=11.8 Hz, 2H); MS (ESI+) m/z 513 (MH2O+H).sup.+.

    Example 203: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 302)

    Example 203A: 4-(4-(trifluoromethoxy)phenyl)-1-trityl-1H-pyrazole

    [1647] Potassium carbonate (0.380 g, 2.75 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole (0.48 g, 1.10 mmol, ArkPharm), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (90 mg, 0.11 mmol), and 1-bromo-4-(trifluoromethoxy)benzene (345 mg, 1.43 mmol) were combined with 1,2-dimethoxyethane (12 mL) and water (1.2 mL). The vial was degassed by sparging with nitrogen for 2 minutes before sealing with a polytetrafluoroethylene-lined cap. The reaction mixture was stirred at 105 C. for 2 hours, cooled to ambient temperature, and then combined with diatomaceous earth (about 10 grams) and concentrated under reduced pressure to a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 20-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (252 mg, 0.54 mmol, 49% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.11 (d, J=0.8 Hz, 1H), 7.87 (d, J=0.8 Hz, 1H), 7.70-7.65 (m, 2H), 7.41-7.32 (m, 9H), 7.32-7.28 (m, 2H), 7.16-7.08 (m, 6H).

    Example 203B: 4-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

    [1648] A mixture of trifluoroacetic acid (3.3 mL), methanol (3.3 mL), and dichloromethane (3.3 mL) was added to the product of Example 203A (0.21 g, 0.45 mmol). The resulting solution was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (4 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (66 mg, 0.29 mmol, 65% yield); MS (APCI.sup.+) m/z 229 (M+H).sup.+.

    Example 203C: methyl 3-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1649] A 30 mL vial was charged with iodomesitylene diacetate (211 mg, 0.58 mmol), 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (197 mg, 1.16 mmol) and toluene (2 mL). The mixture was stirred at 60 C. for 30 minutes. Toluene was then removed under high vacuum. The product of Example 203B (66 mg, 0.29 mmol), tris(2-phenylpyridine)iridium (3.3 mg, 5.0 mol), and copper(II) acetylacetonate (38 mg, 0.145 mmol) were added followed by dioxane (5 mL). The vial was degassed by sparging with nitrogen for 3 minutes before sealing with a polytetrafluoroethylene-lined cap. The reaction was stirred and irradiated using 2 lamps: a 40W Kessil PR160 390 nm photoredox lamp, and an 18W 450 nm HepatoChem blue LED photoredox lamp. Both lamps were placed 3 cm away from the reaction vial set inside a continuously running tap water bath. The reaction temperature was measured to be 12 C. and maintained at that temperature for the duration of the reaction. After 12 hours, the reaction mixture was quenched by exposing to air and partitioned between water (50 mL) and dichloromethane (250 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (15 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100/a gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (43 mg, 0.12 mmol, 42% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.35 (d, J=0.8 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.75-7.68 (m, 2H), 7.39-7.32 (m, 2H), 3.68 (s, 3H), 2.53 (s, 6H); MS (APCI.sup.+) m/z 353 (M+H).sup.+.

    Example 203D: 3-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1650] The reaction and purification conditions described in Example 110B substituting the product of Example 203C for the product of Example 110A gave the title compound. MS (APCI.sup.+) m/z 339 (M+H).sup.+.

    Example 203E: 2-(trimethylsilyl)ethyl (3-(4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1651] The reaction and purification conditions described in Example 125C substituting the product of Example 203D for the product of Example 125B gave the title compound. MS (APCI.sup.+) m/z 454 (M+H).sup.+.

    Example 203F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1652] The reaction and purification conditions described in Example 1C substituting the product of Example 203E for the product of Example 1A, and the product of Example 3B for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.77-7.69 (m, 2H), 7.39 (dd, J=2.7, 0.9 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (br s, 1H), 4.83 (dd, J=10.7, 5.8 Hz, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 2.55 (s, 6H), 2.39 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.74 (td, J=12.4, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 520 (M+H).sup.+.

    Example 204: (2R,4R)-6-chloro-N-[trans-4-{3-[5-(difluoromethyl)pyrazin-2-yl]-2-oxoimidazolidin-1-yl}cyclohexyl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 303)

    [1653] The reaction and purification conditions described in Example 136D substituting 1-(trans-4-aminocyclohexyl)-3-[5-(difluoromethyl)-2-pyrazinyl]-2-imidazolidinone (prepared as described in International Patent Publication WO2019/090081 A1) for the product of Example 136C gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.50-8.45 (m, 1H), 8.31 (dd, J=8.9, 0.8 Hz, 1H), 7.94-7.87 (m, 2H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.04 (t, J=55.6 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (br s, 1H), 4.81 (dd, J=10.7, 5.9 Hz, 1H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 3.95 (dd, J=9.0, 7.1 Hz, 2H), 3.72-3.59 (m, 2H), 3.50-3.45 (m, 2H), 2.35 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 1.89-1.82 (m, 2H), 1.78-1.68 (m, 2H), 1.62 (qt, J=12.2, 2.7 Hz, 2H), 1.54-1.39 (m, 2H); MS (APCI.sup.+) m/z 522 (M+H).sup.+.

    Example 205: (2R,4R)-6-chloro-N-{(1R,2S,4R,5S)-5-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[2.2.1]heptan-2-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 304)

    Example 205A: benzyl ((1R,2S,4R,5S)-5-aminobicyclo[2.2.1]heptan-2-yl)carbamate

    [1654] The product of Example 111D was purified via chiral separation to give 2 enantiomers. Chiral SFC using Column: (S,S)-Whelk-O1, 25030 mm, 10 um, Mobile phase: A: CO.sub.2, B: ethanol (0.1% NH.sub.3), Gradient: 30% B, flow rate: 58 g/minute; column temperature: 40 C.; system back pressure: 100 bar gave the title intermediate as the later eluting isomer. .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm 7.44-7.20 (m, 5H), 5.05 (s, 2H), 3.37 (br dd, J=2.9, 7.8 Hz, 1H), 2.81 (br d, J=4.4 Hz, 1H), 2.20 (br d, J=3.4 Hz, 1H), 2.10 (br d, J=3.9 Hz, 1H), 1.74-1.60 (m, 2H), 1.57-1.50 (m, 1H), 1.46-1.40 (m, 1H), 1.32 (td, J=4.0, 13.4 Hz, 1H), 1.22-1.12 (m, 1H); MS (ESI.sup.+) m/z 261 (M+H).sup.+.

    Example 205B: benzyl ((1R,2S,4R,5S)-5-(4-(3,4-difluorophenyl)-1H-imidazol-1-yl)bicyclo[2.2.1]heptan-2-yl)carbamate

    [1655] The methodologies described in Example 49A substituting the product of Example 205A for tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate, increasing the reaction time from 4.5 hours to 3 days, and eliminating purification by HPLC gave the title intermediate, which was carried forward without purification. MS (APCI.sup.+) m/z 424 (M+H).sup.+.

    Example 205C: (1R,2S,4R,5S)-5-(4-(3,4-difluorophenyl)-1H-imidazol-1-yl)bicyclo[2.2.1]heptan-2-amine

    [1656] To solution of the product of Example 205B (0.160 g, 0.377 mmol) in dichloromethane (0.75 mL) was added trifluoroacetic acid (2.18 mL, 28.2 mmol). This mixture was allowed to stir at 70 C. for 4 hours and then was concentrated in vacuo to provide the title intermediate (0.109 g, 0.377 mmol, quantitative yield). MS (ESI+) m/z 290 (M+H).sup.+.

    Example 205D: (2R)-6-chloro-N-{(1R,2S,4R,5S)-5-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[2.2.1]heptan-2-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1657] The methodologies described in Example 30D substituting the product of Example 1B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting Example 205C for Example 30C gave the title intermediate. MS (APCI.sup.+) m/z 498 (M+H).sup.+.

    Example 205E. (2R,4R)-6-chloro-N-{(1R,2S,4R,5S)-5-[4-(3,4-difluorophenyl)-1H-imidazol-1-yl]bicyclo[2.2.1]heptan-2-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1658] The methodologies described in Example 5 substituting Example 205D for Example 4 and purifying by preparative HPLC (Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in 0.1% trifluoroacetic acid/water) gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.25 (s, 1H), 7.99 (d, J=6.8 Hz, 1H), 7.89 (t, J=9.6 Hz, 1H), 7.66 (s, 1H), 7.59 (q, J=9.1 Hz, 1H), 7.39 (d, J=2.9 Hz, 1H), 7.23-7.18 (m, 1H), 7.09 (s, 1H), 6.89 (d, J=8.7 Hz, 1H), 4.82 (dd, J=10.5, 5.8 Hz, 1H), 4.63 (dd, J=11.8, 2.4 Hz, 1H), 4.34 (m, 1H), 2.63 (m, 1H), 2.33 (m, 3H), 2.04-1.94 (m, 1H), 1.85-1.74 (m, 1H), 1.63-1.52 (m, 3H), 1.17-1.07 (m, 1H); MS (APCI.sup.+) m/z 500 (M+H).sup.+.

    Example 206: (2R,4R)-6-chloro-N-{3-[2-(4-chloro-3-fluorophenyl)-1,3-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 305)

    Example 206A: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone

    [1659] To a solution of tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate (intermediate of Example 181B, 220 mg, 0.977 mmol) in dichloromethane (4 mL) was added HCl (4 N in dioxane, 4 mL, 16 mmol) and the reaction mixture stirred at ambient temperature overnight. Then the solvent was removed under reduced pressure to give the title intermediate as an HCl salt (0.160 g, 0.980 mmol, quantitative yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.81 (s, 3H), 2.21 (s, 6H), 2.14 (s, 3H).

    Example 206B: benzyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate

    [1660] To a solution of Example 206A (160 mg, 1.28 mmol) and NaOH (102 mg, 2.56 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added benzyl chloroformate (Cbz-Cl, 0.201 mL, 1.41 mmol) dropwise. The resulting solution was stirred at ambient temperature overnight. Then volatiles were removed under reduced pressure to give the title intermediate (0.279 g, 0.947 mmol, 74% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.38-7.32 (m, 5H), 4.98 (s, 2H), 4.49 (s, 1H), 2.12 (d, J=4.5 Hz, 6H), 2.09 (s, 3H).

    Example 206C: benzyl (3-(2-bromoacetyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1661] To a solution of Example 206B (0.279 g, 0.947 mmol) in tetrahydrofuran (3 mL) at 0 C. was added phenyltrimethylammonium tribromide (0.356 g, 0.947 mmol) portionwise. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was filtered, washing with tetrahydrofuran (2.5 mL), and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% ethyl acetate in isohexane) to afford the title intermediate (211 mg, 0.499 mmol, 53% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) b ppm 8.09 (s, 1H), 7.39-7.30 (m, 5H), 5.01 (s, 2H), 4.47 (s, 2H), 2.23 (s, 6H).

    Example 206D: benzyl (3-(2-aminoacetyl)bicyclo[1.1.1]pentan-1-yl)carbamate hydrochloride

    [1662] The methodologies described in Example 193D substituting Example 206C for Example 193C gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 8.14 (s, 3H), 7.40-7.34 (m, 5H), 5.01 (s, 2H), 4.02 (s, 2H), 2.24 (s, 6H).

    Example 206E: benzyl (3-(2-(4-chloro-3-fluorobenzamido)acetyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1663] The methodologies described in Example 155A substituting Example 206D for 2-amino-1-(4-chlorophenyl)ethanone hydrochloride, substituting 4-chloro-3-fluorobenzoic acid for 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid, and purifying by column chromatography on silica gel (0-100% ethyl acetate in hexanes) gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (t, J=5.6 Hz, 1H), 8.49 (s, 1H), 7.88-7.85 (m, 2H), 7.77-7.70 (m, 5H), 7.62-7.60 (m, 1H), 5.01 (s, 2H), 4.20 (d, J=5.1 Hz, 2H), 1.99 (s, 6H).

    Example 206F: 3-(2-(4-chloro-3-fluorophenyl)oxazol-5-yl)bicyclo[1.1.1]pentan-1-amine

    [1664] The methodologies described in Example 155B substituting Example 206E for Example 155A gave the title intermediate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.40 (s, 2H), 7.86 (dd, J=10.0, 1.7 Hz, 1H), 7.78-7.73 (m, 2H), 7.09 (s, 1H), 2.07 (s, 6H).

    Example 206G: (2R,4R)-6-chloro-N-{3-[2-(4-chloro-3-fluorophenyl)-1,3-oxazol-5-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1665] The methodologies described in Example 155C substituting Example 206F for Example 155B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.90 (dd, J=9.9, 1.9 Hz, 1H), 7.81-7.75 (m, 2H), 7.40 (dd, J=2.8, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 7.19 (s, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.95-5.50 (m, 1H), 4.84-4.80 (m, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.43 (s, 6H), 1.76-1.69 (m, 1H); MS (ESI+) m/z 489 (M+H).sup.+.

    Example 207: (2S,4R)-6-chloro-N-(3-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 306)

    Example 207A: methyl 3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1666] The reaction and purification conditions described in Example 203C substituting 4-bromo-1H-pyrazole for the product of Example 203B gave the title compound. MS (APCI.sup.+) m/z 271, 273 (M+H).sup.+.

    Example 207B: 3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1667] The reaction and purification conditions described in Example 110B substituting the product of Example 207A for the product of Example 110A gave the title compound. MS (APCI.sup.+) m/z 257, 259 (M+H).sup.+.

    Example 207C: tert-butyl (3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1668] A mixture of the product of Example 207B (100 mg, 0.39 mmol), N,N-diisopropylethylamine (0.136 mL, 0.78 mmol) and tert-butanol (2 mL) was stirred at ambient temperature. Diphenylphosphoryl azide (0.109 mL, 0.506 mmol) was added. The mixture was stirred at 58 C. for 10 hours, cooled, and concentrated under reduced pressure. The residue was taken up in methanol (5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (115 mg, 0.35 mmol, 90% yield).

    [1669] MS (ESI.sup.+) m/z 328, 330 (M+H).sup.+.

    Example 207D: tert-butyl (3-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1670] Potassium carbonate (105 mg, 0.762 mmol), tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (27 mg, 0.092 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (82 mg, 0.366 mmol, Combi-Blocks), and the product of Example 207C (100 mg, 0.305 mmol) were combined with 1,2-dimethoxyethane (5 mL) and water (0.5 mL) in a 20 mL vial. The vial was sealed and degassed three times with a nitrogen backflush each time. It was then heated at 58 C. for 18 hours. The reaction mixture was cooled to ambient temperature, and then partitioned between dichloromethane (230 mL) and aqueous sodium carbonate (1.0 M, 30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 15-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.12 g, 0.28 mmol, 92% yield). MS (APCI.sup.+) m/z 428 (M+H).sup.+.

    Example 207E: (2S,4R)-6-chloro-N-(3-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1671] The reaction and purification conditions described in Example 1C substituting the product of Example 207D for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.42 (d, J=0.8 Hz, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.82-7.76 (m, 1H), 7.59-7.50 (m, 2H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.8, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (d, J=4.6 Hz, 1H), 4.63-4.58 (m, 2H), 2.55 (s, 6H), 2.13 (ddd, J=13.9, 3.8, 2.8 Hz, 1H), 1.93 (ddd, J=13.8, 11.0, 3.6 Hz, 1H); MS (APCI.sup.+) m/z 538 (M+H).sup.+.

    Example 208: (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 307)

    Example 208A: methyl 3-(4-(4-chlorophen yl)-2-oxopyrrolidin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1672] The reaction and purification conditions described in Example 203C substituting 4-(4-chlorophenyl)pyrrolidin-2-one (J-W Pharmlab) for the product of Example 203B gave the title compound. MS (APCI.sup.+) m/z 320 (M+H).sup.+.

    Example 208B: 3-(4-(4-chlorophenyl)-2-oxopyrrolidin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1673] The reaction and purification conditions described in Example 110B substituting the product of Example 208A for the product of Example 110A gave the title compound. (APCI.sup.+) m/z 347 (M+CH.sub.3CN+H).sup.+.

    Example 208C: 2-(trimethylsilyl)ethyl (3-(4-(4-chlorophenyl)-2-oxopyrrolidin-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1674] The reaction and purification conditions described in Example 125C substituting the product of Example 208B for the product of Example 125B gave the title compound. (APCI.sup.+) m/z 421 (M+H).sup.+.

    Example 208D: (2R,4R)-6-chloro-N-{3-[4-(4-chlorophenyl)-2-oxopyrrolidin-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1675] The reaction and purification conditions described in Example 186B substituting the product of Example 208C for the product of Example 186A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm (s, 1H), 7.43-7.30 (m, 5H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 4.80 (dd, J=10.7, 5.8 Hz, 1H), 4.60 (dd, J=11.9, 2.3 Hz, 1H), 3.71 (dd, J=9.4, 8.1 Hz, 1H), 3.63-3.50 (m, 1H), 3.27 (dd, J=9.3, 7.7 Hz, 1H), 2.63 (dd, J=16.5, 8.7 Hz, 1H), 2.46-2.30 (m, 2H), 2.33 (s, 6H), 1.69 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 487 (M+H).sup.+.

    Example 209: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 308)

    [1676] The reaction and purification conditions described in Examples 203A through 203F substituting 2-bromo-5-(trifluoromethoxy)pyridine (Ark Pharm) for 1-bromo-4-(trifluoromethoxy)benzene gave the title compound .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.59-8.55 (m, 1H), 8.44 (d, J=0.8 Hz, 1H), 8.09 (d, J=0.8 Hz, 1H), 7.90-7.86 (m, 1H), 7.86-7.83 (m, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.75 (br s, 1H), 4.83 (dd, J=10.6, 5.9 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 2.56 (s, 6H), 2.43-2.35 (m, 1H), 1.73 (ddd, J=13.0, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 521 (M+H).sup.+.

    Example 210: (2S,4R)-6-chloro-4-hydroxy-N-[trans-4-{2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 309)

    Example 210A: benzyl (trans-4-(2-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)imidazolidin-1-yl)cyclohexyl)carbamate

    [1677] 5-Iodo-2-(trifluoromethyl)pyridine (276 mg, 1.01 mmol Ark Pharm), bis(tri-tert-butylphosphine)palladium(0) (24 mg, 0.047 mmol), the product of Example 37C (247 mg, 0.778 mmol) and cesium carbonate (507 mg, 1.556 mmol) were suspended in dioxane (5 mL) in a 20 mL vial. The vial was degassed by sparging with nitrogen for 2 minutes before sealing with a polytetrafluoroethylene-lined cap. The reaction was stirred at 58 C. for 18 hours, cooled to ambient temperature, and more bis(tri-tert-butylphosphine)palladium(0) (12 mg, 0.043 mmol) was added. The vial was resealed and heated at 100 C. for 4 hours, and then cooled. The resulting reaction mixture was partitioned between ethyl acetate (250 mL) and brine (50 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (66 mg, 0.143 mmol, 18% yield). MS (APCI.sup.+) m/z 463 (M+H).sup.+.

    Example 210B: (2S,4R)-6-chloro-4-hydroxy-N-[trans-4-{2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1678] The reaction and purification conditions described in Example 1C substituting the product of Example 210A for the product of Example 1A, the product of Example 73B for the product of Example 1B, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.95 (d, J=2.6 Hz, 1H), 8.17 (dd, J=8.9, 2.6 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.24 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.64 (br s, 1H), 4.58 (dd, J=10.7, 2.7 Hz, 2H), 3.89 (dd, J=9.3, 6.5 Hz, 2H), 3.71-3.59 (m, 2H), 3.56-3.48 (m, 2H), 2.14-2.04 (m, 1H), 1.97-1.79 (m, 3H), 1.75-1.54 (m, 4H), 1.52-1.37 (m, 2H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 211: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-{2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 310)

    [1679] The reaction and purification conditions described in Example 186B substituting the product of Example 210A for the product of Example 186A, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.95 (d, J=2.6 Hz, 1H), 8.17 (dd, J=8.9, 2.6 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.38 (dd, J=2.6, 1.0 Hz, 1H), 7.19 (dd, J=8.5, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.81 (dd, J=10.7, 6.0 Hz, 1H), 4.62 (dd, J=11.9, 2.3 Hz, 1H), 3.89 (dd, J=9.3, 6.7 Hz, 2H), 3.71-3.58 (m, 2H), 3.54-3.49 (m, 2H), 2.35 (ddd, J=13.0, 5.9, 2.3 Hz, 1H), 1.85 (s, 2H), 1.78-1.55 (m, 5H), 1.53-1.39 (m, 2H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 212: (2R,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 311)

    Example 212A: tert-buty (3-(methoxy(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1680] To a solution of N,O-dimethylhydroxylamine hydrochloride (3.86 g, 39.6 mmol) and 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (6.0 g, 26.4 mmol) in dichloromethane (100 mL) stirred at 0 C. was added N,N-diisopropylethylamine (18.44 mL, 106 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (15.06 g, 39.6 mmol) in sequential order. The ice bath was removed and the reaction mixture was left stirring at ambient temperature for 3 hours. More dichloromethane (100 mL) was added. The resulting solution was washed with aqueous HCl (1.0 M, 100 mL), saturated aqueous sodium bicarbonate (2100 mL) and brine (100 mL) in sequential order. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate in isohexane) to give the title compound (6.27 g, 21.11 mmol, 80% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.59 (s, 1H), 3.63 (s, 3H), 2.69 (s, 3H), 2.14 (s, 6H), 1.37 (s, 9H).

    Example 212B: tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate

    [1681] The product of example 212A (1.00 g, 3.70 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) under a nitrogen atmosphere. The solution was cooled to 78 C. and diisobutylaluminum hydride (1.0 M in hexanes, 8.14 mL) was slowly added. The reaction mixture was stirred at 78 C. for 1 hour. Methanol (0.3 mL) was added, and the reaction was stirred at 78 C. for 10 minutes. Aqueous HCl (1.0 M, 50 mL) and ethyl acetate (50 mL) were added, and the dry-ice bath was removed. The mixture was stirred vigorously while warming up to ambient temperature, and the stirring was continued for 2.5 hours. Phases were separated, and the aqueous phase was extracted with ethyl acetate (2-50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (780 mg, 3.51 mmol, 95%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.59 (s, 1H), 7.64 (s, 1H), 2.12 (s, 6H), 1.38 (s, 9H).

    Example 212C: tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate

    [1682] The product of Example 212B (780 mg, 3.51 mmol) was dissolved in methanol (15 mL), and potassium carbonate (2.91 g, 21.05 mmol) was added. After stirring at ambient temperature for 5 minutes, dimethyl (1-diazo-2-oxopropyl)phosphonate (2.53 mL, 10.52 mmol, Manchester Organics) was slowly added and the resulting mixture was stirred for 16 hours, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (320 mL) and water (20 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate in isohexane) to give the title compound (624 mg, 2.95 mmol, 84% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.60 (s, 1H), 3.09 (s, 1H), 2.13 (s, 6H), 1.36 (s, 9H).

    Example 212D: tert-butyl (3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1683] The product of Example 212C (116 mg, 0.56 mmol), copper sulfate (1.0 mg, 0.006 mmol), tert-butanol (6 mL) and water (2 mL) were combined in a sealed tube. 4-Azido-1 -chloro-2-fluorobenzene (103 mg, 0.60 mmol, Enamine), benzoic acid (6.8 mg, 0.056 mmol), and sodium ascorbate (2.0 mg, 0.010 mmol) were added. The tube was flushed with nitrogen, sealed, and stirred at 80 C. for 2 days. The mixture was cooled to ambient temperature and then poured into ice water (25 mL), and then extracted with ethyl acetate (3-25 mL). The organic layers were combined, washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound that was used without further purification (275 mg (about 77% purity), 0.56 mmol, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.74 (s, 1H), 8.08-8.01 (m, 1H), 7.88-7.78 (m, 2H), 2.25 (s, 6H), 1.39 (s, 9H); MS (ESI.sup.+) m/z 379 (M+H).sup.+.

    Example 212E: (2R,4R)-6-chloro-N-{3-[1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1684] The reaction and purification conditions described in Example 3C substituting the product of Example 212D for the product of Example 3A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.82-8.75 (m, 2H), 8.09-8.02 (m, 1H), 7.88-7.79 (m, 2H), 7.40 (d, J=2.7, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=5.4 Hz, 1H), 4.88-4.79 (m, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.41 (s, 7H), 1.79-1.65 (m, 1H); MS (ESI.sup.+) m/z 489 (M+H).sup.+.

    Example 213: (2R,4R)-6-chloro-N-(3-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 312)

    [1685] The reaction and purification conditions described in Example 186B substituting the product of Example 207D for the product of Example 186A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.41 (d, J=0.8 Hz, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.82-7.74 (m, 1H), 7.60-7.49 (m, 2H), 7.38 (dt, J=10.6, 9.3 Hz, 1H), 7.12 (ddd, J=12.6, 6.7, 3.0 Hz, 1H), 6.87-6.78 (m, 1H), 4.50 (s, 2H), 2.54 (s, 6H); MS (APCI.sup.+) m/z 538 (M+H).sup.+.

    Example 214: (2R,4R)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 313)

    Example 214A: rac-(1R,2S,4R,5S)-5-amino-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide trifluoroacetic acid

    [1686] To a solution of the product of Example 86D (50 mg, 0.194 mmol), (5-(trifluoromethyl)pyridin-2-yl)methanamine, hydrochloric acid (47.5 mg, 0.223 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.972 mmol) in N,N-dimethylformamide (2.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (92 mg, 0.243 mmol) and the mixture was stirred at ambient temperature for 1 hour. N,N-Dimethylformamide was removed under high vacuum and the residue was suspended in methanol (5 mL) and treated with 4 N hydrogen chloride in dioxane (0.486 mL, 1.943 mmol) for 30 minutes at 50 C. Solvent and excess HCl were removed under vacuum and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 15-70% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 55 mg of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.89 (d, J=2.3 Hz, 1H), 8.54 (dt, J=21.4, 5.9 Hz, 1H), 8.17 (dd, J=8.3, 2.7 Hz, 1H), 7.91 (d, J=6.0 Hz, 3H), 7.48 (d, J=8.3 Hz, 1H), 4.80 (d, J=5.4 Hz, 1H), 4.53 (d, J=5.8 Hz, 1H), 4.46 (d, J=5.9 Hz, 2H), 2.63 (dd, J=9.0, 4.5 Hz, 1H), 2.12-2.02 (m, 1H), 1.97 (ddd, J=28.9, 13.2, 7.8 Hz, 1H), 1.89-1.73 (m, 1H), 1.70 (dd, J=12.5, 9.1 Hz, 1H), 1.59-1.49 (m, 1H).

    Example 214B: (2R,4R)-6-chloro-4-hydroxy-N-[(1RS,2SR,4RS,5SR)-5-({[5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-7-oxabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1687] To a solution of the product of Example 214A (53 mg, 0.081 mmol), the product of Example 1B (21.23 mg, 0.094 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.071 mL, 0.407 mmol) in N,N-dimethylformamide (1.5 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (38.7 mg, 0.102 mmol) was added and the mixture was stirred at ambient temperature for 90 minutes. Volatiles were removed under high vacuum and the residue was dissolved in methanol (with a few drops of dichloromethane to completely dissolve) and treated with sodium tetrahydroborate (3.08 mg, 0.081 mmol) at ambient temperature for 30 minutes. Solvent was removed and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give 35 mg of the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (dq, J=2.0, 1.0 Hz, 1H), 8.50 (td, J=6.0, 2.5 Hz, 1H), 8.18 (ddt, J=8.2, 2.2, 1.0 Hz, 1H), 7.96 (dd, J=13.2, 6.9 Hz, 1H), 7.53-7.45 (m, 1H), 7.42 7.36 (m, 1H), 7.19 (dtd, J=8.7, 2.8, 0.7 Hz, 1H), 6.88 (dd, J=8.7, 0.9 Hz, 1H), 4.84-4.76 (m, 1H), 4.71 (d, J=5.4 Hz, 1H), 4.65 (ddd, J=11.8, 4.5, 2.3 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 4.34 (dd, J=8.1, 5.6 Hz, 1H), 3.88 (tt, J=8.1, 3.3 Hz, 1H), 2.60 (dd, J=9.0, 4.6 Hz, 1H), 2.36-2.28 (m, 1H), 2.03 1.95 (m, 2H), 1.81-1.70 (m, 1H), 1.66 (dddd, J=12.4, 10.1, 6.1, 3.8 Hz, 2H); MS (APCI.sup.+) m/z 525.98 (M+H).sup.+.

    Example 215: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 314)

    Example 215A: 3-(dimethylamino)-1-(cis-3-(trifluoromethoxy)cyclobutyl)prop-2-en-1-one

    [1688] The reaction and purification conditions described in Example 199A substituting the product of Example 193B for tert-butyl (3-acetylbicyclo[1.1.1]pentan-1-yl)carbamate gave the title compound, which was used as is in the next step without further characterization or purification.

    Example 215B: 3-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-pyrazole

    [1689] To a solution of the product of Example 215A (695 mg, 2.93 mmol) in anhydrous methanol (10 mL) was added hydrazine hydrate (64% aqueous solution, 0.213 mL). The reaction mixture was stirred at 60 C. for 18 hours, cooled to ambient temperature and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% ethyl acetate in isohexane) to give the title compound. MS (ESI.sup.+) m/z 207 (M+H).sup.+.

    Example 215C: methyl 3-(bis(tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate

    [1690] Triethylamine (4.57 mL, 32.8 mmol) was added to a suspension of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (2.45 g, 13.11 mmol, Fluorochem) in dichloromethane (68 mL). Di-tert-butyl dicarbonate (4.56 mL, 19.66 mmol) was then added, and the reaction mixture was stirred at room temperature for 3 days. Dichloromethane (68 mL) was added to the reaction, and the mixture was washed with water (2100 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile (20 mL). 4-Dimethylaminopyridine (0.32 g, 2.62 mmol) and di-tert-butyl dicarbonate (4.56 mL, 19.66 mmol) were added. The reaction mixture was stirred at ambient temperature overnight. Water (100 mL) was added, and the resulting suspension was extracted with ethyl acetate (3100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound (4.75 g, 12.52 mmol, 96% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 3.61 (s, 3H), 2.33 (s, 6H), 1.44 (s, 18H).

    Example 215D: 3-(bis(tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1691] The reaction and purification conditions described in Example 117B substituting the product of Example 215C for the product of Example 117A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.55 (br s, 1H), 2.29 (s, 6H), 1.44 (s, 18H).

    Example 215E: mesityl-3-iodanediyl bis(3-(bis(tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate)

    [1692] A solution of the product of Example 215D (1.08 g, 3.30 mmol) and iodomesitylene diacetate (0.60 g, 1.65 mmol) in toluene (10 mL) was stirred at 60 C. for 30 minutes. The solvent was removed under reduced pressure and azeotroped with toluene (45 mL) to give the title compound (1.56 g, 1.65 mmol, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.09 (s, 2H), 2.70 (s, 6H), 2.39 (s, 3H), 2.32 (s, 12H), 1.49 (s, 36H).

    Example 215F: di-tert-butyl (3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-2-imidodicarbonate

    [1693] Dioxane (3 mL) was added to a mixture of the product of Example 215E (290 mg, 0.323 mmol) and the product of Example 215B (93 mg, 0.452 mmol). The resulting mixture was degassed under vacuum and then sonicated until all solids were dissolved. Copper(I) thiophene-2-carboxylate (61.6 mg, 0.323 mmol) was added in one portion. The mixture was sonicated for 2 minutes, and then stirred at ambient temperature for 15 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with additional saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (0-40% ethyl acetate in hexanes) to give the title compound (16 mg, 0.032 mmol, 10% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.35 (d, J=2.3 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 4.64 (p, J=7.5 Hz, 1H), 3.21-3.11 (m, 1H), 2.85-2.76 (m, 2H), 2.68 (s, 6H), 2.44-2.36 (m, 2H), 1.54 (s, 18H); MS (ESI.sup.+) m/z 488 (M+H).sup.+.

    Example 215G: (2R,4R)-6-chloro-4-hydroxy-N-(3-{3-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1694] The reaction and purification conditions described in Example 3C substituting the product of Example 215F for the product of Example 3A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.87-4.75 (m, 2H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 3.12-3.02 (m, 1H), 2.74-2.66 (m, 2H), 2.48 (s, 6H), 2.42-2.34 (m, 1H), 2.32-2.23 (m, 2H), 1.78-1.67 (m, 1H); MS (ESI.sup.+) m/z 498 (M+H).sup.+.

    Example 216: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 315)

    Example 216A: tert-butyl (3-(2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1695] To a mixture of the product of Example 151A (184 mg, 0.728 mmol) and copper(II) sulfate (1.3 mg, 0.008 mmol) in tert-butanol (7.8 mL) and water (2.6 mL) in a sealed tube was added azidotrimethylsilane (0.103 mL, 0.78 mmol), benzoic acid (8.9 mg, 0.073 mmol) and sodium ascorbate (2.6 mg, 0.013 mmol) at ambient temperature. The tube was flushed with nitrogen, sealed, and stirred at 80 C. for 3 days. The mixture was cooled to ambient temperature, poured onto ice water (25 mL), and extracted with ethyl acetate (325 mL). The combined organic fractions were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound that was used without further purification or characterization (498 mg, estimated 73% purity based on mass recovery).

    Example 2161: tert-butyl (3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate and tert-butyl (3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-1,2,3-triazol-5-yl)bicyclo[1.1.1]pentan-1-yl)carbamate 1:1

    [1696] To a mixture of the product of Example 217D (68.3 mg, 0.437 mmol), the product of Example 216A (150 mg, 0.437 mmol) and triphenylphosphine (229 mg, 0.875 mmol) in tetrahydrofuran (3.5 mL) at 0 C. was added diisopropyl azodicarboxylate (0.172 mL, 0.875 mmol) in a dropwise fashion. The reaction mixture was stirred at ambient temperature for 20 hours and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in cyclohexane) to give the title compounds (49 mg, 0.09 mmol, 20% yield). MS (ESI) m/z 390 (M+H).sup.+.

    Example 216C: 3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine and 3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-1,2,3-triazol-5-yl)bicyclo[1.1.1]pentan-1-amine (1:1)

    [1697] To a solution of the products of Example 216B (49 mg, 0.088 mmol) in dichloromethane (1 mL) at ambient temperature was added trifluoroacetic acid (0.13 mL) and the reaction mixture was stirred at ambient temperature for 20 hours. The resulting mixture was concentrated in vacuo, taken up in methanol (2 mL), combined with SCX resin (0.2 g), and then loaded onto a column packed with 0.3 g SCX resin. The column was first washed with methanol (10 mL). The resin column was then eluted with ammonia in methanol (0.7 M, 10 mL) and the filtrate was concentrated in vacuo to afford the title compound (23 mg, 0.08 mmol, 90% yield). MS (ESI) m/z 290 (M+H).sup.+.

    Example 216D: (2R)-6-chloro-4-oxo-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1698] The title compound was synthesized using the same procedure as described in Example 155C, substituting the product of Example 216C for the product of Example 155B, and the product of Example 1B for the product of Example 3B, and purified by the following preparative HPLC method: [Waters XSelect C18 5 m CSH column, 30100 mm, 40-70% gradient of acetonitrile in buffer (0.1% formic acid)]. MS (ESI) m/z 497 (M+H).sup.+.

    Example 216E. (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1699] The reaction and purification conditions described in Example 62 substituting the product of Example 216D for the product of Example 53 gave the title compound. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 8.00 (s, 1H), 7.47-7.41, (m, 1H), 7.17 (dd, J=8.8, 2.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.98-4.91 (m, 1H), 4.87-4.73 (m, 2H), 4.63 (dd, J=11.7, 2.4 Hz, 1H), 3.16-3.05 (m, 2H), 2.93-2.80 (m, 2H), 2.60-2.54 (m, 1H), 2.48 (s, 6H), 1.94-1.85 (m, 1H); MS (ESI.sup.+) m/z 499 (M+H).sup.+.

    Example 217: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 316)

    Example 217A: trans-3-(benzyloxy)cyclobutyl 4-nitrobenzoate

    [1700] To a solution of the product of Example 201A (10.0 g, 50.5 mmol), 4-nitrobenzoic acid (8.44 g, 50.5 mmol), and triphenylphosphine (13.2 g, 50.5 mmol) in toluene (200 mL) was added diisopropyl azodicarboxylate (9.82 mL, 50.5 mmol) dropwise at 0 C. The mixture was stirred at 20 C. for 16 hours. Then the reaction mixture was combined with another batch of the same reaction mixture, diluted with water (300 mL), and extracted with ethyl acetate (3300 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 8:1) to afford the title intermediate (27.0 g, 74.2 mmol, 74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.35 (d, J=8.77 Hz, 2H), 8.20 (d, J=8.77 Hz, 2H), 7.26-7.37 (m, 5H), 5.28-5.36 (m, 1H), 4.42 (s, 2H), 4.34 (quin, J=5.92 Hz, 1H), 2.45-2.49 (m, 4H).

    Example 217B: trans-3-(benzyloxy)cyclobutanol

    [1701] To a solution of the product of Example 217A (15 g, 41 mmol) in tetrahydrofuran (150 mL) was added a solution of NaOH (2.0 g, 50 mmol) in water (38 mL) dropwise at 0 C. The reaction mixture was stirred at 20 C. for 10 hours. The reaction mixture was combined with another batch of the same reaction mixture and was concentrated in vacuo. The residue was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with brine (150 mL) and concentrated to afford the title intermediate (15 g, 72 mmol, 96% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.24-7.38 (m, 5H), 4.98 (d, J=4.82 Hz, 1H), 4.33 (s, 2H), 4.24-4.32 (m, 1H), 4.11-4.18 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.07 (m, 2H).

    Example 217C: ((trans-3-(trifluoromethoxy)cyclobutoxy)methyl)benzene

    [1702] The title compound was synthesized using the same procedure as described in Example 130 substituting the product of Example 13N with the product of Example 217B and increasing the reaction time to 48 hours. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.23-7.40 (m, 5H), 4.89-5.00 (m, 1H), 4.38 (s, 2H), 4.19-4.29 (m, 1H), 2.43 (t, J=5.69 Hz, 4H), 2.39-2.40 (m, 1H).

    Example 217D: trans-3-(trifluoromethoxy)cyclobutanol

    [1703] To a solution of the product of Example 217D (12.0 g, 41.4 mmol) in tetrahydrofuran (120 mL) was added 10% palladium on carbon (8.82 g, 4.14 mmol, 50% water) under argon, and the reaction mixture was stirred at 50 C. under hydrogen (50 psi) for 48 hours. Then the suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (50 mL3). The filtrate was concentrated under reduced pressure to afford the title intermediate (5.80 g, 30.7 mmol, 74% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 5.24 (d, J=5.14 Hz, 1H), 4.86-4.99 (m, 1H), 4.28-4.41 (m, 1H), 2.33-2.46 (m, 2H), 2.18-2.29 (m, 2H).

    Example 217E: trans-3-(trifluoromethoxy)cyclobutyl methanesulfonate

    [1704] To a solution of the product of Example 217D (0.055 g, 0.36 mmol) and Hunig's base (N,N-diisopropylethylamine) (0.093 mL, 0.53 mmol) in dichloromethane (1.5 mL) at 0 C. under nitrogen was added methanesulfonyl chloride (0.033 mL, 0.43 mmol) dropwise. The reaction mixture stirred at this temperature for 30 minutes and then at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH.sub.4Cl (aqueous) (2.5 mL) and the phases were separated. The aqueous phase was extracted with additional dichloromethane (2.5 mL). The combined organic layers were concentrated in vacuo to afford the crude title intermediate (0.11 g, 0.35 mmol, quantitative yield), which was carried forward without purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 5.22 (p, J=6.0 Hz, 1H), 5.04 (p, J=5.7 Hz, 1H), 3.20 (s, 3H), 2.73-2.68 (m, 4H).

    Example 217F: 3-benzyl-3H-1,2,3-oxadiazol-1-ium-5-olate

    [1705] Behind a blast shield, to a solution of 2-(benzylamino)acetic acid (250 mg, 1.51 mmol) in 1,2-dimethoxyethane (7.0 mL) under nitrogen was added isoamyl nitrite (0.204 mL, 1.51 mmol). The reaction mixture stirred for 2 hours and was concentrated in vacuo (water bath at 30 C. to prevent decomposition). The crude residue was dispersed in dichloromethane:isohexane (1:15), concentrated in vacuo, and triturated using isohexane to afford 2-(benzyl(nitroso)amino)acetic acid.

    [1706] Behind a blast shield, to a solution of 2-(benzyl(nitroso)amino)acetic acid (294 mg, 1.51 mmol) in dichloromethane (7.00 mL) at 0 C. under nitrogen was added trifluoroacetic anhydride (0.214 mL, 1.51 mmol) dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1.5 hours. Then water (7 mL) was added and the excess trifluoroacetic anhydride was quenched with sodium hydrogen carbonate. The phases were separated, and the aqueous layer was further extracted with dichloromethane (10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford a crude amorphous solid, which was dispersed in dichloromethane:isohexane (1:15). This solution was then concentrated in vacuo to afford the title intermediate (202 mg, 1.03 mmol, 68% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.47 (dd, J=5.0, 2.0 Hz, 3H), 7.41-7.35 (m, 2H), 6.17 (s, 1H), 5.35 (s, 2H).

    Example 217G: tert-butyl (3-(1-benzyl-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1707] To a suspension of the product of Example 217F (250 mg, 1.42 mmol), the product of Example 212C (588 mg, 2.84 mmol), sodium 4,4-(1,10-phenanthroline-4,7-diyl)dibenzenesulfinate (752 mg, 1.49 mmol), sodium L-ascorbate (562 mg, 2.84 mmol), and triethylamine (0.791 mL, 5.68 mmol) in water (5.0 mL) and t-butanol (7.5 mL) was added copper(II) sulfate (238 mg, 1.49 mmol) as a solution in water (2.5 mL). The reaction mixture was heated to 85 C. and stirred for 20 hours. Then the reaction mixture was cooled to ambient temperature and brine (20 mL) was added, followed by ethyl acetate (20 mL). The phases were separated, and the aqueous layer was further extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in isohexane) to afford the title intermediate (395 mg, 1.09 mmol, 77% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.60 (s, 1H), 7.36-7.19 (m, 6H), 5.23 (s, 2H), 2.06 (s, 6H), 1.37 (s, 9H); MS (ESI.sup.+) m/z 340 (M+H).sup.+.

    Example 217H: tert-butyl (3-(1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1708] A solution of the product of Example 217G (200 mg, 0.589 mmol) in acetic acid (6 mL) was flowed through an H-Cube continuous flow hydrogenator (1 mL/minute) with a 10% palladium on carbon catalyst cartridge at 100 C. using controlled H2 mode (100 bar) as a continuous loop for 20 hours. The reaction mixture was then cooled to ambient temperature and diluted with water (20 mL) and ethyl acetate (20 mL). The phases were separated, and the aqueous phase was extracted with additional ethyl acetate (20 mL). The combined organic layers were washed with brine (320 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo, and purified by chromatography on silica gel (0-100% ethyl acetate in cyclohexane) to afford the title intermediate (37 mg, 0.14 mmol, 24% yield). MS (ESI) m, 250 (M+H).sup.+.

    Example 217I: tert-butyl (3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

    [1709] A solution of the product of Example 217H (37 mg, 0.15 mmol), cesium carbonate (145 mg, 0.445 mmol), and the product of Example 217E (87 mg, 0.37 mmol) in N,N-dimethyl formamide (0.5 mL), under nitrogen, was heated to 80 C. and stirred for 22 hours. Then the reaction mixture was diluted with water (10 mL) and ethyl acetate (10 ml), and the phases were separated. The organic phase was washed with 1:1 brine:H.sub.2O (315 mL), dried over Na.sub.2SO.sub.4, filtered, and then concentrated in vacuo to afford a crude residue (73 mg). The crude residues from 2 batches of the same reaction were combined and purified by chromatography on silica gel (0-100% ethyl acetate in cyclohexane) to afford the title intermediate (11 mg, 0.027 mmol, 12% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.39 (s, 1H), 7.26 (s, 1H), 4.59-4.50 (m, 1H), 4.44-4.34 (m, 1H), 3.03-2.95 (m, 2H), 2.90-2.82 (m, 2H), 2.24 (s, 6H), 1.48 (s, 9H).

    Example 217J: 3-(1-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-pyrazol-4-yl)bicyclo[1.1.1]pentan-1-amine

    [1710] To a solution of the product of Example 217I (11 mg, 0.028 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.098 mL, 1.3 mmol) and the reaction mixture was stirred for 3 hours. The solvent was removed under vacuum and co-evaporated with toluene (35 mL) to afford a crude salt, which was purified on SCX resin (washing with methanol then eluted with 0.7M ammonia in methanol) to afford the title intermediate (8.0 mg, 0.026 mmol, 93% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.36 (s, 1H), 7.24 (s, 1H), 4.58-4.48 (m, 1H), 4.42-4.31 (m, 1H), 3.01-2.92 (m, 2H), 2.89-2.79 (m, 2H), 2.05 (s, 6H); MS (ESI.sup.+) m/z 289 (M+H).sup.+.

    Example 217K. (2R)-6-chloro-4-oxo-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1711] To a solution of the product of Example 217J (8.0 mg, 0.028 mmol), the product of Example 1B (9.5 mg, 0.042 mmol). and triethylamine (0.023 mL, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) was added HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (16 mg, 0.042 mmol). After the reaction mixture was stirred for 1 hour, it was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL) and the aqueous phase was extracted with dichloromethane (22 mL). The combined organic phases were then concentrated in vacuo to afford the crude title intermediate (14 mg, 0.028 mmol, quantitative yield), which was carried forward without further purification.

    [1712] MS (ESI.sup.+) m/z 496 (M+H).sup.+.

    Example 217L: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1713] To a solution of Example 217K (14 mg, 0.028 mmol) in methanol (0.5 mL) at ambient temperature under nitrogen, was added sodium borohydride (13 mg, 0.34 mmol), and the reaction mixture was stirred for 15 minutes. Then the reaction mixture was quenched with saturated NH.sub.4Cl (aqueous) (2.5 mL), stirred for 10 minutes, and then was extracted with dichloromethane (22 mL). The combined organic phases were concentrated in vacuo and purified by chromatography on silica gel (50-100% ethyl acetate in isohexane) to afford the title compound (8.4 mg, 0.016 mmol, 57% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.66 (s, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.38 (s, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.85-4.79 (m, 1H), 4.77-4.70 (m, 1H), 4.62-4.57 (m, 1H), 4.54-4.46 (m, 1H), 2.93-2.85 (m, 2H), 2.72-2.63 (m, 2H), 2.39-2.33 (m, 1H), 2.22 (s, 6H), 1.75-1.66 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.95; MS (ESI.sup.+) m/z 498 (M+H).sup.+.

    Example 218: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 317)

    Example 218A: tert-butyl (3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1H-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1714] To a 20 mL vial was added cataCXium Pd G4 (4.8 mg, 6.4 mol), tetrahydroxydiboron (32.8 mg, 0.366 mmol) and the product of Example 207C (30 mg, 0.091 mmol). The vial was sealed, evacuated, and then backfilled with nitrogen. The process was repeated 3 more times. Methanol (1.5 mL) was added to the reaction mixture followed by the addition of Hunig's Base (64 L). The reaction mixture was then heated to 52 C. and stirred for 2 hours. Subsequently, a degassed solution of aqueous potassium phosphate (366 L, 1.0 M) was added via syringe followed by the addition of 2-bromo-5-(trifluoromethyl)pyridine (41.3 mg, 0.183 mmol) as a solution in degassed ethanol (0.36 mL). The reaction mixture was further stirred at 52 C. for 18 hours, cooled to ambient temperature, combined with diatomaceous earth (about 5 g), and concentrated under reduced pressure. The powder was directly purified by reversed-phase flash chromatography [Interchim puriFlash C18XS 15 m 120 g column, flow rate 60 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (20 mg, 0.050 mmol, 55% yield).

    [1715] MS (APCI.sup.+) m/z 395 (M+H).sup.+.

    Example 218B: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1716] The reaction and purification conditions described in Example 1C substituting the product of Example 218A for the product of Example 1A, the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.88-8.85 (m, 1H), 8.56 (d, J=0.7 Hz, 1H), 8.20-8.15 (m, 2H), 7.95-7.90 (m, 11H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (s, 1H), 4.63-4.58 (m, 2H), 2.57 (s, 6H), 2.13 (dt, J=13.8, 3.5 Hz, 1H), 1.94 (ddd, J=13.9, 11.0, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 505 (M+H).sup.+.

    Example 219: (2R,4R)-6-chloro-N-(3-{4-[(3R)-3-(difluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 318)

    [1717] The methodologies described in the reaction sequence of Example 256 were followed substituting (3R)-3-(difluoromethoxy)pyrrolidine (purchased from Fluorochem) for (3S)-3-(trifluoromethoxy)pyrrolidine hydrochloride to give the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.23-7.19 (m, 2H), 7.10 (d, J=0.9 Hz, 1H), 6.93-6.54 (m, 2H), 5.71 (d, J=6.3 Hz, 1H), 4.87-4.79 (m, 2H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.28-3.23 (m, 1H), 3.12 (q, J=7.7 Hz, 1H), 3.06 (dd, J=10.5, 2.5 Hz, 1H), 2.97 (td, J=8.5, 4.9 Hz, 1H), 2.45 (s, 6H), 2.37 (s, 1H), 2.27-2.17 (m, 1H), 1.98 (s, 1H), 1.77-1.67 (m, 1H); MS (ESI.sup.+) m/z 595 (M+H).sup.+.

    Example 220: (2S,4S)-6-chloro-4-hydroxy-N-{3-[4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 319)

    Example 220A: tert-butyl {3-[4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1718] The reaction and purification conditions described in Example 207D substituting (2-methoxypyrimidin-5-yl)boronic acid for 3-fluoro-4-(trifluoromethoxy)phenylboronic acid gave the title compound. MS (APCI.sup.+) m/z 358 (M+H).sup.+.

    Example 220B: (2S,4S)-6-chloro-4-hydroxy-N-{3-[4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1719] The reaction and purification conditions described in Example 186B substituting the product of Example 220A for the product of Example 186A, and the product of Example 10A for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.86 (s, 2H), 8.37 (d, J=0.8 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.83 (dd, J=10.5, 6.0 Hz, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 3.92 (s, 3H), 2.55 (s, 6H), 2.39 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 1.74 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 468 (M+H).sup.+.

    Example 221: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 320)

    [1720] The reaction and purification conditions described in Example 186B substituting the product of Example 220A for the product of Example 186A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.86 (s, 2H), 8.37 (d, J=0.8 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.6, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.83 (dt, J=11.5, 6.1 Hz, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 3.92 (s, 3H), 2.55 (s, 6H), 2.39 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.74 (ddd, J=12.8, 11.9, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 468 (M+H).sup.+.

    Example 222: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 321)

    [1721] The title compound was synthesized using the same procedures as described in Example 287D through Example 287F substituting (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride with (R)-3-(trifluoromethoxy)pyrrolidine (PharmaBlock). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.82 (s, 1H), 7.80 (d, J=1.4 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (d, J=4.7 Hz, 1H), 5.13 (d, J=25.6 Hz, 1H), 4.86-4.76 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.39-3.82 (m, 2H), 3.71 (s, 1H), 3.67-3.47 (m, 1H), 2.54 (s, 6H), 2.36 (ddd, J=12.8, 5.9, 2.4 Hz, 1H), 2.27-2.05 (m, 2H), 1.71 (ddd, J=13.0, 12.1, 10.7 Hz, 1H); MS (ESI) m/z 541.4 (M+H).sup.+.

    Example 223: (2R,4R)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{3-[4-(trifluoromethyl)phenyl]azetidine-1-carbonyl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 322)

    Example 223A: tert-butyl [(3R,6S)-6-{3-[4-(trifluoromethyl)phenyl]azetidine-1-carbonyl}oxan-3-yl]carbamate

    [1722] The methodologies described in Example 30D substituting (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid (purchased from Astatech) for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid, substituting 3-(4-(trifluoromethyl)phenyl)azetidine hydrochloride (purchased from Arispharma) for Example 30C, and substituting Hunig's base (3 equivalents) for triethylamine gave the title intermediate.

    [1723] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.72 (dd, J=8.4, 3.2 Hz, 2H), 7.59 (dd, J=8.4, 2.3 Hz, 2H), 6.80 (d, J=7.8 Hz, 1H), 4.67 (td, J=9.1, 3.4 Hz, 1H), 4.30 (t, J=9.3 Hz, 1H), 4.25 (dd, J=9.4, 6.2 Hz, 1H), 3.97 (tq, J=8.7, 5.8 Hz, 1H), 3.91-3.79 (m, 3H), 3.00 (t, J=10.6 Hz, 1H), 1.92-1.85 (m, 1H), 1.81 (dq, J=13.5, 3.4 Hz, 1H), 1.56 (qd, J=13.4, 3.8 Hz, 1H), 1.41 (dd, J=12.6, 8.7 Hz, 1H), 1.37 (s, 8H); MS (APCI.sup.+) m/z 429 (M+H).sup.+.

    Example 223B: [(2S,5R)-5-aminooxan-2-yl]{3-[4-(trifluoromethyl)phenyl]azetidin-1-yl}methanone

    [1724] The methodologies described in Example 21B substituting the product of Example 223A for the product of Example 21A gave the title intermediate. MS (APCI.sup.+) m/z 329 (M+H).sup.+.

    Example 223C: (2R,4R)-6-chloro-4-hydroxy-N-[(3R,6S)-6-{3-[4-(trifluoromethyl)phenyl]azetidine-1-carbonyl}oxan-3-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1725] The methodologies described in Example 30D substituting the product of Example 223B for the product of Example 30C, substituting the product of Example 3B for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid, and substituting Hunig's base (3 equivalents) for triethylamine gave the title compound as a trifluoroacetic acid salt. .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.63 (dd, J=8.0, 5.2 Hz, 2H), 7.46-7.39 (m, 3H), 7.18 (ddd, J=8.8, 2.6, 0.6 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.37 (t, J=7.4 Hz, 1H), 4.91 (dd, J=8.2, 5.6 Hz, 1H), 4.78 (t, J=9.4 Hz, 1H), 4.68-4.61 (m, 1H), 4.51-4.44 (m, 1H), 4.36 (ddd, J=9.7, 6.1, 3.1 Hz, 1H), 4.16-4.07 (m, 2H), 4.00 (ddd, J=9.6, 6.2, 2.7 Hz, 2H), 3.89 (h, J=6.5 Hz, 1H), 3.23-3.13 (m, 1H), 2.66 (dddd, J=13.7, 5.4, 3.3, 1.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.09 (s, 2H), 1.83-1.72 (m, 1H), 1.54-1.44 (m, 1H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 224: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-{3-[4-(trifluoromethyl)phenyl]azetidine-1-carbonyl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 323)

    Example 224A: tert-butyl [trans-4-{3-[4-(trifluoromethyl)phenyl]azetidine-1-carbonyl}cyclohexyl]carbamate

    [1726] The reaction and purification conditions described in Example 2B substituting 3-(4-(trifluoromethyl)phenyl)azetidine hydrochloride (Aris Pharmaceuticals) for the product of Example 2A, and trans-4-[(tert-butoxycarbonyl)amino]cyclohexane-1-carboxylic acid for the product of Example 1B gave the title compound. MS (APCI.sup.+) m/z 427 (M+H).sup.+.

    Example 224B: (2R,4R)-6-chloro-4-hydroxy-N-[trans-4-{3-[4-(trifluoromethyl)phenyl]azetidine-1-carbonyl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1727] The reaction and purification conditions described in Example 186B substituting the product of Example 224A for the product of Example 186A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.87 (d, J=8.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.19 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.69 (d, J=5.5 Hz, 1H), 4.84-4.78 (m, 1H), 4.64-4.56 (m, 2H), 4.27 (t, J=9.2 Hz, 1H), 4.21 (dd, J=8.5, 6.0 Hz, 1H), 4.00-3.92 (m, 1H), 3.84 (dd, J=9.6, 6.1 Hz, 1H), 3.63-3.54 (m, 1H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.18 (tt, J=11.7, 3.5 Hz, 1H), 1.88-1.68 (m, 5H), 1.45-1.28 (m, 4H); MS (APCI.sup.+) m/z 537 (M+H).sup.+.

    Example 225: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 324)

    [1728] The reaction and purification conditions described in Example 1C substituting the product of Example 272B for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.28-8.22 (m, 1H), 7.89-7.83 (m, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.63 (d, J=4.7 Hz, 1H), 5.21-5.12 (m, 1H), 4.63-4.57 (m, 2H), 4.06-3.99 and 3.85-3.78 (two m, 2H, amide rotamers), 3.71 (s, 1H), 3.69-3.62 and 3.55-3.46 (two m, 1H, amide rotamers), 2.55 (s, 6H), 2.34-2.08 (m, 3H), 1.93 (ddd, J=14.3, 11.0, 3.6 Hz, 1H); MS (ESI.sup.+) m/z 541 (M+H).sup.+.

    Example 226: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 325)

    Example 226A: methyl 3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1729] A suspension of product of Example 207A (87.0 mg, 0.321 mmol), 3-(trifluoromethoxy)pyrrolidine hydrochloride (61.5 mg, 0.321 mmol), cesium carbonate (418 mg, 1.284 mmol) and tBuBrettPhos (7.8 mg, 0.016 mmol) in anhydrous tetrahydrofuran (3.0 mL) was degassed. tBuBrettPhos Pd G3 (13.7 mg, 0.016 mmol) was added, and the reaction mixture was further degassed. The reaction mixture was stirred at 70 C. for 20 hours and then cooled to ambient temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (320 mL). The combined organic fractions were washed with brine (10 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (24.2 mg, 17.5% yield). .sup.1H NMR (500 MHz,) ppm 7.27 (d, J=0.9 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 5.11 (tt, J=5.3, 2.4 Hz, 1H), 3.65 (s, 3H), 3.30-3.25 (m, 1H), 3.20-3.13 (m, 2H), 2.96 (td, J=8.6, 5.0 Hz, 1H), 2.42 (s, 6H), 2.36-2.26 (m, 1H), 2.12-2.03 (m, 1H).

    Example 226B: potassium 3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1730] The title compound was prepared using the procedures described for the synthesis of Example 231E, substituting the product from Example 226A for the product from Example 231D to afford the title compound (150 mg, 100% yield). MS (ESI) m/z 330 (MH).sup..

    Example 226C: 2-(trimethylsilyl)ethyl (3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1731] At 58 C. under a nitrogen atmosphere, diphenyl phosphorazidate (0.088 mL, 0.410 mmol) was added to a solution of the product from Example 226B (101 mg, 0.273 mmol), N-ethyl-N-isopropylpropan-2-amine (0.287 mL, 1.641 mmol) and 2-(trimethylsilyl)ethanol (0.784 mL, 5.47 mmol) in toluene (2.5 mL). The reaction mixture was stirred at 58 C. for 5 hours, allowed to cool, and stand at ambient temperature overnight. The solvent was then removed under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (45 mg, 24.7% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.91 (s, 1H), 7.23 (d, J=0.9 Hz, 1H), 7.11 (d, J=0.9 Hz, 1H), 5.10 (tt, J=5.3, 2.3 Hz, 1H), 4.07-3.99 (m, 2H), 3.27 (dd, J=11.2, 5.3 Hz, 1H), 3.20-3.12 (m, 2H), 2.95 (td, J=8.6, 5.0 Hz, 1H), 2.32 (s, 6H), 2.37-2.25 (m, 1H), 2.11-2.02 (m, 1H), 0.92 (s, 2H), 0.01 (s, 9H); MS (ESI) m/z 447 (M+H).sup.+.

    Example 226D: 3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1732] To a solution of the product from Example 226C (45 mg, 0.101 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.039 mL, 0.504 mmol) and the resulting solution was stirred at ambient temperature for 16 hours. The volatiles were removed in vacuo and the residue was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (32 mg, 55.7% yield). MS (ESI) m/z 303 (M+H).sup.+.

    Example 226E: (2R)-6-chloro-4-oxo-N-(3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1733] The product of Example 226D (32 mg, 0.106 mmol) was combined with (R)-6-chloro-4-oxochroman-2-carboxylic acid (28.8 mg, 0.127 mmol, Example 1B) and N,N-diisopropylethylamine (0.129 mL, 0.741 mmol) in N,N-dimethylformamide (2 mL). (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 48.3 mg, 0.127 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with dichloromethane (2.0 mL) and washed with saturated aqueous sodium bicarbonate solution (2.5 mL). The aqueous phase was further extracted with dichloromethane (22.0 mL). The combined organic phases were passed through a hydrophobic phase separator, then concentrated in vacuo to afford the title compound (82 mg, 100% yield). MS (ESI) m/z 511/513 (M+H).sup.+.

    Example 226F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1734] The methodologies described in Example 5 substituting the product of Example 226E for the product of Example 4 and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] to afford the title compound (13.6 mg, 24.5% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.27 (d, J=1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.6 Hz, 1H), 7.13 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 5.12 (t, J=6.1 Hz, 1H), 4.85-4.78 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.28 (d, J=5.2 Hz, 1H), 3.21-3.15 (m, 2H), 3.00-2.93 (m, 1H), 2.45 (s, 6H), 2.40-2.34 (m, 1H), 2.34-2.28 (m, 1H), 2.12-2.04 (m, 1H), 1.76-1.67 (m, 1H); MS (ESI) m/z 513/515 (M+H).sup.+.

    Example 227: (2R,4R)-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 326)

    Example 227A: 4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1735] To a solution of 4-oxo-6-(trifluoromethyl)-4H-chromene-2-carboxylic acid (200 mg, 0.775 mmol; prepared as described in J. Med. Chem. 2006, 49, 6569-6584.) in methanol (5 mL) was added platinum on carbon (20 mg, 1 weight % loading) and the mixture was stirred under hydrogen atmosphere (70 psi) overnight. The reaction mixture was filtered, and the filter cake was rinsed with ethanol (10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (0-100% ethyl acetate in isohexanes) to give the title compound (125 mg, 0.48 mmol, 62% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.01-7.86 (m, 2H), 7.34 (br d, J=8.6 Hz, 1H), 5.53-5.43 (m, 1H), 3.23 (br dd, J=17.1, 5.5 Hz, 1H), 3.27-3.19 (m, 1H), 3.05 (dd, J=17.1, 7.0 Hz, 1H), 3.11-2.97 (m, 1H).

    Example 227B: ()-(2R)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1736] The product of Example 227A (550 mg, 2.09 mmol) was separated by chiral SFC on a Waters SFC80 Preparative System: [column: CHIRALPAK IC 25030 mm, 10 m chiral column; mobile phase: A for CO.sub.2 and B for 2-propanol (with 0.1% isopropylamine), gradient: 20% B in A; flow rate: 50 g/minute; column temperature: 40 C.; system back pressure: 100 bar]. The later eluting fraction was concentrated and the pH was adjusted to pH=1 with aqueous HCl (1.0 M). The resulting mixture was extracted with ethyl acetate (320 mL). The organic phases were combined and washed with water (10 mL) and then brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (83 mg, 0.31 mmol, 30% yield). Specific rotation: []20 D=55.6, c 2.0 (methanol); MS (ESI.sup.+) m/z 261 (M+H).sup.+.

    Example 227C: (2R,4R)-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1737] The reaction and purification conditions described in Example 186B substituting the product of Example 272B for the product of Example 186A, and the product of Example 227B for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.29-8.22 (m, 1H), 7.90-7.83 (m, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.7, 2.4 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 5.23-5.12 (m, 1H), 4.92-4.84 (m, 1H), 4.76 (dd, J=11.9, 2.3 Hz, 1H), 4.07-3.99 and 3.86-3.79 (two m, amide rotamers, 2H), 3.71 (s, 1H), 3.68-3.61 and 3.55-3.48 (two m, amide rotamers, 1H), 2.56 (s, 6H), 2.43 (ddd, J=13.0, 5.8, 1.9 Hz, 1H), 2.36-2.08 (m, 2H), 1.83-1.71 (m, 1H); MS (APCI.sup.+) m/z 575 (M+H).sup.+.

    Example 228: (2R,4R)-6-chloro-N-(3-{4-[6-(difluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 327)

    Example 228A: tert-butyl (3-{4-[6-(difluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1738] The reaction and purification conditions described in Example 207D substituting 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Enamine) for 3-fluoro-4-(trifluoromethoxy)phenylboronic acid gave the title compound. MS (APCI.sup.+) m/z 393 (M+H).sup.+.

    Example 228B: (2R,4R)-6-chloro-N-(3-{4-[6-(difluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1739] The reaction and purification conditions described in Example 186B substituting the product of Example 228A for the product of Example 186A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.54 (dd, J=2.5, 0.7 Hz, 1H), 8.38 (d, J=0.8 Hz, 1H), 8.14 (dd, J=8.5, 2.5 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.70 (t, J=73.0 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.11 (dd, J=8.5, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.0 Hz, 1H), 4.87-4.79 (m, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 2.55 (s, 6H), 2.39 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.74 (ddd, J=12.9, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 229: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-methyl-2-(trifluoromethyl)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 328)

    [1740] 2-Methyl-2-(trifluoromethyl)pyrrolidine (10 mg, 0.066 mmol), triethylamine (0.037 mL, 0.26 mmol), and the product of Example 272A (13 mg, 0.044 mmol) were combined with N,N-dimethylformamide (0.5 mL) and stirred at ambient temperature. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 32 mg, 0.062 mmol) was added in one portion. After stirring for 1 hour, the reaction mixture was partitioned between aqueous citric acid (10 mL, 10 w/w %) and dichloromethane (220 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added trifluoroacetic acid (0.3 mL). After stirring for 10 minutes, the mixture was concentrated under high vacuum, and triethylamine (0.037 mL, 0.26 mmol), the product of Example 1B (15 mg, 0.066 mmol), N,N-dimethylformamide (0.5 mL) and PyAOP (32 mg, 0.062 mmol) were added sequentially. The resulting mixture was stirred at ambient temperature for 30 minutes, and then partitioned between water (10 mL) and dichloromethane (220 mL). The organic layers were dried over sodium sulfate, concentrated under vacuum, and taken up in methanol (1 mL). Sodium borohydride (8.3 mg, 0.22 mmol) was then added in one portion. After stirring at ambient temperature for 20 minutes, the resulting solution was filtered through a glass microfiber frit and directly purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (17 mg, 0.032 mmol, 72% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.24 (d, J=0.8 Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.82 (dd, J=10.7, 6.0 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 3.94-3.80 and 3.76-3.69 (two m, 2H, amide rotamers), 3.68-3.55 and 3.50-3.40 (two m, 2H, amide rotamers), 2.55 (s, 6H), 2.42-2.35 (m, 1H), 2.32-2.13 (m, 1H), 2.01-1.84 (m, 1H), 1.78-1.67 (m, 1H), 1.32-1.27 (m, 3H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 230: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl)-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 329)

    Example 230A: methyl 3-[4-(hydroxymethyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentane-1-carboxylate

    [1741] Iodomesitylene O1, O1-3,3-dimethyl bis(bicyclo[1.1.1]pentane-1,3-dicarboxylate) (1516 mg, 2.59 mmol; prepared as described in Nature, 2018, 559, 83-88) and (1H-pyrazol-4-yl)methanol (300 mg, 3.06 mmol, Combi-Blocks) were combined with dioxane (26 mL) in a 40 mL vial and the resulting mixture was sonicated under vacuum for 2 minutes and the vial was backfilled with argon. The mixture was further sonicated for 2 minutes until all solids were dissolved. Copper(I) thiophene-2-carboxylate (507 mg, 2.66 mmol) was added in one portion; and the reaction vial was further sonicated for 2 minutes and then stirred at ambient temperature for 50 minutes. The reaction mixture was then diluted with ethyl acetate (50 mL). The resulting solution was filtered over a pad of diatomaceous earth, and the filtrate was washed with saturated aqueous sodium bicarbonate (50 mL). The aqueous phase was further extracted with ethyl acetate (230 mL). All organic fractions were combined, washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10-100% ethyl acetate in heptanes) to give the title compound (109 mg, 0.49 mmol, 19% yield). .sup.1H NMR (600 MHz, CDCl.sub.3) ppm 7.70-7.44 (m, 2H), 4.60 (s, 2H), 3.74 (s, 3H), 2.57 (s, 6H); MS (APCI.sup.+) m/z 223 (M+H).sup.+.

    Example 2301?: 1-[3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl]-1H-pyrazole-4-carboxylic acid

    [1742] OXONE (potassium peroxomonosulfate) (281 mg, 0.46 mmol) was added to an acetonitrile (3.9 mL) solution of the product of Example 230A (85 mg, 0.39 mmol). The resulting reaction mixture was stirred at ambient temperature for 3 hours and then partitioned between aqueous HCl (1.0 M) and ethyl acetate. The organic layer was further extracted with aqueous HCl (1.0 M) for 3 times followed by brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (0-60% ethyl acetate in heptanes) to give the title compound (33 mg, 0.14 mmol, 36% yield).

    [1743] MS (APCI.sup.+) m/z 237 (M+H).sup.+.

    Example 230C: methyl 3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1H-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1744] The product of Example 230B (41 mg, 0.174 mmol), triethylamine (0.048 mL, 0.347 mmol), 3-((trifluoromethoxy)methyl)azetidine hydrochloride (40 mg, 0.208 mmol) and N,N-dimethylformamide (2 mL) were combined and stirred at ambient temperature, and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 79 mg, 0.208 mmol) was added in one portion. The resulting mixture was stirred at ambient for 30 minutes, and then at 50 C. for 10 minutes. Water (0.2 mL) was added, the resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100/6 gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (45 mg, 0.12 mmol, 69% yield). MS (APCI.sup.+) m/z 374 (M+H).sup.+.

    Example 230D: 3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1745] The product of Example 230C (42 mg, 0.113 mmol) was combined with methanol (1 mL) and aqueous NaOH (0.3 mL, 2.5 M) was added. After stirring at ambient temperature for 1 hour, the resulting mixture was partitioned between dichloromethane (210 mL) and aqueous citric acid (10 mL, 10% w/w). The organics were combined and dried over sodium sulfate and concentrated under reduced pressure to give the title compound (35 mg, 0.097 mmol, 87% yield) MS (APCI.sup.+) m/z 360 (M+H).sup.+.

    Example 230E: tert-butyl [3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1746] The reaction and purification conditions described in Example 207C substituting the product of Example 230D for the product of Example 207B gave the title compound. MS (APCI.sup.+) m/z 431 (M+H).sup.+.

    Example 230F: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1747] The reaction and purification conditions described in Example 186B substituting the product of Example 230E for the product of Example 186A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.17 (d, J=0.8 Hz, 1H), 7.79 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 4.47 (t, J=8.5 Hz, 1H), 4.30 (d, J=6.6 Hz, 2H), 4.18-4.11 (m, 1H), 4.06 (t, J=9.3 Hz, 1H), 3.74 (dd, J=9.7, 5.6 Hz, 1H), 3.09-3.00 (m, 1H), 2.54 (s, 6H), 2.38 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 1.73 (ddd, J=12.9, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 541 (M+H).sup.+.

    Example 231: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 330)

    Example 231A: methyl 3-[4-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentane-1-carboxylate

    [1748] Zinc powder (preactivated with 1 M aqueous HCl) (1.531 g, 23.42 mmol) was suspended in anhydrous tetrahydrofuran (3.5 mL) under a nitrogen atmosphere and heated to 65 C. Diiodine (3.0 mg, 0.012 mmol) was added, and the mixture stirred for 5 minutes at 65 C. Then 1,2-dibromoethane (0.158 mL, 1.838 mmol) was added at 65 C., and the mixture was stirred for 5 minutes. Chlorotrimethylsilane (0.226 mL, 1.768 mmol) was then added. The mixture was stirred for 5 minutes at 65 C. and then a solution of 2-bromo-5,8-dioxaspiro[3.4]octane (2.26 g, 11.71 mmol) in N,N-dimethylacetamide (3.5 mL) was added. The reaction mixture was stirred at 65 C. overnight. Stirring was stopped and the solid material was left to settle at room temperature. The solution, decanted from the previous reaction mixture, was slowly added to a solution of CPhos (24.16 mg, 0.055 mmol), CPhos Pd G4 (45.4 mg, 0.055 mmol) and the product of Example 207A (500 mg, 1.844 mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was stirred at 50 C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-50% ethyl acetate/isohexane) to afford the title compound (309 mg, 48.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.67 (s, 1H), 7.40 (s, 1H), 3.89-3.83 (m, 2H), 3.81-3.77 (m, 2H), 3.66 (s, 3H), 3.13-3.03 (m, 1H), 2.63-2.53 (m, 2H), 2.46 (s, 6H), 2.29-2.20 (m, 2H); MS (ESI) m/z 305 (M+H).sup.+.

    Example 231B: methyl 3-[4-(3-oxocyclobutyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentane-1-carboxylate

    [1749] To the product of Example 231A (394 mg, 1.295 mmol) in a mixture of dioxane (3.5 mL) and water (3.5 mL) was added pyridinium p-toluenesulfonate (1627 mg, 6.47 mmol) and the reaction mixture was stirred at 85 C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (320 mL). The organic layer was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (164 mg, 46.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.81 (d, J=1.0 Hz, 1H), 7.50 (s, 1H), 3.67 (s, 3H), 3.55-3.46 (m, 1H), 3.46-3.37 (m, 2H), 3.13-3.03 (m, 2H), 2.47 (s, 6H); MS (ESI) m/z 261 (M+H).sup.+.

    Example 231C: methyl 3-{4-[cis-3-hydroxycyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1750] To a stirred solution of the product of Example 231B (188 mg, 0.722 mmol) in anhydrous tetrahydrofuran (4.0 mL), at 78 C. under a nitrogen atmosphere, was slowly added lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (1.445 mL, 1.445 mmol, 1.0 M) slowly and the resultant reaction mixture was stirred for 2 hours at this temperature. The reaction mixture was quenched with 1 M aqueous HCl (10 mL) and extracted with dichloromethane (310 mL). The combined organic fractions were dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.59 (s, 1H), 7.34 (s, 1H), 5.02 (d, J=6.8 Hz, 1H), 4.01-3.90 (m, 1H), 3.66 (s, 3H), 3.42-3.34 (m, 1H), 2.74-2.64 (m, 1H), 2.57-2.52 (m, 1H), 2.45 (s, 6H), 1.82-1.76 (m, 2H); MS (ESI) m/z 263 (M+H).sup.+.

    Example 231D: methyl 3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1751] A mixture of silver(1) trifluoromethanesulfonate (521 mg, 2.028 mmol), potassium fluoride (175 mg, 3.00 mmol), and Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (399 mg, 1.127 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To the mixture was slowly added a solution of the product of Example 231C (197 mg, 0.751 mmol) in ethyl acetate (8 mL) followed by slow addition of 2-fluoropyridine (0.194 mL, 2.253 mmol) and then trimethyl(trifluoromethyl)silane (0.333 mL, 2.253 mmol). The reaction mixture was stirred at ambient temperature overnight and then filtered through a pad of diatomaceous earth, washed with ethyl acetate (10 mL). The filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel (0-50% ethyl acetate/isohexane) to afford the title compound (117 mg, 44.8% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.46 (s, 1H), 7.30 (s, 1H), 4.61 (p, J=7.4 Hz, 1H), 3.77 (s, 3H), 3.02-2.91 (m, 1H), 2.84-2.75 (m, 2H), 2.59 (s, 6H), 2.31-2.21 (m, 2H); MS (ESI) m/z 331 (M+H).sup.+.

    Example 231E: potassium 3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1752] To a solution of the product of Example 231D (117 mg, 0.354 mmol) in tetrahydrofuran (3 mL) under a nitrogen atmosphere was added potassium trimethylsilanolate (91 mg, 0.708 mmol) and the reaction mixture was stirred at ambient temperature for 1.5 hours. After this time, the solvent was removed under reduced pressure to give the title compound (144 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.64 (s, 1H), 7.35 (s, 1H), 4.73 (p, J=7.4 Hz, 1H), 2.97-2.86 (m, 1H), 2.73-2.64 (m, 2H), 2.21-2.11 (m, 2H), 2.04 (s, 6H); MS (ESI) m/z 317 (M+H).sup.+.

    Example 231F: 2-(trimethylsilyl)ethyl (3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1753] At room temperature and under a nitrogen atmosphere, diphenyl phosphorazidate (0.094 mL, 0.434 mmol) was added to a solution of the product of Example 231E (114 mg, 0.290 mmol), N-ethyl-N-isopropylpropan-2-amine (0.303 mL, 1.737 mmol) and 2-(trimethylsilyl)ethanol (0.830 mL, 5.79 mmol) in toluene (3.0 mL). The reaction mixture was stirred at 58 C. for 5 hours. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (55 mg, 40.4% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.94 (s, 1H), 7.71 (s, 1H), 7.41 (d, J=0.9 Hz, 1H), 4.74 (p, J=7.6 Hz, 1H), 4.05 (t, J=8.4 Hz, 2H), 2.98-2.87 (m, 1H), 2.74-2.65 (m, 2H), 2.35 (s, 6H), 2.20-2.12 (m, 2H), 1.02-0.86 (m, 2H), 0.06 (s, 9H); MS (ESI) m/z 432 (M+H).sup.+.

    Example 231G: 3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1754] To a solution of the product of Example 231F (54 mg, 0.125 mmol) in dichloromethane (1.0 mL) at ambient temperature was added trifluoroacetic acid (0.578 mL, 7.51 mmol) and the reaction mixture was stirred for 40 minutes. The volatiles were removed in vacuo. The residue was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (31 mg, 86.0% yield). MS (ESI) m/z 288 (M+H).sup.+.

    Example 231H: (2R)-6-chloro-4-oxo-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1755] To a solution of the product of Example 231G (30 mg, 0.104 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (35.5 mg, 0.157 mmol, Example 1B) and triethylamine (0.087 mL, 0.627 mmol) in N,N-dimethylformamide (1.0 mL), at ambient temperature under a nitrogen atmosphere, was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 59.6 mg, 0.157 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL) and the aqueous phase was extracted with dichloromethane (22 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (60.9 mg, 100% yield). MS (ESI) m/z 496/498 (M+H).sup.+.

    Example 231I: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1756] The methodologies described in Example 5 substituting the product of Example 231H for the product of Example 4 and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.1% ammonia in water)] to afford the title compound (34 mg, 64.1% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.74 (s, 1H), 7.42 (s, 1H), 7.41-7.37 (m, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.86-4.80 (m, 1H), 4.75 (p, J=7.4 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 2.99-2.88 (m, 1H), 2.75-2.66 (m, 2H), 2.48 (s, 6H), 2.42-2.34 (m, 1H), 2.22-2.13 (m, 2H), 1.78-1.67 (m, 1H); MS (ESI) m/z 498/500 (M+H).sup.+.

    Example 232: (2R,4R)-6-chloro-4-hydroxy-N-(4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 331)

    Example 232A: tert-butyl 1-[4-(methoxycarbonyl)bicyclo[2.2.2]octan-1-yl]-1H-pyrazole-4-carboxylate

    [1757] Iodomesitylene O.sup.1,O.sup.1-4,4-dimethyl bis(bicyclo[2.2.2]octane-1,4-dicarboxylate) (3.2 g, 4.79 mmol; prepared as described in in Nature, 2018, 559, 83-88), tert-butyl 1H-pyrazole-4-carboxylate (1.08 g, 6.42 mmol), and copper(I) thiophene-2-carboxylate (0.55 g, 2.88 mmol) were combined in a 200 mL flask, and dioxane (150 mL) was added in one portion. The resulting mixture was immediately sonicated under vacuum for 5 minutes and then refilled with nitrogen, and stirred at ambient temperature for 18 hours. The reaction was quenched by exposing to air and partitioned between water (50 mL), aqueous saturated sodium bicarbonate (50 mL), and dichloromethane (3100 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (25 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 20 m column, 50150 mm, flow rate 120 mL/minute, 10-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (177 mg, 0.529 mmol, 11% yield). MS (APCI.sup.+) m/z 335 (M+H).sup.+.

    Example 232B: methyl 4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[2.2.2]octane-1-carboxylate

    [1758] The product of Example 232A (94 mg, 0.28 mmol) was combined with trifluoroacetic acid (1.0 mL) and stirred at ambient temperature for 30 minutes and then concentrated under reduced pressure. To the residue was added triethylamine (0.157 mL, 1.12 mmol), (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride (70 mg, 0.365 mmol), N,N-dimethylformamide (1 mL) and 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 205 mg, 0.394 mmol) in sequential order. The resulting mixture was stirred at ambient temperature for 18 hours. Water (0.1 mL) was added, and the resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (64 mg, 0.154 mmol, 55% yield). MS (APCI.sup.+) m/z 416 (M+H).sup.+.

    Example 232C: 4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[2.2.2]octane-1-carboxylic acid

    [1759] Aqueous NaOH solution (0.3 mL, 2.5 M) was added to a mixture of the product of Example 232B (62 mg, 0.149 mmol) in methanol (1 mL). The resulting mixture was stirred at 80 C. for 45 minutes, cooled, and then partitioned between dichloromethane (350 mL) and an aqueous solution of citric acid (30 mL, 10% w/w). The organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (60 mg, 0.149 mmol, 100% yield). MS (APCI.sup.+) m/z 402 (M+H).sup.+.

    Example 232D: 2-(trimethylsilyl)ethyl (4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[2.2.2]octan-1-yl)carbamate

    [1760] The product of Example 232C (59 mg, 0.147 mmol) was azeotroped 3 times with dry toluene. Hunig's base (0.128 mL, 0.735 mmol), 2-(trimethylsilyl)ethanol (0.42 mL) and toluene (5 mL) were added followed by diphenylphosphoryl azide (0.048 mL, 0.22 mmol). Dry nitrogen was bubbled through the reaction mixture for 2-3 minutes, and the resulting mixture was stirred at 70 C. for 18 hours. The reaction was cooled and then concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (18 mg, 0.035 mmol, 24% yield). MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 232E: (2R,4R)-6-chloro-4-hydroxy-N-(4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1H-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1761] The reaction and purification conditions described in Example 186B substituting the product of Example 232D for the product of Example 186A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.17-8.11 (m, 1H), 7.87-7.77 (m, 1H), 7.46 (s, 1H), 7.38 (dd, J=2.8, 1.0 Hz, 1H), 7.19 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.68 (s, 1H), 5.21-5.12 (m, 1H), 4.79 (dd, J=10.7, 6.0 Hz, 1H), 4.58 (dd, J=11.8, 2.3 Hz, 1H), 4.05-4.00 and 3.85-3.78 (two m, amide rotamers, 2H), 3.70 (s, 1H), 3.66-3.61 and 3.53-3.46 (two m, amide rotamers, 1H), 2.32-2.15 (m, 3H), 2.13 (dd, J=11.0, 4.5 Hz, 6H), 2.10-2.04 (m, 6H), 1.76 (ddd, J=12.9, 11.7, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 583 (M+H).sup.+.

    Example 233: (2S,4R)-6-chloro-N-(3-{4-[6-(difluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 332)

    [1762] The reaction and purification conditions described in Example 1C substituting the product of Example 228A for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.54 (dd, J=2.5, 0.8 Hz, 1H), 8.37 (d, J=0.8 Hz, 1H), 8.14 (dd, J=8.5, 2.5 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.69 (t, J=73.1 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 7.11 (dd, J=8.5, 0.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.64 (d, J=4.5 Hz, 1H), 4.64-4.58 (m, 2H), 2.55 (s, 6H), 2.13 (ddd, J=13.9, 3.7, 2.8 Hz, 1H), 1.93 (ddd, J=14.3, 11.0, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 503 (M+H).sup.+.

    Example 234: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-2-[3-(trifluoromethoxy)azetidin-1-yl]ethoxy}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 333)

    Example 234A: 3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentane-1-carboxylic acid

    [1763] To a solution of methyl 3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentane-1-carboxylate (30 g, 124 mmol) in methanol (100 mL) and tetrahydrofuran (200 mL) was added a solution of NaOH (8.95 g, 224 mmol) in water (200 mL) at 0 C. Then the mixture was stirred for 2 hours at 20 C. The mixture was concentrated, and the residue was dissolved in water (800 mL). The mixture was acidified with concentrated hydrochloric acid to pH=3 and extracted with ethyl acetate (3300 mL). The organic phase was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (25 g, yield 89%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.08 (s, 6H), 1.37 (s, 9H).

    Example 234B: tert-butyl {3-[methoxy(methyl)carbamoyl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1764] To a solution of the product of Example 234A (12 g, 53 mmol) in N,N-dimethylformamide (100 mL) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 27.1 g, 71.3 mmol) and N-ethyl-N-isopropylpropan-2-amine (24.57 g, 190 mmol) at 25 C. Then N,O-dimethylhydroxylamine hydrochloride (9.27 g, 95 mmol) was added to this mixture at 0 C. The mixture was stirred at 25 C. for 12 hours. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3500 mL). The combined organic layers were washed with brine (3500 mL), dried over Na.sub.2SO.sub.4. and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1 to 3:2) to give the title compound (12 g, yield 84%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 5.04 (brs, 1H), 3.63 (s, 3H), 3.15 (s, 3H), 2.31 (brs, 6H), 1.35-1.49 (m, 9H).

    Example 234C: tert-butyl (3-acetylbicyclo[1.1.1]/pentan-1-yl)carbamate

    [1765] To a solution of the product of Example 234B (6 g, 22 mmol) in tetrahydrofuran (400 mL) was added methylmagnesium bromide (26.6 mL, 80 mmol, 3 M in diethyl ether) dropwise at 78 C. under nitrogen. Then the mixture was stirred for 2 hours at 0 C. to 20 C. The reaction was quenched with aqueous NH.sub.4Cl, and the mixture was extracted with ethyl acetate (2500 mL). The combined organic phases were dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (5 g, yield 100%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.98 (brs, 1H), 2.18-2.33 (m, 6H), 2.12 (s, 3H), 1.36-1.48 (m, 9H).

    Example 234D: 3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentan-1-yl acetate

    [1766] To a solution of the product of Example 234C (4 g, 17.8 mmol) in chloroform (500 mL) was added sodium bicarbonate (3.58 g, 42.6 mmol) and 3-chlorobenzoperoxoic acid (8.65 g, 42.6 mmol) at 20 C. Then the mixture was stirred at 60 C. for 12 hours. After cooling to 25 C., the resulting mixture was filtered, and the filtrate was washed with 10% aqueous NaHCO.sub.3. The organic phase was dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 10:1) to give the title compound (1.7 g, yield 40%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.29-2.38 (m, 6H), 1.97 (s, 3H), 1.38 (s, 9H).

    Example 234E: tert-butyl (3-hydroxybicyclo[1.1.1]pentan-1-yl)carbamate

    [1767] To a solution of the product of Example 234D (5.5 g, 22.8 mmol) in tetrahydrofuran (300 mL) was added LiAlH.sub.4 (1.384 g, 36.5 mmol) in portions at 0 C. Then the mixture was stirred for 10 minutes at 0 C. One additional vial was set up as described above. The two reactions were quenched with aqueous NH.sub.4Cl slowly at 0 C., respectively, and combined. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (3500 mL). The combined organic phases were dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1 to 3:1) to give the title compound (6.7 g, yield 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.38 (brs, 1H), 6.04-6.11 (m, 1H), 1.82-1.92 (m, 6H), 1.33 (s, 9H).

    Example 234F: (2R)-6-chloro-N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1768] To a solution of the product of Example 234E (0.7 g, 3.51 mmol) in dichloromethane (15 mL), 2,2,2-trifluoroacetic acid (13.53 mL, 176 mmol) was added at 0 C., and the mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under high vacuum to give 3-aminobicyclo[1.1.1]pentan-1-ol as a trifluoroacetate (0.74 g). To a mixture of this 3 -aminobicyclo[1.1.1]pentan-1-ol, trifluoroacetate, the product of Example 1B (0.995 g, 4.39 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.454 mL, 14.05 mmol) in N,N-dimethylformamide (15.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (2.004 g, 5.27 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. After volatiles were removed under high vacuum, the residue was dissolved in tetrahydrofuran (7.5 mL) and treated with 1 N lithium hydroxide (8.78 mL, 8.78 mmol) for 1 hour. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give the title compound (0.97 g). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.82 (s, 1H), 7.66-7.60 (m, 2H), 7.16 (dd, J=8.7, 0.5 Hz, 1H), 6.22 (s, 1H), 5.07 (dd, J=8.3, 5.8 Hz, 1H), 2.98-2.88 (m, 2H), 2.03 (s, 6H).

    Example 234G: (2R)-6chloro-4-oxo-N-{3-[(prop-2-en-1-yl)oxy]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1769] To a mixture of the product of Example 234F (0.97 g, 3.15 mmol), 2,6-di-tert-butylpyridine (1.704 mL, 7.88 mmol), and silver trifluoromethanesulfonate (1.620 g, 6.30 mmol) in dichloromethane (30 mL) was added 3-bromoprop-1-ene (1.098 mL, 12.61 mmol). The resulting suspension was stirred at ambient temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified on a silica column (40 g) using a Biotage Isolera One flash system eluted with 0-50% ethyl acetate/heptane to give the title compound (400 mg). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.68-7.59 (m, 2H), 7.16 (dd, J=8.5, 0.8 Hz, 1H), 5.88 (ddt, J=17.3, 10.5, 5.3 Hz, 1H), 5.25 (dq, J=17.3, 1.8 Hz, 1H), 5.17-5.05 (m, 2H), 3.95 (dt, J=5.3, 1.6 Hz, 2H), 2.98-2.91 (m, 2H), 2.12 (s, 6H).

    Example 234H: [(3-{[(2R)-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)oxy]acetic acid

    [1770] To a mixture of the product of Example 234G (100 mg, 0.288 mmol) in ethyl acetate/acetonitrile/water (1:1:1.5, 3.5 mL) was added sodium periodate (400 mg, 1.869 mmol) followed by ruthenium(III) chloride hydrate (1.296 mg, 5.75 mol), and the dark solution turned into a milky suspension. After 30 minutes, the suspension was filtered and the filtrate was concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesioum sulfate, and filtered. The filtrate was concentrated to give the title compound (102 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.69 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.21 (td, J=6.7, 3.4 Hz, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.64-4.54 (m, 2H), 4.28 (td, J=7.2, 3.7 Hz, 2H), 3.99 (s, 2H), 3.97-3.90 (m, 1H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.15 (s, 6H), 1.69 (td, J=12.6, 10.8 Hz, 1H).

    Example 234I: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-2-[3-(trifluoromethoxy)azetidin-1-yl]ethoxy}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1771] To a mixture of the product of Example 234H (33 mg, 0.090 mmol), 3-(trifluoromethoxy)azetidine, hydrochloric acid (20.02 mg, 0.113 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.047 mL, 0.271 mmol) in N,N-dimethylformamide (1.0 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (51.5 mg, 0.135 mmol) was added. After 30 minutes, the reaction was complete. Volatiles were removed under high vacuum. The crude (2R)-6-chloro-4-oxo-N-(3-{2-oxo-2-[3-(trifluoromethoxy)azetidin-1-yl]ethoxy}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide was dissolved in methanol (1 mL) and treated with sodium tetrahydroborate (51.2 mg, 1.353 mmol) for 15 minutes at ambient temperature. Volatiles were removed again, and the resultant residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm 50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) to give the title compound (34 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.69 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.21 (td, J=6.7, 3.4 Hz, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.64-4.54 (m, 2H), 4.28 (td, J=7.2, 3.7 Hz, 2H), 3.99 (s, 2H), 3.97-3.90 (m, 1H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.15 (s, 6H), 1.69 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 473.53 (M+HH.sub.2O).sup.+.

    Example 235: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-oxo-2-[3-(trifluoromethoxy)pyrrolidin-1-yl]ethoxy}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 334)

    [1772] The title compound was synthesized using the same procedures as described in Example 234I substituting 3-(trifluoromethoxy)azetidine, hydrochloric acid with 3-(trifluoromethoxy)pyrrolidine, hydrochloric acid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.67 (s, 1H), 7.38 (dd, J=2.8, 1.0 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.16 (dp, J=4.5, 2.3 Hz, 1H), 5.10 (tt, J=4.2, 2.1 Hz, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.60 (dd, J=12.0, 2.3 Hz, 1H), 4.16-4.03 (m, 2H), 3.77-3.70 (m, 1H), 3.70-3.61 (m, 1H), 3.61-3.47 (m, 3H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.24-2.18 (m, 1H), 2.14 (s, 6H), 2.09 (ddd, J=15.1, 7.8, 4.0 Hz, 1H), 1.69 (td, J=12.6, 10.9 Hz, 1H); MS (APCI.sup.+) m/z 487.30 (M+HH.sub.2O).sup.+.

    Example 236: (2R,4R)-6-chloro-4-hydroxy-N-[3-(2-oxo-2-{3-[(trifluoromethoxy)methyl]azetidin-1-yl}ethoxy)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 335)

    [1773] The title compound was synthesized using the same procedures as described in Example 234I substituting 3-(trifluoromethoxy)azetidine, hydrochloric acid with 3-((trifluoromethoxy)methyl)azetidine, hydrochloric acid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.68 (s, 1H), 7.38 (dd, J=2.8, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.83-4.77 (m, 1H), 4.60 (dd, J=12.0, 2.2 Hz, 1H), 4.27 (d, J=6.6 Hz, 3H), 3.95 (dd, J=9.1, 1.8 Hz, 4H), 3.64 (dd, J=9.9, 5.5 Hz, 1H), 2.99 (tt, J=8.5, 6.0 Hz, 1H), 2.34 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.14 (s, 6H), 1.69 (ddd, J=13.0, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 505.49 (M+H).sup.+.

    Example 237: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 336)

    Example 237A: tert-butyl [3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1774] The product of Example 207C (60 mg, 0.165 mmol), the product of Example 298B (37.2 mg, 0.181 mmol) and cesium carbonate (214 mg, 0.658 mmol) in anhydrous tetrahydrofuran (1.0 mL) was degassed for 10 minutes, and then tBuBrettPhos Pd G3 (7.03 mg, 8.23 mol) was added with further degassing for 10 minutes. The reaction mixture was heated at 65 C. for 3 hours. The reaction mixture was degassed for 5 minutes under sonication. Additional tBuBrettPhos Pd G3 (7.03 mg, 8.23 mol) was added, and the mixture was further degassed for 5 minutes. The reaction mixture was stirred at 65 C. for 2 days. The reaction mixture was diluted with methanol (5.0 mL) and the resulting suspension filtered through a pad of diatomaceous earth washed with methanol (5.0 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% [0.7 M ammonia in methanol]/dichloromethane) to afford the title compound (40 mg, 34.4% yield).

    [1775] MS (ESI) m/z 417 (M+H).sup.+.

    Example 237B: 3-(4-{(3)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1776] To a solution of the product of Example 237A (40 mg, 0.096 mmol) in dichloromethane (2.0 mL) at ambient temperature was added trifluoroacetic acid (0.444 mL, 5.76 mmol) and the reaction mixture was stirred for 30 minutes. The reaction mixture was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (21 mg, 33.2% yield). MS (ESI) m/z 317 (M+H).sup.+.

    Example 237C: (2R)-6-chloro-4-oxo-N-[3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1777] To a solution of the product of Example 237B (21 mg, 0.066 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (18.05 mg, 0.080 mmol, Example 1B) and triethylamine (0.056 mL, 0.398 mmol) in dichloromethane (1.5 mL), at ambient temperature under nitrogen, was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 37.9 mg, 0.100 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL) and the aqueous phase was extracted with dichloromethane (32.0 mL). The combined organic phases were then passed through a hydrophobic phase separator, washed with brine (2.0 mL), passed through a hydrophobic phase separator, and concentrated in vacuo. The crude material was purified twice by flash chromatography on silica gel (0-10% methanol/dichloromethane then 0-100% ethyl acetate/isohexane) to afford the title compound (11 mg, 21.2% yield). MS (ESI) m/z 525/527 (M+H).sup.+.

    Example 237D: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1778] The methodologies described in Example 5 substituting the product of Example 237C for the product of Example 4 and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] to afford the title compound (6.7 mg, 57.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.09 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.76 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.12-4.00 (m, 2H), 3.13-3.07 (m, 1H), 3.07-3.00 (m, 1H), 3.00-2.92 (m, 1H), 2.84-2.77 (m, 1H), 2.70-2.59 (m, 1H), 2.45 (s, 6H), 2.41-2.34 (m, 1H), 2.10-1.97 (m, 1H), 1.77-1.68 (m, 1H), 1.68-1.59 (m, 1H); MS (ESI) m/z 527/529 (M+H).sup.+.

    Example 238: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 337)

    Example 238A: tert-butyl 3-[(trifluoromethoxy)methyl]azetidine-1-carboxylate

    [1779] The title compound was prepared using the methods described for the synthesis of Example 273E, substituting tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate for the product from Example 273D. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 4.21 (d, J=6.3 Hz, 2H), 4.05 (t, J=8.5 Hz, 2H), 3.74 (t, J=8.8, 5.6 Hz, 2H), 3.03-2.89 (m, 1H), 1.48-1.43 (m, 9H).

    Example 238B: 3-[(trifluoromethoxy)methyl]azetidine, trifluoroacetic acid

    [1780] The product from Example 238A (426 mg, 1.669 mmol) in dichloromethane (16 mL) was mixed with 2,2,2-trifluoroacetic acid (2.55 mL, 33.4 mmol) under cooling with ice and then stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in toluene (5 mL) and concentrated in vacuo (3) to give the title compound (562 mg, 1.67 mmol, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.79 (d, J=45.2 Hz, 2H), 4.28 (d, J=6.3 Hz, 2H), 4.07-4.00 (m, 2H), 3.82-3.76 (m, 2H), 3.23-3.12 (m, 1H).

    Example 238C: methyl 3-(4-{3-[(trifluoromethoxy)methyl]azetidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1781] The title compound was prepared using the methods described for Example 253C, substituting the product from Example 238B for the product from Example 253B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.23 (d, J=0.9 Hz, 1H), 7.03 (d, J=0.9 Hz, 1H), 4.28 (d, J=6.8 Hz, 2H), 3.72 (t, J=7.4 Hz, 2H), 3.66 (s, 3H), 3.40 (dd, J=7.1, 5.7 Hz, 2H), 3.03-2.96 (m, 1H), 2.43 (s, 6H).

    Example 238D: 2-(trimethylsilyl)ethyl [3-(4-{3-[(trifluoromethoxy)methyl]azetidin-1-yl}-1H-pyrazol-1-yl)bibicyclo[1.1.1]pentan-1-yl]carbamate

    [1782] The title compound was prepared using the methods described for the conversion of Example 253C to Example 253E, substituting the product from Example 238C for the product from Example 253C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.92 (s, 1H), 7.19 (d, J=0.9 Hz, 1H), 7.01 (d, J=0.9 Hz, 1H), 4.28 (d, J=6.9 Hz, 2H), 4.05 (t, J=8.4 Hz, 2H), 3.71 (t, J=7.4 Hz, 2H), 3.40 (t, J=6.3 Hz, 2H), 3.03-2.96 (m, 1H), 2.32 (s, 6H), 1.03-0.85 (m, 2H), 0.06 (s, 9H).

    Example 238E: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1783] The title compound was prepared using the methods described for the synthesis of Example 244B, substituting the product from Example 238D for the product from Example 244A. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.46-7.43 (m, 1H), 7.23 (s, 1H), 7.19-7.15 (m, 2H), 6.94 (d, J=8.7 Hz, 1H), 4.93 (dd, J=10.4, 5.9 Hz, 1H), 4.65 (dd, J=11.6, 2.4 Hz, 1H), 4.26 (d, J=6.8 Hz, 2H), 3.85 (t, J=7.6 Hz, 2H), 3.60-3.52 (m, 2H), 3.12-3.01 (m, 1H), 2.65-2.50 (m, 7H), 1.96-1.84 (m, 1H); MS (ESI) m/z 513.3 (M+H).sup.+.

    Example 239: (2S,4S)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 338)

    Example 239A: (+)-(2S)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1784] SFC purification in Example 227B also provided this title compound as the earlier eluting fraction which was processed the same way as described in Example 227B. Specific Rotation: []20 D=+53.0, c 0.35 (methanol); MS (ESI.sup.+) m/z 261 (M+H).sup.+.

    Example 239B: (2S,4S)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1785] The reaction and purification conditions described in Example 186B substituting the product of Example 247A for the product of Example 186A, and the product of Example 239A for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.60-8.56 (m, 1H), 8.46 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.92-7.87 (m, 1H), 7.87-7.83 (m, 1H), 7.75-7.71 (m, 1H), 7.57-7.51 (m, 1H), 7.07 (d, J=8.6 Hz, 1H), 5.83 (s, 1H), 4.89 (dd, J=10.7, 5.8 Hz, 1H), 4.77 (dd, J=11.9, 2.4 Hz, 1H), 2.58 (s, 6H), 2.43 (ddd, J=12.9, 5.8, 2.5 Hz, 1H), 1.78 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 555 (M+H).sup.+.

    Example 240: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 339)

    Example 240A: tert-butyl [3-(4-{[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1786] The product of Example 272B (26 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL) and stirred at ambient temperature. Alane N,N-dimethylethylamine complex (0.48 mL, 0.5 M in toluene) was added in one portion. After stirring at ambient temperature for 30 minutes, water (0.2 mL) was carefully added dropwise, and the resulting mixture was concentrated under vacuum to dryness. The residue was taken up in a solvent mixture of N,N-dimethylformamide (2 mL)/methanol (1 mL)/H.sub.2O(0.5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (16.5 mg, 0.040 mmol, 66% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.72 (br s, 1H), 7.63 (d, J=0.8 Hz, 1H), 7.37 (d, J=0.8 Hz, 1H), 4.94-4.88 (m, 1H), 3.49-3.42 (m, 2H), 2.71-2.63 (m, 3H), 2.34 (s, 6H), 2.30 (ddd, J=8.9, 7.9, 6.4 Hz, 1H), 2.26-2.18 (m, 1H), 1.87-1.79 (m, 1H), 1.39 (s, 9H); MS (APCI.sup.+) m/z 417 (M+H).sup.+.

    Example 240B: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1787] The reaction and purification conditions described in Example 186B substituting the product of Example 240A for the product of Example 186A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.68 (s, 1H), 7.40-7.36 (m, 2H), 7.21 (dd, J=8.7, 2.6 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.96-4.87 (m, 1H), 4.82 (dd, J=10.7, 5.8 Hz, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 3.56-3.41 (m, 2H), 2.73-2.64 (m, 3H), 2.49 (s, 6H), 2.38 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 2.34-2.27 (m, 1H), 2.27-2.17 (m, 1H), 1.89-1.79 (m, 1H), 1.78-1.66 (m, 1H); MS (APCI.sup.+) m/z 527 (M+H).sup.+.

    Example 241: (2R,4R)N-{3-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 340)

    Example 241A: tert-butyl {3-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1788] The reaction and purification conditions described in Example 207D substituting 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (Advanced ChemBlocks) for 3-fluoro-4-(trifluoromethoxy)phenylboronic acid gave the title compound. MS (APCI.sup.+) m/z 373 (M+H).sup.+.

    Example 241B: (2R,4R)N-{3-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1789] The reaction and purification conditions described in Example 186B substituting the product of Example 240A for the product of Example 186A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.66 (dd, J=12.6, 0.8 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (ddd, J=8.8, 2.8, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.00-5.96 (m, 1H), 5.72 (s, 1H), 4.82 (dd, J=10.6, 6.0 Hz, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 4.08-4.04 (m, 1H), 4.03-3.99 (m, 1H), 3.59 (dt, J=18.7, 5.8 Hz, 2H), 2.50 (s, 6H), 2.42-2.35 (m, 2H), 2.32-2.29 (m, 1H), 2.05 and 2.02 (two s, 3H amide rotamers), 2.02 (s, 2H), 1.77-1.68 (m, 1H); MS (APCI.sup.+) m/z 483 (M+H).sup.+.

    Example 242: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)azetidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 341)

    [1790] The reaction and purification conditions described in Examples 272B through 272C substituting 3-(trifluoromethoxy)azetidine hydrochloride for (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride in Example 272B gave the title compound. .sup.1H NMR (600 MHz, DMSO-dh) 6 ppm 7.85 (d, J=0.7 Hz, 1H), 7.69 (d, J=0.7 Hz, 1H), 7.45 (dd, J=2.5, 0.9 Hz, 1H), 7.19 (ddd, J=8.7, 2.6, 0.6 Hz, 1H), 7.05 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.04 (tt, J=6.8, 4.2 Hz, 1H), 4.95 (s, 1H), 4.64 (dd, J=9.7, 3.2 Hz, 1H), 4.62-4.21 (m, 4H), 2.73-2.64 (m, 7H), 2.26-2.20 (m, 1H), 2.19-2.09 (m, 1H); MS (APCI.sup.+) m/z 527 (M+H).sup.+.

    Example 243: (2R,4R)-6-chloro-4-hydroxy-N-[3-(2-oxo-2-{[cis-3-(trifluoromethoxy)cyclobutyl]amino}ethoxy)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 342)

    [1791] The title compound was synthesized using the same procedures as described in Example 234I substituting 3-(trifluoromethoxy)azetidine, hydrochloric acid with cis-3-(trifluoromethoxy)cyclobutanamine, hydrochloric acid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.69 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 4.80 (dd, J=10.7, 5.9 Hz, 1H), 4.64-4.50 (m, 2H), 4.06-3.93 (m, 1H), 3.85 (s, 2H), 2.63 (dtd, J=9.8, 7.1, 2.9 Hz, 2H), 2.39-2.25 (m, 3H), 2.16 (s, 6H), 1.69 (ddd, J=12.8, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 487.33 (M+HH.sub.2O).sup.+.

    Example 244: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-2-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 343)

    Example 244A: tert-buty {3-[4-(4-chloro-2-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1792] To a solution of 4-chloro-2-fluorobenzaldehyde (500 mg, 3.15 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (616 mg, 3.15 mmol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.048 mL, 0.315 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to afford 5-(4-chloro-2-fluorophenyl)-4-(4-methylbenzene-1-sulfonyl)-4,5-dihydro-1,3-oxazole (1.86 g, 3.15 mmol). A portion of the 5-(4-chloro-2-fluorophenyl)-4-(4-methylbenzene-1-sulfonyl)-4,5-dihydro-1,3-oxazole (0.93 g, 1.58 mmol) was combined with tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.47 g, 2.37 mmol) and xylene (16 mL), and the resulting mixture was heated at 135 C. and stirred for 3 days. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (0.34 g, 45%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.06-8.01 (m, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.55 (d, J=4.0, 1.3 Hz, 1H), 7.47 (dd, J=11.1, 2.1 Hz, 1H), 7.32 (dd, J=8.5, 2.1 Hz, 1H), 2.42 (s, 6H), 1.40 (s, 9H).

    Example 244B: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-2-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1793] To a solution of the product from Example 244A (246 mg, 0.651 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL, 26.0 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo, and the residue was dissolved in toluene and concentrated in vacuo (22 mL) to give 3-[4-(4-chloro-2-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-amine (192 mg, 0.651 mmol). A portion of the 3-[4-(4-chloro-2-fluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-amine (60 mg, 0.146 mmol) was combined with the product from Example 1B (50 mg, 0.22 mmol) and triethylamine (0.12 mL, 0.88 mmol) in N,N-dimethylformamide (1 mL), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 84 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature for >2 hours, and the reaction mixture was partitioned between saturated aqueous NaHCO.sub.3 (2.5 mL) and dichloromethane (32 mL). The organic layers were combined, passed through a hydrophobic phase separator, and concentrated in vacuo. The residue was dissolved in methanol (1 mL), and sodium borohydride (70 mg, 1.85 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, and the reaction was partitioned between saturated aqueous NH.sub.4Cl (0.25 mL) and dichloromethane. The volatiles were removed in vacuo, and the residue was purified by C18 HPLC using a solvent gradient of 0-100% acetonitrile in aqueous buffer (0.1% ammonia in water). Solvent was removed by lyophilization to afford the title compound (10.5 mg, 0.020 mmol, 13% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.05 (t, J=8.4 Hz, 1H), 7.90-7.84 (m, 1H), 7.59 (dd, J=4.0, 1.3 Hz, 1H), 7.47 (dd, J=11.1, 2.1 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.32 (dd, J=8.5, 2.1 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.87-4.77 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.57 (s, 6H), 2.41-2.34 (m, 1H), 1.78-1.67 (m, 1H); MS (ESI) m/z 488.2 (M+H).sup.+.

    Example 245: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-2,6-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 344)

    Example 245A: tert-butyl {3-[4-(4-chloro-2,6-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1794] The title compound was prepared using the methods described for the synthesis of Example 244A, substituting 4-chloro-2,6-difluorobenzaldehyde for 4-chloro-2-fluorobenzaldehyde. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.14 (t, J=8.7 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.81-7.72 (m, 1H), 7.58 (dd, J=3.9, 1.3 Hz, 1H), 7.44 (d, J=11.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 2.43 (s, 6H), 1.41 (s, 9H).

    Example 245B: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-2,6-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1795] The title compound was prepared using the methods described for the synthesis of Example 244B, substituting the product from Example 245A for the product from Example 244A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 7.88 (d, J=1.3 Hz, 1H), 7.62-7.57 (m, 1H), 7.44-7.38 (m, 3H), 7.21 (dd, J=8.6, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.88-4.78 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.57 (s, 6H), 2.41-2.34 (m, 1H), 1.77-1.68 (m, 1H); MS (ESI) m/z 506.2 (M+H).sup.+.

    Example 246: 2-(4-chloro-3-fluorophenoxy)-N-[3-(1-methyl-5-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 345)

    Example 246A: methyl 3-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-3-oxopropanoate

    [1796] To a solution of 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid (500 mg, 1.59 mmol, CALICO Life Sciences; AbbVie Inc.; Sidrauski, Carmela; et al. WO2017/193030, 2017, A 1) in tetrahydrofuran (10 mL) at ambient temperature, di(1H-imidazol-1-yl)methanone (310 mg, 1.91 mmol) was added and the mixture was stirred for 1 hour followed by addition of potassium 3-methoxy-3-oxopropanoate (373 mg, 2.39 mmol) and magnesium chloride (182 mg, 1.91 mmol) in one portion. The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was acidified with 0.5 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified on silica gel (10100% ethyl acetate in heptane) to give the title compound (0.5 g). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.3, 2.9 Hz, 1H), 6.85 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 3.68 (s, 2H), 3.63 (s, 3H), 2.27 (s, 6H); MS (APCI.sup.+) m/z 370.52 (M+H).sup.+.

    Example 246B: 2-(4-chloro-3-fluorophenoxy)-N-[3-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl]acetamide

    [1797] A solution of the product of Example 246A (820 mg, 2.218 mmol) and methylhydrazine sulfate (320 mg, 2.218 mmol) in ethanol (5.0 mL) was stirred with heating at 80 C. for 16 hours. Volatiles were removed and the residue was purified on silica gel (010% methanol/dichloromethane) to give the crude title compound (330 mg). Re-purification by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 50 mL/minute) afforded the title compound (280 mg). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.3, 2.8 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 5.31 (s, 1H), 4.48 (s, 2H), 3.46 (s, 3H), 2.21 (s, 6H).

    Example 246C: cis-3-(benzyloxy)cyclobutan-1-ol

    [1798] To a solution of 3-(benzyloxy)cyclobutan-1-one (20 g, 113 mmol) in methanol (200 mL) was added NaBH.sub.4 (4.29 g, 113 mmol) portions at 30 C. over 20 minutes, and the mixture was stirred at 30 C. for 2 hours. The mixture was quenched with 30% aqueous NH.sub.4Cl (100 mL) at 30 C. Two additional vials on 20 g scale were set up as described above. The combined reaction mixtures were concentrated under reduced pressure. The residue was extracted with ethyl acetate (31000 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and filtered.

    [1799] The filtrate was concentrated under reduced pressure to give the title compound (56 g, yield 93%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.22-7.39 (m, 5H), 5.00 (d, J=6.63 Hz, 1H), 4.33 (s, 1H), 4.30-4.36 (m, 1H), 3.68 (sxt, J=7.10 Hz, 1H), 3.54 (quin, J=7.07 Hz, 1H), 2.51-2.60 (m, 2H), 1.73 (qd, J=8.09, 2.88 Hz, 2H).

    Example 246D: trans-3-(benzyloxy)cyclobutyl 4-nitrobenzoate

    [1800] To a solution of the product of Example 246C (13.5 g, 76 mmol), 4-nitrobenzoic acid (12.66 g, 76 mmol) and triphenylphosphine (19.87 g, 76 mmol) in toluene (300 mL) was added diisopropyl azodicarboxylate (14.73 mL, 76 mmol) dropwise at 0 C. The mixture was stirred at 20 C. for 16 hours. The mixture was diluted with water (400 mL), and the mixture was extracted with ethyl acetate (3300 mL). The combined organic phases were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=20:1 to 8:1) to give the title compound (18.4 g, yield 74.2%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.32-8.39 (m, 2H), 8.20 (d, J=8.91 Hz, 2H), 7.28-7.37 (m, 4H), 5.29-5.35 (m, 1H), 4.42 (s, 2H), 4.33 (quin, J=5.80 Hz, 1H), 2.45-2.49 (m, 4H).

    Example 246E: trans-3-(benzyloxy)cyclobutan-1-ol

    [1801] To a solution of the product of Example 246D (18 g, 55.0 mmol) in tetrahydrofuran (200 mL) was added a solution of NaOH (2.64 g, 66.0 mmol) in water (50.0 mL) dropwise at 0 C. The mixture was stirred at 20 C. for 10 hours. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (3300 mL). The combined organic layers were wash with brine (300 mL), dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (8.6 g, yield 88%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.27-7.37 (m, 5H), 4.99 (d, J=5.25 Hz, 1H), 4.33 (s, 2H), 4.23-4.31 (m, 1H), 4.10-4.18 (m, 1H), 2.13-2.22 (m, 2H), 2.00-2.07 (m, 2H).

    Example 246F: ((trans-3-(trifluoromethoxy)cyclobutoxy)methyl)benzene

    [1802] To a mixture of silver trifluoromethanesulfonate (46.1 g, 180 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (23.85 g, 67.3 mmol), and KF (10.43 g, 180 mmol) in a flask wrapped with aluminum foil cooled with a water bath, the product of Example 246E (8.0 g, 44.9 mmol) in ethyl acetate (300 mL) was added, followed by 2-fluoropyridine (11.57 mL, 135 mmol) and (trifluoromethyl)trimethylsilane (19.90 mL, 135 mmol) dropwise to keep the internal temperature lower than 10 C. The mixture was stirred at 20 C. for 48 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (3500 mL). The combined filtrates were concentrated under reduced pressure. The crude residue was purified by silica chromatography eluted with petroleum ether: ethyl acetate=20:1 to give the title compound (5.5 g, yield 49.4%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.17-7.44 (m, 5H), 4.95 (br s, 1H), 4.38 (s, 2H), 4.18-4.32 (m, 1H), 2.37-2.47 (m, 4H).

    Example 246G: trans-3-(trifluoromethoxy)cyclobutan-1-ol

    [1803] To a solution of the product of Example 246F (12.75 g, 51.8 mmol) in tetrahydrofuran (150 mL) was added 5% Pd/C (11.02 g, 5.18 mmol) under argon. The mixture was stirred at 50 C. under H.sub.2 (50 psi) for 48 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with tetrahydrofuran (3500 mL). The combined filtrates were concentrated at 20 C. to dryness to give the title compound (4.0 g, yield 49.5%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 5.26 (d, J=5.13 Hz, 1H), 4.82-5.02 (m, 1H), 4.23-4.45 (m, 1H), 2.34-2.45 (m, 2H), 2.17-2.28 (m, 2H).

    Example 246H: trans-3-(trifluoromethoxy)cyclobutyl 4-methylbenzenesulfonate

    [1804] To a solution of the product of Example 246G (300 mg, 1.922 mmol) and triethylamine (0.670 mL, 4.80 mmol) in dichloromethane (7.5 mL), 4-methylbenzene-1-sulfonyl chloride (550 mg, 2.88 mmol) was added at 0 C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was directly loaded on silica gel and eluted with 030% ethyl acetate in heptane to give the title compound (530 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.83-7.77 (m, 2H), 7.45 (dd, J=46.5, 8.1 Hz, 2H), 5.04-4.93 (m, 2H), 2.54 (t, J=5.9 Hz, 2H), 2.41 (d, J=20.7 Hz, 2H).

    Example 246I: 2 -(4-chloro-3-fluorophenoxy)-N-[3-(1-methyl-5-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl]acetamide

    [1805] A mixture of the product of Example 246B (50 mg, 0.137 mmol), the product of Example 246H (63.6 mg, 0.205 mmol) and potassium carbonate (56.7 mg, 0.410 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70 C. for 18 hours. The crude material was purified by preparative HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 75 mL/minute) to give the title compound (24 mg). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.70 (s, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.3, 2.8 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.1 Hz, 1H), 5.45 (s, 1H), 4.57 (p, J=7.0 Hz, 1H), 4.47 (s, 2H), 4.36 (p, J=6.8 Hz, 1H), 3.48 (s, 3H), 3.01 (dtd, J=9.9, 6.8, 3.3 Hz, 2H), 2.31 (dtd, J=12.8, 6.4, 5.8, 3.0 Hz, 2H), 2.19 (s, 6H); MS (APCI.sup.+) m/z 504.57 (M+H).sup.+.

    Example 247: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 346)

    Example 247A: tert-butyl (3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1806] To a 20 mL vial was added cataCXium A Pd G2 (20 mg, 0.027 mmol), tetrahydroxydiboron (139 mg, 1.55 mmol), and the product of Example 207C (102 mg, 0.31 mmol). The vial was sealed and then evacuated and backfilled with nitrogen. This process was repeated 4 times. Methanol (1.3 mL) was added followed by Hunig's base (271 L). The reaction was then heated to 53 C. and stirred for 5 hours. An adequately degassed solution of aqueous potassium phosphate (1.55 mL, 1.0 M) was added via syringe followed by the addition of 2-bromo-5-(trifluoromethoxy)pyridine (113 mg, 0.47 mmol) as a solution in degassed ethanol (0.33 mL). The reaction was stirred at 53 C. for 24 hours and then cooled to ambient temperature. Methanol (10 mL) and silica gel (10 g) were added, and the mixture was concentrated under reduced pressure. The powder was directly purified by reversed-phase flash chromatography [Interchim puriFlash C18XS 30 m 175 g column, flow rate 80 mL/minute, 7-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (54 mg, 0.13 mmol, 41% yield). MS (APCI.sup.+) m/z 411 (M+H).sup.+.

    Example 247B: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1807] The reaction and purification conditions described in Example 1C substituting the product of Example 247A for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.59-8.56 (m, 1H), 8.44 (d, J=0.8 Hz, 1H), 8.09 (d, J=0.7 Hz, 1H), 7.91-7.86 (m, 1H), 7.85 (dd, J=8.7, 0.8 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (s, 1H), 4.63-4.58 (m, 2H), 2.56 (s, 6H), 2.13 (ddd, J=13.9, 3.7, 2.8 Hz, 1H), 1.93 (ddd, J=13.9, 11.0, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 521 (M+H).sup.+.

    Example 248: (2R,4R)-6-chloro-N-(3-{4-[5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 347)

    Example 248A: tert-butyl (3-{4-[5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1808] A mixture of the product from Example 207C (0.100 g, 0.305 mmol), tetrahydroxydiboron (0.078 g, 0.868 mmol), potassium acetate (0.088 g, 0.899 mmol), methanesulfonato(2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (5.2 mg, 0.0061 mmol), and dicyclohexyl(2, 4, 6-triisopropyl-[1,1-biphenyl]-2-yl)phosphane (5.5 mg, 0.012 mmol) in degassed ethanol (2 mL) was placed in a sealed vessel and heated at 80 C. and stirred for 1 hour. 5-Bromo-3-fluoro-2-(trifluoromethyl)pyridine (74 mg, 0.305 mmol) and potassium carbonate (120 mg, 0.868 mmol) were added and the resulting mixture was heated at 80 C. for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL), and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel using a solvent gradient of 0-60% ethyl acetate in heptanes to give the title compound (30 mg, 24%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.90 (t, J=1.7 Hz, 1H), 8.61 (s, 1H), 8.36-8.30 (m, 1H), 8.24 (d, J=0.8 Hz, 1H), 7.78 (s, 1H), 2.42 (s, 6H), 1.40 (s, 9H); MS (ESI) m/z 413.1 (M+H).sup.+.

    Example 248B: (2R,4R)-6-chloro-N-(3-{4-[5-fluoro-6-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1809] To a solution of the product from Example 248A (30 mg, 0.073 mmol) in 1,4-dioxane (0.5 mL) was added hydrogen chloride (4 N in 1,4-dioxane) (0.5 mL, 2.000 mmol), and the resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and the residue was dried in vacuo. The residue was dissolved in anhydrous N,N-dimethylformamide (1.0 mL), and (2R,4R)-6-chloro-4-hydroxychroman-2-carboxylic acid (18.7 mg, 0.082 mmol, Example 3B), and N,N-diisopropylethylamine (0.036 mL, 0.204 mmol) were added, followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 28.4 mg, 0.075 mmol), and the resulting solution was stirred at room temperature for 90 minutes. The solution was partitioned between 0.2 N aqueous HCl (5 mL) and ethyl acetate (25 mL), and the organic layers were combined and dried over Na.sub.2SO.sub.4. The drying agent was filtered off, and the filtrate was concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel using 0-80% ethyl acetate in heptanes to give the title compound (25 mg, 0.048 mmol, 70.3% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.95-8.89 (m, 2H), 8.65 (s, 1H), 8.34 (dd, J=12.1, 1.8 Hz, 1H), 8.26 (s, 1H), 7.40 (dd, J=2.8, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.77-5.70 (m, 1H), 4.83 (dt, J=11.5, 6.0 Hz, 1H), 4.67 (dd, J=11.9, 2.3 Hz, 1H), 2.57 (s, 6H), 2.39 (ddd, J=13.0, 5.9, 2.4 Hz, 1H); MS (ESI) m/z 523.2 (M+H).sup.+.

    Example 249: (2R,4R)-6-chloro-N-[3-(4-{3-[(difluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 348)

    [1810] The methodologies described in the reaction sequence of Example 300 were followed substituting 3-((difluoromethoxy)methyl)azetidine (purchased from Enamine) for (R)-3-(difluoromethoxy)pyrrolidine to give the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.17 (d, J=0.7 Hz, 1H), 7.78 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.72 (t, J=75.9 Hz, 1H), 5.71 (s, 1H), 4.84-4.80 (m, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 4.44 (t, J=8.7 Hz, 1H), 4.14-4.10 (m, 1H), 4.02 (d, J=6.6 Hz, 3H), 3.74-3.70 (m, 1H), 2.99-2.93 (m, 1H), 2.54 (s, 6H), 2.39 (dd, J=5.8, 2.2 Hz, 1H), 1.76-1.68 (m, 1H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 250: (1S,3S,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-hydroxy-N-[cis-3-(trifluoromethoxy)cyclobutyl]cyclohexane-1-carboxamide (Compound 349)

    Example 250A: ethyl (1S,3S,4S)-4-amino-3-hydroxycyclohexane-1-carboxylate

    [1811] The methodologies described in Example 21B substituting (1S,3S,4S)-ethyl 4-((tert-butoxycarbonyl)amino)-3-hydroxycyclohexanecarboxylate (purchased from Pharmablock) for the product of Example 21A gave the title intermediate. MS (ESI.sup.+) m/z 188 (M+H).sup.+.

    Example 250B: ethyl (1S,3S,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-hydroxycyclohexane-1-carboxylate and ethyl (1S,3S,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-{[1(4-chloro-3-fluorophenoxy)acetyl]oxy}cyclohexane-1-carboxylate

    [1812] The methodologies described in Example 30D substituting 2-(4-chloro-3-fluorophenoxy)acetic acid for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid and substituting the product of Example 250A for the product of Example 30C gave the title intermediate as a mixture of the title intermediates. MS (APCI.sup.+) m/z 374 and 560 (M+H).sup.+.

    Example 250C: (1S,3S,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-hydroxycyclohexane-1-carboxylic acid

    [1813] To a solution of the product of Example 250B (0.022 g, 0.060 mmol) in tetrahydrofuran (0.49 mL) and water (0.05 mL) was added lithium hydroxide (5.7 mg, 0.24 mmol), and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was then diluted with HCl (10% aqueous, 1 drop), concentrated in vacuo, and carried forward without further purification. MS (APCI.sup.+) m/z 346 (M+H).sup.+.

    Example 250D: (1S,3S,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-3-hydroxy-N-[cis-3-(trifluoromethoxy)cyclobutyl]cyclohexane-1-carboxamide

    [1814] The methodologies described in Example 30D substituting the product of Example 106A for the product of Example 30C and substituting the product of Example 250C for 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.06 (d, J=7.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.68 (d, J=5.5 Hz, 1H), 4.57 (q, J=7.3 Hz, 1H), 4.55-4.46 (m, 2H), 3.88 (h, J=7.9 Hz, 1H), 3.47-3.41 (m, 1H), 2.67 (dt, J=11.2, 7.0 Hz, 2H), 2.09 (q, J=8.5, 8.0 Hz, 3H), 1.90 (d, J=12.5 Hz, 1H), 1.81-1.75 (m, 1H), 1.64 (d, J=12.5 Hz, 1H), 1.37-1.10 (m, 4H); MS (APCI.sup.+) m/z 483 (M+H).sup.+.

    Example 251: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 350)

    Example 251A: tert-butyl (3-{4-[6-(trifluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1815] The reaction and purification conditions described in Example 207D substituting 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)pyridine for 3-fluoro-4-(trifluoromethoxy)phenylboronic acid gave the title compound. MS (APCI.sup.+) m/z 411 (M+H).sup.+.

    Example 251B: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1816] The reaction and purification conditions described in Example 186B substituting the product of Example 251A for the product of Example 186A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.65 (dd, J=2.6, 0.7 Hz, 1H), 8.43 (d, J=0.8 Hz, 1H), 8.23 (dd, J=8.5, 2.5 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.32 (dd, J=8.5, 0.7 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.1 Hz, 1H), 4.87-4.80 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.56 (s, 6H), 2.39 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.74 (ddd, J=12.8, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 521 (M+H).sup.+.

    Example 252: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[6-(trifluoromethoxy)pyridin-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 351)

    [1817] The reaction and purification conditions described in Example 1C substituting the product of Example 251A for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.65 (d, J=2.5 Hz, 1H), 8.43 (d, J=0.8 Hz, 1H), 8.23 (dd, J=8.5, 2.5 Hz, 1H), 8.07 (d, J=0.7 Hz, 1H), 7.35-7.29 (m, 2H), 7.27 (dd, J=8.8, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.64 (s, 1H), 4.65-4.57 (m, 2H), 2.56 (s, 6H), 2.13 (dt, J=13.7, 3.3 Hz, 1H), 1.99-1.88 (m, 1H); MS (ESI.sup.+) m/z 521 (M+H).sup.+.

    Example 253: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 352)

    Example 253A: tert-butyl 3-(trifluoromethoxy)azetidine-1-carboxylate

    [1818] A mixture of silver(I) trifluoromethanesulfonate (8.01 g, 31.2 mmol), potassium fluoride (2.68 g, 46.2 mmol), and Selectfluor (1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate) (6.14 g, 17.3 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this reaction mixture was slowly added a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (purchased from Fluorochem, 2 g, 11.6 mmol) in ethyl acetate (31.6 mL) followed by the dropwise addition of 2-fluoropyridine (2.98 mL, 34.6 mmol) and trimethyl(trifluoromethyl)silane (5.12 mL, 34.6 mmol). The reaction mixture was then stirred at ambient temperature for 2 days. The crude reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title intermediate (533 mg, 1.77 mmol, 15% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 5.19-5.11 (m, 1H), 4.27-4.18 (m, 2H), 3.97-3.85 (m, 2H), 1.39 (s, 9H).

    Example 253B: 3-(trifluoromethoxy)azetidine hydrochloride

    [1819] The product of Example 253A (533 mg, 2.03 mmol) in ethyl acetate (0.5 mL) was mixed with hydrogen chloride (4 N in dioxane, 5.08 mL, 20.3 mmol) under cooling with ice and then stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title intermediate (1.06 g, 2.03 mmol, quantitative yield), which was carried forward without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.39 (d, J=130.7 Hz, 2H), 5.27-5.18 (m, 1H), 4.42-4.26 (m, 2H), 4.19-4.06 (m, 2H).

    Example 253C: methyl 3-{4-[3-(trifluoromethoxy)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1820] A mixture of the product of Example 207A (200 mg, 0.738 mmol), the product of Example 253B (143 mg, 0.805 mmol), and cesium carbonate (961 mg, 2.95 mmol) in tetrahydrofuran (3.7 mL) were degassed for 10 minutes. Then tBuBrettPhos Pd G3 (31.5 mg, 0.037 mmol) was added with further degassing for 10 minutes. The reaction mixture was heated at 65 C. for 3 hours. After this time, tBuBrettPhos Pd G3 (31.5 mg, 0.037 mmol) was added and the reaction degassed for 10 minutes. The reaction mixture was then heated at 65 C. for 16 hours, cooled to ambient temperature, and partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with brine (25 mL) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate/hexanes) to give the title intermediate (100 mg, 0.272 mmol, 37% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.33 (d, J=0.9 Hz, 1H), 7.10 (d, J=0.9 Hz, 1H), 5.21-5.17 (m, 1H), 4.05-4.00 (m, 2H), 3.70-3.64 (m, 5H), 2.43 (s, 6H).

    Example 253D: potassium 3-{4-[3-(trifluoromethoxy)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1821] To a solution of the product of Example 253C (100 mg, 0.302 mmol) in tetrahydrofuran (3 mL) under an atmosphere of N.sub.2 was added potassium trimethylsilanolate (77 mg, 0.60 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. Then the volatiles were removed under reduced pressure to give the title intermediate (149 mg, 0.302 mmol, quantitative yield), which was carried forward without further purification. MS (ESI.sup.+) m/z 356 (M+H).sup.+.

    Example 253E: 2-(trimethylsilyl)ethyl (3-{4-[3-(trifluoromethoxy)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1822] At ambient temperature under an atmosphere of N.sub.2, diphenyl phosphorazidate (0.098 mL, 0.45 mmol) was added to a solution of the product of Example 253D (149 mg, 0.302 mmol), N-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.8 mmol) and 2-(trimethylsilyl)ethanol (0.87 mL, 6.0 mmol) in toluene (3 mL). The reaction mixture was stirred at 58 C. for 5 hours, the solvent was then removed under reduced pressure, and the residue was purified by column chromatography on silica gel (0-100% ethyl acetate/hexanes) to afford the title intermediate (62 mg, 0.13 mmol, 43% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.91 (s, 1H), 7.29 (d, J=0.9 Hz, 1H), 7.07 (d, J=0.9 Hz, 1H), 5.20-5.15 (m, 1H), 4.27-4.21 (m, 2H), 3.95-3.90 (m, 2H), 3.69-3.63 (m, 2H), 2.33 (s, 6H), 0.97-0.89 (m, 2H), 0.03 (s, 9H).

    Example 253F: 3-{4-[3-(trifluoromethyl)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1823] To a solution of the product of Example 253E (62 mg, 0.14 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. The volatiles were removed under reduced pressure to give the title intermediate (39 mg, 0.097 mmol, 67% yield), which was carried forward without further purification. MS (ESI) m/z 403 (M+H).sup.+.

    Example 253G: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1824] To a solution of the product of Example 253F (39 mg, 0.10 mmol), the product of Example 1B (34.3 mg, 0.151 mmol), and triethylamine (0.084 mL, 0.61 mmol) in N,N-dimethylformamide (1.0 mL) at ambient temperature under nitrogen was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 57.6 mg, 0.151 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with aqueous saturated NaHCO.sub.3 (2.5 mL) and the aqueous phase was extracted with dichloromethane (22 mL). The combined organic phases were then concentrated in vacuo to afford (2R)-6-chloro-4-oxo-N-(3-{4-[3-(trifluoromethoxy)azetidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (49 mg, 0.10 mmol), which was carried forward without further purification.

    [1825] To a solution of this intermediate (49 mg, 0.098 mmol) in methanol (1.0 mL) at ambient temperature under nitrogen, was added sodium borohydride (44 mg, 1.2 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched with aqueous saturated NH.sub.4Cl (4 mL), stirred for 10 minutes, and then was extracted with dichloromethane (24 mL). The combined organic phases were concentrated in vacuo to afford the crude residue, which was filtered and purified by preparative HPLC (Waters XBridge C18 5 m BEH column, 30100 mm, flow rate 40 mL/minute, 0-100% gradient of acetonitrile in 0.1% ammonia/water) to give the title compound (4.3 mg, 8.5 mol, 9% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.39 (dd, J=2.8, 0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.9, 2.8 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 5.20-5.16 (m, 1H), 4.84-4.79 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.04-4.00 (m, 2H), 3.68-3.65 (m, 2H), 2.45 (s, 6H), 2.40-2.36 (m, 1H), 1.76-1.67 (m, 1H); MS (ESI.sup.+) m/z 499 (M+H).sup.+.

    Example 254: 3-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]bicyclo[1.1.1]pentane-1-carboxamide (Compound 353)

    [1826] The reaction and purification conditions described in Example 2B substituting 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine, hydrochloric acid (PharmaBlock) for the product of Example 2A, and 3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentane-1-carboxylic acid (Prepared as described in WO2017/193030, A1) for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 8.57 (s, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.07 (dd, J=11.3, 2.9 Hz, 1H), 6.85 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.46 (s, 2H), 2.21 (s, 6H), 2.17 (s, 6H); MS (APCI.sup.+) m/z 447 (M+H).sup.+.

    Example 255: (2R,4R)-4-hydroxy-6-(trifluoromethyl)-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 354)

    [1827] The product from Example 265A (17 mg, 0.044 mmol) was combined with trifluoroacetic acid (0.5 mL) and stirred at room temperature for 20 minutes, and the resulting solution was concentrated in vacuo. To the residue was added the product from Example 227B (9.5 mg, 0.037 mmol), N,N-dimethylformamide (1 mL), and triethylamine (0.031 mL, 0.22 mmol), followed by (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 18 mg, 0.047 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (25 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (0.5 mL), and sodium borohydride (6.9 mg, 0.13 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 10 minutes, water (0.1 mL) was added, and the resulting mixture was stirred for 10 minutes and filtered through a glass microfiber filter. The filtrate was subjected to C18 reversed phase preparative HPLC using a solvent gradient of 5-100% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) to give the title compound (17 mg, 86% yield).

    [1828] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.89-8.85 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.19 (d, J=0.7 Hz, 1H), 8.18 (ddd, J=8.4, 2.5, 0.8 Hz, 1H), 7.95-7.90 (m, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.4, 2.6 Hz, 1H), 7.07 (dd, J=8.5, 0.9 Hz, 1H), 5.83 (d, J=5.8 Hz, 1H), 4.91-4.86 (m, 1H), 4.77 (dd, J=11.9, 2.4 Hz, 1H), 2.59 (s, 6H), 2.47-2.40 (m, 1H), 1.78 (ddd, J=13.0, 11.9, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 256: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 355)

    Example 256A: tert-butyl (3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1829] A mixture of the product of Example 207C (500 mg, 1.52 mmol), (3S)-3-(trifluoromethoxy)pyrrolidine hydrochloride (purchased from Pharmablock, 350 mg, 1.83 mmol), tBuBrettPhos Pd G3 (65.1 mg, 0.076 mmol), and cesium carbonate (1.99 g, 6.09 mmol) was purged with argon and dissolved in tetrahydrofuran (7.62 mL). The resulting mixture was then evacuated under sonication for 1-2 minutes, backfilled with argon, and heated at 65 C. for 4 hours. Then additional tBuBrettPhos Pd G3 (65.1 mg, 0.076 mmol) was added and the reaction mixture was resealed, evacuated under sonication for 90 seconds, backfilled with argon, and returned to 65 C. for an additional 20 hours. Then the reaction mixture was diluted with ethyl acetate (30 mL) and filtered over a pad of diatomaceous earth/MgSO.sub.4 using ethyl acetate (30 mL). The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0-14% methanol/dichloromethane) to afford the title intermediate (393 mg, 0.977 mmol, 64% yield). MS (APCI.sup.+) m/z 403 (M+H).sup.+.

    Example 256B: 3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1830] To a solution of the product of Example 256A (393 mg, 0.977 mmol) in dichloromethane (3.9 mL) was added trifluoroacetic acid (0.90 mL, 12 mmol). The reaction mixture stirred at ambient temperature for 2.5 hours and then was concentrated in vacuo to give the title intermediate. MS (APCI.sup.+) m/z 303 (M+H).sup.+.

    Example 256C: (2R)-6-chloro-4-oxo-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1831] To a solution of the product of Example 256B (295 mg, 0.977 mmol) in N,N-dimethylformamide (3 mL, 0.75 mmol) and triethylamine (0.57 mL, 4.1 mmol) was added Example 1B (160 mg, 0.706 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 311 mg, 0.817 mmol). The resulting reaction mixture was stirred at ambient temperature for 70 minutes, diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (30 mL), and back extracted with dichloromethane (20 mL). The combined organic layers were washed with lithium chloride (5% aqueous, 30 mL) to remove N,N-dimethylformamide, dried with Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give the title intermediate. MS (APCI.sup.+) m/z 511 (M+H).sup.+.

    Example 256D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1832] To a solution of the product of Example 256C (499 mg, 0.977 mmol) in methanol (9.8 mL) was added sodium borohydride (73.9 mg, 1.95 mmol) in portions over 2 minutes. After 15 minutes, the reaction mixture was quenched with saturated aqueous ammonium chloride (0.5 mL), diluted with dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL), and back extracted with dichloromethane (220 mL). The combined organic layers were washed with lithium chloride (5% aqueous, 30 mL) to remove N,N-dimethylformamide, dried with Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% 2 N NH.sub.3-methanol/dichloromethane) to afford the title compound, which was further purified using preparative reverse phase HPLC column chromatography (Phenomenex LUNA C18, 50250, 100 A0-95% acetonitrile/0.1% trifluoroacetic acid water). The combined fractions were concentrated in vacuo, and the residue was treated with saturated aqueous ammonium bicarbonate to generate the free base. The aqueous mixture was extracted into dichloromethane. The organic fraction was concentrated in vacuo, and the residue was diluted with a solution of acetonitrile/water (1:1) and lyophilized to afford the title compound (338 mg, 0.659 mmol, 68% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.27 (d, J=0.9 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 5.12 (ddd, J=8.5, 5.2, 2.4 Hz, 1H), 4.82 (dt, J=11.4, 6.0 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.21-3.16 (m, 2H), 2.97 (td, J=8.6, 4.9 Hz, 1H), 2.45 (s, 6H), 2.39 (dd, J=5.9, 2.3 Hz, 1H), 2.32 (dt, J=14.4, 7.2 Hz, 1H), 2.08 (s, 1H), 1.77-1.67 (m, 1H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 56.84; MS (APCI.sup.+) m/z 513 (M+H).sup.+.

    Example 257: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 356)

    [1833] The methodologies described in the reaction sequence of Example 256 were followed substituting (3R)-3-(trifluoromethoxy)pyrrolidine hydrochloride (purchased from Pharmablock) for (3S)-3-(trifluoromethoxy)pyrrolidine hydrochloride to give the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.27 (d, J=0.9 Hz, 1H), 7.24-7.17 (m, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 5.12 (t, J=6.0 Hz, 1H), 4.82 (dt, J=11.6, 6.0 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.29 (dd, J=10.2, 4.5 Hz, 1H), 3.23-3.15 (m, 2H), 2.97 (td, J=8.6, 5.0 Hz, 1H), 2.45 (s, 6H), 2.42-2.26 (m, 2H), 1.72 (q, J=12.0 Hz, 1H); MS (APCI.sup.+) m/z 513 (M+H).sup.+.

    Example 258: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 357)

    Example 258A: tert-butyl (3-azidobicyclo[1.1.1]pentan-1-yl)carbamate

    [1834] To a solution of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (100 mg, 0.504 mmol) in methanol (2.5 mL) was added potassium carbonate (119 mg, 0.857 mmol), copper(II) sulfate pentahydrate (1.259 mg, 5.04 mol), and imidazole-1-sulfonylazide hydrochloric acid (117 mg, 0.555 mmol), and the resulting mixture was stirred at room temperature for 48 hours. The mixture was concentrated in vacuo and the residue was partitioned between pH 3 water (10 mL) and ethyl acetate (310 mL). The organic extracts were combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford the title compound (111 mg, 0.396 mmol, 79% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 2.24 (s, 6H), 1.46 (s, 9H).

    Example 258B: tert-butyl (3-{4-[4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1835] To a mixture of the product from Example 258A (50 mg, 0.223 mmol) and copper sulfate (1.0 mg, 0.006 mmol) in tert-butanol (3 mL) and water (1 mL) was added 1-ethynyl-4-(trifluoromethoxy)benzene (0.038 mL, 0.248 mmol), benzoic acid (6.84 mg, 0.056 mmol) and sodium ascorbate (2.0 mg, 0.010 mmol) at ambient temperature in a microwave tube. The microwave tube was flushed with N.sub.2, sealed, and the mixture was stirred at 80 C. overnight. The mixture was cooled to room temperature and partitioned between water (10 mL) and ethyl acetate (310 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (64 mg, 0.140 mmol, 63% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 7.99-7.95 (m, 2H), 7.47-7.44 (m, 2H), 2.54 (s, 6H), 1.41 (s, 9H).

    Example 258C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1836] The title compound was prepared using the methods described for the synthesis of Example 244B, substituting the product from Example 258B for the product from Example 244A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.99 (s, 1H), 8.81 (s, 1H), 8.01-7.95 (m, 2H), 7.50-7.44 (m, 2H), 7.42-7.38 (m, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (s, 1H), 4.89-4.81 (m, 1H), 4.68 (dd, J=12.0, 2.3 Hz, 1H), 2.69 (s, 6H), 2.45-2.36 (m, 1H), 1.82-1.69 (m, 1H); MS (ESI) m/z 521.2 (M+H).sup.+.

    Example 259: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 358)

    Example 259A: tert-butyl {3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1837] The title compound was prepared using the methods described for the synthesis of Example 258B, substituting 1-chloro-4-ethynyl-2-fluorobenzene for 1-ethynyl-4-(trifluoromethoxy)benzene. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.82 (s, 1H), 7.85 (dd, J=10.6, 1.9 Hz, 1H), 7.78-7.72 (m, 1H), 7.71-7.65 (m, 1H), 7.50 (s, 1H), 2.53 (s, 6H), 1.41 (s, 9H).

    Example 259B: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1838] The title compound was prepared using the methods described for the synthesis of Example 244B, substituting the product from Example 259A for the product from Example 244A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.99 (s, 1H), 8.86 (s, 1H), 7.86 (dd, J=10.5, 1.9 Hz, 1H), 7.74 (dd, J=8.4, 1.9 Hz, 1H), 7.72-7.65 (m, 1H), 7.41-7.38 (m, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.73 (s, 1H), 4.88-4.78 (m, 1H), 4.68 (dd, J=12.0, 2.3 Hz, 1H), 2.68 (s, 6H), 2.45-2.32 (m, 1H), 1.81-1.67 (m, 1H); MS (ESI) m/z 489.4 (M+H).sup.+.

    Example 260: (2R,4R)-6-chloro-N-(3-{4-[(3S)-3-ethoxypyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 359)

    [1839] The reaction and purification conditions described in Example 229 substituting (S)-3-ethoxypyrrolidine hydrochloride (Advanced ChemBlocks) for 2-methyl-2-(trifluoromethyl)pyrrolidine gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90 C.) ppm 8.55 (s, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.6, 1.0 Hz, 1H), 7.16 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.41 (br s, 1H), 4.81 (dd, J=10.4, 5.8 Hz, 1H), 4.62 (dd, J=11.6, 2.6 Hz, 1H), 4.13-4.08 (m, 1H), 3.67-3.49 (m, 4H), 3.49-3.45 (m, 2H), 2.55 (s, 6H), 2.40 (ddd, J=13.0, 5.9, 2.6 Hz, 1H), 2.03-1.92 (m, 2H), 1.79 (ddd, J=13.0, 11.7, 10.4 Hz, 1H), 1.11 (t, J=7.0 Hz, 3H); MS (APCI.sup.+) m/z 501 (M+H).sup.+.

    Example 261: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 360)

    Example 261A: tert-butyl (3-{1-[4-(trifluoromethoxy)phenyl-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1840] To a mixture of tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate (100 mg, 0.482 mmol, US patent publication US2017/007335A1, Mar. 16, 2017 reference example 7) and copper sulfate (0.770 mg, 4.82 mol) in tert-butanol (5 mL) and water (1.7 mL) was added 1-azido-4-(trifluoromethoxy)benzene (105 mg, 0.516 mmol, purchased from Fluorochem), benzoic acid (5.9 mg, 0.048 mmol) and sodium ascorbate (1.91 mg, 9.65 mol) at ambient temperature in a microwave tube. The microwave tube was flushed with N.sub.2, sealed, and stirred at 80 C. for 16 hours. The mixture was cooled to ambient temperature, poured onto ice-water (15 mL), and extracted with ethyl acetate (315 mL). The combined organic phases were washed with brine (25 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title intermediate (204 mg, 0.482 mmol, quantitative yield), which was used without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.70 (s, 1H), 8.03-7.99 (m, 2H), 7.62-7.59 (m, 2H), 2.25 (s, 6H), 1.40 (s, 9H).

    Example 261B: 3-(1-(4-(trifluoromethoxy)phenyl)-11H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine

    [1841] The methodologies described in Example 253F substituting the product of Example 261A for the product of Example 253E gave the title intermediate as a trifluoroacetic acid salt.

    [1842] MS (ESI.sup.+) m/z 311 (M+H).sup.+.

    Example 261C. (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[4-(trifluoromethoxy)phenyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1843] The methodologies described in Example 253G substituting the product of Example 261B for the product of Example 253F gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.78 (s, 1H), 8.75 (s, 1H), 8.04-8.00 (m, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.39 (d, J=2.1 Hz, 1H), 7.21 (dd, J=8.7, 2.6 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.85-4.80 (m, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.43-2.37 (m, 7H), 1.72 (q, J=12.2 Hz, 1H); MS (ESI.sup.+) m/z 521 (M+H).sup.+.

    Example 262: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 361)

    Example 262A: (E)-4-(5-chloro-4-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid

    [1844] A mixture of maleic anhydride (2.0 g, 20.4 mmol) and aluminum chloride (8.16 g, 61.2 mmol) in dichloromethane (20 mL) was stirred at 50 C. for 15 minutes. 1-Chloro-2-fluoro-4-methoxybenzene (2.62 g, 16.32 mmol) was added dropwise, and the resulting mixture was stirred at 50 C. for 12 hours, cooled to 20 C., and then poured into a mixture of concentrated aqueous hydrochloric acid (15 mL, 37%) and cracked ice (about 120 mL). The resultant precipitate was collected by filtration and dried under vacuum to give the title compound (2.8 g, 49% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.93 (br s, 1H), 11.96-11.50 (m, 1H), 11.83 (s, 1H), 11.66 (s, 1H), 8.01-7.75 (m, 1H), 7.17-6.96 (m, 2H), 6.70-6.58 (m, 1H), 6.25 (d, J=12.0 Hz, 1H).

    Example 262B: 6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid

    [1845] To a mixture of the product of Example 262A (15 g, 42.9 mmol) in water (1500 mL) was added aqueous NaOH (69 mL, 1.0 M) at 25 C. and the mixture was stirred at 100 C. for 2 hours and then cooled to ambient temperature. The pH of the mixture was adjusted to 1 with concentrated aqueous HCl (37%). The resulting mixture was extracted with ethyl acetate (31000 mL). The organic layers were combined and washed with brine (200 mL) and then concentrated under reduced pressure. The resulting residue was triturated with a solvent mixture of petroleum ether and ethyl acetate (200 mL, 3:1), filtered, and dried under vacuum to give the title compound (7.1 g, 29 mmol, 68% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 13.55 (br s, 1H), 7.88-7.79 (m, 1H), 7.35 (d, J=10.3 Hz, 1H), 5.43 (dd, J=7.1, 5.5 Hz, 1H), 3.22-3.10 (m, 1H), 2.99 (dd, J=17.1, 7.3 Hz, 1H).

    Example 262C: (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1846] The product of Example 262B (26 g, 98 mmol) was separated by Chiral SFC on a Waters SFC 350 Preparative System: [column: CHIRALPAK AD 25050 mm 10 m chiral column; Mobile phase: A for CO.sub.2 and B for methanol (with 0.1% ammonium hydroxide); Gradient: 40% B in A; Flow rate: 200 g/minute; Column temperature: 40 C.; System back pressure: 100 bar]. The pH of the earlier eluting fraction was adjusted to 1 and extracted with ethyl acetate (3200 mL). The organic layers were combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (8.0 g, 30 mmol, 30%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 13.61 (br s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.34 (d, J=10.4 Hz, 1H), 5.42 (dd, J=7.1, 5.4 Hz, 1H), 3.16 (dd, J=17.1, 5.4 Hz, 1 H), 2.94-3.04 (m, 1H);); MS (ESI.sup.+) m/z 245 (M+H).sup.+.

    Example 262D: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1847] The product from Example 247A (10 mg, 0.024 mmol) was combined with trifluoroacetic acid (0.1 mL, 1.30 mmol), and the mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. To the residue was added triethylamine (0.034 mL, 0.24 mmol), N,N-dimethylformamide (1 mL) and the product from Example 262C (7.2 mg, 0.029 mmol), followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 12 mg, 0.032 mmol). The resulting mixture was stirred at room temperature for 1 hour and partitioned between dichloromethane (210 mL) and water (2 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (1 mL) and sodium borohydride (9.2 mg, 0.24 mmol) was added in 1 portion. The mixture was stirred at room temperature for 15 minutes, saturated aqueous ammonium chloride (0.1 mL) was added, and the resulting mixture was stirred for 10 minutes. The mixture was combined with diatomaceous earth (2 g) and concentrated under reduced pressure to a free flowing powder. The powder was used to purify the crude product using C18 reversed-phase HPLC using a solvent gradient of 5-100% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) to give the title compound as a colorless solid (9 mg, 69% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.59-8.55 (m, 1H), 8.46-8.42 (m, 1H), 8.09 (d, J=0.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.86-7.83 (m, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.78 (s, 1H), 4.80 (dd, J=10.6, 5.8 Hz, 1H), 4.71 (dd, J=11.8, 2.5 Hz, 1H), 2.56 (s, 6H), 2.38 (ddd, J=13.0, 5.8, 2.6 Hz, 1H), 1.75 (dt, J=12.7, 11.1 Hz, 1H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 263: 1-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-N-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazole-4-carboxamide (Compound 362)

    Example 263A: methyl 3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1848] The reaction and purification conditions described in Examples 230C substituting the product of Example 106A for 3-((trifluoromethoxy)methyl)azetidine hydrochloride and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) for (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) gave the title compound. MS (APCI.sup.+) m/z 374 (M+H).sup.+.

    Example 263B: tert-butyl [3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]carbamoyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1849] A solution of the product of Example 263A (41 mg, 0.11 mmol) in methanol (1 mL) was stirred at ambient temperature and aqueous NaOH (0.088 mL, 2.5 M) was added. After stirring for 1 hour, aqueous HCl (0.384 mL, 1.0 M) was added. The resulting solution was dried under a nitrogen blower for about 1 hour to complete dryness. Hunig's base (0.058 mL), t-butanol (3 mL), and diphenylphosphoryl azide (0.036 mL, 0.165 mmol) were added in sequential order, and the resulting mixture was heated to 58 C. and stirred for 24 hours. The reaction mixture was cooled to ambient temperature, and methanol (5 mL) was added. The resulting mixture was concentrated under reduced pressure. The residue was taken up in more methanol (3 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (23.2 mg, 0.054 mmol, 49% yield). MS (APCI.sup.+) m/z 431 (M+H).sup.+.

    Example 263C: 1-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-N-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazole-4-carboxamide

    [1850] The reaction and purification conditions described in Example 1C substituting the product of Example 263B for the product of Example 1A, and 2-(4-chloro-3-fluorophenoxy)acetic acid for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.22 (d, J=0.8 Hz, 1H), 7.88 (d, J=0.7 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.10 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.61 (p, J=7.3 Hz, 1H), 4.53 (s, 2H), 4.09 (h, J=8.2 Hz, 1H), 2.79-2.68 (m, 2H), 2.52 (s, 6H), 2.29-2.18 (m, 2H); MS (APCI.sup.+) m/z 517 (M+H).sup.+.

    Example 264: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 363)

    [1851] The reaction and purification conditions described in Example 186B substituting the product of Example 230E for the product of Example 186A, and the product of Example 262C for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.17 (d, J=0.8 Hz, 1H), 7.78 (d, J=0.7 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.93 (d, J=10.6 Hz, 1H), 5.75 (s, 1H), 4.82-4.78 (m, 1H), 4.71 (dd, J=11.8, 2.4 Hz, 1H), 4.47 (t, J=8.6 Hz, 1H), 4.30 (d, J=6.6 Hz, 2H), 4.17-4.12 (m, 1H), 4.06 (t, J=9.6 Hz, 1H), 3.78-3.70 (m, 1H), 3.10-3.00 (m, 1H), 2.54 (s, 6H), 2.44-2.32 (m, 1H), 1.74 (ddd, J=13.1, 11.9, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 559 (M+H).sup.+.

    Example 265: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 364)

    Example 265A: tert-butyl (3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1852] A 30 mL vial was charged with potassium acetate (179 mg, 1.83 mmol) as a solid. The vial was heated at 80 C. under vacuum for 5 minutes, and then cooled to ambient temperature under nitrogen protection. The product of Example 207C (200 mg, 0.609 mmol), tetrahydroxydiboron (164 mg, 1.828 mmol), XPhos-Pd-G3 (10.3 mg, 0.012 mmol), and XPhos (11.6 mg, 0.024 mmol) were then added as solids. The contents were evacuated and backfilled with nitrogen for two passes. Ethanol (6.1 mL, degassed by bubbling nitrogen through for 10 minutes before use) was added to the reaction vial, and the mixture was stirred at 75 C. for 1 hour. An aqueous solution of potassium carbonate (1.02 mL, 1.8 M, degassed by bubbling nitrogen through for 10 minutes before use) was added via syringe followed by the addition of the 2-bromo-5-(trifluoromethyl)pyridine (207 mg, 0.914 mmol) as a solution in tetrahydrofuran (0.5 mL, degassed by bubbling nitrogen through for 10 minutes before use). The reaction mixture was stirred at 75 C. for 18 hours, cooled to ambient temperature, and partitioned between dichloromethane (280 mL) and water (100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (140 mg, 0.355 mmol, 58% yield). MS (APCI.sup.+) m/z 395 (M+H).sup.+.

    Example 265B: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1853] The product from Example 265A (30 mg, 0.076 mmol) was combined with trifluoroacetic acid (0.3 mL, 3.89 mmol) and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was combined with triethylamine (0.074 mL, 0.53 mmol), N,N-dimethylformamide (1 mL), and the product from Example 1B (20 mg, 0.084 mmol), followed by (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 35 mg, 0.091 mmol). The resulting solution was stirred at room temperature for 1 hour, and the mixture was partitioned between dichloromethane (230 mL) and saturated aqueous sodium bicarbonate (30 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (3 mL) and sodium borohydride (17 mg, 0.46 mmol) was added in 1 portion. The mixture was stirred at room temperature for 20 minutes, saturated aqueous ammonium chloride (0.1 mL) was added, and the resulting mixture was partitioned between dichloromethane (320 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by C18 reversed phase HPLC using a solvent gradient of 5-100% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (34 mg, 0.066 mmol, 87% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.90-8.85 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.21-8.13 (m, 2H), 7.93 (dt, J=8.3, 0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (d, J=5.4 Hz, 1H), 4.83 (dt, J=10.8, 5.4 Hz, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.58 (s, 6H), 2.39 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.79-1.68 (m, 1H); MS (APCI.sup.+) m/z 505 (M+H).sup.+.

    Example 266: (2R,4R)-6-chloro-N-{3-[4-(2-cyclopropylpyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 365)

    Example 266A: tert-butyl {3-[4-(2-cyclopropylpyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1854] The reaction and purification conditions described in Example 207D substituting (2-cyclopropylpyrimidin-5-yl)boronic acid for 3-fluoro-4-(trifluoromethoxy)phenylboronic acid gave the title compound. MS (APCI.sup.+) m/z 368 (M+H).sup.+.

    Example 266B: (2R,4R)-6-chloro-N-{3-[4-(2-cyclopropylpyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1855] The reaction and purification conditions described in Example 186B substituting the product of Example 266A for the product of Example 186A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.88 (s, 2H), 8.42 (d, J=0.8 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.87-4.79 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 2.55 (s, 6H), 2.39 (ddd, J=13.0, 5.9, 2.4 Hz, 1H), 2.23-2.14 (m, 1H), 1.79-1.67 (m, 1H), 1.07-0.95 (m, 4H); MS (ESI.sup.+) m/z 478 (M+H).sup.+.

    Example 267: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)piperidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 366)

    Example 267A: (2R)-6-chloro-4-oxo-N-(3-{4-[4-(trifluoromethoxy)piperidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1856] The product of Example 272A (10 mg, 0.034 mmol), 4-(trifluoromethoxy)piperidine hydrochloride (9.1 mg, 0.044 mmol), and triethylamine (0.019 mL, 0.136 mmol) were combined with N,N-dimethylformamide (1.0 mL) and stirred at ambient temperature. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 24.9 mg, 0.048 mmol) was added in one portion. After stirring for 18 hours, the reaction mixture was partitioned between dichloromethane (230 mL) and water (30 mL). The organic phases were dried over sodium sulfate and concentrated under vacuum. To the resulting residue was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. N,N-Dimethylformamide (1 mL), triethylamine (0.038 mL, 0.27 mmol), the product of Example 1B (8.5 mg, 0.038 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 15.6 mg, 0.041 mmol) were added sequentially. After stirring for 1 hour, water (0.2 mL) was added. The resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (12 mg, 0.022 mmol, 64% yield). MS (APCI.sup.+) m/z 553 (M+H).sup.+.

    Example 267B: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)piperidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1857] The reaction and purification conditions described in Example 6C substituting the product of Example 267A for the product of Example 6B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.15 (d, J=0.7 Hz, 1H), 7.73 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.86-4.79 (m, 1H), 4.72 (tt, J=8.3, 3.9 Hz, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 3.92-3.86 (m, 2H), 3.46-3.35 (m, 2H), 2.54 (s, 6H), 2.38 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 2.01-1.93 (m, 2H), 1.78-1.62 (m, 3H); MS (APCI.sup.+) m/z 555 (M+H).sup.+.

    Example 268: (2R,4R)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 367)

    Example 268A: (2R)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1858] 4-Oxochroman-2-carboxylic acid (Enamine) was purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 6 mL/minute, 80% ethanol in heptane (isocratic gradient)] to give the title compound as the earlier eluting fraction. MS (ESI.sup.+) m/z 193 (M+H).sup.+.

    Example 268B: (2R,4R)-4-hydroxy-N-(3-{4-[5-(trichloromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1859] The reaction and purification conditions described in Example 186B substituting the product of Example 247A for the product of Example 186A, and the product of Example 268A for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 8.60-8.56 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.92-7.87 (m, 1H), 7.85 (dd, J=8.7, 0.8 Hz, 1H), 7.42 (dt, J=7.6, 1.4 Hz, 1H), 7.16 (dddd, J=8.0, 7.2, 1.7, 0.7 Hz, 1H), 6.93 (td, J=7.4, 1.2 Hz, 1H), 6.87 (dd, J=8.2, 1.2 Hz, 1H), 5.54 (d, J=6.1 Hz, 1H), 4.84 (dt, J=11.3, 5.9 Hz, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.57 (s, 6H), 2.39 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 1.76 (ddd, J=12.8, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 487 (M+H).sup.+.

    Example 269: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 368)

    Example 269A: (1H-imidazol-4-yl){3-[(trifluoromethoxy)methyl]azetidin-1-yl}methanone

    [1860] The reaction and purification conditions described in Example 272B substituting 3-((trifluoromethoxy)methyl)azetidine hydrochloride for (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride, and 1H-imidazole-4-carboxylic acid for the product of Example 272A gave the title compound. MS (ESI.sup.+) m/z 250 (M+H).sup.+.

    Example 269B: methyl 3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-imidazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1861] The reaction and purification conditions described in Example 203C substituting the product of Example 269A for the product of Example 203B gave the title compound. MS (APCI.sup.+) m/z 374 (M+H).sup.+.

    Example 269C: tert-butyl [3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1862] The reaction and purification conditions described in Example 263B substituting the product of Example 269B for the product of Example 263A gave the title compound. MS (APCI.sup.+) m/z 431 (M+H).sup.+.

    Example 269D: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1863] The reaction and purification conditions described in Example 186B substituting the product of Example 269C for the product of Example 186A gave the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.60 (d, J=1.4 Hz, 1H), 7.45 (dd, J=2.6, 0.9 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 7.19 (ddd, J=8.6, 2.6, 0.6 Hz, 1H), 7.02 (s, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.97-4.93 (m, 1H), 4.75 (t, J=9.3 Hz, 1H), 4.64 (dd, J=9.5, 3.3 Hz, 1H), 4.42 (dd, J=10.5, 5.4 Hz, 1H), 4.27 (t, J=9.5 Hz, 1H), 4.15 (dd, J=6.8, 1.3 Hz, 2H), 3.94 (dd, J=10.4, 5.3 Hz, 1H), 3.07-2.99 (m, 1H), 2.71-2.62 (m, 1H), 2.63 (s, 6H), 2.22-2.09 (m, 2H); MS (APCI.sup.+) m/z 541 (M+H).sup.+.

    Example 270: (2R,4R)-6,7-difluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 369)

    [1864] The reaction and purification conditions described in Example 186B substituting the product of Example 247A for the product of Example 186A, and the product of Example 90D for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.60-8.56 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.34 (ddd, J=11.4, 9.2, 1.0 Hz, 1H), 6.94 (dd, J=11.8, 7.0 Hz, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.80 (dt, J=11.5, 6.0 Hz, 1H), 4.68 (dd, J=11.9, 2.4 Hz, 1H), 2.57 (s, 6H), 2.38 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 1.74 (ddd, J=13.0, 12.0, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 523 (M+H).sup.+.

    Example 271: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 370)

    [1865] The reaction and purification conditions described in Examples 272B through 272C substituting (R)-3-(trifluoromethoxy)pyrrolidine hydrochloride for (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.29-8.21 (m, 1H), 7.90-7.83 (m, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 5.24-5.11 (m, 1H), 4.88-4.77 (m, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 3.86-3.77 (m, 2H), 3.75-3.63 (m, 2H), 2.55 (s, 6H), 2.38 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 2.32-2.10 (m, 2H), 1.80-1.66 (m, 1H); MS (APCI.sup.+) m/z 541 (M+H).sup.+.

    Example 272: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 371)

    Example 272A: 1-{3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentan-1-yl}-1H-pyrazole-4-carboxylic acid

    [1866] An oven dried 40 mL vial was charged with the product of Example 207C (500 mg, 1.52 mmol) and tetrahydrofuran (5.1 mL), and then cooled to 78 C. using an acetone/dry ice bath. n-Butyllithium (1.28 mL, 2.5 M in hexanes) was added dropwise over a period of 4 minutes while maintaining the internal temperature lower than 70 C. After stirring for 20 minutes at 78 C., carbon dioxide passed through a drying tube containing Drierite was bubbled through the reaction mixture constantly via a cannula needle. After 10 minutes, the reaction vial was removed from the cold bath and was allowed to gradually warm up while the stirring was continued. When the internal temperature reached 1 C., the reaction was quenched with methanol until the mixture became a clear, homogeneous solution. The reaction mixture was warmed up further to ambient temperature and then partitioned between dichloromethane (40 mL) and water (20 mL). Aqueous HCl (3 mL, 1.0 M) was added to the aqueous layer and a milky precipitate formed. The aqueous layer was extracted with dichloromethane (215 mL). All organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (276 mg, 0.94 mmol, 62% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.99 (s, 1H), 7.94 (s, 1H), 2.57 (s, 6H), 1.47 (s, 9H); MS (APCI.sup.+) m/z 294 (M+H).sup.+.

    Example 272B: tert-butyl (3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1867] (S)-3-(Trifluoromethoxy)pyrrolidine hydrochloride (92 mg, 0.48 mmol; PharmaBlock), triethylamine (0.179 mL), and the product of Example 272A (94 mg, 0.32 mmol) were combined with N,N-dimethylformamide (1.0 mL) and stirred at ambient temperature. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 234 mg, 0.45 mmol) was added in one portion. After stirring at ambient temperature for 18 hours, water (0.1 mL) was added, and the resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (130 mg, 0.30 mmol, 94% yield). MS (APCI.sup.+) m/z 431 (M+H).sup.+.

    Example 272C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1868] The product of Example 272B (97 mg, 0.225 mmol) was combined with trifluoroacetic acid (2 mL) and stirred at ambient temperature for 10 minutes and then concentrated under vacuum. Triethylamine (0.22 mL), N,N-dimethylformamide (3 mL), the product of Example 1B (56 mg, 0.248 mmol), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 164 mg, 0.316 mmol) were added in sequential order. The resulting reaction mixture was stirred at ambient temperature for 1 hour, and then partitioned between dichloromethane (250 mL) and water (50 mL). The organic layers were dried over sodium sulfated and concentrated under reduced pressure. The residue was taken up in methanol (3 mL), while stirring, sodium borohydride (51 mg, 1.35 mmol) was carefully added. After stirring for another 15 minutes, saturated aqueous NH.sub.4Cl (0.5 mL) was added. The resulting mixture was stirred for another 10 minutes and then partitioned between dichloromethane (350 mL), water (25 mL) and saturated aqueous sodium bicarbonate (25 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was taken in in N,N-dimethylformamide (3 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (101 mg, 0.187 mmol, 83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.29-8.22 (m, 1H), 7.90-7.83 (m, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.5, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 5.22-5.12 (m, 1H), 4.88-4.77 (m, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 3.87-3.77 (m, 2H), 3.75-3.61 (m, 2H), 2.55 (s, 6H), 2.38 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.32-2.10 (m, 2H), 1.82-1.64 (m, 1H); MS (APCI.sup.+) m/z 541 (M+H).sup.+.

    Example 273: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(1RS,2RS)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 372)

    Example 273A: 4-bromo-1-(oxan-2-yl)-1H-pyrazole

    [1869] Trifluoroacetic acid (0.052 mL, 0.680 mmol) was added to a mixture of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) and 3,4-dihydro-2H-pyran (1.87 mL, 20.4 mmol), and the resulting mixture was stirred at 80 C. for 20 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane (100 mL) and 1 M aqueous NaOH (40 mL). The organic layer was concentrated in vacuo, and the residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to afford the title compound (2.30 g, 9.96 mmol, 73% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) J ppm 8.14 (s, 1H), 7.60 (s, 1H), 5.38 (dd, J=9.9, 2.4 Hz, 1H), 3.94-3.86 (m, 1H), 3.67-3.55 (m, 1H), 2.12-2.01 (m, 1H), 1.95-1.83 (m, 2H), 1.71-1.59 (m, 1H), 1.56-1.49 (m, 2H).

    Example 273B: ethyl (2E)-3-[1-(oxan-2-yl)-1H-pyrazol-4-yl]prop-2-enoate

    [1870] A mixture of the product from Example 273A (2.30 g, 9.96 mmol), ethyl acrylate (1.27 mL, 11.96 mmol) and chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (Pd-162, 0.398 g, 0.996 mmol) was placed in a reaction vessel and flushed with N.sub.2. Dioxane (78 mL) and N,N-diisopropylethylamine (3.48 mL, 19.93 mmol) were added, and the mixture was heated to 90 C. and stirred for 3 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (100 mL) and 1 M aqueous NH.sub.4Cl (100 mL). The aqueous layer was extracted with dichloromethane (100 mL), and the organic layers were combined and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to afford the title compound (2.38 g, 8.56 mmol, 86% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.32 (s, 1H), 7.95 (s, 1H), 7.54 (d, J=16.0 Hz, 1H), 6.37 (d, J=16.0 Hz, 1H), 5.40 (dd, J=9.8, 2.3 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.97-3.88 (m, 1H), 3.68-3.60 (m, 1H), 2.08-2.01 (m, 1H), 1.98-1.87 (m, 2H), 1.74-1.61 (m, 1H), 1.59-1.50 (m, 2H), 1.24 (t, J=7.1 Hz, 3H).

    Example 273C: ethyl rac-(1R,2R)-2-[1-(oxan-2-yl)-1H-pyrazol-4-yl]cyclopropane-1-carboxylate

    [1871] A mixture of trimethylsulfoxonium iodide (4.18 g, 19.01 mmol) and sodium hydride (60% in mineral oil) (0.761 g, 19.01 mmol) in dimethyl sulfoxide (40 mL) was stirred under N.sub.2 at room temperature for 30 minutes. A solution of the product from Example 273B (2.3796 g, 9.51 mmol) in dimethyl sulfoxide (79 mL) was added, and the resulting mixture was stirred under N.sub.2 for 1 hour. In a separate flask, a mixture of trimethylsulfoxonium iodide (4.18 g, 19.01 mmol) and sodium hydride (60% in mineral oil) (0.761 g, 19.01 mmol) in dimethyl sulfoxide (40 mL) was stirred under N.sub.2 for 30 minutes, and the mixture was added to the previous mixture. The combined mixture was stirred at room temperature for 2 days. Saturated aqueous ammonium chloride solution (100 mL) and water (100 mL) were added, and the product was extracted with ethyl acetate (3100 mL). The organic layers were combined, washed with water (2100 mL) and brine (100 mL), and dried over MgSO.sub.4. The volatiles were removed in vacuo, and the residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to afford the title compound (1.11 g, 4.00 mmol, 42.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.77 (s, 1H), 7.37 (s, 1H), 5.29 (dd, J=10.1, 2.5 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H)), 3.92-3.86 (m, 1H), 3.63-3.55 (m, 1H), 2.27-2.20 (m, 1H), 2.07-1.97 (m, 1H), 1.95-1.88 (m, 1H), 1.88-1.82 (m, 1H), 1.81-1.74 (m, 1H), 1.70-1.58 (m, 1H), 1.55-1.45 (m, 2H), 1.38-1.32 (m, 1H), 1.26-1.15 (m, 4H).

    Example 273D: {rac-(1R,2R)-2-[1-(oxan-2-yl)-1H-pyrazol-4-yl]cyclopropyl}methanol

    [1872] A solution of LiAlH.sub.4 (2 M in tetrahydrofuran) (1.14 mL, 2.27 mmol) was added dropwise to a solution of the product from Example 273C (500 mg, 1.89 mmol) in tetrahydrofuran (17.6 mL) at 0 C., and the resulting mixture was stirred at room temperature for 2 hours and then heated at 50 C. for 3 days. The mixture was cooled to room temperature, dichloromethane (50 mL) and an aqueous solution of Rochelle salt (50 mL) were added, and the mixture was stirred at room temperature for 1 hour. The phases were separated, and the organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to give the title compound (447 mg, 1.73 mmol, 91% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.58 (s, 1H), 7.24 (s, 1H), 5.26 (dd, J=10.1, 2.5 Hz, 1H), 4.53 (t, J=5.6 Hz, 1H), 3.92-3.81 (m, 1H), 3.62-3.54 (m, 1H), 3.41-3.34 (m, 1H), 3.34-3.27 (m, 1H), 2.08-1.98 (m, 1H), 1.95-1.88 (m, 1H), 1.87-1.79 (m, 1H), 1.72-1.58 (m, 1H), 1.58-1.46 (m, 3H), 1.14-1.03 (m, 1H), 0.75-0.68 (m, 1H), 0.68-0.55 (m, 1H).

    Example 273E: 1-(oxan-2-yl)-4-{rac-(1R,2R)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-pyrazole

    [1873] A mixture of silver(1) trifluoromethanesulfonate (1.39 g, 5.41 mmol), potassium fluoride (465 mg, 8.01 mmol), and Selectfluor (1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate) (1.06 g, 3.00 mmol) was placed in a flask wrapped with aluminum foil and cooled with a water bath. The flask was flushed with N.sub.2, and to the stirred mixture was slowly added a solution of the product from Example 273D (445 mg, 2.00 mmol) in ethyl acetate (5.5 mL), followed by the dropwise addition of 2-fluoropyridine (0.517 mL, 6.01 mmol) and trimethyl(trifluoromethyl)silane (0.888 mL, 6.01 mmol). The resulting mixture was stirred at room temperature for 2 days and was filtered through diatomaceous earth. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (48 mg, 0.149 mmol, 7.4% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.67 (s, 1H), 7.30 (s, 1H), 5.28 (dd, J=10.1, 2.5 Hz, 1H), 4.13-3.97 (m, 2H), 3.94-3.84 (m, 1H), 3.64-3.50 (m, 1H), 2.09-1.99 (m, 1H), 1.96-1.88 (m, 1H), 1.88-1.82 (m, 1H), 1.81-1.75 (m, 1H), 1.70-1.58 (m, 1H), 1.55-1.47 (m, 2H), 1.39-1.32 (m, 1H), 0.94-0.82 (m, 2H).

    Example 273F: 4-{rac-(1R,2R)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-pyrazole

    [1874] To a solution of the product from Example 273E (336 mg, 1.157 mmol) in dichloromethane (8 mL) was added 2,2,2-trifluoroacetic acid (2 mL, 26.1 mmol) followed by triethylsilane (0.444 mL, 2.78 mmol). The resulting mixture was stirred at room temperature for 20 hours and concentrated in vacuo. The residue was dissolved in methanol (1 mL) and stirred with SCX resin (300 mg) for 30 minutes and filtered. The resin was washed with methanol (20 mL) and 0.7 M NH.sub.3 in methanol (20 mL), and the washes were concentrated in vacuo to afford the title compound (179 mg, 0.825 mmol, 71.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.52 (s, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 4.05 (d, J=7.4 Hz, 2H), 1.83-1.75 (m, 1H), 1.38-1.28 (m, 1H), 0.94-0.78 (m, 2H).

    Example 273G: methyl 3-(4-{rac-(1R,2R)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1875] The title compound was prepared using the methods described for the synthesis of Example 230A, substituting the product from Example 273F for (1H-pyrazol-4-yl)methanol. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.53 (s, 1H), 7.40 (s, 1H), 4.07-4.03 (m, 1H), 4.00-3.94 (m, 1H), 3.75 (s, 3H), 2.54 (s, 6H), 1.86-1.79 (m, 1H), 1.45-1.34 (m, 1H), 1.00-0.90 (m, 2H).

    Example 273H: 2-(trimethylsilyl)ethyl [3-(4-{rac-(1R,2R)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1876] The title compound was prepared using the methods described for the conversion of the product of Example 253C to the product of Example 253E, substituting the product from Example 273G for the product from Example 253C. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.44 (s, 1H), 7.35 (s, 1H), 4.08-3.91 (m, 2H), 2.28 (s, 6H), 1.84-1.75 (m, 1H), 1.42-1.33 (m, 2H), 0.98-0.89 (m, 2H).

    Example 2731: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(1RS,2RS)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1877] The title compound was prepared using the methods described for the synthesis of Example 244B, substituting the product from Example 273H for the product from Example 244A. .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.51 (s, 1H), 7.48-7.41 (m, 1H), 7.40 (s, 1H), 7.19 (dd, J=8.7, 2.7, 0.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 4.98-4.92 (m, 1H), 4.67 (dd, J=11.6, 2.4 Hz, 1H), 4.08-3.94 (m, 2H), 2.62 (s, 6H), 2.61-2.55 (m, 1H), 1.97-1.86 (m, 1H), 1.87-1.76 (m, 1H), 1.45-1.33 (m, 1H), 0.96 (t, J=7.7, 6.4 Hz, 2H); MS (ESI) m/z 498.2 (M+H).sup.+.

    Example 274: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(3S)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 373)

    [1878] The methodologies described in the reaction sequence of Example 256 were followed substituting (3S)-3-[(trifluoromethoxy)methyl]pyrrolidine (prepared similarly to Examples 298A and 298B from tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate) for (3S)-3-(trifluoromethoxy)pyrrolidine hydrochloride to give the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22-7.20 (m, 2H), 7.09 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.1 Hz, 1H), 4.85-4.78 (m, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 4.10-4.01 (m, 2H), 3.12-3.08 (m, 1H), 3.07-3.02 (m, 1H), 2.96 (q, J=7.8 Hz, 1H), 2.83-2.78 (m, 1H), 2.68-2.64 (m, 1H), 2.45 (s, 6H), 2.38 (dd, J=5.6, 1.9 Hz, 1H), 2.10-1.99 (m, 1H), 1.76-1.60 (m, 2H); MS (ESI.sup.+) m/z 527 (M+H).sup.+.

    Example 275: (2R,4R)-6,7-difluoro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 374)

    [1879] The reaction and purification conditions described in Example 186B substituting the product of Example 230E for the product of Example 186A, and the product of Example 90D for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 8.17 (d, J=0.7 Hz, 1H), 7.79 (d, J=0.7 Hz, 1H), 7.34 (ddd, J=11.4, 9.2, 1.0 Hz, 1H), 6.93 (dd, J=11.8, 7.0 Hz, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.79 (dt, J=11.3, 6.0 Hz, 1H), 4.67 (dd, J=11.9, 2.4 Hz, 1H), 4.47 (t, J=8.5 Hz, 1H), 4.30 (d, J=6.6 Hz, 2H), 4.18-4.09 (m, 1H), 4.09-4.02 (m, 1H), 3.77-3.71 (m, 1H), 3.09-3.02 (m, 1H), 2.54 (s, 6H), 2.41-2.33 (m, 1H), 1.73 (ddd, J=13.0, 12.0, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 543 (M+H).sup.+.

    Example 276: (2R,4R)-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 375)

    [1880] The reaction and purification conditions described in Example 186B substituting the product of Example 230E for the product of Example 186A, and the product of Example 268A for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 8.17 (d, J=0.8 Hz, 1H), 7.79 (d, J=0.7 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.20-7.11 (m, 11H), 6.93 (td, J=7.4, 1.2 Hz, 1H), 6.86 (dd, J=8.2, 1.2 Hz, 1H), 5.53 (d, J=6.2 Hz, 1H), 4.87-4.80 (m, 1H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 4.47 (t, J=8.5 Hz, 1H), 4.30 (d, J=6.6 Hz, 2H), 4.17-4.13 (m, 1H), 4.10-4.01 (m, 1H), 3.76-3.72 (m, 1H), 3.11-2.99 (m, 1H), 2.55 (s, 6H), 2.45-2.33 (m, 1H), 1.75 (q, J=12.1 Hz, 1H); MS (APCI.sup.+) m/z 507 (M+H).sup.+.

    Example 277: 1-(3-{[(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-N-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-pyrazole-4-carboxamide (Compound 376)

    [1881] The reaction and purification conditions described in Example 186B substituting the product of Example 263B for the product of Example 186A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.23 (d, J=0.7 Hz, 1H), 7.88 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.85-4.80 (m, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 4.61 (p, J=7.2 Hz, 1H), 4.14-4.05 (m, 1H), 2.78-2.70 (m, 2H), 2.53 (s, 6H), 2.38 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 2.28-2.20 (m, 2H), 1.73 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 541 (M+H).sup.+.

    Example 278: (2R,4R)-6-chloro-N-(3-{4-[3-(2,2-difluoroethyl)azetidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 377)

    [1882] The reaction and purification conditions described in Examples 272B through 272C substituting 3-(2,2-difluoroethyl)azetidine hydrochloride for (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride in Example 272B, and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) for (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) in Example 272C gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.24-8.19 (m, 2H), 7.89 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, JH), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, JH), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.83 (dd, J=10.7, 5.9 Hz, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 3.33-3.30 (m, 2H), 2.65-2.57 (m, 2H), 2.53 (s, 6H), 2.41-2.27 (m, 4H), 1.73 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 507 (M+H).sup.+.

    Example 279: (2S,4R)-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 378)

    Example 279A: (2S,4R)-4-hydroxy-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1883] The product of Example 239A (140 mg, 0.54 mmol) was combined with methanol (1.08 mL) and stirred at ambient temperature. Sodium borohydride (61 mg, 1.61 mmol) was added portionwise over 5 minutes. After stirring for 15 minutes, water (5 mL) was added, and the resulting mixture was stirred at ambient temperature for 1 hour and then concentrated under vacuum. To the residue was added cold trifluoroacetic acid (1.2 mL, pre-chilled to 0 C.) and the resulting solution was allowed to stir at ambient temperature for 3 hours and then concentrated under vacuum. The residue was taken up in cold acetonitrile (20 mL, pre-chilled to 0 C.) and stirred in a 0 C. bath, and aqueous ammonium hydroxide (5.0 M, pre-chilled close to 0 C.) was slowly added. The ice bath was removed, and the reaction was allowed to slowly warm up to ambient temperature and then stirred for 3 hours. The resulting mixture was concentrated under vacuum, and the residue was taken up in a solvent mixture of 1:1 acetonitrile:water, filtered through a glass microfiber frit, and directly purified by preparative HPLC [Phenomenex Kinetex EVO C18, 5 m column, 21.2100 mm, flow rate 25 mL/minute, 0-100% gradient (0% hold for 3 minutes, then 0-30% over 20 minutes, wash for 3 minutes at 100%) of acetonitrile in buffer (0.1% trifluoroacetic acid)] to give the title compound (55 mg, 0.21 mmol, 39% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 13.24 (br s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.53 (dd, J=8.7, 2.4 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 5.77 (d, J=5.2 Hz, 1H), 4.88 (dd, J=7.6, 4.6 Hz, 1H), 4.65 (q, J=4.9 Hz, 1H), 2.21-2.11 (m, 2H); MS (ESI.sup.) m/z 261 (MH).sup..

    Example 279B: (2S,4)-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1884] The reaction and purification conditions described in Example 1C substituting the product of Example 272B for the product of Example 1A, and the product of Example 279A for the product of Example 1B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.03 (s, 1H), 8.29-8.22 (m, J H), 7.90-7.83 (m, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H)), 7.11 (d, J=8.6 Hz, 1H), 5.72 (d, J=4.6 Hz, 1H), 5.21-5.12 (m, 1H), 4.74-4.66 (m, 2H), 4.07-3.99 and 3.86-3.79 (two m, amide rotamers, 2H), 3.73-3.69 (m, 1H), 3.68-3.60 and 3.55-3.44 (two m, amide rotamers, 1H), 2.55 (s, 6H), 2.31-2.11 (m, 3H), 2.05-1.93 (m, 1H); MS (APC.sup.+) m/z 574 (M+H).sup.+.

    Example 280: (2S,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 379)

    Example 280A: tert-butyl (3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1885] The title compound was prepared using the methods described for the synthesis of Example 256A, substituting (3R)-3-(trifluoromethoxy)pyrrolidine for (3S)-3-(trifluoromethoxy)pyrrolidine hydrochloride. MS (ESI) m/z 403.2 (M+H).sup.+.

    Example 280B: (S)-6-chloro-7-fluoro-4-oxochroman-2-carboxylic acid

    [1886] The title compound was prepared using the methods described for Example 262C. It was the second of two enantiomers to elute during the SFC purification.

    Example 280C: (2S,4S)-6-chloro-7-fluoro-4-hydroxychroman-2-carboxylic acid

    [1887] The title compound was prepared using the methods described for the synthesis of Example 3B, substituting the product from Example 280B for the product from Example 1B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.99-2.10 (m, 1H) 2.24-2.39 (m, 1H) 4.68-4.78 (m, 1H) 4.89 (dd, J=8.3, 3.9 Hz, 1H) 6.94 (d, J=10.8 Hz, 1H) 7.44 (d, J=8.6 Hz, 1H) 12.97 (br s, 1H).

    Example 280D: (2S,4R)-6-chloro-7-fluoro-4-hydroxychroman-2-carboxylic acid

    [1888] The title compound was prepared using the methods described for the synthesis of Example 73B, substituting the product from Example 280C for the product from Example 73A.

    [1889] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.02-2.21 (m, 2H) 4.57 (t, J=4.3 Hz, 1H) 4.81 (dd, J=8.7, 3.6 Hz, 1H) 5.32-5.92 (m, 1H) 6.97 (d, J=10.63 Hz, 1H) 7.47 (d, J=8.50 Hz, 1H) 13.25 (br s, 1H).

    Example 280E: (2S,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1890] To a solution of the product from Example 280A (149 mg, 0.370 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroacetic acid (0.567 mL, 7.41 mmol). The solution was stirred at room temperature for one hour and was concentrated in vacuo. The residue was dissolved in methanol (2 mL) and stirred with SCX resin (0.3 g) for 15 minutes, after which time the mixture was loaded onto a column of SCX (1 g) and washed with methanol (35 mL). The product was eluted with 7 N NH.sub.3 in methanol (35 mL). Concentration in vacuo gave 3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine (132 mg, 0.370 mmol, 100% yield). A portion of 3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine (24 mg, 0.068 mmol) and the product from Example 280D (20 mg, 0.081 mmol) were dissolved in N,N-dimethylformamide (1 mL) and triethylamine (0.057 mL, 0.41 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU, 39 mg, 0.10 mmol) was added. The resulting solution was stirred at room temperature overnight and was partitioned between saturated aqueous NaHCO.sub.3 and dichloromethane. The organic extract was passed through a hydrophobic phase separator, washed with brine, passed through a hydrophobic phase separator, and concentrated in vacuo. The residue was purified by C18 reversed-phase preparative HPLC eluting with a gradient of 0-100% acetonitrile in aqueous buffer (0.3% ammonia in water). Lyophilization provided the title compound (3.4 mg, 6.08 mol, 9.0% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.44 (d, J=8.2 Hz, 1H), 7.24-7.21 (m, 2H), 6.92 (d, J=10.4 Hz, 1H), 5.12-5.04 (m, 1H), 4.78-4.67 (m, 2H), 3.44-3.37 (m, 1H), 3.31-3.25 (m, 2H), 3.12-3.06 (m, 1H), 2.61 (s, 6H), 2.45-2.32 (m, 2H), 2.25-2.16 (m, 1H), 2.07-1.95 (m, 1H); MS (ESI) m/z 531.2 (M+H).sup.+.

    Example 281: (2R,4R)-7-bromo-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 380)

    Example 281A: 7-bromo-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1891] The reaction and purification conditions described in Examples 90B through 90C substituting 3-bromo-4-chloroanisole for 3,4-difluoroanisole gave the title compound. MS (APCI.sup.+) m/z 307 (M+H).sup.+.

    Example 281B: (2R)-7-bromo-6-chloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [1892] The product of Example 281A was purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 11 mL/minute, 100% ethanol (isocratic)] to give the title compound as the earlier eluting fraction. MS (APCI.sup.+) m/z 307 (M+H).sup.+.

    Example 281C: (2R,4)-7-bromo-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1893] The reaction and purification conditions described in Example 186B substituting the product of Example 247A for the product of Example 186A, and the product of Example 281B for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.38 (d, J=0.7 Hz, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.85-7.80 (m, 1H), 7.80-7.76 (m, 1H), 7.47 (d, J=1.0 Hz, 1H), 7.23 (s, 1H), 5.74 (s, 1H), 4.73 (dd, J=10.7, 5.3 Hz, 1H), 4.65 (dd, J=11.9, 2.5 Hz, 1H), 2.50 (s, 6H), 2.36-2.30 (m, 1H), 1.65 (ddd, J=12.9, 11.9, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 601 (M+H).sup.+.

    Example 282: 2-(3-bromo-4-chloro-5-fluorophenoxy)-N-[(1R,2S,4R,5S)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]acetamide (Compound 381)

    Example 282A: benzyl [(1R,2S,4R,5S)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]carbamate

    [1894] The reaction and purification conditions described in Example 2B substituting the product of Example 205A for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.51 (d, J=7.0 Hz, 1H), 7.40-7.27 (m, 5H), 7.21 (d, J=6.9 Hz, 1H), 5.04-4.94 (m, 2H), 4.47 (p, J=7.1 Hz, 1H), 3.74 (s, 2H), 3.69 (tt, J=6.9, 6.3 Hz, 1H), 3.51-3.45 (m, 1H), 3.31-3.25 (m, 1H), 2.72 (tdt, J=9.1, 5.7, 2.6 Hz, 2H), 2.18-2.10 (m, 2H), 2.09-2.05 (m, 1H), 2.04-2.00 (m, 1H), 1.60-1.50 (m, 2H), 1.39-1.28 (m, 3H), 1.26 (dt, J=13.1, 4.3 Hz, 1H); MS (APCI.sup.+) m/z 457 (M+H).sup.+.

    Example 282B: tert-butyl 2-(3-bromo-4-chloro-5-fluorophenoxy)acetate

    [1895] tert-Butyl bromoacetate (99 mg, 0.51 mmol), 3-bromo-4-chloro-5-fluorophenol (95 mg, 0.42 mmol), and potassium carbonate (146 mg, 1.05 mmol) were combined with N,N-dimethylformamide (0.6 mL) and stirred at 60 C. for 2 hours. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl acetate (10 mL) and aqueous HCl (10 mL, 0.2 M). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate in heptanes) to give the title compound (142 mg, 0.42 mmol, 99% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 6.99 (dd, J=2.8, 1.8 Hz, 1H), 6.71 (dd, J=10.1, 2.9 Hz, 1H), 4.48 (s, 2H), 1.49 (s, 9H).

    Example 282C: 2-(3-bromo-4-chloro-5-fluorophenoxy)acetic acid

    [1896] To a solution of the product of Example 282B (0.14 g, 0.41 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at ambient temperature for 2 days and then concentrated under high vacuum to give the title compound (0.107 g, 0.38 mmol, 92% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 13.16 (s, 1H), 7.27 (dd, J=2.8, 1.7 Hz, 1H), 7.19 (dd, J=11.0, 2.8 Hz, 1H), 4.80 (s, 2H).

    Example 2821): 2-(3-bromo-4-chloro-5-fluorophenoxy)-N-[(1R,2S,4R,5S)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]acetamide

    [1897] The reaction and purification conditions described in Example 1C substituting the product of Example 282A for the product of Example 1A, and the product of Example 282C for the product of Example 1B, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.92 (d, J=6.9 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.28 (dd, J=2.8, 1.7 Hz, 1H), 7.16 (dd, J=11.0, 2.8 Hz, 1H), 4.54 (M, 2H), 4.48 (p, J=7.0 Hz, 1H), 3.74 (s, 2H), 3.73-3.65 (m, 1H), 3.55-3.48 (m, 2H), 2.78-2.68 (m, 2H), 2.20-2.10 (m, 2H), 2.16-2.12 (m, 2H), 1.64-1.54 (m, 2H), 1.42-1.30 (m, 4H); MS (APCI.sup.+) m/z 589 (M+H).sup.+.

    Example 283: (2R,4R)-6-chloro-N-(3-{4-[(3S)-3-fluoropyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 382)

    [1898] The reaction and purification conditions described in Example 229 substituting (S)-3-fluoropyrrolidine hydrochloride for (2-methyl-2-(trifluoromethyl)pyrrolidine gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.24 (d, J=12.4 Hz, 1H), 7.86 (d, J=11.5 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.71 (d, J=6.2 Hz, 1H), 5.49-5.27 (m, 1H), 4.87-4.78 (m, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 4.03-3.56 (m, 3H), 3.52-3.41 (m, 1H), 2.55 (s, 6H), 2.38 (ddd, J=13.0, 5.9, 2.4 Hz, 1H), 2.26-1.99 (m, 2H), 1.73 (ddd, J=12.9, 12.1, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 475 (M+H).sup.+.

    Example 284: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 383)

    Example 284A: 4-iodo-1-(oxan-2-yl)-1H-pyrazole

    [1899] 2,2,2-Trifluoroacetic acid (0.138 mL, 1.804 mmol) was added to a mixture of 4-iodo-1H-pyrazole (7.0 g, 36.1 mmol) and 3,4-dihydro-2H-pyran (4.95 mL, 54.1 mmol), and the resulting mixture was stirred at 80 C. for 2 hours. The reaction mixture was cooled to ambient temperature and then partitioned between dichloromethane (150 mL) and 1 M aqueous NaOH (80 mL). The organic layer was dried (MgSO.sub.4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (120 g cartridge, 0-100% ethyl acetate/hexanes, dichloromethane loading) to afford the title compound (9.5 g, 33.5 mmol, 93% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.08 (s, 1H), 7.58 (s, 1H), 5.40 (dd, J=10.0, 2.5 Hz, 1H), 3.94-3.86 (m, 1H), 3.67-3.55 (m, 1H), 2.12-2.01 (m, 1H), 1.96-1.83 (m, 2H), 1.71-1.59 (m, 1H), 1.56-1.43 (m, 2H).

    Example 284B: tert-butyl 4-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-3-oxopiperazine-1-carboxylate

    [1900] At room temperature, a suspension of the product of Example 284A (500 mg, 1.798 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (300 mg, 1.498 mmol), copper(I) iodide (143 mg, 0.749 mmol) and potassium phosphate, tribasic (636 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL) was degassed by sparging with N.sub.2 for 10 minutes. N,N-Dimethylethane-1,2-diamine (0.190 mL, 1.498 mmol) was then added, and the reaction mixture was degassed for a further 5 minutes. The reaction mixture was then stirred at 120 C. for 19 hours and allowed to cool to ambient temperature. Water (100 mL) and ethyl acetate (50 mL) were added, and the mixture was filtered through a pad of diatomaceous earth, washing through with ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined extracts were washed with water (250 mL) and brine, dried over MgSO.sub.4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (24 g cartridge, 0-100% methanol/dichloromethane, ELS detection) to give the title compound (470 mg, 1.033 mmol, 68.9% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.13 (s, 1H), 7.72 (s, 1H), 5.36 (dd, J=10.1, 2.4 Hz, 1H), 4.06 (s, 2H), 3.93-3.85 (m, 1H), 3.73-3.55 (m, 5H), 2.10-1.98 (m, 1H), 1.96-1.83 (m, 2H), 1.72-1.58 (m, 1H), 1.56-1.48 (m, 2H), 1.42 (s, 9H).

    Example 284C: tert-butyl 3-oxo-4-(1H-pyrazol-4-yl)piperazine-1-carboxylate

    [1901] At ambient temperature, hydrochloric acid (2.0 M in diethyl ether) (0.919 mL, 1.838 mmol) was added dropwise to a solution of the product of Example 284B (322 mg, 0.919 mmol) in methanol (15 mL). The reaction mixture was stirred at ambient temperature for 45 minutes. Triethylamine (512 L, 3.68 mmol) was added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (4 g cartridge, 0-10% methanol/dichloromethane, ELS detection) to give the title compound (145 mg, 0.463 mmol, 50.4% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.76 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 4.05 (s, 2H), 3.73-3.61 (m, 4H), 1.42 (s, 9H).

    Example 284D: tert-butyl 4-{1-[3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl]-1H-pyrazol-4-yl}-3-oxopiperazine-1-carboxylate

    [1902] A mixture of dimethyl 3,3-{[(2,4,6-trimethylphenyl)-3-iodanediyl]bis(oxycarbonyl)}di(bicyclo[1.1.1]pentane-1-carboxylate) (5.49 g, 9.39 mmol, prepared as described in Nature, 559, 83-88 (2018)) (5.49 g, 9.39 mmol), 1,10-phenanthroline (1.692 g, 9.39 mmol) and the product of Example 284C (2.5 g, 9.39 mmol) in dioxane (75 mL) degassed by purging with nitrogen under sonication for 15 minutes. Then ((thiophene-2-carbonyl)oxy)copper (1.794 g, 9.41 mmol) was added in one portion. The mixture was mixed under sonication for 5 minutes. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was filtered through diatomaceous earth and washed through with acetonitrile (400 mL). The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (120 g cartridge, 0-100% ethyl acetate/hexanes) to afford the title compound (1.00 g, 2.331 mmol, 24.83% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.07 (s, 1H), 7.74 (s, 1H), 4.05 (s, 2H), 3.71-3.61 (m, 7H), 2.47 (s, 6H), 1.41 (s, 9H).

    Example 284E: methyl 3-[4-(2-oxopiperazin-1-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentane-1-carboxylate hydrochloride

    [1903] At ambient temperature, hydrochloric acid (15.75 mL, 63.0 mmol, 4.0 M in dioxane) was added to a suspension of the product of Example 284D (1.23 g, 3.15 mmol) in dioxane (30 mL). The reaction mixture was stirred at ambient temperature for 22 hours. The reaction mixture was concentrated to give the title compound (1.17 g, 2.83 mmol, 90% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.80 (s, 2H), 8.12 (s, 1H), 7.79 (s, J H), 3.89-3.85 (m, 4H), 3.66 (s, 3H), 3.55-3.48 (m, 2H), 2.49 (s, 6H+dimethyl sulfoxide).

    Example 284F: methyl 3-{4-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylate

    [1904] To a solution of the product of Example 284E (549 mg, 1.680 mmol) in acetonitrile (10 mL) was added cesium carbonate (1368 mg, 4.20 mmol), potassium iodide (84 mg, 0.504 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.399 mL, 2.77 mmol), and the reaction mixture was stirred at ambient temperature for 21 hours. Water (50 mL) was added, and the aqueous solution was extracted with ethyl acetate (250 mL); the combined organic layers were then washed with brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g cartridge, 0-100% ethanol/ethyl acetate) to afford the title compound (355 mg, 0.858 mmol, 51.1% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.08 (d, J=1.8 Hz, 1H), 7.75 (s, 0.5H), 7.74 (s, 0.5H), 4.74 (q, J=9.3 Hz, 1H), 4.14 (d, J=11.8 Hz, 1H), 3.74 (s, 2H), 3.65 (s, 3H), 3.65-3.61 (m, 1H), 3.41 (s, 1H), 3.35 (q, J=10.1 Hz, 1H), 3.02 (t, J=5.5 Hz, 1H), 2.48 (s, 6H).

    Example 284G: 3-{4-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentane-1-carboxylic acid

    [1905] At ambient temperature, under an atmosphere of nitrogen, an aqueous solution of sodium hydroxide (1.30 mL, 3.25 mmol) was added to a solution of the product of Example 284F (335 mg, 0.900 mmol) in methanol (2.0 mL). The reaction mixture was stirred at ambient temperature for 1 hour, and was then concentrated. The aqueous solution was adjusted to pH 8 by addition of aqueous citric acid (10% w/v). Toluene (2.0 mL) was then added, and the mixture was concentrated. The residue was purified by reverse phase chromatography (C18 silica, 12 g cartridge, 0-100% acetonitrile (0.1% formic acid)/water (0.1% formic acid) to give the title compound (108 mg, 0.283 mmol, 31.5% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.75 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 3.63 (t, J=5.5 Hz, 2H), 3.41 (s, 2H), 3.39-3.32 (m, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.42 (s, 6H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 68.26 (t, J=9.9 Hz).

    Example 284H: tert-butyl (3-{4-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazoyl-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1906] At 58 C. under an atmosphere of nitrogen, diphenyl phosphorazidate (0.097 mL, 0.452 mmol) was added to a suspension of the product of Example 284G (108 mg, 0.301 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.105 mL, 0.603 mmol) in t-butanol (7.5 mL). The reaction mixture was stirred at 58 C. for 18 hours and then allowed to cool to ambient temperature. The volatiles were then removed under reduced pressure. The residue was purified by flash chromatography on silica gel (12 g cartridge, 0-100% [0.7 M NH.sub.3 in methanol]/CH.sub.2Cl.sub.2) to afford the title compound (81 mg, 0.170 mmol, 56.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.01 (s, 1H), 7.73 (br s, 1H), 7.71 (s, 1H), 3.66-3.61 (m, 2H), 3.41 (s, 2H), 3.35 (q, J=11.2, 10.6 Hz, 2H), 3.01 (t, J=5.5 Hz, 2H), 2.35 (s, 6H), 1.39 (s, 9H).

    Example 2841: 1-[1-(3-aminobicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl]-4-(2,2,2-trifluoroethyl)piperazin-2-one

    [1907] At ambient temperature, trifluoroacetic acid (0.145 mL, 1.886 mmol) was added to a solution of the product of Example 284H (81 mg, 0.189 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at ambient temperature for 2 hours, and was concentrated in vacuo. The residue was purified by catch and release, using an SCX cartridge (800 mg), loading by gravity in methanol (3.0 mL), flushing with methanol (4.0 mL) and with NH.sub.3 (7 N in methanol, 4.0 mL) to give the title compound (59 mg, 0.170 mmol, 90% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.96 (d, J=0.8 Hz, 1H), 7.69 (d, J=0.7 Hz, 1H), 3.66-3.59 (m, 2H), 3.40 (s, 2H), 3.39-3.32 (m, 2H), 3.02-2.99 (m, 2H), 2.39-2.34 (m, 1H), 2.13 (s, 6H).

    Example 284J: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1908] The title compound was synthesized using the same procedure as described in Example 136D substituting Example 136C with Example 2841. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 8.05 (d, J=0.7 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.6, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.81 (dd, J=10.8, 6.0 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.64 (dd, J=6.4, 4.7 Hz, 2H), 3.42 (s, 2H), 3.36 (q, J=10.2 Hz, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.49 (s, 6H+dimethyl sulfoxide), 2.36 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 1.71 (td, J=12.3, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 540.3 (M+H).sup.+.

    Example 285: (2R,4R)-6-chloro-N-{3-[4-(3,3-difluoropyrrolidine-1-carbonyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 384)

    [1909] The reaction and purification conditions described in Example 229, substituting (3,3-difluoropyrrolidine hydrochloride for (2-methyl-2-(trifluoromethyl)pyrrolidine (Enamine), gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (dd, J=8.6, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.73 (d, J=5.7 Hz, 1H), 4.86-4.79 (m, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 4.21-4.08 (m, 1H), 3.97-3.78 (m, 2H), 3.72-3.60 (m, 1H), 2.55 (s, 6H), 2.53-2.33 (m, 3H), 1.73 (td, J=12.4, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 493 (M+H).sup.+.

    Example 286: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 385)

    Example 286A: cis-1-ethynyl-3-(trifluoromethoxy)cyclobutane

    [1910] To a solution of product of Example 167B (874 mg, 5.20 mmol) in methanol (10.0 mL) cooled to 0 C. was added dimethyl (1-diazo-2-oxopropyl)phosphonate (1.623 mL, 6.76 mmol) followed by potassium carbonate (1.653 g, 11.96 mmol) and the resultant reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water (420 mL) followed by brine (20 mL). The organic phases were passed through a hydrophobic phase separator, then concentrated under reduced pressure (300 mbar, 20 C.), to afford the title compound (853 mg, 100% yield). The title compound was used immediately in the subsequent step without further purification.

    Example 286B: tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate

    [1911] To a solution of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (100 mg, 0.504 mmol) in methanol (2.5 mL) were added potassium carbonate (119 mg, 0.857 mmol), copper(II) sulfate pentahydrate (1.3 mg, 5.04 mol), and imidazole-1-sulfonyl azide hydrochloride (117 mg, 0.555 mmol) and the resultant dispersion was stirred at ambient temperature for 48 hours under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and water (10 mL) was added to the residue. The aqueous mixture was acidified to pH 3 with 1 M aqueous HCl and then extracted with ethyl acetate (310 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford the title compound (11 mg, 79.0% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 2.24 (s, 6H), 1.46 (s, 9H), 1H exchangeable proton not observed.

    Example 286C: tert-butyl (3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1912] To a mixture of the product of Example 286B (140 mg, 0.624 mmol) and copper(II) sulfate (2.99 mg, 0.019 mmol) in tert-butanol (3 mL) and water (1 mL) was added the product of Example 286A (123 mg, 0.749 mmol), benzoic acid (19.06 mg, 0.156 mmol) and sodium ascorbate (5.57 mg, 0.028 mmol) at ambient temperature in a microwave tube. The microwave tube was flushed with N.sub.2, sealed, and stirred at 80 C. overnight. The reaction mixture was cooled to ambient temperature and poured onto water (20 mL) and extracted with ethyl acetate (320 mL). The combined organic phases were washed with brine (20 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/hexanes) to afford the title compound (85 mg, 26.8% yield).

    [1913] MS (ESI) m/z 389 (M+H).sup.+.

    Example 286D: 3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1914] To a solution of the product of Example 286C (84 mg, 0.216 mmol) in dichloromethane (2.0 mL) at ambient temperature was added trifluoroacetic acid (1.0 mL, 12.98 mmol) and the reaction mixture was stirred for 30 minutes. The reaction mixture was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (56 mg, 87.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.11-8.06 (m, 1H), 4.82 (p, J=7.5 Hz, 1H), 3.21-3.10 (m, 1H), 2.78-2.66 (m, 2H), 2.48 (s, 2H), 2.41-2.29 (m, 2H), 2.23 (s, 6H); MS (ESI) m/z 289 (M+H).sup.+.

    Example 286E: (2R)-6-chloro-4-oxo-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-11H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1915] To a solution of the product of Example 286D (40 mg, 0.139 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (37.7 mg, 0.167 mmol, Example 1B) and triethylamine (0.116 mL, 0.833 mmol) in N,N-dimethylformamide (2.0 mL), at ambient temperature under nitrogen, was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 79 mg, 0.208 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL) and the aqueous phase was extracted with dichloromethane (32.0 mL). The combined organic phases were then passed through a hydrophobic phase separator, washed with brine (2.0 mL), passed through a hydrophobic phase separator, and concentrated in vacuo to afford the title compound (79 mg, 100% yield). MS (ESI) m/z 497/499 (M+H).sup.+.

    Example 286F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1916] The methodologies described in Example 5 substituting the product of Example 286E for the product of Example 4 and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 25-55% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (32 mg, 45.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.18 (s, 1H), 7.41-7.37 (m, 1H), 7.21 (dd, J=8.6, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=5.8 Hz, 1H), 4.88-4.79 (m, 2H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 3.23-3.13 (m, 1H), 2.79-2.71 (m, 2H), 2.61 (s, 6H), 2.42-2.31 (m, 3H), 1.78-1.67 (m, 1H); MS (ESI) m/z 499/501 (M+H).sup.+.

    Example 287: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 386)

    Example 287A: ethyl (2Z)-3-(dimethylamino)-2-isocyanoprop-2-enoate

    [1917] To a solution of ethyl 2-isocyanoacetate (1.932 mL, 17.68 mmol) in ethanol (20 mL), under nitrogen at 0 C., was added N,N-dimethylformamide dimethyl acetal (4.73 mL, 35.4 mmol) and the reaction mixture warmed to ambient temperature and stirred over 72 hours. The reaction mixture was concentrated in vacuo to afford the title compound. MS (ESI.sup.+) m/z 169.0 (M+H).sup.+.

    Example 287B: ethyl 1-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)-1H-imidazole-4-carboxylate

    [1918] A solution of the product of Example 287A (817 mg, 4.86 mmol) and tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (963 mg, 4.86 mmol, PharmaBlock) in xylene (15 mL) was degassed by purging with nitrogen for 10 minutes. The reaction mixture was then stirred at 150 C. under microwave irradiation (Biotage Initiator EXP EU) for 1 hour, and was then allowed to stand at ambient temperature overnight. Another portion of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (482 mg, 2.429 mmol) was added, the reaction mixture was degassed by purging with nitrogen for 10 minutes, and stirred at 150 C. under microwave irradiation for 1 hour. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (80 g cartridge, 0-10% (0.7 M NH.sub.3 in methanol)/CH.sub.2Cl.sub.2) to afford the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.93 (d, J=1.4 Hz, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.75 (br s, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.39 (s, 6H), 1.38 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).

    Example 287C: 1-{3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentan-1-yl}-1H-imidazole-4-carboxylic acid

    [1919] At ambient temperature, lithium hydroxide hydrate (82 mg, 1.960 mmol) in water (1.000 mL) was added to a solution of the product of Example 287B (420 mg, 1.307 mmol) in tetrahydrofuran (3 mL) and methanol (1.000 mL). The reaction mixture was stirred at ambient temperature for 4 hours and was then concentrated. Water (2.0 mL) was added to the residue, and the suspension was adjusted to pH 5 with aqueous citric acid (10%). Methanol was added until mixture was homogeneous. Diatomaceous earth was added and the solvent was removed in vacuo. The crude mixture was purified by flash chromatography on C18 reverse phase silica (12 g cartridge, 0-100% [0.1% formic acid in acetonitrile]/[0.1% formic acid in water]) to give the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.10 (br s, 1H), 7.87 (s, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.76 (br s, 1H), 2.40 (s, 6H), 1.39 (s, 9H).

    Example 287D: tert-butyl (3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1920] At 0 C., 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.030 mL, 0.225 mmol) was added to a suspension of the product of Example 287C (60 mg, 0.205 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at this temperature for 10 minutes. After this, pyridine (0.025 mL, 0.307 mmol), and then a solution of (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride (41.1 mg, 0.215 mmol, PharmaBlock) in dichloromethane (2.0 mL) were added, and the reaction mixture was stirred at 0 C. for 90 minutes. Water (10 mL) was added, and the suspension was extracted with dichloromethane (10 mL). A small amount of brine was added to the aqueous layer, and the mixture was extracted with dichloromethane (210 mL). The combined extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (12 g cartridge, 0-10% [0.7 M NH.sub.3 in methanol]/CH.sub.2Cl.sub.2) to afford the title compound (67 mg, 0.151 mmol, 73.8% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.77 (s, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.76 (br s, 1H), 5.18-5.08 (m, 1H), 4.40-3.46 (m, 4H), 2.39 (s, 6H), 2.27-2.04 (m, 2H), 1.39 (s, 9H).

    Example 287E: [1-(3-aminobicyclo[1.1.1]pentan-1-yl)-1H-imidazol-4-yl][(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]methanone

    [1921] At ambient temperature, trifluoroacetic acid (0.120 mL, 1.557 mmol) was added to a solution of the product of Example 287D (67 mg, 0.156 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then was concentrated in vacuo. The residue was purified by catch and release (SCX 950 mg cartridge, loaded with methanol (3.0 mL), flushed with methanol (3.0 mL) and NH.sub.3 (7 N in methanol, 3.0 mL)) to give the title compound (46 mg, 0.138 mmol, 89% yield). MS (ESI.sup.+) m/z 331.0 (M+H).sup.+.

    Example 287F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1922] At 0 C., (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (39.7 mg, 0.104 mmol) was added to a solution of the product of Example 287E (23 mg, 0.070 mmol), the product of Example 1B (18.94 mg, 0.084 mmol) and N,N-diisopropylethylamine (0.073 mL, 0.418 mmol) in dichloromethane (2.0 mL). The reaction mixture was then allowed to stir at ambient temperature for 2 hours. Water (10 mL) was added and the suspension was extracted with dichloromethane (10 mL). A small amount of brine was added to the aqueous layer, and the mixture was extracted with dichloromethane (210 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give (2R)-6-chloro-4-oxo-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide which was used without further purification. At 0 C., sodium borohydride (8.56 mg, 0.226 mmol) was added to a solution of (2R)-6-chloro-4-oxo-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (61 mg, 0.113 mmol) in methanol (2.0 mL). The reaction mixture was stirred at this temperature for 2 hours. Saturated aqueous NH.sub.4Cl (10 mL) was added, and the reaction mixture was stirred vigorously for 30 minutes and allowed to stand at ambient temperature overnight. The suspension was extracted with dichloromethane (310 mL). The combined extracts were dried over MgSO.sub.4, filtered and concentrated. The residue (40 mg) was purified by HPLC (Waters XSelect Prep-C18, 5 m column (19 mm50 mm). A 35-65% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water was used over 7.5 minutes, at a flow rate of 30 mL/minute) to give the title compound (17.7 mg, 0.031 mmol, 27.8% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 5.14 (d, J=25.4 Hz, 1H), 4.88-4.77 (m, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 4.45-3.45 (m, 4H), 2.55 (s, 6H), 2.37 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 2.28-2.05 (m, 2H), 1.72 (td, J=12.5, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 541.0 (M+H).sup.+.

    Example 288: 2-(4-chloro-3-fluorophenoxy)-N-[3-(1-methyl-5-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 387)

    Example 288A: (cis-3-(trifluoromethoxy)cyclobutyl)methanol

    [1923] To a solution of the product of Example 25N (26.9 g, 98 mmol) in tetrahydrofuran (400 mL) was added lithium aluminum hydride (4.45 g, 117 mmol) in portions at 0 C. under nitrogen. The mixture was stirred at 0 C. for 0.5 hour. The mixture was quenched with water (5 mL) and stirred at 20 C. for 5 minutes. NaOH (15% aqueous, 5 mL) was added to this solution. After 5 minutes, water (15 mL) was added to this solution. Then the mixture was diluted with ethyl acetate (500 mL). After stirring for 30 minutes, the mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated. The residue was purified by flash column (petroleum ether: ethyl acetate=20:1) to give the title compound (11 g, yield 66.0%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.57 (quin, J=7.4 Hz, 1H), 3.65 (d, J=5.5 Hz, 2H), 2.55-2.37 (m, 2H), 2.19-1.93 (m, 3H), 1.43 (br s, 1H).

    Example 288B: (cis-3-(trifluoromethoxy)cyclobutyl)methyl 4-methylbenzenesulfonate

    [1924] To a solution of the product of Example 288A (280 mg, 1.646 mmol) and triethylamine (0.573 mL, 4.11 mmol) in dichloromethane (7.5 mL), 4-methylbenzene-1-sulfonyl chloride (471 mg, 2.469 mmol) was added dropwise at 0 C., then the reaction mixture was warmed up to ambient temperature and stirred overnight. The reaction mixture was directly loaded onto a silica gel column and eluted with 0-50% ethyl acetate in heptane to give 480 mg of the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) J ppm 7.82-7.77 (m, 2H), 7.52-7.47 (m, 2H), 4.71-4.63 (m, 1H), 4.04 (d, J=6.0 Hz, 2H), 2.43 (s, 3H), 2.35 (tdd, J=9.6, 4.8, 2.2 Hz, 2H), 2.26-2.15 (m, 1H), 1.93-1.84 (m, 2H).

    Example 288C: 2-(4-chloro-3-fluorophenoxy)-N-[3-(1-methyl-5-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-3-yl)bicyclo[1.1.1]pentan-1-yl]acetamide

    [1925] The title compound was synthesized using the same procedures as described in Example 246I substituting the product of Example 246H with the product of Example 288B. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.70 (s, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.86 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 5.53 (s, 1H), 4.75 (p, J=7.4 Hz, 1H), 4.48 (s, 2H), 4.03 (d, J=5.8 Hz, 2H), 3.47 (s, 3H), 2.46 (ddd, J=11.8, 5.9, 2.7 Hz, 2H), 2.41-2.27 (m, 1H), 2.20 (s, 6H), 2.05 (dt, J=11.8, 9.2 Hz, 2H); MS (APCI.sup.+) m/z 518.61 (M+H).sup.+.

    Example 289: (2S,4R)-6-chloro-4-hydroxy-N-[(1R,2S,4R,5S)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 388)

    [1926] The reaction and purification conditions described in Example 1C substituting the product of Example 282A for the product of Example 1A, and the product of Example 73B for the product of Example 1B, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.89 (d, J=6.9 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.23 (dd, J=8.8, 2.6 Hz, 1H), 6.92 (d, J=8.7 Hz, 1H), 5.59 (d, J=4.4 Hz, 1H), 4.62-4.56 (m, 2H), 4.48 (p, J=7.2 Hz, 1H), 3.75 (s, 2H), 3.73-3.66 (m, 1H), 3.58-3.47 (m, 2H), 2.78-2.68 (m, 2H), 2.18-2.10 (m, 3H), 2.10-2.06 (m, 1H), 2.04 (ddd, J=13.9, 3.9, 2.9 Hz, 1H), 1.93 (ddd, J=14.1, 10.6, 3.8 Hz, 1H), 1.59 (ddt, J=12.6, 8.1, 2.2 Hz, 2H), 1.46-1.32 (m, 4H); MS (APCI.sup.+) m/z 533 (M+H).sup.+.

    Example 290: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 389)

    Example 290A: 3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1927] To a solution of the product from Example 280A (149 mg, 0.370 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.57 mL, 7.4 mmol), and the resulting solution was stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo and the residue was diluted with methanol (2 mL) and stirred with SCX resin (0.3 g) for 15 minutes. The mixture was loaded onto a column of SCX resin (1 g), and the resin was washed with methanol (35 mL). The product was then eluted with 7 N ammonia in methanol (35 mL) to give the title compound as an oil (132 mg, 100% yield). MS (ESI) m/z 303.2 (M+H).sup.+.

    Example 290B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1928] To a solution of the product from Example 290A (24 mg, 0.068 mmol), the product from Example 262C (20 mg, 0.082 mmol) and triethylamine (0.057 ml, 0.41 mmol) in N,N-dimethylformamide (1 mL) was added (I-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 39 mg, 0.10 mmol), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was partitioned between aqueous saturated NaHCO.sub.3 (0.5 mL) and dichloromethane (22 mL), and the combined organic layers were then passed through a hydrophobic phase separator, washed with brine (2 mL), passed through a hydrophobic phase separator, and concentrated in vacuo. The residue was dissolved in methanol (1 mL), and sodium borohydride (31 mg, 0.82 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, was quenched with saturated aqueous ammonium chloride (0.5 mL), and was extracted with dichloromethane (32 mL). The combined organic layers were passed through a phase separator, washed with brine (2 mL), passed through a phase separator, and concentrated in vacuo. The crude product was purified by C18 reversed phase preparative HPLC using a solvent gradient of 5-100% acetonitrile in buffer (0.3% ammonia in water) to afford the title compound (5.2 mg, 14% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.51 (d, J=8.3, 1.0 Hz, 1H), 7.22 (s, 2H), 6.86 (d, J=10.3 Hz, 1H), 5.11-5.03 (m, 1H), 4.93-4.89 (m, 1H), 4.70 (dd, J=11.5, 2.5 Hz, 1H), 3.44-3.36 (m, 1H), 3.31-3.26 (m, 2H), 3.13-3.05 (m, 1H), 2.61 (s, 6H), 2.59-2.54 (m, 1H), 2.44-2.32 (m, 1H), 2.27-2.15 (m, 1H), 1.97-1.86 (m, 1H); MS (ESI) m/z 531.2 (M+H).sup.+.

    Example 291: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbothioyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 390)

    Example 291A: tert-butyl (3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbothioyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1929] The product of Example 272B (28 mg, 0.064 mmol) was combined with Lawesson's Reagent (14.5 mg, 0.036 mmol) in dioxane (2.0 mL) and stirred at 70 C. for 10 hours and then at 75 C. for 24 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (1 mL), and the mixture was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (9 mg, 0.02 mmol, 31% yield). MS (APCI.sup.+) m/z 447 (M+H).sup.+.

    Example 291B: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbothioyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1930] The reaction and purification conditions described in Example 272C substituting the product of Example 291A for the product of 272B, and (1-[bis(dimethylamino)methylene]-11H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) for (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.27 and 8.20 (two d, J=0.7 Hz, thioamide rotamers), 7.94 and 7.88 (two d, J=0.7 Hz, 1H, thioamide rotamers), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.6 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=5.2 Hz, 1H), 5.29-5.20 (m, 1H), 4.87-4.79 (m, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 4.30-4.23 and 4.15-4.03 (two in, 2H, thioamide rotamers), 4.03-3.94 and 3.94-3.84 (two m, 2H, thioamide rotamers), 2.59-2.51 (m, 6H), 2.45-2.22 (m, 3H), 1.78-1.67 (m, 1H); MS (APCI.sup.+) m/z 557 (M+H).sup.+.

    Example 292: (2R,4R)-6-chloro-N-(3-{4-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 391)

    Example 292A: 5-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-4-(4-methylbenzene-1-sulfonyl)-4,5-dihydro-1,3-oxazole

    [1931] To a solution of 2,3-difluoro-4-(trifluoromethoxy)benzaldehyde (purchased from Apollo, 500 mg, 2.21 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (432 mg, 2.21 mmol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL, 0.22 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then was concentrated in vacuo to afford the title intermediate (1.14 g, 1.92 mmol, 87% yield), which was carried forward without further purification. MS (ESI.sup.30) m/z 422 (M+H).sup.+.

    Example 292B: tert-butyl (3-{4-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1932] A mixture of the product of Example 292A (1.14 g, 1.92 mmol), tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.571 g, 2.88 mmol) and xylene (20 mL) was heated to 135 C. and stirred for 18 hours. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified by silica gel column chromatography (0-100% ethyl acetate/isohexane) to afford the title intermediate (0.246 g, 0.442 mmol, 23% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.95-7.90 (m, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.78 (s, 1H), 7.71-7.67 (m, 1H), 7.47 (t, J=8.3 Hz, 1H), 2.44 (s, 6H), 1.41 (s, 9H); MS (ESI.sup.+) m/z 446 (M+H).sup.+.

    Example 292C: (2R,4R)-6-chloro-N-(3-{4-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1933] To a solution the product of Example 292B (246 mg, 0.552 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL, 26.0 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. Then the volatiles were removed under reduced pressure to give 3-{4-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-amine (200 mg, 0.550 mmol, quantitative yield), which was carried forward without further purification.

    [1934] The methodologies described in Example 253G substituting this intermediate, 3-{4-[2,3-difluoro-4-(trifluoromethoxy)phenyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-amine, for the product of Example 253F gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.96-7.92 (m, 2H), 7.74 (dd, J=3.8, 1.3 Hz, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (dd, J=8.6, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.91-5.59 (m, 1H), 4.87-4.80 (m, 1H), 4.67 (dd, J=12.0, 2.3 Hz, 1H), 2.59 (s, 6H), 2.41-2.37 (m, 1H), 1.79-1.68 (m, 1H); MS (ESI.sup.30) m/z 556 (M+H).sup.+.

    Example 293: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)piperidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 392)

    Example 293A: tert-butyl (3R)-3-(trifluoromethoxy)piperidine-1-carboxylate

    [1935] A mixture of silver(1) trifluoromethanesulfonate (3.45 g, 13.42 mmol), potassium fluoride (1.155 g, 19.87 mmol), and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate) (2.64 g, 7.45 mmol was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol, Apollo Scientific) in ethyl acetate (15 mL) followed by the dropwise addition of 2-fluoropyridine (1.283 mL, 14.91 mmol) and then trimethyl(trifluoromethyl)silane (2.203 mL, 14.91 mmol). The reaction mixture then stirred at ambient temperature for 2 days. The crude reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, solid loading, 0-50% ethyl acetate/isohexane) to afford the title compound (1.2098 g, 4.27 mmol, 86% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.46 (s, 1H), 3.79-2.97 (m, 4H), 1.94-1.55 (m, 3H), 1.52-1.43 (m, 1H), 1.38 (s, 9H).

    Example 293B: (3R)-3-(trifluoromethoxy)piperidine hydrochloride

    [1936] A solution of the product of Example 293A (625 mg, 2.321 mmol) in ethyl acetate (3 mL) and hydrogen chloride (4 N in dioxane) (5.80 mL, 23.21 mmol) was mixed under cooling with ice and then stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (502 mg, 2.321 mmol, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.93-8.80 (m, 2H), 4.83-4.76 (m, 1H), 3.33-3.27 (m, 1H), 3.22-3.15 (m, 1H), 3.08-2.95 (m, 2H), 2.01-1.92 (m, 1H), 1.88-1.68 (m, 3H).

    Example 293C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)piperidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1937] The title compound was synthesized using the same procedures as described in Example 287D through Example 287F substituting (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride with the product of Example 293B. .sup.1H NMR (500 MHz, CD.sub.3OD) ppm 8.02 (s, 1H), 7.78 (s, 1H), 7.46-7.43 (m, 1H), 7.18 (dd, J=8.7, 2.7, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.99-4.91 (m, 1H), 4.67 (dd, J=11.5, 2.5 Hz, 1H), 4.58-4.50 (m, 1H), 4.08-3.75 (m, 4H), 2.68 (s, 6H), 2.61-2.53 (m, 1H), 2.13-1.84 (m, 5H), 1.72-1.61 (m, 1H); MS (ESI.sup.+) m/z 541.0 (M+H).sup.+.

    Example 294: (2S,4R)-6-chloro-4-hydroxy-N-[(1S,2R,4S,5R)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 393)

    Example 294A: benzyl ((1S,2R,4S,5R)-5-aminobicyclo[2.2.1]heptan-2-yl)carbamate

    [1938] The product of Example 11 ID was purified via chiral separation to give 2 enantiomers. Chiral SFC using Column: (S,S)-Whelk-O1, 25030 mm, 10 um, Mobile phase: A: CO.sub.2, B: ethanol (0.1% NH.sub.3), Gradient: 30% B, flow rate: 58 g/minute; column temperature: 40 C.; system back pressure: 100 bar gave the title intermediate as the earlier eluting isomer. MS (ESI.sup.+) m/z 261 (M+H).sup.+.

    Example 294B: benzyl [(1S,2R,4S,5R)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]carbamate

    [1939] The reaction and purification conditions described in Example 2B substituting the product of Example 294A for the product of Example 2A, and the product of Example 13P for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.51 (d, J=7.0 Hz, 1H), 7.38-7.33 (m, 4H), 7.32-7.29 (m, J H), 7.22 (d, J=7.0 Hz, 1H), 5.03-4.94 (m, 2H), 4.47 (p, J=7.1 Hz, 1H), 3.74 (s, 2H), 3.72-3.67 (m, 1H), 3.51-3.45 (m, 1H), 3.32-3.26 (m, 1H), 2.76-2.68 (m, 2H), 2.20-2.10 (m, 2H), 2.09-2.05 (m, 1H), 2.04-2.00 (m, 1H), 1.58-1.51 (m, 2H), 1.38-1.29 (m, 3H), 1.26 (dt, J=13.2, 4.4 Hz, 1H); MS (APCI.sup.+) m/z 457 (M+H).sup.+.

    Example 294C: (2S,4R)-6-chloro-4-hydroxy-N-[(1S,2R,4S,5R)-5-(2-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1940] The reaction and purification conditions described in Example 1C substituting the product of Example 294B for the product of Example 1A, and the product of Example 73B for the product of Example 1B, and also raising the reaction temperature for the first step from ambient temperature in trifluoroacetic acid to 70 C. in trifluoroacetic acid gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.90 (d, J=6.9 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.23 (dd, J=8.7, 2.7 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.60 (d, J=4.1 Hz, 1H), 4.61-4.56 (m, 2H), 4.48 (p, J=7.1 Hz, 1H), 3.75 (s, 2H), 3.73-3.66 (m, 1H), 3.52 (qd, J=8.1, 3.5 Hz, 2H), 2.77-2.69 (m, 2H), 2.18-2.11 (m, 2H), 2.11-2.06 (m, 2H), 2.04 (ddd, J=13.9, 3.9, 2.9 Hz, 1H), 1.93 (ddd, J=14.1, 10.7, 3.8 Hz, 1H), 1.64-1.55 (m, 2H), 1.37 (dtd, J=17.3, 8.8, 4.6 Hz, 4H); MS (APCI.sup.+) m/z 533 (M+H).sup.+.

    Example 295: (2R,4R)-6-chloro-N-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-imidazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 394)

    [1941] The methodologies described in Example 292 substituting 4-chloro-2,3-difluorobenzaldehyde (purchased from Apollo) for 2,3-difluoro-4-(trifluoromethoxy)benzaldehyde in the first step of the reaction sequence resulted in the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.86 (t, J=7.2 Hz, 1H), 7.74-7.67 (m, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 7.22 (dd, J=8.6, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (s, 1H), 4.86-4.80 (m, 1H), 4.67 (dd, J=12.1, 2.3 Hz, 1H), 2.58 (s, 6H), 2.41-2.37 (m, 1H), 1.74 (q, J=11.9 Hz, 1H); MS (ESI.sup.+) m/z 507 (M+H).sup.+.

    Example 296: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)azetidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 395)

    Example 296A: 3-(trigluoromethoxy)azetidine hydrochloride

    [1942] The title compound was synthesized using the same procedures as described in Example 293A through Example 293B substituting (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate with tert-butyl 3-hydroxyazetidine-1-carboxylate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.46 (s, 1H), 9.07 (s, 1H), 5.20 (tt, J=7.0, 5.2 Hz, 1H), 4.26 (s, 2H), 4.12-3.97 (m, 2H).

    Example 296B: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)azetidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1943] The title compound was synthesized using the same procedures as described in Example 287D through Example 287F substituting (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride with the product of Example 296A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.80 (d, J=1.4 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.3 Hz, 1H), 5.23 (tt, J=7.0, 3.9 Hz, 1H), 4.91-4.84 (m, 1H), 4.81 (dt, J=11.4, 6.0 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.54-4.45 (m, 1H), 4.42-4.32 (m, 1H), 4.02 (d, J=11.4 Hz, 1H), 2.53 (s, 6H), 2.36 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.77-1.65 (m, 1H); MS (ESI.sup.+) m/z 527.2 (M+H).sup.+.

    Example 297: (2S,4R)-6-chloro-4-hydroxy-N-{3-[4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 396)

    [1944] The reaction and purification conditions described in Example 1C substituting the product of Example 220A for the product of Example 1A, and the product of Example 73B for the product of Example 1B gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.86 (s, 2H), 8.37 (d, J=0.8 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (d, J=4.7 Hz, 1H), 4.63-4.58 (m, 2H), 3.92 (s, 3H), 2.55 (s, 6H), 2.13 (ddd, J=13.9, 3.7, 2.8 Hz, 1H), 1.93 (ddd, J=13.9, 11.1, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 468 (M+H).sup.+.

    Example 298: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 397)

    Example 298A: tert-butyl (3R)-3-[(trifluoromethoxy)methyl]pyrrolidine-1-carboxylate

    [1945] A mixture of silver(1) trifluoromethanesulfonate (3.45 g, 13.4 mmol), potassium fluoride (1.16 g, 19.9 mmol), and Selectfluor (1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate) (2.64 g, 7.45 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this reaction mixture was slowly added a solution of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.97 mmol, purchased from Fluorochem) in ethyl acetate (30 mL) followed by the dropwise addition of 2-fluoropyridine (1.3 mL, 14.9 mmol) and trimethyl(trifluoromethyl)silane (2.2 mL, 14.9 mmol). The reaction mixture was stirred at ambient temperature for 2 days, was filtered through a pad of diatomaceous earth, and dry-loaded onto silica. The crude material was purified by silica gel column chromatography (0-50% ethyl acetate/isohexane) to afford the title intermediate (409 mg, 1.44 mmol, 29% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.12-4.02 (m, 2H), 3.44-3.32 (m, 2H), 3.25-3.16 (m, 1H), 3.04-2.95 (m, 1H), 2.60-2.52 (m, 1H), 2.01-1.90 (m, 1H), 1.68-1.57 (m, 1H), 1.39 (s, 9H).

    Example 298B: (3R)-3-[(trifluoromethoxy)methyl]pyrrolidine

    [1946] To the product of Example 298A (409 mg, 1.52 mmol) in dioxane (1 mL) was added hydrogen chloride (4 N in dioxane, 3.8 mL, 15.2 mmol) at ambient temperature and then the reaction mixture stirred overnight. The reaction mixture was concentrated under reduced pressure to give the title intermediate as an HCl salt (309 mg, 1.47 mmol, 97% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.23 (s, 2H), 4.14 (d, J=6.9 Hz, 2H), 3.31-3.26 (m, 1H), 3.26-3.18 (m, 1H), 3.18-3.08 (m, 1H), 2.94-2.87 (m, 1H), 2.70-2.60 (m, 1H), 2.11-2.01 (m, 1H), 1.72-1.61 (m, 1H)); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.88.

    Example 298C: 1-{3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentan-1-yl}-1H-pyrazole-4-carboxylic acid

    [1947] To a solution of the product of Example 207C (200 mg, 0.609 mmol) in tetrahydrofuran (2.5 mL) under nitrogen and cooled to 78 C. was added methylmagnesium bromide (3.0 M in diethyl ether, 0.25 mL, 0.76 mmol) dropwise over 1 minute and the resultant reaction mixture was stirred for 20 minutes. Then it-butyllithium (2.0 M in hexanes, 0.38 mL, 0.76 mmol) was added dropwise over 1 minute and the reaction mixture stirred for 20 minutes. Additional tetrahydrofuran (2.5 mL) was added and gaseous carbon dioxide (268 mg, 6.09 mmol) was bubbled through the reaction mixture (via cannulation from a flask containing solid CO.sub.2) at 78 C. for 30 minutes. The reaction was warmed to ambient temperature, quenched with H.sub.2O (10 mL), and extracted with dichloromethane (10 mL). The aqueous phase was acidified with aqueous 1 N HCl and then extracted with dichloromethane (310 mL). The combined organic layers were concentrated in vacuo to afford the title intermediate (96 mg, 0.32 mmol, 53% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.37 (s, 1H), 8.27 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 2.39 (s, 6H), 1.39 (s, 9H).

    Example 298D: tert-butyl [3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[11.1.1]pentan-1-yl]carbamate

    [1948] To a solution of the product of Example 298C (30 mg, 0.10 mmol) in dichloromethane (0.7 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.015 mL, 0.11 mmol) and the reaction mixture was stirred at ambient temperature for 5 minutes. A solution of the product of Example 298B (19 mg, 0.10 mmol) in pyridine (0.012 mL, 0.15 mmol) was then added and the reaction mixture was stirred for 15 minutes. The reaction mixture was then diluted with dichloromethane (10 mL) and washed with aqueous 10% citric acid (10 mL). The aqueous layer was then extracted with dichloromethane (10 mL). The organic layers were combined, dried over MgSO.sub.4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to afford the title intermediate (12 mg, 0.020 mmol, 20% yield). MS (ESI.sup.+) m/z 445 (M+H).sup.+. Example 298E: [1-(3-aminobicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl]{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidin-1-yl}methanone

    [1949] To a solution of the product of Example 298D (25 mg, 0.056 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. Then the volatiles were removed under reduced pressure. The residue was diluted with methanol (10 mL), stirred with SCX (0.5 g) for 15 minutes, loaded onto a column of SCX, and washed with methanol (310 mL). The product was then eluted with 7 N NH.sub.3 in methanol (310 mL) to give the title intermediate (21 mg, 0.056 mmol, quantitative yield). MS (ESI.sup.+) m/z 345 (M+H).sup.+.

    Example 298F: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(3R)-3-[(trifluoromethoxy)methyl]pyrrolidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1950] The methodologies described in Example 253G substituting the product of Example 298E for the product of Example 253F gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.20 (d, J=6.6 Hz, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 4.85-4.80 (m, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 4.21-4.05 (m, 3H), 3.85-3.76 (m, 1H), 3.72-3.60 (m, 1H), 3.46-3.41 (m, 1H), 2.54 (s, 6H), 2.41-2.37 (m, 1H), 2.15-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.77-1.68 (m, 2H); MS (ESI.sup.+) m/z 555 (M+H).sup.+.

    Example 299: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)piperidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 398)

    Example 299A: (3S)-3-(trifluoromethoxy)piperidine

    [1951] The title compound was synthesized using the same procedures as described in Example 293A through Example 293B substituting (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate with (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.70 (s, 1H), 9.08 (s, 1H), 4.84-4.75 (m, 1H), 3.52-2.93 (m, 5H), 1.98-1.69 (m, 3H).

    Example 299B: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)piperidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1952] The title compound was synthesized using the same procedures as described in Example 287D through Example 287F substituting (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride with the product of Example 299A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 7.80 (d, J=1.4 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 4.49 (tt, J=6.9, 3.4 Hz, 1H), 4.41-3.46 (m, 4H), 2.54 (s, 6H), 2.37 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 1.99 (td, J=8.9, 4.3 Hz, 1H), 1.85-1.77 (m, 1H), 1.77-1.68 (m, 2H), 1.58-1.45 (m, 1H); MS (ESI.sup.+) m/z 555.2 (M+H).sup.+.

    Example 300: (2R,4R)-6-chloro-N-(3-{4-[(3R)-3-(difluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 399)

    Example 300A: tert-butyl (3-{4-[(3R)-3-(difluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1953] To a solution of the product of Example 298C (30 mg, 0.10 mmol), (R)-3-(difluoromethoxy)pyrrolidine (16.8 mg, 0.123 mmol, purchased from Enamine) and triethylamine (0.086 mL, 0.61 mmol) in dichloromethane (1 mL) was added 1-(((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)di(pyrrolidin-1-yl)phosphoranylidene)pyrrolidin-1-ium hexafluorophosphate(V) (80 mg, 0.15 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Then saturated aqueous sodium hydrogen carbonate (2 mL) was added and the phases separated. The aqueous phase was extracted further with dichloromethane (22 mL). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column chromatography (0-100% ethyl acetate/hexanes) to afford the title intermediate (60 mg, 0.10 mmol, quantitative yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.19 (d, J=17.8 Hz, 1H), 7.83 (d, J=16.5 Hz, 1H), 7.76 (s, 1H), 6.77 (t, J=75.8 Hz, 1H), 4.96-4.81 (m, 1H), 3.81-3.67 (m, 2H), 3.65-3.56 (m, 2H), 2.40 (s, 6H), 2.19-2.02 (m, 2H), 1.40 (s, 9H); MS (ESI.sup.+) m/z 413 (M+H).sup.+.

    Example 300B: [1-(3-aminobicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl][(3R)-3-(difluoromethoxy)pyrrolidin-1-yl]methanone

    [1954] The methodologies described in 298E substituting the product of Example 300A for the product of Example 298D gave the title intermediate. MS (ESI.sup.+) m/z 313 (M+H).sup.+.

    Example 300C: (2R,4R)-6-chloro-N-(3-{4-[(3R)-3-(difluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1955] The methodologies described in Example 253G substituting the product of Example 300B for the product of Example 253F gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.24 (d, J=18.0 Hz, 1H), 7.85 (d, J=16.2 Hz, 1H), 7.41-7.36 (m, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.95-6.61 (m, 2H), 5.71 (d, J=6.3 Hz, 1H), 4.85-4.78 (m, 2H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 3.80-3.70 (m, 2H), 3.64-3.56 (m, 2H), 2.55 (s, 6H), 2.42-2.38 (m, 1H), 2.19-2.12 (m, 1H), 2.10-2.00 (m, 1H), 1.76-1.69 (m, 1H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 301: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(3S)-3-[(trifluoromethoxy)methyl]pyrrolidine-1-carbonyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 400)

    [1956] The methodologies described in the reaction sequence of Example 298 were followed substituting (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate for (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate in the first step to afford the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.20 (d, J=6.6 Hz, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 4.85-4.80 (m, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 4.21-4.05 (m, 3H), 3.85-3.76 (m, 1H), 3.72-3.60 (m, 1H), 3.46-3.41 (m, 1H), 2.54 (s, 6H), 2.41-2.37 (m, 1H), 2.15-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.77-1.68 (m, 2H); MS (ESI.sup.+) m/z 555 (M+H).sup.+.

    Example 302: (2R,4R)-6-chloro-N-{3-[4-(3,3-dimethyl-1,3-azasilolidine-1-carbonyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 401)

    Example 302A: tert-butyl {3-[4-(3,3-dimethyl-1,3-azasilolidine-1-carbonyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1957] The reaction and purification conditions described in Example 272B, substituting 3,3-dimethyl-1,3-azasilolidine hydrochloride (Enamine) for (S)-3-(trifluoromethoxy)pyrrolidine hydrochloride gave the title compound. MS (APCI.sup.+) m/z 391 (M+H).sup.+.

    Example 302B: (21R,4R)-6-chloro-N-{3-[4-(3,3-dimethyl-1,3-azasilolidine-1-carbonyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1958] The reaction and purification conditions described in Example 186B, substituting the product of Example 302A for the product of Example 186A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90 C.) ppm 8.54 (s, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.39 (dd, J=2.6, 1.0 Hz, 1H), 7.16 (ddd, J=8.7, 2.7, 0.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.41 (s, 1H), 4.81 (dd, J=10.4, 5.9 Hz, 1H), 4.62 (dd, J=11.6, 2.6 Hz, 1H), 3.73 (t, J=7.5 Hz, 2H), 2.87 (s, 2H), 2.54 (s, 6H), 2.45-2.35 (m, 1H), 1.79 (ddd, J=13.0, 11.7, 10.4 Hz, 1H), 0.88 (t, J=7.5 Hz, 2H), 0.24 (s, 6H); MS (APCI.sup.+) m/z 502 (M+H).sup.+.

    Example 303: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 402)

    Example 303A: benzyl cis-3-(trifluoromethoxy)cyclobutane-1-carboxylate

    [1959] To a mixture of solid silver trifluoromethanesulfonate (394 g, 1536 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (204 g, 576 mmol) and potassium fluoride (89.2 g, 1536 mmol) was added a solution of (cis)-benzyl 3-hydroxycyclobutanecarboxylate (88 g, 90% purity by .sup.1H NMR, 384 mmol) in ethyl acetate (1800 mL), followed by 2-fluoropyridine (132 mL, 1536 mmol) and (trifluoromethyl)trimethylsilane (274 g, 960 mmol) dropwise. After 36 hours, the reaction mixture was filtered through Celite and concentrated in vacuo to give the crude product, which was purified by column chromatography eluting with a 20:1 mixture of petroleum ether and ethyl acetate to give the title compound (90 g, 90% purity by .sup.1H NMR, 295 mmol, 76.8% yield).

    [1960] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.43-7.32 (m, 5H), 5.15 (s, 2H), 4.58 (p, J=7.5 Hz, 1H), 2.87-2.70 (m, 1H), 2.65 (dtd, J=9.6, 7.3, 2.6 Hz, 2H), 2.60-2.49 (m, 2H), 1.27 (t, J=7.1 Hz, 1H).

    Example 303B: cis-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid

    [1961] To a solution of the product of Example 303A (90 g, 90% purity by .sup.1H NMR, 295 mmol) in tetrahydrofuran (500 mL) was added palladium(II) hydroxide on carbon (30 g, 214 mmol) and the reaction mixture was placed under a hydrogen gas atmosphere (15 psi). After 1 hour, the reaction mixture was vented and then filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a 20.1 mixture of petroleum ether and ethyl acetate to give the title compound (60 g, 90% purity by .sup.1H NMR, 293 mmol, 99% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 11.66 (br s, 1H), 4.60 (p, J=7.4 Hz, 1H), 2.85-2.62 (m, 3H), 2.61-2.49 (m, 2H).

    Example 303C: [cis-3-(trifluoromethoxy)cyclobutyl]methanol

    [1962] To a solution of the product of Example 303B (30.0 g, 90% purity by .sup.1H NMR, 146 mmol) in tetrahydrofuran (600 mL) at 0 C. was added lithium aluminum hydride (6.68 g, 176 mmol) portionwise. After 30 minutes, the reaction was quenched with water (5 mL) and stirred for 5 minutes, then 15% aqueous sodium hydroxide (5 mL) was added, followed by water (15 mL). The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a 20:1 mixture of petroleum ether and ethyl acetate to give the title compound (17.00 g, 90% purity by .sup.1H NMR, 90 mmol, 61.6% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.57 (p, J=7.4 Hz, 1H), 3.65 (d, J=5.5 Hz, 2H), 2.55-2.37 (m, 2H), 2.19-1.93 (m, 3H), 1.43 (br s, 1H).

    Example 303D: cis-1-(bromomethyl)-3-(trifluoromethoxy)cyclobutane

    [1963] To a solution of [cis-3-(trifluoromethoxy)cyclobutyl]methanol (74 mg, 0.304 mmol, Example 303C), and carbon tetrabromide (126 mg, 0.381 mmol) in dichloromethane (1.0 mL) was added triphenylphosphine (120 mg, 0.457 mmol) as a solution in dichloromethane (1.0 mL) and the subsequent reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure (500 mbar), at 40 C., and pentane (3.0 mL) was added. The resultant suspension was filtered, and the pentane solution concentrated under reduced pressure (500 mbar), at 40 C., to afford the title compound (71.0 mg, 100% yield). The material was used immediately in the subsequent step.

    Example 303E: tert-butyl {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [1964] To a solution of the product of Example 207C (300 mg, 0.868 mmol) in anhydrous tetrahydrofuran (9.0 mL), under a nitrogen atmosphere and cooled to 0 C., was added sodium hydride (52.1 mg, 1.303 mmol) and the reaction stirred for 30 minutes. The reaction mixture was then cooled to 78 C. and n-butyllithium (2.0 M in hexanes, 0.651 mL, 1.303 mmol) was added dropwise over 1 minute, and the reaction mixture was stirred at this temperature for 30 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.266 mL, 1.303 mmol) was added and the reaction mixture was stirred at 78 C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) then warmed to room temperature and acidified with aqueous 1 M HCl (1 mL). The aqueous phase was extracted with ethyl acetate (210 mL) and the combined organic fractions were then dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% ethyl acetate/isohexane) to afford the title compound (337 mg, 56.9% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.95 (s, 1H), 7.61 (s, 1H), 2.36 (s, 6H), 1.24 (s, 12H), 1.07 (s, 9H), 1H exchangeable proton not observed.

    Example 303F: tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1965] To a stirred solution of product of Example 303E (337 mg, 0.494 mmol) in tetrahydrofuran (3.0 mL), at 0 C. under a nitrogen atmosphere, was added aqueous sodium hydroxide (2 M, 0.494 mL, 0.988 mmol) followed by hydrogen peroxide (27% solution in water) (0.112 mL, 0.988 mmol) and the reaction mixture was stirred at this temperature for 2 hours. Aqueous 1 M HCl (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (215 mL). The combined organic phases were washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (50-100% ethyl acetate/isohexane) to afford the title compound (139 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.47 (s, 1H), 7.70 (br s, 1H), 7.17 (s, 1H), 7.03 (s, 1H), 2.28 (s, 6H), 1.39 (s, 9H).

    Example 303G: tert-butyl [3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1966] To a solution of the product of Example 303F (40 mg, 0.151 mmol) and potassium carbonate (37.9 mg, 0.274 mmol) in N,N-dimethylformamide (1 mL) under a nitrogen atmosphere was added the product of Example 303D (31.9 mg, 0.137 mmol), and the subsequent reaction mixture was stirred at room temperature for 3 hours and then heated to 60 C. and stirred for 18 hours. The reaction mixture was cooled to room temperature and additional product of Example 303A (31.9 mg, 0.137 mmol) and potassium carbonate (37.9 mg, 0.274 mmol) were added followed by stirring at 65 C. for 2 hours. Cesium carbonate (179 mg, 0.548 mmol) was added, and the reaction was stirred at 65 C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5.0 mL) then washed with saturated aqueous sodium hydrogen carbonate (5.0 mL) followed by water/brine (1:1, 35.0 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (7 mg, 9.42% yield). MS (ESI) ml: 418 (M+H).sup.+.

    Example 303H: 3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1967] To a solution of product of Example 303G (7 mg, 0.017 mmol) in dichloromethane (0.5 mL) under a nitrogen atmosphere was added trifluoroacetic acid (0.065 mL, 0.838 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (5 mg, 67.7% yield). MS (ESI) m/z 318 (M+H).sup.+.

    Example 303I: (2R)-6-chloro-4-oxo-N-[3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1968] To a solution of the product of Example 303H (5 mg, 0.016 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (3.57 mg, 0.016 mmol, Example 1B) and triethylamine (0.013 mL, 0.095 mmol) in N,N-dimethylformamide (0.5 mL) at room temperature under nitrogen was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 8.99 mg, 0.024 mmol), and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL), and the aqueous phase was extracted with dichloromethane (52.0 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (8.4 mg, 100%). MS (ESI) m/z 526/528 (M+H).sup.+.

    Example 303J: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]/pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1969] The methodologies described in Example 5 substituting Example 303I (8.4 mg, 0.016 mmol) for Example 4 and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (3.1 mg, 36.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.57 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.23-7.18 (m, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.85-4.79 (m, 1H), 4.77-4.70 (m, J H), 4.66-4.62 (m, 1H), 3.85 (d, J=5.9 Hz, 2H), 2.45 (s, 6H), 2.39-2.34 (m, 1H), 2.33-2.23 (m, 1H), 2.05-1.97 (m, 2H), 1.76-1.67 (m, 1H), 2H of cyclobutyl methylene underneath solvent peak; MS (ESI) m/z 528/530 (M+H).sup.+.

    Example 304: (2R,4R)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 403)

    Example 304A: 3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1970] A solution of the product from Example 247A (438 mg, 0.854 mmol) in trifluoroacetic acid (3 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The crude product was purified by C18 preparative HPLC using a solvent gradient of 5-100% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) to give the title compound (254 mg, 96% yield).

    Example 304B: (2R,4R)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1971] To a solution of the product from Example 304A (11 mg, 0.035 mmol) and the product from Example 227B (9 mg, 0.035 mmol) in N,N-dimethylformamide (1 mL) and triethylamine (0.029 mL, 0.21 mmol) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 17 mg, 0.045 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was partitioned between dichloromethane (25 mL) and saturated aqueous sodium bicarbonate (10 mL), and the organic layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (0.5 mL) and sodium borohydride (6.5 mg, 0.17 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 10 minutes, water (0.1 mL) was added, and the mixture was filtered. The filtrate was subjected to C18 HPLC using a solvent gradient of 5-100% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) to give the title compound (14 mg, 73% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.59-8.57 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.86-7.83 (m, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.56-7.52 (m, 1H), 7.07 (d, J=9.0 Hz, 1H), 5.84 (br s, 1H), 4.89 (dd, J=10.7, 5.8 Hz, 1H), 4.77 (dd, J=11.9, 2.4 Hz, 1H), 2.57 (s, 6H), 2.45-2.41 (m, 1H), 1.78 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 555 (M+H).sup.+.

    Example 305: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 404)

    Example 305A: methyl 3-(1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1972] The title compound was prepared using the methods described for synthesis of Example 230A, substituting pyrazole for (1H-pyrazol-4-yl)methanol. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.55 (dd, J=1.8, 0.6 Hz, 1H), 7.42 (dd, J=2.3, 0.7 Hz, 1H), 6.28 (dd, J=2.3, 1.8 Hz, 1H), 3.74 (s, 3H), 2.58 (s, 6H).

    Example 305B: methyl 3-(4-iodo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [1973] To the product of Example 305A (3.52 g, 18.31 mmol) in acetonitrile (40 mL) was added N-iodosuccinimide (8.24 g, 36.6 mmol) portionwise. The reaction mixture was stirred at room temperature for 2.5 hours and was then concentrated in vacuo. The crude material was dissolved in dichloromethane (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL). The aqueous layer was extracted with additional dichloromethane (2100 mL) and the combined organic layers were dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (4.67 g, 79% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.06 (s, 1H), 7.58 (s, 1H), 3.66 (s, 3H), 2.48 (s, 6H); MS (ESI) m/z 319 (M+H).sup.+.

    Example 305C: 3-(4-iodo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

    [1974] The reaction and purification conditions described in Example 110B substituting the product of Example 305B for the product of Example 110A gave the title compound (4.24 g, 90% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.72 (s, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 2.42 (s, 6H); MS (ESI) m/z 303 (MH).sup..

    Example 305D: tert-butyl [3-(4-iodo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1975] At 58 C. under atmosphere of nitrogen, diphenyl phosphoryl azide (3.61 mL, 16.73 mmol) was added to a solution of Example 305C (4.24 g, 13.94 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.77 mL, 27.9 mmol) in t-butanol (75 mL). The reaction mixture was stirred at 58 C. for 19 hours. The reaction was diluted with methanol (25 mL) and dry-loaded onto silica in vacuo. The material was purified by chromatography on silica gel (220 g cartridge, 0-10% dichloromethane/methanol (0.7 N NH.sub.3)) to afford the title compound (3.59 g, 9.09 mmol, 65.2% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.98 (s, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 2.34 (s, 6H), 1.38 (s, 9H); MS (ESI.sup.+) m/z 376 (M+H).sup.+.

    Example 305E: 4-(2,2,2-trifluoroethyl)piperazin-2-one

    [1976] To a suspension of piperazin-2-one (1.0 g, 9.99 mmol), cesium carbonate (4.88 g, 14.98 mmol) and potassium iodide (0.497 g, 3.00 mmol) in acetonitrile (150 mL) was slowly added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.439 mL, 9.99 mmol) and the reaction mixture was stirred at room temperature for 22 hours. Water (100 mL) was added, and the aqueous solution was extracted with ethyl acetate (3100 mL). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel (0-10% [0.7 M ammonia in methanol]/dichloromethane) to afford the title compound (548 mg, 28.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.80 (s, 1H), 3.27 (q, J=10.0 Hz, 2H), 3.16-3.11 (m, 4H), 2.78 (dd, J=6.3, 4.6 Hz, 2H).

    Example 305F: tert-butyl (3-{4-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [1977] At room temperature, a suspension of the product of Example 305D (500 mg, 1.333 mmol), 4-(2,2,2-trifluoroethyl)piperazin-2-one (202 mg, 1.111 mmol, Example 305E), copper (I) iodide (106 mg, 0.555 mmol) and potassium phosphate, tribasic (471 mg, 2.221 mmol) in N,N-dimethylformamide (8 mL) was degassed for 10 minutes. N,N-Dimethylethane-1,2-diamine (0.141 mL, 1.111 mmol) was then added, and the reaction mixture was then stirred at 60 C. for 19 hours and allowed to cool to room temperature. The reaction mixture was filtered through a pad of diatomaceous earth, washing through with ethyl acetate (200 mL). The filtrate was washed with water (2100 mL) and brine (50 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel [0.7 M ammonia in methanol]/dichloromethane) to afford the title compound (312 mg, 55.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.01 (s, 1H), 7.80-7.67 (m, 2H), 3.63 (t, J=5.5 Hz, 2H), 3.41 (s, 2H), 3.35 (q, J=10.1 Hz, 2H), 3.01 (t, J=5.5 Hz, 2H), 2.35 (s, 6H), 1.39 (s, 9H); MS (ESI) m/z 430 (M+H).sup.+.

    Example 305G: 1-[1-(3-aminobicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl]-4-(2,2,2-trifluoroethyl)piperazin-2-one

    [1978] To a solution of the product of Example 305F (38 mg, 0.066 mmol) in dichloromethane (1 mL), under a nitrogen atmosphere, was added trifluoroacetic acid (0.068 mL, 0.883 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in methanol (3 mL) and purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (18 mg, 47.8% yield). MS (ESI) m/z 330 (M+H).sup.+.

    Example 305H: 3-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [1979] At room temperature, under an atmosphere of nitrogen, borane-methyl sulfide complex (0.025 mL, 0.263 mmol) was added dropwise to a solution of the product of Example 305G (18 mg, 0.032 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 20 hours. Another portion of borane-methyl sulfide complex (0.011 mL, 0.116 mmol) was then added, and the reaction mixture was stirred at room temperature for 2.5 hours. Aqueous HCl (0.5 M, 10 mL) was slowly added, and the mixture was stirred vigorously for 30 minutes. The mixture was then adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with dichloromethane (310 mL). The combined organic fractions were dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (10 mg, 59.0% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.23 (d, J=0.9 Hz, 1H), 7.17 (d, J=0.9 Hz, 1H), 3.19 (q, J=10.2 Hz, 2H), 2.87-2.80 (m, 4H), 2.74-2.64 (m, 4H), 2.08 (s, 6H), 2 exchangeable protons not observed; MS (ESI) m/z 316 (M+H).sup.+.

    Example 305I: (2R)-6-chloro-4-oxo-N-(3-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1980] To a solution of the product of Example 305H (10 mg, 0.032 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (8.62 mg, 0.038 mmol, Example 1B) and N,N-diisopropylethylamine (0.033 mL, 0.190 mmol) in dichloromethane (1 mL), at room temperature under nitrogen, was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 18.09 mg, 0.048 mmol) and the reaction mixture was stirred for 4 hours. Water (10 mL) and brine (5 mL) were added, and the mixture was extracted with dichloromethane (210 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford the title compound (23 mg, 80%). MS (ESI) m/z 524/526 (M+H).sup.+.

    Example 305J: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1981] The methodologies described in Example 5 substituting Example 305I for the product of Example 4 and purifying by preparative HPLC [Waters XSelect Prep-C18, 5 m column, 19 mm50 mm, flow rate of 30 mL/minute, 25-55% gradient of 0.1% formic acid in acetonitrile in buffer (0.1% formic acid in water)] afforded the title compound (2.3 mg, 8.6%). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.43 (dd, J=2.7, 1.0 Hz, 1H), 7.32 (d, J=1.5 Hz, 2H), 7.16 (dd, J=8.8, 2.6 Hz, 1H), 6.92 (d, J=8.7 Hz, 1H), 4.92 (dd, J=10.4, 5.9 Hz, 1H), 4.64 (dd, J=11.6, 2.4 Hz, 1H), 3.10 (q, J=9.8 Hz, 2H), 2.97 (dd, J=6.4, 3.6 Hz, 4H), 2.81 (dd, J=6.2, 3.8 Hz, 4H), 2.59 (s, 6H), 2.55 (ddd, J=13.0, 5.9, 2.5 Hz, 1H), 1.89 (ddd, J=13.0, 11.6, 10.4 Hz, 1H), 2 exchangeable protons not observed; MS (ESI) m/z 526/528 (M+H).sup.+.

    Example 306: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1RS,3RS)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 405)

    Example 306A: 3-hydroxycyclopentyl benzoate

    [1982] To a solution of cyclopentane-1,3-diol (4 g, 39.2 mmol) in pyridine (80 mL), under an atmosphere of nitrogen, was added benzoyl chloride (4.55 mL, 39.2 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous phase was further extracted with dichloromethane (100 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound as a mixture of isomers (5.04 g, 62.4% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.98-7.90 (m, 2H), 7.67-7.61 (m, 1H), 7.55-7.48 (m, 2H), 5.40-5.34 (m, 0.3H), 5.25-5.17 (m, 0.7H), 4.69-4.62 (m, 1H), 4.33-4.26 (m, 0.3H), 4.18-4.11 (m, 0.7H), 2.32-2.24 (m, 0.7H), 2.22-2.13 (m, 0.3H), 2.01-1.83 (m, 2.3H), 1.81-1.60 (m, 2.3H), 1.58-1.51 (m, 0.4H).

    Example 306B: trans-3-(trifluoromethoxy)cyclopentyl benzoate and Example 306C: cis-3-(trifluoromethoxy)cyclopentyl benzoate

    [1983] A mixture of silver(1) trifluoromethanesulfonate (16.95 g, 66.0 mmol), potassium fluoride (5.68 g, 98 mmol), and Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (12.99 g, 36.7 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To the mixture was slowly added a solution of the product of Example 306A (5.04 g, 24.44 mmol) in ethyl acetate (50 mL) followed by slow addition of 2-fluoropyridine (6.31 mL, 73.3 mmol) and then trimethyl(trifluoromethyl)silane (10.84 mL, 73.3 mmol). The reaction mixture then stirred at room temperature for 3 days. The crude reaction mixture was filtered through a pad of diatomaceous earth, washed with ethyl acetate (100 mL), and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (10-30% ethyl acetate/isohexane) to afford the title compounds as separate relative diastereomers: The trans isomer (1.32 g, 19.30% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.99-7.94 (m, 2H), 7.69-7.63 (m, 1H), 7.55-7.49 (m, 2H), 5.41 (tt, J=5.5, 3.3 Hz, 1H), 5.08 (qd, J=5.5, 3.7 Hz, 1H), 2.28 (q, J=4.8 Hz, 2H), 2.25-2.13 (m, 2H), 1.88 (tdd, J=17.4, 11.9, 3.8 Hz, 2H); 19F NMR (471 MHz, DMSO-d.sub.6) ppm 56.73.

    [1984] The cis isomer (2.66 g, 38.9/6 yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.98-7.90 (m, 2H), 7.68-7.62 (m, 1H), 7.57-7.49 (m, 2H), 5.36-5.28 (m, 1H), 5.00-4.94 (m, 1H), 2.47-2.38 (m, 1H), 2.17-1.88 (m, 5H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 56.66.

    Example 306D: cis-3-(trifluoromethoxy)cyclopentan-1-ol

    [1985] To a solution of the product of Example 306C (555 mg, 2.024 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) under an atmosphere of nitrogen, was added aqueous 2 M sodium hydroxide (5.06 mL, 10.12 mmol), and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was partitioned between dichloromethane (10 mL) and water (5 mL). The aqueous phase was further extracted with dichloromethane (210 mL). The combined organic fractions were dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (455 mg, 79% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.79-4.73 (m, 1H), 4.72 (d, J=3.9 Hz, 1H), 4.11-4.04 (m, 1H), 2.27-2.19 (m, 1H), 1.96-1.85 (m, 2H), 1.73-1.57 (m, 3H).

    Example 306E: cis-3-(trifluoromethoxy)cyclopeityl methanesuelfonate

    [1986] To a solution of the product of Example 306D (303 mg, 1.069 mmol) and triethylamine (0.179 mL, 1.282 mmol) in dichloromethane (5 mL) under an atmosphere of nitrogen, and cooled to 0 C., was added methanesulfonyl chloride (0.091 mL, 1.175 mmol) dropwise, and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (25 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (279 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 5.11 (tq, J=6.1, 2.7 Hz, 1H), 4.94-4.87 (m, 1H), 3.18 (s, 3H), 2.43 (dt, J=15.8, 6.8 Hz, 1H), 2.10-1.88 (m, 5H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 56.88.

    Example 306F: tert-butyl [3-(4-{[trans-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1987] To a solution of the product of Example 306E (94 mg, 0.377 mmol), and cesium carbonate (368 mg, 1.131 mmol) in N,N-dimethylformamide (2 mL), at under a nitrogen atmosphere, was added the product of Example 303F (100 mg, 0.377 mmol) and the subsequent reaction mixture stirred at room temperature for 18 hours. Additional product of Example 306E (187 mg, 0.754 mmol) as a solution in N,N-dimethylformamide (1 mL) and cesium carbonate (246 mg, 0.754 mmol) were added, and the reaction was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (5 mL) then washed with saturated aqueous sodium hydrogen carbonate (5 mL) followed by water/brine (1:1, 35 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (48 mg, 30.8% yield). MS (ESI) m/z 418 (M+H).sup.+.

    Example 306G: 3-(4-{[cis-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1988] To a solution of product of Example 306F (48 mg, 0.115 mmol) in dichloromethane (2 mL), under a nitrogen atmosphere, was added trifluoroacetic acid (0.447 mL, 5.80 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude residue was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (31 mg, 84.0% yield).

    [1989] MS (ESI) m/z 318 (M+H).sup.+.

    Example 306H: (2R)-6-chloro-4-oxo-N-[3-(4-{[(1RS,3RS)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1990] To a solution of the product of Example 306G (31.0 mg, 0.098 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (22.1 mg, 0.098 mmol, Example 1B) and triethylamine (0.082 mL, 0.586 mmol) in N,N-dimethylformamide (1 mL), at room temperature under nitrogen, was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 55.7 mg, 0.147 mmol), and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL) and the aqueous phase was extracted with dichloromethane (52 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (51.5 mg, 100%). MS (ESI) m/z 526/528 (M+H).sup.+.

    Example 3061: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1RS,3RS)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1.]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1991] The methodologies described in Example 5 substituting the product of Example 306H for the product of Example 4 and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (16.7 mg, 31.6% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.57 (d, J=0.9 Hz, 11H), 7.40-7.38 (m, 1H), 7.23 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 5.01-4.96 (m, 1H), 4.85-4.79 (m, 1H), 4.67-4.58 (m, 2H), 2.46 (s, 6H), 2.40-2.33 (m, 1H), 2.26-2.00 (m, 4H), 1.87-1.67 (m, 3H); MS (ESI) m/z 528/530 (M+H).sup.+.

    Example 307: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 406)

    Example 307A: (2R,4S)-6-chloro-4-hydroxychroman-2-carboxylic acid

    [1992] The title compound was prepared using the procedures described in in Example 279A substituting the product of Example 1B for the product of Example 239A and then purified by the following HPLC condition: [Waters XBridge C18 OBD Prep Column, 130 , 5 m, 50 mm100 mm, flow rate 90 mL/minute, 3-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid)]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 13.20 (d, J=73.7 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.22 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.78 (dd, J=8.7, 3.8 Hz, 1H), 4.58 (t, J=4.8 Hz, 1H), 2.18-2.02 (m, 2H); MS (ESI.sup.) m/z 227 (MH).sup..

    Example 307B: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [1993] The title compound was prepared and purified using the procedures described in Example 1C substituting the product of Example 272B for the product of Example 1A, and the product of Example 307A for the product of Example 1B, and then further purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 20 mL/minute, 100% ethanol (isocratic gradient)]. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.28-8.22 (m, 1H), 7.89-7.83 (m, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.64-5.61 (m, 1H), 5.21-5.18 and 5.15-5.12 (two m, 1H, amide rotamers), 4.62-4.57 (m, 2H), 4.05-4.00 and 3.87-3.77 (two m, 2H, amide rotamers), 3.71 (s, 1H), 3.69-3.62 and 3.54-3.48 (two m, 1H, amide rotamers), 2.55 (s, 6H), 2.33-2.14 (m, 2H), 2.14-2.10 (m, 1H), 1.93 (ddd, J=13.9, 11.0, 3.7 Hz, 1H); MS (APC.sup.+) m/z 541 (M+H).sup.+.

    Example 308: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 407)

    [1994] The titled compound was prepared using the reaction and purification conditions described in Example 1C substituting the product of Example 247A for the product of Example 1A, and the product of Example 307A for the product of Example 1B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.58 (d, J=2.7 Hz, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.81 (m, 2H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (d, J=4.4 Hz, 1H), 4.65-4.57 (m, 2H), 2.57 (s, 6H), 2.13 (dt, J=13.9, 3.5 Hz, 1H), 1.93 (ddd, J=14.1, 11.0, 3.7 Hz, 1H); MS (APC.sup.+) m/z 521 (M+H).sup.+.

    Example 309: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1RS,3SR)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 408)

    Example 309A: trans-3-(trifluoromethoxy)cyclopentan-1-ol

    [1995] To a solution of the product of Example 306B (1.32 g, 4.810 mmol) in tetrahydrofuran (8 mL) and methanol (12 mL) under an atmosphere of nitrogen, was added aqueous 2 M sodium hydroxide (12 mL, 24.07 mmol), and the reaction mixture stirred at room temperature for 18 hours. Dichloromethane (20 mL) and water (10 mL) were added and the phases were separated. The aqueous phase was further extracted with dichloromethane (220 mL). The combined organic fractions were dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (443 mg, 54% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.92 (dt, J=10.6, 5.9 Hz, 1H), 4.69 (d, J=3.9 Hz, 1H), 4.27-4.19 (m, 1H), 2.17-2.06 (m, 1H), 1.94-1.83 (m, 3H), 1.74-1.66 (m, 1H), 1.54-1.46 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 56.65.

    Example 309B: trans-3-(trifluoromethoxy)cyclopentyl methanesulfonate

    [1996] To a solution of the product of Example 309A (190 mg, 1.117 mmol) and triethylamine (0.187 mL, 1.340 mmol) in dichloromethane (10 mL) under an atmosphere of nitrogen, and cooled to 0 C., was added methanesulfonyl chloride (0.095 mL, 1.228 mmol) dropwise and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (210 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (277 mg, 100% yield). The crude material was assumed to be quantitative and used immediately in the subsequent step.

    Example 309C. tert-butyl [3-(4-{[(1R,3S)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [1997] To a solution of the product of Example 309B (94 mg, 0.377 mmol) and cesium carbonate (0.491 g, 1.508 mmol) in N,N-dimethylformamide (1 mL) under a nitrogen atmosphere was added the product of Example 303F (100 mg, 0.377 mmol) as a solution in N,N-dimethylformamide (1 mL) and the subsequent reaction was mixture stirred at room temperature for 2 hours. Additional product of Example 309B (94 mg, 0.377 mmol) as a solution in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (5 mL) then washed with saturated aqueous sodium hydrogen carbonate (5 mL) followed by water/brine (1:1, 35 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (53 mg, 33.7% yield). MS (ESI) m/z 418 (M+H).sup.+.

    Example 309D: 3-(4-{[cis-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [1998] To a solution of product of Example 309C (53 mg, 0.127 mmol) in dichloromethane (3 mL), under a nitrogen atmosphere, was added trifluoroacetic acid (0.294 mL, 3.81 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude material was purified on SCX resin (washing with methanol then eluted with 0.7 M ammonia in methanol) to afford the title compound (41 mg, 100.0% yield). MS (ESI) m/z 318 (M+H).sup.+.

    Example 309E: (2R)-6-chloro-4-oxo-N-[3-(4-{[(1RS,3SR)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-benzopyran-2-carboxamide

    [1999] To a solution of the product of Example 309D (41.0 mg, 0.130 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (29.6 mg, 0.130 mmol, Example 1B) and triethylamine (0.109 mL, 0.783 mmol) in N,N-dimethylformamide (1 mL), at room temperature under nitrogen, was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 74.4 mg, 0.196 mmol), and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL), and the aqueous phase was extracted with dichloromethane (52 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (68.4 mg, 100%). MS (ESI) m/z 526/528 (M+H).sup.+.

    Example 309F: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1RS,3SR)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2000] The methodologies described in Example 5 substituting Example 309E for Example 4 and purifying by chromatography on silica gel (0-100% ethyl acetate/isohexane) afforded the title compound (45.0 mg, 64.3% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.6, 1.0 Hz, 1H), 7.24 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.92-4.84 (m, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.52-4.45 (m, 1H), 2.46 (s, 6H), 2.42-2.33 (m, 3H), 2.05-1.83 (m, 4H), 1.76-1.68 (m, 1H); MS (ESI) m/z 528/530 (M+H).sup.+.

    Example 310: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 409)

    Example 310A: 1-trityl-1H-pyrazol-4-ol

    [2001] The title compound was prepared using the methods described for the synthesis of Example 303F, substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole (4.25 g, 9.74 mmol) for the product from Example 303E. The crude material was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in isohexane to afford the title compound (2.88 g, 83% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.53 (d, J=1.0 Hz, 1H), 7.39-7.29 (m, 9H), 7.22 (d, J=1.0 Hz, 1H), 7.09-7.03 (m, 6H), 6.78 (d, J=0.9 Hz, 1H).

    Example 310B: 4-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1-(triphenylmethyl)-1H-pyrazole

    [2002] To a solution of the product from Example 310A (500 mg, 1.532 mmol), trans-3-(trifluoromethoxy)cyclobutanol (478 mg, 3.06 mmol, Example 217D), and (2-biphenyl)dicyclohexylphosphine (1.07 g, 3.06 mmol) in toluene (10 mL), at ambient temperature under a nitrogen atmosphere and in the presence of activated molecular sieves, was added di-tert-butyl azodicarboxylate (705 mg, 3.06 mmol), and the resulting mixture was stirred at ambient temperature for 18 hours. The mixture was filtered, washed with ethyl acetate (210 mL), and concentrated in vacuo. The crude material was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate in isohexane to afford the title compound (561 mg, 63% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.41 (d, J=0.9 Hz, 1H), 7.39-7.32 (m, 9H), 7.08-7.04 (m, 6H), 7.00 (d, J=0.9 Hz, 1H), 4.52 (p, J=7.1 Hz, 1H), 4.14 (p, J=6.8 Hz, 1H), 2.89-2.80 (m, 2H), 2.23-2.14 (m, 2H).

    Example 310C: 4-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazole

    [2003] To a solution of the product from Example 310B (561 mg, 0.966 mmol) in dichloromethane (10 mL), at 0 C. under a nitrogen atmosphere, was added triethylsilane (0.309 mL, 1.932 mmol) followed by trifluoroacetic acid (3.72 mL, 48.3 mmol), and the resulting mixture was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was concentrated in vacuo, and the residue was concentrated in vacuo from toluene (25 mL). The crude material was purified by column chromatography on silica gel using a solvent gradient of 50-100% ethyl acetate in isohexane to afford the title compound as a colorless solid (222 mg, 99% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 12.41 (s, 1H), 7.31 (s, 2H), 4.60-4.51 (m, 1H), 4.19-4.10 (m, 1H), 3.01-2.88 (m, 2H), 2.27-2.15 (m, 2H).

    Example 310D: methyl 3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [2004] The title compound was prepared using the methods described for the synthesis of Example 230A, substituting the product from Example 310C for the (1H-pyrazol-4-yl)methanol.

    [2005] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.54 (d, J=0.9 Hz, 1H), 7.25 (d, J=0.9 Hz, 1H), 4.58-4.51 (m, 1H), 4.18-4.11 (m, 1H), 3.66 (s, 3H), 3.00-2.93 (m, 2H), 2.43 (s, 6H), 2.21 (s, 2H).

    Example 310E: 2-(trimethylsilyl)ethyl [3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2006] The title compound was prepared using the methods described for the synthesis of Example 231E and Example 231F, substituting the product from Example 310D for the product from Example 231D. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.93 (s, 1H), 7.49 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.59-4.51 (m, 1H), 4.18-4.11 (m, 1H), 4.09-3.99 (m, 2H), 3.01-2.92 (m, 2H), 2.33 (s, 6H), 2.24-2.16 (m, 2H), 0.99-0.87 (m, 2H), 0.02 (s, 9H).

    Example 310F: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[cis-3-(trifluoromethoxy)cyclobutyl]oxy}-1-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2007] The title compound was prepared using the methods described for the synthesis of Example 244B, substituting the product from Example 310E for the product from Example 244A. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.52 (d, J=0.9 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.24 (d, J=0.8 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.82 (dt, J=11.3, 6.0 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.55 (p, J=7.1 Hz, 1H), 4.15 (p, J=6.8 Hz, 1H), 3.01-2.93 (m, 2H), 2.46 (s, 6H), 2.40-2.34 (m, 1H), 2.25-2.17 (m, 2H), 1.72 (q, J=12.0 Hz, 1H); MS (ESI) m/z 514.4 (M+H).sup.+.

    Example 311: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 410)

    Example 311A: benzyl [3-({[cis-3-(trifluoromethoxy)cyclobutane-1-carbonyl]amino}acetyl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2008] To a solution of the product from Example 250 (126 mg, 0.682 mmol) in N,N-dimethylformamide (4 mL) was added the product from Example 206D (200 mg, 0.644 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 324 mg, 0.853 mmol). The resulting mixture was stirred at ambient temperature for 16 hours and was concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and washed with HCl (1 M, 10 mL), sodium bicarbonate solution (saturated, 10 mL) and brine (310 mL). The organic layer was then passed through a phase separator and the solvent was removed in vacuo to give the title compound (47 mg, 18% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.16 (t, J=5.6 Hz, 1H), 8.07 (s, 1H), 7.46-7.27 (m, 5H), 5.00 (s, 2H), 4.76 (p, J=7.6 Hz, 1H), 4.02 (d, J=5.3 Hz, 2H), 2.49-2.37 (m, 2H), 2.30-2.22 (m, 2H), 2.18 (s, 6H).

    Example 311B: benzyl (3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2009] The product from Example 311A (47 mg, 0.096 mmol) and POCl.sub.3 (200 L, 2.15 mmol) was heated at 40 C. for 3 hours and concentrated in vacuo to give the title compound (45 mg, 98%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.13 (s, 1H), 7.41-7.26 (m, 5H), 6.85 (s, 1H), 5.00 (s, 2H), 4.86-4.80 (m, 1H), 3.26-3.19 (m, 1H), 2.84-2.71 (m, 2H), 2.45-2.37 (m, 2H), 2.20 (s, 6H).

    Example 311C: 3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-amine

    [2010] To a solution of the product from Example 311B (235 mg, 0.223 mmol) in ethanol (5 mL) was added 10% palladium on carbon (237 mg, 0.223 mmol) and the resulting mixture was stirred under 1 atmosphere of H.sub.2 for 2 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (159 mg, 100% yield). MS (ESI) m/z 289.2 (M+H).sup.+.

    Example 311D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2011] The title compound was prepared using the methods described for synthesis of Examples 309E and 309F, substituting the product from Example 311C for the product from Example 309D. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.22-7.19 (m, 1H), 6.90-6.87 (m, 2H), 4.87-4.79 (m, 2H), 4.61 (dd, J=12.0, 2.3 Hz, 1H), 3.28-3.20 (m, 1H), 2.81-2.76 (m, 2H), 2.47-2.38 (m, 2H), 2.33 (s, 6H), 1.74-1.66 (m, 1H); MS (ESI) m/z 499.3 (M+H).sup.+.

    Example 312: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 411)

    Example 312A: tert-buty [3-(4-{[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2012] To a solution of tert-butyl [3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (prepared as described in International Patent Publication WO2020223538 A1) (76 mg, 0.232 mmol) and 2-(trifluoromethoxy)ethanamine, hydrochloric acid (115 mg, 0.695 mmol) in anhydrous 1,4-dioxane (2 mL), under nitrogen, was added tBuBrettPhos Pd G3 (19.79 mg, 0.023 mmol) followed by solid sodium tert-butoxide (111 mg, 1.158 mmol), and the reaction mixture was heated to 60 C. and stirred for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between dichloromethane (5 mL) and saturated aqueous sodium hydrogen carbonate (5 mL), the phases were separated, and the aqueous layer was further extracted with dichloromethane (25 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-10% methanol/dichloromethane) to afford the title compound (40.7 mg, 42% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.14 (s, 1H), 7.04 (d, J=0.9 Hz, 1H), 4.66 (t, J=6.6 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 3.15 (q, J=5.8 Hz, 2H), 2.28 (s, 6H), 1.39 (s, 9H); MS (ESI.sup.+) m/z 377 (M+H).sup.+.

    Example 312B: tert-butyl [3-(4-{methyl[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2013] To a solution of the product of Example 312A (41 mg, 0.109 mmol) in a mixture of dichloromethane (2 mL) and methanol (2 mL) was added triethylamine (0.023 mL, 0.163 mmol) at ambient temperature. To the solution were added successively acetic acid (0.022 mL, 0.381 mmol), formaldehyde (37 weight % in water, 0.032 mL, 0.436 mmol) and sodium triacetoxyhydroborate (23.09 mg, 0.109 mmol). The mixture was stirred at the same temperature for 1 hour. Additional formaldehyde (37 weight % in water, 0.032 mL, 0.436 mmol) and sodium triacetoxyhydroborate (23.09 mg, 0.109 mmol) were added, and the reaction mixture was stirred at the same temperature for 3 days. Additional formaldehyde (37 weight % in water, 0.041 mL, 0.545 mmol) was added followed by sodium triacetoxyhydroborate (23.09 mg, 0.109 mmol), and the reaction mixture was stirred at the same temperature for 1 hour. Formaldehyde (37 weight % in water, 0.162 mL, 2.179 mmol) and sodium triacetoxyhydroborate (23.09 mg, 0.109 mmol) and more sodium triacetoxyhydroborate (23.09 mg, 0.109 mmol) were added with further stirring for 1 hour. Formaldehyde (37 weight % in water, 0.162 mL, 2.179 mmol) was added with further stirring for 30 minutes. Saturated aqueous sodium hydrogen carbonate (3 mL) was added, and the reaction mixture was stirred for 10 minutes. Then dichloromethane (5 mL) was added. The organic phase was passed through a hydrophobic phase separator, concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (0-100% methanol/dichloromethane) to afford the title compound (21 mg, 45% yield). MS (ESI.sup.+) m/z 391 (M+H).sup.+.

    Example 312C: tert-butyl [3-(4-{methyl[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2014] Example 312B (32 mg, 0.082 mmol) in dichloromethane (3 mL) was mixed with trifluoroacetic acid (0.125 mL, 1.639 mmol) and stirred at ambient temperature for 1 hour. Additional trifluoroacetic acid (0.125 mL, 1.639 mmol) was added, and the reaction mixture was stirred for an additional 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified via catch and release on SCX resin (washing with methanol then eluting with 7 M NH.sub.3 in methanol) to afford the title compound (21.2 mg, 69% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.23 (s, 1H), 7.20 (s, 1H), 4.17 (t, J=5.4 Hz, 2H), 3.37 (t, J=5.3, 4.2 Hz, 2H), 2.80 (s, 3H), 2.29 (s, 6H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 62.3; MS (ESI.sup.+) m/z 291 (M+H).sup.+.

    Example 312D: (2R)-6-chloro-N-[3-(4-{methyl[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazoyl-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2015] To a solution of the product of Example 312C (21 mg, 0.072 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (Example 1B, 18.03 mg, 0.080 mmol) and triethylamine (0.060 mL, 0.434 mmol) in N,N-dimethylformamide (1 mL), at ambient temperature under nitrogen, was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 41.3 mg, 0.109 mmol), and the reaction mixture was stirred for 2 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (0.5 mL), and the aqueous phase was extracted with dichloromethane (22 mL). The combined organic phases were then passed through a hydrophobic phase separator, washed with brine (2 mL), passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (36.1 mg, 100% yield). MS (ESI.sup.+) m/z 499 (M+H).sup.+.

    Example 312E: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2016] To a solution of the product of Example 312D (36.1 mg, 0.072 mmol) in methanol (1 mL), at ambient temperature under nitrogen, was added sodium borohydride (32.9 mg, 0.868 mmol), and the reaction mixture was stirred for 20 minutes and then quenched with saturated aqueous ammonium chloride (0.5 mL) and extracted with dichloromethane (32 mL). The organic phases were then passed through a phase separator, washed with brine (2 mL), and passed through another phase separator. Volatiles were removed under reduced pressure, and the crude residue was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] to afford the title compound (10.1 mg, 27% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.44 (d, J=2.7, 1.0 Hz, 1H), 7.24 (d, J=8.9, 1.0 Hz, 2H), 7.17 (dd, J=8.7, 2.7, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.98-4.90 (m, 1H), 4.65 (dd, J=11.6, 2.4 Hz, 1H), 4.17 (t, J=5.4 Hz, 2H), 3.36 (t, J=5.4 Hz, 2H), 2.80 (s, 3H), 2.60 (s, 6H), 2.59-2.53 (m, 1H), 1.96-1.86 (m, 1H); MS (ESI.sup.+) m/z 502 (M+H).sup.+.

    Example 313: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 412)

    Example 313A: methyl 3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

    [2017] A 100 mL round bottom flask was charged with 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.20 g, 12.93 mmol), iodomesitylene diacetate (2.40 g, 6.59 mmol), and toluene (20 mL). The mixture was stirred at 60 C. for 30 minutes. Toluene was removed under high vacuum. To the resulting residue was added copper(II) acetylacetonate (535 mg, 2.04 mmol), 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol), and tris(2-phenylpyridine)iridium (38 mg, 0.058 mmol) followed by dioxane (35 mL). The reaction mixture was degassed by sparging with nitrogen for 3 minutes before sealing the vessel with a rubber septum. The flask was positioned inside a running water cooled bath, and the reaction mixture was stirred and irradiated using 2 lamps: a 40W Kessil PR160-390 nm photoredox lamp and a PAR20-18W CREE XPE 450 nm blue LED lamp. Both lamps were placed 3 cm away from the reaction flask inside the water bath. The bath temperature was maintained at 18 C. After 18 hours, the lamps were turned off, and the reaction mixture was quenched by exposing to air while stirring for several minutes and then partitioned between saturated sodium bicarbonate (100 mL) and dichloromethane (250 mL). The organic fractions were combined, dried over sodium sulfate, and then concentrated under vacuum. The residue was taken up in methanol (20 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 120 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.62 g, 2.29 mmol, 34% yield). MS (APCI.sup.+) m/z 271 (M+H).sup.+.

    Example 313B: 3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylicacid

    [2018] The product of Example 313A (337 mg, 1.24 mmol) was dissolved in methanol (3 mL) and stirred at ambient temperature. Aqueous NaOH (1.24 mL, 2.5 M) was added. After stirring for 1 hour, the reaction mixture was partitioned between dichloromethane (350 mL) and aqueous citric acid solution (30 mL, 10 w/w %). The organic fractions were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (311 mg, 1.21 mmol, 97% yield). MS (APCI.sup.+) m/z 257 (M+H).sup.+.

    Example 313C: tert-butyl [3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2019] A mixture of the product of Example 313B (100 mg, 0.39 mmol), N,N-diisopropylethylamine (0.136 mL, 0.78 mmol) and tert-butanol (2 mL) was combined and stirred at ambient temperature. Diphenylphosphoryl azide (0.109 mL, 0.506 mmol) was added. The mixture was stirred at 58 C. for 10 hours, cooled, and concentrated under reduced pressure. The residue was taken up in methanol (5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (115 mg, 0.35 mmol, 90% yield). MS (ESI.sup.+) m/z 328 (M+H).sup.+.

    Example 313D: (1-{3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentan-1-yl}-1H-pyrazol-4-yl)boronic acid

    [2020] A 60 mL vial was charged with potassium acetate (0.947 g, 9.65 mmol), the product of Example 313C (1.056 g, 3.22 mmol), 4,4,4, 4, 5,5,5, 5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (1.226 g, 4.83 mmol)), XPhos-Pd-G3 (0.054 g, 0.064 mmol), and XPhos (0.061 g, 0.129 mmol). The contents were evacuated and backfilled with nitrogen for 4 passes. Ethanol (32 mL, previously degassed by bubbling nitrogen through for 10 minutes prior to use) was added. The vial was stirred at 65 C. for 2 hours. The reaction mixture was cooled to ambient temperature and filtered through a glass microfiber frit, and the filter cake was rinsed with more ethanol (50 mL). The filtrate was combined with diatomaceous earth and concentrated under reduced pressure to a free flowing powder, and the powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 15 m 120 g column, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate)] to give the title compound (0.62 g, 2.12 mmol, 66% yield). MS (ESI.sup.+) m/z 294 (M+H).sup.+.

    Example 313E: tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]penrtan-1-yl]carbamate

    [2021] To a solution of the product of Example 313D (200 mg, 0.68 mmol) in tetrahydrofuran (10 mL) at 0 C. was added aqueous sodium hydroxide (0.6 mL, 2.0 M) followed by hydrogen peroxide (153 L, 30% w/w %). The reaction mixture was stirred at 0 C. for 5 minutes. The ice bath was removed to allow the reaction mixture to slowly warm up to ambient temperature over a period of 20 minutes, and the mixture was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure briefly to remove the volatile tetrahydrofuran. Then dimethyl sulfoxide (1 mL), N,N-dimethylformamide (1 mL), and methanol (1 mL) were added, and the mixture was stirred for 10 minutes, filtered, and directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 20-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.62 g, 2.12 mmol, 66% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.47 (s, 1H), 7.69 (s, 1H), 7.16 (d, J=0.9 Hz, 1H), 7.03 (d, J=0.9 Hz, 1H), 2.28 (s, 6H), 1.39 (s, 9H); MS (APCI) m/z 266 (M+H).sup.+.

    Example 313F: tert-butyl (3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2022] The product of Example 313E (47.8 mg, 0.180 mmol) was combined with cesium carbonate (235 mg, 0.721 mmol) and N,N-dimethylformamide (0.9 mL) and stirred at ambient temperature. 1-Bromo-2-(trifluoromethoxy)ethane (39 L, 0.32 mmol) was added in one portion. The resulting mixture was stirred for 2 hours and filtered through a glass microfiber frit. The filtrate was directly purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (51 mg, 0.135 mmol, 75% yield). MS (ESI) m/z 378 (M+H).sup.+.

    Example 313G: 3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2023] To a solution of the product of Example 313F (3.63 g, 9.62 mmol) in dichloromethane (50 mL), under nitrogen, was added trifluoroacetic acid (25 mL, 324 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford a crude residue. The crude residue was purified via catch and release on SCX resin (washing with methanol then eluted with 0.7 M NH.sub.3 in methanol) to afford the title compound (2.67 g, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.54 (d, J=0.9 Hz, 1H), 7.25 (d, J=0.9 Hz, 1H), 4.36-4.27 (m, 2H), 4.10-4.07 (m, 2H), 2.10 (s, 6H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.93, MS (ESI.sup.+) m/z 278 (M+H).sup.+.

    Example 313H: (2R)-6-chloro-4-oxo-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2024] To a solution of the product from Example 313G (75 mg, 0.27 mmol) in N,N-dimethylformamide (100 mL) was added (R)-6-chloro-4-oxochroman-2-carboxylic acid (61 mg, 0.27 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 154 mg, 0.41 mmol). The resulting solution was cooled in an ice/water bath while triethylamine (0.23 mL, 1.62 mmol) was added dropwise. Once the base addition was complete, the cooling bath was removed, and the solution was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL) and extracted with dichloromethane (52 mL). The combined organic phases were passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (132 mg, 0.271 mmol, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.13 (s, 1H), 7.69-7.61 (m, 3H), 7.30 (d, J=0.9 Hz, 1H), 7.18 (dd, J=8.5, 0.8 Hz, 1H), 5.17-5.10 (m, 1H), 4.36-4.29 (m, 2H), 4.13-4.07 (m, 2H), 3.03-2.92 (m, 2H), 2.49-2.40 (m, 6H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.90; MS (ESI.sup.30) m/z 486 (M+H).sup.+.

    Example 313I. (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo-[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2025] To a solution of the product from Example 313H (132 mg, 19.35 mmol) in methanol (3 mL) was added sodium borohydride (123 mg, 3.25 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (2.5 mL) and extracted with dichloromethane (52 mL). The combined organic phases were passed through a hydrophobic phase separator and concentrated in vacuo. The crude residue was dissolved in dimethyl sulfoxide (2 mL), filtered and purified by preparative HPLC [Waters XBridge BEH C18 OBD prep column, 130 , 5 m, 30 mm100 mm, flow rate 40 mL/minute, 35-100% gradient of acetonitrile in buffer (0.3% ammonia in water)] to give the title compound (82 mg, 61%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.6, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.82 (dt, J=11.3, 6.0 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.35-4.32 (m, 2H), 4.10 (dd, J=5.6, 2.9 Hz, 2H), 2.46 (s, 6H), 2.40-2.35 (m, 1H), 1.83-1.62 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.89; MS (ESI.sup.+) m/z 488 (M+H).sup.+.

    Example 314: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 413)

    Example 314A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2026] A solution of the product from Example 313G (25 mg, 0.090 mmol), (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (23.16 mg, 0.095 mmol), and triethylamine (0.075 mL, 0.541 mmol) in dichloromethane (1 mL) was cooled in an ice bath, and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 37.7 mg, 0.099 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was partitioned between saturated sodium bicarbonate (2.5 mL) and dichloromethane (52 mL), and the combined organic phases were washed with brine (2 mL), passed through a hydrophobic phase separator, and concentrated in vacuo to afford the title compound (45.4 mg, 0.090 mmol, 100% yield). MS (ESI.sup.+) m/z 504 (M+H).sup.+.

    Example 314B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2027] To a solution of the product from Example 314A (45 mg, 0.089 mmol) in methanol (1 mL) was added sodium borohydride (40.5 mg, 1.072 mmol), and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (2.5 mL) and extracted with dichloromethane (52 mL). The combined organic phases were passed through a hydrophobic phase separator and concentrated in vacuo. The crude residue was dissolved in dimethyl sulfoxide (2 mL), filtered and purified by preparative HPLC [Waters XBridge BEH C18 OBD prep column, 130A, 5 m, 30 mm100 mm, flow rate 40 mL/minute, 25-100% gradient of acetonitrile in buffer (0.3% ammonia in water)] to give the title compound (30 mg, 0.058 mmol, 65.1% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.76 (s, 1H), 4.79 (dd, J=10.6, 5.8 Hz, 1H), 4.70 (dd, J=11.9, 2.4 Hz, 1H), 4.36-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.40-2.32 (m, 1H), 1.78-1.68 (m, 1H); 19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.89, 116.85; MS (ESI.sup.+) m/z 506 (M+H).sup.+.

    Example 315: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 414)

    Example 315A: tert-butyl [3-(1,3-oxazol-5-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2028] To a solution of tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate (Example 128B, 920 mg, 4.350 mmol) and potassium carbonate (1444 mg, 10.450 mmol) in anhydrous methanol (20 mL), under nitrogen, was added 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (850 mg, 4.35 mmol), and the reaction mixture was heated to 65 C. and then stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (10 mL) and water (10 mL). The phases were separated, and the aqueous phase was further extracted with dichloromethane (210 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford a crude residue, which was suspended in dichloromethane (20 mL) and the insoluble impurities removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (0-50% ethyl acetate/iso-hexane) to afford the title compound (280 mg, 25% yield). .sup.1HNMR (500 MHz, DMSO-d.sub.6) ppm 8.23 (s, 1H), 7.67 (s, 1H), 6.93 (s, 1H), 2.20 (s, 6H), 1.38 (s, 9H); MS (ESI) m/z 251 (M+H).sup.+.

    Example 315B: tert-butyl [3-(2-chloro-1,3-oxazol-5-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2029] To a solution of the product of Example 315A (150 mg, 0.599 mmol) and perchloroethane (284 mg, 1.199 mmol) in anhydrous tetrahydrofuran (4.5 mL), at 0 C. under nitrogen, was added lithium bis(trimethylsilyl)amide (1.318 mL, 1.318 mmol, 1 M in tetrahydrofuran), and the reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with water (10 mL), and the aqueous phase was extracted with ethyl acetate (210 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude residue, which was purified by chromatography on silica gel (0-100% ethyl acetate/heptane) to afford the title compound (95 mg, 45% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.06 (s, 1H), 2.21 (s, 6H), 1.38 (s, 9H); MS (ESI) m/z 285 (M+H).sup.+.

    Example 315C: tert-butyl (3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2030] To a solution of the product of Example 315B (47 mg, 0.165 mmol) and 2-(trifluoromethoxy)ethanol (0.024 mL, 0.248 mmol) in anhydrous tetrahydrofuran (2 mL), at 0 C. under nitrogen, was added sodium hydride [60 weight % dispersion in mineral oil](19.8 mg, 0.495 mmol), and the reaction mixture was stirred at this temperature for 1 hour and then warmed to ambient temperature and stirred for 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL), and the aqueous phase was extracted with dichloromethane (35 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford a crude residue, which was purified by chromatography on silica gel (0-100% ethyl acetate/heptane) to afford the title compound (54 mg, 69% yield). MS (ESI) m/z 379 (M+H).sup.+.

    Example 315D: 3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-amine

    [2031] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 315C gave the title compound (28 mg, 71% yield). MS (ESI) m/z 279 (M+H).sup.+.

    Example 315E: (2R)-6-chloro-4-oxo-N-(3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2032] A solution of the product of Example 315D (28.0 mg, 0.101 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (22.8 mg, 0.101 mmol), and triethylamine (0.042 mL. 0.302 mmol) in dichloromethane (1.25 mL), at 0 C. under nitrogen, was stirred for 5 minutes. Then propylphosphonic anhydride solution [50 weight % in ethyl acetate](T3P, 0.072 mL. 0.121 mmol) was added, and the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL), and the aqueous phase was extracted with dichloromethane (35 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (49.2 mg, 100% yield). MS (ESI) m/z 487 (M+H).sup.+.

    Example 315F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2033] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 315E and purifying by reverse phase chromatography on C18 silica gel (15-75% acetonitrile/[10 mM ammonium bicarbonate in water]) afforded the title compound (13.5 mg, 26% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.78 (s, 1H), 7.40-7.36 (m, 1H), 7.20 (dd, J=8.7, 2.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.68 (s, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.85-4.77 (m, 1H), 4.60 (dd, J=11.9, 2.3 Hz, 1H), 4.58-4.53 (m, 2H), 4.45-4.39 (m, 2H), 2.38-2.33 (m, 1H), 2.30 (s, 6H), 1.70 (q, J=12.0 Hz, 1H): .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.06; MS (ESI) m/z 489 (M+H).sup.+.

    Example 316: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 415)

    Example 316A: tert-butyl (3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2034] To a solution of the product of Example 315B (47.0 mg, 0.165 mmol) and 3-(trifluoromethoxy)propan-1-ol (35.7 mg, 0.248 mmol) in anhydrous tetrahydrofuran (2 mL), at 0 C. under nitrogen, was added sodium hydride [60 weight % dispersion in mineral oil](19.8 mg, 0.495 mmol), and the reaction mixture was stirred at this temperature for 1 hour and then warmed to ambient temperature and stirred for 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and the aqueous mixture was extracted with dichloromethane (35 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford a crude residue, which was purified by chromatography on silica gel (0-100% ethyl acetate/heptane) to afford the title compound (67 mg, 63% yield). MS (ESI) m/z 393 (M+H).sup.+.

    Example 316B: 3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-amine

    [2035] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 316A gave the title compound (35 mg, 70% yield). MS (ESI) m/z 293 (M+H).sup.+.

    Example 316C. (2R)-6-chloro-4-oxo-N-(3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2036] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 316B gave the title compound (60.0 mg, 100% yield). MS (ESI) m/z 501 (M+H).sup.+.

    Example 316D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo-[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2037] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 316C and purifying by reverse phase chromatography on C18 silica gel (15-75% acetonitrile/[10 mM ammonium bicarbonate in water]) afforded the title compound (25.8 mg, 42% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (dd, J=8.6, 2.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.65 (s, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.84-4.77 (m, 1H), 4.60 (dd, J=12.0, 2.3 Hz, 1H), 4.39 (t, J=6.2 Hz, 2H), 4.19 (t, J=6.2 Hz, 2H), 2.38-2.32 (m, 1H), 2.29 (s, 6H), 2.17-2.10 (m, 2H), 1.74-1.65 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.01; MS (ESI) m/z 504 (M+H).sup.+.

    Example 317: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 416)

    Example 317A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2038] A solution of the product of Example 315D (24.0 mg, 0.086 mmol), (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (21.1 mg, 0.086 mmol), and triethylamine (0.036 mL, 0259 mmol) in dichloromethane (1.0 mL), at 0 C. under nitrogen, was stirred for 5 minutes. Then propylphosphonic anhydride solution [50 weight % in ethyl acetate](T3P, 0.062 mL, 0.104 mmol) was added, and the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and the aqueous phase was extracted with dichloromethane (35 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (43.5 mg, 100% yield). MS (ESI) m/z 505 (M+H).sup.+.

    Example 317B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2039] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 317A and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (14.5 mg, 33% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.92 (d, J=10.5 Hz, 1H), 6.68 (s, 1H), 5.74 (d, J=5.6 Hz, 1H), 4.78 (s, 1H), 4.66 (dd, J=11.7, 2.3 Hz, 1H), 4.58-4.53 (m, 2H), 4.44-4.39 (m, 2H), 2.35 (d, J=10.7 Hz, 1H), 2.29 (s, 6H), 1.71 (q, J=11.9 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.06, 116.88; MS (ESI) m/z 507 (M+H).sup.+.

    Example 318: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 417)

    Example 318A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2040] The methodologies described in Example 317A substituting the product of Example 315D with the product of Example 316B gave the title compound (46.2 mg, 100% yield). MS (ESI) m/z 519 (M+H).sup.+.

    Example 318B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]-1,3-oxazol-5-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2041] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 318A and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (21.2 mg, 45% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.78 (s, 1H), 7.48 (d, J=8.6 Hz, 1H), 6.92 (d, J=10.5 Hz, 1H), 6.65 (s, 1H), 5.74 (t, J=5.3 Hz, 1H), 4.81-4.75 (m, 1H), 4.66 (dd, J=11.9, 2.4 Hz, 1H), 4.39 (t, J=6.1 Hz, 2H), 4.19 (t, J=6.2 Hz, 2H), 2.35 (ddd, J=13.1, 5.8, 2.5 Hz, 1H), 2.29 (s, 6H), 2.13 (p, J=6.2 Hz, 2H), 1.75-1.66 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.01, 116.88; MS (ESI) m/z 521 (M+H).sup.+.

    Example 319: (2R,4R)-6-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 418)

    [2042] The product of Example 313F (20 mg, 0.053 mmol) was combined with trifluoroacetic acid (0.5 mL) and stirred at ambient temperature for 20 minutes and then concentrated under high vacuum. To the residue was added (2R)-6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (11.7 mg, 0.056 mmol, Princeton Bio), triethylamine (0.052 mL), N,N-dimethylformamide (1 mL), and tri(pyrrolidin-1-yl)[(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy]phosphanium hexafluoridophosphate (PyAOP, 33.2 mg, 0.064 mmol) in sequential order. The resulting mixture was stirred at ambient temperature for 10 minutes, and then partitioned between dichloromethane (320 mL) and aqueous sodium carbonate (20 mL, 1.0 M). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (1 mL), and sodium borohydride (14.0 mg, 0.37 mmol) was added. The resulting mixture was stirred at ambient temperature for 15 minutes and then partitioned between dichloromethane (320 mL) and aqueous sodium carbonate (20 mL, 1.0 M). The combined organic fractions were combined and dried over sodium sulfate and concentrated under reduced pressured. The residue was taken up in N,N-dimethylformamide (1 mL) and filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (19.3 mg, 0.041 mmol, 77% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.84 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.15 (ddd, J=9.4, 3.2, 1.0 Hz, 1H), 7.01 (tdd, J=8.2, 3.5, 0.7 Hz, 1H), 6.88 (dd, J=8.9, 4.8 Hz, 1H), 5.68 (s, 1H), 4.84-4.81 (m, 1H), 4.61 (dd, J=12.0, 2.2 Hz, 1H), 4.35-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.38 (ddd, J=12.9, 6.0, 2.3 Hz, 1H), 1.72 (td, J=12.4, 10.8 Hz, 1H); MS (ESI) m/z 472 (M+H).sup.+.

    Example 320: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 419)

    Example 320A: tert-butyl 2-[(1r,4r)-4-(ethoxycarbonyl)cyclohexyl]hydrazine-1-carboxylate

    [2043] A solution of ethyl 4-oxocyclohexanecarboxylate (20 g, 118 mmol), tert-butyl hydrazinecarboxylate (23.29 g, 176 mmol) and acetic acid (6.73 mL) in dichloromethane (300 mL) was stirred for 1 hour at 20 C. and then cooled to 0 C. Sodium triacetoxyborohydride (49.8 g, 235 mmol) was slowly added at 0 C. The ice bath was removed to allow the reaction mixture to warm up to ambient temperature, and then the mixture was stirred for 12 hours. The reaction was quenched by addition of ethanol (500 mL). The reaction mixture was then partition between water (500 mL) and dichloromethane (3500 mL). The combined organic layers were washed with aqueous sodium carbonate solution (2500 mL, 2.0 M), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO.sub.2, 33-50% ethyl acetate in petroleum ether) to give the title compound (13 g, 40.9 mmol, 17% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.19-4.08 (m, 2H), 2.81 (br s, 1H), 2.28-2.17 (m, 1H), 2.07-1.91 (m, 4H), 1.62-1.34 (m, 11H), 1.29-1.21 (m, 3H), 1.18-1.05 (m, 2H).

    Example 320B: methyl (1r,4r)-4-hydrazinylcyclohexane-1-carboxylate-hydrogen chloride

    [2044] The product of Example 320A (12 g, 41.9 mmol) was combined with hydrogen chloride solution in methanol (120 mL, 4.0 M). The resulting mixture was stirred at 20 C. for 4 hours and then concentrated under reduced pressure to give the title compound (9 g, 34.4 mmol, 82% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm 3.67 (s, 3H), 3.08-2.98 (m, 1H), 2.43-2.28 (m, 1H), 2.22-2.08 (m, 4H), 1.55-1.32 (m, 4H).

    Example 320C: methyl (1r,4r)-4-(1H-pyrazol-1-yl)cyclohexane-1-carboxylate

    [2045] A solution of the product of Example 320B (9 g, 34.4 mmol) and 1,1,3,3-tetramethoxypropane (6.23 g, 38.0 mmol) in methanol (90 mL) was stirred at 80 C. for 2 hours. The mixture was diluted with ethyl acetate (50 mL) and then washed with water (50 mL). The aqueous layer was further extracted with ethyl acetate (250 mL). All organic layers were combined, washed with brine (30 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give the title compound (6 g, 28.8 mmol, 84% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.50 (d, J=1.5 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 6.23 (t, J=2.1 Hz, 1H), 4.19-4.06 (m, 1H), 3.74-3.64 (m, 3H), 2.43-2.34 (m, 1H), 2.29-2.10 (m, 4H), 1.89-1.76 (m, 2H), 1.71-1.56 (m, 2H).

    Example 320): methyl (1r,4r)-4-(4-bromo-1H-pyrazol-1-yl)cyclohexane-1-carboxylate

    [2046] To a solution of the product of Example 320C (6.0 g, 28.8 mmol) in acetone (60 mL) was added N-bromosuccinimide (5.13 g, 28.8 mmol). The reaction mixture was stirred at 20 C. for 12 hours, diluted with ethyl acetate (100 mL), and then washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO.sub.2, 25% ethyl acetate in petroleum ether) to give the title compound (6.8 g, 23.7 mmol, 82% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.46 (s, 1H), 7.44-7.42 (m, 1H), 4.16-4.04 (m, 1H), 3.75-3.66 (m, 1H), 2.43-2.33 (m, 1H), 2.27-2.12 (m, 4H), 1.85-1.71 (m, 2H), 1.70-1.57 (m, 2H).

    Example 320E: (1r,4r)-4-(4-bromo-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid

    [2047] To a solution of the product of Example 320D (6.5 g, 22.64 mmol) in a solvent mixture of methanol (65 mL) and tetrahydrofuran (65.0 mL) was added aqueous NaOH (22.64 mL, 2.0 M). The reaction mixture was stirred at 20 C. for 4 hours, and then acidified by aqueous HCl (1.0 M) to pH 3. The resulting mixture was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (6.0 g, 22 mmol, 97% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.98 (s, 1H), 7.51 (s, 1H), 4.23-4.04 (m, 1H), 2.35-2.20 (m, 1H), 2.12-1.94 (m, 4H), 1.82-1.64 (m, 2H), 1.58-1.39 (m, 2H).

    Example 320F: benzyl [(1r,4r)-4-(4-bromo-1H-pyrazol-1-yl)cyclohexyl]carbamate

    [2048] To a solution of the product of Example 320E (3 g, 10.98 mmol) and triethylamine (6.12 mL) in toluene (30 mL) stirring at 45 C. was added diphenylphosphoryl azide (3.33 g, 12.08 mmol) and benzyl alcohol (1.782 g, 16.5 mmol). The reaction was heated to 55 C. and stirred for 4 hours, and then concentrated under reduced pressure. The residue was taken up in ethyl acetate (50 mL), washed with water (3100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by precipitation from tert-butyl methyl ether (30 mL) to give the title compound (4.5 g, 11.4 mmol, 51.8% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm 7.78 (s, JH), 7.44 (s, 1H), 7.41-7.23 (m, 5H), 5.07 (s, 2H), 4.20-4.07 (m, 1H), 3.49 (br t, J=11.8 Hz, 1H), 2.09 (br t, J=12.6 Hz, 4H), 1.94-1.81 (m, 2H), 1.50-1.35 (m, 2H).

    Example 320G: {1-[(1r,4r)-4-{[(benzyloxy)carbonyl]amino}cyclohexyl]-1H-pyrazol-4-yl}boronic acid

    [2049] To a 20 mL vial was added cataCXium Pd G4 (59 mg, 0.079 mmol), tetrahydroxydiboron (475 mg, 5.30 mmol) and the product of Example 320F (456 mg, 1.206 mmol). The vessel was evacuated and backfilled with nitrogen. The process was repeated 4 times. Methanol (4.0 mL) was added followed by N,N-diisopropylethylamine) (925 L, 5.30 mmol). The reaction was again evacuated and backfilled with nitrogen 4 times, and then heated to 60 C. for 80 minutes. The resulting mixture was cooled, and combined with diatomaceous earth (15 g) and concentrated under reduced pressure to a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (198 mg, 0.58 mmol, 48% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.84 (s, 1H), 7.66 (s, 2H), 7.63 (s, 1H), 7.40-7.23 (m, 5H), 5.01 (s, 2H), 4.09 (tt, J=11.8, 3.8 Hz, 1H), 3.32-3.29 (m, 1H), 2.04-1.99 (m, 2H), 1.95-1.89 (m, 2H), 1.75 (qd, J=12.7, 3.5 Hz, 2H), 1.37 (qd, J=12.9, 3.4 Hz, 2H); MS (ESI.sup.+) m/z 344 (M+H).sup.+.

    Example 320H: benzyl [(1r,4r)-4-(4-hydroxy-1H-pyrazol-1-yl)cyclohexyl]carbamate

    [2050] To a stirred solution of the product of Example 320G (0.19 g, 0.554 mmol) in tetrahydrofuran (2.0 mL) at 0 C. under nitrogen protection was added aqueous NaOH (0.49 mL, 2.5 M) followed by hydrogen peroxide solution (0.124 mL, 30 w/w %). The resulting mixture was stirred at 0 C. for 5 minutes. The ice bath was removed to allow the reaction mixture to slowly warm up to ambient temperature over 20 minutes, and then the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was concentrated under vacuum briefly to remove most of the organic solvent, and then dimethyl sulfoxide (1 mL), N,N-dimethylformamide (1 mL), and methanol (1 mL) were added. The mixture was stirred for 10 minutes, filtered, and directly purified by reversed-phase flash chromatography [Custom packed YMC TriArt C18 Hybrid 20 m column, 25150 mm, flow rate 70 mL/minute, 12-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.106 g, 0.34 mmol, 61% yield). MS (ESI) m/z 316 (M+H).sup.+.

    Example 320I: benzyl [(1r,4r)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]carbamate

    [2051] The product of Example 320H (39.7 mg, 0.126 mmol) was combined with cesium carbonate (164 mg, 0.504 mmol) and N,N-dimethylformamide (1.26 mL), and the mixture was stirred at ambient temperature. 1-Bromo-2-(trifluoromethoxy)ethane (27 L, 0.227 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 18 hours, filtered through a glass microfiber frit that was rinsed with methanol (3 mL). The filtrate and wash were combined and directly purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (18 mg, 0.042 mmol, 34% yield). MS (ESI) m/z 428 (M+H).sup.+.

    Example 320J: (1r,4r)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexan-1-amine

    [2052] The product of Example 320I (16.5 mg, 0.039 mmol) was combined with trifluoroacetic acid (0.5 mL) and stirred at 65 C. for 40 minutes. The resulting reaction mixture was cooled to ambient temperature and then concentrated under high vacuum. The residue was taken up in methanol (1 mL) and purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (7.0 mg, 0.024 mmol, 62% yield). MS (ESI) m/z 294 (M+H).sup.+.

    Example 320K: (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2053] 6-Chloro-7-fluoro-4-oxochromane-2-carboxylic acid (26 g, 98 mmol, Princeton Bio) was separated by chiral SFC on a Waters SFC 350 Preparative System: [column: CHIRALPAK AD 25050 mm 10 m chiral column; Mobile phase: A for CO.sub.2 and B for methanol (with 0.1% ammonium hydroxide); Gradient: 40% B in A; Flow rate: 200 g/minute; Column temperature: 40 C.; System back pressure: 100 bar]. The pH of the earlier eluting fraction was adjusted to 1 with aqueous 1.0 M HCl and extracted with ethyl acetate (3200 mL). The organic layers were combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (8.0 g, 30 mmol, 30%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 13.61 (br s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.34 (d, J=10.4 Hz, 1H), 5.42 (dd, J=7.1, 5.4 Hz, 1H), 3.16 (dd, J=17.1, 5.4 Hz, 1H), 2.94-3.04 (m, 1H); MS (ESI.sup.+) m/z 245 (M+H).sup.+.

    Example 320L: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1H-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2054] The product of Example 320J (6.4 mg, 0.022 mmol) was combined with triethylamine (0.015 mL, 0.109 mmol), the product of Example 320K (5.6 mg, 0.023 mmol, and N,N-dimethylformamide (1 mL), and the mixture was stirred at ambient temperature. Tri(pyrrolidin-1-yl)[(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy]phosphanium hexafluoridophosphate (PyAOP, 13.6 mg, 0.026 mmol) was added. After stirring the resultant mixture at ambient temperature for 20 minutes, methanol (1 mL) was added, followed by sodium borohydride (5.8 mg, 0.153 mmol). The mixture was stirred for 15 minutes and filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (6.7 mg, 0.013 mmol, 59% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.96 (d, J=8.1 Hz, 1H), 7.60 (d, J=1.0 Hz, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 5.73 (d, J=5.5 Hz, 1H), 4.83-4.75 (m, 1H), 4.69 (dd, J=11.8, 2.4 Hz, 1H), 4.35-4.30 (m, 2H), 4.11-4.06 (m, 2H), 4.01 (tt, J=11.8, 3.9 Hz, 1H), 3.69 (tdt, J=11.8, 7.9, 4.0 Hz, 1H), 2.35 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 2.05-1.97 (m, 2H), 1.93-1.84 (m, 2H), 1.82-1.69 (m, 3H), 1.55-1.41 (m, 2H); MS (ESI) m/z 522 (M+H).sup.+.

    Example 321: (2R,4R)-6-chloro-N-(3-{4-[2-(difluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 420)

    Example 32A: 2-hydroxyethyl 4-methylbenzene-1-sulfonate

    [2055] To a solution of ethylene glycol (0.558 mL, 10.01 mmol), in anhydrous dichloromethane (50 mL), at 0 C. under nitrogen, was added silver oxide (3.48 g, 15.01 mmol), potassium iodide (0.33 g, 2.00 mmol), and p-toluenesulfonyl chloride (2.10 g, 11.01 mmol). The subsequent reaction mixture was stirred at this temperature for 2 hours, then warmed to ambient temperature and filtered through a pad of diatomaceous earth that was then washed with dichloromethane (500 mL). The filtrate and wash were concentrated in vacuo and the crude residue was purified by chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (0.97 g, 44% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.81-7.75 (m, 2H), 7.51-7.45 (m, 2H), 4.96 (t, J=5.6 Hz, 1H), 4.01-3.94 (m, 2H), 3.53 (q, J=5.0 Hz, 2H), 2.42 (s, 3H).

    Example 321B: 2-[(4-methylbenzene-1-sulfonyl)oxy]ethylformate

    [2056] A solution of the product of Example 321A (969 mg, 4.48 mmol), and copper(I) iodide (171 mg, 0.896 mmol) in anhydrous acetonitrile (13 mL), under nitrogen, was heated to 50 C. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.695 mL, 6.72 mmol) in anhydrous acetonitrile (7 mL) was added dropwise over 15 minutes, and the subsequent reaction mixture was stirred at this temperature for 1 hour. The reaction was cooled to ambient temperature and concentrated in vacuo to afford a crude residue which was purified by flash chromatography on silica gel (0-100% ethyl acetate/iso-hexane) affording the intended difluorinated compound which upon standing hydrolysed to the title compound (1037.0 mg, 93% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.16 (s, 1H), 7.82-7.76 (m, 2H), 7.52-7.46 (m, 2H), 4.29-4.21 (m, 4H), 2.43 (s, 3H).

    Example 321C: tert-butyl {3-[4-(2-hydroxyethoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2057] To a solution of tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (170 mg, 0.641 mmol), and cesium carbonate (835 mg, 2.56 mmol) in N,N-dimethylformamide (3 mL), under nitrogen, was added the product of Example 321B (188 mg, 0.769 mmol), and the subsequent reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogen carbonate (10 mL) followed by water/brine (1:1, 310 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (160 mg, 65% yield). MS (ESI.sup.+) m/z 310 (M+H).sup.+.

    Example 321D: tert-butyl (3-{4-[2-(difluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2058] A solution of the product of Example 321C (100.0 mg, 0.323 mmol), and copper(I) iodide (12.3 mg, 0.065 mmol) in anhydrous acetonitrile (2 mL), under nitrogen, was heated to 50 C. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.050 mL, 0.485 mmol) in anhydrous acetonitrile (0.75 mL) was added dropwise over 1 minute, and the subsequent reaction mixture was stirred at this temperature for 30 minutes. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford a crude residue which was purified by flash chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (13 mg, 11% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.56 (s, 1H), 7.26 (s, 1H), 6.71 (t, J=75.9 Hz, 1H), 4.10-4.04 (m, 2H), 4.05-4.00 (m, 2H), 2.31 (s, 6H), 1.39 (s, 9H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 82.67; MS (ESI.sup.+) m/z 360 (M+H).sup.+.

    Example 321E. 3-{4-[2-(difluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2059] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 321D gave the title compound (9 mg, 96% yield). MS (ESI) m/z 260 (M+H).sup.+.

    Example 321F: (2R)-6-chloro-N-(3-{4-[2-(difluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2060] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 321E gave the title compound (16.4 mg, 100% yield). MS (ESI) m/z 468 (M+H).sup.+.

    Example 321G: (2R,4R)-6-chloro-N-(3-{4-[2-(difluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2061] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 321F and purifying by chromatography on silica gel (0-10% methanol/dichloromethane) afforded the title compound (12.6 mg, 75% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.61 (d, J=0.9 Hz, 1H), 7.39 (d, J=2.6 Hz, 1H), 7.28 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.6, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.71 (t, J=75.8 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 4.08 (dd, J=6.4, 2.7 Hz, 2H), 4.04 (dd, J=6.2, 2.9 Hz, 2H), 2.46 (s, 6H), 2.38-2.33 (m, 1H), 1.72 (q, J=11.9 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 82.67; MS (ESI) m/z 470 (M+H).sup.+.

    Example 322: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 421)

    [2062] The product of Example 320J (4.0 mg, 0.014 mmol) and (R)-6-chloro-4-oxochroman-2-carboxylic acid (3.3 mg, 0.014 mmol) were combined with triethylamine (0.010 mL, 0.07 mmol) and N,N-dimethylformamide (1 mL). While the mixture was stirred at ambient temperature, tri(pyrrolidin-1-yl)[(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy]phosphanium hexafluoridophosphate (PyAOP, 8.5 mg, 0.016 mmol) was added. After stirring the resultant mixture at ambient temperature for 20 minutes, methanol (1 mL) was added, followed by sodium borohydride (3.6 mg, 0.1 mmol). The mixture was stirred for 15 minutes and N,N-dimethylformamide (1 mL) was added. The resulting solution was filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TiArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (4.8 mg, 0.0095 mmol, 70% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.94 (d, J=8.1 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.40-7.36 (m, 1H), 7.22 (d, J=0.9 Hz, 1H), 7.20 (ddd, J=8.6, 2.7, 0.8 Hz, 1H), 6.89 (dd, J=8.7, 0.8 Hz, 1H), 5.69 (d, J=6.3 Hz, 1H), 4.82 (dt, J=11.4, 6.0 Hz, 1H), 4.63 (dd, J=11.9, 2.2 Hz, 1H), 4.35-4.31 (m, 2H), 4.10-4.06 (m, 2H), 4.00 (tt, J=11.8, 3.9 Hz, 1H), 3.69 (tdt, J=11.8, 8.0, 4.0 Hz, 1H), 2.35 (ddd, J=13.0, 6.0, 2.3 Hz, 1H), 2.04-1.99 (m, 2H), 1.91-1.84 (m, 2H), 1.81-1.70 (m, 3H), 1.50 (pd, J=12.4, 3.3 Hz, 2H); MS (ESI) m/z 504 (M+H).sup.+.

    Example 323: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(1r,4R)-4-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 422)

    Example 323A: benzyl [(1r,4r)-4-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}cyclohexyl]carbamate

    [2063] The reaction and purification conditions described in Example 320I substituting 1-bromo-3-(trifluoromethoxy)propane for 1-bromo-2-(trifluoromethoxy)ethane gave the title compound. MS (APCI.sup.+) m/z 442 (M+H).sup.+.

    Example 323B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{(1r,4R)-4-(4-[3-(trifluoromethoxy)propoxy-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2064] Trifluoroacetic acid (1.0 mL) was added to the product of Example 323A (8 mg, 0.018 mmol), and the mixture was stirred at 70 C. for 40 minutes. The reaction mixture was cooled and then concentrated under high vacuum. The residue was taken up in N,N-dimethylformamide (0.5 mL). Triethylamine (0.025 mL, 0.18 mmol) was added to the mixture, followed by the product of Example 320K (4.7 mg, 0.019 mmol), and tri(pyrrolidin-1-yl)[(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy]phosphanium hexafluoridophosphate (PyAOP, 12.28 mg, 0.024 mmol). The resultant mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to 0 C. Methanol (1 mL) was added, followed by sodium borohydride (3.4 mg, 0.091 mmol). The ice bath was removed to allow the reaction mixture to warm up to ambient temperature over 10 minutes, and the reaction mixture was stirred for another 10 minutes. The resulting mixture was partitioned between dichloromethane (325 mL), water (10 mL) and aqueous sodium carbonate (10 mL, 1.0 M). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (8.1 mg, 0.015 mmol, 83% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.96 (d, J=8.1 Hz, 1H), 7.56 (d, J=0.9 Hz, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 5.73 (s, 1H), 4.79 (dd, J=10.7, 5.8 Hz, 1H), 4.68 (dd, J=11.8, 2.4 Hz, 1H), 4.19 (t, J=6.3 Hz, 2H), 4.05-3.94 (m, 1H), 3.91 (t, J=6.2 Hz, 2H), 3.74-3.65 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.96 (m, 4H), 1.93-1.85 (m, 2H), 1.75 (p, J=12.3, 11.8 Hz, 3H), 1.55-1.42 (m, 2H); MS (ESI) m/z 536 (M+H).sup.+.

    Example 324: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 423)

    [2065] The reaction and purification conditions described in Example 323B substituting (R)-6-chloro-4-oxochroman-2-carboxylic acid for the product of Example 320K gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.94 (d, J=8.1 Hz, 1H), 7.56 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.18 (d, J=0.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (s, 1H), 4.82 (dd, J=10.8, 6.0 Hz, 1H), 4.63 (dd, J=11.9, 2.2 Hz, 1H), 4.19 (t, J=6.3 Hz, 2H), 4.00 (tt, J=11.7, 3.9 Hz, 1H), 3.91 (t, J=6.1 Hz, 2H), 3.69 (tdt, J=11.8, 7.9, 4.0 Hz, 1H), 2.39-2.31 (m, 1H), 2.09-1.98 (m, 4H), 1.91-1.85 (m, 2H), 1.82-1.68 (m, 3H), 1.56-1.42 (m, 2H); MS (ESI) m/z 518 (M+H).sup.+.

    Example 325: (2R,4R)-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 424)

    Example 325A: (2R)-4-oxo-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2066] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 313G and substituting (R)-6-chloro-4-oxochroman-2-carboxylic acid with ()-(2R)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid gave the title compound (101 mg, 100% yield). MS (ESI.sup.+) m/z 520 (M+H).sup.+.

    Example 325B: (2R,4R)-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2067] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 325A and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (45.5 mg, 47% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.53 (dd, J=8.7, 2.4 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.84 (s, 1H), 4.88 (dd, J=10.7, 5.8 Hz, 1H), 4.75 (dd, J=11.9, 2.4 Hz, 1H), 4.36-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.47 (s, 6H), 2.44-2.38 (m, 1H), 1.82-1.71 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.91, 59.97; MS (ESI.sup.+) m/z 522 (M+H).sup.+.

    Example 326: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-(2,2,2-trifluoroethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 425)

    Example 326A: 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate

    [2068] To a stirred solution of 2-(2,2,2-trifluoroethoxy)ethanol (0.194 mL, 1.735 mmol), and triethylamine (0.290 mL, 2.082 mmol) in dichloromethane (7 mL), under nitrogen at 0 C., was added methanesulfonyl chloride (0.148 mL, 1.908 mmol) dropwise, and the reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (5 mL) and extracted with dichloromethane (25 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (470 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.39-4.30 (m, 2H), 4.13 (q, J=9.4 Hz, 2H), 3.90-3.82 (m, 2H), 3.18 (s, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 72.95.

    Example 326B: tert-butyl (3-{4-[2-(2,2,2-trifluoroethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2069] To a solution of tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (30 mg, 0.113 mmol), and cesium carbonate (147 mg, 0.452 mmol) in N,N-dimethylformamide (0.8 mL), under nitrogen, was added the product of Example 326A (36.8 mg, 0.136 mmol) in N,N-dimethylformamide (0.2 mL), and the subsequent reaction mixture was stirred at ambient temperature for 3 hours. After which additional 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (Example 326A, 36.8 mg, 0.136 mmol) in N,N-dimethylformamide (0.1 mL) was added, and the mixture was stirred at this temperature for 20 hours. After which additional 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (Example 326A, 36.8 mg, 0.136 mmol) in N,N-dimethylformamide (0.1 mL) was added, and the mixture was stirred at this temperature for 3 days. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogen carbonate (10 mL) followed by water/brine (1:1, 35 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (44 mg, 100% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.45 (d, J=0.9 Hz, 1H), 7.32 (d, J=0.9 Hz, 1H), 4.45-4.38 (m, 2H), 4.09-3.91 (m, 4H), 2.47 (s, 6H), 1.49 (s, 9H); MS (ESI) m/z 392 (M+H).sup.+.

    Example 326C: 3-{4-[2-(2,2,2-trifluoroethoxy)ethoxy-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2070] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 326B gave the title compound (30 mg, 87% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.42 (s, 1H), 7.31 (s, 1H), 4.10-3.98 (m, 4H), 3.95-3.87 (m, 2H), 2.29 (s, 6H); MS (ESI) m/z 292 (M+H).sup.+.

    Example 326D: (2R)-6-chloro-4-oxo-N-(3-{4-[2-(2,2,2-trifluoroethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2071] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 326C gave the title compound (58 mg, 100% yield). MS (ESI) m/z 500 (M+H).sup.+.

    Example 326E: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-(2,2,2-trifluoroethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2072] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 326D and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 25-55% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (32.1 mg, 60% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.48 (s, 1H), 7.46 (d, J=2.5, 1.0 Hz, 1H), 7.34 (s, 1H), 7.19 (dd, J=8.7, 2.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.98-4.92 (m, 1H), 4.67 (dd, J=11.6, 2.4 Hz, 1H), 4.10-4.07 (m, 2H), 4.03 (q, J=9.0 Hz, 2H), 3.96-3.89 (m, 2H), 2.62 (s, 6H), 2.60-2.55 (m, 1H), 1.97-1.86 (m, 1H); .sup.19F NMR (471 MHz, methanol-d.sub.4) ppm 76.10; MS (ESI) m/z 502 (M+H).sup.+.

    Example 327: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-(2-methoxyethoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 426)

    Example 327A: tert-butyl {3-[4-(2-methoxyethoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2073] To a solution of tert-butyl [3-(4-hydroxy-11H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (30 mg, 0.113 mmol), and cesium carbonate (147 mg, 0.452 mmol) in N,N-dimethylformamide (0.5 mL), under nitrogen, was added 1-bromo-2-methoxyethane (0.016 mL, 0.170 mmol), and the subsequent reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium hydrogen carbonate (5 mL) followed by water/brine (1:1, 35 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (31 mg, 85% yield). MS (ESI) m/z 324 (M+H).sup.+.

    Example 327B: 3-[4-(2-methoxyethoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-amine

    [2074] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 327A gave the title compound (22 mg, 98% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.40 (s, 1H), 7.29 (s, 1H), 4.05-4.01 (m, 2H), 3.71-3.67 (m, 2H), 3.42 (s, 3H), 2.28 (s, 6H); MS (ESI.sup.30) m/z 224 (M+H).sup.+.

    Example 327C: (2R)-6-chloro-N-{3-[4-(2-methoxyethoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2075] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 327B gave the title compound (43 mg, 100% yield). MS (ESI.sup.+) m/z 432 (M+H).sup.+.

    Example 3271D: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-(2-methoxyethoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2076] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 327C and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 15-45% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (21.6 mg, 48% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.47-7.43 (m, 2H), 7.31 (s, 1H), 7.20-7.15 (m, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.98-4.90 (m, 1H), 4.66 (dd, J=11.6, 2.4 Hz, 1H), 4.08-3.99 (m, 2H), 3.73-3.65 (m, 2H), 3.42 (s, 3H), 2.64-2.52 (m, 7H), 1.97-1.86 (m, 1H); MS (ESI.sup.+) m/z 434 (M+H).sup.+.

    Example 328: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 427)

    Example 328A: tricyclo[1.1.1]pentane

    [2077] In a heat dried round-bottomed flask, 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (19.5 g, 59.1 mmol) in pentane (16 mL) and diethyl ether (2.5 mL) was cooled to approximately50 C. in an isopropanol/dry ice bath. 3.5 M Methyllithium in diethoxymethane (45.8 mL, 142 mmol) was added dropwise over 30 minutes, keeping the internal temperature between 50 to 40 C. After the addition and stirring at the same temperature for 1 hour, the mixture was warmed to 0 C. and stirred for another hour. The addition funnel was then replaced with a short path distillation head, and the reaction mixture was distilled using house vacuum at 0 C., with the receptacle flask cooled to 78 C. with an acetone/dry ice bath to give 64 mL of solution which based on NMR analysis using dichloromethane as an internal standard gave a 0.68 M solution (2.87 g) of the title compound. This stock solution was stored in a 80 C. freezer for future use. .sup.1H NMR (600 MHz, CDCl.sub.3) ppm 2.03 (s, 6H).

    Example 328B: N,N-dibenzyl-3-(2-fluoropyridin-4-yl)bicyclo[1.1.1]pentan-1-amine

    [2078] A 40 mL vial was dried using a heat gun and cooled to ambient temperature under argon. The vial was charged with dibenzylamine (1.30 mL, 6.80 mmol) and tetrahydrofuran (3.4 mL). The vial was placed into an ice/water bath and the contents were cooled to 0 C. Isopropylmagnesium chloride lithium chloride complex solution (5.75 mL, 7.48 mmol, 1.3M in THF) was then added dropwise. After the addition, the reaction mixture was warmed to ambient temperature and stirred for 2 hours. The product of Example 328A (10 mL, 6.80 mmol) and undecane (0.709 mL, 3.40 mmol) were added into the vial under argon. The vial was then sealed using polytetrafluoroethylene caps and heated to 50 C. for 3 hours using a heating block. The vial was placed into ice/water bath, zinc chloride (1.9 M in 2-methyltetrahydrofuran) (7.52 mL, 14.28 mmol) was added dropwise, and the mixture was then warmed to ambient temperature and stirred for 30 minutes. To this mixture, 4-bromo-2-fluoropyridine (1.519 mL, 14.28 mmol) was added followed by P(t-Bu).sub.3 Pd G4 (100 mg, 0.170 mmol). The vial was heated at 50 C. for 60 minutes and then cooled with an ice/water bath. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (300 mL). The resulting suspension was passed through a pad of diatomaceous earth and that was then washed with more ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate (2-150 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified on silica gel (020% ethyl acetate in heptane) to give the title compound (0.53 g). .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 8.05 (dt, J=5.2, 0.7 Hz, 1H), 7.43-7.38 (m, 4H), 7.33-7.27 (m, 4H), 7.25-7.20 (m, 2H), 6.92 (ddd, J=5.1, 2.2, 1.3 Hz, 1H), 6.68-6.62 (m, 1H), 3.71 (s, 4H), 1.97 (s, 6H).

    Example 328C: N,N-dibenzyl-3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-amine

    [2079] To a solution of the product of Example 328B (185 mg, 0.516 mmol) and 3-(trifluoromethoxy)propan-1-ol (223 mg, 1.548 mmol) in tetrahydrofuran (2.5 mL) at ambient temperature was added potassium bis(trimethylsilyl)amide (1.032 mL, 1.032 mmol) (1 M in tetrahydrofuran) dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and purified on silica gel (0-30% ethyl acetate in heptane) to give the title compound (247 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.01 (d, J=5.3 Hz, 1H), 7.38 (d, J=7.1 Hz, 4H), 7.33-7.26 (m, 4H), 7.24-7.17 (m, 2H), 6.76 (dd, J=5.2, 1.4 Hz, 1H), 6.57-6.51 (m, 1H), 4.29 (t, J=6.2 Hz, 2H), 4.19 (t, J=6.3 Hz, 2H), 3.65 (s, 4H), 2.07 (p, J=6.4 Hz, 2H), 1.91 (s, 6H).

    Example 328D: 3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-amine

    [2080] To a mixture of the product of Example 328C (243 mg, 0.504 mmol) in tetrahydrofuran (5 mL) in a 20 mL Barnstead reactor with glass liner was added 5% Pd/C (wet JM #9) (120 mg, 0.525 mmol), and the mixture was stirred at 60 psi hydrogen and 25 C. for 16 hours. The reaction mixture was cooled to ambient temperature, and solids were removed by filtration and washed with methanol (10 mL). The filtrate and wash were concentrated, and the residue was purified on silica gel (010% methanol/dichloromethane) to give the title compound (103 mg).

    [2081] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.03 (d, J=5.2 Hz, 1H), 6.81 (dd, J=5.2, 1.4 Hz, 1H), 6.62-6.55 (m, 1H), 4.31 (t, J=6.2 Hz, 2H), 4.21 (t, J=6.3 Hz, 2H), 2.14-2.00 (m, 2H), 1.95 (s, 6H).

    Example 328E: 4-(S-chloro-4-fluoro-2-hydroxyphenyl)-4-oxobut-2-enoic acid

    [2082] A mixture of furan-2,5-dione (30 g, 306 mmol) and aluminum chloride (122 g, 918 mmol) in dichloromethane (400 mL) was stirred at 50 C. for 15 minutes. 1-Chloro-2-fluoro-4-methoxybenzene (39.3 g, 245 mmol) was then added to the mixture dropwise, and the mixture was stirred at 50 C. for 12 hours. The mixture was cooled to 20 C. and poured into a mixture of concentrated hydrochloric acid (150 mL, 12 N) and ice water (1200 mL). The precipitate was collected by filtration and dried under reduced pressure (vacuum pump) to give the title compound (37.4 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 12.97 (br s, 1H), 11.50-11.96 (m, 1H), 7.77-7.97 (m, 1H), 6.96-7.18 (m, 2H), 6.59-6.69 (m, 1H), 6.19-6.31 (m, 1H).

    Example 328F: 6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2083] To a mixture of the product of Example 328E (15 g, 42.9 mmol) in water (1500 mL) was added NaOH (68.7 mL, 68.7 mmol) at 25 C., and the mixture was stirred at 100 C. for 2 hours. The mixture was cooled to 20 C. and acidified with concentrated hydrochloric acid to pH=1. The resulting mixture was extracted with ethyl acetate (3500 mL). The organic phase was washed with brine (200 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated under vacuum, and the residue was triturated with a mixture of solvents (200 mL, petroleum ether: ethyl acetate=3:1) to give the title compound (7.2 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 13.55 (br s, 1H), 7.79-7.88 (m, 1H), 7.79-7.88 (m, 1H), 7.79-7.88 (m, 1H), 7.79-7.88 (m, 1H), 7.35 (d, J=10.26 Hz, 1H), 5.43 (dd, J=7.13, 5.50 Hz, 1H), 3.10-3.22 (m, 1H), 2.99 (dd, J=17.13, 7.25 Hz, 1H).

    Example 328G: (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2084] The product of Example 328F (26 g, 98 mmol) was separated by Chiral SFC (Instrument: Waters SFC80 preparative SFC; Column: CHIRALPAK IC, 25050 mm i.d., 10 m; Mobile phase: A for CO.sub.2 and B for CH.sub.3OH (0.1% NH.sub.40H); Gradient: B %=40% isocratic mode; Flow rate. 200 g/minute; Wavelength:220 nm; Column temperature: 40 C.; System back pressure: 100 bar) to give two separated peaks. The fractions of Peak 1 were concentrated and the residue was acidified with 1 N HCl to pH=1. The mixture was extracted with ethyl acetate (3-200 mL). The combined organic fractions were washed with water (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated under reduced pressure to give the titled compound (8 g, [].sup.25D=47.19). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 13.60 (br s, 1H), 7.84 (d, J=8.50 Hz, 1H), 7.34 (d, J=10.38 Hz, 1H), 5.43 (dd, J=7.13, 5.38 Hz, 1H), 3.16 (dd, J=17.07, 5.44 Hz, 1H), 2.99 (dd, J=17.13, 7.13 Hz, 1H).

    Example 328H: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2085] To a solution of the product of Example 328D (25 mg, 0.083 mmol), the product of Example 328G (21.24 mg, 0.087 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.043 mL, 0.248 mmol) in N,N-dimethylformamide (1 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.207 mL, 0.103 mmol) was added, and the mixture was stirred for 15 minutes. Volatiles were removed under high vacuum, and the residue was dissolved in methanol (1 mL) and treated with sodium tetrahydroborate (31.3 mg, 0.827 mmol) for 15 minutes. The reaction mixture was concentrated, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 75 mL/minute) to give the title compound (38 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.76 (s, 1H), 8.07 (d, J=5.2 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 6.99-6.82 (m, 2H), 6.66 (d, J=1.1 Hz, 1H), 4.79 (dd, J=10.5, 5.8 Hz, 1H), 4.67 (dd, J=11.9, 2.4 Hz, 1H), 4.33 (t, J=6.3 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 2.44-2.32 (m, 1H), 2.31 (s, 6H), 2.10 (p, J=6.4 Hz, 2H), 1.72 (td, J=12.6, 10.8 Hz, 1H).

    Example 329: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 428)

    [2086] The title compound was prepared using the methodologies described in Example 328H substituting (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid with (R)-6-chloro-4-oxochroman-2-carboxylic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.75 (s, 1H), 8.07 (d, J=5.2 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (dd, J=7.2, 4.6 Hz, 2H), 6.66 (s, 1H), 4.82 (dd, J=10.7, 5.8 Hz, 1H), 4.61 (dd, J=12.0, 2.3 Hz, 1H), 4.33 (t, J=6.2 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 2.44-2.33 (m, 1H), 2.31 (s, 6H), 2.10 (p, J=6.4 Hz, 2H), 1.78-1.65 (m, 1H).

    Example 330: (2R,4R)-6,7-difluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 429)

    Example 330A: (2R)-6,7-difluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2087] 6,7-Difluoro-4-oxochromane-2-carboxylic acid (Princeton Bio) was purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 6 mL/minute, 80% ethanol and 0.1% trifluoroacetic acid in heptane (isocratic gradient)] to give the title compound as the earlier eluting fraction. MS (ESI) m/z 227 (MH).sup..

    Example 330B: (2R,4R)-6,7-difluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy) ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2088] The reaction and purification conditions described in Example 319 substituting the product of Example 330A for (2R)-6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.36-7.31 (m, 1H), 7.30 (d, J=0.9 Hz, 1H), 6.93 (dd, J=11.8, 7.0 Hz, 1H), 5.72 (d, J=4.6 Hz, 1H), 4.80-4.77 (m, 1H), 4.66 (dd, J=11.9, 2.4 Hz, 1H), 4.35-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.37 (ddd, J=12.9, 5.7, 2.3 Hz, 1H), 1.72 (ddd, J=12.9, 12.0, 10.6 Hz, 1H); MS (ESI) m/z 490 (M+H).sup.+.

    Example 331: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 430)

    Example 331A: tert-butyl [3-(4-{[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2089] To a mixture of tert-butyl (3-(4-bromo-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (160 mg, 0.487 mmol), 3-(trifluoromethoxy)propan-1-amine, hydrochloric acid (232 mg, 1.295 mmol), solid sodium tert-butoxide (234.2 mg, 2.438 mmol), and tBuBrettPhos Pd G3 (41.62 mg, 0.049 mmol), was added degassed anhydrous 1,4-dioxane (4.0 mL), and the reaction mixture was sealed and then heated to 60 C. and stirred for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between dichloromethane (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL), the phases were separated, and the aqueous phase was further extracted with dichloromethane (210 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-10% methanol/dichloromethane) to afford the title compound (97 mg, 50% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.08 (s, 1H), 7.00 (d, J=0.9 Hz, 1H), 4.48 (t, J=6.2 Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 2.90 (q, J=6.5 Hz, 2H), 2.28 (s, 6H), 1.89-1.83 (m, 2H), 1.39 (s, 9H), .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.70, MS (ESI.sup.+) m/z 391 (M+H).sup.+. Example 331B: tert-butyl [3-(4-{methyl[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2090] To a solution of the product of Example 331A (61 mg, 0.156 mmol) in a mixture of dichloromethane (1.0 mL) and methanol (2.0 mL), at ambient temperature, was added triethylamine (0.033 mL, 0.234 mmol). To this solution were added successively acetic acid (0.031 mL, 0.547 mmol), formaldehyde (37 weight % in water) (0.047 mL, 0.625 mmol) and sodium triacetoxyhydroborate (66.2 mg, 0.312 mmol), and the mixture was stirred at ambient temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate (2.5 mL) was added, and the mixture was stirred for 15 minutes and then extracted with dichloromethane (32 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (58 mg, 90% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.00 (t, J=7.1 Hz, 2H), 2.60 (s, 3H), 2.30 (s, 6H), 1.84 (p, J=6.6 Hz, 2H), 1.39 (s, 9H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.78; MS (ESI.sup.30) m/z 405 (M+H).sup.+.

    Example 331C: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-methyl-N-[3-(trifluoromethoxy)propyl]-1H-pyrazol-4-amine

    [2091] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 331B gave the title compound (43 mg, 97.0% yield). .sup.1H NMR (500 MHz, DMSO-dr) J ppm 7.14 (d, J=1.0 Hz, 1H), 7.10 (d, J=1.0 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 2.99 (dd, J=7.9, 6.3 Hz, 2H), 2.59 (s, 3H), 2.09 (s, 6H), 1.83 (p, J=6.5 Hz, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.78; MS (ESI) m/z 305 (M+H).sup.+.

    Example 331D: (2R)-6-chloro-N-[3-(4-{methyl[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2092] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 331C gave the title compound (16.4 mg, 100% yield). MS (ESI) m/z 513 (M+H).sup.+.

    Example 331E: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2093] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 331D and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 40-70% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (14.7 mg, 20% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.24 (d, J=1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.82 (dt, J=11.4, 5.9 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.12 (t, J=6.3 Hz, 2H), 3.04-2.98 (m, 2H), 2.61 (s, 3H), 2.45 (s, 6H), 2.40-2.34 (m, 1H), 1.84 (p, J=6.6 Hz, 2H), 1.76-1.67 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.77; MS (ESI) m/z 515 (M+H).sup.+.

    Example 332: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 431)

    Example 332A: tert-butyl (3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2094] To a solution of tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl]carbamate (200 mg, 0.754 mmol), and cesium carbonate (982 mg, 3.02 mmol), under nitrogen, in N,N-dimethylformamide (4 mL) was added 1-bromo-3-(trifluoromethoxy)propane (187 mg, 0.905 mmol), and the subsequent reaction mixture was stirred at ambient temperature for 3 days. After which, additional 1-bromo-3-(trifluoromethoxy)propane (78 mg, 0.377 mmol) was added, and the reaction mixture was stirred at this temperature for 1 hour. After which, additional 1-bromo-3-(trifluoromethoxy)propane (78 mg, 0.377 mmol) was added, and the reaction mixture was stirred at this temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogen carbonate (10 mL) followed by water/brine (1:1, 310 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (351 mg, 60% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.72 (s, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 4.18 (t, J=6.3 Hz, 2H), 3.92 (t, J=6.2 Hz, 2H), 2.31 (s, 6H), 2.10-2.01 (m, 2H), 1.39 (s, 9H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.93; MS (ESI.sup.+) m/z 392 (M+H).sup.+.

    Example 3321: 3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2095] To a solution of the product of Example 332A (348 mg, 0.445 mmol) in dichloromethane (6 mL), under nitrogen, was added trifluoroacetic acid (1.028 mL, 13.34 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford a crude residue. The crude residue was purified via catch and release on SCX resin (washing with methanol and then eluted with 0.7 M ammonia in methanol), and then the crude material was purified by chromatography on silica gel (0-10% methanol/dichloromethane) to afford the title compound (114 mg, 79% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.49 (s, 1H), 7.21 (s, 1H), 4.18 (t, J=6.3 Hz, 2H), 3.91 (t, J=6.2 Hz, 2H), 2.34 (s, 2H), 2.09 (s, 6H), 2.07-2.01 (m, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.93; MS (ESI.sup.+) m/z 292 (M+H).sup.+.

    Example 332C: (2R)-6-chloro-4-oxo-N-(3-{4-[3-(trichloromethoxy)propoxyl-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2096] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 332B gave the title compound (60.1 mg, 69.0% yield). MS (ESI) m/z 500 (M+H).sup.+.

    Example 3321D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2097] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 332C and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (23.2 mg, 37% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.82 (dt, J=11.4, 6.1 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.19 (t, J=6.3 Hz, 2H), 3.93 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.37 (dq, J=10.7, 3.8, 3.1 Hz, 1H), 2.05 (p, J=6.2 Hz, 2H), 1.76-1.67 (m, 1H); .sub.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.92; MS (ESI) m/z 502 (M+H).sup.+.

    Example 333: (2S,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 432)

    [2098] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 313G and substituting (R)-6-chloro-4-oxochroman-2-carboxylic acid with (2S,4R)-6-chloro-7-fluoro-4-hydroxychroman-2-carboxylic acid and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 25-55% gradient of acetonitrile in buffer (0.3% ammonia in water)] gave the title compound (12.4 mg, 47% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 6.98 (d, J=10.6 Hz, 1H), 5.66 (s, 1H), 4.66-4.54 (m, 2H), 4.36-4.30 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.15-2.07 (m, 1H), 1.97-1.88 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.90,115.71; MS (ESI.sup.+) m/z 506 (M+H).sup.+.

    Example 334: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 433)

    Example 334A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2099] The methodologies described in Example 312D substituting the product of Example 332B for the product of Example 312C and (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid for (R)-6-chloro-4-oxochroman-2-carboxylic acid gave the title compound (176 mg, 60% yield). MS (ESI.sup.+) m/z 518 (M+H).sup.+.

    Example 334B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2100] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 334A and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (10.7 mg, 28% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.51 (d, J=8.4, 1.0 Hz, 1H), 7.46 (d, J=0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 6.86 (d, J=10.3 Hz, 1H), 4.93-4.87 (m, 1H), 4.70 (dd, J=11.5, 2.5 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 4.01 (t, J=6.0 Hz, 2H), 2.60 (s, 6H), 2.59-2.52 (m, 1H), 2.13 (p, J=6.2 Hz, 2H), 1.95-1.86 (m, 1H); .sup.19F NMR (471 MHz, methanol-d.sub.4) ppm 62.31, 117.64; MS (ESI.sup.+) m/z 520 (M+H).sup.+.

    Example 335: (2S,4R)-6,7-dichloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 434)

    Example 335A: (2S)-6,7-dichloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2101] 6,7-Dichloro-4-oxochroman-2-carboxylic acid (Princeton Bio) was purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 20 mL/minute, 15% methanol in ethanol (isocratic)] to give the title compound as the later eluting fraction. MS (APCI.sup.+) m/z 259 (MH).sup..

    Example 335B: (2S,4R)-6,7-dichloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2102] The product of Example 335A (0.15 g, 0.58 mmol) was combined with methanol (5 mL) and stirred at ambient temperature. Sodium borohydride (0.261 g, 6.90 mmol) was added portionwise over 2 minutes. After stirring at ambient temperature for 30 minutes, the resulting mixture was concentrated under high vacuum to dryness. To the residue was added trifluoroacetic acid (5 mL) which was pre-chilled to 0 C., and the resulting solution was allowed to stir at ambient temperature for 2 hours, before concentration under reduced pressure. The residue was taken up in acetonitrile (20 mL) and cooled to 0 C. Aqueous ammonium hydroxide solution (10 mL, 5 M) pre-chilled to below 5 C. was slowly added to the cold mixture. The ice bath was removed, and the mixture was allowed to slowly warm up to ambient temperature over 15 minutes, and then stirred for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was taken up in a solvent mixture of methanol (10 mL) and water (1 mL) and filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [Phenomenex Kinetex F5 column, 100 , 5 m, 30100 mm, flow rate 40 mL/minute, 45% of methanol in buffer (0.1% trifluoroacetic acid), isocratic] to give the title compound (58 mg, 0.22 mmol, 38% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 13.25 (s, 1H), 7.52 (d, J=0.7 Hz, 1H), 7.16 (s, 1H), 5.73 (s, 1H), 4.83 (dd, J=7.0, 5.2 Hz, 1H), 4.57 (t, J=5.1 Hz, 1H), 2.16-2.09 (m, 2H); MS (ESI) m/z 261 (MH).sup..

    Example 335C: (2S,4R)-6,7-dichloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2103] The product of Example 313F (15 mg, 0.040 mmol) was combined with trifluoroacetic acid (0.1 mL) and stirred at ambient temperature for 10 minutes, and then the mixture was concentrated under high vacuum. To the resulting residue was added triethylamine (0.028 mL, 0.20 mmol), N,N-dimethylformamide (1 mL), the product of Example 335B (11 mg, 0.042 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (20 mg, 0.052 mmol) in sequential order, and the mixture was stirred at ambient temperature for 30 minutes, and then quenched with water (0.1 mL). The resulting solution was filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (12.7 mg, 0.024 mmol, 61% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.52 (d, J=0.6 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.20 (s, 1H), 5.70 (s, 1H), 4.64 (dd, J=10.6, 2.9 Hz, 1H), 4.60 (t, J=4.0 Hz, 1H), 4.35-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.12 (ddd, J=13.9, 4.2, 3.0 Hz, 1H), 1.94 (ddd, J=14.1, 10.7, 3.7 Hz, 1H); MS (ESI) m/z 522 (M+H).sup.+.

    Example 336: (2R,4R)-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 435)

    Example 336A: (2R)-4-oxo-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2104] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 332B and (R)-6-chloro-4-oxochroman-2-carboxylic acid with ()-(2R)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid gave the title compound (36.6 mg, 100% yield). MS (ESI.sup.+) m/z 534 (M+H).sup.+.

    Example 336B: (21R,4R)-4-hydroxy-N-(3-(4-(3-(trifluoromethoxy)propoxy)-1H-pyrazol-1-yl)bicyclo[1.1.1]-pentan-1-yl)-6-(trifluoromethyl)chroman-2-carboxamide

    [2105] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 336A and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (10.7 mg, 28% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.79 (s, 1H), 7.51 (dd, J=8.6, 2.4 Hz, 1H), 7.48 (d, J=0.9 Hz, 1H), 7.33 (d, J=0.9 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 5.05-4.97 (m, 1H), 4.77 (dd, J=11.6, 2.5 Hz, 1H), 4.22 (t, J=6.3 Hz, 2H), 4.02 (t, J=6.0 Hz, 2H), 2.65-2.59 (m, 7H), 2.14 (p, J=6.1 Hz, 2H), 2.03-1.89 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 62.31, 63.18; MS (ESI.sup.+) m/z 536 (M+H).sup.+.

    Example 337: (2R,4S)-6,7-dichloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 436)

    Example 337A: (2R)-6,7-dichloro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2106] 6,7-Dichloro-4-oxochroman-2-carboxylic acid (Princeton Bio) was purified by preparative chiral HPLC [CHIRALPAK AD-H 5 m column, 20250 mm, flow rate 20 mL/minute, 15% methanol in ethanol (isocratic)] to give the title compound as the earlier eluting fraction. MS (APCI.sup.+) m/z 259 (MH).sup..

    Example 337B: (2R,4S)-6,7-dichloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2107] The reaction and purification conditions described in Example 335B substituting the product of Example 337A for the product of Example 335A gave the title compound. MS (ESI) m/z 261 (MH).sup..

    Example 337C: (21,4S)-6,7-dichloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2108] The reaction and purification conditions described in Example 335C substituting the product of Example 337B for the product of Example 335B gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.52 (s, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.20 (s, 1H), 5.70 (s, 1H), 4.64 (dd, J=10.6, 3.0 Hz, 1H), 4.62-4.58 (m, 1H), 4.36-4.30 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.12 (ddd, J=13.9, 4.2, 3.0 Hz, 1H), 1.94 (ddd, J=14.1, 10.6, 3.7 Hz, 1H); MS (ESI) m/z 522 (M+H).sup.+.

    Example 338: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 437)

    Example 338A: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-[2-(trifluoromethoxy)ethyl]-1H-pyrazol-4-amine

    [2109] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 312A gave the title compound (35 mg, 81% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.10 (s, 1H), 7.01 (s, 1H), 4.62 (t, J=6.6 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 3.15 (q, J=5.7 Hz, 2H), 2.07 (s, 6H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.68.

    Example 338B: (2R)-6-chloro-4-oxo-N-[3-(4-{[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2110] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 338A gave the title compound (10.0 mg, 28% yield). MS (ESI.sup.30) m/z 484 (M+H).sup.+.

    Example 338C: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[2-(trifluoromethoxy)ethyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2111] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 338B and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (10 mg, 28% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.86-4.78 (m, 1H), 4.68 (t, J=6.6 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.12 (t, J=5.4 Hz, 2H), 3.17 (q, J=5.7 Hz, 2H), 2.43 (s, 6H), 2.41-2.33 (m, 1H), 1.77-1.66 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.68; MS (ESI.sup.+) m/z 487 (M+H).sup.+.

    Example 339: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[3-(trifluoromethoxy)propoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 438)

    Example 339A: N,N-dibenzyl-3-(6-fluoropyridin-3-yl)bicyclo[1.1.1]pentan-1-amine

    [2112] The title compound was prepared using the methodologies described in Example 328B substituting 4-bromo-2-fluoropyridine with 5-bromo-2-fluoropyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.03-7.98 (m, 1H), 7.76 (td, J=8.2, 2.5 Hz, 1H), 7.43-7.34 (m, 4H), 7.34-7.25 (m, 4H), 7.25-7.13 (m, 2H), 7.06 (dd, J=8.4, 2.7 Hz, 1H), 3.66 (s, 4H), 1.95 (s, 6H).

    Example 339B: N,N-dibenzyl-3-{6-[3-(trifluoromethoxy)propoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-amine

    [2113] The title compound was prepared using the methodologies described in Example 328C substituting the product of Example 328B with the product of Example 339A. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.91 (dd, J=2.4, 0.8 Hz, 1H), 7.49 (dd, J=8.5, 2.5 Hz, 1H), 7.41-7.36 (m, 4H), 7.30 (dd, J=8.4, 6.9 Hz, 4H), 7.24-7.18 (m, 2H), 6.70 (dd, J=8.5, 0.8 Hz, 1H), 4.28 (t, J=6.3 Hz, 2H), 4.19 (t, J=6.3 Hz, 2H), 3.65 (s, 4H), 2.12-2.04 (m, 2H), 1.90 (s, 6H).

    Example 339C: 3-{6-[3-(trifluoromethoxy)propoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-amine

    [2114] The title compound was prepared using the methodologies described in Example 328D substituting the product of Example 328C with the product of Example 339B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.65 (s, 3H), 8.04 (dd, J=2.5, 0.8 Hz, 1H), 7.64 (dd, J=8.4, 2.5 Hz, 1H), 6.79 (dd, J=8.5, 0.8 Hz, 1H), 4.32 (t, J=6.3 Hz, 2H), 4.21 (t, J=6.3 Hz, 2H), 2.27 (s, 6H), 2.15-2.06 (m, 2H).

    Example 339D: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[3-(trifluoromethoxy)propoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2115] The title compound was prepared using the methodologies described in Example 328H substituting the product of Example 328D with the product of Example 339C and substituting (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid with (R)-6-chloro-4-oxochroman-2-carboxylic acid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 8.02 (dd, J=2.5, 0.8 Hz, 1H), 7.60 (dd, J=8.5, 2.5 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.77 (dd, J=8.5, 0.8 Hz, 1H), 5.69 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.61 (dd, J=12.0, 2.3 Hz, 1H), 4.31 (t, J=6.3 Hz, 2H), 4.21 (t, J=6.3 Hz, 2H), 2.41-2.33 (m, 1H), 2.30 (s, 6H), 2.10 (p, J=6.3 Hz, 2H), 1.77-1.66 (m, 1H).

    Example 340: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 439)

    Example 340A: (2R)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol

    [2116] To a solution of (R)-propane-1,2-diol (1 g, 13.14 mmol) and imidazole (0.895 g, 13.14 mmol) in dichloromethane (10 mL), at 0 C. under nitrogen, was added tert-butylchlorodimethylsilane (1.981 g, 13.14 mmol) as a solution in dichloromethane (10 mL), and the subsequent reaction mixture was stirred at 0 C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound (2.31 g, 83% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.46 (s, 1H), 3.62-3.53 (m, 1H), 3.47 (dd, J=9.9, 5.4 Hz, 1H), 3.28 (dd, J=9.9, 6.4 Hz, 1H), 1.02 (d, J=6.2 Hz, 3H), 0.86 (s, 9H), 0.03 (d, J=0.9 Hz, 6H).

    Example 340B: (2R)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl methanesulfonate

    [2117] To a stirred solution of the product of Example 340A (2.31 g, 12.14 mmol), and triethylamine (2.030 mL, 14.56 mmol) in dichloromethane (30 mL), at 0 C. under nitrogen, was added methanesulfonyl chloride (1.033 mL, 13.35 mmol) dropwise, and the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with dichloromethane (230 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (3.21 g, 89/o yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.69 (pd, J=6.3, 3.9 Hz, 1H), 3.73-3.61 (m, 2H), 3.14 (s, 3H), 1.28 (d, J=6.4 Hz, 3H), 0.87 (s, 9H), 0.06 (d, J=1.7 Hz, 6H).

    Example 340C: tert-butyl [3-(4-{[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2118] To a solution of tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (123 mg, 0.464 mmol) and cesium carbonate (604 mg, 1.854 mmol) in N,N-dimethylformamide (2 mL), under nitrogen, was added the product of Example 340B (249 mg, 0.927 mmol) and the subsequent reaction mixture was heated to 80 C. and stirred for 1.5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium hydrogen carbonate (5 mL) followed by water/brine (1:1, 35 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude residue which was purified by flash chromatography on silica gel (20-70% ethyl acetate/iso-hexane) to afford the title compound (95 mg, 45% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 7.48 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H), 4.04 (p, J=5.8 Hz, 1H), 3.67-3.58 (m, 2H), 2.30 (s, 6H), 1.39 (s, 9H), 1.15 (d, J=6.2 Hz, 3H), 0.85 (s, 9H), 0.02 (d, J=9.0 Hz, 6H); MS (ESI.sup.+) m/z 438 (M+H).sup.+.

    Example 340D: tert-butyl [3-(4-{[(2S)-1-hydroxypropan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2119] To a solution of the product of Example 340C (145 mg, 0.331 mmol) in anhydrous tetrahydrofuran (3 mL), at 0 C. under nitrogen, was added tetra-n-butylammonium fluoride (0.663 mL, 0.663 mmol, 1 M in tetrahydrofuran), and the reaction mixture was warmed to ambient temperature and stirred for 4 hours. The reaction mixture was quenched with aqueous saturated ammonium chloride (5 mL) and extracted with dichloromethane (25 mL). The combined organic layers were passed through a hydrophobic phase separator and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (93 mg, 85% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 7.48 (s, 1H), 7.20 (d, J=0.9 Hz, 1H), 4.76 (t, J=5.8 Hz, 1H), 4.02-3.93 (m, 1H), 3.51-3.36 (m, 2H), 2.30 (s, 6H), 1.39 (s, 9H), 1.15 (d, J=6.2 Hz, 3H); MS (ESI.sup.30) m/z 324 (M+H).sup.+.

    Example 340E: tert-butyl [3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2120] A mixture of silver(I) trifluoromethanesulfonate (200 mg, 0.776 mmol), potassium fluoride (66.8 mg, 1.150 mmol), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor, 153 mg, 0.431 mmol) was stirred, under nitrogen, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of the product of Example 340D (93 mg, 0.288 mmol) in ethyl acetate (3 mL) followed by the dropwise addition of 2-fluoropyridine (0.074 mL, 0.863 mmol) and then trimethyl(trifluoromethyl)silane (0.128 mL, 0.863 mmol), and the reaction mixture was then stirred at ambient temperature for 2 days. The crude reaction mixture was filtered through a pad of diatomaceous earth, the pad was then washed with ethyl acetate (20 mL), and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (48 mg, 41% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.72 (s, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 4.33-4.28 (m, 1H), 4.22 (dd, J=10.8, 2.9 Hz, 1H), 4.09 (dd, J=10.8, 6.0 Hz, 1H), 2.31 (s, 6H), 1.39 (s, 9H), 1.23 (d, J=6.4 Hz, 3H): .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.83; MS (ESI) m/z 392 (M+H).sup.+.

    Example 340F: 3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [2121] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 340E gave the title compound (32 mg, 85% yield). MS (ESI.sup.+) m/z 292 (M+H).sup.+.

    Example 340G: (2R)-6-chloro-4-oxo-N-3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2122] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 340F gave the title compound (19.0 mg, 100% yield). MS (ESI) m/z 500 (M+H).sup.+.

    Example 340H: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2123] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 340G and purifying by chromatography on silica gel (0-100% ethyl acetate/iso-hexane) afforded the title compound (8.2 mg, 42% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.63 (s, 1H), 7.39 (d, J=2.6 Hz, 1H), 7.28 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 4.36-4.28 (m, 1H), 4.23 (dd, J=10.8, 2.9 Hz, 1H), 4.10 (dd, J=10.8, 6.0 Hz, 1H), 2.46 (s, 6H), 2.40-2.34 (m, 1H), 1.76-1.67 (m, 1H), 1.24 (d, J=6.3 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.82; MS (ESI) m/z 502 (M+H).sup.+.

    Example 341: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(2R)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 440)

    Example 341A: (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol

    [2124] To a solution of (S)-propane-1,2-diol (1 g, 13.14 mmol) and imidazole (0.895 g, 13.14 mmol) in anhydrous dichloromethane (10 mL), at 0 C. under nitrogen, was added tert-butylchlorodimethylsilane (1.981 g, 13.14 mmol) as a solution in anhydrous dichloromethane (10 mL), and the subsequent reaction mixture was stirred at 0 C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound (2.44 g, 88% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.46 (s, 1H), 3.62-3.53 (m, 1H), 3.47 (dd, J=9.9, 5.4 Hz, 1H), 3.28 (dd, J=9.9, 6.4 Hz, 1H), 1.02 (d, J=6.2 Hz, 3H), 0.86 (s, 9H), 0.03 (d, J=0.9 Hz, 6H).

    Example 341B: (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl methanesulfonate

    [2125] To a stirred solution of the product of Example 341A (2.44 g, 12.82 mmol), and triethylamine (2.144 mL, 15.38 mmol) in anhydrous dichloromethane (30 mL), at 0 C. under nitrogen, was added methanesulfonyl chloride (1.091 mL, 14.10 mmol) dropwise, and the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with dichloromethane (230 mL). The combined organic fractions were passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (3.33 g, 87% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.69 (pd, J=6.3, 3.9 Hz, 1H), 3.73-3.61 (m, 2H), 3.14 (s, 3H), 1.28 (d, J=6.4 Hz, 3H), 0.87 (s, 9H), 0.06 (d, J=1.7 Hz, 6H).

    Example 341C: tert-butyl [3-(4-{[(2R)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2126] To a solution of tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (200 mg, 0.754 mmol), and cesium carbonate (982 mg, 3.02 mmol) in N,N-dimethylformamide (4 mL), under nitrogen, was added the product of Example 341B (405 mg, 1.508 mmol), and the subsequent reaction mixture was heated to 80 C. and stirred for 1.5 hours.

    [2127] The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium hydrogen carbonate (5 mL) followed by water/brine (1:1, 35 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude residue which was purified by flash chromatography on silica gel (20-70% % ethyl acetate/iso-hexane) to afford the title compound (126 mg, 36% yield). MS (ESI.sup.+) m/z 438 (M+H).sup.+.

    Example 341D: tert-butyl [3-(4-{[(2R)-1-hydroxypropan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2128] To a solution of the product of Example 341C (126 mg, 0.288 mmol) in anhydrous tetrahydrofuran (3 mL), at 0 C. under nitrogen, was added tetra-n-butylammonium fluoride (0.576 mL, 0.576 mmol, 1 M in tetrahydrofuran), and the reaction mixture was warmed to ambient temperature and stirred for 4 hours. The reaction mixture was quenched with aqueous saturated ammonium chloride (5 mL) and extracted with dichloromethane (25 mL). The combined organic layers were passed through a hydrophobic phase separator and concentrated in vacuo to afford the crude residue which was purified by flash chromatography on silica gel (50-100% ethyl acetate/iso-hexane) to afford the title compound (83 mg, 89% yield). MS (ESI.sup.+) m/z 324 (M+H).sup.+.

    Example 341E: tert-butyl [3-(4-{[(2R)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2129] A mixture of silver(I) trifluoromethanesulfonate (178 mg, 0.693 mmol), potassium fluoride (59.6 mg, 1.027 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) and (Selectfluor, 136 mg, 0.385 mmol) was stirred, under nitrogen in a flask wrapped with aluminum foil. The flask was cooled in a water bath. The product of Example 341D (83 mg, 0.257 mmol) was dissolved in ethyl acetate (3 mL), and the resulting solution was added slowly to the previously described mixture. 2-Fluoropyridine (0.066 mL, 0.770 mmol) followed by trimethyl(trifluoromethyl)silane (0.114 mL, 0.770 mmol) were slowly added to the reaction mixture via syringe. The resulting mixture was stirred at ambient temperature for 3 days and then was filtered through a pad of diatomaceous earth that was subsequently washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the crude residue was purified by chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (56 mg, 25% yield). MS (ESI) m/z 392 (M+H).sup.+.

    Example 341F: 3-(4-{[(2R)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [2130] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 341E gave the title compound (17 mg, 21.6% yield). MS (ESI) m/z 292 (M+H).sup.+.

    Example 341G: (2R)-6-chloro-4-oxo-N-[3-(4-{[(2R)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2131] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 341F gave the title compound (29.2 mg, 100% yield). MS (ESI) m/z 500 (M+H).sup.+.

    Example 341H: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(2R)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2132] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 341G and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (7.0 mg, 24% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.28 (d, J=0.9 Hz, 1H), 7.23-7.19 (m, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.35-4.28 (m, 1H), 4.23 (dd, J=10.8, 2.9 Hz, 1H), 4.10 (dd, J=10.8, 6.0 Hz, 1H), 2.46 (s, 6H), 2.40-2.34 (m, 1H), 1.76-1.67 (m, 1H), 1.24 (d, J=6.3 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.82; MS (ESI) m/z 502 (M+H).sup.+.

    Example 342: (2R,4R)-4-hydroxy-N-[3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 441)

    Example 342A: (2R)-4-oxo-N-[3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2133] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 340F and (R)-6-chloro-4-oxochroman-2-carboxylic acid with ()-(2R)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid gave the title compound (38.5 mg, 100% yield). MS (ESI) m/z 534 (M+H).sup.+.

    Example 342B: (2R,4R)-4-hydroxy-N-[3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]oxy}-1H-pivraol-1-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2134] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 342A and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] gave the title compound (9 mg, 23% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (d, J=2.0 Hz, 1H), 7.63 (d, J=1.1 Hz, 1H), 7.56-7.50 (m, 1H), 7.28 (d, J=0.9 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 4.90-4.83 (m, 1H), 4.77-4.71 (m, 1H), 4.36-4.27 (m, 1H), 4.23 (dd, J=10.8, 2.9 Hz, 1H), 4.10 (dd, J=10.8, 6.0 Hz, 1H), 2.46 (s, 6H), 2.44-2.37 (m, 1H), 1.77 (q, J=11.8 Hz, 1H), 1.24 (d, J=6.4 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.82, 59.94; MS (ESI.sup.+) m/z 536 (M+H).sup.+.

    Example 343: (2R,4R)-6,7-dichloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 442)

    [2135] The reaction and purification conditions described in Example 319 substituting the product of Example 337A for (2R)-6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.54 (d, J=1.0 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.16 (s, 1H), 5.79 (s, 1H), 4.81 (dd, J=10.5, 5.8 Hz, 1H), 4.71 (dd, J=11.9, 2.5 Hz, 1H), 4.37-4.30 (m, 2H), 4.14-4.07 (m, 2H), 2.46 (s, 6H), 2.38 (ddd, J=12.9, 5.7, 2.4 Hz, 1H), 1.78-1.65 (m, 1H); MS (ESI) m/z 522 (M+H).sup.+.

    Example 344: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(2S)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 443)

    Example 344A: tert-butyl (3-{4-[(2S)-2-hydroxypropoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2136] To a solution of tert-butyl [3-(4-hydroxy-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (300 mg, 1.131 mmol), and cesium carbonate (1474 mg, 4.52 mmol) in N,N-dimethylformamide (10 mL), under nitrogen, was added (S)-2-methyloxirane (0.792 mL, 11.31 mmol) as a solution in N,N-dimethylformamide (5 mL), and the subsequent reaction mixture was heated to 80 C. and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and then washed with saturated aqueous sodium hydrogen carbonate (30 mL) followed by water/brine (1:1, 330 mL). The organic phase was dried over magnesium sulfate, filtered, and then concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the tide compound (166 mg, 41% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.71 (s, 1H), 7.50 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.80 (d, J=4.8 Hz, 1H), 3.90-3.83 (m, 1H), 3.69-3.61 (m, 2H), 2.30 (s, 6H), 1.39 (s, 9H), 1.09 (d, J=6.3 Hz, 3H).

    Example 344B: tert-butyl (3-{4-[(2S)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2137] The methodologies described in Example 341E substituting the product of Example 341D with the product of Example 344A gave the title compound (14 mg, 6% yield). MS (ESI.sup.+) m/z 392 (M+H).sup.+.

    Example 344C: 3-{4-[(2S)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2138] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 344B gave the title compound (9 mg, 86% yield). MS (ESI.sup.+) m/z 292 (M+H).sup.+.

    Example 344D: (2R)-6-chloro-4-oxo-N-(3-{4-[(2S)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2139] The methodologies described in Example 315E substituting the product of Example 315D with the product of Example 344C gave the title compound (13.7 mg, 100% yield). MS (ESI.sup.+) m/z 500 (M+H).sup.+.

    Example 344E: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(2S)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2140] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 344D and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 20-50% gradient of acetonitrile in buffer (0.1% formic acid in water)] gave the title compound (5.9 mg, 92% yield).

    [2141] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.29 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.6, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.84-4.79 (m, 1H), 4.78-4.72 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.00-3.91 (m, 2H), 2.46 (s, 6H), 2.40-2.37 (m, 1H), 1.76-1.68 (m, 1H), 1.35 (d, J=6.4 Hz, 3H); MS (ESI.sup.+) ml: 502 (M+H).sup.+.

    Example 345: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 444)

    Example 345A: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-[3-(trifluoromethoxy)propyl]-1H-pyrazol-4-amine

    [2142] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 331A gave the title compound (21.3 mg, 55% yield). MS (ESI.sup.+) m/z 291 (M+H).sup.+.

    Example 345B: (2R)-6-chloro-4-oxo-N-[3-(4-{[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2143] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 345A gave the title compound (36.6 mg, 100% yield). MS (ESI.sup.+) m/z 499 (M+H).sup.+.

    Example 345C. (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[3-(trifluoromethoxy)propyl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2144] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 345B and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] gave the title compound (5.1 mg, 13.0% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.44 (d, 1H), 7.22 (d, J=5.7, 0.9 Hz, 2H), 7.17 (dd, J=8.7, 2.6, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.97-4.90 (m, 1H), 4.65 (dd, J=11.7, 2.4 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H), 2.59 (s, 6H), 2.58-2.53 (m, 1H), 2.01-1.95 (m, 2H), 1.95-1.86 (m, 1H); MS (ESI) m/z 501 (M+H).sup.+.

    Example 346: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[(2S)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 445)

    Example 346A: tert-butyl [(2S)-1-(trifluoromethoxy)propan-2-yl]carbamate

    [2145] The methodologies described in Example 341E substituting the product of Example 341D with tert-butyl [(2S)-1-hydroxypropan-2-yl]carbamate gave the title compound (1.31 g, 45% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 6.94 (d, J=8.1 Hz, 1H), 3.97-3.87 (m, 2H), 3.78-3.67 (m, 1H), 1.38 (s, 9H), 1.06 (d, J=6.9 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.74.

    Example 346B: (2S)-1-(trifluoromethoxy)propan-2-amine, hydrochloric acid

    [2146] To the product of Example 346A (500 mg, 1.953 mmol) in dioxane (5 mL) was added hydrogen chloride (4 N in dioxane) (4.88 mL, 19.53 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. Additional dioxane (10 mL) was added and stirring was continued for 1 day. The reaction mixture was concentrated under reduced pressure to give the title compound (369 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.34 (s, 3H), 4.29-4.12 (m, 2H), 3.60-3.51 (m, 1H), 1.23 (d, J=6.7 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.18.

    Example 346C: tert-butyl [3-(4-{[(2S)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2147] The methodologies described in Example 312A substituting 2-(trifluoromethoxy)ethanamine, hydrochloric acid with the product of Example 346B gave the title compound (140 mg, 16.2% yield). MS (ESI.sup.+) m/z 391 (M+H).sup.+.

    Example 3461): tert-butyl [3-(4-{methyl[(2S)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2148] The methodologies described in Example 312B substituting the product of Example 312A with the product of Example 346C gave the title compound (19 mg, 50% yield). MS (ESI.sup.+) m/z 405 (M+H).sup.+.

    Example 346E: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-methyl-N-[(2S)-1-(trifluoromethoxy)propan-2-yl]-1H-pyrazol-4-amine

    [2149] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 346D gave the title compound (11 mg, 47% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.25 (s, 1H), 7.21 (s, 1H), 4.14-4.06 (m, 1H), 4.05-3.96 (m, 1H), 3.77-3.65 (m, 1H), 2.65 (s, 3H), 2.30 (s, 6H), 1.16 (d, J=6.9, 1.8 Hz, 3H); 2 exchangeable protons not observed; .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 62.3; MS (ESI.sup.+) m/z 305 (M+H).sup.+.

    Example 346F: (2R)-6-chloro-N-[3-(4-(methyl[(2S)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2150] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 346E gave the title compound (18.5 mg, 100% yield). MS (ESI.sup.+) m/z 513/515 (M+H).sup.+.

    Example 346G: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[(2S)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2151] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 346F and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] gave the title compound (1.8 mg, 9% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.45 (d, J=2.7, 1.0 Hz, 1H), 7.27 (d, J=12.0, 1.0 Hz, 2H), 7.18 (dd, J=8.7, 2.7, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.98-4.90 (m, 1H), 4.66 (dd, J=11.6, 2.4 Hz, 1H), 4.14-3.97 (m, 2H), 3.79-3.65 (m, 1H), 2.66 (s, 3H), 2.61 (s, 6H), 2.60-2.54 (m, 1H), 1.95-1.86 (m, 1H), 1.17 (d, J=6.8 Hz, 3H); 2 exchangeable protons not observed; MS (ESI.sup.+) m/z 515/517 (M+H).sup.+.

    Example 347: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{6-[2-(trifluoromethoxy)ethoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 446)

    Example 347A: 2-[(5-bromopyridin-2-yl)oxy]ethan-1-ol

    [2152] To a solution of ethylene glycol (21.16 g, 341 mmol) in N,N-dimethylformamide (100 mL) was added NaH (6.82 g, 170 mmol) at 0 C., and the mixture was stirred at 0 C. for 30 minutes. 5-Bromo-2-fluoropyridine (10 g, 56.8 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with water (300 mL) and then extracted with ethyl acetate (500 mL). The organic phase was washed with brine (300 mL), dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (1:10 ethyl acetate/petroleum ether) to give the title compound (8.0 g, yield 64.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.16 (d, J=2.50 Hz, 1 H), 7.66 (dd, J=8.76, 2.50 Hz, 1H), 6.71 (d, J=8.88 Hz, 1H), 4.36-4.47 (m, 2H), 3.89-4.00 (m, 2H).

    Example 347B: 5-bromo-2-[2-(trifluoromethoxy)ethoxy]pyridine

    [2153] To a mixture of silver trifluoromethanesulfonate (33.0 g, 128 mmol), Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (17.06 g, 48.2 mmol), and potassium fluoride (7.46 g, 128 mmol) in a flask wrapped with aluminum foil and cooled with an ice/water bath, the product of Example 347A (7 g, 32.1 mmol) in ethyl acetate (140 mL) was added, followed by 2-fluoropyridine (8.27 mL, 96 mmol) and trifluoromethyl)trimethylsilane (14.24 mL, 96 mmol) dropwise to keep the internal temperature lower than 10 C. The mixture was stirred at ambient temperature for 48 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (3500 mL). The filtrate and washes were diluted with trifluoroacetic acid (500 mL) and water (1000 mL). The organic phase was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (1:30 ethyl acetate/petroleum ether). The material from the first chromatography was further purified by preparative HPLC (performed on a Gilson 281 semi-preparative HPLC system using a Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm80 mm) column. A gradient of acetonitrile (A) and 0.075% trifluoroacetic acid in water (B) was used, at a flow rate of 80 mL/minute. A linear gradient was used from about 30% of A to about 100% of A over about 30 minutes. The detection method was UV at wavelength of 220 nm and 254 nm). The solution was extracted with n-pentane (4500 mL), and the organic phase was concentrated under atmospheric distillation (45 C.) to give the title compound (1.15 g, yield 12.49%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.18 (d, J=2.38 Hz, 1H), 7.68 (dd, J=8.75, 2.50 Hz, 1H), 6.73 (d, J=8.88 Hz, 1H), 4.46-4.65 (m, 2H), 4.18-4.36 (m, 2H), 1.22-1.36 (m, 13H), 0.89 (t, J=7.00 Hz, 13H).

    Example 347C: N,N-dibenzyl-3-{6-[2-(trifluoromethoxy)ethoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-amine

    [2154] The title compound was prepared using the methodologies described in Example 328B substituting 4-bromo-2-fluoropyridine with the product of Example 347B. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.92 (dd, J=2.5, 0.8 Hz, 1H), 7.52 (dd, J=8.5, 2.4 Hz, 1H), 7.41-7.33 (m, 4H), 7.36-7.25 (m, 5H), 7.27-7.17 (m, 2H), 6.76 (dd, J=8.5, 0.8 Hz, 1H), 4.48-4.43 (m, 2H), 4.40-4.35 (m, 2H), 3.65 (s, 4H), 1.91 (s, 6H).

    Example 347D: 3-{6-[2-(trifluoromethoxy)ethoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-amine

    [2155] The title compound was prepared using the methodologies described in Example 328D substituting the product of Example 328C with the product of Example 347C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.96 (dd, J=2.4, 0.8 Hz, 1H), 7.56 (dd, J=8.5, 2.5 Hz, 1H), 6.78 (dd, J=8.5, 0.8 Hz, 1H), 4.47 (q, J=5.6, 4.8 Hz, 2H), 4.42-4.36 (m, 2H), 2.23 (s, 2H), 1.95 (s, 6H). Example 347E: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{6-[2-(trifluoromethoxy)ethoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2156] The title compound was prepared using the methodologies described in Example 328H substituting the product of Example 328D with the product of Example 347D. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.73 (s, 1H), 8.05-8.00 (m, 1H), 7.63 (dd, J=8.5, 2.4 Hz, 1H), 7.49 (dd, J=8.7, 1.0 Hz, J H), 6.94 (d, J=10.6 Hz, 1H), 6.85-6.78 (m, 1H), 4.79 (dd, J=10.8, 5.7 Hz, 1H), 4.67 (dd, J=11.8, 2.3 Hz, 1H), 4.52-4.46 (m, 2H), 4.43-4.37 (m, 2H), 2.42-2.33 (m, 1H), 2.31 (s, 6H), 1.73 (td, J=12.2, 10.6 Hz, 1H).

    Example 348: (2R,4S)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 447)

    [2157] The product of Example 320J (8.7 mg, 0.03 mmol), (2R,4S)-6-chloro-4-hydroxychroman-2-carboxylic acid (6.8 mg, 0.03 mmol), and triethylamine (0.012 mL, 0.089 mmol) were combined with N,N-dimethylformamide (0.8 mL) and stirred at ambient temperature. (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (12.4 mg, 0.033 mmol) was added. The reaction mixture was stirred for 20 minutes and then water (0.1 mL) was added. The resulting solution was filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (9.5 mg, 0.019 mmol, 63% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.01 (d, J=8.1 Hz, 1H), 7.59 (d, J=0.8 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.25 (dd, J=8.7, 2.7 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.61 (s, 1H), 4.62-4.57 (m, 2H), 4.35-4.30 (m, 2H), 4.11-4.06 (m, 2H), 4.00 (tt, J=11.8, 3.9 Hz, 1H), 3.69 (tdt, J=11.8, 8.0, 4.0 Hz, 1H), 2.13-2.06 (m, 1H), 2.05-1.97 (m, 2H), 1.96-1.82 (m, 3H), 1.82-1.71 (m, 2H), 1.55-1.42 (m, 2H); MS (ESI) m/z 504 (M+H).sup.+.

    Example 349: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[(2R)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 448)

    Example 349A: tert-butyl [(2R)-1-(trifluoromethoxy)propan-2-yl]carbamate

    [2158] The methodologies described in Example 340E substituting the product of Example 340D with tert-butyl [(2R)-1-hydroxypropan-2-yl]carbamate gave the title compound (1138 mg, 30% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 6.94 (d, J=8.0 Hz, 1H), 3.96-3.88 (m, 2H), 3.78-3.68 (m, 1H), 1.38 (s, 9H), 1.06 (d, J=6.9 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.76.

    Example 349B: (2R)-1-(trifluoromethoxy)propan-2-amine, hydrochloric acid

    [2159] The methodologies described in Example 346B substituting the product of Example 346A with the product of Example 349A gave the title compound (282 mg, 100% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.33 (s, 3H), 4.30-4.11 (m, 2H), 3.60-3.51 (m, 1H), 1.23 (d, J=6.7 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.18.

    Example 349C: tert-butyl [3-(4-{[(2R)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2160] The methodologies described in Example 312A substituting 2-(trifluoromethoxy)ethanamine, hydrochloric acid with the product of Example 349B gave the title compound (77 mg, 29% yield). MS (ESI.sup.+) m/z 391 (M+H).sup.+.

    Example 349D: tert-butyl [3-(4-{methyl[(2R)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2161] The methodologies described in Example 312B substituting the product of Example 312A with the product of Example 349C gave the title compound (32 mg, 53% yield). MS (ESI.sup.+) m/z 405 (M+H).sup.+.

    Example 349E: 1-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-methyl-N-[(2R)-1-(trifluoromelhoxy)propan-2-yl]-1H-pyrazol-4-amine

    [2162] The methodologies described in Example 313G substituting the product of Example 313F with the product of Example 349D gave the title compound (19 mg, 90% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.25 (s, 1H), 7.21 (s, 1H), 4.14-3.95 (m, 2H), 3.76-3.67 (m, 1H), 2.65 (s, 3H), 2.35 (s, 6H), 1.16 (d, J=6.9, 2.0 Hz, 3H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 62.21; MS (ESI.sup.+) m/z 305 (M+H).sup.+.

    Example 349F: (2R)-6-chloro-N-[3-(4-{methyl[(2R)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2163] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 349E gave the title compound (32.0 mg, 100% yield). MS (ESI.sup.+) ml: 513 (M+H).sup.+.

    Example 349G: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{methyl[(2R)-1-(trifluoromethoxy)propan-2-yl]amino}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2164] The methodologies described in Example 312E substituting the product of Example 312D with the product of Example 349F and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] gave the title compound (2.8 mg, 8% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.45 (d, J=2.6, 1.0 Hz, 1H), 7.27 (d, J=12.0, 1.0 Hz, 2H), 7.17 (dd, J=8.7, 2.7, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.98-4.90 (m, 1H), 4.65 (dd, J=11.7, 2.4 Hz, 1H), 4.15-3.97 (m, 2H), 3.78-3.66 (m, 1H), 2.66 (s, 3H), 2.61 (s, 6H), 2.59-2.53 (m, 1H), 1.96-1.86 (m, 1H), 1.17 (d, J=6.8 Hz, 3H); MS (ESI.sup.+) m/z 515 (M+H).sup.+.

    Example 350: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(2R)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 449)

    Example 350A: tert-butyl (3-{4-[(2R)-2-hydroxypropoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2165] To a solution of tert-butyl [3-(4-hydroxy-11H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (200 mg, 0.754 mmol), and cesium carbonate (982 mg, 3.02 mmol) in N,N-dimethylformamide (7.5 mL), under nitrogen, was added (R)-2-methyloxirane (0.528 mL, 7.54 mmol) as a solution in N,N-dimethylformamide (5 mL), and the subsequent reaction mixture was heated to 80 C. and stirred for 1 hour. Additional (R)-2-methyloxirane (0.264 mL, 3.77 mmol) was added, and the reaction mixture stirring was continued at this temperature for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium hydrogen carbonate (30 mL) followed by water/brine (1:1, 330 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (69 mg, 27% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.77-7.63 (m, 1H), 7.50 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.80 (d, J=4.8 Hz, 1H), 3.89-3.82 (m, 1H), 3.70-3.62 (m, 2H), 2.30 (s, 6H), 1.39 (s, 9H), 1.09 (d, J=6.4 Hz, 3H).

    Example 350B: tert-butyl (3-{4-[(2R)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2166] A mixture of silver(I) trifluoromethanesulfonate (206 mg, 0.802 mmol), potassium fluoride (69.0 mg, 1.187 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor, 158 mg, 0.445 mmol) was stirred, under nitrogen in a flask wrapped with aluminum foil. The flask was cooled in a water bath. The product of Example 350A (96 mg, 0.297 mmol) was dissolved in ethyl acetate (3 mL), and the resulting solution was added slowly to the previously described mixture. 2-Fluoropyridine (0.077 mL, 0.891 mmol) and trimethyl(trifluoromethyl)silane (0.132 mL, 0.891 mmol) were slowly added to the reaction mixture via syringe. The resulting mixture was stirred at ambient temperature for 3 days, then was filtered through a pad of diatomaceous earth, and the pad was washed with ethyl acetate (100 mL). The filtrate and wash were concentrated in vacuo, and the crude residue was purified by chromatography on silica gel (0-100% ethyl acetate/iso-hexane) to afford the title compound (25 mg, 11% yield). MS (ESI.sup.+) m/z 392 (M+H).sup.+.

    Example 350C: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(2R)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2167] To a solution of the product of Example 350B (25 mg, 0.064 mmol) in dichloromethane (0.5 mL), under nitrogen, was added trifluoroacetic acid (0.5 mL, 6.53 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified via catch and release on SCX resin (washing with methanol then eluted with 0.7 M NH.sub.3 in methanol) to give the intermediate amine, 3-{4-[(2R)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine (10 mg). The intermediate amine (10.0 mg, 0.034 mmol) was dissolved in dichloromethane (1.0 mL), and to this solution was added (R)-6-chloro-4-oxochroman-2-carboxylic acid (8.6 mg, 0.038 mmol) and triethylamine (0.029 mL. 0.206 mmol). The subsequent mixture was stirred for 5 minutes, under nitrogen, then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (19.6 mg. 0.051 mmol) was added, and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (0.5 mL), and the aqueous phase was extracted with dichloromethane (22 mL). The combined organic phases were then passed through a hydrophobic phase separator, washed with brine (2 mL) then passed through a hydrophobic phase separator and concentrated in vacuo to give the intermediate coupled compound, (2R)-6-chloro-4-oxo-N-(3-{4-[(2R)-2-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (17.2 mg). The intermediate coupled compound (17.2 mg, 0.034 mmol) was dissolved in methanol (1 mL), at ambient temperature under nitrogen, and sodium borohydride (15.4 mg, 0.408 mmol) was added. The subsequent reaction mixture was stirred for 20 minutes, then quenched with saturated aqueous ammonium chloride (0.5 mL) and extracted with dichloromethane (32 mL). The combined organic phases were then passed through a phase separator, washed with brine (2 mL), passed through a phase separator, and the solvent was removed under reduced pressure. The crude residue was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] to afford the title compound (0.8 mg, 5% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.50 (d, J=0.9 Hz, 1H), 7.46 (dd, J=2.6, 1.0 Hz, 1H), 7.35 (d, J=0.9 Hz, 1H), 7.22-7.16 (m, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.52 (s, 1H), 4.95 (dd, J=10.3, 5.9 Hz, 1H), 4.74-4.67 (m, 1H), 4.67 (dd, J=11.6, 2.4 Hz, 1H), 4.04-3.95 (m, 2H), 2.62 (s, 6H), 2.62-2.54 (m, 1H), 1.97-1.87 (m, 1H), 1.44 (d, J=6.5 Hz, 3H); MS (ESI) m/z 502 (M+H).sup.+.

    Example 351: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[2-(trifluoromethoxy)ethoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 450)

    [2168] The title compound was prepared using the methodologies described in Example 328H substituting the product of Example 328D with the product of Example 347D and substituting (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid with (R)-6 -chloro-4-oxochroman-2-carboxylic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.63 (dd, J=8.5, 2.5 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.20 (dd, J=8.6, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.61 (dd, J=12.0, 2.3 Hz, 1H), 4.52-4.44 (m, 2H), 4.40 (dd, J=5.3, 3.2 Hz, 2H), 2.37 (ddd, J=12.7, 6.1, 2.7 Hz, 1H), 2.31 (s, 6H), 1.72 (q, J=11.9 Hz, 1H).

    Example 352: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 451)

    [2169] The methodologies described in Example 312D substituting the product of Example 312C with the product of Example 313G and (R)-6-chloro-4-oxochroman-2-carboxylic acid with 2-(4-chloro-3-fluorophenoxy)acetic acid and purifying by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (48.0 mg, 53% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.09 (dd, J=11.4, 2.9 Hz, 1H), 6.90-6.82 (m, 1H), 4.52 (s, 2H), 4.35-4.31 (m, 2H), 4.12-4.08 (m, 2H), 2.45 (s, 6H): .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.90,114.03;

    [2170] MS (ESI.sup.+) m/z 463 (M+H).sup.+.

    Example 353: 2-[(2-methoxypyrimidin-5-yl)oxy]-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 452)

    Example 353A: [(2-methoxypyrimidin-5-yl)oxy]acetic acid

    [2171] To a solution of 2-methoxypyrimidin-5-ol (6.1 g, 48.4 mmol) in N,N-dimethylformamide (50 mL) at ambient temperature was added potassium carbonate (13.37 g, 97 mmol) and tert-butyl bromoacetate (8.16 mL, 55.6 mmol). This mixture was warmed to 65 C. and stirred for 1.5 hours. The mixture was cool to ambient temperature and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with more ethyl acetate (315 mL). The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give tert-butyl [(2-methoxypyrimidin-5-yl)oxy]acetate, which was used without further purification. To a mixture of the crude tert-butyl [(2-methoxypyrimidin-5-yl)oxy]acetate (11.53 g, 48 mmol) in methanol (90 mL) and water (30.0 mL) was added 5 M aqueous NaOH solution (48.0 mL, 240 mmol). This mixture was stirred at ambient temperature for 12 hours and then was concentrated under reduced pressure to give a residue which was dissolved in water. The pH was adjusted to 1 with 1 N HCl, and the resulting solid was isolated by filtration to give the title compound (5.9 g). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.37 (s, 2H), 4.79 (s, 2H), 3.87 (s, 3H).

    Example 353B: 2-[(2-methoxypyrimidin-5-yl)oxy]-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)acetamide

    [2172] To a solution of the product of Example 328D (25 mg, 0.083 mmol), the product of Example 353A (15.99 mg, 0.087 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.043 mL, 0.248 mmol) in N,N-dimethylformamide (1 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.207 mL, 0.103 mmol) was added, and the reaction mixture was stirred at ambient temperature for 15 minutes. The solution was concentrated under high vacuum, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 25 minutes, at a flow rate of 75 mL/minute) to give the title compound (33 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 8.33 (s, 2H), 8.03 (d, J=5.3 Hz, 1H), 6.84 (dd, J=5.2, 1.4 Hz, 1H), 6.62 (d, J=1.3 Hz, 1H), 4.52 (s, 2H), 4.29 (t, J=6.3 Hz, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.83 (s, 3H), 2.26 (s, 6H), 2.06 (p, J=6.3 Hz, 2H).

    Example 354: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 453)

    [2173] The title compound was prepared using the methodologies described in Example 353B substituting the product of Example 353A with 2-(4-chloro-3-fluorophenoxy)acetic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.07 (d, J=5.2 Hz, 1H), 7.55-7.41 (m, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.91-6.83 (m, 2H), 6.66 (d, J=1.2 Hz, 1H), 4.50 (s, 2H), 4.32 (t, J=6.2 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 2.30 (s, 6H), 2.10 (p, J=6.3 Hz, 2H).

    Example 355: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 454)

    [2174] A solution of the product of Example 332B (15.0 mg, 0.051 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (10.54 mg, 0.051 mmol), and triethylamine (0.043 mL, 0.309 mmol), in N,N-dimethylformamide (0.40 mL), at 0 C. under nitrogen, was stirred for 5 minutes. Then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (23.50 mg, 0.062 mmol) was added, and the reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2.5 mL), and the aqueous phase was extracted with dichloromethane (52 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo. The crude residue was purified by preparative HPLC [Waters XBridge C18 5 m OBD column, 30100 mm, flow rate 40 mL/minute, 40-70% gradient of acetonitrile in buffer (0.3% ammonia in water)] to afford the title compound (12.0 mg, 48% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.59 (d, J=0.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.09 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.52 (s, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.92 (t, J=6.2 Hz, 2H), 2.44 (s, 6H), 2.05 (p, J=6.2 Hz, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.93, 114.03; MS (ESI) m. 478 (M+H).sup.+.

    Example 356: 2-(4-chloro-3-fluorophenoxy)-N-(3-{6-[3-(trifluoromethoxy)propoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 455)

    [2175] The title compound was prepared using the methodologies described in Example 353B substituting the product of Example 328D with the product of Example 339C and substituting the product of Example 353A with 2-(4-chloro-3-fluorophenoxy)acetic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.75 (s, 1H), 8.01 (dd, J=2.5, 0.8 Hz, 1H), 7.60 (dd, J=8.5, 2.5 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 6.76 (dd, J=8.5, 0.8 Hz, 1H), 4.50 (s, 2H), 4.31 (t, J=6.3 Hz, 2H), 4.21 (t, J=6.3 Hz, 2H), 2.29 (s, 6H), 2.10 (p, J=6.3 Hz, 2H).

    Example 357: 2-(4-chloro-3-fluorophenoxy)-N-(3-{6-[2-(trifluoromethoxy)ethoxy]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 456)

    [2176] The title compound was prepared using the methodologies described in Example 353B substituting the product of Example 328D with the product of Example 347D and substituting the product of Example 353A with 2-(4-chloro-3-fluorophenoxy)acetic acid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.75 (s, 1H), 8.02 (dd, J=2.4, 0.8 Hz, 1H), 7.63 (dd, J=8.5, 2.4 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.3, 2.9 Hz, 1H), 6.87 (ddd, J=8.9, 2.8, 1.1 Hz, 1H), 6.81 (dd, J=8.5, 0.8 Hz, 1H), 4.49 (d, J=10.6 Hz, 4H), 4.42-4.38 (m, 2H), 2.29 (s, 6H).

    Example 358: 2-(4-chloro-3-fluorophenoxy)-N-[(1r,4r)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]acetamide (Compound 457)

    [2177] The product of Example 320J (9 mg, 0.031 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (6.9 mg, 0.034 mmol) and triethylamine (0.013 mL, 0.092 mmol) were combined with N,N-dimethylformamide (0.8 mL) and stirred at ambient temperature. Tri(pyrrolidin-1-yl)[(3H-[1,2,3]triazolo[4,5-h]pyridin-3-yl)oxy]phosphanium hexafluoridophosphate (PyAOP, 19.2 mg, 0.037 mmol) was added. After stirring at ambient temperature for 20 minutes, water (0.1 mL) was added. The resulting mixture was filtered through a glass microfiber frit. The filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (11.5 mg, 0.024 mmol, 78% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.02 (d, J=8.0 Hz, 1H), 7.59 (d, J=0.9 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.51 (s, 2H), 4.35-4.30 (m, 2H), 4.11-4.05 (m, 2H), 4.01 (tt, J=11.8, 3.9 Hz, 1H), 3.74-3.63 (m, 1H), 2.04-1.97 (m, 2H), 1.87 (dd, J=2H), 1.75 (qd, J=12.9, 3.5 Hz, 2H), 1.45 (qd, J=13.0, 3.4 Hz, 2H); MS (ESI) m/z 480 (M+H).sup.+.

    Example 359: 6,7-dichloro-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1,4-benzodioxine-2-carboxamide (Compound 458)

    [2178] The reaction and purification conditions described in Example 335C substituting 6,7-dichloro-2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (prepared as described in International Patent Publication WO2020223536 A1) for the product of Example 335B gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.01 (s, 1H), 7.62 (d, J=0.9 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 4.87 (dd, J=5.0, 3.0 Hz, 1H), 4.40-4.27 (m, 4H), 4.13-4.06 (m, 2H), 2.43 (s, 6H); MS (ESI) m/z 508 (M+H).sup.+.

    Example 360: (2R,4R)-6,7-dichloro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 459)

    [2179] The reaction and purification conditions described in Example 320L substituting the product of Example 337A for the product of Example 320K gave the title compound .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.97 (d, J=8.1 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.54 (d, J=1.0 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 7.18 (s, 1H), 5.79 (d, J=4.8 Hz, 1H), 4.85-4.77 (m, 1H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 4.36-4.30 (m, 2H), 4.12-4.06 (m, 2H), 4.01 (tt, J=11.7, 3.8 Hz, 1H), 3.76-3.64 (m, 1H), 2.37 (ddd, J=13.1, 5.9, 2.4 Hz, 1H), 2.06-1.98 (m, 2H), 1.94-1.85 (m, 2H), 1.84-1.66 (m, 3H), 1.57-1.43 (m, 2H); MS (ESI) m/z 538 (M+H).sup.+.

    Example 361: (2R,4R)-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 460)

    Example 361A: (R)N((S)-4-amino-3-hydroxybicyclo[2.2.2]octan-1-yl)-4-oxo-6-(trifluoromethyl)chromane-2-carboxamide

    [2180] The product of Example 227B (37.3 mg, 0.143 mmol), the product of Example 13H (40 mg, 0.137 mmol) and triethylamine (0.057 mL, 0.410 mmol) were combined with N,N-dimethylformamide (2 mL) and stirred at ambient temperature. (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 56.1 mg, 0.148 mmol) was added. After stirring for 30 minutes, the resulting mixture was partitioned between dichloromethane (330 mL) and saturated aqueous sodium bicarbonate (30 mL). The organic layers were combined and dried over sodium sulfate and concentrated under high vacuum. Trifluoroacetic acid (1.0 mL) was added to the residue, and the mixture was stirred for 10 minutes and then concentrated under reduced pressure. The residue was taken up in methanol (2 mL), filtered through a glass microfiber frit and purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 25100 mm, flow rate 25 mL/minute, 2-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (48 mg, 0.12 mmol, 88% yield).

    [2181] MS (ESI.sup.+) m/z 399 (M+H).sup.+.

    Example 361B: (2R,4R)-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2182] The product of Example 361A (48 mg, 0.12 mmol), triethylamine (0.050 mL, 0.361 mmol), and the product of Example 13P (27.1 mg, 0.127 mmol) were added to N,N-dimethylformamide (1 mL) sequentially and stirred at ambient temperature. (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 52.7 mg, 0.139 mmol) was then added. The resulting mixture was stirred for 30 minutes and then partitioned between dichloromethane (330 mL) and aqueous sodium carbonate (30 mL, 1.0 M). The organic layers were combined and dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL), and sodium borohydride (22.8 mg, 0.60 mmol) was added in 3 portions over 3 minutes. The resulting mixture was stirred for 20 minutes, and then partitioned between dichloromethane (530 mL) and aqueous sodium carbonate (30 mL, 1.0 M). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (5 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (46 mg, 0.077 mmol, 64% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.70 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.4, 2.6 Hz, 1H), 7.42 (s, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.94 (s, 1H), 5.76 (d, J=6.1 Hz, 1H), 5.21 (d, J=4.7 Hz, 1H), 4.83 (dt, J=11.3, 5.8 Hz, 1H), 4.65 (dd, J=11.8, 2.3 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.94 (dt, J=8.5, 3.8 Hz, 1H), 3.76-3.67 (m, 3H), 2.79-2.71 (m, 2H), 2.34-2.28 (m, 2H), 2.28-2.21 (m, 1H), 2.16-2.09 (m, 2H), 1.98-1.93 (m, 1H), 1.91-1.69 (m, 8H); MS (ESI.sup.+) m/z 597 (M+H).sup.+.

    Example 362: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 461)

    [2183] The product of Example 109A (28 mg, 0.071 mmol) was combined with trifluoroacetic acid (0.5 mL) and stirred at ambient temperature for 10 minutes. The mixture was concentrated under high vacuum. To the residue was added triethylamine (0.069 mL, 0.497 mmol), the product of Example 262C (18.2 mg, 0.075 mmol), and N,N-dimethylformamide (1 mL) in sequential order. While the mixture was stirring, (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 44.4 mg, 0.085 mmol) was added, and the reaction mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was partitioned between dichloromethane (330 mL) and aqueous sodium carbonate (30 mL, 1.0 M). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in methanol (1 mL) and sodium borohydride (18.8 mg, 0.497 mmol) was added. The mixture was stirred for 10 minutes, and then partitioned between dichloromethane (330 mL) and aqueous sodium carbonate (30 mL, 1.0 M). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was taken up in N,N-dimethylformamide (1 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (29.2 mg, 0.056 mmol, 79% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.66 (s, 1H), 8.35 (s, 1H), 7.48 (dd, J=8.7, 1.1 Hz, 1H), 6.92 (d, J=10.6 Hz, 1H), 5.73 (s, 1H), 4.80-4.75 (m, 1H), 4.64 (dd, J=11.8, 2.4 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.70 (p, J=6.9 Hz, 1H), 2.79-2.68 (m, 2H), 2.34 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 2.26 (s, 6H), 2.21-2.09 (m, 2H), 1.70 (ddd, J=13.0, 11.9, 10.6 Hz, 1H); MS (ESI) m/z 505 (MH2O+H).sup..

    Example 363: (2R,4R)-6-chloro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 462)

    Example 363A: tert-butyl [3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2184] To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.109 g, 0.549 mmol) in isopropyl alcohol (1.373 mL) was added 6-methoxy-3-nitropicolinaldehyde (0.1 g, 0.549 mmol). The mixture was heated to 80 C. for 2 hours and then cooled. Tri-n-butylphosphine (0.406 mL, 1.647 mmol) was added, and the resultant mixture was stirred for 3 hours at 80 C. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0 to 100%) to give the title compound (0.16 g, 0.484 mmol, 88% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.37 (d, J=0.9 Hz, 1H), 7.99 (dd, J=9.2, 0.9 Hz, 1H), 6.80 (d, J=9.2 Hz, 1H), 3.87 (s, 3H), 2.49 (s, 6H), 1.41 (s, 9H); MS (ESI.sup.+) m/z 331 (M+H).sup.+.

    Example 363B: 3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-amine-hydrogen chloride

    [2185] To a solution of tert-butyl [3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]carbamate (0.16 g, 0.484 mmol) in dichloromethane (2.421 mL) was added 4 N hydrochloric acid in dioxane (1.211 mL, 4.84 mmol). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.12 g, 0.450 mmol, 93% yield). MS (ESI.sup.+) m/z 231 (M+H).sup.+.

    Example 363C: (2R)-6-chloro-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2186] To a solution of 3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-amine-hydrogen chloride (0.026 g, 0.097 mmol) in dichloromethane (0.443 mL) were added (R)-6-chloro-4-oxochroman-2-carboxylic acid (0.023 g, 0.102 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 0.041 g, 0.107 mmol), and N,N-diisopropylethylamine (0.051 mL, 0.292 mmol) at ambient temperature. The reaction mixture was stirred for 1 hour at ambient temperature. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0 to 100%) to give the title compound (0.03 g, 0.068 mmol, 70.1% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.21 (s, 1H), 8.41 (d, J=0.9 Hz, 1H), 8.00 (dd, J=9.2, 0.9 Hz, 1H), 7.69-7.63 (m, 2H), 7.20 (dd, J=8.6, 0.7 Hz, 1H), 6.81 (d, J=9.2 Hz, 1H), 5.17 (dd, J=8.4, 5.9 Hz, 1H), 3.87 (s, 3H), 3.01 (d, J=3.6 Hz, 1H), 2.99 (d, J=1.1 Hz, 1H), 2.61 (s, 6H); MS (ESI.sup.+) m/z 439 (M+H).sup.+.

    Example 3631): (2R,4R)-6-chloro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2187] To a suspension of (2R)-6-chloro-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxamide (0.03 g, 0.068 mmol) in methanol (0.684 mL) was added sodium borohydride (10.34 mg, 0.273 mmol). This mixture was allowed to stir at ambient temperature for 30 minutes. The reaction mixture was diluted with a drop of saturated aqueous ammonium chloride. The reaction mixture was concentrated and purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0 to 100%) to give the title compound (0.015 g, 0.034 mmol, 49.8% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.42 (d, J=0.9 Hz, 1H), 8.00 (dd, J=9.2, 0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.8, 0.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.81 (d, J=9.2 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.83 (dt, J=11.7, 6.1 Hz, 1H), 4.67 (dd, J=12.0, 2.3 Hz, 1H), 3.87 (s, 3H), 2.64 (s, 6H), 2.42-2.37 (m, 1H), 1.78-1.71 (m, 1H); MS (ESI.sup.+) m/z 441 (M+H).sup.+.

    Example 364: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 463)

    Example 364A: tert-butyl (3-{4-[(1E)-3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2188] 2-Propanol (3 mL) and water (1 mL) were added to a mixture of (tris(dibenzylideneacetone)dipalladium(0)) (67.0 mg, 0.073 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (42.8 mg, 0.146 mmol), potassium carbonate (303 mg, 2.194 mmol), (E)-3-(tert-butyldimethylsilyloxy)propene-1-yl-boronic acid pinacol ester (262 mg, 0.878 mmol), and the product of Example 207C (240 mg, 0.731 mmol) in a sealed tube. The tube was evacuated and then refilled with a nitrogen backflush, and the process was repeated 3 times. The vial was sealed and then stirred at 64 C. for 18 hours. The reaction mixture was cooled and then partitioned between dichloromethane (330 mL) and aqueous sodium carbonate (1.0 M, 30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.14 g, 0.334 mmol, 46% yield).

    [2189] MS (ESI.sup.+) m/z 420 (M+H).sup.+.

    Example 364B: tert-butyl {3-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2190] The product of Example 364A(137 mg, 0.326 mmol) was dissolved in tetrahydrofuran (7 mL) and palladium on carbon (5 w/w %, wet load, 30 mg) was added. The reaction mixture was stirred at 25 C. under 60 psi hydrogen atmosphere for 1 hour, filtered through a frit and concentrated under vacuum to give the title compound (0.14 g, 0.332 mmol, 100% yield). MS (APCI.sup.+) m/z 422 (M+H).sup.+.

    Example 364C: tert-butyl {3-[4-(3-hydroxypropyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2191] Tetrabutylammonium fluoride (0.5 mL, 1 M in tetrahydrofuran) was added to a solution of the product of Example 364B (0.14 g, 0.332 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred for 3 days and then concentrated under reduced pressure. The residue was taken up in methanol (1 mL), filtered through a glass microfiber frit and purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (103 mg, 0.335 mmol, 101% yield).

    [2192] MS (APCI.sup.+) m/z 308 (M+H).sup.+.

    Example 364D: tert-butyl (3-{4-[3-(trifluoromethoxy)propyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2193] A solution the product of Example 364C (90 mg, 0.293 mmol) in anhydrous ethyl acetate (1.46 mL) in a 20 mL sealed tubed wrapped with aluminum foil was cooled to 0 C. Potassium fluoride (68 mg, 1.17 mmol), Selectfluor (156 mg, 0.439 mmol) and silver trifluoromethanesulfonate (226 mg, 0.878 mmol) were added. While the mixture was stirring, 2-fluoropyridine (0.075 mL, 0.878 mmol) was added followed by dropwise addition of (trifluoromethyl)trimethylsilane (0.44 mL, 2.0 M solution in tetrahydrofuran) over a period of 5 minutes. The ice bath was removed, and the resulting mixture was allowed to warm to ambient temperature over a period of 30 minutes and stirred under nitrogen protection for 18 hours. The reaction mixture was diluted with ethyl acetate (3 mL) and filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate (5-10 mL). The resulting filtrate was concentrated under reduced pressure, taken up in methanol (3 mL), filtered through a glass microfiber frit, and purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (28.3 mg, 0.075 mmol, 26% yield). MS (ESI.sup.+) m/z 376 (M+H).sup.+.

    Example 364E: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 463)

    [2194] The reaction and purification conditions described in Example 362 substituting the product of Example 364D for the product of Example 109A, and the product of Example 1B for the product of Example 262C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.61 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.35 (s, 1H), 7.21 (dd, J=8.8, 2.7 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.71 (s, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 4.07 (t, J=6.3 Hz, 2H), 2.50-2.45 (m, 8H), 2.37 (ddd, J=12.9, 5.8, 2.3 Hz, 1H), 1.95-1.85 (m, 2H), 1.79-1.65 (m, 1H); MS (ESI.sup.+) m/z 486 (M+H).sup.+.

    Example 365: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 464)

    Example 365A: tert-butyl {3-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2195] The product of Example 303F (55 mg, 0.207 mmol) was combined with cesium carbonate (270 mg, 0.829 mmol) and N,N-dimethylformamide (1.04 mL) and stirred at ambient temperature. 4-Bromo-1,1,1-trifluorobutane (71 mg, 0.37 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 2 hours, filtered through a glass microfiber frit that was rinsed with methanol (3 mL), and then directly purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 3-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (63 mg, 0.168 mmol, 81% yield). MS (ESI.sup.+) m/z 376 (M+H).sup.+.

    Example 365B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2196] The reaction and purification conditions described in Example 362 substituting the product of Example 365A for the product of Example 109A gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.79 (dt, J=11.2, 6.0 Hz, 1H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.43-2.31 (m, 3H), 1.91-1.83 (m, 2H), 1.73 (ddd, J=13.0, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 504 (M+H).sup.+.

    Example 366: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 465)

    Example 366A: benzyl 5-hydroxypentanoate

    [2197] A solution of delta-valerolactone (4.63 mL, 49.9 mmol) and sodium hydroxide (2 g, 50.0 mmol) in water (50 mL) was stirred at 70 C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was then azeotroped with toluene (25 mL) and dried at 60 C. The solid was dispersed in acetone (50 mL) and refluxed overnight with (bromomethyl)benzene (7.13 mL, 59.9 mmol) and tetrabutylammonium iodide (TBAI, 0.805 g, 2.179 mmol). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude title compound was taken on directly to the next trifluoromethylation step without further purification.

    Example 3661: benzyl 5-(trifluoromethoxy)pentanoate

    [2198] The methodologies described in Example 199E substituting the product of Example 199D with the product of Example 366A gave the title compound (1.48 g, 9% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.43-7.25 (m, 5H), 5.09 (s, 2H), 4.07 (t, J=6.0 Hz, 2H), 2.42 (t, J=7.0 Hz, 2H), 1.72-1.54 (m, 4H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.71.

    Example 366C: 1,1-dichloro-6-(trifluoromethoxy)hexan-2-one

    [2199] To a solution of dicyclohexylamine (0.721 mL, 3.62 mmol) in tetrahydrofuran (3.3 mL), at 78 C. under nitrogen, was added n-butyllithium (2.5 M in hexanes, 1.448 mL, 3.62 mmol) and the resultant mixture was stirred at this temperature for 30 minutes, resulting in the formation of a precipitate which upon warming to 0 C. formed a homogenous solution. To a solution of the product of Example 366B (500 mg, 1.810 mmol) and dichloromethane (0.233 mL, 3.62 mmol) in tetrahydrofuran (11.3 mL), at 78 C. under nitrogen, was slowly added the prepared solution of lithium dicyclohexylamine dropwise over 1 hour ensuring the internal temperature did not rise above 70 C. The resultant reaction mixture was stirred at 70 C. for 1 hour. The reaction was quenched with 2 M aqueous phosphoric acid (10.86 mL, 21.72 mmol), and the mixture was warmed to room temperature and stirred vigorously for 16 hours. The mixture was extracted with ethyl acetate (3200 mL), and the combined organic fractions were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford a crude residue. The crude residue was purified by flash chromatography (0-10% ethyl acetate/isohexane) to afford the title compound (300 mg, 38% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 6.83 (s, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.82 (t, J=6.8 Hz, 2H), 1.72-1.57 (m, 4H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.73.

    Example 366D: N-(1,1-dichloro-6-(trifluoromethoxy)hexan-2-ylidene)-4-methylbenzenesulfonohydrazide

    [2200] To a solution of the product of Example 366C (298 mg, 0.683 mmol) in acetonitrile (7.7 mL), under nitrogen, was added 4-methylbenzenesulfonohydrazide (127 mg, 0.683 mmol), portion wise, and the reaction mixture stirred at room temperature for 18 hours and used as a solution directly in the next step.

    Example 366E. tert-butyl (3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2201] To a solution of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (234 mg, 1.178 mmol) and N,N-diisopropylethylamine (1.234 mL, 7.07 mmol) in ethanol (7.7 mL), under nitrogen at 0 C., was added a solution of the product of Example 366D (496 mg, 1.178 mmol) in acetonitrile (7.7 mL), dropwise, and the resultant mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (0-10% [0.7 M ammonia in methanol]/dichloromethane) to afford the title product (172 mg, 36% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.84 (s, 1H), 4.06 (t, J=5.9 Hz, 2H), 2.76 (t, J=7.1 Hz, 2H), 2.60 (s, 6H), 1.85-1.73 (m, 4H), 1.48 (s, 9H); .sup.19F NMR (471 MHz, methanol-d.sub.4) ppm 62.16; MS (ESI+) m/z 391 (M+H).sup.+.

    Example 366F: 3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2202] The methodologies described in Example 190C substituting the product of Example 190B with the product of Example 366E gave the title compound (106 mg, 79% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.81 (s, 1H), 4.06 (t, J=5.9 Hz, 2H), 2.75 (t, J=7.1 Hz, 2H), 2.41 (s, 6H), 1.83-1.70 (m, 4H); MS (ESI.sup.+) m/z 291 (M+H).sup.+.

    Example 366G: (2R)-6-chloro-4-oxo-N-(3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2203] A solution of the product of Example 366F (30 mg, 0.103 mmol), (R)-6-chloro-4-oxochroman-2-carboxylic acid (23.42 mg, 0.103 mmol) and triethylamine (0.043 mL, 0.310 mmol) in dichloromethane (1 mL), at 0 C. under nitrogen, was stirred for 5 minutes after which was added propylphosphonic anhydride solution [50 weight % in ethyl acetate](T3P, 0.074 mL, 0.124 mmol), and the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 (2 mL), and the aqueous phase was extracted with dichloromethane (32 mL). The combined organic phases were then passed through a hydrophobic phase separator and concentrated in vacuo to afford the title compound (51.6 mg, 100% yield). MS (ESI) m/z 499/501 (M+H).sup.+.

    Example 366H: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2204] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 366G and purifying by preparative HPLC [Waters XBridge C18 5 m ODB column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (19.9 mg, 37% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.88 (s, 1H), 7.46 (d, J=2.6, 1.0 Hz, 1H), 7.19 (dd, J=8.7, 2.7, 0.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 4.98-4.91 (m, 1H), 4.68 (dd, J=11.5, 2.5 Hz, 1H), 4.08 (t, J=5.9 Hz, 2H), 2.80-2.74 (m, 8H), 2.62-2.52 (m, 1H), 1.99-1.88 (m, 1H), 1.85-1.72 (m, 4H); .sup.19F NMR (471 MHz, methanol-d.sub.4) ppm 62.13; MS (ESI.sup.+) m/z 502/504 (M+H).sup.+.

    Example 367: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 466)

    Example 367A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1.]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2205] The methodologies described in Example 366G substituting (R)-6-chloro-4-oxochroman-2-carboxylic acid with (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Example 262C) gave the title compound (53.4 mg, 100% yield). MS (ESI.sup.+) m/z 517/519 (M+H).sup.+.

    Example 367B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[4-(trifluoromethoxy)butyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2206] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 367A and purifying by preparative HPLC [Waters XBridge C18 5 m ODB column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (13.5 mg, 24% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.87 (s, 1H), 7.52 (d, J=8.3, 1.0 Hz, 1H), 6.86 (d, J=10.3 Hz, 1H), 4.94-4.88 (m, 1H), 4.72 (dd, J=11.4, 2.6 Hz, 1H), 4.07 (t, J=5.9 Hz, 2H), 2.80-2.71 (m, 8H), 2.61-2.53 (m, 1H), 1.97-1.87 (m, 1H), 1.85-1.71 (m, 4H); .sup.19F NMR (471 MHz, methanol-d.sub.4) ppm 62.15,117.59; MS (ESI.sup.+) m/z 519/521 (M+H).sup.+.

    Example 368: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(4-{[2-(trifluoromethoxy)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 467)

    Example 368A: tert-buty (3-azidobicyclo[1.1.1]pentan-1-yl)carbamate

    [2207] A vial was charged with tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (363 mg, 1.829 mmol) and methanol (16 mL) and placed under a nitrogen atmosphere. To this was added potassium carbonate (452 mg, 3.27 mmol), copper(I) sulfate pentahydrate (5.5 mg, 0.022 mmol), imidazole-1-sulfonyl azide, and sulfuric acid (0.498 g, 1.829 mmol), and the resultant dispersion was stirred at room temperature for 23 hours. The reaction mixture was concentrated in vacuo, and water (5 mL) was added to the residue. The mixture was acidified to pH 2 with aqueous HCl (1 M, 6 mL) and then extracted with ethyl acetate (230 mL). The combined organic fractions were dried over MgSO.sub.4, filtered, and reduced to 10% of the volume in vacuo. Tetrahydrofuran (10 mL) was added, and the volatiles were reduced to 10% of the volume in vacuo. The procedure was repeated twice. After that, the volatiles were mostly removed in vacuo to afford a solution of the title compound (40 weight % in tetrahydrofuran, 1.07 g, 99% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.41 (s, 1H), 2.12 (s, 6H), 1.38 (s, 9H).

    Example 368B: 3-(2-(trifluoromethoxy)ethoxy)prop-1-yne

    [2208] Prop-2-yn-1-ol (0.08 mL, 1.341 mmol) was added, under an atmosphere of nitrogen, to a suspension of NaH (60 weight % in paraffin oil, 0.064 g, 1.610 mmol) in anhydrous tetrahydrofuran (1 mL) at 0 C. The reaction mixture was stirred at this temperature for 30 minutes after which a solution of 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (0.270 g, 1.030 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added. The reaction mixture was stirred at 0 C. for 5 hours. Ice cold water (1 mL) was added to the reaction mixture, followed by methyl tert-butyl ether (5 mL), and the layers were separated. The organic layer was dried over MgSO.sub.4, filtered, and concentrated under a flow of compressed air at room temperature to afford the title compound (216 mg, 50% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.22-4.17 (m, 4H), 3.32 (s, 2H), 3.08 (s, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.94.

    Example 368C. tert-butyl [3-(4-{[2-(trifluoromethoxy)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2209] The product of Example 368B (190 mg, 0.452 mmol), copper(I) iodide (128 mg, 0.674 mmol) and triethylamine (0.1 mL, 0.717 mmol) were added to a degassed solution of the product of Example 368A (40 weight % in tetrahydrofuran, 189 mg, 0.337 mmol) in anhydrous tetrahydrofuran (3 mL), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was reduced in vacuo. The residue was taken up in dichloromethane (40 mL), passed through a plug of diatomaceous earth, and reduced in vacuo. The crude residue was purified by flash chromatography on silica gel (0-10% methanol/dichloromethane) to afford the title compound (104 mg, 67% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.22 (s, 1H), 7.39 (s, 1H), 4.56 (s, 2H), 3.70 (d, J=3.4 Hz, 4H), 2.49 (d, J=4.8 Hz, 6H), 1.40 (s, 9H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.87; MS (ESI.sup.+) m/z 393 (M+H).sup.+.

    Example 368D: 3-(4-{[2-(trifluoromethoxy)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-amine

    [2210] The methodologies described in Example 190C substituting the product of Example 190B with the product of Example 368C gave the title compound (58 mg, 87% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.20 (s, 1H), 4.56 (s, 2H), 4.19-4.16 (m, 2H), 3.70-3.66 (m, 2H), 2.35 (s, 6H); MS (ESI.sup.+) m/z 293 (M+H).sup.+.

    Example 368E: (2R)-6-chloro-7-fluoro-4-oxo-N-[3-(4-{[2-(trifluoromethoxy)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2211] The methodologies described in Example 366G substituting the product of Example 366F with the product of Example 368D and (R)-6-chloro-4-oxochroman-2-carboxylic acid with (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Example 262C) gave the title compound (53.4 mg, 100% yield). MS (ESI.sup.+) m/z 519/521 (M+H).sup.+.

    Example 368F. (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(4-{[2-(trifluoromethoxy)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2212] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 368E and purifying by preparative HPLC [Waters X-Select CSH C18 5 m ODB column, 30100 mm, flow rate 40 mL/minute, 30-60% gradient of acetonitrile in buffer (0.1% formic acid in water)] gave the title compound (13.6 mg, 27% yield).

    [2213] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.27 (s, 1H), 7.49 (dd, J=8.6, 1.1 Hz, 1H), 6.93 (d, J=10.6 Hz, 1H), 5.76 (d, J=6.2 Hz, 1H), 4.80 (dt, J=11.2, 6.1 Hz, 1H), 4.72 (dd, J=11.7, 2.4 Hz, 1H), 4.57 (s, 2H), 4.22-4.15 (m, 2H), 3.72-3.67 (m, 2H), 2.63 (s, 6H), 2.39-2.34 (m, 1H), 1.81-1.68 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.86, 116.82; MS (ESI.sup.+) m/z 521/523 (M+H).sup.+.

    Example 369: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 468)

    Example 369A: tert-butyl [3-(hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl]carbamate

    [2214] To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (300 mg, 1.243 mmol) in ethanol (4 mL) was added a 35% aqueous solution of hydrazine (0.704 mL, 4.97 mmol), and the reaction mixture was stirred at 90 C. in a sealed tube for 18 hours. The reaction mixture was cooled, and a white precipitate formed which was isolated by filtration, washed with ethanol (5 mL) and dried under a flow of air to give the title compound (221 mg, 70% yield). The filtrate was concentrated to give additional clean title compound (92.9 mg, 29% yield). .sup.1H NMR (500 MHz, DMSO-dr) ppm 9.80-8.66 (m, 1H), 7.52 (s, 1H), 4.16 (d, J=4.3 Hz, 2H), 2.02 (s, 6H), 1.37 (s, 9H); MS (ESI) m/z 242 (M+H).sup.+.

    Example 369B: 2-(trifluoromethoxy)ethyl 2-{3-[(tert-butoxycarbonyl)amino]bicyclo[1.1.1]pentane-1-carbonyl}hydrazine-1-carboxylate

    [2215] To a solution of 2-(trifluoromethoxy)ethanol (0.075 ml, 0.769 mmol) in acetonitrile (1.5 mL) stirred at 5 C. was added N,N-carbonyldiimidazole (CDI, 187 mg, 1.153 mmol), and the reaction mixture was stirred for 1 hour. Then the product of Example 369A (50 mg, 0.207 mmol) was added, and the reaction mixture was stirred for 18 hours. An additional portion of the product of Example 369A (100 mg, 0.414 mmol) was added, and the stirring was continued for an additional 18 hours. Then the reaction mixture was heated to 45 C. and stirred for an additional 18 hours. The reaction mixture was concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (0-80% ethyl acetate/isohexane) to afford the title compound (156 mg, 49% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.64 (s, 1H), 9.17 (s, 1H), 7.56 (s, 1H), 4.25 (s, 4H), 2.08 (s, 6H), 1.37 (s, 9H); MS (ESI.sup.+) m/z 398 (M+H).sup.+.

    Example 369C: tert-butyl (3-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2216] To a suspension of the product of Example 369B (156 mg, 0.393 mmol) and cesium carbonate (512 mg, 1.570 mmol) in acetonitrile (5 mL), at room temperature under nitrogen, was added p-toluenesulfonyl chloride (150 mg, 0.785 mmol), and the resultant reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (5 mL), and the phases were separated. The aqueous phase was further extracted with ethyl acetate (210 mL). The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (40 mg, 26% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 4.69-4.64 (m, 2H), 4.48-4.43 (m, 2H), 2.29 (s, 6H), 1.38 (s, 9H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 59.11; MS (ESI.sup.+) m/z 380 (M+H).sup.+.

    Example 369D: 3-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-amine

    [2217] The methodologies described in Example 190C substituting the product of Example 190B with the product of Example 369C gave the title compound (28.3 mg, 83% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 4.80-4.56 (m, 2H), 4.49-4.17 (m, 2H), 2.23 (s, 6H); MS (ESI.sup.+) m/z 280 (M+H).sup.+.

    Example 369E: (2R)-6-chloro-4-oxo-N-(3-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2218] The methodologies described in Example 366G substituting the product of Example 366F with the product of Example 369D gave the title compound (22.8 mg, 34% yield). MS (ESI.sup.+) m/z 488/490 (M+H).sup.+.

    Example 369F: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2219] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 369E and purifying by preparative HPLC [Waters XBridge C18 5 m ODB column, 30100 mm, flow rate 40 mL/minute, 25-55% gradient of acetonitrile in buffer (0.1% ammonia in water)] afforded the title compound (11.8 mg, 49% yield). .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.42 (dd, J=2.7, 0.9 Hz, 1H), 7.16 (dd, J=8.8, 2.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.94-4.89 (m, 1H), 4.72-4.68 (m, 2H), 4.62 (dd, J=11.6, 2.4 Hz, 1H), 4.47-4.40 (m, 2H), 2.56 (s, 6H), 2.55-2.51 (m, 1H), 2.02-1.81 (m, 1H); MS (ESI.sup.+) m/z 490/492 (M+H).sup.+.

    Example 370: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl)bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 469)

    Example 370A: N,N-dibenzyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]bicyclo[1.1.1]pentan-1-amine

    [2220] To a solution of dibenzylamine (1.302 mL, 6.80 mmol) in tetrahydrofuran (3.40 mL, 3.40 mmol) was added isopropylmagnesium chloride lithium chloride complex solution (5.75 mL, 7.48 mmol, 1.3 M in tetrahydrofuran) dropwise. It was at stirred ambient temperature for 2 hours and then tricyclo[1.1.1.0.sup.1,3]pentane (5 mL, 3.40 mmol, 0.68 M in ether) was added dropwise. The mixture was heated to 50 C. for 3 hours. The reaction mixture was cooled to ambient temperature and then zinc chloride (1.9 M in 2-methyltetrahydrofuran) (4.12 mL, 7.82 mmol) was added dropwise. The resultant mixture was stirred at ambient temperature for 30 minutes followed by addition of 4-bromo-2-(methylthio)pyrimidine (1.464 g, 7.14 mmol) in tetrahydrofuran (3.40 mL, 3.40 mmol). Then [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.055 g, 0.085 mmol) was added. The reaction mixture was heated to 50 C. for 1 hour. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0 to 50%) to give the title compound (0.37 g, 0.955 mmol, 28.1% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.48 (d, J=5.1 Hz, 1H), 7.41-7.37 (m, 4H), 7.30 (dd, J=8.4, 6.9 Hz, 4H), 7.23-7.20 (m, 2H), 7.00 (d, J=5.1 Hz, 1H), 3.67 (s, 4H), 2.46 (s, 3H), 1.96 (s, 6H); MS (ESI.sup.+) m/z 388 (M+H).sup.+.

    Example 370B: N,N-dibenzyl-3-[2-(methanesulfonyl)pyrimidin-4-yl]bicyclo[1.1.1]pentan-1-amine

    [2221] To a solution of N,N-dibenzyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]bicyclo[1.1.1]pentan-1-amine (0.2 g, 0.516 mmol) in ethanol (1.720 mL) was added a 30% solution of hydrogen peroxide (0.132 mL, 1.290 mmol) followed by ammonium molybdate tetrahydrate (0.019 g, 0.015 mmol). The reaction mixture was stirred for 2 hours. Water was added to the reaction mixture followed by a couple of extractions with dichloromethane. The combined organic fractions were dried with magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0 to 50%) to give the title compound (0.19 g, 0.453 mmol, 88% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.4) ppm 8.91 (d, J=5.1 Hz, 1H), 7.66 (d, J=5.1 Hz, 1H), 7.44-7.37 (m, 4H), 7.31 (dd, J=8.3, 6.9 Hz, 4H), 7.25-7.19 (m, 2H), 3.69 (s, 4H), 3.36 (s, 3H), 2.05 (s, 6H); MS (ESI.sup.+) m/z 420 (M+H).sup.+.

    Example 370C: N,N-dibenzyl-3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-amine

    [2222] To a solution of N,N-dibenzyl-3-[2-(methanesulfonyl)pyrimidin-4-yl]bicyclo[1.1.1]pentan-1-amine (0.2 g, 0.477 mmol) and 2-(trifluoromethoxy)ethanol (0.051 mL, 0.524 mmol) in tetrahydrofuran (2.167 mL)/N,N-dimethylformamide (0.217 mL) was added potassium hexamethyldisilazide (0.572 mL, 0.572 mmol, 1.0 M in tetrahydrofuran) at ambient temperature. The reaction mixture was stirred for 1 hour. Water was added to the reaction mixture followed by a couple of extractions with ethyl acetate. The combined organic fractions were dried with magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0-70%) to give the title compound (0.205 g, 0.437 mmol, 92% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.46 (dd, J=5.0, 0.6 Hz, 1H), 7.41-7.38 (m, 4H), 7.31 (dd, J=8.3, 7.0 Hz, 4H), 7.24-7.19 (m, 2H), 6.98 (dd, J=5.0, 0.7 Hz, 1H), 4.51-4.47 (m, 2H), 4.41-4.38 (m, 2H), 3.67 (s, 4H), 1.96 (s, 6H); MS (ESI.sup.+) m/z 470 (M+H).sup.+.

    Example 370D: 3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-amine

    [2223] To a solution of N,N-dibenzyl-3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-amine (200 mg, 0.426 mmol) in tetrahydrofuran (3 mL)/methanol (6 mL) was added concentrated hydrochloric acid (13 L) followed by addition of 10% palladium on carbon (40 mg). The reactor was purged several times with nitrogen gas. The reactor was then purged with hydrogen gas a few times with the pressure set to approximately 1 atmosphere with the final venting. The reaction mixture was stirred for 4 hours. The reaction mixture was filtered and concentrated. The residue was purified by HPLC [Waters XBridge C18 OBD column, 5 m, 30100 (50100 for bigger size column) mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid/water)] to give the title compound as a trifluoroacetic acid salt. MS (ESI.sup.+) m/z 290 (M+H).sup.+.

    Example 370E: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2224] A solution of (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (0.016 g, 0.065 mmol) and 2,6-lutidine (0.022 mL, 0.186 mmol) in dichloromethane (0.282 mL) and N,N-dimethylformamide (0.028 mL) was stirred for 10 minutes and then 3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-amine-2,2,2-trifluoroacetate (0.025 g, 0.062 mmol) in dichloromethane (0.282 mL) was added. The reaction mixture was stirred for 1 hour at ambient temperature. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel eluted with ethyl acetate/heptane (0 to 100%) to give the title compound (0.028 g, 0.054 mmol, 88% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.06 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.27 (d, J=10.2 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 5.17 (dd, J=7.8, 6.1 Hz, 1H), 4.56-4.51 (m, 2H), 4.46-4.40 (m, 2H), 3.00 (s, 1H), 2.98 (d, J=2.0 Hz, 1H), 2.34 (s, 6H); MS (ESI.sup.+) m/z 516 (M+H).sup.+.

    Example 370F: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2225] To a suspension of (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (0.028 g, 0.054 mmol) in methanol (0.543 mL) was added sodium borohydride (8.21 mg, 0.217 mmol). This mixture was allowed to stir at ambient temperature for 30 minutes. The reaction mixture was quenched with a drop of saturated aqueous ammonium chloride. The reaction mixture was concentrated, and the residue was purified by flash column chromatography on silica gel eluted with methanol/dichloromethane (0 to 20%) to give the title compound (0.018 g, 0.030 mmol, 54.4% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.80 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.75 (d, J=6.2 Hz, 1H), 4.79 (dt, J=11.7, 6.3 Hz, 1H), 4.68 (dd, J=11.9, 2.4 Hz, 1H), 4.54 (t, J=4.2 Hz, 2H), 4.45-4.41 (m, 2H), 2.37 (s, 7H), 1.73 (q, J=11.8 Hz, 1H); MS (ESI.sup.+) m/z 518 (M+H).sup.+.

    Example 371: (2R,4R)-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 470)

    Example 371A: (2R)-4-oxo-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2226] The methodologies described in Example 366G substituting the product of Example 366F with 3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-amine (Example 286D) and (R)-6-chloro-4-oxochroman-2-carboxylic acid with ()-(2R)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Example 227B) gave the title compound (43.9 mg, 100% yield). MS (ESI.sup.+) m/z 531 (M+H).sup.+.

    Example 371B: (2R,4R)-4-hydroxy-N-(3-(4-((1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)chroman-2-carboxamide

    [2227] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 371A and purifying by preparative HPLC [Waters XBridge C18 5 m ODB column, 30100 mm, flow rate 40 mL/minute, 35-65% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (13.7 mg, 44% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 8.19 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.7, 2.4 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 5.83 (s, 1H), 4.87 (d, J=10.5 Hz, 1H), 4.83 (q, J=7.5 Hz, 1H), 4.77 (dd, J=11.9, 2.4 Hz, 1H), 3.23-3.13 (m, 1H), 2.79-2.71 (m, 2H), 2.61 (s, 6H), 2.46-2.40 (m, 1H), 2.40-2.30 (m, 2H), 1.82-1.73 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.68, 59.96; MS (ESI.sup.+) m/z 533 (M+H).sup.+.

    Example 372: (2R,4R)-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 471)

    Example 372A: (2R)-4-oxo-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2228] The methodologies described in Example 366G substituting the product of Example 366F with 3-(4-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-amine (Example 188D) and (R)-6-chloro-4-oxochroman-2-carboxylic acid with ()-(2R)-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Example 227B) gave the title compound (30.5 mg, 100/6 yield) as a brown residue. MS (ESI.sup.+) m/z 530 (M+H).sup.+.

    Example 372B: (2R,4R)-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2229] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 372A and purifying by preparative HPLC [Waters XBridge C18 5 m ODB column, 30100 mm, flow rate 40 mL/minute, 25-55% gradient of acetonitrile in buffer (0.3% ammonia in water)] afforded the title compound (9.5 mg, 31% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.08 (d, J=1.4 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 5.82 (d, J=6.2 Hz, 1H), 4.90-4.85 (m, 1H), 4.79-4.73 (m, 2H), 2.99-2.92 (m, 1H), 2.62-2.58 (m, 2H), 2.48 (s, 6H), 2.45-2.39 (m, 1H), 2.31 (q, J=9.9 Hz, 2H), 1.80-1.72 (m, 1H); MS (ESI.sup.+) m/z 532 (M+H).sup.+.

    Example 373: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 472)

    Example 373A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2230] The methodologies described in Example 366G substituting the product of Example 366F with 3-(4-(cis-3-(trifluoromethoxy)cyclobutyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-amine (the product of Example 188D) and (R)-6-chloro-4-oxochroman-2-carboxylic acid with (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Example 262C) gave the title compound (77.0 mg, 100% yield). MS (ESI.sup.+) m/z 514/516 (M+H).sup.+.

    Example 373B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2231] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 373A and purifying by flash chromatography on silica gel (0-10% methanol/dichloromethane) afforded the title compound (42.3 mg, 59% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.52-7.45 (m, 1H), 7.07 (d, J=1.3 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (d, J=6.2 Hz, 1H), 4.82-4.74 (m, 2H), 4.70 (dd, J=11.8, 2.5 Hz, 1H), 2.99-2.92 (m, 1H), 2.64-2.60 (m, 2H), 2.47 (s, 6H), 2.38-2.35 (m, 1H), 2.33-2.27 (m, 2H), 1.77-1.69 (m, 1H); MS (ESI.sup.+) m/z 516/518 (M+H).sup.+.

    Example 374: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 473)

    Example 374A: (2R)-6-chloro-7-fluoro-4-oxo-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-H1-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2232] The methodologies described in Example 366G substituting the product of Example 366F with 3-{4-[cis-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-amine (Example 286D) and (R)-6-chloro-4-oxochroman-2-carboxylic acid with (2R)-6-chloro-7-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Example 262C) gave the title compound (275 mg, 99% yield). MS (ESI.sup.+) m/z 515/517 (M+H).sup.+.

    Example 374B: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2233] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 374A and purifying by reverse phase chromatography on C18 silica gel (15-75% acetonitrile/[10 mM ammonium bicarbonate in water]) afforded the title compound (70.2 mg, 33% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.18 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.76 (d, J=6.1 Hz, 1H), 4.86-4.77 (m, 2H), 4.72 (dd, J=11.8, 2.4 Hz, 1H), 3.21-3.15 (m, 1H), 2.78-2.72 (m, 2H), 2.60 (s, 6H), 2.40-2.34 (m, 3H), 1.78-1.70 (m, 1H); MS (ESI.sup.+) m/z 517/519 (M+H).sup.+.

    Example 375: (2S,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 474)

    [2234] The reaction and purification conditions described in Example 378 substituting the product of Example 247A for the product of Example 265A gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 8.60-8.56 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.92-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.99 (d, J=10.6 Hz, 1H), 5.66 (d, J=4.0 Hz, 1H), 4.65 (dd, J=10.9, 2.8 Hz, 1H), 4.63-4.59 (m, 1H), 2.57 (s, 6H), 2.17-2.09 (m, 1H), 1.95 (ddd, J=14.2, 10.9, 3.6 Hz, 1H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 376: (2R,4R)-6-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 475)

    Example 376A: rac-(2R,4R)-6-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2235] The reaction and purification conditions described in Example 383 substituting the product of Example 247A for the product of Example 265A, and 6-fluoro-4-oxochroman-2-carboxylic acid (Enamine) for the product of Example 262C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.58 (d, J=2.7 Hz, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.81 (m, 2H), 7.20-7.12 (m, J H), 7.01 (td, J=8.6, 3.2 Hz, 1H), 6.89 (dd, J=9.0, 4.8 Hz, 1H), 5.70 (s, 1H), 4.88-4.79 (m, 1H), 4.63 (dd, J=12.0, 2.2 Hz, 1H), 2.39 (ddd, J=12.8, 5.8, 2.2 Hz, 1H), 1.73 (td, J=12.6, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 505 (M+H).sup.+.

    Example 376B: (2R,4R)-6-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromelhoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2236] The product of Example 376A (79 mg, 0.157 mmol) was separated by chiral SFC on a Waters SFC 350 Preparative System [column: Whelk-O (S, S) 21250 mm 5 m chiral column; Mobile phase: A for CO.sub.2 and B for methanol; Gradient: 30% B in A; Flow rate: 80 g/minute; Column temperature: 40 C.; System back pressure: 100 bar] to give the title compound as the earlier eluting fraction (27.6 mg, 0.055 mmol, 35%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 8.60-8.55 (m, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.92-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.16 (ddd, J=9.4, 3.2, 1.0 Hz, 1H), 7.05-6.97 (m, 1H), 6.89 (dd, J=8.9, 4.8 Hz, 1H), 5.69 (s, 1H), 4.83 (dd, J=10.7, 6.0 Hz, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.57 (s, 6H), 2.43-2.35 (m, 1H), 1.73 (td, J=12.4, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 505 (M+H).sup.+.

    Example 377: (2R,4S)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 476)

    Example 377A: (2R,4R)-6-chloro-7-fluoro-4-hydroxychroman-2-carboxylic acid Sodium borohydride (2.47 g, 65.3 mmol) was added to a solution of the product of Example 262C (4.4 g, 16.33 mmol) in methanol (60 mL) at 0 C. The ice bath was removed, and the reaction mixture was allowed to stir at ambient temperature for 12 hours and then cooled back to 0 C. Water (100 mL) was added and the mixture was stirred for 15 minutes, and then extracted with ethyl acetate (3100 mL). The combined extracts were dried over MgSO.SUB.4., and then concentrated under reduced pressure to give the title compound (4 g, 14.60 mmol, 89% yield). MS (ESP) m/z 245 (MH).SUP.

    Example 377B: (2R,4)-6-chloro-7-fluoro-4-hydroxychroman-2-carboxylic acid

    [2237] The reaction and purification conditions described in Example 73B substituting the product of Example 377A for the product of Example 73A gave the title compound. MS (ESI.sup.+) m/z 229 (MH2O+H).sup.+.

    Example 377C: (2R,4S)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2238] The reaction and purification conditions described in Example 378 substituting the product of Example 247A for the product of Example 265A, and the product of Example 377B for the product of Example 280D gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.99 (s, 1H), 8.60-8.56 (m, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.92-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.98 (d, J=10.6 Hz, 1H), 5.65 (d, J=3.8 Hz, 1H), 4.65 (dd, J=10.9, 2.8 Hz, 1H), 4.63-4.60 (m, 1H), 2.57 (s, 6H), 2.13 (ddd, J=13.9, 3.9, 2.9 Hz, 1H), 1.95 (ddd, J=14.2, 11.0, 3.6 Hz, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 378: (2S,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 477)

    [2239] The product of Example 265A (25 mg, 0.063 mmol) was combined with trifluoroacetic acid (0.3 mL) and stirred at ambient temperature for 30 minutes and then concentrated under high vacuum. Triethylamine (0.088 mL, 0.634 mmol), N,N-dimethylformamide (1 mL), the product of Example 280D (15.6 mg, 0.063 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 27.7 mg, 0.073 mmol) were added sequentially. The resulting mixture was stirred at ambient temperature for 30 minutes. Water (0.1 mL) was added, and the resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [Waters XBridge C18 OBD Prep Column, 130 , 5 m, 30 mm100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (23.5 mg, 0.045 mmol, 71% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 8.89-8.84 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.21-8.14 (m, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.99 (d, J=10.6 Hz, 1H), 5.65 (s, 1H), 4.65 (dd, J=10.8, 2.8 Hz, 1H), 4.63-4.58 (m, 1H), 2.58 (s, 6H), 2.13 (dt, J=13.9, 3.4 Hz, 1H), 1.95 (ddd, J=14.2, 10.9, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 379: (2R,4S)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 478)

    [2240] The reaction and purification conditions described in Example 378 substituting the product of Example 377B for the product of Example 280D gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 8.89-8.85 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.20-8.15 (m, 2H), 7.95-7.90 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.98 (d, J=10.6 Hz, 1H), 5.65 (s, 1H), 4.65 (dd, J=10.9, 2.8 Hz, 1H), 4.63-4.59 (m, 1H), 2.58 (s, 6H), 2.13 (ddd, J=13.9, 3.9, 2.9 Hz, 1H), 1.95 (ddd, J=13.9, 10.9, 3.6 Hz, 1H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 380: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[1-(trifluoromethyl)-1H,1H-[4,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 479)

    Example 380A: tert-butyl {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2241] To a solution of the product of Example 207C (1.0 g, 3.05 mmol), potassium acetate (0.897 g, 9.14 mmol), and bis(pinacolato)diboron (0.928 g, 3.66 mmol) in degassed ethanol (20 mL) under nitrogen protection was added XPhos (0.058 g, 0.122 mmol) followed by XPhos-Pd-G 3 (0.052 g, 0.061 mmol). The subsequent reaction mixture was stirred at 80 C. for 8 hours and then left stirring at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was partitioned between ethyl acetate (15 mL) and water (20 mL). The aqueous phase was further extracted with ethyl acetate (2-15 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give the title compound (1.143 g, 3.05 mmol, 100% yield). MS (API.sup.+) m/z 376 (M+H).sup.+.

    Example 380B: tert-butyl {3-[1-(trifluoromethyl)-1H,1H-[4,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}carbamate

    [2242] The reaction and purification conditions described in Example 207D substituting the product of Example 380A for 3-fluoro-4-(trifluoromethoxy)phenylboronic acid, and 4-bromo-1-(trifluoromethyl)-1H-pyrazole for the product of Example 207C gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.70-8.66 (m, J H), 8.24-8.20 (m, 1H), 8.16-8.12 (m, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.75 (br s, 1H), 2.39 (s, 6H), 1.40 (s, 9H); MS (ESI.sup.+) m/z 384 (M+H).sup.+.

    Example 380C: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[1-(trifluoromethyl)-1H,1H-[4,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2243] The reaction and purification conditions described in Example 362 substituting the product of Example 380B for the product of Example 109A gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.69 (s, 1H), 8.24-8.22 (m, 1H), 8.19 (d, J=0.8 Hz, 1H), 7.87 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.76 (s, 1H), 4.80 (dd, J=10.6, 5.8 Hz, 1H), 4.72 (dd, J=11.9, 2.4 Hz, 1H), 2.54 (s, 6H), 2.38 (ddd, J=13.0, 5.7, 2.5 Hz, 1H), 1.81-1.68 (m, 1H); MS (APCI.sup.+) m/z 512 (M+H).sup.+.

    Example 381: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{6-[4-(trifluoromethyl)-1H-imidazol-1-yl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 480)

    Example 381A: N,N-dibenzyl-3-{6-[4-(trifluoromethyl)-1H-imidazol-1-yl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-amine

    [2244] To a solution of the product of Example 339A (350 mg, 0.976 mmol) and 4-(trifluoromethyl)-1H-imidazole (399 mg, 2.93 mmol) in tetrahydrofuran (5.0 mL) at ambient temperature was added potassium bis(trimethylsilyl)amide (1.953 mL, 1.953 mmol) (1 M in tetrahydrofuran) dropwise, and the mixture was stirred at 65 C. for 48 hours. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The aqueous mixture was extracted with ethyl acetate (50 mL). The organic fraction was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified on silica gel (0-50% ethyl acetate in heptane) to give the title compound (55 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.66 (d, J=1.3 Hz, 1H), 8.55 (q, J=1.4 Hz, 1H), 8.32 (dd, J=2.2, 0.9 Hz, 1H), 7.84 (qd, J=8.4, 1.5 Hz, 2H), 7.44-7.37 (m, 4H), 7.31 (t, J=7.6 Hz, 4H), 7.26-7.17 (m, 2H), 3.68 (s, 4H), 2.01 (s, 6H).

    Example 381B: 3-{6-[4-(trifluoromethyl)-1H-imidazol-1-yl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-amine

    [2245] The title compound was prepared using the methodologies described in Example 328D substituting the product of Example 328C with the product of Example 381A. MS (APCI.sup.+) m/z 295.67 (M+H).sup.+.

    Example 381C: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{6-[4-(trifluoromethyl)-1H-imidazol-1-yl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2246] To a solution of the product of Example 381B, the product of Example 262C (14.84 mg, 0.061 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.173 mmol) in N,N-dimethylformamide (1 mL), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.144 mL, 0.072 mmol) was added, and the mixture was stirred for 15 minutes. Volatiles were removed under high vacuum, and the residue was dissolved in methanol (1 mL) and treated with sodium tetrahydroborate (21.86 mg, 0.578 mmol) for another 15 minutes. The reaction mixture was concentrated, and the residue was purified by HPLC (Phenomenex Luna C18(2) 10 m 100 AXIA column (250 mm50 mm). A 30-100% gradient of acetonitrile in buffer [0.1% trifluoroacetic acid in water] was used over 25 minutes, at a flow rate of 75 mL/minute) to give the title compound (13.8 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.69 (s, 1H), 8.58 (t, J=1.4 Hz, 1H), 8.43 (d, J=2.3 Hz, 1H), 7.97 (dd, J=8.4, 2.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 4.80 (dd, J=10.6, 5.8 Hz, 1H), 4.69 (dd, J=11.9, 2.4 Hz, 1H), 2.40 (s, 6H), 2.41-2.33 (m, 1H), 1.74 (td, J=12.2, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 521.55 (M+H).sup.+.

    Example 382: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 481)

    Example 382A: benzyl [4-(4-bromo-1H-pyrazol-1-yl)cyclohexyl]carbamate

    [2247] A 100 mL round-bottom flask was charged with iodomesitylene diacetate (0.95 g, 2.61 mmol), (trans)-4-(((benzyloxy)carbonyl)amino)cyclohexanecarboxylic acid (1.447 g, 5.22 mmol) and toluene (50 mL). The flask was heated to 60 C. in a rotary evaporator bath, and the solvent was removed under vacuum over a time period of 10 minutes. The evaporation step was repeated 3 more times with 50 mL of toluene each time. After further removal of residual toluene under high vacuum, 4-bromo-1H-pyrazole (0.575 g, 3.91 mmol), tris(2-phenylpyridine)iridium (0.014 g, 0.021 mmol), copper(I) thiophene-2-carboxylate (0.149 g, 0.783 mmol) and 4,7-diphenyl-1,10-phenanthroline (0.390 g, 1.174 mmol) were added. The flask was sealed with a rubber septum, and vacuum was applied while the flask was under sonication, and then dioxane (26 mL) was added via a cannula needle. The flask was sonicated under vacuum for 5 more minutes while still under vacuum, refilled with nitrogen, and then put inside a running water cooled bath and was stirred and irradiated using 2 PAR20-18W CREE XPE 450 nm blue LED lamps. The bath temperature was maintained at 22 C. After 4 hours, the reaction mixture was exposed to air and stirred for 20 minutes and then filtered through a thick pad of cotton, and the filter cake was rinsed with methanol (20 mL). The filtrate was combined with diatomaceous earth (30 g) and concentrated under reduced pressure to a free flowing powder, and the powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 30 m 175 g column, flow rate 120 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (198 mg, 0.445 mmol, 17% yield). MS (ESI.sup.+) ml: 378/380 (M+H).sup.+.

    Example 382B: benzyl (4-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}cyclohexyl)carbamate

    [2248] A 30 mL vial was charged with potassium acetate (93 mg, 0.952 mmol) as a solid. The vial was heated at 80 C. under vacuum for 5 minutes, and then cooled to ambient temperature under nitrogen. Once cooled, the product of Example 382A (120 mg, 0.317 mmol), tetrahydroxydiboron (85 mg, 0.952 mmol), XPhos-Pd-G3 (5.4 mg, 6.34 mol), and XPhos (6.0 mg, 0.013 mmol) were added as solids. The contents were again evacuated and backfilled with nitrogen for 2 passes. Absolute ethanol (3.2 mL, degassed by bubbling nitrogen through for 10 minutes) was added, and the vial was stirred at 70 C. for 1 hour. Aqueous potassium carbonate solution (0.53 mL, 1.8 M, degassed by bubbling nitrogen through for 10 minutes) was added via syringe followed by the addition of 2-bromo-5-(trifluoromethoxy)pyridine (115 mg, 0.476 mmol) as a solution in ethanol (0.5 mL, degassed by bubbling nitrogen through for 10 minutes). The reaction mixture was stirred at 62 C. for 18 hours, cooled, and filtered through a glass microfiber frit, and rinsed with ethanol (5 mL). The filtrate was combined with diatomaceous earth (10 g) and concentrated under reduced pressure to a free flowing powder, and the powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 15 m 120 g column, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate)] to give the title compound (15 mg, 0.033 mmol, 10.3% yield).

    [2249] MS (APCI.sup.+) m/z 461 (M+H).sup.+.

    Example 382C: (2R)-(trans)-6-chloro-4-oxo-N-(4-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2250] The product of Example 382B (15 mg, 0.033 mmol) was combined with trifluoroacetic acid (1 mL) and stirred at 70 C. for 30 minutes, and then concentrated under high vacuum. To the residue was added triethylamine (0.045 mL, 0.326 mmol), N,N-dimethylformamide (0.5 mL), the product of Example 1B (7.4 mg, 0.033 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 22.1 mg, 0.042 mmol) in sequential order, and the reaction mixture was stirred for 10 minutes. Water (0.1 mL) was added, and the resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [XBridge BEH C18 OBD Prep Column, 130 , 5 m, 30 mm100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound as the earlier eluting fraction (11.5 mg, 0.021 mmol, 66% yield). MS (APCI.sup.+) m/z 535 (M+H).sup.+.

    Example 382D: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}cyclohexyl-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2251] The product of Example 382C (11 mg, 0.021 mmol) was combined with methanol (0.5 mL) and stirred at 0 C. NaBH.sub.4 (3.9 mg, 0.103 mmol) was added in one portion. After stirring for 5 minutes, the ice bath was removed, and the reaction mixture was allowed to stir at ambient temperature for 15 minutes, filtered through a glass microfiber frit, and directly purified by preparative HPLC [XBridge BEH C18 OBD Prep Column, 130 , 5 m, 30 mm100 mm, flow rate 40 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (3.3 mg, 0.006 mmol, 30% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.58-8.55 (m, 1H), 8.42 (d, J=0.8 Hz, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.89-7.84 (m, 1H), 7.82-7.77 (m, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.70 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 4.21 (tt, J=11.6, 3.8 Hz, 1H), 3.79-3.69 (m, 1H), 2.40-2.33 (m, 1H), 2.14-2.09 (m, 2H), 1.95-1.83 (m, 4H), 1.74 (ddd, J=12.9, 11.9, 10.7 Hz, 1H), 1.61-1.49 (m, 2H); MS (ESI.sup.+) m, 537 (M+H).sup.+.

    Example 383: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 482)

    [2252] The product of Example 265A (25 mg, 0.063 mmol) was combined with trifluoroacetic acid (0.3 mL) and stirred at ambient temperature for 30 minutes, and the resulting solution was concentrated under vacuum. To the residue was added triethylamine (0.062 mL, 0.444 mmol), N,N-dimethylformamide (1.0 mL), and the product of Example 262C (15.5 mg, 0.063 mmol) followed by (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP, 43 mg, 0.082 mmol), and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (230 mL), and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in methanol (3 mL), and sodium borohydride (14.4 mg, 0.38 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 20 minutes, and saturated ammonium chloride solution (0.1 mL) was added, and the resulting mixture was partitioned between saturated aqueous sodium bicarbonate (20 mL) and dichloromethane (220 mL). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in N,N-dimethylformamide (1 mL) and directly purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 20150 mm, flow rate 25 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (24 mg, 0.046 mmol, 72% yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.89-8.85 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.21-8.15 (m, 2H), 7.95-7.90 (m, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.77 (s, 1H), 4.81 (dd, J=10.6, 5.8 Hz, 1H), 4.72 (dd, J=11.8, 2.5 Hz, 1H), 2.58 (s, 6H), 2.38 (ddd, J=12.9, 5.7, 2.5 Hz, 1H), 1.75 (ddd, J=12.9, 11.9, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 523 (M+H).sup.+.

    Example 384: (2R,4R)-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 483)

    Example 384A: ethyl 4-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]-2,4-dioxobutanoate

    [2253] 1-(4-Fluoro-2-hydroxy-5-(trifluoromethyl)phenyl)ethanone (40 g, 124 mmol, Toronto Research Chemicals) and diethyl oxalate (56.0 mL, 414 mmol) were dissolved in N,N-dimethylformamide (230 mL) and stirred at 0 C. Potassium tert-butoxide (1.0 M in tetrahydrofuran, 414 mL) was slowly added to the reaction mixture, and the resulting mixture was stirred at 0 C. for 2 hours. Water (1.5 L) and ethyl acetate (0.5 L) were slowly added, and the mixture was stirred for 5 minutes. The layers were then separated, and the aqueous phase was extracted with ethyl acetate (3600 mL). The combined organic phases were concentrated under reduced pressure to give the title compound (40 g, 83% purity, 104 mmol, 100% yield).

    [2254] MS (ESI.sup.) m/z 321 (MH).sup..

    Example 384B: ethyl 7-fluoro-4-oxo-6-(trifluoromethyl)-4H-chromene-2-carboxylate

    [2255] The product of Example 384A (40 g,124 mmol) was stirred in ethanol (400 mL). Aqueous HCl (49 mL, 12.0 M) was slowly added. The resulting mixture was stirred at 100 C. for 12 hours, cooled to ambient temperature, and then chilled to 0 C. The precipitated solids were collected by filtration to give the title compound (13.5 g, 44.5 mmol, 36% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.34 (d, J=7.9 Hz, 1H), 8.18 (d, J=11.2 Hz, 1H), 7.07 (s, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

    [2256] Example 384C: ethyl 7-fluoro-4-oxo-6-(trifluoromethyl)-4H-1-benzopyran-2-carboxylate Copper(II) acetate (0.075 g, 0.411 mmol) and (S)-()-5,5-bis[di(3,5-xylyl)phosphino]-4,4-bi-1,3-benzodioxole (0.333 g, 0.460 mmol) were combined with tetrahydrofuran (150 mL). The mixture was evacuated and then refilled with argon for 3 passes, and then stirred at 25 C. for 30 minutes. Diethoxymethylsilane (4.41 g, 32.9 mmol) was slowly added via a syringe pump over a period of 1 hour under argon protection. Then a solution of the product of Example 384B (5.0 g, 16.44 mmol) in tetrahydrofuran (50 mL) was added, and the resulting mixture was stirred at 25 C. for 4 hours. Additional diethoxy(methyl)silane (2.21 g, 16.44 mmol) was added via syringe under argon atmosphere, the resulting mixture was evacuated and refilled with argon for three passes, and then stirred at 25 C. for 12 hours. Volatiles were removed on a rotary evaporator. The resulting crude product was purified by flash chromatography on silica gel eluting with 3-10% ethyl acetate in petroleum ether to give the title compound (2.5 g, 80% purity, 6.53 mmol, 40% yield). MS (ESI.sup.+) m/z 307 (M+H).sup.+.

    Example 3841): ()-(2R)-7-fluoro-4-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

    [2257] To solution of the product of Example 384C (300 mg, 0.98 mmol) in acetic acid (4 mL) was added aqueous HCl (1.5 mL, 12 M). The mixture was stirred at 60 C. for 1 hour. The reaction mixture was cooled and concentrated under high vacuum to give the title compound (220 mg, 0.781 mmol, 80% yield). .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm 8.14 (d, J=8.2 Hz, 1H), 7.12 (d, J=11.6 Hz, 1H), 5.41 (dd, J=7.3, 5.4 Hz, 1H), 3.28-3.21 (m, 1H), 3.13-3.04 (m, 1H); specific rotation: []20 D=47.7, (c 0.28, methanol).

    Example 384E: (2R,4R)-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2258] The reaction and purification conditions described in Example 320L substituting the product of Example 313G for the product of Example 320J, and the product of Example 384D for the product of Example 320K gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 6.99 (d, J=12.1 Hz, 1H), 5.85 (d, J=5.8 Hz, 1H), 4.88-4.76 (m, 2H), 4.37-4.30 (m, 2H), 4.14-4.07 (m, 2H), 2.47 (s, 6H), 2.41 (ddd, J=13.0, 5.6, 2.6 Hz, 1H), 1.84-1.71 (m, 1H); MS (ESI.sup.+) m/z 540 (M+H).sup.+.

    Example 385: (2R,4R)-7-fluoro-4-hydroxy-6-(trifluoromethyl)-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 484)

    [2259] The reaction and purification conditions described in Example 383 substituting the product of Example 384D for the product of Example 262C gave the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.90-8.84 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.22-8.14 (m, 2H), 7.93 (dt, J=8.3, 0.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.00 (d, J=12.1 Hz, 1H), 5.86 (s, 1H), 4.89-4.78 (m, 2H), 2.58 (s, 6H), 2.42 (ddd, J=13.1, 5.6, 2.6 Hz, 1H), 1.79 (ddd, J=13.0, 11.7, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 557 (M+H).sup.+.

    Example 386: (2R,4R)-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 485)

    Example 386A: 3-{4-[5-(trifluoromelhoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2260] Trifluoroacetic acid (3 mL) was added to the product of Example 247A (438 mg, 0.854 mmol) and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methanol (3 ML), filtered, and directly purified by preparative HPLC [TriArt C18 Hybrid 5 m column, 50100 mm, flow rate 140 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (254 mg, 0.819 mmol, 96% yield). MS (APCI.sup.+) m/z 311 (M+H).sup.+.

    Example 386B: (2R,4R)-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide

    [2261] The reaction and purification conditions described in Example 320L substituting the product of Example 384D for the product of Example 320K gave the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.60-8.56 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.90-7.88 (m, 1H), 7.85 (dd, J=8.7, 0.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.00 (d, J=12.0 Hz, 1H), 5.87 (s, 1H), 4.86-4.79 (m, 2H), 2.57 (s, 6H), 2.42 (ddd, J=13.0, 5.7, 2.6 Hz, 1H), 1.79 (ddd, J=13.1, 11.7, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 573 (M+H).sup.+.

    Example 387: (2R,4R)-7-fluoro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 486)

    [2262] The reaction and purification conditions described in Example 320L substituting the product of Example 384D for the product of Example 320K gave the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.02 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 7.01 (d, J=11.9 Hz, 1H), 5.83 (d, J=6.1 Hz, 1H), 4.83 (dt, J=10.9, 5.8 Hz, 1H), 4.79 (dd, J=11.8, 2.5 Hz, 1H), 4.36-4.30 (m, 2H), 4.11-4.06 (m, 2H), 4.02 (tt, J=11.8, 3.9 Hz, 1H), 3.69 (tdt, J=11.8, 8.0, 4.0 Hz, 1H), 2.39 (ddd, J=13.1, 5.8, 2.5 Hz, 1H), 2.05-1.98 (m, 2H), 1.93-1.85 (m, 2H), 1.83-1.71 (m, 3H), 1.55-1.41 (m, 2H); MS (ESI.sup.+) m/z 556 (M+H).sup.+.

    Example 388: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 487)

    Example 388A: 2-(trifluoromethoxy)ethyl formate

    [2263] A stirred mixture of acetic anhydride (4.3 mL, 45.6 mmol) and formic acid (1.8 mL, 46.9 mmol) was heated to 60 C., under a nitrogen atmosphere, for 30 minutes, and then was cooled to room temperature. This resulting acetic formic anhydride was used in the next reaction without further purification. In another flask, to a stirred solution of 2-(trifluoromethoxy)ethanol (2.2 g, 4.57 mmol) and pyridine (4.4 mL, 54.4 mmol) in dichloromethane (45 mL) at 0 C., was added dropwise the freshly prepared acetic formic anhydride, under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then cooled to 0 C. and quenched with saturated aqueous NH.sub.4Cl (40 mL). The resulting two phases were separated, and the aqueous phase was extracted with dichloromethane (40 mL). The organic phase was washed with 1 M aqueous HCl solution (80 mL) and then stirred with saturated aqueous NaHCO.sub.3 (80 mL) for 10 minutes. The phases were separated. The organic phase was dried by passing through a hydrophobic phase separator and then loaded onto a silica plug and eluted with dichloromethane (80 mL). The organic phase was partially reduced in vacuo to afford the title compound (1.57 g, 70% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) h ppm 8.08 (q, J=0.8 Hz, 1H), 4.44-4.38 (m, 2H), 4.20-4.13 (m, 2H); .sup.19F NMR (376 MHz, CDCl.sub.3) J ppm 61.20.

    Example 388B: 1,1-dichloro-2-(2-(trifluoromethoxy)ethoxy)ethene

    [2264] To a stirred solution of triphenylphosphine (8.34 g, 31.8 mmol) in dichloromethane (20 mL) was added carbon tetrachloride (1.5 mL, 15.54 mmol), at room temperature under nitrogen atmosphere. After being stirred for 10 minutes, triethylamine (6.6 mL, 47.4 mmol) was added to the reaction mixture, and the mixture was stirred for 10 minutes. At 0 C., a cold solution of the product of Example 388A (1.57 g, 3.18 mmol) in dichloromethane (10 mL) was slowly added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was cooled to 0 C. and quenched with saturated aqueous NH.sub.4Cl (40 mL). The phases were separated, and the aqueous phase was extracted with dichloromethane (60 mL). The organic phase was dried by passing through a hydrophobic phase separator and then reduced in vacuo. The crude residue was purified on a silica plug eluted with isohexane/methyl tert-butyl ether (3:2, 100 mL). The fraction collected was partially reduced in vacuo, and the resultant solid was removed by filtration and rinsed with methyl tert-butyl ether (1 mL). The combined filtrates were partially reduced in vacuo to obtain the title compound (574 mg, 43% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.19-7.17 (m, 1H), 4.30-4.24 (m, 2H), 4.25-4.20 (m, 2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 59.01.

    Example 388C: (2-(trifluoromethoxy)ethoxy)ethyne

    [2265] To a solution of the product of Example 388B (570 mg, 1.368 mmol) in tetrahydrofuran (27 mL) was added n-butyllithium (2.5 M in hexanes, 3.3 mL, 8.25 mmol), and the reaction mixture was stirred at 78 C. for 1 hour. The stirred mixture was allowed to warm to 40 C. and anhydrous methanol (2 mL) was added. The reaction mixture was allowed to warm to room temperature and then was diluted with methyl tert-butyl ether (15 mL) and quenched with saturated aqueous NH.sub.4Cl (30 mL). The phases were separated, and the aqueous phase was extracted with additional methyl tert-butyl ether (250 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the title compound (1.31 g, 37% yield) which was used directly in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.30 (t, J=5.2 Hz, 2H), 3.41-3.36 (m, 2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 59.24.

    Example 388D: tert-butyl (3-{4-[2-(trifluoromethoxy)ethoxy]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)carbamate

    [2266] The product of Example 368A (0.203 g, 0.407 mmol), the product of Example 388C (1.31 g, 0.510 mmol) and triethylamine (0.11 mL, 0.789 mmol) were dissolved in degassed anhydrous tetrahydrofuran (4 mL). Copper(I) iodide (0.083 g, 0.436 mmol) was added, and the reaction mixture was stirred at room temperature for 19 hours. Dichloromethane (20 mL) was added, and the reaction mixture was filtered through diatomaceous earth and rinsed with dichloromethane (220 mL). The combined filtrates were concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/isohexane) to afford the title compound (0.083 g, 43% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.87 (s, 1H), 7.44 (s, 1H), 4.40-4.37 (m, 2H), 4.35 (d, J=5.0 Hz, 2H), 2.45 (s, 6H), 1.40 (s, 9H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 58.93; MS (ESI.sup.+) m/z 379 (M+H).sup.+.

    Example 388E: 3-{4-[2-(trifluoromethoxy)ethoxy]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-amine

    [2267] The methodologies described in Example 190C substituting the product of Example 190B with the product of Example 388D gave the title compound (26 mg, 57% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.81 (s, 1H), 4.39 (dd, J=6.3, 2.5 Hz, 2H), 4.34 (d, J=5.1 Hz, 2H), 2.23 (s, 6H), .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 58.93; MS (ESI.sup.+) m/z 279 (M+H).sup.+.

    Example 388F: (R)-6-chloro-4-oxo-N-(3-(4-(2-(trifluoromethoxy)ethoxy)-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)chroman-2-carboxamide

    [2268] The methodologies described in Example 366G substituting the product of Example 366F with the product of Example 388E gave the title compound (41 mg, 87% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.21 (s, 1H), 7.90 (s, 1H), 7.72-7.60 (m, 2H), 7.23-7.12 (m, 1H), 5.16 (dd, J=8.5, 5.8 Hz, 1H), 4.44-4.33 (m, 4H), 3.03-2.94 (m, 2H), 2.58 (s, 6H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 58.93; MS (ESI.sup.+) m/z 487/489 (M+H).sup.+.

    Example 388G: (2R,4R)-6-chloro-4-hydroxy-N-(3-(4-(2-(trifluoromethoxy)ethoxy)-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)chroman-2-carboxamide

    [2269] The methodologies described in Example 217L substituting the product of Example 217K with the product of Example 388F and purifying by flash chromatography on silica gel (0-100% ethyl acetate/hexanes) afforded the title compound (28 mg, 73% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 7.91 (s, 1H), 7.41-7.36 (m, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.82 (dd, J=10.9, 5.7 Hz, 1H), 4.66 (dd, J=11.8, 2.3 Hz, 1H), 4.40 (dd, J=6.2, 2.5 Hz, 2H), 4.36 (d, J=5.2 Hz, 2H), 2.60 (s, 6H), 2.40-2.35 (m, 1H), 1.80-1.67 (m, 1H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 58.92 ppm; MS (ESI.sup.+) m/z 489/491 (M+H).sup.+.

    [2270] The following compounds were prepared using methodologies similar to those described in the above examples.

    Example 389: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 488)

    [2271] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.48 (dd, J=8.6, 1.0 Hz, 1H), 7.39 (s, 1H), 7.00-6.93 (m, 2H), 5.71 (d, J=6.2 Hz, 1H), 5.22 (d, J=4.7 Hz, 1H), 4.75 (dt, J=10.9, 6.1 Hz, 1H), 4.60 (dd, J=11.7, 2.3 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.94 (dt, J=9.0, 3.9 Hz, 1H), 3.77-3.67 (m, 4H), 2.80-2.71 (m, 2H), 2.34-2.07 (m, 6H), 2.00-1.68 (m, 9H); MS (APCI.sup.+) m/z 581 [M+H].sup.+.

    Example 390: (2R,4R)-4-hydroxy-N-[(2S)-2-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 489)

    [2272] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.02 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 7.01 (d, J=11.9 Hz, 1H), 5.83 (d, J=6.1 Hz, 1H), 4.83 (dt, J=10.9, 5.8 Hz, 1H), 4.79 (dd, J=11.8, 2.5 Hz, 1H), 4.36-4.30 (m, 2H), 4.11-4.06 (m, 2H), 4.02 (tt, J=11.8, 3.9 Hz, 1H), 3.69 (tdt, J=11.8, 8.0, 4.0 Hz, 1H), 2.39 (ddd, J=13.1, 5.8, 2.5 Hz, 1H), 2.05-1.98 (m, 2H), 1.93-1.85 (m, 2H), 1.83-1.71 (m, 3H), 1.55-1.41 (m, 2H); MS (ESI.sup.+) m/z 556 (M+H).sup.+.

    Example 391: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(2S)-2-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 490)

    [2273] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.47 (dd, J=8.6, 1.0 Hz, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.73 (s, 1H), 5.09-5.05 (m, 1H), 4.78-4.73 (m, 1H), 4.65 (dd, J=11.2, 2.6 Hz, 1H), 4.47 (p, J=7.2 Hz, 1H), 4.07-4.03 (m, 1H), 3.72-3.65 (m, 1H), 3.68 (s, 2H), 2.76-2.69 (m, 2H), 2.33 (ddd, J=13.2, 5.8, 2.6 Hz, 1H), 2.28 (ddd, J=12.7, 9.5, 2.8 Hz, 1H), 2.16-2.06 (m, 2H), 1.96-1.89 (m, 2H), 1.89-1.70 (m, 8H); MS (ESI.sup.+) m/z 581 (M+H).sup.+.

    Example 392: (2S,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 491)

    [2274] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.73 (s, 1H), 8.35 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 6.96 (d, J=10.6 Hz, 1H), 5.61 (d, J=3.7 Hz, 1H), 4.61-4.56 (m, 2H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.70 (p, J=7.1 Hz, 1H), 2.77-2.70 (m, 2H), 2.25 (s, 6H), 2.17-2.12 (m, 2H), 2.08 (ddd, J=14.0, 4.0, 2.9 Hz, 1H), 1.90 (ddd, J=14.1, 10.9, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 393: (2S,4R)-6,7-dichloro-4-hydroxy-N-[3-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 492)

    [2275] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.73 (s, 1H), 8.35 (s, 1H), 7.51 (s, 1H), 7.19 (s, 1H), 5.67 (s, 1H), 4.63-4.56 (m, 2H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.70 (p, J=6.8 Hz, 1H), 2.79-2.68 (m, 2H), 2.25 (s, 6H), 2.20-2.04 (m, 2H), 1.91 (ddd, J=14.1, 10.5, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 539 (M+H).sup.+.

    Example 394: (2R,4R)-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 493)

    [2276] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.71 (s, 1H), 8.36 (s, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.55-7.49 (m, 1H), 7.05 (dd, J=8.6, 0.9 Hz, 1H), 5.79 (d, J=6.2 Hz, 1H), 4.90-4.82 (m, 1H), 4.70 (dd, J=12.0, 2.4 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.73 (s, 2H), 3.72-3.67 (m, 1H), 2.78-2.70 (m, 2H), 2.39 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 2.26 (s, 6H), 2.20-2.10 (m, 2H), 1.73 (ddd, J=13.0, 12.0, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 395: (2R,4R)-6,7-dichloro-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 494)

    [2277] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.67 (s, 1H), 8.36 (s, 1H), 7.53 (d, J=1.0 Hz, 1H), 7.15 (s, 1H), 5.78 (s, 1H), 4.79 (dd, J=10.7, 5.8 Hz, 1H), 4.65 (dd, J=11.9, 2.4 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.73 (s, 2H), 3.72-3.67 (m, 1H), 2.78-2.69 (m, 2H), 2.35 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 2.26 (s, 6H), 2.19-2.10 (m, 2H), 1.73-1.63 (m, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 396: (2R,4S)-6,7-dichloro-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 495)

    [2278] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.73 (s, 1H), 8.35 (s, 1H), 7.51 (s, 1H), 7.19 (s, 1H), 5.67 (s, 1H), 4.63-4.55 (m, 2H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.70 (d, J=6.9 Hz, 1H), 2.79-2.68 (m, 2H), 2.25 (s, 6H), 2.19-2.04 (m, 3H), 1.91 (ddd, J=14.0, 10.5, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 397: (2R,4S)-6-chloro-7-fluoro-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 496)

    [2279] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.73 (s, 1H), 8.35 (s, 1H), 7.46 (d, J=8.6 Hz, 1H), 6.96 (d, J=10.6 Hz, 1H), 5.61 (s, 1H), 4.62-4.54 (m, 2H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.72-3.65 (m, 1H), 2.79-2.68 (m, 2H), 2.25 (s, 6H), 2.19-2.04 (m, 3H), 1.90 (ddd, J=14.1, 10.8, 3.6 Hz, 1H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 398: (2R,4R)-6-chloro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 497)

    [2280] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.96 (t, J=1.1 Hz, 1H), 8.43 (d, J=0.9 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.23-7.20 (m, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.89 (d, J=1.4 Hz, 1H), 4.84 (dd, J=10.6, 5.9 Hz, 1H), 4.68 (dd, J=11.9, 2.3 Hz, 1H), 3.86 (s, 3H), 2.69 (s, 6H), 2.40 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.79-1.71 (m, 1H); MS (ESI.sup.+) m/z 441 (M+H).sup.+.

    Example 399: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 498)

    [2281] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.99 (s, 1H), 8.97-8.93 (m, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.50 (dd, J=8.6, 1.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 6.88 (d, J=1.3 Hz, 1H), 5.76 (d, J=6.1 Hz, 1H), 4.84-4.78 (m, 1H), 4.74 (dd, J=11.8, 2.5 Hz, 1H), 3.85 (s, 3H), 2.69 (s, 6H), 2.39 (ddd, J=13.0, 5.7, 2.5 Hz, 1H), 1.76 (ddd, J=13.0, 11.8, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 459 (M+H).sup.+.

    Example 400: (2R,4R)-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 499)

    [2282] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.04 (s, 1H), 8.95 (t, J=1.1 Hz, 1H), 8.43 (d, J=0.9 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.54 (ddt, J=8.5, 2.4, 0.7 Hz, 1H), 7.08 (dd, J=8.6, 0.9 Hz, 1H), 6.88 (d, J=1.3 Hz, 1H), 5.83 (d, J=6.2 Hz, 1H), 4.90 (dt, J=11.4, 5.9 Hz, 1H), 4.79 (dd, J=11.9, 2.4 Hz, 1H), 3.85 (s, 3H), 2.70 (s, 6H), 2.44 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 1.79 (ddd, J=12.9, 11.9, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 475 (M+H).sup.+.

    Example 401: (2R,4R)-6-chloro-4-hydroxy-N-[3-(6-methoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 500)

    [2283] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.55 (dd, J=9.0, 0.7 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.93 (dt, J 1.9, 0.8 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.71 (dd, J=9.0, 2.2 Hz, 1H), 5.76-5.72 (m, 1H), 4.84 (dt, J=11.4, 5.9 Hz, 1H), 4.67 (dd, J=11.9, 2.3 Hz, 1H), 3.78 (s, 3H), 2.62 (s, 6H), 2.40 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.74 (ddd, J=12.8, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 440 (M+H).sup.+.

    Example 402: (2R,4R)-6-chloro-4-hydroxy-N-[3-(5-methoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 501)

    [2284] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.23 (d, J=1.0 Hz, 1H), 7.53 (dt, J=9.2, 0.9 Hz, 1H), 7.40 (dd, J=2.8, 1.0 Hz, 1H), 7.22 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.96 (dd, J=2.5, 0.8 Hz, 1H), 6.93 (dd, J=9.3, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.84 (dt, J=11.5, 6.1 Hz, 1H), 4.67 (dd, J=12.0, 2.3 Hz, 1H), 3.76 (s, 3H), 2.63 (s, 6H), 2.39 (ddd, J=12.8, 5.9, 2.4 Hz, 1H), 1.74 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 440 (M+H).sup.+.

    Example 403: (2R,4R)-6-chloro-N-{3-[5-(difluoromethoxy)-2H-indazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 502)

    [2285] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.46 (d, J=1.0 Hz, 1H), 7.70 (dt, J=9.2, 0.9 Hz, 1H), 7.45-7.42 (m, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.33-7.05 (m, 3H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.84 (dt, J=11.5, 6.1 Hz, 1H), 4.68 (dd, J=12.0, 2.4 Hz, 1H), 2.66 (s, 6H), 2.40 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.75 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 476 (M+).sup.+.

    Example 404: (2R,4R)-6,7-dichloro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 503)

    [2286] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.95 (t, J=1.1 Hz, 1H), 8.43 (d, J=0.9 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H), 7.17 (s, 1H), 6.88 (d, J=1.4 Hz, 1H), 5.81 (d, J=5.3 Hz, 1H), 4.82 (dt, J=10.5, 5.3 Hz, 1H), 4.75 (dd, J=11.8, 2.5 Hz, 1H), 3.85 (s, 3H), 2.69 (s, 6H), 2.40 (ddd, J=12.9, 5.7, 2.6 Hz, 1H), 1.74 (ddd, J=13.1, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 476 (M+H).sup.+.

    Example 405: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(6-methoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 504)

    [2287] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.55 (dd, J=9.1, 0.7 Hz, 1H), 7.50 (dd, J=8.7, 1.0 Hz, 1H), 6.97-6.93 (m, 2H), 6.71 (dd, J=9.0, 2.2 Hz, 1H), 5.76 (d, J=6.2 Hz, 1H), 4.81 (dt, J=11.2, 6.0 Hz, 1H), 4.73 (dd, J=11.8, 2.4 Hz, 1H), 3.78 (s, 3H), 2.62 (s, 6H), 2.39 (ddd, J=13.1, 5.7, 2.5 Hz, 1H), 1.82-1.70 (m, 1H); MS (ESI.sup.+) m/z 458 (M+H).sup.+.

    Example 406: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(5-methoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 505)

    [2288] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.23 (d, J=1.0 Hz, 1H), 7.53 (dt, J=9.2, 0.9 Hz, 1H), 7.50 (dd, J=8.6, 1.1 Hz, 1H), 6.97-6.91 (m, 3H), 5.76 (d, J=6.1 Hz, 1H), 4.81 (dt, J=11.2, 5.8 Hz, 1H), 4.73 (dd, J=11.8, 2.4 Hz, 1H), 3.76 (s, 3H), 2.63 (s, 6H), 2.41-2.36 (m, 1H), 1.76 (ddd, J=13.0, 11.8, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 458 (M+H).sup.+.

    Example 407: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 506)

    [2289] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.42 (d, J=0.9 Hz, 1H), 8.00 (dd, J=9.2, 0.9 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 6.94 (d, J=10.6 Hz, 1H), 6.81 (d, J=9.2 Hz, 1H), 5.76 (d, J=6.0 Hz, 1H), 4.82 (dd, J=10.9, 5.8 Hz, 1H), 4.73 (dd, J=11.9, 2.5 Hz, 1H), 3.87 (s, 3H), 2.63 (s, 6H), 2.39 (ddd, J=13.0, 5.6, 2.4 Hz, 1H), 1.76 (q, J=11.8 Hz, 1H); MS (ESI.sup.+) m/z 459 (M+H).sup.+.

    Example 408: (2R,4R)-6,7-dichloro-4-hydroxy-N-[3-(5-methoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 507)

    [2290] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.23 (d, J=1.0 Hz, 1H), 7.55 (d, J 1.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.17 (s, 1H), 6.96 (dd, J=2.5, 0.8 Hz, 1H), 6.93 (dd, J=9.2, 2.4 Hz, 1H), 5.81 (d, J=5.8 Hz, 1H), 4.87-4.78 (m, 1H), 4.74 (dd, J=11.8, 2.5 Hz, 1H), 3.76 (s, 3H), 2.63 (s, 6H), 2.40 (ddd, J=13.0, 5.7, 2.5 Hz, 1H), 1.74 (ddd, J=13.1, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 475 (M+H).sup.+.

    Example 409: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 508)

    [2291] .sup.1H NMR (500 MHz, DMSO d.sub.6) ppm 8.39 (d, J=0.9 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.98 (dd, J=9.2, 0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.77 (d, J= : 9.2 Hz, 1H), 5.70 (d, J=6.4 Hz, 1H), 4.83 (dt, J=11.6, 6.1 Hz, 1H), 4.65 (dd, J=11.9, 2.2 Hz, 1H), 4.42 (ddt, J=11.7, 7.5, 3.8 Hz, 1H), 3.87 (s, 3H), 3.78 (tdt, J=11.7, 7.8, 3.9 Hz, 1H), 2.37 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.18-2.11 (m, 2H), 2.04-1.91 (m, 4H), 1.75 (ddd, J=12.9, 11.9, 10.7 Hz, 1H), 1.65-1.54 (m, 2H); MS (ESI) m/z 457 (M+H).sup.+.

    Example 410: (2R,4R)-6-chloro-4-hydroxy-N-{3-[5-(trifluoromethoxy)-2H-indazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 509)

    [2292] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.54 (d, J=1.0 Hz, 1H), 7.76 (dt, J=9.3, 0.9 Hz, 1H), 7.72 (dt, J=1.9, 1.0 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.26-7.18 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=5.1 Hz, 1H), 4.88-4.80 (m, 1H), 4.68 (dd, J=11.9, 2.3 Hz, 1H), 2.67 (s, 6H), 2.40 (ddd, J=12.8, 5.8, 2.3 Hz, 1H), 1.75 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 494 (M+H).sup.+.

    Example 411: (2R,4R)-6-chloro-4-hydroxy-N-{3-[5-(methoxymethyl)-2H-indazol-2-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 510)

    [2293] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.41 (d, J=0.9 Hz, 1H), 7.62-7.57 (m, 2H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.24-7.18 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.0 Hz, 1H), 4.88-4.79 (m, 1H), 4.67 (dd, J=11.9, 2.3 Hz, 1H), 4.44 (s, 2H), 3.28 (s, 3H), 2.66 (s, 6H), 2.40 (ddd, J=12.9, 5.8, 2.4 Hz, 1H), 1.80-1.68 (m, 1H); MS (ESI.sup.+) m/z 454 (M+H).sup.+.

    Example 412: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{5-[(trifluoromethoxy)acetyl]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 511)

    [2294] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.66 (d, J=5.5 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (s, 1H), 4.93 (s, 2H), 4.80 (dd, J=10.4, 5.8 Hz, 1H), 4.70 (dd, J=11.9, 2.4 Hz, 1H), 4.56 (d, J=4.9 Hz, 2H), 4.42 (d, J=4.5 Hz, 2H), 2.51 (s, 6H), 2.37 (ddd, J=12.9, 5.7, 2.4 Hz, 1H), 1.80-1.67 (m, 1H); MS (ESI.sup.+) m/z 545 (M+H).sup.+.

    Example 413: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{5-[2-(trifluoromethoxy)ethyl]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 512)

    [2295] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 7.46 (s, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (d, J=6.2 Hz, 1H), 4.84-4.75 (m, 11H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 4.19 (t, J=5.6 Hz, 2H), 3.71 (s, 4H), 3.04 (t, J=5.6 Hz, 2H), 2.47 (s, 6H), 2.41-2.31 (m, 1H), 1.79-1.68 (m, 1H); MS (ESI) m/z 531 (M+H).sup.+.

    Example 414: (2R,4R)-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 513)

    [2296] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.64-7.59 (m, 1H), 7.58-7.51 (m, 1H), 7.36-7.31 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.81 (d, J=5.1 Hz, 1H), 4.90-4.85 (m, 1H), 4.75 (dd, J=11.9, 2.4 Hz, 1H), 4.07 (t, J=6.3 Hz, 2H), 2.53-2.49 (m, 2H), 2.48 (s, 6H), 2.44-2.39 (m, 1H), 1.94-1.86 (m, 2H), 1.77 (ddd, J=13.0, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 520 (M+H).sup.+.

    Example 415: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 514)

    [2297] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.61 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.1 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (s, 1H), 4.80 (dd, J=10.5, 5.8 Hz, 1H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 4.07 (t, J=6.3 Hz, 2H), 2.52-2.50 (m, 2H), 2.47 (s, 6H), 2.39-2.34 (m, 1H), 1.93-1.86 (m, 2H), 1.73 (ddd, J=12.9, 11.8, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 504 (M+H).sup.+.

    Example 416: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 515)

    [2298] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.68 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.41 (d, J=0.7 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (s, 1H), 4.80 (dd, J=10.5, 5.8 Hz, 1H), 4.70 (dd, J=11.8, 2.5 Hz, 1H), 4.19 (t, J=6.9 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.48 (s, 6H), 2.39-2.33 (m, 1H), 1.73 (ddd, J=13.0, 11.9, 10.5 Hz, 1H); MS (APCI.sup.+) m/z 490 (M+H).sup.+.

    Example 417: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 516)

    [2299] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.05 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.72 (s, 1H), 4.83 (s, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 2.73-2.69 (m, 2H), 2.61 (s, 6H), 2.43-2.36 (m, 1H), 2.00 (p, J=6.7 Hz, 2H), 1.77-1.69 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm58.69; MS (ESI.sup.+) m/z 487/489 (M+H).sup.+.

    Example 418: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 517)

    [2300] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.21 (ddd, J=8.8, 2.8, 0.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=5.8 Hz, 1H), 4.86-4.79 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.44-2.30 (m, 3H), 1.92-1.82 (m, 2H), 1.72 (ddd, J=13.1, 12.2, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 486 (M+H).sup.+.

    Example 419: (2R)-6-chloro-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 518)

    [2301] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.82 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.61 (d, J=2.5 Hz, 1H), 6.52 (dd, J=8.5, 2.6 Hz, 1H), 6.18 (t, J=2.6 Hz, 1H), 4.47 (dd, J=7.4, 3.0 Hz, 1H), 4.35-4.30 (m, 2H), 4.14-4.07 (m, 2H), 3.45 (dt, J=12.1, 3.2 Hz, 1H), 3.20 (ddd, J=12.2, 7.3, 2.0 Hz, 1H), 2.44 (s, 6H); MS (ESI.sup.+) m/z 473 (M+H).sup.+.

    Example 420: (2S)-6-chloro-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 519)

    [2302] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.84 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.61 (d, J=2.5 Hz, 1H), 6.52 (dd, J=8.5, 2.5 Hz, 1H), 4.47 (dd, J=7.3, 2.9 Hz, 1H), 4.35-4.30 (m, 2H), 4.11-4.09 (m, 2H), 3.45 (dd, J=12.2, 3.0 Hz, 1H), 3.20 (dd, J=12.2, 7.3 Hz, 1H), 2.44 (s, 6H); MS (ESI.sup.+) m/z 473 (M+H).sup.+.

    Example 421: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[4-(4,4,4-trifluorobutyl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 520)

    [2303] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (s, 1H), 4.80 (dd, J=10.6, 5.8 Hz, 1H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 2.49-2.46 (m, 2H), 2.47 (s, 6H), 2.37 (ddd, J=13.0, 5.7, 2.4 Hz, 1H), 2.31-2.19 (m, 2H), 1.78-1.68 (m, 3H); MS (ESI.sup.+) m/z 488 (M+H).sup.+.

    Example 422: (2R,4R)-6-chloro-N-(3-{4-[(4,4-difluoropentyl)oxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 521)

    [2304] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.46 (dd, J=2.7, 1.0 Hz, 1H), 7.44 (d, J=0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 7.19 (dd, J=8.7, 0.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.00-4.92 (m, 1H), 4.67 (dd, J=11.6, 2.4 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 2.66-2.51 (m, 7H), 2.12-1.98 (m, 2H), 1.98-1.86 (m, 3H), 1.63 (t, J=18.4 Hz, 3H); MS (ESI.sup.+) m/z 482/484 (M+H).sup.+.

    Example 423: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[2-(trifluoromethoxy)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 522)

    [2305] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.27 (s, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.25-7.20 (m, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.2 Hz, 1H), 4.83 (dt, J=11.4, 6.0 Hz, 1H), 4.66 (dd, J=12.0, 2.3 Hz, 1H), 4.57 (s, 2H), 4.21-4.16 (m, 2H), 3.72-3.67 (m, 2H), 2.63 (s, 6H), 2.40-2.36 (m, 1H), 1.78-1.68 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.86; MS (ESI.sup.+) m/z 503/505 (M+H).sup.+.

    Example 424: (2R,4R)-6-fluoro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 523)

    [2306] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.92 (d, J=8.1 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 7.15 (ddd, J=9.3, 3.2, 1.0 Hz, 1H), 7.00 (tdd, J=8.8, 3.3, 0.7 Hz, 1H), 6.88 (dd, J=8.9, 4.8 Hz, 1H), 5.66 (d, J=5.5 Hz, 1H), 4.84-4.79 (m, 1H), 4.60 (dd, J=12.0, 2.2 Hz, 1H), 4.35-4.31 (m, 2H), 4.11-4.06 (m, 2H), 4.00 (tt, J=11.7, 3.9 Hz, 1H), 3.70 (tdt, J=11.9, 8.0, 4.0 Hz, 1H), 2.36 (ddd, J=12.8, 6.0, 2.3 Hz, 1H), 2.04-1.99 (m, 2H), 1.92-1.85 (m, 2H), 1.81-1.68 (m, 3H), 1.56-1.44 (m, 2H); MS (ESI.sup.+) m/z 488 (M+H).sup.+.

    Example 425: (2R,4R)-6-chloro-4-hydroxy-N-{(1r,4R)-4-[4-(2,2,2-trifluoroethoxy)-1H-pyrazol-1-yl]cyclohexyl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 524)

    [2307] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.95 (d, J=8.1 Hz, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (br s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.63 (dd, J=11.9, 2.3 Hz, 1H), 4.56 (q, J=9.0 Hz, 2H), 4.02 (tt, J=11.6, 3.9 Hz, 1H), 3.76-3.63 (m, 1H), 2.35 (ddd, J=13.0, 6.0, 2.3 Hz, 1H), 2.02 (dd, J=12.8, 4.0 Hz, 2H), 1.92-1.85 (m, 2H), 1.83-1.66 (m, 3H), 1.56-1.45 (m, 2H); MS (ESI.sup.+) m/z 474 (M+H).sup.+.

    Example 426: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 525)

    [2308] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.82 (dt, J=10.8, 6.1 Hz, 1H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 4.57-4.52 (m, 2H), 4.44-4.42 (m, 2H), 2.40-2.36 (m, 7H), 1.72 (ddd, J=12.9, 12.0, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 500 (M+H).sup.+.

    Example 427: (2R,4R)-6-chloro-4-hydroxy-N-{(1r,4R)-4-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]cyclohexyl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 526)

    [2309] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.95 (d, J=8.1 Hz, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 7.18 (d, J=0.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (s, 1H), 4.82 (dd, J=10.8, 5.9 Hz, 1H), 4.63 (dd, J=11.9, 2.2 Hz, 1H), 4.06-3.95 (m, 1H), 3.89 (t, J=6.2 Hz, 2H), 3.76-3.63 (m, 1H), 2.46-2.28 (m, 3H), 2.04-1.96 (m, 2H), 1.95-1.82 (m, 4H), 1.82-1.68 (m, 3H), 1.56-1.40 (m, 2H); MS (ESI.sup.+) m/z 502 (M+H).sup.+.

    Example 428: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-((1r,4R)-4-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]cyclohexyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 527)

    [2310] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.96 (d, J=8.1 Hz, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 5.74 (s, 1H), 4.79 (dd, J=10.6, 5.8 Hz, 1H), 4.69 (dd, J=11.8, 2.4 Hz, 1H), 4.00 (tt, J=11.5, 3.8 Hz, 1H), 3.89 (t, J=6.2 Hz, 2H), 3.75-3.63 (m, 1H), 2.46-2.28 (m, 3H), 2.06-1.95 (m, 2H), 1.95-1.82 (m, 4H), 1.82-1.68 (m, 3H), 1.57-1.40 (m, 2H); MS (ESI.sup.+) m/z 520 (M+H).sup.+.

    Example 429: (2R,4R)-6-chloro-4-hydroxy-N-(3-{1-[3-(trifluoromethoxy)propyl]-1H-pyrazol-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 528)

    [2311] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.66 ppm (s, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.38 (dd, J=2.7, 0.9 Hz, 1H), 7.31 (d, J=0.8 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.4 Hz, 1H), 4.81 (dt, J=11.6, 6.0 Hz, 1H), 4.59 (dd, J=12.0, 2.2 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 4.05 (t, J=6.2 Hz, 2H), 2.38-2.32 (m, 1H), 2.21 (s, 6H), 2.13 (p, J=6.6 Hz, 2H), 1.70 (td, J=12.4, 10.8 Hz, 1H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) ppm 58.95; MS (ESI.sup.+) m/z 486/488 (M+H).sup.+.

    Example 430: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1r,3S)-3-(trifluoromethoxy)cyclobutyl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 529)

    [2312] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.32 (d, J=0.7 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (br s, 1H), 4.91 (p, J=6.8 Hz, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 2.55 (d, J=7.8 Hz, 2H), 2.47 (s, 6H), 2.46-2.33 (m, 2H), 2.34-2.24 (m, 2H), 2.18-2.08 (m, 2H), 1.79-1.65 (m, 1H); MS (APCI.sup.+) m/z 512 (M+H).sup.+.

    Example 431: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(4-{[(1r,3S)-3-(trifluoromethoxy)cyclobutyl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 530)

    [2313] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.32 (d, J=0.7 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (s, 1H), 4.91 (p, J=6.8 Hz, 1H), 4.83-4.76 (m, 1H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 2.55 (d, J=7.9 Hz, 2H), 2.47 (s, 6H), 2.46-2.34 (m, 2H), 2.33-2.25 (m, 2H), 2.13 (ddt, J=10.7, 7.1, 3.5 Hz, 2H), 1.73 (ddd, J=13.0, 11.9, 10.6 Hz, 1H); MS (APCI.sup.+) m/z 530 (M+H).sup.+.

    Example 432: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 531)

    [2314] 1H), 7.29 (d, J=0.8 Hz, 1K), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1K), 6.89 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.68-4.61 (m, 2H), 2.53 (d, J=7.3 Hz, 2H), 2.47 (s, 6H), 2.47-2.41 (m, 2H), 2.37 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 2.08-1.97 (m, 1H), 1.87-1.79 (m, 2H), 1.72 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 512 (M+H).sup.+.

    Example 433: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[3-(4-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]methyl}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 532)

    [2315] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.1 Hz, 1H), 7.30 (d, J=0.7 Hz, 1H), 6.93 (d, J=10.5 Hz, 1H), 5.75 (s, 1H), 4.80 (dd, J=10.6, 5.8 Hz, 1H), 4.70 (dd, J=11.8, 2.5 Hz, 1H), 4.68-4.60 (m, 1H), 2.53 (d, J=7.3 Hz, 2H), 2.47 (s, 6H), 2.46-2.42 (m, 2H), 2.37 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 2.06-1.98 (m, 1H), 1.87-1.79 (m, 2H), 1.73 (ddd, J=13.0, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 530 (M+H).sup.+.

    Example 434: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[3-(2,2,2-trifluoroethoxy)azetidine-1-carbonyl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 533)

    [2316] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.83 (dd, J=8.1, 2.2 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.85-4.75 (m, 2H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 4.58-4.52 (m, 1H), 4.41 (ddd, J=11.2, 3.9, 1.6 Hz, 1H), 4.30 (ddd, J=11.3, 6.5, 1.6 Hz, 1H), 4.14 (qd, J=9.3, 1.5 Hz, 2H), 3.92 (ddd, J=11.3, 3.8, 1.6 Hz, 1H), 2.39 (s, 6H), 2.40-2.34 (m, 1H), 1.72 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 552.35 (M+H).sup.+.

    Example 435: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]pyridin-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 534)

    [2317] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.63 (d, J=2.2 Hz, 1H), 8.39 (s, 1H), 7.86 (dd, J=8.0, 2.2 Hz, 1H), 7.42-7.33 (m, 1H), 7.16 (dd, J=8.7, 2.6 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 5.10 (s, 1H), 4.81 (dd, J=10.5, 5.9 Hz, 1H), 4.59 (dd, J=11.7, 2.6 Hz, 1H), 3.84 (dd, J=13.0, 4.8 Hz, 1H), 3.61 (dd, J=8.8, 5.6 Hz, 2H), 2.45-2.35 (m, 1H), 2.39 (s, 6H), 2.31-2.19 (m, 1H), 2.14 (d, J=13.2 Hz, 1H), 1.85-1.72 (m, 1H); MS (APCI.sup.+) m/z 551.7 (M+H).sup.+.

    Example 436: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[3-(trifluoromethyl)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 535)

    [2318] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.27-8.22 (m, 1H), 7.86 (s, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (br s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 3.99-3.93 and 3.84-3.79 (two m, 1H, amide rotamers), 3.78-3.68 and 3.63-3.46 (two m, 3H, amide rotamers), 2.55 (s, 6H), 2.38 (ddd, J=12.8, 5.9, 2.4 Hz, 1H), 2.31-2.13 (m, 1H), 2.12-1.93 (m, 1H), 1.77-1.68 (m, 1H); MS (ESI.sup.+) m/z 525 (M+H).sup.+.

    Example 437: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[3-(trifluoromethoxy)azetidine-1-carbonyl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 536)

    [2319] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.78 (s, 1H), 8.54 (d, J=2.3 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.84 (dd, J=8.1, 2.2 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.25 (tt, J=7.0, 3.9 Hz, 1H), 4.97 (ddd, J=11.5, 6.4, 1.7 Hz, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.63 (ddd, J=11.9, 6.3, 3.1 Hz, 2H), 4.48 (ddd, J=11.6, 6.7, 1.7 Hz, 1H), 4.16-4.10 (m, 1H), 2.40 (s, 6H), 2.41-2.32 (m, 1H), 1.72 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 538.63 (M+H).sup.+.

    Example 438: (2R,4R)-6-chloro-4-hydroxy-N-[3-(6-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}pyridin-3-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 537)

    [2320] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.77 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 7.93 7.87 (m, 1H), 7.82 (dd, J=8.0, 2.2 Hz, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.6, 2.6 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.71-4.63 (m, 1H), 4.62 (dd, J=12.0, 2.3 Hz, 1H), 4.34 (dd, J=21.7, 6.1 Hz, 3H), 4.20-4.12 (m, 1H), 3.84 (dd, J=10.3, 5.5 Hz, 1H), 3.04 (ddd, J=14.7, 8.3, 6.0 Hz, 1H), 2.39 (s, 6H), 2.40-2.34 (m, 1H), 1.78-1.67 (m, 1H); MS (APCI.sup.+) m/z 552.33 (M+H).sup.+.

    Example 439: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(1RS,3RS)-3-(trifluoromethoxy)cyclopentyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 538)

    [2321] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.91 (d, J=0.6 Hz, 1H), 7.45 (dd, J=2.6, 1.0 Hz, 1H), 7.18 (dd, J=8.7, 2.6, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.01-4.97 (m, 1H), 4.96-4.92 (m, 1H), 4.67 (dd, J=11.6, 2.5 Hz, 1H), 3.53-3.44 (m, 1H), 2.74 (s, 6H), 2.60-2.52 (m, 1H), 2.40-2.23 (m, 3H), 2.14-2.04 (m, 1H), 2.04-1.87 (m, 2H), 1.83-1.73 (m, 1H); MS (ESI.sup.+) m/z 513/515 (M+H).sup.+.

    Example 440: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(1RS,3SR)-3-(trifluoromethoxy)cyclopentyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 539)

    [2322] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.91 (d, J=0.7 Hz, 1H), 7.45 (dd, J=2.6, 1.0 Hz, 1H), 7.18 (dd, J=8.8, 2.6, 0.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 4.98-4.89 (m, 2H), 4.67 (dd, J=11.5, 2.5 Hz, 1H), 3.31-3.23 (m, 1H), 2.74 (s, 6H), 2.67-2.51 (m, 2H), 2.22-1.87 (m, 6H); MS (ESI.sup.+) m/z 513/515 (M+H).sup.+.

    Example 441: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(1S*,3R*)-3-(trifluoromethoxy)cyclopentyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 540)

    [2323] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.92 (s, 1H), 7.46 (dd, J=2.7, 1.0 Hz, 1H), 7.19 (dd, J=8.7, 2.6, 0.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 4.99-4.91 (m, 2H), 4.69 (dd, J=11.5, 2.5 Hz, 1H), 3.32-3.24 (m, 1H), 2.76 (s, 6H), 2.68-2.53 (m, 2H), 2.22-1.88 (m, 6H); .sup.19F NMR (471 MHz, methanol-d.sub.4) ppm 59.90; MS (ESI.sup.+) m/z 513/515 (M+H).sup.+. Stereochemistry on the cyclopentyl ring was arbitrarily assigned.

    Example 442: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{3-[(trifluoromethoxy)methyl]cyclobutyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 541)

    [2324] .sup.1H NMR (500 MHz, CDCl.sub.3) ppm 7.46 (dd, J=2.6, 0.8 Hz, 1H), 7.31 (s, 1H), 7.18 (dd, J=8.7, 2.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.95 (dd, J=8.8, 5.5 Hz, 1H), 4.69-4.60 (m, 1H), 3.97 (d, J=6.2 Hz, 1H), 3.60-3.47 (m, 1H), 2.75 (d, J=3.5 Hz, 6H), 2.67 (ddd, J=13.6, 5.6, 3.3 Hz, 2H), 2.56-2.49 (m, 2H), 2.45-2.27 (m, 2H), 2.19-2.02 (m, 3H); MS (ESI.sup.+) m/z 513/515 (M+H).sup.+.

    Example 443: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{(1RS,2RS)-2-[(trifluoromethoxy)methyl]cyclopropyl}-1H-1,2,3-triazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 542)

    [2325] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 8.57 (s, 1H), 7.87 (s, 1H), 7.46 (d, J=2.6 Hz, 1H), 7.19 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 4.95 (dd, J=10.3, 5.8 Hz, 1H), 4.68 (dd, J=11.5, 2.5 Hz, 1H), 4.11 (dd, J=10.8, 6.8 Hz, 1H), 4.02 (dd, J=10.8, 7.5 Hz, 1H), 2.74 (s, 6H), 2.58 (ddd, J=13.2, 5.9, 2.5 Hz, 1H), 2.13-2.00 (m, 1H), 1.93 (dd, J=23.4, 11.7 Hz, 1H), 1.67 (d, J=7.6 Hz, 1H), 1.32 (s, 1H), 1.24-1.15 (m, 1H), 1.13-1.02 (m, 1H); MS (ESI.sup.+) m/z 499/201 (M+H).sup.+.

    Example 444: ((1RS,2RS)-2-[1-(3-{[(2R,4R)-6-chloro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl]cyclopropyl)methyl ethyl carbonate (Compound 543)

    [2326] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.84 (s, 1H), 7.46 (dd, J=2.7, 1.0 Hz, 1H), 7.19 (ddd, J=8.7, 2.6, 0.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 4.95 (dd, J=10.3, 5.8 Hz, 1H), 4.68 (dd, J=11.5, 2.5 Hz, 1H), 4.23-4.02 (m, 4H), 2.74 (s, 6H), 2.58 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 2.05 (dt, J=9.3, 4.9 Hz, 1H), 1.93 (ddd, J=13.0, 11.6, 10.3 Hz, 1H), 1.64 (tt, J=12.5, 7.0 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H), 1.14 (dt, J=8.6, 5.1 Hz, 1H), 1.07 (dt, J=8.9, 5.2 Hz, 1H); MS (ESI.sup.+) m/z 503/505 (M+H).sup.+.

    Example 445: (2R,4R)-6-chloro-N-(3-{4-[(1s,3S)-3-(difluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 544)

    [2327] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.14 (s, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.65 (t, J=75.8 Hz, 1H), 5.72 (d, J=6.1 Hz, 1H), 4.87-4.78 (m, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 4.64-4.54 (m, 1H), 3.18-3.09 (m, 1H), 2.71-2.64 (m, 2H), 2.60 (s, 6H), 2.41-2.35 (m, 1H), 2.28-2.19 (m, 2H), 1.77-1.68 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 81.65; MS (ESI.sup.+) m/z 481/483 (M+H).sup.+.

    Example 446: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 545)

    [2328] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.58 (d, J=2.7 Hz, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.81 (m, 2H), 7.33 (d, J=2.7 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.64 (d, J=4.4 Hz, 1H), 4.65-4.57 (m, 2H), 2.57 (s, 6H), 2.13 (dt, J=13.9, 3.5 Hz, 1H), 1.93 (ddd, J=14.1, 11.0, 3.7 Hz, 1H); MS (ESI) m/z 521 (M+H).sup.+.

    Example 447: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 546)

    [2329] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.89-8.84 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.21-8.14 (m, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.65 (br s, 1H), 4.64-4.58 (m, 2H), 2.58 (s, 6H), 2.13 (dt, J=13.9, 3.6 Hz, 1H), 1.94 (ddd, J=14.1, 11.1, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 505 (M+H).sup.+.

    Example 448: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 547)

    [2330] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.61 (d, J=0.8 Hz, 1H), 7.38 (dd, J=2.8, 1.0 Hz, 1H), 7.20 (dd, J=8.6, 2.6 Hz, 1H), 7.00 (s, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.80 (t, J=2.4 Hz, 1H), 6.28 (dd, J=2.8, 1.7 Hz, 1H), 5.71 (s, 1H), 4.89-4.77 (m, 3H), 4.64 (dd, J=12.0, 2.1 Hz, 1H), 2.49 (s, 6H), 2.42-2.30 (m, 1H), 1.72 (q, J=11.9 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 71.09 (t, J=9.4 Hz); MS (ESI.sup.+) m/z 507/509 (M+H).sup.+.

    Example 449: (2S,4R)-4-hydroxy-6-(trifluoromethyl)-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 548)

    [2331] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.04 (s, 1H), 8.88-8.84 (m, 1H), 8.56 (d, J=0.7 Hz, 1H), 8.19 (d, J=0.7 Hz, 1H), 8.17 (ddd, J=8.4, 2.5, 0.8 Hz, 1H), 7.92 (dt, J=8.4, 0.8 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.58 (dd, J=9.1, 2.1 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.73 (s, 1H), 4.73-4.67 (m, 2H), 2.58 (s, 6H), 2.17 (ddd, J=13.9, 4.1, 2.9 Hz, 1H), 2.00 (ddd, J=14.1, 10.7, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 450: (2R,4S)-4-hydroxy-6-(trifluoromethyl)-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 549)

    [2332] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.05 (s, 1H), 8.89-8.85 (m, 1H), 8.57 (d, J=0.8 Hz, 1H), 8.21-8.15 (m, 2H), 7.93 (dt, J=8.3, 0.8 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.58 (dd, J=9.0, 2.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 5.73 (s, 1H), 4.74-4.66 (m, 2H), 2.58 (s, 6H), 2.21-2.13 (m, 1H), 2.00 (ddd, J=14.1, 10.6, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 451: (2S,4R)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 550)

    [2333] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.04 (s, 1H), 8.60-8.56 (m, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.91-7.87 (m, 1H), 7.86-7.83 (m, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.58 (ddd, J=8.5, 2.4, 0.7 Hz, 1H), 7.11 (dd, J=8.6, 0.8 Hz, 1H), 5.72 (d, J=4.3 Hz, 1H), 4.74-4.66 (m, 2H), 2.57 (s, 6H), 2.17 (ddd, J=13.9, 4.1, 2.9 Hz, 1H), 2.00 (ddd, J=14.1, 10.7, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 555 (M+H).sup.+.

    Example 452: (2R,4S)-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 551)

    [2334] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.03 (s, 1H), 8.61-8.55 (m, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.81 (m, 2H), 7.66 (d, J=2.4 Hz, 1H), 7.58 (dd, J=8.8, 2.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 5.72 (d, J=4.1 Hz, 1H), 4.75-4.66 (m, 2H), 2.57 (s, 6H), 2.22-2.13 (m, 1H), 2.00 (ddd, J=14.0, 10.6, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 555 (M+H).sup.+.

    Example 453: rac-(2R,4R)-6-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 552)

    [2335] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.58 (d, J=2.7 Hz, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.81 (m, 2H), 7.20-7.12 (m, 1H), 7.01 (td, J=8.6, 3.2 Hz, 1H), 6.89 (dd, J=9.0, 4.8 Hz, 1H), 5.70 (s, 1H), 4.88-4.79 (m, 1H), 4.63 (dd, J=12.0, 2.2 Hz, 1H), 2.39 (ddd, J=12.8, 5.8, 2.2 Hz, 1H), 1.73 (td, J=12.6, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 505 (M+H).sup.+.

    Example 454: (2R,4R)-6,7-difluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 553)

    [2336] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.89-8.85 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.21-8.15 (m, 2H), 7.93 (dt, J=8.4, 0.8 Hz, 1H), 7.34 (ddd, J=11.5, 9.3, 1.0 Hz, 1H), 6.94 (dd, J=11.8, 6.9 Hz, 1H), 5.74 (d, J=5.5 Hz, 1H), 4.82-4.77 (m, 1H), 4.69 (dd, J=11.9, 2.4 Hz, 1H), 2.58 (s, 6H), 2.42-2.35 (m, 1H), 1.74 (ddd, J=12.9, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 507 (M+H).sup.+.

    Example 455: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-(5-methylpyridin-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 554)

    [2337] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.37-8.31 (m, 2H), 8.03 (d, J=0.7 Hz, 1H), 7.61-7.56 (m, 2H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.22 (dd, J=8.7, 2.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.83 (dd, J=10.8, 5.9 Hz, 1H), 4.66 (dd, J=12.1, 2.3 Hz, 1H), 2.55 (s, 6H), 2.39 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 2.28 (s, 3H), 1.73 (td, J=12.4, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 451 (M+H).sup.+.

    Example 456: (2R,4R)-4-hydroxy-N-{3-[4-(5-methylpyridin-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 555)

    [2338] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.37-8.32 (m, 2H), 8.03 (d, J=0.8 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.54 (dd, J=8.6, 2.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.83 (s, 1H), 4.89 (dd, J=10.6, 5.8 Hz, 1H), 4.77 (dd, J=11.9, 2.4 Hz, 1H), 2.56 (s, 6H), 2.43 (ddd, J=12.9, 5.7, 2.4 Hz, 1H), 2.28 (s, 3H), 1.78 (td, J=12.3, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 485 (M+H).sup.+.

    Example 457: (2R,4R)-6-chloro-4-hydroxy-N-{3-[1-(trifluoromethyl)-1H,1H-[3,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 556)

    [2339] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.45 (d, J=2.9 Hz, 1H), 8.35 (d, J=0.8 Hz, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.93-6.88 (m, 2H), 5.71 (d, J=5.9 Hz, 1H), 4.87-4.79 (m, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 2.56 (s, 6H), 2.39 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.73 (ddd, J=12.9, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 494 (M+H).sup.+.

    Example 458: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 557)

    [2340] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.14 (p, J=1.1 Hz, 1H), 8.78 (s, 1H), 8.42 (dd, J=2.2, 0.9 Hz, 1H), 8.28 (d, J=0.7 Hz, 1H), 7.95 (dd, J=8.4, 2.2 Hz, 1H), 7.92 (dd, J=8.3, 0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 4.83 (dt, J=11.6, 6.1 Hz, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.41 (s, 6H), 2.42-2.35 (m, 1H), 1.73 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (APCI.sup.+) m/z 503.72 (M+H).sup.+.

    Example 459: (2R,4R)-4-hydroxy-6-(rifluoromethyl)-N-(3-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 558)

    [2341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.17 (s, 1H), 8.88 (s, 1H), 8.49-8.41 (m, 1H), 8.30 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.8, 2.4 Hz, 1H), 7.38 (dd, J=5.1, 1.5 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 5.78 (s, 1H), 4.89 (dd, J=10.5, 5.8 Hz, 1H), 4.78-4.65 (m, 1H), 3.17 (s, 1H), 2.43 (s, 6H), 2.48-2.38 (m, 1H), 1.78 (td, J=12.6, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 537.76 (M+H).sup.+.

    Example 460: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[4-(trifluoromethyl)-1H-imidazol-1-yl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 559)

    [2342] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.69 (d, J=1.1 Hz, 1H), 8.58 (p, J=1.3 Hz, 1H), 8.43 (dd, J=2.3, 0.8 Hz, 1H), 7.97 (dd, J=8.4, 2.3 Hz, 1H), 7.88 (dd, J=8.3, 0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.24-7.17 (m, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (s, 1H), 4.83 (dd, J=10.7, 5.9 Hz, 1H), 4.63 (dd, J=12.0, 2.3 Hz, 1H), 2.41 (s, 6H), 2.42-2.34 (m, 1H), 1.79-1.68 (m, 1H); MS (APCI.sup.+) m/z 503.70 (M+H).sup.+.

    Example 461: (2R,4R)-6-chloro-4-hydroxy-N-(3-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 560)

    [2343] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.19-9.14 (m, 1H), 8.81 (s, 1H), 8.46 (dd, J=5.0, 0.8 Hz, 1H), 8.31-8.26 (m, 1H), 7.79 (dd, J=1.5, 0.8 Hz, 1H), 7.42-7.35 (m, 2H), 7.24 7.16 (m, 1H), 6.93-6.86 (m, 1H), 5.70 (s, 1H), 4.83 (dd, J=10.7, 5.9 Hz, 1H), 4.66-4.59 (m, 1H), 2.42 (s, 5H), 2.43-2.35 (m, 1H), 1.73 (ddd, J=12.9, 12.0, 10.8 Hz, 1H); MS (APCI.sup.+) m/z 503.71 (M+H).sup.+.

    Example 462: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 561)

    [2344] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.17 (t, J=1.1 Hz, 2H), 8.82 (s, 2H), 8.45 (dd, J=14.9, 5.1 Hz, 2H), 8.30 (s, 2H), 7.81-7.78 (m, 2H), 7.49 (dd, J=8.6, 1.1 Hz, 2H), 7.38 (dd, J=5.0, 1.5 Hz, 2H), 6.95 (d, J=10.5 Hz, 2H), 5.75 (s, 2H), 4.80 (dd, J=10.6, 5.8 Hz, 2H), 4.69 (dd, J=11.9, 2.4 Hz, 2H), 3.17 (s, 1H), 2.42 (s, 1 1H), 2.43-2.36 (m, 2H), 2.39-2.33 (m, 1H), 1.80-1.70 (m, 2H), 1.54 (s, 1H); MS (APCI.sup.+) m/z 521.61 (M+H).sup.+.

    Example 463: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[1-(trifluoromethyl)-1H,1H-[3,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 562)

    [2345] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.45 (d, J=2.8 Hz, 1H), 8.35 (d, J=0.8 Hz, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 5.76 (s, 1H), 4.81 (dd, J=10.6, 5.8 Hz, 1H), 4.72 (dd, J=11.8, 2.4 Hz, 1H), 2.56 (s, 6H), 2.38 (ddd, J=13.0, 5.8, 2.3 Hz, 1H), 1.81-1.68 (m, 1H); MS (ESI.sup.+) m/z 512 (M+H).sup.+.

    Example 464: (2R,4R)-6-chloro-4-hydroxy-N-{3-[1-(2,2,2-trifluoroethyl)-1H,1H-[4,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 563)

    [2346] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 8.05 (d, J=0.8 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J=0.7 Hz, 1H), 7.73 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=5.7 Hz, 1H), 5.11 (q, J=9.1 Hz, 2H), 4.85-4.80 (m, 1H), 4.65 (dd, J=12.0, 2.3 Hz, 1H), 2.52 (s, 6H), 2.38 (ddd, J=13.0, 5.9, 2.4 Hz, 1H), 1.73 (ddd, J=13.0, 12.1, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 508 (M+H).sup.+.

    Example 465: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-{3-[1-(2,2,2-trifluoroethyl)-1H,1H-[4,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 564)

    [2347] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.05 (d, J=0.8 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 7.73 (d, J=0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.75 (d, J=6.2 Hz, 1H), 5.12 (q, J=9.2 Hz, 2H), 4.80 (dt, J=10.4, 5.9 Hz, 1H), 4.71 (dd, J=11.8, 2.4 Hz, 1H), 2.52 (s, 6H), 2.38 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 1.75 (ddd, J=13.0, 11.8, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 526 (M+H).sup.+.

    Example 466: (2R,4R)-6,7-dichloro-4-hydroxy-N-{3-[1-(2,2,2-trifluoroethyl)-1H,1H-[4,4-bipyrazol]-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 565)

    [2348] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 8.05 (d, J=0.8 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.80 (d, J=0.7 Hz, 1H), 7.73 (d, J=0.8 Hz, 1H), 7.54 (d, J=1.0 Hz, 1H), 7.17 (s, 1H), 5.80 (d, J=5.8 Hz, 1H), 5.12 (q, J=9.1 Hz, 2H), 4.86-4.78 (m, 1H), 4.72 (dd, J=11.8, 2.5 Hz, 1H), 2.52 (s, 6H), 2.43-2.35 (m, 1H), 1.78-1.67 (m, 1H); MS (ESI.sup.+) m/z 542 (M+H).sup.+.

    Example 467: (2R,4R)-6,7-dichloro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 566)

    [2349] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.58-8.57 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.90-7.87 (m, 1H), 7.85 (dd, J=8.7, 0.8 Hz, 1H), 7.54 (d, J=1.0 Hz, 1H), 7.17 (s, 1H), 5.80 (d, J=5.7 Hz, 1H), 4.82 (dt, J=10.8, 5.4 Hz, 1H), 4.73 (dd, J=11.8, 2.5 Hz, 1H), 2.57 (s, 6H), 2.39 (ddd, J=12.9, 5.7, 2.6 Hz, 1H), 1.73 (ddd, J=13.0, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 555 (M+H).sup.+.

    Example 468: (2R,4R)-6,7-dichloro-4-hydroxy-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 567)

    [2350] .sup.1H NMR (400 MHz, DMSO d.sub.6) ppm 8.92 (s, 1H), 8.89-8.84 (m, 1H), 8.57 (d, J=0.7 Hz, 1H), 8.21-8.14 (m, 2H), 7.92 (d, J=8.4 Hz, 1H), 7.54 (d, J=1.1 Hz, 1H), 7.17 (s, 1H), 5.84-5.78 (m, 1H), 4.85-4.78 (m, 1H), 4.73 (dd, J=11.8, 2.5 Hz, 1H), 2.58 (s, 6H), 2.40 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 1.80-1.67 (m, 1H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 469: (2R,4R)-6-chloro-N-(3-{4-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 568)

    [2351] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.72-8.68 (m, 1H), 8.50 (d, J=0.8 Hz, 1H), 8.14 (d, J=0.8 Hz, 1H), 8.01-7.95 (m, 1H), 7.85 (dd, J=8.2, 0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.25-7.19 (m, 1H), 7.11 (t, J=55.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (s, 1H), 4.83 (dd, J=10.7, 5.9 Hz, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 2.57 (s, 6H), 2.43-2.35 (m, 1H), 1.79-1.68 (m, 1H); MS (ESI.sup.+) m/z 487 (M+H).sup.+.

    Example 470: (2R,4R)-6-chloro-N-(3-{4-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-7-fluoro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 569)

    [2352] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.72-8.68 (m, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 8.02-7.94 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.11 (t, J=55.5 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.77 (br s, 1H), 4.81 (dd, J=10.6, 5.8 Hz, 1H), 4.72 (dd, J=11.8, 2.4 Hz, 1H), 2.57 (s, 6H), 2.38 (ddd, J=13.1, 5.9, 2.4 Hz, 1H), 1.82-1.68 (m, 1H); MS (ESI.sup.+) m/z 505 (M+H).sup.+.

    Example 471: (2R,4R)-6-chloro-N-{3-[4-(5-cyclopropylpyridin-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 570)

    [2353] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.90 (s, 1H), 8.33 (dd, J=2.4, 0.8 Hz, 1H), 8.32 (d, J=0.8 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H), 7.59-7.53 (m, 1H), 7.41-7.35 (m, 2H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.72 (d, J=6.3 Hz, 1H), 4.83 (dt, J=11.5, 6.0 Hz, 1H), 4.66 (dd, J=11.9, 2.3 Hz, 1H), 2.55 (s, 6H), 2.39 (ddd, J=12.8, 5.8, 2.3 Hz, 1H), 1.98-1.89 (m, 1H), 1.79-1.68 (m, 1H), 1.01-0.96 (m, 2H), 0.75-0.71 (m, 2H); MS (ESI.sup.+) m/z 477 (M+H).sup.+.

    Example 472: (2R,4R)-6-chloro-N-{3-[4-(5-cyclopropylpyridin-2-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-7-fluoro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 571)

    [2354] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 8.34-8.33 (m, 1H), 8.32 (d, J=0.7 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H), 7.56 (dd, J=8.2, 0.8 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.38 (dd, J=8.3, 2.4 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.76 (d, J=6.0 Hz, 1H), 4.80 (dt, J=11.1, 5.7 Hz, 1H), 4.71 (dd, J=11.8, 2.4 Hz, 1H), 2.55 (s, 6H), 2.38 (ddd, J=13.1, 5.8, 2.6 Hz, 1H), 1.93 (tt, J=8.4, 5.1 Hz, 1H), 1.75 (ddd, J=13.0, 11.8, 10.5 Hz, 1H), 1.01-0.94 (m, 2H), 0.76-0.68 (m, 2H); MS (ESI.sup.+) m/z 495 (M+H).sup.+.

    Example 473: (2R)-6-chloro-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 572)

    [2355] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 8.86 (dd, J=2.2, 1.2 Hz, 1H), 8.56 (d, J=0.7 Hz, 1H), 8.19-8.16 (m, 2H), 7.94-7.90 (m, 1H), 6.79 (d, J=8.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 6.53 (dd, J=8.5, 2.5 Hz, 1H), 6.18 (d, J=3.0 Hz, 1H), 4.49 (dd, J=7.3, 3.0 Hz, 1H), 3.46 (dt, J=12.1, 3.2 Hz, 1H), 3.22 (ddd, J=12.1, 7.3, 1.9 Hz, 1H), 2.55 (s, 6H); MS (ESI.sup.+) ml: 490 (M+H).sup.+.

    Example 474: (2S)-6-chloro-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 573)

    [2356] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88 (s, 1H), 8.86 (dt, J=2.2, 1.0 Hz, 1H), 8.56 (d, J=0.6 Hz, 1H), 8.18 (d, J=0.7 Hz, 1H), 7.95 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 6.79 (d, J 8.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 6.53 (dd, J=8.5, 2.5 Hz, 1H), 6.19 (t, J=2.6 Hz, 1H), 4.50 (dd, J=7.3, 2.9 Hz, 1H), 3.47 (dt, J=12.1, 3.1 Hz, 1H), 3.22 (ddd, J=12.1, 7.3, 1.9 Hz, 1H), 2.55 (s, 6H); MS (ESI.sup.+) m/z 490 (M+H).sup.+.

    Example 475: 6-chloro-7-fluoro-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 574)

    [2357] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.55 (s, 1H), 8.17 (d, J=11.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 1H), 6.87 (d, J=10.2 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 6.02 (t, J=2.7 Hz, 1H), 4.57 (dd, J=6.7, 3.0 Hz, 1H), 3.43 (dt, J=12.2, 3.0 Hz, 1H), 3.24 (ddd, J=12.2, 6.7, 2.2 Hz, 1H), 2.55 (s, 6H); MS (ESI.sup.+) m/z 508 (M+H).sup.+.

    Example 476: (2R,4R)-6-chloro-N-(3-{4-[5-(difluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 575)

    [2358] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 8.37 (d, J=2.8 Hz, 1H), 8.36 (d, J=0.7 Hz, 1H), 8.02 (d, J=0.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.67-7.59 (m, 1H), 7.36 (dd, J=2.7, 1.0 Hz, 1H), 7.25 (t, J=73.6 Hz, 1H), 7.18 (dd, J=8.6, 2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.68 (d, J=6.0 Hz, 1H), 4.84-4.74 (m, 1H), 4.62 (dd, J=11.9, 2.3 Hz, 1H), 2.53 (s, 6H), 2.35 (ddd, J=12.8, 5.9, 2.3 Hz, 1H), 1.70 (td, J=12.5, 11.1 Hz, 1H); MS (ESI.sup.+) m/z 503 (M+H).sup.+.

    Example 477: (2R,4R)-6-chloro-N-(3-{4-[5-(difluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-7-fluoro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 576)

    [2359] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 8.41 (d, J=2.9 Hz, 1H), 8.39 (d, J=0.7 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.81-7.74 (m, 1H), 7.71-7.63 (m, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.29 (t, J=73.6 Hz, 1H), 6.94 (d, J=10.5 Hz, 1H), 5.76 (d, J=5.7 Hz, 1H), 4.85-4.76 (m, 1H), 4.72 (dd, J=11.8, 2.4 Hz, 1H), 2.56 (s, 6H), 2.38 (ddd, J=13.0, 5.8, 2.5 Hz, 1H), 1.75 (ddd, J=13.0, 11.8, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 521 (M+H).sup.+.

    Example 478: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 577)

    [2360] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.88-8.83 (m, 1H), 8.53 (d, J=0.8 Hz, 1H), 8.18-8.14 (m, 1H), 8.13 (d, J=0.7 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.90-7.85 (m, 1H), 7.39 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (ddd, J=8.6, 2.7, 0.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.71 (s, 1H), 4.83 (dd, J=10.7, 6.0 Hz, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 4.23 (tt, J=11.6, 3.7 Hz, 1H), 3.80-3.69 (m, 1H), 2.37 (ddd, J=12.9, 5.9, 2.3 Hz, 1H), 2.18-2.07 (m, 2H), 1.96-1.83 (m, 4H), 1.75 (ddd, J=12.9, 11.9, 10.7 Hz, 1H), 1.62-1.48 (m, 2H); MS (ESI.sup.+) m/z 521 (M+H).sup.+.

    Example 479: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(1r,4R)-4-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 578)

    [2361] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.88-8.83 (m, 1H), 8.53 (s, 1H), 8.15 (dd, J=8.5, 2.5 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 6.96 (d, J=10.6 Hz, 1H), 5.75 (d, J=6.3 Hz, 1H), 4.85-4.77 (m, 1H), 4.70 (dd, J=11.7, 2.4 Hz, 1H), 4.29-4.18 (m, 1H), 3.80-3.68 (m, 1H), 2.37 (ddd, J=13.0, 5.8, 2.4 Hz, 1H), 2.17-2.07 (m, 2H), 2.00-1.82 (m, 4H), 1.81-1.69 (m, 1H), 1.62-1.45 (m, 2H); MS (ESI.sup.+) m/z 539 (M+H).sup.+.

    Example 480: (2R,4R)-4-hydroxy-N-(3-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 579)

    [2362] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.53 (dd, J=8.6, 2.4 Hz, 1H), 7.27 (d, J=0.9 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 5.15-5.08 (m, 1H), 4.88 (dd, J=10.7, 5.8 Hz, 1H), 4.75 (dd, J=11.9, 2.4 Hz, 1H), 3.30-3.26 (m, 1H), 3.22-3.14 (m, 2H), 3.01-2.93 (m, 1H), 2.46 (s, 6H), 2.45-2.38 (m, 1H), 2.38-2.27 (m, 1H), 2.11-2.05 (m, 1H), 1.82-1.71 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 56.84, 59.96; MS (ESI.sup.+) m/z 547 (M+H).sup.+.

    Example 481: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 580)

    [2363] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.60 (s, 1H), 7.41-7.34 (m, 2H), 7.21 (dd, J=8.7, 2.6 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (br s, 1H), 4.82 (dd, J=10.8, 5.9 Hz, 1H), 4.64 (dd, J=11.9, 2.3 Hz, 1H), 3.15 (q, J=10.3 Hz, 2H), 2.97-2.89 (m, 2H), 2.47 (s, 6H), 2.46-2.32 (m, 4H), 1.83-1.75 (m, 2H), 1.75-1.65 (m, 1H), 1.59-1.45 (m, 2H); MS (ESI.sup.+) m/z 525 (M+H).sup.+.

    Example 482: (2R,4R)-6-chloro-4-hydroxy-N-[(1R,4R)-4-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 581)

    [2364] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.94 (d, J=8.1 Hz, 1H), 7.39 (dd, J=2.7, 1.1 Hz, 1H), 7.27 (d, J=0.9 Hz, 1H), 7.20 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.69 (d, J=6.3 Hz, 1H), 5.15-5.08 (m, 1H), 4.86-4.78 (m, 1H), 4.63 (dd, J=11.9, 2.2 Hz, 1H), 4.00 (tt, J=11.8, 3.9 Hz, 1H), 3.75-3.64 (m, 1H), 3.31-3.25 (m, 1H), 3.21-3.13 (m, 2H), 2.94 (td, J=8.5, 5.1 Hz, 1H), 2.39-2.28 (m, 2H), 2.11-2.04 (m, 1H), 2.04-1.97 (m, 2H), 1.92-1.84 (m, 2H), 1.83-1.68 (m, 3H), 1.56-1.43 (m, 2H); MS (ESI.sup.+) m/z 529 (M+H).sup.+.

    Example 483: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(1R,4R)-4-{4-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 582)

    [2365] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.97 (d, J=8.1 Hz, 1H), 7.49 (dd, J=8.5, 1.0 Hz, 1H), 7.27 (d, J=1.1 Hz, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.95 (d, J=10.61 Hz, 1H), 5.74 (d, J=6.0 Hz, 1H), 5.14-5.08 (m, 1H), 4.83-4.75 (m, 1H), 4.69 (dd, J=11.8, 2.4 Hz, 1H), 4.00 (tt, J=11.7, 3.9 Hz, 1H), 3.75-3.63 (m, 1H), 3.30-3.24 (m, 1H), 3.21-3.13 (m, 2H), 2.94 (td, J=8.5, 5.1 Hz, 1H), 2.39-2.27 (m, 2H), 2.13-2.04 (m, 1H), 2.04-1.97 (m, 2H), 1.93-1.84 (m, 2H), 1.83-1.68 (m, 3H), 1.55-1.41 (m, 2H); MS (ESI.sup.+) m/z 547 (M+H).sup.+.

    Example 484: (2R,4R)-6-chloro-4-hydroxy-N-(3-{4-[(1R,5S,6s)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 583)

    [2366] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 7.54-7.53 (m, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.28 (d, J=0.8 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (s, 1H), 4.82 (dd, J=10.7, 5.9 Hz, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 3.29-3.23 (m, 2H), 3.11 (d, J=8.7 Hz, 2H), 2.70-2.66 (m, 2H), 2.45 (s, 6H), 2.39-2.34 (m, 1H), 1.87 (t, J=3.3 Hz, 1H), 1.72 (ddd, J=13.0, 12.1, 10.7 Hz, 1H), 1.59-1.56 (m, 2H); MS (ESI.sup.+) m/z 523 (M+H).sup.+.

    Example 485: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1r,3R)-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 584)

    [2367] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.57 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.26 (d, J=0.8 Hz, 1H), 7.22-7.20 (m, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.99-4.96 (m, 1H), 4.84-4.80 (m, 1H), 4.64 (dd, J=12.1, 2.3 Hz, 1H), 3.90 (d, J=6.8 Hz, 2H), 2.54-2.52 (m, 2H), 2.45 (s, 6H), 2.41-2.37 (m, 2H), 2.27-2.22 (m, 2H), 1.75-1.68 (m, 1H); MS (ESI.sup.+) m/z 528/530 (M+H).sup.+.

    Example 486: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 585)

    [2368] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.28-8.22 (m, 1H), 7.89-7.83 (m, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.64-5.61 (m, 1H), 5.21-5.18 and 5.15-5.12 (two m, 1H, amide rotamers), 4.62-4.57 (m, 2H), 4.05-4.00 and 3.87-3.77 (two m, 2H, amide rotamers), 3.71 (s, 1H), 3.69-3.62 and 3.54-3.48 (two m, 1H, amide rotamers), 2.55 (s, 6H), 2.33-2.14 (m, 2H), 2.14-2.10 (m, 1H), 1.93 (ddd, J=13.9, 11.0, 3.7 Hz, 1H); MS (APCI.sup.+) m/z 541 (M+H).sup.+.

    Example 487: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1RS,3RS)-3-(trifluoromethoxy)cyclopentyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 586)

    [2369] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.6, 1.0 Hz, 1H), 7.24 (d, J=0.9 Hz, 1H), 7.21 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.92-4.84 (m, 1H), 4.86-4.78 (m, 1H), 4.64 (dd, J=12.0, 2.3 Hz, 1H), 4.52-4.45 (m, 1H), 2.46 (s, 6H), 2.42-2.33 (m, 3H), 2.05-1.83 (m, 4H), 1.76-1.68 (m, 1H); MS (ESI.sup.+) m/z 528/530 (M+H).sup.+.

    Example 488: (2R,4R)-6-chloro-4-hydroxy-N-[3-(4-{[(1r,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 587)

    [2370] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.54 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.23 (d, J=0.9 Hz, 1H), 7.21 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.71 (d, J=6.2 Hz, 1H), 5.05-4.97 (m, 1H), 4.86-4.78 (m, 1H), 4.70-4.61 (m, 2H), 2.66-2.59 (m, 2H), 2.54-2.51 (m, 2H), 2.45 (s, 6H), 2.40-2.34 (m, 1H), 1.76-1.67 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.74; MS (ESI.sup.+) m/z 514/516 (M+H).sup.+.

    Example 489: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-(((1r,3R)-3-[(trifluoromethoxy)methyl]cyclobutyl}oxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 588)

    [2371] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.47 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.23-7.19 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.85-4.79 (m, 1H), 4.64 (dd, J=12.0, 2.2 Hz, 1H), 4.57 (p, J=6.6 Hz, 1H), 4.14 (d, J=7.3 Hz, 2H), 2.62-2.57 (m, 1H), 2.45 (s, 6H), 2.40-2.36 (m, 1H), 2.27-2.22 (m, 2H), 2.20-2.14 (m, 2H), 1.75-1.68 (m, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.43; MS (ESI.sup.+) m/z 528/530 (M+H).sup.+.

    Example 490: (2R,4R)-6-chloro-4-hydroxy-N-{3-[4-({(1s,3S)-3-[(trifluoromethoxy)methyl]cyclobutyl}oxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 589)

    [2372] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.86 (s, 1H), 7.49 (s, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.22-7.19 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.3 Hz, 1H), 4.82 (dt, J=11.4, 5.9 Hz, 1H), 4.64 (dd, J=12.0, 2.2 Hz, 1H), 4.35 (q, J=7.2 Hz, 1H), 4.09 (d, J=6.2 Hz, 2H), 2.45 (s, 6H), 2.38 (d, J=3.9 Hz, 1H), 2.28-2.21 (m, 1H), 1.83-1.77 (m, 2H), 1.72 (q, J=12.1 Hz, 1H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.44; MS (ESI) m/z 528/530 (M+H).sup.+.

    Example 491: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 590)

    [2373] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.59 (s, 1H), 7.67 (d, J=0.9 Hz, 1H), 7.49 (dd, J=8.6, 1.0 Hz, 1H), 7.29 (d, J=0.8 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 5.73 (s, 1H), 4.83-4.75 (m, 1H), 4.68 (dd, J=11.8, 2.3 Hz, 1H), 4.37-4.30 (m, 2H), 4.14-4.08 (m, 2H), 2.35 (ddd, J=13.3, 5.9, 2.4 Hz, 1H), 2.30-2.26 (m, 2H), 2.11-2.04 (m, 2H), 2.04-1.93 (m, 4H), 1.75 (td, J=12.1, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 520 (M+H).sup.+.

    Example 492: 7-fluoro-6-(trifluoromethyl)-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 591)

    [2374] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.56 (d, J=0.7 Hz, 1H), 8.53 (dd, J=8.4, 1.4 Hz, 1H), 8.20-8.17 (m, 2H), 7.92 (d, J=8.4 Hz, 1H), 6.94-6.87 (m, 2H), 6.16 (d, J 2.7 Hz, 1H), 4.69 (dd, J=6.2, 3.1 Hz, 1H), 3.46 (dt, J=12.3, 2.8 Hz, 1H), 3.30-3.27 (m, 1H), 2.56 (s, 6H); MS (ESI.sup.+) m/z 542 (M+H).sup.+.

    Example 493: 7-fluoro-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 592)

    [2375] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.87 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 6.93-6.85 (m, 2H), 6.15 (s, 1H), 4.66 (dd, J=6.3, 3.1 Hz, 1H), 4.35-4.29 (m, 2H), 4.12-4.08 (m, 2H), 3.44 (dt, J=12.3, 2.9 Hz, 1H), 3.29-3.24 (m, 1H), 2.44 (s, 6H); MS (ESI.sup.+) m/z 525 (M+H).sup.+.

    Example 494: (2R,4R)-7-fluoro-4-hydroxy-N-(3-{2-[2-(trifluoromethoxy)ethoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 593)

    [2376] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.85 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 7.00 (d, J=12.1 Hz, 1H), 5.85 (d, J=6.1 Hz, 1H), 4.84 (dd, J=10.8, 5.6 Hz, 1H), 4.78 (dd, J=11.8, 2.5 Hz, 1H), 4.57-4.51 (m, 2H), 4.46-4.39 (m, 2H), 2.42 (dd, J=5.8, 2.5 Hz, 1H), 2.37 (s, 6H), 1.82-1.72 (m, 1H); MS (ESI.sup.+) m/z 552 (M+H).sup.+.

    Example 495: (2R,4R)-6-chloro-4-hydroxy-N-(4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 594)

    [2377] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.58 (s, 1H), 7.67 (d, J=0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.29 (d, J=0.9 Hz, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (s, 1H), 4.82 (dd, J=10.8, 5.9 Hz, 1H), 4.63 (dd, J=11.9, 2.2 Hz, 1H), 4.37-4.30 (m, 2H), 4.14-4.08 (m, 2H), 2.36 (ddd, J=13.0, 6.1, 2.3 Hz, 1H), 2.30-2.26 (m, 2H), 2.10-2.04 (m, 2H), 2.04-1.94 (m, 4H), 1.81-1.68 (m, 1H); MS (ESI.sup.+) m/z 502 (M+H).sup.+.

    Example 496: 2-(4-chloro-3-fluorophenoxy)-N-(4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)acetamide (Compound 595)

    [2378] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.63 (s, 1H), 7.66 (d, J=0.9 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.29 (d, J=0.8 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.51 (s, 2H), 4.36-4.30 (m, 2H), 4.13-4.07 (m, 2H), 2.27 (s, 2H), 2.10-2.02 (m, 2H), 2.02-1.91 (m, 4H); MS (ESI.sup.+) m/z 478 (M+H).sup.+.

    Example 497: 2-(3,4-dichlorophenoxy)-N-[(1r,4r)-4-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)cyclohexyl]acetamide (Compound 596)

    [2379] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.38 (d, J=1.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.97 (dd, J=9.2, 0.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.27 (d, J=2.9 Hz, 1H), 7.00 (dd, J=9.0, 3.0 Hz, 1H), 6.77 (d, J=9.2 Hz, 1H), 4.54 (s, 2H), 4.43 (tt, J=11.7, 3.9 Hz, 1H), 3.86 (s, 3H), 3.81-3.73 (m, 1H), 2.16-2.11 (m, 2H), 1.99 (td, J=12.5, 11.5, 3.5 Hz, 2H), 1.95-1.89 (m, 2H), 1.58-1.49 (m, 2H); MS (ESI.sup.+) m/z 450 (M+H).sup.+.

    Example 498: 2-(4-chloro-3-fluorophenoxy)-N-[(2S)-2-hydroxy-4-(5-methoxy-2H-indazol-2-yl)bicyclo[2.2.2]octan-1-yl]acetamide (Compound 597)

    [2380] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.19 (d, J=0.9 Hz, 1H), 7.52-7.48 (m, 2H), 7.42 (s, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.95 (dd, J=2.4, 0.7 Hz, 1H), 6.88 (dd, J=9.2, 2.4 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.1 Hz, 1H), 5.28 (d, J=4.4 Hz, 1H), 4.51 (d, J=1.4 Hz, 2H), 4.29-4.24 (m, 1H), 3.75 (s, 3H), 2.60 (ddd, J=12.8, 9.4, 3.2 Hz, 1H), 2.23-2.18 (m, 3H), 2.17-2.06 (m, 4H), 2.05-1.98 (m, 2H); MS (ESI.sup.+) m/z 474 (M+H).sup.+.

    Example 499: 2-(4-chloro-3-fluorophenoxy)-N-[(1r,4r)-4-(4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl)cyclohexyl]acetamide (Compound 598)

    [2381] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.87-8.83 (m, 1H), 8.52 (d, J=0.7 Hz, 1H), 8.17-8.13 (m, 1H), 8.12 (d, J=0.7 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.90-7.84 (m, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.53 (s, 2H), 4.23 (tt, J=11.6, 3.8 Hz, 1H), 3.79-3.68 (m, 1H), 2.14-2.08 (m, 2H), 1.95-1.82 (m, 4H), 1.50 (qd, J=14.2, 13.5, 4.1 Hz, 2H); MS (ESI.sup.+) m/z 497 (M+H).sup.+.

    Example 500: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 599)

    [2382] .sup.1H NMR (500 MHz, DMSO-d.sub.6) (rotamers) ppm 8.99 (s, 1H), 8.80 (s, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.10 (dd, J=11.3, 2.9 Hz, 1H), 6.91-6.85 (m, 1H), 5.24-5.14 (m, 1H), 4.55 (s, 2H), 4.34-4.21 (m, 0.5H), 4.20-4.08 (m, 1H), 3.97-3.88 (m, 0.5H), 3.77 (d, J=3.0 Hz, 1H), 3.75-3.68 (m, 0.5H), 3.61-3.52 (m, 0.5H), 2.66 (s, 6H), 2.32-2.11 (m, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 56.70, 56.76, 114.00; MS (ESI+) m/z 518/520 (M+H).sup.+.

    Example 501: 2-(4-chloro-3-fluorophenoxy)-N-[3-(6-{3-[(trifluoromethoxy)methyl]azetidine-1-carbonyl}pyridin-3-yl)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 600)

    [2383] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.80 (s, 1H), 8.52 (dd, J=2.2, 0.9 Hz, 1H), 7.90 (dd, J=8.1, 0.9 Hz, 1H), 7.82 (dd, J=8.1, 2.2 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.09 (dd, J=11.3, 2.9 Hz, 1H), 6.87 (ddd, J=9.0, 2.8, 1.1 Hz, 1H), 4.70-4.64 (m, 1H), 4.51 (s, 2H), 4.38-4.30 (m, 3H), 4.16 (ddd, J=10.1, 8.5, 1.0 Hz, 1H), 3.87 3.81 (m, 1H), 3.04 (ddd, J=14.3, 8.1, 5.8 Hz, 1H), 2.37 (s, 6H); MS (APCI.sup.+) m/z 528.64 (M+H).sup.+.

    Example 502: 2-(4-chloro-3-fluorophenoxy)-N-(3-{6-[3-(2,2,2-trifluoroethoxy)azetidine-1-carbonyl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 601)

    [2384] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.81 (s, 11H), 8.52 (dd, J=2.2, 0.8 Hz, 1H), 7.90 (dd, J=8.0, 0.8 Hz, 1H), 7.82 (dd, J=8.1, 2.2 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.09 (dd, J=11.4, 2.9 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.78 (ddd, J=11.2, 6.3, 1.6 Hz, 1H), 4.55 (tt, J=6.4, 3.8 Hz, 1H), 4.51 (s, 2H), 4.41 (ddd, J=11.2, 3.9, 1.6 Hz, 1H), 4.30 (ddd, J=11.3, 6.6, 1.6 Hz, 1H), 4.14 (qd, J=9.3, 1.0 Hz, 2H), 3.92 (ddd, J=11.3, 3.8, 1.6 Hz, 1H), 2.38 (s, 6H); MS (APCI.sup.+) m/z 528.62 (M+H).sup.+.

    Example 503: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[3-(trifluoromethoxy)propoxy]pyridin-4-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 602)

    [2385] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.07 (d, J=5.2 Hz, 1H), 7.55 7.41 (m, 1H), 7.08 (dd, J=11.4, 2.9 Hz, 1H), 6.91-6.83 (m, 2H), 6.66 (d, J=1.2 Hz, 1H), 4.50 (s, 2H), 4.32 (t, J=6.2 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 2.30 (s, 6H), 2.10 (p, J=6.3 Hz, 2H); MS (APCI.sup.+) m/z 489.2 (M+H).sup.+.

    Example 504: 2-(4-chloro-3-fluorophenoxy)-N-(3-{6-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 603)

    [2386] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.81 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.82 (dd, J=8.0, 2.1 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.09 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.67 (dd, J=10.6, 8.3 Hz, 1H), 4.51 (s, 2H), 4.34 (dd, J=17.5, 6.2 Hz, 3H), 4.20-4.11 (m, 1H), 3.84 (dd, J=10.3, 5.5 Hz, 1H), 3.04 (dq, J=14.4, 8.1, 6.8 Hz, 1H), 2.38 (s, 6H); MS (APCI.sup.+) m/z 528.62 (M+H).sup.+.

    Example 505: N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-2-[4-(trifluoromethyl)phenoxy]acetamide (Compound 604)

    [2387] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.28-8.22 (m, 1H), 7.89-7.83 (m, 1H), 7.71-7.66 (m, 2H), 7.18-7.12 (m, 2H), 5.20-5.13 (m, 1H), 4.60 (s, 2H), 4.05-3.99 and 3.85-3.77 (two m, 2H, amide rotamers), 3.71 (s, 1H), 3.68-3.62 and 3.54-3.48 (two m, 1H, amide rotamers), 2.54 (s, 6H), 2.32-2.10 (m, 2H); MS (APCI.sup.+) m/z 533 (M+H).sup.+.

    Example 506: 2-(4-chloro-3-fluorophenoxy)-N-(3-{6-[3-(trifluoromethoxy)azetidine-1-carbonyl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 605)

    [2388] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.81 (s, 1H), 8.54 (dd, J=2.2, 0.9 Hz, 1H), 7.92 (dd, J=8.0, 0.8 Hz, 1H), 7.84 (dd, J=8.1, 2.2 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.09 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 5.25 (tt, J=6.9, 3.9 Hz, 1H), 4.96 (ddd, J=11.6, 6.5, 1.7 Hz, 1H), 4.63 (dd, J=11.8, 3.9 Hz, 1H), 4.52-4.45 (m, 3H), 4.16-4.10 (m, 1H), 2.38 (s, 6H); MS (APCI.sup.+) m/z 514.65 (M+H).sup.+.

    Example 507: 2-(3,4-dichlorophenoxy)-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 606)

    [2389] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90 C.) ppm 8.61 (s, 1H), 8.12 (d, J=0.7 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.24 (d, J=2.9 Hz, 1H), 6.99 (dd, J=8.9, 2.9 Hz, 1H), 5.13-5.09 (m, 1H), 4.51 (s, 2H), 3.91-3.82 (m, 1H), 3.79-3.64 (m, 3H), 2.54 (s, 6H), 2.31-2.12 (m, 2H); MS (APCI.sup.+) m/z 533 (M+H).sup.+.

    Example 508: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 607)

    [2390] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.59 (d, J=0.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.09 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.52 (s, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.92 (t, J=6.2 Hz, 2H), 2.44 (s, 6H), 2.05 (p, J=6.2 Hz, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.93, 114.03; MS (ESI.sup.+) m/z 478/480 (M+H).sup.+.

    Example 509: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 608)

    [2391] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.59 (d, J=0.8 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.36 (d, J=0.8 Hz, 1H), 7.09 (dd, J=11.3, 2.8 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.52 (s, 2H), 3.15 (q, J=10.3 Hz, 2H), 2.97-2.89 (m, 2H), 2.46 (s, 6H), 2.45-2.33 (m, 3H), 1.83-1.75 (m, 2H), 1.52 (qd, J=12.4, 3.8 Hz, 2H); MS (ESI.sup.+) m/z 501 (M+H).sup.+.

    Example 510: 2-(4-chloro-3-fluorophenoxy)-N-[(1S,4r)-4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}cyclohexyl]acetamide (Compound 609)

    [2392] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90 C.) ppm 8.13 (s, 1H), 7.75 (s, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.44 (t, J=8.8 Hz, 1H), 7.02 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=8.9, 2.9, 1.3 Hz, 1H), 5.11 (tt, J=4.8, 2.6 Hz, 1H), 4.49 (s, 2H), 4.19 (tt, J=11.4, 3.9 Hz, 1H), 3.90-3.80 (m, 1H), 3.79-3.62 (m, 4H), 2.32-2.13 (m, 2H), 2.13-2.04 (m, 2H), 1.98-1.79 (m, 4H), 1.56-1.42 (m, 2H); MS (ESI.sup.+) m/z 533 (M+H).sup.+.

    Example 511: 2-(4-chloro-3-fluorophenoxy)-N-[(1r,4r)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]acetamide (Compound 610)

    [2393] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.02 (d, J=8.0 Hz, 1H), 7.59 (d, J=0.9 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 7.07 (dd, J=11.4, 2.8 Hz, 1H), 6.85 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.51 (s, 2H), 4.35-4.30 (m, 2H), 4.11-4.05 (m, 2H), 4.01 (tt, J=11.8, 3.9 Hz, 1H), 3.74-3.63 (m, 1H), 2.04-1.97 (m, 2H), 1.87 (dd, J=13.6, 4.0 Hz, 2H), 1.75 (qd, J=12.9, 3.5 Hz, 2H), 1.45 (qd, J=13.0, 3.4 Hz, 2H); MS (ESI.sup.+) m/z 480 (M+H).sup.+.

    Example 512: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-imidazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 611)

    [2394] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.91 (s, 1H), 7.82-7.77 (m, 2H), 7.50 (t, J=8.9 Hz, 1H), 7.08 (dd, J=110.3, 2.8 Hz, 1H), 6.86 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 5.18-5.07 (m, 1H), 4.52 (s, 2H), 4.39-3.44 (m, 3H), 3.71 (s, 1H), 2.52 (s, 6H), 2.30-2.01 (m, 2H); MS (ESI+) m/z 517/519 (M+H).sup.+.

    Example 513: 2-(4-chloro-3-fluorophenoxy)-N-[3-(4-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methoxy}-1H-pyrazol-1-yl)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 612)

    [2395] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.56 (d, J=0.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.25 (d, J=0.9 Hz, 1H), 7.09 (dd, J=11.4, 2.9 Hz, 1H), 6.90-6.84 (m, 1H), 4.73 (p, J=7.4 Hz, 1H), 4.52 (s, 2H), 3.84 (d, J=5.9 Hz, 2H), 2.47-2.40 (m, 2H), 2.44 (s, 6H), 2.32-2.22 (m, 1H), 2.01 (q, J=9.7 Hz, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.60, 114.03; MS (ESI+) m/z 504/506 (M+H).sup.+.

    Example 514: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[3-(trifluoromethoxy)propyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 613)

    [2396] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.89 (s, 1H), 7.61 (d, J=0.8 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.34 (d, J=0.7 Hz, 1H), 7.09 (dd, J=11.4, 2.9 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.52 (s, 2H), 4.07 (t, J=6.3 Hz, 2H), 2.49-2.47 (m, 2H), 2.46 (s, 6H), 1.94-1.83 (m, 2H); MS (ESI.sup.+) m/z 462 (M+H).sup.+.

    Example 515: 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(1S,4r)-4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}cyclohexyl]acetamide (Compound 614)

    [2397] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.27-8.20 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.71 (t, J=8.8 Hz, 1H), 7.12 (dd, J=12.8, 2.4 Hz, 1H), 7.00-6.93 (m, 1H), 5.21-5.11 (m, 1H), 4.62 (s, 2H), 4.26-4.16 (m, 1H), 4.05-3.95 and 3.88-3.47 (two m, 4H, amide rotamers), 2.31-2.09 (m, 2H), 2.08-2.01 (m, 2H), 1.93-1.80 (m, 4H), 1.54-1.39 (m, 2H); MS (ESI.sup.+) m/z 567 (M+H).sup.+.

    Example 516: 2-[2-hydroxy-4-(trifluoromethyl)phenoxy]-N-(3-{4-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 615)

    [2398] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.63 (s, 1H), 9.14 (s, 1H), 8.20 (s, 1H), 7.16-7.05 (m, 3H), 4.87-4.80 (m, 1H), 4.58 (s, 2H), 3.22-3.14 (m, 1H), 2.79-2.71 (m, 2H), 2.64 (s, 6H), 2.37-2.33 (m, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.68, 60.14; MS (ESI+) m/z 507 (M+H).sup.+.

    Example 517: 2-(4-chloro-2-hydroxyphenoxy)-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 616)

    [2399] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.13 (s, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 6.76 (dd, J=8.6, 2.6 Hz, 1H), 4.45 (s, 2H), 4.36-4.29 (m, 2H), 4.13-4.08 (m, 2H), 2.49 (s, 6H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 58.89; MS (ESI+) m/z 462/464 (M+H).sup.+.

    Example 518: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 617)

    [2400] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.34 (s, 1H), 6.97 (dd, J=10.9, 2.9 Hz, 1H), 6.85 (dd, J=8.9, 2.9, 1.2 Hz, 1H), 4.53 (s, 2H), 4.32-4.27 (m, 2H), 4.17-4.12 (m, 2H), 2.60 (s, 6H); MS (ESI.sup.+) m/z 463/465 (M+H).sup.+.

    Example 519: 2-(4-chloro-2-hydroxyphenoxy)-N-(3-{4-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 618)

    [2401] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.96 (s, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.78 (dd, J=8.6, 2.5 Hz, 1H), 4.79 (p, J=7.6 Hz, 1H), 4.53 (s, 2H), 3.30-3.21 (m, 1H), 2.87-2.78 (m, 2H), 2.75 (s, 6H), 2.50-2.39 (m, 2H); MS (ESI.sup.+) m/z 473/475 (M+H).sup.+.

    Example 520: 2-(4-chloro-3-fluorophenoxy)-N-(3-{6-[3-(trifluoromethyl)pyrrolidine-1-carbonyl]pyridin-3-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 619)

    [2402] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.81 (s, 1H), 8.52 (ddd, J=18.8, 2.2, 0.9 Hz, 1H), 7.82 (ddd, J=8.0, 4.9, 2.2 Hz, 1H), 7.74 (ddd, J=17.3, 8.0, 0.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.09 (dd, J=11.4, 2.8 Hz, 1H), 6.87 (ddd, J=9.0, 2.8, 1.1 Hz, 1H), 4.51 (s, 2H), 3.99 (dd, J=11.9, 8.1 Hz, 1H), 3.87-3.67 (m, 3H), 3.60 (ddd, J=20.2, 12.3, 7.2 Hz, 1H), 3.30 (q, J=9.2, 7.4 Hz, 1H), 2.38 (J=1.7 Hz, 6H), 2.23-2.14 (m, 1H), 2.06-1.95 (m, 1H); MS (APCI.sup.+) m/z 512.6 (M+H).sup.+.

    Example 521: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1H-1,2,3-triazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 620)

    [2403] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.17 (s, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.10 (dd, J=11.4, 2.8 Hz, 1H), 6.88 (ddd, J=9.1, 2.9, 1.2 Hz, 1H), 4.82 (q, J=7.5 Hz, 1H), 4.54 (s, 2H), 3.17 (tt, J=10.0, 7.5 Hz, 1H), 2.79-2.70 (m, 2H), 2.59 (s, 6H), 2.39-2.31 (m, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ppm 57.68 and 114.01; MS (ESI.sup.+) m/z 475/477 (M+H).sup.+.

    Example 522: 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-(3-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 621)

    [2404] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.28-8.22 (m, 1H), 7.89-7.83 (m, 1H), 7.72 (t, J=8.8 Hz, 1H), 7.15 (dd, J=12.9, 2.4 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 5.21-5.12 (m, 1H), 4.64 (s, 2H), 4.05-3.99 and 3.86-3.78 (two m, 2H, amide rotamers), 3.71 (s, 1H), 3.67-3.62 and 3.55-3.45 (two m, 1H, amide rotamers), 2.54 (s, 6H), 2.34-2.10 (m, 2H); MS (ESI.sup.+) m/z 551 (M+H).sup.+.

    Example 523: 2-(3,4-dichlorophenoxy)-N-[3-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 622)

    [2405] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 8.95 (dd, J=1.0 Hz, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.30 (d, J=2.9 Hz, 1H), 7.02 (dd, J=8.9, 2.9 Hz, 1H), 6.88 (d, J=1.4 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 3H), 2.68 (s, 6H); MS (ESI.sup.+) m/z 434 (M+H).sup.+.

    Example 524: 2-(3,4-dichlorophenoxy)-N-[3-(5-ethoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 623)

    [2406] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.21 (d, J=0.9 Hz, 1H), 7.57 (d, J 8.9 Hz, 1H), 7.51 (dt, J9.2, 0.9 Hz, 1H), 7.30 (d, J2.9 Hz, 1H), 7.02 (dd, J9.0, 2.9 Hz, 1H), 6.94 (dd, J=2.4, 0.8 Hz, 1H), 6.91 (dd, J=9.2, 2.4 Hz, 1H), 4.56 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 2.61 (s, 6H), 1.35 (t, J=7.0 Hz, 3H); MS (ESI.sup.+) m/z 447 (M+H).sup.+.

    Example 525: 2-(4-chloro-3-fluorophenoxy)-N-(4-{4-[(3S)-3-(trifluoromethoxy)pyrrolidine-1-carbonyl]-1H-pyrazol-1-yl}bicyclo[2.2.2]octan-1-yl)acetamide (Compound 624)

    [2407] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.16-8.10 (m, 1H), 7.85-7.78 (m, 1H), 7.62 (s, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.04 (dd, J=11.4, 2.9 Hz, 1H), 6.82 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 5.21-5.11 (m, 1H), 4.47 (s, 2H), 4.05-3.99 and 3.85-3.76 (two m, 2H, amide rotamers), 3.73-3.68 (m, 1H), 3.68-3.60 and 3.54-3.46 (two m, 1H, amide rotamers), 2.32-2.16 (m, 2H), 2.15-2.08 (m, 6H), 2.08-2.00 (m, 6H); MS (APCI.sup.+) m/z 559 (M+H).sup.+.

    Example 526: 2-(4-chloro-3-fluorophenoxy)-N-(3-{4-[(1R,5S,6s)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 625)

    [2408] .sup.1H NMR (600 MHz, DMSO d.sub.6) ppm 8.88 (s, 1H), 7.53 (d, J=0.6 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.27 (d, J=0.8 Hz, 1H), 7.09 (dd, J=11.3, 2.9 Hz, 1H), 6.87 (ddd, J=9.0, 2.9, 1.2 Hz, 1H), 4.52 (s, 2H), 3.29-3.21 (m, 2H), 3.10 (d, J=8.7 Hz, 2H), 2.70-2.65 (m, 2H), 2.43 (s, 6H), 1.87 (t, J=3.3 Hz, 1H), 1.59-1.56 (m, 2H); MS (ESI.sup.+) m/z 499 (M+H).sup.+.

    Example 527: (2R,4R)-6-chloro-4-hydroxy-N-(4-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 626)

    [2409] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.86 (dt, J=2.1, 1.0 Hz, 1H), 8.63 (s, 1H), 8.58 (d, J=0.7 Hz, 1H), 8.21-8.13 (m, 2H), 7.96-7.89 (m, 1H), 7.40 (dd, J=2.8, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.71 (d, J=6.1 Hz, 1H), 4.83 (dt, J=11.3, 5.8 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 2.43-2.33 (m, 3H), 2.21-2.16 (m, 2H), 2.14-2.08 (m, 2H), 2.07-2.01 (m, 2H), 1.76 (ddd, J=12.9, 12.0, 10.7 Hz, 1H); MS (ESI.sup.+) m/z 519 (M+H).sup.+.

    Example 528: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(4-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 627)

    [2410] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.88-8.84 (m, 1H), 8.65 (s, 1H), 8.58 (d, J=0.7 Hz, 1H), 8.18 (d, J=0.7 Hz, 1H), 8.18-8.15 (m, 1H), 7.95-7.91 (m, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 6.96 (d, J=10.5 Hz, 1H), 5.74 (d, J=6.2 Hz, 1H), 4.80 (dt, J=11.3, 6.0 Hz, 1H), 4.70 (dd, J=11.8, 2.4 Hz, 1H), 2.43-2.39 (m, 2H), 2.37 (ddd, J=13.0, 5.8, 2.4 Hz, 1H), 2.21-2.16 (m, 2H), 2.14-2.01 (m, 4H), 1.77 (ddd, J=13.0, 11.8, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 537 (M+H).sup.+.

    Example 529: (2R,4R)-6-chloro-4-hydroxy-N-(4-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 628)

    [2411] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.58 (s, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.20 (ddd, J=8.8, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.82 (dt, J=10.8, 6.0 Hz, 1H), 4.62 (dd, J=11.9, 2.2 Hz, 1H), 4.19 (t, J=6.3 Hz, 2H), 3.94 (t, J=6.2 Hz, 2H), 2.40-2.32 (m, 1H), 2.30-2.25 (m, 2H), 2.10-2.03 (m, 4H), 2.02-1.95 (m, 4H), 1.74 (ddd, J=12.9, 11.9, 10.8 Hz, 1H); MS (ESI.sup.+) m/z 516 (M+H).sup.+.

    Example 530: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(4-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 629)

    [2412] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.60 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.49 (dd, J=8.7, 1.0 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 5.74 (d, J=6.2 Hz, 1H), 4.83-4.75 (m, 1H), 4.68 (dd, J=11.8, 2.4 Hz, 1H), 4.19 (t, J=6.3 Hz, 2H), 3.94 (t, J=6.2 Hz, 2H), 2.35 (ddd, J=13.0, 5.9, 2.4 Hz, 1H), 2.30-2.25 (m, 2H), 2.10-2.02 (m, 4H), 2.02-1.93 (m, 4H), 1.75 (ddd, J=13.0, 11.9, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 534 (M+H).sup.+.

    Example 531: 2-(4-chloro-3-fluorophenoxy)-N-(4-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[2.1.1]hexan-1-yl)acetamide (Compound 630)

    [2413] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.64 (s, 1H), 7.62 (d, J=0.9 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.25 (d, J=0.9 Hz, 1H), 7.08 (dd, J=11.4, 2.8 Hz, 1H), 6.86 (ddd, J=8.9, 2.9, 1.2 Hz, 1H), 4.51 (s, 2H), 4.19 (t, J=6.3 Hz, 2H), 3.93 (t, J=6.2 Hz, 2H), 2.29-2.23 (m, 2H), 2.10-2.02 (m, 4H), 2.02-1.92 (m, 4H); MS (ESI.sup.+) m/z 492 (M+H).sup.+.

    Example 532: (2S,4R)-6-chloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 631)

    [2414] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.26 (dd, J=8.7, 2.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.63 (d, J=4.3 Hz, 1H), 4.62-4.56 (m, 2H), 4.35-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.12 (dt, J=13.8, 3.3 Hz, 1H), 1.96-1.88 (m, 1H); MS (ESI.sup.+) m/z 488 (M+H).sup.+.

    Example 533: (2R,4S)-6-chloro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 632)

    [2415] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.30 (d, J=0.9 Hz, 1H), 7.26 (dd, J=8.8, 2.7 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 5.63 (d, J=4.5 Hz, 1H), 4.63-4.56 (m, 2H), 4.36-4.30 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.16-2.08 (m, 1H), 1.92 (ddd, J=13.8, 11.0, 3.7 Hz, 1H); M S (ESI.sup.+) m/z 488 (M+H).sup.+.

    Example 534: (2R,43)-7-fluoro-4-hydroxy-N-(3-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 633)

    [2416] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 9.01 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.64 (d, J=0.9 Hz, 1H), 7.31 (d, J=0.9 Hz, 1H), 7.04 (d, J=12.1 Hz, 1H), 5.73 (d, J=4.5 Hz, 1H), 4.72 (dd, J=10.5, 3.0 Hz, 1H), 4.67 (q, J=4.1 Hz, 1H), 4.36-4.31 (m, 2H), 4.13-4.08 (m, 2H), 2.46 (s, 6H), 2.15 (ddd, J=13.9, 4.3, 3.1 Hz, 1H), 1.99 (ddd, J=14.1, 10.6, 3.6 Hz, 1H); MS (ESI.sup.+) m/z 540 (M+H).sup.+.

    Example 535: (2R,4S)-7-fluoro-4-hydroxy-N-(3-{4-[5-(trifluoromethoxy)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 634)

    [2417] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.05 (s, 1H), 8.59-8.57 (m, 1H), 8.45 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.93-7.81 (m, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.04 (d, J=12.2 Hz, 1H), 5.73 (d, J=4.2 Hz, 1H), 4.74 (dd, J=10.5, 3.0 Hz, 1H), 4.70-4.65 (m, 1H), 2.57 (s, 6H), 2.21-2.12 (m, 1H), 2.00 (ddd, J=14.0, 10.5, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 573 (M+H).sup.+.

    Example 536: (2R,4R)-7-fluoro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 635)

    [2418] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.27 (d, J=0.8 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.85 (d, J=5.2 Hz, 1H), 4.87-4.76 (m, 2H), 4.19 (t, J=6.3 Hz, 2H), 3.93 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.41 (ddd, J=13.1, 5.7, 2.6 Hz, 1H), 2.06 (p, J=6.2 Hz, 2H), 1.78 (ddd, J=13.0, 11.7, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 554 (M+H).sup.+.

    Example 537: (2R,4S)-7-fluoro-4-hydroxy-N-(3-{4-[3-(trifluoromethoxy)propoxy]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 636)

    [2419] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.03 (d, J=12.1 Hz, 1H), 5.73 (d, J=4.2 Hz, 1H), 4.72 (dd, J=10.5, 3.0 Hz, 1H), 4.69-4.64 (m, 1H), 4.19 (t, J=6.3 Hz, 2H), 3.93 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.15 (ddd, J=14.0, 4.3, 3.1 Hz, 1H), 2.10-1.93 (m, 3H); MS (ESI.sup.+) m/z 554 (M+H).sup.+.

    Example 538: (2R,4R)-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 637)

    [2420] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.90 (d, J=8.2 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 7.15 (td, J=7.9, 1.8 Hz, 1H), 6.92 (td, J=7.4, 1.2 Hz, 1H), 6.85 (dd, J=8.2, 1.2 Hz, 1H), 5.54-5.49 (m, 1H), 4.85-4.80 (m, 1H), 4.60 (dd, J=11.8, 2.2 Hz, 1H), 4.36-4.30 (m, 2H), 4.11-4.06 (m, 2H), 4.06-3.95 (m, 1H), 3.77-3.64 (m, 1H), 2.35 (ddd, J=12.8, 6.0, 2.3 Hz, 1H), 2.05-1.97 (m, 2H), 1.94-1.84 (m, 2H), 1.83-1.69 (m, 3H), 1.58-1.44 (m, 2H); MS (ESI.sup.+) m/z 470 (M+H).sup.+.

    Example 539: (2R,4R)-6,7-difluoro-4-hydroxy-N-[(1r,4R)-4-{4-[2-(trifluoromethoxy)ethoxy]-1H-pyrazol-1-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 638)

    [2421] .sup.1H NMR (500 MHz, DMSO-di) ppm 7.95 (d, J=8.0 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.34 (ddd, J=11.5, 9.2, 1.0 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 6.95 (dd, J=11.9, 7.0 Hz, 1H), 5.72 (d, J=5.3 Hz, 1H), 4.81-4.75 (m, 1H), 4.65 (dd, J=11.8, 2.3 Hz, 1H), 4.36-4.30 (m, 2H), 4.11-4.06 (m, 2H), 4.01 (tt, J=11.7, 3.9 Hz, 1H), 3.69 (tdt, J=11.8, 8.0, 3.9 Hz, 1H), 2.35 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 2.04-1.98 (m, 2H), 1.92-1.84 (m, 2H), 1.82-1.67 (m, 3H), 1.55-1.41 (m, 2H); MS (ESI.sup.+) m/z 506 (M+H).sup.+.

    Example 540: (2R,4R)-7-fluoro-4-hydroxy-N-{3-[4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 639)

    [2422] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.94 (s, 1H), 8.82 (s, 2H), 8.34 (d, J=0.7 Hz, 1H), 7.99 (d, J=0.7 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 6.96 (d, J=12.1 Hz, 1H), 5.83 (br s, 1H), 4.85-4.74 (m, 2H), 3.89 (s, 3H), 2.52 (s, 6H), 2.38 (ddd, J=13.0, 5.6, 2.6 Hz, 1H), 1.75 (ddd, J=13.2, 11.7, 10.3 Hz, 1H); MS (ESI.sup.+) m/z 520 (M+H).sup.+.

    Example 541: (2R,4S)-7-fluoro-4-hydroxy-6-(trifluoromethyl)-N-(3-{4-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-1-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 640)

    [2423] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.03 (s, 1H), 8.85-8.80 (m, 1H), 8.53 (s, 1H), 8.17-8.10 (m, 2H), 7.89 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.01 (d, J=12.1 Hz, 1H), 5.71 (d, J=4.5 Hz, 1H), 4.70 (dd, J=10.5, 3.0 Hz, 1H), 4.67-4.61 (m, 1H), 2.54 (s, 6H), 2.13 (dt, J=13.9, 4.0 Hz, 1H), 1.97 (ddd, J=14.0, 10.6, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 557 (M+H).sup.+.

    Example 542: (2R,4R)-7-fluoro-4-hydroxy-N-{3-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 641)

    [2424] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.92 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.27 (d, J=0.8 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.85 (d, J=6.0 Hz, 1H), 4.84 (dd, J=10.7, 5.5 Hz, 1H), 4.82-4.78 (m, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.44-2.28 (m, 3H), 1.87 (ddt, J=10.1, 7.8, 6.2 Hz, 2H), 1.77 (ddd, J=13.0, 11.7, 10.5 Hz, 1H); MS (ESI.sup.+) m/z 538 (M+H).sup.+.

    Example 543: (2R,4S)-7-fluoro-4-hydroxy-N-{3-[4-(4,4,4-trifluorobutoxy)-1H-pyrazol-1-yl]bicyclo[1.1.1]pentan-1-yl}-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 642)

    [2425] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.58 (d, J=0.9 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.03 (d, J=12.1 Hz, 1H), 5.72 (d, J=4.3 Hz, 1H), 4.72 (dd, J=10.6, 3.0 Hz, 1H), 4.67 (q, J=4.1 Hz, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.46 (s, 6H), 2.42-2.31 (m, 2H), 2.15 (ddd, J=14.0, 4.3, 3.0 Hz, 1H), 1.99 (ddd, J=14.1, 10.6, 3.7 Hz, 1H), 1.87 (ddt, J=11.2, 7.8, 6.2 Hz, 2H); MS (ESI.sup.+) m/z 538 (M+H).sup.+.

    Example 544: (2R,4S)-7-fluoro-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 643)

    [2426] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.80 (s, 1H), 8.36 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.02 (d, J=12.1 Hz, 1H), 5.71 (d, J=4.5 Hz, 1H), 4.71-4.60 (m, 2H), 4.48 (p, J=7.1 Hz, 1H), 3.73 (s, 2H), 3.73-3.67 (m, 1H), 2.78-2.69 (m, 2H), 2.26 (s, 6H), 2.19-2.08 (m, 3H), 1.96 (ddd, J=14.1, 10.5, 3.7 Hz, 1H); MS (ESI.sup.+) m/z 557 (M+H).sup.+.

    Example 545: (2R,4R)-7-fluoro-4-hydroxy-N-[3-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 644)

    [2427] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.72 (s, 1H), 8.36 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 6.98 (d, J=12.1 Hz, 1H), 5.83 (d, J=5.5 Hz, 1H), 4.85-4.78 (m, 1H), 4.75 (dd, J=11.8, 2.5 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.69 (p, J=6.8 Hz, 1H), 2.78-2.70 (m, 2H), 2.38 (ddd, J=13.1, 5.7, 2.6 Hz, 1H), 2.26 (s, 6H), 2.19-2.11 (m, 2H), 1.74 (ddd, J=13.1, 11.8, 10.6 Hz, 1H); MS (ESI.sup.) m/z 555 (MH).sup..

    Example 546: (2R,4R)-7-fluoro-4-hydroxy-N-[(1S,2R,4S,5R)-5-(2-{[(1s,3S)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 645)

    [2428] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.87 (d, J=7.0 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.02 (d, J=12.1 Hz, 1H), 5.82 (d, J=5.2 Hz, 1H), 4.85-4.78 (m, 1H), 4.76 (dd, J=11.7, 2.5 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.75 (s, 2H), 3.74-3.67 (m, 1H), 3.58-3.48 (m, 2H), 2.78-2.68 (m, 2H), 2.34 (ddd, J=13.1, 5.8, 2.6 Hz, 1H), 2.20-2.08 (m, 4H), 1.79 (ddd, J=13.0, 11.7, 10.6 Hz, 1H), 1.65-1.56 (m, 2H), 1.46-1.33 (m, 4H); MS (ESI.sup.+) m/z 585 (M+H).sup.+.

    Example 547: (2R,4R)-7-fluoro-4-hydroxy-N-[(1R,2S,4R,5S)-5-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.1]heptan-2-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 646)

    [2429] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.88 (d, J=6.9 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.05-6.98 (m, 1H), 5.82 (d, J=6.0 Hz, 1H), 4.81 (dt, J=11.2, 5.8 Hz, 1H), 4.75 (dd, J=11.7, 2.4 Hz, 1H), 4.48 (p, J=7.2 Hz, 1H), 3.75 (s, 2H), 3.74-3.65 (m, 1H), 3.57-3.47 (m, 2H), 2.79-2.67 (m, 2H), 2.34 (ddd, J=13.1, 5.8, 2.4 Hz, 1H), 2.20-2.05 (m, 4H), 1.79 (ddd, J=13.0, 11.8, 10.7 Hz, 1H), 1.67-1.55 (m, 2H), 1.44-1.32 (m, 4H); MS (ESI.sup.+) m/z 585 (M+H).sup.+.

    Example 548: (2R,4R)-7-fluoro-4-hydroxy-N-[(3S)-3-hydroxy-4-(2-{[(1s,3R)-3-(trifluoromethoxy)cyclobutyl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 647)

    [2430] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 7.70 (d, J=8.3 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.02 (d, J=12.1 Hz, 1H), 6.94 (s, 1H), 5.80 (br s, 1H), 5.21 (s, 1H), 4.78 (dd, J=10.6, 5.8 Hz, 1H), 4.70 (dd, J=11.7, 2.4 Hz, 1H), 4.48 (p, J=7.1 Hz, 1H), 3.94 (dd, J=9.6, 3.4 Hz, 1H), 3.76-3.67 (m, 3H), 2.79-2.71 (m, 2H), 2.34-2.28 (m, 2H), 2.30-2.20 (m, 1H), 2.16-2.08 (m, 2H), 2.00-1.92 (m, 1H), 1.91-1.85 (m, 2H), 1.85-1.69 (m, 6H); MS (ESI.sup.+) m/z 615 (M+H).sup.+.

    Example 549: (2R,4R)-6-chloro-4-hydroxy-N-(3-{6-[3-(trifluoromethoxy)propoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 648)

    [2431] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.76 (s, 1H), 8.69 (d, J=1.1 Hz, 1H), 7.38 (dd, J=2.7, 1.0 Hz, 1H), 7.20 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.83 (d, J=1.1 Hz, 1H), 5.70 (d, J=6.0 Hz, 1H), 4.82 (dd, J=10.7, 5.6 Hz, 1H), 4.61 (dd, J=11.9, 2.2 Hz, 1H), 4.42 (t, J=6.3 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 2.40-2.36 (m, 1H), 2.34 (s, 6H), 2.13 (p, J=6.3 Hz, 2H), 1.77-1.66 (m, 1H); MS (ESI.sup.+) m/z 514 (M+H).sup.+.

    Example 550: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{6-[3-(trifluoromethoxy)propoxy]pyrimidin-4-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 649)

    [2432] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.79 (s, 1H), 8.69 (d, J=1.1 Hz, 1H), 7.48 (dd, J=8.5, 1.0 Hz, 1H), 6.94 (d, J=10.6 Hz, 1H), 6.84 (d, J=1.1 Hz, 1H), 5.76 (d, J=6.0 Hz, 1H), 4.79 (dt, J=11.2, 5.8 Hz, 1H), 4.67 (dd, J=11.9, 2.4 Hz, 1H), 4.42 (t, J=6.2 Hz, 2H), 4.22 (t, J=6.3 Hz, 2H), 2.38 (dd, J=5.9, 2.4 Hz, 1H), 2.34 (s, 6H), 2.13 (p, J=6.3 Hz, 2H), 1.72 (ddd, J=13.0, 12.0, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 532 (M+H).sup.+.

    Example 551: (2R,4R)-6-chloro-4-hydroxy-N-(3-{5-[(2,2,2-trifluoroethoxy)methyl]-2H-indazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 650)

    [2433] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.97 (s, 1H), 8.46 (d, J=1.0 Hz, 1H), 7.66 (dd, J=1.7, 0.9 Hz, 1H), 7.63 (dd, J=8.9, 1.0 Hz, 1H), 7.40 (dd, J=2.7, 1.0 Hz, 1H), 7.25-7.20 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 5.73 (d, J=6.0 Hz, 1H), 4.84 (dt, J=10.9, 5.7 Hz, 1H), 4.71-4.65 (m, 3H), 4.06 (q, J=9.3 Hz, 2H), 2.66 (s, 6H), 2.40 (ddd, J=12.9, 5.9, 2.4 Hz, 1H), 1.79-1.70 (m, 1H); MS (ESI.sup.+) m/z 522 (M+H).sup.+.

    Example 552: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-(3-{5-[(2,2,2-trifluoroethoxy)methyl]-2H-indazol-2-yl}bicyclo[1.1.1]pentan-1-yl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 651)

    [2434] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.98 (s, 1H), 8.46 (d, J=1.0 Hz, 1H), 7.66 (dd, J=1.6, 0.9 Hz, 1H), 7.63 (dt, J=9.0, 1.0 Hz, 1H), 7.50 (dd, J=8.6, 1.1 Hz, 1H), 7.23 (dd, J=8.9, 1.6 Hz, 1H), 6.95 (d, J=10.6 Hz, 1H), 5.77 (d, J=5.8 Hz, 1H), 4.81 (dt, J=10.8, 5.6 Hz, 1H), 4.73 (dd, J=11.8, 2.4 Hz, 1H), 4.69 (s, 2H), 4.07 (q, J=9.4 Hz, 2H), 2.66 (s, 6H), 2.43-2.35 (m, 1H), 1.76 (ddd, J=12.9, 11.8, 10.6 Hz, 1H); MS (ESI.sup.+) m/z 540 (M+H).sup.+.

    Example 553: (2R,4R)-6-chloro-4-hydroxy-N-[4-(5-methoxy-2H-indazol-2-yl)bicyclo[2.1.1]hexan-1-yl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 652)

    [2435] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.65 (s, 1H), 8.26 (d, J=1.0 Hz, 1H), 7.53 (dt, J=9.3, 0.9 Hz, 1H), 7.39 (dd, J=2.7, 1.0 Hz, 1H), 7.21 (ddd, J=8.7, 2.7, 0.7 Hz, 1H), 6.98-6.96 (m, 1H), 6.93-6.90 (m, 2H), 5.71 (d, J=6.4 Hz, 1H), 4.83 (dt, J=11.3, 6.0 Hz, 1H), 4.65 (dd, J=11.9, 2.3 Hz, 1H), 3.76 (s, 3H), 2.47-2.45 (m, 2H), 2.40-2.36 (m, 1H), 2.26-2.21 (m, 2H), 2.21-2.18 (m, 2H), 2.09-2.05 (m, 2H), 1.80-1.73 (m, 1H); MS (ESI.sup.+) m/z 454 (M+H).sup.+.

    Example 554: 7-fluoro-N-[3-(5-methoxy-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 653)

    [2436] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.95 (s, 1H), 8.22 (d, J=1.0 Hz, 1H), 7.52 (dt, J=9.2, 0.9 Hz, 1H), 6.96-6.89 (m, 4H), 6.18-6.14 (m, 1H), 4.70 (dd, J=6.2, 3.1 Hz, 1H), 3.76 (s, 3H), 3.46 (dt, J=12.3, 2.9 Hz, 1H), 3.29 (dd, J=6.3, 2.3 Hz, 1H), 2.61 (s, 6H); MS (ESI.sup.+) m/z 477 (M+H).sup.+.

    Example 555: 7-fluoro-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (Compound 654)

    [2437] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 8.96 (s, 1H), 8.41 (d, J=0.9 Hz, 1H), 8.00 (dd, J=9.2, 0.9 Hz, 1H), 6.93-6.89 (m, 2H), 6.81 (d, J=9.3 Hz, 1H), 6.18-6.14 (m, 1H), 4.70 (dd, J=6.2, 3.1 Hz, 1H), 3.87 (s, 3H), 3.46 (dt, J=12.3, 3.0 Hz, 1H), 3.30-3.28 (m, 1H), 2.61 (s, 6H); MS (ESI.sup.+) m/z 478 (M+H).sup.+.

    Example 556: rac-(2R,4R)-7-fluoro-4-hydroxy-N-[3-(5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)bicyclo[1.1.1]pentan-1-yl]-6-(trifluoromethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 655)

    [2438] .sup.1H NMR (600 MHz, DMSO-d.sub.6) ppm 9.00 (s, 1H), 8.43 (d, J=0.9 Hz, 1H), 8.00 (dd, J=9.2, 0.9 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.00 (d, J=11.9 Hz, 1H), 6.81 (d, J=9.2 Hz, 1H), 5.86 (d, J=5.9 Hz, 1H), 4.87-4.81 (m, 2H), 3.87 (s, 3H), 2.64 (s, 6H), 2.42 (ddd, J=13.1, 5.7, 2.6 Hz, 1H), 1.80 (ddd, J=13.0, 11.7, 10.4 Hz, 1H); MS (ESI.sup.+) m/z 493 (M+H).sup.+.

    Example 557: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 656)

    [2439] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.92 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.20 (dd, J=8.7, 2.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.56 (d, J=1.2 Hz, 1H), 5.69 (d, J=6.4 Hz, 1H), 4.81 (dt, J=11.4, 6.0 Hz, 1H), 4.62 (dd, J=12.0, 2.2 Hz, 1H), 4.57-4.51 (m, 2H), 4.45-4.39 (m, 2H), 3.67-3.60 (m, 1H), 2.52-2.51 (m, 1H), 2.38-2.31 (m, 1H), 2.00-1.93 (m, 2H), 1.88-1.79 (m, 2H), 1.72 (q, J=11.9 Hz, 1H), 1.47-1.32 (m, 4H); MS (ESI.sup.+) m/z 505 (M+H).sup.+.

    Example 558: (2R,4R)-6-chloro-7-fluoro-4-hydroxy-N-[(1r,4R)-4-{2-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-5-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 657)

    [2440] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.94 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 6.94 (d, J=10.6 Hz, 1H), 6.56 (d, J=1.2 Hz, 1H), 5.73 (d, J=6.2 Hz, 1H), 4.83-4.74 (m, 1H), 4.68 (dd, J=11.8, 2.3 Hz, 1H), 4.57-4.51 (m, 2H), 4.45-4.39 (m, 2H), 3.67-3.59 (m, 1H), 2.52-2.51 (m, 1H), 2.35-2.31 (m, 1H), 2.00-1.92 (m, 2H), 1.88-1.80 (m, 2H), 1.73 (q, J=11.9 Hz, 1H), 1.44-1.33 (m, 4H); MS (ESI.sup.+) m/z 523/525 (M+H).sup.+.

    Example 559: (2R,4R)-6-chloro-4-hydroxy-N-[(1r,4R)-4-{5-[2-(trifluoromethoxy)ethoxy]-1,3-oxazol-2-yl}cyclohexyl]-3,4-dihydro-2H-1-benzopyran-2-carboxamide (Compound 658)

    [2441] .sup.1H NMR (500 MHz, methanol-d.sub.4) ppm 7.50-7.41 (m, 1H), 7.19 (dd, J=8.7, 0.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.19 (s, 1H), 4.99-4.91 (m, 1H), 4.66 (dd, J=11.6, 2.4 Hz, 1H), 4.41-4.28 (m, 4H), 3.89-3.76 (m, 1H), 2.79-2.68 (m, 1H), 2.62-2.49 (m, 1H), 2.22-2.12 (m, 2H), 2.11-1.99 (m, 2H), 1.97-1.85 (m, 1H), 1.73-1.60 (m, 2H), 1.59-1.43 (m, 2H); MS (ESI.sup.+) m/z 505/507 (M+H).sup.+.

    TABLE-US-00003 TABLE 3 The following compounds can be prepared using methodologies similar to those described in the above examples. [00729]embedded image 6-chloro-4-hydroxy-N-[(25)-2- hydroxy-4-{5-[(1s,3R)- 3-(trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[2.2.2]octan-1- yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00730]embedded image 6-chloro-4-hydroxy-N-[(3S)- 3-hydroxy-4-{5-[(1s,3R)- 3-(trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[2.2.2]octan-1-yl]- 3,4-dihydro-2H-1- benzopyran-2-carboxamide [00731]embedded image 6-chloro-4-hydroxy-N-[4- (2-{[(1s,3s)-3- (trifluoromethoxy)cyclobutyl] oxy}acetamido)bicyclo[2.2.1] heptan-1-yl]-3,4-dihydro-2H-1- benzopyran-2- carboxamide [00732]embedded image 6-chloro-4-hydroxy-N-(4- {5-[(1s,3s)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[2.2.1]heptan-1-yl)- 3,4-dihydro-2H-1- benzopyran-2-carboxamide [00733]embedded image (2R,4R)-6-chloro-4-hydroxy- N-(3-{5-[(1s,3S)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[1.1.1]pentan-1-yl)- 3,4-dihydro-2H-1- benzopyran-2-carboxamide [00734]embedded image (2S,4S)-6-chloro-4-hydroxy- N-(3-{5-[(1s,3R)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[1.1.1]pentan-1- yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00735]embedded image (2R,4S)-6-chloro-4-hydroxy- N-(3-{5-[(1s,3S)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[1.1.1]pentan-1- yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00736]embedded image (2S,4R)-6-chloro-4-hydroxy- N-(3-{5-[(1s,3R)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[1.1.1]pentan-1- yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00737]embedded image 6-chloro-4-hydroxy-N-[3- (5-{(1R,2R)-2- [(trifluoromethoxy)methyl] cyclopropyl}-1,3,4- oxadiazol-2-yl)bicyclo[1.1.1] pentan-1-yl]-3,4- dihydro-2H-1-benzopyran-2- carboxamide [00738]embedded image 6-chloro-N-{3-[5-(4-chloro- 3-fluorophenyl)-1,3,4- oxadiazol-2-yl]bicyclo[1.1.1] pentan-1-yl}-4-hydroxy- 3,4-dihydro-2H-1-benzopyran- 2-carboxamide [00739]embedded image 6-chloro-N-{(2S)-4-[4-(4- chloro-3-fluorophenyl)-1H- imidazol-1-yl]-2-hydroxybicyclo [2.2.2]octan-1-yl}-4- hydroxy-3,4-dihydro-2H- 1-benzopyran-2- carboxamide [00740]embedded image 6-chloro-N-{(2S)-4-[5-(4- chloro-3-fluorophenyl)- 1,3,4-oxadiazol-2-yl]-2- hydroxybicyclo[2.2.2]octan-1- yl}-4-hydroxy-3,4-dihydro- 2H-1-benzopyran-2- carboxamide [00741]embedded image 6-chloro-4-methyl-N- (3-{4-[(1s,3s)-3- (trifluoromethoxy)cyclobutyl]- 1H-imidazol-1- yl}bicyclo[1.1.1]pentan-1- yl)-3,4-dihydro-2H-1,4- benzoxazine-2-carboxamide [00742]embedded image 6-chloro-4-methyl-N- (3-{5-[(1s,3s)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[1.1.1]pentan-1- yl)-3,4-dihydro-2H-1,4- benzoxazine-2-carboxamide [00743]embedded image 6-chloro-N-[(2S)-2-hydroxy- 4-{4-[(1s,3R)-3- (trifluoromethoxy)cyclobutyl]- 1H-imidazol-1- yl}bicyclo[2.2.2]octan-1-yl]- 4-methyl-3,4-dihydro- 2H-1,4-benzoxazine-2-carboxamide [00744]embedded image 6-chloro-N-[(2S)-2- hydroxy-4-15-[(1s,3R)-3- (trifluoromethoxy)cyclobutyl]- 1,3,4-oxadiazol-2- yl}bicyclo[2.2.2]octan-1- yl]-4-methyl-3,4-dihydro- 2H-1,4-benzoxazine-2-carboxamide [00745]embedded image 6-chloro-4-methyl-N-[3- (2-{[(1s,3s)-3- (trifluoromethoxy)cyclobutyl] oxy}acetamido)bicyclo [1.1.1]pentan-1-yl]-3,4- dihydro-2H-1,4-benzoxazine-2- carboxamide [00746]embedded image 6-chloro-N-[(2S)-2-hydroxy- 4-(2-{[(1s,3R)-3- (trifluoromethoxy)cyclobutyl] oxy}acetamido)bicyclo[ 2.2.2]octan-1-yl]-4-methyl- 3,4-dihydro-2H-1,4- benzoxazine-2-carboxamide [00747]embedded image 6-chloro-4-hydroxy-N- [(2S)-2-hydroxy-4-{[(1s,3R)-3- (trifluoromethoxy)cyclobutane-1- carbonyl]amino}bicyclo [2.2.2]octan-1-yl]-3,4- dihydro-2H-1-benzopyran- 2-carboxamide [00748]embedded image 6-chloro-4-hydroxy- N-(3-{4-[(1s,3s)-3- (trifluoromethoxy) cyclobutyl]-1,3-oxazol-2- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00749]embedded image 6-chloro-4-hydroxy-N- [(2S)-2-hydroxy-4-{4-[(1s,3R)- 3-(trifluoromethoxy) cyclobutyl]-1H-imidazol-1- yl}bicyclo[2.2.2]octan- 1-yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00750]embedded image (25,4R)-6-chloro-4- hydroxy-N-(3-{4-[cis-3- (trifluoromethoxy) cyclobutyl]-1H-pyrazol-1- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00751]embedded image (2S,4R)-6-chloro-4- hydroxy-N-(3-{2-[cis-3- (trifluoromethoxy)cyclobutyl]- 1,3-oxazol-5- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00752]embedded image (2S,4R)-6-chloro-4- hydroxy-N-[3-(4-{[cis-3- (trifluoromethoxy) cyclobutyl]oxy}-1H-pyrazol-1- yl)bicyclo[1.1.1]pentan- 1-yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00753]embedded image (2R,4R)-6-chloro-4-hydroxy- N-[3-(2-{[cis-3- (trifluoromethoxy)cyclobutyl] oxy}-1,3-oxazol-5- yl)bicyclo[1.1.1]pentan-1- yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00754]embedded image (28,4R)-6-chloro-4- hydroxy-N-[3-(2-{[cis-3- (trifluoromethoxy)cyclobutyl] oxy}-1,3-oxazol-5- yl)bicyclo[1.1.1]pentan-1- yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00755]embedded image (2S,4R)-6-chloro-4-hydroxy- N-[3-(4-{(1RS,2RS)-2- [(trifluoromethoxy)methyl] cyclopropyl}-1H-pyrazol- 1-yl)bicyclo[1.1.1]pentan- 1-yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00756]embedded image (2R,4R)-6-chloro-4-hydroxy- N-(3-{2-[cis-3- (trifluoromethoxy)cyclobutyl]- 2H-1,2,3-triazol-4- yl}bicyclo[1.1.1]pentan-1-yl)- 3,4-dihydro-2H-1- benzopyran-2-carboxamide [00757]embedded image (2S,4R)-6-chloro-4-hydroxy- N-(3-{2-[cis-3- (trifluoromethoxy)cyclobutyl]-2H- 1,2,3-triazol-4- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00758]embedded image (2S,4R)-6-chloro-4-hydroxy- N-(3-{4-[3- (trifluoromethoxy)azetidin- 1-yl]-1H-pyrazol-1- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00759]embedded image (2S,4R)-6-chloro-4-hydroxy- N-(3-{4-[3- (trifluoromethoxy)pyrrolidin- 1-yl]-1H-pyrazol-1- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00760]embedded image (2R,4R)-6-chloro-7-fluoro- 4-hydroxy-N-(3-{4-[cis-3- (trifluoromethoxy)cyclobutyl]- 1H-pyrazol-1- yl}bicyclo[1.1.1]pentan- 1-yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00761]embedded image (2S,4R)-6-chloro-7-fluoro- 4-hydroxy-N-(3-{4-[cis-3- (trifluoromethoxy)cyclobutyl]- 1H-pyrazol-1- yl}bicyclo[1.1.1]pentan-1- yl)-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00762]embedded image (2R,4R)-6-chloro-7-fluoro- 4-hydroxy-N-[3-(4-{[cis-3- (trifluoromethoxy)cyclobutyl] oxy}-1H-pyrazol-1- yl)bicyclo[1.1.1]pentan-1- yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide [00763]embedded image (2S,4R)-6-chloro-7-fluoro- 4-hydroxy-N-[3-(4-{[cis-3- (trifluoromethoxy)cyclobutyl] oxy}-1H-pyrazol-1- yl)bicyclo[1.1.1 ]pentan-1- yl]-3,4-dihydro-2H-1- benzopyran-2-carboxamide

    Example 560: Activity of exemplary compounds in an in vitro model of vanishing cell white matter disease (VWMD)

    [2442] In order to test exemplary compounds of the invention in a cellular context, a stable VWMD cell line was first constructed. The ATF4 reporter was prepared by fusing the human full-length ATF4 5-UTR (NCBI Accession No. BC022088.2) in front of the firefly luciferase (FLuc) coding sequence lacking the initiator methionine as described in Sidrauski et al (eLife 2013). The construct was used to produce recombinant retroviruses using standard methods and the resulting viral supernatant was used to transduce HEK293T cells, which were then subsequently selected with puromycin to generate a stable cell line.

    [2443] HEK293T cells carrying the ATF4 luciferase reporter were plated on polylysine coated 384-well plates (Greiner Bio-one) at 30,000 cells per well. Cells were treated the next day with 1 g/mL tunicamycin and 200 nM of a compound of Formula (I) for 7 hours. Luminescence was measured using One Glo (Promega) as specified by the manufacturer. Cells were maintained in DMEM with L-glutamine supplemented with 10% heat-inactivated FBS (Gibco) and Antibiotic-Antimycotic solution (Gibco).

    [2444] Table 4 below summarizes the EC.sub.50 data obtained using the ATF4-Luc assay for exemplary compounds of the invention. In this table, A represents an EC.sub.50 of less than 10 nM; B an EC.sub.50 greater than or equal to 10 nM and less than 50 nM; C an EC.sub.50 greater than or equal to 50 nM and less than 250 nM; D an EC.sub.50 greater than or equal to 250 nM and less than 500 nM; E an EC.sub.50, greater than or equal to 500 nM and less than 2 M; F an EC.sub.50 of greater than 2 M; and G indicates that data is not available.

    TABLE-US-00004 TABLE 4 EC.sub.50 values of exemplary compounds of the invention in the ATF4-Luc assay. Compound No. ATF4-Luc EC.sub.50 100 F 101 F 102 B 103 C 104 B 105 A 106 B 107 A 108 A 109 B 110 A 111 B 112 A 113 B 114 A 115 A 116 A 117 A 118 E 119 B 120 B 121 B 122 B 123 C 124 B 125 C 126 B 127 B 128 E 129 B 130 D 131 C 132 C 133 G 134 D 135 C 136 C 137 C 138 C 139 E 140 C 141 B 142 F 143 C 144 C 145 C 146 D 147 D 148 B 149 A 150 F 151 C 152 B 153 A 154 B 155 B 156 A 157 F 158 F 159 B 160 C 161 A 162 B 163 B 164 A 165 B 166 A 167 B 168 D 169 A 170 D 171 A 172 B 173 B 174 A 175 C 176 B 177 C 178 B 179 C 180 C 181 A 182 F 183 B 184 G 185 F 186 B 187 C 188 F 189 B 190 C 191 A 192 B 193 C 194 A 195 A 196 B 197 F 198 D 199 C 200 C 201 A 202 A 203 A 204 B 205 C 206 E 207 A 208 A 209 G 210 A 211 A 212 A 213 C 214 B 215 A 216 F 217 C 218 E 219 E 220 A 221 C 222 B 223 B 224 F 225 E 226 E 227 F 228 F 229 B 230 C 231 B 232 C 233 E 234 B 235 C 236 A 237 A 238 B 239 B 240 A 241 C 242 A 243 C 244 A 245 C 246 B 247 C 248 B 249 C 250 C 251 F 252 A 253 B 254 A 255 B 256 A 257 C 258 A 259 B 260 B 261 C 262 A 263 B 264 A 265 B 266 B 267 C 268 C 269 D 270 A 271 B 272 B 273 C 274 B 275 C 276 A 277 C 278 E 279 A 280 C 281 A 282 A 283 C 284 C 285 A 286 E 287 A 288 B 289 B 290 C 291 E 292 A 293 A 294 B 295 B 296 E 297 B 298 C 299 E 300 C 301 E 302 A 303 C 304 A 305 A 306 A 307 A 308 A 309 F 310 C 311 A 312 A 313 D 314 C 315 B 316 A 317 B 318 C 319 D 320 B 321 B 322 A 323 A 324 A 325 A 326 A 327 A 328 C 329 A 330 A 331 A 332 A 333 C 334 C 335 C 336 C 337 B 338 A 339 D 340 C 341 B 342 B 343 A 344 A 345 C 346 A 347 A 348 C 349 B 350 A 351 A 352 B 353 C 354 A 355 B 356 A 357 A 358 A 359 B 360 A 361 A 362 C 363 A 364 A 365 A 366 C 367 A 368 B 369 A 370 B 371 A 372 B 373 C 374 C 375 D 376 C 377 D 378 A 379 A 380 A 381 B 382 C 383 A 384 D 385 A 386 A 387 C 388 C 389 A 390 A 391 A 392 D 393 C 394 A 395 B 396 C 397 C 398 C 399 D 400 B 401 D 402 A 403 A 404 G 405 G 40 G 407 G 408 G 409 A 410 A 411 B 412 A 413 A 414 A 415 A 416 A 417 A 418 B 419 A 420 B 421 A 422 A 423 A 424 A 425 A 426 D 427 A 428 A 429 A 430 B 431 A 432 A 433 A 434 A 435 A 436 A 437 B 438 B 439 A 440 B 441 B 442 A 443 B 444 A 445 E 446 B 447 C 448 E 450 C 451 A 452 D 453 A 454 A 455 C 456 C 457 A 458 B 459 A 460 A 461 A 462 A 463 A 464 A 465 A 466 A 467 A 468 A 469 A 470 A 471 A 472 A 473 A 474 A 475 A 476 A 477 A 478 A 479 A 480 A 481 A 482 A 483 A 484 A 485 A 486 A 487 A 488 A 489 A 490 A 491 A 492 A 493 A 494 A 495 A 496 A 497 B 498 B 499 B 500 B 501 B 502 C 503 A 504 A 505 A 506 A 507 A 508 B 509 B 510 B 511 B 512 B 513 A 514 A 515 B 516 A 517 A 518 B 519 B 520 B 521 B 522 A 523 A 524 B 525 B 526 B 527 A 528 B 529 B 530 B 531 B 532 A 533 A 534 B 535 B 536 A 537 A 538 A 539 B 540 B 541 A 542 A 543 A 544 A 545 A 546 B 547 A 548 A 549 A 550 A 551 A 552 A 553 A 554 A 555 A 556 A 557 B 558 B 559 B 560 B 561 A 562 A 563 A 564 A 565 A 566 A 567 A 568 A 569 A 570 A 571 A 572 A 573 B 574 A 575 A 576 A 577 A 578 A 579 A 580 A 581 B 582 B 583 A 584 A 585 A 586 B 587 A 588 B 589 B 590 B 591 B 592 B 593 B 594 C 595 D 596 A 597 B 598 A 599 A 600 A 601 B 602 A 603 A 604 A 605 A 606 A 607 A 608 B 609 A 610 A 611 A 612 A 613 B 614 A 615 B 616 A 617 A 618 B 619 B 620 A 621 A 622 B 623 A 624 A 625 A 626 B 627 A 628 C 629 B 630 C 631 B 632 B 633 A 634 A 635 A 636 A 637 C 638 A 639 A 640 A 641 A 642 B 643 A 644 A 645 A 646 A 647 A 648 A 649 A 650 A 651 A 652 B 653 C 654 B 655 A 656 G 657 G 658 G

    EQUIVALENTS AND SCOPE

    [2445] In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

    [2446] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

    [2447] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

    [2448] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.