COMPOUNDS

Abstract

The present invention relates to macrocyclic compounds, such as macrocyclic sulfonyl triazoles. The present invention further relates to associated salts, solvates, prodrugs and pharmaceutical compositions, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.

Claims

1. A compound of formula (I): ##STR00231## or a pharmaceutically acceptable salt or solvate thereof, wherein: J is —SO—, —SO.sub.2—, —SO(═NH)— or —SO(═NR.sup.j)—; Q.sup.1 and Q.sup.2 are each independently selected from O, S, N, NH, NR.sup.q, CH, CHal or CR.sup.qq, provided that at least one of Q.sup.1 and Q.sup.2 is selected from N, NH and NR.sup.q; Q.sup.3 is selected from O, S, N, NH and NR.sup.q; and Q.sup.4 and Q.sup.5 are each independently selected from C and N, provided that at least one of Q.sup.4 and Q.sup.5 is C; such that ring Q is a 5-membered heteroaryl ring; X is —O—, —NH—, —NR.sup.x—, —CH.sub.2—, —CH(Hal)-, —C(Hal).sub.2-, —CH(R.sup.xx)—, —C(Hal)(R.sup.xx)— or —C(R.sup.xx).sub.2—; L is a saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted, and wherein the hydrocarbylene group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton; -J-, ring Q, —X— and -L- together form a ring, such that the minimum single ring size that encompasses all or part of each of -J-, ring Q, —X— and -L- is from 8 to 30 atoms; each R.sup.j, R.sup.q and R.sup.x is independently selected from a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton; each R.sup.qq is independently selected from —OH, —NO.sub.2, —NH.sub.2, —N.sub.3, —SH, —SO.sub.2H, —SO.sub.2NH.sub.2, or a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton; each R.sup.xx is independently selected from —OH, —NO.sub.2, —NH.sub.2, —N.sub.3, —SH, —SO.sub.2H, —SO.sub.2NH.sub.2, or a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton, or any two R.sup.x may, together with the carbon atom to which they are attached, form a saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; and each Hal is independently selected from F, Cl, Br or I.

2. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein: (i) J is —SO.sub.2—; and/or (ii) Q.sup.1 and Q.sup.2 are each independently selected from N, NH and NR.sup.q, optionally wherein Q.sup.1 and Q.sup.2 are both N; and/or (iii) Q.sup.3 is selected from O, S, N and NH, optionally wherein Q.sup.3 is NH; and/or (iv) Q.sup.4 and Q.sup.5 are both C.

3-7. (canceled)

8. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein: (i) X is —O—, —NH—, —NR.sup.x—, —CH.sub.2—, —CH(F)—, —CH(Cl)— or —CH(R.sup.xx)—; or (ii) X is —O— or —NH—; or (iii) X is —NH—.

9-10. (canceled)

11. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ia): ##STR00232## wherein: J, Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, Q.sup.5, ring Q and X are as previously defined; -J-, ring Q, —X—, -L.sup.1-, -L.sup.2-, -L.sup.3- and -L.sup.4- together form a ring, such that the minimum single ring size that encompasses all or part of each of -J-, ring Q, —X—, -L.sup.1-, -L.sup.2-, -L.sup.3- and -L.sup.4- is from 8 to 30 atoms; L.sup.1 is a bond, a divalent 3- to 7-membered monocyclic group, a divalent 5- to 12-membered bicyclic group, or a divalent 7- to 18-membered tricyclic group, any of which may optionally be substituted with one or more monovalent substituents and/or π-bonded substituents; L.sup.2 is an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or more heteroatoms independently selected from N, O and S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more monovalent substituents, and/or one or more π-bonded substituents; L.sup.3 is a bond, a divalent 3- to 7-membered monocyclic group, a divalent 5- to 12-membered bicyclic group, or a divalent 7- to 18-membered tricyclic group, any of which may optionally be substituted with one or more monovalent substituents and/or π-bonded substituents; and L.sup.4 is a divalent 3- to 7-membered monocyclic group, a divalent 5- to 12-membered bicyclic group, or a divalent 7- to 18-membered tricyclic group, any of which may optionally be substituted with one or more monovalent substituents and/or π-bonded substituents.

12. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 11, wherein: (i) L.sup.1 is a divalent 3- to 7-membered monocyclic group, a divalent 5- to 12-membered bicyclic group, or a divalent 7- to 18-membered tricyclic group, any of which may optionally be substituted with one or more monovalent substituents and/or π-bonded substituents; or (ii) L.sup.1 is a divalent 5- to 12-membered spiro bicyclic group, which may optionally be substituted with one or more monovalent substituents and/or π-bonded substituents.

13. (canceled)

14. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 11, wherein the ring of the divalent monocyclic, bicyclic or tricyclic group of L.sup.4 that is directly attached to X is aromatic.

15. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ic) or (Ic′): ##STR00233## wherein: L.sup.1 is a divalent 3- to 7-membered monocyclic group, or a divalent 7- to 11-membered bicyclic group, wherein the divalent 3- to 7-membered monocyclic group or divalent 7- to 11-membered bicyclic group may optionally be substituted with one or more halo groups and/or one or more oxo (═O) groups and/or one or more substituents R.sup.L; L.sup.2 is an alkylene or alkenylene group, wherein the alkylene or alkenylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein one or more carbon atoms in the backbone of the alkylene or alkenylene group may optionally be replaced by one or more heteroatoms independently selected from N and O, and wherein the alkylene or alkenylene group may optionally be substituted with one or more halo groups and/or one or more oxo (═O) groups; L.sup.3 is a divalent phenyl or 5- or 6-membered heteroaryl group, wherein the divalent phenyl or 5- or 6-membered heteroaryl group may optionally be substituted with one or more halo groups and/or one or more substituents R.sup.L; L.sup.4 is a divalent phenyl or 5- or 6-membered heteroaryl group, wherein the divalent phenyl or 5- or 6-membered heteroaryl group may optionally be substituted with one or more halo groups and/or one or more substituents R.sup.L; for a compound having the formula (Ic), the ring atom of L.sup.4 that is directly attached to L.sup.3 is at the α-position relative to the ring atom of L.sup.4 that is directly attached to the nitrogen atom of the —NH— group; for a compound having the formula (Ic′), the ring atom of L.sup.4 that is directly attached to L.sup.3 is at the α-position relative to the ring atom of L.sup.4 that is directly attached to the oxygen atom of the —O— group; each R.sup.L is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, —R.sup.11—R.sup.12, —R.sup.11—CN, —R.sup.11—N(R.sup.13).sub.2, —R.sup.11—OR.sup.13, —R.sup.11—COR.sup.13, —R.sup.11—COOR.sup.13, —R.sup.11—CON(R.sup.13).sub.2, —R.sup.11—C(═NR.sup.13)R.sup.13, —R.sup.11—C(═NR.sup.13)N(R.sup.13).sub.2, —R.sup.11—C(═NOR.sup.13)R.sup.13, —R.sup.II—SO.sub.2R.sup.13 or —R.sup.II—SO.sub.2N(R.sup.13).sub.2 group, and/or any two R.sup.L attached to the same divalent phenyl or 5- or 6-membered heteroaryl group of L.sup.3 or L.sup.4 may, together with the atoms of the divalent phenyl or 5- or 6-membered heteroaryl group to which they are attached, form a fused 5- or 6-membered cyclic group, wherein the fused 5- or 6-membered cyclic group may optionally be substituted with one or more halo groups and/or one or two oxo (═O) groups and/or one, two or three substituents independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, —R.sup.11—R.sup.12, —R.sup.11—CN, —R.sup.11—N(R.sup.13).sub.2, —R.sup.11—OR.sup.13, —R.sup.11—COR.sup.13, —R.sup.11—COOR.sup.13, —R.sup.11—CON(R.sup.13).sub.2, —R.sup.11—C(═NR.sup.13)R.sup.13, —R.sup.11—C(═NR.sup.13)N(R.sup.13).sub.2, —R.sup.11—C(═NOR.sup.13)R.sup.13, —R.sup.11—SO.sub.2R.sup.13 or —R.sup.11—SO.sub.2N(R.sup.13).sub.2 group; each R.sup.11 is independently selected from a bond, or a C.sub.1-C.sub.4 alkylene group, wherein the C.sub.1-C.sub.4 alkylene group may be straight-chained or branched, or be or include a C.sub.3-C.sub.4 cycloalkylene group, and wherein the C.sub.1-C.sub.4 alkylene group may optionally be substituted with one or more halo groups; each R.sup.12 is independently selected from a 3- to 6-membered cyclic group, wherein the 3- to 6-membered cyclic group may optionally be substituted with one or more halo groups and/or one, two or three substituents independently selected from —CN, —R.sup.14, —OH, —OR.sup.14, —NH.sub.2, —NHR.sup.14 and —N(R.sup.14).sub.2; each R.sup.13 is independently selected from hydrogen or a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, or 3- to 6-membered cyclic group, wherein the 3- to 6-membered cyclic group may optionally be substituted with one or more halo groups and/or one, two or three substituents independently selected from —CN, —R.sup.14, —OH, —OR.sup.14, —NH.sub.2, —NHR.sup.14 and —N(R.sup.14).sub.2, or any two R.sup.13 attached to the same nitrogen atom may together form a C.sub.2-C.sub.5 alkylene or C.sub.2-C.sub.5 haloalkylene group; each R.sup.14 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; for a compound having the formula (Ic), the minimum single ring size that encompasses all or part of each of -L.sup.1-, -L.sup.2-, -L.sup.3-, -L.sup.4- and ##STR00234##  is from 8 to 30 atoms; and for a compound having the formula (Ic′), the minimum single ring size that encompasses all or part of each of -L.sup.1-, -L.sup.2-, -L.sup.3-, -L.sup.4- and ##STR00235##  is from 8 to 30 atoms.

16. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 15, wherein: (i) the divalent phenyl or 5- or 6-membered heteroaryl group of L.sup.4 is substituted at the α′-position, relative to the ring atom of L.sup.4 that is directly attached to the nitrogen atom of the —NH— group where the compound has the formula (Ic), or relative to the ring atom of L.sup.4 that is directly attached to the oxygen atom of the —O— group where the compound has the formula (Ic′), with a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, or 3- to 6-membered cyclic group, wherein the 3- to 6-membered cyclic group may optionally be substituted with one or more halo groups; or (ii) the divalent phenyl or 5- or 6-membered heteroaryl group of L.sup.4 is ortho-fused to a 5- or 6-membered cyclic group across the α′,β′-positions, relative to the ring atom of L.sup.4 that is directly attached to the nitrogen atom of the —NH— group where the compound has the formula (Ic), or relative to the ring atom of L.sup.4 that is directly attached to the oxygen atom of the —O— group where the compound has the formula (Ic′), wherein the ortho-fused 5-or 6-membered cyclic group is optionally substituted with one or more halo groups.

17. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the minimum single ring size that encompasses: all or part of each of -J-, ring Q, —X— and -L-, is from 12 to 24 atoms, or from 14 to 20 atoms.

18. (canceled)

19. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound: (i) has the formula (Id): ##STR00236## wherein: A.sup.1 and A.sup.3 are each independently selected from C and N, and A.sup.2, A.sup.4 and A.sup.5 are each independently selected from N, CH, CY.sup.1, CR.sup.A, NH and NR.sup.A, such that ring A.sup.d is a 5-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, CH, CY.sup.1 and CR.sup.B, such that ring B is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; each R.sup.A is independently selected from —OH, —NH.sub.2, —CN or a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.A contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —R.sup.B1, —OH, —OR.sup.B1, —NH.sub.2, —NHR.sup.B1 or —N(R.sup.B1).sub.2 group, wherein each R.sup.B1 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 fluoroalkyl group; each Y.sup.1 is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein L.sup.2 has a chain length of from 2 to 8 atoms, and wherein L.sup.2 may optionally be substituted with one or more fluoro groups and/or one or two oxo (═O) groups and/or one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a C.sub.1-C.sub.4 alkyl, —O—C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl or —O—C.sub.1-C.sub.4 fluoroalkyl group, or wherein any two R.sup.L2 may together form a C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group, wherein one carbon atom in the backbone of the C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group may optionally be replaced by a single oxygen atom; R.sup.4 is selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.3-C.sub.6 fluorocycloalkyl group, and R.sup.5 is selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or R.sup.4 and R.sup.5 together form a divalent group selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—, wherein the divalent group formed by R.sup.4 and R.sup.5 may optionally be fluoro-substituted; and R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or (ii) has the formula (e): ##STR00237## wherein: A.sup.6, A.sup.7, A.sup.8 and A.sup.9 are each independently selected from N, CH, CY.sup.1 and CR.sup.A, such that ring A.sup.e is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, CH, CY.sup.1 and CR.sup.B, such that ring B is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; each R.sup.A is independently selected from —OH, —NH.sub.2, —CN or a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.A contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —R.sup.B1, —OH, —OR.sup.B1, —NH.sub.2, —NHR.sup.B1 or —N(R.sup.B1).sub.2 group, wherein each R.sup.B1 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 fluoroalkyl group; each Y.sup.1 is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein L.sup.2 has a chain length of from 2 to 8 atoms, and wherein L.sup.2 may optionally be substituted with one or more fluoro groups and/or one or two oxo (═O) groups and/or one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a C.sub.1-C.sub.4 alkyl, —O—C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl or —O—C.sub.1-C.sub.4 fluoroalkyl group, or wherein any two R.sup.L2 may together form a C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group, wherein one carbon atom in the backbone of the C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.5 fluoroalkylene group may optionally be replaced by a single oxygen atom; R.sup.4 is selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.6 cycloalkyl or C.sub.1-C.sub.6 fluorocycloalkyl group, and R.sup.5 is selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or R.sup.4 and R.sup.5 together form a divalent group selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—, wherein the divalent group formed by R.sup.4 and R.sup.5 may optionally be fluoro-substituted; and R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group; or (iii) has the formula (If): ##STR00238## wherein: A.sup.10 and A.sup.13 are each independently selected from N, CH, CY.sup.2 and CR.sup.AA, and each A.sup.1 and A.sup.12 is independently selected from O, NH, NR.sup.AAA, C═O, CH.sub.2, CH(Y.sup.2), CH(R.sup.AA), C(Y.sup.2).sub.2, C(Y.sup.2)(R.sup.AA) and C(R.sup.AA).sub.2, such that ring A.sup.f contains one or two atoms independently selected from oxygen and nitrogen in its ring structure; fa is 1, 2 or 3, and fb is 1, 2 or 3, provided that fa+fb≤5; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, CH, CY.sup.1 and CR.sup.B, such that ring B is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; each R.sup.AA is independently selected from —OH, —NH.sub.2, —CN, or a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.AAA is independently selected from a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AAA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —R.sup.B1, —OH, —OR.sup.B1, —NH.sub.2, —NHR.sup.B1 or —N(R.sup.B1).sub.2 group, wherein each R.sup.B1 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 fluoroalkyl group; each Y.sup.1 and Y.sup.2 is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein L.sup.2 has a chain length of from 2 to 8 atoms, and wherein L.sup.2 may optionally be substituted with one or more fluoro groups and/or one or two oxo (═O) groups and/or one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a C.sub.1-C.sub.4 alkyl, —O—C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl or —O—C.sub.1-C.sub.4 fluoroalkyl group, or wherein any two R.sup.L2 may together form a C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group, wherein one carbon atom in the backbone of the C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.5 fluoroalkylene group may optionally be replaced by a single oxygen atom; R.sup.4 is selected from a C.sub.3-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.6 cycloalkyl or C.sub.6-C.sub.6 fluorocycloalkyl group, and R.sup.5 is selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or R.sup.4 and R.sup.5 together form a divalent group selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—, wherein the divalent group formed by R.sup.4 and R.sup.5 may optionally be fluoro-substituted; and R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group; or (iv) has the formula (Ig): ##STR00239## wherein: A.sup.14 and A.sup.19 are each independently selected from N, CH, CY.sup.2 and CR.sup.AA, and each A.sup.15, A.sup.16, A.sup.17 and A.sup.18 is independently selected from O, NH, NR.sup.AAA, C═O, CH.sub.2, CH(Y.sup.2), CH(R.sup.AA), C(Y.sup.2).sub.2, C(Y.sup.2)(R.sup.AA) and C(R.sup.AA).sub.2, such that ring G.sup.1 contains zero, one or two atoms independently selected from oxygen and nitrogen in its ring structure, and ring G.sup.2 contains zero, one or two atoms independently selected from oxygen and nitrogen in its ring structure; ga is 0, 1, 2, 3 or 4 and gb is 0, 1, 2, 3 or 4 provided that 1≤ga+gb≤5; gc is 0, 1, 2, 3, or 4 and gd is 0, 1, 2, 3, or 4 provided that 1≤gc+gd≤5; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, CH, CY.sup.1 and CR.sup.B, such that ring B is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; each R.sup.AA is independently selected from —OH, —NH.sub.2, —CN, or a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.AAA is independently selected from a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AAA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —R.sup.B1, —OH, —OR.sup.B1, —NH.sub.2, —NHR.sup.B1 or —N(R.sup.B1).sub.2 group, wherein each R.sup.B1 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 fluoroalkyl group; each Y.sup.1 and Y.sup.2 is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein L.sup.2 has a chain length of from 2 to 8 atoms, and wherein L.sup.2 may optionally be substituted with one or more fluoro groups and/or one or two oxo (═O) groups and/or one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a C.sub.1-C.sub.4 alkyl, —O—C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl or —O—C.sub.1-C.sub.4 fluoroalkyl group, or wherein any two R.sup.L2 may together form a C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group, wherein one carbon atom in the backbone of the C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.5 fluoroalkylene group may optionally be replaced by a single oxygen atom; R.sup.4 is selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.6 cycloalkyl or C.sub.3-C.sub.6 fluorocycloalkyl group, and R.sup.5 is selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or R.sup.4 and R.sup.5 together form a divalent group selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—, wherein the divalent group formed by R.sup.4 and R.sup.5 may optionally be fluoro-substituted; and R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group; or (v) has the formula (Ig′): ##STR00240## wherein: A.sup.14 and A.sup.19 are each independently selected from N, CH, CY.sup.2 and CR.sup.AA, and each A.sup.15, A.sup.16, A.sup.17 and A.sup.18 is independently selected from O, NH, NR.sup.AAA, C═O, CH.sub.2, CH(Y.sup.2), CH(R.sup.AA), C(Y.sup.2).sub.2, C(Y.sup.2)(R.sup.AA) and C(R.sup.AA).sub.2, such that ring G.sup.1 contains zero, one or two atoms independently selected from oxygen and nitrogen in its ring structure, and ring G.sup.2 contains zero, one or two atoms independently selected from oxygen and nitrogen in its ring structure; ga is 0, 1, 2, 3, or 4 and gb is 0, 1, 2, 3, or 4 provided that 1≤ga+gb≤5; gc is 0, 1, 2, 3, or 4 and gd is 0, 1, 2, 3, or 4 provided that 1≤gc+gd≤5; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, CH, CY.sup.1 and CR.sup.B, such that ring B is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; each R.sup.AA is independently selected from —OH, —NH.sub.2, —CN, or a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.AAA is independently selected from a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AAA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —R.sup.B1, —OH, —OR.sup.B1, —NH.sub.2, —NHR.sup.B1 or —N(R.sup.B1).sub.2 group, wherein each R.sup.B1 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 fluoroalkyl group; each Y.sup.1 and Y.sup.2 is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein L.sup.2 has a chain length of from 2 to 8 atoms, and wherein L.sup.2 may optionally be substituted with one or more fluoro groups and/or one or two oxo (═O) groups and/or one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a C.sub.1-C.sub.4 alkyl, —O—C.sub.1-C.sub.4 alkyl C.sub.1-C.sub.4 fluoroalkyl or —O—C.sub.1-C.sub.4 fluoroalkyl group, or wherein any two R.sup.L2 may together form a C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group, wherein one carbon atom in the backbone of the C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.5 fluoroalkylene group may optionally be replaced by a single oxygen atom; R.sup.4 is selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.6 cycloalkyl or C.sub.1-C.sub.6 fluorocycloalkyl group, and R.sup.5 is selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or R.sup.4 and R.sup.5 together form a divalent group selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—, wherein the divalent group formed by R.sup.4 and R.sup.5 may optionally be fluoro-substituted; and R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group; or (vi) has the formula (Ih): ##STR00241## wherein: each A.sup.20, A.sup.23, A.sup.24 and A.sup.28 is independently selected from N, CH, CY.sup.2 and CR.sup.AA, and each A.sup.21, A.sup.22, A.sup.25, A.sup.26 and A.sup.27 is independently selected from O, NH, NR.sup.AAA, C═O, CH.sub.2, CH(Y.sup.2), CH(R.sup.AA), C(Y.sup.2).sub.2, C(Y.sup.2)(R.sup.AA) and C(R.sup.AA).sub.2, such that the divalent bridged bicyclic group defined by A.sup.20, A.sup.21, A.sup.22, A.sup.23, A.sup.24, A.sup.25, A.sup.26, A.sup.27 and A.sup.28 contains zero, one, two or three atoms independently selected from oxygen and nitrogen in its ring structure; ha is 0, 1 or 2; hb is 0, 1 or 2; he is 1, 2 or; hd is 0, 1 or 2; he is 0, 1 or 2; 1≤ha+hb+he+hd+he≤7; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, CH, CY.sup.1 and CR.sup.B, such that ring B is a 6-membered aryl ring or a 6-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; each R.sup.AA is independently selected from —OH, —NH.sub.2, —CN, or a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.AAA is independently selected from a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AAA contains, in total, from 1 to 6 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —R.sup.B1, —OH, —OR.sup.B1, —NH.sub.2, —NHR.sup.B1 or —N(R.sup.B1).sub.2 group, wherein each R.sup.B1 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 fluoroalkyl group; each Y.sup.1 and Y.sup.2 is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene group, wherein the straight-chained alkylene group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein L.sup.2 has a chain length of from 2 to 8 atoms, and wherein L.sup.2 may optionally be substituted with one or more fluoro groups and/or one or two oxo (═O) groups and/or one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a C.sub.1-C.sub.4 alkyl, —O—C.sub.1-C.sub.4 alkyl C.sub.1-C.sub.4 fluoroalkyl or —O—C.sub.1-C.sub.4 fluoroalkyl group, or wherein any two R.sup.L2 may together form a C.sub.1-C.sub.5 alkylene or C.sub.1-C.sub.5 fluoroalkylene group, wherein one carbon atom in the backbone of the C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.5 fluoroalkylene group may optionally be replaced by a single oxygen atom; R.sup.4 is selected from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.6 cycloalkyl or C.sub.1-C.sub.6 fluorocycloalkyl group, and R.sup.5 is selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group, or R.sup.4 and R.sup.5 together form a divalent group selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—, wherein the divalent group formed by R.sup.4 and R.sup.5 may optionally be fluoro-substituted; and R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br or a methyl or fluoromethyl group.

20-24. (canceled)

25. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, which is (a) a compound selected from the group consisting of: ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## or (b) a pharmaceutically acceptable salt or solvate of the selected compound.

26. A prodrug of the compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

27. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, and a pharmaceutically acceptable excipient.

28. A method of treating or preventing a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

29. (canceled)

30. The method as claimed in claim 28, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an auto-immune disease; (iii) cancer; (iv) an infection; (v) a central nervous system disease; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) pain; (xvii) a condition associated with diabetes; (xviii) a condition associated with arthritis; (xix) a headache; (xx) a wound or burn; and (xxi) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

31. The method as claimed in claim 28, wherein the disease, disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) familial cold autoinflammatory syndrome (FCAS); (iv) neonatal onset multisystem inflammatory disease (NOMID); (v) familial Mediterranean fever (FMF); (vi) pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA); (vii) hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS); (viii) Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS); (ix) systemic juvenile idiopathic arthritis; (x) adult-onset Still's disease (AOSD); (xi) relapsing polychondritis; (xii) Schnitzler's syndrome; (xiii) Sweet's syndrome; (xiv) Behcet's disease; (xv) anti-synthetase syndrome; (xvi) deficiency of interleukin 1 receptor antagonist (DIRA); and (xvii) haploinsufficiency of A20 (HA20).

32. A method of inhibiting NLRP3 in a subject, the method comprising administering the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, to the subject thereby inhibiting NLRP3.

33. A method of analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 by a compound, comprising contacting a cell or non-human animal with the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

34. The method as claimed in claim 28, wherein the compound or the pharmaceutically acceptable salt or solvate thereof is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

35. A method of treating or preventing a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the prodrug or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 26, to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

Description

EXAMPLES—COMPOUND SYNTHESIS

[0626] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0627] 2-MeTHF 2-methyltetrahydrofuran [0628] Ac acetyl [0629] AcCl acetyl chloride [0630] Ac.sub.2O acetic anhydride [0631] AcOH acetic acid [0632] app apparent [0633] aq aqueous [0634] B.sub.2Pin.sub.2 bis(pinacolato)diboron, also called 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) [0635] Boc tert-butyloxycarbonyl [0636] br broad [0637] Cbz carboxybenzyl [0638] CDI 1,1-carbonyl-diimidazole [0639] conc concentrated [0640] d doublet [0641] DABCO 1,4-diazabicyclo[2.2.2]octane [0642] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene [0643] DCE 1,2-dichloroethane, also called ethylene dichloride [0644] DCM dichloromethane [0645] dd double doublet [0646] ddd double double doublet [0647] DIAD diisopropyl azodicarboxylate [0648] DIPEA, DIEA N,N-diisopropylethylamine, also called Hunig's base [0649] DIBAL diisobutylaluminum hydride [0650] DMA dimethylacetamide [0651] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0652] DME dimethoxyethane [0653] DMEDA N,N-dimethyl-1,2-ethanediamine [0654] DMF N,N-dimethylformamide [0655] DMF-DMA N,N-dimethylformamide dimethyl acetal [0656] DMSO dimethyl sulfoxide [0657] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0658] eq or equiv equivalent [0659] (ES+) electrospray ionization, positive mode [0660] Et ethyl [0661] EtOAc ethyl acetate [0662] EtOH ethanol [0663] Ex example [0664] FC flash column chromatography on silica gel [0665] h hour(s) [0666] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0667] HPLC high performance liquid chromatography [0668] Hz hertz [0669] Int intermediate [0670] KOAc potassium acetate [0671] KO.sup.tBu potassium tert-butoxide [0672] LC liquid chromatography [0673] LHMDS lithium bis(trimethylsilyl)amide [0674] m multiplet [0675] m-CPBA 3-chloroperoxybenzoic acid [0676] Me methyl [0677] MeCN acetonitrile [0678] MeOH methanol [0679] (M+H).sup.+ protonated molecular ion [0680] MHz megahertz [0681] min minute(s) [0682] MS mass spectrometry [0683] Ms mesyl, also called methanesulfonyl [0684] MsCl mesyl chloride, also called methanesulfonyl chloride [0685] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0686] m/z mass-to-charge ratio [0687] NaOMe sodium methoxide [0688] NaO.sup.tBu sodium tert-butoxide [0689] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0690] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0691] NHMDS sodium bis(trimethylsilyl)amide [0692] NMP N-methylpyrrolidine [0693] NMR nuclear magnetic resonance (spectroscopy) [0694] p pentuplet [0695] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) [0696] PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), also called Pd(dppf)Cl.sub.2 [0697] PE petroleum ether [0698] Ph phenyl [0699] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0700] prep-HPLC preparative high performance liquid chromatography [0701] prep-TLC preparative thin layer chromatography [0702] PTSA p-toluenesulfonic acid [0703] q quartet [0704] quant. quantitative [0705] RP reversed phase [0706] RT room temperature [0707] s singlet [0708] sat saturated [0709] SCX solid supported cation exchange (resin) [0710] SEM 2-(trimethylsilyl)ethoxymethyl [0711] sept septuplet [0712] SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl [0713] SPhos-Pd-G3 (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate [0714] t triplet [0715] TBDMS tert-butyl dimethylsilyl [0716] tBu tert-butyl [0717] T3P propylphosphonic anhydride [0718] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0719] TEA triethylamine [0720] Tf triflyl, also called trifluoromethanesulfonyl [0721] TFA 2,2,2-trifluoroacetic acid [0722] TFAA trifluoroacetic anhydride [0723] THF tetrahydrofuran [0724] TLC thin layer chromatography [0725] TMS trimethylsilyl [0726] wt % weight percent or percent by weight [0727] XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0728] Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [0729] XPhos-Pd-G3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate

[0730] Experimental Methods

[0731] Nuclear Magnetic Resonance

[0732] Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million.

[0733] LC-MS

[0734] LC-MS Methods: Using Agilent 1100 & DAD detector. Mobile Phase A: 0.1% HCOOH in water (v/v); B: acetonitrile. Column: EVO C18 3.0×50 mm, 5 μm.

[0735] Preparative Reversed Phase HPLC General Methods

[0736] Neutral prep-HPLC (x-y % MeCN in water): C18 column, eluting with a H.sub.2O-MeCN gradient using UV detection at 214 and 254 nm.

[0737] Basic prep-HPLC (x-y % MeCN in water): C18 column, eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient using UV detection at 214 and 254 nm.

[0738] Acidic prep-HPLC (x-y % MeCN in water): C18 column, eluting with a water (0.1% formic acid)-MeCN (0.1% formic acid) gradient using UV detection at 214 and 254 nm.

Synthesis of Intermediates

Intermediate A1: 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane

[0739] ##STR00042##

[0740] 2-(Trimethylsilyl)ethoxymethyl chloride (20.7 mL, 0.117 mol) was added to a mixture of 3,5-dibromo-4H-1,2,4-triazole (25.0 g, 0.110 mol), and K.sub.2CO.sub.3 (22.8 g, 0.165 mol) in MeCN (250.0 mL). The mixture was stirred at 22° C. for 4 h. The mixture was filtered, and the filtrate was concentrated. The product was purified by FC (0-50% EtOAc/hexanes) to provide the title compound as an oil (32.2 g, 82%).

[0741] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.43 (s, 2H), 3.71-3.58 (m, 2H), 1.00-0.87 (m, 2H), −0.02 (s, 9H).

Intermediate A2: methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]propanoate

[0742] ##STR00043##

Step A: N-indan-4-ylacetamide

[0743] ##STR00044##

[0744] Acetic anhydride (12.8 mL, 134 mmol) was added to a mixture of indan-4-amine (14.4 mL, 116 mmol) and TEA (21.4 mL, 152 mmol) in DCM (225 mL) at 0° C. The mixture was stirred at 22° C. for 1 h and diluted with aq. HCl (1M, 50.0 mL). The aqueous phase was extracted with DCM (3×50.0 mL), and the combined organic layers were washed with sat. aq. NaHCO.sub.3 (50.0 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to provide the title compound as a solid (20.1 g, 99%).

[0745] LCMS m/z 176.49 (M+H).sup.+ (ES.sup.+).

[0746] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71 (d, J=8.0 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 7.02 (d, J=7.4 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.18 (s, 3H), 2.09 (dd, J=14.9, 7.3 Hz, 2H).

Step B: N-(5-bromoindan-4-yl)acetamide

[0747] ##STR00045##

[0748] Pd(OAc).sub.2 (98.0%, 1.27 g, 5.53 mmol) was added to a mixture of N-indan-4-ylacetamide (94.0%, 20.6 g, 111 mmol) and PTSA (98.5%, 11.7 g, 60.8 mmol) in toluene (250 mL). The mixture was stirred at 22° C. for 5 min, and NBS (99.0%, 21.9 g, 122 mmol) was added. The mixture was stirred at 22° C. for 18 h and then diluted with sat. aq. Na.sub.2S203 (200 mL), and EtOAc (500 mL). The organic phase was washed with sat aq. NaHCO.sub.3 (250 mL) and stirred with Na.sub.2SO.sub.4 and activated carbon (3 g) for 1 h. The mixture was filtered on Celite washing with DCM (200 mL). The filtrate was concentrated to 200 mL. The mixture was diluted with hexanes (500 mL) and then filtered. The solid was washed with hexanes (200 mL) and dried to provide the title compound as a solid (24.1 g, 86%).

[0749] LCMS m/z 255 (M+H).sup.+ (ES.sup.+).

[0750] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.34 (d, J=7.8 Hz, 1H), 7.03 (brs, 1H), 6.99 (d, J=8.0 Hz, 1H), 2.89 (dt, J=15.2, 7.4 Hz, 4H), 2.22 (s, 3H), 2.12-2.01 (m, 2H).

Step C: (5-bromoindan-4-yl)ammonium chloride

[0751] ##STR00046##

[0752] HCl (12.0 M, 158 mL, 1.90 mol) was added to a mixture of N-(5-bromoindan-4-yl)-acetamide (24.1 g, 94.8 mmol) in water (158 mL). The mixture was stirred at 100° C. for 18 h and filtered. The solid was washed with water (300 mL) and EtOAc (100 mL) and dried to provide the title compound as a solid (17 g, 72%).

[0753] LCMS m/Z 214.1 (M-Cl).sup.+ (ES.sup.+).

[0754] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.14 (d, J=7.9 Hz, 1H), 6.48 (d, J=7.9 Hz, 1H), 6.01 (s, 3H), 2.80-2.75 (m, 2H), 2.75-2.70 (m, 2H), 1.99 (p, J=7.5 Hz, 2H).

Step D: 5-(2-fluoro-4-pyridyl)indan-4-amine

[0755] ##STR00047##

[0756] Pd(dppf)Cl.sub.2-DCM (99.0%, 1.78 g, 2.16 mmol) was added to a degassed mixture of (5-bromoindan-4-yl)ammonium chloride (10.4 g, 41.7 mmol), (2-fluoro-4-pyridyl)boronic acid (98.0%, 7.34 g, 51.1 mmol), and K.sub.2CO.sub.3 (99.0%, 18.0 g, 129 mmol) in 1,4-dioxane and water (5:1, 158.5 mL) at 22° C. under N.sub.2. The mixture was stirred at 80° C. for 3 h, and activated carbon was added (2.00 g). The mixture was stirred at 20° C. for 30 min, then filtered on Celite, washing with EtOAc (200 mL). The filtrate was diluted with EtOAc (300 mL) and sat. aq. NaHCO.sub.3 (300 mL). The organic phase was washed with brine (300 mL) and stirred with Na.sub.2SO.sub.4 and activated carbon (2.00 g) for 10 min. The mixture was filtered on celite, washing with EtOAc (100 mL), and the filtrate was concentrated. The residue was filtered on silica gel, washing with 10% EtOAc in hexanes (1.00 L). The filtrate was concentrated to provide the title compound as a solid (10.9 g, 70%).

[0757] LCMS m/z 229.4 (M+H).sup.+ (ES.sup.+).

[0758] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.24 (d, J=5.1 Hz, 1H), 7.32 (ddd, J=5.1, 2.0, 1.4 Hz, 1H), 7.06 (d, J=0.8 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 3.78 (s, 2H), 2.97 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.27-2.07 (m, 2H).

[0759] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.83 (s)

Step E: 5-bromo-N-[5-(2-fluoro-4-pyridyl)indan-4-yl]-2-(2-trimethylsilylethoxy-methyl)-1,2,4-triazol-3-amine

[0760] ##STR00048##

[0761] LHMDS (1.00 M, 150 mL, 150 mmol) was added over 15 min to a mixture of 5-(2-fluoro-4-pyridyl)indan-4-amine (10.9 g, 47.8 mmol) and 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane (Intermediate A1) (41.5 g, 116 mmol) in 2-MeTHF (50.0 mL) at 0° C. The mixture was stirred at 0° C. for 3 h and at 20° C. for 1 h. The mixture was diluted with EtOAc (500 mL) and sat. aq. NH.sub.4Cl (400 mL). The organic phase was washed with sat. aq. NaHCO.sub.3 (300 mL) and brine (300 mL). The organic phase was mixed with Na.sub.2SO.sub.4 and activated carbon. The mixture was filtered on Celite, and the filtrate was concentrated. The residue was filtered on a silica pad, washing with hexanes (250 mL). A precipitate formed. The suspension was filtered, and the solid was rinsed with hexanes (100 mL) and dried to provide a solid. The silica pad was re-washed with 5% EtOAc in hexanes (500 mL). The filtrate was concentrated, diluted with hexanes (300 mL), filtered, and dried to provide a solid. The silica pad was re-washed again with 10% EtOAc in hexanes (1.00 L), and the filtrate was concentrated and dried to provide a solid. All solid materials were combined to provide the title compound as a solid (10.5 g, 44%).

[0762] LCMS m/z 504.3 (M+H).sup.+ (ES.sup.+).

[0763] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20 (d, J=5.1 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.20-7.16 (m, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.94 (s, 1H), 6.18 (s, 1H), 5.26 (s, 2H), 3.56-3.47 (m, 2H), 3.02 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.22-2.07 (m, 2H), 0.79-0.70 (m, 2H), 0.01 (s, 9H).

[0764] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.39 (s).

Step F: methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]propanoate

[0765] ##STR00049##

[0766] DIPEA (2.51 mL, 14.7 mmol) was added to a mixture of 5-bromo-N-[5-(2-fluoro-4-pyridyl)indan-4-yl]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine (3.70 g, 7.33 mmol), Pd.sub.2(dba).sub.3 (0.672 g, 0.733 mmol), Xantphos (0.424 g, 0.733 mmol), and methyl 3-sulfanylpropanoate (1.62 mL, 14.7 mmol) in dioxane (50.0 mL) at 22° C. under N.sub.2. The mixture was stirred at 100° C. for 16 h and diluted with water (100 mL). The aqueous phase was extracted with EtOAc (3×100 mL), and the combined organic phases were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-50% EtOAc/hexanes) to provide the title compound as an oil (3.20 g, 80%).

[0767] LCMS m/z 566.4 (M+Na).sup.+ (ES.sup.+).

[0768] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (d, J=5.2 Hz, 1H), 7.20 (dd, J=4.6, 2.6 Hz, 2H), 7.11 (d, J=7.7 Hz, 1H), 6.95 (s, 1H), 6.09 (s, 1H), 5.23 (s, 2H), 3.69 (s, 3H), 3.55-3.44 (m, 2H), 3.22 (t, J=7.3 Hz, 2H), 3.00 (t, J=7.4 Hz, 2H), 2.76 (td, J=7.3, 3.1 Hz, 4H), 2.11 (p, J=7.5 Hz, 2H), 0.81-0.63 (m, 2H), −0.00 (s, 9H).

[0769] .sup.19F NMR (471 MHz, CDCl.sub.3) δ −67.52 (s).

Intermediate A3: sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate

[0770] ##STR00050##

Step A: methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]propanoate

[0771] ##STR00051##

[0772] m-CPBA (3.30 g, 14.7 mmol) was added to a mixture of methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-sulfanyl]propanoate (Intermediate A2) (3.20 g, 5.89 mmol) in DCM (60.0 mL) at 0° C. under N.sub.2. The mixture was stirred at 22° C. for 4 h and diluted with Na.sub.2S.sub.2O.sub.3 (aq. sat., 50 mL). The aqueous phase was extracted with CHCl.sub.3 (3×100 mL), and the combined organic phases were dried (Na.sub.2SO.sub.4), filtered and concentrated. The product was purified by FC (0-100% EtOAc/hexanes) to provide the title compound as a solid (3.01 g, 88%).

[0773] LCMS m/z 576.1 (M+H).sup.+ (ES.sup.+).

[0774] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.19 (d, J=5.1 Hz, 1H), 7.24 (s, 1H), 7.20 (dt, J=5.1, 1.5 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.94 (s, 1H), 6.49 (s, 1H), 5.39 (s, 2H), 3.71 (s, 3H), 3.64-3.43 (m, 4H), 3.02 (t, J=7.4 Hz, 2H), 2.79 (ddd, J=21.2, 11.4, 5.7 Hz, 4H), 2.13 (dq, J=14.8, 7.5 Hz, 2H), 0.91-0.72 (m, 2H), 0.01 (s, 9H).

[0775] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.40 (s).

Step B: sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxy-methyl)-1,2,4-triazole-3-sulfinate

[0776] ##STR00052##

[0777] Sodium 2-methylbutan-2-olate (1.00 M in THF, 12.5 mL, 12.5 mmol) was added to a mixture of methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]propanoate (79%, 2.78 g, 3.81 mmol) in THF (50.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. Dowex MAC-3 Hydrogen form (7.11 g, 22.9 mmol) was added, and the mixture was stirred at 22° C. for 10 min. The mixture was filtered, washing with Et.sub.2O (20 mL). The filtrate was concentrated. The residue was diluted with hexanes (30.0 mL) and concentrated four times. The product was dried to provide the title compound as a solid (2.01 g, 82%).

[0778] LCMS m/z 490.4 (M-Na+2H).sup.+ (ES.sup.+).

[0779] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27 (d, J=5.3 Hz, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.24 (s, 2H), 7.12 (s, 1H), 5.25 (s, 2H), 3.56-3.42 (m, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.3 Hz, 2H), 2.00 (dd, J=14.6, 7.2 Hz, 2H), 0.91-0.74 (m, 2H), −0.03 (s, 9H).

Intermediate A4: ammonium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate

[0780] ##STR00053##

[0781] tBuONa (361 mg, 3.75 mmol) was added to a mixture of methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-sulfonyl]propanoate (Intermediate A3, Step A) (1.80 g, 3.13 mmol) in THF (30.0 mL) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 2 h and diluted with aq. NH.sub.4Cl (1.00 mL). The mixture was concentrated. The product was purified by basic prep HPLC (0-100% MeCN in water) to provide the title compound as a solid (506 mg, 32%).

[0782] LCMS m/z 490.3 (M-NH.sub.4+2H).sup.+ (ES.sup.+).

[0783] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.31 (d, J=4.4 Hz, 1H), 7.24 (br, 2H), 7.14 (br, 4H), 7.11 (s, 1H), 5.23 (s, 2H), 3.55-3.45 (m, 2H), 2.95 (t, J=7.3 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.04-1.93 (m, 2H), 0.85-0.76 (m, 2H), −0.03 (s, 9H).

[0784] .sup.19F NMR (376 MHz, DMSO-d6) δ −69.20 (s).

Intermediate A5: 3-hydroxypropyl-methyl-piperidin-1-ium-4-yl-ammonium dichloride

[0785] ##STR00054##

Step A: tert-butyl4-[3-hydroxypropyl(methyl)amino]piperidine-1-carboxylate

[0786] ##STR00055##

[0787] tert-Butyl 4-(methylamino)piperidine-1-carboxylate (2.50 g, 11.7 mmol) was added to a mixture of 3-bromopropan-1-ol (1.12 ml, 12.8 mmol) and DIPEA (3.00 mL, 17.5 mmol) in MeCN (50.0 ml) at 22° C. under N.sub.2. The mixture was stirred at 60° C. for 16 h and concentrated. The product was purified by neutral prep HPLC (0-40% MeCN in water) to provide the title compound as an oil (790 mg, 25%).

[0788] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.18 (s, 2H), 3.92-3.72 (m, 2H), 2.74-2.68 (m, 2H), 2.67-2.63 (m, 2H), 2.59 (tt, J=11.9, 3.7 Hz, 1H), 2.28 (s, 3H), 1.70 (td, J=11.5, 5.7 Hz, 4H), 1.61 (s, 1H), 1.45 (s, 9H), 1.49-1.36 (m, 2H).

Step B: 3-hydroxypropyl-methyl-piperidin-1-ium-4-yl-ammonium dichloride

[0789] ##STR00056##

[0790] 4 M HCl in dioxane (7.25 ml, 29.2 mmol) was added to a mixture of tert-butyl 4-[3-hydroxypropyl(methyl)amino]piperidine-1-carboxylate (790 mg, 2.90 mmol) in MeOH (3.5 ml) at 22° C. under N.sub.2. The mixture was stirred at 22° C. for 4 h and diluted with Et.sub.2O (20.0 ml). The mixture was filtered washing with Et.sub.2O (2×20 mL). The filtrate was concentrated to provide the title compound as a solid (600 mg, 84%).

[0791] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.94 (s, 1H), 9.22 (s, 1H), 9.03 (d, J=9.8 Hz, 1H), 3.76-3.44 (m, 4H), 3.40 (m, 2H), 3.23-3.11 (m, 1H), 3.11-3.00 (m, 1H), 2.92 (s, 2H), 2.68 (d, J=4.9 Hz, 3H), 2.25 (m, 1H), 2.17 (m, 1H), 2.03-1.78 (m, 4H).

Intermediate A6: 5-bromo-6-methyl-4-nitro-indane

[0792] ##STR00057##

Step A: N-indan-5-ylacetamide

[0793] ##STR00058##

[0794] TEA (11.8 mL, 84.5 mmol) was added to a mixture of indan-5-amine (7.50 g, 56.3 mmol) in DCM (125 mL) at 0° C. The mixture was stirred for 20 min, and acetyl chloride (12.1 mL, 169 mmol) was added. The mixture was stirred for 30 min at 0° C., and at 22° C. for 16 h. The mixture was diluted with MeOH (20.0 mL, and water (30.0 mL). The aqueous phase was extracted with DCM (3×40.0 mL), and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by FC (20-60% EtOAc/hexanes) to provide the title compound as a solid (9.0 g, 91%).

[0795] LCMS m/z 176.2 (M+H).sup.+ (ES.sup.+).

[0796] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.44 (s, 1H), 7.18-7.10 (m, 3H), 2.86 (dd, J=17.7, 7.5 Hz, 4H), 2.14 (s, 3H), 2.05 (p, J=7.4 Hz, 2H).

Step B: N-(6-bromoindan-5-yl)acetamide

[0797] ##STR00059##

[0798] Bromine (3.29 mL, 64.2 mmol) was a e to a mixture of N-indan-5-ylacetamide (9.00 g, 51.4 mmol) in acetic acid (175 mL) at 0° C. The mixture was stirred at 22° C. for 1.5 h. The mixture was diluted with water, and the precipitate was filtered, washed with water (50.0 mL), and dried to provide the title compound as a solid (13.0 g, 99%).

[0799] LCMS m/z 255.2 (M+H).sup.+ (ES.sup.+).

[0800] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.11 (s, 1H), 7.37 (s, 1H), 2.86 (q, J=7.4 Hz, 5H), 2.22 (s, 3H), 2.06 (dd, J=14.9, 7.4 Hz, 2H).

Step C: N-(6-bromo-4-nitro-indan-5-yl)acetamide

[0801] ##STR00060##

[0802] Fuming HNO.sub.3 (4.96 ml, 108 mmol) was added to a mixture of N-(6-bromoindan-5-yl)acetamide (13.7 g, 53.9 mmol) in TFA (60.0 mL) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 45 min and poured into ice (200 mL). The aqueous phase was extracted with DCM (4×150 mL), and the combined organic phases were washed with brine (200 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to provide the title compound as a solid (16.1 g, 99%).

[0803] LCMS m/z 300.0 (M+H).sup.+ (ES.sup.+).

[0804] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.65 (s, 1H), 7.38 (s, 1H), 3.09 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.21 (s, 3H), 2.18-2.13 (m, 2H).

Step D: N-(6-methyl-4-nitro-indan-5-yl)acetamide

[0805] ##STR00061##

[0806] 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.89 g, 3.53 mmol) was added to a mixture of N-(6-bromo-4-nitro-indan-5-yl)acetamide (10.6 g, 35.3 mmol), methylboronic acid (6.35 g, 163 mmol), and K.sub.2CO.sub.3 (22.5 g, 163 mmol) in 1,4-dioxane (250 mL) and water (70.0 mL) at 22° C. under N.sub.2. The mixture was stirred at 80° C. for 16 h and poured into ice. The aqueous phase was extracted with EtOAc (4×200 mL), and the combined organic phases were washed with brine (300 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-2% MeOH/DCM) to provide the title compound as a solid (4.47 g, 54%).

[0807] LCMS m/z 235.3 (M+H).sup.+ (ES.sup.+).

[0808] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 1H), 7.31 (s, 1H), 3.09 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.12 (p, J=7.6 Hz, 2H).

Step E: 6-methyl-4-nitro-indan-5-amine

[0809] ##STR00062##

[0810] HCl (6M in water, 134 mL, 804 mmol) was added to a mixture of N-(6-methyl-4-nitro-indan-5-yl)acetamide (6.06 g, 25.9 mmol) at 22° C. under N.sub.2. The mixture was stirred at 100° C. for 16 h and poured into a mixture of ice (140 mL) and NaOH (36.2 g, 905 mmol). The aqueous phase was extracted with EtOAc (3×250 mL), and the combined organic phases were washed with brine (200 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to provide the title compound as a solid (4.82 g, 97%).

[0811] LCMS m/z 193.2 (M+H).sup.+ (ES.sup.+).

[0812] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.14 (s, 1H), 5.80 (s, 2H), 3.29 (t, J=7.5 Hz, 2H), 2.81 (dd, J=11.5, 4.3 Hz, 2H), 2.19 (t, J=2.8 Hz, 3H), 2.09-1.99 (m, 2H).

Step F: 5-bromo-6-methyl-4-nitro-indane

[0813] ##STR00063##

[0814] Isoamyl nitrite (0.240 ml, 1.79 mmol) was added to a mixture of 6-methyl-4-nitro-indan-5-amine (0.150 g, 0.780 mmol), cupric bromide (1.74 mg, 0.0078 mmol) and copper(I) bromide (134 mg, 0.936 mmol) in MeCN (2.60 ml) at 0° C. under N.sub.2. The mixture was stirred at 60° C. for 3 h and diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3×20.0 mL), and the combined organic phases were washed with brine (10.0 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-100% EtOAc/hexanes) to provide the title compound as a solid (120 mg, 60%).

[0815] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.49 (s, 1H), 2.90 (dt, J=10.4, 7.5 Hz, 4H), 2.40 (s, 3H), 2.08 (p, J=7.6 Hz, 2H).

Intermediate A7: 3-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol

[0816] ##STR00064##

Step A: tert-butyl 7-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2,7-diazaspiro[3.4]octane-2-carboxylate

[0817] ##STR00065##

[0818] Sodium triacetoxyborohydride (699 mg, 3.30 mmol) was added to a mixture of tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (500 mg, 2.36 mmol) and 3-[tert-butyl(dimethyl)silyl]oxypropanal (444 mg, 2.36 mmol) in DCE (10.0 ml) at 22° C. under N.sub.2. The mixture was stirred at 22° C. for 4 h and diluted with aq. NaHCO.sub.3 (20.0 mL). The aqueous phase was extracted with EtOAc (3×30.0 mL), and the combined organic phases were washed with brine (30.0 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-10% MeOH/DCM) to provide the title compound as an oil (241 mg, 26.6%).

[0819] LCMS m/z 384.6 (M).sup.+ (ES.sup.+).

[0820] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.86 (d, J=8.5 Hz, 2H), 3.82 (d, J=8.6 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 2.73 (s, 2H), 2.59 (s, 2H), 2.51 (s, 2H), 2.05 (t, J=6.9 Hz, 2H), 1.80-1.63 (m, 2H), 1.43 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H).

Step B: 3-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol

[0821] ##STR00066##

[0822] A mixture of TFA (5.89 ml, 79.3 mmol) and tert-butyl 7-[3-[tert-butyl(dimethyl)silyl]-oxypropyl]-2,7-diazaspiro[3.4]octane-2-carboxylate (610 mg, 1.59 mmol) was stirred at 22° C. for 1 h and diluted with water (50.0 ml). The aqueous phase was washed with Et.sub.2O (2×50 mL) and concentrated. The residue was passed through an Amberlite IRA-402(OH) ion exchange column eluting with MeOH, and concentrated to provide the title compound as an oil (270 mg, 98%).

[0823] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.85-3.76 (m, 2H), 3.55 (s, 4H), 2.81 (s, 2H), 2.72-2.62 (m, 2H), 2.59 (t, J=7.1 Hz, 2H), 2.02 (t, J=7.1 Hz, 2H), 1.71 (dt, J=10.6, 5.6 Hz, 2H).

[0824] Two exchangeable protons not observed.

Intermediate A8: 2-(1,8-diazoniaspiro[4.5]decan-1-yl)ethanol di-(2,2,2-trifluoroacetate)

[0825] ##STR00067##

Step A: tert-butyl 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,8-diazaspiro[4.5]decane-8-carboxylate

[0826] ##STR00068##

[0827] Cs.sub.2CO.sub.3 (793 mg, 2.43 mmol) was added to a mixture of tert-butyl 1,8-diazaspiro[4.5]-decane-8-carboxylate (450 mg, 1.87 mmol) and 2-bromoethoxy-tert-butyl-dimethylsilane (422 uL, 1.97 mmol) in DMF (7.50 mL) at 22° C. The mixture was stirred at 45° C. for 19 h and diluted with sat. aq. NH.sub.4Cl (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (3×50 mL, and the combined organic phases were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by neutral prep HPLC (0-1000% MeCN in water) to provide the title compound as an oil (370 mg, 49%).

[0828] LCMS m/z 399.5 (M).sup.+ (ES.sup.+).

[0829] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.10 (s, 2H), 3.68 (dt, J=13.7, 7.0 Hz, 2H), 2.84 (dd, J=15.2, 9.0 Hz, 2H), 2.71 (s, 2H), 2.56 (t, J=7.0 Hz, 2H), 1.98-1.69 (m, 4H), 1.69-1.49 (m, 2H), 1.45 (d, J=1.0 Hz, 9H), 1.39-1.15 (m, 2H), 0.94 (t, J=31.1 Hz, 9H), 0.06 (dd, J=4.9, 1.6 Hz, 6H).

Step B: 2-(1,8-diazoniaspiro[4.5]decan-1-yl)ethanol di-(2,2,2-trifluoroacetate)

[0830] ##STR00069##

[0831] Synthesized according to the procedure outlined for 3-(2,6-diazaspiro[3.4]octan-6-yl)-propan-1-ol (Intermediate A7, Step B), from TFA (3.73 ml, 50.2 mmol) and tert-butyl 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1,8-diazaspiro[4.5]decane-8-carboxylate (400 mg, 1.00 mmol) for 30 min at 22° C., to provide the title compound as an oil (288 mg, 69%).

[0832] LCMS m/z 186.2 (M-2TFA+2H).sup.+ (ES.sup.+).

[0833] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.27 (s, 1H), 3.42 (t, J=6.8 Hz, 2H), 3.36 (bs, 3H), 2.87 (d, J=11.9 Hz, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.56-2.29 (m, 4H), 1.73-1.55 (m, 4H), 1.40 (td, J=12.5, 4.4 Hz, 2H), 1.14 (d, J=10.7 Hz, 2H).

[0834] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −73.49 (d, J=3.3 Hz).

Intermediate A9: 2-(2,6-diazaspiro[3.4]octan-6-yl)ethanol di-(2,2,2-trifluoroacetic acid)

[0835] ##STR00070##

Step A: tert-butyl 7-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2,7-diazaspiro[3-4]octane-2-carboxylate

[0836] ##STR00071##

[0837] Synthesized according to the procedure outlined for tert-butyl 1-[2-[tert-butyl-(dimethyl)silyl]oxyethyl]-1,8-diazaspiro[4.5]decane-8-carboxylate (Intermediate A8, Step A), from Cs.sub.2CO.sub.3 (146 mg, 0.447 mmol), tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (73.0 mg, 0.344 mmol) and 2-bromoethoxy-tert-butyl-dimethyl-silane (0.104 mL, 0.481 mmol) in DMF (1.00 mL) at 22° C. for 16 h, to provide the title compound as an oil (98.0 mg, 77%).

[0838] LCMS m/z 371.4 (M+H).sup.+ (ES.sup.+).

[0839] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 3.72 (s, 4H), 3.64 (t, J=6.3 Hz, 2H), 2.67 (s, 2H), 2.54-2.44 (m, 4H), 1.93 (t, J=7.1 Hz, 2H), 1.36 (s, 9H), 0.85 (d, J=2.9 Hz, 9H), 0.03 (d, J=3.2 Hz, 6H).

Step B: 2-(2,6-diazaspiro[3.4]octan-6-yl)ethanol di-(2,2,2-trifluoroacetic acid)

[0840] ##STR00072##

[0841] Synthesized according to the procedure outlined for 3-(2,6-diazaspiro[3.4]octan-6-yl)-propan-1-ol (Intermediate A7, Step B), from TFA (0.982 ml, 13.2 mmol) and tert-butyl 7-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2,7-diazaspiro[3.4]octane-2-carboxylate (98.0 mg, 0.264 mmol) for 4 h at 22° C., to provide the title compound as an oil (49 mg, 48%).

[0842] LCMS m/z 157.1 (M-2TFA+H).sup.+ (ES.sup.+).

[0843] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.32 (br, 3H), 4.76 (br, 1H), 3.92 (d, J=10.3 Hz, 2H), 3.89 (d, J=10.1 Hz, 2H), 3.53 (t, J=5.6 Hz, 2H), 3.06-2.96 (m, 2H), 2.80-2.72 (m, 2H), 2.72-2.65 (m, 2H), 2.10 (t, J=5.9 Hz, 2H).

[0844] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −73.53 (s).

Intermediate A10: sodium 5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate

[0845] ##STR00073##

Step A: 5-bromo-6-methyl-indan-4-amine

[0846] ##STR00074##

[0847] Zn dust (7.92 g, 119 mmol) was added to a mixture of 5-bromo-6-methyl-4-nitro-indane (Intermediate A6) (4.66 g, 18.2 mmol) and NH.sub.4Cl (6.44 g, 119 mmol) in 1,4-dioxane and water (3:1, 120 mL) at 0° C. under N.sub.2. The mixture was stirred at 22° C. for 2 h and filtered through a pad of Celite washing with EtOAc (250 mL). The filtrate was concentrated. The product was purified by FC (50-100% EtOAc/hexanes) to provide the title compound as a solid (3.81 g, 93%).

[0848] LCMS m/z 226.7 (M+H).sup.+ (ES.sup.+).

[0849] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.60 (d, J=0.5 Hz, 1H), 4.01 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.4 Hz, 2H), 2.35 (d, J=0.5 Hz, 3H), 2.15-2.07 (m, 2H).

Step B: 5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-amine

[0850] ##STR00075##

[0851] (2-Fluoro-4-pyridyl)boronic acid (1.79 g, 12.5 mmol) was added to a mixture of 5-bromo-6-methyl-indan-4-amine (2.82 g, 12.5 mmol), Pd.sub.2(dba).sub.3 (760 mg, 1.28 mmol), S-Phos (1.08 g, 2.58 mmol) and K.sub.3PO.sub.4 (8.29 g, 38.3 mmol) in toluene (30.0 mL) at 22° C. under N.sub.2. The mixture was stirred at 100° C. for 1 h and (2-fluoro-4-pyridyl)boronic acid (1.82 g, 12.7 mmol) was added. The mixture was stirred at 100° C. for 1 h and (2-fluoro-4-pyridyl)boronic acid (1.75 g, 12.2 mmol) was added. The mixture was stirred at 100° C. for 1 h, and activated charcoal (1 g) was added. The mixture was stirred at 22° C. for 10 min, filtered over Celite washing with EtOAc (400 mL), and the filtrate was concentrated. The product was purified by FC (0-30% EtOAc/hexanes) to provide the title compound as a solid (1.57 g, 46%).

[0852] LCMS m/z 242.9 (M+H).sup.+ (ES.sup.+).

[0853] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.29 (d, J=5.1 Hz, 1H), 7.14 (ddd, J=5.1, 2.3, 1.3 Hz, 1H), 6.97 (s, 1H), 6.46 (s, 1H), 4.30 (s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.65 (t, J=7.3 Hz, 2H), 2.04-1.94 (m, 2H), 1.88 (s, 3H).

[0854] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −68.62 (s).

Step C: 5-bromo-N-[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine

[0855] ##STR00076##

[0856] Synthesized according to the procedure outlined for 5-bromo-N-[5-(2-fluoro-4-pyridyl)indan-4-yl]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine (Intermediate A2, Step E) from LHMDS (1.00 M in THF, 11.0 mL, 11.0 mmol), 5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-amine (1.03 g, 3.81 mmol) and 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane (Intermediate A1) (3.33 g, 9.32 mmol) in THF (7.50 mL) at 23° C. for 1 h. The product was further purified by FC (0-30% EtOAc/hexanes) to provide the title compound as a solid (1.16 g, 59%).

[0857] LCMS m/z 518.8 (M−H).sup.− (ES.sup.−).

[0858] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.19 (d, J=5.1 Hz, 1H), 7.17 (s, 1H), 7.10-7.04 (m, 1H), 6.92 (s, 1H), 5.15 (s, 2H), 3.38-3.30 (m, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.04 (s, 3H), 2.02-1.95 (m, 2H), 0.78-0.70 (m, 2H), −0.05 (s, 9H).

[0859] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −69.20 (s).

Step D: methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]propanoate

[0860] ##STR00077##

[0861] Synthesized according to the procedure outlined for methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-sulfanyl]propanoate (Intermediate A2, Step F), from DIPEA (1.00 mL, 5.78 mmol), Pd.sub.2(dba).sub.3 (273 mg, 0.289 mmol), Xantphos (178 mg, 0.301 mmol), 5-bromo-N-[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine (1.55 g, 2.99 mmol), and methyl 3-sulfanylpropanoate (660 μL, 5.84 mmol) in dioxane (10.0 mL) at 100° C. for 17 h, to provide the title compound as an oil (1.28 g, 69%).

[0862] LCMS m/z 556.9 (M−H).sup.− (ES.sup.−).

[0863] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 7.13 (s, 1H), 7.07 (ddd, J=5.1, 2.1, 1.3 Hz, 1H), 6.91 (s, 1H), 5.12 (s, 2H), 3.59 (s, 3H), 3.36-3.29 (m, 2H), 3.08 (t, J=7.0 Hz, 2H), 2.91 (t, J=7.4 Hz, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.62 (t, J=7.4 Hz, 2H), 2.03 (s, 3H), 2.02-1.93 (m, 2H), 0.78-0.70 (m, 2H), −0.06 (s, 9H).

[0864] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −69.27 (s).

Step E: methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]propanoate

[0865] ##STR00078##

[0866] Synthesized according to the procedure outlined for methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-sulfonyl]propanoate (Intermediate A3, Step A), from m-CPBA (77%, 1.44 g, 6.43 mmol) and methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]propanoate (1.28 g, 2.18 mmol) in DCM (10.0 mL) at 22° C. for 1.5 h, except that the FC used 0-50% EtOAc/hexanes, to provide the title compound as a solid (90%, 1.07 g, 75%).

[0867] LCMS m/z 588.5 (M−H).sup.− (ES.sup.−).

[0868] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.77 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.20 (s, 1H), 7.10 (ddd, J=5.1, 2.1, 1.3 Hz, 1H), 6.92 (s, 1H), 5.31 (s, 2H), 3.60 (s, 3H), 3.54 (t, J=7.2 Hz, 2H), 3.37-3.30 (m, 2H), 2.94 (t, J=7.4 Hz, 2H), 2.70-2.61 (m, 4H), 2.05 (s, 3H), 2.03-1.95 (m, 2H), 0.79-0.71 (m, 2H), −0.05 (s, 9H).

[0869] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −69.04 (s).

Step F: sodium 5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate

[0870] ##STR00079##

[0871] Synthesized according to the procedure outlined for sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3, Step B), from sodium 2-methylbutan-2-olate (1.40 M in THF, 1.74 mL, 2.44 mmol) and methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]propanoate (0.959 g, 1.63 mmol) in THF (25 mL) at 0° C. for 90 min, to afford the title compound as a solid (475 mg, 56%).

[0872] LCMS m/504.7 (M-Na+2H).sup.+ (ES.sup.+).

[0873] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (d, J=5.1 Hz, 1H), 7.72 (s, 1H), 7.13-7.06 (m, 2H), 6.95 (s, 1H), 5.12 (s, 2H), 3.38-3.32 (m, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.58 (s, 2H), 2.03 (s, 3H), 2.01-1.90 (m, 2H), 0.83-0.66 (m, 2H), −0.02-−0.06 (m, 9H).

[0874] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −69.16 (s).

Intermediate A11: 2-(3-iodopyrazol-1-yl)-2-methyl-propan-1-ol

[0875] ##STR00080##

Step A: tert-butyl 2-(3-iodopyrazol-1-yl)-2-methyl-propanoate

[0876] ##STR00081##

[0877] tert-Butyl 2-bromo-2-methyl-propanoate (7.51 mL, 39.5 mmol) was added to a mixture of 3-iodo-1H-pyrazole (6.48 g, 33.4 mmol) and NHMDS (1.0 M in THF, 7.51 mL, 39.5 mmol) in DMF (50.0 mL) at 0° C. under N.sub.2. The mixture was stirred at 55° C. for 16 h. The mixture was cooled to 22° C. and concentrated. The product was purified by FC (0-30% EtOAc/hexanes) to provide the title compound as an oil (8.04 g, 72%).

[0878] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.37 (d, J=2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 1.79 (s, 6H), 1.39 (s, 9H).

Step B: 2-(3-iodopyrazol-1-yl)-2-methyl-propan-1-ol

[0879] ##STR00082##

[0880] DIBAL (1M in THF, 71.7 mL, 71.7 mmol) was added to a mixture of tert-butyl 2-(3-iodopyrazol-1-yl)-2-methyl-propanoate (8.04 g, 23.9 mmol) in THF (250 mL) at −78° C. under N.sub.2. The mixture was stirred at −78° C. for 2 h and at 22° C. for 2 h, and diluted with aq. NaOH (2.5 M, 20.0 mL). The mixture was stirred for 30 min at 22° C. and filtered. The filtrate was concentrated, and the product was purified by FC (0-50% EtOAc/hexanes) to provide the title compound as an oil (3.95 g, 62%).

[0881] LCMS m/z 267.1 (M+H).sup.+ (ES.sup.+).

[0882] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (d, J=2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 3.79 (s, 2H), 2.73 (s, 1H), 1.53 (s, 6H).

Intermediate A12: 3-(3-iodopyrazol-1-yl)-3-methyl-butan-1-ol

[0883] ##STR00083##

Step A: ethyl 3-(3-iodopyrazol-1-yl)-3-methyl-butanoate

[0884] ##STR00084##

[0885] Ethyl 3-methylbut-2-enoate (2.28 mL, 16.4 mmol) was added to a mixture of 3-iodo-1H-pyrazole (1.06 g, 5.46 mmol) and DBU (1.63 mL, 10.9 mmol) in anhydrous MeCN (50.0 mL). The mixture was stirred at 60° C. for 16 h and diluted with sat. aq. NaHCO.sub.3 (50.0 mL). The aqueous phase was extracted with EtOAc (100 mL), and the organic phase was washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to provide the title compound as an oil (1.72 g, 98%).

[0886] LCMS m/z 323.4 (M+H).sup.+ (ES.sup.+).

[0887] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (d, J=2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 2.88 (s, 2H), 1.70 (s, 6H), 1.16 (t, J=7.1 Hz, 3H).

Step B: 3-(3-iodopyrazol-1-yl)-3-methyl-butan-1-ol

[0888] ##STR00085##

[0889] Borane tetrahydrofuran complex (1.00 M, 26.7 mL, 26.7 mmol) was added to a solution of ethyl 3-(3-iodopyrazol-1-yl)-3-methyl-butanoate (1.72 g, 5.34 mmol) in THF (50.0 mL) at 20° C. The mixture was stirred at 70° C. for 2 h and diluted with sat. aq. Rochelle's salt (50.0 mL). The mixture was stirred at 20° C. for 1 h. The aqueous phase was extracted with EtOAc (100 mL), and the organic phase was washed with water (50.0 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to provide the title compound as an oil (1.46 g, 98%).

[0890] LCMS m/z 281.6 (M+H).sup.+ (ES.sup.+).

Intermediate A13: methyl 2-methyl-2-(3-sulfanylphenyl)propanoate

[0891] ##STR00086##

Step A: methyl 2-[3-(3-methoxy-3-oxo-propyl)sulfanylphenyl]-2-methyl-propanoate

[0892] ##STR00087##

[0893] DIPEA (6.75 mL, 39.0 mmol) was added to a mixture of methyl 2-(3-bromophenyl)-methyl-propionate (5.00 g, 18.9 mmol), methyl 3-sulfanylpropanoate (4.14 mL, 37.7 mmol), Pd.sub.2(dba).sub.3 (1.68 g, 2.83 mmol), and XantPhos (3.34 g, 5.66 mmol) in 1,4-dioxane (40.0 mL) at 22° C. under N.sub.2. The mixture was degassed, stirred at 100° C. for 18 h, and diluted with aq. HCl (1M, 50.0 mL). The aqueous phase was extracted with DCM (3×75.0 mL), and the combined organic phases were washed with sat. aq. NaHCO.sub.3 (75.0 mL), brine (75.0 ml), dried (Na.sub.2SO.sub.4), filtered and concentrated. The product was purified by FC (0-30% EtOAc/hexanes) to provide the title compound as an oil (3.00 g, 54%).

[0894] LCMS m/z 297.4 (M+H).sup.+ (ES.sup.+).

[0895] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.35-7.30 (m, 1H), 7.28-7.26 (m, 1H), 7.25-7.22 (m, 1H), 7.17 (dt, J=7.2, 1.9 Hz, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.16 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.4 Hz, 2H), 1.57 (s, 6H).

Step B: methyl 2-methyl-2-(3-sulfanylphenyl)propanoate

[0896] ##STR00088##

[0897] NaOMe (25 wt % in MeOH, 4.59 mL, 19.7 mmol) was added to a mixture of methyl 2-[3-(3-methoxy-3-oxo-propyl)sulfanylphenyl]-2-methyl-propanoate (3.00 g, 10.1 mmol) in a mixture of THF and MeOH (1:1 v/v, 30.0 mL) at 0° C. under N.sub.2. The mixture was stirred at 22° C. for 6 h and diluted with aq. HCl (1 M, 50 mL). The aqueous phase was extracted with DCM (3×100 mL), and the organic phases were combined, washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The product was purified by FC (0-20% EtOAc/hexanes) to provide the title compound as an oil (1.78 g, 84%), which was stored in the freezer under an atmosphere of nitrogen.

[0898] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.22-7.10 (m, 4H), 3.66 (s, 3H), 3.46 (s, 1H), 1.55 (s, 6H).

Intermediate A14: 2-(methyl(piperidin-4-yl)amino)ethan-1-ol

[0899] ##STR00089##

[0900] tert-Butyl 4-(methylamino)piperidine-1-carboxylate (1.00 g, 4.67 mmol) and K.sub.2CO.sub.3 (1.93 g, 14.0 mmol) were suspended in MeCN (20 mL). 2-bromoethan-1-ol (331 μL, 4.67 mmol) was added and the reaction stirred at 80° C. for 24 h. A further equivalent of 2-bromoethan-1-ol (331 μL, 4.67 mmol) was added and the reaction stirred for a further 24 h. The reaction was concentrated in vacuo and the resulting residue dissolved in DCM (100 mL), washed with brine (100 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-100% (0.7 M ammonia/MeOH)/DCM) to afford the Boc-protected product. This was taken up in HCl (4 M in dioxane) (5 mL, 4.0 M, 20 mmol) and EtOH (3 mL) and stirred at RT for 18 h. The reaction was concentrated in vacuo and the resulting residue dissolved in 0.7 M NH.sub.3 in MeOH (10 mL). The solution was concentrated in vacuo and the resulting residue dissolved in MeOH (30 mL) and stirred with SCX (10 g) for 45 min. The SCX resin was washed with methanol (100 mL), then the product was eluted with 0.7 M NH.sub.3 in MeOH (150 mL). The resulting solution was concentrated in vacuo to afford the title compound (386 mg, 52%) as a straw-coloured oil.

[0901] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 3.41 (t, J=6.6 Hz, 2H) 3.03-2.89 (m, 2H), 2.49-2.29 (m, 5H), 2.17 (s, 3H), 1.63-1.55 (m, 2H), 1.31-1.20 (m, 2H). 2 exchangeable protons not observed.

Intermediate A15: 2-methyl-2-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0902] ##STR00090##

Step A: tert-butyl 6-(1-methoxy-2-methyl-1-oxopropan-2-yl)-2,6-diazaspiro[3.4]-octane-2-carboxylate

[0903] ##STR00091##

[0904] tert-Butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.00 g, 4.71 mmol) and K.sub.2CO.sub.3 (1.95 g, 14.1 mmol) were suspended in MeCN (30 mL). Methyl 2-bromo-2-methylpropanoate (610 μL, 4.71 mmol) was added and the reaction stirred at 80° C. for 24 h. The reaction was concentrated in vacuo and the resulting residue dissolved in DCM (100 mL), washed with brine (100 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (1.09 g, 73%) as a yellow oil.

[0905] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 3.77-3.63 (m, 4H), 3.61 (s, 3H), 2.85 (s, 2H), 2.72 (t, J=6.9 Hz, 2H), 1.90 (t, J=6.9 Hz, 2H), 1.37 (s, 9H), 1.26 (s, 6H).

Step B: 2-methyl-2-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol, di-(2,2,2-trifluoroacetic

[0906] ##STR00092##

[0907] LiBH.sub.4 (4 M in THF) (7.06 mL, 28.2 mmol) was added drop-wise to a stirred solution of tert-butyl 6-(1-methoxy-2-methyl-1-oxopropan-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (1.47 g, 4.71 mmol) in THF (15 mL) cooled to 0° C. The mixture was warmed to RT and stirred at 50° C. for a further 16 h. The mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried using a phase separator and concentrated in vacuo. The resulting residue was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the Boc-protected product. This was taken up in TFA (10 mL) and stirred at RT for 2 h. The reaction was concentrated in vacuo and the TFA residues were removed as an azeotrope with toluene (×3) to afford the title compound (2.01 g, 98%) as a light yellow oil, which began to form crystals on standing.

[0908] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.71 (bs, 1H), 9.13 (bs, 1H), 8.87 (bs, 1H), 4.14-4.02 (m, 2H), 4.00-3.93 (m, 1H), 3.90-3.80 (m, 1H), 3.66-3.57 (m, 1H), 3.54-3.40 (m, 3H), 3.39-3.28 (m, 2H), 2.33-2.20 (m, 2H), 1.20 (s, 6H). One exchangeable proton not observed.

Intermediate A16: 2-((azetidin-3-ylmethyl)(methyl)amino)ethan-1-ol

[0909] ##STR00093##

Step A: tert-butyl 3-(((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)methyl)-azetidine-1-carboxylate

[0910] ##STR00094##

[0911] 2-((tert-butyldimethylsilyl)oxy)-N-methylethan-1-amine (1.33 g, 7.00 mmol) then sodium triacetoxyborohydride (1.72 g, 8.10 mmol) was added to a solution of tert-butyl 3-formylazetidine-1-carboxylate (1.00 g, 5.40 mmol) in THF (30 mL) at RT. The mixture was stirred for 24 h then partitioned between EtOAc (150 mL) and sat. aq. NaHCO.sub.3 solution (50 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by FC (0-5% MeOH/DCM) to afford the title compound (1.71 g, 84%) as an oil.

[0912] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 4.01 (t, J=8.2 Hz, 2H), 3.72 (t, J=6.3 Hz, 2H), 3.59 (dd, J=8.6, 5.1 Hz, 2H), 2.76-2.63 (m, 3H), 2.54 (t, J=6.3 Hz, 2H), 2.27 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.08 (s, 6H).

Step B: 2-((azetidin-3-ylmethyl)(methyl)amino)ethan-1-ol

[0913] ##STR00095##

[0914] TFA (10.0 mL) was added to a solution of tert-butyl 3-(((2-((tert-butyldimethylsilyl)-oxy)ethyl)(methyl)amino)methyl)azetidine-1-carboxylate (1.70 g, 4.74 mmol) in DCM (20 mL) at RT. The mixture was stirred for 24 h, evaporated, and the residue loaded onto SCX column with MeOH, washed with MeOH then eluted with 0.7M NH.sub.3/MeOH to afford the title compound (460 mg, 64%) as an oil.

[0915] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.73 (t, J=7.9 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.41 (t, J=7.4 Hz, 2H), 3.03-2.90 (m, 3H), 2.67 (d, J=7.2 Hz, 2H), 2.53 (t, J=5.4 Hz, 2H), 2.23 (s, 3H).

Intermediate A17: (R)-2-(methyl(pyrrolidin-3-ylmethyl)amino)ethan-1-ol

[0916] ##STR00096##

Step A: tert-butyl (R)-3-((2-hydroxyethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0917] ##STR00097##

[0918] HATU (6.36 g, 16.7 mmol) was added portionwise to a solution of (R)-1-(tert-butoxy-carbonyl)pyrrolidine-3-carboxylic acid (3.00 g, 13.9 mmol), 2-(methylamino)ethan-1-ol (1.40 mL, 17.4 mmol) and DIPEA (4.00 mL, 23.0 mmol) in DMF (30 mL) cooled on an icebath. The mixture was warmed to RT, stirred overnight and partitioned between EtOAc (300 mL) and water (150 mL). The organic layer was washed with 1M HCl (2×50 mL), water (50 mL) and brine (50 mL), dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by FC (0-5% MeOH/DCM) to afford the title compound (996 mg, 24%) as an oil.

[0919] .sup.1H NMR (500 MHz, CDCl.sub.3, rotamers present) δ 3.81 (t, J=5.2 Hz, 2H), 3.69-3.52 (m, 4H), 3.52-3.44 (m, 1H), 3.41-3.22 (m, 2H), 3.16 and 2.99 (2×s, 3H), 2.64 (br s, 1H), 2.23-2.02 (m, 2H), 1.47 (s, 9H).

Step B: tert-butyl (S)-3-(((2-hydroxyethyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate

[0920] ##STR00098##

[0921] 1 M Borane tetrahydrofuran complex in THF (14.5 mL, 14.5 mmol) was added to a solution of tert-butyl (R)-3-((2-hydroxyethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (990 mg, 3.64 mmol) in THF (15 mL) and heated at 65° C. for 8 h. The mixture was cooled, MeOH (30 mL) added carefully, the mixture heated at 60° C. for 5 h then the solvent evaporated. The crude product was purified by FC (0-15% MeOH/DCM) to afford the title compound (485 mg, 46%) as an oil.

[0922] .sup.1H NMR (500 MHz, CDCl3) δ 3.62 (t, J=5.3 Hz, 2H), 3.58-3.25 (m, 3H), 3.06-2.95 (m, 1H), 2.79 (br s, 1H), 2.59 (br s, 2H), 2.50-2.38 (m, 3H), 2.32 (s, 3H), 2.06-1.97 (m, 1H), 1.68-1.53 (m, 1H), 1.47 (s, 9H).

Step C: (R)-2-(methyl(pyrrolidin-3-ylmethyl)amino)ethan-1-ol

[0923] ##STR00099##

[0924] Synthesized according to the procedure outlined for 2-((azetidin-3-ylmethyl)(methyl)-amino)ethan-1-ol (Intermediate A16, Step B) from tert-butyl (S)-3-(((2-hydroxy-ethyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (470 mg, 1.82 mmol), TFA (3.0 mL) and DCM (5 mL) at RT to afford the title compound (300 mg, 83%) as an oil.

[0925] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 4.25 (br s, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.90-2.69 (m, 3H), 2.49-2.43 (m, 1H), 2.41-2.34 (m, 2H), 2.26-2.20 (m, 2H), 2.19-2.13 (m, 4H) 1.79-1.71 (m, 1H), 1.34-1.23 (m, 1H).

Intermediate A18: 4-(methyl(piperidin-4-yl)amino)butan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0926] ##STR00100##

Step A: tert-butyl 4-((4-ethoxy-4-oxobutyl)(methyl)amino)piperidine-1-carboxylate

[0927] ##STR00101##

[0928] tert-Butyl 4-(methylamino)piperidine-1-carboxylate (1.00 g, 4.67 mmol) and K.sub.2CO.sub.3 (1.93 g, 14.0 mmol) were suspended in MeCN (20 mL). Ethyl 4-bromobutanoate (668 μL, 4.67 mmol) was added and the reaction stirred at 80° C. for 48 h. The reaction was concentrated in vacuo and the resulting residue dissolved in DCM (100 mL), washed with brine (100 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM)) to afford the title compound (1.023 g, 66%) as a colourless oil.

[0929] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 4.03 (q, J=7.1 Hz, 2H), 4.00-3.38 (m, 2H), 2.77-2.57 (m, 2H), 2.47-2.39 (m, 1H), 2.36 (t, J=6.9 Hz, 2H), 2.27 (t, J=7.2 Hz, 2H), 2.12 (s, 3H), 1.68-1.57 (m, 4H), 1.39 (s, 9H), 1.28-1.15 (m, 5H).

Step B: 4-(methyl(piperidin-4-yl)amino)butan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0930] ##STR00102##

[0931] LiBH.sub.4 (4 M in THF) (4.67 mL, 18.7 mmol) was added drop-wise to a stirred solution of tert-butyl 4-((4-ethoxy-4-oxobutyl)(methyl)amino)piperidine-1-carboxylate (1.02 g, 3.12 mmol) in THF (15 mL) cooled to 0° C. The mixture was warmed to RT and stirred for 48 h, before heating to 50° C. and stirring for a further 5 h. The mixture was then partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried using a phase separator and concentrated in vacuo. The resulting residue was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM)) to afford the Boc-protected product. This was taken up in TFA (5 mL) and stirred at RT for 2 h. The reaction was concentrated in vacuo and the TFA residues were removed as an azeotrope with toluene (×3) to afford the title compound (612 mg, 47%) as a colourless oil.

[0932] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.09-9.82 (m, 1H), 8.98-8.81 (m, 1H), 8.69-8.52 (m, 1H), 4.42 (t, J=5.8 Hz, 1H), 3.60-3.49 (m, 1H), 3.49-3.40 (m, 3H), 3.21-3.03 (m, 3H), 3.02-2.87 (m, 2H), 2.76-2.70 (m, 3H), 2.14 (d, J=13.2 Hz, 2H), 1.93-1.60 (m, 5H), 1.51-1.42 (m, 1H).

Intermediate A19: (S)-2-(methyl(pyrrolidin-3-ylmethyl)amino)ethan-1-ol, 2,2,2-trifluoroacetic acid

[0933] ##STR00103##

Step A: tert-butyl (S)-3-((2-hydroxyethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0934] ##STR00104##

[0935] HATU (10.6 g, 27.9 mmol) was added portionwise to a solution of (S)-1-(tert-butoxy-carbonyl)pyrrolidine-3-carboxylic acid (5.00 g, 23.2 mmol), 2-(methylamino)ethan-1-ol (2.50 mL, 31.1 mmol) and DIPEA (6.70 mL, 38.5 mmol) in DMF (60 mL) at 0° C. The mixture was warmed to RT, stirred overnight and partitioned between EtOAc (300 mL) and water (150 mL). The organic phase was washed with 1M HCl (75 mL), water (50 mL) and brine (50 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by FC (0-5% MeOH/DCM) to afford the title compound (1.50 g, 12%) as an oil.

[0936] LCMS m/z 217.0 (M-.sup.tBu+H).sup.+ (ES.sup.+).

Step B: (S)-2-(methyl(pyrrolidin-3-ylmethyl)amino)ethan-1-ol, 2,2,2-trifluoroacetic acid

[0937] ##STR00105##

[0938] 1M Borane tetrahydrofuran complex in THF (7.02 mL, 7.02 mmol) was added portionwise to a solution of tert-butyl (S)-3-((2-hydroxyethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (0.956 g, 1.76 mmol) in THF (20 mL) and stirred at RT for 16 h. Additional 1M borane tetrahydrofuran complex in THF (7.02 mL, 7.02 mmol) was added and the reaction stirred at RT for 3 h. MeOH (30 mL) was carefully added and the reaction stirred at 60° C. for 3 h. The volatiles were removed under reduced pressure and the crude loaded onto SCX (10 g, pre-washed) and rinsed with MeOH (20 mL), then the product eluted with 0.7 M NH.sub.3 in MeOH (3×20 mL). The ammoniacal solution was concentrated under reduced pressure to afford tert-butyl (R)-3-(((2-hydroxyethyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (661 mg, 1.7 mmol, 95%) as a yellow oil. The residue was taken up in DCM/TFA (1:1, 10 mL) and stirred at RT for 3 h. The volatiles were removed under reduced pressure azeotroping with MeOH (2×20 mL). The residue was loaded onto SCX (10 g, pre-washed with MeOH) and rinsed with MeOH (20 mL). The product was eluted with 0.7 M NH.sub.3 in MeOH (2×30 mL). The ammoniacal solution was concentrated under reduced pressure to afford the title compound (226 mg, 45%) as a yellow oil.

[0939] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 4.60 (br s, 2H), 3.63-3.52 (m, 2H), 3.17-3.11 (m, 1H), 3.11-3.04 (m, 1H), 3.03-2.97 (m, 1H), 2.82-2.70 (m, 1H), 2.58-2.45 (m, 2H), 2.43-2.33 (m, 3H), 2.25 (s, 3H), 2.03-1.90 (m, 1H), 1.49 (m, 1H). One exchangeable proton not observed.

Intermediate A20: 3-(1,7-diazaspiro[3.5]nonan-1-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0940] ##STR00106##

Step A: tert-butyl 1-(3-hydroxypropyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate

[0941] ##STR00107##

[0942] A solution of tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate (500 mg, 2.21 mmol), 3-bromo-1-propanol (204 μL, 2.25 mmol) and Et.sub.3N (0.70 mL, 5.0 mmol) in anhydrous THF (15 mL) was stirred at RT for 3 days. The reaction mixture was filtered and concentrated to dryness to give crude product. The crude product was purified by FC (0-100% EtOAc/(3:1 EtOAc:EtOH with 2% NH.sub.40H)) to afford the title compound (537 mg, 60%) as a pale yellow oil.

[0943] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 3.88 (m, 2H), 3.40 (t, J=6.3 Hz, 2H), 3.13 (s, 2H), 2.74-2.60 (m, 2H), 2.46 (t, J=7.9 Hz, 2H), 1.87 (t, J=7.1 Hz, 2H), 1.71 (m, 2H), 1.39 (m, 13H). One exchangeable proton not observed.

Step B: 3-(1,7-diazaspiro[3.5]nonan-1-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0944] ##STR00108##

[0945] tert-Butyl 1-(3-hydroxypropyl)-1,7-diazaspiro[3-5]nonane-7-carboxylate (537 mg, 1.32 mmol) was dissolved in TFA (3 mL) and the mixture was stirred at RT for 24 h. The mixture was concentrated to dryness to afford the title compound (602 mg, 94%) as a thick orange oil.

[0946] LCMS m/z 185.4 (M-2TFA+H).sup.+ (ES.sup.+).

[0947] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.36 (br s, 1H), 8.97-8.79 (m, 1H), 8.66-8.56 (m, 1H), 4.58-4.33 (m, 2H), 4.14-3.82 (m, 2H), 3.53-3.31 (m, 3H), 3.26-2.94 (m, 2H), 2.94-2.79 (m, 1H), 2.47-2.27 (m, 5H), 2.14-2.02 (m, 2H), 2.00-1.84 (m, 2H).

[0948] .sup.19F NMR (471 MHz, DMSO-d.sub.6) δ −74.62.

Intermediate A21: 4-(3-((dimethylamino)methyl)azetidin-3-yl)butan-1-ol

[0949] ##STR00109##

Step A: 1-benzhydryl-3-(4-((tert-butyldimethylsilyl)oxy)butyl)azetidine-3-carbonitrile

[0950] ##STR00110##

[0951] 1M LiHMDS in THF (21.1 mL, 21.1 mmol) was added dropwise to 1-benzhydryl-azetidine-3-carbonitrile (5.00 g, 20.1 mmol) in THF (100 mL) cooled to −78° C. over 10 min. The mixture was left to stir at −78° C. for 30 min. tert-Butyl(4-iodobutoxy)-dimethylsilane (5.49 mL, 20.1 mmol) was then added in one portion and the mixture was left to warm to RT over 2.5 hours. The mixture was quenched with sat. aq. NH.sub.4Cl (50 mL), water (20 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give an orange oil. The crude product was purified by FC (0-50% EtOAc/heptane) to afford the title compound (5.31 g, 59%) as a pale yellow oil.

[0952] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.43-7.38 (m, 4H), 7.29 (t, J=7.6 Hz, 4H), 7.22-7.17 (m, 2H), 4.53 (s, 1H), 3.59 (t, J=6.1 Hz, 2H), 3.35 (d, J=7.3 Hz, 2H), 3.08 (d, J=7.3 Hz, 2H), 1.90-1.83 (m, 2H), 1.49 (p, J=6.6 Hz, 2H), 1.43-1.34 (m, 2H), 0.85 (s, 9H), 0.03 (s, 6H).

[0953] LCMS m/z 435.5 (M+H).sup.+ (ES.sup.+).

Step B: 4-(3-(aminomethyl)-1-benzhydrylazetidin-3-yl)butan-1-ol

[0954] ##STR00111##

[0955] To a solution of 1-benzhydryl-3-(4-((tert-butyldimethylsilyl)oxy)butyl)azetidine-3-carbonitrile (5.31 g, 11.8 mmol) in THF (100 mL) at RT was added LiAlH.sub.4 (1 M in THF) (41.5 mL, 41.5 mmol) drop-wise and the resultant reaction mixture refluxed for 3 h. The reaction was allowed to cool to RT and the reaction mixture was then treated dropwise with water (5 mL), NaOH (2M aq solution, 10 mL) and water (10 mL) and then stirred vigorously for 30 min. The mixture was then filtered and the filtrate concentrated in vacuo to afford the title compound (4.12 g, 96%) as a white solid.

[0956] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.40 (d, J=7.3 Hz, 4H), 7.25 (t, J=7.6 Hz, 4H), 7.15 (t, J=7.3 Hz, 2H), 4.41 (s, 1H), 4.32 (s, 1H), 3.38 (t, J=6.5 Hz, 2H), 2.87 (d, J=7.1 Hz, 2H), 2.72-2.61 (m, 4H), 1.56-1.47 (m, 2H), 1.46-1.27 (m, 4H), 1.27-1.12 (m, 2H).

Step C: 4-(1-benzhydryl-3-((dimethylamino)methyl)azetidin-3-yl)butan-1-ol

[0957] ##STR00112##

[0958] A mixture of 4-(3-(aminomethyl)-1-benzhydrylazetidin-3-yl)butan-1-ol (4.12 g, 12.7 mmol), formaldehyde (25 mL, 37% wt) and formic acid (25 mL) was refluxed for 3.5 h. The reaction mixture was then allowed to cool to RT before being concentrated in vacuo. The resulting residue was mixed with ice, basified with aq. NaOH (2 N) and extracted with DCM (150 mL). The organics were then washed with water and brine, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (4.77 g, 85%) as a yellow oil.

[0959] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.43-7.37 (m, 4H), 7.26 (t, J=7.5 Hz, 4H), 7.19-7.12 (m, 2H), 4.40 (s, 1H), 4.12 (t, J=6.6 Hz, 1H), 3.43-3.36 (m, 1H), 2.94 (dd, J=7.3, 3.8 Hz, 2H), 2.69 (d, J=7.1 Hz, 2H), 2.30 (d, J=2.4 Hz, 2H), 2.02 (d, J=1.4 Hz, 6H), 1.76-1.57 (m, 3H), 1.43 (p, J=6.8 Hz, 1H), 1.36-1.23 (m, 2H). One exchangeable proton not observed.

Step D: 4-(3-((dimethylamino)methyl)azetidin-3-yl)butan-1-ol

[0960] ##STR00113##

[0961] 4-(1-Benzhydryl-3-((dimethylamino)methyl)azetidin-3-yl)butan-1-ol (4.77 g, 13.5 mmol) was dissolved in EtOH (80 mL) to which was added 20 wt % palladium hydroxide on carbon (452 mg, 644 μmol). The reaction mixture was then hydrogenated at 4 bar pressure for 24 h at 40° C. The catalyst was then filtered off and the filtrate concentrated under reduced pressure. .sup.1H NMR showed incomplete deprotection. The residue was dissolved in EtOH (80 mL) and AcOH (2 mL) and then 20 wt % palladium hydroxide on carbon (452 mg, 644 μmol) was added and the resultant mixture was hydrogenated at 4 bar pressure for 20 h at 40° C. The catalyst was then filtered off and the filtrate concentrated under reduced pressure. The crude was loaded onto SCX (20 g, pre-washed with MeOH), then rinsed with MeOH (50 mL) and the product was eluted with 7 M NH.sub.3 in MeOH (100 mL). The ammoniacal solution was concentrated under reduced pressure to afford the title compound (1.14 g, 96%) as a yellow oil.

[0962] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.69-3.61 (m, 2H), 3.44-3.38 (m, 2H), 3.32-3.26 (m, 2H), 2.43 (s, 2H), 2.12 (s, 6H), 1.81-1.74 (m, 2H), 1.61-1.52 (m, 2H), 1.39-1.30 (m, 2H). Two exchangeable protons not observed.

Intermediate A22: (S)-3-(methyl(pyrrolidin-3-yl)amino)propan-1-ol

[0963] ##STR00114##

[0964] tert-Butyl (S)-3-(methylamino)pyrrolidine-1-carboxylate (1.00 g, 4.99 mmol) and 3-((tert-butyldimethylsilyl)oxy)propanal (1.41 g, 7.49 mmol) were dissolved in DCE (50 mL) and sodium triacetoxyborohydride (2.12 g, 9.99 mmol) was added slowly. The reaction was stirred at RT for 24 h. The reaction was quenched with sat. aq. NaHCO.sub.3 (100 mL) and extracted with DCM (2×75 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-50% (0.7 M ammonia/MeOH)/DCM)) to afford the protected product as a light yellow oil. This was taken up in HCl (4 M in dioxane) (5 mL) and stirred at RT for 20 h. The reaction was concentrated in vacuo and the resulting residue dissolved in 0.7 M NH.sub.3 in MeOH. The solution was concentrated in vacuo and the resulting residue dissolved in methanol (30 mL) and stirred with SCX (10 g) for 45 min. The SCX resin was washed with methanol (100 mL), then the product was eluted with 0.7 M NH.sub.3 in MeOH (150 mL). The resulting solution was concentrated in vacuo to afford the title compound (502 mg, 60%) as an orange oil.

[0965] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 4.38-3.91 (m, 3H), 3.42 (t, J=6.3 Hz, 2H), 2.97-2.89 (m, 1H), 2.87-2.70 (m, 3H), 2.43-2.49 (m, 2H), 2.10 (s, 3H), 1.84-1.73 (m, 1H), 1.59-1.43 (m, 3H).

Intermediate A23: (1-(piperidin-4-yl)azetidin-3-yl)methanol

[0966] ##STR00115##

Step A: tert-butyl 4-(3-(hydroxymethyl)azetidin-1-yl)piperidine-1-carboxylate

[0967] ##STR00116##

[0968] Sodium triacetoxyborohydride (2.80 g, 13.2 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.00 g, 10.0 mmol) and azetidin-3-ylmethanol (900 mg, 10.3 mmol) in DCE (25 mL) at RT. The mixture was stirred for 4 days then partitioned between DCM (150 mL) and sat. aq. NaHCO.sub.3 (50 mL). The organic layer was washed with brine (20 mL), dried (MgSO.sub.4), filtered, evaporated and the residue purified by FC (0-20% MeOH/DCM) to afford the title compound (973 mg, 34%) as a gum which solidified on standing.

[0969] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 3.94 (br s, 2H), 3.77 (d, J=5.3 Hz, 2H), 3.38 (t, J=7.4 Hz, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.85 (t, J=12.0 Hz, 2H), 2.70-2.61 (m, 1H), 2.27-2.20 (m, 1H), 1.67 (br d, J=12.9 Hz, 2H), 1.46 (s, 9H), 1.29-1.19 (m, 2H). One exchangeable proton not observed.

Step B: (1-(piperidin-4-yl)azetidin-3-yl)methanol

[0970] ##STR00117##

[0971] A solution of tert-butyl 4-(3-(hydroxymethyl)azetidin-1-yl)piperidine-1-carboxylate (963 mg, 3.56 mmol) and TFA (10 mL) in DCM (20 mL) was stirred at RT for 4 h then evaporated. The residue was purified on SCX resin (loading in MeOH, washing with MeOH then eluting with 0.7M NH.sub.3/MeOH) to afford the title compound (562 mg, 88%) as a solid.

[0972] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 4.50 (br s, 1H), 3.46 (d, J=6.7 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 2.86 (dt, J=12.4, 3.9 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 2.42-2.32 (m, 3H), 1.97-1.91 (m, 1H), 1.56-1.49 (m, 2H), 0.99-0.88 (m, 2H). One exchangeable proton not observed.

Intermediate A24: 4-(2,6-diazaspiro[3.4]octan-6-yl)butan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0973] ##STR00118##

Step A: tert-butyl 6-(4-ethoxy-4-oxobutyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0974] ##STR00119##

[0975] tert-Butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (0.800 g, 3.77 mmol) and K.sub.2CO.sub.3 (1.56 g, 11.3 mmol) were suspended in MeCN (20 mL). Ethyl 4-bromobutanoate (539 μL, 3.77 mmol) was added and the reaction stirred at 80° C. for 24 h. The reaction was concentrated in vacuo and the resulting residue dissolved in DCM (100 mL), washed with brine (100 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (690 mg, 53%) as a colourless oil.

[0976] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 4.04 (q, J=7.1 Hz, 2H), 3.80-3.65 (m, 4H), 2.59 (s, 2H), 2.44 (t, J=7.1 Hz, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.29 (t, J=7.3 Hz, 2H), 1.96-1.91 (m, 2H), 1.65 (p, J=7.2 Hz, 2H), 1.37 (s, 9H), 1.18 (t, J=7.1 Hz, 3H).

Step B: 4-(2,6-diazaspiro[3.4]octan-6-yl)butan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0977] ##STR00120##

[0978] LiBH.sub.4 (4M in THF) (3.17 mL, 12.7 mmol) was added drop-wise to a stirred solution of tert-butyl 6-(4-ethoxy-4-oxobutyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (690 mg, 2.11 mmol) in THF (15 mL) cooled to 0° C. The mixture was warmed to RT and stirred for 48 h, before heating to 50° C. and stirring for a further 5 h. The mixture was then partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried using a phase separator and concentrated in vacuo. The resulting residue was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the Boc-protected product. This was taken up in TFA (5 mL) and stirred at RT for 2 h. The reaction was concentrated in vacuo and the TFA residues were removed as azeotrope with methanol (×3) to afford the title compound (242 mg, 28%) as a colourless oil.

[0979] LCMS m/z 185.4 (M-2TFA+H).sup.+ (ES.sup.+).

Intermediate A25: 3-(4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)propan-1-ol-4-oxa-1,9-diazaspiro[5.5]undecane (1/1), di-(2,2,2-trifluoroacetic acid)

[0980] ##STR00121##

[0981] Acetic acid (0.5 mL, 9 mmol) was added to a solution of tert-butyl 4-oxa-1,9-diazaspiro-[5.5]undecane-9-carboxylate (1.00 g, 3.90 mmol) and 3-((tert-butyl-dimethylsilyl)oxy)-propanal (955 mg, 5.07 mmol) in anhydrous THF (35 mL) and the solution stirred at RT for 15 min before sodium triacetoxyborohydride (2.48 g, 11.7 mmol) was added portionwise. The reaction was stirred at RT for 18 h. The mixture was diluted with EtOAc (50 mL) and basified with 1 M aq. NaOH to pH˜9. The organic phase was separated, the aqueous further extracted with EtOAc (100 mL), the organic phases combined, dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The residue was loaded onto a pre-washed plug of SCX (15 g), the plug washed with MeOH (100 mL) and the product eluted with 0.7 N NH.sub.3 in MeOH (150 mL). The ammoniacal solution was concentrated under reduced pressure to afford a yellow oil (889.4 mg). This oil was taken up in DCM/TFA (1:1, 20 mL) and stirred at RT for 3 h. The volatiles were removed under reduced pressure and the residue azeotroped with MeOH (2×30 mL) to afford the title compound (1.36 g, 58%) as the di-TFA salt.

[0982] LCMS m/z 215.3 (M+H).sup.+ (ES.sup.+).

Intermediate A26: 4-(3-((dimethylamino)methyl)pyrrolidin-3-yl)butan-1-ol

[0983] ##STR00122##

Step A: 1-benzyl-3-(4-((tert-butyldimethylsilyl)oxy)butyl)pyrrolidine-3-carbonitrile

[0984] ##STR00123##

[0985] 1M LiHMDS in THF (14.6 mL, 14.6 mmol) was added dropwise to 1-benzylpyrrolidine-3-carbonitrile (2.59 g, 13.9 mmol) in THF (50 mL) cooled to −78° C. over 10 minutes. The mixture was left to stir at −78° C. for 30 minutes. tert-Butyl(4-iodobutoxy)dimethyl-silane (3.79 mL, 13.9 mmol) was then added in one portion and the mixture was left to warm to RT over 2.5 h. The mixture was quenched with sat. aq. NH.sub.4Cl (50 mL), and the resulting mixture was diluted with water (20 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give an orange oil. The crude product was purified by FC (0-50% EtOAc/heptane) to afford the title compound (2.60 g, 50%) as a pale yellow oil.

[0986] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.35-7.28 (m, 4H), 7.27-7.22 (m, 1H), 3.64-3.51 (m, 4H), 2.94 (d, J=9.5 Hz, 1H), 2.81-2.69 (m, 1H), 2.47-2.39 (m, 1H), 2.35 (m, 1H), 2.25-2.15 (m, 1H), 1.89-1.80 (m, 1H), 1.67-1.59 (m, 2H), 1.53-1.33 (m, 4H), 0.85 (s, 9H), 0.02 (s, 6H).

Step B: 4-(3-(aminomethyl)-1-benzylpyrrolidin-3-yl)butan-1-ol

[0987] ##STR00124##

[0988] To a solution of 1-benzyl-3-(4-((tert-butyldimethylsilyl)oxy)butyl)pyrrolidine-3-carbonitrile (2.60 g, 6.91 mmol) in THF (60 mL) at RT was added 1M LiAlH.sub.4 in THF (20.7 mL, 20.7 mmol) drop-wise and the resultant reaction mixture refluxed for 3.5 h. The reaction was allowed to cool to RT and the reaction mixture was then treated dropwise with water (5 mL), NaOH (2M aq. soln, 10 mL) and water (15 mL) and then stirred vigorously for 30 min. The mixture was then filtered and the filtrate concentrated in vacuo to afford the title compound (1.93 g, 99%) as a pale yellow oil.

[0989] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.33-7.25 (m, 4H), 7.24-7.18 (m, 1H), 3.53-3.44 (m, 2H), 3.38 (t, J=6.5 Hz, 2H), 2.44 (s, 2H), 2.42-2.32 (m, 2H), 1.57-1.45 (m, 1H), 1.45-1.29 (m, 6H), 1.28-1.13 (m, 3H). Three exchangeable protons not observed.

Step C: 4-(1-benzyl-3-((dimethylamino)methyl)pyrrolidin-3-yl)butan-1-ol

[0990] ##STR00125##

[0991] A mixture of 4-(3-(aminomethyl)-1-benzylpyrrolidin-3-yl)butan-1-ol (1.93 g, 6.84 mmol), formaldehyde (20 mL, 37% wt) and formic acid (20 mL) was refluxed for 18 h. The reaction mixture was then allowed to cool to RT before being concentrated in vacuo. The resulting residue was mixed with ice, basified with aq. NaOH (2N) and extracted with DCM (100 mL). The organics were then washed with water and brine, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (1.75 g, 86%) as a thick yellow oil.

[0992] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.32-7.26 (m, 4H), 7.24-7.18 (m, 1H), 4.08 (t, J=6.5 Hz, 1H), 3.56-3.44 (m, 2H), 3.38 (t, J=6.5 Hz, 1H), 2.49-2.41 (m, 2H), 2.32-2.18 (m, 4H), 2.15 (s, 6H), 1.61-1.47 (m, 3H), 1.46-1.33 (m, 4H), 1.33-1.18 (m, 2H).

Step D: 4-(3-((dimethylamino)methyl)pyrrolidin-3-yl)butan-1-ol

[0993] ##STR00126##

[0994] 4-(1-benzyl-3-((dimethylamino)methyl)pyrrolidin-3-yl)butan-1-ol (1.75 g, 5.90 mmol) was dissolved in EtOH (35 mL) and acetic acid (676 μL, 11.8 mmol), to which was added palladium hydroxide on carbon (415 mg, 20% wt, 590 μmol). The reaction mixture was then hydrogenated at 4 bar pressure for ˜70 h at 40° C. The catalyst was then filtered off and the filtrate concentrated in vacuo, azeotroping with toluene, to afford the crude title compound (1.82 g) as a brown oil. The product used without further purification.

[0995] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 3.41-3.35 (m, 2H), 3.10-3.02 (m, 1H), 2.80 (app s, 1H), 2.26-2.15 (m, 8H), 1.82 (app s, 5H), 1.64 (t, J=7.4 Hz, 1H), 1.43-1.32 (m, 4H), 1.29-1.19 (m, 2H).

Intermediate A27: 3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid)

[0996] ##STR00127##

[0997] To a solution of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.10 g, 5.55 mmol) in MeCN (15 mL) was added K.sub.2CO.sub.3 (2.30 g, 16.6 mmol) and 3-bromo-propan-1-ol (502 μL, 5.55 mmol). The resulting suspension was stirred at 80° C. for 24 h, then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL), washed with brine (50 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the Boc-protected product as a colourless oil. This was taken up in TFA (5 mL) and stirred at RT for 2 h, before being concentrated in vacuo to afford the title compound (1.51 g, 70%) as a light brown oil.

[0998] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 4.58-4.39 (m, 3H), 3.52-3.27 (m, 6H), 3.25-3.09 (m, 3H), 2.14-2.00 (m, 1H), 1.85-1.72 (m, 2H). Three exchangeable protons not observed.

Intermediate A28: sodium 5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-sulfinate

[0999] ##STR00128##

Step A: 5-bromo-2,3-dihydro-1H-inden-4-ol

[1000] ##STR00129##

[1001] NBS (5.3 g, 30 mmol) was added portionwise over 30 minutes to a stirred solution of 2,3-dihydro-1H-inden-4-ol (4.0 g, 30 mmol) and diisopropylamine (0.42 mL, 3.0 mmol) in DCM (80 mL) cooled in an ice bath. The mixture was then left to stir at RT for 18 h. The mixture was diluted with 1M aq. HCl (100 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were concentrated to dryness to give a yellow oil. The crude product was purified by RP FC (C18, 15-100% (0.1% formic acid in MeCN)/(0.1% formic acid in water)) to afford the title compound (4.0 g, 62%) as a white solid.

[1002] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.26 (s, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.64 (d, J=7.9 Hz, 1H), 2.83 (t, J=7.4 Hz, 2H), 2.79 (t, J=7.5 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H).

Step B: 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-ol

[1003] ##STR00130##

[1004] (2-fluoropyridin-4-yl)boronic acid (2.6 g, 19 mmol) was added to a stirred mixture of 5-bromo-2,3-dihydro-1H-inden-4-ol (4.0 g, 19 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.77 g, 0.94 mmol) and K.sub.2CO.sub.3 (7.8 g, 56 mmol) in 9:1 1,4-dioxane:water (11 mL). The mixture was degassed with a stream of nitrogen gas for 15 min then heated to 90° C. for 18 h. The mixture was left to cool to RT and filtered through a pad of Celite, washing through with EtOAc (2×15 mL). The filtrate was concentrated to dryness on silica (30 g). The crude product was purified by FC (0-30% EtOAc/isohexane (elution˜10%)) to afford a yellow/green solid. The material was triturated with 1:4 MTBE:heptane (100 mL) and filtered to afford the title compound (1.39 g, 23%) as an off-white solid.

[1005] LCMS m/z 230.3 (M+H).sup.+ (ES.sup.+); 228.6 (M−H).sup.− (ES.sup.−).

[1006] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.08 (s, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.52 (ddd, J=5.3, 2.3, 1.4 Hz, 1H), 7.30 (d, J=1.3 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 2.87 (td, J=7.3, 5.2 Hz, 4H), 2.03 (p, J=7.4 Hz, 2H).

[1007] .sup.19F NMR (471 MHz, DMSO-d.sup.6) δ −69.86.

Step C: 4-(4-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)oxy)-2,3-dihydro-1H-inden-5-yl)-2-fluoropyridine

[1008] ##STR00131##

[1009] A stirred mixture of 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane (2.46 g, 6.88 mmol) (Intermediate A1), 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-ol (1.58 g, 6.88 mmol) and K.sub.2CO.sub.3 (1.90 g, 13.8 mmol) in NMP (30 mL) was heated to 100° C. for 24 h. The reaction was diluted with EtOAc (100 mL) and washed with water (50 mL). The aqueous layer was re-extracted with EtOAc (50 mL), and the combined organics washed with brine (75 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-20% EtOAc/isohexane) to afford the title compound (3.08 g, 76%) as a thick colourless oil.

[1010] LCMS m/z 505.3/507.3 (M+H).sup.+ (ES.sup.+).

[1011] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.24 (d, J=5.2 Hz, 1H), 7.51-7.31 (m, 3H), 7.23 (d, J=1.5 Hz, 1H), 5.38 (s, 2H), 3.56 (t, J=8.0 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.72-2.65 (m, 2H), 2.07 (p, J=7.5 Hz, 2H), 0.88-0.73 (m, 2H), −0.06 (s, 9H).

Step D: methyl 3-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thio)propanoate

[1012] ##STR00132##

[1013] 4-(4-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)oxy)-2,3-dihydro-1H-inden-5-yl)-2-fluoropyridine (3.08 g, 5.25 mmol) was dissolved in 1,4-dioxane (70 mL) and the mixture was degassed with N.sub.2 for 10 min. Methyl 3-mercaptopropanoate (1.16 mL, 10.5 mmol), XantPhos (455 mg, 787 μmol) and Pd.sub.2(dba).sub.3 (360 mg, 393 μmol) were added followed by DIPEA (1.83 mL, 10.5 mmol) and the reaction mixture was degassed with N.sub.2 (10 min), then evacuated and back-filled with N.sub.2 (3 times). The reaction mixture was warmed up to 100° C. and stirred for 24 h. The reaction was cooled to RT and diluted with water (200 mL). The organics were then extracted with EtOAc (2×150 mL), and the combined organics dried using a phase separator and then concentrated in vacuo. The crude product was purified by FC (0-40% EtOAc/isohexane) to afford the title compound (3.22 g, 99%) as a yellow oil.

[1014] LCMS m/z 545-5 (M+H).sup.+.

[1015] .sup.1H NMR (500 MHz, DMSO-d.sup.6) δ 8.24 (d, J=5.2 Hz, 1H), 7.43-7.35 (m, 3H), 7.22 (s, 1H), 5-35 (s, 2H), 3.63-3.54 (m, 5H), 3.10 (t, J=7.0 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.73-2.63 (m, 4H), 2.07 (p, J=7.4 Hz, 2H), 0.83 (t, J=8.0 Hz, 2H), −0.05 (s, 9H).

Step E: methyl 3-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)propanoate

[1016] ##STR00133##

[1017] m-CPBA (3.06 g, 13.3 mmol) was added to solution of methyl 3-((5-((5-(2-fluoro-pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thio)propanoate (3.22 g, 5-32 mmol) in DCM (75 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 18 h. The reaction was quenched with sat. aq. Na.sub.2SO.sub.3 (250 mL) and then extracted with DCM (3×150 mL). The combined organics were then washed with sat. aq. NaHCO.sub.3 (400 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (3.236 g, 100%) as a brown oil.

[1018] LCMS m/z 577.4 (M+H).sup.+.

[1019] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.23 (d, J=5.2 Hz, 1H), 7.46-7.40 (m, 3H), 7.24 (s, 1H), 5.55 (s, 2H), 3.65-3.54 (m, 7H), 3.02 (t, J=7.4 Hz, 2H), 2.73 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.08 (p, J=7.4 Hz, 2H), 0.85 (t, J=8.1 Hz, 2H), −0.05 (s, 9H).

Step F: sodium 5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-sulfinate

[1020] ##STR00134##

[1021] To a solution of methyl 3-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)propanoate (3.24 g, 5.22 mmol) in THF (70 mL) at 0° C. was added sodium 2-methylbutan-2-olate (2.5 M in THF) (3.13 mL, 7.83 mmol) and the reaction was then stirred at 0° C. for 1 h. The reaction was then concentrated in vacuo and the resulting residue was diluted with hexanes (75 mL) and concentrated in vacuo (×3), to afford the title compound (2.96 g, 99%) as a light brown solid.

[1022] LCMS m/z 491.7 (M-Na+2H).sup.+ (ES.sup.+).

[1023] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.24 (d, J=5.2 Hz, 1H), 7.46-7.39 (m, 2H), 7.35 (d, J=7.7 Hz, 1H), 7.22 (s, 1H), 5.31 (s, 2H), 3.55 (t, J=8.1 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.05 (p, J=7.5 Hz, 2H), 0.84 (t, J=8.0 Hz, 2H), −0.05 (s, 9H).

Intermediate A29: di-sodium (4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropyl-phenyl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amide

[1024] ##STR00135##

Step A: 4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylaniline

[1025] ##STR00136##

[1026] A solution of 2-bromo-4-fluoro-6-isopropylaniline (0.750 g, 3.23 mmol) in anhydrous 1,4-dioxane (30 mL) was added to a mixture of (2-fluoropyridin-4-yl)boronic acid (0.460 g, 3.26 mmol) and Pd(dppf)Cl.sub.2.DCM (0.130 g, 0.160 mmol) followed by a solution of K.sub.2CO.sub.3 (1.75 g, 12.7 mmol) in water (3 mL). The resulting suspension was evacuated and backfilled with N.sub.2 twice before stirring at 95° C. for 18 h. The reaction was diluted with EtOAc (100 mL) and washed with water/brine (3:1, 100 mL). The crude was directly loaded onto silica for purification and the volatiles were removed. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (626 mg, 74%) as a purple gum.

[1027] LCMS m/z 249.0 (M+H).sup.+ (ES.sup.+).

[1028] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.30 (d, J=5.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.04 (br s, 1H), 6.96 (dd, J=9.9, 2.9 Hz, 1H), 6.71 (dd, J=8.5, 2.9 Hz, 1H), 3.64 (br s, 2H), 2.97-2.87 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).

Step B: 3-bromo-N-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine

[1029] ##STR00137##

[1030] LiHMDS (1.0 M in THF) (40.0 mL, 40.0 mmol) was added over 15 min to a mixture of 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane (7.19 g, 20.1 mmol) (Intermediate A1) and 4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylaniline (5.00 g, 20.1 mmol) in THF (100 mL) cooled to 0° C. The reaction was stirred at RT for 2 h. The reaction was quenched with sat. aq. NH.sub.4Cl (60 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by FC (0-20% EtOAc/isohexane) to afford the title compound (5.89 g, 51%) as a thick orange oil.

[1031] LCMS m/z 524.7/526.3 (M+H).sup.+ (ES.sup.+).

[1032] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.78 (s, 1H), 8.19 (d, J=5.1 Hz, 1H), 7.36 (dd, J=9.9, 3.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.19 (dd, J=8.7, 3.0 Hz, 1H), 7.13 (s, 1H), 5.23 (s, 2H), 3.50-3.41 (m, 2H), 3.19-3.09 (m, 1H), 1.15 (d, J=6.9 Hz, 6H), 0.83-0.78 (m, 2H), −0.03 (s, 9H).

Step C: methyl 3-((5-((4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thio)propanoate

[1033] ##STR00138##

[1034] Pd.sub.2(dba).sub.3 (770 mg, 841 μmol) and XantPhos (975 mg, 1.68 mmol) were evacuated and backfilled with N.sub.2 twice before a solution of 3-bromo-N-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (5.89 g, 11.2 mmol) in anhydrous 1,4-dioxane (250 mL) was added followed by DIPEA (4.00 mL, 23.0 mmol) and methyl 3-mercaptopropanoate (2.50 mL, 22.6 mmol). The resulting solution was evacuated and backfilled twice at 60° C., then the reaction was stirred at 100° C. for 18 h. The reaction was diluted with water (300 mL), the organic phase separated, the aqueous further extracted with EtOAc (3×200 mL), the combined organic phases dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by FC (0-40% EtOAc/isohexane) to afford the title compound (5.96 g, 85%) as a yellow oil, which solidified upon standing.

[1035] LCMS m/z 564.4 (M+H).sup.+ (ES.sup.+); 562.5 (M−H).sup.− (ES.sup.−).

[1036] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.34 (dd, J=10.0, 3.0 Hz, 1H), 7.32-7.27 (m, 1H), 7.17 (dd, J=8.7, 3.0 Hz, 1H), 7.14-7.11 (m, 1H), 5.21 (s, 2H), 3.58 (s, 3H), 3.49-3.40 (m, 2H), 3.20-3.10 (m, 1H), 3.02 (t, J=7.0 Hz, 2H), 2.61 (t, J=7.0 Hz, 2H), 1.13 (d, J=6.9 Hz, 6H), 0.84-0.76 (m, 2H), −0.03 (s, 9H).

Step D: methyl 3-((5-((4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)propanoate

[1037] ##STR00139##

[1038] m-CPBA (6.08 g, 75.0% wt, 26.4 mmol) was added to solution of methyl 3-((5-((4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)amino)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thio)propanoate (5.96 g, 10.6 mmol) in DCM (200 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 18 h. The reaction was quenched with sat. aq. Na.sub.2SO.sub.3 (200 mL) and then extracted with DCM (3×400 mL). The combined organics were then washed with sat. aq. NaHCO.sub.3 (100 mL), dried (MgSO.sub.4) and concentrated under reduced pressure to afford crude title compound (5-47 g, 85%) as an orange solid.

[1039] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.05 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.39 (dd, J=9.9, 3.0 Hz, 1H), 7.30 (dt, J=5.2, 1.7 Hz, 1H), 7.21 (dd, J=8.7, 3.0 Hz, 1H), 7.13 (s, 1H), 5.39 (s, 2H), 3.59 (s, 3H), 3.49-3.41 (m, 4H), 3.20-3.13 (m, 1H), 2.53 (t, J=7.3 Hz, 2H), 1.14 (d, J=6.7 Hz, 6H), 0.85-0.77 (m, 2H), −0.03 (s, 9H).

Step E: di-sodium (4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amide

[1040] ##STR00140##

[1041] Sodium 2-methylbutan-2-olate (3.95 mL, 2.5 M, 9.88 mmol) was added to a solution of methyl 3-((5-((4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)propanoate (5.47 g, 9.00 mmol) in anhydrous THF (150 mL) at 0° C. The reaction was stirred at this temperature for 2 h. Additional sodium 2-methylbutan-2-olate (3.95 mL, 2.5 M, 9.88 mmol) was added and the reaction stirred for 30 min before being concentrated under reduced pressure. The traces of solvent were azeotroped with hexanes (×4) to afford crude title compound (5.34 g, 91%) as a dark yellow solid.

[1042] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.94 (s, 1H), 7.44 (s, 1H), 7.25 (s, 1H), 6.96-6.76 (m, 2H), 4.99 (s, 2H), 3.61-3.49 (m, 2H), 1.07 (d, J=6.9 Hz, 6H), 0.84-0.79 (m, 2H), −0.03 (s, 9H). One proton overlapped with water signal in DMSO-d.sub.6.

Intermediate A30: di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amide

[1043] ##STR00141##

[1044] To a solution of methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]propanoate (Intermediate A3, Step A) (12.2 g, 16.0 mmol) in THF (250 mL) at 0° C. was added sodium 2-methylbutan-2-olate (2.5 M in THF) (9.62 mL, 24.1 mmol) and the reaction was then stirred at 0° C. for 1 h. Additional sodium 2-methylbutan-2-olate (6.42 mL, 16.0 mmol) was added and the reaction stirred for a further 1 h at 0° C. The reaction was then concentrated in vacuo and the resulting residue was diluted with hexanes (75 mL) and concentrated in vacuo (×4), to afford crude title compound (10.8 g, 99.7%) as a brown solid.

[1045] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.99 (d, J=5.3 Hz, 1H), 7.58-7.54 (m, 1H), 7.52 (d, J=1.3 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.56 (d, J=7.7 Hz, 1H), 5.04 (s, 2H), 3.60-3.50 (m, 2H), 2.79 (t, J=7.4 Hz, 2H), 1.85 (p, J=7.4 Hz, 2H), 0.84-0.74 (m, 2H), −0.07 (s, 9H). Two aliphatic protons obscured.

Intermediate A31: 3-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol bis(2,2,2-trifluoroacetate)

[1046] ##STR00142##

Step A: tert-butyl 6-(3-hydroxypropyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[1047] ##STR00143##

[1048] A solution of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (2.40 g, 11.3 mmol), 3-bromo-1-propanol (1.15 mL, 12.7 mmol) and TEA (3.20 mL, 23.0 mmol) in anhydrous THF (50 mL) was stirred at RT for 18 h. The volatiles were removed under reduced pressure, the residue partitioned between EtOAc (20 mL) and water (20 mL) and the phases separated. The aqueous was further extracted with EtOAc (20 mL), the organic phases were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by FC, 0-10% ((0.7 M Ammonia/MeOH)/DCM) to afford the title compound (1.57 g, 40% yield, 77% purity) as an orange oil.

[1049] LCMS m/z 271.4 (M+H).sup.+ (ES.sup.+), 215.4 (M-.sup.tBu+H).sup.+ (ES.sup.+).

Step B: 3-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol bis(2,2,2-trifluoroacetate)

[1050] ##STR00144##

[1051] To a solution of tert-butyl 6-(3-hydroxypropyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (1.57 g, 77% wt, 4.47 mmol) in DCM (5 mL) was added TFA (5 mL, 0.06 mol). The reaction mixture was stirred at RT for 2 h after which the reaction mixture was concentrated in vacuo to give the title compound (4.4 g, 170% yield, 70% purity) as a clear yellow oil.

[1052] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.56 (s, 1H), 9.22-8.71 (m, 2H), 4.44 (t, J=6.1 Hz, 2H), 4.12-4.04 (m, 2H), 4.01 (s, 2H), 3.91 (t, J=14.3 Hz, 2H), 3.63 (s, 1H), 3.38-3.29 (m, 1H), 3.24 (d, J=7.4 Hz, 2H), 3.10 (d, J=13.0 Hz, 1H), 2.49-2.38 (m, 1H), 2.23 (q, J=9.0, 8.5 Hz, 1H), 2.08 (qd, J=8.9, 6.0 Hz, 2H).

Preparation of Examples

Example 1: 26-methyl-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,26,33-heptazahexacyclo-[25.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaene 2,2-dioxide

[1053] ##STR00145##

Step A: 3-[[1-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-4-piperidyl]-methyl-amino]propan-1-ol

[1054] ##STR00146##

[1055] NCS (160 mg, 1.20 mmol) was added to a mixture of ammonium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A4) (489 mg, 1.00 mmol) in DCM (9.00 mL) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 1 h and a mixture of 3-hydroxypropyl-methyl-piperidin-1-ium-4-yl-ammonium dichloride (Intermediate A5) (262 mg, 1.52 mmol) and DIPEA (0.520 mL, 3.00 mmol) in DCM (3.00 mL) was added. The mixture and stirred for 1 h at 0° C. and diluted with water (7.00 mL). The aqueous phase was extracted with EtOAc (2×100 mL), and the combined organic phases were washed with brine (20.0 mL), dried (MgSO.sub.4), filtered, and concentrated. The product was purified by FC (0-20% MeOH/DCM) to provide the title compound as a solid (419 mg, 63%).

[1056] LCMS m/z 660.2 (M+H).sup.+ (ES.sup.+).

[1057] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (d, J=5.1 Hz, 1H), 7.25-7.18 (m, 2H), 7.14 (d, J=7.7 Hz, 1H), 6.97 (s, 1H), 6.42-6.30 (m, 1H), 5.37 (s, 2H), 3.96-3.87 (m, 2H), 3.83-3.74 (m, 2H), 3.58-3.42 (m, 2H), 3.02 (t, J=7.4 Hz, 2H), 2.79 (t, J=7.4 Hz, 2H), 2.73-2.68 (m, 2H), 2.59-2.48 (m, 3H), 2.29 (s, 3H), 2.17-2.06 (m, 2H), 1.84-1.76 (m, 2H), 1.76-1.58 (m, 5H), 0.82-0.73 (m, 2H), −0.00 (s, 9H).

[1058] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.37 (s).

Step B: trimethyl-[2-[(26-methyl-2,2-dioxo-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,26,33-heptazahexacyclo[25.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaen-5-yl)methoxy]ethyl]silane

[1059] ##STR00147##

[1060] tBuOK (1 M in THF, 5.89 mL, 5.89 mmol) was added to a mixture of 3-[[1-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-4-piperidyl]-methyl-amino]propan-1-ol (389 mg, 0.589 mmol) in THF (260 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 h, diluted with EtOH (10.0 mL) and concentrated. The product was purified by FC (0-20% MeOH/DCM) to provide the title compound (139 mg, 37%).

[1061] LCMS m/z 640.6 (M+H).sup.+ (ES.sup.+).

[1062] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.07 (d, J=5.3 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.08-7.01 (m, 1H), 6.80-6.75 (m, 1H), 6.22 (s, 1H), 5.41 (s, 2H), 4.32-4.24 (m, 2H), 3.63-3.45 (m, 4H), 3.01 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.3 Hz, 2H), 2.66-2.50 (m, 2H), 2.33-2.25 (m, 1H), 2.21 (s, 3H), 2.19-2.06 (m, 3H), 1.96-1.88 (m, 2H), 1.78-1.66 (m, 2H), 1.64-1.53 (m, 3H), 0.91-0.83 (m, 2H), 0.01 (s, 9H).

Step C: 26-methyl-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,26,33-heptazahexacyclo-[25.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaene 2,2-dioxide

[1063] ##STR00148##

[1064] A mixture of trimethyl-[2-[(26-methyl-2,2-dioxo-22-oxa-2λ.sup.6-thia-1,4,5,7,20,26,33-heptazahexacyclo[25.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaen-5-yl)methoxy]ethyl]silane (17.0 mg, 0.0266 mmol) in DCM (1.00 mL) and TFA (1.00 mL) was stirred at 22° C. for 2 h and concentrated. The product was purified by basic prep HPLC (0-100% MeCN in water) to provide the title compound as a solid (6.85 mg, 51%).

[1065] LCMS m/z 509.9 (M+H).sup.+ (ES.sup.+).

[1066] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.99 (s, 1H), 8.95 (s, 1H), 8.12 (d, J=5.4 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.09-7.05 (m, 1H), 6.70 (s, 1H), 4.20 (t, J=5.4 Hz, 2H), 3.45-3.37 (m, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.4 Hz, 2H), 2.65-2.61 (m, 1H), 2.53-2.51 (m, 1H), 2.37-2.35 (m, 2H), 2.28-2.22 (m, 1H), 2.17 (s, 3H), 2.07-1.99 (m, 2H), 1.80-1.71 (m, 2H), 1.60-1.54 (m, 2H), 1.44-1.34 (m, 2H).

Example 2: 26-oxa-16λ.SUP.6.-thia-11,13,14,17,22,28,34-heptazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene 16,16-dioxide

[1067] ##STR00149##

Step A: 3-[2-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-2,7-diazaspiro[3.4]octan-7-yl]propan-1-ol

[1068] ##STR00150##

[1069] Synthesized according to the procedure outlined for 3-[[1-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-4-piperidyl]-methyl-amino]propan-1-ol (Example 1, Step A), from NCS (45.1 mg, 0.338 mmol) and ammonium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A4) (80% purity, 180 mg, 0.281 mmol) in DCM (3.00 mL) at 0° C. for 30 min, and 3-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol (Intermediate A7) (91.0 mg, 0.535 mmol) and DIPEA (0.072 ml, 0.422 mmol) in DCM (5.00 ml) at 22° C. for 30 min, to provide the title compound as a solid (128 mg, 69%).

[1070] LCMS m/z 658.5 (M+H).sup.+ (ES.sup.+).

[1071] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.20 (d, J=5.1 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.19 (d, J=5.1 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.93 (s, 1H), 6.40 (s, 1H), 5.40 (s, 2H), 3.91 (dd, J=19.6, 8.1 Hz, 4H), 3.79-3.69 (m, 2H), 3.57-3.48 (m, 2H), 3.01 (t, J=7.4 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.67 (dd, J=14.4, 8.5 Hz, 4H), 2.60 (t, J=7.0 Hz, 2H), 2.18-2.04 (m, 2H), 1.88 (t, J=7.1 Hz, 2H), 1.72-1.62 (m, 2H), 1.25 (s, 1H), 0.77-0.72 (m, 2H), −0.00 (s, 9H).

[1072] .sup.19F NMR (471 MHz, CDCl.sub.3) δ −67.24 (s).

Step B: 2-[(16,16-dioxo-26-oxa-16λ.SUP.6.-thia-11,13,14,17,22,28,34-heptazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12(34),14,27(31),28-octaen-13-yl)methoxy]ethyl-trimethyl-silane, formic acid

[1073] ##STR00151##

[1074] Synthesized according to the procedure outlined for trimethyl-[2-[(26-methyl-2,2-dioxo-22-oxa-2λ.sup.6-thia-1,4,5,7,20,26,33-heptazahexacyclo[25.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]-tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaen-5-yl)methoxy]ethyl]silane (Example 1, Step B), from tBuOK (1M in THF, 1.52 mL, 1.52 mmol) and 3-[2-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-sulfonyl]-2,7-diazaspiro[3.4]octan-7-yl]propan-1-ol (100 mg, 0.152 mmol) in THF (74.0 mL) at 0° C. for 1 h. The product was purified by FC (0-10% MeOH/DCM) followed by basic prep HPLC (0-60% MeCN in water) provided the title compound as a solid (58 mg, 56%).

[1075] LCMS m/z 638.8 (M−HCO.sub.2H+H).sup.+ (ES.sup.+).

[1076] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (dd, J=5.3, 0.7 Hz, 1H), 8.17 (s, 1H), 7.22 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.98 (dd, J=5.3, 1.4 Hz, 1H), 6.66 (dd, J=1.4, 0.7 Hz, 1H), 6.29 (s, 1H), 5.43 (s, 2H), 4.25 (s, 2H), 3.95-3.86 (m, 4H), 3.61-3.56 (m, 2H), 2.99 (dd, J=17.6, 10.2 Hz, 8H), 2.69 (t, J=7.4 Hz, 2H), 2.29 (t, J=7.1 Hz, 2H), 2.08 (dd, J=12.6, 5.3 Hz, 4H), 0.76-0.67 (m, 2H), −0.06 (s, 9H). One exchangeable proton not observed.

Step C: 26-oxa-16λ.SUP.6.-thia-11,13,14,17,22,28,34-heptazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene 16,16-dioxide, formic acid

[1077] ##STR00152##

[1078] TFA (2.00 mL, 26.9 mmol) was added to a mixture of 2-[(16,16-dioxo-26-oxa-16λ.sup.6-thia-11,13,14,17,22,28,34-heptazaheptacyclo[25.3.1.1.sup.12,15.1.sup.17,19.1.sup.19,22.0.sup.2,10.0.sup.5,9]tetratriaconta-1(30),2,4,9,12(34),14,27(31),28-octaen-13-yl)methoxy]ethyl-trimethyl-silane, formic acid (58 mg, 0.091 mmol) in DCM (2.00 mL) at 0° C. The mixture was stirred at 22° C. for 1.5 h and concentrated. The residue was diluted with MeOH (2.00 mL) and passed through a column of Amberlite IRA-402(OH) resin (3.10 g), eluting with MeOH (50.0 mL), followed by HCO.sub.2H in MeOH (7M, 100 ml). The mixture was concentrated to provide the title compound as a solid (12.0 mg, 26%).

[1079] LCMS m/z 508.6 (M−HCO.sub.2H+H).sup.+ (ES.sup.+).

[1080] .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.21 (s, 1H), 8.20 (d, J=5.3 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.13 (d, J=4.5 Hz, 1H), 6.78 (s, 1H), 4.43 (s, 2H), 3.93 (dd, J=22.9, 9.0 Hz, 4H), 3.41 (d, J=24.3 Hz, 4H), 3.26 (s, 2H), 3.03 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.13 (dt, J=14.8, 7.6 Hz, 4H).

[1081] Three exchangeable protons not observed.

Example 3: 25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,33-heptazaheptacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tritriaconta-1(29),2,4,9,12,14,26(30),27-octaene 16,16-dioxide

[1082] ##STR00153##

Step A: 2-[2-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-2,7-diazaspiro[3.4]octan-7-yl]ethanol

[1083] ##STR00154##

[1084] Synthesized according to the procedure outlined for 3-[[1-[[5-[[5-(2-fluoro-4-pyridyl)-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-4-piperidyl]-methyl-amino]propan-1-ol (Example 1, Step A), from NCS (95.5 mg, 0.715 mmol) and sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (305 mg, 0.596 mmol) in DMF (5.00 mL) at 0° C. under N.sub.2 for 45 min, and 2-(2,6-diazaspiro-[3.4]octan-6-yl)-ethanol di-(2,2,2-trifluoroacetic acid) (Intermediate A9) (458 mg, 1.19 mmol) and DIPEA (0.51 mL, 2.98 mmol) in DMF (2.00 mL) for 1 h at 0° C., to provide the title compound as a solid (61.0 mg, 16%).

[1085] LCMS m/z 644.2 (M+H).sup.+ (ES.sup.+).

[1086] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.19 (d, J=5.0 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.21-7.19 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.95-6.93 (m, 1H), 6.44 (s, 1H), 5.40 (s, 2H), 3.92 (d, J=8.4 Hz, 2H), 3.90 (d, J=8.5 Hz, 2H), 3.64-3.57 (m, 2H), 3.57-3.50 (m, 2H), 3.01 (t, J=7.4 Hz, 2H), 2.82-2.72 (m, 5H), 2.68-2.61 (m, 4H), 2.17-2.07 (m, 2H), 1.92 (t, J=7.0 Hz, 2H), 0.81-0.73 (m, 2H), −0.00 (s, 9H).

[1087] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.41 (s).

Step B: 2-[(16,16-dioxo-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,33-heptazaheptacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tritriaconta-1(29),2,4,9,12(33),14,26(30),27-octaen-13-yl)methoxy]ethyl-trimethyl-silane, formic acid

[1088] ##STR00155##

[1089] Synthesized according to the procedure outlined for trimethyl-[2-[(26-methyl-2,2-dioxo-22-oxa-2λ.sup.6-thia-1,4,5,7,20,26,33-heptazahexacyclo[25.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]-tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaen-5-yl)methoxy]ethyl]silane (Example 1, Step B), from tBuOK (1M in THF, 0.947 mL, 0.947) and 2-[2-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-sulfonyl]-2,7-diazaspiro[3.4]octan-7-yl]-ethanol (61.0 mg, 0.0947 mmol) in THF (45.0 mL) at 0° C. for 3 h to provide the title compound as a solid (11.0 mg, 1900).

[1090] LCMS m/z 624.2 (M−HCO.sub.2H+H).sup.+ (ES.sup.+).

[1091] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (d, J=5.9 Hz, 1H), 8.12 (s, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.05-6.94 (m, 2H), 6.76 (s, 1H), 5.27 (s, 2H), 4.63-4.56 (m, 2H), 3.99 (d, J=9.2 Hz, 2H), 3.95 (d, J=9.1 Hz, 2H), 3.58-3.51 (m, 2H), 3.23-3.18 (m, 2H), 3.14 (t, J=7.1 Hz, 2H), 3.09-3.06 (m, 2H), 3.02 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.31 (t, J=7.1 Hz, 2H), 2.19-2.08 (m, 2H), 0.87-0.80 (m, 2H), −0.03 (s, 9H). One exchangeable proton not observed.

Step C: 25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,33-heptazaheptacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tritriaconta-1(29),2,4,9,12,14,26(30),27-octaene 16,16-dioxide

[1092] ##STR00156##

[1093] A mixture of 2-[(16,16-dioxo-25-oxa-16λ.sup.6-thia-11,13,14,17,22,27,33-heptazaheptacyclo-[24.3.1.1.sup.12,15.1.sup.17,19.1.sup.19,22.0.sup.2,10.0.sup.5,9]tritriaconta-1(29),2,4,9,12(33),14,26(30),27-octaen-13-yl)methoxy]ethyl-trimethyl-silane, formic acid (12.0 mg, 0.0192 mmol) in DCM (2.00 mL) and TFA (1.00 mL) was stirred at 22° C. for 4 h and concentrated. The product was purified by basic prep HPLC (0-100% MeCN in water) to provide the title compound as a solid (7.84 mg, 83%).

[1094] LCMS m/z 494.8 (M+H).sup.+ (ES.sup.+).

[1095] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.22 (br, 1H), 9.22 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 7.02 (d, J=5.3 Hz, 1H), 6.62 (s, 1H), 4.40-4.30 (m, 2H), 3.86-3.80 (m, 4H), 2.98 (t, J=7.3 Hz, 2H), 2.73 (t, J=7.1 Hz, 2H), 2.68-2.62 (m, 2H), 2.59-2.54 (m, 2H), 2.43-2.31 (m, 2H), 2.11-2.01 (m, 2H), 2.01-1.91 (m, 2H).

Example 4: 3-methyl-26-oxa-16λ.SUP.6.-thia-11,13,14,17,22,28,34-heptazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene 16,16-dioxide

[1096] ##STR00157##

Step A: 3-[2-[[5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-2,7-diazaspiro[3.4]octan-7-yl]propan-1-ol

[1097] ##STR00158##

[1098] Synthesized according to the procedure outlined for 3-[[1-[[5-[[5-(2-fluoro-4-pyridyl)-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-4-piperidyl]-methyl-amino]propan-1-ol (Example 1, Step A), from NCS (107 mg, 0.804 mmol) and sodium 5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A10) (352 mg, 0.670 mmol) in DCM (7.50 mL) at 0° C. for 1 h, and 3-(2,6-diazaspiro[3.4]octan-6-yl)-propan-1-ol (Intermediate A7) (148 mg, 0.871 mmol) and DIPEA (0.348 mL, 2.01 mmol) in DCM (2.50 mL) for 1 h at 0° C., to provide the title compound as a solid (235 mg, 52%).

[1099] LCMS m/z 672.2 (M+H).sup.+ (ES.sup.+).

[1100] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (d, J=5.1 Hz, 1H), 7.11 (s, 1H), 7.07-7.05 (m, 1H), 6.82-6.80 (m, 1H), 6.06 (s, 1H), 5.30 (d, J=3.3 Hz, 1H), 5.28 (d, J=4.1 Hz, 1H), 3.98-3.87 (m, 6H), 3.76 (t, J=5.3 Hz, 2H), 3.42-3.32 (m, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.77-2.64 (m, 5H), 2.59 (t, J=7.0 Hz, 2H), 2.12-2.07 (m, 2H), 2.06 (s, 3H), 1.89 (t, J=7.1 Hz, 2H), 1.72-1.65 (m, 2H), 0.72-0.65 (m, 2H), 0.00 (s, 9H).

[1101] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −66.66 (s).

Step B: trimethyl-[2-[(3-methyl-16,16-dioxo-26-oxa-16λ.SUP.6.-thia-11,13,14,17,22,28,34-heptazaheptacyclo[25.3.1.1.SUP.12,15.1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12(34),14,27(31),28-octaen-13-yl)methoxy]ethyl]silane

[1102] ##STR00159##

[1103] Synthesized according to the procedure outlined for trimethyl-[2-[(26-methyl-2,2-dioxo-22-oxa-2λ.sup.6-thia-1,4,5,7,20,26,33-heptazahexacyclo[25.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]-tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaen-5-yl)methoxy]ethyl]silane (Example 1, Step B), from tBuOK (1M in THF, 2.81 mL, 2.81 mmol) and 3-[2-[[5-[[5-(2-fluoro-4-pyridyl)-6-methyl-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-2,7-diazaspiro[3.4]octan-7-yl]propan-1-ol (189 mg, 0.281 mmol) in THF (145 mL) at 0° C. for 2 h to provide the title compound as a solid (123 mg, 67%).

[1104] LCMS m/z 652.3 (M+H).sup.+ (ES.sup.+).

[1105] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20 (dd, J=5.2, 0.6 Hz, 1H), 7.07 (s, 1H), 6.78 (dd, J=5.2, 1.4 Hz, 1H), 6.54-6.52 (m, 1H), 5.94 (s, 1H), 5.31 (s, 2H), 4.71-4.63 (m, 1H), 4.06-3.99 (m, 1H), 3.97-3.92 (m, 1H), 3.88-3.80 (m, 2H), 3.73-3.69 (m, 1H), 3.45-3.31 (m, 2H), 3.05-2.87 (m, 2H), 2.79-2.60 (m, 4H), 2.59-2.45 (m, 4H), 2.23-2.08 (m, 4H), 2.05 (s, 3H), 2.03-1.87 (m, 2H), 0.72 (t, J=7.9 Hz, 2H), −0.03 (s, 9H).

Step C: 3-methyl-26-oxa-16λ.SUP.6.-thia-11,13,14,17,22,28,34-heptazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene 16,16-dioxide

[1106] ##STR00160##

[1107] A mixture of trimethyl-[2-[(3-methyl-16,16-dioxo-26-oxa-1A-thia-11,13,14,17,22,28,34-heptazaheptacyclo[25.3.1.1.sup.12,15.1.sup.17,19.1.sup.19,22.0.sup.2,10.0.sup.5,9]tetratriaconta-1(30),2,4,9,12(34),14,27(31),28-octaen-13-yl)methoxy]ethyl]silane (141 mg, 0.216 mmol) in DCM (2.00 mL) and TFA (2.00 mL) was stirred at 22° C. for 4 h and concentrated. The product was purified by basic prep HPLC (0-1000% MeCN in water) to provide the title compound as a solid (66.0 mg, 59%).

[1108] LCMS m/z 522.0 (M+H).sup.+ (ES.sup.+).

[1109] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.98 (br, 1H), 8.74 (s, 1H), 8.15 (dd, J=5.2, 0.6 Hz, 1H), 7.17 (s, 1H), 6.85 (dd, J=5.2, 1.3 Hz, 1H), 6.48 (s, 1H), 4.69-4.54 (m, 1H), 4.04-3.92 (m, 1H), 3.91-3.84 (m, 1H), 3.78-3.66 (m, 2H), 3.48-3.40 (m, 1H), 2.97-2.88 (m, 2H), 2.66 (t, J=6.9 Hz, 2H), 2.63-2.60 (m, 1H), 2.60-2.53 (m, 2H), 2.46-2.36 (m, 1H), 2.27-2.19 (m, 1H), 2.17-2.08 (m, 1H), 2.04 (s, 3H), 2.02-1.91 (m, 4H), 1.77-1.69 (m, 2H).

Example 5: 8-oxa-28λ.SUP.6.-thia-5,10,23,25,26,29,34-heptazaheptacyclo-[27.2.2.1.SUP.9,13..1.SUP.24,27..0.SUP.1,5..0.SUP.14,22..0.SUP.17,21.]pentatriaconta-9(35),10,12,14,16,21,24,26-octaene 28,28-dioxide

[1110] ##STR00161##

Step A: 2-[8-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-1,8-diazaspiro[4.5]decan-1-yl]ethanol

[1111] ##STR00162##

[1112] Synthesized according to the procedure outlined for 3-[[1-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-4-piperidyl]-methyl-amino]propan-1-ol (Example 1, Step A), from NCS (144 mg, 1.08 mmol) and sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (500 mg, 0.977 mmol) in DCM:DMF (4:1 v/v, 20 mL) at 0° C. for 30 min, and 2-(1,8-diazoniaspiro[4.5]decan-1-yl)ethanol di-(2,2,2-trifluoroacetate) (Intermediate A8) (270 mg, 1.47 mmol) and DIPEA (0.836 mL, 4.89 mmol) in DMF (4 mL) at 22° C. for 15 min, to provide the title compound as a solid (264 mg, 40%).

[1113] LCMS m/z 672.1 (M+H).sup.+ (ES.sup.+).

[1114] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (s, 1H), 8.18 (d, J=5.2 Hz, 2H), 7.30 (t, J=6.9 Hz, 3H), 7.09 (s, 2H), 5.42 (s, 2H), 4.27 (s, 1H), 3.63-3.46 (m, 3H), 3.40-3.36 (m, 2H), 2.98 (t, J=7.6 Hz, 2H), 2.75-2.70 (m, 3H), 2.48-2.41 (m, 3H), 2.12-1.93 (m, 3H), 1.69-1.65 (m, 2H), 1.57-1.53 (m, 2H), 1.48-1.44 (m, 2H), 1.27 (d, J=11.9 Hz, 2H), 0.85 (dd, J=10.4, 6.0 Hz, 2H), −0.03 (s, 9H).

[1115] .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −69.07 (s).

Step B: 2-[(28,28-dioxo-8-oxa-28λ.SUP.6.-thia-5,10,23,25,26,29,34-heptazaheptacyclo-[27.2.2.1.SUP.9,13..1.SUP.24,27..0.SUP.1,5..0.SUP.14,22..0.SUP.17,21.]pentatriaconta-9(35),10,12,14,16,21,24(34),26-octaen-25-yl)methoxy]ethyl-trimethyl-silane

[1116] ##STR00163##

[1117] Synthesized according to the procedure outlined for trimethyl-[2-[(26-methyl-2,2-dioxo-22-oxa-2λ.sup.6-thia-1,4,5,7,20,26,33-heptazahexacyclo[25.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]-tritriaconta-3,6(33),8,13,15,17,19,21(32)-octaen-5-yl)methoxy]ethyl]silane (Example 1, Step B), from tBuOK (1M in THF, 2.98 mL, 2.98 mmol) and 2-[8-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfonyl]-1,8-diazaspiro[4.5]decan-1-yl]ethanol (200 mg, 0.298 mmol) in THF (110 mL) at 0° C. for 2 h, to provide the title compound as a solid (50.0 mg, 25%).

[1118] LCMS m/z 650.7 (M−H).sup.− (ES.sup.−).

[1119] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (d, J=5.1 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.91 (dd, J=5.2, 1.2 Hz, 1H), 6.81 (s, 1H), 6.19 (s, 1H), 5.30 (s, 2H), 4.22-4.17 (m, 2H), 3.69 (dt, J=13.4, 6.7 Hz, 2H), 3.48-3.37 (m, 2H), 3.28 (t, J=9.6 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.84-2.78 (m, 2H), 2.78 (t, J=7.3 Hz, 2H), 2.68-2.62 (m, 2H), 2.11 (p, J=7.5 Hz, 2H), 1.91-1.69 (m, 2H), 1.69-1.60 (m, 2H), 1.56-1.52 (m, 2H), 1.39-1.31 (m, 2H), 0.83-0.63 (m, 2H), −0.03 (s, 9H).

Step C: 8-oxa-28λ.SUP.6.-thia-5,10,23,25,26,29,34-heptazaheptacyclo-[27.2.2.1.SUP.9,13..1.SUP.24,27..0.SUP.1,5..0.SUP.14,22..0.SUP.17,21.]pentatriaconta-9(35),10,12,14,16,21,24,26-octaene 28,28-dioxide, formic acid

[1120] ##STR00164##

[1121] Synthesized according to the procedure outlined for 26-oxa-16λ.sup.6-thia-11,13,14,17,22,28,34-heptazaheptacyclo[25.3.1.1.sup.12,15.1.sup.17,19.1.sup.19,22.0.sup.2,10.0.sup.0,9]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene 16,16-dioxide, formic acid (Example 2, Step C), from TFA (0.481 mL, 6.29 mmol) and 2-[(28,28-dioxo-8-oxa-28λ.sup.6-thia-5,10,23,25,26,29,34-heptazaheptacyclo[27.2.2.1.sup.9,13.1.sup.24,27.0.sup.1,5.0.sup.14,22.0.sup.17,21]pentatriaconta-9(35),10,12,14,16,21,24(34),26-octaen-25-yl)methoxy]ethyl-trimethyl-silane (50.0 mg, 0.0767 mmol in DCM (2.50 mL) at 22° C. for 1 h to provide the title compound as a solid (30 mg, 48%).

[1122] LCMS m/z 522.3 (M−HCO.sub.2H+H).sup.+ (ES.sup.+).

[1123] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.85 (bs, 1H), 9.14 (s, 1H), 8.15 (d, J=5.1 Hz, 1H), 7.94 (dd, J=8.3, 1.3 Hz, 1H), 7.54 (dt, J=45.9, 7.4 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 6.98 (dd, J=5.2, 1.4 Hz, 1H), 6.62 (s, 1H), 4.22-4.18 (m, 2H), 3.28-3.21 (m, 2H), 3.20-3.13 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.1 Hz, 4H), 2.58-2.52 (m, 2H), 2.06 (p, J=7.5 Hz, 2H), 1.73-1.67 (m, 2H), 1.60-1.35 (m, 4H), 1.35-1.16 (m, 2H).

Example 6: 21,21-dimethyl-23-oxa-16λ.SUP.6.-thia-11,13,14,20,25,29,30-heptazahexacyclo-[22.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]triaconta-1(27),2,4,9,12(30),14,17(29),18,24(28),25-decaene 16,16-dioxide

[1124] ##STR00165##

Step A

(a) 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-thiol; and

[1125] (b) 5-[[5-(2-methoxy-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl-1,2,4-triazole-3-thiol

##STR00166##

[1126] tBuOK (1.0 M in THF, 2.57 mL, 2.57 mmol) was added to a mixture of methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]propanoate (Intermediate A2) (700.0 mg, 1.29 mmol) in THF (10.0 mL) at 22° C. under N.sub.2. The mixture was stirred at 22° C. for 5 min and diluted with aq. HCl (1.0 M, 5.00 mL). The aqueous phase was extracted with EtOAc (3×50.0 mL), and the combined organic phases were dried (Na.sub.2SO.sub.4), filtered, and concentrated to provide a mixture of the title compounds as a solid (1:1, 400 mg, 61%).

[1127] (a) LCMS m/z 458.3 (M+H).sup.+ (ES.sup.+).

[1128] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.46.

[1129] (b) LCMS m/z 470.3 (M+H).sup.+ (ES.sup.+).

Step B: 2-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]pyrazol-1-yl]-2-methyl-propan-1-ol

[1130] ##STR00167##

[1131] DMEDA (3.52 mL, 32.7 mmol) was added to a degassed mixture of the product of step A (1:1 mixture, 749 mg, 1.64 mmol), CuI (623 mg, 3.27 mmol), and 2-(3-iodopyrazol-1-yl)-2-methyl-propan-1-ol (Intermediate A11) (435 mg, 1.64 mmol) in dioxane (10.0 mL) at 22° C. under N.sub.2. The mixture was stirred at 70° C. for 1 h and diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3×20.0 mL), and the combined organic phases were washed with brine (20.0 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-100% EtOAc/hexanes), and by basic prep HPLC (29-39% MeCN in water) to provide the title compound as a solid (125 mg, 13%).

[1132] LCMS m/z 596.4 (M+H).sup.+ (ES.sup.+).

[1133] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.15 (d, J=5.1 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.22-7.15 (m, 2H), 7.09 (d, J=7.7 Hz, 1H), 6.92 (s, 1H), 6.37 (d, J=2.4 Hz, 1H), 6.14 (s, 1H), 5.20 (s, 2H), 3.76 (s, 2H), 3.52-3.41 (m, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.08 (p, J=7.5 Hz, 2H), 1.54 (s, 6H), 0.78-0.66 (m, 2H), −0.02 (s, 9H). One exchangeable proton not observed.

[1134] .sup.19F NMR (471 MHz, CDCl.sub.3) δ −67.47 (s).

Step C: 2-[(21,21-dimethyl-23-oxa-16-thia-11,13,14,20,25,29,30-heptazahexacyclo-[22.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]triaconta-1(27),2,4,9,12(30),14,17(29),18,24(28),25-decaen-13-yl)methoxy]ethyl-trimethyl-silane

[1135] ##STR00168##

[1136] A mixture of 2-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]pyrazol-1-yl]-2-methyl-propan-1-ol (300 mg, 0.504 mmol) in THF (250 mL) was added to a mixture of tBuOK (1M in THF, 5.04 mL, 5.04 mmol) in THF (50.0 mL) over the course of 4 h at 22° C. The mixture was stirred at 22° C. for 1 h, diluted with EtOH (20.0 mL), and concentrated. The product was purified by FC (0-10% MeOH/DCM) to provide the title compound as a solid (78%, 190 mg, 51%).

[1137] LCMS m/z 576.2 (M+H).sup.+ (ES.sup.+).

[1138] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (dd, J=5.3, 0.5 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.76 (dd, J=5.3, 1.4 Hz, 1H), 6.45 (d, J=2.3 Hz, 1H), 6.30 (d, J=0.8 Hz, 1H), 6.10 (s, 1H), 5.24 (s, 2H), 4.57 (s, 2H), 3.59-3.51 (m, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.20-2.11 (m, 2H), 1.72 (s, 6H), 0.98-0.88 (m, 2H), 0.02 (s, 9H).

Step D: 2-[(21,21-dimethyl-16,16-dioxo-23-oxa-16λ.SUP.6.-thia-11,13,14,20,25,29,30-heptazahexacyclo[22.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]triaconta-1(27),2,4,9,12(30),14,17(29),18,24(28),25-decaen-13-yl)methoxy]ethyl-trimethyl-silane

[1139] ##STR00169##

[1140] m-CPBA (162 mg, 0.722 mmol) was added to a mixture of 2-[(21,21-dimethyl-23-oxa-16-thia-11,13,14,20,25,29,30-heptazahexacyclo[22.3.1.1.sup.12,15.1.sup.17,20.0.sup.2,10.0.sup.5,9]triaconta-1(27),2,4,9,12(30),14,17(29),18,24(28),25-decaen-13-yl)methoxy]ethyl-trimethyl-silane (78%, 180 mg, 0.241 mmol) in DCM (15.0 mL) at 0° C. The mixture was stirred at 22° C. for 1 h and diluted with sat. aq. Na.sub.2S.sub.2O.sub.4 (10.0 mL). The aqueous phase was extracted with DCM (3×15.0 mL), and the combined organic phases were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-35% MeOH/DCM) to provide the title compound as a solid (50.0 mg, 27%).

[1141] LCMS m/z 608.2 (M+H).sup.+ (ES.sup.+).

[1142] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=4.8 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.84 (d, J=2.5 Hz, 1H), 6.74 (dd, J=5.3, 1.4 Hz, 1H), 6.39 (s, 1H), 6.24 (s, 1H), 5.27 (s, 2H), 4.49 (s, 2H), 3.58 (dd, J=9.2, 7.9 Hz, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.87 (t, J=7.4 Hz, 2H), 2.17-2.09 (m, 2H), 1.74 (s, 6H), 0.97-0.87 (m, 2H), 0.00 (s, 9H).

Step E: 21,21-dimethyl-23-oxa-16λ.SUP.6.-thia-11,13,14,20,25,29,30-heptazahexacyclo-[22.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]triaconta-1(27),2,4,9,12(30),14,17(29),18,24(28),25-decaene 16,16-dioxide

[1143] ##STR00170##

[1144] TFA (2.00 mL) was added to a mixture of 2-[(21,21-dimethyl-16,16-dioxo-23-oxa-16λ.sup.6-thia-11,13,14,20,25,29,30-heptazahexacyclo[22.3.1.1.sup.12,15.1.sup.17,20.0.sup.2,10.0.sup.5,9]triaconta-1(27),2,4,9,12(30),14,17(29),18,24(28),25-decaen-13-yl)methoxy]ethyl-trimethyl-silane (50.0 mg, 0.0823 mmol) in DCM (5.00 mL) at 22° C. under N.sub.2. The mixture was stirred at 22° C. for 1 h and concentrated. The product was purified by basic prep HPLC (45-65% MeCN in water) to provide the title compound as a solid (12.0 mg, 24%).

[1145] LCMS m/z 478.3 (M+H).sup.+ (ES.sup.+).

[1146] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 8.37 (s, 1H), 8.11 (d, J=2.5 Hz, 1H), 7.84 (d, J=5.3 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 6.86 (dd, J=5.3, 1.5 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 6.14 (d, J=0.8 Hz, 1H), 4.49 (s, 2H), 3.08-2.77 (m, 4H), 2.16-1.92 (m, 2H), 1.67 (s, 6H).

Example 7: 21,21-dimethyl-24-oxa-16λ.SUP.6.-thia-11,13,14,20,26,30,31-heptazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12,14,17(30),18,25(29),26-decaene 16,16-dioxide

[1147] ##STR00171##

Step A: 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-thiol

[1148] ##STR00172##

[1149] tBuOK (1.00 M, 4.71 mL, 4.71 mmol) was added to a mixture of methyl 3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]propanoate (Intermediate A2) (1.28 g, 2.35 mmol) in degassed THF (20 mL) at 22° C. The mixture was stirred at 22° C. for 30 min and Dowex MAC-3 Hydrogen form (3.00 g, 9.66 mmol) was added. The mixture was stirred at 20° C. for 30 min and filtered, washing with THF (20.0 mL). The filtrate was concentrated to provide the title compound as a solid which was directly engaged in the next step.

[1150] LCMS m/z 458.6 (M+H).sup.+ (ES.sup.+).

Step B: 3-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]pyrazol-1-yl]-3-methyl-butan-1-ol

[1151] ##STR00173##

[1152] A mixture of the product of step A (1.08 g, 2.35 mmol) in degassed dioxane (15.0 mL) was added to a mixture of CuI (896 mg, 4.71 mmol) and DMEDA (5.07 mL, 47.1 mmol) in degassed dioxane (5.00 mL). 3-(3-Iodopyrazol-1-yl)-3-methyl-butan-1-ol (Intermediate A12) (659 mg, 2.35 mmol) was added to the mixture. The mixture was stirred at 70° C. for 18 h and filtered on Celite, washing with EtOAc (80.0 mL). The filtrate was concentrated and purified by FC (0-50% EtOAc/hexanes) to provide the title compound as a solid (643 mg, 45% over 2 steps).

[1153] LCMS m/z 608.7 (M−H).sup.− (ES.sup.−).

[1154] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (d, J=5.3 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.22-7.15 (m, 2H), 7.09 (d, J=7.6 Hz, 1H), 6.93 (s, 1H), 6.43 (d, J=2.3 Hz, 1H), 6.10 (s, 1H), 5.17 (s, 2H), 3.51 (t, J=5.5 Hz, 2H), 3.48-3.42 (m, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.12-2.07 (m, 2H), 2.07-2.02 (m, 2H), 1.64 (s, 6H), 0.77-0.63 (m, 2H), −0.02 (s, 9H). One exchangeable proton not observed.

[1155] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −67.46 (s).

Step C: 2-[(21,21-dimethyl-24-oxa-16-thia-11,13,14,20,26,30,31-heptazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12(31),14,17(30),18,25(29),26-decaen-13-yl)methoxy]ethyl-trimethyl-silane

[1156] ##STR00174##

[1157] A mixture of 3-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]pyrazol-1-yl]-3-methyl-butan-1-ol (320 mg, 0.525 mmol) in THF (400 mL) was added to a mixture of tBuOK (1.00 M, 5.25 mL, 5.25 mmol) in THF (100.0 mL) over 90 min at 0° C. The mixture was stirred at 0° C. for 90 min and Dowex MAC-3 Hydrogen form (2500 mg, 8.05 mmol) was added. The mixture was stirred at 20° C. for 10 min, filtered and concentrated to provide the title compound as a solid which was directly engaged in the next step.

[1158] LCMS m/z 588.8 (M−H).sup.− (ES.sup.−).

Step D: 2-[(21,21-dimethyl-16,16-dioxo-24-oxa-16λ.SUP.6.-thia-11,13,14,20,26,30,31-heptazahexacyclo[23.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12(31),14,17(30),18,25(29),26-decaen-13-yl)methoxy]ethyl-trimethyl-silane

[1159] ##STR00175##

[1160] m-CPBA (77.0%, 353 mg, 1.58 mmol) was added to a solution of 2-[(21,21-dimethyl-24-oxa-16-thia-11,13,14,20,26,30,31-heptazahexacyclo[23.3.1.1.sup.12,15.1.sup.17,20.0.sup.2,10.0.sup.5,9]-hentriaconta-1(28),2,4,9,12(31),14,17(30),18,25(29),26-decaen-13-yl)methoxy]ethyl-trimethyl-silane from step C (310 mg, 0.526 mmol) in DCM (100 mL) at 20° C. The mixture was stirred at 20° C. for 1 h and diluted with sat. aq. NaS.sub.2O.sub.3 (100 mL) and sat. aq. NaHCO.sub.3 (100 mL). The aqueous phase was extracted with EtOAc (100 mL), and the combined organic phases were washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was diluted with MeCN (15.0 mL), and m-CPBA (77.0%. 353 mg, 1.58 mmol) was added. The mixture was stirred at 20° C. for 4 h, and m-CPBA (77.0%, 100 mg, 0.447 mmol) was added. The mixture was stirred at 20° C. for 2 h and diluted with sat. aq. NaS.sub.2O.sub.3 (100 mL) and sat. aq. NaHCO.sub.3 (100 mL). The aqueous phase was extracted with EtOAc (100 mL), and the combined organic phases were washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The product was purified by FC (0-100% MeOH/DCM) to provide the title compound as a solid (179 mg, 43% over 2 steps).

[1161] LCMS m/z 620.8 (M−H).sup.− (ES.sup.−).

Step E: 21,21-dimethyl-24-oxa-16λ.SUP.6.-thia-11,13,14,20,26,30,31-heptazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12,14,17(30),18,25(29),26-decaene 16,16-dioxide

[1162] ##STR00176##

[1163] A mixture of 2-[(21,21-dimethyl-16,16-dioxo-24-oxa-16λ.sup.6-thia-11,13,14,20,26,30,31-heptazahexacyclo[23.3.1.1.sup.12,15.1.sup.17,20.0.sup.2,10.0.sup.5,9]hentriaconta-1(28),2,4,9,12(31),14,17(30),18,25(29),26-decaen-13-yl)methoxy]ethyl-trimethyl-silane (100 mg, 0.161 mmol) in HCl (4 M in dioxane, 0.804 mL, 3.22 mmol) was stirred at 20° C. for 18 h and concentrated. The residue was diluted with MeOH (2.00 ml) and ethylenediamine (0.100 mL). The mixture was stirred at 22° C. for 20 min and concentrated. The product was purified by basic prep HPLC (0-70% MeCN in water) and triturated with DMSO and water (0.500 and 5.00 mL) to provide the title compound as a solid (8.30 mg, 10%).

[1164] LCMS m/z 492.3 (M+H).sup.+ (ES.sup.+).

[1165] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.50 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 7.90 (d, J=4.8 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.00 (d, J=7.1 Hz, 1H), 6.79 (d, J=4.8 Hz, 1H), 6.75 (s, 1H), 6.01 (s, 1H), 4.15 (s, 2H), 2.95 (t, J=6.7 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.25 (s, 2H), 2.10-2.02 (m, 2H), 1.63 (s, 6H).

Example 8: 22,22-dimethyl-24-oxa-16 λ.SUP.6.-thia-11,13,14,26,31-pentazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,21..0.SUP.2,10..0.SUP.5,9.] hentriaconta-1(28),2,4,9,12,14,17,19,21(30),25(29),26-undecaene 16,16-dioxide

[1166] ##STR00177##

Step A: methyl 2-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]phenyl]-2-methyl-propanoate

[1167] ##STR00178##

[1168] DMEDA (0.44 mL, 3.96 mmol) was added to a mixture of 5-bromo-N-[5-(2-fluoro-4-pyridyl)indan-4-yl]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine (Intermediate A2, Step E) (100 mg, 198 μmol), methyl 2-methyl-2-(3-sulfanylphenyl)propanoate (Intermediate A13) (80%, 73.0 mg, 278 μmol), and CuI (75-9 mg, 396 μmol) in 1,4-dioxane (1.60 mL) at 22° C. under N.sub.2. The mixture was degassed by bubbling N.sub.2 through the mixture for 20 min, stirred at 100° C. for 6 h, and diluted with water (10.0 mL). The aqueous phase was extracted with EtOAc (3×10.0 mL), and the combined organic phases were washed with brine (10.0 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The product was purified by FC (0-600% EtOAc/hexanes) to provide the title compound as a solid (47.2 mg, 38%).

[1169] LCMS m/z 632.8 (M−H).sup.− (ES.sup.−).

[1170] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.16 (d, J=5.1 Hz, 1H), 7.45 (s, 1H), 7.25-7.06 (m, 6H), 6.93 (s, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 3.63 (s, 3H), 3.53-3.46 (m, 2H), 2.96 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.06 (p, J=7.3 Hz, 2H), 1.53 (s, 6H), 0.77-0.70 (m, 2H), −0.01 (s, 9H).

Step B: 2-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxy-methyl)-1,2,4-triazol-3-yl]sulfanyl]phenyl]-2-methyl-propan-1-ol

[1171] ##STR00179##

[1172] LiAlH.sub.4 (2M in THF, 684 uL, 1.37 mmol) was added to a mixture of methyl 2-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]phenyl]-2-methyl-propanoate (431 mg, 652 μmol) in THF (9.66 mL) at 0° C. under N.sub.2. The mixture was stirred at 22° C. for 90 min and slowly diluted with water (60.0 μL), aq. NaOH (15 w %, 60.0 uL), and water (180 μL). The mixture was stirred at 22° C. for 15 min, dried (MgSO.sub.4, 250 mg), and filtered, washing with DCM (120 mL). The filtrate was concentrated to provide the title compound as a solid (385 mg, 97%).

[1173] LCMS m/z 606.4 (M+H).sup.+ (ES.sup.+).

[1174] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.12 (d, J=5.2 Hz, 1H), 7.54 (d, J=1.1 Hz, 1H), 7.31-7.26 (m, 3H), 7.22-7.04 (m, 3H), 6.92 (s, 1H), 6.15 (s, 1H), 5.26 (s, 2H), 3.54 (d, J=6.7 Hz, 2H), 3.52-3.43 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.07 (p, J=7.5 Hz, 2H), 1.69 (t, J=6.8 Hz, 1H), 1.30 (s, 6H), 0.78-0.69 (m, 2H), −0.01 (s, 9H).

Step C: 2-[(22,22-dimethyl-24-oxa-16-thia-11,13,14,26,31-pentazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,21..0.SUP.2,10..0.SUP.5,9.] hentriaconta-1(28),2,4,9,12(31),14,17,19,21(30),25 (29),26-undecaen-13-yl)methoxy]ethyl-trimethyl-silane

[1175] ##STR00180##

[1176] A mixture of 2-[3-[[5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]sulfanyl]phenyl]-2-methyl-propan-1-ol (423 mg, 0.635 mmol) in THF (500 mL) was added over 5 h to a mixture of tBuOK (1M in THF, 6.35 mL, 6.35 mmol) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, diluted with EtOH (20.0 mL), and concentrated. The product was purified by FC (0-50% EtOAc/hexanes) to provide the title compound as a solid (79.9 mg, 18%).

[1177] LCMS m/z 586.3 (M+H).sup.+ (ES.sup.+).

[1178] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.99 (d, J=5.3 Hz, 1H), 7.28-7.04 (m, 7H), 6.79 (dd, J=5.3, 1.5 Hz, 1H), 6.57 (s, 1H), 4.88 (s, 2H), 4.35 (s, 2H), 3.45-3.30 (m, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.4 Hz, 2H), 2.19 (p, J=7.5 Hz, 2H), 1.40 (s, 6H), 0.83-0.77 (m, 2H), −0.02 (s, 9H).

Step D: 2-[(22,22-dimethyl-16,16-dioxo-24-oxa-16λ.SUP.6.-thia-11,13,14,26,31-pentazahexacyclo[23.3.1.1.SUP.12,15..1.SUP.17,21..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12(31),14,17,19,21(30),25(29),26-undecaen-13-yl)methoxy]ethyl-trimethyl-silane

[1179] ##STR00181##

[1180] m-CPBA (84.9 mg, 379 μmol) was added to a mixture of 2-[(22,22-dimethyl-24-oxa-16-thia-11,13,14,26,31-pentazahexacyclo[23.3.1.1.sup.12,15.1.sup.17,21.0.sup.2,10.0.sup.5,9]hentriaconta-1(28),2,4,9,12(31),14,17,19,21(30),25(29),26-undecaen-13-yl)methoxy]ethyl-trimethyl-silane (88.8 mg, 152 μmol) in DCM (3.50 mL) at 0° C. under N.sub.2. The mixture was stirred at 22° C. for 3 h and diluted with sat. aq. Na.sub.2S.sub.2O.sub.3 (5.00 mL). The aqueous phase was extracted with DCM (3×10.0 mL) and the combined organic phases were washed with brine (10.0 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was purified by FC (0-60% EtOAc/hexanes) to provide the title compound as a solid (44.5 mg, 47.5%).

[1181] LCMS m/z 618.3 (M+H).sup.+ (ES.sup.+).

[1182] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.95 (t, J=1.8 Hz, 1H), 7.86-7.76 (m, 1H), 7.71 (dd, J=6.9, 1.7 Hz, 1H), 7.51 (d, J=5.3 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 6.79 (d, J=0.8 Hz, 1H), 6.61 (dd, J=5.3, 1.4 Hz, 1H), 6.51 (s, 1H), 5.28 (s, 2H), 4.38 (s, 2H), 3.61-3.42 (m, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.4 Hz, 2H), 2.17 (dq, J=14.9, 7.5 Hz, 2H), 1.53 (s, 6H), 0.94-0.87 (m, 2H), 0.00 (s, 9H).

Step E: 22,22-dimethyl-24-oxa-16 λ.SUP.6.-thia-11,13,14,26,31-pentazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,21..0.SUP.2,10..0.SUP.5,9.] hentriaconta-1(28),2,4,9,12,14,17,19,21(30),25(29),26-undecaene 16,16-dioxide

[1183] ##STR00182##

[1184] TFA (1.50 ml, 20.2 mmol) was added to a mixture of 2-[(22,22-dimethyl-16,16-dioxo-24-oxa-16λ.sup.6-thia-11,13,14,26,31-pentazahexacyclo[23.3.1.1.sup.12,15.1.sup.17,21.0.sup.2,10.0.sup.5,9]-hentriaconta-1(28),2,4,9,12(31),14,17,19,21(30),25(29),26-undecaen-13-yl)methoxy]-ethyl-trimethyl-silane (44.5 mg, 72.0 μmol) in DCM (1.5 ml) at 0° C., and the solution was stirred at 22° C. for 2 h and concentrated. The residue was diluted with DCM (2.00 ml) and ethylenediamine (0.100 ml), and the mixture was stirred at 22° C. for 40 min and concentrated. The product was purified by basic prep HPLC (0-70% MeCN in water) and triturated with DMSO and water to provide the title compound as a solid (21.5 mg, 61%).

[1185] LCMS m/z 488.3 (M+H).sup.+ (ES.sup.+).

[1186] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.95 (s, 1H), 9.06 (s, 1H), 7.88 (d, J=5.2 Hz, 1H), 7.77 (dd, J=12.2, 8.0 Hz, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.36 (s, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.81 (dd, J=5.3, 1.2 Hz, 1H), 6.27 (s, 1H), 4.22 (s, 2H), 2.91 (t, J=7.4 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.01 (p, J=7.4 Hz, 2H), 1.37 (s, 6H).

Example 9: 25-methyl-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,25,32-heptaazahexacyclo-[24.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide

[1187] ##STR00183##

Step A: 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)-amino)ethan-1-ol

[1188] ##STR00184##

[1189] NCS (125 mg, 938 μmol) was added to a solution of sodium 5-[[5-(2-fluoro-4-pyridyl)-indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (0.500 g, 782 μmol) in DCM (9 mL) and stirred at 0° C. for 1 h. 2-(methyl(piperidin-4-yl)amino)ethan-1-ol (Intermediate A14) (186 mg, 1.17 mmol) and DIPEA (204 μL, 1.17 mmol) were then added in DCM (3 mL) at 0° C. and the reaction stirred at RT for 16 h. The reaction was washed with water (10 mL) and extracted with EtOAc (3×50 mL). The combined organics were then washed with brine (50 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-20% MeOH/DCM) to afford the title compound (0.170 g, 30%) as a yellow oil.

[1190] LCMS m/z 646.5 (M+H).sup.+ (ES.sup.+).

[1191] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.04 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.35-7.32 (m, 1H), 7.31 (d, J=5.0 Hz, 2H), 7.12 (s, 1H), 5.42 (s, 2H), 4.30 (s, 1H), 3.82 (s, 1H), 3.62-3.54 (m, 2H), 3.54-3.48 (m, 2H), 3.45-3.38 (m, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.7 Hz, 2H), 2.48-2.40 (m, 2H), 2.34 (t, J=12.0 Hz, 2H), 2.16 (s, 3H), 2.03 (p, J=7.3 Hz, 2H), 1.75-1.68 (m, 2H), 1.47-1.34 (m, 2H), 0.89-0.81 (m, 2H), −0.03 (s, 9H).

Step B: 25-methyl-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,25,32-heptaazahexacyclo-[24.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide

[1192] ##STR00185##

[1193] To a solution of 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (0.170 g, 232 μmol) in THF (20 mL) at 0° C. was added potassium tert-butoxide (260 mg, 2.32 mmol). The reaction was warmed to RT and stirred for 18 h. The reaction was diluted with EtOH (10 mL) and concentrated in vacuo. The resulting residue was purified by FC (0-20% MeOH/DCM). The isolated material was then taken up in DCM (3 mL) and TFA (3 mL) and stirred at RT for 90 min. The reaction was concentrated and the resulting residue purified by acidic prep HPLC (15-40% MeOH in water) to provide the title compound (8.00 mg, 7%) as a flocculent white solid.

[1194] LCMS m/z 496.4 (M+H).sup.+ (ES.sup.+).

[1195] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.39-12.78 (m, 1H), 9.10-8.71 (m, 1H), 8.10 (br s, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.21 (br s, 1H), 7.02-6.43 (m, 2H), 4.65 (br s, 1H), 4.33 (br s, 1H), 3.46 (br s, 1H), 3.23-3.08 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.91-2.71 (m, 3H), 2.67-2.57 (m, 1H), 2.44-2.30 (m, 1H), 2.29 (br s, 1H), 2.16 (br s, 1H), 2.06 (p, J=7.5 Hz, 2H), 1.84 (br s, 2H), 1.65-1.40 (m, 2H). Two aliphatic protons obscured by water peak.

Example 10: 23,23-dimethyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,33-heptaazaheptacyclo[24.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tritriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1196] ##STR00186##

Step A: 2-(2-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]-octan-6-yl)-2-methylpropan-1-ol

[1197] ##STR00187##

[1198] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (122 mg, 915 μmol), sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (0.500 g, 762 μmol), DIPEA (531 μL, 3.05 mmol) and 2-methyl-2-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid) (Intermediate A15) (469 mg, 1.14 mmol) in DCM (13 mL) at 0° C. to afford the title compound (214 mg, 33%) as a colourless oil.

[1199] LCMS m/z 672.5 (M+H).sup.+ (ES.sup.+); 670.5 (M−H).sup.− (ES.sup.−).

[1200] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.10 (s, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.36-7.28 (m, 3H), 7.11 (s, 1H), 5.46 (s, 2H), 4.28 (br s, 1H), 3.79-3.66 (m, 4H), 3.58 (t, J=8.1 Hz, 2H), 3.20-3.16 (m, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.73 (t, J=7.4 Hz, 2H), 2.68-2.58 (m, 2H), 2.57-2.50 (m, 2H), 2.03 (p, J=7.3 Hz, 2H), 1.63 (t, J=6.9 Hz, 2H), 0.93-0.80 (m, 8H), −0.02 (s, 9H).

Step B: 23,23-dimethyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,33-heptaazaheptacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tritriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1201] ##STR00188##

[1202] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (3.31 mL, 3.31 mmol) and 2-(2-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)-2-methylpropan-1-ol (214 mg, 248 μmol) in THF (150 mL) at 0° C. followed by TFA (3 mL), DCM (3 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (39 mg, 29%) as a white solid.

[1203] LCMS m/z 522.5 (M+H).sup.+ (ES.sup.+); 520.3 (M−H).sup.− (ES.sup.−).

[1204] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.21 (br s, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.04 (dd, J=5.3, 1.4 Hz, 1H), 6.67 (s, 1H), 4.11 (s, 2H), 3.81-3.65 (m, 4H), 2.98 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.0 Hz, 2H), 2.55 (s, 2H), 2.06 (p, J=7.5 Hz, 2H), 1.95 (t, J=6.9 Hz, 2H), 1.03 (s, 6H).

[1205] One exchangeable proton not observed.

Example 11: 21-methyl-24-oxa-16λ.SUP.6.-thia-11,13,14,17,21,26,31-heptaazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,19..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12,14,25(29),26-octaene-16,16-dioxide

[1206] ##STR00189##

Step A: 2-(((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)azetidin-3-yl)methyl)-(methyl)amino)ethan-1-ol

[1207] ##STR00190##

[1208] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (122 mg, 915 μmol), sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (0.500 g, 762 μmol), DIPEA (204 μL, 1.17 mmol) and 2-((azetidin-3-ylmethyl)(methyl)amino)-ethan-1-ol (Intermediate A16) (113 mg, 782 μmol) in DCM (12 mL) at 0° C. to afford the title compound (122.6 mg, 15%) as a yellow oil.

[1209] LCMS m/z 632.4 (M+H).sup.+ (ES.sup.+).

[1210] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.12 (d, J=5.2 Hz, 1H), 7.23-7.16 (m, 2H), 7.11-7.08 (m, 2H), 6.96-6.90 (m, 1H), 5.38 (s, 2H), 4.00-3.94 (m, 2H), 3.68-3.63 (m, 2H), 3.54-3.46 (m, 4H), 3.00-2.93 (m, 2H), 2.79-2.73 (m, 2H), 2.66 (s, 1H), 2.65-2.58 (m, 1H), 2.58-2.50 (m, 2H), 2.47-2.40 (m, 2H), 2.15 (s, 3H), 2.10-2.02 (m, 2H), 0.82-0.73 (m, 2H), −0.05 (s, 9H).

Step B: 21-methyl-24-oxa-16λ.SUP.6.-thia-11,13,14,17,21,26,31-heptaazahexacyclo-[23.3.1.1.SUP.12,15..1.SUP.17,19..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12,14,25(29),26-octaene-16,16-dioxide

[1211] ##STR00191##

[1212] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (1.25 mL, 1.25 mmol) and 2-(((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-azetidin-3-yl)methyl)(methyl)amino)ethan-1-ol (22.6 mg, 124.2 μmol) in 1,4-dioxane (60 mL) at 0° C. followed by TFA (3 mL), DCM (3 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (6 mg, 10%) as a white solid.

[1213] LCMS m/z 482.4 (M+H).sup.+ (ES.sup.+); 480.4 (M−H).sup.− (ES.sup.−).

[1214] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.96 (br s, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.09-7.04 (m, 1H), 6.67 (s, 1H), 4.26-4.20 (m, 2H), 3.78 (t, J=8.0 Hz, 2H), 3.52-3.45 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.66-2.60 (m, 2H), 2.21 (s, 3H), 2.11-2.00 (m, 3H). Two aliphatic protons overlapped with DMSO-d.sub.6 signal. One exchangeable proton not observed.

Example 12: (20S)-22-methyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,32-heptaazahexacyclo[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1215] ##STR00192##

Step A: (S)-2-(((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)pyrrolidin-3-yl)-methyl)(methyl)amino)ethan-1-ol

[1216] ##STR00193##

[1217] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (257 mg, 1.92 mmol), sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (1.02 g, 1.59 mmol), DIPEA (0.4 mL, 2 mmol) and (R)-2-(methyl(pyrrolidin-3-ylmethyl)-amino)ethan-1-ol (300 mg, 1.54 mmol) (Intermediate A17) (469 mg, 1.14 mmol) in DCM (25 mL) at 0° C. to afford the title compound (421 mg, 34%) as a orange oil.

[1218] LCMS m/z 646.6 (M+H).sup.+ (ES.sup.+); 644.2 (M−H).sup.− (ES.sup.−).

Step B: (20S)-22-methyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,32-heptaazahexacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1219] ##STR00194##

[1220] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (6.5 mL, 6.5 mmol) and (S)-2-(((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-pyrrolidin-3-yl)methyl)(methyl)amino)ethan-1-ol (421 mg, 521 μmol) in 1,4-dioxane (350 mL) at 0° C. followed by TFA (5 mL), DCM (5 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (60 mg, 21%) as a white solid.

[1221] LCMS m/z 496.4 (M+H).sup.+ (ES.sup.+); 494.4 (M−H).sup.− (ES.sup.−).

[1222] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.92 (s, 1H), 8.95 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.01 (dd, J=5.3, 1.5 Hz, 1H), 6.59 (s, 1H), 4.33-4.28 (m, 1H), 4.26-4.18 (m, 1H), 3.42-3.35 (m, 1H), 3.26-3.19 (m, 1H), 2.97 (t, J=7.5 Hz, 2H), 2.81-2.76 (m, 2H), 2.75-2.69 (m, 2H), 2.65 (t, J=9.6 Hz, 1H), 2.60-2.54 (m, 1H), 2.41-2.34 (m, 1H), 2.33-2.26 (m, 1H), 2.24 (s, 3H), 2.22-2.14 (m, 1H), 2.09-2.01 (m, 2H), 1.93-1.85 (m, 1H), 1.46-1.35 (m, 1H).

Example 13: 27-methyl-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,27,34-heptaazahexacyclo-[26.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]tetratriaconta-3,5,8,13,15,17,19,21(33)-octaene-2,2-dioxide

[1223] ##STR00195##

Step A: 4-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)-amino)butan-1-ol

[1224] ##STR00196##

[1225] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (149 mg, 1.11 mmol), sodium 5-[[5-(2-fluoro-4-pyridyl)indan-4-yl]amino]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-sulfinate (Intermediate A3) (620 mg, 928 μmol), DIPEA (646 μL, 3.71 mmol) and 4-(methyl(piperidin-4-yl)amino)butan-1-ol, di-(2,2,2-trifluoroacetic acid) (Intermediate A18) (585 mg, 1.42 mmol) in DCM (12 mL) at 0° C. to afford the title compound (93 mg, 11%) as a colourless oil.

[1226] LCMS m/z 674.5 (M+H).sup.+ (ES.sup.+); 672.4 (M−H).sup.− (ES.sup.−).

[1227] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.39-7.27 (m, 3H), 7.12 (s, 1H), 5.43 (s, 2H), 4.48 (br s, 1H), 3.63-3.48 (m, 4H), 3.43-3.35 (m, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.40-2.24 (m, 5H), 2.12 (s, 3H), 2.04 (p, J=7.4 Hz, 2H), 1.74-1.65 (m, 2H), 1.44-1.35 (m, 6H), 0.87 (t, J=8.3 Hz, 2H), −0.02 (s, 9H).

Step B: 27-methyl-22-oxa-2λ.SUP.6.-thia-1,4,5,7,20,27,34-heptaazahexacyclo-[26.2.2.1.SUP.3,6..1.SUP.17,21..0.SUP.8,16..0.SUP.9,13.]tetratriaconta-3,5,8,13,15,17,19,21(33)-octaene-2,2-dioxide

[1228] ##STR00197##

[1229] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (1.14 mL, 1.14 mmol) and 4-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-piperidin-4-yl)(methyl)amino)butan-1-ol (90 mg, 114 μmol) in THF (200 mL) at 0° C. followed by TFA (3 mL), DCM (3 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (9 mg, 15%) as a white solid.

[1230] LCMS m/z 524.4 (M+H).sup.+ (ES.sup.+); 522.7 (M−H).sup.− (ES.sup.−).

[1231] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.93 (br s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H). 7.19 (d, J=7.6 Hz, 1H), 7.01 (d, J=5.3 Hz, 1H), 6.65 (s, 1H), 4.23 (t, J=5.3 Hz, 2H), 3.53-3.46 (m, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.44 (t, J=6.3 Hz, 2H), 2.39-2.30 (m, 2H), 2.11 (s, 3H), 2.04 (p, J=7.4 Hz, 2H), 1.74-1.67 (m, 2H), 1.60-1.42 (m, 7H). One exchangeable proton not observed.

Example 14: (20R)-22-methyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,32-heptaazahexacyclo[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1232] ##STR00198##

Step A: (R)-2-(((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)pyrrolidin-3-yl)-methyl)(methyl)amino)ethan-1-ol

[1233] ##STR00199##

[1234] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (240 mg, 1.80 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.940 g, 1.50 mmol), DIPEA (391 μL, 2.25 mmol) and (S)-2-(methyl(pyrrolidin-3-ylmethyl)amino)ethan-1-ol, 2,2,2-trifluoroacetic acid (226 mg, 0.83 mmol) (Intermediate A19) in DCM (12 mL) at 0° C. to afford the title compound (201 mg, 16%) as a yellow oil.

[1235] LCMS m/z 646.5 (M+H).sup.+ (ES.sup.+); 644.4 (M−H).sup.− (ES.sup.−).

[1236] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.19 (d, J=5.2 Hz, 1H), 7.25-7.20 (m, 2H), 7.13 (d, J=7.7 Hz, 1H), 6.99-6.94 (m, 1H), 6.49 (s, 1H), 5.36 (s, 2H), 3.93 (s, 1H), 3.65-3.56 (m, 2H), 3.53-3.47 (m, 2H), 3.39-3.30 (m, 2H), 3.16-3.09 (m, 2H), 3.01 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.63-2.56 (m, 2H), 2.52-2.42 (m, 2H), 2.36-2.25 (m, 4H), 2.16-2.07 (m, 2H), 1.69-1.56 (m, 2H), 0.81-0.72 (m, 2H), −0.01 (s, 9H).

Step B: (20R)-22-methyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,22,27,32-heptaazahexacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1237] ##STR00200##

[1238] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KOtBu in THF (2.5 mL, 2.5 mmol) and (R)-2-(((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-pyrrolidin-3-yl)methyl)(methyl)amino)ethan-1-ol (201 mg, 249 μmol) in THF (180 mL) at 0° C. followed by TFA (6 mL), DCM (6 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (12 mg, 9%) as a white solid.

[1239] LCMS m/z 496.4 (M+H).sup.+ (ES.sup.+); 494.4 (M−H).sup.− (ES.sup.−).

[1240] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.93 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.01 (dd, J=5.2, 1.5 Hz, 1H), 6.59 (s, 1H), 4.34-4.28 (m, 1H), 4.25-4.18 (m, 1H), 3.26-3.19 (m, 1H), 2.97 (t, J=7.4 Hz, 2H), 2.82-2.76 (m, 2H), 2.76-2.68 (m, 1H), 2.65 (t, J=9.5 Hz, 1H), 2.60-2.53 (m, 1H), 2.41-2.34 (m, 1H), 2.33-2.26 (m, 1H), 2.24 (s, 3H), 2.22-2.14 (m, 1H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 1H), 1.46-1.34 (m, 2H). One exchangeable proton not observed. One aliphatic proton overlapped with water in DMSO-d.sup.6 peak.

Example 15: 8-oxa-28λ.SUP.6.-thia-4,10,23,25,26,29,34-heptaazaheptacyclo-[27.2.2.1.SUP.9,13..1.SUP.24,27..0.SUP.1,4..0.SUP.14,22..0.SUP.17,21.]pentatriaconta-9(35),10,12,14,16,21,24,26-octaene-28,28-dioxide

[1241] ##STR00201##

Step A: 3-(7-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-1,7-diazaspiro[3-5]-nonan-1-yl)propan-1-ol

[1242] ##STR00202##

[1243] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (128 mg, 956 μmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (500 mg, 796 μmol), DIPEA (555 μL, 3.19 mmol) and 3-(1,7-diazaspiro[3.5]nonan-1-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid) (Intermediate A20) (0.60 g, 1.2 mmol) in DCM (15 mL) at 0° C. to afford the title compound (0.44 g, 41%) as a sticky brown gum.

[1244] LCMS m/z 672.5 (M+H).sup.+ (ES.sup.+); 670.5 (M−H).sup.− (ES.sup.−).

[1245] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.11 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.35-7.27 (m, 3H), 7.09 (s, 1H), 5.41 (s, 2H), 3.70-3.57 (m, 9H), 3.55-3.48 (m, 2H), 3.43 (t, J=6.1 Hz, 2H), 3.20-3.07 (m, 7H), 2.99 (t, J=7.4 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.04-1.98 (m, 2H), 0.87-0.80 (m, 2H), −0.03 (s, 9H). One exchangeable proton not observed.

[1246] .sup.19F NMR (471 MHz, DMSO-d.sub.6) δ −73.45.

Step B: 8-oxa-28λ.SUP.6.-thia-4,10,23,25,26,29,34-heptaazaheptacyclo-[27.2.2.1.SUP.9,13..1.SUP.24,27..0.SUP.1,4..0.SUP.14,22..0.SUP.17,21.]pentatriaconta-9(35),10,12,14,16,21,24,26-octaene-28,28-dioxide

[1247] ##STR00203##

[1248] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (4.6 mL, 4.6 mmol) and 3-(7-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-1,7-diaza-spiro[3.5]-nonan-1-yl)propan-1-ol (0.44 g, 0.46 mmol) in THF (170 mL) at 0° C. followed by TFA (5 mL), DCM (5 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (16 mg, 6%) as a white solid.

[1249] LCMS m/z 522.5 (M+H).sup.+ (ES.sup.+); 520.4 (M−H).sup.− (ES.sup.−).

[1250] .sup.1H NMR (500 MHz, DMSO-d.sup.6) δ 12.97 (s, 1H), 9.06 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 6.97 (dd, J=5.3, 1.5 Hz, 1H), 6.61 (d, J=1.4 Hz, 1H), 4.35 (t, J=5.3 Hz, 2H), 3.17-3.01 (m, 3H), 2.95 (t, J=7.2 Hz, 2H), 2.69 (t, J=7.4 Hz, 2H), 2.45-2.37 (m, 2H), 2.08-1.96 (m, 2H), 1.82 (t, J=7.1 Hz, 2H), 1.78-1.66 (m, 2H), 1.57-1.47 (m, 3H). 4 protons obscured by water signal.

Example 16: 19-[(dimethylamino)methyl]-24-oxa-16λ.SUP.6.-thia-11,13,14,17,26,31-hexaazahexacyclo[23.3.1.1.SUP.12,15..1.SUP.17,19..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12,14,25(29),26-octaene-16,16-dioxide

[1251] ##STR00204##

Step A: 4-(3-((dimethylamino)methyl)-1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-sulfonyl)azetidin-3-yl)butan-1-ol

[1252] ##STR00205##

[1253] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (236 mg, 1.77 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.875 g, 1.39 mmol), DIPEA (383 μL, 3.20 mmol) and 4-(3-((dimethylamino)methyl)azetidin-3-yl)butan-1-ol (Intermediate A21) (0.60 g, 1.2 mmol) in DCM (15 mL) at 0° C. to afford the title compound (0.44 g, 41%) as a sticky brown gum.

[1254] LCMS m/z 674.5 (M+H).sup.+ (ES.sup.+); 672.0 (M−H).sup.− (ES.sup.−).

[1255] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.17 (d, J=5.2 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.20-7.16 (m, 1H), 7.11 (d, J=7.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 6.53 (s, 1H), 5.38 (s, 2H), 3.90 (s, 1H), 3.72-3.66 (m, 4H), 3.63-3.57 (m, 2H), 3.55-3.49 (m, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.13-2.02 (m, 10H), 1.68-1.59 (m, 2H), 1.54-1.46 (m, 2H), 1.31-1.22 (m, 2H), 0.78-0.72 (m, 2H), −0.02 (s, 9H).

Step B: 19-[(dimethylamino)methyl]-24-oxa-16λ.SUP.6.-thia-11,13,14,17,26,31-hexaazahexacyclo[23.3.1.1.SUP.12,15..1.SUP.17,19..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,12,14,25(29),26-octaene-16,16-dioxide

[1256] ##STR00206##

[1257] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (3.00 mL, 3.00 mmol) and 4-(3-((dimethylamino)methyl)-1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)azetidin-3-yl)butan-1-ol (376 mg, 447 μmol) in THF (250 mL) at 0° C. followed by TFA (7 mL), DCM (7 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (110 mg, 29%) as a white solid.

[1258] LCMS m/z 524.4 (M+H).sup.+ (ES.sup.+); 522.3 (M−H).sup.− (ES.sup.−).

[1259] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.13 (s, 1H), 9.07 (s, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.01 (dd, J=5.2, 1.4 Hz, 1H), 6.65 (s, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.52 (s, 4H), 2.97 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.15 (s, 6H), 2.09-2.00 (m, 2H), 1.68-1.61 (m, 2H), 1.47-1.37 (m, 2H), 1.27-1.17 (m, 2H). Two exchangeable protons not observed.

Example 17: (20S)-21-methyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,21,27,32-heptaazahexacyclo[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.0,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1260] ##STR00207##

Step A: (S)-3-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)pyrrolidin-3-yl)-(methyl)amino)propan-1-ol

[1261] ##STR00208##

[1262] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (192 mg, 1.44 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.640 g, 1.20 mmol), DIPEA (836 μL, 4.80 mmol) and (S)-3-(methyl(pyrrolidin-3-yl)amino)propan-1-ol (Intermediate A22) (285 mg, 1.80 mmol) in DCM (12 mL) at 0° C. to afford the title compound (225 mg, 23%) as a colourless oil.

[1263] LCMS m/z 646.5 (M+H).sup.+ (ES.sup.+); 644.5 (M−H).sup.− (ES.sup.−).

[1264] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.11-8.99 (m, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.35-7.27 (m, 3H), 7.10 (s, 1H), 5.42 (s. 2H), 4.36 (t, J=5.0 Hz, 1H), 3.53 (t, J=8.1 Hz, 2H), 3.46-3.34 (m, 3H), 3.17-3.09 (m, 1H), 3.02-2.91 (m, 3H), 2.82-2.64 (m, 3H), 2.34-2.23 (m, 2H), 2.09-1.98 (m, 5H), 1.97-1.89 (m, 1H), 1.63-1.52 (m, 1H), 1.48 (p, J=6.8 Hz, 2H), 0.85 (t, J=8.1 Hz, 2H), −0.03 (s, 9H). One proton obscured by water peak.

Step B: (20S)-21-methyl-25-oxa-16λ.SUP.6.-thia-11,13,14,17,21,27,32-heptaazahexacyclo-[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1265] ##STR00209##

[1266] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (2.90 mL, 2.90 mmol) and (S)-3-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-pyrrolidin-3-yl)(methyl)amino)propan-1-ol (220 mg, 290 μmol) in THF (100 mL) at 0° C. followed by TFA (3 mL), DCM (3 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (44 mg, 29%) as a white solid.

[1267] LCMS m/z 496.5 (M+H).sup.+ (ES.sup.+); 494.2 (M−H).sup.− (ES.sup.−).

[1268] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.83 (br s, 1H), 8.97 (br s, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.99 (dd, J=5.2, 1.5 Hz, 1H), 6.63 (s, 1H), 4.29-4.17 (m, 2H), 3.48-3.41 (m, 1H), 3.31-3.27 (m, 2H), 3.08-2.93 (m, 3H), 2.89-2.75 (m, 2H), 2.66-2.58 (m, 1H), 2.45-2.28 (m, 2H), 2.16 (s, 3H), 2.06 (p, J=7.5 Hz, 2H), 1.95-1.86 (m, 1H), 1.82-1.67 (m, 2H), 1.56-1.44 (m, 1H).

Example 18: 6-oxa-26λ.SUP.6.-thia-2,8,21,23,24,27,32-heptaazaheptacyclo-[25.2.2.1.SUP.2,4..1.SUP.7,11..1.SUP.22,25..0.SUP.12,20..1.SUP.15,19.]tetratriaconta-7(33),8,10,12,14,19,22,24-octaene-26,26-dioxide

[1269] ##STR00210##

Step A: (1-(1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)azetidin-3-yl)methanol

[1270] ##STR00211##

[1271] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (140 mg, 1.05 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.550 g, 876 μmol), DIPEA (230 μL, 1.32 mmol) and (1-(piperidin-4-yl)azetidin-3-yl)methanol (Intermediate A23) (150 mg, 881 μmol) in DCM (12 mL) at 0° C. to afford the title compound (195 mg, 20%) as a colourless oil.

[1272] LCMS m/z 658-5 (M+H).sup.+ (ES.sup.+); 656.3 (M−H).sup.− (ES.sup.−).

Step B: 6-oxa-26λ.SUP.6.-thia-2,8,21,23,24,27,32-heptaazaheptacyclo-[25.2.2.1.SUP.2,4..1.SUP.7,11..1.SUP.22,25..0.SUP.12,20..1.SUP.15,19.]tetratriaconta-7(33),8,10,12,14,19,22,24-octaene-26,26-dioxide

[1273] ##STR00212##

[1274] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (3.00 mL, 3.00 mmol) and (1-(1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-piperidin-4-yl)azetidin-3-yl)methanol (195 mg, 297 μmol) in THF (250 mL) at 0° C. followed by TFA (5 mL), DCM (5 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (5 mg, 3%) as a white solid.

[1275] LCMS m/z 508.5 (M+H).sup.+ (ES.sup.+); 506.5 (M−H).sup.− (ES.sup.−).

[1276] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.12 (s, 1H), 9.04 (s, 1H), 8.20 (d, J=5.3 Hz, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=5.3, 1.5 Hz, 1H), 6.67 (s, 1H), 4.31 (s, 2H), 3.25-3.10 (m, 4H), 3.04-2.90 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 2.59-2.55 (m, 1H), 2.39-2.29 (m, 1H), 2.08-2.00 (m, 2H), 1.58-1.43 (m, 4H). Two aliphatic protons overlapped with water peak.

Example 10: 27-oxa-16λ.SUP.6.-thia-11,13,14,17,22,29,35-heptaazaheptacyclo-[26.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]pentatriaconta-1(31),2,4,9,12,14,28(32),29-octaene-16,16-dioxide

[1277] ##STR00213##

Step A: 4-(2-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]-octan-6-yl)butan-1-ol

[1278] ##STR00214##

[1279] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (192 mg, 1.44 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.550 g, 876 μmol), DIPEA (836 μL, 4.80 mmol) and 4-(2,6-diazaspiro[3.4]octan-6-yl)butan-1-ol, di-(2,2,2-trifluoroacetic acid) (Intermediate A24) (667 mg, 1.63 mmol) in DCM (12 mL) at 0° C. to afford the title compound (158 mg, 16%) as a colourless oil.

[1280] LCMS m/z 672.5 (M+H).sup.+ (ES.sup.+); 670.5 (M−H).sup.− (ES.sup.−).

[1281] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.10 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.50-7.34 (m, 3H), 7.27 (s, 1H), 5.60 (s, 2H), 4.38 (br s, 1H), 3.80-3.59 (m, 6H), 3.40 (t, J=6.4 Hz, 2H), 3.02 (t, J=7.4 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.45-2.25 (m, 6H), 2.09 (p, J=7.4 Hz, 2H), 1.63 (t, J=8.0 Hz, 2H), 1.56-1.45 (m, 4H), 0.87 (t, J=8.1 Hz, 2H), −0.03 (s, 9H).

Step B: 27-oxa-16λ.SUP.6.-thia-11,13,14,17,22,29,35-heptaazaheptacyclo-[26.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]pentatriaconta-1(31),2,4,9,12,14,28(32),29-octaene-16,16-dioxide

[1282] ##STR00215##

[1283] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (2.00 mL, 2.00 mmol) and 4-(2-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]-octan-6-yl)butan-1-ol (158 mg, 200 μmol) in THF (100 mL) at 0° C. followed by TFA (5 mL), DCM (5 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (26 mg, 24%) as a white solid.

[1284] LCMS m/z 522.5 (M+H).sup.+ (ES.sup.+); 520.5 (M−H).sup.− (ES.sup.−).

[1285] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.26 (br s, 1H), 9.04 (br s, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 6.72 (s, 1H), 4.38-4.25 (m, 2H), 3.75 (s, 4H), 2.96 (t, J=7.5 Hz, 2H), 2.65 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.1 Hz, 2H), 2.34 (t, J=6.3 Hz, 2H), 2.15 (s, 2H), 2.09-1.97 (m, 4H), 1.76-1.67 (m, 2H), 1.47 (p, J=7.0 Hz, 2H).

Example 20: 27-oxa-16λ.SUP.6.-thia-11,13,14,17,22,29,35-heptaazaheptacyclo-[26.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]pentatriaconta-1(31),2,4,9,12,14,28(32),29-octaene-16,16-dioxide

[1286] ##STR00216##

Step A: 3-(9-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-4-oxa-1,9-diazaspiro-[5.5]undecan-1-yl)propan-1-ol and 3-((4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)-sulfonyl)-N-(5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (1/1)

[1287] ##STR00217##

[1288] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (451 mg, 1.44 mmol), di-sodium (s-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (1.77 g, 2.82 mmol), DIPEA (1.50 mL, 8.61 mmol) and 3-(4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)propan-1-ol-4-oxa-1,9-diazaspiro[5-5]-undecane (1/1), di-(2,2,2-trifluoroacetic acid) (1.36 g, 2.28 mmol) (Intermediate A25) (667 mg, 1.63 mmol) in DCM (140 mL) at 0° C. to afford the title compound (1.04 g, 34%) as a pale yellow solid.

[1289] LCMS m/z 702.4 (M+H).sup.+ (ES.sup.+); 700.5 (M−H).sup.− (ES.sup.−).

Step B: 27-oxa-16λ.SUP.6.-thia-11,13,14,17,22,29,35-heptaazaheptacyclo-[26.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]pentatriaconta-1(31),2,4,9,12,14,28(32),29-octaene-16,16-dioxide

[1290] ##STR00218##

[1291] 1M potassium 2-methylpropan-2-olate in THF (7.73 mL, 7.73 mmol) was added to a solution of 3-(9-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-4-oxa-1,9-diazaspiro-[5.5]undecan-1-yl)propan-1-ol and 3-((4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)-sulfonyl)-N-(5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine (1/1) (1.04 g, 773 μmol) in anhydrous THF (800 mL) at 0° C. The reaction was stirred at this temperature for 45 min before EtOH (25 mL) was added and the reaction mixture concentrated under reduced pressure. The crude product was purified by FC (0-8% (0.7 M ammonia/MeOH)/DCM) to afford protected triazole as an orange oil. The product was taken up in DCM/TFA (1:1, 20 mL) and the reaction stirred at RT for 1.5 h. The volatiles were removed under reduced pressure and traces of TFA were azeotroped with MeOH (3×10 mL). The crude was taken up in DMSO (3 mL) and purified by basic prep HPLC (10-40% MeCN in water) to afford the title compound (23 mg, 4.9%) as a white solid.

[1292] LCMS m/z 552.5 (M+H).sup.+ (ES.sup.+); 550.5 (M−H).sup.− (ES.sup.−).

[1293] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.91 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 6.98 (dd, J=5.2, 1.4 Hz, 1H), 6.65 (s, 1H), 4.21 (t, J=5.4 Hz, 2H), 3.58-3.52 (m, 2H), 3.44 (s, 2H), 3.23-3.13 (m, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.67-2.58 (m, 2H), 2.46-2.39 (m, 2H), 2.07-1.99 (m, 2H), 1.81-1.65 (m, 4H), 1.41-1.33 (m, 2H). Two aliphatic protons overlapped with water signal in DMSO-d.sub.6. One exchangeable proton not observed.

Example 21: 20-[(dimethylamino)methyl]-25-oxa-16λ.SUP.6.-thia-11,13,14,17,27,32-hexaazahexacyclo[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1294] ##STR00219##

Step A: 4-(3-((dimethylamino)methyl)-1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-sulfonyl)pyrrolidin-3-yl)butan-1-ol

[1295] ##STR00220##

[1296] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (180 mg, 1.35 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.750 g, 1.12 mmol), DIPEA (294 μL, 1.69 mmol) and 4-(3-((dimethylamino)methyl)pyrrolidin-3-yl)butan-1-ol (Intermediate A26) (282 mg, 1.12 mmol) in DCM (20 mL) at 0° C. to afford the title compound (0.222 g, 15%) as a yellow oil.

[1297] LCMS m/z 688.5 (M+H).sup.+ (ES.sup.+).

[1298] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.02 (s, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.34-7.26 (m, 3H), 7.08 (s, 1H), 5.40 (s, 2H), 4.34 (t, J=5.1 Hz, 1H), 3.82 (s, 1H), 3.58-3.49 (m, 2H), 3.38-3.33 (m, 2H), 3.28-3.21 (m, 2H), 3.02-2.92 (m, 4H), 2.74-2.64 (m, 2H), 2.11 (d, J=2.1 Hz, 6H), 2.06-1.98 (m, 2H), 1.55 (t, J=7.1 Hz, 2H), 1.32 (p, J=6.7 Hz, 3H), 1.27-1.12 (m, 4H), 0.88-0.80 (m, 2H), −0.03 (s, 9H).

Step B: 20-[(dimethylamino)methyl]-25-oxa-16λ.SUP.6.-thia-11,13,14,17,27,32-hexaazahexacyclo[24.3.1.1.SUP.12,15..1.SUP.17,20..0.SUP.2,10..0.SUP.5,9.]dotriaconta-1(29),2,4,9,12,14,26(30),27-octaene-16,16-dioxide

[1299] ##STR00221##

[1300] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1 M KO.sup.tBu in THF (1.09 mL, 1.09 mmol) and 4-(3-((dimethylamino)methyl)-1-((5-((5-(2-fluoro-pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)pyrrolidin-3-yl)butan-1-ol (0.222 g, 174 μmol) in THF (250 mL) at 0° C. followed by TFA (3 mL), DCM (3 mL) and basic prep HPLC (10-40% MeCN in water) to afford the title compound (11 mg, 12%) as a white solid.

[1301] LCMS m/z 538.5 (M+H).sup.+ (ES.sup.+).

[1302] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.16 (d, J=5.2 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 6.99 (dd, J=5.2, 1.5 Hz, 1H), 6.61 (s, 1H), 4.24 (t, J=5.7 Hz, 2H), 3.10 (d, J=9.7 Hz, 1H), 2.96 (t, J=7.5 Hz, 2H), 2.79-2.67 (m, 3H), 2.28 (m, 1H), 2.21 (s, 6H), 2.10-2.00 (m, 2H), 1.70-1.53 (m, 4H), 1.38-1.21 (m, 4H). Two exchangeable protons not observed, 3 aliphatic protons obscured by water peak.

Example 22: (19S,21S)-27-oxa-16λ.SUP.6.-thia-11,13,14,17,23,29,33-heptaazaheptacyclo-[26.3.1.1.SUP.12,15..0.SUP.2,10..0.SUP.5,9..0.SUP.17,21..0.SUP.19,23.]tritriaconta-1(31),2,4,9,12,14,28(32),29-octaene-16,16-dioxide

[1303] ##STR00222##

Step A: 3-((1S,4S)-5-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,5-diazabicyclo-[2.2.1]heptan-2-yl)propan-1-ol

[1304] ##STR00223##

[1305] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (150 mg, 1.12 mmol), di-sodium (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-amide (Intermediate A30) (0.500 g, 937 μmol), DIPEA (653 μL, 3.75 mmol) and 3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propan-1-ol, di-(2,2,2-trifluoroacetic acid) (Intermediate A27) (282 mg, 1.12 mmol) in DCM (9 mL) at 0° C. to afford the title compound (348 mg, 38%) as a colourless solid.

[1306] LCMS m/z 644.5 (M+H).sup.+ (ES.sup.+); 642.4 (M−H).sup.− (ES.sup.−).

[1307] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.03 (br s, 1H), 8.19 (d, J=5.3 Hz, 1H), 7.36-7.27 (m, 3H), 7.11 (s, 1H), 5.42 (s, 2H), 4.39 (br s, 1H), 4.04 (s, 1H), 3.52 (t, J=8.3 Hz, 2H), 3.45-3.36 (m, 3H), 3.08-2.95 (m, 3H), 2.75-2.66 (m, 3H), 2.48-2.39 (m, 2H), 2.03 (p, J=7.3 Hz, 2H), 1.55-1.41 (m, 3H), 0.91-0.78 (m, 3H), −0.02 (s, 9H). Two aliphatic protons obscured by solvent peak.

Step B: (19S,21S)-27-oxa-16λ.SUP.6.-thia-11,13,14,17,23,29,33-heptaazaheptacyclo-[26.3.1.1.SUP.12,15..0.SUP.2,10..0.SUP.5,9..0.SUP.17,21..0.SUP.19,23.]tritriaconta-1(31),2,4,9,12,14,28(32),29-octaene-16,16-dioxide

[1308] ##STR00224##

[1309] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1.6 M KO.sup.tBu in THF (1.35 mL, 2.17 mmol) and 3-((1S,4S)-5-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propan-1-ol (164 mg, 217 μmol) in THF (200 mL) at 0° C. followed by TFA (2.5 mL), DCM (2.5 mL) and basic prep HPLC (20-50% MeCN in water) to afford the title compound (6 mg, 5%) as a white solid.

[1310] LCMS m/z 494.3 (M+H).sup.+ (ES.sup.+); 492.3 (M−H).sup.− (ES.sup.−).

[1311] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.86 (br s, 1H), 9.08 (br s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 7.01 (dd, J=5.2, 1.4 Hz, 1H), 6.69 (s, 1H), 4.36-4.28 (m, 1H), 4.22 (s, 1H), 4.14-4.03 (m, 1H), 3.50 (s, 1H), 3.30 (s, 1H), 3.24-3.16 (m, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.66-2.59 (m, 1H), 2.48-2.29 (m, 3H), 2.06 (p, J=7.4 Hz, 2H), 1.85-1.58 (m, 4H).

Example 23: 11,26-dioxa-16λ.SUP.6.-thia-13,14,17,22,28,34-hexaazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene-16,16-dioxide

[1312] ##STR00225##

Step A: 3-(2-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]-octan-6-yl)propan-1-ol

[1313] ##STR00226##

[1314] NCS (165 mg, 1.24 mmol) was added to a solution of sodium 5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-sulfinate (600 mg, 1.03 mmol) (Intermediate A28) in DCM (9 mL) and stirred at 0° C. for 30 min. 3-(2,6-Diazaspiro[3.4]octan-6-yl)propan-1-ol bis(2,2,2-trifluoroacetate) (1.03 g, 1.55 mmol) (Intermediate A31) was dissolved in DCM (3 mL) and DIPEA (0.74 mL, 4.12 mmol) was added. The resulting solution was added to the reaction and stirred at 0° C. for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried using a phase separator, then concentrated in vacuo. The crude product was purified by FC (0-100% MeOH/DCM) to afford the title compound (245 mg, 29%) as a colourless solid.

[1315] LCMS m/z 659.5 (M+H).sup.+ (ES.sup.+); 657.4 (M−H).sup.− (ES.sup.−).

[1316] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.24 (d, J=5.2 Hz, 1H), 4.17-4.04 (m, 3H), 7.27 (s, 1H), 5.59 (s, 2H), 4.38 (br s, 1H), 3.77-3.67 (m, 4H), 3.64 (t, J=8.1 Hz, 2H), 3.44-3.36 (m, 2H), 3.02 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.43-2.29 (m, 6H), 2.09 (p, J=7.4 Hz, 2H), 1.63 (t, J=7.0 Hz, 2H), 1.51 (p, J=7.0 Hz, 2H), 0.87 (t, J=8.0 Hz, 2H), −0.03 (s, 9H).

Step B: 11,26-dioxa-16λ.SUP.6.-thia-13,14,17,22,28,34-hexaazaheptacyclo-[25.3.1.1.SUP.12,15..1.SUP.17,19..1.SUP.19,22..0.SUP.2,10..0.SUP.5,9.]tetratriaconta-1(30),2,4,9,12,14,27(31),28-octaene-16,16-dioxide

[1317] ##STR00227##

[1318] KO.sup.tBu 1.6M in THF (1.96 mL, 3.13 mmol) was added to a solution of 3-(2-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]-octan-6-yl)propan-1-ol (243 mg, 313 μmol) in anhydrous THF (200 mL) at 0° C. and the reaction was stirred at this temperature for 30 min. To the reaction mixture was added water (150 mL) and the reaction was extracted with EtOAc (2×100 mL), dried using a phase separator and concentrated in vacuo. The resulting crude product was purified by FC (0-100% (0.7 M ammonia/MeOH)/DCM) to afford the SEM-protected product. This was taken up in 1:1 DCM:TFA (5 mL) and stirred at RT for 2 h, before being concentrated in vacuo and purified by basic prep HPLC (10-40% MeCN in water) to afford the title compound (13 mg, 7%) as a light yellow solid LCMS m/z 509.4 (M+H).sup.+ (ES.sup.+); 507.3 (M−H).sup.− (ES.sup.−).

[1319] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.23 (d, J=5.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.13 (d, J=5.3 Hz, 1H), 6.91 (s, 1H), 4.32-4.21 (m, 2H), 3.87-3.62 (m, 6H), 3.04-2.88 (m, 4H), 2.47 (t, J=7.0 Hz, 2H), 2.23 (t, J=7.3 Hz, 2H), 2.05-1.93 (m, 4H). One exchangeable proton not observed. Two protons obscured by DMSO peak.

Example 24: 4-fluoro-6-(propan-2-yl)-23-oxa-13λ.SUP.6.-thia-8,10,11,14,19,25,31-heptaazahexacyclo[22.3.1.1.SUP.9,12..1.SUP.14,16..1.SUP.16,19..0.SUP.2,7.]hentriaconta-1(27),2(7),3,5,9,11,24(28),25-octaene-13,13-dioxide

[1320] ##STR00228##

Step A: 3-(2-((5-((4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)-2,6-diazaspiro[3.4]-octan-6-yl)propan-1-ol

[1321] ##STR00229##

[1322] Synthesized according to the procedure outlined for 2-((1-((5-((5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)sulfonyl)piperidin-4-yl)(methyl)amino)ethan-1-ol (Example 9, Step A), from NCS (148 mg, 1.11 mmol), di-sodium (4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)(3-sulfinato-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amide (Intermediate A29) (0.600 g, 921 μmol), DIPEA (700 μL, 4.02 mmol) and 3-(2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol (261 mg, 921 μmol) (Intermediate A7) in DCM (35 mL) at 0° C. to afford the title compound (0.120 g, 11%) as a thick yellow oil.

[1323] LCMS m/z 678.5 (M+H).sup.+ (ES.sup.+).

Step B: 4-fluoro-6-(propan-2-yl)-23-oxa-13λ.SUP.6.-thia-8,10,11,14,19,25,31-heptaazahexacyclo[22.3.1.1.SUP.9,12..1.SUP.14,16..1.SUP.16,19..0.SUP.2,7.]hentriaconta-1(27),2(7),3,5,9,11,24(28),25-octaene-13,13-dioxide

[1324] ##STR00230##

[1325] Synthesized according to the procedure outlined for 25-methyl-22-oxa-2λ.sup.6-thia-1,4,5,7,20,25,32-heptaazahexacyclo[24.2.2.1.sup.3,6.1.sup.17,21.0.sup.8,16.0.sup.9,13]dotriaconta-3,5,8,13,15,17,19,21(31)-octaene-2,2-dioxide (Example 9, Step B) from 1.6 M KO.sup.tBu in THF (1.11 mL, 1.77 mmol) and 3-(2-((5-((4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-sulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)propan-1-ol (120 mg, 117 μmol) in THF (145 mL) at 0° C. followed by TFA (3 mL), DCM (3 mL) and basic prep HPLC (3-35% MeCN in water) to afford the title compound (1.1 mg, 1%) as a white solid.

[1326] LCMS m/z 528.1 (M+H).sup.+ (ES.sup.+).

[1327] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.17-8.11 (m, 1H), 7.32 (dd, J=10.0, 3.0 Hz, 1H), 7.13 (dd, J=8.8, 3.0 Hz, 1H), 7.03 (dd, J=5.3, 1.5 Hz, 1H), 6.76 (s, 1H), 6.53 (s, 1H), 4.33-4.24 (m, 2H), 3.70-3.55 (m, 4H), 3.19-3.10 (m, 2H), 2.41-2.32 (m, 1H), 2.22 (s, 2H), 1.99 (t, J=7.1 Hz, 2H), 1.81-1.72 (m, 2H), 1.20-1.07 (m, 6H). Two aliphatic protons overlapped with DMSO-d.sub.6 signal; one exchangeable proton not observed.

Examples —Biological Studies

[1328] NLRP and Pyroptosis

[1329] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1R) from the cell.

[1330] THP-1 Cells: Culture and Preparation

[1331] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells were routinely passaged and grown to confluency (˜10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

[1332] THP-1 Cells Pyroptosis Assay

[1333] The following method step-by-step assay was followed for compound screening. [1334] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 40 μl of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1335] 2. Add 5 μl compound (8 points half-log dilution, with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1336] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1337] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [1338] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1339] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [1340] 7. Then add 50 μl of resazurin (Sigma #R7017) (FAC 100 μM resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37° C. and 5% CO.sub.2 [1341] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1342] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters) 96-well Plate Map

TABLE-US-00001 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 uM) Compound 8-point half-log dilution Low Drug free control

[1343] The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

[1344] Human Whole Blood IL-1β Release Assay

[1345] For systemic delivery, the ability to inhibit NLRP3 when the compounds are present within the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated in accordance with the following protocol.

[1346] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1347] 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1348] 2. Add 10 μl compound (8 points half-log dilution with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1349] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1350] 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells [1351] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1352] 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date) [1353] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1354] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[1355] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

TABLE-US-00002 TABLE 1 NLRP3 inhibitory activity (≤0.1 μM = ‘+++++’, ≤0.5 μM = ‘++++’, ≤1 μM = ‘+++’, ≤5 μM = ‘++’, ≤10 μM = not determined = ‘ND’). Example THP HWB No IC.sub.50 IC.sub.50  1 ++ ++  2† +++++ +++++  3 +++++ ++++  4 +++++ ++++  5† ++++ ++++  6 ++ ND  7 + ND  8 ++ +  9 ++++ ++++ 10 +++++ ++++ 11 +++++ ++++ 12 ++++ ++++ 13 +++ ND 14 ++++ ND 15 +++++ ND 16 +++ ND 17 ++++ ND 18 ++ ND 19 ++++ ND 20 ++++ ND 21 +++ ND 22 ++ ND 23 ++ ND 24 +++++ ND † = tested as the formic acid salt.

[1356] As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in the human whole blood assay.

[1357] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.