1. Patent Search
  2. Details

MACROCYCLIC SULFONYLUREA DERIVATIVES USEFUL AS NLRP3 INHIBITORS

20220289766 · 2022-09-15

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to macrocyclic compounds, such as macrocyclic sulfonyl ureas. 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 NLRP.sub.3 inhibition.

    ##STR00001##

    Claims

    1. A compound of formula (I): ##STR00261## or a pharmaceutically acceptable salt or solvate thereof, wherein: J is —SO—, —SO.sub.2— or —SO(═NR.sup.j)—; Q is O or S; X is —NR.sup.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-N(R.sup.1)—C(=Q)-X— and -L- together form a ring, such that the minimum single ring size that encompasses all or part of each of -J-, —N(R.sup.1)—, —C(=Q)-, —X— and -L- is from 8 to 30 atoms; and each R.sup.j, R.sup.1 and R.sup.2 is independently selected from hydrogen 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.

    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 is O; and/or (iii) R.sup.1 is hydrogen and X is —NH—; and/or (iv) L is a saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, wherein the hydrocarbylene group includes an aromatic cyclic group directly attached to X, wherein the ring atom of the aromatic cyclic group that is directly attached to X is a carbon atom, wherein the hydrocarbylene group may optionally include one or more further 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; and or (v) the minimum single ring size that encompasses all or part of each of -J-, —N(R.sup.1)—, —C(=Q)-, —X— and -L- is from 12 to 24 atoms, or from 14 to 20 atoms.

    3. (canceled)

    4. (canceled)

    5. (canceled)

    6. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ia): ##STR00262## wherein: J, R.sup.1, Q and X are as previously defined; -J-N(R.sup.1)—C(=Q)-X— and -L.sup.1-L.sup.2-L.sup.3-L.sup.4- together form a ring, such that the minimum single ring size that encompasses all or part of each of -J-, —N(R.sup.1)—, —C(=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, and optionally wherein the ring of the divalent monocyclic, bicyclic or tricyclic group of L.sup.4 that is directly attached to X is aromatic.

    7. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 6, wherein: (i) L.sup.1 is a bond, or (ii) L.sup.1 is a divalent 3- to 7-membered monocyclic group, or a divalent 7- to 11-membered bicyclic group, either of which may optionally be substituted with one or more monovalent substituents and/or π-bonded substituents.

    8. (canceled)

    9. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed claim 6, wherein: i) L.sup.2 is an alkylene or alkenylene group, wherein the alkylene or alkenylene group may be straight-chained or branched, or include a single monocyclic group, 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, O and S, and wherein the alkylene or alkenylene group may optionally be substituted with one or more monovalent substituents, and/or one or more π-bonded substituents; or (i) L.sup.2 is an alkylene or alkenylene group, wherein the alkylene or alkenylene group is straight-chained or branched, 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, O and S, and wherein the alkylene or alkenylene group may optionally be substituted with one or more monovalent substituents, and/or one or more π-bonded substituents.

    10. (canceled)

    11. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 6, wherein: (i) L.sup.3 is a bond, or (i) L.sup.3 is a divalent phenyl or 5- or 6-membered monocyclic heteroaryl group, any of which may optionally be substituted with one or more monovalent substituents.

    12. (canceled)

    13. (canceled)

    14. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ib): ##STR00263## wherein: J is —SO—, —SO.sub.2— or —SO(═NH)—; X is —NH—; -J-NH—C(═O)—X— and -L.sup.1-L.sup.2-L.sup.3-L.sup.4- together form a ring, such that the minimum single ring size that encompasses all or part of each of -J-NH—C(═O)—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, 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; 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; 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 X; 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.sub.3, —R.sup.11—NO.sub.2, —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, 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.sub.3, —R.sup.11—NO.sub.2, —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, —NO.sub.2, —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, —NO.sub.2, —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; and 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.

    15. (canceled)

    16. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 14, wherein: (i) 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; and/or (ii) L.sup.2 is an alkylene or alkenylene group, wherein the alkylene or alkenylene group may be straight-chained or branched, or include a single monocyclic group, 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, wherein the alkylene or alkenylene group may optionally be substituted with one or more halo groups and wherein L.sup.2 contains in total from 2 to 15 carbon, nitrogen and oxygen atoms; and/or (iii) the minimum single ring size that encompasses all or part of each of -J-NH—C(═O)—X—, -L.sup.1-, -L.sup.2-, -L.sup.3- and -L.sup.4- is from 12 to 24 atoms, or from 14 to 20 atoms.

    17. (canceled)

    18. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 14, 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 X, 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 X, wherein the ortho-fused 5- or 6-membered cyclic group is optionally substituted with one or more halo groups.

    19. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ib): ##STR00264## wherein: J is —SO—, —SO.sub.2— or —SO(═NH)—; X is —NH—; -J-NH—C(═O)—X— and -L.sup.1-L.sup.2-L.sup.3-L.sup.4- together form a ring, such that the minimum single ring size that encompasses all or part of each of -J-NH—C(═O)—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, 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; L.sup.3 is a bond; L.sup.4 is a phenyl or 5- or 6-membered heteroaryl group, wherein a ring atom of the phenyl or 5- or 6-membered heteroaryl group is directly attached to X, wherein a first 5- or 6-membered cyclic group is fused to the phenyl or 5- or 6-membered heteroaryl group across the α,β positions of the phenyl or 5- or 6-membered heteroaryl group, relative to the ring atom that is directly attached to X, wherein a ring atom of the first fused 5- or 6-membered cyclic group is directly attached to L.sup.2, wherein optionally a second 5- or 6-membered cyclic group is fused to the phenyl or 5- or 6-membered heteroaryl group, wherein the phenyl or 5- or 6-membered heteroaryl group may optionally be further substituted with one or more halo groups and/or one or more substituents R.sup.L, and wherein either fused 5- or 6-membered cyclic 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; 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.sub.3, —R.sup.11—NO.sub.2, —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, —NO.sub.2, —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, —NO.sub.2, —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; and 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.

    20. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 19, wherein: (i) 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; and/or (ii) L.sup.2 is an alkylene group, wherein the alkylene group may be straight-chained or branched, or include a single monocyclic group, wherein the alkylene group may optionally be substituted with one or more halo groups, and wherein L.sup.2 contains in total from 2 to 15 carbon atoms; and/or (iii) the ring atom of the first fused 5- or 6-membered cyclic group of L.sup.4 that is directly attached to L.sup.2 is also directly attached to the ring atom at the α-position of the phenyl or 5- or 6-membered heteroaryl group of L.sup.4; and/or (iv) the minimum single ring size that encompasses all or part of each of -J-NH—C(═O)—X—, -L.sup.1-, -L.sup.2-, -L.sup.3- and -L.sup.4- is from 12 to 24 atoms, or from 14 to 20 atoms.

    21. (canceled)

    22. (canceled)

    23. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 6, wherein the minimum single ring size that encompasses all or part of each of -J-, —N(R.sup.1)—, —C(=Q)-, —X—, -L.sup.1-, -L.sup.2-, -L.sup.3- and -L.sup.4- is from 12 to 24 atoms, or from 14 to 20 atoms.

    24. (canceled)

    25. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ic): ##STR00265## 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, C—H, C-Hal and N—H, such that ring A.sup.C 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, C—H and C-Hal, 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; m is 0, 1 or 2; n is 0, 1 or 2; 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 10 carbon, nitrogen and oxygen atoms, or wherein any two R.sup.A attached to A.sup.4 and A.sup.5 may together 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 Hal groups and/or one or two groups independently selected from oxo (═O) and R.sup.AA; 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 10 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —NO.sub.2, —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 Hal is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene or alkenylene group, wherein the straight-chained alkylene or alkenylene 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 two oxo (═O) groups and/or with one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a fluoro, 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 with the atom(s) of the alkylene or alkenylene group to which they are attached form a 3- to 7-membered cyclic group, wherein the 3- to 7-membered cyclic group may optionally be substituted with one or more Hal groups and/or one or two oxo (═O) groups; 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 —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 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; R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br, or a —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group; and each R.sup.20 is independently selected from hydrogen or F.

    26. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Id): ##STR00266## wherein: B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, C—H and C-Hal, 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; n is 0, 1 or 2; each R.sup.B is independently selected from a —CN, —NO.sub.2, —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 Hal is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene or alkenylene group, wherein the straight-chained alkylene or alkenylene 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 two oxo (═O) groups and/or with one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a fluoro, 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 with the atom(s) of the alkylene or alkenylene group to which they are attached form a 3- to 7-membered cyclic group, wherein the 3- to 7-membered cyclic group may optionally be substituted with one or more Hal groups and/or one or two oxo (═O) groups; 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 —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 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; R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br, or a —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group; and each R.sup.20 is independently selected from hydrogen or F.

    27. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ie): ##STR00267## wherein: A.sup.7, A.sup.8, A.sup.9 and A.sup.10 are each independently selected from N, C—H and C-Hal, 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, C—H and C-Hal, 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; q is 0, 1 or 2; n is 0, 1 or 2; 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 10 carbon, nitrogen and oxygen atoms, or wherein any two R.sup.A attached to A.sup.8 and A.sup.9 or to A.sup.9 and A.sup.10 may together 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 Hal groups and/or one or two groups independently selected from oxo (═O) and R.sup.AA; 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 10 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —NO.sub.2, —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 Hal is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene or alkenylene group, wherein the straight-chained alkylene or alkenylene 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 two oxo (═O) groups and/or with one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a fluoro, 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 with the atom(s) of the alkylene or alkenylene group to which they are attached form a 3- to 7-membered cyclic group, wherein the 3- to 7-membered cyclic group may optionally be substituted with one or more Hal groups and/or one or two oxo (═O) groups; 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 —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 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; R.sup.6 and R.sup.7 are each independently selected from hydrogen, F, Cl, Br, or a —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group; and each R.sup.20 is independently selected from hydrogen or F.

    28. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (If): wherein: ##STR00268## 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, C—H, C-Hal and N—H, such that ring A.sup.f 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, C—H and C-Hal, 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; D.sup.1 is selected from C—R.sup.4 and N—R.sup.44, D.sup.2 is selected from N, O, S, C—R.sup.5 and N—R.sup.55, D.sup.3 is selected from N, O, S, C—R.sup.6 and N—R.sup.66, and D.sup.4 is selected from C and N, such that ring D.sup.f is a 5-membered heteroaryl ring containing at least two carbon atoms in its ring structure; m is 0, 1 or 2; n is 0, 1 or 2; 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 10 carbon, nitrogen and oxygen atoms, or wherein any two R.sup.A attached to A.sup.4 and A.sup.5 may together 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 Hal groups and/or one or two groups independently selected from oxo (═O) and R.sup.AA; 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 10 carbon, nitrogen and oxygen atoms; each R.sup.B is independently selected from a —CN, —NO.sub.2, —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—C.sub.4 fluoroalkyl group; each Hal is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene or alkenylene group, wherein the straight-chained alkylene or alkenylene 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 two oxo (═O) groups and/or with one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a fluoro, 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 with the atom(s) of the alkylene or alkenylene group to which they are attached form a 3- to 7-membered cyclic group, wherein the 3- to 7-membered cyclic group may optionally be substituted with one or more Hal groups and/or one or two oxo (═O) groups; R.sup.4 and R.sup.44 are each 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, R.sup.5 is selected from hydrogen, F, Cl, Br, or a —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group, and R.sup.55 is selected from hydrogen or a methyl, fluoromethyl or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group, or R.sup.4 and R.sup.5 together, or R.sup.4 and R.sup.55 together, or R.sup.44 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 may optionally be fluoro-substituted, and wherein any oxygen atom of the divalent group is not directly attached to a nitrogen atom; R.sup.6 is selected from hydrogen, F, Cl, Br, or a —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group; R.sup.66 is selected from hydrogen or a methyl, fluoromethyl or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group; and each R.sup.20 is independently selected from hydrogen or F.

    29. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ig): ##STR00269## 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, C—H, C-Hal and N—H, such that ring A.sup.g is a 5-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; m is 0, 1 or 2; 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 10 carbon, nitrogen and oxygen atoms, or wherein any two R.sup.A attached to A.sup.4 and A.sup.5 may together 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 Hal groups and/or one or two groups independently selected from oxo (═O) and R.sup.AA; 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 10 carbon, nitrogen and oxygen atoms; E.sup.1 is N, C—H or C-Hal, and E.sup.2 and E.sup.3 are each independently selected from O, N—H, N—R.sup.e, CH.sub.2, CH(Hal), CH(R.sup.e), C(Hal).sub.2, C(Hal)(R.sup.e) and C(R.sup.e).sub.2, such that E.sup.1, E.sup.2 and E.sup.3 together contain at most one nitrogen or oxygen atom; each R.sup.e is independently selected from a methyl or fluoromethyl group; each Hal is independently selected from F, Cl or Br; L.sup.2 is a straight-chained alkylene or alkenylene group, wherein the straight-chained alkylene or alkenylene 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 two oxo (═O) groups and/or with one or more groups R.sup.L2, wherein each R.sup.L2 is independently selected from a fluoro, 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 with the atom(s) of the alkylene or alkenylene group to which they are attached form a 3- to 7-membered cyclic group, wherein the 3- to 7-membered cyclic group may optionally be substituted with one or more Hal groups and/or one or two oxo (═O) groups; 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 —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 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; R.sup.6 is hydrogen, F, Cl, Br, or a —CN, methyl, fluoromethyl, —OC(R.sup.20).sub.3 or —C(R.sup.20).sub.2—OC(R.sup.20).sub.3 group; and each R.sup.20 is independently selected from hydrogen or F.

    30. 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: ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## or (b) a pharmaceutically acceptable salt or solvate of the selected compound.

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

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

    33. 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.

    34. (canceled)

    35. The method as claimed in claim 33, 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.

    36. The method as claimed in claim 33, 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) hyperimmunoglobulinemia 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).

    37. 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.

    38. 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.

    39. The method as claimed in claim 33, wherein the compound or the pharmaceutically acceptable salt or solvate thereof is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

    40. 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 31, 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

    [0542] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

    Abbreviations

    [0543] 2-MeTHF 2-methyltetrahydrofuran [0544] AcCl acetyl chloride [0545] Ac.sub.2O acetic anhydride [0546] AcOH acetic acid [0547] app apparent [0548] aq aqueous [0549] 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) [0550] Boc tert-butyloxycarbonyl [0551] br broad [0552] Cbz carboxybenzyl [0553] CDI 1,1-carbonyl-diimidazole [0554] conc concentrated [0555] d doublet [0556] DABCO 1,4-diazabicyclo[2.2.2]octane [0557] DCE 1,2-dichloroethane, also called ethylene dichloride [0558] DCM dichloromethane [0559] dd double doublet [0560] ddd double double doublet [0561] DIAD diisopropyl azodicarboxylate [0562] DIPEA N,N-diisopropylethylamine, also called Hünig's base [0563] DMA dimethylacetamide [0564] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0565] DME dimethoxyethane [0566] DMF N,N-dimethylformamide [0567] DMSO dimethyl sulfoxide [0568] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0569] eq or equiv equivalent [0570] (ES.sup.+) electrospray ionization, positive mode [0571] Et ethyl [0572] EtOAc ethyl acetate [0573] EtOH ethanol [0574] Ex example [0575] FC flash column chromatography on silica gel [0576] h hour(s) [0577] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0578] HPLC high performance liquid chromatography [0579] Hz hertz [0580] Int intermediate [0581] KOAc potassium acetate [0582] KO.sup.tBu potassium tert-butoxide [0583] LC liquid chromatography [0584] m multiplet [0585] m-CPBA 3-chloroperoxybenzoic acid [0586] Me methyl [0587] MeCN acetonitrile [0588] MeOH methanol [0589] (M+H).sup.+ protonated molecular ion [0590] MHz megahertz [0591] min minute(s) [0592] MS mass spectrometry [0593] Ms mesyl, also called methanesulfonyl [0594] MsCl mesyl chloride, also called methanesulfonyl chloride [0595] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0596] m/z mass-to-charge ratio [0597] NaO.sup.tBu sodium tert-butoxide [0598] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0599] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0600] NMP N-methylpyrrolidine [0601] NMR nuclear magnetic resonance (spectroscopy) [0602] p pentuplet [0603] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) [0604] PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), also called Pd(dppf)Cl.sub.2 [0605] PE petroleum ether [0606] Ph phenyl [0607] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0608] prep-HPLC preparative high performance liquid chromatography [0609] prep-TLC preparative thin layer chromatography on silica [0610] PTSA p-toluenesulfonic acid [0611] q quartet [0612] RP reversed phase [0613] RT room temperature [0614] s singlet [0615] sat saturated [0616] SCX solid supported cation exchange (resin) [0617] sept septuplet [0618] SPhos-Pd-G3 (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate [0619] t triplet [0620] T.sub.3P propylphosphonic anhydride [0621] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0622] TEA triethylamine [0623] Tf triflyl, also called trifluoromethanesulfonyl [0624] TFA 2,2,2-trifluoroacetic acid [0625] THF tetrahydrofuran [0626] TLC thin layer chromatography [0627] TMS trimethylsilyl [0628] wt % weight percent or percent by weight [0629] XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [0630] XPhos-Pd-G3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate

    Experimental Methods

    Nuclear Magnetic Resonance

    [0631] NMR spectra were recorded at 300, 400 or 500 MHz. 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. Spectra were recorded using one of the following machines: [0632] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0633] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0634] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0635] an Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module, or [0636] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

    LC-MS

    [0637] LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.1×30 mm, 5 μm.

    Preparative Reversed Phase HPLC General Methods

    [0638] Acidic prep HPLC (x-y % MeCN in water): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, x % MeCN; 0.2-5.5 min, ramped from x % MeCN to y % MeCN; 5.5-5.6 min, ramped from y % MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

    [0639] Acidic prep HPLC (x-y % MeOH in water): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM aq formic acid-MeOH gradient over 7.5 min using UV detection at 254 nm. Gradient information: 0.0-1.5 min, x % MeOH; 1.5-6.8 min, ramped from x % MeOH to y % MeOH; 6.8-6.9 min, ramped from y % MeOH to 95% MeOH; 6.9-7.5 min, held at 95% MeOH.

    [0640] Basic prep HPLC (x-y % MeCN in water): Waters X-Bridge Prep column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, x % MeCN; 0.2-5.5 min, ramped from x % MeCN to y % MeCN; 5.5-5.6 min, ramped from y % MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

    Synthesis of Intermediates

    Intermediate A1: 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0641] ##STR00031##

    Step A: lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate

    [0642] ##STR00032##

    [0643] A solution of n-BuLi (100 mL, 250 mmol, 2.5M in hexanes) was added slowly to a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (36.2 g, 238 mmol) in THF (500 mL), keeping the temperature below −65° C. The mixture was stirred for 1.5 h, then sulfur dioxide was bubbled through for 10 min. The mixture was allowed to warm to RT, the solvent evaporated and the residue triturated with MTBE (300 mL) and filtered. The solid was washed with MTBE and isohexane and dried to afford the crude title compound (54.89 g, 99%).

    [0644] LCMS m/z 215 (M−Li).sup.− (ES.sup.−).

    [0645] .sup.1H NMR (DMSO-d.sub.6) δ 7.26 (d, J=1.6 Hz, 1H), 6.10 (d, J=1.7 Hz, 1H), 5.99 (dd, J=10.0, 2.5 Hz, 1H), 3.92-3.87 (m, 1H), 3.56-3.49 (m, 1H), 2.25-2.15 (m, 1H), 2.00-1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.66-1.46 (m, 3H).

    Step B: N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide

    [0646] ##STR00033##

    [0647] NCS (12.0 g, 90 mmol) was added to a suspension of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (20 g, 90 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 4 h, quenched with water (100 mL), and then partitioned between DCM (300 mL) and water (200 mL). The organic phase was washed with water (200 mL), dried (MgSO.sub.4), filtered and evaporated to ˜50 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (24 g, 93 mmol) and triethylamine (40 mL, 287 mmol) in DCM (300 mL) cooled in an ice bath. After stirring for 1 h, the mixture was warmed to RT, and then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2×250 mL), water (250 mL), dried (MgSO.sub.4), filtered, and evaporated to afford the crude title compound (41.02 g, 97%) as a brown oil.

    [0648] LCMS m/z 494.2 (M+Na).sup.+ (ES.sup.+).

    Step C: N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0649] ##STR00034##

    [0650] A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1M HCl (30 mL) in THF (300 mL) and MeOH (50 mL) was stirred at RT for 18 h. The solvent was evaporated and the residue partitioned between EtOAc (400 mL) and aq 1M HCl (200 mL). The organic layer was washed with 10% brine (200 mL), dried (MgSO.sub.4), filtered and evaporated. The residue was triturated with MTBE, filtered and dried to afford the title compound (24.87 g, 69%) as an off-white solid.

    [0651] LCMS m/z 388 (M+H).sup.+ (ES.sup.+); 386 (M−H).sup.− (ES.sup.−).

    [0652] .sup.1H NMR (CDCl.sub.3) δ 7.88 (d, J=2.4 Hz, 1H), 7.06-7.02 (m, 4H), 6.79-6.75 (m, 4H), 6.63 (d, J=2.4 Hz, 1H), 4.31 (s, 4H), 3.78 (s, 6H). One exchangeable proton not observed.

    Step D: 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0653] ##STR00035##

    [0654] N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1.69 g, 4-36 mmol) and K.sub.2CO.sub.3 (1.5 g, 10.85 mmol) were suspended in MeCN (20 mL) under N.sub.2. 5-Bromopentan-1-ol (1.0 g, 4.79 mmol) was added and the mixture was heated to 50° C. for 4 h. After cooling to RT, water (20 mL) and EtOAc (20 mL) were added, the layers were separated and the organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (1.13 g, 49%) as a thick colourless oil.

    [0655] LCMS m/z 496.3 (M+Na).sup.+ (ES.sup.+)

    [0656] .sup.1H NMR (DMSO-d.sub.6) δ 7.97 (d, J=2.3 Hz, 1H), 7.08-6.94 (m, 4H), 6.90-6.75 (m, 4H), 6.71 (d, J=2.3 Hz, 1H), 4.39 (t, J=5.1 Hz, 1H), 4.25-4.15 (m, 6H), 3.72 (s, 6H), 3.44-3.34 (m, 2H), 1.80 (p, J=7.2 Hz, 2H), 1.51-1.38 (m, 2H), 1.32-1.21 (m, 2H).

    [0657] The following intermediates were synthesised following the general procedure for Intermediate A1:

    TABLE-US-00001 Intermediate Structure .sup.1H NMR LCMS A2 [00036]embedded image   1-(2-(2-hydroxyethoxy)ethyl)- N,N-bis(4-methoxybenzyl)-1H- .sup.1H NMR (DMSO-d.sub.6) δ 7.96 (d, J = 2.3 Hz, 1H), 7.05-6.96 (m, 4H), 6.86-6.77 (m, 4H), 6.71 (d, J = 2.3 Hz, 1H), 4.62 (t, J = 5.2 Hz, 1H), 4.38 (t, J = 5.3 Hz, 2H), 4.19 (s, 4H), 3.80 (t, J = 5.3 Hz, 2H), 3.71 (s, 6H), 3.51-3.45 (m, 2H), 3.45-3.40 (m, 2H). m/z 498.3 (M + Na).sup.+ (ES.sup.+) pyrazole-3-sulfonamide A3 [00037]embedded image   1-(4-hydroxybutyl)-N,N-bis(4- methoxybenzyl)-1H-pyrazole-3- .sup.1H NMR (DMSO-d.sub.6) δ 7.96 (d, J = 2.3 Hz, 1H), 7.04-6.98 (m, 4H), 6.84-6.77 (m, 4H), 6.70 (d, J = 2.3 Hz, 1H), 4.48 (t, J = 5.1 Hz, 1H), 4.22 (t, J = 7.1 Hz, 2H), 4.19 (s, 4H), 3.71 (s, 6H), 3.45-3.38 (m, 2H), 1.87-1.79 (m, 2H), 1.43-1.33 (m, 2H). m/z 482.3 (M + Na).sup.+ (ES.sup.+) sulfonamide A4 [00038]embedded image   1-(6-hydroxyhexyl)-N,N-bis(4- methoxybenzyl)-1H-pyrazole-3- sulfonamide .sup.1H NMR (DMSO-d.sub.6) δ 7.96 (d, J = 2.3 Hz, 1H), 7.07-6.94 (m, 4H), 6.85-6.76 (m, 4H), 6.70 (d, J = 2.4 Hz, 1H), 4.34 (t, J = 5.1 Hz, 1H), 4.25- 4.13 (m, 6H), 3.71 (s, 6H), 3.40-3.33 (m, 2H), 1.78 (p, J = 7.2 Hz, 2H), 1.44-1.36 (m, 2H), 1.36-1.27 (m, 2H), 1.27-1.18 (m, 2H). m/z 510.3 (M + Na).sup.+ (ES.sup.+) A6 [00039]embedded image   1-(3-hydroxypropyl)-N,N-bis(4- .sup.1H NMR (DMSO-d.sub.6) δ 7.95 (d, J = 2.3 Hz, 1H), 7.04-6.97 (m, 4H), 6.84-6.77 (m, 4H), 6.70 (d, J = 2.3 Hz, 1H), 4.66 (t, J = 5.0 Hz, 1H), 4.27 (t, J = 7.1 Hz, 2H), 4.19 (s, 4H), 3.71 (s, 6H), 3.40 (td, J = 6.1, 4.9 Hz, 2H), 1.94 (p, J = 6.6 Hz, 2H). m/z 468.3 (M + Na).sup.+ (ES.sup.+) methoxybenzyl)-1H-pyrazole-3- sulfonamide A7 [00040]embedded image .sup.1H NMR (CDCl.sub.3) δ 7.50 (d, J = 2.3 Hz, 1H), 7.12-6.96 (m, 4H), 6.81-6.71 (m, 4H), 6.64 (d, J = 2.3 Hz, 1H), 4.31 (s, 4H), 4.29-4.25 (m, 2H), 3.98-3.94 (m, 2H), 3.77 (s, 6H), 2.39 (s, 1H). m/z 454.6 (M + Na).sup.+ (ES.sup.+) 1-(2-hydroxyethyl)-N,N-bis(4- methoxybenzyl)-1H-pyrazole-3- sulfonamide

    Intermediate A5: 11-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide

    [0658] ##STR00041##

    [0659] N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (0.47 g, 1.067 mmol) and K.sub.2CO.sub.3 (0.37 g, 2.68 mmol) were suspended in dry MeCN (10 mL) under N.sub.2. 5-bromopentan-1-ol (0.21 mL, 1.388 mmol) was added and the mixture was heated to 50° C. for 18 h. After cooling to RT, water (10 mL) and EtOAc (10 mL) were added, the layers were separated and the organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.17 g, 33.0%) as a white solid.

    [0660] LCMS m/z 474.3 (M+Na).sup.+ (ES.sup.+).

    [0661] .sup.1H NMR (DMSO-d.sub.6) δ 8.34 (s, 1H), 7.80 (s, 1H), 7.12-6.97 (m, 4H), 6.88-6.70 (m, 4H), 4.38 (t, J=5.1 Hz, 1H), 4.16-4.09 (m, 6H), 3.71 (s, 6H), 3.37 (td, J=6.4, 5.0 Hz, 2H), 1.78 (p, J=7.2 Hz, 2H), 1.43 (p, J=6.7 Hz, 2H), 1.27-1.20 (m, 2H).

    Intermediate A8: 1-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0662] ##STR00042##

    [0663] 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A7) (1.902 g, 3.92 mmol) was dissolved in THF (20 mL), to which was added DIPEA (0.959 mL, 5.49 mmol). Then methanesulfonyl chloride (0.321 mL, 4.12 mmol) was added dropwise at 0° C., and the reaction stirred for 2 h. KI (0.065 g, 0.392 mmol) and 2-(methylamino)ethanol (0.945 mL, 11.77 mmol) were added and the reaction stirred at 60° C. for 16 h. Additional 2-(methylamino)ethanol (0.945 mL, 11.77 mmol) and KI (0.065 g, 0.392 mmol) were added and the reaction heated at 60° C. for 72 h, then concentrated in vacuo and the resulting residue taken up in EtOAc (50 mL). Organics were washed with water (50 mL) and the aqueous layer extracted with EtOAc (50 mL). The combined organics were dried (phase separator) and concentrated in vacuo. The crude product was purified by FC (0-10% MeOH/DCM) to afford the title compound (1.172 g, 55%) as a thick colourless oil.

    [0664] LCMS m/z 489.4 (M+H).sup.+ (ES.sup.+).

    [0665] .sup.1H NMR (CDCl.sub.3) δ 7.48 (d, J=2.3 Hz, 1H), 7.10-7.02 (m, 4H), 6.80-6.73 (m, 4H), 6.63 (d, J=2.3 Hz, 1H), 4.30 (s, 4H), 4.27 (t, J=6.3 Hz, 2H), 3.77 (s, 6H), 3.53 (t, J=5.3 Hz, 2H), 2.90 (t, J=6.3 Hz, 2H), 2.61-2.54 (m, 2H), 2.29 (s, 3H). One exchangeable proton not observed.

    Intermediate Aq: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0666] ##STR00043##

    Step A: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate

    [0667] ##STR00044##

    [0668] N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (2.00 g, 5.16 mmol) and K.sub.2CO.sub.3 (2.140 g, 15.49 mmol) were suspended in DMF (30 mL). Methyl 2-bromo-2-methylpropanoate (1.00 mL, 7.74 mmol) was added and the mixture was heated to 80° C. overnight. The reaction mixture was cooled to RT, diluted with water (20 mL), poured onto brine (200 mL) and washed with MTBE (2×50 mL). The combined organic layers were dried (MgSO.sub.4) and evaporated in vacuo. The crude product was purified by FC (0-70% EtOAc/isohexane) to afford the title compound (2.45 g, 94%) as a clear colourless oil.

    [0669] LCMS m/z 510.6 (M+Na).sup.+ (ES.sup.+).

    [0670] .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J=2.5 Hz, 1H), 7.05-6.95 (m, 4H), 6.85-6.78 (m, 4H), 6.78 (d, J=2.5 Hz, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 3.65 (s, 3H), 1.81 (s, 6H).

    Step B: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0671] ##STR00045##

    [0672] Methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (3.28 g, 6.73 mmol) was dissolved in THF (30 mL) and cooled to 0° C. LiAlH.sub.4 (2 M in THF, 3.36 mL, 6.73 mmol) was added drop-wise and the reaction was stirred at RT for 16 h, quenched with slow addition of water (20 mL), then diluted with brine (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried (phase separator) and concentrated in vacuo to afford the title compound (3-43 g, 100%) as a white solid.

    [0673] LCMS m/z 482.3 (M+Na).sup.+ (ES.sup.+).

    [0674] .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (d, J=2.5 Hz, 1H), 7.04-6.98 (m, 4H), 6.84-6.80 (m, 4H), 6.69 (d, J=2.5 Hz, 1H), 5.14 (t, J=5.5 Hz, 1H), 4.20 (s, 4H), 3.72 (s, 6H), 3.61 (d, J=5.6 Hz, 2H), 1.50 (s, 6H).

    Intermediate A10: 1-(1-(2-hydroxyethoxy)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0675] ##STR00046##

    Step A: methyl 2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)acetate

    [0676] ##STR00047##

    [0677] Prepared according to the general procedure of 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step D) from 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A9) and methyl 2-bromoacetate to afford the title compound (254 mg, 55%) as a colourless oil.

    [0678] LCMS m/z 532.2 (M+H).sup.+ (ES.sup.+).

    [0679] .sup.1H NMR (DMSO-d.sub.6) δ 8.09 (d, J=2.5 Hz, 1H), 7.05-6.99 (m, 4H), 6.83-6.79 (m, 4H), 6.72 (d, J=2.5 Hz, 1H), 4.20 (s, 4H), 4.09 (s, 2H), 3.76 (s, 2H), 3.72 (s, 6H), 3.64 (s, 3H), 1.54 (s, 6H).

    Step B: 1-(1-(2-hydroxyethoxy)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0680] ##STR00048##

    [0681] Prepared according to the general procedure of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A9, Step B) to afford the title compound (216 mg, 91%) as a colourless oil.

    [0682] .sup.1H NMR (DMSO-d.sub.6) δ 8.04 (d, J=2.5 Hz, 1H), 7.05-6.99 (m, 4H), 6.83-6.79 (m, 4H), 6.70 (d, J=2.5 Hz, 1H), 4.59 (t, J=5.4 Hz, 1H), 4.20 (s, 4H), 3.72 (s, 6H), 3.66 (s, 2H), 3.45 (q, J=5.3 Hz, 2H), 3.36 (t, J=5.3 Hz, 2H), 1.53 (s, 6H).

    Intermediate A11: 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)-N,2-dimethylpropanamide

    [0683] ##STR00049##

    Step A: 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid, Sodium Salt

    [0684] ##STR00050##

    [0685] A mixture of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (12.60 g, 25.8 mmol) (Intermediate A9, Step A) and NaOH (2M aq. sol.) (20.48 mL, 41.0 mmol) in THF (77 mL) and MeOH (18 mL) was stirred at RT for 48 h. 2 M NaOH (2.05 mL, 4.10 mmol) was added and the reaction was stirred for a further 3 h. Solvents were removed in vacuo and the residue dried azeotropically with toluene (3×100 mL). The resulting solid was stirred with MTBE (100 mL) for 2 h and filtered to afford the title compound (13.1 g, 62%) as a white solid.

    [0686] LCMS m/z 474.3 (M+2H—Na).sup.+ (ES.sup.+), 472.2 (M−H).sup.− (ES.sup.−).

    [0687] .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (d, J=2.4 Hz, 1H), 7.02-7.00 (m, 4H), 6.82-6.79 (m, 4H), 6.62 (d, J=2.4 Hz, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 1.63 (s, 6H).

    Step B: 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)-N,2-dimethylpropanamide

    [0688] ##STR00051##

    [0689] 2-(Methylamino)ethanol (0.32 mL, 3.98 mmol) was added to a stirred solution of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid, sodium salt (1.00 g, 2.018 mmol), HATU (0.92 g, 2.420 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.71 mL, 4.07 mmol) in DMF (10 mL) at RT. The mixture was stirred at RT for 18 h. The reaction mixture was partitioned between EtOAc (20 mL) and brine (200 mL). The organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.87 g, 72%) as a colourless solid.

    [0690] LCMS m/z 553.3 (M+Na).sup.+ (ES.sup.+).

    [0691] .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J=2.5 Hz, 1H), 7.08-7.02 (m, 4H), 6.84 (d, J=2.4 Hz, 1H), 6.83-6.79 (m, 4H), 4.66 (br s, 1H), 4.20 (s, 4H), 3.72 (s, 6H), 3.47 (br s, 1H), 2.36-2.18 (m, 2H), 1.73 (s, 6H). One exchangeable proton not observed, 3H obscured by water signal.

    Intermediate A12: 1-cyclopropyl-5-(((3-hydroxypropyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0692] ##STR00052##

    Step A: 1-cyclopropyl-3-nitro-1H-pyrazole

    [0693] ##STR00053##

    [0694] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in DCE (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol, 1.57 eq) at 25° C. The mixture was stirred at 25° C. for 0.5 h. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol, 1 eq) was added and the resulting mixture was warmed to 70° C. and stirred at 70° C. for 15.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by FC (PE:EtOAc, 30:1 to 3:1) to give impure product (26.7 g). The impure product was dissolved in pyrrolidine (10 mL) and the resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove pyrrolidine. The residue was diluted with H.sub.2O (33 mL) and the pH was adjusted to 5-6 with aqueous HCl solution (1N). Then the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×33 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as yellow oil.

    [0695] .sup.1H NMR (CDCl.sub.3): δ 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H) and 1.13-1.07 (m, 2H).

    Step B: i-cyclopropyl-1H-pyrazol-3-amine

    [0696] ##STR00054##

    [0697] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 5 eq) in H.sub.2O (150 mL). Then the reaction mixture was warmed to 60° C. and iron power (39.38 g, 705.24 mmol, 3 eq) was added in portions. The reaction mixture was stirred at 60° C. for 16 h and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 30:1 to 1:1) to give the title compound (20 g, 69%) as yellow oil.

    [0698] LCMS m/z 124.2 (M+H).sup.+ (ES.sup.+).

    [0699] .sup.1H NMR (CDCl.sub.3): δ 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H) and 0.90-0.87 (m, 2H).

    Step C: 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride

    [0700] ##STR00055##

    [0701] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in MeCN (500 mL) and H.sub.2O (50 mL) at 0° C. was added conc. HCl solution (50 mL). Then an aqueous solution of NaNO.sub.2 (12.77 g, 185-13 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting solution was stirred at 0° C. for 40 min. AcOH (50 mL), CuCl.sub.2 (10.37 g, 77.14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the resulting mixture for 20 min at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (250 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (2×150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 100:0 to 1:1) to give the title compound (14 g, 44%) as yellow oil.

    [0702] .sup.1H NMR (CDCl.sub.3): δ 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H) and 1.16-1.12 (m, 2H).

    Step D: 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0703] ##STR00056##

    [0704] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added TEA (27.42 g, 270.99 mmol, 2 eq) and bis(4-methoxybenzyl)amine (34.87 g, 135.49 mmol, 1 eq). The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (0.5% NH.sub.3.H.sub.2O-MeCN) to give the title compound (30 g, 52% yield, 99.8% purity on LCMS).

    [0705] LCMS m/z 428.2 (M+H).sup.+ (ES.sup.+).

    [0706] .sup.1H NMR (CDCl.sub.3): δ 7.49 (d, 1H), 7.08-7.06 (m, 4H), 6.79-6.77 (m, 4H), 6.62 (d, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 3.68-3.64 (m, 1H), 1.15-1.13 (m, 2H) and 1.09-1.06 (m, 2H).

    Step E: 1-cyclopropyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0707] ##STR00057##

    [0708] To a solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (4.00 g, 9.36 mmol) in THF (50 mL) at −78° C. was slowly added nBuLi (2.5 M in THF, 4.12 mL, 10.29 mmol) and the mixture was stirred at −78° C. for 1 h. Morpholine-4-carbaldehyde (2.81 mL, 28.1 mmol) was added slowly and the stirring was continued for 3 h. The reaction was quenched with sat aq NH.sub.4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (phase separator) and concentrated in vacuo. The residue was purified by FC (0-80% EtOAc/isohexane) to afford the title compound (3.386 g, 72%) as a clear colourless oil that solidified slowly to afford a white solid.

    [0709] .sup.1H NMR (DMSO-d.sub.6) δ 10.02 (s, 1H), 7.35 (s, 1H), 7.14-6.94 (m, 4H), 6.89-6.74 (m, 4H), 4.31-4.25 (m, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 1.15-1.11 (m, 4H).

    Step F: 1-cyclopropyl-5-(((3-hydroxypropyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0710] ##STR00058##

    [0711] 3-(Methylamino)propan-1-ol (0.307 mL, 3.16 mmol) was added to a solution of 1-cyclopropyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.800 g, 1.581 mmol) in THF (20 mL) and the reaction was stirred at RT for 1 h. Sodium triacetoxyhydroborate (0.502 g, 2.371 mmol) and acetic acid (0.018 mL, 0.316 mmol) were added and the solution was stirred at RT for 4 h. Additional sodium triacetoxyhydroborate (0.502 g, 2.371 mmol) and acetic acid (0.018 mL, 0.316 mmol) were added and the reaction stirred for a further 16 h. Water (30 mL) was added and the product was extracted into EtOAc (3×30 mL). The organic extracts were combined, dried (MgSO.sub.4) and the solvent was removed in vacuo. The crude product was purified by FC (0-5% MeOH/DCM) to afford the title compound (0.406 g, 48%) as a thick colourless oil.

    [0712] LCMS m/z 529.3 (M+H).sup.+ (ES.sup.+).

    [0713] .sup.1H NMR (DMSO-d.sub.6) δ 7.06-6.99 (m, 4H), 6.86-6.78 (m, 4H), 6.58 (s, 1H), 4.19 (s, 4H), 3.82-3.77 (m, 1H), 3.72 (s, 6H), 3.63 (s, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.15 (s, 3H), 1.69-1.57 (m, 2H), 1.11-0.99 (m, 4H). One exchangeable proton not observed.

    Intermediate A13: 1-cyclopropyl-5-((3-hydroxypropoxy)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0714] ##STR00059##

    Step A: 1-cyclopropyl-5-(hydroxymethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0715] ##STR00060##

    [0716] To a solution of 1-cyclopropyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A12, Step E) (0.830 g, 1.640 mmol) in THF (20 mL) at 0° C. was added sodium borohydride (0.068 g, 1.804 mmol). The reaction mixture was allowed to warm to RT and stirred for 4 h. The solution was concentrated in vacuo and the resulting residue was redissolved in EtOAc (20 mL) and washed with brine (20 mL). The organic phase was dried (MgSO.sub.4) and evaporated in vacuo to afford the title compound (0.910 g, quantitative yield) as a colourless oil.

    [0717] LCMS m/z 480.3 (M+Na).sup.+ (ES.sup.+).

    [0718] .sup.1H NMR (CDCl.sub.3) δ 7.12-7.00 (m, 4H), 6.81-6.69 (m, 4H), 6.52 (s, 1H), 4.77 (s, 2H), 4.29 (s, 4H), 3.79 (s, 6H), 3.60 (tt, J=7.4, 3.8 Hz, 1H), 1.24-1.19 (m, 2H), 1.10-1.04 (m, 2H). One exchangeable proton not observed.

    Step B: methyl 3-((3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-cyclopropyl-1H-pyrazol-5-yl)methoxy)propanoate

    [0719] ##STR00061##

    [0720] To a solution of 1-cyclopropyl-5-(hydroxymethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.910 g, 1.651 mmol) in THF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (0.073 g, 1.816 mmol) and the reaction stirred for 30 min. Methyl 3-bromopropanoate (0.216 mL, 1.981 mmol) was then added and the reaction was allowed to warm to RT and then heated at 60° C. for 18 h. The reaction was cooled to 0° C. and additional sodium hydride (60% dispersion in mineral oil) (0.146 g, 3.632 mmol) added. The reaction was stirred for 30 min, at which point methyl 3-bromopropanoate (0.432 mL, 3.962 mmol) was added and the reaction heated at 60° C. for 3 h. Additional sodium hydride (60% dispersion in mineral oil) (0.146 g, 3.632 mmol) and methyl 3-bromopropanoate (0.432 mL, 3.962 mmol) were added and the reaction stirred for a further 2 h. The reaction was quenched with MeOH (˜50 mL) and concentrated in vacuo. The resulting residue was taken up in EtOAc (50 mL), washed with water (50 mL) and the organic layer extracted. The aqueous layer was re-extracted with EtOAc (2×20 mL), the organics combined, passed through a phase separator and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.611 g, 65% yield) as a thick colourless oil.

    [0721] LCMS m/z 566.2 (M+Na).sup.+ (ES.sup.+).

    [0722] .sup.1H NMR (CDCl.sub.3) δ 7.09-7.04 (m, 4H), 6.79-6.74 (m, 4H), 6.60 (s, 1H), 4.61 (s, 2H), 4.29 (s, 4H), 3.78 (s, 6H), 3.75 (t, J=6.1 Hz, 2H), 3.69 (s, 3H), 3.58 (tt, J=7.4, 3.8 Hz, 1H), 2.61 (t, J=6.1 Hz, 2H), 1.22-1.17 (m, 2H), 1.08-1.00 (m, 2H).

    Step C: 1-cyclopropyl-5-((3-hydroxypropoxy)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0723] ##STR00062##

    [0724] To a solution of methyl 3-((3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-cyclopropyl-1H-pyrazol-5-yl)methoxy)propanoate (0.611 g, 1.079 mmol) in THF (15 mL) at 0° C. was added lithium borohydride (4 M in THF) (1.079 mL, 4.32 mmol) dropwise. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched via the slow addition of water and the resulting mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL). The organic phase was separated and the aqueous layer re-extracted with EtOAc (2×25 mL). The organics were combined, passed through a phase separator and then concentrated in vacuo to afford the title compound (0.581 g, quantitative yield) as a thick colourless oil.

    [0725] LCMS m/z 538.3 (M+Na).sup.+ (ES.sup.+).

    [0726] .sup.1H NMR (DMSO-d.sub.6) δ 7.04-6.99 (m, 4H), 6.83-6.78 (m, 4H), 6.70 (s, 1H), 4.62 (s, 2H), 4.45 (t, J=5.1 Hz, 1H), 4.19 (s, 4H), 3.75-3.68 (m, 7H), 3.52 (t, J=6.4 Hz, 2H), 3.50-3.44 (m, 2H), 1.70 (p, J=6.4 Hz, 2H), 1.08-1.00 (m, 4H).

    Intermediate A14: 5-((dimethylamino)methyl)-1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0727] ##STR00063##

    [0728] 1-(5-Hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step D) (750 mg, 1.584 mmol) was dissolved in dry THF (25 mL) and cooled to −78° C. n-BuLi (2.5M in hexanes) (1.58 mL, 3.95 mmol) was then added, immediately followed by N-methyl-N-methylenemethanaminium iodide (439 mg, 2.375 mmol). The reaction was stirred for 1 h, whilst allowing to warm to RT. The reaction was quenched with water (50 mL), extracted with MTBE (2×50 mL), dried using a phase separator and concentrated in vacuo. The resulting residue was dissolved in MeOH and stirred with SCX (3 g) for 30 min. The resin was then washed with MeOH (100 mL), then the desired 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 (175 mg, 20%) as a yellow oil.

    [0729] .sup.1H NMR (DMSO-d.sub.6) δ 7.04-7.00 (m, 4H), 6.82-6.79 (m, 4H), 6.57 (s, 1H), 4.38 (t, J=5.1 Hz, 1H), 4.24-4.14 (m, 6H), 3.72 (s, 6H), 3.47 (s, 2H), 3.38 (t, J=6.4 Hz, 2H), 2.16 (s, 6H), 1.78 (p, J=7.4 Hz, 2H), 1.45 (p, J=7.3 Hz, 2H), 1.29 (p, J=7.3 Hz, 2H).

    Intermediate A15: 5-hydroxy-N,N-bis(4-methoxybenzyl)pentane-1-sulfonamide

    [0730] ##STR00064##

    Step A: methyl 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)pentanoate

    [0731] ##STR00065##

    [0732] A suspension of methyl 5-(chlorosulfonyl)pentanoate (0.25 g, 1.165 mmol) and bis(4-methoxybenzyl)amine (0.30 g, 1.165 mmol) in DCM (20 mL) was cooled to 0° C. TEA (0.40 mL, 2.81 mmol) was then added dropwise at 0° C. and the mixture was stirred at RT for 18 h. The mixture was concentrated in vacuo, dissolved in DCM (5 mL) and a few drops of MeOH, then purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.30 g, 56%) as a colourless oil.

    [0733] LCMS m/z 458.3 (M+Na).sup.+ (ES.sup.+).

    [0734] .sup.1H NMR (CDCl.sub.3) δ 7.24-7.16 (m, 4H), 6.91-6.86 (m, 4H), 4.26 (s, 4H), 3.82 (s, 6H), 3.67 (s, 3H), 2.87-2.77 (m, 2H), 2.29 (t, J=7.3 Hz, 2H), 1.85-1.75 (m, 2H), 1.71-1.63 (m, 2H).

    Step B: 5-hydroxy-N,N-bis(4-methoxybenzyl)pentane-1-sulfonamide

    [0735] ##STR00066##

    [0736] 4M Lithium borohydride in THF (0.49 mL, 1.960 mmol) was added dropwise to a stirred solution of methyl 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)pentanoate (0.30 g, 0.647 mmol) in THF (6.5 mL) at 0° C. The mixture was stirred for 1 h. Additional lithium borohydride (0.50 mL, 2.00 mmol) was added and mixture was stirred for a further 16 h at RT. The mixture was then quenched with water (10 mL) and stirred at RT for 15 min. The mixture was then partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to give the title compound (0.31 g, 98%) as a colourless oil.

    [0737] LCMS m/z 430.3 (M+Na).sup.+ (ES.sup.+).

    [0738] .sup.1H NMR (DMSO-d.sub.6) δ 7.20-7.15 (m, 4H), 6.91-6.85 (m, 4H), 4.37 (t, J=5.1 Hz, 1H), 4.20 (s, 4H), 3.74 (s, 6H), 3.40-3.32 (m, 2H), 3.02-2.95 (m, 2H), 1.61 (p, J=7.5 Hz, 2H), 1.43-1.26 (m, 4H).

    Intermediate A16: 5-((dimethylamino)methyl)-1-(3-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0739] ##STR00067##

    [0740] Prepared according to the general procedure for 5-((dimethylamino)methyl)-1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A14) from 1-(3-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A6).

    [0741] LCMS m/z 503.2 (M+H).sup.+ (ES.sup.+).

    [0742] .sup.1H NMR (DMSO-d.sub.6) δ 7.05-7.00 (m, 4H), 6.83-6.78 (m, 4H), 6.58 (s, 1H), 4.80 (br s, 1H), 4.25 (t, J=7.0 Hz, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 3.48 (s, 2H), 3.39-3.35 (m, 2H), 2.16 (s, 6H), 1.92 (p, J=6.6 Hz, 2H).

    Intermediate A17: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0743] ##STR00068##

    Step A: 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

    [0744] ##STR00069##

    [0745] A solution of 4-fluoro-1H-pyrazole (2 g, 23.24 mmol), 3,4-dihydro-2H-pyran (9 mL, 99 mmol) and TFA (0.40 mL, 5.19 mmol) in THF (25 mL) was heated to reflux overnight. The reaction was concentrated in vacuo and the crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (4-33 g, 93%) as a pale yellow oil.

    [0746] .sup.1H NMR (CDCl.sub.3) δ 7.48 (d, J=4.7 Hz, 1H), 7.40 (d, J=4.3 Hz, 1H), 5.34-5.24 (m, 1H), 4.07-4.04 (m, 1H), 3.77-3.61 (m, 1H), 2.12-1.94 (m, 3H), 1.76-1.55 (m, 3H).

    Step B: lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate

    [0747] ##STR00070##

    [0748] n-BuLi (2.5 M in THF) (5 mL, 12.50 mmol) was added slowly to a solution of 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2 g, 11.75 mmol) in THF (25 mL) keeping the temperature below −65° C. The mixture was stirred for 1.5 h then SO.sub.2 was bubbled through for 10 min. The mixture was allowed to warm to RT, the solvent evaporated and the residue triturated with MTBE (50 mL) and filtered. The solid was washed with MTBE, isohexane and dried to afford the title compound (1.91 g, 64%) as a white solid.

    [0749] .sup.1H NMR (DMSO-d.sub.6) δ 7.25 (d, J=4.6 Hz, 1H), 6.08 (dd, J=10.2, 2.5 Hz, 1H), 3.93-3.86 (m, 1H), 3.54-3.46 (m, 1H), 2.19-2.08 (m, 1H), 1.98-1.89 (m, 1H), 1.71-1.64 (m, 1H), 1.64-1.51 (m, 1H), 1.51-1.43 (m, 2H).

    Step C: 4-fluoro-N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide

    [0750] ##STR00071##

    [0751] NCS (2.78 g, 20.82 mmol) was added to a suspension of lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (5.00 g, 20.82 mmol) in DCM (100 mL) cooled in an ice bath. The mixture was stirred for 18 h, quenched with water (10 mL) then partitioned between DCM (50 mL) and water (20 mL). The aqueous layer was extracted with DCM (2×100 mL) and the organic layers were dried (MgSO.sub.4) and concentrated in vacuo to ˜100 mL. The solution was added to a mixture of bis(4-methoxybenzyl)amine (5.63 g, 21.86 mmol) and TEA (3-4 mL, 24.39 mmol) in DCM (30 mL) cooled in an ice bath. The mixture was allowed to warm to RT and stirred for 18 h, then partitioned between DCM (60 mL) and water (40 mL). The aqueous layer was extracted with DCM (2×30 mL) and the combined organic layers were dried (MgSO.sub.4) and concentrated to dryness to afford a yellow oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (5.05 g, 40%) as a yellow crystalline solid.

    [0752] LCMS m/z 512.1 (M+Na).sup.+ (ES.sup.+).

    [0753] .sup.1H NMR (DMSO-d.sub.6) δ 7.86 (d, J=4.5 Hz, 1H), 7.03-6.95 (m, 4H), 6.86-6.78 (m, 4H), 5.79 (dd, J=9.6, 2.6 Hz, 1H), 4.42 (d, J=15.4 Hz, 2H), 4.23 (d, J=15.5 Hz, 2H), 3.95-3.80 (m, 1H), 3.72 (s, 6H), 3.61-3.50 (m, 1H), 2.41-2.19 (m, 1H), 2.08-1.93 (m, 1H), 1.93-1.80 (m, 1H), 1.70-1.65 (m, 1H), 1.55-1.44 (m, 2H).

    Step D: 4-fluoro-N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-sulfonamide

    [0754] ##STR00072##

    [0755] HCl (4 M in dioxane, 1 mL, 4.00 mmol) was added to a solution of 4-fluoro-N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (4.25 g, 6.95 mmol) in DCM (50 mL). The mixture was heated at 40° C. for 3 days and concentrated in vacuo. The product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (3.54 g, quantitative yield) as a thick yellow oil.

    [0756] LCMS m/z 512.2 (M+Na).sup.+ (ES.sup.+).

    [0757] .sup.1H NMR (DMSO-d.sub.6) δ 8.30 (d, J=4.6 Hz, 1H), 7.09-7.03 (m, 4H), 6.86-6.81 (m, 4H), 5.43 (dd, J=9.3, 2.5 Hz, 1H), 4.37-4.19 (m, 4H), 3.93-3.87 (m, 1H), 3.73 (s, 6H), 3.70-3.62 (m, 1H), 2.08-1.95 (m, 1H), 1.94-1.81 (m, 2H), 1.74-1.62 (m, 1H), 1.61-1.46 (m, 2H).

    Step E: 4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0758] ##STR00073##

    [0759] Concentrated HCl (10 mL, 120 mmol) was added to 4-fluoro-N,N-bis(4-methoxy-benzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-sulfonamide (3.50 g, 6.86 mmol) in MeOH (80 mL) at RT. The mixture was stirred at RT for 18 h. The methanol was removed in vacuo and the remaining aqueous suspension was quenched with sat aq NaHCO.sub.3 drop-wise to pH 8. EtOAc (50 mL) was added and the organic layer was collected. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were concentrated in vacuo to afford a white solid which was triturated with MTBE (50 mL) to give a first crop of title compound (1.90 g). The filtrate was concentrated to dryness and purified by FC (0-100% EtOAc/isohexane). Both batches were combined to afford the title compound (2.59 g, 92%) as a white solid.

    [0760] LCMS m/z 427.3 (M+Na).sup.+ (ES.sup.+); 404.1 (M−H).sup.− (ES.sup.−).

    [0761] .sup.1H NMR (DMSO-d.sub.6) δ 8.11-7.87 (m, 1H), 7.13-6.99 (m, 4H), 6.87-6.72 (m, 4H), 4.24 (s, 4H), 3.72 (s, 6H). One exchangeable proton not observed.

    Step F: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazol-1-yl)-2-methylpropanoate

    [0762] ##STR00074##

    [0763] 4-Fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1.00 g, 2.466 mmol) and K.sub.2CO.sub.3 (1.10 g, 7.96 mmol) were suspended in dry DMF (45 mL). Methyl 2-bromo-2-methylpropanoate (0.48 mL, 3.71 mmol) was added and the mixture was warmed to 80° C. for 3 h. The reaction mixture was cooled to RT, diluted with water (20 mL), poured onto brine (100 mL) and extracted with MTBE (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (1.22 g, 92%) as a thick colourless oil.

    [0764] LCMS m/z 527.7 (M+Na).sup.+ (ES.sup.+).

    [0765] .sup.1H NMR (DMSO-d.sub.6) δ 8.41 (d, J=4.5 Hz, 1H), 7.09-6.96 (m, 4H), 6.88-6.75 (m, 4H), 4.23 (s, 4H), 3.72 (s, 6H), 3.66 (s, 3H), 1.76 (s, 6H).

    Step G: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0766] ##STR00075##

    [0767] LiBH.sub.4 (4 M solution in THF) (1.81 mL, 7.24 mmol) was added dropwise to a stirred solution of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazol-1-yl)-2-methylpropanoate (1.22 g, 2.413 mmol) in THF (25 mL) at 0° C. The mixture was stirred for 17 h. The mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to afford the title compound (1.01 g, 83%) as a sticky colourless foam.

    [0768] LCMS m/z 500.1 (M+Na).sup.+ (ES.sup.+).

    [0769] .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J=4.6 Hz, 1H), 7.10-7.00 (m, 4H), 6.87-6.78 (m, 4H), 5.18-5.09 (m, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 3.55 (d, J=3.8 Hz, 2H), 1.44 (s, 6H).

    Intermediate A18: 4-fluoro-1-(3-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0770] ##STR00076##

    [0771] 4-Fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A17, Step E) (0.99 g, 2.442 mmol) and K.sub.2CO.sub.3 (1.00 g, 7.24 mmol) were suspended in dry MeCN (10 mL) under a nitrogen atmosphere. 3-Bromopropan-1-ol (0.30 mL, 3.32 mmol) was added and the mixture was heated to 50° C. for 19 h. After cooling to RT, water (20 mL) and EtOAc (20 mL) were added and the layers separated. The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.88 g, 69%) as a thick colourless oil.

    [0772] LCMS m/z 486.1 (M+Na).sup.+ (ES.sup.+).

    [0773] .sup.1H NMR (DMSO-d.sub.6) δ 8.13 (d, J=4.7 Hz, 1H), 7.09-7.00 (m, 4H), 6.86-6.75 (m, 4H), 4.66 (t, J=5.0 Hz, 1H), 4.24 (s, 4H), 4.17 (t, J=7.1 Hz, 2H), 3.72 (s, 6H), 3.40 (td, J=6.1, 4.9 Hz, 2H), 1.90 (p, J=6.5 Hz, 2H).

    Intermediate A19: 4-fluoro-1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0774] ##STR00077##

    [0775] Prepared according to the general procedure for 4-fluoro-1-(3-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A18) from 4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A17, Step E) and 2-bromoethanol to afford the title compound (0.88 g, 70%) as a thick colourless oil.

    [0776] LCMS m/z 472.1 (M+Na).sup.+ (ES.sup.+).

    [0777] .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J=4.6 Hz, 1H), 7.06-6.99 (m, 4H), 6.85-6.80 (m, 4H), 5.03 (t, J=5.3 Hz, 1H), 4.23 (s, 4H), 4.17 (t, J=5.4 Hz, 2H), 3.75 (q, J=5.4 Hz, 2H), 3.72 (s, 6H).

    Intermediate A20: 3-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)benzene-sulfonamide

    [0778] ##STR00078##

    [0779] A solution of 2-(3-(benzylthio)phenyl)ethanol (1.21 g, 4.95 mmol) in MeCN (25 mL), AcOH (0.3 mL) and water (0.6 mL) was cooled to −10° C. (ice/acetone bath). 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (1.50 g, 7.61 mmol) was then added and the mixture was stirred at −10° C. for 4 h. The mixture was then partitioned between DCM (50 mL) and water (50 mL) and the organic layer was collected. The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a thick yellow paste. The thick yellow paste was suspended in DCM (25 mL) and cooled with an ice bath. Bis(4-methoxybenzyl)amine (1.30 g, 5.05 mmol) was added, followed by TEA (1.5 mL, 10.76 mmol). The mixture was stirred for 17 h, quenched with water (20 mL) then partitioned between DCM (50 mL) and water (40 mL). The organic phase was collected, dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown oil. The brown oil was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (1.40 g, 60%) as a white solid.

    [0780] LCMS m/z 464.1 (M+Na).sup.+ (ES.sup.+).

    [0781] .sup.1H NMR (DMSO-d.sub.6) δ 7.72-7.61 (m, 2H), 7.57-7.44 (m, 2H), 7.02-6.93 (m, 4H), 6.83-6.75 (m, 4H), 4.69 (t, J=5.1 Hz, 1H), 4.18 (s, 4H), 3.71 (s, 6H), 3.63 (td, J=6.7, 5.0 Hz, 2H), 2.80 (t, J=6.7 Hz, 2H).

    Intermediate A21: 1-(4-hydroxytetrahydrofuran-3-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0782] ##STR00079##

    [0783] N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1 g, 2.58 mmol) and potassium carbonate (1.00 g, 7.24 mmol) were suspended in dry MeCN (10 mL). 3,6-Dioxabicyclo[3.1.0]hexane (0.3 mL, 4.18 mmol) was added and the mixture was heated to reflux overnight. Further 3,6-dioxabicyclo[3.1.0]hexane (0.3 mL, 4.18 mmol) was added and the mixture was heated for a further 1 h. The mixture was cooled to RT and partitioned between DCM (20 mL) and water (10 mL). The organic phase was dried by passing through a hydrophobic frit then concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford an enantiomeric mixture of the trans-isomers of the title compound (0.96 g, 78%) as a clear colourless oil that crystallized on standing.

    [0784] LCMS m/z 474.6 (M+H).sup.+ (ES.sup.+).

    [0785] .sup.1H NMR (CDCl.sub.3) δ 7.51 (d, J=2.4 Hz, 1H), 7.11-7.02 (m, 4H), 6.82-6.74 (m, 4H), 6.66 (d, J=2.4 Hz, 1H), 4.80-4.76 (m, 1H), 4.55-4.51 (m, 1H), 4.37-4.25 (m, 5H), 4.14 (dd, J=10.1, 5.3 Hz, 1H), 4.09 (dd, J=10.1, 3.6 Hz, 1H), 3.82-3.79 (m, 1H), 3.79 (s, 6H). One exchangeable proton was not observed.

    Intermediate A22: 1-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0786] ##STR00080##

    Step A: 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-carboxylic acid

    [0787] ##STR00081##

    [0788] NaOH (0.780 g, 19.50 mmol) was added to a solution of dihydro-2H-pyran-4(3H)-one (0.360 mL, 3.90 mmol) and N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (1.5 g, 3.87 mmol) in THF (25 mL) at 0° C. and the solution stirred for 10 min. CHCl.sub.3 (1.60 mL, 19.84 mmol) was added dropwise to the solution and the mixture was allowed to warm to RT and stirred overnight. The mixture was diluted with water (150 mL) and acidified with aq 1 M HCl (100 mL). The mixture was extracted with DCM (2×150 mL), the organic phases combined, dried (MgSO.sub.4), filtered, directly loaded onto silica and purified by FC (0-100% EtOAc/isohexane) to afford the title compound (302 mg, 14%) as a white solid.

    [0789] LCMS m/z 538.4 (M+Na).sup.+ (ES.sup.+).

    [0790] .sup.1H NMR (DMSO-d.sub.6) δ 13.55 (br s, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.05-6.97 (m, 4H), 6.84-6.79 (m, 5H), 4.19 (s, 4H), 3.74-3.66 (m, 8H), 2.47-2.33 (m, 4H). Two aliphatic protons overlapped with water in DMSO-d.sub.6 signal.

    Step B: methyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-carboxylate

    [0791] ##STR00082##

    [0792] 2M TMS-diazomethane in diethyl ether (0.293 mL, 0.586 mmol) was added to a solution of 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-carboxylic acid (302 mg, 0.586 mmol) in MeOH/toluene (2:3, 10 mL) at 0° C. and the reaction was stirred for 1 h. Additional 2M TMS-diazomethane in diethyl ether (0.293 mL, 0.586 mmol) was added and the mixture stirred for 3 h. The mixture was partitioned between water (20 mL) and EtOAc (20 mL), the organic phase separated, the aqueous further extracted with EtOAc (2×50 mL), the organic phase combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (0.25 g, 74%) as a colourless oil.

    [0793] LCMS m/z 552.3 (M+Na).sup.+ (ES.sup.+).

    [0794] .sup.1H NMR (DMSO-d.sub.6) δ 8.27 (d, J=2.6 Hz, 1H), 7.06-7.00 (m, 4H), 6.86 (d, J=2.5 Hz, 1H), 6.84-6.79 (m, 4H), 4.19 (s, 4H), 3.74-3.67 (m, 8H), 3.65 (s, 3H), 3.39-3.33 (m, 2H), 2.49-2.43 (m, 2H), 2.42-2.35 (m, 2H).

    Step C: 1-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0795] ##STR00083##

    [0796] LiBH4 (4 M in THF) (0.36 mL, 1.440 mmol) was added to a solution of methyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-carboxylate (254 mg, 0.480 mmol) in anhydrous THF (10 mL) at 0° C. The reaction was stirred for 3 h. The reaction mixture was partition between EtOAc (50 mL) and water (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc (2×50 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (214 mg, 83%) as a white sticky foam.

    [0797] LCMS m/z 524.4 (M+Na).sup.+ (ES.sup.+).

    [0798] .sup.1H NMR (DMSO-d.sub.6) δ 8.08 (d, J=2.5 Hz, 1H), 7.05-6.99 (m, 4H), 6.84-6.78 (m, 4H), 6.76 (d, J=2.4 Hz, 1H), 5.12 (t, J=5.6 Hz, 1H), 4.20 (s, 4H), 3.75-3.68 (m, 8H), 3.51 (d, J=5.9 Hz, 2H), 3.27-3.19 (m, 2H), 2.34-2.25 (m, 2H), 1.98-1.92 (m, 2H).

    Intermediate A23: 1-((3-hydroxycyclopentyl)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0799] ##STR00084##

    Step A: methyl 3-oxocyclopentanecarboxylate

    [0800] ##STR00085##

    [0801] A solution of 3-oxocyclopentanecarboxylic acid (1 g, 7.80 mmol, 1 eq) in MeOH (10 mL) was cooled to 0° C. H.sub.2SO.sub.4 (78 mg, 98 wt. % in aqueous solution, 0.1 eq) was added to the above mixture. Then the resulting mixture was heated to 80° C. and stirred for 6 h. The mixture was concentrated in vacuum. The residue was quenched with H.sub.2O (30 mL) and extracted with EtOAc (40 mL×3). The organic phases were washed with the aqueous saturated NaHCO.sub.3 solution (50 mL) and H.sub.2O (50 mL). Then the organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (petroleum ether:EtOAc 10:1 to 1:1) to give the title compound (1 g, 90% yield) as a yellow oil.

    [0802] .sup.1H NMR (CDCl.sub.3): δ 3.72 (s, 3H), 3.16-3.10 (m, 1H), 2.53-2.44 (m, 2H) and 2.43-2.12 (m, 4H).

    Step B: 3-(hydroxymethyl)cyclopentanol

    [0803] ##STR00086##

    [0804] To a solution of LiAlH.sub.4 (721 mg, 18.99 mmol, 3 eq) in THF (20 mL) was added dropwise a solution of methyl 3-oxocyclopentanecarboxylate (900 mg, 6.33 mmol, 1 eq) in THF (5 mL) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 1 h. The mixture was warmed to 20° C. and stirred for 12 h. The reaction mixture was diluted with THF (20 mL), and then the mixture was quenched with sodium sulfate decahydrate (1 g). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc 3:1 to 0:1) to give the title compound (550 mg, 75% yield) as a yellow oil.

    [0805] .sup.1H NMR (DMSO-d.sub.6): δ 4.43-4.38 (m, 2H), 4.05-4.02 (m, 1H), 3.33-3.31 (m, 1H), 3.25-3.22 (m, 1H), 1.96-1.81 (m, 2H), 1.61-1.55 (m, 2H), 1.47-1.36 (m, 2H) and 1.16-1.09 (m, 1H).

    Step C: (3-hydroxycyclopentyl)methyl methanesulfonate

    [0806] ##STR00087##

    [0807] To a solution of 3-(hydroxymethyl)cyclopentanol (500 mg, 4.30 mmol, 1 eq) and TEA (871 mg, 8.61 mmol, 2 eq) in DCM (10 mL) was added a solution of MsCl (493 mg, 4.30 mmol, 1 eq) in DCM (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The mixture was quenched with ice water (20 mL) and extracted with DCM (20 mL×3). The organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum to give the title compound (0.6 g, crude) as a yellow oil, which was used directly in the next step.

    Step D: 1-((3-hydroxycyclopentyl)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0808] ##STR00088##

    [0809] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (1.20 g, 3.09 mmol, 1 eq) in DMF (10 mL) was added K.sub.2CO.sub.3 (1.07 g, 7.72 mmol, 2.5 eq) and (3-hydroxycyclopentyl)methyl methanesulfonate (600 mg, 3.09 mmol, 1 eq) at 20° C. The mixture was heated to 50° C., and stirred at 50° C. for 16 h. The mixture was quenched with H.sub.2O (50 mL) and extracted with DCM (50 mL×3). The organic phases were washed with brine (150 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc 2:1 to 0:1) to give the title compound (400 mg, two steps yield: 19%, 75% purity in LCMS) as a yellow oil.

    [0810] LCMS: m/z 486.0 (M+H).sup.+ (ES.sup.+).

    [0811] .sup.1H NMR (DMSO-d.sub.6): δ 7.97 (d, 1H), 7.03-7.00 (m, 4H), 6.82-6.79 (m, 4H), 6.70 (d, 1H), 4.59 (d, 1H), 4.21-4.17 (m, 6H), 3.71 (s, 6H), 3.70-3.68 (m, 1H), 1.86-1.80 (m, 1H), 1.68-1.60 (m, 1H), 1.57-1.49 (m, 2H), 1.47-1.37 (m, 2H) and 1.28-1.22 (m, 1H).

    Intermediate B1: 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0812] ##STR00089##

    [0813] A mixture of 5-bromo-2,3-dihydro-1H-inden-4-amine (10 g, 47.2 mmol), (2-fluoro-pyridin-4-yl)boronic acid (6.64 g, 47.2 mmol) and K.sub.2CO.sub.3 (19.6 g, 142 mmol) in dioxane (200 mL) and water (50 mL) was degassed with N.sub.2. PdCl.sub.2(dppf) (1.7 g, 2.32 mmol) was added and the reaction heated at 80° C. for 20 h. After cooling at RT, the reaction was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (8.64 g, 79%) as a white solid.

    [0814] LCMS m/z 299.1 (M+H).sup.+ (ES.sup.+).

    [0815] .sup.1H NMR (DMSO-d.sub.6) δ 8.24 (d, J=5.2 Hz, 1H), 7.38 (ddd, J=5.2, 2.2, 1.4 Hz, 1H), 7.16 (d, J=1.4 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 4.82 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.5 Hz, 2H).

    Intermediate B2: 5-(2-fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

    [0816] ##STR00090##

    Step A: N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

    [0817] ##STR00091##

    [0818] Nitric acid (150 mL, 2350 mmol) was slowly added to sulfuric acid (150 mL) cooled to 0° C. while keeping the temperature below 20° C. The mixture was stirred for 10 min and added dropwise to a stirred mixture of N-(6-bromo-2,3-dihydro-1H-inden-5-yl)-acetamide (58 g, 228 mmol) in AcOH (300 mL) and sulfuric acid (150 mL), keeping the temperature below 30° C. The mixture was stirred at RT for 4 h and then poured onto ice/water (4.5 L total volume, 2.5 kg ice) and left to stand at RT for 18 h. The solid was filtered, washed with water (2.5 L), and dried to afford the title compound (55 g, 80%) as an ochre powder. LCMS m/z 299.0/301.0 (M+H).sup.+ (ES.sup.+).

    [0819] .sup.1H NMR (DMSO-d.sub.6) δ 9.99 (s, 1H), 7.85 (s, 1H), 3.01-2.88 (m, 4H), 2.07 (p, J=7.5 Hz, 2H), 2.00 (s, 3H).

    Step B: N-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

    [0820] ##STR00092##

    [0821] A mixture of N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (30.0 g, 100 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.02 mL, 100 mmol) and K.sub.2CO.sub.3 (34.7 g, 251 mmol) in dioxane (500 mL) and H.sub.2O (140 mL) was degassed with N.sub.2 for 15 min. PdCl.sub.2(dppf).DCM (4.10 g, 5.01 mmol) was added and the reaction was heated at 100° C. for 16 h, diluted with brine (300 mL) and extracted with EtOAc (2×800 mL). The organic layers were dried (MgSO.sub.4) and evaporated. The residue was triturated with EtOAc/isohexanes (1:1 mixture, 400 mL) and the resultant solid was filtered, rinsing with hexanes, and dried in vacuo to afford the title compound (15.33 g, 56%) as a brown solid.

    [0822] LCMS m/z 235.2 (M+H).sup.+ (ES.sup.+).

    [0823] .sup.1H NMR (DMSO-d.sub.6) δ 9.65 (s, 1H), 7.41 (s, 1H), 2.98-2.87 (m, 4H), 2.20 (s, 3H), 2.07-2.03 (m, 2H), 1.99 (s, 3H).

    Step C: 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine

    [0824] ##STR00093##

    [0825] N-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (15.33 g, 65.4 mmol) was suspended in a mixture of EtOH (126 mL) and conc. aq HCl (126 mL). The mixture was heated to reflux overnight and concentrated in vacuo. The residue was basified by portionwise addition of 2 M aq NaOH (˜500 mL). The aqueous layer was extracted with DCM (5×200 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (15.18 g, 84%) as a brown solid.

    [0826] LCMS m/z 193.4 (M+H).sup.+ (ES.sup.+).

    [0827] .sup.1H NMR (DMSO-d.sub.6) δ 7.21 (s, 1H), 6.61 (s, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.16 (s, 3H), 2.00-1.94 (m, 2H).

    Step D: 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene

    [0828] ##STR00094##

    [0829] A solution of 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine (4.9 g, 20.39 mmol) and isopentyl nitrite (3.0 mL, 22.33 mmol) in MeCN (400 mL) was heated to 55° C. whereupon CuBr.sub.2 (4.56 g, 20.39 mmol) was added. The mixture was heated to 70° C. and stirred for 1 h. The reaction was allowed to cool to RT and 1 M aq HCl (200 mL) was added. The reaction mixture was extracted with DCM (3×200 mL). The organic phases were concentrated in vacuo and the crude product was purified by FC (0-20% EtOAc/isohexane) to afford the title compound (3.2 g, 60%) as a pale yellow solid.

    [0830] LCMS m/z 279.2 (M+Na).sup.+ (ES.sup.+).

    [0831] .sup.1H NMR (DMSO-d.sub.6) δ 7.50 (s, 1H), 2.94-2.86 (m, 4H), 2.41 (s, 3H), 2.09 (p, J=7.6 Hz, 2H).

    Step E: 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine

    [0832] ##STR00095##

    [0833] A stirred mixture of 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (8.42 g, 32.9 mmol), sat aq NH.sub.4Cl (50 mL) and iron powder (7.34 g, 132 mmol) in 3:2 EtOH/water (80 mL) was stirred at 80° C. for 2 h. After cooling to RT, the reaction was diluted with EtOAc (20 mL) and filtered through a pad of Celite. The filtrate was diluted with water (10 mL). The layers were separated and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (6.52 g, 75%) as a pink solid.

    [0834] LCMS m/z 226/227 (M+H).sup.+ (ES.sup.+).

    [0835] .sup.1H NMR (DMSO-d.sub.6) δ 6.48 (s, 1H), 4.94 (br s, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.24 (s, 3H), 2.02-1.95 (m, 2H).

    Step F: 5-(2-fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

    [0836] ##STR00096##

    [0837] To a solution of 4-bromo-2-fluoropyridine (0.905 mL, 8.81 mmol) in dioxane (60 mL) was added B.sub.2Pin.sub.2 (2.460 g, 9.69 mmol), KOAc (3.46 g, 35.2 mmol) and Pd(dppf)Cl.sub.2.DCM (0.360 g, 0.440 mmol). The reaction mixture was degassed with N.sub.2 and heated at 100° C. for 3 h. After cooling to RT, a solution of 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (2.096 g, 8.81 mmol) in dioxane (20 mL) was added followed by a solution of K.sub.2CO.sub.3 (4.87 g, 35.2 mmol) in water (35 mL). The reaction was heated at 100° C. for 18 h. After cooling, EtOAc (150 mL) was added and the organics were washed with water (2×100 mL) and brine (100 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-30% EtOAc/isohexane) to afford the title compound (1.06 g, 47%) as a pale yellow solid.

    [0838] LCMS m/z 243.2 (M+H).sup.+ (ES.sup.+).

    [0839] .sup.1H NMR (DMSO-d.sub.6) δ 8.29 (d, J=5.1 Hz, 1H), 7.16-7.11 (m, 1H), 6.97 (s, 1H), 6.46 (s, 1H), 4.30 (s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 1.99 (p, J=7.4 Hz, 2H), 1.88 (s, 3H).

    Intermediate B3: 3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenol

    [0840] ##STR00097##

    [0841] PdCl.sub.2(dppf) (0.10 g, 0.137 mmol) was added to 5-bromo-2,3-dihydro-1H-inden-4-amine (0.769 g, 3.63 mmol), (3-hydroxyphenyl)boronic acid (0.5 g, 3.63 mmol) and K.sub.2CO.sub.3 (1.50 g, 10.85 mmol) in dioxane (200 mL) and water (50 mL) previously degassed with N.sub.2. The reaction was heated at 80° C. for 20 h. The mixture was cooled to RT and partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was dried (MgSO.sub.4), and evaporated. The residue was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (0.65 g, 79%) as a white solid.

    [0842] LCMS m/z 226.2 (M+H).sup.+ (ES.sup.+).

    [0843] .sup.1H NMR (DMSO-d.sub.6) δ 9.44 (s, 1H), 7.23 (t, J=7.9 Hz, 1H), 6.83-6.75 (m, 3H), 6.75-6.69 (m, 1H), 6.56 (d, J=7.5 Hz, 1H), 4.41 (s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.3 Hz, 2H), 2.02 (p, J=7.4 Hz, 2H).

    Intermediate B4: 4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylaniline

    [0844] ##STR00098##

    [0845] Prepared according to the general procedure of 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 2-bromo-4-fluoro-6-isopropylaniline and (2-fluoropyridin-4-yl)boronic acid to afford the title compound (626 mg, 74%) as a purple gum.

    [0846] LCMS m/z 249.0 (M+H).sup.+ (ES.sup.+).

    [0847] .sup.1H NMR (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).

    Intermediate B: 5-(2,3-difluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0848] ##STR00099##

    [0849] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-2,3-dihydro-1H-inden-4-amine and (2,3-difluoropyridin-4-yl)boronic acid to afford the title compound (104 mg, 30%) as an off-white solid.

    [0850] LCMS m/z 247.4 (M+H).sup.+ (ES.sup.+).

    [0851] .sup.1H NMR (DMSO-d.sub.6) δ 8.02 (d, J=5.0 Hz, 1H), 7.31 (t, J=4.9 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 4.85 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.4 Hz, 2H).

    Intermediate B6: 6-fluoro-5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0852] ##STR00100##

    Step A: N-(6-fluoro-2,3-dihydro-1H-inden-5-yl)acetamide

    [0853] ##STR00101##

    [0854] AcCl (1.8 mL, 25.3 mmol) was added dropwise to a solution of 6-fluoro-2,3-dihydro-1H-inden-5-amine (3.50 g, 23.15 mmol) and TEA (5.00 mL, 35.9 mmol) in DCM (40 mL) cooled with an ice bath. The mixture was warmed to RT and partitioned between EtOAc (200 mL) and 1 M aq HCl (100 mL), the organic layer separated, washed with water (100 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was triturated with isohexane, filtered and dried to afford the title compound (4.04 g, 89%) as a white solid.

    [0855] LCMS m/z 194.0 (M+H).sup.+ (ES.sup.+).

    [0856] .sup.1H NMR (CDCl.sub.3) δ 8.09 (d, J=7.5 Hz, 1H), 7.28 (br s, 1H), 6.95 (d, J=10.9 Hz, 1H), 2.93-2.83 (m, 4H), 2.22 (s, 3H), 2.15-2.05 (m, 2H).

    Step B: N-(6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

    [0857] ##STR00102##

    [0858] Nitric acid (15 mL, 235 mmol) was added dropwise to sulfuric acid (15 mL) cooled to 0° C., keeping the temperature below 20° C. This mixture was stirred for 10 min then added dropwise to a stirred suspension of N-(6-fluoro-2,3-dihydro-1H-inden-5-yl)-acetamide (4 g, 20.70 mmol) in AcOH (30 mL) and sulfuric acid (15 mL) keeping the temperature below 35° C. The mixture was stirred at RT for 4 h then poured into ice/water (300 mL) and extracted with EtOAc (300 mL). The organic layer was washed with sat aq NaHCO.sub.3 (200 mL), water (50 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was triturated with TBME (15 mL), filtered and dried to afford the title compound (2.54 g, 51%) as a solid.

    [0859] LCMS m/z 238.9 (M+H).sup.+ (ES.sup.+).

    [0860] .sup.1H NMR (CDCl.sub.3) δ 7.62 (br s, 1H), 7.26 (d, J=9.1 Hz, 1H), 3.15 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 2.22 (s, 3H), 2.17 (p, J=7.5 Hz, 2H).

    Step C: 6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-amine

    [0861] ##STR00103##

    [0862] A mixture of N-(6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (2.53 g, 10.62 mmol) in conc. H.sub.2SO.sub.4 (1 mL) and EtOH (25 mL) was heated under reflux for 24 h. The solvent was evaporated, water (20 mL) added, the mixture basified with aq 50% NaOH solution and extracted with DCM (2×100 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered and evaporated to afford the title compound (1.89 g, 90%) as an orange solid.

    [0863] LCMS m/z 196.9 (M+H).sup.+ (ES.sup.+).

    [0864] .sup.1H NMR (CDCl.sub.3) δ 7.12 (d, J=10.3 Hz, 1H), 5.81 (br s, 2H), 3.33 (t, J=7.4 Hz, 2H), 2.87 (t, J=7.4 Hz, 2H), 2.14-2.06 (m, 2H).

    Step D: 5-bromo-6-fluoro-4-nitro-2,3-dihydro-1H-indene

    [0865] ##STR00104##

    [0866] 6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-amine (1.88 g, 9.58 mmol) was added portion-wise over 20 min to a stirred mixture of isopentyl nitrite (1.70 mL, 12.65 mmol) and Cu(II)Br (2.6 g, 11.64 mmol) in MeCN (80 mL) at 60° C. After addition, the mixture was heated for 1 h, cooled and partitioned between aq 1 M HCl (200 mL) and DCM (300 mL). The organic layer was washed with water (100 mL), dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by FC (0-15% EtOAc/isohexane) to afford the title compound (2.21 g, 62%) as yellow solid.

    [0867] LCMS m/z 196.9 (M+H).sup.+ (ES.sup.+).

    [0868] .sup.1H NMR (CDCl.sub.3) δ 7.18 (d, J=7.8 Hz, 1H), 3.07-2.96 (m, 4H), 2.21 (p, J=7.6 Hz, 2H).

    Step E: 5-bromo-6-fluoro-2,3-dihydro-1H-inden-4-amine

    [0869] ##STR00105##

    [0870] A mixture of 5-bromo-6-fluoro-4-nitro-2,3-dihydro-1H-indene (2.2 g, 5.92 mmol), NH.sub.4Cl (450 mg, 8.41 mmol) and Fe powder (2 g, 35.8 mmol) in EtOH (20 mL) and water (10 mL) was heated at 80° C. for 24 h. The mixture was diluted with EtOAc (50 mL), filtered through Celite and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo, partitioned between EtOAc (100 mL) and aq sat NaHCO.sub.3 solution (20 mL), the organic layer washed with water (20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by FC (0-30% DCM/isohexane) to afford the title compound (1.14 g, 81%) as a pale yellow solid.

    [0871] LCMS m/z 229.9/231.8 (M+H).sup.+ (ES.sup.+).

    [0872] .sup.1H NMR (CDCl.sub.3) δ 6.48 (d, J=8.4 Hz, 1H), 4.15 (br s, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.19-2.11 (m, 2H).

    Step F: 6-fluoro-5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0873] ##STR00106##

    [0874] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-6-fluoro-2,3-dihydro-1H-inden-4-amine and (2-fluoropyridin-4-yl)boronic acid to afford the title compound (0.33 g, 57%) as a pale yellow solid.

    [0875] LCMS m/z 247.3 (M+H).sup.+ (ES.sup.+).

    [0876] .sup.1H NMR (DMSO-d.sub.6) δ 8.29 (d, J=5.1 Hz, 1H), 7.31-7.23 (m, 1H), 7.10 (s, 1H), 6.39 (d, J=9.9 Hz, 1H), 4.96 (s, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.69-2.62 (m, 2H), 2.02 (p, J=7.5 Hz, 2H).

    [0877] Intermediate B7: 5-(2-fluoropyridin-4-yl)-6-methyl-2,3-dihydrobenzofuran-4-amine

    ##STR00107##

    Step A: N-(3-methoxy-5-methylphenyl)pivalamide

    [0878] ##STR00108##

    [0879] Pivaloyl chloride (4.7 mL, 38.2 mmol) was added dropwise to a solution of 3-methoxy-5-methylaniline (5 g, 36.4 mmol) and TEA (6 mL, 43.0 mmol) in DCM (100 mL) cooled with an ice bath. The mixture was warmed to RT, stirred for 2 h then partitioned between DCM (100 mL) and aq 1 M HCl (100 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered and evaporated. The residue was purified by FC (0-10% DCM/TBME) to afford the title compound (6.91 g, 81%) as an off white solid.

    [0880] LCMS m/z 222.1 (M+H).sup.+ (ES.sup.+).

    [0881] .sup.1H NMR (CDCl.sub.3) δ 7.27 (br s, 1H), 7.17 (t, J=2.2 Hz, 1H), 6.87-6.84 (br s, 1H), 6.52-6.50 (br m, 1H), 3.81 (s, 3H), 2.32 (s, 3H), 1.33 (s, 9H).

    Step B: N-(2-(2-hydroxyethyl)-3-methoxy-5-methylphenyl)pivalamide

    [0882] ##STR00109##

    [0883] 2.5M BuLi (27 mL, 67.5 mmol) in hexane was added dropwise to a solution of N-(3-methoxy-5-methylphenyl)pivalamide (5.90 g, 26.7 mmol) in THF (100 mL) cooled in an ice bath. The mixture was stirred for 2 h, 2.5-3.3 M oxirane (16.00 mL, 40.0 mmol) in THF was added and the mixture allowed to warm to RT overnight. The mixture was quenched with aq. NH.sub.4Cl solution (20 mL), the solvent evaporated and the residue partitioned between EtOAc (100 mL) and water (30 mL). The organic layer was separated, dried (MgSO.sub.4), filtered, evaporated and the residue was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (5.64 g, 75%) as an orange solid.

    [0884] LCMS m/z 266.1 (M+H).sup.+ (ES.sup.+).

    [0885] .sup.1H NMR (CDCl.sub.3) δ 8.75 (s, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 3.94-3.88 (m, 2H), 3.81 (s, 3H), 2.86 (t, 2H), 2.35 (s, 3H), 1.96-1.91 (br s, 1H), 1.33 (s, 9H).

    Step C: 6-methyl-2,3-dihydrobenzofuran-4-amine

    [0886] ##STR00110##

    [0887] A mixture of N-(2-(2-hydroxyethyl)-3-methoxy-5-methylphenyl)pivalamide (5.62 g, 21.18 mmol) in conc. HBr (50 mL) was heated at 100° C. for 5 h. The mixture was cooled in an ice bath, the pH adjusted to 9 with solid NaOH and extracted with EtOAc (200 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered, concentrated in vacuo and the residue purified by FC (0-40% EtOAc/isohexane) to afford the title compound (1.67 g, 51%) as an oil.

    [0888] LCMS m/z 150.0 (M+H).sup.+ (ES.sup.+).

    [0889] .sup.1H NMR (CDCl.sub.3) δ 6.14 (s, 1H), 6.08 (s, 1H), 4.60 (t, J=8.6 Hz, 2H), 3.55 (br s, 2H), 3.00 (t, J=8.6 Hz, 2H), 2.24 (s, 3H).

    Step D: N-(6-methyl-2,3-dihydrobenzofuran-4-yl)acetamide

    [0890] ##STR00111##

    [0891] AcCl (900 μL, 12.66 mmol) was added dropwise to a solution of 6-methyl-2,3-dihydrobenzofuran-4-amine (1.75 g, 11.73 mmol) and TEA (2.50 mL, 17.94 mmol) in DCM (25 mL) cooled in an ice bath. The mixture was warmed to RT and partitioned between EtOAc (100 mL) and aq 1 M HCl (50 mL). The organic layer was separated, washed with water (50 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was triturated with TBME/isohexane, filtered and dried to afford the title compound (1.87 g, 81%) as a white solid.

    [0892] LCMS m/z 192.0 (M+H).sup.+ (ES.sup.+).

    [0893] .sup.1H NMR (CDCl.sub.3) δ 7.05 (s, 1H), 6.93 (br s, 1H), 6.47 (s, 1H), 4.60 (t, J=8.6 Hz, 2H), 3.11 (t, J=8.6 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H).

    Step E: N-(5-bromo-6-methyl-2,3-dihydrobenzofuran-4-yl)acetamide

    [0894] ##STR00112##

    [0895] A mixture of N-(6-methyl-2,3-dihydrobenzofuran-4-yl)acetamide (1.85 g, 9.67 mmol), PTSA (1.00 g, 5.26 mmol) and Pd(OAc).sub.2 (0.109 g, 0.484 mmol) in toluene (25 mL) was stirred at RT under air for 10 min, then NBS (1.8 g, 10.11 mmol) was added in one portion and the reaction was stirred for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with sat aq NaHCO.sub.3 (50 mL). The organic phase was separated, washed with aq 20% Na.sub.2S.sub.2O.sub.3 (50 mL), water (30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was triturated with TBME (40 mL), filtered and dried to afford the title compound (2.15 g, 74%) as an off white solid.

    [0896] LCMS m/z 269.9/271.9 (M+H).sup.+ (ES.sup.+).

    [0897] .sup.1H NMR (CDCl.sub.3) δ 7.19 (s, 1H), 6.63 (s, 1H), 4.60 (t, J=8.7 Hz, 2H), 3.20 (t, J=8.7 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H).

    Step F: 5-bromo-6-methyl-2,3-dihydrobenzofuran-4-amine

    [0898] ##STR00113##

    [0899] A mixture of N-(5-bromo-6-methyl-2,3-dihydrobenzofuran-4-yl)acetamide (2.14 g, 7.92 mmol) in sulfuric acid (1 mL) and MeOH (20 mL) was heated under reflux for 24 h. The solvent was evaporated in vacuo, water (20 mL) added, the mixture basified with aq 50% NaOH solution and extracted with DCM (2×100 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered and evaporated to afford the title compound (1.43 g, 75%) as an off white solid.

    [0900] LCMS m/z 227.9/229.8 (M+H)+ (ES+).

    [0901] .sup.1H NMR (CDCl.sub.3) δ 6.25 (s, 1H), 4.62 (t, J=8.6 Hz, 2H), 4.36 (br s, 2H), 3.07 (t, J=8.6 Hz, 2H), 2.34 (s, 3H).

    Step G: 5-(2-fluoropyridin-4-yl)-6-methyl-2,3-dihydrobenzofuran-4-amine

    [0902] ##STR00114##

    [0903] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-6-methyl-2,3-dihydrobenzo-furan-4-amine and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford the title compound (234 mg, 72%) as an off-white solid.

    [0904] LCMS m/z 245.3 (M+H).sup.+ (ES.sup.+).

    [0905] .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J=5.0 Hz, 1H), 7.15-7.12 (m, 1H), 6.97-6.95 (m, 1H), 6.03 (s, 1H), 4.55 (s, 2H), 4.50 (t, J=8.6 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H), 1.87 (s, 3H).

    Intermediate B8: 5-(2-fluoro-6-methylpyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0906] ##STR00115##

    [0907] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-2,3-dihydro-1H-inden-4-amine and 2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford the title compound (289 mg, 82%) as an off-white solid.

    [0908] LCMS m/z 243.3 (M+H).sup.+ (ES.sup.+).

    [0909] .sup.1H NMR (DMSO-d.sub.6) δ 7.23 (s, 1H), 6.92 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 4.79 (s, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.45 (s, 3H), 2.03 (p, J=7.3 Hz, 2H).

    Intermediate B9: 5-(2,5-difluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0910] ##STR00116##

    [0911] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-2,3-dihydro-1H-inden-4-amine and (2,5-difluoropyridin-4-yl)boronic acid to afford the title compound (0.18 g, 24%) as a yellow solid.

    [0912] LCMS m/z 247.0 (M+H).sup.+ (ES.sup.+).

    [0913] .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (s, 1H), 7.28-7.04 (m, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 4.83 (s, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.3 Hz, 2H), 2.02 (p, J=7.6 Hz, 2H).

    Intermediate B10: 5-(2,6-difluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0914] ##STR00117##

    [0915] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-2,3-dihydro-1H-inden-4-amine and (2,6-difluoropyridin-4-yl)boronic acid to afford the title compound (713 mg, 82%) as a white solid.

    [0916] LCMS m/z 246.8 (M+H).sup.+ (ES.sup.+).

    [0917] .sup.1H NMR (CDCl.sub.3) δ 7.00-6.97 (m, 3H), 6.78 (d, J=7.7 Hz, 1H), 3.76 (s, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.18 (p, J=7.5 Hz, 2H).

    Intermediate B11: 5-(2-fluoro-3-methylpyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0918] ##STR00118##

    [0919] To a solution of 4-bromo-2-fluoro-3-methylpyridine (0.510 g, 2.68 mmol) in dioxane (10 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.750 g, 2.95 mmol), potassium acetate (1.054 g, 10-74 mmol), and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.110 g, 0.134 mmol). The reaction mixture was degassed (N.sub.2, 5 min) and evacuated and backfilled with N.sub.2 (×3) and stirred at 100° C. for 2 h. The reaction mixture was cooled to RT. A solution of 5-bromo-2,3-dihydro-1H-inden-4-amine (0.569 g, 2.68 mmol) in dioxane (10 mL) was added followed by a solution of potassium carbonate (1.484 g, 10.74 mmol) in water (3 mL). The temperature was increased to 100° C. and the reaction was stirred for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (30 mL) and washed with water (2×30 mL) and brine (30 mL). The organic extract was dried (phase separator) and concentrated in vacuo. The crude product was purified by FC (0-40% EtOAc/isohexane) to afford the title compound (0.43 g, 62%) as a pale orange solid.

    [0920] LCMS m/z 243.3 (M+H).sup.+ (ES.sup.+).

    [0921] .sup.1H NMR (DMSO-d.sub.6) δ 8.10-7.98 (m, 1H), 7.11-7.01 (m, 1H), 6.75-6.65 (m, 1H), 6.60-6.52 (m, 1H), 4.53 (s, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.75-2.64 (m, 2H), 2.08-1.99 (m, 5H).

    Intermediate B12: 5-(2-fluoro-5-methylpyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0922] ##STR00119##

    [0923] Prepared according to the general procedure for 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) from 5-bromo-2,3-dihydro-1H-inden-4-amine and (2-fluoro-5-methylpyridin-4-yl)boronic acid to afford the title compound (156 mg, 45%) as an off-white solid.

    [0924] LCMS m/z 243.4 (M+H).sup.+ (ES.sup.+).

    [0925] .sup.1H NMR (DMSO-d.sub.6) δ 8.12 (s, 1H), 6.88 (d, J=2.9 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 6.56 (d, J=7.5 Hz, 1H), 4.50 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.08 (s, 3H), 2.02 (p, J=7.4 Hz, 2H).

    Intermediate B13: 5-(2-fluoro-5-methylpyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

    [0926] ##STR00120##

    [0927] A mixture of 2-fluoro-4-hydrazineylpyridine (1.75 g, 13.8 mmol), 2-formyl-3-methyl-butanenitrile (1.90 g, 17.1 mmol) and acetic acid (840 mg, 800 μL, 14.0 mmol) in dioxane (30 mL) was heated at 65° C. for 12 h. The mixture was partitioned between EtOAc (200 mL) and sat aq NaHCO.sub.3 solution (100 mL), the organic layer separated, washed with water (50 mL), dried and evaporated. The residue was purified by FC (0-50% EtOAc/isohexane) to afford a solid (3.0 g) that was stirred in dioxane (20 mL) and 4M HCl in dioxane (15 mL) for 3 h (precipitate formed). A further portion of 4M HCl in dioxane (15 mL) was added and the mixture was heated at 40° C. for 24 h then 50° C. for 48 h. The solvent was evaporated and the residue partitioned between EtOAc (150 mL) and sat aq NaHCO.sub.3 solution (50 mL), the organic layer separated, washed with water (50 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by FC (0-50% TBME/isohexane) to afford the title compound (767 mg, 24%) as a white solid.

    [0928] LCMS m/z 221.2 (M+H).sup.+ (ES.sup.+); 219.2 (M−H)-(ES.sup.−).

    [0929] .sup.1H NMR (CDCl.sub.3) δ 8.27 (d, J=5.6 Hz, 1H), 7.68 (dt, J=5.7, 1.6 Hz, 1H), 7.47 (s, 1H), 7.43 (br s, 1H), 3.66 (br s, 2H), 2.71 (sept, J=6.9 Hz, 1H), 1.27 (d, J=6.9 Hz, 6H).

    Intermediate C1: 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)-pentyl)-1H-pyrazole-3-sulfonamide

    [0930] ##STR00121##

    Step A: 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0931] ##STR00122##

    [0932] A mixture of 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1) (0.40 g, 0.845 mmol) and KO.sup.tBu (104 mg, 0.929 mmol) in THF (5 mL) was stirred at RT for 1 h. 5-(2-Fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) (0.193 g, 0.845 mmol) was added and the reaction was stirred at RT for a further 18 h and diluted with water (20 mL) and EtOAc (20 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organics were dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.43 g, 47%) as a thick yellow gum.

    [0933] LCMS m/z 682.5 (M+H).sup.+ (ES.sup.+).

    [0934] .sup.1H NMR (DMSO-d.sub.6) δ 8.15 (d, J=5.3 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.05-6.97 (m, 5H), 6.86-6.75 (m, 5H), 6.73-6.72 (m, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 4.65 (br s, 2H), 4.25 (q, J=6.6 Hz, 4H), 4.19 (s, 4H), 3.70 (s, 6H), 2.82 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.3 Hz, 2H), 2.02 (p, J=7.4 Hz, 2H), 1.87 (p, J=7.2 Hz, 2H), 1.76 (p, J=6.8 Hz, 2H), 1.38 (p, J=7.8 Hz, 2H).

    Step B: 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-1H-pyrazole-3-sulfonamide

    [0935] ##STR00123##

    [0936] A solution of 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.43 g, 0.397 mmol) in TFA (5 mL) was stirred at RT for 5 h. The mixture was quenched with MeOH (5 mL) and concentrated in vacuo. The residue was purified by FC (0-10% MeOH/DCM) to afford the title compound (0.18 g, 96%) as a bright yellow foam.

    [0937] LCMS m/z 442.3 (M+H).sup.+ (ES.sup.+).

    [0938] .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.38 (s, 2H), 7.01 (dd, J=5.3, 1.5 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.77 (s, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 4.27 (t, J=6.6 Hz, 2H), 4.20 (t, J=7.1 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.5 Hz, 2H), 1.86 (p, J=7.3 Hz, 2H), 1.77 (p, J=6.9 Hz, 2H), 1.40 (p, J=7.8 Hz, 2H). Two exchangeable protons not observed.

    [0939] The following intermediates were synthesised following the general procedure for Intermediate C1, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00002 Int Structure From .sup.1H NMR LCMS C2 [00124]embedded image   1-(5-((4-(4-amino-6-methyl- A1 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.37 (s, 2H), 6.74 (dd, J = 5.2, 1.4 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 6.53 (s, 1H), 6.44 (s, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.19 (t, J = 7.1 Hz, 2H), 4.14 (s, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.90-1.81 (m, 5H), 1.77 (p, J = 6.8 Hz, 2H), 1.44-1.32 (m, 2H). m/z 456.3 (M + H).sup.+ (ES.sup.+) 2,3-dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)pentyl)- 1H-pyrazole-3-sulfonamide C3 [00125]embedded image   1-(2-(2-((4-(4-amino-2,3- dihydro-1H-inden-5- A2 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.15 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.39 (s, 2H), 7.01 (dd, J = 5.2, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.81-6.74 (m, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 4.68 (br s, 2H), 4.43-4.23 (m, 4H), 3.85 (t, J = 5.3 Hz, 2H), 3.76 (dd, J = 5.7, 3.8 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.6 Hz, 2H). m/z 444.3 (M + H).sup.+ (ES.sup.+) 442.2 (M − H).sup.− (ES.sup.−) yl)pyridine-2- yl)oxy)ethoxy)ethyl)-1H- pyrazole-3-sulfonamide C4 [00126]embedded image A3 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J = 5.3 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.39 (s, 2H), 7.01 (dd, J = 5.3, 1.5 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.81-6.75 (m, 1H), 6.65-6.52 (m, 2H), 4.71 (br s, 2H), 4.31 (t, J = 6.5 Hz, 2H), 4.25 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.98-1.88 (m, 2H), 1.76-1.65 (m, 2H). m/z 428.3 (M + H).sup.+ (ES.sup.+) 426.2 (M − H).sup.− (ES.sup.−) 1-(4-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)butyl)- 1H-pyrazole-3-sulfonamide C5 [00127]embedded image   1-(6-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)hexyl)- 1H-pyrazole-3-sulfonamide A4 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.38 (s, 2H), 7.00 (dd, J = 5.3, 1.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 4.78 (br s, 2H), 4.27 (t, J = 6.6 Hz, 2H), 4.17 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.82 (p, J = 7.3 Hz, 2H), 1.73 (p, J = 6.8 Hz, 2H), 1.44 (p, J = 7.5 Hz, 2H), 1.35-1.27 (m, 2H). m/z 456.4 (M + H).sup.+ (ES.sup.+) 454.2 (M − H).sup.− (ES.sup.−) C6 [00128]embedded image A5 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7.72 (s, 1H), 7.23 (s, 2H), 7.00 (dd, J = 5.3, 1.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.67 (s, 2H), 4.26 (t, J = 6.6 Hz, 2H), 4.18 (t, J = 7.0 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H), 1.85 (p, J = 7.2 Hz, 2H), 1.76 (p, J = 6.8 Hz, 2H), 1.44- 1.30 (m, 2H). m/z 442.4 (M + H).sup.+ (ES.sup.+) 440.3 (M − H).sup.− (ES.sup.−) 1-(5-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)pentyl)- 1H-pyrazole-4-sulfonamide C7 [00129]embedded image A6 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.40 (s, 2H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 1.3 Hz, 1H), 6.60-6.57 (m, 2H), 4.73 (br s, 2H), 4.36 (t, J = 7.0 Hz, 2H), 4.28 (t, J = 6.3 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.28 (p, J = 6.6 Hz, 2H), 2.04 (p, J = 7.4 Hz, 2H). m/z 414.3 (M + H).sup.+ (ES.sup.+) 412.2 (M − H).sup.− (ES.sup.−) 1-(3-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)propyl)- 1H-pyrazole-3-sulfonamide C8 [00130]embedded image A8 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J = 5.3 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.45 (s, 2H), 7.09 (dd, J = 5.3, 1.4 Hz, 1H), 6.91-6.81 (m, 2H), 6.64 (d, J = 2.3 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.93-4.36 (m, 4H), 3.00-2.78 (m, 5H), 2.70 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.5 Hz, 2H). Three exchangeable protons not observed, four aliphatic protons obscured by solvent. m/z 457.3 (M + H − TFA).sup.+ (ES.sup.+) 1-(2-((2-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)ethyl)- (methyl)amino)ethyl)-1H- pyrazole-3-sulfonamide 2,2,2-trifluoroacetate C9 [00131]embedded image   1-(5-((4-(2-amino-5-fluoro-3- isopropylphenyl)pyridin-2- yl)oxy)pentyl)-1H-pyrazole- A1 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.23- 8.18 (m, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.38 (s, 2H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.97 (dd, J = 10.2, 3.0 Hz, 1H), 6.81-6.80 (m, 1H), 6.77 (dd, J = 8.9, 3.0 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.20 (t, J = 7.1 Hz, 2H), 3.13-3.02 (m, 1H), 1.86 (p, J = 7.3 Hz, 2H), 1.77 (p, J = 6.8 Hz, 2H), 1.46- 1.34 (m, 2H), 1.19 (d, J = 6.7 Hz, 6H). Two exchangeable protons not observed. m/z 462.3 (M + H).sup.+ (ES.sup.+) 3-sulfonamide C10 [00132]embedded image A9 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.3 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.40 (s, 2H), 7.04 (d, J = 5.3 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.62-6.56 (m, 2H), 4.68 (br s, 2H), 4.53 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.68 (s, 6H). m/z 428.3 (M + H).sup.+ (ES.sup.+) 426.3 (M − H).sup.− (ES.sup.−) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C11 [00133]embedded image A10 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.37 (s, 2H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 6.61-6.52 (m, 2H), 4.66 (s, 2H), 4.38- 4.34 (m, 2H), 3.73 (s, 2H), 3.70-3.67 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H), 1.53 (s, 6H). m/z 472.4 (M + H).sup.+ (ES.sup.+) 1-(1-(2-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)pyridin- 2-yl)oxy)ethoxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C12 [00134]embedded image A11 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J = 5.3 Hz, 1H), 7.99 (br s, 1H), 7.47 (s, 2H), 7.03 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.66 (s, 2H), 4.42 (br s, 2H), 3.76-3.55 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.43-2.28 (m, 3H), 2.03 (p, J = 7.4 Hz, 2H), 1.71 (br s, 6H). m/z 499.3 (M + H).sup.+ (ES.sup.+) 497.2 (M − H).sup.− (ES.sup.−) N-(2-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)ethyl)- N,2-dimethyl-2-(3- sulfamoyl-1H-pyrazol-1- yl)propanamide C13 [00135]embedded image A12 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J = 5.3 Hz, 1H), 7.52 (s, 2H), 7.05 (dd, J = 5.3, 1.4 Hz, 1H), 6.92-6.83 (m, 2H), 6.80 (d, J = 1.5 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.62 (br s, 3H), 4.38 (t, J = 6.2 Hz, 2H), 3.97-3.79 (m, 1H), 3.35 (br s, 2H), 2.83 (t, J = 7.5 Hz, 4H), 2.70 (t, J = 7.4 Hz, 2H), 2.21 (br. s, 2H), 2.02 (p, J = 7.5 Hz, 2H), 1.21-1.03 (m, 4H). Three exchangeable protons not observed. m/z 497.4 (M + H − TFA).sup.+ (ES.sup.+) 5-(((3-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)propyl)- (methyl)amino)methyl)-1- cyclopropyl-1H-pyrazole-3- sulfonamide 2,2,2- trifluoroacetate C15 [00136]embedded image A13 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (d, J = 5.4 Hz, 1H), 7.39 (s, 2H), 7.04 (dd, J = 5.3, 1.5 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 4.66 (s, 2H), 4.42-4.35 (m, 2H), 3.97 (s, 1H), 3.71-3.67 (m, 1H), 3.65 (t, J = 6.2 Hz, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.11-2.00 (m, 4H), 1.13-0.97 (m, 4H). One exchangeable proton not observed. m/z 484.3 (M + H − TFA).sup.+ (ES.sup.+) 5-((3-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)propoxy)- methyl)-1-cyclopropyl-1H- pyrazole-3-sulfonamide 2,2,2-trifluoroacetate C16 [00137]embedded image A13, Step A + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J = 5.3 Hz, 1H), 7.40 (s, 2H), 7.09 (dd, J = 5.3, 1.4 Hz, 1H), 6.90-6.84 (m, 2H), 6.70 (s, 1H), 6.58 (d, J = 7.7 Hz, 1H), 5.55 (s, 2H), 4.70 (s, 2H), 3.79 (sept, J = 3.6 Hz, 1H), 2.83 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.17-1.13 (m, 2H), 1.08- 1.03 (m, 2H). m/z 426.3 (M + H).sup.+ (ES.sup.+) 5-(((4-(4-amino-2,3-dihydro- 1H-inden-5-yl)-pyridin-2- yl)oxy)methyl)-1-cyclopropyl- 1H-pyrazole-3-sulfonamide C17 [00138]embedded image A14 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.40 (br s, 2H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.63-6.37 (m, 2H), 4.65 (s, 2H), 4.28 (t, J = 6.6 Hz, 2H), 4.23- 4.06 (m, 2H), 3.18 (d, J = 4.1 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 7.70 (t, J = 7.5 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.85 (p, J = 7.5 Hz, 2H), 1.78 (p, J = 7.5 Hz, 2H), 1.44 (p, J = 7.5 Hz, 2H). 6 protons obscured by DMSO peak and thus not observed. m/z 499.3 (M + H).sup.+ (ES.sup.+) 1-(5-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)pentyl)-5- ((dimethylamino)methyl)- 1H-pyrazole-3-sulfonamide C19 [00139]embedded image A15 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 6.74 (s, 2H), 6.60 (d, J = 7.6 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 3.03-2.93 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.79-1.70 (m, 4H), 1.58- 1.46 (m, 2H). Two exchangeable protons not observed. m/z 376.3 (M + H).sup.+ (ES.sup.+) 5-((4-(4-amino-2,3-dihydro- 1H-inden-5-yl)-pyridin-2- yl)oxy)pentane-1- sulfonamide C20 [00140]embedded image A7 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.19- 8.15 (m, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.40 (br. s, 2H), 7.04 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.78-6.75 (m, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 4.77-4.63 (m, 4H), 4.63-4.57 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.05-1.98 (m, 2H). m/z 400.2 (M + H).sup.+ (ES.sup.+) 1-(2-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)ethyl)-1H- pyrazole-3-sulfonamide C22 [00141]embedded image A16 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.38 (s, 2H), 7.02 (dd, J = 5.2, 1.5 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 6.81-6.77 (m, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.49 (s, 1H), 4.66 (s, 2H), 4.34 (t, J = 6.0 Hz, 2H), 4.30 (t, J = 6.1 Hz, 2H), 3.45 (s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.27 (p, J = 6.6 Hz, 2H), 2.13 (s, 6H), 2.03 (p, J = 7.4 Hz, 2H). m/z 471.2 (M + H).sup.+ (ES.sup.+) 1-(3-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)propyl)-5- ((dimethylamino)methyl)- 1H-pyrazole-3-sulfonamide C23 [00142]embedded image A18 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.3 Hz, 1H), 8.12 (d, J = 4.7 Hz, 1H), 7.69 (s, 2H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.82-6.76 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.68 (s, 2H), 4.32-4.21 (m, 4H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.26 (p, J = 6.6 Hz, 2H), 2.02 (p, J = 7.2 Hz, 2H). m/z 432.2 (M + H).sup.+ (ES.sup.+) 1-(3-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)propyl)-4- fluoro-1H-pyrazole-3- sulfonamide C24 [00143]embedded image A9 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.40 (s, 2H), 6.79 (dd, J = 5.2, 1.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.56 (t, J = 1.0 Hz, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.67- 2.59 (m, 2H), 2.03-1.95 (m, 2H), 1.87 (s, 3H), 1.68 (s, 6H). Two exchangeable protons not observed. m/z 442.3 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-6-methyl- 2,3-dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C25 [00144]embedded image A19 + B1 .sup.1H NMR (CDCl.sub.3) δ 8.19 (d, J = 5.4 Hz, 1H), 7.53 (d, J = 4.9 Hz, 1H), 7.14 (dd, J = 5.5, 1.4 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.95-6.91 (m, 1H), 6.81 (d, J = 7.7 Hz, 1H), 4.72 (dd, J = 5.5, 4.3 Hz, 2H), 4.55-4.48 (m, 2H), 3.01-2.83 (m, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.17 (p, J = 7.5 Hz, 2H). Four exchangeable protons not observed. m/z 418.1 (M + H).sup.+ (ES.sup.+) 1-(2-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)ethyl)-4- fluoro-1H-pyrazole-3- sulfonamide C26 [00145]embedded image A17 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (d, J = 4.5 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.69 (s, 2H), 6.80 (dd, J = 5.2, 1.3 Hz, 1H), 6.62-6.58 (m, 1H), 6.58 (s, 1H), 4.50 (d, J = 4.8 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.4 Hz, 2H), 2.05-1.95 (m, 2H), 1.89 (s, 3H), 1.64 (s, 6H). Two exchangeable protons not observed. m/z 460.2 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-6-methyl- 2,3-dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)-2- methylpropan-2-yl)-4-fluoro- 1H-pyrazole-3-sulfonamide C27 [00146]embedded image A17 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J = 4.5 Hz, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.69 (s, 2H), 7.04 (dd, J = 5.3, 1.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 4.49 (s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.5 Hz, 2H), 1.63 (s, 6H). Three exchangeable protons not observed. m/z 446.1 (M + H − TFA).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)-2- methylpropan-2-yl)-4-fluoro- 1H-pyrazole-3-sulfonamide 2,2,2-trifluoroacetate C28 [00147]embedded image A7 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.23 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.41 (s 2H), 6.80 (dd, J = 5.2, 1.4 Hz, 1H), 6.62-6.55 (m, 2H), 6.44 (s, 1H), 4.72-4.57 (m, 4H), 4.17 (s, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.99 (p, J = 7.3 Hz, 2H), 1.87 (s, 3H). m/z 414.1 (M + H).sup.+ (ES.sup.+) 1-(2-((4-(4-amino-6-methyl- 2,3-dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)ethyl)- 1H-pyrazole-3-sulfonamide C29 [00148]embedded image A19 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.23 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 4.8 Hz, 1H), 7.72 (s, 2H), 6.80 (dd, J = 5.2, 1.3 Hz, 1H), 6.60 (s, 1H), 6.45 (s, 1H), 4.70-4.57 (m, 2H), 4.53 (t, J = 5.2 Hz, 2H), 4.16 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 1.99 (p, J = 7.4 Hz, 2H), 1.87 (s, 3H). m/z 432.1 (M + H).sup.+ (ES.sup.+) 1-(2-((4-(4-amino-6-methyl- 2,3-dihydro-1H-inden-5- yl)pyridin-2-yl)oxy)ethyl)-4- fluoro-1H-pyrazole-3- sulfonamide C30 [00149]embedded image A17 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 5.3 Hz, 1H), 7.70 (s, 2H), 7.06 (dd, J = 5.3, 1.5 Hz, 1H), 6.93 (dd, J = 10.2, 3.0 Hz, 1H), 6.83 (br s, 1H), 6.74 (dd, J = 8.9,3.0 Hz, 1H). 4.52-4.47 (m, 4H), 3.06 (sept, J = 6.7 Hz, 1H), 1.64 (s, 6H), 1.17 (d, J = 6.7 Hz, 6H). m/z 492.4 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(2-amino-5-fluoro-3- isopropylphenyl)pyridin-2- yl)oxy)-2-methylpropan-2- yl)-4-fluoro-1H-pyrazole-3- sulfonamide C31 [00150]embedded image A20 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (dd, J = 5.3, 0.7 Hz, 1H), 7.80-7.78 (m, 1H), 7.71- 7.66 (m, 1H), 7.59-7.54 (m, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.33 (s, 2H), 7.01 (dd, J = 5.3, 1.4 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.77-6.74 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.68 (br s, 2H), 4.53 (t, J = 6.7 Hz, 2H), 3.15 (t, J = 6.7 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H). m/z 410.4 (M + H).sup.+ (ES.sup.+) 3-(2-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)ethyl)- benzenesulfonamide C32 [00151]embedded image A9 + B5 .sup.1H NMR (DMSO-d.sub.6) δ 8.05 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.41 (s, 2H), 6.94 (t, J = 4.9 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 4.73-4.56 (m, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.01 (p, J = 7.4 Hz, 2H), 1.69 (s, 6H). m/z 446.4 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)-3- fluoropyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C33 [00152]embedded image A9 + B12 .sup.1H NMR (DMSO-d.sub.6) δ 8.06- 8.00 (m, 2H), 7.39 (s, 2H), 6.65 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.50 (s, 1H), 4.54-4.32 (m, 4H), 2.84 (t, J = 7.5 Hz, 2H), 2.73-2.66 (m, 2H), 2.06-1.96 (m, 5H), 1.66 (s, 6H). m/z 442.4 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)-5- methylpyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C34 [00153]embedded image A9 + B6 .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.40 (s, 2H), 6.92 (d, J = 5.3 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.36 (d, J = 9.7 Hz, 1H), 4.79 (s, 2H), 4.52 (s, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.5 Hz, 2H), 1.68 (s, 6H). m/z 446.4 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-6-fluoro- 2,3-dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C35 [00154]embedded image A21 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.14 (d, J = 5.3 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.47 (br s, 2H), 7.06 (dd, J = 5.3, 1.4 Hz, 1H), 6.89-6.85 (m, 2H), 6.66 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.74-5.69 (m, 1H), 5.28- 5.22 (m, 1H), 4.38-4.31 (m, 2H), 4.01 (dd, J = 9.7, 4.8 Hz, 1H), 3.96 (dd, J = 10.4, 2.5 Hz, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.02 (p, J =7.5 Hz, 2H). Two exchangeable protons not observed. m/z 442.4 (M + H).sup.+ (ES.sup.+) + [00155]embedded image (Enantiomeric mixture) 1-((anti)-4-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)- tetrahydrofuran-3-yl)-1H- pyrazole-3-sulfonamide C36 [00156]embedded image A9 + B8 .sup.1H NMR (DMSO-d.sub.6) δ 8.05 (d, J = 2.4 Hz, 1H), 7.40 (s, 2H), 6.89 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.63-6.58 (m, 2H), 6.56 (s, 1H), 4.50 (s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.41 (s, 3H), 2.03 (p, J = 7.5 Hz, 2H), 1.67 (s, 6H). Two exchangeable protons not observed. m/z 442.4 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)-6- methylpyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C37 [00157]embedded image A9 + B7 .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 5.2 Hz, 1H), 7.40 (s, 2H), 6.78 (dd, J = 5.2, 1.4 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.55 (s, 1H), 6.01 (s, 1H), 4.55-4.43 (m, 4H), 4.39 (s, 2H), 2.93 (t, J = 8.6 Hz, 2H), 1.85 (s, 3H), 1.68 (s, 6H). m/z 444.5 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-6-methyl- 2,3-dihydrobenzofuran-5-yl)- pyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C38 [00158]embedded image A9 + B9 .sup.1H NMR (DMSO-d.sub.6) δ 8.13 (d, J = 1.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.39 (s, 2H), 6.78 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 5.0 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 4.66 (s, 2H), 4.47 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.07-1.95 (m, 2H), 1.66 (s, 6H). m/z 446.4 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)-5- fluoropyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C39 [00159]embedded image A22 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.40 (br s, 2H), 7.01 (dd, J = 5.3, 1.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.75 (br s, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 4.65 (br s, 2H), 4.45 (br s, 2H), 3.83-3.76 (m, 2H), 3.39-3.33 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.19-2.11 (m, 2H), 2.05-1.99 (m, 2H). Two aliphatic protons overlapped with DMSO-d.sub.6 signal. m/z 470.5 (M + H).sup.+ (ES.sup.+) 1-(4-(((4-(4-amino-2,3- dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)methyl)- tetrahydro-2H-pyran-4-yl)- 1H-pyrazole-3-sulfonamide C40 [00160]embedded image A19 + B6 .sup.1H NMR (DMSO-d.sub.6) δ 8.23 (dd, J = 5.2 Hz, 1H), 8.16 (d, J = 4.7 Hz, 1H), 7.72 (s, 2H), 6.94 (d, J = 5.3, 1H), 6.74 (s, 1H), 6.38 (d, J = 9.8 Hz, 1H), 4.81 (s, 2H), 4.65 (dd, J = 5.8, 4.5 Hz, 2H), 4.53 (t, J = 5.1 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.08-1.97 (m, 2H). m/z 436.4 (M + H).sup.+ (ES.sup.+) 1-(2-((4-(4-amino-6-fluoro- 2,3-dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)ethyl)-4- fluoro-1H-pyrazole-3- sulfonamide C41 [00161]embedded image A17 + B6 .sup.1H NMR (DMSO-d.sub.6) δ 8.29 (d, J = 4.6 Hz, 1H), 8.19 (dd, J = 5.3, 0.7 Hz, 1H), 7.69 (s, 2H), 6.92 (dt, J = 5.2, 1.2 Hz, 1H), 6.71 (d, J = 1.2 Hz, 1H), 6.37 (d, J = 9.8 Hz, 1H), 4.79 (s, 2H), 4.49 (s, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.06-2.00 (m, 2H), 1.64 (s, 6H). m/z 464.7 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-6-fluoro- 2,3-dihydro-1H-inden-5-yl)- pyridin-2-yl)oxy)-2- methylpropan-2-yl)-4-fluoro- 1H-pyrazole-3-sulfonamide C44 [00162]embedded image A19 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 4.7 Hz, 1H), 7.71 (s, 2H), 7.06 (dd, J = 5.2, 1.5 Hz, 1H), 6.93 (dd, J = 10.2, 3.0 Hz, 1H), 6.84 (dd, J = 1.5, 0.7 Hz, 1H), 6.73 (dd, J = 8.9, 3.0 Hz, 1H), 4.64 (dd, J = 5.7, 4.5 Hz, 2H), 4.52 (t, J = 5.1 Hz, 2H), 4.48 (s, 2H), 3.05 (p, J = 6.8 Hz, 1H), 1.17 (d, J = 6.7 Hz, 6H). m/z 438.5 (M + H).sup.+ (ES.sup.+) 1-(2-((4-(2-amino-5-fluoro-3- isopropylphenye-pyridin-2- yl)oxy)ethyl)-4-fluoro-1H- pyrazole-3-sulfonamide C45 [00163]embedded image A9 + B11 .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 5.1 Hz, 1H), 7.39 (s, 2H), 6.73 (d, J = 5.1 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 4.55-4.41 (m, 2H), 4.32 (s, 2H), 2.86-2.78 (m, 2H), 2.72-2.65 (m, 2H), 2.05- 1.98 (m, 2H), 1.85 (s, 3H), 1.71 (s, 6H). m/z 442.5 (M + H).sup.+ (ES.sup.+) 1-(1-((4-(4-amino-2,3- dihydro-1H-inden-5-yl)-3- methylpyridin-2-yl)oxy)-2- methylpropan-2-yl)-1H- pyrazole-3-sulfonamide C47 [00164]embedded image A17 + B13 .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J = 4.6 Hz, 1H), 8.13 (d, J = 5.7 Hz 1H) 7.69 (s, 2H), 7.39 (dd, J = 5.7, 1.9 Hz, 1H), 7.36 (s, 1H), 7.11 (d, J = 1.9 Hz, 1H), 5.21 (s, 2H), 4.50 (s, 2H), 2.85- 2.76 (m, 1H), 1.63 (s, 6H), 1.12 (d, J = 6.9 Hz, 6H). m/z 438.4 (M + H).sup.+ (ES.sup.+) 436.3 (M − H).sup.− (ES.sup.−) 1-(1-((4-(5-amino-4- isopropyl-1H-pyrazol-1- yl)pyridin-2-yl)oxy)-2- methylpropan-2-yl)-4-fluoro- 1H-pyrazole-3-sulfonamide

    Intermediate C14: 1-(5-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)pentyl)-1H-pyrazole-3-sulfonamide

    [0940] ##STR00165##

    Step A: 1-(5-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)pentyl)-N,N-bis(4-mnethoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0941] ##STR00166##

    [0942] DIAD (0.146 mL, 0.741 mmol) was added dropwise to 3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenol (Intermediate B3) (0.15 g, 0.659 mmol), 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1) (0.30 g, 0.570 mmol) and PPh.sub.3 (0.194 g, 0.741 mmol) in THF (20 mL) at RT. The mixture was stirred at RT for 5 h, concentrated on to silica (2 g) and purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.36 g, 65%) as a thick yellow gum.

    [0943] LCMS m/z 681.5 (M+H).sup.+ (ES.sup.+).

    [0944] .sup.1H NMR (DMSO-d.sub.6) δ 7.98 (d, J=2.3 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.05-6.95 (m, 4H), 6.92 (d, J=7.6 Hz, 1H), 6.88-6.82 (m, 2H), 6.81-6.76 (m, 5H), 6.71 (d, J=2.4 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 4.42 (s, 2H), 4.24 (t, J=7.0 Hz, 2H), 4.18 (s, 4H), 3.96 (t, J=6.4 Hz, 2H), 3.69 (s, 6H), 2.81 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 2.07-1.97 (m, 2H), 1.86 (p, J=7.1 Hz, 2H), 1.80-1.71 (m, 2H), 1.43-1.33 (m, 2H).

    Step B: 1-(5-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)pentyl)-1H-pyrazole-3-sulfonamide

    [0945] ##STR00167##

    [0946] Prepared according to the general procedure of 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-1H-pyrazole-3-sulfonamide (Intermediate C1, Step B), from 1-(5-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)pentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide, to afford the title compound (0.22 g, 94%) as an orange gum.

    [0947] LCMS m/z 441.3 (M+H).sup.+ (ES.sup.+).

    [0948] .sup.1H NMR (DMSO-d.sub.6) δ 7.89 (d, J=2.3 Hz, 1H), 7.39-7.35 (m, 3H), 7.35-7.30 (m, 1H), 6.95-6.91 (m, 1H), 6.89-6.85 (m, 2H), 6.82 (d, J=7.5 Hz, 1H), 6.61-6.53 (m, 1H), 4.20 (t, J=7.1 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.3 Hz, 2H), 2.04 (p, J=7.4 Hz, 2H), 1.86 (p, J=7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.44-1.34 (m, 2H). Two exchangeable protons not observed.

    Intermediate C18: 1-(1-((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

    [0949] ##STR00168##

    Step A: N-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)-2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N,2-dimethylpropanamide

    [0950] ##STR00169##

    [0951] A mixture of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N-2-hydroxyethyl)-N,2-dimethylpropanamide (Intermediate A11) (0.87 g, 1-443 mmol) and potassium tert-butoxide (0.25 g, 2.228 mmol) in THF (5 mL) was stirred at RT for 1 h. 5-(2-Fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) (0.35 g, 1.472 mmol) was then added and the mixture was stirred at RT for a further 18 h. The mixture was partitioned between EtOAc (30 mL) and water (15 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give the title compound (0.75 g, 67%) as a yellow foam.

    [0952] LCMS m/z 739.4 (M+H).sup.+ (ES.sup.+).

    [0953] .sup.1H NMR (DMSO-d.sub.6) δ 8.16-8.06 (m, 1H), 7.07-6.97 (m, 5H), 6.85-6.76 (m, 6H), 6.74 (s, 1H), 6.57 (d, J=7.6 Hz, 1H), 4.64 (s, 2H), 4.41 (s, 2H), 4.22-4.16 (m, 5H), 3.71 (s, 6H), 3.66 (s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.43-2.23 (m, 3H), 2.05-1.98 (m, 2H), 1.74 (s, 6H).

    Step B: 1-(1-((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)-(methyl)amino)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0954] ##STR00170##

    [0955] BH.sub.3.THF (1 M in THF) (1184 μL, 1.184 mmol) was added to a suspension of N-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)-2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-N,2-dimethylpropanamide (250 mg, 0.338 mmol) in THF (5 mL). The mixture was heated to 70° C. for 16 h. The reaction mixture was then left to cool to RT and quenched slowly by dropwise addition with MeOH (20 mL) followed by 6M aq NaOH (60 mL). The reaction mixture was stirred vigorously at RT for 5 h. The reaction mixture was diluted with DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried using a phase separator, filtered and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (115 mg, 44%) as a colourless oil.

    [0956] LCMS m/z 725.5 (M+H).sup.+ (ES.sup.+).

    [0957] .sup.1H NMR (DMSO-d.sub.6) δ 8.15 (d, J=5.3 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.08-6.96 (m, 5H), 6.84-6.76 (m, 5H), 6.72 (s, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 4.64 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 4.18 (s, 4H), 3.70 (s, 6H), 2.82 (t, J=7.5 Hz, 2H), 2.77 (s, 2H), 2.70 (t, J=7.3 Hz, 2H), 2.59 (t, J=6.1 Hz, 2H), 2.07-1.95 (m, 5H), 1.56 (s, 6H).

    Step C: 1-(1-((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

    [0958] ##STR00171##

    [0959] 1-(1-((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)-amino)-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (115 mg, 0.159 mmol) was dissolved in TFA (4 mL) and stirred at RT for 24 h. The reaction was concentrated in vacuo and the resulting residue purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (74 mg, 90%) as a yellow oil.

    [0960] LCMS m/z 485.4 (M+H).sup.+ (ES.sup.+).

    [0961] .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J=5.3 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.36 (s, 2H), 7.01 (dd, J=5.3, 1.5 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.77-6.76 (m, 1H), 6.61-6.57 (d, 7.6 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.66 (s, 2H), 4.28 (t, J=5.9 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.75 (s, 2H), 2.70 (t. J=7.3 Hz, 2H), 2.67 (t, J=5.9 Hz, 2H), 2.03 (p, J=7.4 Hz, 2H), 1.96 (s, 3H), 1.53 (s, 6H).

    Intermediate C21: 1-(3-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)propyl)-1H-pyrazole-3-sulfonamide

    [0962] ##STR00172##

    Step A: 1-(3-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)propyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0963] ##STR00173##

    [0964] Prepared according to the general procedure of 1-(5-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)pentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate C14, Step A) from 1-(3-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A6) and 3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenol (Intermediate B3) to afford to afford the title compound (0.19 g, 12%) as a thick yellow gum.

    [0965] LCMS m/z 653.4 (M+H).sup.+ (ES.sup.+).

    [0966] .sup.1H NMR (DMSO-d.sub.6) δ 8.01 (d, J=2.3 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.01-6.96 (m, 5H), 6.96-6.93 (m, 1H), 6.92-6.89 (m, 1H), 6.89-6.85 (m, 1H), 6.82-6.75 (m, 4H), 6.73 (d, J=2.3 Hz, 1H), 6.55 (d, J=7.6 Hz, 1H), 4.42 (dd, J=13.2, 6.3 Hz, 2H), 4.17 (s, 4H), 3.99 (t, J=6.1 Hz, 2H), 3.70 (s, 6H), 2.82 (t, J=7.5 Hz, 2H), 2.69 (t, J=7.3 Hz, 2H), 2.26 (p, J=6.5 Hz, 2H), 2.06-1.98 (m, 2H). Two exchangeable protons not observed.

    Step B: 1-(3-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)propyl)-1H-pyrazole-3-sulfonamide

    [0967] ##STR00174##

    [0968] Prepared according to the general procedure of 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-1H-pyrazole-3-sulfonamide (Intermediate C1, Step B) from 1-(3-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenoxy)propyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (0.08 g, 82%) as an orange gum.

    [0969] LCMS m/z 413.3 (M+H).sup.+ (ES.sup.+).

    [0970] .sup.1H NMR (DMSO-d.sub.6) δ 7.91 (d, J=2.3 Hz, 1H), 7.38 (s, 2H), 7.37-7.31 (m, 1H), 6.95 (dt, J=7-5, 1.2 Hz, 1H), 6.92-6.87 (m, 2H), 6.82 (d, J=7.5 Hz, 1H), 6.59 (s, 1H), 6.58 (d, J=2.3 Hz, 1H), 4.36 (t, J=7.1 Hz, 2H), 4.01 (t, J=6.1 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.3 Hz, 2H), 2.26 (p, J=6.5 Hz, 2H), 2.05-1.99 (m, 2H). Two exchangeable protons not observed.

    Intermediate C42: 1-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)-6-fluoropyridin-2-yl)oxy)ethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

    [0971] ##STR00175##

    Step A: 1-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)-6-fluoropyridin-2-yl)oxy)ethyl)-4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0972] ##STR00176##

    [0973] To a solution of 4-fluoro-1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A19) (433 mg, 1.670 mmol), 5-(2,6-difluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B10) (751 mg, 1.587 mmol) and THF (15 mL) was added 60% NaH in mineral oil (200 mg, 5.01 mmol) at 0° C. The reaction mixture was left to stir at RT for 3 h. To the reaction mixture was added aq 1 N HCl (100 mL), the product was extracted with EtOAc (3×50 mL), the combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude product was purified by FC (10- 100% EtOAc/isohexane) to afford the title compound (860 mg, 69% yield) as a colourless oil.

    [0974] LCMS m/z 675.8 (M+H).sup.+ (ES.sup.+).

    [0975] .sup.1H NMR (DMSO-d.sub.6) δ 8.24 (d, J=4.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 4H), 6.84-6.68 (m, 7H), 6.55 (d, J=7.7 Hz, 1H), 4.77 (s, 2H), 4.61 (t, J=4.9 Hz, 2H), 4.55 (t, J=4.9 Hz, 2H), 4.20 (s, 4H), 3.68 (d, J=1.1 Hz, 6H), 2.82 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.05-1.99 (m, 2H).

    Step B: 1-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)-6-fluoropyridin-2-yl)oxy)ethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

    [0976] ##STR00177##

    [0977] Prepared according to the general procedure for 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-1H-pyrazole-3-sulfonamide (Intermediate C1, Step B) from 1-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)-6-fluoropyridin-2-yl)-oxy)ethyl)-4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (401 mg, 96%) as a white gum.

    [0978] LCMS m/z 436.5 (M+H).sup.+ (ES.sup.+).

    [0979] .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J=4.6 Hz, 1H), 7.71 (s, 2H), 6.87 (d, J=7.6 Hz, 1H), 6.74 (dt, J=3.5, 1.1 Hz, 2H), 6.57 (d, J=7.7 Hz, 1H), 4.79 (s, 2H), 4.59 (dd, J=5.7, 4.3 Hz, 2H), 4.51 (dd, J=5.7, 4.2 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.69 (t, J=7.3 Hz, 2H), 2.02 (q, J=7.5 Hz, 2H).

    Intermediate C43: 1-(1-((4-(2-amino-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide

    [0980] ##STR00178##

    [0981] Prepared according to the general procedure for 1-(2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)-6-fluoropyridin-2-yl)oxy)ethyl)-4-fluoro-1H-pyrazole-3-sulfonamide (Intermediate C42) from 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A9) and 4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylaniline (Intermediate B4).

    [0982] LCMS m/z 448.5 (M+H).sup.+ (ES.sup.+).

    [0983] .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J=5.2 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.39 (s, 2H), 7.04 (dd, J=5.2, 1.5 Hz, 1H), 6.92 (dd, J=10.2, 3.0 Hz, 1H), 6.80 (d, J=1.4 Hz, 1H), 6.73 (dd, J=8.9, 3.0 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 4.53 (s, 2H), 4.47 (s, 2H), 3.05 (p, J=6.6 Hz, 1H), 1.67 (s, 6H), 1.17 (d, J=6.9 Hz, 6H).

    Intermediate C46: 1-((3-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)-cyclopentyl)methyl)-1H-pyrazole-3-sulfonamide

    [0984] ##STR00179##

    Step A: 1-((3-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)cyclopentyl)-methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0985] ##STR00180##

    [0986] To a solution of 1-((3-hydroxycyclopentyl)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A23) (300 mg, 463.35 μmol, 1 eq) in THF (10 mL) was added KO.sup.tBu (52 mg, 463.35 μmol, 1 eq). The mixture was stirred at 25° C. for 1 h. Then to the above mixture was added 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) (106 mg, 463.35 μmol, 1 eq) and the resulting reaction mixture was warmed to 65° C. and stirred for 6 h. Then a second batch of KO.sup.tBu (52 mg, 463.35 μmol, 1 eq) was added to the above reaction mixture. The mixture was stirred at 70° C. for 12 h. Then a third batch of KO.sup.tBu (52 mg, 463.35 μmol, 1 eq) was added to the above reaction mixture. The mixture was stirred at 70° C. for 6 h. The mixture was quenched with H.sub.2O (50 mL) and extracted with EtOAc (50 mL×3). The organic phases were washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc 4:1 to 2:1) to give the title compound (0.3 g, 82% yield, 88% purity on LCMS) as a yellow oil. LCMS: m/z 694.2 (M+H).sup.+ (ES.sup.+).

    [0987] .sup.1H NMR (DMSO-d.sub.6): δ 8.13 (d, 1H), 7.98 (d, 1H), 7.01-6.97 (m, 5H), 6.80-6.77 (m, 5H), 6.77 (d, 1H), 6.70 (d, 1H), 6.57-6.54 (m, 1H), 5.38-5.35 (m, 1H), 4.65 (s, 2H), 4.26-4.24 (m, 2H), 4.19-4.16 (m, 4H), 3.69 (s, 6H), 2.81 (t, 2H), 2.68 (t, 2H), 2.21-2.14 (m, 1H), 2.04-2.00 (m, 2H), 1.96-1.94 (m, 2H), 1.86-1.80 (m, 1H), 1.69-1.63 (m, 1H), 1.56-1.46 (m, 2H).

    Step B: 1-((3-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)cyclopentyl)-methyl)-1H-pyrazole-3-sulfonamide

    [0988] ##STR00181##

    [0989] A solution of 1-((3-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)- cyclopentyl)methyl)-N,N-bis(4-methoxybenzyl)-1H- pyrazole-3-sulfonamide (300 mg, 380.48 μmol, 1 eq) in TFA (5 mL) was stirred at 20° C. for 3 h. The mixture was concentrated in vacuum. The residue was dissolved in sat aq NaHCO.sub.3 solution (70 mL) and then extracted with EtOAc (50 mL×3). The organic phases were washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc 2:1) to give the title compound (120 mg, 69.54% yield) as a yellow oil.

    [0990] LCMS: m/z 454.1.1 (M+H).sup.+ (ES.sup.+).

    [0991] .sup.1H NMR (DMSO-d.sub.6): δ 8.15 (d, 1H), 7.89 (d, 1H), 7.38 (s, 2H), 6.98 (dd, 1H), 6.84 (d, 1H), 6.74 (d, 1H), 6.59-6.56 (m, 2H), 5.38-5.35 (m, 1H), 4.66 (s, 2H), 4.24-4.19 (m, 2H), 2.82 (t, 2H), 2.67 (t, 2H), 2.26-2.14 (m, 2H), 2.05-2.01 (m, 2H), 1.98-1.94 (m, 1H), 1.87-1.81 (m, 1H), 1.71-1.67 (m, 1H), 1.57-1.46 (m, 2H).

    Intermediate D1: N,N-bis(4-methoxybenzyl)-1-(pent-4-en-1-yl)-1H-pyrazole-3-sulfonamide

    [0992] ##STR00182##

    Step A: 1-(5-bromopentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0993] ##STR00183##

    [0994] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (10 g, 25.81 mmol, 1 eq) in DMF (100 mL) was added K.sub.2CO.sub.3 (7.13 g, 51.62 mmol, 2 eq) at 25° C., and the mixture was stirred at 25° C. for 0.5 h. Then 1,5-dibromopentane (7.12 g, 30.97 mmol, 1.2 eq) was added and the resulting mixture was stirred at 50° C. for 3 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 8:1 to 5:1) to give the title compound (6.3 g, 45.50% yield) as a yellow oil.

    [0995] .sup.1H NMR (DMSO-d.sub.6): δ 7.96 (d, 1H), 7.02 (d, 4H), 6.80 (d, 4H), 6.71 (d, 1H), 4.23-4.20 (m, 6H), 3.73 (s, 6H), 3.51 (t, 2H), 1.83-1.80 (m, 4H), 1.35-1.32 (m, 2H).

    Step B: N,N-bis(4-methoxybenzyl)-1-(pent-4-en-1-yl)-1H-pyrazole-3-sulfonamide

    [0996] ##STR00184##

    [0997] To a solution of 1-(5-bromopentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2 g, 3.73 mmol, 1 eq) in THF (20 mL) was slowly added NaH (0.6 g, 15.00 mmol, 60% purity in mineral oil, 4.02 eq) in portions at 0° C. After the addition, the reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was quenched with sat aq NH.sub.4Cl solution (100 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 20:1 to 4:1) to give the title compound (1.3 g, 73.18% yield, 95.6% purity on LCMS) as a colourless oil.

    [0998] LCMS: m/z 456.2 (M+H).sup.+ (ES.sup.+).

    [0999] .sup.1H NMR (CDCl.sub.3): δ 7.41 (d, 1H), 7.06 (d, 4H), 6.77 (d, 4H), 6.64 (d, 1H), 5.82-5.74 (m, 1H), 5.05 (d, 2H), 4.31 (s, 4H), 4.18 (t, 2H), 3.78 (s, 6H), 2.06-1.98 (m, 4H).

    Intermediate D2: 1-allyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1000] ##STR00185##

    [1001] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (1.0 g, 2.58 mmol, 1 eq) and K.sub.2CO.sub.3 (713 mg, 5.16 mmol, 2.0 eq) in DMF (10 mL) at 25° C. was added 3-bromoprop-1-ene (375 mg, 3.10 mmol, 1.2 eq). The reaction mixture was stirred at 60° C. for 3 h. Water (100 mL) and EtOAc (100 mL) were added, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 2:1) to give the title compound (0.9 g, 81.40% yield, 100% purity on LCMS) as a yellow oil.

    [1002] LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

    [1003] .sup.1H NMR (CDCl.sub.3): δ 7.45 (d, 1H), 7.06 (d, 4H), 6.77 (d, 4H), 6.67 (d, 1H), 6.06-5.96 (m, 1H), 5.34 (dd, 1H), 5.26 (dd, 1H), 4.80 (d, 2H), 4.32 (s, 4H), 3.79 (s, 6H).

    Intermediate D.SUP.3: 1.-(but-3-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1004] ##STR00186##

    Step A: 1-(4-bromobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1005] ##STR00187##

    [1006] A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (10 g, 25.81 mmol, 1 eq) and K.sub.2CO.sub.3 (10.70 g, 77.43 mmol, 3 eq) in DMF (100 mL) was stirred at 25° C. for 0.5 h. Then 1,4-dibromobutane (7.24 g, 33-55 mmol, 1.3 eq) was added and the resulting reaction mixture was heated to 70° C. and stirred for 3 h. The mixture was quenched with water (150 mL) and extracted with EtOAc (100 mL×3). Then the combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 4:1) to give the title compound (5.5 g, 38.34% yield, 94% purity on LCMS) as a yellow oil.

    [1007] LCMS: m/z 522.1 (M+H).sup.+ (ES.sup.+).

    [1008] .sup.1H NMR (CDCl.sub.3): δ 7.43 (d, 1H), 7.07 (d, 4H), 6.78 (d, 4H), 6.66 (d, 1H), 4.43 (s, 4H), 4.22 (t, 2H), 3.81 (s, 6H), 3.41 (t, 2H), 2.09-2.02 (m, 2H), 1.87-1.82 (m, 2H).

    Step B: 1-(but-3-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1009] ##STR00188##

    [1010] To a solution of 1-(4-bromobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.9 g, 1.72 mmol, 1 eq) in THF (10 mL) was added NaH (276 mg, 6.89 mmol, 60% purity in mineral oil, 4 eq) at 0° C. Then the reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was quenched with sat aq NH.sub.4Cl (100 mL) and extracted with EtOAc (100 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 20:1 to 3:1) to give the title compound (0.35 g, 44.27% yield, 96.2% purity on LCMS) as a yellow oil.

    [1011] LCMS: m/z 442.4 (M+H).sup.+ (ES.sup.+).

    [1012] .sup.1H NMR (CDCl.sub.3): δ 7.43 (d, 1H), 7.06 (d, 4H), 6.77 (d, 4H), 6.62 (d, 1H), 5.77-5.68 (m, 1H), 5.10-5.06 (m, 2H), 4.31 (s, 4H), 4.24 (t, 2H), 3.78 (s, 6H), 2.66-2.60 (s, 2H).

    Intermediate E1: 1-allyl-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

    [1013] ##STR00189##

    Step A: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one

    [1014] ##STR00190##

    [1015] A suspension of AlCl.sub.3 (225.67 g, 1.69 mol, 1 eq) in DCM (1 L) was cooled to −10° C. under N.sub.2 atmosphere. Then a mixture of 2,3-dihydro-1H-indene (200 g, 1.69 mol, 1 eq) and 3-chloropropanoyl chloride (214.88 g, 1.69 mol, 1 eq) in DCM (400 mL) was added dropwise to the suspension. After addition, the mixture was warmed to 27° C. and stirred for 2 h. The reaction mixture was added slowly to an aq HCl solution (2 N, 2.8 L) below 10° C. The layers were separated and the aqueous layer was extracted with DCM (1 L). The combined organic layers were washed with water (1 L), sat aq NaHCO.sub.3 solution (1 L) and brine (500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was triturated with petroleum ether (500 mL) to give the title compound (260.44 g, 73.74% yield) as a white solid.

    [1016] LCMS: m/z 209.1 (M+H).sup.+ (ES.sup.+).

    [1017] .sup.1H NMR (CDCl.sub.3): δ 7.84 (s, 1H), 7.79-7.76 (m, 1H), 7.34-7.32 (d, 1H), 3.96-3.93 (t, 2H), 3.48-3.44 (t, 2H), 3.00-2.96 (t, 4H), 2.18-2.11 (m, 2H).

    Step B: 2,3,6,7-tetrahydro-s-indacen-1(5H)-one

    [1018] ##STR00191##

    [1019] To conc. H.sub.2SO.sub.4 (1.84 kg, 18.39 mol, 98 wt. % in aq solution, 37.25 eq) was added 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (103 g, 493.57 mmol, 1 eq). Then the reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was poured into ice-water (4.5 L) and the resulting suspension was filtered. The filter cake was dissolved in EtOAc (500 mL) and washed with sat aq Na.sub.2CO.sub.3 solution (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuum to give the title compound (60 g, 69.17% yield, 98% purity on LCMS) as a yellow solid.

    [1020] LCMS: m/z 173.2 (M+H).sup.+ (ES.sup.+).

    [1021] .sup.1H NMR (CDCl.sub.3): δ 7.58 (s, 1H), 7.30 (s, 1H), 3.08-2.96 (m, 2H), 2.95-2.91 (m, 4H), 2.70 (t, 2H), 2.15-2.05 (m, 2H).

    Step C: 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one

    [1022] ##STR00192##

    [1023] To a solution of 2,3,6,7-tetrahydro-s-indacen-1(5H)-one (54.88 g, 318.66 mmol, 1 eq) in 665 mL of H.sub.2SO.sub.4 was added dropwise a mixture of H.sub.2SO.sub.4 (22.76 mL, 427.00 mmol, 1.34 eq) and HNO.sub.3 (22.83 mL, 497.11 mmol, 98% purity, 1.56 eq) at 0˜10° C. After addition, the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water (1 L) and extracted with DCM (1 L×3). The combined organic layers were washed with sat aq NaHCO.sub.3 solution (400 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 5:1) to give the title compound (30 g, yield: 43.34%) as a yellow solid.

    [1024] .sup.1H NMR (CDCl.sub.3): δ 7.45 (s, 1H), 3.47 (t, 2H), 3.11-2.97 (m, 4H), 2.76 (t, 2H), 2.22-2.18 (m, 2H).

    Step D: 1-allyl-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

    [1025] ##STR00193##

    [1026] To a solution of 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (20 g, 92.07 mmol, 1 eq) in THF (200 mL) was added allylmagnesium bromide (1 M, 138.11 mL, 1.5 eq) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 3 h. The reaction mixture was quenched with water (100 mL) and filtered through a pad of silica gel. The filter cake was washed with EtOAc (80 mL×3) and the filtrate was concentrated in vacuum to remove THF. The aqueous layer was extracted with EtOAc (80 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 9:1) and then further purified by reversed phase flash chromatography (water (0.1% TFA)-MeCN) to give a racemic mixture of the title compound (2.8 g, 11-73% yield) as a brown oil.

    [1027] LCMS: m/z 242.2 (M−OH).sup.+ (ES.sup.+).

    [1028] .sup.1H NMR (CDCl.sub.3): δ 7.28 (s, 1H), 5.67-5.62 (m, 1H), 5.15-5.05 (m, 2H), 3.62 (s, 1H), 3.26-3.14 (m, 1H), 3.10-2.92 (m, 4H), 2.87-2.68 (m, 2H) 2.67-2.52 (m, 1H), 2.46-2.35 (m, 1H), 2.28-2.06 (m, 3H).

    Preparation of Examples

    Example 1: 24-Oxa-14λ.SUP.6.-thia-11,13,18,26,30-pentaazapentacyclo-[23.3.1.1.SUP.15,18..0.SUP.2,10..0.SUP.5,9.]-triaconta-1(29),2(10),3,5(9),15(30),16,25,27-octaene-12,14,14-trione

    [1029] ##STR00194##

    [1030] Triphosgene (0.075 g, 0.254 mmol) was added to a solution of 1-(5-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)pentyl)-1H-pyrazole-3-sulfonamide (Intermediate Ci) (0.17 g, 0.385 mmol) in THF (10 mL). Et.sub.3N (0.107 mL, 0.770 mmol) was added and the mixture was stirred for 90 min at RT. The mixture was concentrated in vacuo and redissolved in THF (10 mL). NaO.sup.tBu (2 M in THF, 0.578 mL, 1.155 mmol) was then added and the mixture was stirred at RT for 6 h, concentrated in vacuo and purified by basic prep HPLC (20-50% MeCN in water) to afford the title compound (28 mg, 15% yield) as a colourless solid.

    [1031] LCMS m/z 468.3 (M+H).sup.+ (ES.sup.+); 466.3 (M−H).sup.− (ES.sup.−).

    [1032] .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (d, J=5.3 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.82 (dd, J=5.3, 1.5 Hz, 1H), 6.63 (br s, 1H), 6.38 (d, J=2.2 Hz, 1H), 6.06 (br s, 2H), 4.17 (t, J=5.4 Hz, 2H), 4.10 (t, J=6.2 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.86-2.77 (m, 2H), 2.00 (p, J=7.5 Hz, 2H), 1.85-1.76 (m, 2H), 1.68-1.57 (m, 2H), 1.32-1.11 (m, 2H).

    [1033] The following examples were synthesised following the general procedure for Example 1, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00003 Ex Structure From .sup.1H NMR LCMS  2 [00195]embedded image C.sub.2 .sup.1H NMR (DMSO-d.sub.6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.84 (br s, 1H), 7.04 (s, 1H), 6.74 (d, J = 5.1 Hz, 1H), 6.59-6.46 (m, 1H), 6.17 (s, 1H), 4.62-4.39 (m, 1H), 4.29-4.07 (m, 2H), 4.07-3.88 (m, 1H), 3.02-2.63 (m, 4H), 2.09- 1.96 (m, 2H), 1.93 (s, 3H), 1.86-1.52 (m, 4H), 1.31-1.08 (m, 2H). Two exchangeable protons not observed. m/z 482.3 (M + H).sup.+ (ES.sup.+) 480.3 (M − H).sup.− (ES.sup.−) 3-methyl-24-oxa-14λ.sup.6-thia- 11,13,18,26,30-pentaaza- pentacyclo[23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- triaconta-1(29),2(10),3,5(9), 15(30), 16,25,27-octaene- 12,14,14-trione  3 [00196]embedded image C.sub.3 .sup.1H NMR (DMSO-d.sub.6) δ 8.10 (d, J = 5.2 Hz, 1H), 7.75 (s, 1H), 7.55 (br s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 5.3, 1.5 Hz, 1H), 6.53 (s, 1H), 6.46 (br s, 1H), 4.32 (t, J = 5.0 Hz, 2H), 4.28- 4.22 (m, 2H), 3.85 (t, J = 5.1 Hz, 2H), 3.72-3.62 (m, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.7 Hz, 2H), 2.03 (p, J = 7.5 m/z 470.3 (M + H).sup.+ (ES.sup.+) 468.2 (M − H).sup.− (ES.sup.−) 21,24-dioxa-14λ.sup.6-thia- Hz, 2H). One 11,13,18,26,30- exchangeable proton not pentaazapentacyclo- observed. [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(29),2(10),3,5(9),15(30), 16,25,27-octaene-12,14,14-trione  4 [00197]embedded image C.sub.4 .sup.1H NMR (DMSO-d.sub.6) δ 8.16-8.05 (m, 1H), 7.81 (br s, 1H), 7.61 (br s, 1H), 7.30-7.14 (m, 1H), 7.12- 7.00 (m, 1H), 6.92-6.81 (m, 1H), 6.61-6.51 (m, 1H), 6.45 (br s, 1H), 4.23 (br s, 2H), 3.94 (br s, 2H), 3.00-2.89 (m, 2H), 2.82 (br s, 2H), 2.12- 2.00 (m, 2H), 2.01-1.86 (m, 2H), 1.86-1.66 (m, 2H). One exchangeable m/z 454.3 (M + H).sup.+ (ES.sup.+) 452.2 (M − H).sup.− (ES.sup.−) 23-oxa-14λ.sup.6-thia-11,13,18,25,29- proton not observed. pentaazapentacyclo- [22.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]nonacosa- 1(28),2(10),3,5(9),15(29),16, 24,26-octaene-12,14,14-trione  5 [00198]embedded image C.sub.5 .sup.1H NMR (DMSO-d.sub.6) δ 8.13 (d, J = 5.3 Hz, 1H), 7.72 (br s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.88 (dd, J = 5.2, 1.5 Hz, 1H), 6.58 (br s, 1H), 6.51 (br s, 1H), 4.20-4.00 (m, 4H), 2.91 (t, J = 7.4 Hz, 2H), 2.88- 2.77 (m, 2H), 2.00 (p, J = 7.4 Hz, 2H), 1.85-1.75 (m, 2H), 1.71-1.62 (m, 2H), 1.41-1.25 (m, 4H). Two exchangeable protons not observed. m/z 482.2 (M + H).sup.+ (ES.sup.+) 480.2 (M − H).sup.− (ES.sup.−) 25-oxa-14λ.sup.6-thia-11,13,18,27,31- pentaazapentacyclo- [24.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9] hentriaconta- 1(30),2(10),3,5(9),15(31),16, 26,28-octaene-12,14,14-trione  6 [00199]embedded image C6 .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (br s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.89-7.58 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 5.1 Hz, 1H), 6.44 (br s, 1H), 4.35-4.05 (m, 4H), 2.95 (t, J = 7.5 Hz, 2H), 2.89- 2.75 (m, 2H), 2.06 (p, J = 7.5 Hz, 2H), 1.93-1.79 (m, 2H), 1.69-1.58 (m, 2H), 1.22-1.01 (m, 2H). One exchangeable proton m/z 468.3 (M + H).sup.+ (ES.sup.+) 466.2 (M − H).sup.− (ES.sup.−) 24-oxa-14λ.sup.6-thia-11,13,17,18,26- not observed. pentaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione  7 [00200]embedded image C.sub.7 .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J = 5.2 Hz, 1H), 7.92 (br s, 1H), 7.51 (br s, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 5.3, 1.5 Hz, 1H), 6.64 (br s, 1H), 6.08 (br s, 1H), 4.40 (br s, 2H), 4.34 (br s, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.27 (br s, 2H), 2.03 (p, J = 7.5 Hz, 2H). One m/z 440.3 (M + H).sup.+ (ES.sup.+) 438.2 (M − H).sup.− (ES.sup.−) 22-oxa-14λ.sup.6-thia-11,13,18,24,28- exchangeable proton not pentaazapentacyclo- observed. [21.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]octacosa- 1(26),2,4,9,15(28),16,23(27),24- octaene-12,14,14-trione  8 [00201]embedded image C8 .sup.1H NMR (DMSO-d.sub.6) δ 8.12 (d, J = 5.2 Hz, 1H), 7.72 (s, 1H), 7.65-7.47 (br s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.2, 1.5 Hz, 1H), 6.53 (br s, 1H), 6.44 (s, 1H), 4.32- 4.09 (m, 4H), 2.91 (t, J = 7.4 Hz, 4H), 2.87- 2.68 (m, 4H), 2.34 (s, 3H), 2.02 (p, J = 7.4 Hz, 2H). One exchangeable proton not observed. m/z 483.4 (M + H).sup.+ (ES.sup.+) 21-methyl-24-oxa-14λ.sup.6-thia- 11,13,18,21,26,30- hexaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione  9 [00202]embedded image C.sub.14 .sup.1H NMR (DMSO-d.sub.6) δ 7.79 (br s, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 8.5 Hz, 2H), 6.61 (br s, 2H), 4.19 (br s, 2H), 3.81 (br s, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.81 (br s, 2H), 2.01 (p, J = 7.5 Hz, 2H), 1.84 (t, J = 7.2 Hz, 2H), 1.71-1.62 (M, 2H), 1.30 (p, J = 8.5 Hz, 2H). Two exchangeable protons m/z 467.3 (M + H).sup.+ (ES.sup.+) 465.2 (M − H).sup.− (ES.sup.−) 24-oxa-14λ.sup.6-thia-11,13,18,30- not observed. tetraazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione 10 [00203]embedded image C.sub.9 .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J = 5.3 Hz, 1H), 7.76 (s, 1H), 7.57 (s, 1H), 7.22 (dd, J = 10.2, 3.0 Hz, 1H), 6.93 (dd, J = 8.7, 3.0 Hz, 1H), 6.88- 6.8 (m, 1H), 6.56 (s, 1H), 6.49 (s, 1H), 4.32- 4.12 (m, 4H), 3.22-3.07 (m, 1H), 1.82 (br s, 2H), 1.72-1.58 (m, 2H), 1.40- 1.06 (m, 8H). One exchangeable proton not observed. m/z 488.3 (M + H).sup.+ (ES.sup.+) 4-fluoro-6-(propan-2-yl)-21- oxa-11λ.sup.6-thia-8,10,15,23,27- pentaazatetracyclo- [20.3.1.1.sup.12,15.0.sup.2,7]heptacosa- 1(25),2(7),3,5,12(27),13,22(26),2 3-octaene-9,11,11-trione 11 [00204]embedded image C.sub.10 .sup.1H NMR (DMSO-d.sub.6) δ 8.03 (d, J = 5.2 Hz, 1H), 7.97 (br s, 1H), 7.61 (br s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 5.2, 1.5 Hz, 1H), 6.49 (br s, 1H), 6.36 (br s, 1H), 4.59 (br s, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.4 Hz, 2H). 1.69 (s, 6H). One exchangeable proton not observed. m/z 454.3 (M + H).sup.+ (ES.sup.+) 452.2 (M − H).sup.− (ES.sup.−) 19,19-dimethyl-21-oxa-14λ.sup.6- thia-11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(25),2,4,9,15(27), 16,22(26),23-octaene-12,14,14-trione 12 [00205]embedded image C.sub.11 .sup.1H NMR (DMSO-d.sub.6) δ 8.13 (d, J = 5.2 Hz, 1H), 7.93 (br s, 1H), 7.63 (br s, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.3, 1.5 Hz, 1H), 6.61 (br s, 1H), 6.44 (br s, 1H), 4.33-4.16 (m, 2H), 3.75-3.62 (m, 4H), 2.94 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.05 (p, J = 7.5 Hz, 2H). 1.54 (s, 6H). One m/z 498.2 (M + H).sup.+ (ES.sup.+) 496.1 (M − H).sup.− (ES.sup.−) 19,19-dimethyl-21,24-dioxa- exchangeable proton not 14λ.sup.6-thia-11,13,18,26,30- observed. pentaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione 13 [00206]embedded image C.sub.12 .sup.1H NMR (DMSO-d.sub.6) δ 10.94 (br s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 8.06- 7.65 (m, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.83-6.59 (m, 1H), 6.54-6.39 (m, 1H), 4.45 (br s, 1H), 3.70- 3.42 (m, 2H), 3.10- 2.73 (m, 6H), 2.42-2.28 (m, 2H), 2.04 (p, J = 7.5 Hz, 2H), 1.75 (br s, 6H). m/z 525.3 (M + H).sup.+ (ES.sup.+) 523.2 (M − H).sup.− (ES.sup.−) 19,19,21-trimethyl-24-oxa-14λ.sup.6- thia-11,13,18,21,26,30- hexaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14,2o-tetrone 14 [00207]embedded image C.sub.13 .sup.1H NMR (DMSO-d.sub.6) δ 10.90 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.19 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 5.3 Hz, 1H), 6.63-6.42 (m, 2H), 4.26 (s, 2H), 3.75 (s, 1H), 3.61 (s, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.82 (s, 2H), 2.35 (s, 5H), 2.05 (q, J = 7.4 Hz, 2H), 1.79 (t, J = 5.9 Hz, 2H), 1.04-0.87 (m, 4H). One exchangeable proton not m/z 523.4 (M + H).sup.+ (ES.sup.+) 17-cyclopropyl-20-methyl-24- observed. oxa-14λ.sup.6-thia-11,13,16,17,20, 26- hexaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15,18(30),25(29),26- octaene-12,14,14-trione 15 [00208]embedded image C.sub.15 .sup.1H NMR (DMSO-d.sub.6) δ 8.07 (d, J = 5.3 Hz, 1H), 7.84 (s, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 6.59 (s, 1H), 6.53 (s, 1H), 4.64 (s, 2H), 4.42-4.34 (m, 2H), 3.70 (s, 1H), 3.50-3.43 (m, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.84 (s, 2H), 2.09- 2.00 (m, 2H), 1.95-1.87 (m, 2H), 1.10-0.96 (m, 4H). One exchangeable m/z 510.2 (M + H).sup.+ (ES.sup.+) 17-cyclopropyl-20,24-dioxa- proton not observed. 14λ.sup.6-thia-11,13,16,17,26- pentaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15,18(30),25(29),26- octaene-12,14,14-trione 16 [00209]embedded image C16 .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J = 5.1 Hz, 1H), 7.36 (br s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 5.1 Hz, 1H), 6.55-6.47 (m, 1H), 6.17 (m, 1H), 5.48 (s, 2H), 3.62-3.52 (m, 1H), 2.90 (t, J = 7.3 Hz, 2H), 2.79 (m, 2H), 2.01 (p, J = 7.3 Hz, 2H), 1.12-0.93 (m, 4H). One exchangeable proton not observed. m/z 452.3 (M + H).sup.+ (ES.sup.+) 17-cyclopropyl-20-oxa-14λ.sup.6- thia-11,13,16,17,22- pentaazapentacyclo- [19.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]hexacosa- 1(24),2,4,9,15,18(26),21(25),22- octaene-12,14,14-trione 17 [00210]embedded image C.sub.17 .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J = 5.3 Hz, 1H), 7.17 (m, 1H), 7.04 (d, 7.6 Hz, 1H), 6.86 (dd, J = 5.1, 1.4 Hz, 1H), 6.57- 6.37 (m, 2H), 4.38-4.11 (m, 4H), 3.43 (s, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.87-2.77 (m, 2H), 2.14 (s, 6H), 2.03 (p, J = 7.4 Hz, 2H), 1.93-1.83 (m, 2H), 1.67 (p, J = 7.6 Hz, 2H), 1.38-1.28 (m, 2H). Two exchangeable m/z 525.3 (M + H).sup.+ (ES.sup.+) 17-[(dimethylamino)-methyl]- protons not observed. 24-oxa-14λ.sup.6-thia- 11,13,18,26,30- pentaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione 18 [00211]embedded image C.sub.18 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J = 5.2 Hz, 1H), 8.00-7.71 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz, 1H), 6.63-6.40 (m, 2H), 4.27- 4.11 (m, 2H), 3.02-2.75 (m, 6H), 2.69-2.57 (m, 2H), 2.37 (s, 3H), 2.04 (p, J = 7.4 Hz, 2H), 1.53 (s, 6H). One exchangeable proton not observed. m/z 511.3 (M + H).sup.+ (ES.sup.+) 19,19,21-trimethyl-24-oxa-14λ.sup.6- thia-11,13,18,21,26,30- hexaazapentacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione 19 [00212]embedded image C.sub.19 .sup.1H NMR (DMSO-d.sub.6) δ 8.22-8.15 (m, 1H), 7.75 (br s, 1H), 7.25-7.12 (m, 2H), 6.95-6.88 (m, 1H), 6.86.6.87 (m, 1H), 4.60- 4.40 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.89-2.76 (m, 4H), 2.04 (p, J = 8.2 Hz, 2H), 1.77-1.60 (m, 4H), 1.55-1.46 (m, 2H). One exchangeable proton not observed. m/z 402.5 (M + H).sup.+ (ES.sup.+) 20-oxa-14λ.sup.6-thia-11,13,22- triazatetracyclo- [19.3.1.0.sup.2,10.0.sup.5,9]triaconta- 1(24),2,4,9,21(25),22-hexaene- 12,14,14-trione 20 [00213]embedded image C.sub.20 .sup.1H NMR (DMSO-d.sub.6) δ 8.05 (d, J = 5.2 Hz, 1H), 7.88 (br s, 1H), 7.69 (br s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.84-6.79 (m, 1H), 6.56-6.44 (m, 2H), 4.80 (br s, 2H), 4.48 (br s, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H). One exchangeable proton not observed. m/z 426.2 (M + H).sup.+ (ES.sup.+) 21-oxa-14λ.sup.6-thia-11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(25),2,4,9,15(27),16,22(26),23- octaene-12,14,14-trione 21 [00214]embedded image C.sub.21 .sup.1H NMR (DMSO-d.sub.6) δ 8.02-7.87 (m, 1H), 7.42- 7.20 (m, 2H), 7.19-7.09 (m, 1H), 7.06-6.96 (m, 1H), 6.95-6.77 (m, 2H), 6.75-6.60 (m, 1H), 6.60- 6.41 (m, 1H), 4.45-4.29 (m, 2H), 3.79-3.69 (m, 2H), 2.98-2.85 (m, 2H), 2.85-2.70 (m, 2H), 2.35- 2.14 (m, 2H), 2.14-1.91 (m, 2H). One exchangeable proton not m/z 439.3 (M + H).sup.+ (ES.sup.+) 22-oxa-14λ.sup.6-thia-11,13,18,28- observed. tetraazapentacyclo- [21.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]-octacosa- 1(26),2,4,9,15(28),16,23(27),24- octaene-12,14,14-trione 22 [00215]embedded image C.sub.22 .sup.1H NMR (DMSO-d.sub.6) δ 8.12 (d, J = 5.3 Hz, 1H), 7.52 (br s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 5.2 Hz, 1H), 6.58 (br s, 1H), 6.06 (br s, 1H), 4.56-4.26 (m, 4H), 3.51 (s, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.85-2.72 (m, 2H), 2.31-2.23 (m, 2H), 2.16 (s, 6H), 2.07-1.96 (m, 2H). One m/z 497.2 (M + H).sup.+ (ES.sup.+) 17-[(dimethylamino)-methyl]- exchangeable proton not 22-oxa-14λ.sup.6-thia-11,13,18,24,28- observed. pentaazapentacyclo- [21.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]octacosa- 1(26),2,4,9,15(28),16,23(27),24- octaene-12,14,14-trione 23 [00216]embedded image C.sub.23 .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 7.51 (s 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 5.2, 1.5 Hz, 1H), 6.29 (s, 1H), 4.30 (s, 4H), 2.93 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.24 (s, 2H), 2.03 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. m/z 458.2 (M + H).sup.+ (ES.sup.+) 16-fluoro-22-oxa-14λ.sup.6-thia- 11,13,18,24,28- pentaazapentacyclo- [21.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]octacosa- 1(26),2,4,9,15(28),16,23(27),24- octaene-12,14,14-trione 25 [00217]embedded image C.sub.25 .sup.1H NMR (DMSO-d.sub.6) δ 8.05 (d, J = 5.2 Hz, 1H), 7.99 (s, 1H), 7.70 (s 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 6.59 (s, 1H), 4.76 (s, 2H), 4.35 (s, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. m/z 444.1 (M + H).sup.+ (ES.sup.+) 16-fluoro-21-oxa-14λ.sup.6-thia- 11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(25),2,4,9,15(27),16,22(26),23- octaene-12,14,14-trione 26 [00218]embedded image C.sub.26 .sup.1H NMR (DMSO-d.sub.6) δ 8.16-8.11 (m, 2H), 7.22 (br s, 1H), 7.07-7.05 (m, 1H), 6.76-6.75 (m, 1H), 6.04 (br s, 1H), 4.04 m- 4.81 (m, 1H), 4.21-4.19 (m, 1H), 2.90-2.86 (m, 2H), 2.74-2.71 (m, 2H), 2.02-1.95 (m, 5H), 1.73- 1.71 (m, 3H), 1.49-1.48 (m, 3H). One exchangeable proton not observed. m/z 486.4 (M + H).sup.+ (ES.sup.+) 16-fluoro-19,19-dimethyl-21- oxa-14λ.sup.6-thia-11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(25),2,4,9,15(27),16,22(26),23- octaene-12,14,14-trione 34 [00219]embedded image C.sub.34 .sup.1H NMR (DMSO-d.sub.6) δ 8.01 (d, J = 5.3 Hz, 1H), 7.85 (br s, 1H), 7.42 (br s, 1H), 7.04-6.93 (m, 1H), 6.75 (d, J = 5.2 Hz, 1H), 6.37 (s, 1H), 6.26 (s, 1H), 4.54 (s, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.65 (s, 6H). One exchangeable proton not observed. m/z 472.4 (M + H).sup.+ (ES.sup.+) 3-fluoro-19,19-dimethyl-21-oxa- 14λ.sup.6-thia-11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(25),2,4,9,15(27),16,22(26),23- octaene-12,14,14-trione 35 [00220]embedded image   [00221]embedded image C.sub.35 .sup.1H NMR (DMSO-d.sub.6) δ 10.82 (br s, 1H), 8.17- 8.01 (m, 2H), 7.89 (br s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 5.1 Hz, 1H), 6.76 (br s, 1H), 6.68 (br s, 1H), 5.70 (br s, 1H), 5.13 (br s, 1H), 4.39- 4.27 (m, 2H), 4.19 (br s, 1H), 3.87-3.80 (m, 1H), 2.92 (t, J = 7.5 Hz, 2H), 2.79 (br s, 2H), 2.08- 1.99 (m, 2H). m/z 468.3 (M + H).sup.+ (ES.sup.+) (Enantiomeric mixture) (anti)-21,24-dioxa-14λ.sup.6-thia- 11,13,18,26,30- pentaazahexacyclo- [23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9.0.sup.19,23]- triaconta- 1(28),2,4,9,15(30),16,25(29),26- octaene-12,14,14-trione 36 [00222]embedded image C.sub.36 .sup.1H NMR (DMSO-d.sub.6) δ 7.74 (d, J = 2.4 Hz, 1H), 7.37 (br s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.29 (d, J = 2.4 Hz, 2H), 4.45 (s, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 1.99 (p, J = 7.5 Hz, 2H), 1.61 (s, 6H). One exchangeable proton not observed. m/z 468.5 (M + H).sup.+ (ES.sup.+) 19,19,24-trimethyl-21-oxa-14λ.sup.6- thia-11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(26),2,4,9,15(27),16,22,24- octaene-12,14,14-trione 39 [00223]embedded image C.sub.39 .sup.1H NMR (DMSO-d.sub.6) δ 8.04 (br s, 1H), 7.94 (d, J = 5.2 Hz, 1H), 7.71 (br s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 5.2, 1.5 Hz, 1H), 6.52 (br s, 1H), 6.47 (s, 1H), 4.73 (br s, 2H), 3.83-3.75 (m, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.60-2.51 (m, 2H), 2.14- 1.99 (m, 4H). Two aliphatic protons overlapped with water in DMSO-d.sub.6 signal. One exchangeable proton not m/z 496.4 (M + H).sup.+ (ES.sup.+) 21′-oxa-14′λ.sup.6-thia- observed. 11′,13′,18′,23′,27′-pentaaza- spiro[oxane-4,19′-pentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosan]-1′(25′),2′,4′, 9′,15′(27′),16′,22′(26′),23′- octaene-12′,14′,14′-trione 40 [00224]embedded image C.sub.40 .sup.1H NMR (DMSO-d.sub.6) δ 11.12 (s, 1H), 8.09 (m, 2H), 7.74 (s, 1H), 7.11 (d, J = 9.4 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 6.42 (s, 1H), 4.80 (s, 2H), 4.43 (s, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.05 (p, J = 7.0 Hz, 2H). m/z 461.7 (M + H).sup.+ (ES.sup.+) 459.8 (M − H).sup.− (ES.sup.−) 3,16-difluoro-21-oxa-14λ.sup.6-thia- 11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(25),2(10),3, 5(9),15(27),16,22(26),23- octaene-12,14,14-trione 42 [00225]embedded image C.sub.42 .sup.1H NMR (DMSO-d.sub.6) δ 11.10 (s, 1H), 8.17-7.97 (m, 1H), 7.84-7.66 (m, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.52 (t, J = 8.9 Hz, 2H), 4.74 (s, 2H), 4.48- 4.27 (m, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.07-2.00 (m, 2H). m/z 462.4 (M + H).sup.+ (ES.sup.+) 16,24-difluoro-21-oxa-14λ.sup.6-thia- 11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(26),2,4,9,15(27),16,22,24- octaene-12,14,14-trione 43 [00226]embedded image C.sub.43 .sup.1H NMR (DMSO-d.sub.6) δ 10.83 (br s, 1H), 8.07 (d, J = 5.2 Hz, 1H), 8.04- 7.98 (m, 1H), 7.57 (br s, 1H), 7.20 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.83 (dd, J = 5.2, 1.5 Hz, 1H), 6.56 (br s, 1H), 6.34 (s, 1H), 4.87 (br s, 1H), 4.46-4.22 (m, 1H), 3.14-3.03 (m, 1H), 1.74 (s, 3H), 1.63 (s, 3H), 1.21- 1.08 (m, 6H). m/z 474.2 (M + H).sup.+ (ES.sup.+) 4-fluoro-16,16-dimethyl-6- (propan-2-yl)-18-oxa-11λ.sup.6-thia- 8,10,15,20,24- pentaazatetracyclo- [17.3.1.1.sup.12,15.0.sup.2,7]tetracosa- 1(22),2(7),3,5,12(24),13,19(23), 20-octaene-9,11,11-trione 47 [00227]embedded image C.sub.47 .sup.1H NMR (DMSO-d.sub.6) δ 11.93 (s, 1H), 8.29 (s, 1H), 8.10-8.01 (m, 2H), 7.61 (s, 1H), 7.19 (dd, J = 5.7, 1.9 Hz, 1H), 6.80 (s, 1H), 4.51 (s, 2H), 2.76 (sept, J = 6.9 Hz, 1H), 1.64 (s, 6H), 1.14 (d, J = 6.9 Hz, 6H). m/z 464.4 (M + H).sup.+ (ES.sup.+) 12-fluoro-15,15-dimethyl-5- (propan-2-yl)-17-oxa-10λ.sup.6-thia- 2,3,7,9,14,19,23- heptaazatetracyclo- [16.3.1.1.sup.11,14.0.sup.2,6]tricosa- 1(21),3,5,11(23),12,18(22),19- heptaene-8,10,10-trione

    Example 3b: 21,24-dioxa-14λ.SUP.6.-thia-11,13,18,26,30-pentaazapentacyclo-[23.3.1.1.SUP.15,18..0.SUP.2,10..0.SUP.5,9.]triaconta-1(29),2(10),3,5 (9),15(30),16,25,27-octaene-12,14,14-trione, sodium salt

    [1034] ##STR00228##

    [1035] 21,24-Dioxa-14λ.sup.6-thia-11,13,18,26,30-pentaazapentacyclo[23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]-triaconta-1(29),2(10),3,5(9),15(30),16,25,27-octaene-12,14,14-trione (Example 3) (38.83 mg, 0.080 mmol) was dissolved in 0.5 M aq NaOH (160 μl, 0.080 mmol). Water (1 mL) was added and the mixture was frozen. The mixture was freeze-dried overnight to afford the title compound (20 mg, 50%) as a solid.

    [1036] LCMS m/z 470.3 (M+H).sup.+ (ES.sup.+); 468.2 (M−H).sup.− (ES.sup.−).

    [1037] .sup.1H NMR (DMSO-d.sub.6) δ 8.08-7.93 (m, 1H), 7.60-7.50 (m, 1H), 7.05 (br s, 1H), 7.00-6.93 (m, 1H), 6.86-6.76 (m, 1H), 6.61 (br s, 1H), 6.36-6.24 (m, 1H), 4.27-4.10 (m, 4H), 3.83 (t, J=5.0 Hz, 2H), 3.74-3.60 (m, 2H), 2.96-2.77 (m, 4H), 2.07-1.92 (m, 2H). One exchangeable proton not observed.

    Example 24: 3,19,19-trimethyl-21-oxa-14λ.SUP.6.-thia-11,13,18,23,27-pentaazapentacyclo-[20.3.1.1.SUP.15,18..0.SUP.2,10..0.SUP.5,9.]heptacosa-1(25),2(10),3,5(9),15(27),16,22(26),23-octaene-12,14,14-trione, Sodium Salt

    [1038] ##STR00229##

    Step A: 3,19,19-trimethyl-21-oxa-14λ.SUP.6.-thia-11,13,18,23,27-pentaazapentacyclo-[20.3.1.1.SUP.15,18..0.SUP.2,10..0.SUP.5,9.]heptacosa-1(25),2(10),3,5(9),15(27),16,22(26),23-octaene-12,14,14-trione

    [1039] ##STR00230##

    [1040] Prepared according to the general procedure for 24-oxa-14λ.sup.6-thia-11,13,18,26,30-pentaazapentacyclo-[23.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]triaconta-1(29),2(10),3,5(9),15(30),16,25,27-octaene-12,14,14-trione (Example 1) from 1-(1-((4-(4-amino-6-methyl-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate C24) to afford the title compound (69 mg, 33%) as an off-white solid.

    Step B: 3,19,19-trimethyl-21-oxa-14λ.SUP.6.-thia-11,13,18,23,27-pentaazapentacyclo-[20.3.1.1.SUP.15,18..0.SUP.2,10..0.SUP.5,9.]heptacosa-1(25),2(10),3,5(9),15(27),16,22(26),23-octaene-12,14,14-trione, sodium salt

    [1041] ##STR00231##

    [1042] 0.1 M NaOH (1280 μL, 0.128 mmol) was added to 3,19,19-trimethyl-21-oxa-14λ.sup.6-thia-11,13,18,23,27-pentaazapentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa-1(25),2(10),3,5(9), 15(27),16,22(26),23-octaene-12,14,14-trione and the solution was frozen. The mixture was freeze-dried overnight to afford the title compound (62 mg, 98%) as a white solid.

    [1043] LCMS m/z 468.1 (M+H).sup.+ (ES.sup.+).

    [1044] .sup.1H NMR (DMSO-d.sub.6) δ 7.98 (d, J=5.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 6.93 (s, 1H), 6.78 (s, 1H), 6.61 (dd, J=5.1, 1.4 Hz, 1H), 6.27 (d, J=2.3 Hz, 1H), 6.17 (s, 1H), 4.82 (d, J=10.9 Hz, 1H), 4.18 (d, J=10.9 Hz, 1H), 2.91-2.66 (m, 4H), 2.04-1.93 (m, 2H), 1.92 (s, 3H), 1.71 (s, 3H), 1.53 (s, 3H).

    [1045] The following examples were synthesised following the general procedure for Example 24, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00004 Ex. Structure From .sup.1H NMR LCMS 27 [00232]embedded image C.sub.27 .sup.1H NMR (DMSO-d.sub.6) δ 7.94 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 4.7 Hz, 1H), 7.57 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.76-6.69 (m, 1H), 6.54 (s, 1H), 4.49 (s, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.00 (p, J = 7.5 Hz, 2H), 1.58 (s, 6H). m/z 472.3 (M + H).sup.+ (ES.sup.+) Sodium salt 16-fluoro-19,19-dimethyl-21-oxa- 14λ.sup.6-thia-11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(25),2,4,9,15(27), 16,22(26),23-octaene-12,14,14- trione, sodium salt 28 [00233]embedded image C.sub.28 .sup.1H NMR (DMSO-d.sub.6) δ 7.98 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 6.1 Hz, 1H), 7.24-7.17 (m, 1H), 6.88 (s, 2H), 6.54 (d, J = 2.4 Hz, 1H), 5.90-5.83 (m, 1H), 5.76-5.70 (m, 1H), 5.62-5.56 (m, 1H), 4.87 (d, J = 8.8 Hz, 1H), 2.81 (t, J = 7.4 Hz, 2H), 2.74-2.67 (m, 1H), 2.67-2.61 (m, m/z 440.4 (M + H).sup.+ (ES.sup.+) Sodium salt 1H), 2.02 (s, 3H), 1.89 3-methyl-21-oxa-14λ.sup.6-thia- (p, J = 7.9 Hz, 2H). 11,13,18,23,27-pentaazapentacyclo- One exchangeable [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- proton not observed. 1(25),2(10),3,5(9),15(27),16,22(26), 23-octaene-12,14,14-trione, sodium salt 29 [00234]embedded image C.sub.29 .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 6.2 Hz, 1H), 7.12-6.86 (m, 3H), 5.93-5.85 (m, 1H), 5.77-5.71 (m, 1H), 5.55 (dd, J = 15.6, 1.5 Hz, 1H), 4.90 (dd, J = 9.0, 1.4 Hz, 1H), 2.81 (t, J = 7.4 Hz, 2H), 2.76-2.67 (m, 1H), 2.65-2.59 (m, 1H), m/z 458.4 (M + H).sup.+ (ES.sup.+) Sodium salt 2.02 (s, 3H), 1.93-1.85 16-fluoro-3-methyl-21-oxa-14λ.sup.6- (m, 2H). One thia-11,13,18,23,27-pentaaza- exchangeable proton pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- not observed. heptacosa-1(25),2(10),3,5(9), 15(27),16,22(26),23-octaene- 12,14,14-trione, sodium salt 30 [00235]embedded image C.sub.30 .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 4.6 Hz, 1H), 7.32 (s′1H), 7.09 (dd, J = 10.2, 3,0 Hz, 1H), 6.83 (dd, J = 8.7, 3.0 Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 6.53 (s, 1H), 4.68-4.59 (m, 1H), 4.39-4.30 (m, 1H), 3.25 (sept, J = 7.0 Hz, 1H), 1.65 (s, 3H), 1.51 (s, 3H), 1.23- 1.06 (m, 6H). m/z 492.4 (M + H).sup.+ (ES.sup.+) Sodium salt 4,13-difluoro-16,16-dimethyl-6- (propan-2-yl)-18-oxa-11λ.sup.6-thia- 8,10,15,20,24-pentaazatetracyclo- [17.3.1.1.sup.12,15.0.sup.2,7]tetracosa- 1(22),2(7),3,5,12(24),13,19 (23),20- octaene-9,11,11-trione, sodium salt 31 [00236]embedded image C.sub.31 .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.39- 7.14 (m, 3H), 7.14- 6.88 (m, 2H), 6.87- 6.67 (m, 2H), 4.63 (s, 2H), 3.06-2.68 (m, 6H), 1.99 (s, 2H). One exchangeable proton not observed. m/z 436.3 (M + H).sup.+ (ES.sup.+) Sodium salt 22-oxa-14λ.sup.6-thia-11,13,24-triaza- pentacyclo-[21.3.1.1.sup.15,19.0.sup.2,10.0.sup.5,9]- octacosa-1(26),2,4,9,15(28),16,18, 23(27),24-nonaene-12,14,14-trione, sodium salt 32 [00237]embedded image C.sub.32 .sup.1H NMR (DMSO-d.sub.6) δ 7.83-7.79 (m, 1H), 7.68 (br s, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.62-6.58 (m, 1H), 6.18 (d, J = 2.4 Hz, 1H), 5.45 (d, J = 11.5 Hz, 1H), 4.03 (d, J = 11.5 Hz, 1H), 2.97- 2.83 (m, 3H), 2.82- 2.72 (m, 1H), 2.05- 1.96 (m, 2H), 1.74 (s, 3H), 1.57 (s, 3H). m/z 472.3 (M + H).sup.+ (ES.sup.+) Sodium salt 26-fluoro-19,19-dimethyl-21-oxa- 14λ.sup.6-thia-11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(26),2,4,9,15(27),16, 22,24-octaene-12,14,14-trione, sodium salt 33 [00238]embedded image C.sub.33 .sup.1H NMR (DMSO-d.sub.6) δ 7.83 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.13 (br s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 6.12 (br s, 1H), 4.74-4.59 (m, 1H), 4.27-4.09 (m, 1H), 2.93-2.72 (m, 4H), 2.00 (p, J = 7.5 Hz, 2H), 1.91 (s, 3H), 1.74-1.42 (m, 6H). m/z 468.3 (M + H).sup.+ (ES.sup.+) Sodium salt 19,19,25-trimethyl-21-oxa-14λ.sup.6- thia-11,13,18,23,27-pentaaza- pentacyclo-[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(26),2,4,9, 15(27),16,22,24-octaene-12,14,14- trione, sodium salt 37 [00239]embedded image C.sub.37 .sup.1H NMR (DMSO-d.sub.6) δ 8.01 (d, J = 5.1 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 6.80 (br s, 1H), 6.65 (dd, J = 5.1, 1.2 Hz, 1H), 6.48 (s, 1H), 6.28 (d, J = 2.3 Hz, 1H), 6.08 (br s, 1H), 4.83-4.74 (m, 1H), 4.49 (t, J = 8.7 Hz, 2H), 4.23-4.15 (m, 1H), 3.21-3.07 (m, 1H), 3.03-2.91 (m, 1H), 1.90 (s, 3H), 1.72 (br s, 3H), 1.52 (br s, m/z 470.4 (M + H).sup.+ (ES.sup.+) Sodium salt 3H). 3,19,19-trimethyl-6,21-dioxa-14λ.sup.6- thia-11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(25),2(10),3,5(9), 15(27),16,22(26),23-octaene- 12,14,14-trione, sodium salt 38 [00240]embedded image C.sub.38 .sup.1H NMR (DMSO-d.sub.6) δ 7.79 (s, 1H), 7.76- 7.62 (m, 1H), 6.93- 6.54 (m, 3H), 6.26 (d, J = 2.4 Hz, 1H), 4.45 (s, 2H), 2.89-2.71 (m, 4H), 2.03-1.86 (m, 2H), 1.61 (s, 6H). One exchangeable proton not observed. m/z 472.5 (M + H).sup.+ (ES.sup.+) Sodium salt 25-fluoro-19,19-dimethyl-21-oxa- 14λ.sup.6-thia-11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(25),2,4,9, 15(27),16,22(26),23-octaene- 12,14,14-trione, sodium salt 41 [00241]embedded image C.sub.41 .sup.1H NMR (DMSO-d.sub.6) δ 7.97 (d, J = 4.6 Hz, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.65 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 5.1 Hz, 1H), 6.44 (s, 1H), 4.52 (s, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.05- 1.96 (m, 2H), 1.58 (s, 6H). m/z 489.8 (M + H).sup.+ (ES.sup.+) Sodium salt 3,16-difluoro-19,19-dimethyl-21- oxa-14λ.sup.6-thia-11,13,18,23,27- pentaazapentacyclo- [20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]heptacosa- 1(25),2,4,9,15(27),16,22(26),23- octaene-12,14,14-trione, sodium salt 44 [00242]embedded image C44 .sup.1H NMR (DMSO-d.sub.6) δ 7.92 (s, 1H), 7.85 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 7.11 (dd, J = 10.2, 3.0 Hz, 1H), 6.87 (dd, J = 8.7, 3.0 Hz, 1H), 6.83-6.72 (m, 2H), 5.14 (s, 2H), 4.25 (s, 2H), 3.27-3.20 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). m/z 464.1 (M + H).sup.+ (ES.sup.+) Sodium salt 4,13-difluoro-6-(propan-2-yl)-18- oxa-11λ.sup.6-thia-8,10,15,20,24- pentaazatetracyclo[17.3.1.1.sup.12,15.0.sup.2,7]- tetracosa-1(22),2(7),3,5,12(24),13, 19(23),20-octaene-9,11,11-trione, sodium salt 45 [00243]embedded image C.sub.45 .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (br s, 1H), 7.83 (br s, 1H), 7.25-7.06 (m, 2H), 6.90 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 5.1 Hz, 1H), 6.41 (br s, 1H), 5.26 (br s, 1H), 4.15-4.05 (m, 1H), 3.00-2.80 (m, 4H), 2.15-1.91 (m, 2H), 1.82 (s, 3H), 1.51 (s, 3H), 1.40 (br s, 3H). m/z 468.5 (M + H).sup.+ (ES.sup.+) Sodium salt 19,19,26-trimethyl-21-oxa-14λ.sup.6- thia-11,13,18,23,27-pentaaza- pentacyclo[20.3.1.1.sup.15,18.0.sup.2,10.0.sup.5,9]- heptacosa-1(25),2,4,9, 15(27),16,22(26),23-octaene- 12,14,14-trione, sodium salt

    Example 46: 24-oxa-14λ.SUP.6.-thia-11,13,18,26,31-pentaazahexacyclo-[23.3.1.1.SUP.15,18..1.SUP.20,23..0.SUP.2,10..0.SUP.5,9.]hentriaconta-1(28),2,4,9,15(31),16,25(29),26-octaene-12,14,14-trione

    [1046] ##STR00244##

    [1047] To a solution of 1-((3-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)-cyclopentyl)methyl)-1H-pyrazole-3-sulfonamide (Intermediate C46) (120 mg, 264.58 μmol, 1 eq) and TEA (53 mg, 529.15 μmol, 2 eq) in THF (10 mL) was added triphosgene (47 mg, 158.75 μmol, 0.6 eq) at 0° C. The mixture was warmed to 20° C. and stirred for 1 h. The mixture was filtered and to the filtrate was added NaO.sup.tBu (76.28 mg, 793.73 μmol, 3 eq) at 0° C. The mixture was stirred at 50° C. for 2 h. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge, 150 mm×25 mm×5 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 14%-44%, 10 min) to give an enantiomeric mixture of a single cis- or trans-isomer of the title compound (8.15 mg, 6.29% yield, 97.95% purity on HPLC) as a white solid.

    [1048] LCMS: m/z 480.1 (M+H).sup.+ (ES.sup.+).

    [1049] .sup.1H NMR (CD.sub.3OD) δ 8.07 (d, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.10 (d, 1H), 6.88-6.82 (m, 2H), 6.43 (s, 1H), 5.13 (s, 1H), 4.44-4.40 (m, 1H), 4.29-4.24 (m, 1H), 3.01-2.89 (m, 4H), 2.61-2.53 (m, 1H), 2.15-1.99 (m, 4H), 1.93-1.75 (m, 4H). Two exchangeable protons not observed.

    Example 48: 5λ.SUP.6.-thia-2,4,9,27-tetraazapentacyclo[14.9.1.1.SUP.6,9..0.SUP.19,26..0.SUP.21,25.]heptacosa-1(25),6(27),7,19(26),20-pentaene-3,5,5-trione

    [1050] ##STR00245##

    Step A: 1-(6-(1-hydroxy-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)hex-4-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1051] ##STR00246##

    [1052] To a solution of 1-allyl-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol (Intermediate E1) (200 mg, 771.31 μmol, 1 eq) and N,N-bis(4-methoxybenzyl)-1-(pent-4-en-1-yl)-1H-pyrazole-3-sulfonamide (Intermediate D1) (351 mg, 771.31 μmol, 1 eq) in DCE (3 mL) was added benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium; tricyclohexylphosphane (131 mg, 154.26 μmol, 0.2 eq) at 25° C. The reaction mixture was stirred at 70° C. for 3 h under N.sub.2. The reaction mixture was concentrated in vacuum. The residue was re-dissolved with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc, 1:1) to give the title compound as a mixture of stereoisomers (0.3 g, 55.50% yield, 98% purity on LCMS) as a colourless gum.

    [1053] LCMS: m/z 669.4 (M−OH).sup.+ (ES.sup.+).

    [1054] .sup.1H NMR (CDCl.sub.3): δ 7.30-7.28 (m, 2H), 7.05 (d, 4H), 6.76 (d, 4H), 6.70-6.61 (m, 1H), 5.53-5.36 (m, 2H), 4.30 (s, 2H), 4.29 (s, 2H), 4.17-4.12 (m, 2H), 3.79 (s, 6H), 3.26-3.13 (m, 1H), 3.08-2.92 (m, 4H), 2.87-2.65 (m, 2H), 2.63-2.45 (m, 2H), 2.43-2.04 (m, 5H), 2.02-1.88 (m, 2H). One exchangeable proton not observed.

    Step B: 1-(6-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)hexyl)-N,N-bis(4-methoxy-benzyl)-1H-pyrazole-3-sulfonamide

    [1055] ##STR00247##

    [1056] A mixture of 1-(6-(1-hydroxy-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)hex-4-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.3 g, 436.80 μmol, 1 eq), Pd/C (30 mg, 10% purity loading on activated carbon) and methanesulfonic acid (84 mg, 873.60 μmol, 2 eq) in MeOH (30 mL) was stirred at 20° C. for 12 h under H.sub.2 atmosphere (15 psi). The reaction mixture was filtered through a pad of silica gel, and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:1) to give a racemic mixture of the title compound (70 mg, 23.93% yield, 96% purity on LCMS) as a colourless gum.

    [1057] LCMS: m/z 643.5 (M+H).sup.+ (ES.sup.+).

    [1058] .sup.1H NMR (CDCl.sub.3): δ 7.41 (d, 1H), 7.05 (d, 4H), 6.75 (d, 4H), 6.64 (d, 1H), 6.59 (s, 1H), 4.31 (s, 4H), 4.18-4.10 (m, 2H), 3.79 (s, 6H), 3.03-2.83 (m, 4H), 2.76-2.67 (m, 3H), 2.20-2.05 (m, 4H), 1.95-1.88 (m, 3H), 1.46-1.29 (m, 7H). Two exchangeable protons not observed.

    Step C: 1-(6-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)hexyl)-1H-pyrazole-3-sulfonamide

    [1059] ##STR00248##

    [1060] To a solution of 1-(6-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)hexyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (70 mg, 108.89 μmol, 1 eq) in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was stirred at 30° C. for 12 h. The reaction mixture was concentrated in vacuum. The residue was diluted with MeOH (4 mL) and filtered. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc, 1:1) to give a racemic mixture of the title compound (55 mg, 87.02% yield, 89% purity on LCMS, TFA salt) as a white solid.

    [1061] LCMS: m/z 403.3 (M+H).sup.+ (ES.sup.+).

    [1062] .sup.1H NMR (CD.sub.3OD): δ 7.71 (d, 1H), 6.70 (s, 1H), 6.64 (d, 1H), 4.20 (t, 2H), 3.19-3.13 (m, 1H), 2.97-2.65 (m, 6H), 2.17-2.04 (m, 3H), 2.04-1.81 (m, 4H), 1.45-1.25 (m, 7H). Four exchangeable protons not observed.

    Step D: 5λ.SUP.6.-thia-2,4,9,27-tetraazapentacyclo[14.9.1.1.SUP.6,9..0.SUP.19,26..0.SUP.21,25.]heptacosa-1(25),6(27),7,19(26),20-pentaene-3,5,5-trione

    [1063] ##STR00249##

    [1064] To a solution of 1-(6-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)hexyl)-1H-pyrazole-3-sulfonamide (55 mg, 106.47 μmol, 1 eq, TFA salt) and TEA (43 mg, 425.88 μmol, 4 eq) in THF (1.5 mL) was added triphosgene (16 mg, 53.24 μmol, 0.5 eq) at 0° C. The mixture was stirred at 20° C. for 0.5 h. Then the mixture was filtered. To the filtrate was added t-BuONa (10 mg, 106.47 μmol, 1 eq). The resulting mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×25 mm×5 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 19%-49%, 9 min) to give a racemic mixture of the title compound (1 mg, 2.17% yield, 99% purity on LCMS) as a white solid.

    [1065] LCMS: m/z 429.2 (M+H).sup.+ (ES.sup.+).

    [1066] .sup.1H NMR (CD.sub.3OD): δ 7.66 (s, 1H), 6.90 (s, 1H), 6.79 (s, 1H), 4.26 (t, 2H), 3.12-3.01 (m, 1H), 2.96-2.62 (m, 6H), 2.15-1.65 (m, 6H), 1.48-0.96 (m, 8H). Two exchangeable protons not observed.

    Example 49: 10λ.SUP.6.-thia-6,11,13,25-tetraazapentacyclo[12.9.1.1.SUP.6,9..0.SUP.15,19..0.SUP.21,24.]pentacosa-7,9(25),14,19,21(24)-pentaene-10,10,12-trione

    [1067] ##STR00250##

    Step A: 1-(4-(1-hydroxy-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)but-2-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1068] ##STR00251##

    [1069] To a solution of 1-allyl-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol (Intermediate E1) (0.5 g, 1.93 mmol, 1 eq) and 1-allyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate D2) (826 mg, 1.93 mmol, 1 eq) in DCE (7 mL) was added benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium; tricyclohexylphosphane (327 mg, 385.65 μmol, 0.2 eq). The reaction mixture was stirred at 70° C. for 12 h under N.sub.2. The reaction mixture was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 2:1) to give the title compound as a mixture of stereoisomers (0.5 g, 39.09% yield, 99% purity on LCMS) as a red oil.

    [1070] LCMS: m/z 641.2 (M−OH).sup.+ (ES.sup.+).

    [1071] .sup.1H NMR (CDCl.sub.3): δ 7.31 (s, 1H), 7.30 (s, 1H), 7.05 (d, 4H), 6.78 (d, 4H), 6.62 (d, 1H), 5.78-5.70 (m, 2H), 4.73-4.66 (m, 2H), 4.30 (d, 4H), 3.79 (s, 6H), 3.62 (s, 1H), 3.23-3.15 (m, 1H), 3.04-2.95 (m, 4H), 2.86-2.77 (m, 2H), 2.62-2.59 (m, 1H), 2.38-2.31 (m, 1H), 2.27-2.13 (m, 3H).

    Step B: 1-(4-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1072] ##STR00252##

    [1073] To a solution of 1-(4-(1-hydroxy-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)but-2-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.5 g, 753.69 μmol, 1 eq) and MsOH (145 mg, 1.51 mmol, 2.0 eq) in MeOH (15 mL) was added Pd/C (0.1 g, 10% purity on active carbon) under N.sub.2. The suspension was degassed in vacuum and purged with H.sub.2 several times. The mixture was stirred at 25° C. for 12 h under H.sub.2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was re-dissolved in EtOAc (50 mL) and sat aq Na.sub.2CO.sub.3 solution (50 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc, 1:1) to give a racemic mixture of the title compound (0.15 g, 32.37% yield, 100% purity on LCMS) as a yellow oil.

    [1074] LCMS: m/z 615.3 (M+H).sup.+ (ES.sup.+).

    [1075] .sup.1H NMR (CDCl.sub.3): δ 7.41 (d, 1H), 7.05 (d, 4H), 6.77 (d, 4H), 6.64 (d, 1H), 6.59 (s, 1H), 4.31 (s, 4H), 4.23-4.16 (m, 2H), 3.78 (s, 6H), 3.71-3.60 (m, 2H), 3.02-2.80 (m, 4H), 2.76-2.67 (m, 3H), 2.21-2.09 (m, 3H), 1.96-1.86 (m, 2H), 1.78-1.35 (m, 5H).

    Step C: 1-(4-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)butyl)-1H-pyrazole-3-sulfonamide

    [1076] ##STR00253##

    [1077] To a solution of 1-(4-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.15 g, 243.98 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01 mmol, 110.71 eq). The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was slurried with MeOH (10 mL), filtered and washed with MeOH (10 mL×5). The filtrate was concentrated under reduced pressure. The residue was re-dissolved in EtOAc (50 mL) and sat aq Na.sub.2CO.sub.3 (50 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (EtOAc:PE, 2:1) to give a racemic mixture of the title compound (64 mg, 62.90% yield, 90% purity on LCMS) as a yellow oil.

    [1078] LCMS: m/z 375.2 (M+H).sup.+ (ES.sup.+).

    [1079] .sup.1H NMR (CDCl.sub.3): δ 7.41 (d, 1H), 6.71 (d, 1H), 6.61 (s, 1H), 5.49 (br s, 2H), 4.27-4.17 (m, 2H), 3.85-3.59 (m, 2H), 2.99-2.84 (m, 4H), 2.76-2.65 (m, 3H), 2.22-2.09 (m, 3H), 1.96-1.84 (m, 3H), 1.72-1.65 (m, 1H), 1.52-1.43 (m, 1H), 1.38-1.27 (m, 2H).

    Step D: 10λ.SUP.6.-thia-6,11,13,25-tetraazapentacyclo[12.9.1.1.SUP.6,9..0.SUP.15,19..0.SUP.21,24.]pentacosa-7,9(25),14,19,21(24)-pentaene-10,10,12-trione

    [1080] ##STR00254##

    [1081] To a solution of 1-(4-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)butyl)-1H-pyrazole-3-sulfonamide (32 mg, 76.73 μmol, 1 eq) in THF (1 mL) was added TEA (19 mg, 191.83 μmol, 2.5 eq) and bis(trichloromethyl) carbonate (9 mg, 30.69 μmol, 0.4 eq). The reaction mixture was stirred at 25° C. for 10 min. The reaction mixture was filtered and to the filtrate was added t-BuONa (7 mg, 74.91 μmol) in THF (3 mL). The reaction mixture was stirred at 50° C. for 0.5 h. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×25 mm×5 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 13%-46%, 10 min) to give a racemic mixture of the title compound (5.16 mg, 17.20% yield, 99.9% purity on HPLC) as a white solid.

    [1082] LCMS: m/z 401.2 (M+H).sup.+ (ES.sup.+).

    [1083] .sup.1H NMR (CD.sub.3OD): δ 7.76 (d, 1H), 6.92 (s, 1H), 6.79 (d, 1H), 4.38-4.26 (m, 2H), 2.91-2.79 (m, 5H), 2.74-2.68 (m, 2H), 2.15-2.02 (m, 4H), 1.84-1.71 (m, 2H), 1.57-1.51 (m, 1H), 1.42-1.40 (m, 1H), 1.01-0.99 (m, 2H). Two exchangeable protons not observed.

    Example 50: 5λ.SUP.6.-thia-2,4,9,26-tetraazapentacyclo[13.9.1.1.SUP.6,9..0.SUP.18,25..0.SUP.20,24.]hexacosa-1(24),6(26),7,18(25),19-pentaene-3,5,5-trione

    [1084] ##STR00255##

    Step A: 1-(5-(1-hydroxy-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pent-3-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1085] ##STR00256##

    [1086] A mixture of 1-allyl-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-ol (Intermediate E1) (200 mg, 771.31 μmol, 1 eq), benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium; tricyclohexylphosphane (131 mg, 154.26 μmol, 0.2 eq) and 1-(but-3-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate D3) (341 mg, 771.31 μmol, 1 eq) in DCE (3 mL) was stirred at 70° C. for 4 h under N.sub.2. The reaction mixture was concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc, 1:1) to give the title compound as a mixture of stereoisomers (190 mg, 35.52% yield, 97% purity on LCMS) as a colourless gum.

    [1087] LCMS: m/z 655.4 (M−OH).sup.+ (ES.sup.+).

    [1088] .sup.1H NMR (CDCl.sub.3): δ 7.35 (d, 1H), 7.29 (d, 1H), 7.05 (d, 4H), 6.76 (d, 4H), 6.59 (d, 1H), 5.44-5.40 (m, 2H), 4.29 (s, 4H), 4.17-4.12 (m, 2H), 3.78 (s, 6H), 3.25-3.18 (m, 1H), 3.09-2.93 (m, 4H), 2.85-2.43 (m, 5H), 2.27-2.06 (m, 4H). One exchangeable proton not observed.

    Step B: 1-(5-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1089] ##STR00257##

    [1090] A mixture of 1-(5-(1-hydroxy-8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pent-3-en-1-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (190 mg, 282.41 μmol, 1 eq), methanesulfonic acid (54 mg, 564.81 μmol, 2 eq) and Pd/C (20 mg, 282.41 μmol, 10% purity loading on activated carbon) in MeOH (30 mL) was stirred at 20° C. for 12 h under H.sub.2 atmosphere (15 psi). The reaction mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuum. The residue was re-dissolved with sat aq Na.sub.2CO.sub.3 solution (10 mL) and extracted with EtOAc (8 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc, 1:1) to give a racemic mixture of the title compound (60 mg, 33.79% yield) as a brown gum.

    [1091] LCMS: m/z 629.5 (M+H).sup.+ (ES.sup.+).

    [1092] .sup.1H NMR (CDCl.sub.3): δ 7.40 (d, 1H), 7.05 (d, 4H), 6.76 (d, 4H), 6.64 (d, 1H), 6.60 (s, 1H), 4.31 (s, 4H), 4.17 (t, 2H), 3.77 (s, 6H), 2.98-2.86 (m, 4H), 2.74-2.64 (m, 3H), 2.22-2.07 (m, 4H), 1.95-1.88 (m, 4H), 1.52-1.33 (m, 4H). Two exchangeable protons not observed.

    Step C: 1-(5-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pentyl)-1H-pyrazole-3-sulfonamide

    [1093] ##STR00258##

    [1094] A solution of 1-(5-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (55 mg, 87.47 μmol, 1 eq) in DCM (3 mL) and TFA (3 mL) was stirred at 25° C. for 12 h. The mixture was quenched with sat aq NaHCO.sub.3 solution (30 mL). Then the aqueous phase was extracted with DCM (10 mL×2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc, 1:2) to give a racemic mixture of the title compound (20 mg, 58.85% yield) as a colourless oil.

    [1095] LCMS: m/z 389.4 (M+H).sup.+ (ES.sup.+).

    [1096] .sup.1H NMR (CDCl.sub.3): δ 7.41 (d, 1H), 6.71 (d, 1H), 6.60 (s, 1H), 4.21-4.15 (m, 2H), 3.57 (s, 2H), 3.03-2.86 (m, 4H), 2.73-2.69 (m, 3H), 2.15-2.10 (m, 3H), 2.01-1.90 (m, 3H), 1.66-1.52 (m, 1H), 1.51-1.30 (m, 5H). Two exchangeable protons not observed.

    Step D: 1-(5-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pentyl)-1H-pyrazole-3-sulfonyl isocyanate

    [1097] ##STR00259##

    [1098] To a solution of 1-(5-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pentyl)-1H-pyrazole-3-sulfonamide (20 mg, 51.48 μmol, 1 eq) and TEA (16 mg, 154.43 μmol, 3 eq) in THF (3 mL) was added triphosgene (6 mg, 20.59 μmol, 0.4 eq) at 0° C. Then the solution was stirred at 25° C. for 10 min. The mixture was filtered to give the filtrate (theoretical amount: 21.3 mg) as a crude product, which was used in the next step without purification.

    Step E: 5λ.SUP.6.-thia-2,4,9,26-tetraazapentacyclo[13.9.1.1.SUP.6,9..0.SUP.18,25..0.SUP.20,24.]hexacosa-1(24),6(26),7,18(25),19-pentaene-3,5,5-trione

    [1099] ##STR00260##

    [1100] To a solution of 1-(5-(8-amino-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)pentyl)-1H-pyrazole-3-sulfonyl isocyanate (21.3 mg, 48.25 μmol, 1 eq) in THF (3 mL) was added t-BuONa (5 mg, 48.25 μmol, 1 eq) and the solution was stirred at 50° C. for 10 min. The mixture was concentrated in vacuum, and the residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×25 mm×5 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 17%-47%, 9 min) to give a racemic mixture of the title compound (1.72 mg, two steps yield: 8.55%, 100% purity on LCMS) as a white solid.

    [1101] LCMS: m/z 415.2 (M+H).sup.+ (ES.sup.+).

    [1102] .sup.1H NMR (CD.sub.3OD): δ 7.67 (d, 1H), 6.87 (s, 1H), 6.72 (d, 1H), 4.24 (t, 2H), 2.88-2.86 (m, 1H), 2.91-2.66 (m, 6H), 2.08-1.95 (m, 4H), 1.83-1.67 (m, 2H), 1.52-1.39 (m, 1H), 1.31-0.93 (m, 5H). Two exchangeable protons not observed.

    Examples—Biological Studies

    NLRP3 and Pyroptosis

    [1103] 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-1β) from the cell.

    THP-1 Cells: Culture and Preparation

    [1104] 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 (>900%) 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 μg/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.

    THP-1 Cells Pyroptosis Assay

    [1105] The following method step-by-step assay was followed for compound screening. [1106] 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) [1107] 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 [1108] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1109] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [1110] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1111] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [1112] 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 [1113] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1114] 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

    [1115]

    TABLE-US-00005 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) Low Drug free control Compound 8-point half-log dilution

    [1116] The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

    Human Whole Blood IL-1β Release Assay

    [1117] 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.

    [1118] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1119] 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1120] 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 [1121] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1122] 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells [1123] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1124] 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 201 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) [1125] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1126] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

    [1127] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

    TABLE-US-00006 TABLE 1 NLRP.sub.3 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 ++++ ++ 7 +++ +++ 8 +++ +++ 9 +++ ++ 10 +++ ++ 11 ++++ ++++ 12 ++++ +++ 13 ++++ +++ 14 ++++ ++ 15 +++++ ++++ 16 ++ ND 17 +++++ +++ 18 ++++ +++ 19 +++ +++ 20 +++++ ++++ 21 ++ ND 22 ++++ ++++ 23 ++++ ++++ 24 +++++ ++++ 25 +++++ +++++ 26 +++++ ++++ 27 +++++ ++++ 28 +++++ ++++ 29 +++++ ++++ 30 +++++ ++++ 31 +++++ ++++ 32 ++++ ++++ 33 +++ ++ 34 +++++ ++++ 35 +++++ ++++ 36 +++++ +++ 37 +++++ +++++ 38 ++++ ++ 39 +++++ ++++ 40 +++++ ++++ 41 +++++ ++++ 42 +++++ ++++ 43 ++++ ++++ 44 +++++ ++++ 45 ++ ++ 46 ++ ++ 47 +++ +++ 48 ++ + 49 ++ ND 50 ++++ ++

    [1128] 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.

    [1129] 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.