1. Patent Search
  2. Details

MACROCYCLIC SULFONYLAMIDE DERIVATIVES USEFUL AS NLRP3 INHIBITORS

20220389031 · 2022-12-08

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to macrocyclic compounds, such as macrocyclic sulfonyl amides. 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): ##STR00416## 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 —C(R.sup.2).sub.2—; L is a saturated or unsaturated hydrocarbylene group, wherein the hydrocarbylene group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbylene group may optionally be substituted, and wherein the hydrocarbylene group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton; -J-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; each R.sup.j and R.sup.1 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; and each R.sup.2 is independently selected from hydrogen or a halo, —OH, —NO.sub.2, —NH.sub.2, —N.sub.3, —SH, —SO.sub.2H, —SO.sub.2NH.sub.2, or a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include one or more cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton, or wherein two R.sup.2 may, together with the carbon atom to which they are attached, form a cyclic group, wherein the cyclic group may optionally be substituted.

    2. A compound or a 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 —CH.sub.2—; 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 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. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ia): ##STR00417## 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. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 6, wherein: (i) 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; and/or (ii) 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; and/or (iii) 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.

    8. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in 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 (ii) 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.

    9. (canceled)

    10. (canceled)

    11. (canceled)

    12. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ib): ##STR00418## wherein: J is —SO—, —SO.sub.2— or —SO(═NH)—; X is —CH.sub.2—; -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.

    13. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 12, 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.

    14. (canceled)

    15. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 12, 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.

    16. (canceled)

    17. (canceled)

    18. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ic): ##STR00419## 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.

    19. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Id): ##STR00420## wherein: A.sup.6 and A.sup.7 are each independently selected from C and N, and A.sup.8, A.sup.9 and A.sup.10 are each independently selected from N, C—H, C-Hal and N—H, such that ring A.sup.d is a 5-membered heteroaryl ring containing one, two or three nitrogen atoms in its ring structure; B.sup.1, B.sup.2, B.sup.3 and B.sup.4 are each independently selected from N, 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; p 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.

    20. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ie): ##STR00421## wherein: A.sup.11, A.sup.12, A.sup.13 and A.sup.14 are each independently selected from N, C—H and C-Hal, such that ring Ae 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.12 and A.sup.13 or to A.sup.13 and A.sup.14 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.

    21. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (If): ##STR00422## wherein: A.sup.15, A.sup.16, A.sup.17 and A.sup.18 are each independently selected from N, C—H and C-Hal, such that ring A.sup.f 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; r 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.15 and A.sup.16 or to A.sup.16 and A.sup.17 or to A.sup.17 and A18 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.

    22. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the compound has the formula (Ig): ##STR00423## wherein: A.sup.19 and A.sup.22 are each independently selected from N, CH, CY and CR.sup.AG, and each A.sup.20 and A.sup.21 is independently selected from O, NH, NR.sup.AGG, C═O, CH.sub.2, CH(Y), CH(R.sup.AG), C(Y).sub.2, C(Y)(R.sup.AG) and C(R.sup.AG).sub.2, such that ring Ag contains one or two atoms independently selected from oxygen and nitrogen in its ring structure; ga is 1, 2 or 3, and gb is 1, 2 or 3, provided that ga+gb≤5; each Y is independently selected from F, Cl or Br; each R.sup.AG 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.AG contains, in total, from 1 to 10 carbon, nitrogen and oxygen atoms; each R.sup.AGG is independently selected from a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group is straight-chained or branched, or is or includes a cyclic group, wherein the saturated hydrocarbyl group optionally includes one or two heteroatoms independently selected from O and N in its carbon skeleton, wherein the saturated hydrocarbyl group is optionally substituted with one or more fluoro groups and/or one or two oxo (═O) groups, and wherein each R.sup.AGG contains, in total, from 1 to 10 carbon, nitrogen and oxygen atoms; 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.

    23. A compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, which is (a) a compound selected from the group consisting of: ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434## or (b) a pharmaceutically acceptable salt or solvate of the selected compound.

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

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

    26. 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 a compound or a 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.

    27. (canceled)

    28. The method as claimed in claim 26 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.

    29. The method as claimed in claim 26, 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).

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

    31. 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 a compound or a 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.

    32. The method as claimed in claim 26, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

    33. A pharmaceutical composition comprising a prodrug or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 24, and a pharmaceutically acceptable excipient.

    Description

    EXPERIMENTAL METHODS

    Nuclear Magnetic Resonance

    [0742] 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: [0743] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0744] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0745] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0746] 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 [0747] 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

    [0748] LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200G6110A, 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

    [0749] Acidic prep HPLC (x-y % MeCN in water): Waters X-Select CSH column C18, 5 m (19×50 mm), flow rate 28 mL min-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.

    [0750] Acidic prep HPLC (x-y % MeOH in water): Waters X-Select CSH column C18, 5 m (19×50 mm), flow rate 28 mL min-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.

    [0751] Basic prep HPLC (x-y % MeCN in water): Waters X-Bridge Prep column C18, 5 μm (19×50 mm), flow rate 28 mL min-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-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0752] ##STR00034##

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

    [0753] ##STR00035##

    [0754] A solution of n-BuLi (100 mL, 250 mmol, 2.5 M 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%).

    [0755] LCMS m/z 215 (M−Li).sup.− (ES.sup.−).

    [0756] .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

    [0757] ##STR00036##

    [0758] 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 1 M 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.

    [0759] LCMS m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

    [0760] ##STR00037##

    [0761] A mixture of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (41 g, 87 mmol) and aq 1 M 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 1 M 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.

    [0762] LCMS m/z 388 (M+H).sup.+ (ES.sup.+); 386 (M−H).sup.− (ES.sup.−).

    [0763] .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: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate

    [0764] ##STR00038##

    [0765] N,N-bis(4-Methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.00 g, 5.16 mmol) and K.sub.2CO.sub.3 (2.14 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 concentrated 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.

    [0766] LCMS m/z 510.6 (M+Na).sup.+ (ES.sup.+).

    [0767] .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 E: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0768] ##STR00039##

    [0769] Methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methyl-propanoate (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), diluted with brine (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo to afford the title compound (3.43 g, 100%) as a white solid.

    [0770] LCMS m/z 482.3 (M+Na).sup.+ (ES.sup.+).

    [0771] .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 A2: 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0772] ##STR00040##

    [0773] N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (1 g, 2.58 mmol) and K.sub.2CO.sub.3 (0.892 g, 6.45 mmol) were suspended in MeCN (25 mL) under N.sub.2. 2-Bromoethanol (0.2 mL, 2.84 mmol) was added and the mixture was heated to 50° C. for 4 h. After cooling to RT, water (50 mL) and EtOAc (75 mL) were added and the organic layer separated, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (682.4 mg, 58%) as a thick colourless oil.

    [0774] LCMS m/z 454.1 (M+Na).sup.+ (ES.sup.+).

    [0775] .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (d, J=2.3 Hz, 1H), 7.04-6.98 (m, 4H), 6.85-6.79 (m, 4H), 6.71 (d, J=2.3 Hz, 1H), 5.01 (t, J=5.2 Hz, 1H), 4.27 (t, J=5.5 Hz, 2H), 4.20 (s, 4H), 3.78 (q, J=5.4 Hz, 2H), 3.72 (s, 6H).

    Intermediate A3: 5-((dimethylamino)methyl)-1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0776] ##STR00041##

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

    [0777] ##STR00042##

    [0778] Prepared according to the general procedure of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A2) to afford the title compound (1.13 g, 49%) as a thick colourless oil.

    [0779] LCMS m/z 496.3 (M+Na).sup.+ (ES.sup.+).

    [0780] .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).

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

    [0781] ##STR00043##

    [0782] 1-(5-Hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1.25 g, 2.64 mmol) was dissolved in THF (50 mL) and cooled to −78° C. n-BuLi (2.5 M in hexanes, 2.64 mL, 6.60 mmol) was added immediately followed by N-methyl-N-methylenemethanaminium iodide (1.95 g, 10.54 mmol). The reaction was stirred for 1 h while allowing to warm to RT. The reaction was quenched with water (50 mL), extracted with MTBE (2×50 mL), dried (phase separator) and concentrated in vacuo. The resulting residue was dissolved in MeOH (100 mL) and stirred with SCX (7.5 g) for 30 min. The resin was washed with methanol (150 mL) and the desired product was eluted with 0.7 M ammonia in methanol (250 mL). The resulting solution was concentrated in vacuo to afford the title compound (416 mg, 29%) as a yellow oil.

    [0783] .sup.1H NMR (DMSO-d.sub.6) δ 7.04-6.99 (m, 4H), 6.83-6.78 (m, 4H), 6.57 (s, 1H), 4.38 (t, J=5.1 Hz, 1H), 4.23-4.15 (m, 6H), 3.72 (s, 6H), 3.47 (s, 2H), 3.40-3.35 (m, 2H), 2.17 (s, 6H), 1.78 (p, J=7.5 Hz, 2H), 1.45 (p, J=6.7 Hz, 2H), 1.33-1.25 (m, 2H).

    Intermediate A4: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxy-benzyl)-1H-pyrazole-3-sulfonamide

    [0784] ##STR00044##

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

    [0785] ##STR00045##

    [0786] 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.

    [0787] .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

    [0788] ##STR00046##

    [0789] 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.

    [0790] .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

    [0791] ##STR00047##

    [0792] 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 triethylamine (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.

    [0793] LCMS m/z 512.1 (M+Na).sup.+ (ES.sup.+).

    [0794] .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)-1H-pyrazole-3-sulfonamide

    [0795] ##STR00048##

    [0796] 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.

    [0797] LCMS m/z 512.2 (M+Na).sup.+ (ES.sup.+).

    [0798] .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

    [0799] ##STR00049##

    [0800] 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.

    [0801] LCMS m/z 427.3 (M+Na).sup.+ (ES.sup.+); 404.1 (M−H).sup.− (ES.sup.−).

    [0802] .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

    [0803] ##STR00050##

    [0804] 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.

    [0805] LCMS m/z 527.7 (M+Na).sup.+ (ES.sup.+).

    [0806] .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

    [0807] ##STR00051##

    [0808] 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.

    [0809] LCMS m/z 500.1 (M+Na).sup.+ (ES.sup.+).

    [0810] .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 A5: 5-(2-hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0811] ##STR00052##

    [0812] A solution of n-BuLi (2.5 M in hexanes) (2 mL, 5.00 mmol) was added dropwise to a stirred solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.067 g, 4.81 mmol) in THF (35 mL) at −78° C. The reaction was stirred for 1 h and oxirane (2.5 M in THF) (7.70 mL, 19.25 mmol) was added. The reaction mixture was left at −78° C. for 1 h. The reaction mixture was warmed up to RT and stirred for 48 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by FC (0-10% MeOH/DCM) to afford the title compound (1.33 g, 56%) as a yellow oil.

    [0813] LCMS m/z 496.4 (M+Na).sup.+ (ES.sup.+).

    [0814] .sup.1H NMR (DMSO-d.sub.6) δ 7.06-6.97 (m, 4H), 6.85-6.78 (m, 4H), 6.51 (s, 1H), 4.87 (t, J=5.2 Hz, 1H), 4.68 (sept, J=6.6 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 3.70-3.63 (m, 2H), 2.84 (t, J=6.5 Hz, 2H), 1.38 (d, J=6.6 Hz, 6H).

    Intermediate A6: 3-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)benzene-sulfonamide

    [0815] ##STR00053##

    Step A: 3-(2-hydroxyethyl)benzene-1-sulfonyl chloride

    [0816] ##STR00054##

    [0817] 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. 1,3-Dichloro-5,5-dimethyl-imidazolidine-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). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo to afford the crude title compound which was used without further purification in the next step.

    Step B: 3-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

    [0818] ##STR00055##

    [0819] bis-(4-Methoxybenzyl)amine (1.30 g, 5.05 mmol) was added to a suspension of 3-(2-hydroxyethyl)benzene-1-sulfonyl chloride (1.09 g, 4.95 mmol) in DCM (25 mL) cooled in an ice bath, followed by Et.sub.3N (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 dried (MgSO.sub.4) and concentrated in vacuo. The crude was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (1.40 g, 60% over 2 steps) as a white solid.

    [0820] LCMS m/z 464.1 (M+Na).sup.+ (ES.sup.+).

    [0821] .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 A7: 3-(2-hydroxyethyl)-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

    [0822] ##STR00056##

    Step A: methyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-bromobenzoate

    [0823] ##STR00057##

    [0824] A solution of methyl 3-(benzylthio)-5-bromobenzoate (3.76 g, 11.15 mmol) in MeCN (54 mL), AcOH (0.7 mL) and water (1.4 mL) was cooled to −10° C. (ice/acetone bath). 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.30 g, 16.72 mmol) was then added and the mixture was stirred at −10° C. for 4 h. The mixture was then partitioned between DCM (250 mL) and water (200 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 methyl 3-bromo-5-(chloro-sulfonyl)benzoate (3.50 g, 11.15 mmol) as a thick yellow oil. To a suspension of methyl 3-bromo-5-(chlorosulfonyl)benzoate (3.50 g, 11-15 mmol) in DCM (25 mL) was added bis(4-methoxybenzyl)amine (2.87 g, 11.15 mmol) whilst being cooled with an ice bath, followed by TEA (3 mL, 21.52 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 (2.77 g, 43%) as a white solid.

    [0825] .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (app t, J=1.7 Hz, 1H), 8.01 (app d, J=1.7 Hz, 2H), 7.19-7.02 (m, 4H), 6.87-6.71 (m, 4H), 4.32 (s, 4H), 3.90 (s, 3H), 3.71 (s, 6H).

    Step B: 3-bromo-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-benzene-sulfonamide

    [0826] ##STR00058##

    [0827] MeMgBr (3 M in Et.sub.2O) (3.5 mL, 10.50 mmol) was added dropwise to a stirred solution of methyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-bromobenzoate (2.47 g, 4.25 mmol) in THF (2 mL) cooled to 0° C. The mixture was stirred at 0° C. for 1 h then left to warm to RT with stirring over 1 h. Additional MeMgBr (3 M in Et.sub.2O) (3.5 mL, 10.50 mmol) was added and the mixture stirred for a further 1 h. The mixture was quenched with water (20 mL) and brine (50 mL) at 0° C. and extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (2.50 g, 96%) as a colourless oil which crystallised to give a white solid.

    [0828] .sup.1H NMR (DMSO-d.sub.6) δ 7.89 (t, J=1.7 Hz, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.63 (t, J=1.7 Hz, 1H), 7.06-6.99 (m, 4H), 6.83-6.78 (m, 4H), 5.42 (s, 1H), 4.25 (s, 4H), 3.71 (s, 6H), 1.43 (s, 6H).

    Step C: tert-butyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(2-hydroxypropan-2-yl)phenyl)acetate

    [0829] ##STR00059##

    [0830] (2-(tert-Butoxy)-2-oxoethyl)zinc(II) bromide 0.44 M (29 mL, 12.76 mmol) was added to a solution of 3-bromo-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-benzenesulfonamide (2.50 g, 4.07 mmol), Pd.sub.2(dba).sub.3 (0.186 g, 0.203 mmol) and QPhos (0.289 g, 0.407 mmol) in anhydrous THF (250 mL) and the reaction was stirred at 70° C. for 21 h. The reaction mixture was left to cool to RT and the mixture was quenched with water (50 mL) and the THF removed in vacuo. The red/grey emulsion obtained was diluted with EtOAc (100 mL) and filtered. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a red oil which was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (2.10 g, 73%) as a red oil.

    [0831] LCMS m/z 592.4 (M+Na).sup.+ (ES.sup.+).

    [0832] .sup.1H NMR (DMSO-d.sub.6) δ 7.81-7.77 (m, 1H), 7.65-7.61 (m, 1H), 7.59-7.57 (m, 1H), 6.99-6.93 (m, 4H), 6.81-6.75 (m, 4H), 5.29 (s, 1H), 4.17 (s, 4H), 3.70 (s, 6H), 3.69 (s, 2H), 1.42 (s, 6H), 1.39 (s, 9H).

    Step D: 3-(2-hydroxyethyl)-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-benzenesulfonamide

    [0833] ##STR00060##

    [0834] 4 M LiBH.sub.4 in THF (2.76 mL, 11.0 mmol) was added dropwise to a stirred solution of tert-butyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(2-hydroxypropan-2-yl)-phenyl)acetate (2.1 g, 3.69 mmol) in THF (50 mL) cooled to 0° C. The mixture was stirred for 2 h. Additional 4 M LiBH.sub.4 in THF (2.76 mL, 11.06 mmol) was added and allowed to stir for 1 h. Additional 4 M LiBH.sub.4 in THF (2.76 mL, 11.06 mmol) was added and the reaction was allowed to stir overnight. Additional 4 M LiBH.sub.4 in THF (2.76 mL, 11.06 mmol) was added and the reaction allowed to stir for a further 16 h. The mixture was then partitioned between water (30 mL) and EtOAc (50 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo to afford the title compound (1.8 g, 88%) as a dark red oil.

    [0835] LCMS m/z 522.3 (M+Na).sup.+ (ES.sup.+).

    [0836] .sup.1H NMR (DMSO-d.sub.6) δ 7.76-7.73 (m, 1H), 7.61-7.58 (m, 1H), 7.51-7.48 (m, 1H), 7.01-6.96 (m, 4H), 6.82-6.76 (m, 4H), 5.24 (s, 1H), 4.69 (t, J=5.1 Hz, 1H), 4.18 (s, 4H) 3.71 (s, 6H), 3.66-3.59 (m, 2H), 2.80 (t, J=6.7 Hz, 2H), 1.43 (s, 6H).

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

    [0837] ##STR00061##

    [0838] 4-Fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4, Step E) (1.00 g, 2.466 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were suspended in dry acetonitrile (10 mL) under a N.sub.2 atmosphere. 2-bromoethanol (0.23 mL, 3.21 mmol) was added and the mixture was heated to 50° C. for 3 h. After cooling to RT, water (20 mL) and EtOAc (20 mL) were added. The organic phase was dried (MgSO.sub.4), filtered and concentrated to dryness 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, 70%) as a thick colourless oil.

    [0839] LCMS m/z 472.1 (M+Na).sup.+ (ES.sup.+).

    [0840] .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 A9: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide

    [0841] ##STR00062##

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

    [0842] ##STR00063##

    [0843] A solution of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonamide (2.12 g, 4.50 mmol) in methanol (45 mL, 45.0 mmol) and dioxane (45 mL), to which was added conc aq HCl (7.50 mL, 4.50 mmol), was stirred at 50° C. for 3 h. The mixture was partitioned between EtOAc (150 mL) and water (100 mL), the phases separated and the aqueous further extracted with EtOAc (2×100 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated under reduced pressure to 1/10 of the volume and directly loaded onto the column for purification by FC (0-100% EtOAc/isohexane) to afford the title compound (1.50 g, 81%) as a white solid.

    [0844] LCMS m/z 386.3 (M−H).sup.− (ES.sup.−).

    [0845] .sup.1H NMR (DMSO-d.sub.6) δ 13.64 (s, 1H), 8.10 (s, 2H), 7.09-7.02 (m, 4H), 6.85-6.74 (m, 4H), 4.12 (s, 4H), 3.71 (s, 6H).

    Step B: methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methyl-propanoate

    [0846] ##STR00064##

    [0847] A suspension of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (403.5 mg, 1.041 mmol), methyl 2-bromo-2-methylpropanoate (0.140 mL, 1.041 mmol) and K.sub.2CO.sub.3 (430 mg, 3.11 mmol) in MeCN (10 mL) was stirred at RT for 18 h, then at 50° C. for 4.5 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 mL), the aqueous phase was separated and further extracted with EtAOc (3×50 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by FC (20-100% EtOAc/isohexane) to afford the title compound (424 mg, 82%) as a white solid.

    [0848] LCMS m/z 488.4 (M+H).sup.+ (ES.sup.+).

    [0849] .sup.1H NMR (DMSO-d.sub.6) δ 8.40 (s, 1H), 7.86 (s, 1H), 7.11-7.06 (m, 4H), 6.85-6.80 (m, 4H), 4.17 (s, 4H), 3.72 (s, 6H), 3.65 (s, 3H), 1.77 (s, 6H).

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

    [0850] ##STR00065##

    [0851] LiBH.sub.4 (4 M in THF) (0.65 mL, 2.60 mmol) was added to a solution of methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (423.8 mg, 0.869 mmol) in anhydrous THF (5 mL) at 0° C. The reaction was stirred for 1.5 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 (392 mg, 93%) as a white sticky solid which was used without further purification.

    [0852] LCMS m/z 460.5 (M+H).sup.+ (ES.sup.+).

    [0853] .sup.1H NMR (DMSO-d.sub.6) δ 8.14 (s, 1H), 7.80 (s, 1H), 7.09-7.04 (m, 4H), 6.84-6.80 (m, 4H), 5.08 (t, J=5.6 Hz, 1H), 4.15 (s, 4H), 3.71 (d, J=1.5 Hz, 6H), 3.58 (d, J=5.7 Hz, 2H), 1.45 (s, 6H).

    Intermediate A10: 2-(3-hydroxypropoxy)-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

    [0854] ##STR00066##

    Step A: 2-chloro-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

    [0855] ##STR00067##

    [0856] A suspension of 2-chloropyridine-3-sulfonyl chloride (1.5 g, 7.07 mmol) and bis(4-methoxybenzyl)amine (1.820 g, 7.07 mmol) in DCM (20 mL) was cooled to 0° C. (ice bath). TEA (2.51 mL, 17.68 mmol) was then added dropwise at 0° C. and the mixture was stirred at RT for 4 h. The mixture was diluted with water (30 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow oil. The yellow oil was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (1.5 g, 49%) as a colourless solid.

    [0857] LCMS m/z 433/435 (M+H).sup.+ (ES.sup.+).

    Step B: 2-(3-hydroxypropoxy)-N,N-bis(4-methoxybenzyl)pyridine-3-sulfonamide

    [0858] ##STR00068##

    [0859] A mixture of propane-1,3-diol (2 mL, 3.46 mmol) and KO.sup.tBu (0.778 g, 6.93 mmol) in THF (10 mL) was stirred at RT for 10 min. 2-Chloro-N,N-bis(4-methoxybenzyl)-pyridine-3-sulfonamide (1.5 g, 3.46 mmol) was then added and the mixture was stirred at RT for a further 24 h. The mixture was then diluted with water (20 mL) and EtOAc (20 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (360 mg, 21%) as a colourless oil.

    [0860] LCMS m/z 495.4 (M+Na).sup.+ (ES.sup.+).

    Intermediate A11: 1-(1-hydroxy-2-methylpropan-2-yl)-4-methoxy-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0861] ##STR00069##

    Step A: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-ol

    [0862] ##STR00070##

    [0863] 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.6 g, 56.1 mmol) was dissolved in THF (90 mL) and cooled to 0° C. NaOH (2 M) (56.1 mL, 112 mmol) was added and the mixture was stirred for 10 min before hydrogen peroxide (30% aq) (11.46 mL, 112 mmol) was added in 0.5 mL portions over the course of 10 min. The reaction was stirred for a further 3 h whilst allowing the reaction mixture to warm to RT. Sodium sulfite (sat aq) (150 mL) was added and stirred for 5 min. The pH of the reaction mixture was adjusted to pH 9, via addition of 2 M aq HCl, and then extracted with EtOAc (2×100 mL). The combined organics were washed with water (150 mL), brine (150 mL) and dried (MgSO.sub.4). The organic layer was dry loaded onto silica and purified by FC (20-100% EtOAc/isohexane) to afford the title compound (2.77 g, 16.47 mmol) as a white solid. The combined aqueous layers were concentrated in vacuo and the resulting residue dissolved in MeOH, dry loaded onto silica and purified by FC (20-100% EtOAc/isohexane) affording further material which was combined with the first batch to afford the title compound (5.42 g, 58%).

    [0864] LCMS m/z 84.9 (M+H-THP).sup.+ (ES.sup.+).

    [0865] .sup.1H NMR (DMSO-d.sub.6) δ 8.47 (s, 1H), 7.27 (s, 1H), 7.05 (s, 1H), 5.18 (dd, J=10.1, 2.5 Hz, 1H), 3.98-3.77 (m, 1H), 3.68-3.50 (m, 1H), 2.04-1.96 (m, 1H), 1.93-1.87 (m, 1H), 1.83-1.79 (m, 1H), 1.67-1.57 (m, 1H), 1.52-1.45 (m, 2H).

    Step B: 4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

    [0866] ##STR00071##

    1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-ol (2.675 g, 15.90 mmol) was dissolved in dry DMF (10 mL), Cs.sub.2CO.sub.3 (6.22 g, 19.09 mmol) was added and the suspension was cooled to 0° C. under N.sub.2. MeI (1.09 mL, 17.49 mmol) was added and the reaction mixture was allowed to reach RT and stirred for 16 h. The mixture was concentrated in vacuo and the residue was partitioned between water (10 mL) and EtOAc (20 mL). The aqueous was washed with more EtOAc (10×20 mL). The combined organics were dried (MgSO.sub.4), filtered and concentrated in vacuo to give a yellow liquid. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (5.00 g, 56%) as a colourless liquid.

    [0867] LCMS m/z 99.0 (M+H-THP).sup.+ (ES.sup.+).

    [0868] .sup.1H NMR (CDCl.sub.3) δ 7.30 (s, 1H), 7.26 (s, 1H), 5.28 (dt, J=9.5, 2.3 Hz, 1H), 4.06-4.00 (m, 1H), 3.74 (s, 3H), 3.68 (td, J=11.1, 3.0 Hz, 1H), 2.30-1.86 (m, 3H), 1.86-1.46 (m, 3H).

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

    [0869] ##STR00072##

    [0870] In a dry 500 mL 3 neck-flask equipped with thermometer and nitrogen inlet, 4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (5.00 g, 27.4 mmol) was dissolved in dry THF (200 mL) and cooled to −78° C. n-Butyllithium (2.5 M in hexanes) (12.07 ml, 30.2 mmol) was added in 0.5 mL portions over 10 min ensuring the internal reaction temperature did not exceed −65° C. The reaction mixture was stirred at −78° C. for 1 h. SO.sub.2 gas was bubbled through the reaction mixture for 10 min and the mixture was allowed to reach RT overnight. The reaction mixture was filtered and the resulting solid washed with TBME, then isohexane, and then dried via desiccator to afford lithium 4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (5.52 g, 80%) as a white solid.

    [0871] .sup.1H NMR (DMSO-d.sub.6): δ 7.12 (s, 1H), 6.19 (dd, J=10.1, 2.4 Hz, 1H), 3.98-3.84 (m, 1H), 3.67 (s, 3H), 3.52-3.47 (m, 1H), 2.20-2.02 (m, 1H), 1.98-1.86 (m, 1H), 1.73-1.64 (m, 1H), 1.62-1.51 (m, 1H), 1.51-1.43 (m, 2H).

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

    [0872] ##STR00073##

    [0873] NCS (2.92 g, 21.88 mmol) was added to a suspension of lithium 4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (5.52 g, 21.88 mmol) in DCM (60 mL) cooled in an ice bath. The mixture was stirred for 1 h, quenched with water (50 mL) then partitioned between DCM (50 mL) and water (40 mL). The organic phase was washed with water (40 mL), dried using a phase separator, and concentrated in vacuo to −20 mL. This solution was then added to a mixture of bis(4-methoxybenzyl)amine (6.19 g, 24.07 mmol) and TEA (9.15 mL, 65.6 mmol) in DCM (50 mL) cooled in an ice bath. After stirring for 1 h the mixture was warmed to RT then partitioned between DCM (60 mL) and water (40 mL). The organic layer was washed with water (40 mL), aq 1 M HCl (2×40 mL), and water (40 mL), dried using a phase separator, and concentrated in vacuo to afford the title compound (9.27 g, 79%) as an orange oil.

    [0874] LCMS m/z 524.2 (M+Na).sup.+ (ES.sup.+).

    [0875] .sup.1H NMR (DMSO-d.sub.6) δ 7.67 (s, 1H), 6.97 (d, J=8.5 Hz, 4H), 6.81 (d, J=8.4 Hz, 4H), 5.84 (dd, J=9.8, 2.4 Hz, 1H), 4.42-4.15 (m, 4H), 3.88-3.82 (m, 1H), 3.75 (s, 3H), 3.71 (s, 6H), 3.57-3.50 (m, 1H), 2.32-2.24 (m, 1H), 2.02-1.95 (m, 1H), 1.89-1.80 (m, 1H), 1.70-1.57 (m, 1H), 1.53-1.45 (m, 2H).

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

    [0876] ##STR00074##

    [0877] 1 M HCl (aq) (20 mL) was added to a solution of 4-methoxy-N,N-bis(4-methoxy-benzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (9.274 g, 18.49 mmol) in THF (50 mL) and MeOH (25 mL). The mixture was stirred at RT for 4 h then concentrated to −20 mL. The resulting residue was partitioned between EtOAc (100 mL) and water (40 mL), the organic layer washed with water (40 mL), dried using a phase separator, and concentrated in vacuo. The resulting solid precipitate was filtered, washed with TBME and isohexane, and dried to afford the title compound (6.106 g, 79%) as a white solid.

    [0878] LCMS m/z 418.2 (M+H).sup.+ (ES.sup.+).

    [0879] .sup.1H NMR (DMSO-d.sub.6) δ 13.26 (s, 1H), 7.76 (s, 1H), 7.00 (d, J=8.7 Hz, 4H), 6.79 (d, J=8.6 Hz, 4H), 4.21 (s, 4H), 3.73 (s, 3H), 3.71 (s, 6H).

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

    [0880] ##STR00075##

    [0881] A suspension of 4-methoxy-N,N-bis(4-methoxybenzyl)-1H-pyrazole-5-sulfonamide (2 g, 4.79 mmol), methyl 2-bromo-2-methylpropanoate (0.70 mL, 5.41 mmol) and K.sub.2CO.sub.3 (1.980 g, 14.32 mmol) in MeCN (30 mL) was stirred at 50° C. for 5 h. The reaction mixture was partitioned between water (70 mL) and EtOAc (100 mL), and the aqueous phase was separated and further extracted with EtOAc (2×100 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to afford methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-methoxy-1H-pyrazol-1-yl)-2-methylpropanoate as a colourless oil. The crude was taken up in dry THF (30 mL) and the solution cooled to 0° C., then LiBH.sub.4 (4 M in THF) (7.50 mL, 15.00 mmol) was added and the resulting solution was stirred at RT for 1.5 h. The reaction was quenched by the careful addition of MeOH, then the mixture was partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was separated and further extracted with EtOAc (2×100 mL). The organic phases were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by FC (50-100% EtOAc/isohexane) to afford the title compound (1.81 g, 3.51 mmol) as a colourless oil.

    [0882] LCMS m/z 512.5 (M+Na).sup.+ (ES.sup.+).

    [0883] .sup.1H NMR (DMSO-d.sub.6) δ 7.80 (s, 1H), 7.07-6.92 (m, 4H), 6.88-6.67 (m, 4H), 4.20 (s, 4H), 3.73-3.69 (m, 9H), 3.57 (d, J=5.5 Hz, 2H), 1.45 (s, 6H). One exchangeable proton not observed.

    Intermediate A12: 4-fluoro-1-(1-(hydroxymethyl)cyclopropyl)-N,N-bis(4-methoxy-benzyl)-1H-pyrazole-3-sulfonamide

    [0884] ##STR00076##

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

    [0885] ##STR00077##

    [0886] 60 wt % NaH in mineral oil (0.50 g, 12.50 mmol) was added portion wise to a solution of 4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4, Step E) (2.00 g, 4.93 mmol) in NMP (30 mL) cooled to 0° C. The mixture was stirred at 0° C. for 10 min until gas evolution ceased. Methyl 2,4-dibromobutanoate (1.05 mL, 7.43 mmol) was then added and the mixture was left to warm to RT with stirring over 18 h. The mixture was then quenched with water (10 mL) and partitioned between brine (300 mL) and MTBE (100 mL). The aqueous layer was discarded and the organic layer was washed with brine (300 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown oil. The crude product was purified by FC (0-60% EtOAc/isohexane) to afford the title compound (1.72 g, 60%) as a thick colourless oil.

    [0887] LCMS m/z 526.4 (M+Na).sup.+ (ES.sup.+).

    [0888] .sup.1H NMR (DMSO-d.sub.6) δ 8.35 (d, J=4.6 Hz, 1H), 7.08-7.00 (m, 4H), 6.88-6.76 (m, 4H), 4.25 (s, 4H), 3.73 (s, 6H), 3.65 (s, 3H), 1.80-1.72 (m, 2H), 1.66-1.58 (m, 2H).

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

    [0889] ##STR00078##

    [0890] 4 M LiBH.sub.4 in THF (1.30 mL, 5.20 mmol) was added dropwise to a stirred solution of methyl 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazol-1-yl)-cyclopropanecarboxylate (1.72 g, 2.94 mmol) in THF (30 mL) cooled to 0° C. The mixture was stirred for 17 h. 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 (1.36 g, 89%) as a thick pale yellow oil which was used without further purification.

    [0891] LCMS m/z 498.4 (M+Na).sup.+ (ES.sup.+).

    [0892] .sup.1H NMR (DMSO-d.sub.6) δ 8.15 (d, J=4.7 Hz, 1H), 7.06-6.98 (m, 4H), 6.86-6.78 (m, 4H), 5.12 (t, J=5.8 Hz, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 3.62 (d, J=6.0 Hz, 2H), 1.14-1.07 (m, 2H), 1.07-0.96 (m, 2H).

    Intermediate A13: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide

    [0893] ##STR00079##

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

    [0894] ##STR00080##

    [0895] A solution of bis(4-methoxybenzyl)amine (1.49 g, 5.78 mmol) in DCM (5 mL, 3.85 mmol) was prepared. The reaction mixture was then cooled to 0° C. followed by the dropwise addition of 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.75 g, 3.85 mmol) and TEA (1.61 mL, 11.56 mmol) in DCM (5 mL). The resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (10 mL) and DCM (10 mL) and the organic layer dried (phase separator) and concentrated in vacuo to yield a yellow oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (760 mg, 40%) as a colourless oil.

    [0896] LCMS m/z 416.8 (M+H).sup.+ (ES.sup.+).

    [0897] .sup.1H NMR (DMSO-d.sub.6) δ 13.01 (s, 1H), 7.00-6.93 (m, 4H), 6.86-6.80 (m, 4H), 4.15 (s, 4H), 3.72 (s, 6H), 2.31 (s, 6H).

    Step B: methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoate

    [0898] ##STR00081##

    [0899] A suspension of N,N-bis(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide (670 mg, 1.61 mmol), methyl 2-bromo-2-methylpropanoate (0.271 ml, 2.10 mmol) and potassium carbonate (669 mg, 4.84 mmol) in DMF (20 mL) was stirred at 80° C. for 16 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 mL), the aqueous phase was separated and further extracted with EtOAc (3×50 mL). The organic phases were combined, washed with brine (30 mL), extracted, dried (phase separator), and concentrated in vacuo. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (318 mg, 36%) as a pale yellow oil.

    [0900] LCMS m/z 516.1 (M+H).sup.+ (ES.sup.+).

    [0901] .sup.1H NMR (DMSO-d.sub.6) δ 6.99-6.94 (m, 4H), 6.87-6.82 (m, 4H), 4.17 (s, 4H), 3.73 (s, 9H), 2.27 (d, J=3.7 Hz, 6H), 1.74 (s, 6H).

    Step C: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide

    [0902] ##STR00082##

    [0903] 4 M LiBH.sub.4 in THF (0.5 mL, 2.00 mmol) was added dropwise to a stirred solution of methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoate (318 mg, 0.617 mmol) in THF (12 mL) cooled to 0° C. The mixture was stirred for 16 h. Additional 4 M LiBH.sub.4 in THF (0.5 mL, 2.000 mmol) was added at 0° C. and allowed to stir for a further 60 h. 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 (phase separator) and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (206 mg, 62%) as a sticky colourless oil.

    [0904] LCMS m/z 488.0 (M+H).sup.+ (ES.sup.+).

    [0905] .sup.1H NMR (DMSO-d.sub.6) δ 6.99-6.92 (m, 4H), 6.87-6.79 (m, 4H), 5.08-5.02 (m, 1H), 4.18-4.12 (m, 4H), 3.75-3.70 (m, 6H), 3.68-3.63 (m, 2H), 3.35-3.27 (m, 3H), 2.27-2.22 (m, 3H), 1.56-1.49 (m, 6H).

    Intermediate A14: 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide

    [0906] ##STR00083##

    [0907] N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9, Step A) (1.50 g, 3.68 mmol) and K.sub.2CO.sub.3 (1.27 g, 9.19 mmol) were suspended in MeCN (25 mL) under a N.sub.2 atmosphere. 2-Bromoethanol (0.30 mL, 4.05 mmol) was added and the mixture was heated to 50° C. for 4 h. After cooling to RT, water (50 mL) and EtOAc (75 mL) were added and the organics separated. The organic phase was 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 (1.29 g, 80%) as a white solid.

    [0908] LCMS m/z 432.4 (M+H).sup.+ (ES.sup.+).

    [0909] .sup.1H NMR (DMSO-d.sub.6) δ 8.30 (s, 1H), 7.81 (s, 1H), 7.08-7.03 (m, 4H), 6.84-6.78 (m, 4H), 4.98 (t, J=5.3 Hz, 1H), 4.19 (t, J=5.5 Hz, 2H), 4.13 (s, 4H), 3.76 (q, J=5.4 Hz, 2H), 3.71 (s, 6H).

    Intermediate A15: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-sulfonamide

    [0910] ##STR00084##

    Step A: methyl 2-methyl-2-(3-methyl-1H-pyrazol-1-yl)propanoate

    [0911] ##STR00085##

    [0912] A solution of 5-methyl-1H-pyrazole (1.00 mL, 12.94 mmol) and methyl 2-bromo-2-methylpropanoate (2.2 mL, 17.00 mmol) in THF (20 mL) was cooled to 0° C. and NaH (60 wt %) (673 mg, 16.83 mmol) was added and stirred for 10 min. Then methyl 2-bromo-2-methylpropanoate (2.2 mL, 17.00 mmol) was added and stirred at RT over the weekend. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 mL), and the aqueous phase was separated and further extracted with EtAOc (3×50 mL). The organic phases were combined, washed with brine (30 mL), extracted, dried (phase separator), and concentrated under reduced pressure. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (1.0 g, 40%) as a colourless oil.

    [0913] .sup.1H NMR (DMSO-d.sub.6) δ 7.74 (d, J=2.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 3.61 (s, 3H), 2.14 (s, 3H), 1.71 (s, 6H).

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

    [0914] ##STR00086##

    [0915] To a solution of chlorosulfonic acid (2.0 mL, 30 mmol) in CHCl.sub.3 (5 mL) at 0° C. was added a solution of methyl 2-methyl-2-(3-methyl-1H-pyrazol-1-yl)propanoate (1.0 g, 5.5 mmol) in CHCl.sub.3 (5 mL) over 2 min. The mixture was refluxed at 60° C. and stirred for 24 h. The reaction was cooled to RT and thionyl chloride (0.44 mL, 6.0 mmol) was added and the reaction was heated at 60° C. for a further 2 h. The reaction mixture was cooled to RT and added to a stirred mixture of DCM (50 mL) and ice water (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organics were dried (MgSO.sub.4), filtered and concentrated in vacuo to afford an orange oil (1.00 g). The orange oil was dissolved in DCM (10 mL) and bis(4-methoxybenzyl)amine (1.4 g, 55 mmol) followed by the slow addition of TEA (1.1 mL, 8.2 mmol) at 0° C. The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was diluted with water (30 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude yellow oil was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (1.17 g, 36%) as a yellow oil, which solidified on standing to form a yellow solid.

    [0916] LCMS m/z 502.2 (M+H).sup.+ (ES.sup.+).

    [0917] .sup.1H NMR (DMSO-d.sub.6) δ 8.29 (s, 1H), 7.06-6.97 (m, 4H), 6.88-6.74 (m, 4H), 4.20 (s, 4H), 3.72 (s, 6H), 3.64 (s, 3H), 2.24 (s, 3H), 1.75 (s, 6H).

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

    [0918] ##STR00087##

    [0919] LiBH.sub.4 (4 M in THF) (2 mL, 9.33 mmol) was added dropwise to a stirred solution of methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanoate (1.17 g, 2.33 mmol) in THF (15 mL) cooled to 0° C. The mixture was stirred for 18 h. The mixture was then partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (1.04 g, 82%) as a pale yellow oil.

    [0920] LCMS m/z 474.5 (M+H).sup.+ (ES.sup.+).

    [0921] .sup.1H NMR (DMSO-d.sub.6) δ 8.03 (s, 1H), 7.05-6.98 (m, 4H), 6.84-6.79 (m, 4H), 5.05 (t, J=5.5 Hz, 1H), 4.18 (s, 4H), 3.71 (s, 6H), 3.56 (d, J=5.7 Hz, 2H), 2.26 (s, 3H), 1.43 (s, 6H).

    Intermediate A16: 2-fluoro-5-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)benzene-sulfonamide

    [0922] ##STR00088##

    [0923] A solution of 2-(3-(benzylthio)-4-fluorophenyl)ethanol (4.17 g, 15.90 mmol) in MeCN (90 mL), AcOH (1.05 mL) and water (2.1 mL) was cooled to −10° C. (ice/acetone bath). 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (4.70 g, 23.84 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. The resulting residue was taken up in DCM (100 mL) and cooled to 0° C. bis-(4-Methoxybenzyl)amine (4.17 g, 16.21 mmol) and TEA (4.43 mL, 31.8 mmol) were then added to the solution, which was then allowed to warm to RT and stirred for 18 h. The reaction mixture was quenched with water (75 mL) then partitioned between DCM (100 mL) and water (25 mL). The organic phase was separated, and the aqueous layer re-extracted with DCM (2×50 mL). The organics were combined, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-80% EtOAc/isohexane) to afford the title compound (2.68 g, 32%) as a pale yellow oil.

    [0924] LCMS m/z 482.5 (M+Na).sup.+ (ES.sup.+).

    [0925] .sup.1H NMR (DMSO-d.sub.6) δ 7.62 (dd, J=7.0, 2.3 Hz, 1H), 7.56-7.52 (m, 1H), 7.36-7.29 (m, 1H), 7.02-6.96 (m, 4H), 6.81-6.77 (m, 4H), 4.68 (t, J=5.1 Hz, 1H), 4.27 (s, 4H), 3.71 (s, 6H), 3.64-3.58 (m, 2H), 2.75 (t, J=6.5 Hz, 2H).

    Intermediate A17: 3-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-benzenesulfonamide

    [0926] ##STR00089##

    Step A: methyl 2-(3-(benzylthio)phenyl)acetate

    [0927] ##STR00090##

    [0928] Benzyl mercaptan (1.54 mL, 13.10 mmol) was added to a stirred, N.sub.2-degassed solution of methyl 2-(3-bromophenyl)acetate (3 g, 13.10 mmol), XantPhos (0.76 g, 1.310 mmol), DIPEA (4.57 mL, 26.2 mmol) and Pd.sub.2(dba).sub.3 (0.60 g, 0.655 mmol) in 1,4-dioxane (80 mL) at RT. The mixture was then heated to 100° C. for 17 h. The mixture was filtered through Celite® and dry-loaded onto silica gel (30 g). The crude product was purified by FC (0-40% DCM/isohexane) to afford the title compound (3.22 g, 89%) as an orange oil.

    [0929] .sup.1H NMR (DMSO-d.sub.6) δ 7.37-7.33 (m, 2H), 7.31-7.27 (m, 2H), 7.26-7.20 (m, 4H), 7.09-7.04 (m, 1H), 4.23 (s, 2H), 3.64 (s, 2H), 3.60 (s, 3H).

    Step B: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)phenyl)acetate

    [0930] ##STR00091##

    [0931] A solution of methyl 2-(3-(benzylthio)phenyl)acetate (1.62 g, 5.95 mmol) in MeCN (29 mL), AcOH (0.4 mL) and water (0.8 mL) was cooled to −10° C. (ice/acetone bath). 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.758 g, 8.92 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 to dryness to give crude methyl 2-(3-(chloro-sulfonyl)phenyl)acetate as a thick yellow paste. bis-(4-Methoxybenzyl)amine (1.53 g, 5.95 mmol) was added to a suspension of methyl 2-(3-(chlorosulfonyl)phenyl)acetate (1.48 g, 5.95 mmol) in DCM (25 mL) cooled in an ice bath 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 to dryness to give a brown oil. The brown oil was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (2.45 g, 79%) as a white solid. Yield over 2 steps.

    [0932] LCMS m/z 492.0 (M+Na).sup.+ (ES.sup.+).

    [0933] .sup.1H NMR (DMSO-d.sub.6) δ 7.79-7.69 (m, 2H), 7.62-7.50 (m, 2H), 7.02-6.94 (m, 4H), 6.85-6.73 (m, 4H), 4.19 (s, 4H), 3.84 (s, 2H), 3.71 (s, 6H), 3.64 (s, 3H).

    Step C: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)phenyl)-2-methylpropanoate

    [0934] ##STR00092##

    [0935] Methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)phenyl)acetate (2.00 g, 4.26 mmol) was dissolved in THF (2 mL) at RT and 1 M lithium bis(trimethylsilyl)amide in THF (9 mL, 9.37 mmol) was added. The mixture was stirred at RT for 5 min and iodomethane (583 μL, 9.37 mmol) was added. The mixture was stirred at RT for 1 h. Additional 1 M lithium bis(trimethylsilyl)amide in THF (9 mL, 9.37 mmol) and iodomethane (583 μL, 9.37 mmol) were added and the mixture was stirred for a further 1 h, but no change was recorded. The mixture was then quenched with 1 M HCl (30 mL) and diluted with DCM (100 mL). The organic layer was collected and aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give a brown oil. The crude product was purified twice by FC (0-50% EtOAc/isohexane, and then again with 0-50% EtOAc/isohexane) to afford the title compound (0.54 g, 23%) as a yellow oil.

    [0936] LCMS m/z 520.0 (M+Na).sup.+ (ES.sup.+).

    [0937] .sup.1H NMR (DMSO-d.sub.6) δ 7.76 (dt, J=7.7, 1.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.58 (t, J=7.7 Hz, 1H), 6.99-6.92 (m, 4H), 6.81-6.77 (m, 4H), 4.20 (s, 4H), 3.71 (s, 6H), 3.60 (s, 3H), 1.53 (s, 6H).

    Step D: 3-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)benzene-sulfonamide

    [0938] ##STR00093##

    [0939] 4 M LiBH.sub.4 in THF (0.4 mL, 1.7 mmol) was added slowly to a stirred solution of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)phenyl)-2-methylpropanoate (0.54 g, 0.87 mmol) in THF (9 mL) cooled to 0° C. The mixture was then stirred for 17 h at RT. Additional 4 M LiBH.sub.4 in THF (0.4 mL, 1.7 mmol) was then added and the mixture was stirred for a further 3 h at RT. The mixture was then cooled to 0° C. and carefully quenched with water (20 mL) followed by 1 M aq HCl (20 mL). The mixture was extracted with EtOAc (3×30 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give a yellow oil. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.47 g, 92%) as a thick colourless oil.

    [0940] LCMS m/z 492.5 (M+Na).sup.+ (ES.sup.+).

    [0941] .sup.1H NMR (DMSO-d.sub.6) δ 7.74 (t, J=1.9 Hz, 1H), 7.72-7.64 (m, 2H), 7.55-7.49 (m, 1H), 6.99-6.92 (m, 4H), 6.80-6.75 (m, 4H), 4.80 (t, J=5.2 Hz, 1H), 4.18 (s, 4H), 3.70 (s, 6H), 3.45 (d, J=5.2 Hz, 2H), 1.23 (s, 6H).

    Intermediate A18: 3-cyclopropyl-5-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-benzenesulfonamide

    [0942] ##STR00094##

    Step A: methyl 2-(3-(benzylthio)-5-bromophenyl)acetate

    [0943] ##STR00095##

    [0944] Prepared according to the general procedure of methyl 2-(3-(benzylthio)phenyl)acetate (Intermediate A17, Step A) from methyl 2-(3,5-dibromophenyl)acetate and benzyl mercaptan to afford the title compound (7.00 g, 59%) as a yellow oil.

    [0945] .sup.1H NMR (DMSO-d.sub.6) δ 7.41-7.34 (m, 3H), 7.34-7.27 (m, 3H), 7.27-7.21 (m, 2H), 4.29 (s, 2H), 3.68 (s, 2H), 3.61 (s, 3H).

    Step B: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-bromophenyl)acetate

    [0946] ##STR00096##

    [0947] Prepared according to the general procedure of methyl 2-(3-(N,N-bis(4-methoxy-benzyl)sulfamoyl)phenyl)acetate (Intermediate A17, Step B) from methyl 2-(3-(benzylthio)-5-bromophenyl)acetate to afford the title compound (6.64 g, 55%) as an off-white solid.

    [0948] LCMS m/z 546.2/548.3 (M−H).sup.− (ES.sup.−).

    [0949] .sup.1H NMR (DMSO-d.sub.6) δ 7.80 (t, J=1.7 Hz, 1H), 7.75 (t, J=1.7 Hz, 1H), 7.68 (t, J=1.8 Hz, 1H), 7.07-7.02 (m, 4H), 6.84-6.79 (m, 4H), 4.25 (s, 4H), 3.85 (s, 2H), 3.73 (s, 6H), 3.65 (s, 3H).

    Step C: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-cyclopropylphenyl)-acetate

    [0950] ##STR00097##

    [0951] Prepared according to the general procedure of methyl 2-(2-cyclopropyl-6-(2-fluoro-pyridin-4-yl)phenyl)acetate (Intermediate B6, Step B) from methyl 2-(3-(N,N-bis-(4-methoxybenzyl)sulfamoyl)-5-bromophenyl)acetate and cyclopropyl boronic acid to afford the title compound (881 mg, 43%) as a light brown solid.

    [0952] LCMS m/z 508.5 (M−H).sup.− (ES.sup.−).

    [0953] .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (m, 1H), 7.32 (m, 1H), 7.26 (m, 1H), 7.03-6.98 (m, 4H), 6.83-6.77 (m, 4H), 4.18 (s, 4H), 3.78 (s, 2H), 3.72 (s, 6H), 3.63 (s, 3H), 2.05-1.98 (m, 1H), 1.03-0.97 (m, 2H), 0.72-0.66 (m, 2H).

    Step D: 3-cyclopropyl-5-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-benzene-sulfonamide

    [0954] ##STR00098##

    [0955] Methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-cyclopropylphenyl)acetate (881 mg, 1.729 mmol) was dissolved in dry THF (30 mL), placed under N.sub.2 and cooled to 0° C. LiAlH.sub.4 (2 M in THF) (978 μL, 1.956 mmol) was added drop-wise, and the reaction mixture warmed to RT, then allowed to stir for 16 h. The reaction was 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 using a phase separator and concentrated in vacuo to afford the title compound (824 mg, 98%) as a yellow solid.

    [0956] .sup.1H NMR (DMSO-d.sub.6) δ 7.42 (t, J=1.7 Hz, 1H), 7.26 (t, J=1.8 Hz, 1H), 7.21 (t, J=1.7 Hz, 1H), 7.03-6.98 (m, 4H), 6.83-6.77 (m, 4H), 4.68 (t, J=5.1 Hz, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 3.65-3.59 (m, 2H), 2.76 (t, J=6.7 Hz, 2H), 2.03-1.96 (m, 1H), 1.02-0.96 (m, 2H), 0.72-0.67 (m, 2H).

    Intermediate A19: 4-fluoro-1-(4-hydroxy-2-methylbutan-2-yl)-N,N-bis(4-methoxy-benzyl)-1H-pyrazole-3-sulfonamide

    [0957] ##STR00099##

    Step A: ethyl 3-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazol-1-yl)-3-methylbutanoate

    [0958] ##STR00100##

    [0959] A solution of 4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4, Step E) (1.5 g, 3.7 mmol) and ethyl 3-methylbut-2-enoate (0.77 mL, 5.5 mmol) in MeCN (20 mL) was treated with DBU (0.56 mL, 3.7 mmol) and allowed to stir at 50° C. for 18 h. The reaction mixture was cooled to RT and concentrated in vacuo to afford a colourless oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (528 mg, 26%) as a colourless oil.

    [0960] LCMS m/z 555.9 (M+Na).sup.+ (ES.sup.+).

    [0961] .sup.1H NMR (DMSO-d.sub.6) δ 8.30 (d, J=4.5 Hz, 1H), 7.10-7.00 (m, 4H), 6.88-6.78 (m, 4H), 4.23 (s, 4H), 3.96 (q, J=7.1 Hz, 2H), 3.73 (s, 6H), 2.90 (s, 2H), 1.60 (s, 6H), 1.09 (t, J=7.1 Hz, 3H).

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

    [0962] ##STR00101##

    [0963] Prepared according to the general procedure of 3-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (Intermediate A17, Step D) from ethyl 3-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazol-1-yl)-3-methylbutanoate and lithium borohydride to afford the title compound (267 mg, 54%) as a colourless oil.

    [0964] LCMS m/z 514.4 (M+Na).sup.+ (ES.sup.+).

    [0965] .sup.1H NMR (DMSO-d.sub.6) δ 8.25 (d, J=4.5 Hz, 1H), 7.05 (d, J=8.6 Hz, 4H), 6.83 (d, J=8.6 Hz, 4H), 4.47 (t, J=5.0 Hz, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 3.30-3.23 (m, 2H), 1.98 (t, J=7.1 Hz, 2H), 1.51 (s, 6H).

    Intermediate A20: 1-(1-(hydroxymethyl)cyclopropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide

    [0966] ##STR00102##

    Step A: methyl 1-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-cyclopropane-1-carboxylate

    [0967] ##STR00103##

    [0968] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9, Step A) (1.83 g, 4.72 mmol) in NMP (30 mL) at 0° C. was added NaH (60% dispersion in mineral oil) (472 mg, 11.8 mmol) portion-wise. The mixture was stirred at 0° C. for 10 min until effervescence had ceased. Methyl 2,4-dibromo-butanoate (1.00 mL, 7.08 mmol) was then added and the reaction allowed to warm to RT whilst stirring over 20 h. The mixture was then quenched with water (10 mL) and partitioned between brine (300 mL) and MTBE (100 mL). The aqueous layer was re-extracted with MTBE (100 mL) and EtOAc (100 mL). The organic layers were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by FC (0-80% EtOAc/isohexane) to afford the title compound (0.91 g, 1.7 mmol, 37%) as a white solid.

    [0969] LCMS m/z 486.4 (M+H).sup.+ (ES.sup.+).

    [0970] .sup.1H NMR (DMSO-d.sub.6) δ 8.47 (s, 1H), 7.84 (s, 1H), 7.07 (d, J=8.5 Hz, 4H), 6.85-6.77 (m, 4H), 4.16 (s, 4H), 3.72 (s, 6H), 3.64 (s, 3H), 1.77-1.73 (m, 2H), 1.69-1.65 (m, 2H).

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

    [0971] ##STR00104##

    [0972] Prepared according to the general procedure of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-sulfonamide (Intermediate A15, Step C) from methyl 1-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-cyclopropane-1-carboxylate and lithium borohydride to afford the title compound (0.95 g, 94%) as a thick colourless oil.

    [0973] LCMS m/z 458.5 (M+H).sup.+ (ES.sup.+).

    [0974] .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (s, 1H), 7.78 (s, 1H), 7.06 (d, J=8.4 Hz, 4H), 6.81 (d, J=8.4 Hz, 4H), 5.05 (t, J=5.7 Hz, 1H), 4.14 (s, 4H), 3.71 (s, 6H), 3.64 (d, J=5.6 Hz, 2H), 1.16-1.13 (m, 2H), 1.06-1.02 (m, 2H).

    Intermediate A21: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide

    [0975] ##STR00105##

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

    [0976] ##STR00106##

    [0977] Prepared according to the general procedure of methyl 2-(4-(N,N-bis(4-methoxy-benzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (Intermediate A9, Step B) from N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide and methyl 2-bromo-2-methylpropanoate to afford the title compound (1.43 g, 90%) as a colourless oil.

    [0978] LCMS m/z 488.3 (M+H).sup.+ (ES.sup.+).

    [0979] .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (d, J=1.4 Hz, 1H), 7.97 (d, J=1.4 Hz, 1H), 7.09-6.97 (m, 4H), 6.85-6.76 (m, 4H), 4.21 (s, 4H), 3.71 (s, 6H), 3.69 (s, 3H), 1.81 (s, 6H).

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

    [0980] ##STR00107##

    [0981] To a mixture of methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-imidazol-1-yl)-2-methylpropanoate (1.4 g, 2.6 mmol) and THF (20 mL) was added LiBH.sub.4 (4 M in THF) (3 mL, 13 mmol) at 0° C. The reaction mixture was left to stir at RT for 48 h. The reaction mixture was quenched with sat aq NH.sub.4Cl (100 mL), the product was extracted with EtOAc (3×30 mL), the combined organic extracts were passed through a phase separator and concentrated in vacuo to give the crude material as a colourless gum. The crude product was purified by FC (50-100% EtOAc/isohexane) to afford the title compound (840 mg, 67%) as a white solid.

    [0982] LCMS m/z 460.4 (M+H).sup.+ (ES.sup.+).

    [0983] .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (s, 1H), 7.87 (s, 1H), 7.03 (d, J=8.1 Hz, 4H), 6.80 (d, J=8.9 Hz, 4H), 5.24 (t, J=5.4 Hz, 1H), 4.20 (s, 4H), 3.71 (s, 6H), 3.53 (d, J=5.4 Hz, 2H), 1.47 (s, 6H).

    Intermediate A22: 2-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-2H-1,2,3-triazole-4-sulfonamide

    [0984] ##STR00108##

    Step A: methyl 2-(4-(benzylthio)-2H-1,2,3-triazol-2-yl)-2-methylpropanoate

    [0985] ##STR00109##

    [0986] Methyl 2-bromo-2-methylpropanoate (4.1 mL, 32 mmol) was added to a stirred suspension of 4-(benzylthio)-2H-1,2,3-triazole (5.00 g, 93 wt %, 24 mmol) and potassium carbonate (10 g, 73 mmol) in DMF (100 mL) at RT. The mixture was then heated to 70° C. for 3 days. The reaction mixture was left to cool to RT and partitioned between brine (1 L) and MTBE (300 mL). The organic layer was collected, dried (MgSO.sub.4), filtered and concentrated to dryness to give a yellow oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (3.15 g, 44%) as a thick colourless oil.

    [0987] LCMS m/z 292.2 (M+H).sup.+ (ES.sup.+).

    [0988] .sup.1H NMR (DMSO-d.sub.6) δ 7.77 (s, 1H), 7.33-7.16 (m, 5H), 4.19 (s, 2H), 3.63 (s, 3H), 1.81 (s, 6H).

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

    [0989] ##STR00110##

    [0990] NCS (5-77 g, 43.2 mmol) was added to a solution of methyl 2-(4-(benzylthio)-2H-1,2,3-triazol-2-yl)-2-methylpropanoate (3.15 g, 10.8 mmol) in AcOH (40 mL) and water (20 mL). The mixture was stirred for 4 h then partitioned between DCM (200 mL) and sat aq NaHCO.sub.3 (400 mL), dried (MgSO.sub.4) and filtered. bis(4-Methoxybenzyl)amine (2.78 g, 10.8 mmol) and TEA (2.19 g, 3.01 mL, 21.6 mmol) were then added and the mixture was stirred at RT for 20 h. The mixture was concentrated to ˜100 mL and poured onto 1 M aq HCl (300 mL). The mixture was filtered and the organic layer was separated. The aqueous layer was extracted with DCM (2×100 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness to give a yellow oil. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (0.58 g, 8%) as a thick yellow oil.

    [0991] LCMS m/z 511.4 (M+Na).sup.+ (ES.sup.+).

    [0992] .sup.1H NMR (DMSO-d.sub.6) δ 8.32 (s, 1H), 7.10-7.02 (m, 4H), 6.87-6.80 (m, 4H), 4.25 (s, 4H), 3.72 (s, 6H), 3.67 (s, 3H), 1.87 (s, 6H).

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

    [0993] ##STR00111##

    [0994] Prepared according to the general procedure of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (Intermediate A21, Step B) from methyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2H-1,2,3-triazol-2-yl)-2-methylpropanoate and lithium borohydride to afford the title compound (0.38 g, 98%) as a white solid.

    [0995] LCMS m/z 483.3 (M+Na).sup.+ (ES.sup.+).

    [0996] .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (s, 1H), 7.05 (d, J=8.4 Hz, 4H), 6.83 (d, J=8.3 Hz, 4H), 5.13 (t, J=5.7 Hz, 1H), 4.24 (s, 4H), 3.77-3.65 (m, 8H), 1.56 (s, 6H).

    Intermediate A23: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-sulfonamide

    [0997] ##STR00112##

    Step A: methyl 2-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylpropanoate

    [0998] ##STR00113##

    [0999] 3-Bromo-1H-pyrazolo[3,4-b]pyridine (2.50 g, 12.6 mmol) and potassium carbonate (5.23 g, 37.9 mmol) were suspended in dry DMF (75 mL). Methyl 2-bromo-2-methyl-propanoate (2.12 mL, 16.4 mmol) was added and the mixture was warmed to 80° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (100 mL) and water (100 mL) and poured on to brine (500 mL). The organics were separated and the aqueous re-extracted with EtOAc (2×100 mL). The organics were combined, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-30% EtOAc/isohexane) to afford the title compound (1.44 g, 38%) as a colourless oil.

    [1000] LCMS m/z 298.3/300.3 (M+H).sup.+ (ES.sup.+).

    [1001] .sup.1H NMR (DMSO-d.sub.6) δ 8.63 (dd, J=4.5, 1.5 Hz, 1H), 8.15 (dd, J=8.1, 1.6 Hz, 1H), 7.36 (dd, J=8.1, 4.5 Hz, 1H), 3.61 (s, 3H), 1.92 (s, 6H).

    Step B: methyl 2-(3-(benzylthio)-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylpropanoate

    [1002] ##STR00114##

    [1003] Prepared according to the general procedure of methyl 2-(3-(benzylthio)phenyl)acetate (Intermediate A17, Step A) from methyl 2-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylpropanoate and benzyl mercaptan to afford the title compound (1.13 g, 83%) as a thick yellow oil.

    [1004] LCMS m/z 342.3 (M+H).sup.+ (ES.sup.+).

    [1005] .sup.1H NMR (DMSO-d.sub.6) δ 8.51 (dd, J=4.5, 1.5 Hz, 1H), 8.03 (dd, J=8.1, 1.5 Hz, 1H), 7.36-7.10 (m, 6H), 4.31 (s, 2H), 3.59 (s, 3H), 1.88 (s, 6H).

    Step C: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylpropanoate

    [1006] ##STR00115##

    [1007] Prepared according to the general procedure of methyl 2-(3-(N,N-bis(4-methoxy-benzyl)sulfamoyl)phenyl)acetate (Intermediate A17, Step B) from methyl 2-(3-(benzylthio)-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylpropanoate to afford the title compound (1.38 g, 68%) as a thick pale yellow oil.

    [1008] LCMS m/z 539.5 (M+H).sup.+ (ES.sup.+).

    [1009] .sup.1H NMR (DMSO-d.sub.6) δ 8.67 (dd, J=4.5, 1.5 Hz, 1H), 8.37 (dd, J=8.2, 1.5 Hz, 1H), 7.44 (dd, J=8.2, 4.5 Hz, 1H), 7.05 (d, J=8.3 Hz, 4H), 6.75 (d, J=8.4 Hz, 4H), 4.36 (s, 4H), 3.68 (s, 6H), 3.64 (s, 3H), 1.91 (s, 6H).

    Step D: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazolo-[3,4-b]pyridine-3-sulfonamide

    [1010] ##STR00116##

    [1011] Prepared according to the general procedure of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (Intermediate A21, Step B) from methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylpropanoate and lithium borohydride to afford the title compound (1.13 g, 84%) as a white solid.

    [1012] LCMS m/z 511.3 (M+H).sup.+ (ES.sup.+).

    [1013] .sup.1H NMR (DMSO-d.sub.6) δ 8.67 (dd, J=4.5, 1.6 Hz, 1H), 8.35 (dd, J=8.2, 1.6 Hz, 1H), 7.41 (dd, J=8.2, 4.4 Hz, 1H), 7.07-7.00 (m, 4H), 6.78-6.71 (m, 4H), 4.98 (t, J=5.8 Hz, 1H), 4.33 (s, 4H), 4.02 (d, J=5.9 Hz, 2H), 3.68 (s, 6H), 1.73 (s, 6H).

    Intermediate A24: 4-fluoro-1-(3-(hydroxymethyl)pyridin-2-yl)-N,N-bis(4-methoxy-benzyl)-1H-pyrazole-3-sulfonamide

    [1014] ##STR00117##

    Step A: 4-fluoro-1-(3-formylpyridin-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1015] ##STR00118##

    [1016] 4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4, Step E) (250 mg, 617 μmol), 2-chloronicotinaldehyde (96.0 mg, 678 μmol), 18-crown-6 (8.15 mg, 30.8 μmol), KI (5.12 mg, 30.8 μmol) and K.sub.2CO.sub.3 (256 mg, 1.85 mmol) were taken up in MeCN (6 mL), heated to 70° C. and stirred for 18 h. This experiment was carried out twice. The two reaction mixtures were combined and the mixture was diluted with water (25 mL) and transferred into a separatory funnel. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were collected, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (170 mg, 22%) as a sticky colourless oil.

    [1017] .sup.1H NMR (CDCl.sub.3) δ 10.27 (d, J=0.8 Hz, 1H), 8.62 (dd, J=4.7, 1.8 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.34-8.26 (m, 1H), 7.46 (ddd, J=7.7, 4.7, 0.8 Hz, 1H), 7.13 (d, J=8.6 Hz, 4H), 6.75 (d, J=8.7 Hz, 4H), 4.42 (s, 4H), 3.73 (s, 6H).

    Step B: 4-fluoro-1-(3-(hydroxymethyl)pyridin-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1018] ##STR00119##

    [1019] Prepared according to the general procedure of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (Intermediate A21, Step B) from 4-fluoro-1-(3-formylpyridin-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and lithium borohydride to afford the title compound (0.20 g, 76%) as a white solid.

    [1020] LCMS m/z 535.3 (M+Na).sup.+ (ES.sup.+).

    [1021] .sup.1H NMR (DMSO-d.sub.6) δ 8.79 (d, J=4.4 Hz, 1H), 8.47 (dd, J=4.8, 1.8 Hz, 1H), 8.29-8.21 (m, 1H), 7.60 (dd, J=7.7, 4.7 Hz, 1H), 7.18-7.04 (m, 4H), 6.83-6.76 (m, 4H), 5.51 (t, J=5.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.36 (s, 4H), 3.68 (s, 6H).

    Intermediate A25: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-5-carboxylic acid

    [1022] ##STR00120##

    [1023] 4-Fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4) (1.0 g, 1.8 mmol) was dissolved in THF (20 mL) and cooled to −78° C. nBuLi (2.5 M in hexane) (1.6 mL, 4.1 mmol) was added drop-wise, and stirred for 5 min. CO.sub.2 gas was bubbled through the reaction mixture for 5 min and stirred at −78° C. for 10 min, and then allowed to warm to RT and stirred for 1 h. The reaction was quenched with slow addition of sat aq NH.sub.4Cl (10 mL), extracted with EtOAc (2×25 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by FC (0-10% MeOH/DCM) to afford the title compound (425 mg, 42%) as a colourless oil.

    [1024] LCMS m/z 544.4 (M+Na).sup.+ (ES.sup.+).

    [1025] .sup.1H NMR (DMSO-d.sub.6) δ 7.16-7.09 (m, 4H), 6.89-6.81 (m, 4H), 4.61 (s, 2H), 4.33 (s, 4H), 3.73 (s, 6H), 1.47 (s, 6H). Two exchangeable protons not observed.

    Intermediate A26: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-sulfonamide

    [1026] ##STR00121##

    Step A: methyl 2-(3-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropanoate

    [1027] ##STR00122##

    [1028] 3-bromo-1H-pyrazolo[3,4-c]pyridine (2.50 g, 12.6 mmol) and potassium carbonate (5.23 g, 37.9 mmol) were dissolved in DMF (77 mL). Methyl 2-bromo-2-methyl-propanoate (2.97 g, 16.4 mmol) was added dropwise to the solution which was heated to 80° C. and stirred for 18 h. The solution was diluted with EtOAc (100 mL) and transferred to a separating funnel then washed with a 3:1 brine/water solution (400 mL). The aqueous was washed twice with EtOAc (2×100 mL) and the combined organic layers were washed with brine (200 mL), dried with MgSO.sub.4 and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (2.96 g, 75%) as a thick yellow oil.

    [1029] LCMS m/z 298.2/300.2 (M+H).sup.+ (ES.sup.+).

    [1030] .sup.1H NMR (CDCl.sub.3) δ 8.85 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.53 (dd, J=5.6, 1.2 Hz, 1H), 3.74 (d, J=1.0 Hz, 3H), 2.00 (s, 6H).

    Step B: methyl 2-(3-(benzylthio)-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropanoate

    [1031] ##STR00123##

    [1032] Prepared according to the general procedure of methyl 2-(3-(benzylthio)phenyl)acetate (Intermediate A17, Step A) from methyl 2-(3-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropanoate and benzyl mercaptan to afford the title compound (3.0 g, 94%) as a thick yellow oil.

    [1033] LCMS m/z 342.3 (M+H).sup.+ (ES.sup.+).

    [1034] .sup.1H NMR (DMSO-d.sub.6) δ 8.97 (d, J=1.3 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 7.57 (dd, J=5.6, 1.2 Hz, 1H), 7.28-7.17 (m, 5H), 4.30 (s, 2H), 3.68 (s, 3H), 1.93 (s, 6H).

    Step C: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropanoate

    [1035] ##STR00124##

    [1036] Prepared according to the general procedure of methyl 2-(3-(N,N-bis(4-methoxy-benzyl)sulfamoyl)phenyl)acetate (Intermediate A17, Step B) from methyl 2-(3-(benzylthio)-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropanoate to afford the title compound (3.47 g, 59%) as a thick pale yellow oil.

    [1037] LCMS m/z 539.4 (M+H).sup.+ (ES.sup.+).

    [1038] .sup.1H NMR (DMSO-d.sub.6) δ 9.16 (d, J=5.3 Hz, 1H), 8.45 (t, J=5.4 Hz, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.05 (d, J=8.3 Hz, 4H), 6.80-6.72 (m, 4H), 4.36 (d, J=4.6 Hz, 4H), 3.75 (d, J=2.7 Hz, 3H), 3.69 (s, 6H), 1.96 (s, 6H).

    Step D: 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-sulfonamide

    [1039] ##STR00125##

    [1040] Prepared according to the general procedure of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-imidazole-4-sulfonamide (Intermediate A21, Step B) from methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropanoate and lithium borohydride to afford the title compound (355 mg, 7%) as a white solid.

    [1041] LCMS m/z 515.5 (M+H).sup.+ (ES.sup.+).

    [1042] .sup.1H NMR (DMSO-d.sub.6) δ 7.02 (d, J=8.6 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 5.08 (br s, 1H), 4.21 (s, 4H), 4.01 (s, 2H), 3.72 (s, 6H), 3.57 (s, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.54 (t, J=5.8 Hz, 2H), 1.47 (s, 6H). One exchangeable proton not observed.

    Intermediate A27: potassium 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-5-carboxylate

    [1043] ##STR00126##

    Step A: N,N-bis(4-methoxybenzyl)-7,7-dimethyl-4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide

    [1044] ##STR00127##

    [1045] 2.5 M butyllithium in hexanes (5.76 mL, 14.4 mmol) was added dropwise to a solution of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1) (3.23 g, 7.03 mmol) in 9:1 THF:DMPU (50 mL) cooled to −78° C. The mixture was stirred at −78° C. for 10 min and CO.sub.2 gas was bubbled in for a further 5 min. The mixture was then stirred for 5 min and left to warm to RT over 1 h. Acetic acid (30 mL) was added and the mixture was stirred at RT overnight. The mixture was poured onto sat aq NaHCO.sub.3 (200 mL). The mixture was extracted with EtOAc (3×30 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated to dryness. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (1.11 g, 23%) as a thick colourless oil.

    [1046] .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 1H), 7.10-7.03 (m, 4H), 6.87-6.81 (m, 4H), 4.63 (s, 2H), 4.27 (s, 4H), 3.72 (s, 6H), 1.51 (s, 6H).

    Step B: potassium 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-hydroxy-2-methyl-propan-2-yl)-1H-pyrazole-5-carboxylate

    [1047] ##STR00128##

    [1048] To a stirred solution of N,N-bis(4-methoxybenzyl)-7,7-dimethyl-4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (1.11 g, 2.29 mmol) in dry THF (25 mL) under a N.sub.2 atmosphere at RT was added potassium trimethylsilanolate (587 mg, 4.57 mmol). The reaction mixture was stirred for 18 h. The reaction mixture was concentrated to dryness, dissolved in THF (10 mL) and diluted with MTBE (100 mL). The supernatant was decanted and the pale yellow gummy residue was washed with MTBE (50 mL). The supernatant was decanted and the vessel concentrated to dryness to give the title compound (1.17 g, 85%) as a pale yellow solid.

    [1049] LCMS m/z 526.3 (M+H+Na−K).sup.+ (ES.sup.+); 502.3 (M−K).sup.− (ES.sup.−).

    [1050] .sup.1H NMR (DMSO-d.sub.6) δ 7.07-6.93 (m, 4H), 6.87-6.77 (m, 4H), 6.45 (s, 1H), 4.18 (s, 4H), 3.72 (s, 6H), 3.69 (s, 2H), 3.21-3.16 (m, 1H), 1.58 (s, 6H).

    Intermediate A28: 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-5-sulfonamide

    [1051] ##STR00129##

    [1052] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A1, Step C) (4 g, 10.3 mmol) and K.sub.2CO.sub.3 (4.28 g, 31.0 mmol) in MeCN (50 mL) was added 5-bromopentan-1-ol (5.17 g, 31.0 mmol) at 20° C. Then the mixture was stirred at 70° C. for 12 h. The mixture was poured into water (300 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product as a mixture of regioisomers. The residue was purified by FC (PE:EtOAc, 3:1 to 1:1) to give the title compound as the minor regioisomer (800 mg, 16-36% yield) as a yellow oil.

    [1053] LCMS: m/z 512.2 (M+K)+(ES.sup.+).

    [1054] .sup.1H NMR (CDCl.sub.3) δ 7.50 (d, 1H), 7.00-6.97 (m, 4H), 6.85-6.82 (m, 4H), 6.57 (d, 1H), 4.36-4.30 (m, 6H), 3.81 (s, 6H), 3.64 (t, 2H), 2.05-1.92 (m, 2H), 1.61-1.57 (m, 2H), 1.43-1.39 (m, 2H). One exchangeable proton not observed.

    Intermediate A29: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

    [1055] ##STR00130##

    Step A: ethyl 3-amino-1H-pyrazole-4-carboxylate

    [1056] ##STR00131##

    [1057] To a solution of ethyl 2-cyano-3-ethoxyacrylate (20 g, 118 mmol) in EtOH (200 mL) was added N.sub.2H.sub.4.H.sub.2O (6.12 g, 120 mmol, 98% purity). The reaction solution was stirred at 20° C. for 3 h, then concentrated under reduced pressure. The residue was triturated with MTBE (200 mL) to give the title compound (13.3 g, 72.5% yield) as a yellow solid.

    [1058] LCMS: m/z 156.1 (M+H).sup.+ (ES.sup.+).

    [1059] .sup.1H NMR (CDCl.sub.3): δ 9.68 (s, 1H), 7.57 (d, 1H), 4.30 (br s, 2H), 4.23 (q, 2H), 1.32 (t, 3H).

    Step B: ethyl 3-(chlorosulfonyl)-1H-pyrazole-4-carboxylate

    [1060] ##STR00132##

    [1061] To a solution of conc HCl (22 mL, 36% purity in water) and H.sub.2O (22 mL) was added ethyl 3-amino-1H-pyrazole-4-carboxylate (10.8 g, 69.6 mmol). Then a solution of NaNO.sub.2 (5.04 g, 73.1 mmol) in H.sub.2O (10.8 mL) was added slowly to the mixture keeping the temperature below 3° C. The mixture was stirred at 0° C. for 1 h to give a diazonium salt solution. SO.sub.2 gas was bubbled into AcOH (80 mL) at 0-5° C. for 0.5 h, then CuCl.sub.2 (4.68 g, 34.8 mmol) was added into the sulfur dioxide solution. The above diazonium salt solution was added dropwise into the saturated sulphur dioxide solution at 0° C., then the mixture was stirred at 20° C. for 0.5 h. Water (200 mL) and DCM (200 mL) were added into the reaction mixture and the layers were separated. The aqueous phase was extracted with DCM (200 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 FC (PE:EtOAc, 20:1 to 1:1) to give the title compound (5 g, 24.8% yield) as a yellow solid.

    [1062] .sup.1H NMR (DMSO-d.sub.6): δ 7.76 (s, 1H), 4.13-4.15 (m, 2H), 1.23 (t, 3H). One exchangeable proton not observed.

    Step C: ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-4-carboxylate

    [1063] ##STR00133##

    [1064] To a solution of 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (4.85 g, 18.9 mmol) in DCM (50 mL) was added TEA (6.36 g, 62.9 mmol), followed by another solution of ethyl 3-(chlorosulfonyl)-1H-pyrazole-4-carboxylate (5.0 g, 17.3 mmol, 82.5% purity) in THF (100 mL). The reaction mixture was stirred at 20° C. for 12 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA). The eluting phase was adjusted to pH 8 with solid NaHCO.sub.3, and the aqueous phase was extracted with EtOAc (200 mL×3). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give the title compound (8.0 g, 97.4% yield) as a yellow solid.

    [1065] LCMS: m/z 460.1 (M+H).sup.+ (ES.sup.+).

    [1066] .sup.1H NMR (DMSO-d.sub.6): δ 8.52 (s, 1H), 7.01 (d, 4H), 6.77 (d, 4H), 4.36 (s, 4H), 4.23 (q, 2H), 3.70 (s, 6H), 1.26 (t, 3H). One exchangeable proton not observed.

    Step D: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-4-carboxylic acid

    [1067] ##STR00134##

    [1068] To a solution of ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-4-carboxylate (8.0 g, 17.4 mmol) in THF (80 mL) was added a solution of LiOH.H.sub.2O (4 g, 95.3 mmol) in H.sub.2O (80 mL). The reaction mixture was stirred at 65° C. for 12 h, then washed with EtOAc (200 mL×2). The aqueous layer was adjusted to pH 2 with 1 M aq HCl and extracted with EtOAc (200 mL×2). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give the title compound (7.0 g, 93.2% yield) as a white solid.

    [1069] LCMS: m/z 454.1 (M+Na).sup.+ (ES.sup.+).

    [1070] .sup.1H NMR (DMSO-d.sub.6): δ 13.96 (br s, 1H), 12.74 (br s, 1H), 8.47 (s, 1H), 7.02-6.79 (m, 4H), 6.79-6.76 (m, 4H), 4.35 (s, 4H), 3.70 (s, 6H).

    Step E: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

    [1071] ##STR00135##

    [1072] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-4-carboxylic acid (2 g, 4.64 mmol) and dimethylamine (567 mg, 6.96 mmol, HCl salt) in DMF (30 mL) was added DIPEA (1.50 g, 11.6 mmol) and T.sub.3P (4.43 g, 6.96 mmol, 50% purity in EtOAc) at 0° C. The solution was stirred at 25° C. for 2 h, then quenched with H.sub.2O (80 mL) and extracted with EtOAc (50 mL×2). The organic phases were washed with brine (60 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:0 to 0:1) to give the title compound (2.1 g, 98.7% yield) as a colourless oil.

    [1073] LCMS: m/z 459.3 (M+H).sup.+ (ES.sup.+).

    [1074] .sup.1H NMR (CDCl.sub.3): δ 13.02 (s, 1H), 7.85 (s, 1H), 7.00 (d, 4H), 6.72 (d, 4H), 4.33 (s, 4H), 3.74 (s, 6H), 3.11 (s, 3H), 2.96 (s, 3H).

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

    [1075] ##STR00136##

    [1076] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide (1.5 g, 3.27 mmol) and methyl 2-bromo-2-methylpropanoate (1.18 g, 6.54 mmol) in MeCN (40 mL) was added K.sub.2CO.sub.3 (904 mg, 6.54 mmol) and the mixture was stirred at 65° C. for 1 h. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 2:1 to 1:2) to give the title compound (1.8 g, 98.5% yield) as a colourless oil.

    [1077] LCMS: m/z 559.2 (M+H).sup.+ (ES.sup.+).

    [1078] .sup.1H NMR (CDCl.sub.3): δ 7.70 (s, 1H), 7.07 (d, 4H), 6.77 (d, 4H), 4.31 (s, 4H), 3.78 (s, 6H), 3.70 (s, 3H), 3.11 (s, 3H), 3.03 (s, 3H), 1.63 (s, 6H).

    Step G: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

    [1079] ##STR00137##

    [1080] To a solution of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(dimethyl-carbamoyl)-1H-pyrazol-1-yl)-2-methylpropanoate (2.3 g, 4.12 mmol) in EtOH (40 mL) was added NaBH.sub.4 (467 mg, 12.4 mmol) in portions at 0° C. The resultant solution was stirred at 25° C. for 2 h, then quenched with 1 M aq HCl to pH 5 at 0° C. under N.sub.2. The mixture was diluted with H.sub.2O (100 mL) and extracted with EtOAc (50 mL×3). The 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, 1:1 to 0:1) to give the title compound (2.15 g, 98.4% yield) as a white solid.

    [1081] LCMS: m/z 531.1 (M+H).sup.+ (ES.sup.+).

    [1082] .sup.1H NMR (CDCl.sub.3): δ 7.58 (s, 1H), 7.00 (d, 4H), 6.69 (d, 4H), 4.25 (s, 4H), 3.70-3.67 (m, 8H), 3.02 (s, 3H), 2.92 (s, 3H), 1.44 (s, 6H). One exchangeable proton not observed.

    Intermediate A30: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-sulfonamide

    [1083] ##STR00138##

    Step A: 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazole-3-carboxylic acid

    [1084] ##STR00139##

    [1085] To a solution of 4-fluoro-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4, Step E) (13.5 g, 33.3 mmol) in THF (200 mL) was added slowly n-BuLi (2.5 M, 26.6 mL) at −70° C. under N.sub.2. The mixture was stirred for 0.5 h, then CO.sub.2 (solid) was added slowly into the reaction mixture. The reaction mixture was stirred at 20° C. for 1 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (3 g, 20.1% yield) as a yellow solid.

    [1086] LCMS: m/z 448.1 (M−H).sup.− (ES.sup.−).

    [1087] .sup.1H NMR (DMSO-d.sub.6): δ 7.00 (d, 4H), 6.76 (d, 4H), 4.15 (s, 4H), 3.70 (s, 6H). Two exchangeable protons not observed.

    Step B: 4-fluoro-N,N-bis(4-methoxybenzyl)-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-5-sulfonamide

    [1088] ##STR00140##

    [1089] To a solution of 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazole-3-carboxylic acid (500 mg, 1.11 mmol) in DMF (10 mL) was added DIPEA (431 mg, 3.34 mmol) and HATU (635 mg, 1.67 mmol). The mixture was stirred at 20° C. for 10 min, then 1-methylpiperazine (134 mg, 1.33 mmol) was added at 20° C. The reaction mixture was stirred at 20° C. for 12 h, then 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 (DCM:MeOH, 30:1 to 20:1) to give the title compound (400 mg, 67.6% yield) as a yellow oil.

    [1090] LCMS: m/z 532.2 (M+H).sup.+ (ES.sup.+).

    [1091] .sup.1H NMR (CDCl.sub.3): δ 7.08 (d, 4H), 6.78 (d, 4H), 4.38 (s, 4H), 3.79 (s, 6H), 3.73-3.78 (m, 2H), 3.62-3.59 (m, 2H), 2.55-2.51 (m, 4H), 2.40 (s, 3H). One exchangeable proton not observed.

    Step C: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrazol-1-yl)-2-methylpropanoate

    [1092] ##STR00141##

    [1093] To a solution of 4-fluoro-N,N-bis(4-methoxybenzyl)-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-5-sulfonamide (1.5 g, 2.82 mmol) in MeCN (10 mL) was added K.sub.2CO.sub.3 (975 mg, 7.05 mmol) and methyl 2-bromo-2-methylpropanoate (613 mg, 3.39 mmol). The mixture was stirred at 70° C. for 2 h. Additional K.sub.2CO.sub.3 (975 mg, 7.05 mmol) and methyl 2-bromo-2-methylpropanoate (613 mg, 3.39 mmol) were added to the reaction mixture three times until the reaction was completed. The mixture was quenched with H.sub.2O (150 mL) and extracted with EtOAc (200 mL×3). The organic phases were washed with brine (200 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (DCM:MeOH, 20:1 to 10:1) to give the title compound (1.5 g, 84.2% yield) as a yellow solid.

    [1094] LCMS: m/z 632.2 (M+H).sup.+ (ES.sup.+).

    [1095] .sup.1H NMR (DMSO-d.sub.6): δ 7.11 (d, 4H), 6.83 (dd, 4H), 4.33 (s, 4H), 3.70-3.74 (m, 8H), 3.67 (s, 3H), 3.67-3.64 (m, 2H), 2.38-2.34 (m, 4H), 2.24 (s, 3H), 1.71 (s, 6H).

    Step D: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-sulfonamide

    [1096] ##STR00142##

    [1097] To a solution of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)-2-methylpropanoate (500 mg, 792 μmol) in THF (10 mL) was added dropwise BH.sub.3-Me.sub.2S (10 M, 2.37 mL) at 0° C. under N.sub.2. The mixture was stirred at 20° C. for 0.5 h, then heated to 60° C. and stirred at 60° C. for 3 h. The reaction mixture was cooled to 20° C. and MeOH (20 mL) was added under N.sub.2. The mixture was stirred at 20° C. for 1 h, then heated to 60° C. for 12 h. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (320 mg, 57.5% yield, TFA salt) as a yellow oil.

    [1098] LCMS: m/z 590.6 (M−TFA+H).sup.+ (ES.sup.+).

    [1099] .sup.1H NMR (DMSO-d.sub.6): δ 9.60 (br s, 1H), 7.08 (dd, 4H), 6.83 (d, 4H), 5.13 (br s, 1H), 4.27 (s, 4H), 3.74-3.71 (m, 8H), 3.64 (s, 2H), 3.45-3.43 (m, 2H), 3.04-2.97 (m, 2H), 2.97-2.85 (m, 2H), 2.81 (s, 3H), 2.38-2.30 (m, 2H), 1.55 (s, 6H).

    Intermediate A31: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxy-benzyl)-5-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-3-sulfonamide

    [1100] ##STR00143##

    [1101] To a solution of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)-2-methylpropanoate (Intermediate A30, Step C) (600 mg, 950 μmol) in THF (15 mL) was added LiAlH.sub.4 (108 mg, 2.85 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 1 h, then quenched with EtOAc (10 mL) and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.28 g, 48.8% yield, TFA salt) as a yellow solid.

    [1102] LCMS: m/z 604.5 (M-TFA+H).sup.+ (ES.sup.+).

    [1103] .sup.1H NMR (DMSO-d.sub.6): δ 7.12 (d, 4H), 6.86 (dd, 4H), 4.61 (s, 2H), 4.35-4.33 (m, 4H), 3.74-3.69 (m, 10H), 3.13-3.07 (m, 2H), 2.86-2.84 (m, 2H), 2.68-2.64 (m, 3H), 1.47 (s, 6H). One exchangeable proton and TFA proton not observed.

    Intermediate A-32: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

    [1104] ##STR00144##

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

    [1105] ##STR00145##

    [1106] To a solution of 5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1H-pyrazole-3-carboxylic acid (Intermediate A30, Step A) (0.6 g, 1.33 mmol) in DMF (5 mL) was added DIPEA (518 mg, 4.00 mmol) and HATU (761 mg, 2.00 mmol). Then morpholine (139 mg, 1.60 mmol) was added to the mixture at 20° C. The reaction mixture was stirred at 20° C. for 12 h, then purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.45 g, 65.0% yield) as a yellow gum.

    [1107] LCMS: m/z 519.1 (M+H).sup.+ (ES.sup.+).

    [1108] .sup.1H NMR (DMSO-d.sub.6): δ 7.07 (d, 4H), 6.81 (d, 4H), 4.30 (s, 4H), 3.71 (s, 6H), 3.67-3.56 (m, 6H), 3.42-3.41 (m, 2H). One exchangeable proton not observed.

    Step B: methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)-2-methylpropanoate

    [1109] ##STR00146##

    [1110] To a solution of 4-fluoro-N,N-bis(4-methoxybenzyl)-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide (0.4 g, 771 μmol) in DMF (8 mL) was added Cs.sub.2CO.sub.3 (754 mg, 2.31 mmol) and methyl 2-bromo-2-methylpropanoate (279 mg, 1.54 mmol). The reaction mixture was stirred at 60° C. for 12 h, then water (100 mL) and EtOAc (100 mL) were added and the mixture was separated. The aqueous layer was extracted with EtOAc (100 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 FC (PE:EtOAc, 1:0 to 1:1) to give the title compound (0.37 g, 78.2% yield) as a yellow oil.

    [1111] LCMS: m/z 641.1 (M+Na).sup.+ (ES.sup.+).

    [1112] .sup.1H NMR (CDCl.sub.3): δ 7.11 (dd, 4H), 6.81 (dd, 4H), 4.38 (s, 4H), 3.80 (s, 6H), 3.77 (s, 3H), 3.75-3.73 (m, 4H), 3.69-3.68 (m, 2H), 3.50-3.49 (m, 2H), 1.83 (s, 6H).

    Step C: 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

    [1113] ##STR00147##

    [1114] To a solution of methyl 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)-2-methylpropanoate (0.7 g, 1.13 mmol) in THF (7 mL) was added BH.sub.3-Me.sub.2S (10 M, 7 mL) at 0° C. under N.sub.2. The reaction mixture was stirred at 20° C. for 0.5 h, then stirred at 60° C. for 12 h. The reaction mixture was quenched with MeOH (20 mL) at 0° C., then stirred at 75° C. for 2 h. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.62 g, 93.5% yield) as a yellow gum.

    [1115] LCMS: m/z 577.2 (M+H).sup.+ (ES.sup.+).

    [1116] .sup.1H NMR (CDCl.sub.3): δ 7.12 (d, 4H), 6.80 (dd, 4H), 5.58 (br s, 1H), 4.40 (s, 4H), 4.34-4.31 (m, 2H), 3.97-3.89 (m, 4H), 3.80 (s, 6H), 3.71 (s, 2H), 3.22-3.30 (m, 4H), 1.67 (s, 6H).

    Intermediate A33: 1-(1-amino-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide

    [1117] ##STR00148##

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

    [1118] ##STR00149##

    [1119] To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9, Step A) (2 g, 5.16 mmol) in MeCN (30 mL) was added 2-bromo-2-methylpropanamide (1.11 g, 6.69 mmol) and K.sub.2CO.sub.3 (1.43 g, 10.4 mmol). The reaction mixture was stirred at 60° C. for 16 h, then quenched with H.sub.2O (30 mL) and extracted with EtOAc (20 mL×2). The organic phases were washed with brine (30 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 2:3 to 0:1) to give the title compound (2 g, 82.0% yield) as a white solid.

    [1120] LCMS: m/z 473.2 (M+H).sup.+ (ES.sup.+).

    [1121] .sup.1H NMR (CDCl.sub.3): δ 7.73 (s, 1H), 7.58 (s, 1H), 7.15 (d, 4H), 6.83 (d, 4H), 6.03 (br s, 1H), 5.36 (br s, 1H), 4.24 (s, 4H), 3.80 (s, 6H), 1.79 (s, 6H).

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

    [1122] ##STR00150##

    [1123] To a solution of 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methyl-propanamide (2 g, 4.23 mmol) in THF (20 mL) was added BH.sub.3-Me.sub.2S (10 M, 1.27 mL) at 0° C. in portions under N.sub.2. The resultant mixture was stirred at 60° C. for 12 h, then quenched with MeOH (30 mL) and then 1 M aq HCl (10 mL) at 0° C. The mixture was stirred at 25° C. for 30 min, then concencentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (1.21 g, 57.8% yield, HCl salt) as a white solid.

    [1124] LCMS: m/z 459.1 (M−HCl+H).sup.+ (ES.sup.+).

    [1125] .sup.1H NMR (DMSO-d.sub.6): δ 8.33 (s, 1H), 8.13 (br s, 3H), 7.91 (s, 1H), 7.09 (d, 4H), 6.82 (d, 4H), 4.18 (s, 4H), 3.72 (s, 6H), 2.51 (s, 2H), 1.58 (s, 6H).

    Intermediate B1: 2-(2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1126] ##STR00151##

    Step A: methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)acetate

    [1127] ##STR00152##

    [1128] A solution of K.sub.2CO.sub.3 (44.9 g, 325 mmol) in water (50 mL) was added to methyl 2-(2,6-dichlorophenyl)acetate (17.8 g, 81 mmol), (2-fluoropyridin-4-yl)boronic acid (11.45 g, 81 mmol), XPhos (3.87 g, 8.13 mmol) and Pd.sub.2(dba).sub.3 (3.72 g, 4.06 mmol) in dioxane (500 mL) and the suspension was evacuated and backfilled with N.sub.2 three times whilst stirring at 60° C., then the reaction was stirred at 90° C. for 1 h. The mixture was diluted with EtOAc (200 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was separated, dried (MgSO.sub.4) and the product was purified by FC (0-20% EtOAc/isohexane) to afford the title compound (11.5 g, 47%) as a white solid.

    [1129] LCMS m/z 280.1/282.2 (M+H).sup.+ (ES.sup.+).

    [1130] .sup.1H NMR (CDCl.sub.3) δ 8.33 (d, J=5.1 Hz, 1H), 7.61 (dd, J=8.1, 1.3 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.33-7.30 (m, 1H), 7.30-7.26 (m, 1H), 7.14 (br s, 1H), 3.72 (s, 2H), 3.59 (s, 3H).

    Step B: methyl 2-(2-(2-fluoropyridin-4-yl)-6-(prop-1-en-2-yl)phenyl)acetate

    [1131] ##STR00153##

    [1132] Dioxane (200 mL) was added to methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)-acetate (11.5 g, 41.1 mmol), Pd.sub.2dba.sub.3 (1.05 g, 1.240 mmol) and XPhos (1.2 g, 2.52 mmol), under N.sub.2, followed by 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.75 ml, 41.2 mmol) and a solution of K.sub.2CO.sub.3 (17.05 g, 123 mmol) in water (20 mL). The reaction was heated at 95° C. for 20 h. After cooling to RT, the mixture was diluted with EtOAc (100 mL) and washed with 3:1 water/brine (2×200 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-30% EtOAc/isohexane) to afford the title compound (10.77 g, 90%) as a pale yellow oil.

    [1133] LCMS m/z 286.1 (M+H).sup.+ (ES.sup.+).

    [1134] .sup.1H NMR (DMSO-d.sub.6) δ 8.29 (d, J=5.1 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29-7.25 (m, 2H), 7.20 (dd, J=7.6, 1.4 Hz, 1H), 7.14-7.10 (m, 1H), 5.31-5.18 (m, 1H), 4.90-4.76 (m, 1H), 3.64 (br s, 2H), 3.46 (br s, 3H), 2.00 (br s, 3H).

    Step C: methyl 2-(2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate

    [1135] ##STR00154##

    [1136] Methyl 2-(2-(2-fluoropyridin-4-yl)-6-(prop-1-en-2-yl)phenyl)acetate (275 mg, 0.964 mmol) and 10% Pd/C (103 mg, 0.096 mmol) were suspended in EtOH (20 mL). The reaction was stirred at RT under 2 atm H.sub.2 for 18 h. The reaction mixture was filtered through a glass fibre filter, washing with MeOH, and concentrated in vacuo to afford the title compound (290 mg, 99%) as a pale yellow oil.

    [1137] LCMS m/z 288.0 (M+H).sup.+ (ES.sup.+).

    [1138] .sup.1H NMR (CDCl.sub.3) δ 8.23 (d, J=5.2 Hz, 1H), 7.41 (dd, J=7.9, 1.5 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.17-7.14 (m, 1H), 7.04 (dd, J=7.4, 1.5 Hz, 1H), 6.91 (t, J=1.6 Hz, 1H), 3.68 (s, 3H), 3.59 (s, 2H), 3.06 (sept, J=6.8 Hz, 1H), 1.25 (d, J=6.8 Hz, 6H).

    Step D: 2-(2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1139] ##STR00155##

    [1140] 2 M NaOH (486 μL, 0.972 mmol) was added to a solution of methyl 2-(2-(2-fluoro-pyridin-4-yl)-6-isopropylphenyl)acetate (254 mg, 0.884 mmol) in THF (5 mL) and the reaction stirred at RT for 3 h. Additional 2 M NaOH (486 μL, 0.972 mmol) was added and the reaction heated at 60° C. for 16 h. Further 2 M NaOH (972 μL, 1.944 mmol) was added and the reaction heated at 60° C. for 4 days. The reaction mixture was diluted with EtOAc (20 mL) and acidified to pH <4 using aq 1 M HCl. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo to afford the title compound (0.210 g, 82%) as an orange oil.

    [1141] LCMS m/z 274.2 (M+H).sup.+ (ES.sup.+).

    [1142] .sup.1H NMR (DMSO-d.sub.6) δ 12.38 (s, 1H), 8.30 (d, J=5.1 Hz, 1H), 7.48-7.41 (m, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.29-7.25 (m, 1H), 7.12-7.05 (m, 2H), 3.53 (s, 2H), 3.07 (sept, J=6.8 Hz, 1H), 1.20 (d, J=6.7 Hz, 6H).

    Intermediate B2: tert-butyl 2-(2-(2-fluoropyridin-4-yl)-6-isopropyl-3-methyl-phenyl)acetate

    [1143] ##STR00156##

    Step A: 2-(2-fluoropyridin-4-yl)-6-isopropyl-3-methylphenol

    [1144] ##STR00157##

    [1145] N.sub.2 was bubbled through a stirred mixture of 2-bromo-6-isopropyl-3-methylphenol (2 g, 8.73 mmol), (2-fluoropyridin-4-yl)boronic acid (1.2 g, 8.52 mmol) and K.sub.2CO.sub.3 (3.62 g, 26.2 mmol) in dioxane (30 mL) and water (5 mL) for 5 min. PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 (319 mg, 0.436 mmol) was added and the mixture heated at 80° C. for 20 h. The mixture was cooled to RT, then partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was dried (MgSO.sub.4) and evaporated and the residue was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (1.26 g, 58% yield) as a white solid.

    [1146] LCMS m/z 246.1 (M+H).sup.+ (ES.sup.+).

    [1147] .sup.1H NMR (DMSO-d.sub.6) δ 8.27 (d, J=5.0 Hz, 1H), 8.08 (s, 1H), 7.21 (dt, J=5.2, 1.6 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 3.29-3.21 (m, 1H), 1.97 (s, 3H), 1.16 (d, J=6.8 Hz, 6H).

    Step B: 2-(2-fluoropyridin-4-yl)-6-isopropyl-3-methylphenyl trifluoromethane-sulfonate

    [1148] ##STR00158##

    [1149] A solution of 2-(2-fluoropyridin-4-yl)-6-isopropyl-3-methylphenol (1.27 g, 5.18 mmol) in DCM (20 mL) was cooled to 0° C. Pyridine (0.63 mL, 7.76 mmol) and Tf.sub.2O (7.76 mL, 7.76 mmol) were added sequentially to the stirred solution and the reaction mixture was warmed to RT and stirred for 18 h. The reaction was then diluted with DCM (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried (phase separator) and concentrated in vacuo to afford the title compound (1.72 g, 87%) as a light brown solid.

    [1150] .sup.1H NMR (DMSO-d.sub.6) δ 8.37 (d, J=5.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 6.49 (d, J=8.1 Hz, 1H), 7.28-735 (m, 1H), 7.29 (s, 1H), 3.22 (sept, J=6.8 Hz, 1H), 2.12 (s, 3H), 1.26 (d, J−6.8 Hz, 6H).

    Step C: tert-butyl 2-(2-(2-fluoropyridin-4-yl)-6-isopropyl-3-methylphenyl)acetate

    [1151] ##STR00159##

    [1152] (2-(tert-Butoxy)-2-oxoethyl)zinc(II) bromide (0.33 M in THF, 6.02 mL, 1.987 mmol) was added to a solution of 2-(2-fluoropyridin-4-yl)-6-isopropyl-3-methylphenyl trifluoromethanesulfonate (300 mg, 0.795 mmol), tetrabutylammonium bromide (384 mg, 1.192 mmol) and Xantphos-Pd-G3 (151 mg, 0.159 mmol) in THF (2 mL). The reaction was degassed with N.sub.2 and stirred at 70° C. for 72 h under N.sub.2. The reaction was cooled to RT, quenched with water (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (215 mg, 78%) as an off-white solid.

    [1153] LCMS m/z 344.3 (M+H).sup.+ (ES.sup.+).

    [1154] .sup.1H NMR (DMSO-d.sub.6) δ 8.33 (d, J=5.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.16-7.11 (m, 1H), 6.95-6.92 (m, 1H), 3.42-3.31 (m, 2H), 3.03 (sept, J=6.8 Hz, 1H), 1.93 (s, 3H), 1.32 (s, 9H), 1.20-1.16 (m, 6H).

    Intermediate B3: tert-butyl 2-(5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-acetate

    [1155] ##STR00160##

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

    [1156] ##STR00161##

    [1157] 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, 2.323 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.

    [1158] LCMS m/z 229.1 (M+H).sup.+ (ES.sup.+).

    [1159] .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).

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

    [1160] ##STR00162##

    [1161] Sodium nitrite (1.04 g, 15.07 mmol) in water (10 mL) was added to a solution of 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (2.65 g, 11.61 mmol) in H.sub.2SO.sub.4 (2 M in THF, 50 mL) at 0° C. and the reaction was stirred for 40 min. This solution was added slowly to H.sub.2SO.sub.4 (2 M in THF, 50 mL) and the reaction was stirred at 50° C. for 40 min, diluted with water (100 mL) and extracted with EtOAc (150 mL). The aqueous phase was basified to pH ˜8 with 2 M NaOH and extracted with EtOAc (150 mL). The combined organic phases were dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-60% EtOAc/isohexane) to afford the title compound (1.71 g, 59%) as a yellow solid.

    [1162] LCMS m/z 230.1 (M+H).sup.+ (ES.sup.+).

    [1163] .sup.1H NMR (DMSO-d.sub.6) δ 9.08 (br s, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.54-7.49 (m, 1H), 7.30 (s, 1H), 7.19 (d, J=7.7 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 2.90-2.84 (m, 4H), 2.03 (p, J=7.5 Hz, 2H).

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

    [1164] ##STR00163##

    [1165] 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.20 g, 8.95 mmol) was added portion-wise to a solution of 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-ol (1.71 g, 7.46 mmol) and DIPEA (3.26 mL, 18.65 mmol) in DCM (25 mL). The reaction was stirred for 2 days, then diluted with DCM (35 ml), washed with aq 1 M HCl (2×100 mL) and sat aq NaHCO.sub.3 (100 mL). The organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by FC (0-50% EtOAc/isohexane) then taken up in DCM (100 mL) and washed with sat aq NaHCO.sub.3 (100 mL). The organic phase was dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (2.18 g, 81%).

    [1166] LCMS m/z 362.0 (M+H).sup.+ (ES.sup.+).

    [1167] .sup.1H NMR (DMSO-d.sub.6) δ 8.34 (d, J=5.2 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.47 (dt, J=5.2, 1.7 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.35 (br s, 1H), 3.07-3.01 (m, 4H), 2.15 (p, J=7.5 Hz, 2H).

    Step D: tert-butyl 2-(5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate

    [1168] ##STR00164##

    [1169] Zn dust (12.97 g, 198 mmol) was suspended in 1 M HCl (100 mL) and stirred at RT for 1 h under N.sub.2. The supernatant was removed with a syringe and the zinc washed with EtOH (2×100 mL) and THF (2×100 mL). The Zn dust was dried under vacuum for 16 h and taken up in THF (150 mL). TMSCl (1.70 mL, 13.30 mmol) and 1,2-dibromoethane (1.14 mL, 13.23 mmol) were added and the mixture was heated to reflux for 1 h. tert-Butyl 2-bromoacetate (15 mL, 66.1 mmol) was added dropwise whilst maintaining controlled reflux and the reaction was heated to reflux for 1 h. The supernatant containing the crude (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (34.3 mL, 15.08 mmol) was added to a solution of 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (2.18 g, 6.03 mmol), Pd.sub.2(dba).sub.3 (0.55 g, 0.601 mmol) and XPhos (0.58 g, 1.217 mmol) in THF (10 mL) and the solution was stirred at 70° C. for 1 h. After cooling to RT, the reaction was diluted with EtOAc (100 mL) and water (200 mL) and the residue was filtered. The phases were separated. The aqueous phase was extracted with EtOAc (2×150 mL), the combined organics were dried (MgSO.sub.4), loaded onto silica and purified by FC (0-50% EtOAc/isohexane) followed by FC (0-10% MTBE/isohexane) to afford the title compound (1.64 g, 75%) as a colourless oil.

    [1170] LCMS m/z 328.1 (M+H).sup.+ (ES.sup.+).

    [1171] .sup.1H NMR (DMSO-d.sub.6) δ 8.29 (d, J=5.1 Hz, 1H), 7.28-7.24 (m, 2H), 7.10-7.05 (m, 2H), 3.51 (s, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.4 Hz, 2H), 2.06 (p, J=7.5 Hz, 2H), 1.33 (s, 9H).

    Intermediate B4: tert-butyl 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)-acetate

    [1172] ##STR00165##

    Step A: 2-bromo-4-fluoro-6-isopropylaniline

    [1173] ##STR00166##

    [1174] NBS (7.16 g, 40.2 mmol) was added portion wise to a solution of 4-fluoro-2-isopropyl-aniline (6.16 g, 40.2 mmol) in DCM (150 mL) at 0° C. The reaction was stirred at 0° C. for 1.5 h. The reaction was diluted with DCM (100 mL), washed with water (200 mL) and the organic phase was further washed with sat aq Na.sub.2S.sub.2O.sub.3 (200 mL). The organic phase was separated, dried (MgSO.sub.4), filtered and purified by FC (0-30% EtOAc/isohexane) to afford the title compound (6.62 g, 69%) as a deep purple oil.

    [1175] LCMS m/z 232.1, 234.0 (M+H).sup.+ (ES.sup.+).

    [1176] .sup.1H NMR (CDCl.sub.3) δ 7.06 (dd, J=7.7, 2.9 Hz, 1H), 6.85 (dd, J=9.8, 2.9 Hz, 1H), 3.98 (br s, 2H), 2.95-2.85 (m, 1H), 1.25 (d, J=6.8 Hz, 6H).

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

    [1177] ##STR00167##

    [1178] A solution of 2-bromo-4-fluoro-6-isopropylaniline (5.60 g, 24.13 mmol) in dry 1,4-dioxane (200 mL) was added to a mixture of (2-fluoropyridin-4-yl)boronic acid (3.40 g, 24.13 mmol) and Pd(dppf)Cl.sub.2.DCM (1.0 g, 1.225 mmol) followed by a solution of potassium carbonate (13.30 g, 96 mmol) in water (20 mL). The resulting suspension was evacuated and backfilled with N.sub.2 twice before stirring at 95° C. for 1 h. The reaction was diluted with EtOAc (200 mL) and washed with water (250 mL). The organic phase was separated, dried (MgSO.sub.4), filtered and directly loaded onto silica for purification. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (4.93 g, 79%) as a purple oil.

    [1179] LCMS m/z 249.3 (M+H).sup.+ (ES.sup.+).

    [1180] .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J=5.1 Hz, 1H), 7.43-7.39 (m, 1H), 7.23-7.20 (m, 1H), 6.97 (dd, J=10.2, 3.0 Hz, 1H), 6.79 (dd, J=9.0, 3.0 Hz, 1H), 4.63 (br s, 2H), 3.13-3.03 (m, 1H), 1.18 (d, J=6.7 Hz, 6H).

    Step C: 4-(2-bromo-5-fluoro-3-isopropylphenyl)-2-fluoropyridine

    [1181] ##STR00168##

    [1182] To a mixture of 4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylaniline (6.5 g, 24.87 mmol), CuBr (4.91 g, 34.2 mmol) and CuBr.sub.2 (0.032 g, 0.143 mmol) was added MeCN (75 mL). The suspension was cooled to 0° C. over 10 min. Neat isopentyl nitrite (4.6 mL, 34.2 mmol) was added to the solution dropwise and then the reaction mixture was left to stir at 50° C. for 2 h. The reaction mixture was left to cool to RT, filtered through a pad of Celite® and concentrated in vacuo. The crude product was purified by FC (0-15% EtOAc/isohexane) to afford the title compound (4.98 g, 53%) as a pink solid.

    [1183] LCMS m/z 312.1, 314.2 (M+H).sup.+ (ES.sup.+).

    [1184] .sup.1H NMR (DMSO-d.sub.6) δ 8.34 (d, J=5.1 Hz, 1H), 7.44-7.36 (m, 2H), 7.28 (s, 1H), 7.24 (dd, J=8.5, 3.0 Hz, 1H), 3.40 (p, J=6.8 Hz, 1H), 1.25 (d, J=6.8 Hz, 6H).

    Step D: tert-butyl 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate

    [1185] ##STR00169##

    [1186] 4-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-fluoropyridine (2.46 g, 7.88 mmol) and XPhos (0.752 g, 1.577 mmol) were suspended in dry THF (5 mL). The mixture was degassed (N.sub.2) for 5 min, then evacuated and back-filled with N.sub.2 (×3), then Pd.sub.2(dba).sub.3 (0.722 g, 0.789 mmol) was added and the reaction evacuated and back-filled with N.sub.2 (×3). (2-(tert-Butoxy)-2-oxoethyl)zinc(II) bromide (0.41 M in THF) (57-7 mL, 23.66 mmol) was added and the reaction stirred at reflux for 3 h. The reaction was diluted with MTBE (200 mL) and filtered. The filtrate was washed with brine (200 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-30% EtOAc/isohexane) to afford the title compound (2.44 g, 80%) as a yellow oil.

    [1187] LCMS m/z 348.5 (M+H).sup.+ (ES.sup.+).

    [1188] .sup.1H NMR (DMSO-d.sub.6) δ 8.33 (d, J=5.9 Hz, 1H), 7.32-7.26 (m, 2H), 7.11-7.09 (m, 1H), 7.00 (dd, J=8.8, 2.8 Hz, 1H), 2.50 (s, 2H), 3.12-3.05 (m, 1H), 1.34 (s, 9H), 1.20 (d, J=6.8 Hz, 6H).

    Intermediate B5: methyl 2-(4-fluoro-2-isopropyl-6-(2-oxo-1,2-dihydropyridin-4-yl)-phenyl)acetate

    [1189] ##STR00170##

    Step A: 2-(4-fluoro-2-isopropyl-6-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)acetic acid

    [1190] ##STR00171##

    [1191] A mixture of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (2.2 g, 7.25 mmol) in dioxane and aq 1 M HCl (15 mL) was heated at 70° C. for 5 h, conc HCl (0.5 mL) added and heated for a further 48 h. A further portion of conc HCl (1 mL) was added, and the mixture was heated at 70° C. for 48 h. The mixture was cooled, filtered and washed with water (5 mL). The solid was evaporated from MeOH (2×20 mL) and dried to afford the title compound (1.00 g, 46%) as an off-white solid.

    [1192] LCMS m/z 288.2 (M−H).sup.− (ES.sup.−).

    [1193] .sup.1H NMR (DMSO-d.sub.6) δ 12.40 (br s, 1H), 11.76 (br s, 1H), 7.43 (d, J=6.6 Hz, 1H), 7.22 (dd, J=10.5, 2.8 Hz, 1H), 6.90 (dd, J=8.9, 2.8 Hz, 1H), 6.17 (d, J=1.7 Hz, 1H), 6.07 (dd, J=6.6, 1.7 Hz, 1H), 3.54 (s, 2H), 3.07-2.96 (m, 1H), 1.18 (d, J=6.7 Hz, 6H).

    Step B: methyl 2-(4-fluoro-2-isopropyl-6-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)-acetate

    [1194] ##STR00172##

    [1195] AcCl (3 mL, 42.2 mmol) was added dropwise to MeOH (20 mL) cooled with an ice bath. The mixture was allowed to warm to RT, then 2-(4-fluoro-2-isopropyl-6-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)acetic acid (990 mg, 3.42 mmol) was added and the mixture stirred for 24 h. The solvent was evaporated, and the residue purified by FC (0-10% MeOH/DCM) to afford the title compound (1.04 g, 98%) as a white powder.

    [1196] LCMS m/z 303.8 (M+H).sup.+ (ES.sup.+).

    [1197] .sup.1H NMR (CDCl.sub.3) δ 7.86-7.78 (br m, 1H), 7.12 (dd, J=10.1, 2.6 Hz, 1H), 6.88-6.76 (m, 2H), 6.72-6.64 (br m, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 3.10-3.01 (m, 1H), 1.25 (d, J=6.8 Hz, 6H). One exchangeable proton not observed.

    Intermediate B6: 2-(2-cyclopropyl-6-(2-fluoropyridin-4-yl)phenyl)acetic acid

    [1198] ##STR00173##

    Step A: methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)acetate

    [1199] ##STR00174##

    [1200] A solution of potassium carbonate (33.0 g, 240 mmol) in water (36 mL) was added to a solution of methyl 2-(2,6-dichlorophenyl)acetate (13.0 g, 59 mmol), (2-fluoropyridin-4-yl)boronic acid (8.40 g, 59 mmol), XPhos (2.80 g, 5.9 mmol) and Pd.sub.2(dba).sub.3 (2.70 g, 2.95 mmol) in anhydrous 1,4-dioxane (365 mL) and the suspension was evacuated and backfilled with N.sub.2 three times whilst stirring at 60° C., then the reaction was stirred at 90° C. for 1.5 h. The solvent was removed and the resultant liquor was diluted with EtOAc (200 mL) and washed with water (200 mL) and brine (200 mL). The organic phase was separated, dried (MgSO.sub.4) and filtered. The crude product was purified by FC (0-20% EtOAc/isohexane) to afford methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)-phenyl)acetate (4.8 g, 17 mmol, 28%) as a pale yellow solid. Fractions containing methyl 2-(2,6-bis(2-fluoropyridin-4-yl)phenyl)acetate and methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)acetate were re-purified by FC (0-20% EtOAc/isohexane) to afford methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)acetate as an off-white solid (1.63 g). In total 6.43 g (39%) of title compound were obtained.

    [1201] .sup.1H NMR (CDCl.sub.3) δ 8.27 (d, J=5.0 Hz, 1H), 7.50 (dd, J=8.1, 1.3 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.16 (m, 2H), 6.93-6.89 (m, 1H), 3.72 (s, 3H), 3.68 (s, 2H).

    Step B: methyl 2-(2-cyclopropyl-6-(2-fluoropyridin-4-yl)phenyl)acetate

    [1202] ##STR00175##

    [1203] A suspension of methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)acetate (2.00 g, 7.15 mmol), potassium phosphate (5.46 g, 25.7 mmol), cyclopropylboronic acid (921 mg, 10.7 mmol) and tricyclohexylphosphane (100 mg, 358 μmol) in toluene (50 mL) and water (8 mL) was degassed with N.sub.2 (5 min), then evacuated and back-filled with N.sub.2 (3×). Palladium (II) acetate (80.3 mg, 358 μmol) was added and the reaction mixture was refluxed for 18 h. The reaction was allowed to cool to RT before dilution with EtOAc (200 mL), washed with water (200 mL) then brine (100 mL) followed by removal of the solvent under reduced pressure. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (0.56 g, 23%) as a pale yellow oil.

    [1204] .sup.1H NMR (CDCl.sub.3) δ 8.24 (d, J=5.1, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19-7.14 (m, 2H), 7.07 (dd, J=7.6, 1.4 Hz, 1H), 6.94-6.92 (m, 1H), 3.75 (s, 2H), 3.68 (s, 3H), 1.86 (m, J=8.5, 5.4 Hz, 1H), 0.99-0.93 (m, 2H), 0.72-0.66 (m, 2H).

    Step C: 2-(2-cyclopropyl-6-(2-fluoropyridin-4-yl)phenyl)acetic acid

    [1205] ##STR00176##

    [1206] To a stirred solution of methyl 2-(2-cyclopropyl-6-(2-fluoropyridin-4-yl)phenyl)acetate (580 mg, 2.03 mmol) in dry 1,4-dioxane (10 mL) was added 2 M aq NaOH (2 mL) The reaction mixture was stirred for 3.5 h at 90° C. The solution was acidified to ˜pH 2 then diluted with EtOAc (25 mL) and transferred into a separatory funnel. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (25 mL, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by FC (0-70% EtOAc/isohexane) to afford the title compound (440 mg, 64%) as a pale yellow oil.

    [1207] .sup.1H NMR (CDCl.sub.3) δ 8.26 (d, J=5.1 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.21-7.14 (m, 2H), 7.08 (dd, J=7.6, 1.4 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 3.81 (s, 2H), 1.90 (ddd, J=13.9, 8.5, 5.5 Hz, 1H), 1.03-0.98 (m, 2H), 0.74-0.70 (m, 2H). One exchangeable proton not observed.

    Intermediate B7: tert-butyl 2-(3,4-difluoro-2-(2-fluoropyridin-4-yl)-6-isopropyl-phenyl)acetate

    [1208] ##STR00177##

    Step A: 4,5-difluoro-2-(prop-1-en-2-yl)aniline

    [1209] ##STR00178##

    [1210] To a solution of 2-bromo-4,5-difluoroaniline (10 g, 48 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.1 g, 48 mmol) and PdCl.sub.2(dppf). DCM (2.0 g, 2.4 mmol) in anhydrous 1,4-dioxane (200 mL) was added a solution of K.sub.2CO.sub.3 (20 g, 0.14 mol) in water (20 mL) and the resulting suspension was evacuated and backfilled with N.sub.2 twice before stirring at 100° C. for 3 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was separated, the aqueous was further extracted with EtOAc (20 mL), the organic phases were combined, dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by FC (0-30% EtOAc/isohexane) to afford the title compound (5.65 g, 57%) as a pale pink oil.

    [1211] LCMS m/z 170.1 (M+H).sup.+ (ES.sup.+).

    [1212] .sup.1H NMR (DMSO-d.sub.6) δ 6-95 (dd, J=11.8, 9.2 Hz, 1H), 6.60 (dd, J=13.3, 7.5 Hz, 1H), 5.27-5.23 (m, 1H), 5.02-4.97 (m, 1H), 4.95 (s, 2H), 1.97 (s, 3H).

    Step B: 4,5-difluoro-2-isopropylaniline

    [1213] ##STR00179##

    [1214] 4,5-difluoro-2-(prop-1-en-2-yl)aniline (5.65 g, 33.4 mmol) and Pd/C (10%) (1.8 g, 10 wt %, 1.67 mmol) were suspended in EtOH (70 mL). The resulting mixture was stirred at RT under 5 atm H.sub.2 for 6 h. The reaction mixture was filtered through a glass fibre filter and concentrated under reduced pressure to afford the title compound (5.21 g, 82%) as a light purple oil.

    [1215] LCMS m/z 172.2 (M+H).sup.+ (ES.sup.+).

    [1216] .sup.1H NMR (DMSO-d.sub.6) δ 6.99 (dd, J=12.6, 9.2 Hz, 1H), 6.59 (dd, J=13.1, 7.6 Hz, 1H), 5.43 (s, 2H), 2.96-2.86 (m, 1H), 1.11 (d, J=6.8 Hz, 6H).

    Step C: 2-bromo-3,4-difluoro-6-isopropylaniline

    [1217] ##STR00180##

    [1218] Prepared according to the general procedure of 2-bromo-4-fluoro-6-isopropylaniline (Intermediate B4, Step A) from 4,5-difluoro-2-isopropylaniline and NBS to afford the title compound (6.8 g, 83%) as a purple oil.

    [1219] LCMS m/z 250.1/252.1 (M+H).sup.+ (ES.sup.+).

    [1220] .sup.1H NMR (DMSO-d.sub.6) δ 7.10 (dd, J=12.0, 8.9 Hz, 1H), 5.20 (s, 2H), 3.05 (sept, J=6.8 Hz, 1H), 1.13 (d, J=6.7 Hz, 6H).

    Step D: 3,4-difluoro-2-(2-fluoropyridin-4-yl)-6-isopropylaniline

    [1221] ##STR00181##

    [1222] Prepared according to the general procedure of 4,5-difluoro-2-(prop-1-en-2-yl)aniline (Intermediate B7, Step A) from 2-bromo-3,4-difluoro-6-isopropylaniline and 2-fluoropyridine-4-boronic acid to afford the title compound (5.82 g, 76%) as an orange oil.

    [1223] LCMS m/z 267.2 (M+H).sup.+ (ES.sup.+).

    [1224] .sup.1H NMR (DMSO-d.sub.6) δ 8.35 (d, J=5.1 Hz, 1H), 7.34 (d, J=4.5 Hz, 1H), 7.22 (s, 1H), 7.13 (dd, J=12.2, 9.0 Hz, 1H), 4.75 (s, 2H), 3.12-2.97 (m, 1H), 1.16 (d, J=6.7 Hz, 6H).

    Step E: 4-(2-bromo-5,6-difluoro-3-isopropylphenyl)-2-fluoropyridine

    [1225] ##STR00182##

    [1226] Prepared according to the general procedure of 4-(2-bromo-5-fluoro-3-isopropyl-phenyl)-2-fluoropyridine (Intermediate B4, Step C) from 3,4-difluoro-2-(2-fluoro-pyridin-4-yl)-6-isopropylaniline to afford the title compound (4.52 g, 60%) as a light pink solid.

    [1227] LCMS m/z 330.1/332.1 (M+H).sup.+ (ES.sup.+).

    [1228] .sup.1H NMR (DMSO-d.sub.6) δ 8.41 (d, J=5.1 Hz, 1H), 7.69 (dd, J=12.0, 8.4 Hz, 1H), 7.44-7.41 (m, 1H), 7.36 (s, 1H), 1.23 (d, J=6.8 Hz, 6H). One proton obscured by water signal.

    Step F: tert-butyl 2-(3,4-difluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate

    [1229] ##STR00183##

    [1230] Prepared according to the general procedure of tert-butyl 2-(4-fluoro-2-(2-fluoro-pyridin-4-yl)-6-isopropylphenyl)acetate (Intermediate B4, Step D) from 4-(2-bromo-5,6-difluoro-3-isopropylphenyl)-2-fluoropyridine and (2-isopropoxy-2-oxoethyl)zinc(II) bromide to afford the title compound (4.41 g, 83%) as an orange oil.

    [1231] .sup.1H NMR (DMSO-d.sub.6) δ 8.39 (d, J=5.1 Hz, 1H), 7.53 (dd, J=12.3, 8.2 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 7.16 (s, 1H), 3.47-3.36 (m, 2H), 3.11-3.01 (m, 1H), 1.31 (s, 9H), 1.19 (d, J=6.7 Hz, 6H).

    Intermediate B8: tert-butyl 2-(3,4-difluoro-6-(2-fluoropyridin-4-yl)-2-isopropyl-phenyl)acetate

    [1232] ##STR00184##

    Step A: 4,5-difluoro-2-(2-fluoropyridin-4-yl)aniline

    [1233] ##STR00185##

    [1234] Prepared according to the general procedure of 4,5-difluoro-2-(prop-1-en-2-yl)aniline (Intermediate B7, Step A) from 2-bromo-4,5-difluoroaniline and 2-fluoropyridine-4-boronic acid to afford the title compound (6.91 g, 63%) as a pale orange solid.

    [1235] LCMS m/z 225.1 (M+H).sup.+ (ES.sup.+).

    [1236] .sup.1H NMR (DMSO-d.sub.6) δ 8.27 (d, J=5.2 Hz, 1H), 7.42 (dt, J=5.2, 1.8 Hz, 1H), 7.25-7.17 (m, 2H), 6.74 (dd, J=13.2, 7.4 Hz, 1H), 5.33 (s, 2H).

    Step B: 2-bromo-3,4-difluoro-6-(2-fluoropyridin-4-yl)aniline

    [1237] ##STR00186##

    [1238] Prepared according to the general procedure of 2-bromo-4-fluoro-6-isopropylaniline (Intermediate B4, Step A) from 4,5-difluoro-2-(2-fluoropyridin-4-yl)aniline and NBS to afford the title compound (7.72 g, 79%) as a brown solid.

    [1239] LCMS m/z 303.0/305.0 (M+H).sup.+ (ES.sup.+).

    [1240] .sup.1H NMR (DMSO-d.sub.6) δ 8.31 (d, J=5.2 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (dd, J=10.9, 8.7 Hz, 1H), 7.25-7.20 (m, 1H), 5.32 (br s, 2H).

    Step C: 3,4-difluoro-6-(2-fluoropyridin-4-yl)-2-(prop-1-en-2-yl)aniline

    [1241] ##STR00187##

    [1242] Prepared according to the general procedure of 4,5-difluoro-2-(prop-1-en-2-yl)aniline (Intermediate B7, Step A) from 2-bromo-3,4-difluoro-6-(2-fluoropyridin-4-yl)-aniline and isopropenylboronic acid pinacol ester to afford the title compound (7.11 g, 95%) as a pale orange solid.

    [1243] LCMS m/z 265.2 (M+H).sup.+ (ES.sup.+).

    [1244] .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J=5.2 Hz, 1H), 7.44-7.39 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (dd, J=11.2, 8.8 Hz, 1H), 5.54-5.50 (m, 1H), 5.11-5.06 (m, 1H), 4.74 (s, 2H), 2.00 (s, 3H).

    Step D: 3,4-difluoro-6-(2-fluoropyridin-4-yl)-2-isopropylaniline

    [1245] ##STR00188##

    [1246] Prepared according to the general procedure of 4,5-difluoro-2-isopropylaniline (Intermediate B7, Step B) from 3,4-difluoro-6-(2-fluoropyridin-4-yl)-2-(prop-1-en-2-yl)aniline to afford the title compound (6.52 g, 97%) as an orange oil.

    [1247] LCMS m/z 267.3 (M+H).sup.+ (ES.sup.+).

    [1248] .sup.1H NMR (DMSO-d.sub.6) δ 8.27 (d, J=5.2 Hz, 1H), 7.38 (dt, J=5.2, 1.8 Hz, 1H), 7.22-7.16 (m, 1H), 7.02 (dd, J=11.0, 8.8 Hz, 1H), 4.90 (s, 2H), 3.27 (p, J=7.1 Hz, 1H), 1.29 (dd, J=7.0, 1.6 Hz, 6H).

    Step E: 4-(2-bromo-4,5-difluoro-3-isopropylphenyl)-2-fluoropyridine

    [1249] ##STR00189##

    [1250] Prepared according to the general procedure of 4-(2-bromo-5-fluoro-3-isopropyl-phenyl)-2-fluoropyridine (Intermediate B4, Step C) from 3,4-difluoro-6-(2-fluoro-pyridin-4-yl)-2-isopropylaniline to afford the title compound (4.52 g, 60%) as a pale yellow oil.

    [1251] LCMS m/z 330.1/332.1 (M+H).sup.+ (ES.sup.+).

    [1252] .sup.1H NMR (DMSO-d.sub.6) δ 8.34 (d, J=5.1 Hz, 1H), 7.56 (dd, J=10.6, 8.2 Hz, 1H), 7.40 (dt, J=5.1, 1.7 Hz, 1H), 7.27 (s, 1H), 3.63 (tt, J=8.2, 6.3 Hz, 1H), 1.36 (dd, J=7.1, 1.7 Hz, 6H).

    Step F: tert-butyl 2-(3,4-difluoro-6-(2-fluoropyridin-4-yl)-2-isopropylphenyl)acetate

    [1253] ##STR00190##

    [1254] Prepared according to the general procedure of tert-butyl 2-(4-fluoro-2-(2-fluoro-pyridin-4-yl)-6-isopropylphenyl)acetate (Intermediate B4, Step D) from 4-(2-bromo-4,5-difluoro-3-isopropylphenyl)-2-fluoropyridine and (2-isopropoxy-2-oxoethyl)zinc(II) bromide to afford the title compound (5.62 g, 88%) as an orange oil.

    [1255] .sup.1H NMR (DMSO-d.sub.6) δ 8.33 (d, J=5.1 Hz, 1H), 7.30 (dd, J=10.6, 8.0 Hz, 1H), 7.27-7.22 (m, 1H), 7.07 (s, 1H), 3.50 (s, 2H), 3.12 (p, J=6.9 Hz, 1H), 1.37 (s, 9H), 1.34-1.29 (m, 6H).

    Intermediate B9: 5-(2-bromo-3-isopropylphenyl)-3-chloropyridazine

    [1256] ##STR00191##

    Step A: 2-chloro-6-(prop-1-en-2-yl)aniline

    [1257] ##STR00192##

    [1258] To a solution of 2,6-dichloroaniline (40 g, 247 mmol) in dioxane (400 mL) and H.sub.2O (40 mL) was added potassium trifluoro(prop-1-en-2-yl)borate (38.4 g, 259 mmol), K.sub.2CO.sub.3 (68.2 g, 494 mmol) and Pd(dppf)Cl.sub.2.DCM (10.1 g, 12.3 mmol) under N.sub.2. The mixture was warmed to 90° C. and stirred at 90° C. for 12 h. The reaction mixture was quenched with H.sub.2O (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:0 to 1:0) to give the title compound (25 g, 60.4%) as a yellow oil.

    [1259] LCMS: m/z 168.1 (M+H).sup.+ (ES.sup.+).

    [1260] .sup.1H NMR (DMSO-d.sub.6) δ 7.14 (dd, 1H), 8.90 (dd, 1H), 6.57 (t, 1H), 5.28 (t, 1H), 4.99 (d, 1H), 4.84 (br s, 2H), 2.00 (s, 3H).

    Step B: 2-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

    [1261] ##STR00193##

    [1262] To a solution of 2-chloro-6-(prop-1-en-2-yl)aniline (15 g, 89.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (34.1 g, 134 mmol) and AcOK (26.4 g, 268 mmol) in dioxane (250 mL) was added XPhos (3.41 g, 7.16 mmol) and Pd.sub.2(dba).sub.3 (3.28 g, 3.58 mmol) at 20° C. under N.sub.2. The reaction mixture was warmed to 100° C. and stirred at 100° C. for 12 h. The reaction mixture was quenched with H.sub.2O (300 mL) and extracted with EtOAc (300 mL×3). The organic phases were washed with brine (300 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:0 to 100:1) to give the title compound (23 g, 76.3%) as a yellow oil.

    [1263] LCMS: m/z 260.2 (M+H).sup.+ (ES.sup.+).

    [1264] .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (dd, 1H), 7.00 (dd, 1H), 6.51 (t, 1H), 5.23 (t, 1H), 5.18 (br s, 2H), 4.93 (s, 1H), 1.99 (s, 3H), 1.29 (s, 12H).

    Step C: 5-(2-amino-3-(prop-1-en-2-yl)phenyl)pyridazin-3-ol

    [1265] ##STR00194##

    [1266] To a solution of 2-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (3 g, 11.6 mmol) and 5-chloropyridazin-3-ol (1.51 g, 11.6 mmol) in dioxane (30 mL) and H.sub.2O (4 mL) was added Pd(dppf)Cl.sub.2.DCM (473 mg, 579 μmol) and K.sub.2CO.sub.3 (3.20 g, 23.2 mmol) under N.sub.2. The reaction mixture was heated to 100° C. and stirred at 100° C. for 1 h. The reaction mixture was quenched with H.sub.2O (80 mL) and extracted with EtOAc (80 mL×3). The combined organic phases were washed with brine (80 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 2:1 to 1:1) to give the title compound (2.1 g, 72.6%) as a yellow oil.

    [1267] LCMS: m/z 228.2 (M+H).sup.+ (ES.sup.+).

    [1268] .sup.1H NMR (DMSO-d.sub.6) δ 12.98 (br s, 1H), 7.90 (d, 1H), 7.04-6.98 (m, 2H), 6.81 (s, 1H), 6.68 (t, 1H), 5.30 (d, 1H), 5.00 (d, 1H), 4.76 (br s, 2H), 2.02 (s, 3H).

    Step D: 5-(2-amino-3-isopropylphenyl)pyridazin-3-ol

    [1269] ##STR00195##

    [1270] To a solution of 5-(2-amino-3-(prop-1-en-2-yl)phenyl)pyridazin-3-ol (2.1 g, 9.24 mmol) in MeOH (25 mL) was added Pd/C (0.1 g, 10 wt % on charcoal) under N.sub.2. The suspension was degassed under reduced pressure and purged with H.sub.2 several times. The reaction mixture was stirred at 25° C. for 36 h under H.sub.2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuum to give the title compound (1.9 g, 89.7%) as a green solid.

    [1271] LCMS: m/z 230.1 (M+H).sup.+ (ES.sup.+).

    [1272] .sup.1H NMR (DMSO-d.sub.6) δ 12.94 (br s, 1H), 7.87 (d, 1H), 7.12 (d, 1H), 6.90 (t, 1H), 6.78 (d, 1H), 6.67 (t, 1H), 4.89 (br s, 2H), 3.10-3.02 (m, 1H), 1.17 (d, 6H).

    Step E: 5-(2-bromo-3-isopropylphenyl)pyridazin-3-ol

    [1273] ##STR00196##

    [1274] To a solution of 5-(2-amino-3-isopropylphenyl)pyridazin-3-ol (1.3 g, 5.67 mmol) in MeCN (26 mL) was added a solution of HBr (3.87 g, 17.7 mmol, 37 wt % in AcOH) in H.sub.2O (2.6 mL) at 0° C., followed by a solution of NaNO.sub.2 (469 mg, 6.80 mmol) in H.sub.2O (2.6 mL) at 0° C. Then the resulting mixture was stirred at 0° C. for 0.5 h. To the above solution was added CuBr (976 mg, 6.80 mmol) and CuBr.sub.2 (507 mg, 2.27 mmol). The reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was quenched with H.sub.2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 3:1 to 2:1) to give the title compound (1.2 g, 72.2%) as a yellow solid.

    [1275] LCMS: m/z 295.0 (M+H).sup.+ (ES.sup.+).

    [1276] .sup.1H NMR (DMSO-d.sub.6) δ 13.17 (br s, 1H), 7.91 (s, 1H), 7.51-7.44 (m, 2H), 7.32-7.25 (m, 1H), 6.83 (s, 1H), 3.43-3.37 (m, 1H), 1.31 (d, 6H).

    Step F: 5-(2-bromo-3-isopropylphenyl)-3-chloropyridazine

    [1277] ##STR00197##

    [1278] A solution of 5-(2-bromo-3-isopropylphenyl)pyridazin-3-ol (1.2 g, 4.09 mmol) in POCl.sub.3 (19.8 g, 129 mmol) was heated to 80° C. and stirred at 80° C. for 1 h. The reaction mixture was slowly quenched with H.sub.2O (150 mL) at 20° C. The mixture was adjusted to pH=7 with solid NaOH at 25° C. and then extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (150 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 8:1 to 5:1) to give the title compound (1 g, 78.4%) as a yellow solid.

    [1279] LCMS: m/z 312.9 (M+H).sup.+ (ES.sup.+).

    [1280] .sup.1H NMR (CDCl.sub.3) δ 9.19 (s, 1H), 7.57 (d, 1H), 7.46-7.40 (m, 2H), 7.13-7.10 (m, 1H), 3.54-3.47 (m, 1H), 1.30 (d, 6H).

    Intermediate B10: tert-butyl 2-(4-cyano-2-(2-fluoropyridin-4-yl)-6-isopropyl-phenyl)acetate

    [1281] ##STR00198##

    Step A: 4-amino-3-(prop-1-en-2-yl)benzonitrile

    [1282] ##STR00199##

    [1283] To a solution of 4-amino-3-bromobenzonitrile (6 g, 30.5 mmol) in dioxane (60 mL) and H.sub.2O (12 mL) was added potassium trifluoro(prop-1-en-2-yl)borate (5-41 g, 36.5 mmol), Pd(dppf)Cl.sub.2.DCM (1.24 g, 1.52 mmol) and Na.sub.2CO.sub.3 (6.46 g, 60.9 mmol). The mixture was stirred at 90° C. for 12 h under N.sub.2. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 30:1 to 10:1) to give the title compound (4 g, 82.5% yield, 99.3% purity on LCMS) as a yellow oil.

    [1284] LCMS: m/z 159.2 (M+H).sup.+ (ES.sup.+).

    [1285] .sup.1H NMR (CDCl.sub.3): δ 7.35-7.28 (m, 2H), 6.67 (d, 1H), 5.37 (d, 1H), 5.09 (s, 1H), 4.33 (br s, 2H), 2.05 (s, 3H).

    Step B: 4-amino-3-isopropylbenzonitrile

    [1286] ##STR00200##

    [1287] To a solution of 4-amino-3-(prop-1-en-2-yl)benzonitrile (4 g, 25.3 mmol) in MeOH (50 mL) was added Pd/C (0.5 g, 10% purity loading on active carbon) under N.sub.2. The mixture 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 through the celite and the filtrate was concentrated in vacuum to give the title compound (4 g, 98.7% yield) as a yellow oil.

    [1288] LCMS: m/z 161.2 (M+H).sup.+ (ES.sup.+).

    [1289] .sup.1H NMR (CDCl.sub.3): δ 7.40 (d, 1H), 7.30 (d, 1H), 6.65 (d, 1H), 4.13 (br s, 2H), 2.86-2.79 (m, 1H), 1.27 (d, 6H).

    Step C: 4-amino-3-bromo-5-isopropylbenzonitrile

    [1290] ##STR00201##

    [1291] To a solution of 4-amino-3-isopropylbenzonitrile (4 g, 25.0 mmol) in MeCN (50 mL) was added NBS (4.67 g, 26.2 mmol). The mixture was stirred at 25° C. for 1 h, then quenched with sat aq Na.sub.2SO.sub.3 (50 mL) and extracted with EtOAc (100 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 5:1 to 3:1) to give the title compound (5.4 g, 90.5% yield) as a yellow solid.

    [1292] LCMS: m/z 240.8 (M+H).sup.+ (ES.sup.+).

    [1293] .sup.1H NMR (CDCl.sub.3): 7.60 (d, 1H), 7.34 (d, 1H), 4.70 (br s, 2H), 2.97-2.78 (m, 1H), 1.28 (d, 6H).

    Step D: 4-amino-3-(2-fluoropyridin-4-yl)-5-isopropylbenzonitrile

    [1294] ##STR00202##

    [1295] To a solution of 4-amino-3-bromo-5-isopropylbenzonitrile (4.9 g, 20.5 mmol) and (2-fluoropyridin-4-yl)boronic acid (3.03 g, 21.5 mmol) in dioxane (10 mL) and H.sub.2O (2 mL) was added Pd(dppf)Cl.sub.2.DCM (837 mg, 1.02 mmol) and Na.sub.2CO.sub.3 (4.34 g, 41.0 mmol). The mixture was stirred at 90° C. for 12 h under N.sub.2. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 3:1) to give the title compound (5 g, 95.6% yield) as a yellow solid.

    [1296] LCMS: m/z 256.3 (M+H).sup.+ (ES.sup.+).

    [1297] .sup.1H NMR (CDCl.sub.3): δ 8.35 (d, 1H), 7.47 (d, 1H), 7.28-7.26 (m, 2H), 7.03 (s, 1H), 4.31 (br s, 2H), 2.90-2.84 (m, 1H), 1.32 (d, 6H).

    Step E: 4-bromo-3-(2-fluoropyridin-4-yl)-5-isopropylbenzonitrile

    [1298] ##STR00203##

    [1299] To a solution of 4-amino-3-(2-fluoropyridin-4-yl)-5-isopropylbenzonitrile (5 g, 19.6 mmol) in MeCN (100 mL) was added HBr (73-7 mmol, 10 mL, 40% purity in H.sub.2O) in H.sub.2O (1 mL) at 0° C. Then a solution of NaNO.sub.2 (1.62 g, 23.5 mmol) in H.sub.2O (1 mL) was added. The mixture was stirred at 0° C. for 30 min, then CuBr.sub.2 (2.19 g, 9.79 mmol) and CuBr (140 mg, 979 μmol) were added. The mixture was stirred at 25° C. for 2 h, then quenched with sat aq Na.sub.2SO.sub.3 (100 mL) and extracted with EtOAc (150 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 30: 1 to 10:1) to give the title compound (5.9 g, 94.4% yield) as a yellow solid.

    [1300] LCMS: m/z 319.2, 321.2 (M+H).sup.+ (ES.sup.+).

    [1301] .sup.1H NMR (CDCl.sub.3): δ 8.33 (d, 1H), 7.63 (d, 1H), 7.38 (d, 1H), 7.18 (dd, 1H), 6.94 (s, 1H), 3.56-3.50 (m, 1H), 1.32 (d, 6H).

    Step F: tert-butyl 2-(4-cyano-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate

    [1302] ##STR00204##

    [1303] To a solution of 4-bromo-3-(2-fluoropyridin-4-yl)-5-isopropylbenzonitrile (5.8 g, 18.2 mmol) and palladium; tri-tert-butylphosphane (464 mg, 909 μmol) in THF (50 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.51 M in THF, 107 mL) under N.sub.2. The mixture was stirred at 70° C. for 2 h, then quenched with water (150 mL) and extracted with EtOAc (200 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% HCl)-MeCN) to give the title compound (4 g, 54.6% yield, 97% purity on LCMS, HCl salt) as a yellow solid.

    [1304] LCMS: m/z 355.4 (M−HCl+H).sup.+ (ES.sup.+).

    [1305] .sup.1H NMR (CD.sub.3OD): δ 8.29 (d, 1H), 7.81 (d, 1H), 7.49 (d, 1H), 7.28-7.26 (m, 1H), 7.05 (s, 1H), 3.64 (s, 2H), 3.25-3.14 (m, 1H), 1.41 (s, 9H), 1.30 (d, 6H). HCl proton not observed.

    Intermediate B11: tert-butyl 2-(4-(difluoromethoxy)-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate

    [1306] ##STR00205##

    Step A: 2-bromo-4-(difluoromethoxy)aniline

    [1307] ##STR00206##

    [1308] To a solution of 4-(difluoromethoxy)aniline (20 g, 126 mmol) in MeCN (200 mL) was added dropwise a solution of NBS (20.1 g, 113 mmol) in MeCN (200 mL) at 0° C. The mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with H.sub.2O (250 mL) and extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 200:1 to 20:1) to give the title compound (24 g, 80.2% yield) as a yellow oil.

    [1309] LCMS: m/z 238.03 (M+H).sup.+ (ES.sup.+).

    [1310] .sup.1H NMR (CDCl.sub.3): δ 7.25 (s, 1H), 6.94 (dd, 1H), 6.74 (d, 1H), 6.38 (t, 1H), 4.10 (br s, 2H).

    Step B: 4-(difluoromethoxy)-2-(prop-1-en-2-yl)aniline

    [1311] ##STR00207##

    [1312] To a solution of 2-bromo-4-(difluoromethoxy)aniline (10 g, 42.0 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (6.84 g, 46.2 mmol) in dioxane (200 mL) and H.sub.2O (40 mL) were added Pd(dppf)Cl.sub.2.DCM (3.43 g, 4.20 mmol) and Na.sub.2CO.sub.3 (11.1 g, 105 mmol). The mixture was stirred at 95° C. for 12 h under N.sub.2. The reaction mixture was diluted with H.sub.2O (300 mL) and extracted with DCM (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:0 to 20:1) to give the title compound (7 g, 83.7% yield) as a yellow oil.

    [1313] LCMS: m/z 200.2 (M+H).sup.+ (ES.sup.+).

    [1314] .sup.1H NMR (CDCl.sub.3): δ 6.84 (d, 2H), 6.64 (d, 1H), 6.39 (t, 1H), 5.32 (s, 1H), 5.08 (s, 1H), 3.80 (br s, 2H), 2.06 (s, 3H).

    Step C: 4-(difluoromethoxy)-2-isopropylaniline

    [1315] ##STR00208##

    [1316] To a solution of 4-(difluoromethoxy)-2-(prop-1-en-2-yl)aniline (7 g, 35.1 mmol) in MeOH (200 mL) was added Pd/C (2 g, 10% purity loading on active carbon) under N.sub.2. The mixture was degassed under vacuum and purged three times with H.sub.2. The mixture was stirred at 25° C. for 12 h under H.sub.2 (15 psi). The reaction mixture was filtered and diluted with H.sub.2O (300 mL) and extracted with EtOAc (300 mL×2). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:0 to 10:1) to give the title compound (7 g, 99.0% yield) as a yellow solid.

    [1317] LCMS: m/z 202.1 (M+H).sup.+ (ES.sup.+).

    [1318] .sup.1H NMR (CDCl.sub.3): δ 6.92 (d, 1H), 6.82 (dd, 1H), 6.60 (d, 1H), 6.39 (t, 1H), 3.52 (br s, 2H), 2.92-2.85 (m, 1H), 1.25 (d, 6H).

    Step D: 2-bromo-4-(difluoromethoxy)-6-isopropylaniline

    [1319] ##STR00209##

    [1320] To a solution of 4-(difluoromethoxy)-2-isopropylaniline (6.9 g, 34.3 mmol) in MeCN (300 mL) was added dropwise a solution of NBS (6.1 g, 34.3 mmol) in MeCN (300 mL) at 0° C. The mixture was stirred at 25° C. for 3 h. The reaction solution was diluted with H.sub.2O (300 ml) and extracted with DCM (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 100:1 to 10:1) to give the title compound (9 g, 93.7% yield) as a grey oil.

    [1321] LCMS: m/z 280.1 (M+H).sup.+ (ES.sup.+).

    [1322] .sup.1H NMR (CDCl.sub.3): δ 7.15 (d, 1H), 6.91 (d, 1H), 6.38 (t, 1H), 4.12 (br s, 2H), 2.93-2.86 (m, 1H), 1.25 (d, 6H).

    Step E: 4-(difluoromethoxy)-2-(2-fluoropyridin-4-yl)-6-isopropylaniline

    [1323] ##STR00210##

    [1324] To a solution of (2-fluoropyridin-4-yl)boronic acid (4.70 g, 33.4 mmol) and 2-bromo-4-(difluoromethoxy)-6-isopropylaniline (8.5 g, 30.4 mmol) in H.sub.2O (60 mL) and dioxane (240 mL) were added Pd(dppf)Cl.sub.2.DCM (2.48 g, 3.03 mmol) and Na.sub.2CO.sub.3 (8.04 g, 75.9 mmol). The mixture was stirred at 95° C. for 12 h under N.sub.2, then diluted with H.sub.2O (600 mL) and extracted with DCM (600 mL×3). The combined organic phases were washed with brine (600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 20:1 to 10:1) to give the title compound (8.2 g, 91.2% yield) as a yellow solid.

    [1325] LCMS: m/z 296.9 (M+H).sup.+ (ES.sup.+).

    [1326] .sup.1H NMR (CDCl.sub.3): δ 8.31 (d, 1H), 7.31 (d, 1H), 7.05 (s, 1H), 7.02 (d, 1H), 7.80 (d, 1H), 6.43 (t, 1H), 3.76 (br s, 2H), 2.95-2.88 (m, 1H), 1.28 (d, 6H).

    Step F: 4-(2-bromo-5-(difluoromethoxy)-3-isopropylphenyl)-2-fluoropyridine

    [1327] ##STR00211##

    [1328] To a solution of 4-(difluoromethoxy)-2-(2-fluoropyridin-4-yl)-6-isopropylaniline (7.5 g, 25.3 mmol) in MeCN (200 mL) was added 3-methylbutyl nitrite (3.56 g, 30.4 mmol) at 0° C., followed by CuBr (4.36 g, 30.4 mmol) at 0° C. Then the resulting mixture was stirred at 60° C. for 1 h, then quenched with sat aq NaHCO.sub.3 (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:0 to 10:1) to give the title compound (5 g, 54.8% yield) as a yellow oil.

    [1329] LCMS: m/z 361.8 (M+H).sup.+ (ES.sup.+).

    [1330] .sup.1H NMR (CDCl.sub.3): δ 8.29 (d, 1H), 7.20 (dd, 1H), 7.14 (d, 1H), 6.94 (s, 1H), 6.90 (d, 1H), 6.54 (t, 1H), 3.54-3.46 (m, 1H), 1.28 (d, 6H).

    Step G: tert-butyl 2-(4-(difluoromethoxy)-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)-acetate

    [1331] ##STR00212##

    [1332] To a solution of 4-(2-bromo-5-(difluoromethoxy)-3-isopropylphenyl)-2-fluoropyridine (2 g, 5.55 mmol) in THF (50 mL) was added dicyclohexyl-[2-(2,4,6-triisopropylphenyl)-phenyl]phosphane (265 mg, 555 μmol) and Pd.sub.2(dba).sub.3 (254 mg, 278 μmol) under N.sub.2. (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M in THF, 36.2 mL) was added and the reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was diluted with sat aq NaHCO.sub.3 (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 95:5 to 95:5) to give the title compound (2.1 g, 95.6% yield) as a yellow oil.

    [1333] LCMS: m/z 396.1 (M+H).sup.+ (ES.sup.+).

    [1334] .sup.1H NMR (CDCl.sub.3): δ 8.38 (d, 1H), 7.31 (s, 2H), 7.04 (s, 1H), 6.94 (s, 1H), 6.65 (t, 1H), 3.58 (s, 2H), 3.24-3.18 (m, 1H), 1.55 (s, 9H), 1.38 (d, 6H).

    Intermediate B12: tert-butyl 2-(4-cyano-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropylphenyl)acetate

    [1335] ##STR00213##

    Step A: 4-amino-5-bromo-2-fluorobenzonitrile

    [1336] ##STR00214##

    [1337] To a solution of 4-amino-2-fluorobenzonitrile (7 g, 51.4 mmol) in MeCN (200 mL) was added NBS (9.15 g, 51.4 mmol) in portions at 25° C. Then the solution was stirred at 50° C. for 3 h. The solution was quenched with H.sub.2O (30 mL) and extracted with EtOAc (30 mL×2). The organic phases were washed with brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 5:1 to 4:1) to give the title compound (10.8 g, 97.7% yield) as a yellow solid.

    [1338] LCMS: m/z 216.8 (M+H).sup.+ (ES.sup.+).

    [1339] .sup.1H NMR (CDCl.sub.3): δ 7.61 (d, 1H), 6.52 (d, 1H), 4.82 (br s, 2H).

    Step B: 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)benzonitrile

    [1340] ##STR00215##

    [1341] To a solution of 4-amino-5-bromo-2-fluorobenzonitrile (6 g, 27.9 mmol) and (2-fluoro-pyridin-4-yl)boronic acid (3.93 g, 27.9 mmol) in dioxane (100 mL) and H.sub.2O (20 mL) was added Pd(dppf)Cl.sub.2.DCM (1.14 g, 1.40 mmol) and Na.sub.2CO.sub.3 (7.39 g, 69.8 mmol) under N.sub.2. The solution was stirred at 100° C. for 2 h under N.sub.2, then quenched with H.sub.2O (200 mL) and extracted with EtOAc (200 mL×2). The organic phases were washed with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 2:1 to 1:1) to give the title compound (6.3 g, 97.7% yield) as a yellow solid.

    [1342] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

    [1343] .sup.1H NMR (CD.sub.3OD): δ 8.29 (d, 1H), 7.44 (d, 1H), 7.38 (dd, 1H), 7.17 (s, 1H), 6.64 (d, 1H). Two exchangeable protons not observed.

    Step C: 4-amino-3-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)benzonitrile

    [1344] ##STR00216##

    [1345] To a solution of 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)benzonitrile (6 g, 26.0 mmol) in MeCN (120 mL) was added NBS (4.62 g, 26.0 mmol) and the solution was stirred at 25° C. for 1 h. The solution was quenched with sat aq Na.sub.2SO.sub.3 (10 mL) and extracted with DCM (10 mL×3). The organic phases were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was triturated with a mixture (PE:EtOAc, 3:1, 50 mL) to give the title compound (8 g, 99.4% yield) as a grey solid.

    [1346] LCMS: m/z 312.0 (M+H).sup.+ (ES.sup.+).

    [1347] .sup.1H NMR (DMSO-d.sub.6): δ 8.29 (d, 1H), 7.59 (d, 1H), 7.37 (dd, 1H), 7.23 (s, 1H), 6.53 (br s, 2H).

    Step D: 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-(prop-1-en-2-yl)benzonitrile

    [1348] ##STR00217##

    [1349] To a solution of 4-amino-3-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)benzonitrile (8 g, 25.8 mmol) in dioxane (150 mL) and H.sub.2O (30 mL) was added potassium trifluoro-(prop-1-en-2-yl)borate (4.96 g, 33.5 mmol), Na.sub.2CO.sub.3 (6.84 g, 64.5 mmol) and Pd(dppf)Cl.sub.2.DCM (1.05 g, 1.29 mmol) under N.sub.2. The mixture was stirred at 100° C. for 3 h. The residue was purified by FC (PE:EtOAc, 1:1) to give the title compound (6.1 g, 87.2% yield) as a yellow solid.

    [1350] LCMS: m/z 271.9 (M+H).sup.+ (ES.sup.+).

    [1351] .sup.1H NMR (CDCl.sub.3): δ 8.27 (d, 1H), 7.19-7.17 (m, 2H), 6.94 (s, 1H), 5.50 (s, 1H), 5.09 (s, 1H), 4.53 (br s, 2H), 2.01 (s, 3H).

    Step E: 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzonitrile

    [1352] ##STR00218##

    [1353] To a solution of 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-(prop-1-en-2-yl)-benzonitrile (4 g, 14.8 mmol) in MeOH (30 mL) and EtOAc (30 mL) was added Rh/Al.sub.2O.sub.3 (30 mg) under N.sub.2. The mixture was stirred at 35° C. for 48 h under H.sub.2 (15 psi). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 8:1 to 5:1) to give the title compound (2.2 g, 54.6% yield) as a yellow solid.

    [1354] LCMS: m/z 274.1 (M+H).sup.+ (ES.sup.+).

    [1355] .sup.1H NMR (CDCl.sub.3): δ 8.34 (d, 1H), 7.24 (dd, 1H), 7.17 (d, 1H), 6.99 (s, 1H), 4.44 (br s, 2H), 3.11-3.04 (m, 1H), 1.43 (dd, 6H).

    Step F: 4-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzonitrile

    [1356] ##STR00219##

    [1357] To a solution of 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzonitrile (2.1 g, 7.68 mmol) in MeCN (40 mL) was added a solution of HBr (7.00 mL, 51.6 mmol, 40% purity in H.sub.2O) in H.sub.2O (4 mL) at 0° C., followed by a solution of NaNO.sub.2 (636 mg, 9.22 mmol) in H.sub.2O (4 mL) at 0° C. The resulting mixture was stirred at 0° C. for 45 min, then CuBr.sub.2 (858 mg, 3.84 mmol) and CuBr (55 mg, 384 μmol) were added and the resulting mixture was stirred at 25° C. for 1 h. The mixture was quenched with H.sub.2O (30 mL) and extracted with EtOAc (20 mL×3). The organic phases were washed with brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 33:1 to 26:1) to give the title compound (1.62 g, 62.5% yield) as a white solid.

    [1358] LCMS: m/z 336.9 (M+H).sup.+ (ES.sup.+).

    [1359] .sup.1H NMR (CDCl.sub.3): δ 8.33 (d, 1H), 7.38 (dd, 1H), 7.14 (d, 1H), 6.91 (s, 1H), 3.75-3.68 (m, 1H), 1.43 (dd, 6H).

    Step G: tert-butyl 2-(4-cyano-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropylphenyl)-acetate

    [1360] ##STR00220##

    [1361] To a solution of 4-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzonitrile (1.6 g, 4.75 mmol) in THF (10 mL) was added palladium; tri-tert-butylphosphane (121 mg, 237 μmol) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M in THF, 47.5 mL) under N.sub.2. The solution was stirred at 70° C. for 1 h, then the mixture was quenched with sat aq NH.sub.4Cl (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.6 g, 34.0% yield) as a yellow solid.

    [1362] LCMS: m/z 373.1 (M+H).sup.+ (ES.sup.+).

    [1363] .sup.1H NMR (CDCl.sub.3): δ 8.30 (d, 1H), 7.34 (dd, 1H), 7.11 (dd, 1H), 6.89 (s, 1H), 3.51 (s, 2H), 3.14-3.09 (m, 1H), 1.48 (s, 9H), 1.41 (dd, 6H).

    Intermediate B13: tert-butyl 2-(4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropylphenyl)acetate

    [1364] ##STR00221##

    Step A: 2-bromo-4-(difluoromethoxy)-5-fluoroaniline

    [1365] ##STR00222##

    [1366] To a solution of 4-(difluoromethoxy)-3-fluoroaniline (4 g, 22.6 mmol) in MeCN (40 mL) was added NBS (4.22 g, 23.7 mmol). The mixture was stirred at 25° C. for 2 h, then poured into water (100 mL) and extracted with EtOAc (150 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 30:1 to 10:1) to give the title compound (5.5 g, 95.1% yield) as red oil.

    [1367] LCMS: m/z 258.2 (M+H).sup.+ (ES.sup.+).

    [1368] .sup.1H NMR (CDCl.sub.3): δ 7.32 (d, 1H), 6.60-6.24 (m, 2H), 4.15 (br s, 2H).

    Step B: 4-(difluoromethoxy)-5-fluoro-2-(2-fluoropyridin-4-yl)aniline

    [1369] ##STR00223##

    [1370] To a solution of 2-bromo-4-(difluoromethoxy)-5-fluoroaniline (5.5 g, 19.5 mmol, 90.8% purity) in dioxane (80 mL) and H.sub.2O (16 mL) was added Pd(dppf)Cl.sub.2.DCM (796 mg, 975 μmol), Na.sub.2CO.sub.3 (4.13 g, 39.0 mmol) and (2-fluoropyridin-4-yl)boronic acid (2.89 g, 20.5 mmol). The mixture was stirred at 90° C. for 12 h under N.sub.2, then poured into water (100 mL) and extracted with EtOAc (200 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 20:1 to 5:1) to give the title compound (5.1 g, 96.1% yield) as a yellow solid.

    [1371] LCMS: m/z 273.1 (M+H).sup.+ (ES.sup.+).

    [1372] .sup.1H NMR (CDCl.sub.3): δ 8.32 (d, 1H), 7.29-7.27 (m, 1H), 7.07-6.98 (m, 2H), 6.57 (s, 1H), 6.47 (t, 1H), 3.90 (br s, 2H).

    Step C: 2-bromo-4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)aniline

    [1373] ##STR00224##

    [1374] To a solution of 4-(difluoromethoxy)-5-fluoro-2-(2-fluoropyridin-4-yl)aniline (6.1 g, 22.4 mmol) in MeCN (5 mL) was added NBS (4.19 g, 23.5 mmol). The mixture was stirred at 25° C. for 2 h, then concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 10:1 to 5:1) to give the title compound (7.8 g, 99.1% yield) as a yellow solid.

    [1375] LCMS: m/z 351.1 (M+H).sup.+ (ES.sup.+).

    [1376] .sup.1H NMR (CDCl.sub.3): δ 8.34 (d, 1H), 7.29-7.27 (m, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 6.49 (t, 1H), 4.38 (br s, 2H).

    Step D: 4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-(prop-1-en-2-yl)-aniline

    [1377] ##STR00225##

    [1378] To a solution of 2-bromo-4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)aniline (7.5 g, 21.4 mmol) in dioxane (80 mL) and H.sub.2O (16 mL) was added Pd(dppf)Cl.sub.2.DCM (872 mg, 1.07 mmol), Na.sub.2CO.sub.3 (6.79 g, 64.1 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (3.79 g, 25.6 mmol). The mixture was stirred at 100° C. for 12 h under N.sub.2, then poured into water (200 mL) and extracted with EtOAc (200 mL×3). The organic layers were 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 (6 g, 90.0% yield) as a yellow solid.

    [1379] LCMS: m/z 313.3 (M+H).sup.+ (ES.sup.+).

    [1380] .sup.1H NMR (CDCl.sub.3): δ 8.31 (d, 1H), 7.31 (d, 1H), 7.05 (s, 1H), 6.96 (d, 1H), 6.48 (t, 1H), 5.54 (t, 1H), 5.15 (s, 1H), 4.04 (br s, 2H), 2.09 (s, 3H).

    Step E: 4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropylaniline

    [1381] ##STR00226##

    [1382] To a solution of 4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-(prop-1-en-2-yl)aniline (6 g, 19.2 mmol) in MeOH (200 mL) was added Pd/C (600 mg, 10% loading 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 to give the title compound (5.8 g, 96.1% yield) as a yellow oil.

    [1383] LCMS: m/z 315.1 (M+H).sup.+ (ES.sup.+).

    [1384] .sup.1H NMR (CDCl.sub.3): δ 8.31 (d, 1H), 7.27-7.26 (m, 1H), 7.02 (d, 1H), 6.88 (d, 1H), 6.46 (t, 1H), 3.86 (br s, 2H), 3.15-3.09 (m, 1H), 1.41 (dd, 6H).

    Step F: 4-(2-bromo-5-(difluoromethoxy)-4-fluoro-3-isopropylphenyl)-2-fluoropyridine

    [1385] ##STR00227##

    [1386] To a solution of 4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropyl-aniline (5.8 g, 18.5 mmol) in MeCN (100 mL) was added CuBr.sub.2 (4.95 g, 22.2 mmol), CuBr (265 mg, 1.85 mmol) and isopentyl nitrite (3.24 g, 27.7 mmol). The mixture was stirred at 50° C. for 0.5 h, then quenched with 1N aq HCl (50 mL) and extracted with EtOAc (100 mL×3). The organic layers were 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 (6.5 g, 92.0% yield, 98.8% purity on LCMS) as colourless oil.

    [1387] LCMS: m/z 378.0 (M+H).sup.+ (ES.sup.+).

    [1388] .sup.1H NMR (CDCl.sub.3): δ 8.29 (d, 1H), 7.18-7.16 (m, 1H), 7.05 (d, 1H), 6.93 (s, 1H), 6.57 (t, 1H), 3.74-3.64 (m, 1H), 1.41 (dd, 6H).

    Step G: tert-butyl 2-(4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropylphenyl)acetate

    [1389] ##STR00228##

    [1390] To a solution of 4-(2-bromo-5-(difluoromethoxy)-4-fluoro-3-isopropylphenyl)-2-fluoropyridine (6 g, 15.9 mmol), Pd.sub.2(dba).sub.3 (726 mg, 793 μmol) and XPhos (756 mg, 1.59 mmol) in THF (60 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.51 M in THF, 93.3 mL). The mixture was stirred at 70° C. for 2 h under N.sub.2, then quenched with sat aq NH.sub.4Cl (200 mL) and extracted with EtOAc (200 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) to give the title compound (6 g, 91.47% yield) as a yellow solid.

    [1391] LCMS: m/z 414.1 (M+H).sup.+ (ES.sup.+).

    [1392] .sup.1H NMR (CDCl.sub.3): δ 8.27 (d, 1H), 7.15-7.13 (m, 1H), 6.97 (d, 1H), 6.91 (s, 1H), 6.56 (t, 1H), 3.44 (s, 2H), 3.13-3.03 (m, 1H), 1.46 (s, 9H), 1.39 (d, 6H).

    Intermediate B14: 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1393] ##STR00229##

    [1394] To a solution of tert-butyl 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)-acetate (Intermediate B4) (4.0 g, 11.5 mmol) in DCM (20 mL) was added TFA (270 mmol, 20 mL). The reaction solution was stirred at 20° C. for 12 h, then concentrated in vacuum to give the title compound (4.0 g, crude, TFA salt) as a red solid.

    [1395] LCMS: m/z 292.1 (M-TFA+H).sup.+ (ES.sup.+).

    Intermediate B1s: tert-butyl 2-(2-(2-fluoropyridin-4-yl)-6-isopropyl-4-(methoxy-methyl)phenyl)acetate

    [1396] ##STR00230##

    Step A: methyl 4-amino-3-(prop-1-en-2-yl)benzoate

    [1397] ##STR00231##

    [1398] To a solution of methyl 4-amino-3-bromobenzoate (4.0 g, 17.4 mmol) in dioxane (80 mL) and H.sub.2O (16 mL) was added potassium trifluoro(prop-1-en-2-yl)borate (5.15 g, 34.8 mmol), K.sub.2CO.sub.3 (7.21 g, 52.2 mmol) and Pd(dppf)Cl.sub.2.DCM (1.42 g, 1.74 mmol). The reaction mixture was stirred at 95° C. for 3 h under N.sub.2. Water (100 mL) and EtOAc (100 mL) were added into the reaction mixture and the mixture was separated. The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 1:0 to 10:1) to give the title compound (2.8 g, 83.4% yield, 99.0% purity on LCMS) as a yellow oil.

    [1399] LCMS: m/z 192.2 (M+H).sup.+ (ES.sup.+).

    [1400] .sup.1H NMR (CDCl.sub.3): δ 7.76-7.74 (m, 2H), 6.66 (dd, 1H), 5.34 (dd, 1H), 5.08 (d, 1H), 4.27 (br s, 2H), 3.86 (s, 3H), 2.08 (s, 3H).

    Step B: methyl 4-amino-3-isopropylbenzoate

    [1401] ##STR00232##

    [1402] To a solution of methyl 4-amino-3-(prop-1-en-2-yl)benzoate (6.5 g, 34.0 mmol) in MeOH (120 mL) was added Pd/C (600 mg, 10% purity loaded on active carbon) under N.sub.2. The mixture was degassed in vacuum and purged with H.sub.2 several times. The mixture was stirred at 20° C. for 12 h under H.sub.2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 1:0 to 2:1) to give the title compound (4.7 g, 70.7% yield, 98.8% purity on LCMS) as a white solid.

    [1403] LCMS: m/z 194.2 (M+H).sup.+ (ES.sup.+).

    [1404] .sup.1H NMR (CDCl.sub.3): δ 7.85 (d, 1H), 7.73 (dd, 1H), 6.64 (d, 1H), 4.09 (br s, 2H), 3.87 (s, 3H), 2.91-2.79 (m, 1H), 1.29 (d, 6H).

    Step C: methyl 4-amino-3-bromo-5-isopropylbenzoate

    [1405] ##STR00233##

    [1406] To a solution of methyl 4-amino-3-isopropylbenzoate (4.7 g, 24.3 mmol) in MeCN (80 mL) was added NBS (4-33 g, 24.3 mmol) in portions at 0° C. The reaction mixture was stirred at 20° C. for 2 h. Water (50 mL) and EtOAc (50 mL) were added into the reaction mixture and the mixture was separated. 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 under reduced pressure. The residue was purified by FC (PE:EtOAc, 1:0 to 10:1) to give the title compound (6.2 g, 92.6% yield, 98.9% purity on LCMS) as a yellow solid.

    [1407] LCMS: m/z 272.0 (M+H).sup.+ (ES.sup.+).

    [1408] .sup.1H NMR (CDCl.sub.3): δ 8.03 (d, 1H), 7.78 (d, 1H), 4.60 (br s, 2H), 3.87 (s, 3H), 2.91-2.82 (m, 1H) and 1.30 (d, 6H).

    Step D: methyl 4-amino-3-(2-fluoropyridin-4-yl)-5-isopropylbenzoate

    [1409] ##STR00234##

    [1410] To a solution of methyl 4-amino-3-bromo-5-isopropylbenzoate (5-7 g, 21.0 mmol) in dioxane (110 mL) and H.sub.2O (22 mL) was added (2-fluoropyridin-4-yl)boronic acid (3.54 g, 25.1 mmol), Pd(dppf)Cl.sub.2.DCM (1.71 g, 2.09 mmol) and K.sub.2CO.sub.3 (8.68 g, 62.8 mmol). After the addition, the reaction mixture was stirred at 100° C. for 3 h under N.sub.2. Water (100 mL) and EtOAc (100 mL) were added into the reaction mixture and the mixture was separated. The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 1:0 to 3:1) to give the title compound (5-7 g, 91.6% yield, 97.0% purity on LCMS) as a yellow solid.

    [1411] LCMS: m/z 289.1 (M+H).sup.+ (ES.sup.+).

    [1412] .sup.1H NMR (CDCl.sub.3): δ 8.31 (d, 1H), 7.91 (d, 1H), 7.69 (d, 1H), 7.34-7.30 (m, 1H), 7.06 (s, 1H), 4.26 (br s, 2H), 3.88 (s, 3H), 2.93-2.86 (m, 1H), 1.34 (d, 6H).

    Step E: methyl 4-bromo-3-(2-fluoropyridin-4-yl)-5-isopropylbenzoate

    [1413] ##STR00235##

    [1414] To a solution of methyl 4-amino-3-(2-fluoropyridin-4-yl)-5-isopropylbenzoate (4.7 g, 16.3 mmol) in MeCN (20 mL) was added CuBr (2.81 g, 19.6 mmol), CuBr.sub.2 (364 mg, 1.63 mmol) and isopentyl nitrite (2.86 g, 24.5 mmol) at 25° C. After the addition, the reaction mixture was stirred at 50° C. for 0.5 h. Water (200 mL) and EtOAc (200 mL) were added into the reaction mixture and the mixture was separated. The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 1:0 to 5:1) to give the title compound (4.3 g, 73.3% yield, 97.9% purity on LCMS).

    [1415] LCMS: m/z 351.9 (M+H).sup.+ (ES.sup.+).

    [1416] .sup.1H NMR (CDCl.sub.3): δ 8.30 (d, 1H), 8.02 (d, 1H), 7.76 (d, 1H), 7.22-7.20 (m, 1H), 6.97 (t, 1H), 3.94 (s, 3H), 3.59-3.49 (m, 1H), 1.33 (d, 6H).

    Step F: (4-bromo-3-(2-fluoropyridin-4-yl)-5-isopropylphenyl)methanol

    [1417] ##STR00236##

    [1418] To a solution of methyl 4-bromo-3-(2-fluoropyridin-4-yl)-5-isopropylbenzoate (4.6 g, 13.1 mmol) in MeOH (100 mL) was added NaBH.sub.4 (4.94 g, 131 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 24 h, then cooled to RT, slowly poured into cold sat aq NH.sub.4Cl (500 mL), and extracted with EtOAc (200 mL×2). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by FC (PE:EtOAc, 1:0 to 5:1) to give the title compound (3.6 g, 82.8% yield, 97.4% purity on LCMS) as a white solid.

    [1419] LCMS: m/z 323.9 (M+H).sup.+ (ES.sup.+).

    [1420] .sup.1H NMR (CDCl.sub.3): δ 8.26 (d, 1H), 7.37 (d, 1H), 7.21 (dd, 1H), 7.12 (d, 1H), 6.95 (t, 1H), 4.72 (s, 2H), 3.57-3.47 (m, 1H), 1.30 (d, 6H). One exchangeable proton not observed.

    Step G: 4-(2-bromo-3-isopropyl-5-(methoxymethyl)phenyl)-2-fluoropyridine

    [1421] ##STR00237##

    [1422] To a solution of (4-bromo-3-(2-fluoropyridin-4-yl)-5-isopropylphenyl)methanol (2.5 g, 7.71 mmol) in DMF (25 mL) was added Ag.sub.2O (1.79 g, 7.71 mmol) and MeI (1.44 mL, 23.1 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h, then poured into water (30 mL) and extracted with EtOAc (40 mL×3). The organic layers were washed with sat aq NaCl (20 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 30:1 to 10:1) to give the title compound (2 g, 76.7% yield) as a yellow oil.

    [1423] LCMS: m/z 338.0 (M+H).sup.+ (ES.sup.+).

    [1424] .sup.1H NMR (CDCl.sub.3): δ 8.26 (d, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 6.96 (s, 1H), 4.45 (s, 2H), 3.54-3.42 (m, 4H), 1.30 (d, 6H).

    Step H: tert-butyl 2-(2-(2-fluoropyridin-4-yl)-6-isopropyl-4-(methoxymethyl)phenyl)-acetate

    [1425] ##STR00238##

    [1426] To a solution of 4-(2-bromo-3-isopropyl-5-(methoxymethyl)phenyl)-2-fluoropyridine (2 g, 5.91 mmol), Pd.sub.2(dba).sub.3 (271 mg, 296 μmol) and XPhos (282 mg, 591 μmol) in THF (20 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M in THF, 34.8 mL). The mixture was stirred at 70° C. for 12 h under N.sub.2, then quenched with sat aq NH.sub.4Cl (50 mL) and extracted with EtOAc (50 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 30:1 to 15:1) to give the title compound (1.4 g, 63.4% yield, 100% purity on LCMS) as a yellow oil.

    [1427] LCMS: m/z 374.4 (M+H).sup.+ (ES.sup.+).

    [1428] .sup.1H NMR (CDCl.sub.3): δ 8.23 (d, 1H), 7.36 (d, 1H), 7.18 (d, 1H), 7.03 (d, 1H), 6.94 (s, 1H), 4.46 (s, 2H), 3.48 (s, 2H), 3.43 (s, 3H), 3.13-3.06 (m, 1H), 1.44 (s, 9H), 1.27 (d, 6H).

    Intermediate B16: tert-butyl 2-(3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropyl-4-(methoxymethyl)phenyl)acetate

    [1429] ##STR00239##

    Step A: methyl 4-amino-5-bromo-2-fluorobenzoate

    [1430] ##STR00240##

    [1431] To a solution of methyl 4-amino-2-fluorobenzoate (24.5 g, 145 mmol) in MeCN (250 mL) was added dropwise a solution of NBS (23.2 g, 130 mmol) in MeCN (250 mL) at 0° C. The mixture was stirred at 25° C. for 12 h, then diluted with H.sub.2O (500 mL) and extracted with EtOAc (500 mL×3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 100:1 to 10:1) to give the title compound (12.5 g, 34.8% yield) as a yellow oil.

    [1432] LCMS: m/z 250.0 (M+H).sup.+ (ES.sup.+).

    [1433] .sup.1H NMR (CDCl.sub.3): δ 8.04 (d, 1H), 6.46 (d, 1H), 4.60 (br s, 2H) and 3.88 (s, 3H).

    Step B: methyl 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)benzoate

    [1434] ##STR00241##

    [1435] To a solution of methyl 4-amino-5-bromo-2-fluorobenzoate (12 g, 48.4 mmol) and (2-fluoropyridin-4-yl)boronic acid (7.50 g, 53.2 mmol) in dioxane (200 mL) and H.sub.2O (50 mL) were added Na.sub.2CO.sub.3 (12.8 g, 121 mmol) and Pd(dppf)Cl.sub.2.DCM (3.95 g, 4.84 mmol) under N.sub.2. The mixture was stirred at 95° C. for 12 h, then diluted with H.sub.2O (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 3:1 to 0:1) to give the title compound (10 g, 78.23% yield) as a yellow solid.

    [1436] LCMS: m/z 264.9 (M+H).sup.+ (ES.sup.+).

    [1437] .sup.1H NMR (CDCl.sub.3): δ 8.29 (d, 1H), 7.74 (d, 1H), 7.27-7.25 (m, 1H), 7.01 (s, 1H), 6.46 (d, 1H), 4.32 (br s, 2H), 3.88 (s, 3H).

    Step C: methyl 4-amino-3-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)benzoate

    [1438] ##STR00242##

    [1439] To a solution of methyl 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)benzoate (10 g, 37.9 mmol) in DCM (200 mL) and DMF (50 mL) was added NBS (8.08 g, 45.4 mmol) at 0° C. The mixture was stirred at 25° C. for 3 h, then washed with H.sub.2O (200 mL) and extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The crude product was triturated with EtOAc (50 mL) to give the title compound (9 g, 69.3% yield) as a yellow solid.

    [1440] LCMS: m/z 344.8 (M+H).sup.+ (ES.sup.+).

    [1441] .sup.1H NMR (CDCl.sub.3): δ 8.33 (d, 1H), 7.72 (d, 1H), 7.28-7.25 (m, 1H), 7.01 (s, 1H), 4.82 (br s, 2H), 3.89 (s, 3H).

    Step D: methyl 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-(prop-1-en-2-yl)benzoate

    [1442] ##STR00243##

    [1443] To a solution of methyl 4-amino-3-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)benzoate (8 g, 23.3 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (5.18 g, 35.0 mmol) in dioxane (200 mL) and H.sub.2O (40 mL) were added Pd(dppf)Cl.sub.2.DCM (1.90 g, 2.33 mmol) and Na.sub.2CO.sub.3 (6.18 g, 58.3 mmol). The reaction mixture was stirred at 95° C. for 12 h under N.sub.2, then washed with sat aq NaHCO.sub.3 (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 3:1 to 0:1) to give the title compound (6.5 g, 91.6% yield) as a yellow solid.

    [1444] LCMS: m/z 305.1 (M+H).sup.+ (ES.sup.+).

    [1445] .sup.1H NMR (CDCl.sub.3): δ 8.24 (d, 1H), 7.61 (d, 1H), 7.22 (dd, 1H), 6.98 (s, 1H), 5.46 (d, 1H), 5.05 (s, 1H), 4.42 (br s, 2H), 3.81 (s, 3H), 2.00 (s, 3H).

    Step E: methyl 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzoate

    [1446] ##STR00244##

    [1447] To a solution of methyl 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-(prop-1-en-2-yl)-benzoate (5.7 g, 18.7 mmol) in MeOH (100 mL) and EtOAc (100 mL) was added Pd/C (0.6 g, 10% purity loaded on active carbon) under N.sub.2. The suspension was degassed under vacuum and purged with H.sub.2 three times. The mixture was stirred at 25° C. for 12 h under H.sub.2 (15 psi), then diluted with EtOAc (200 mL) and filtered through Celite. The filtrate was diluted with H.sub.2O (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 4:1 to 3:1) to give the title compound (5.74 g, 100% yield) as a white solid.

    [1448] LCMS: m/z 307.1 (M+H).sup.+ (ES.sup.+).

    [1449] .sup.1H NMR (CDCl.sub.3): δ 8.31 (d, 1H), 7.59 (d, 1H), 7.28 (s, 1H), 7.02 (s, 1H), 4.33 (br s, 2H), 3.88 (s, 3H) 3.11-3.07 (m, 1H), 1.32 (d, 6H).

    Step F: methyl 4-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzoate

    [1450] ##STR00245##

    [1451] To a solution of methyl 4-amino-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzoate (5 g, 16.3 mmol) in MeCN (50 mL) was added isopentyl nitrite (2.29 g, 19.6 mmol) at 0° C., followed by CuBr (2.81 g, 19.6 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 3 h, then diluted with H.sub.2O (100 mL) and extracted with EtOAc (100 mL×3). 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, 5:1 to 4:1) to give the title compound (3.3 g, 54.6% yield) as a white solid.

    [1452] LCMS: m/z 371.9 (M+H).sup.+ (ES.sup.+).

    [1453] .sup.1H NMR (CDCl.sub.3): δ 8.30 (d, 1H), 7.68 (d, 1H), 7.19 (dd, 1H), 6.94 (s, 1H), 3.94 (s, 3H), 3.75-3.70 (m, 1H), 1.26 (d, 6H).

    Step G: methyl 4-(2-(tert-butoxy)-2-oxoethyl)-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzoate

    [1454] ##STR00246##

    [1455] To a solution of methyl 4-bromo-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzoate (2.7 g, 7.29 mmol) in THF (30 mL) was added palladium; tri-tert-butylphosphane (373 mg, 729 μmol) under N.sub.2. Then (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M in THF, 43.76 mL) was added and the reaction mixture was stirred at 70° C. for 20 min. The reaction mixture was quenched with sat aq NaHCO.sub.3 (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 90:1 to 80:1) to give the title compound (2.8 g, 94.7% yield) as a yellow oil.

    [1456] LCMS: m/z 406.2 (M+H).sup.+ (ES.sup.+).

    [1457] .sup.1H NMR (CDCl.sub.3): δ 8.26 (d, 1H), 7.65 (d, 1H), 7.15 (d, 1H), 6.92 (s, 1H), 3.93 (s, 3H), 3.50 (s, 2H), 3.15-3.08 (m, 1H), 1.45 (s, 9H), 1.40 (d, 6H).

    Step H: tert-butyl 2-(3-fluoro-6-(2-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-isopropyl-phenyl)acetate

    [1458] ##STR00247##

    [1459] To a mixture of methyl 4-(2-(tert-butoxy)-2-oxoethyl)-2-fluoro-5-(2-fluoropyridin-4-yl)-3-isopropylbenzoate (2.3 g, 5.67 mmol) in MeOH (30 mL) was added NaBH.sub.4 (1.07 g, 28.4 mmol) at 25° C. under N.sub.2. The reaction mixture was stirred at 60° C. for 12 h, then quenched with 0.5 M aq HCl (40 mL), and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine (40 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 5:1) to give the title compound (0.5 g, 23.4% yield) as a yellow oil.

    [1460] LCMS: m/z 378.0 (M+H).sup.+ (ES.sup.+).

    [1461] .sup.1H NMR (CDCl.sub.3): δ 8.25 (d, 1H), 7.18-7.14 (m, 2H), 6.91 (s, 1H), 4.79 (s, 2H), 3.47 (s, 2H), 3.11-3.05 (m, 1H), 1.45 (s, 9H), 1.38 (s, 6H). One exchangeable proton not observed.

    Step I: tert-butyl 2-(3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropyl-4-(methoxymethyl)-phenyl)acetate

    [1462] ##STR00248##

    [1463] To a solution of tert-butyl 2-(3-fluoro-6-(2-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-isopropylphenyl)acetate (0.55 g, 1-46 mmol) in THF (10 mL) was added NaH (117 mg, 2.91 mmol, 60% purity in mineral oil) at 0° C. The mixture was stirred at 25° C. for 20 min, then methyl iodide (414 mg, 2.91 mmol) was added at 25° C. The reaction mixture was stirred at 25° C. for 3 h, then quenched with H.sub.2O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 20:1 to 10:1) to give the title compound (0.48 g, 84.2% yield) as a yellow solid.

    [1464] LCMS: m/z 392.2 (M+H).sup.+ (ES.sup.+).

    [1465] .sup.1H NMR (CDCl.sub.3): δ 8.25 (d, 1H), 7.17-7.11 (m, 2H), 6.92 (s, 1H), 4.55 (s, 2H), 3.50 (s, 2H), 3.48 (s, 3H), 3.10-3.04 (m, 1H), 1.45 (s, 9H), 1.37 (d, 6H).

    Intermediate B17: methyl 2-(4-fluoro-2-isopropyl-6-(2-(((trifluoromethyl)sulfonyl)-oxy)pyridin-4-yl)phenyl)acetate

    [1466] ##STR00249##

    Step A: 2-(4-fluoro-2-(2-hydroxypyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1467] ##STR00250##

    [1468] To a solution of 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B14) (4.5 g, 11.1 mmol, TFA salt) in H.sub.2O (100 mL) was added NaOH (8.88 g, 222 mmol). The mixture was stirred at 80° C. for 24 h, adjusted to pH 7 with 1 M aq HCl, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (1.9 g, 59.2% yield) as a light yellow solid.

    [1469] LCMS: m/z 290.1 (M+H).sup.+ (ES.sup.+).

    [1470] .sup.1H NMR (DMSO-d.sub.6): δ 7.43 (d, 1H), 7.21 (dd, 1H), 6.89 (dd, 1H), 6.16 (s, 1H), 6.07 (dd, 1H), 3.54 (s, 2H), 3.03-2.99 (m, 1H), 1.18 (d, 6H). Two exchangeable protons not observed.

    Step B: methyl 2-(4-fluoro-2-(2-hydroxypyridin-4-yl)-6-isopropylphenyl)acetate

    [1471] ##STR00251##

    [1472] A solution of 2-(4-fluoro-2-(2-hydroxypyridin-4-yl)-6-isopropylphenyl)acetic acid (1.9 g, 6.57 mmol) and conc H.sub.2SO.sub.4 (1.05 mL, 19.7 mmol) in MeOH (140 mL) was stirred at 50° C. for 12 h. The mixture was adjusted to pH 7 with sat aq NaOH, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (1.97 g, 98.9% yield) as a white solid.

    [1473] LCMS: m/z 304.1 (M+H).sup.+ (ES.sup.+).

    [1474] .sup.1H NMR (DMSO-d.sub.6): δ 7.43 (d, 1H), 7.23 (dd, 1H), 6.92 (dd, 1H), 6.14 (s, 1H), 6.04 (dd, 1H), 3.64 (s, 2H), 3.59 (s, 3H), 3.01-2.98 (m, 1H), 1.17 (d, 6H). One exchangeable proton not observed.

    Step C: methyl 2-(4-fluoro-2-isopropyl-6-(2-(((trifluoromethyl)sulfonyl)oxy)pyridin-4-yl)phenyl)acetate

    [1475] ##STR00252##

    [1476] To a solution of methyl 2-(4-fluoro-2-(2-hydroxypyridin-4-yl)-6-isopropylphenyl)-acetate (1.4 g, 4.62 mmol) in DCM (20 mL) was added TEA (1.87 g, 18.5 mmol) and Tf.sub.2O (1.95 g, 6.92 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h, then quenched with 1 M aq HCl (10 mL) and extracted with DCM (15 mL×2). The organic phases were concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 30:1 to 20:1) to give the title compound (1.6 g, 79.6% yield) as a colourless oil.

    [1477] LCMS: m/z 436.0 (M+H).sup.+ (ES.sup.+).

    [1478] .sup.1H NMR (CDCl.sub.3): δ 8.44 (d, 1H), 7.36 (dd, 1H), 7.19 (s, 1H), 7.14 (dd, 1H), 6.78 (dd, 1H), 3.67 (s, 3H), 3.52 (s, 2H), 3.07-3.04 (m, 1H), 1.23 (d, 6H).

    Intermediate C1: 2-(2-(2-((5-(5-((dimethylamino)methyl)-3-sulfamoyl-1H-pyrazol-1-yl)pentyl)oxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1479] ##STR00253##

    [1480] Step A: 2-(2-(2-((5-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-((dimethylamino)-methyl)-1H-pyrazol-1-yl)pentyl)oxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    ##STR00254##

    [1481] 5-((Dimethylamino)methyl)-1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A3) (416 mg, 0.784 mmol) was dissolved in THF (5 mL) and treated with NaH (60 wt % dispersion in mineral oil, 32 mg, 0.80 mmol). The reaction was stirred at RT for 1 h, then cooled to 0° C. 2-(2-(2-Fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B1) (214 mg, 0.784 mmol) was added and the reaction allowed to warm to RT and stirred for 3 h. The reaction was diluted with brine (30 mL), extracted with EtOAc (2×30 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (360 mg, 47%) as a grey solid.

    [1482] LCMS m/z 784.3 (M+H).sup.+ (ES.sup.+); 782.3 (M−H).sup.− (ES.sup.−).

    [1483] .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J=5.2 Hz, 1H), 7.41-7.38 (m, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.04-6.98 (m, 5H), 6.87 (d, J=5.2 Hz, 1H), 6.82-6.87 (m, 4H), 6.64 (s, 1H), 6.58 (s, 1H), 4.27 (t, J=6.6 Hz, 2H), 4.25-4.16 (m, 6H), 3.70 (s, 6H), 3.50 (s, 2H), 3.47 (s, 2H), 3.04 (sept, J=6.6 Hz, 1H), 2.15 (s, 6H), 1.85 (p, J=7.5 Hz, 2H), 1.76 (p, J=7.5 Hz, 2H), 1.48-1.36 (m, 2H), 1.19 (d, J=6.7 Hz, 6H). One exchangeable proton not observed.

    Step B: 2-(2-(2-((5-(5-((dimethylamino)methyl)-3-sulfamoyl-1H-pyrazol-1-yl)pentyl)-oxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1484] ##STR00255##

    [1485] A solution of 2-(2-(2-((5-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-((dimethyl-amino)methyl)-1H-pyrazol-1-yl)pentyl)oxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (360 mg, 0.367 mmol) in TFA (5 mL) was stirred at RT for 18 h. The mixture was diluted with MeOH (1 mL) and filtered. The resulting filtrate was concentrated in vacuo, re-dissolved in MeOH (5 mL) and filtered. The filtrate was concentrated in vacuo to afford the title compound (250 mg, 95%) as a yellow oil.

    [1486] LCMS m/z 544.2 (M+H).sup.+ (ES.sup.+); 542.1 (M−H).sup.− (ES.sup.−).

    [1487] .sup.1H NMR (DMSO-d.sub.6) δ 10.08 (br s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.54 (br s, 2H), 7.44-7.39 (m, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.04 (dd, J=7-5, 1.4 Hz, 1H), 6.88 (dd, J=5.2, 1-3 Hz, 1H), 6.85 (s, 1H), 6.68-6.65 (m, 1H), 4.53 (s, 2H), 4.32-4.23 (m, 4H), 3.17 (s, 2H), 3.04 (sept, J=6.7 Hz, 1H), 2.81 (s, 6H), 1.92-1.71 (m, 4H), 1.44 (p, J=7.6 Hz, 2H), 1.20 (d, J=6.8 Hz, 6H).

    [1488] The following intermediates were synthesised following the general procedure for Intermediate C1, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00001 Int Structure From .sup.1H NMR LCMS C2 [00256]embedded image A1 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.42-7.37 (m, 3H), 7.33 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.91 (dd, J = 5.2, 1.4 Hz, 1H), 6.66-6.65 (m, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.55 (s, 2H), 3.04 (app p), J = 6.7 Hz, 1H), 1.66 (s, 6H), 1.19 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed and two masked by water peak. m/z 473.2 (M + H).sup.+ (ES.sup.+) C3 [00257]embedded image A1 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J = 5.2 Hz, 1H), 8.02 (d, J =2.4 Hz, 1H), 7.40 (br s, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.54- 6.51 (m, 1H), 4.58 (s, 2H), 3.30 (d, J = 5.8 Hz, 2H), 2.99-2.94 (m, 1H), 1.91 (s, 3H), 1.66, 1.65 (2 × s, 2 × 3H), 1.17 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. — C4 [00258]embedded image A2 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.44-7.39 (m, 3H), 7.34 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.93 (dd, J = 5.2, 1.4 Hz, 1H), 6.68 (s, 1H), 6.59 (d, J = 2.3 Hz, 1H), 4.71- 4.65 (m, 2H), 4.63-4.58 (m, 2H), 3.51 (s, 2H), 3.06-3.00 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 445.1 (M + H).sup.+ (ES.sup.+) C5 [00259]embedded image A4 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.24 (d, J = 4.5 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.69 (s, 2H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.91 (dd, J = 5.2, 1.5 Hz, 1H), 6.68 (d, J = 1.4 Hz, 1H), 4.52 (s, 2H), 3.50 (s, 2H), 3.03 (sept, J = 6.7 Hz, 1H), 1.62 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 491.2 (M + H).sup.+ (ES .sup.+) 489.2 (M − H).sup.+ (ES.sup.−) C27 [00260]embedded image A4 + B6 .sup.1H NMR (DMSO-d.sub.6) δ 8.26-8.23 (m, 1H), 8.17 (dd, J = 5.2, 0.7 Hz, 1H), 7.69 (s, 2H) 7.26 (t, J = 7.7 Hz, 1H), 7.11 (dd, J = 7.8, 1.4 Hz, 1H), 7.06 (dd, J = 7.6, 1.4 Hz, 1H), 6.93 (dd, J = 5.2, 1.5 Hz, 1H), 6.69 (m, 1H) 4.53 (d, J = 3.2 Hz, 2H), 3.64 (s, 2H), 1.88 (ddt, J = 10.8, 8.4, 3.8 Hz, 1H), 1.63 (s, 6H), 0.97-0.87 (m, 2H), 0.69-0.59 (m, 2H). One exchangeable proton not observed. m/z 489.1 (M + H).sup.+ (ES.sup.+) C28 [00261]embedded image A17 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 12.42 (s, 1H), 8.18-8.12 (m, 1H), 7.93 (t, J = 1.9 Hz, 1H), 7.73-7.65 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.42-7.36 (m, 1H), 7.33-7.24 (m, 3H), 7.02 (dd, J = 7.5, 1.4 Hz, 1H), 6.87 (dd, J = 5.2, 1.5 Hz, 1H), 6.64-6.58 (m, 1H), 4.37 (s, 2H), 3.49 (s, 2H), 3.02 (sept, J = 6.8 Hz, 1H), 1.43 (s, 6H), 1.18 (d, J = 6.8 Hz, 6H). m/z 483.5 (M + H).sup.+ (ES.sup.+) 481.4 (M − H).sup.− (ES.sup.−) C29 [00262]embedded image A11 + B1 .sup.1H NMR (CD.sub.3OD) δ 8.14 (d, J = 5.3 Hz, 1H), 7.72 (s, 1H), 7.44-7.40 (m, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.05 (dd, J = 7.5, 1.4 Hz, 1H), 6.98 (dd, J = 5.3, 1.5 Hz, 1H), 6.81 (d, J = 1.4 Hz, 1H), 4.59 (s, 2H), 3.81 (s, 3H), 3.65- 3.54 (m, 2H), 3.14 (sept, J = 6.8 Hz, 1H), 1.72 (s, 6H), 1.27 (d, J = 6.8 Hz, 6H). Three exchangeable protons not observed. m/z 503.5 (M + H).sup.+ (ES.sup.+) C30 [00263]embedded image A18 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J = 5.2 Hz, 1H), 7.54 (t, J = 1.7 Hz, 1H), 7.38 (t, J = 1.7 Hz, 1H), 7.29-7.20 (m, 4H), 6.96- 6.84 (m, 2H), 6.69 (s, 1H), 4.52 (t, J = 6.9 Hz, 2H), 3.48 (s, 2H), 3.10 (t, J = 6.8 Hz, 2H), 3.04 (sept, J = 6.9 Hz, 1H), 2.05-1.97 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H), 1.05- 0.97 (m, 2H), 0.73-0.68 (m, 2H). One exchangeable proton not observed. m/z 513.4 (M + H).sup.+ (ES.sup.+) 511.3 (M − H).sup.− (ES.sup.−) C31 [00264]embedded image A19 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (d, J = 4.5 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.69 (s, 2H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.87 (dd, J = 5.2, 1.4 Hz, 1H), 6.62 (s, 1H), 4.15 (t, J = 7.0 Hz, 2H), 3.50 (s, 2H), 3.03 (p, J = 6.8 Hz, 1H), 1.60 (s, 6H), 1.20-1.15 (m, 8H). One exchangeable proton not observed. m/z 505.4 (M + H).sup.+ (ES.sup.+) 503.4 (M − H).sup.− (ES.sup.−) C32 [00265]embedded image A20 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 7.43-7.38 (m, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.23 (s, 2H), 7.05-6.99 (m, 1H), 6.89 (dd, J = 5.1, 1.4 Hz, 1H), 6.67 (s, 1H), 4.60 (s, 2H), 3.50 (s, 2H), 3.10-2.96 (m, 1H), 1.40-1.26 (m, 4H), 1.19 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 471.4 (M + H).sup.+ (ES.sup.+) C33 [00266]embedded image A21 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 12.43 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.12 (s, 2H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.91 (dd, J = 5.1, 1.4 Hz, 1H), 6.70 (s, 1H), 4.49 (s, 2H), 3.50 (s, 2H), 3.03 (p, J = 6.7 Hz, 1H), 1.65 (s, 6H), 1.19 (d, J = 6.7 Hz, 6H). m/z 473.4 (M + H).sup.+ (ES.sup.+) 471.3 (M − H).sup.− (ES.sup.−) C36 [00267]embedded image A22 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 12.43 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.78 (s, 2H), 7.39 (dd, J = 8.0, 1.4 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.02 (dd, J = 7.5, 1.4 Hz, 1H), 6.90 (dd, J = 5.2, 1.4 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 4.71 (s, 2H), 3.49 (s, 2H), 3.02 (sept, J = 6.8 Hz, 1H), 1.74 (s, 6H), 1.18 (d, J = 6.7 Hz, 6H). m/z 474.5 (M + H).sup.+ (ES.sup.+) 472.0 (M − H).sup.− (ES.sup.−) C37 [00268]embedded image A23 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.66 (dd, J = 4.5, 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 1.7 Hz, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.82 (s, 2H), 7.42 (dd, J = 8.1,4.5 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.00-6.93 (m, 1H), 6.84 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (s, 1H), 5.01 (s, 2H), 3.45 (s, 2H), 3.06- 2.95 (m, 1H), 1.91 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 524.4 (M + H).sup.+ (ES.sup.+) C38 [00269]embedded image A24 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.83 (d, J = 4.5 Hz, 1H), 8.52-8.50 (m, 1H), 8.10 (d, J = 5.3 Hz, 1H), 8.09- 8.05 (m, 1H), 7.98 (s, 2H), 7.55 (dd, J = 7.8, 4.7 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.09-7.05 (m, 1H), 6.91 (dd, J = 5.2, 1.4 Hz, 1H), 6.84 (s, 1H), 5.77 (s, 2H), 3.52 (s, 2H), 3.05 (m, 1H), 3.52 (s, 6H). One exchangeable proton not observed. —

    Intermediate C6: 2-(5-(2-(2-(4-fluoro-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid

    [1489] ##STR00270##

    [1490] KO.sup.tBu (172 mg, 1.529 mmol) was added to a solution of tert-butyl 2-(5-(2-fluoro-pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (Intermediate B13) (250 mg, 0.764 mmol) and 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A4) (365 mg, 0.764 mmol) in THF (12 mL) at 0° C. The mixture was stirred at RT for 48 h before additional KO.sup.tBu (56 mg, 0.766 mmol) was added and stirred for 4 h. The mixture was diluted with water (10 mL) and DCM (10 mL). The aqueous phase was extracted with DCM (3×10 mL) and the combined organic phases were dried (MgSO.sub.4) and concentrated in vacuo. TFA (5 mL) was added to the residue and stirred at RT for 16 h. The mixture was concentrated in vacuo. MeOH (2 mL) was added and the mixture evaporated in vacuo. The crude was purified by FC (0-40% MeOH/DCM) to afford the title compound (187 mg, 50%) as a white solid.

    [1491] LCMS m/z 489.1 (M+H).sup.+ (ES.sup.+).

    [1492] .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (d, J=4.6 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.70 (s, 2H), 7.22 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.91 (dd, J=5.3, 1.4 Hz, 1H), 6.68 (s, 1H), 4.53 (s, 2H), 3.46 (s, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.05 (p, J=7.4 Hz, 3H), 1.63 (s, 6H).

    [1493] The following intermediates ‘Int.’ were synthesised following the general procedure for Intermediate C6, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00002 Int. Structure From .sup.1H NMR LCMS C7 [00271]embedded image A6 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 12.43 (br s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.69 (dt, J = 7.5, 1.7 Hz, 1H), 7.56-7-53 (m, 1H), 7.51-7.48 (m, 1H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.33-7.30 (m, 3H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.89 (dd, J = 5.2, 1.4 Hz, 1H), 6.71-6.59 (m, 1H), 4-53 (t, J = 6.8 Hz, 2H), 3.51 (s, 2H), 3.20- 3.08 (m, 2H), 3.03 (p, J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H). m/z 455.0 (M + H).sup.+ (ES.sup.+) 453.4 (M − H).sup.− (ES.sup.−) C8 [00272]embedded image A8 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (d, J = 5.3 Hz, 1H), 8.12 (d, J = 4.6 Hz, 1H), 7.72 (s, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 7.4, 1.5 Hz, 1H), 6.93 (dd, J = 5.2, 1.5 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 4.66 (t, J = 5.1 Hz, 2H), 4.53 (d, J = 5.3 Hz, 2H), 3.51 (s, 2H), 3.05 (d, J = 6.7 Hz, 1H), 1.20 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 463.2 (M + H).sup.+ (ES.sup.+) C9 [00273]embedded image A6 + B3 .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J = 5.2 Hz, 1H), 7.81- 7.77 (m, 1H), 7.69 (dt, J = 7.5, 1.6 Hz, 1H), 7.56-7-53 (m, 1H), 7.51 (t, J = 7.6 Hz, lH), 7.32 (br s, 2H), 7.21 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.89 (dd, J = 5.2, 1.5 Hz, 1H), 6.67-6.65 (m, 1H), 4.53 (t, J = 6.8 Hz, 2H), 3.46 (s, 2H), 3.15 (t, J = 6.9 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. m/z 453.4 (M + H).sup.+ (ES.sup.+) C10 [00274]embedded image A5 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 12.44 (s, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.37-7.30 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 5.3 Hz, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 4.78-4.68 (m, 1H), 4.54 (t, J = 6.4 Hz, 2H), 3.52 (s, 2H), 3.21 (t, J = 6.5 Hz, 2H), 3.07-2.98 (m, 1H), 1.40 (d, J = 6.5 Hz, 6H), 1.19 (d, J = 6.8 Hz, 6H). m/z 487 (M + H).sup.+ (ES.sup.+) C12 [00275]embedded image A4 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.26-8.21 (m, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.70 (s, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.55 (s, 1H), 4.60-4.49 (m, 2H), 3.30 (s, 2H), 2.97 (p, J = 6.8 Hz, 1H), 1.91 (d, J = 2.1 Hz, 3H), 1.62 (d, J = 6.2 Hz, 6H), 1.17 (dd, J = 6.7, 1.7 Hz, 6H). One exchangeable proton not observed. m/z 505.4 (M + H).sup.+ (ES.sup.+) C13 [00276]embedded image A8 + B2 .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.72 (s, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.77 (dd, J = 5.2,1.4 Hz, 1H), 6.57 (s, 1H), 5.76 (s, 1H), 4.74- 4.61 (m, 2H), 4.56-4.51 (m, 2H), 3.02-2.92 (m, 2H), 1.91 (s, 3H), 1.17 (dd, J = 6.8, 2.5 Hz, 6H). One exchangeable proton not observed. m/z 477.4 (M + H).sup.+ (ES.sup.+) C14 [00277]embedded image A8 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J = 5-2 Hz, 1H), 8.12 (d, J = 4.7 Hz, 1H), 7.72 (s, 2H), 6.96-6.89 (m, 2H), 6.73 (s, 1H), 4.66 (t, J = 5.2 Hz, 2H), 4.52 (t, J = 5.2 Hz, 2H), 3.48 (s, 2H), 3.08-2.99 (m, 1H), 1.19 (d, J = 6.7 Hz, 6H). 2 protons obscured by solvent signal. m/z 481.4 (M + H).sup.+ (ES.sup.+) C15 [00278]embedded image A4 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.25 (d, J = 4.6 Hz, 1H), 8.19 (dd, J = 5.2, 0.7 Hz, 1H), 7.70 (s, 2H), 7.24 (dd, J = 10.5, 2.8 Hz, 1H), 6.94- 6.90 (m, 2H), 6.71 (t, J = 1.1 Hz, 1H), 4.53 (s, 2H), 3.47 (s, 2H), 3.08-2.99 (m, 1H), 1.63 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 509.4 (M + H).sup.+ (ES.sup.+) C16 [00279]embedded image A9 + B1 m/z 473.4 (M + H).sup.+ (ES.sup.+) C18 [00280]embedded image A10 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 12.47 (s, 1H), 8.35 (dd, J = 5.0, 1.9 Hz, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8.11 (dd, J = 7.5, 1.9 Hz, 1H), 7.30 (s, 2H), 7.24 (dd, J = 10.4, 2.7 Hz, 1H), 7.15 (dd, J = 7.5, 5.0 Hz, 1H), 6.95-6.85 (m, 2H), 6.71 (d, J = 1.3 Hz, 1H), 4.58 (t, J = 6.2 Hz, 2H), 4.48 (t, J = 6.3 Hz, 2H), 3.48 (s, 2H), 3.09- 2.97 (m, 1H), 2.28 (t, J = 6.3 Hz, 2H), 1.19 (d, J = 6.8 Hz, 6H). m/z 504.4 (M + H).sup.+ (ES.sup.+) C19 [00281]embedded image A11 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.29 (s, 2H), 7.23 (dd, J = 10.5, 2.8 Hz, 1H), 6.94- 6.89 (m, 2H), 6.71 (d, J = 1.2 Hz, 1H), 4.52 (s, 2H), 3.72 (s, 3H), 3.47 (s, 2H), 3.10-2.92 (m, 1H), 1.62 (s, 6H), 1.18 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 520.8 (M + H).sup.+ (ES.sup.+) C20 [00282]embedded image A12 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 12.47 (s, 1H), 8.23-8.09 (m, 2H), 7.73 (s, 2H), 7.23 (dd, J = 10.5, 2.8 Hz, 1H), 6.95-6.83 (m, 2H), 6.72 (dd, J = 1.5, 0.7 Hz, 1H), 4.57 (s, 2H), 3.47 (s, 2H), 3.08-2.96 (m, 1H), 1.40- 1.23 (m, 4H), 1.18 (d, J = 6.7 Hz, 6H). m/z 507.4 (M + H).sup.+ (ES.sup.+) C21 [00283]embedded image A14 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.25 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.24 (s, 2H), 7.02 (dd, J = 7.5, 1.4 Hz, 1H), 6.91 (dd, J = 5.2, 1.4 Hz, 1H), 6.68-6.64 (m, 1H), 4.67 (t, J = 5.2 Hz, 2H), 4.57 (t, J = 5.2 Hz, 2H), 3.50 (s, 2H), 3.10-2.95 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 445.8 (M + H).sup.+ (ES.sup.+) C22 [00284]embedded image A14 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 12.47 (s, 1H), 8.25 (s, 1H), 8.22-8.20 (m, 1H), 7.74 (s, 1H), 7.30-7.15 (m, 3H), 6.99-6.81 (m, 2H), 6.71-6.63 (m, 1H), 4.70- 4.63 (m, 2H), 4.57 (t, J = 5.2 Hz, 2H), 3.47 (s, 2H), 3.09-2.95 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H). m/z 463.5 (M + H).sup.+ (ES.sup.+) C23 [00285]embedded image A13 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J = 5.1 Hz, 1H), 7.27- 7.21 (m, 1H), 7.05 (s, 2H), 6.94-6.89 (m, 2H), 6.69 (s, 1H), 4.60 (s, 2H), 3.47 (s, 2H), 3.03 (d, J = 23.3 Hz, 1H), 2.64-2.63 (m, 3H), 2.23 (s, 3H), 1.69 (s, 6H), 1.19 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 519.4 (M + H).sup.+ (ES.sup.+) C24 [00286]embedded image A15 + B1 .sup.1H NMR (DMSO-d.sub.6) δ 8.17 (dd, J = 5.2, 0.7 Hz, 1H), 8.09 (s, 1H), 7.39 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.15 (s, 2H), 7.03 (dd, J = 7.5, 1.4 Hz, 1H), 6.90 (dd, J = 5.2, 1.5 Hz, 1H), 6.68-6.62 (m, 1H), 4.53 (s, 2H), 3.50 (s, 2H), 3.08-2.97 (m, 1H), 2.29 (s, 3H), 1.60 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 487.6 (M + H).sup.+ (ES.sup.+) C25 [00287]embedded image A9 + B4 .sup.1H NMR (DMSO-d.sub.6) δ 12.46 (s, 1H), 8.26 (d, J = 0.7 Hz, 1H), 8.18 (dd, J = 5.2, 0.7 Hz, 1H), 7.76 (d, J = 0.7 Hz, 1H), 7.25-7.18 (m, 3H), 6.93-6.88 (m, 2H), 6.66 (dd, J = 1.4, 0.7 Hz, 1H), 4.57 (s, 2H), 3.46 (s, 2H), 3.07-2.97 (m, 1H), 1.64 (s, 6H), 1.18 (d, J = 6.8 Hz, 6H). m/z 491.5 (M + H).sup.+ (ES.sup.+) C34 [00288]embedded image A4 + B7 .sup.1H NMR (DMSO-d.sub.6) δ 8.25 (d, J = 4.9 Hz, 2H), 7.70 (s, 2H), 7.52-7.41 (m, 1H), 6.92-6.87 (m, 1H), 6.74 (s, 1H), 4.58- 4.49 (m, 2H), 3.39 (s, 2H), 3.06-2.95 (m, 1H), 1.62 (s, 6H), 1.17 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 527.3 (M + H).sup.+ (ES.sup.+) 525.3 (M − H).sup.− (ES.sup.−) C35 [00289]embedded image A9 + B7 .sup.1H NMR (DMSO-d.sub.6) δ 8.27 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H), 7.47 (dd, J = 12.2, 8.2 Hz, 1H), 7.21 (s, 2H), 6.92- 6.88 (m, 1H), 6.70 (s, 1H), 4.58 (d, J = 9.2 Hz, 2H), 3.39 (d, J = 6.7 Hz, 2H), 3.04-2.96 (m, 1H), 1.64 (s, 6H), 1.17 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 509.0 (M + H).sup.+ (ES.sup.+) 507.3 (M − H).sup.− (ES.sup.−) C42 [00290]embedded image A9 + B8 .sup.1H NMR (DMSO-d.sub.6) δ 8.26 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.76 (s, 1H), 7.25-7.17 (m, 3H), 6.87 (dd, J = 5-2, 1.4 Hz, 1H), 6.65 (s, 1H), 4.57 (s, 2H), 3.48 (s, 2H), 3.14-3.03 (m, 1H), 1.64 (s, 6H), 1.30 (d, J = 6.9 Hz, 6H). One exchangeable proton not observed. m/z 509.3 (M + H).sup.+ (ES.sup.+)

    Intermediate C11: 2-(2-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy)-pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1494] ##STR00291##

    Step A: 2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(2-hydroxypropan-2-yl)-phenethoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1495] ##STR00292##

    [1496] 3-(2-hydroxyethyl)-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)benzene-sulfonamide (Intermediate A7) (0.5 g, 1.00 mmol) and 2-(2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B1) (0.274 g, 1.00 mmol) were dissolved in THF (20 mL) and cooled to 0° C. NaH (60% dispersion in mineral oil) (0.120 g, 3.00 mmol) was then added and the reaction was stirred for 10 min at this temperature before warming to RT and stirring for 5 h. The mixture was then diluted with EtOAc (50 mL) and acidified to pH <3 with 1 M HCl. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organic layer was then dried (phase separator), and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (268 mg, 32%) as a pale yellow oil.

    [1497] LCMS m/z 753.5 (M+H).sup.+ (ES.sup.+).

    [1498] .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J=5.2 Hz, 1H), 7.80-7.76 (m, 1H), 7.71-7.67 (m, 1H), 7.61-7.57 (m, 1H), 7.40 (dd, J=7.9, 1.4 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 6.94 (dd, J=7-5, 1.4 Hz, 1H), 6.93-6.90 (m, 4H), 6.88 (dd, J=5.2, 1.5 Hz, 1H), 6.77-6.72 (m, 4H), 6.63 (s, 1H), 4.52 (t, J=6.7 Hz, 2H), 4.16 (s, 4H), 4.14-4.08 (m, 1H), 3.68 (s, 6H), 3.47 (s, 2H), 3.15 (t, J=6.7 Hz, 2H), 3.09-3.00 (m, 1H), 1.42 (s, 6H), 1.19 (d, J=6.8 Hz, 6H). One exchangeable proton not observed.

    Step B: 2-(2-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy)pyridin-4-yl)-6-isopropylphenyl) acetic acid

    [1499] ##STR00293##

    [1500] 2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(2-hydroxypropan-2-yl)-phenethoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (268 mg, 0.356 mmol) was dissolved in MeCN (6 mL). A solution of CAN (976 mg, 1.780 mmol) in water (2 mL) was added portionwise over 5 min. The orange mixture was stirred for 2 h. H.sub.2O (5 mL) and DCM (20 mL) was added and the organic phase was separated, washed with brine (10 mL), dried using a phase separator, and concentrated in vacuo to give a yellow oil. The crude product was purified by FC (0-10% MeOH/DCM) to afford the title compound (58 mg, 32%) as a clear colourless oil.

    [1501] LCMS m/z 513.4 (M+H).sup.+ (ES.sup.+).

    [1502] .sup.1H NMR (DMSO-d.sub.6) δ 8.23-8.17 (m, 1H), 7.84 (s, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.36-7.26 (m, 3H), 7.03 (d, J=7.1 Hz, 1H), 6.90 (d, J=5.2 Hz, 1H), 6.69 (s, 1H), 4.53 (t, J=6.8 Hz, 2H), 3.50 (s, 2H), 3.15 (q, J=7.0 Hz, 2H), 3.05 (s, 1H), 1.44 (s, 6H), 1.19 (d, J=6.7 Hz, 6H). Two exchangeable protons not observed.

    Intermediate C17: 2-(5-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy)-pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid

    [1503] ##STR00294##

    Step A: tert-butyl 2-(5-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(2-hydroxy-propan-2-yl)phenethoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate

    [1504] ##STR00295##

    [1505] 3-(2-hydroxyethyl)-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)benzene-sulfonamide (Intermediate A7) (0.4 g, 0.801 mmol) and tert-butyl 2-(5-(2-fluoro-pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (Intermediate B3) (0.26 g, 0.801 mmol) were dissolved in THF (7 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil) (0.096 g, 2.402 mmol) was then added and the reaction was stirred for 10 min at this temperature before warming to RT and stirring for 24 h. The mixture was then diluted EtOAc (50 mL), washed with brine (50 mL), dried (phase separator), and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (245 mg, 34.5%) as a pink oil.

    [1506] LCMS m/z 807.7 (M+H).sup.+ (ES.sup.+); 805.8 (M−H).sup.− (ES.sup.−).

    [1507] .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J=5.5 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 7.68 (t, J=1.7 Hz, 1H), 7.58 (t, J=1.7 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 6.96-6.88 (m, 5H), 6.85 (dd, J=5.3, 1.4 Hz, 1H), 6.76-6.70 (m, 4H), 6.60-6.57 (m, 1H), 5.26 (s, 1H), 4.52 (t, J=6.6 Hz, 2H), 4.15 (s, 4H), 3.68 (s, 6H), 3.40 (s, 2H), 3.14 (t, J=6.6 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.03 (p, J−7.5 Hz, 2H), 1.42 (s, 6H), 1.32 (s, 9H).

    Step B: 2-(5-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid

    [1508] ##STR00296##

    [1509] tert-Butyl 2-(5-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(2-hydroxypropan-2-yl)-phenethoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (245 mg, 0.304 mmol) was dissolved in MeCN (6 mL). A solution of CAN (832 mg, 1.518 mmol) in water (2 mL) was added portion-wise over 5 min. The orange mixture was stirred for 2 h. Water (5 mL) and DCM (20 mL) were added and the organic phase was separated, washed with brine (10 mL), dried using a phase separator, and concentrated in vacuo to give a yellow oil. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford tert-butyl 2-(5-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (135 mg, 78%) as a clear colourless oil. This was dissolved in a 2:1 mixture of TFA and water (4 mL) and stirred at RT for 20 h. The reaction was concentrated in vacuo. The resulting residue was suspended in toluene (2 mL) then concentrated in vacuo (2×), to afford the title compound (120 mg, 72%) as a light brown solid.

    [1510] LCMS m/z 511.5 (M+H).sup.+ (ES.sup.+); 509.2 (M−H).sup.− (ES.sup.−).

    [1511] .sup.1H NMR (DMSO-d.sub.6) δ 8.18 (d, J=5.2 Hz, 1H), 7.84 (t, J=1.9 Hz, 1H), 7.66-7.59 (m, 2H), 7.33-7.28 (m, 2H), 7.21 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.90 (dd, J=5.2, 1.5 Hz, 1H), 6.70 (s, 1H), 4.53 (t, J=6.8 Hz, 2H), 3.44 (s, 2H), 3.14 (t, J=6.8 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.04 (p, J=7.5 Hz, 2H), 1.44 (s, 6H). Two exchangeable protons not observed.

    Intermediate C26: 2-(4-fluoro-2-(2-(4-fluoro-3-sulfamoylphenethoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1512] ##STR00297##

    Step A: methyl 2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluorophenethoxy)-pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate

    [1513] ##STR00298##

    [1514] DIAD (300 μL, 1.543 mmol) was added to a mixture of 2-fluoro-5-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (Intermediate A16) (540 mg, 1.18 mmol), methyl 2-(4-fluoro-2-isopropyl-6-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)-acetate (Intermediate B5) (300 mg, 0.989 mmol) and PPh.sub.3 (400 mg, 1.53 mmol) in THF (15 mL) at RT. After 7 h a further portion of PPh.sub.3 (400 mg, 1.53 mmol) and DIAD (300 μL, 1.543 mmol) were added, stirred for 24 h then partitioned between TBME (80 mL) and water (50 mL), the organic layer separated, dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by FC (0-50% EtOAc/isohexane) to afford the title compound (554 mg, 45%) as a gum.

    [1515] .sup.1H NMR (CDCl.sub.3) δ 8.15 (dd, J=5.2, 0.7 Hz, 1H), 7.86 (dd, J=6.8, 2.3 Hz, 1H), 7.52-7.47 (m, 1H), 7.12 (dd, J=9.9, 8.4 Hz, 1H), 7.06 (dd, J=10.2, 2.8 Hz, 1H), 7.00-6.95 (m, 4H), 6.81 (dd, J=5.2, 1.5 Hz, 1H), 6.78-6.73 (m, 4H), 6.71 (dd, J=8.5, 2.8 Hz, 1H), 6.64-6.62 (m, 1H), 4.58 (t, J=6.6 Hz, 2H), 4.34 (s, 4H), 3.78 (s, 6H), 3.66 (s, 3H), 3.54 (s, 2H), 3.14 (t, J=6.6 Hz, 2H), 3.08-3.00 (m, 1H), 1.24 (d, J=6.8 Hz, 6H).

    Step B: 2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluorophenethoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1516] ##STR00299##

    [1517] A mixture of methyl 2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-phenethoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (700 mg, 0.564 mmol) in THF (5 mL), water (1 mL) and aq 1 M NaOH (800 μL, 0.800 mmol) was stirred at RT for 24 h. A further portion of aq 1 M NaOH (800 μL, 0.800 mmol) was added and the mixture heated at 50° C. for 24 h, cooled to RT, MeOH (1 mL) added and stirred for 4 days. After heating the solution at 50° C. for 6 h, the mixture was cooled, the organic solvent evaporated and the residue taken to pH 6 with aq 1 M HCl and extracted with TBME (2×15 mL). The organic layer was dried (MgSO.sub.4), filtered, evaporated and the residue purified by FC (0-60% EtOAc/isohexane) to afford the title compound (345 mg, 67%) as a gum.

    [1518] LCMS m/z 729.35 (M−H).sup.−(ES.sup.−).

    [1519] .sup.1H NMR (DMSO-d.sub.6) δ 12.46 (s, 1H), 8.20 (dd, J=5.2, 0.7 Hz, 1H), 7.72 (dd, J=7.0, 2.3 Hz, 1H), 7.68-7.63 (m, 1H), 7.36 (dd, J=10.5, 8.4 Hz, 1H), 7.23 (dd, J=10.5, 2.8 Hz, 1H), 6.99-6.93 (m, 4H), 6.87 (dd, J=5.2, 1.5 Hz, 1H), 6.81 (dd, J=8.9, 2.8 Hz, 1H), 6.79-6.73 (m, 4H), 6.64 (s, 1H), 4.52 (t, J=6.6 Hz, 2H), 4.26 (s, 4H), 3.69 (s, 6H), 3.43 (s, 2H), 3.11 (t, J=6.6 Hz, 2H), 3.02 (sept, J=6.5 Hz, 1H), 1.19-1.17 (d, J=6.5 Hz, 6H).

    Step C: 2-(4-fluoro-2-(2-(4-fluoro-3-sulfamoylphenethoxy)pyridin-4-yl)-6-isopropyl-phenyl)acetic acid

    [1520] ##STR00300##

    [1521] To a vial containing 2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-phenethoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (300 mg, 0.39 mmol) was added TFA (5.0 mL). The reaction mixture was left to stir at RT for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by FC (0-10% MeOH/DCM) to afford the title compound (194 mg, 96%) as a colourless solid.

    [1522] LCMS m/z 491.2 (M+H).sup.+ (ES.sup.+); 489.7 (M−H).sup.− (ES.sup.−).

    [1523] .sup.1H NMR (DMSO-d.sub.6) δ 8.21 (d, J=5.2 Hz, 1H), 7.74 (dd, J=7.1, 2-3 Hz, 1H), 7.62 (s, 2H), 7.58 (ddd, J=7.6, 4.7, 2.4 Hz, 1H), 7.35 (dd, J=10.2, 8.4 Hz, 1H), 7.23 (dd, J=10.5, 2.8 Hz, 1H), 6.94-6.87 (m, 2H), 6.68 (s, 1H), 4.50 (t, J=6.7 Hz, 2H), 3.47 (s, 2H), 3.11 (t, J=6.7 Hz, 2H), 3.03 (p, J=6.5 Hz, 1H), 1.18 (d, J=6.7 Hz, 6H). One exchangeable proton not observed.

    Intermediate C39: 2-(2-(2-(2-(5-(dimethylcarbamoyl)-4-fluoro-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1524] ##STR00301##

    Step A: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-((4-(2-(2-(tert-butoxy)-2-oxoethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-1H-pyrazole-5-carboxylic acid

    [1525] ##STR00302##

    [1526] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-5-carboxylic acid (Intermediate A25) (0.280 g, 537 μmol) in THF (6 mL) at 0° C. was added sodium hydride (60 wt % dispersion in mineral oil) (64.4 mg, 1.61 mmol) and the reaction left to stir for 15 min. tert-Butyl 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate (Intermediate B4) (187 mg, 537 μmol) was then added to the reaction mixture, which was then warmed to RT and stirred for 16 h. The reaction was quenched with water and then the pH adjusted to ≤3 with 1 M aq HCl. The mixture was then extracted with EtOAc (2×20 mL), the organics passed through a phase separator and then concentrated in vacuo. The crude product was purified by FC (15-100% MeCN (0.1% formic acid)/water (0.1% formic acid)) to afford the title compound (0.135 g, 29%) as a white solid.

    [1527] LCMS m/z 849.7 (M+H).sup.+ (ES.sup.+).

    [1528] .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J=5.2 Hz, 1H), 7.22 (dd, J=10.4, 2.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 4H), 6.88 (dd, J=5.1, 1.5 Hz, 1H), 6.76 (m, 5H), 6.53 (s, 1H), 4.79 (s, 2H), 4.20 (s, 4H), 3.68 (s, 6H), 3.36 (s, 2H), 3.05-2.89 (m, 1H), 1.71 (s, 6H), 1.28 (d, J=1.3 Hz, 9H), 1.16 (d, J=6.6 Hz, 6H). One exchangeable proton not observed.

    Step B: 2-(2-(2-(2-(5-(dimethylcarbamoyl)-4-fluoro-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1529] ##STR00303##

    [1530] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-((4-(2-(2-(tert-butoxy)-2-oxoethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-1H-pyrazole-5-carboxylic acid (0.234 g, 276 μmol) in DMF (3 mL) was added DIPEA (35.6 mg, 276 μmol) and HATU (115 mg, 303 μmol). The reaction was stirred at RT for 10 min and then dimethylamine hydrochloride (24.7 mg, 303 μmol) was added. The reaction was then heated at 80° C. for 65 h. The reaction was diluted with EtOAc (20 mL) and washed with water (50 mL) and then brine (3×50 mL). The organics were then passed through a phase separator and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane). The isolated material was taken up in TFA (5 mL) and stirred for 16 h at RT. The reaction was then concentrated in vacuo and the resulting crude product was purified by FC (0-8% MeOH/DCM) to afford the title compound (0.09 g, 50%) as a pale yellow glass.

    [1531] LCMS m/z 580.5 (M+H).sup.+ (ES.sup.+).

    [1532] .sup.1H NMR (DMSO-d.sub.6) δ 12.46 (s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.85 (s, 2H), 7.23 (dd, J=10.5, 2.8 Hz, 1H), 6.95-6.87 (m, 2H), 6.67 (d, J=1.4 Hz, 1H), 3.66-3.37 (m, 4H), 3.07-2.96 (m, 1H), 2.92 (s, 3H), 2.85 (s, 3H), 1.66 (s, 6H), 1.21-1.13 (m, 6H).

    Intermediate C40: 2-(2-(2-(2-(6-ethyl-3-sulfamoyl-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridin-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1533] ##STR00304##

    Step A: tert-butyl 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate

    [1534] ##STR00305##

    [1535] 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-sulfonamide (375 mg, 729 μmol) (Intermediate A26) and tert-butyl 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate (253 mg, 729 μmol) (Intermediate B4) were combined under N.sub.2 then dissolved in THF (7 mL). The mixture was cooled to 0° C. then sodium hydride (60 wt % in mineral oil) (87 mg, 2.19 mmol) was added. The reaction was allowed to warm to RT and stirred for 16 h. The mixture was quenched with water (30 mL), transferred to a separating funnel and extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO.sub.4, filtered then concentrated in vacuo onto silica. The crude product was purified by FC (0-100% EtOAc/isohexane) then flushed with 10% MeOH (0.7 M NH.sub.3) in DCM to afford the title compound (515 mg, 80%) as a flocculent white solid.

    [1536] LCMS m/z 842.1 (M)+(ES.sup.+).

    [1537] .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J=5.2 Hz, 1H), 7.23 (dd, J=10.5, 2.8 Hz, 1H), 6.96-6.90 (m, 4H), 6.88 (dd, J=5.2, 1.4 Hz, 1H), 6.80-6.71 (m, 5H), 6.61 (s, 1H), 4.55 (s, 2H), 4.13 (s, 4H), 4.04 (d, J=2.7 Hz, 2H), 3.68 (s, 6H), 3.39 (s, 2H), 3.00 (m, 1H), 2.74 (t, J=5.7 Hz, 2H), 1.64 (s, 6H), 1.31 (s, 9H), 1.17 (d, J=6.8 Hz, 6H). One CH.sub.2 under DMSO peak, one exchangeable proton not observed.

    Step B: tert-butyl 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate

    [1538] ##STR00306##

    [1539] tert-Butyl 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropyl-phenyl)acetate (515 mg, 612 μmol) and Pd/C (10 wt %) (65.1 mg, 61.2 μmol) were combined and purged by evacuating and back-filling with N.sub.2 (×3). MeCN (4 mL) and EtOH (2 mL) were added then the mixture was placed under H.sub.2 (5 bar) for 16 h. The mixture was filtered through a glass fibre filter disc and rinsed with EtOH (20 mL) followed by the removal of solvents in vacuo to afford the title compound (502 mg, 85%) as a white solid.

    [1540] LCMS m/z 870.1 (M)+(ES.sup.+).

    [1541] .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (dd, J=5.3, 0.7 Hz, 1H), 7.24 (dd, J=10.5, 2.8 Hz, 1H), 6.97-6.92 (m, 4H), 6.89 (dd, J=5.2, 1.4 Hz, 1H), 6.80-6.71 (m, 5H), 6.59 (dd, J=1.5, 0.7 Hz, 1H), 4.59 (s, 2H), 4.14 (s, 4H), 3.79 (s, 2H), 3.68 (s, 6H), 3.40 (s, 2H), 3.01 (p, J=6.7 Hz, 1H), 2.61-2.51 (m, 6H), 1.67 (s, 6H), 1.31 (s, 9H), 1.18 (d, J=6.7 Hz, 6H), 1.05 (m, 3H).

    Step C: 2-(2-(2-(2-(6-ethyl-3-sulfamoyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]-pyridin-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1542] ##STR00307##

    [1543] tert-Butyl 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (0.487 g, 560 μmol) was dissolved in TFA (5 mL) and stirred at RT for 6 h. The mixture was then concentrated to dryness, co-evaporated with toluene (10 mL) twice to dryness and purified by FC (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (514 mg, 96%) as a sticky colourless foam.

    [1544] LCMS m/z 574.5 (M+H).sup.+ (ES.sup.+); 572.4 (M−H).sup.− (ES.sup.−).

    [1545] .sup.1H NMR (DMSO-d.sub.6) δ 9.98 (s, 1H), 8.24-8.17 (m, 1H), 7.58 (s, 2H), 7.25 (dd, J=10.5, 2.8 Hz, 1H), 6.94 (dd, J=5.2, 1.4 Hz, 1H), 6.91 (dd, J=8.9, 2.8 Hz, 1H), 6.79-6.78 (m, 1H), 4.90 (d, J=14.9 Hz, 1H), 4.61-4.45 (m, 3H), 3.80-3.54 (m, 2H), 3.48 (s, 2H), 3.40-3.19 (m, 2H), 3.08-2.84 (m, 3H), 1.70 (d, J=4.0 Hz, 6H), 1.30 (t, J=7.3 Hz, 3H), 1.18 (d, J=6.8 Hz, 6H).

    [1546] .sup.19F NMR (DMSO-d.sub.6) δ −115.08 (t, J=9.8 Hz).

    Intermediate C41: 2-(2-(2-(2-(5-(dimethylcarbamoyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1547] ##STR00308##

    Step A: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-((4-(2-(2-(tert-butoxy)-2-oxoethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-1H-pyrazole-5-carboxylic acid, formic acid salt

    [1548] ##STR00309##

    [1549] Prepared according to the general procedure of 3-(N,N-bis(4-methoxybenzyl)-sulfamoyl)-1-(1-((4-(2-(2-(tert-butoxy)-2-oxoethyl)-5-fluoro-3-isopropylphenyl)-pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-1H-pyrazole-5-carboxylic acid (Intermediate C39, Step A) from potassium 3-(N,N-bis(4-methoxybenzyl)-sulfamoyl)-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-5-carboxylate (Intermediate A27) and tert-butyl 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropyl-phenyl)acetate (Intermediate B4) to afford the title compound (0.88 g, 41%) as a thick orange oil.

    [1550] LCMS m/z 831.7 (M+H− formic acid).sup.+ (ES.sup.+).

    [1551] .sup.1H NMR (DMSO-d.sub.6) δ 14.19-12.49 (m, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.22 (dd, J=10.5, 2.8 Hz, 1H), 7.05 (s, 1H), 6.99-6.91 (m, 4H), 6.87 (dd, J=5.2, 1.4 Hz, 1H), 6.77-6.70 (m, 5H), 6.51 (d, J=1.2 Hz, 1H), 4.85 (s, 2H), 4.14 (s, 4H), 3.67 (s, 6H), 3.37 (s, 2H), δ 3.04-2.94 (m, 1H), 1.77 (s, 6H), 1.29 (s, 9H), 1.17 (d, J=6.7 Hz, 6H). One exchangeable proton not observed.

    Step B: tert-butyl 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(dimethyl-carbamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropyl-phenyl)acetate

    [1552] ##STR00310##

    [1553] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-((4-(2-(2-(tert-butoxy)-2-oxoethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-1H-pyrazole-5-carboxylic acid, formic acid salt (0.88 g, 0.93 mmol) in DMF (3 mL) was added DIPEA (0.65 mL, 3.7 mmol), dimethylamine hydrochloride (84 mg, 1.0 mmol) and HATU (0.39 g, 1.0 mmol). The reaction was stirred at RT for 4 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (50 mL) and then brine (3×50 mL). The organics were then passed through a phase separator and concentrated to dryness. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (0.60 g, 60%) as a pale yellow glass.

    [1554] LCMS m/z 859.0 (M+H).sup.+ (ES.sup.+).

    [1555] .sup.1H NMR (DMSO-d.sub.6) δ 8.22 (d, J=5.2 Hz, 1H), 7.23 (dd, J=10.5, 2.8 Hz, 1H), 6.97-6.92 (m, 4H), 6.90 (dd, J=5.2, 1.4 Hz, 1H), 6.85 (s, 1H), 6.80-6.73 (m, 5H), 6.56 (s, 1H), 4.66 (s, 2H), 4.15 (s, 4H), 3.67 (s, 6H), 3.38 (s, 2H), 3.05-2.95 (m, 1H), 2.92 (s, 3H), 2.81 (s, 3H), 1.66 (s, 6H), 1.30 (s, 9H), 1.21-1.12 (m, 6H). 19F NMR (DMSO-d.sub.6) δ −114.90 (t, J=9.5 Hz).

    Step C: 2-(2-(2-(2-(5-(dimethylcarbamoyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1556] ##STR00311##

    [1557] tert-Butyl 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(dimethylcarbamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (558 mg, 650 μmol) was dissolved in TFA (5 mL) and stirred at RT for 24 h. The reaction was concentrated in vacuo and the resulting residue purified by FC (0-10% MeOH/DCM) to afford the title compound (326 mg, 88%) as a clear colourless oil.

    [1558] LCMS m/z 562.4 (M+H).sup.+ (ES.sup.+); 560.3 (M−H).sup.− (ES.sup.−).

    [1559] .sup.1H NMR (DMSO-d.sub.6) δ 12.47 (br s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.52 (s, 2H), 7.22 (dd, J=10.6, 2.8 Hz, 1H), 6.95-6.87 (m, 2H), 6.69 (s, 1H), 6.66 (s, 1H), 4.65 (s, 2H), 3.47 (s, 2H), 3.07-2.99 (m, 1H), 2.89 (s, 3H), 2.81 (s, 3H), 1.68 (s, 6H), 1.18 (d, J=6.8 Hz, 6H).

    Intermediate C43: 2-(2-isopropyl-6-(2-((5-(5-sulfamoyl-1H-pyrazol-1-yl)pentyl)-oxy)pyridin-4-yl)phenyl)acetic acid

    [1560] ##STR00312##

    Step A: 2-(2-(2-((5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)pentyl)-oxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1561] ##STR00313##

    [1562] To a solution of 1-(5-hydroxypentyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-5-sulfonamide (Intermediate A28) (500 mg, 1.06 mmol) and 2-(2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B1) (288 mg, 1.06 mmol) in THF (6 mL) was added NaH (127 mg, 60 wt % in mineral oil, 3.17 mmol) at 0° C. Then the mixture was stirred at 40° C. for 12 h. The mixture was poured into MeOH (100 mL) slowly, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.54 g, 70.8%) as a yellow oil.

    [1563] LCMS: m/z 727.1 (M+H).sup.+ (ES.sup.+).

    [1564] .sup.1H NMR (CDCl.sub.3) δ 8.21 (d, 1H), 7.57 (d, 1H), 7.40-7.39 (m, 1H), 7.35 (t, 1H), 7.08 (d, 1H), 7.00 (d, 4H), 6.86-6.82 (m, 5H), 6.55 (d, 1H), 6.54 (d, 1H), 4.38-4.30 (m, 8H), 3.80 (s, 6H), 3.62 (s, 2H), 3.17-3.13 (m, 1H), 1.99-1.96 (m, 2H), 1.82-1.77 (m, 2H), 1.53-1.50 (m, 2H), 1.28 (d, 6H). One exchangeable proton not observed.

    Step B: 2-(2-isopropyl-6-(2-((5-(5-sulfamoyl-1H-pyrazol-1-yl)pentyl)oxy)pyridin-4-yl)-phenyl)acetic acid

    [1565] ##STR00314##

    [1566] To a solution of 2-(2-(2-((5-(5-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-pentyl)oxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (700 mg, 0.96 mmol) in DCM (5 mL) was added TFA (7.70 g, 67.5 mmol) at 20° C. Then the mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated in vacuum. The residue was triturated with MeOH (100 mL), filtered and the filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 3:1 to 1:1) to give the title compound (430 mg, 91.8%) as a yellow oil.

    [1567] LCMS: m/z 487.1 (M+H).sup.+ (ES.sup.+).

    [1568] .sup.1H NMR (CDCl.sub.3) δ 8.12 (d, 1H), 7.44 (d, 1H), 7.32-7.29 (m, 2H), 7.01-6.99 (m, 1H), 6.79 (d, 1H), 6.66 (s, 2H), 5.79 (br s, 2H), 4.34 (t, 2H), 4.22 (t, 2H), 3.52 (s, 2H), 3.05-3.02 (m, 1H), 1.98-1.93 (m, 2H), 1.75-1.72 (m, 2H), 1.43-1.41 (m, 2H), 1.22 (d, 6H). One exchangeable proton not observed.

    Intermediate C44: 2-(2-isopropyl-6-(6-(2-(3-sulfamoyl-1H-pyrazol-1-yl)ethoxy)-pyridazin-4-yl)phenyl)acetic acid

    [1569] ##STR00315##

    Step A: 1-(2-((5-(2-bromo-3-isopropylphenyl)pyridazin-3-yl)oxy)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [1570] ##STR00316##

    [1571] To a solution of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate A2) (640 mg, 1.48 mmol) in THF (10 mL) was added NaH (89 mg, 2.22 mmol, 60 wt % in mineral oil) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then to the above mixture was added 5-(2-bromo-3-isopropylphenyl)-3-chloropyridazine (Intermediate B9) (462 mg, 1.48 mmol) at 0° C. The resulting mixture was warmed to 20° C. and stirred at 20° C. for 15 h. The reaction mixture was quenched with H.sub.2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 2:1 to 1:1) to give the title compound (850 mg, 81.1%) as a yellow oil.

    [1572] LCMS: m/z 708.2 (M+H).sup.+ (ES.sup.+).

    [1573] .sup.1H NMR (DMSO-d.sub.6) δ 8.97 (d, 1H), 8.09 (d, 1H), 7.54-7.46 (m, 2H), 7.23-7.20 (m, 2H), 6.96 (m, 4H), 6.75 (m, 5H), 4.91 (t, 2H), 4.74 (t, 2H), 4.16 (s, 4H), 3.68 (s, 6H), 3.41-3.36 (m, 1H), 1.24 (d, 6H).

    Step B: (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide

    [1574] ##STR00317##

    [1575] A mixture of zinc (3.35 g, 51.3 mmol) in 1 M HCl aqueous solution (50 mL) was stirred at 20° C. for 0.5 h. The mixture was filtered and the filter cake was dried to give activated zinc. To a mixture of activated zinc (2.5 g) and chloro(trimethyl)silane (139 mg, 1.28 mmol) in THF (30 mL) was added tert-butyl 2-bromoacetate (2.5 g, 12.82 mmol) dropwise at 50° C. under N.sub.2. The mixture was stirred at 50° C. for 1 h. The reaction mixture was cooled to 20° C. to give the title compound (3.34 g, theoretical amount) in THF (30 mL) as a colourless liquid.

    Step C: tert-butyl 2-(2-(6-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethoxy)pyridazin-4-yl)-6-isopropylphenyl)acetate

    [1576] ##STR00318##

    [1577] To a solution of 1-(2-((5-(2-bromo-3-isopropylphenyl)pyridazin-3-yl)oxy)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (800 mg, 1.13 mmol) in THF (10 mL) at 25° C. was added the above THF solution of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.427 M, 13.3 mL), XPhos (54 mg, 113 μmol) and Pd.sub.2(dba).sub.3 (52 mg, 56.6 μmol) under N.sub.2. The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was quenched with H.sub.2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 ml×2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:2 to 1:3) to give the title compound (700 mg, 83.3%) as a yellow oil.

    [1578] LCMS: m/z 742.4 (M+H).sup.+ (ES.sup.+).

    [1579] .sup.1H NMR (DMSO-d.sub.6) δ 8.84 (d, 1H), 8.05 (d, 1H), 7.46 (d, 1H), 7.37 (t, 1H), 7.07-7.03 (m, 2H), 6.95 (d, 4H), 6.74 (d, 4H), 6.72 (d, 1H), 4.89 (t, 2H), 4.72 (t, 2H), 4.16 (s, 4H), 3.67 (s, 6H), 3.50 (s, 2H), 3.11-3.03 (m, 1H), 1.30 (s, 9H), 1.19 (d, 6H).

    Step D: 2-(2-isopropyl-6-(6-(2-(3-sulfamoyl-1H-pyrazol-1-yl)ethoxy)pyridazin-4-yl)-phenyl)acetic acid

    [1580] ##STR00319##

    [1581] To a solution of tert-butyl 2-(2-(6-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethoxy)pyridazin-4-yl)-6-isopropylphenyl)acetate (700 mg, 944 μmol) in DCM (7 mL) was added TFA (7 mL). The mixture was stirred at 20° C. for 12 h. The reaction mixture was treated with MeOH (20 mL) and filtered. The filtrate was concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 1:3 to 0:1 and then DCM:MeOH, 1:0 to 10:1) to give the title compound (300 mg, 71.4%) as a yellow oil.

    [1582] LCMS: m/z 446.0 (M+H).sup.+ (ES.sup.+).

    [1583] .sup.1H NMR (DMSO-d.sub.6) δ 12.54 (br s, 1H), 8.85 (d, 1H), 7.96 (d, 1H), 7.48-7.35 (m, 4H), 7.12-7.08 (m, 2H), 6.60 (d, 1H), 4.87 (t, 2H), 4.67 (t, 2H), 2.53 (s, 2H), 3.12-3.04 (m, 1H), 1.19 (d, 6H).

    Intermediate C46: 2-(4-cyano-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1584] ##STR00320##

    Step A: tert-butyl 2-(2-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-cyano-6-isopropylphenyl)acetate

    [1585] ##STR00321##

    [1586] To a solution of tert-butyl 2-(4-cyano-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)-acetate (Intermediate B10) (0.5 g, 1.28 mmol, HCl salt) in THF (10 mL) was added NaH (169 mg, 4.23 mmol, 60% purity in mineral oil) and 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9) (648 mg, 1.41 mmol). The mixture was stirred at 25° C. for 2 h under N.sub.2, then quenched with sat aq NH.sub.4Cl (30 mL) and extracted with EtOAc (50 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) to give the title compound (0.8 g, 69.9% yield, 97.8% purity on LCMS) as a white solid.

    [1587] LCMS: m/z 794.4 (M+H).sup.+ (ES.sup.+).

    [1588] .sup.1H NMR (CDCl.sub.3): δ 8.16 (d, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.62 (d, 1H), 7.22 (d, 1H), 7.07 (d, 4H), 6.84-6.73 (m, 5H), 6.59 (s, 1H), 4.58 (s, 2H), 4.22 (s, 4H), 3.78 (s, 6H), 3.50 (s, 2H), 3.09-3.06 (m, 1H), 1.60 (s, 6H), 1.42 (s, 9H), 1.26 (d, 6H).

    Step B: 2-(4-cyano-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)-propoxy)pyridin-4-yl)phenyl)acetic acid

    [1589] ##STR00322##

    [1590] To a solution of tert-butyl 2-(2-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-cyano-6-isopropylphenyl)acetate (1 g, 1.26 mmol) in DCM (1 mL) was added TFA (135 mmol, 10 mL). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) to give the title compound (0.55 g, 87.8% yield, 100% purity on LCMS) as a white solid.

    [1591] LCMS: m/z 498.3 (M+H).sup.+ (ES.sup.+).

    [1592] .sup.1H NMR (CD.sub.3OD): δ 8.35-8.24 (m, 2H), 7.86 (s, 1H), 7.78 (s, 1H), 7.54-7.51 (m, 1H), 7.38-7.29 (m, 2H), 4.68 (s, 2H), 3.71 (s, 2H), 3.25-3.20 (m, 1H), 1.77 (s, 6H), 1.30 (d, 6H). Three exchangeable protons not observed.

    Intermediate C47: 2-(4-(difluoromethoxy)-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1593] ##STR00323##

    Step A: tert-butyl 2-(2-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-(difluoromethoxy)-6-isopropylphenyl)acetate

    [1594] ##STR00324##

    [1595] To a mixture of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9) (930 mg, 2.02 mmol) in THF (20 mL) was added NaH (202 mg, 5.06 mmol, 60% purity in mineral oil) in one portion at 25° C. under N.sub.2. The mixture was stirred at 25° C. for 15 min, then tert-butyl 2-(4-(difluoro-methoxy)-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetate (Intermediate B11) (0.8 g, 2.02 mmol) in THF (20 mL) was added at 25° C. under N.sub.2. The reaction mixture was stirred at 25° C. for 12 h, then quenched with 0.5 M aq HCl (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by FC (PE:EtOAc, 5:1 to 4:1) to give the title compound (1.3 g, 77.0% yield) as a yellow oil.

    [1596] LCMS: m/z 835.3 (M+H).sup.+ (ES.sup.+).

    [1597] .sup.1H NMR (CDCl.sub.3): δ 8.13 (d, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.08-7.05 (m, 5H), 6.83 (d, 1H), 6.79-6.75 (m, 5H), 6.61 (s, 1H), 6.49 (t, 1H), 4.56 (s, 2H), 4.21 (s, 4H), 3.76 (s, 6H), 3.24 (s, 2H), 3.09-3.03 (m, 1H), 1.69 (s, 6H), 1.39 (s, 9H), 1.23 (d, 6H).

    Step B: 2-(4-(difluoromethoxy)-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1598] ##STR00325##

    [1599] A mixture of tert-butyl 2-(2-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-(difluoromethoxy)-6-isopropylphenyl)-acetate (1.3 g, 1.56 mmol) in DCM (7 mL) and TFA (94.5 mmol, 7 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuum and the residue was treated with MeCN (3 mL), then filtered to obtain the filtrate. The filtrate was concentrated in vacuum and the residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.5 g, 59.6% yield) as a white solid.

    [1600] LCMS: m/z 539.1 (M+H).sup.+ (ES.sup.+).

    Intermediate C48: 2-(4-cyano-3-fluoro-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1601] ##STR00326##

    Step A: tert-butyl 2-(6-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-cyano-3-fluoro-2-isopropylphenyl)acetate

    [1602] ##STR00327##

    [1603] To a solution of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9) (583 mg, 1.27 mmol) in THF (30 mL) was added NaH (145 mg, 3.63 mmol, 60% purity in mineral oil) in portions at 0° C. The solution was stirred at 0° C. for 0.5 h, then tert-butyl 2-(4-cyano-3-fluoro-6-(2-fluoro-pyridin-4-yl)-2-isopropylphenyl)acetate (Intermediate B12) (450 mg, 1.21 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The mixture was quenched with EtOH (10 mL) and the mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.61 g, 54.5% yield, TFA salt) as a yellow solid.

    [1604] LCMS: m/z 812.3 (M-TFA+H).sup.+ (ES.sup.+).

    [1605] .sup.1H NMR (CDCl.sub.3): δ 8.15 (d, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.20 (d, 1H), 7.07 (d, 4H), 6.83-6.76 (m, 5H), 6.55 (s, 1H), 4.57 (s, 2H), 4.25 (s, 4H), 3.78 (s, 6H), 3.47 (s, 2H), 3.09-3.05 (m, 1H), 1.69 (s, 6H), 1.42 (s, 9H), 1.36 (d, 6H). TFA proton not observed.

    Step B: 2-(4-cyano-3-fluoro-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1606] ##STR00328##

    [1607] A solution of tert-butyl 2-(6-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-cyano-3-fluoro-2-isopropylphenyl)-acetate (0.6 g, 648 μmol, TFA salt) in DCM (3 mL) and TFA (2.63 mL, 35.5 mmol) was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuum and the residue was purified by reverse phase flash chromatography (water (0.1% HCl)-MeCN) to give the title compound (350 mg, 97.9% yield, HCl salt) as a yellow solid.

    [1608] LCMS: m/z 516.2 (M−HCl+H).sup.+ (ES.sup.+).

    [1609] .sup.1H NMR (CD.sub.3OD): δ 8.29-8.26 (m, 2H), 7.79 (s, 1H), 7.59 (d, 1H), 7.19 (dd, 1H), 7.14 (s, 1H), 4.72 (s, 2H), 3.70 (s, 2H), 2.25-2.28 (m, 1H), 1.77 (s, 6H), 1.40 (dd, 6H). Three exchangeable protons and HCl proton not observed.

    Intermediate C40: 2-(4-(difluoromethoxy)-3-fluoro-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1610] ##STR00329##

    Step A: tert-butyl 2-(6-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-(difluoromethoxy)-3-fluoro-2-isopropylphenyl)-acetate

    [1611] ##STR00330##

    [1612] To a solution of tert-butyl 2-(4-(difluoromethoxy)-3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropylphenyl)acetate (Intermediate B13) (0.5 g, 1.21 mmol) in THF (10 mL) was added NaH (145 mg, 3.63 mmol, 60% purity in mineral oil) and 1-(1-hydroxy-2-methyl-propan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9) (556 mg, 1.21 mmol). The mixture was stirred at 25° C. for 1 h, then quenched with MeOH (10 mL) and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) to give the title compound (0.7 g, 67.5% yield, 99.5% purity on LCMS) as a yellow solid.

    [1613] LCMS: m/z 853.3 (M+H).sup.+ (ES.sup.+).

    [1614] .sup.1H NMR (CDCl.sub.3): δ 8.15 (d, 1H), 7.74 (s, 1H), 7.65 (s, 1H), 7.08 (d, 4H), 6.91-6.84 (m, 2H), 6.77 (d, 4H), 6.63 (s, 1H), 6.52 (t, 1H), 4.54 (s, 2H), 4.22 (s, 4H), 3.77 (s, 6H), 3.41 (s, 2H), 3.10-3.00 (m, 1H), 2.45 (s, 6H), 1.43 (s, 9H), 1.37 (d, 6H).

    Step B: 2-(4-(difluoromethoxy)-3-fluoro-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1615] ##STR00331##

    [1616] To a solution of tert-butyl 2-(6-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-(difluoromethoxy)-3-fluoro-2-isopropylphenyl)acetate (0.7 g, 821 μmol) in DCM (7 mL) was added TFA (94.5 mmol, 7 mL). The mixture was stirred at 25° C. for 2 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) to give the title compound (0.4 g, 72.2% yield, 99.3% purity on LCMS, TFA salt) as a white solid.

    [1617] LCMS: m/z 557.4 (M−TFA+H).sup.+ (ES.sup.+).

    [1618] .sup.1H NMR (CD.sub.3OD): δ 8.24 (s, 1H), 8.16 (d, 1H), 7.80 (s, 1H), 7.07-7.00 (m, 1H), 6.95-6.93 (m, 1H), 6.76-6.74 (m, 2H), 4.66 (s, 2H), 3.55 (s, 2H), 3.20-3.12 (m, 1H), 1.75 (s, 6H), 1.39 (d, 6H). Three exchangeable protons and TFA proton not observed.

    Intermediate C50: 2-(2-(2-(2-(4-(dimethylcarbamoyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1619] ##STR00332##

    Step A: 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(dimethylcarbamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic

    [1620] ##STR00333##

    [1621] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-hydroxy-2-methyl-propan-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide (Intermediate A29) (0.5 g, 942 μmol) in THF (30 mL) was added NaH (113 mg, 2.83 mmol, 60% purity in mineral oil) in portions at 0° C. under N.sub.2. Then 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B14) (382 mg, 942 μmol, TFA salt) was added and the resulting mixture was stirred at 40° C. for 6 h. The mixture was quenched with EtOH (30 mL) at 0° C., then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.05% HCl)-MeCN) to give the title compound (0.57 g, 72.2% yield, HCl salt) as a white solid.

    [1622] LCMS: m/z 802.1 (M−HCl+H).sup.+ (ES.sup.+).

    [1623] .sup.1H NMR (CDCl.sub.3): δ 8.13 (d, 1H), 7.85 (s, 1H), 7.00-6.97 (m, 5H), 6.86-6.81 (m, 2H), 6.81-6.67 (m, 5H), 4.44 (s, 2H), 4.23 (s, 4H), 3.73 (s, 6H), 3.23 (s, 2H), 3.13-3.10 (m, 1H), 3.01 (s, 3H), 2.98 (s, 3H), 1.69 (s, 6H), 1.15 (d, 6H). One exchangeable proton and HCl proton not observed.

    Step B: 2-(2-(2-(2-(4-(dimethylcarbamoyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1624] ##STR00334##

    [1625] A solution of 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(dimethyl-carbamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropyl-phenyl)acetic acid (0.55 g, 656 μmol, HCl salt) in TFA (3 mL) and DCM (3 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuum and the residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (345 mg, 77.8% yield, TFA salt) as a white solid.

    [1626] LCMS: m/z 562.2 (M-TFA+H).sup.+ (ES.sup.+).

    [1627] .sup.1H NMR (CDCl.sub.3): δ 8.22 (d, 1H), 7.74 (s, 1H), 7.08 (dd, 1H), 6.91 (d, 1H), 6.74 (dd, 1H), 6.08 (s, 1H), 5.67 (br s, 2H), 4.43 (s, 2H), 3.33 (s, 2H), 3.13-3.05 (m, 7H), 1.80 (s, 6H), 1.24 (d, 6H). One exchangeable proton and TFA proton not observed.

    Intermediate C51: 2-(2-isopropyl-4-(methoxymethyl)-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1628] ##STR00335##

    Step A: tert-butyl 2-(2-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropyl-4-(methoxymethyl)phenyl)acetate

    [1629] ##STR00336##

    [1630] To a solution of tert-butyl 2-(2-(2-fluoropyridin-4-yl)-6-isopropyl-4-(methoxymethyl)-phenyl)acetate (Intermediate B15) (0.5 g, 1.34 mmol) in THF (10 mL) was added NaH (161 mg, 4.02 mmol, 60% purity in mineral oil) and 1-(1-hydroxy-2-methyl-propan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9) (615 mg, 1.34 mmol). The mixture was stirred at 25° C. for 12 h under N.sub.2, then quenched with sat aq NH.sub.4Cl (10 mL) and extracted with DCM (20 mL×3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.8 g, 72.8% yield, 99% purity on LCMS) as a yellow solid.

    [1631] LCMS: m/z 813.6 (M+H).sup.+ (ES.sup.+).

    [1632] .sup.1H NMR (CD.sub.3OD): δ 8.14 (d, 1H), 8.05 (s, 1H), 7.68 (s, 1H), 7.38 (d, 1H), 7.00 (dd, 4H), 6.92 (s, 1H), 6.90 (d, 1H), 6.72 (dd, 4H), 6.65 (s, 1H), 4.57 (s, 2H), 4.42 (s, 2H), 4.17 (s, 4H), 3.74 (s, 6H), 3.49 (s, 2H), 3.37 (s, 3H), 3.14-3.06 (m, 1H), 1.73 (s, 6H), 1.39 (s, 9H), 1.26 (d, 6H).

    Step B: 2-(2-isopropyl-4-(methoxymethyl)-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1633] ##STR00337##

    [1634] To a solution of tert-butyl 2-(2-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropyl-4-(methoxymethyl)phenyl)-acetate (0.8 g, 984 μmol) in DCM (10 mL) was added TFA (10 mL, 135 mmol). The mixture was stirred at 25° C. for 12 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.4 g, 77.9% yield, 99% purity on LCMS) as a white solid.

    [1635] LCMS: m/z 517.3 (M+H).sup.+ (ES.sup.+).

    [1636] .sup.1H NMR (CD.sub.3OD): δ 8.23 (s, 1H), 8.15 (d, 1H), 7.79 (s, 1H), 7.40 (d, 1H), 7.02 (s, 1H), 7.01 (d, 1H), 6.85 (s, 1H), 4.62 (s, 2H), 4.47 (s, 2H), 3.58 (s, 2H), 3.40 (s, 3H), 3.15-3.06 (m, 1H), 1.74 (s, 6H), 1.26 (d, 6H). Three exchangeable protons not observed.

    Intermediate C52: 2-(3-fluoro-2-isopropyl-4-(methoxymethyl)-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1637] ##STR00338##

    Step A: tert-butyl 2-(6-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-3-fluoro-2-isopropyl-4-(methoxymethyl)phenyl)-acetate

    [1638] ##STR00339##

    [1639] To a mixture of 1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A9) (564 mg, 1.23 mmol) in THF (2 mL) was added NaH (123 mg, 3.07 mmol, 60% purity in mineral oil) at 25° C. under N.sub.2. The reaction mixture was stirred at 25° C. for 15 min, then tert-butyl 2-(3-fluoro-6-(2-fluoropyridin-4-yl)-2-isopropyl-4-(methoxymethyl)phenyl)acetate (Intermediate B16) (0.48 g, 1.23 mmol) was added at 25° C. under N.sub.2. The resulting reaction mixture was stirred at 25° C. for 12 h, then quenched with 0.5 M aq HCl (10 mL) and extracted with EtOAc (10 mL×3). 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 reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.8 g, 78.5% yield) as a white solid.

    [1640] LCMS: m/z 832.6 (M+H).sup.+ (ES.sup.+).

    [1641] .sup.1H NMR (CDCl.sub.3): δ 8.17 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.20-7.10 (m, 5H), 7.00-6.97 (m, 1H), 6.79-6.75 (m, 5H), 4.60 (d, 2H), 4.50 (s, 2H), 4.25 (s, 4H), 3.75 (s, 6H), 3.44 (s, 2H), 3.42 (s, 3H), 3.08-3.03 (m, 1H), 1.70 (s, 6H), 1.45 (s, 9H), 1.35 (d, 6H).

    Step B: 2-(3-fluoro-2-isopropyl-4-(methoxymethyl)-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid

    [1642] ##STR00340##

    [1643] To a solution of tert-butyl 2-(6-(2-(2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-3-fluoro-2-isopropyl-4-(methoxymethyl)-phenyl)acetate (0.7 g, 842 μmol) in DCM (6 mL) was added TFA (6 mL, 81.0 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuum and the residue was treated with MeCN (5 mL) and filtered. The filtrate was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.32 g, 71.1% yield) as a white solid.

    [1644] LCMS: m/z 535.4 (M+H).sup.+ (ES.sup.+).

    [1645] .sup.1H NMR (CDCl.sub.3): δ 8.26 (d, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.15-7.10 (m, 2H), 6.88 (s, 1H), 4.55 (s, 2H), 4.51 (s, 2H), 3.53 (s, 2H), 3.46 (s, 3H), 3.08-3.03 (m, 1H), 1.70 (s, 6H), 1.40 (d, 6H). Three exchangeable protons not observed.

    Intermediate C53: 2-(4-fluoro-2-(2-(2-(4-fluoro-5-((4-methylpiperazin-1-yl)-methyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropyl-phenyl)acetic acid

    [1646] ##STR00341##

    Step A: 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-((4-methyl-piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1647] ##STR00342##

    [1648] To a solution of 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxy-benzyl)-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazole-3-sulfonamide (Intermediate A30) (320 mg, 455 μmol, TFA salt) in THF (10 mL) was added NaH (46 mg, 1.14 mmol, 60% purity in mineral oil) at 0° C. The mixture was stirred at 0° C. for 0.5 h, then 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B14) (96 mg, 327 μmol, TFA salt) was added and the resulting mixture was stirred at 20° C. for 0.5 h. The mixture was heated to 50° C. for 12 h, then cooled to 20° C. and additional NaH (64 mg, 1.59 mmol, 60% purity in mineral oil) and 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B14) (184 mg, 455 μmol, TFA salt) were added. The reaction mixture was stirred at 50° C. for 24 h, then quenched with MeOH (5 mL) and adjusted to pH=7 with 1 M HCl. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (200 mg, 45.1% yield, TFA salt) as a yellow solid.

    [1649] LCMS: m/z 861.4 (M−TFA+H).sup.+ (ES.sup.+).

    [1650] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): δ 8.11 (d, 1H), 7.15 (dd, 1H), 6.88 (d, 4H), 6.83 (dd, 1H), 6.69 (d, 4H), 6.59 (dd, 1H), 6.50 (s, 1H), 4.65 (s, 2H), 4.08 (s, 4H), 3.65-3.60 (m, 8H), 3.36-3.31 (m, 4H), 2.96-2.84 (m, 5H), 2.74 (s, 3H), 2.38-2.30 (m, 2H), 1.69 (s, 6H), 1.11 (d, 6H). One exchangeable proton and TFA proton not observed.

    Step B: 2-(4-fluoro-2-(2-(2-(4-fluoro-5-((4-methylpiperazin-1-yl)methyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1651] ##STR00343##

    [1652] To a solution 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (200 mg, 205 μmol, TFA salt) in DCM (3 mL) was added TFA (4.62 g, 40.5 mmol). The mixture was stirred at 20° C. for 12 h, then treated with MeOH (3 mL), filtered and the filtrate was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (134 mg, 88.9% yield, TFA salt) as a yellow oil.

    [1653] LCMS: m/z 621.2 (M−TFA+H).sup.+ (ES.sup.+).

    [1654] .sup.1H NMR (DMSO-d.sub.6): δ 12.5 (br s, 1H), 9.44 (br s, 1H), 8.20 (d, 1H), 7.71 (s, 2H), 7.24 (dd, 1H), 6.95-6.90 (m, 2H), 6.69 (s, 1H), 4.70 (s, 2H), 3.46 (s, 2H), 3.39 (d, 2H), 3.05-2.99 (m, 1H), 2.94-2.88 (m, 2H), 2.87-2.81 (m, 2H), 2.75 (s, 3H), 2.38-2.32 (m, 2H), 1.73 (s, 6H), 1.18 (d, 6H). One exchangeable proton not observed.

    Intermediate C54: 1-(1-((4-(2-(carboxymethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-3-sulfamoyl-1H-pyrazole-5-carboxylic acid

    [1655] ##STR00344##

    Step A: 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-((4-(2-(carboxymethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-1H-pyrazole-5-carboxylic acid

    [1656] ##STR00345##

    [1657] To a solution of 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxy-benzyl)-5-(4-methylpiperazine-1-carbonyl)-1H-pyrazole-3-sulfonamide (Intermediate A31) (250 mg, 348 μmol, TFA salt) in THF (15 mL) was added NaH (35 mg, 871 μmol, 60% purity in mineral oil) at 0° C. in portions under N.sub.2. The mixture was stirred at 25° C. for 30 min, then 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropyl-phenyl)acetic acid (Intermediate B14) (112 mg, 275 μmol, TFA salt) was added and the resulting mixture was stirred at 25° C. for 1 h. The mixture was quenched with 1 M aq HCl (10 mL) at 0° C. and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.16 g, 57.9% yield) as a yellow solid.

    [1658] LCMS: m/z 793.5 (M+H).sup.+ (ES.sup.+).

    [1659] .sup.1H NMR (DMSO-d.sub.6): δ 8.17 (d, 1H), 7.21 (dd, 1H), 7.01 (d, 4H), 6.88 (dd, 1H), 6.75 (d, 4H), 6.71 (dd, 1H), 6.58 (s, 1H), 4.80 (s, 2H), 4.24 (s, 4H), 3.69 (s, 6H), 3.40 (s, 2H), 3.01-2.98 (m, 1H), 1.73 (s, 6H), 1.17 (d, 6H). Two exchangeable protons not observed.

    Step B: 1-(1-((4-(2-(carboxymethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-3-sulfamoyl-1H-pyrazole-5-carboxylic acid

    [1660] ##STR00346##

    [1661] A solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(1-((4-(2-(carboxymethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)oxy)-2-methylpropan-2-yl)-4-fluoro-1H-pyrazole-5-carboxylic acid (160 mg, 202 μmol) in DCM (3 mL) and TFA (3 mL) was stirred at 25° C. for 1 h. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.13 g, 96.6% yield, TFA salt) as a yellow solid.

    [1662] LCMS: m/z 553.3 (M-TFA+H).sup.+ (ES.sup.+).

    [1663] .sup.1H NMR (CD.sub.3OD): δ 8.11 (d, 1H), 7.13 (dd, 1H), 6.94 (dd, 1H), 6.81 (dd, 1H), 6.73 (s, 1H), 4.91 (s, 2H), 3.54 (s, 2H), 3.14-3.11 (m, 1H), 1.78 (s, 6H), 1.24 (d, 6H). Four exchangeable protons and TFA proton not observed.

    Intermediate C55: 2-(4-fluoro-2-(2-(2-(4-fluoro-5-(morpholinomethyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1664] ##STR00347##

    Step A: 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(morpholino-methyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)-acetic acid

    [1665] ##STR00348##

    [1666] To a solution of 4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-N,N-bis(4-methoxy-benzyl)-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide (Intermediate A32) (0.3 g, 520 μmol) in THF (3 mL) was added NaH (73 mg, 1.82 mmol, 60% purity in mineral oil) at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 0.5 h, then a solution of 2-(4-fluoro-2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B14) (232 mg, 572 μmol, TFA salt) in THF (1 mL) was added to the mixture at 0° C. The reaction mixture was stirred at 20° C. for 12 h under N.sub.2, then quenched with 0.5 M aq HCl and 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 reverse phase flash chromatography (water (0.1% NH.sub.3.H.sub.2O)-MeCN) to give the title compound (0.15 g, 34.0% yield) as a yellow solid.

    [1667] LCMS: m/z 848.2 (M+H).sup.+ (ES.sup.+).

    [1668] .sup.1H NMR (CDCl.sub.3): δ 8.23 (d, 1H), 7.12-7.09 (m, 5H), 6.96 (d, 1H), 6.88 (s, 1H), 6.80-6.76 (m, 5H), 4.71 (s, 2H), 4.37 (s, 4H), 4.31 (s, 2H), 3.99-3.96 (m, 4H), 3.77 (s, 6H), 3.52 (s, 2H), 3.39-3.20 (m, 3H), 3.11-3.05 (m, 2H), 1.84 (s, 6H), 1.26 (d, 6H). One exchangeable proton not observed.

    Step B: 2-(4-fluoro-2-(2-(2-(4-fluoro-5-(morpholinomethyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1669] ##STR00349##

    [1670] To a solution of 2-(2-(2-(2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-fluoro-5-(morpholinomethyl)-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (150 mg, 177 μmol) in DCM (3 mL) was added TFA (6.00 mL, 81.0 mmol). The mixture was stirred at 20° C. for 12 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.1 g, 78.3% yield) as a yellow solid.

    [1671] LCMS: m/z 608.3 (M+H).sup.+ (ES.sup.+).

    [1672] .sup.1H NMR (DMSO-d.sub.6): δ 8.20 (d, 1H), 7.71 (s, 2H), 7.23 (dd, 1H), 6.93-6.88 (m, 2H), 6.67 (s, 1H), 4.73 (s, 2H), 3.55 (s, 3H), 3.51-3.41 (m, 7H), 3.04-2.99 (m, 1H), 2.35-2.33 (m, 2H), 1.73 (s, 6H), 1.18 (d, 6H). One exchangeable proton not observed.

    Intermediate C56: 2-(4-fluoro-2-isopropyl-6-(2-((2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propyl)amino)pyridin-4-yl)phenyl)acetic acid

    [1673] ##STR00350##

    Step A: 2-(2-(2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropyl)amino)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

    [1674] ##STR00351##

    [1675] To a solution of 1-(1-amino-2-methylpropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (Intermediate A33) (700 mg, 1.41 mmol, HCl salt) in 2-methylbutan-2-ol (20 mL) was added methyl 2-(4-fluoro-2-isopropyl-6-(2-(((trifluoro-methyl)sulfonyl)oxy)pyridin-4-yl)phenyl)acetate (Intermediate B17) (616 mg, 1.41 mmol), LiHMDS (1 M in THF, 2.83 mL) and [2-(2-aminophenyl)phenyl]-methyl-sulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (112 mg, 141 μmol) at 25° C. under N.sub.2. The mixture was stirred at 90° C. for 12 h, then quenched with 1 M aq HCl (3 mL) and concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (0.12 g, 11.6% yield) as a yellow solid.

    [1676] LCMS: m/z 730.3 (M+H).sup.+ (ES.sup.+).

    [1677] .sup.1H NMR (CD.sub.3OD): δ 7.90 (s, 1H), 7.82 (d, 1H), 7.64 (s, 1H), 7.23 (dd, 1H), 7.11 (d, 4H), 6.89-6.78 (m, 7H), 4.21 (s, 4H), 3.85 (s, 2H), 3.75 (s, 6H), 3.57 (s, 2H), 3.17-3.14 (m, 1H), 1.66 (s, 6H), 1.26 (d, 6H). Two exchangeable protons not observed.

    Step B: 2-(4-fluoro-2-isopropyl-6-(2-((2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)-propyl)amino)pyridin-4-yl)phenyl)acetic acid

    [1678] ##STR00352##

    [1679] A solution of 2-(2-(2-((2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)-2-methylpropyl)amino)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (100 mg, 137 μmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at 25° C. for 1 h. The solution was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (82 mg, 99.2% yield, TFA salt) as a yellow solid.

    [1680] LCMS: m/z 490.3 (M-TFA+H).sup.+ (ES.sup.+).

    [1681] .sup.1H NMR (CDCl.sub.3): δ 7.94-7.90 (m, 2H), 7.72 (s, 1H), 6.96 (dd, 1H), 6.66 (dd, 1H), 6.51 (dd, 1H), 6.05 (s, 1H), 4.64-4.61 (m, 1H), 3.72 (d, 2H), 3.40 (s, 2H), 3.22-3.01 (m, 1H), 1.64 (s, 6H), 1.25 (d, 6H). Three exchangeable protons not observed.

    Intermediate D1: 2-(2-isopropyl-6-(2-(2-(methyl(1-sulfamoylpiperidin-3-yl)amino)-ethoxy)pyridin-4-yl)phenyl)acetic acid

    [1682] ##STR00353##

    Step A: 2-(2-(2-(2,2-diethoxyethoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1683] ##STR00354##

    [1684] To a solution of 2,2-diethoxyethanol (1.47 g, 11.0 mmol) in DMF (40 mL) was added NaH (439 mg, 11.0 mmol, 60% purity in mineral oil) in portions at 0° C. under N.sub.2. Then to the above solution was added 2-(2-(2-fluoropyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate B1) (1.00 g, 3.66 mmol) in portions and the resulting mixture was stirred at 40° C. for 3 h. The mixture was quenched with H.sub.2O (60 mL) and then extracted with EtOAc (2×40 mL). The combined organic phases were washed with brine (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give the title compound (1.3 g, crude) as a colourless oil.

    [1685] LCMS: m/z 388.1 (M+H).sup.+ (ES.sup.+).

    [1686] .sup.1H NMR (CDCl.sub.3): δ 8.14 (d, 1H), 7.39-7.32 (m, 2H), 7.05 (d, 1H), 6.86 (d, 1H), 6.75 (s, 1H), 4.89 (t, 1H), 4.40 (d, 2H), 3.78-3.72 (m, 4H), 3.67 (s, 2H), 3.11-3.04 (m, 1H), 1.26-1.22 (m, 12H). One exchangeable proton not observed.

    Step B: 2-(2-isopropyl-6-(2-(2-oxoethoxy)pyridin-4-yl)phenyl)acetic acid

    [1687] ##STR00355##

    [1688] To a solution of 2-(2-(2-(2,2-diethoxyethoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (1.10 g, 2.84 mmol) in dioxane (21 mL) and H.sub.2O (30 mL) was added conc H.sub.2SO.sub.4 (1.11 g, 11.4 mmol) and the mixture was stirred at 80° C. for 4 h. The reaction mixture was adjusted to pH 7 with sat aq Na.sub.2CO.sub.3 solution. The reaction mixture was concentrated in vacuum to remove most of the dioxane. The aqueous layer was purified directly by reverse phase flash chromatography (0.1% TFA in H.sub.2O-MeCN) to give the title compound (1.12 g, 84.6% yield over two steps, TFA salt) as a light yellow solid.

    [1689] LCMS: m/z 314.1 (M+H).sup.+ (ES.sup.+).

    [1690] .sup.1H NMR (CD.sub.3OD): δ 8.58 (d, 1H), 7.60-7.54 (m, 2H), 7.46-7.33 (m, 1H), 7.17 (d, 1H), 6.95-6.71 (m, 1H), 4.93-4.90 (m, 2H), 3.67 (s, 2H), 3.31-3.11 (m, 1H), 1.28-1.25 (m, 6H). Two protons not observed. TFA proton not observed.

    Step C: 2-(2-(2-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)(methyl)amino)ethoxy)-pyridin-4-yl)-6-isopropylphenyl)acetic acid

    [1691] ##STR00356##

    [1692] To a solution of 2-(2-isopropyl-6-(2-(2-oxoethoxy)pyridin-4-yl)phenyl)acetic acid (330 mg, 772 μmol, TFA salt) in MeOH (2 mL) and AcOH (0.01 mL) was added tert-butyl 3-(methylamino)piperidine-1-carboxylate (248 mg, 1.16 mmol) and the mixture was stirred at 25° C. for 30 min. To above mixture was added NaBH.sub.3CN (146 mg, 2.32 mmol) and the resulting mixture was stirred at 25° C. for 1 h. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA in H.sub.2O-MeCN) to give the title compound (0.3 g, 62.1%, di-TFA salt) as a white solid.

    [1693] LCMS: m/z 512.3 (M+H).sup.+ (ES.sup.+).

    [1694] .sup.1H NMR (CDCl.sub.3): δ 8.24 (d, 1H), 7.43-7.32 (m, 2H), 7.05-6.95 (m, 3H), 4.80-4.75 (m, 2H), 4.51-4.45 (m, 1H), 4.02-3.95 (m, 1H), 3.68-3.57 (m, 4H), 3.34-3.30 (m, 1H), 3.14-3.10 (m, 1H), 3.02-2.76 (m, 5H), 2.31-2.28 (m, 1H), 1.88-1.85 (m, 1H), 1.73-1.61 (m, 1H), 1.59-1.54 (m, 1H), 1.43 (s, 9H), 1.26 (d, 6H). One exchangeable proton not observed. TFA protons not observed.

    Step D: methyl 2-(2-isopropyl-6-(2-(2-(methyl(piperidin-3-yl)amino)ethoxy)pyridin-4-yl)phenyl)acetate

    [1695] ##STR00357##

    [1696] To a solution of 2-(2-(2-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)(methyl)amino)-ethoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (0.3 g, 479 μmol, di-TFA salt) in MeOH (20 mL) was added conc H.sub.2SO.sub.4 (47 mg, 479 μmol). Then the mixture was stirred at 60° C. for 12 h. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA in H.sub.2O-MeCN) to give the title compound (0.3 g, 81.5%, tri-TFA salt) as a yellow oil.

    [1697] LCMS: m/z 426.3 (M+H).sup.+ (ES.sup.+).

    [1698] .sup.1H NMR (CDCl.sub.3): δ 8.14 (d, 1H), 7.39-7.33 (m, 2H), 7.02 (d, 1H), 6.96 (d, 1H), 6.79 (s, 1H), 4.74 (s, 2H), 4.11-4.02 (m, 1H), 3.66-3.60 (m, 8H), 3.51-3.25 (m, 2H), 3.06-3.01 (m, 1H), 3.01-2.91 (m, 4H), 2.30-2.28 (m, 1H), 2.15-1.77 (m, 3H), 1.24 (d, 6H). One exchangeable proton not observed. TFA protons not observed.

    Step E: methyl 2-(2-isopropyl-6-(2-(2-(methyl(1-sulfamoylpiperidin-3-yl)amino)-ethoxy)pyridin-4-yl)phenyl)acetate

    [1699] ##STR00358##

    [1700] To a solution of methyl 2-(2-isopropyl-6-(2-(2-(methyl(piperidin-3-yl)amino)ethoxy)-pyridin-4-yl)phenyl)acetate (0.25 g. 326 μmol, tri-TFA salt) in dioxane (5 mL) was added DIPEA (168 mg, 1.30 mmol) and sulfuric diamide (188 mg, 1.95 mmol). Then the solution was stirred at 110° C. for 2 h under microwave irradiation. The solution was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA in H.sub.2O-MeCN) to give the title compound (90 mg, 37.7%, di-TFA salt) as a white solid.

    [1701] LCMS: m/z 505.4 (M+H).sup.+ (ES.sup.+).

    [1702] .sup.1H NMR (CD.sub.3OD): δ 8.21 (d, 1H), 7.43-7.35 (m, 2H), 7.04 (d, 1H), 6.98 (dd, 1H), 6.84 (s, 1H), 4.79-4.74 (m, 2H), 3.69-3.54 (m, 9H), 3.30-3.27 (m, 2H), 3.10-3.05 (m, 5H), 2.07-1.78 (m, 4H), 1.24 (d, 6H). Two exchangeable protons not observed. TFA protons not observed.

    Step F: 2-(2-isopropyl-6-(2-(2-(methyl(1-sulfamoylpiperidin-3-yl)amino)ethoxy)-pyridin-4-yl)phenyl)acetic acid

    [1703] ##STR00359##

    [1704] To a solution of methyl 2-(2-isopropyl-6-(2-(2-(methyl(1-sulfamoylpiperidin-3-yl)-amino)ethoxy)pyridin-4-yl)phenyl)acetate (90 mg, 123 μmol, di-TFA salt) in MeOH (3 mL) and H.sub.2O (2 mL) was added LiOH.H.sub.2O (21 mg, 491 μmol) and the solution was stirred at 40° C. for 3 h. The solution was adjusted to pH=7 with 1 M HCl and the mixture was concentrated in vacuum to remove most of the methanol. The aqueous layer was purified by reverse phase flash chromatography (0.1% TFA in H.sub.2O-MeCN) to give the title compound (85 mg, 96.3%, di-TFA salt) as a colourless oil.

    [1705] LCMS: m/z 491.2 (M+H).sup.+ (ES.sup.+).

    [1706] .sup.1H NMR (CDCl.sub.3): δ 8.19 (d, 1H), 7.53-7.27 (m, 2H), 7.04 (d, 1H), 6.95 (dd, 1H), 6.83 (s, 1H), 4.73 (s, 2H), 3.69-3.58 (m, 7H), 3.27-3.22 (m, 1H), 3.19-2.81 (m, 5H), 1.90-1.65 (m, 4H), 1.26-1.22 (m, 6H). Three exchangeable protons not observed. TFA protons not observed.

    Preparation of Examples

    Example 1: 16,16-dimethyl-6-(propan-2-yl)-18-oxa-11λ.SUP.6.-thia-10,15,20,24-tetraaza-tetracyclo[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

    [1707] ##STR00360##

    [1708] DMAP (70.8 mg, 0.580 mmol) and EDC (111 mg, 0.580 mmol) were added to a solution of 2-(2-isopropyl-6-(2-(2-methyl-2-(3-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C2) (137 mg, 0.290 mmol) in DMF (2 mL) and the reaction was stirred at RT for 18 h. The crude product was purified by acidic prep-HPLC (50-80% MeCN in water) to afford the title compound (10.78 mg, 8%) as a flocculent white solid.

    [1709] LCMS m/z 455.2 (M+H).sup.+ (ES.sup.+); 453.2 (M−H).sup.− (ES.sup.−).

    [1710] .sup.1H NMR (DMSO-d.sub.6) δ 11.93 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.03 (s, 1H), 7.38-7.32 (m, 1H), 7.29 (t, J=7.6 Hz, 1H), 6.94-6.90 (m, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.71 (s, 1H), 5.73 (s, 1H), 4.50 (s, 2H), 3.41-3.35 (m, 2H), 2.97-2.92 (m, 1H), 1.66 (s, 6H), 1.17 (d, J=6.7 Hz, 6H).

    [1711] The following examples ‘Ex’ 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 [00361]embedded image C3 .sup.1H NMR (DMSO-d.sub.6) (major conformer) δ 11.86 (br s, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.05- 8.00 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 5.1 Hz, 1H), 6.70 (s, 1H), 5.63 (s, 1H), 4.72 (d, J = 10.6 Hz, 1H), 4.27 (d, J = 10.5 Hz, 1H), 3.57-3.53 (m, 1H), 2.97-2.93 (m, 1H), 2.87 (sept, J = 6.8 Hz, 1H), 1,86 (s, 3H), 1.82 (s, 3H), 1.52 (s, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H). m/z 469.2 (M + H).sup.+ (ES.sup.+) 467.1 (M − H).sup.− (ES.sup.−) 3 [00362]embedded image C1 .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.41 (dd, J = 7.9 Hz, 1.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.09 (br s, 1H), 7.02 (dd, J = 7.5, 1.4 Hz, 1H), 6.85 (dd, J = 5.2, 1.5 Hz, 1H), 6.30- 6.27 (m, 1H), 4.45-4.22 (m, 6H), 3.59-347 (m, 2H), 2.90 (sept, J = 6.4 Hz, 1H), 7.76-2.63 (m, 6H), 1.90-1.82 (m, 2H), 1.73-1.65 (m, 2H), 1.34- 1.24 (m, 2H), 1.20 (d, J = 6.8 Hz, 6H). m/z 526.3 (M + H).sup.+ (ES.sup.+) 524.2 (M − H).sup.− (ES.sup.−) 4 [00363]embedded image C4 .sup.1H NMR (DMSO-d.sub.6) δ 12.03 (br s, 1H), 8.23 (d, J = 5.2 Hz, 1H), 8.03 (br s, 1H), 7.39-7.33 (m, 1H), 7.33-7.27 (m, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 5.1 Hz, 1H), 6.74 (s, 1H), 6.01 (br s, 1H), 4.75 (br s, 2H),4.55 (br s, 2H), 3.45-3.37 (m, 2H), 2.95-2.87 (m, 1H), 1.18 (d, J = 6.7 Hz, 6H). m/z 427.1 (M + H).sup.+ (ES.sup.+) 425.2 (M − H).sup.− (ES.sup.−) 5 [00364]embedded image C5 .sup.1H NMR (DMSO-d.sub.6) δ 12.14 (br s, 1H), 8.21 (d, J = 5.2 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 6.98-6.90 (m, 1H), 6.88 (d, J = 5.1 Hz, 1H), 5.88 (br s, 1H), 4.49 (s, 2H), 3.37 (s, 2H), 2.96 (sept, J = 6.8 Hz, 1H), 1.61 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). m/z 473.4 (M + H).sup.+ (ES.sup.+) 471.3 (M − H).sup.− (ES.sup.−) 7 [00365]embedded image C7 .sup.1H NMR (DMSO-d.sub.6) δ 12.40-11.46 (br s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.63 (dd, J = 7.6, 1.8 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.34 (d,J = 7.8 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 6.93 (dd, J = 7.3,1.4 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.09 (s, 1H), 4.69 (br s, 2H), 3.49 (br s, 2H), 3.08 (t, J = 5.8 Hz, 2H), 2.96 (sept, J = 6.7 Hz, 1H), 1.18 (d, J = 6.8 Hz, 6H). m/z 437.5 (M + H).sup.+ (ES.sup.+) 435.3 (M − H).sup.− (ES.sup.−) 8 [00366]embedded image C8 .sup.1H NMR (DMSO-d.sub.6) δ 12.29 (s, 1H), 8.23 (d, J = 5.2 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.1Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 6.13 (s, 1H), 4-74 (br s, 1H), 4.46 (br s, 2H), 3.50-3-37 (m, 4H), 1.18 (d, J = 6.7 Hz, 6H). m/z 445.4 (M + H).sup.+ (ES.sup.+) 443.3 (M − H).sup.− (ES.sup.−) 9 [00367]embedded image C9 .sup.1H NMR (DMSO-d.sub.6) δ 11.93 (br s, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.66-7.63 (m, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.19-7.14 (m, 2H), 6.89 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H), 6.03 (br s, 1H), 4.71 (br s, 2H), 3.51 (br s, 2H), 3.11 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H). m/z 435.5 (M + H).sup.+ (ES.sup.+) 433.3 (M − H).sup.− (ES.sup.−) 10 [00368]embedded image C10 .sup.1H NMR (DMSO-d.sub.6) δ 11.87 (s, 1H), 7.89 (s, 1H), 7.38-7.23 (m, 2H), 6.95 (dd, J = 7.3, 1.5 Hz, 1H), 6.83-6.68 (m, 1H), 6.30 (s, 1H), 6.10 (s, 1H), 5.03-4.58 (m, 3H), 3.61 (s, 2H), 3.13 (t, J = 5.6 Hz, 2H), 3.02 (dt, J = 12.5, 6.7 Hz, 1H), 1.43 (d, J = 6.5 Hz, 6H), 1.17 (d, J = 6.7 Hz, 6H). m/z 469.5 (M + H).sup.+ (ES.sup.+) 11 [00369]embedded image C11 .sup.1H NMR (DMSO-d.sub.6) δ 8.23-8.16 (m, 1H), 7.79 (s, 1H), 7.73-7-68 (m, 1H), 7.36 (dd, J = 7.9, 1.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.96 (dd, J = 7.5, 1.4 Hz, 1H), 6.86 (d, J = 4-3 Hz, 1H), 6.11 (s, 1H), 5.27 (s, 1H), 4.69 (s, 2H), 3.52 (s, 2H), 3.08 (t, J = 5.5 Hz, 2H), 3.00-2.90 (m, 1H), 1.45 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 495.1 (M + H).sup.+ (ES.sup.+) 12 [00370]embedded image C12 .sup.1H NMR (DMSO-d.sub.6) δ 12.07 (s, 1H), 8.35-8.18 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 5.1 Hz, 1H), 5.73 (s, 1H), 4.77-4.65 (m, 1H), 4.27 (d, J = 10.6 Hz, 1H), 3.67-3.52 (m, 1H), 3.02- 2.94 (m, 1H), 2.88 (p, J = 6.7 Hz, 1H), 1.88 (s, 3H), 1.77 (s, 3H), 1.49 (s, 3H), 1.15 (dd, J = 18.9, 6.8 Hz, 6H). m/z 487.4 (M + H).sup.+ (ES.sup.+) 13 [00371]embedded image C13 .sup.1H NMR (DMSO-d.sub.6) δ 12.22 (s, 1H), 8.26 (s, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 5.96 (s, 1H), 5.04 (s, 1H), 4.60-4.39 (m, 3H), 3.70-3.56 (m, 1H), 3.03- 2.92 (m, 1H), 2.83 (p, J = 6.9 Hz, 1H), 1.91 (s, 3H), 1.15 (dd, J = 6.9, 1.7 Hz, 6H). m/z 459.3 (M + H).sup.+ (ES.sup.+) 14 [00372]embedded image C14 .sup.1H NMR (DMSO-d.sub.6) δ 12.30 (s, 1H), 8.25 (d, J = 5.2 Hz, 2H), 7.21 (dd, J = 10.6, 2.8 Hz, 1H), 6.94 (d, J = 5.2 Hz, 1H), 6.88 (dd, J = 8.6, 2.7 Hz, 1H), 6.09 (s, 1H), 4.75 (s, 2H), 4.48 (s, 2H), 3.39 (s, 2H), 2.97-2.88 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H). m/z 463.7 (M + H).sup.+ (ES.sup.+) 15 [00373]embedded image C15 .sup.1H NMR (DMSO-d.sub.6) δ 12.15 (s, 1H), 8.28 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.20 (dd, J = 10.7, 2.8 Hz, 1H), 6.95-6.90 (m, 1H), 6.84 (dd, J = 8.6, 2.7 Hz, 1H), 5.83 (s, 1H), 4.52 (s, 2H), 3.40 (s, 1H), 3.18 (d, J = 3.5 Hz, 1H), 2.98 (p, J = 6.7 Hz, 1H), 1.63 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). m/z 491.3 (M + H).sup.+ (ES.sup.+) 19 [00374]embedded image C19 .sup.1H NMR (DMSO-d.sub.6) δ 11.92 (s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.19 (d, J = 10.5 Hz, 1H), 6.95-6.74 (m, 2H), 5.99 (s, 1H), 4.54 (s, 2H), 3.70 (s, 3H), 2.96-2.85 (m, 1H), 1.60 (s, 6H), 1.16 (d, J = 6.8 Hz, 6H). Peak containing two protons obscured by water peak at 3.31 ppm. m/z 503.4 (M + H).sup.+ (ES.sup.+) 21 [00375]embedded image C21 .sup.1H NMR (DMSO-d.sub.6) δ 11.77 (s, 1H), 8.10 (s, 1H), 7.95 (d, J = 5.1 Hz, 1H), 7.71 (s, 1H), 7.40-7.28 (m, 2H), 6.98 (dd, J = 7.3, 1.5 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 6.40 (s, 1H), 4.78 (s, 2H), 4.51 (t, J = 4.9 Hz, 2H), 3.52 (s, 2H), 3.07-2.92 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H). — 22 [00376]embedded image C22 .sup.1H NMR (DMSO-d.sub.6) δ 8.09 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.70 (s, 1H), 7.19 (dd, J = 10.6, 2.8 Hz, 1H), 6.87 (dd, J = 8.7, 2.7 Hz, 1H), 6.82 (d, J = 5.2 Hz, 1H), 6.41 (s, 1H), 4.79 (s, 2H), 4.51 (t, J = 4.8 Hz, 2H), 3.50 (s, 2H), 3.06-2.94 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. m/z 445.5 (M + H).sup.+ (ES.sup.+) 24 [00377]embedded image C24 .sup.1H NMR (DMSO-d.sub.6) δ 11.78 (br s, 1H), 7.95 (d, J = 5.1 Hz, 1H), 7.88 (br s, 1H), 7.38-7.27 (m, 2H), 6.93 (dd, J = 7.3, 1.5 Hz, 1H), 6.76 (br s, 1H), 6.37 (br s, 1H), 4.61 (br s, 2H), 3.50 (br s, 2H), 3.09- 2.92 (m, 1H), 2.17 (s, 3H), 1.63 (s, 6H), 1.18 (d, J = 6.7 Hz, 6H). m/z 469.5 (M + H).sup.+ (ES.sup.+)

    Example 6: 16-fluoro-19,19-dimethyl-21-oxa-14λ.SUP.6.-thia-13,18,23,27-tetraazapentacyclo[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

    [1712] ##STR00378##

    [1713] 2-(5-(2-(2-(4-Fluoro-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate C6) (45 mg, 0.092 mmol) was dissolved in NMP (2 mL), to which was added HATU (52 mg, 0.137 mmol) and DIPEA (48 μL, 0.275 mmol). The reaction was stirred at RT for 18 h. The mixture was purified by basic prep HPLC (20-50% MeCN in water) to afford the title compound (8 mg, 18%) as a white solid.

    [1714] LCMS m/z 471.4 (M+H).sup.+ (ES.sup.+).

    [1715] .sup.1H NMR (DMSO-d.sub.6) δ 12.12 (s, 1H), 8.28 (d, J=4.2 Hz, 1H), 8.20 (d, J=5.1 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.86 (dd, J=5.2, 1.4 Hz, 1H), 5.85 (s, 1H), 4.53 (s, 2H), 3.38 (s, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.03 (p, J=7.5 Hz, 2H), 1.63 (s, 6H).

    Example 17: 17-(2-hydroxypropan-2-yl)-22-oxa-14λ.SUP.6.-thia-13,24-diazapentacyclo-[21.3.1.1.SUP.15,19..0.SUP.2,10..0.SUP.5,9.]octacosa-1(26),2,4,9,15,17,19(28),23(27),24-nonaene-12,14,14-trione

    [1716] ##STR00379##

    [1717] CDI (57 mg, 0.352 mmol) was dissolved in MeCN (10 mL), to which was added 2-(5-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate C17) (192 mg, 0.377 mmol). The mixture was stirred at RT for 1 h. DBU (53 μL, 0.355 mmol) in MeCN (10 mL) was then added and the mixture was stirred at RT for 24 h. The reaction was concentrated in vacuo and the resulting residue purified by acidic prep HPLC (35-65% MeCN in water) to afford the title compound (6 mg, 3%) as a white solid.

    [1718] LCMS m/z 493.4 (M+H).sup.+ (ES.sup.+).

    [1719] .sup.1H NMR (CDCl.sub.3) δ 7.97-7.87 (m, 2H), 7.85-7.73 (m, 2H), 7.47 (s, 1H), 7.29 (s, 1H), 7.06 (d, J=7.8 Hz, 1H), 6.69 (d, J=5.2 Hz, 1H), 6.46 (br s, 1H), 5.00-4.79 (m, 2H), 3.77-3.65 (m, 2H), 3.14 (t, J=5.6 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.18 (p, J=7.5 Hz, 2H), 1.60 (s, 6H). One exchangeable proton not observed.

    [1720] The following examples ‘Ex’ were synthesised following the general procedure for Example 17, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00004 Ex Structure From .sup.1H NMR LCMS 16 [00380]embedded image C16 .sup.1H NMR (DMSO-d.sub.6) δ 11.75 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.95 (dd, J = 7.3, 1.5 Hz, 1H), 6.80 (s, 1H), 6.37 (s, 1H), 4.57 (s, 2H), 3.59- 3.50 (m, 2H), 3.07-2.98 (m, 1H), 1.69 (s, 6H), 1.18 (d, J = 6.8 Hz, 6H). m/z 455.4 (M + H).sup.+ (ES.sup.+) 18 [00381]embedded image C18 .sup.1H NMR (DMSO-d.sub.6) δ 12.38 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.25- 8.19 (m, 1H), 7.20 (dd, J = 10.6, 2.8 Hz, 1H), 7.14 (s, 1H), 6.91-6.82 (m, 3H), 4.66-4.38 (m, 4H), 3.32 (s, 2H), 3.03 (s, 1H), 2.34-2.18 (m, 2H), 1.18 (d, J = 5.9 Hz, 6H). m/z 486.0 (M + H).sup.+ (ES.sup.+) 20 [00382]embedded image C20 .sup.1H NMR (DMSO-d.sub.6) δ 12.35 (s, 1H), 8.38 (d, J = 4.3 Hz, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.22 (dd, J = 10.7, 2.8 Hz, 1H), 6.97- 6.90 (m, 1H), 6.88 (dd, J = 8.7, 2.7 Hz, 1H), 6.12 (s, 1H), 4.67 (br s, 2H), 3.43 (br s, 2H), 3.02- 2.81 (m, 1H), 1.42-1.30 (m, 2H), 1.29-1.20 (m, 2H), 1.17 (d, J = 6.7 Hz, 6H). m/z 489.5 (M + H).sup.+ (ES.sup.+) 23 [00383]embedded image C23 .sup.1H NMR (DMSO-d.sub.6) δ 8.11 (d, J = 5.1 Hz, 1H), 7.12 (dd, J = 10.9, 2.8 Hz, 1H), 6.82-6.79 (m, 1H), 6.79-6.72 (m, 1H), 6.18 (s, 1H), 4.70-4.58 (m, 2H), 3.42 (d, J = 18.4 Hz, 1H), 3.33 (d, J = 18.3 Hz, 1H), 2.44 (s, 3H), 2.21 (s, 3H), 1.80 (s, 3H), 1.72 (s, 3H), 1.24-1.18 (m, 6H). CH of .sup.iPr masked by water peak and one exchangeable proton not observed. m/z 501.0 (M + H).sup.+ (ES.sup.+) 25 [00384]embedded image C25 .sup.1H NMR (DMSO-d.sub.6) δ 11.75 (br s, 1H), 8.03 (s, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.68 (s, 1H), 7.18 (dd, J = 10.6, 2.8 Hz, 1H), 6.90-6.72 (m, 2H), 6.37 (br s, 1H), 4.60 (br s, 2H), 3.53 (br s, 2H), 3.12-2.93 (m, 1H), 1.69 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). m/z 473.5 (M + H).sup.+ (ES.sup.+) 26 [00385]embedded image C26 .sup.1H NMR (DMSO-d.sub.6) δ 8.25 (d, J = 5.1 Hz, 1H), 7.57 (s, 1H), 7.30 (dd, J = 10.3, 8.4 Hz, 1H), 7.18 (dd, J = 10.7, 2.8 Hz, 1H), 7.02-6.97 (m, 1H), 6.94-6.84 (m, 2H), 6.52 (s, 1H), 4.66 (s, 2H), 3.16-2.95 (m, 2H), 2.91 (t, J = 5.5 Hz, 2H), 1.92 (p, J = 5.8 Hz, 1H), 1.20 (d, J = 6.7 Hz, 6H). One exchangeable proton not observed. m/z 473.2 (M + H).sup.+ (ES.sup.+) m/z 471.3 (M − H).sup.− (ES.sup.−) 27 [00386]embedded image C27 .sup.1H NMR (DMSO-d.sub.6) δ 12.20 (s, 1H), 8.28-8.19 (m, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.96 (dd, J = 7.5, 1.3 Hz, 1H), 6.88 (dd, J = 5.1, 1.5 Hz, 1H), 5.90 (br s, 1H), 4.51 (br s, 2H), 3.56 (br s, 2H), 1.81 (m, 1H), 1.61 (s, 6H), 0.96-0.85 (m, 2H), 0.61 (d, J = 5.1 Hz, 2H). m/z 471.1 (M + H).sup.+ (ES.sup.+) 28 [00387]embedded image C28 .sup.1H NMR (DMSO-d.sub.6) δ 11.95 (s, 1H), 8.13-8.07 (m, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.70-7.66 (m, 1H), 7.57 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 7.9, 1.5 Hz, 1H), 7.28 (t, J = 7.1 Hz, 1H), 6.93 (dd, J = 7.4, 1.4 Hz, 1H), 6.79 (d, J = 4.9 Hz, 1H), 5.90 (s, 1H), 4.48 (s, 2H), 3.45 (s, 2H), 2.99-2.85 (m, 1H), 1.42 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). m/z 465.4 (M + H).sup.+ (ES.sup.+) 463.4 (M − H).sup.− (ES.sup.−) 29 [00388]embedded image C29 .sup.1H NMR (DMSO-d.sub.6) δ 11.94 (s, 1H), 8.20 (d, J = 5.3 Hz, 1H), 7.88 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 4.7 Hz, 1H), 6.01 (s, 1H), 4.55 (s, 2H), 3.70 (s, 3H), 2.93-2.84 (m, 1H), 1.60 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). Two aliphatic protons obscured by water peak. m/z 485.4 (M + H).sup.+ (ES.sup.+) 33 [00389]embedded image C33 .sup.1H NMR (DMSO-d.sub.6) δ 11.73 (s, 1H), 8.11 (s, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.61 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.85-6.67 (m, 1H), 6.41 (s, 1H), 3.54 (s, 2H), 3.31 (s, 2H), 3.00-2.89 (m, 1H), 1.68 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). m/z 455.4 (M + H).sup.+ (ES.sup.+) 37 [00390]embedded image C37 .sup.1H NMR (DMSO-d.sub.6) δ 12.51 (s, 1H), 8.79-8.68 (m, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 42.1 Hz, 1H), 7.46 (dd, J = 8.2, 4.5 Hz, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 6.77 (s, 1H), 5.89 (s, 1H), 4.97 (s, 2H), 3.50 (d, J = 25.3 Hz, 2H), 2.94 (d, J = 7.9 Hz, 1H), 1.96 (d, J = 27.3 Hz, 6H), 1.31-1.13 (m, 6H). m/z 528.4 (M + Na).sup.+ (ES.sup.+)

    Example 30: 14-cyclopropyl-4-fluoro-6-(propan-2-yl)-19-oxa-11λ.SUP.6.-thia-10,21-diazatetracyclo[18.3.1.11.SUP.2,16..0.SUP.2,7.]pentacosa-1(23),2(7),3,5,12(25),13,15,20(24),21-nonaene-9,11,11-trione

    [1721] ##STR00391##

    [1722] 2-(2-(2-(3-cyclopropyl-5-sulfamnoylphenethoxy)pyridin-4-yl)-4-fluoro-6-isopropyl-phenyl)acetic acid (Intermediate C30) (150 mg, 293 μmol) was dissolved in DMF (2 mL), to which was added DMAP (107 mg, 878 μmol) and DIC (111 mg, 0.14 mL, 878 μmol). The mixture was stirred at RT for 48 h. The reaction was diluted with 1 M aq HCl (15 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (2×25 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by FC (0-100% EtOAc/isohexane) to afford the title compound (30 mg, 20%) as a white solid.

    [1723] LCMS m/z 495.5 (M+H).sup.+ (ES.sup.+); 493.4 (M−H).sup.− (ES.sup.−).

    [1724] .sup.1H NMR (DMSO-d.sub.6) δ 11.91 (br s, 1H), 8.22 (d, J=5.1 Hz, 1H), 7.43-7.34 (m, 2H), 7.20 (dd, J=10.6, 2.8 Hz, 1H), 6.96-6.77 (m, 3H), 6.00 (s, 1H), 4.71 (br s, 2H), 3.52 (br s, 2H), 3.06 (t, J=5.8 Hz, 2H), 2.99-2.88 (m, 1H), 2.09-2.01 (m, 1H), 1.17 (d, J=6.8 Hz, 6H), 1.06-1.00 (m, 2H), 0.78-0.70 (m, 2H).

    [1725] The following examples ‘Ex.’ were synthesised following the general procedure for Example 30, from the intermediate compounds indicated in the ‘From’ column:

    TABLE-US-00005 Ex. Structure From .sup.1H NMR LCMS 31 [00392]embedded image C31 .sup.1H NMR (DMSO-d.sub.6) δ 12.28 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7-33 (t, J = 7.6 Hz, 1H), 6.96 (dd, J = 7.5, 1.4 Hz, 1H), 6.83 (dd, J = 5.2, 1.4 Hz, 1H), 5.83 (s, 1H), 4.28 (s, 2H), 2.93 (p, J = 6.9 Hz, 1H), 2.34 (s, 2H), 1.60 (s, 6H), 1.57-1.49 (m, 1H), 1.18 (d, J = 6.7 Hz, 6H), 0.95 (t, J = 7.3 Hz, 1H). m/z 487.4 (M + H).sup.+ (ES.sup.+) 485.3 (M − H).sup.− (ES.sup.−) 32 [00393]embedded image C32 .sup.1H NMR (DMSO-d.sub.6) δ 11.81 (s, 1H), 8.01 (br s, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.71 (s, 1H), 7.39- 7.30 (m, 2H), 6.99 (dd, J = 7.2, 1.5 Hz, 1H), 6.82 (br s, 1H), 6.47 (s, 1H), 4.70 (br s, 2H), 3.58 (s, 2H), 3.09-2.95 (m, 1H), 1.36 (app br s, 2H), 1.26 (app s, 2H), 1.18 (d, J = 6.7 Hz, 6H). m/z 453.4 (M + H).sup.+ (ES.sup.+) 34 [00394]embedded image C34 .sup.1H NMR (DMSO-d.sub.6) δ 12.14 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 8.28-8.23 (m, 1H), 7.43 (dd, J = 12.3, 8.1 Hz, 1H), 6.98 (d, J = 5.1 Hz, 1H), 5.85 (s, 1H), 4.76 (s, 1H), 4.33- 4.24 (m, 1H), 3.78-3.67 (m, 1H), 3.09-2.92 (m, 2H), 1.77 (s, 3H), 1.48 (s, 3H), 1.15 (s, 6H). m/z 508.9 (M + H).sup.+ (ES.sup.+) 506.9 (M − H).sup.− (ES.sup.−) 35 [00395]embedded image C35 .sup.1H NMR (DMSO-d.sub.6) δ 11.77 (s, 1H), 8.08 (s, 1H), 8.05-8.00 (m, 1H), 7.67 (s, 1H), 747-7.37 (m, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 5.25 (s, 1H), 4.03-3-89 (m, 1H), 3.81- 3.67 (m, 1H), 3.16 (s, 1H), 3.06-2.95 (m, 1H), 1.77 (s, 3H), 1.63 (s, 3H), 1.24-1.06 (m, 6H). m/z 491.4 (M + H).sup.+ (ES.sup.+) 489.2 (M − H).sup.− (ES.sup.−) 36 [00396]embedded image C36 .sup.1H NMR (DMSO-d.sub.6) δ 12.31 (br s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.40- 7.33 (m, 2H), 7.29 (t, J = 7.7 Hz, 1H), 6.91 (dd, J = 11.1, 6.2 Hz, 2H), 5.77 (br s, 1H), 4.66 (br s, 2H), 3.45 (br s, 2H), 2.98 (sept, J = 6.8 Hz, 1H), 1.76 (s, 6H), 1.17 (d, J = 6.7 Hz, 6H). m/z 456.4 (M + H).sup.+ (ES.sup.+) 454.3 (M − H).sup.− (ES.sup.−) 38 [00397]embedded image C38 .sup.1H NMR (DMSO-d.sub.6) δ 12.41 (s, 1H), 8.72 (s, 1H), 8.60 (d, J = 4.7 Hz, 1H), 8.32-8.26 (m, 2H), 7.66 (dd, J = 7.7, 4.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.02-6.91 (m, 2H), 5.93 (br s, 1H), 5.58 (br s, 2H), 3.49, (br s, 2H) 3.08 (br s, 1H), 1.21 (d, J = 6.8 Hz, 6H). m/z 508.4 (M + H).sup.+ (ES.sup.+) 39 [00398]embedded image C39 .sup.1H NMR (DMSO-d.sub.6) δ 12.35 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 7.19 (dd, J = 10.7, 2.8 Hz, 1H), 6.94 (dd, J = 5.1, 1.4 Hz, 1H), 6.86 (dd, J = 8.5, 2.8 Hz, 1H), 5.93 (s, 1H), 4.72 (s, 2H), 4.42 (s, 2H), 3.69- 3.55 (m, 1H), 3.02 (d, J = 10.7 Hz, 6H), 1.17 (d, J = 6.7 Hz, 6H), 1.00 (d, J = 6.5 Hz, 6H). m/z 562.4 (M + H).sup.+ (ES.sup.+) 40 [00399]embedded image C40 .sup.1H NMR (DMSO-d.sub.6) δ 8.23 (s, 1H), 7.19 (dd, J = 10.7, 2.8 Hz, 1H), 6.89 (s, 1H), 6.84 (dd, J = 8.6, 2.7 Hz, 1H), 5.93 (s, 1H), 4.58 (br s, 2H), 3.39 (s, 2H), 2.96 (br s, 2H), 2.83 (br s, 2H), 1.66 (br s, 6H), 1.20 (s, 3H), 1.16 (d, J = 6.7 Hz, 6H). Five aliphatic protons overlapped with DMSO and water peaks; one exchangeable proton not observed. m/z 556.4 (M + H).sup.+ (ES.sup.+) 41 [00400]embedded image C41 .sup.1H NMR (DMSO-d.sub.6) δ 12.17 (br s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.18 (dd, J = 10.8, 2.8 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz, 1H), 6.84 (dd, J = 8.6, 2.8 Hz, 1H), 6.76 (s, 1H), 5.92 (s, 1H), 4.57 (br s, 2H), 3.06-2.90 (m, 7H), 1.62 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H). One CH.sub.2 obscured by water peak. m/z 544.4 (M + H).sup.+ (ES.sup.+) 542.3 (M − H).sup.− (ES.sup.−) 42 [00401]embedded image C42 .sup.1H NMR (DMSO-d.sub.6) δ 11.76 (s, 1H), 8.11 (s, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H), 7.13 (dd, J = 10.5, 7.8 Hz, 1H), 6.83 (s, 1H), 6.32 (s, 1H), 4.55 (s, 2H), 3.49 (s, 2H), 3.17- 3.06 (m, 1H), 1.69 (s, 6H), 1.39-1.21 (m, 6H). m/z 491.4 (M + H).sup.+ (ES.sup.+) 489.4 (M − H).sup.− (ES.sup.−)

    Example 41: 6-(propan-2-yl)-22-oxa-11λ.SUP.6.-thia-10,15,16,24-tetraazatetracyclo-[21.3.1.0.SUP.2,7..0.SUP.12,16.]heptacosa-1(26),2(7),3,5,12,14,23(27),24-octaene-9,11,11-trione

    [1726] ##STR00402##

    [1727] To a solution of 2-(2-isopropyl-6-(2-((5-(5-sulfamoyl-1H-pyrazol-1-yl)pentyl)oxy)-pyridin-4-yl)phenyl)acetic acid (Intermediate C43) (330 mg, 678 μmol) in THF (20 mL) was added TEA (275 mg, 2.71 mmol) and BOP (600 mg, 1.36 mmol) at 20° C. The mixture was stirred for 0.5 h. Then DMAP (331 mg, 2.71 mmol) was added into the mixture and the resulting mixture was stirred at 20° 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 %: 15%-45%, 9 min) to give the title compound (42.8 mg, 13.4%) as a white solid.

    [1728] LCMS: m/z 469.1 (M+H).sup.+ (ES.sup.+).

    [1729] .sup.1H NMR (CD.sub.3OD) δ 8.12 (d, 1H), 7.47 (d, 1H), 7.37 (d, 1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.86 (d, 1H), 6.82 (dd, 1H), 6.61 (t, 1H), 4.44 (t, 2H), 4.37 (t, 2H), 3.55 (s, 2H), 3.14-3.09 (m, 1H), 1.98-1.95 (m, 2H), 1.75-1.72 (m, 2H), 1.57-1.53 (m, 2H), 1.27 (d, 6H). One exchangeable proton not observed.

    Example 44: 6-(propan-2-yl)-18-oxa-11λ.SUP.6.-thia-10,15,20,21,24-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

    [1730] ##STR00403##

    [1731] To a solution of 2-(2-isopropyl-6-(6-(2-(3-sulfamoyl-1H-pyrazol-1-yl)ethoxy)pyridazin-4-yl)phenyl)acetic acid (Intermediate C44) (200 mg, 449 μmol) in THF (15 mL) was added TEA (182 mg, 1.80 mmol) and BOP (398 mg, 898 μmol) at 20° C. The mixture was stirred at 20° C. for 1 h, then DMAP (219 mg, 1.80 mmol) was added and the resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was adjusted to pH 7 with TFA, and then the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 μm; mobile phase: [A: water (0.1% TFA); B: MeCN]; B %: 38%-48%, 7 min), and then by prep-HPLC (column: Waters Xbridge C18, 150 mm×50 mm×10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 10%-40%, 10 min) to give the title compound (8.82 mg, 4.59% yield, 99.8% purity by HPLC) as a white solid.

    [1732] LCMS: m/z 428.1 (M+H).sup.+ (ES.sup.+).

    [1733] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O) δ 8.77 (s, 1H), 7.89 (s, 1H), 7.38 (d, 1H), 7.32 (t, 1H), 7.69 (d, 1H), 6.62 (s, 1H), 6.42 (s, 1H), 4.92 (t, 2H), 4.55 (t, 2H), 3.42 (s, 2H), 3.00-2.90 (m, 1H), 1.15 (d, 6H). One exchangeable proton not observed.

    Example 45: 17-methyl-6-(propan-2-yl)-20-oxa-11λ.SUP.6.-thia-10,12,17,22-tetraaza-tetracyclo[19.3.1.1.SUP.12,16..0.SUP.2,7.]hexacosa-1(24),2(7),3,5,21(25),22-hexaene-9,11,11-trione

    [1734] ##STR00404##

    [1735] To a solution of 2-(2-isopropyl-6-(2-(2-(methyl(1-sulfamoylpiperidin-3-yl)amino)-ethoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate D1) (85 mg, 118 μmol, di-TFA salt) in DCM (40 mL) was added TEA (36 mg, 355 μmol) and BOP (78 mg, 177 μmol). The resulting mixture was stirred at 25° C. for 1 h. To the mixture was added DMAP (43 mg, 355 μmol) and the mixture was stirred at 25° C. for 10 h. The reaction mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA in H.sub.2O-MeCN) and then 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 %: 18%-48%, 10 min) to give the title compound (39.2 mg, 70.1% yield, 100% purity on LCMS) as a white solid.

    [1736] LCMS: m/z 473.3 (M+H).sup.+ (ES.sup.+).

    [1737] .sup.1H NMR (CD.sub.3OD): δ 8.21 (d, 1H), 7.43-7.33 (m, 2H), 7.07 (d, 1H), 6.90 (d, 1H), 6.62 (s, 1H), 4.58-4.39 (m, 2H), 3.91-3.86 (m, 1H), 3.69-3.66 (m, 1H), 3.53-3.48 (m, 2H), 3.17-3.08 (m, 2H), 3.01-2.97 (m, 2H), 2.84 (t, 1H), 2.69 (t, 1H), 2.51 (s, 3H), 2.11-2.04 (m, 1H), 1.85-1.80 (m, 1H), 1.66-1.50 (m, 2H), 1.26 (d, 6H). One exchangeable proton not observed.

    Example 46: 6-isopropyl-16,16-dimethyl-9,11,11-trioxo-18-oxa-11λ.SUP.6.-thia-10,14,15,20-tetrazatetra-cyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24),13,19,21-octaene-4-carbonitrile

    [1738] ##STR00405##

    [1739] To a solution of 2-(4-cyano-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C46) (0.55 g, 1.11 mmol) in DCM (50 mL) was added TEA (447 mg, 4.42 mmol) and BOP (978 mg, 2.21 mmol). The mixture was stirred at 25° C. for 1 h and then DMAP (540 mg, 4.42 mmol) was added. The reaction mixture was stirred at 25° C. for another 1 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) and then purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×50 mm×10 m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 10%-40%, 11 min) to give the title compound (114.14 mg, 21.0% yield, 97.7% purity on LCMS) as a white solid.

    [1740] LCMS: m/z 480.1 (M+H).sup.+ (ES.sup.+).

    [1741] .sup.1H NMR (CD.sub.3OD): δ 8.14 (d, 1H), 7.92 (d, 1H), 7.72 (s, 1H), 7.64 (d, 1H), 7.34 (d, 1H), 6.75 (d, 1H), 6.50 (s, 1H), 4.68-4.55 (m, 2H), 3.69 (s, 2H), 3.18-3.10 (m, 1H), 1.76 (s, 6H), 1.27 (d, 6H). One exchangeable proton not observed.

    Example 47: 4-(difluoromethoxy)-6-isopropyl-16,16-dimethyl-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,14,15,20-tetrazatetracyclo[17-3-1-1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24), 13,19,21-octaen-9-one

    [1742] ##STR00406##

    [1743] To a solution of 2-(4-(difluoromethoxy)-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C47) (0.5 g, 928 μmol) in DCM (10 mL) was added dropwise TEA (376 mg, 3.71 mmol) and BOP (821 mg, 1.86 mmol) at 25° C. After addition, the mixture was stirred at this temperature for 1 h, and then DMAP (454 mg, 3.71 mmol) was added to the reaction mixture at 25° C. The resulting mixture was stirred at 25° C. for 20 min, then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) and then purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×25 mm×5 μm; mobile phase: [A: water (10 mM NH.sub.4HCO), B: MeCN]; B %: 16%-46%, 10 min) to give the title compound (150 mg, 30.4% yield, 98% purity on HPLC) as a white solid.

    [1744] LCMS: m/z 521.1 (M+H).sup.+ (ES.sup.+).

    [1745] .sup.1H NMR (CDCl.sub.3): δ 8.04 (d, 1H), 7.97 (d, 1H), 7.72 (s, 1H), 7.12 (d, 1H), 6.80 (d, 1H), 6.72 (s, 1H), 6.54 (t, 1H), 6.50 (s, 1H), 4.63 (s, 2H), 3.62 (s, 2H), 3.07-3.01 (m, 1H), 1.74 (s, 6H), 1.27 (d, 6H). One exchangeable proton not observed.

    Example 48: 5-fluoro-6-isopropyl-16,16-dimethyl-9,11,11-trioxo-18-oxa-11λ.SUP.6.-thia-10,14,15,20-tetrazatetracyclo[17-3-1-1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24),13,19,21-octaene-4-carbonitrile

    [1746] ##STR00407##

    [1747] To a solution of 2-(4-cyano-3-fluoro-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C48) (0.35 g, 634 μmol, HCl salt) in DCM (100 mL) was added TEA (257 mg, 2.54 mmol) and BOP (561 mg, 1.27 mmol). The solution was stirred at 25° C. for 1 h, then DMAP (232 mg, 1.90 mmol) was added and the solution was stirred at 25° C. for another 1 h. The solution was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) and then 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 the title compound (122 mg, 38.3% yield, 99.5% purity on LCMS) as a white solid.

    [1748] LCMS: m/z 498.1 (M+H).sup.+ (ES.sup.+).

    [1749] .sup.1H NMR (DMSO-d.sub.6): δ 11.85 (br s, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.68 (s, 1H), 7.60 (d, 1H), 6.86 (s, 1H), 6.33 (s, 1H), 4.59 (s, 2H), 3.67 (s, 2H), 3.21-3.18 (m, 1H), 1.69 (s, 6H), 1.28 (d, 6H).

    Example 49: 4-(difluoromethoxy)-5-fluoro-6-isopropyl-16,16-dimethyl-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,14,15,20-tetrazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5, 12(24),13,19,21-octaen-9-one

    [1750] ##STR00408##

    [1751] To a solution of 2-(4-(difluoromethoxy)-3-fluoro-2-isopropyl-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C49) (0.4 g, 592 μmol, 99.3% purity, TFA salt) in DCM (100 mL) was added BOP (524 mg, 1.18 mmol) and TEA (240 mg, 2.37 mmol). The mixture was stirred at 25° C. for 1 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (0.1% TFA) and then purified by prep-HPLC (column: Waters Xbridge C18, 150 mm×50 mm×10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 18%-48%, 10 min) to give the title compound (115 mg, 35.4% yield, 98.7% purity on LCMS) as a white solid.

    [1752] LCMS: m/z 539.1 (M+H).sup.+ (ES.sup.+).

    [1753] .sup.1H NMR (CD.sub.3OD): δ 8.22 (s, 1H), 7.97 (d, 1H), 7.68 (s, 1H), 6.95 (d, 1H), 6.68 (m, 1H), 6.76 (d, 1H), 6.51 (s, 1H), 4.60 (s, 2H), 3.54 (s, 2H), 3.17-3.14 (m, 1H), 1.79 (s, 6H), 1.39 (d, 6H). One exchangeable proton not observed.

    Example 50: 4-fluoro-6-isopropyl-N,N,16,16-tetramethyl-9,11,11-trioxo-18-oxa-11λ.SUP.6.-thia-10,15,20,24-tetrazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24),13,19, 21-octaene-13-carboxamide

    [1754] ##STR00409##

    [1755] To a solution of 2-(2-(2-(2-(4-(dimethylcarbamoyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (Intermediate C50) (150 mg, 222 μmol, TFA salt) in DCM (60 mL) was added TEA (84 mg, 833 μmol) and BOP (147 mg, 333 μmol), and then the mixture was stirred at 25° C. for 1 h. To the mixture was added DMAP (102 mg, 833 μmol) and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched with H.sub.2O (10 mL) and then adjusted with 0.5 M aq HCl to pH 6. The layers were separated and the organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini NX-C18, 75 mm×30 mm×3 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 14%-44%, 8 min) to give the title compound (65.1 mg, 53.9% yield, 100% purity on LCMS) as a white solid.

    [1756] LCMS: m/z 544.4 (M+H).sup.+ (ES.sup.+).

    [1757] .sup.1H NMR (CD.sub.3OD): δ 8.17 (d, 1H), 8.02 (s, 1H), 7.09 (d, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 6.33 (s, 1H), 4.65 (s, 2H), 3.42 (s, 2H), 3.05-2.97 (m, 7H), 1.71 (s, 6H), 1.23 (d, 6H). One exchangeable proton not observed.

    Example 51: 6-isopropyl-4-(methoxymethyl)-16,16-dimethyl-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,14,15,20-tetrazatetracyclo[17-3-1-1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24),13,19, 21-octaen-9-one

    [1758] ##STR00410##

    [1759] To a solution of 2-(2-isopropyl-4-(methoxymethyl)-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C51) (0.4 g, 774 μmol) in DCM (50 mL) was added TEA (431.0 μL, 3.10 mmol) and BOP (685 mg, 1.55 mmol). The mixture was stirred at 25° C. for 1 h, then DMAP (378 mg, 3.10 mmol) was added. The resulting mixture was stirred at 25° C. for another 1 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) and then 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 %: 7%-43%, 9 min) to give the title compound (133 mg, 34.0% yield, 99% purity on LCMS) as a white solid.

    [1760] LCMS: m/z 499.4 (M+H).sup.+ (ES.sup.+).

    [1761] .sup.1H NMR (CD.sub.3OD): δ 8.16 (s, 1H), 7.89 (d, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 6.94 (s, 1H), 6.73 (d, 1H), 6.50 (s, 1H), 4.61 (s, 2H), 4.45 (s, 2H), 3.60 (s, 2H), 3.38 (s, 3H), 3.11-3.04 (m, 1H), 1.77 (s, 6H), 1.25 (d, 6H). One exchangeable proton not observed.

    Example 52: 5-fluoro-6-isopropyl-4-(methoxymethyl)-16,16-dimethyl-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,14,15,20-tetrazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5, 12(24),13,19,21-octaen-9-one

    [1762] ##STR00411##

    [1763] To a solution of 2-(3-fluoro-2-isopropyl-4-(methoxymethyl)-6-(2-(2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C52) (320 mg, 599 μmol) in DCM (5 mL) was added dropwise TEA (242 mg, 2.39 mmol) and BOP (529 mg, 1.20 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, then DMAP (146 mg, 1.20 mmol) was added at 25° C. and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) then prep-HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 12%-42%, 8 min) to give the title compound (98.9 mg, 31.9% yield) as a white solid.

    [1764] LCMS: m/z 517.1 (M+H).sup.+ (ES.sup.+).

    [1765] .sup.1H NMR (DMSO-d.sub.6): δ 8.10 (s, 1H), 7.97 (d, 1H), 7.65 (s, 1H), 7.00 (d, 1H), 6.80-6.75 (m, 1H), 6.33 (s, 1H), 4.55 (s, 2H), 4.43 (s, 2H), 3.49 (s, 2H), 3.30 (s, 3H), 3.10-3.03 (m, 1H), 1.68 (s, 6H), 1.26 (d, 6H). One exchangeable proton not observed.

    Example 53: 4,13-difluoro-6-isopropyl-16,16-dimethyl-14-[(4-methylpiperazin-1-yl)-methyl]-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,15,20,24-tetrazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]-tetracosa-1(23),2(7),3,5,12(24),13,19,21-octaen-9-one

    [1766] ##STR00412##

    [1767] To a solution of 2-(4-fluoro-2-(2-(2-(4-fluoro-5-((4-methylpiperazin-1-yl)methyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate C53) (120 mg, 163 μmol, TFA salt) in THF (15 mL) was added TEA (66 mg, 653 μmol) and BOP (144 mg, 327 μmol). The mixture was stirred at 20° C. for 1 h, then DMAP (80 mg, 653 μmol) was added. The mixture was stirred at 20° C. for 2 h, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) and then prep-HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 18%-48%, 8 min) to give the title compound (9.12 mg, 9.26% yield, 99.9% purity on HPLC) as a white solid.

    [1768] LCMS: m/z 603.4 (M+H).sup.+ (ES.sup.+).

    [1769] .sup.1H NMR (CDCl.sub.3): δ 12.22 (br s, 1H), 7.97 (s, 1H), 7.05 (dd, 1H), 6.77 (s, 1H), 6.69 (dd, 1H), 6.40 (s, 1H), 3.83-3.58 (m, 6H), 3.13-2.80 (m, 12H), 1.80 (s, 6H), 1.24 (d, 6H).

    Example 54: 4,13-difluoro-6-isopropyl-16,16-dimethyl-14-(4-methylpiperazine-1-carbonyl)-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,15,20,24-tetrazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]-tetracosa-1(23),2(7),3,5,12(24),13,19,21-octaen-9-one

    [1770] ##STR00413##

    [1771] To a solution of 1-(1-((4-(2-(carboxymethyl)-5-fluoro-3-isopropylphenyl)pyridin-2-yl)-oxy)-2-methylpropan-2-yl)-4-fluoro-3-sulfamoyl-1H-pyrazole-5-carboxylic acid (Intermediate C54) (0.13 g, 235 μmol) in DCM (40 mL) was added TEA (95 mg, 941 μmol) and BOP (208 mg, 471 μmol). The mixture was stirred at 25° C. for 1 h, then DMAP (86 mg, 706 μmol) was added and the resulting mixture was stirred for another 1 h to achieve cyclisation. To the mixture was added TEA (45 mg, 449 μmol) and BOP (199 mg, 449 μmol) and the mixture was stirred at 25° C. for 10 min. Next 1-methyl-piperazine (45 mg, 449 μmol) was added and the resulting mixture was stirred at 25° C. for 20 min, then concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) and further 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 %: 10%-43%, 9 min) to give the title compound (27.3 mg, 19.3% yield, 98.1% purity on LCMS) as a white a solid.

    [1772] LCMS: m/z 617.3 (M+H).sup.+ (ES.sup.+).

    [1773] .sup.1H NMR (CD.sub.3OD): δ 8.19 (d, 1H), 7.09-7.06 (m, 1H), 6.88 (dd, 1H), 6.74-6.72 (m, 1H), 6.22 (s, 1H), 4.99-4.91 (m, 1H), 4.28-4.25 (m, 1H), 3.88-3.60 (m, 5H), 3.29-3.08 (m, 2H), 2.75-2.69 (m, 4H), 2.45 (s, 3H), 1.78-1.73 (m, 3H), 1.62-1.60 (m, 3H), 1.27-1.21 (m, 6H). One exchangeable proton not observed.

    Example 55: 4,13-difluoro-6-isopropyl-16,16-dimethyl-14-(morpholinomethyl)-11,11-dioxo-18-oxa-11λ.SUP.6.-thia-10,15,20,24-tetrazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24),13,19,21-octaen-9-one

    [1774] ##STR00414##

    [1775] To a solution of 2-(4-fluoro-2-(2-(2-(4-fluoro-5-(morpholinomethyl)-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-6-isopropylphenyl)acetic acid (Intermediate C55) (0.1 g, 165 μmol) in THF (15 mL) was added TEA (67 mg, 658 μmol) and BOP (146 mg, 329 μmol). The reaction mixture was stirred at 20° C. for 0.5 h, then DMAP (80 mg, 658 μmol) was added. The resulting mixture was stirred at 20° C. for 12 h, then concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 16%-46%, 8 min) to give the title compound (15.8 mg, 16.0% yield) as a white solid.

    [1776] LCMS: m/z 590.3 (M+H).sup.+ (ES.sup.+).

    [1777] .sup.1H NMR (CD.sub.3OD): δ 8.14 (d, 1H), 7.09 (dd, 1H), 6.85 (d, 1H), 6.74 (dd, 1H), 6.24 (s, 1H), 4.81-4.75 (m, 2H), 3.69-3.66 (m, 4H), 3.62-3.59 (m, 2H), 3.50-3.45 (m, 2H), 3.10-3.00 (m, 1H), 2.50-2.41 (m, 4H), 1.81 (s, 6H), 1.24 (d, 6H). One exchangeable proton not observed.

    Example 56: 4-fluoro-6-isopropyl-16,16-dimethyl-11,11-dioxo-11λ.SUP.6.-thia-10,14,15,18, 20-pentazatetracyclo[17.3.1.1.SUP.12,15..0.SUP.2,7.]tetracosa-1(23),2(7),3,5,12(24),13,19,21-octaen-9-one

    [1778] ##STR00415##

    [1779] To a solution of 2-(4-fluoro-2-isopropyl-6-(2-((2-methyl-2-(4-sulfamoyl-1H-pyrazol-1-yl)propyl)amino)pyridin-4-yl)phenyl)acetic acid (Intermediate C56) (0.08 g, 133 μmol, TFA salt) in DCM (40 mL) was added TEA (40 mg, 398 μmol) and BOP (117 mg, 265 μmol). The mixture was stirred at 25° C. for 1 h, then DMAP (49 mg, 398 μmol) was added and the resulting mixture was stirred for another 0.5 h. The mixture was concentrated in vacuum. The residue was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) and then prep-HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 μm; mobile phase: [A: water (10 mM NH.sub.4HCO), B: MeCN]; B %: 10%-40%, 8 min) to give the title compound (19.62 mg, 31.3% yield, 99.7% purity on LCMS) as a white solid.

    [1780] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

    [1781] .sup.1H NMR (CD.sub.3CN): δ 7.96 (s, 1H), 7.80 (d, 1H), 7.65 (s, 1H), 7.09 (dd, 1H), 6.68 (dd, 1H), 6.31 (dd, 1H), 5.74 (br s, 1H), 5.37 (br s, 1H), 3.67-3.58 (m, 4H), 3.15-3.09 (m, 1H), 1.65 (s, 6H), 1.21 (d, 6H). One exchangeable proton not observed.

    Examples—Biological Studies

    NLRP3 and Pyroptosis

    [1782] 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

    [1783] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells were routinely passaged and grown to confluency (˜10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

    THP-1 Cells Pyroptosis Assay

    [1784] The following method step-by-step assay was followed for compound screening. [1785] 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) [1786] 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 [1787] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1788] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [1789] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1790] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [1791] 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 [1792] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1793] 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

    [1794]

    TABLE-US-00006 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

    [1795] The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

    Human Whole Blood IL-1β Release Assay

    [1796] 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.

    [1797] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [1798] 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [1799] 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 [1800] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [1801] 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells [1802] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [1803] 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) [1804] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [1805] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

    [1806] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

    TABLE-US-00007 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 + ND  7 ++ ND  8 ++ ND  9 + ND 10 ++ ++ 11 ++++ ++ 12 +++ +++ 13 ++ ++ 14 ++ ND 15 ++++ ++ 16 ++++ ++++ 17 +++ ++ 18 ++ ND 19 ++++ +++ 20 +++ ++ 21 ++ + 22 ++ + 23 + ND 24 +++ ++ 25 +++++ ++++ 26 ++ ND 27 ++ +++ 28 ++ ND 29 ++++ ++++ 30 +++ ND 31 ++ ++ 32 +++ ++++ 33 +++ ++ 34 ++++ ++ 35 +++++ +++ 36 ++ ++ 37 +++ ++ 38 ++ ++ 39 ++ ++ 40 ++ ++ 41 ++ ++ 42 +++++ ++++ 43 ++ ND 44 ++ + 45 ++ ND 46 ++ ND 47 ++++ ND 48 ++ ND 49 +++ ND 50 + ND 51 +++++ ND 52 ++++ ND 53 +++++ ND 54 +++ ND 55 ++++ ND 56 +++++ ND

    [1807] 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.

    [1808] 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.