Sulfonylureas and sulfonylthioureas as NLRP3 inhibitors

Abstract

The present invention relates to sulfonylureas and sulfonylthioureas comprising a 5-membered heteroaryl ring attached to the sulfonyl group, wherein the heteroaryl ring is di-substituted at the 3- and 4-positions relative to the point of attachment of the sulfonyl group, wherein at least one of the di-substituents contains a nitrogen atom. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP.sub.3.

Claims

1. A compound of formula (I): ##STR00513## or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is selected from O or S; ring A is monocyclic; V, X and Y are each independently selected from C and N, and W and Z are each independently selected from N, O, S, NH and CH, provided that at least one of V, W, X, Y and Z is N, O, S or NH; R.sup.X and R.sup.Y are each independently any saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include 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; R.sup.1 is a cyclic group substituted at the α-position, wherein R.sup.1 may optionally be further substituted; m is 0, 1 or 2; and each R.sup.2 is independently a halo, —OH, —NO.sub.2, —NH.sub.2, —N.sub.3, —SH, or a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include 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; provided that at least one of R.sup.X and R.sup.Y comprises a nitrogen atom; and provided that the compound is not: ##STR00514##

2. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein at least one of V, W, X, Y and Z is N or NH.

3. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein any monovalent R.sup.X or R.sup.Y contains from 1 to 7 carbon atoms.

4. The compound or a pharmaceutically acceptable salt or solvate or prodrug thereof, as claimed in claim 1, wherein: (i) R.sup.X is a monovalent group having the formula: ##STR00515## wherein: p is 0 or 1; q is 0 or 1; r is 0 or 1; R.sup.10 is hydrogen or a C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl group; and R.sup.11 is a C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl group, or R.sup.11 together with any one of R.sup.13, R.sup.14 or R.sup.15 forms a C.sub.1-C.sub.4 alkylene group; or R.sup.10 and R.sup.11 together form a C.sub.2-C.sub.5 alkylene group; each R.sup.13, R.sup.14 and R.sup.15 is independently selected from hydrogen or a halo, —CN, —OH, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl, —O—(C.sub.1-C.sub.4 alkyl) or —O—(C.sub.3-C.sub.4 cycloalkyl) group, and/or any two R.sup.13, two R.sup.14 or two R.sup.15 may together with the carbon atom to which they are attached form a C═O group, and/or any two R.sup.13, R.sup.14 or R.sup.15 may together form a C.sub.1-C.sub.4 alkylene group; wherein any alkylene group may optionally include one or two heteroatoms independently selected from 0 and N in its carbon skeleton; wherein any alkyl or alkylene group may optionally be substituted with one or more halo, —CN, —OH, —NH.sub.2, oxo (═O), —OMe, —O-halomethyl, —NHMe, —NH(halomethyl), —NMe.sub.2, —NMe(halomethyl) and/or —N(halomethyl).sub.2 groups; and wherein any cycloalkyl group may optionally be substituted with one or more halo, —CN, —OH, —NH.sub.2, oxo (═O), methyl, halomethyl, —OMe, —O-halomethyl, —NHMe, —NH(halomethyl), —NMe.sub.2, —NMe(halomethyl) and/or —N(halomethyl).sub.2 groups; or (ii) R.sup.X is a monovalent group having the formula: ##STR00516## wherein: p is 0 or 1; q is 0 or 1; r is 0 or 1; R.sup.10 is a C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl group; and R.sup.11 is a C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl group, or R.sup.11 together with any one of R.sup.13, R.sup.14 or R.sup.15 forms a C.sub.1-C.sub.4 alkylene group; or R.sup.10 and R.sup.11 together form a C.sub.2-C.sub.5 alkylene group; R.sup.12 is a C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.4 cycloalkyl group; each R.sup.13, R.sup.14 and R.sup.15 is independently selected from hydrogen or a halo, —CN, —OH, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl, —O—(C.sub.1-C.sub.4 alkyl) or —O—(C.sub.3-C.sub.4 cycloalkyl) group, and/or any two R.sup.13, two R.sup.14 or two R.sup.15 may together with the carbon atom to which they are attached form a C═O group, and/or any two R.sup.13, R.sup.14 or R.sup.15 may together form a C.sub.1-C.sub.4 alkylene group; wherein any alkylene group may optionally include one or two heteroatoms independently selected from 0 and N in its carbon skeleton; wherein any alkyl or alkylene group may optionally be substituted with one or more halo, —CN, —OH, —NH.sub.2, oxo (═O), —OMe, —O-halomethyl, —NHMe, —NH(halomethyl), —NMe.sub.2, —NMe(halomethyl) and/or —N(halomethyl).sub.2 groups; and wherein any cycloalkyl group may optionally be substituted with one or more halo, —CN, —OH, —NH.sub.2, oxo (═O), methyl, halomethyl, —OMe, —O-halomethyl, —NHMe, —NH(halomethyl), —NMe.sub.2, —NMe(halomethyl) and/or —N(halomethyl).sub.2 groups.

5. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R.sup.X and R.sup.Y do not comprise an oxygen atom that is directly attached to a sp.sup.2 hybridised atom.

6. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the group: ##STR00517## including any optional substituents, contains from 8 to 17 atoms other than hydrogen or halogen.

7. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein: (i) Q is O; and/or (ii) each R.sup.2 is independently selected from halo; —CN; —NO.sub.2; —N.sub.3; —R.sup.β; —OH; —OR.sup.β; —R.sup.α-halo; —R.sup.α—CN; —R.sup.α—NO.sub.2; —R.sup.α—N.sub.3; —R.sup.α—R.sup.β; —R.sup.α—OH; —R.sup.α—OR.sup.β; —SH; —SR.sup.β; —SORB; —SO.sub.2H; —SO.sub.2R.sup.β; —SO.sub.2NH.sub.2; —SO.sub.2NHR.sup.β; SO.sub.2N(R.sup.β).sub.2; —R.sup.α—SH; —R.sup.α—SR.sup.β; —R.sup.α—SOR.sup.β; —R.sup.α—SO.sub.2H; —R.sup.α—SO.sub.2R.sup.β; —R.sup.α—SO.sub.2NH.sub.2; R.sup.α—SO.sub.2NHR.sup.β; —R.sup.α—SO.sub.2N(R.sup.β).sub.2; —NH.sub.2; NHR.sup.β; —N(R.sup.β).sub.2; —R.sup.α—NH.sub.2; —R.sup.α—NHR.sup.β; —R.sup.α—N(R.sup.β).sub.2; —CHO; —COR.sup.β; —COOH; —COOR.sup.β; —OCOR.sup.β; —R.sup.α—CHO; —R.sup.α—COR.sup.β; —R.sup.α—COOH; —R.sup.α—COOR.sup.β; or —R.sup.α—OCOR.sup.β; wherein each —R.sup.α— is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, 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 N, O or S, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or —RP groups; and wherein each —R.sup.β is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group, and wherein any —R.sup.β may optionally be substituted with one or more C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —O(C.sub.3-C.sub.7 cycloalkyl), halo, —OH, —NH.sub.2, —CN, —C≡CH, oxo (═O), or 4- to 6-membered heterocyclic group.

8. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R.sup.1 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α-position, and wherein R.sup.1 may optionally be further substituted, and optionally wherein: (i) R.sup.1 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α and α′ positions, and wherein R.sup.1 may optionally be further substituted; or (ii) R.sup.1 is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α,β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α′,β′ positions, and wherein R.sup.1 may optionally be further substituted.

9. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein the substituent at the α-position of the cyclic group of R.sup.1 is a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to the α-ring atom of the cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group may optionally be further substituted.

10. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R.sup.1 is a cyclic group substituted at the α and α′ positions, wherein R.sup.1 may optionally be further substituted, and wherein optionally each substituent at the α and α′ positions comprises a carbon atom.

11. The compound or pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, which is (a) a compound selected from the group consisting of: ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550## ##STR00551## ##STR00552## or (b) a pharmaceutically acceptable salt or solvate of the selected compound.

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

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

14. The method as claimed in claim 13, 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) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

15. The method as claimed in claim 13, 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).

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

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

18. The method as claimed in claim 13, wherein the compound or the pharmaceutically acceptable salt or solvate thereof is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

19. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R.sup.X and R.sup.Y do not comprise a nitrogen atom that is directly attached to a sp.sup.2 hybridised atom.

20. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R.sup.X and R.sup.Y contain only atoms selected from the group consisting of carbon, hydrogen, nitrogen and halogen atoms.

21. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein: Q is O; V is C, X and Y are each independently selected from C and N, and W and Z are each independently selected from N, NH and CH, provided that at least one of W, X, Y and Z is C or CH, and at least two of W, X, Y and Z are N or NH; R.sup.X is a saturated hydrocarbyl group, wherein the hydrocarbyl group is straight-chained or branched, or is or includes cyclic groups, wherein the hydrocarbyl group may optionally be substituted with one or more groups selected from halo, —CN, —OH, —NH.sub.2 and oxo (═O), wherein the hydrocarbyl group includes at least one heteroatom N in its carbon skeleton, and wherein the hydrocarbyl group may optionally include one or two further heteroatoms independently selected from N and O in its carbon skeleton; R.sup.Y is a saturated hydrocarbyl group, wherein the saturated hydrocarbyl group may be straight-chained or branched, or is or includes cyclic groups, wherein the saturated hydrocarbyl group may optionally be substituted with one or more groups selected from halo, —CN, —OH, —NH.sub.2 and oxo (═O), and wherein the saturated hydrocarbyl group may optionally include one or two heteroatoms N or O in its carbon skeleton; R.sup.X contains from 1 to 11 atoms other than hydrogen or halogen; R.sup.Y contains from 1 to 11 atoms other than hydrogen or halogen; m is 0; and R.sup.1 is phenyl or a 5- or 6-membered heteroaryl group, wherein (i) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α position with a substituent selected from —R.sup.4, —OR.sup.4 and —COR.sup.4, wherein R.sup.4 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.4 is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.44, —OR.sup.44 and —COR.sup.44, wherein R.sup.44 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.44 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted with one, two or three substituents independently selected from halo, —NO.sub.2, —CN, —COOR.sup.45, —CONH.sub.2, —CONHR.sup.45 or —CON(R.sup.45).sub.2, wherein each —R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (ii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α,β positions and which is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.4, —OR.sup.4 and —COR.sup.4, wherein R.sup.4 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.4 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted with one or two substituents independently selected from halo, —NO.sub.2, —CN, —COOR.sup.45, —CONH.sub.2, —CONHR.sup.45 or —CON(R.sup.45).sub.2, wherein each —R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (iii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α,β positions and which is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is substituted with a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α′,β′ positions and which is optionally substituted with one or more halo groups; and optionally the phenyl group is further substituted with a substituent selected from halo, —NO.sub.2, —CN, —COOR.sup.45, —CONH.sub.2, —CONHR.sup.45 or —CON(R.sup.45).sub.2, wherein each —R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (iv) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.42—OR.sup.43, —R.sup.42—N(R.sup.43).sub.2, —R.sup.42—CN or —R.sup.42—C≡CR.sup.43, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the α-ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R.sup.42 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.43 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.4, —OR.sup.4 and —COR.sup.4, wherein R.sup.4 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.4 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted with one, two or three substituents independently selected from halo, —NO.sub.2, —CN, —COOR.sup.45, —CONH.sub.2, —CONHR.sup.45 or —CON(R.sup.45).sub.2, wherein each —R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group; or (v) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.42—OR.sup.43, —R.sup.42—N(R.sup.43).sub.2, —R.sup.42—CN or —R.sup.42—C≡CR.sup.43, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the α-ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R.sup.42 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.43 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α′,β′ positions and which is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted with one or two substituents independently selected from halo, —NO.sub.2, —CN, —COOR.sup.45, —CONH.sub.2, —CONHR.sup.45 or —CON(R.sup.45).sub.2, wherein each —R.sup.45 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group.

22. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 21, wherein R.sup.X is a saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or may be or include cyclic groups, wherein the saturated hydrocarbyl group may be unsubstituted or optionally substituted with one or more fluoro and/or chloro groups, wherein the saturated hydrocarbyl group includes at least one heteroatom N in its carbon skeleton, and wherein the saturated hydrocarbyl group may optionally include one or two further heteroatoms independently selected from N and O in its carbon skeleton; and R.sup.Y is a saturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or may be or include cyclic groups, wherein the saturated hydrocarbyl group may be unsubstituted or optionally substituted with one or more fluoro and/or chloro groups, and wherein the saturated hydrocarbyl group may optionally include one or two oxygen atoms in its carbon skeleton.

23. A prodrug of a compound of formula (I): ##STR00553## or a pharmaceutically acceptable salt or solvate of the prodrug, wherein: Q is selected from O or S; ring A is monocyclic; V, X and Y are each independently selected from C and N, and W and Z are each independently selected from N, O, S, NH and CH, provided that at least one of V, W, X, Y and Z is N, O, S or NH; R.sup.X and R.sup.Y are each independently any saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include 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; R.sup.1 is a cyclic group substituted at the α-position, wherein R.sup.1 may optionally be further substituted; m is 0, 1 or 2; and each R.sup.2 is independently a halo, —OH, —NO.sub.2, —NH.sub.2, —N.sub.3, —SH, or a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include 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; provided that at least one of R.sup.X and R.sup.Y comprises a nitrogen atom; and provided that the compound is not: ##STR00554##

24. A method of treating, or delaying onset or reducing risk of a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the prodrug or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 23, to the subject, thereby treating or delaying onset or reducing risk of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

Description

EXAMPLES—COMPOUND SYNTHESIS

(1) All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

(2) 2-MeTHF 2-methyltetrahydrofuran Ac.sub.2O acetic anhydride AcOH acetic acid aq aqueous Boc tert-butyloxycarbonyl br broad Cbz carboxybenzyl CDI 1,1-carbonyl-diimidazole conc concentrated d doublet DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2-dichloroethane, also called ethylene dichloride DCM dichloromethane DIPEA N,N-diisopropylethylamine, also called Hünig's base DMA dimethylacetamide DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eq or equiv equivalent (ES+) electrospray ionization, positive mode Et ethyl EtOAc ethyl acetate EtOH ethanol h hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HPLC high performance liquid chromatography LC liquid chromatography m multiplet m-CPBA 3-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeOH methanol (M+H)+ protonated molecular ion MHz megahertz min minute(s) MS mass spectrometry Ms mesyl, also called methanesulfonyl MsCl mesyl chloride, also called methanesulfonyl chloride MTBE methyl tert-butyl ether, also called tert-butyl methyl ether m/z mass-to-charge ratio NaOtBu sodium tert-butoxide NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide NMP N-methylpyrrolidine NMR nuclear magnetic resonance (spectroscopy) Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) PE petroleum ether Ph phenyl PMB p-methoxybenzyl prep-HPLC preparative high performance liquid chromatography prep-TLC preparative thin layer chromatography PTSA p-toluenesulfonic acid q quartet RP reversed phase RT room temperature s singlet Sept septuplet sat saturated SCX solid supported cation exchange (resin) t triplet T3P propylphosphonic anhydride TBME tert-butyl methyl ether, also called methyl tert-butyl ether TEA triethylamine TFA 2,2,2-trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography wt % weight percent or percent by weight

Experimental Methods

(3) Nuclear Magnetic Resonance

(4) 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: a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, a Bruker 400 MHz spectrometers using ICON-NMR, under TopSpin program control, a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, 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 an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

(5) LC-MS

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

(7) Reversed Phase HPLC Conditions for the LCMS Analytical Methods

(8) Methods 1a and 1b: Waters Xselect CSH C18 XP column (4.6×30 mm, 2.5 μm) at 40° C.; flow rate 2.5-4.5 mL min.sup.−1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 1b) over 4 min employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01 min, held at 5% water-95% acetonitrile, flow rate increased to 4.5 mL min.sup.−1; 3.01-3.50 min, held at 5% water-95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate reduced to 3.50 mL min.sup.−1; 3.60-3.90 min, held at 95% water-5% acetonitrile; 3.90-4.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 2.5 mL min.sup.−1.

(9) Method 1c: Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.1×50 mm, 2.5 μm) at 35° C.; flow rate 0.6 mL/min; mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); over 4 min employing UV detection at 215 and 238 nm. Gradient information: 0-0.5 min, held at 80% A-20% B; 0.5-2.0 min, ramped from 80% A-20% B to 100% B.

(10) Reversed Phase HPLC Conditions for the UPLC Analytical Methods

(11) Methods 2a and 2b: Waters BEH C18 (2.1×30 mm, 1.7 μm) at 40° C.; flow rate 0.77 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm. Gradient information: 0-0.11 min, held at 95% water-5% acetonitrile, flow rate 0.77 mL min.sup.−1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95% acetonitrile, flow rate 0.77 mL min.sup.−1; 2.49-2.56 min, returned to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 0.77 mL min.sup.−1.

(12) Preparative Reversed Phase HPLC General Methods

(13) Method 1 (acidic preparation): Waters X-Select CSH column C18, 5 μm (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, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

(14) Method 2 (basic preparation): 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, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

(15) Method 3: Phenomenex Gemini column, 10 μm (150×25 mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35% to 100% acetonitrile; 9.2-15.2 minutes, held at 100% acetonitrile.

(16) Method 4: Revelis C18 reversed-phase 12 g cartridge [carbon loading 18%; surface area 568 m.sup.2/g; pore diameter 65 Angstrom; pH (5% slurry) 5.1; average particle size 40 μm], flow rate=30 mL/min eluting with a water-methanol gradient over 35 minutes using UV detection at 215, 235, 254 and 280 nm. Gradient information: 0-5 minutes, held at 0% methanol; 5-30 minutes, ramped from 0% to 70% methanol; 30-30.1 minutes, ramped from 70% to 100% methanol; 30.1-35 minutes, held at 100% methanol.

Synthesis of Intermediates

Intermediate P1: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide

Step A: 2-Amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

(17) ##STR00090##

(18) Zinc (167 mg, 2.55 mmol) was added portionwise to 5-methyl-2-nitro-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one (1.4 g, 7.14 mmol) in AcOH (1.0 mL) and THF (1.5 mL). The reaction mixture was left to stir at room temperature for 2 days. The reaction mixture was filtered through a pad of Celite®, washed with DCM (2×15 mL) and the filtrate concentrated under reduced pressure to give a yellow solid. The solid was suspended in DCM (5 mL), filtered and the filtrate was evaporated to dryness to give the title compound (2.2 g, 74%) as a yellow solid.

(19) .sup.1H NMR (DMSO-d.sub.6) δ 5.80 (s, 1H), 4.83 (s, 2H), 4.10-3.93 (m, 2H), 3.72-3.55 (m, 2H), 2.97 (s, 3H).

(20) LCMS; m/z 167 (M+H).sup.+ (ES.sup.+).

Step B: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonyl Chloride

(21) ##STR00091##

(22) A mixture of aqueous HCl (2.2 mL) in water (8 mL) and acetonitrile (8 mL) was cooled to −10° C. and treated with a solution of NaNO.sub.2 (0.50 g, 7.25 mmol) in water (0.9 mL) dropwise maintaining the internal temperature below 0° C. The solution was stirred for 10 minutes and then treated with a solution of 2-amino-5-methyl-6,7-dihydropyrazolo [1,5-a]pyrazin-4(5H)-one (0.997 g, 6 mmol) in acetonitrile (8 mL) (which was pre-cooled to 0° C.) at 0° C. The resulting reaction mixture was stirred at 0° C. for 50 minutes. Cold AcOH (4.8 mL), CuCl.sub.2 dihydrate (0.30 g, 2.23 mmol) and CuCl (0.03 g, 0.30 mmol) were sequentially added to the reaction mixture and the reaction mixture was purged with SO.sub.2 gas for 20 minutes at 0° C. The reaction was stirred for a further 45 minutes, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic phase was washed with water (25 mL) and saturated brine (25 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a brown oil. The brown oil was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (577 mg, 30%) as a yellow crystalline solid.

(23) .sup.1H NMR (CDCl.sub.3) δ 7.39 (s, 1H), 4.63-4.45 (m, 2H), 3.95-3.83 (m, 2H), 3.19 (s, 3H).

Step C: 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide

(24) ##STR00092##

(25) 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonyl chloride (577 mg, 1.826 mmol) in THF (4 mL) was treated with 0.5 M ammonia in 1,4-dioxane (11.00 mL, 5.50 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was suspended in water (10 mL) and filtered. The yellow powder obtained was then washed with DCM (2×5 mL) and dried under vacuum to afford the title compound (332 mg, 77%) as a white powder.

(26) .sup.1H NMR (DMSO-d.sub.6) δ 7.57 (s, 2H), 6.93 (s, 1H), 4.59-4.34 (m, 2H), 3.90-3.71 (m, 2H), 3.01 (s, 3H).

(27) LCMS; m/z 231 (M+H).sup.+ (ES.sup.+).

Intermediate P2: 1-(2-(Dimethylamino)ethyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

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

(28) ##STR00093##

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

(30) .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).

(31) LCMS; m/z 215 (M−H).sup.− (ES.sup.−).

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

(32) ##STR00094##

(33) 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 hours, 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 hour, the mixture was warmed to room temperature, and then partitioned between DCM (300 mL) and water (250 mL). The organic layer was washed with water (250 mL), aq 1M HCl (2×250 mL), water (250 mL), dried (MgSO.sub.4), filtered, and evaporated to afford the crude title compound (41.02 g, 97%) as a brown oil.

(34) LCMS; m/z 494.2 (M+Na).sup.+ (ES.sup.+).

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

(35) ##STR00095##

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

(37) .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). Exchangeable proton not visible.

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

Step D: 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(39) ##STR00096##

(40) N,N-Bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (3.94 g, 10.17 mmol) and potassium carbonate (4.22 g, 30.5 mmol) were suspended in dry acetonitrile (30 mL). 2-Bromoethanol (0.937 mL, 13.22 mmol) was added, the mixture was warmed to 50° C. overnight, then water (20 mL) was added and the organic layer was collected. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica (80 g column, 0-75% EtOAc/isohexane) to afford the title compound (3 g, 66%) as a clear colourless oil.

(41) .sup.1H NMR (CDCl.sub.3) δ 7.50 (d, J=2.3 Hz, 1H), 7.12-7.01 (m, 4H), 6.82-6.74 (m, 4H), 6.66 (d, J=2.3 Hz, 1H), 4.32 (s, 4H), 4.30-4.24 (m, 2H), 4.01-3.94 (m, 2H), 3.78 (s, 6H).

(42) OH proton not visible.

(43) LCMS; m/z 454.4 (M+Na).sup.+ (ES.sup.+).

Step E: 1-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(44) ##STR00097##

(45) 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.00 g, 4.63 mmol) and DIPEA (1.4 mL, 8.04 mmol) were dissolved in THF (20 mL) and cooled to 0° C. Methanesulfonyl chloride (0.40 mL, 5.17 mmol) was added and the mixture was stirred at 0° C. for 1 hour. Dimethylamine (40% in water) (3 mL, 23.69 mmol) was added and the reaction mixture was stirred at room temperature over the weekend. The mixture was concentrated to dryness and the yellow residue partitioned between water (30 mL) and EtOAc (70 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×70 mL). The combined organic layers were dried (MgSO.sub.4) and evaporated to give a yellow oil. The crude product was loaded onto a column of SCX (7 g) in MeOH. The column was washed with DCM:MeOH (9:1) and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (1.36 g, 61%) as a thick orange oil.

(46) .sup.1H NMR (CDCl.sub.3) δ 7.54 (d, J=2.3 Hz, 1H), 7.14-6.97 (m, 4H), 6.81-6.71 (m, 4H), 6.62 (d, J=2.3 Hz, 1H), 4.35-4.21 (m, 6H), 3.78 (s, 6H), 2.77 (t, J=6.5 Hz, 2H), 2.29 (s, 6H).

(47) LCMS; m/z 459.5 (M+H).sup.+ (ES.sup.+).

Step F: 1-(2-(Dimethylamino)ethyl)-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(48) ##STR00098##

(49) A solution of n-BuLi (2.5M in hexanes) (0.44 mL, 1.100 mmol) was added dropwise to a stirred solution of 1-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.5 g, 1.090 mmol) in THF (14 mL) at −78° C. The reaction was stirred for 1 hour and N-methyl-N-methylenemethanaminium iodide (0.403 g, 2.181 mmol) was added. The reaction mixture was left at −78° C. for 1 hour. Then the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was separated, dried over MgSO.sub.4, filtered and concentrated to dryness. The crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (208 mg, 35%) as a yellow oil.

(50) .sup.1H NMR (DMSO-d.sub.6) δ 7.09-6.94 (m, 4H), 6.89-673 (m, 4H), 6.56 (s, 1H), 4.28 (t, J=6.9 Hz, 2H), 4.20 (s, 4H), 3.71 (s, 6H), 3.48 (s, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.19 (s, 6H), 2.16 (s, 6H).

(51) LCMS; m/z 517 (M+H).sup.+ (ES.sup.+).

Step G: 1-(2-(Dimethylamino)ethyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

(52) ##STR00099##

(53) 1-(2-(Dimethylamino)ethyl)-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (207 mg, 0.401 mmol) was dissolved in TFA (3 mL) and stirred at room temperature for 17 hours. The mixture was evaporated to dryness, dissolved in DCM:MeOH (9:1) and loaded onto SCX (1 g). The column was washed with DCM:MeOH (9:1) (2×20 mL), then the product was eluted with 0.7 NH.sub.3 in DCM:MeOH (9:1) (2×10 mL). The resultant mixture was concentrated in vacuo to afford the title compound (82 mg, 73%) as a white solid.

(54) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.46 (s, 1H), 4.25 (t, J=7.0 Hz, 2H), 3.47 (s, 2H), 2.64 (t, J=7.0 Hz, 2H), 2.19 (s, 6H), 2.16 (s, 6H).

(55) LCMS; m/z 276 (M+H).sup.+ (ES.sup.+).

Intermediate P3: 1-(2-(Dimethylamino)ethyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

Step A: 1-(2-(Dimethylamino)ethyl)-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(56) ##STR00100##

(57) Prepared according to the general procedure of 1-(2-(dimethylamino)ethyl)-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P2, Step F) from 1-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P2, Step E) and acetone to afford the title compound (373 mg, 33%) as a white solid.

(58) .sup.1H NMR (DMSO-d.sub.6) δ 7.10-6.94 (m, 4H), 6.88-6.72 (m, 4H), 6.40 (s, 1H), 5.63 (s, 1H), 4.54-4.45 (m, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 2.69 (t, J=7.3 Hz, 2H), 2.20 (s, 6H), 1.50 (s, 6H).

(59) LCMS; m/z 518 (M+H).sup.+ (ES.sup.+).

Step B: 1-(2-(Dimethylamino)ethyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

(60) ##STR00101##

(61) Prepared according to the general procedure of 1-(2-(dimethylamino)ethyl)-5 ((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P2, Step G) from 1-(2-(dimethylamino)ethyl)-5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (140 mg, 67%) as pale yellow solid on standing.

(62) .sup.1H NMR (DMSO-d6) δ 7.34 (s, 2H), 6.38 (s, 1H), 5.63 (s, 1H), 4.64-4.35 (m, 2H), 2.79-2.65 (m, 2H), 2.21 (s, 6H), 1.52 (s, 6H).

(63) LCMS; m/z 277 (M+H).sup.+ (ES.sup.+).

Intermediate P4: 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide

(64) ##STR00102##

(65) Borane tetrahydrofuran complex (0.87 mL, 0.87 mmol) was added to a solution of 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (Intermediate P1) (50 mg, 0.217 mmol) in THF (5 mL) at room temperature. The mixture was stirred for 5 minutes and then heated to reflux overnight for 2 days. The reaction mixture was cooled to room temperature, MeOH (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the crude product was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (30 mg, 61%) as a colourless solid.

(66) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.36 (s, 1H), 4.14 (t, J=5.6 Hz, 2H), 3.60 (s, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.40 (s, 3H).

Intermediate P5: 1-(2-(Dimethylamino)ethyl)-5-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 1-(2-(Dimethylamino)ethyl)-5-iodo-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(67) ##STR00103##

(68) n-BuLi (2.5 M in hexanes) (0.951 mL, 2.377 mmol) was added dropwise to a solution of 1-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P2, Step E) (1.09 g, 2.377 mmol) in anhydrous THF (15 mL) at −78° C., maintaining the temperature below −65° C. The solution was stirred for 1 hour at −78° C., before a solution of diiodine (0.784 g, 3.09 mmol) in THF (5 mL) was added. The mixture was stirred for 5 minutes at this temperature, then the temperature was raised to room temperature and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and diluted with DCM (20 mL), then the mixture was poured onto 10 wt % aqueous sodium thiosulfate (30 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness to give a yellow oil. The crude product was purified by chromatography on silica gel (24 g column, 0-5% MeOH/DCM) to afford the title compound (0.48 g, 32%) as a yellow wax.

(69) .sup.1H NMR (DMSO-d.sub.6) δ 7.07-7.00 (m, 4H), 6.84 (s, 1H), 6.83-6.77 (m, 4H), 4.28 (t, J=6.8 Hz, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 2.63 (t, J=6.8 Hz, 2H), 2.20 (s, 6H).

(70) LCMS; m/z 585.4 (M+H).sup.+ (ES.sup.+).

Step B: 1-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-5-(prop-1-en-2-yl)-1H-pyrazole-3-sulfonamide

(71) ##STR00104##

(72) Nitrogen was bubbled through a mixture of 1-(2-(dimethylamino)ethyl)-5-iodo-N,N— bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.48 g, 0.772 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.185 mL, 0.984 mmol), palladium acetate (0.037 g, 0.164 mmol), tricyclohexylphosphine in toluene (20 wt %) (0.460 g, 0.328 mmol), and caesium carbonate (2.67 g, 8.20 mmol) in toluene (10 mL) and water (5 mL) for 15 minutes and then the reaction mixture was heated at 100° C. for 18 hours. Then the reaction mixture was cooled to room temperature and filtered through a pad of Celite®. The filter cake was washed with DCM (3×10 mL) and the organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and evaporated to give a brown residue which was purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (191 mg, 35%) as an orange oil.

(73) .sup.1H NMR (DMSO-d.sub.6) δ 7.09-7.01 (m, 4H), 6.84-6.76 (m, 4H), 6.65 (s, 1H), 5.53-5.40 (m, 1H), 5.35-5.21 (m, 1H), 4.26 (t, J=6.7 Hz, 2H), 4.21 (s, 4H), 3.71 (s, 6H), 2.61 (t, J=6.7 Hz, 2H), 2.13 (s, 6H), 2.07-2.02 (m, 3H).

(74) LCMS; m/z 499.5 (M+H).sup.+ (ES.sup.+).

Step C: 1-(2-(Dimethylamino)ethyl)-5-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(75) ##STR00105##

(76) 1-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-5-(prop-1-en-2-yl)-1H-pyrazole-3-sulfonamide (191 mg, 0.287 mmol) and 5% palladium on carbon (61 mg, 0.014 mmol) were suspended in EtOH (3 mL) and hydrogenated at 5 bar for 17 hours. The reaction mixture was filtered through a pad of Celite® and washed with EtOH (2×5 mL). The filtrate was evaporated to dryness, redissolved in MeOH (3 mL) and loaded onto a column of SCX (1 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (174 mg, 92%) as a thick orange oil.

(77) .sup.1H NMR (DMSO-d.sub.6) δ 7.15-6.96 (m, 4H), 6.90-6.77 (m, 4H), 6.44 (s, 1H), 4.29-4.15 (m, 6H), 3.72 (s, 6H), 3.09 (sept, J=6.8 Hz, 1H), 2.63 (t, J=6.6 Hz, 2H), 2.19 (s, 6H), 1.21 (d, J=6.8 Hz, 6H).

(78) LCMS; m/z 501.5 (M+H).sup.+ (ES.sup.+).

Step D: 1-(2-(Dimethylamino)ethyl)-5-isopropyl-1H-pyrazole-3-sulfonamide

(79) ##STR00106##

(80) Prepared according to the general procedure of 1-(2-(dimethylamino)ethyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P2, Step G) from 1-(2-(dimethylamino)ethyl)-5-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (68 mg, 73%) as a colourless glass.

(81) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.39 (s, 1H), 4.16 (t, J=6.9 Hz, 2H), 3.08 (sept, J=6.7 Hz, 1H), 2.63 (t, J=6.9 Hz, 2H), 2.18 (s, 6H), 1.21 (d, J=6.8 Hz, 6H).

(82) LCMS; m/z 261.3 (M+H).sup.+ (ES.sup.+).

Intermediate P6: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

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

(83) ##STR00107##

(84) To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in 1,2-dichloroethane (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol, 1.57 eq) at 25° C. The mixture was stirred at 25° C. for 30 minutes. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol, 1 eq) was added and the reaction mixture was warmed to 70° C. and stirred at 70° C. for 15.5 hours. Then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=30:1 to 3:1) to give crude product (26.7 g). The crude product was dissolved in pyrrolidine (10 mL) and the resulting mixture was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyrrolidine. The residue was diluted with H.sub.2O (33 mL) and the pH was adjusted to 5-6 with aqueous HCl solution (1N). The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×33 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 29.7%) as a yellow oil.

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

Step B: 1-Cyclopropyl-1H-pyrazol-3-amine

(86) ##STR00108##

(87) To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 41.09 mL, 5 eq) in H.sub.2O (150 mL). Then the reaction mixture was warmed to 60° C. and iron powder (39.38 g, 705.24 mmol, 3 eq) was added to the reaction mixture in portions. The reaction mixture was stirred at 60° C. for 16 hours and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=30:1 to 1:1) to give the title compound (20 g, 69.08%) as a yellow oil.

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

(89) LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-Cyclopropyl-1H-pyrazole-3-sulfonyl Chloride

(90) ##STR00109##

(91) To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in acetonitrile (500 mL) and H.sub.2O (50 mL) at 0° C. was added concentrated HCl solution (50 mL). Then an aqueous solution of NaNO.sub.2 (12.77 g, 185.13 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting solution was stirred at 0° C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (10.37 g, 77-14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added into the reaction mixture. Then SO.sub.2 gas (15 psi) was bubbled into the reaction mixture for 20 minutes at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (250 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (2×150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=100:0 to 1:1) to give the title compound (14 g, 43.91%) as a yellow oil.

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

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

(93) ##STR00110##

(94) To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added triethylamine (27.42 g, 270.99 mmol, 37.72 mL, 2 eq) and bis(4-methoxybenzyl)amine (34.87 g, 135.49 mmol, 1 eq). The mixture was stirred at 25° C. for 1 hour. Then the reaction mixture was diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (acetonitrile/NH.sub.3. H.sub.2O (0.5% NH.sub.3. H.sub.2O)) and the collected eluting solution was concentrated under reduced pressure to remove most of the acetonitrile. Then the mixture was extracted with EtOAc (3×1000 mL). The combined organic layers were washed with brine (2×500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (30 g, 51.69% yield, 99.8% HPLC purity).

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

(96) LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

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

(97) ##STR00111##

(98) A solution of n-BuLi (2.5 M, 8.89 mL, 1 eq) was added dropwise to a stirred solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (10 g, 22.22 mmol, 1 eq) in THF (250 mL) at −78° C. The reaction mixture was stirred for 1 hour at −78° C. Then N-methyl-N-methylenemethanaminium iodide (8.22 g, 44.44 mmol, 2 eq) was added. The reaction mixture was stirred at −78° C. for 30 minutes and warmed to 25° C. for 30 minutes. Then the reaction mixture was diluted with saturated aqueous NH.sub.4Cl solution (150 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=10:1 to 0:1) to give the title compound (9 g, 81.82% yield, 97.9% LCMS purity) as a yellow oil.

(99) .sup.1H NMR (DMSO-d.sub.6) δ 7.03-7.00 (m, 4H), 6.83-6.78 (m, 4H), 6.56 (s, 1H), 4.20 (s, 4H), 3.82-3.76 (m, 1H), 3.71 (s, 6H), 3.57 (s, 2H), 2.19 (s, 6H), 1.09-0.99 (m, 4H).

(100) LCMS: m/z 485.2 (M+H).sup.+ (ES.sup.+).

Step F: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

(101) ##STR00112##

(102) To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (9 g, 18.57 mmol, 1 eq) in DCM (30 mL) was added TFA (154.0 g, 1.35 mol, 100 mL, 72.73 eq). The reaction mixture was stirred at 25° C. for 12 hours and then concentrated under reduced pressure. The residue was treated with MeOH (300 mL) and a solid formed. The mixture was filtered and the filtrate was collected. The pH of the filtrate was adjusted to 8-9 with ion exchange resin (Amberlyst® A-21). The mixture was filtered and the filtrate was concentrated. The residue was purified by reversed phase prep-HPLC (column: Phenomenex Gemini; C18 250 mm*50 mm*10 μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-MeCN]; B %: 1%-45%, 35 minutes) to give the title compound (3.97 g, 87.6% yield, 100% .sup.1H NMR purity) as a white solid.

(103) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (br s, 2H), 6.48 (s, 1H), 3.78-3.74 (m, 1H), 3.56 (s, 2H), 2.20 (s, 6H), 1.11-1.02 (m, 4H).

(104) LCMS: m/z 245.2 (M+H).sup.+ (ES.sup.+).

Intermediate P7: 5-((Dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis-(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide

(105) ##STR00113##

(106) To a solution of 1-ethyl-1H-pyrazole-3-sulfonyl chloride (41.0 g, 210 mmol) in THF (400 mL) was added TEA (63.9 g, 631 mmol) and bis(4-methoxybenzyl)amine (10.8 g, 42.1 mmol). The mixture was stirred at 25° C. for 1.5 hours. The reaction mixture was diluted with water (800 mL) and extracted with EtOAc (3×800 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3 in water/MeCN) to give the title compound (18.7 g, 21%) as a yellow oil.

(107) .sup.1H NMR (CDCl.sub.3) δ 7.44 (d, 1H), 7.06 (d, 4H), 6.77 (d, 4H), 6.64 (d, 1H), 4.32 (s, 4H), 4.27-4.21 (m, 2H), 3.79 (s, 6H), 1.52 (t, 3H).

(108) LCMS: m/z 416.1 (M+H).sup.+ (ES.sup.+).

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

(109) ##STR00114##

(110) A solution of n-BuLi (2.5 M in hexanes) (3 mL, 7.50 mmol) was added dropwise to a stirred solution of 1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (3 g, 7.22 mmol) in THF (45 mL) at −78° C. The reaction was stirred for 1 hour and then N,N— dimethylmethyleneiminium iodide (2.67 g, 14.44 mmol) was added. The reaction mixture was left at −78° C. for 1 hour, quenched with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on the SiO.sub.2 (120 g column, 0-10% MeOH/DCM) to afford the title compound (1.75, 49%) as a yellow solid.

(111) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-6.99 (m, 4H), 6.85-6.78 (m, 4H), 6.57 (s, 1H), 4.27-4.17 (m, 6H), 3.72 (s, 6H), 3.47 (s, 2H), 2.16 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).

(112) LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-((Dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide

(113) ##STR00115##

(114) 5-((Dimethylamino)methyl)-1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1.75 g, 3.70 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The solution was stirred for 16 hours, concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The residue was dissolved in a mixture of DCM (10 mL) and MeOH (20 mL). SCX (14 g) was added and the suspension was stirred at room temperature for 1 hour. The SCX was filtered off and washed with MeOH (3×10 mL) and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (705 mg, 81%) as a white solid.

(115) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.47 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.47 (s, 2H), 2.17 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).

(116) LCMS; m/z 233.4 (M+H).sup.+ (ES.sup.+).

Intermediate P8: 1-(1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium 2,2,2-trifluoroacetate

Step A: N,N-Bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(117) ##STR00116##

(118) Prepared according to the general procedure of N,N-bis-(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7, Step A) from 1-isopropyl-H-pyrazole-3-sulfonyl chloride to afford the title compound (16.6 g, 80%) as a white solid.

(119) .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (d, J=2.4 Hz, 1H), 7.07-6.96 (m, 4H), 6.85-6.76 (m, 4H), 6.70 (d, J=2.4 Hz, 1H), 4.61 (sept, J=6.7 Hz, 1H), 4.20 (s, 4H), 3.71 (s, 6H), 1.44 (d, J=6.7 Hz, 6H).

(120) LCMS; m/z 452.2 (M+Na)+(ES.sup.+).

Step B: 5-(1-Hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(121) ##STR00117##

(122) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and acetaldehyde to afford the title compound (2.14 g, 65%) as a white solid.

(123) .sup.1H NMR (DMSO-d.sub.6) δ 7.07-6.99 (m, 4H), 6.84-6.78 (m, 4H), 6.51 (s, 1H), 5.49 (d, J=6.0 Hz, 1H), 4.96-4.76 (m, 2H), 4.19 (s, 4H), 3.72 (s, 6H), 1.44 (d, J=6.5 Hz, 3H), 1.39 (t, J=6.4 Hz, 6H).

(124) LCMS; m/z 496.4 (M+Na)+(ES.sup.+).

Step C: 5-(1-(Dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(125) ##STR00118##

(126) 5-(1-Hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1 g, 2.112 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.103 mL, 6.33 mmol) were dissolved in THF (20 mL) and cooled to 0° C. MsCl (0.327 mL, 4.22 mmol) was added and the mixture was stirred at 0° C. for 1 hour. Dimethylamine (2 M in THF) (10 mL, 20.00 mmol) and KI (0.175 g, 1.056 mmol) were added and the reaction mixture was stirred at room temperature over the weekend. The mixture was concentrated to dryness and the yellow residue partitioned between water (20 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO.sub.4) and evaporated to give a yellow oil. The crude product was purified by chromatography on SiO.sub.2 (40 g column, 0-10% MeOH/DCM) to afford impure product (800 mg) as a brown oil. The impure product was loaded onto a column of SCX (4 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (555 mg, 52%) as a yellow oil.

(127) .sup.1H NMR (DMSO-d.sub.6) δ 7.07-6.96 (m, 4H), 6.86-6.76 (m, 4H), 6.49 (s, 1H), 4.93-4.84 (m, 1H), 4.21 (s, 4H), 4.01-3.90 (m, 1H), 3.72 (s, 6H), 2.13 (s, 6H), 1.43-1.32 (m, 6H), 1.24 (d, J=6.7 Hz, 3H).

(128) LCMS; m/z 501.5 (M+H).sup.+ (ES.sup.+).

Step D: 1-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium Iodide

(129) ##STR00119##

(130) MeI (0.139 mL, 2.217 mmol) was added to a stirred solution of 5-(1-(dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (555 mg, 1.109 mmol) in MeCN (75 mL). The reaction mixture was stirred at room temperature for 16 hours. The resultant colourless precipitate was collected by filtration, washing with MeCN (5 mL), and dried in vacuo to afford the title compound (241 mg, 34%) as a colourless solid. The filtrate and washing were combined and concentrated to afford additional material (450 mg, 60%) as a yellow solid.

(131) .sup.1H NMR (DMSO-d.sub.6) δ 7.26 (s, 1H), 7.12-7.02 (m, 4H), 6.88-6.80 (m, 4H), 5.13 (q, J=6.8 Hz, 1H), 5.09-4.97 (m, 1H), 4.31 (d, J=15.4 Hz, 2H), 4.23 (d, J=15.4 Hz, 2H), 3.73 (s, 6H), 3.02 (s, 9H), 1.69 (d, J=6.8 Hz, 3H), 1.51 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.3 Hz, 3H).

(132) LCMS; m/z 515.5 (M)+(ES.sup.+).

Step E: 1-(1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium 2,2,2-trifluoroacetate

(133) ##STR00120##

(134) 1-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium iodide (150 mg, 0.233 mmol) was dissolved in DCM (1.5 mL) and TFA (1.5 mL) was added. The solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude was dissolved in MeOH, filtered and dried under vacuum to afford the title compound (100 mg, 99%) as a solid.

(135) .sup.1H NMR (DMSO-d.sub.6) δ 7.52 (s, 2H), 7.15 (s, 1H), 5.22-5.08 (m, 1H), 5.08-4.98 (m, 1H), 3.04 (s, 9H), 1.73 (d, J=6.8 Hz, 3H), 1.53 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.3 Hz, 3H).

(136) LCMS; m/z 275.4 (M)+(ES.sup.+).

Intermediate P9: N,N,N-Trimethyl-1-(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)ethan-1-aminium 2,2,2-trifluoroacetate

Step A: N,N-Bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(137) ##STR00121##

(138) A solution of 1-methyl-1H-pyrazole-3-sulfonyl chloride (13.0 g, 72.0 mmol) in DCM (30 mL) was added slowly to a solution of bis-(4-methoxybenzyl)amine (20 g, 78 mmol) and triethylamine (20 mL, 143 mmol) in DCM (250 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. The mixture was washed with water (200 mL), hydrochloric acid (aqueous, 1 M, 200 mL) and water (200 mL), then dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated with TBME (250 mL), filtered and then purified by chromatography on silica gel (330 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (27.7 g, 93%) as a white solid.

(139) .sup.1H NMR (CDCl.sub.3) δ 7.42 (d, J=2.3 Hz, 1H), 7.11-7.07 (m, 4H), 6.81-6.77 (m, 4H), 6.65 (d, J=2.3 Hz, 1H), 4.33 (s, 4H), 3.99 (s, 3H) and 3.81 (s, 6H).

(140) LCMS; m/z 402 (M+H).sup.+ (ES.sup.+).

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

(141) ##STR00122##

(142) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide and acetaldehyde to afford the title compound (1.9 g, 38%) as a colourless oil.

(143) .sup.1H NMR (DMSO-d.sub.6) δ 7.11-6.90 (m, 4H), 6.86-6.74 (m, 4H), 6.53 (s, 1H), 5.49 (d, J=5.7 Hz, 1H), 4.86 (dt, J=12.5, 6.4 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.71 (s, 6H), 1.42 (d, J=6.5 Hz, 3H).

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

(144) ##STR00123##

(145) Prepared according to the general procedure of 5-(1-(dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P8, Step C) from 5-(1-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide and 2 M dimethylamine in THF to afford the title compound (0.39 g, 96%) as a very pale yellow viscous oil.

(146) LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

Step D: 1-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazol-5-yl)-N,N,N-trimethylmethanaminium Iodide

(147) ##STR00124##

(148) Prepared according to the general procedure of 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium iodide (Intermediate P8, Step D) from 5-(1-(dimethylamino)ethyl)-N,N— bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (435 mg, 82%) as a yellow solid.

(149) .sup.1H NMR (DMSO-d.sub.6) δ 7.28 (s, 1H), 7.10-7.05 (m, 4H), 6.87-6.81 (m, 4H), 5.04 (q, J=6.8 Hz, 1H), 4.28 (d, J=15.4 Hz, 2H), 4.23 (d, J=15.3 Hz, 2H), 4.04 (s, 3H), 3.73 (s, 6H), 3.02 (s, 9H), 1.68 (d, J=6.8 Hz, 3H).

(150) LCMS; m/z 487.4 (M)+(ES.sup.+).

Step E: N,N,N-Trimethyl-1-(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)ethan-1-aminium 2,2,2-trifluoroacetate

(151) ##STR00125##

(152) Prepared according to the general procedure of 1-(1-isopropyl-3-sulfamoyl-H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium 2,2,2-trifluoroacetate (Intermediate P8, Step E) from 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazol-5-yl)-N,N,N-trimethylmethanaminium iodide to afford the title compound (70 mg, 101%) as an orange oil.

(153) .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (s, 2H), 7.16 (s, 1H), 5.04 (q, J=6.8 Hz, 1H), 4.02 (s, 3H), 3.04 (s, 9H), 1.71 (d, J=6.8 Hz, 3H).

(154) LCMS; m/z 247.3 (M)+(ES.sup.+).

Intermediate P10: 1-Cyclopropyl-5-(1-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide

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

(155) ##STR00126##

(156) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P6, Step D) and acetaldehyde to afford the title compound (0.61 g, 31%) as an orange oil.

(157) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-7.01 (m, 4H), 6.83-6.78 (m, 4H), 6.55 (s, 1H), 5.50 (d, J=5.7 Hz, 1H), 5.01 (p, J=6.4 Hz, 1H), 4.19 (s, 4H), 3.85-3.77 (m, 1H), 3.72 (s, 6H), 1.46 (d, J=6.5 Hz, 3H), 1.18-0.95 (m, 4H).

(158) LCMS; m/z 494.4 (M+Na)+(ES.sup.+).

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

(159) ##STR00127##

(160) MsCl (0.11 mL, 1.47 mmol) was added to a solution of 1-cyclopropyl-5-(1-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.60 g, 1.221 mmol) and DIPEA (0.30 mL, 1.71 mmol) in anhydrous DCM (6 mL) at 0° C. The reaction mixture was stirred for 1 hour at 0° C. Then the temperature was raised to room temperature and the reaction mixture stirred overnight. The reaction was quenched by addition of saturated aqueous NaHCO.sub.3 solution (1 mL), then diluted with DCM (40 mL), and the layers were separated. The aqueous phase was extracted with further portions of DCM (2×40 mL), and the combined organic layers were washed with saturated aqueous NaHCO.sub.3 solution (20 mL), H.sub.2O (20 mL) and brine (20 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give an orange oil (0.523 g). The oil was dissolved in anhydrous THF (4 mL) at room temperature, treated with dimethylamine (2 M in THF) (2.27 mL, 4.55 mmol), heated to 50° C. and stirred overnight. The mixture was transferred into a microwave vial and stirred at 60° C. over the weekend. The mixture was quenched with aqueous NaHCO.sub.3 (15 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (20 mL), passed through a phase separator and the solvent was removed in vacuo. The residue was dissolved in MeOH (20 mL), SCX (˜8 g) was added and the suspension was stirred for 30 minutes at room temperature. The mixture was transferred to a cartridge, washed with MeOH and the product was eluted with 0.7 M NH.sub.3 in MeOH to afford the title compound (217 mg, 81%) as a brown oil.

(161) .sup.1H NMR (DMSO-d.sub.6) δ 7.03 (d, J=8.6 Hz, 4H), 6.81 (d, J=8.6 Hz, 4H), 6.53 (s, 1H), 4.19 (s, 4H), 4.05 (q, J=6.8 Hz, 1H), 3.91-3.82 (m, 1H), 3.72 (s, 6H), 2.15 (s, 6H), 1.27 (d, J=6.8 Hz, 3H), 1.18-1.09 (m, 1H), 1.08-1.01 (m, 2H), 1.01-0.92 (m, 1H).

(162) LCMS; m/z 499.5 (M+H).sup.+ (ES.sup.+).

Step C: 1-Cyclopropyl-5-(1-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide

(163) ##STR00128##

(164) A mixture of 1-cyclopropyl-5-(1-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (215 mg, 0.431 mmol) and TFA (2.5 mL) in DCM (2 mL) was stirred at room temperature overnight. The volatiles were evaporated, the residue dissolved in MeOH (25 mL), SCX (˜8 g) was added and the suspension was stirred at room temperature for 30 minutes. The mixture was transferred to a cartridge, washed sequentially with DCM/MeOH (9:1) and MeOH, and the product was eluted with 0.7 M NH.sub.3 in MeOH to afford the title compound (103 mg, 80%) as a brown oil.

(165) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.48 (s, 1H), 4.05 (q, J=6.8 Hz, 1H), 3.88-3.78 (m, 1H), 2.16 (s, 6H), 1.28 (d, J=6.8 Hz, 3H), 1.23-1.15 (m, 1H), 1.08-0.96 (m, 3H).

(166) LCMS m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate P11: 5-(1-(Azetidin-1-yl)propyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide

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

(167) ##STR00129##

(168) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P6, Step D) and propionaldehyde to afford the title compound (0.50 g, 39%) as an orange oil.

(169) .sup.1H NMR (DMSO-d.sub.6) δ 7.04-7.00 (m, 4H), 6.83-6.78 (m, 4H), 6.53 (s, 1H), 5.48 (d, J=5.8 Hz, 1H), 4.76 (q, J=6.2 Hz, 1H), 4.18 (s, 4H), 3.84-3.76 (m, 1H), 3.72 (s, 6H), 1.84-1.72 (m, 2H), 1.16-0.95 (m, 4H), 0.91 (t, J=7.4 Hz, 3H).

(170) LCMS; m/z 508.4 (M+Na)+(ES.sup.+).

Step B: 5-(1-(Azetidin-1-yl)propyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(171) ##STR00130##

(172) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step B) from 1-cyclopropyl-5-(1-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and azetidine to afford the title compound as a pale yellow oil (178 mg, 72%).

(173) .sup.1H NMR (DMSO-d.sub.6) δ 7.00 (d, J=8.7 Hz, 4H), 6.80 (d, J=8.7 Hz, 4H), 6.47 (s, 1H), 4.19 (s, 4H), 3.96-3.87 (m, 1H), 3.72 (s, 6H), 3.68 (dd, J=8.2, 4.1 Hz, 1H), 3.10 (q, J=6.7 Hz, 2H), 3.03-2.96 (m, 2H), 1.99-1.85 (m, 2H), 1.77-1.63 (m, 1H), 1.61-1.49 (m, 1H), 1.14-0.98 (m, 4H), 0.69 (t, J=7.4 Hz, 3H).

(174) LCMS; m/z 525.5 (M+Na)+(ES.sup.+).

Step C: 5-(1-(Azetidin-1-yl)propyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide

(175) ##STR00131##

(176) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(1-(azetidin-1-yl)propyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound as a white foam (70 mg, 78%).

(177) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.41 (s, 1H), 3.92-3.81 (m, 1H), 3.68 (dd, J=8.0, 4.1 Hz, 1H), 3.11 (q, J=6.8 Hz, 2H), 3.03 (q, J=6.8 Hz, 2H), 1.93 (p, J=6.8 Hz, 2H), 1.74-1.62 (m, 1H), 1.62-1.49 (m, 1H), 1.23-1.13 (m, 1H), 1.12-1.00 (m, 3H), 0.70 (t, J=7.4 Hz, 3H).

(178) LCMS; m/z 285.3 (M+H).sup.+ (ES.sup.+).

Intermediate P12: 1-Cyclopropyl-5-(1-(dimethylamino)propyl)-1H-pyrazole-3-sulfonamide

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

(179) ##STR00132##

(180) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step B) from 1-cyclopropyl-5-(1-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P11, Step A) and dimethylamine (2 M in THF) to afford the title compound (147 mg, 62%) as a brown oil.

(181) .sup.1H NMR (DMSO-d.sub.6) δ 7.01 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.55 (s, 1H), 4.20 (s, 4H), 3.91-3.84 (m, 1H), 3.84-3.78 (m, 1H), 3.72 (s, 6H), 2.14 (s, 6H), 1.87-1.77 (m, 1H), 1.76-1.63 (m, 1H), 1.16-0.94 (m, 4H), 0.79 (t, J=7.3 Hz, 3H).

(182) LCMS; m/z 513.5 (M+H).sup.+ (ES.sup.+).

Step B: 1-Cyclopropyl-5-(1-(dimethylamino)propyl)-1H-pyrazole-3-sulfonamide

(183) ##STR00133##

(184) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 1-cyclopropyl-5-(1-(dimethylamino)propyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (77 mg, 100%) as a tan solid.

(185) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.47 (s, 1H), 3.86 (dd, J=9.2, 5.4 Hz, 1H), 3.82-3.74 (m, 1H), 2.16 (s, 6H), 1.90-1.77 (m, 1H), 1.76-1.62 (m, 1H), 1.20-1.11 (m, 1H), 1.11-0.98 (m, 3H), 0.80 (t, J=7.3 Hz, 3H).

(186) LCMS; m/z 273.3 (M+H).sup.+ (ES.sup.+).

Intermediate P13: 5-(1-(Azetidin-1-yl)ethyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide

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

(187) ##STR00134##

(188) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step B) from 1-cyclopropyl-5-(1-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step A) and azetidine to afford the title compound (246 mg, 91%) as a brown oil.

(189) .sup.1H NMR (DMSO-d.sub.6) δ 7.00 (d, J=8.7 Hz, 4H), 6.80 (d, J=8.7 Hz, 4H), 6.44 (s, 1H), 4.19 (s, 4H), 3.92-3.81 (m, 1H), 3.77 (q, J=6.5 Hz, 1H), 3.72 (s, 6H), 3.16-3.00 (m, 4H), 1.93 (p, J=6.9 Hz, 2H), 1.17 (d, J=6.5 Hz, 3H), 1.15-0.95 (m, 4H).

(190) LCMS; m/z 511.5 (M+H).sup.+ (ES.sup.+).

Step B: 5-(1-(Azetidin-1-yl)ethyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide

(191) ##STR00135##

(192) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(1-(azetidin-1-yl)ethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (108 mg, 86%) as a beige foam.

(193) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.40 (s, 1H), 3.87-3.80 (m, 1H), 3.77 (q, J=6.5 Hz, 1H), 3.16-3.02 (m, 4H), 1.93 (p, J=7.0 Hz, 2H), 1.17 (d, J=6.5 Hz, 3H), 1.16-1.01 (m, 4H).

(194) LCMS; m/z 271.3 (M+H).sup.+ (ES.sup.+).

Intermediate P14: 5-(1-(Azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide, Enantiomer A and

Intermediate P15: 5-(1-(Azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide, Enantiomer B

(195) ##STR00136##

(196) Prepared by chiral resolution of 51-(azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P41): racemic 5-(1-(azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P41) (16 g) was separated by SFC to give Intermediate P14, Enantiomer A (5.45 g, 98.34% ee) and Intermediate P15, Enantiomer B (5.49 g, 99.72% ee).

(197) SFC Separation Method:

(198) Instrument: Waters UPC.sup.2 analytical SFC (SFC-H)

(199) Column: ChiralPak AD, 150×4.6 mm I.D., 3 μm

(200) Mobile phase: A for CO.sub.2 and B for MeOH (0.05% DEA)

(201) Gradient: B 5-40%

(202) Flow rate: 2.5 mL/min

(203) Back pressure: 100 bar

(204) Column temperature: 35° C.

(205) Wavelength: 220 nm

(206) Intermediate P14: .sup.1H NMR (DMSO-d.sub.6) δ 7.39 (br s, 2H), 6.46 (s, 1H), 3.90 (s, 3H), 3.80-3.60 (m, 1H), 3.18-2.96 (m, 4H), 2.05-1.90 (m, 2H), 1.10 (s, 3H).

(207) LCMS; m/z 245.0 (M+H).sup.+ (ES.sup.+).

(208) SFC: retention time: 3.026 min.

(209) Intermediate P15: .sup.1HNMR (DMSO-d.sub.6) δ 7.36 (s, 2H), 6.42 (s, 1H), 3.89 (s, 3H), 3.75-3.61 (m, 1H), 3.10-2.96 (m, 4H), 1.96-1.92 (m, 2H), 1.13 (d, 3H).

(210) LCMS; m/z 245.0 (M+H).sup.+ (ES.sup.+).

(211) SFC: retention time: 3.132 min.

Intermediate P16: 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(212) ##STR00137##

(213) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P9, Step A) and N-methyl-N-methylenemethanaminium iodide to afford the title compound (1.9 g, 38%) as a colourless oil.

(214) .sup.1H NMR (DMSO-d.sub.6) δ 7.07-7.01 (m, 4H), 6.84-6.78 (m, 4H), 6.58 (s, 1H), 4.21 (s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.47 (s, 2H) and 2.16 (s, 6H).

(215) LCMS; m/z 459.8 (M+H).sup.+ (ES.sup.+).

Step B: 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(216) ##STR00138##

(217) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (337 mg, 79%) as a white solid.

(218) .sup.1H NMR (DMSO-d.sub.6) δ 7.36 (br s, 2H), 6.51 (s, 1H), 3.86 (s, 3H), 3.32 (s, 2H) and 2.23 (s, 6H).

(219) LCMS; m/z 219.3 (M+H).sup.+ (ES.sup.+).

Intermediate P17: 1-Methyl-5-(1-(3-methylazetidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-methyl-5-(1-(3-methylazetidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide

(220) ##STR00139##

(221) Prepared according to the general procedure of 5-(1-(dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P8, Step C) from 5-(1-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P9, Step B) and 3-methylazetidine hydrochloride to afford the title compound (867 mg, 67%) as a yellow oil.

(222) .sup.1H NMR (DMSO-d.sub.6) δ 7.01 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.43 (s, 1H), 4.19 (s, 4H), 3.91 (s, 3H), 3.71 (s, 6H), 3.59 (q, J=6.5 Hz, 1H), 3.35-3.31 (m, 1H), 3.21-3.14 (m, 1H), 2.67-2.58 (m, 2H), 2.44-2.32 (m, 1H), 1.12 (d, J=6.5 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H).

(223) LCMS; m/z 499.5 (M+H).sup.+ (ES.sup.+).

Step B: 1-Methyl-5-(1-(3-methylazetidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide

(224) ##STR00140##

(225) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from N,N-bis(4-methoxybenzyl)-1-methyl-5-(1-(3-methylazetidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide to afford the title compound (283 mg, 66%) as a pale tan solid.

(226) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.39 (s, 1H), 3.88 (s, 3H), 3.58 (q, J=6.6 Hz, 1H), 3.38-3.30 (m, 1H), 3.24-3.16 (m, 1H), 2.64 (app. q, J=6.8 Hz, 2H), 2.44-2.32 (m, 1H), 1.12 (d, J=6.6 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H).

(227) LCMS; m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate P18: 5-(Azetidin-1-ylmethyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide

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

(228) ##STR00141##

(229) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P6, Step D) and morpholine-4-carbaldehyde to afford the title compound (732 mg, 33%) as a colourless oil that solidified slowly.

(230) .sup.1H NMR (DMSO-d.sub.6) δ 10.02 (s, 1H), 7.35 (s, 1H), 7.05 (d, J=8.7 Hz, 4H), 6.82 (d, J=8.7 Hz, 4H), 4.32-4.25 (m, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 1.14 (s, 2H), 1.13-1.11 (m, 2H).

(231) LCMS; m/z 456.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(Azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(232) ##STR00142##

(233) To a solution of 1-cyclopropyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (730 mg, 1.603 mmol) in THF (10 mL) was added azetidine hydrochloride (300 mg, 3.21 mmol), triethylamine (0.44 mL, 3.16 mmol) and 4 Å molecular sieves. The mixture was stirred for 1 hour before NaBH(OAc).sub.3 (509 mg, 2.404 mmol) was added and stirring was continued overnight. The mixture was filtered over a pad of Celite® with EtOAc and the solvent was removed in vacuo. The residue was dissolved in MeOH (10 mL), SCX was added, and the suspension was stirred for 30 minutes and transferred into a cartridge. The solid was washed with MeOH and the product was eluted with 0.7 M NH.sub.3 in MeOH. The solvent was evaporated to afford the title compound (691 mg, 84%) as a pale yellow oil.

(234) .sup.1H NMR (DMSO-d.sub.6) δ 7.01 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.50 (s, 1H), 4.17 (s, 4H), 3.76-3.70 (m, 7H), 3.68 (s, 2H), 3.18 (t, J=7.0 Hz, 4H), 2.00 (p, J=7.0 Hz, 2H), 1.04 (s, 2H), 1.02 (s, 2H).

(235) LCMS; m/z 497.6 (M+H).sup.+ (ES.sup.+).

Step C: 5-(Azetidin-1-ylmethyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide

(236) ##STR00143##

(237) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (345 mg, 95%) as a beige solid.

(238) .sup.1H NMR (DMSO-d.sub.6) δ 7.36 (s, 2H), 6.43 (s, 1H), 3.78-3.62 (m, 4H), 3.26-3.16 (m, 3H), 2.01 (p, J=7.0 Hz, 2H), 1.11-0.97 (m, 4H).

(239) LCMS; m/z 257.3 (M+H).sup.+ (ES.sup.+).

Intermediate P19: 5-((Dimethylamino)methyl)-1-neopentyl-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-neopentyl-1H-pyrazole-3-sulfonamide

(240) ##STR00144##

(241) A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P2, Step C) (500 mg, 1.290 mmol), K.sub.2CO.sub.3 (360 mg, 2.60 mmol), KI (214 mg, 1.290 mmol) and 1-bromo-2,2-dimethylpropane (300 mg, 1.986 mmol) in DMF (10 mL) was heated at 100° C. for 24 hours. The mixture was cooled and partitioned between EtOAc (80 mL) and water (60 mL). The organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered and evaporated. The residue was purified by chromatography on silica gel (40 g column, 0-40% EtOAc/isohexane) to afford the title compound (426 mg, 69%) as an oil.

(242) .sup.1H NMR (CDCl.sub.3) δ 7.38 (d, J=2.3 Hz, 1H), 7.11-7.07 (m, 4H), 6.80-6.76 (m, 4H), 6.68 (d, J=2.3 Hz, 1H), 4.34 (s, 4H), 3.98 (s, 2H), 3.80 (s, 6H), 0.97 (s, 9H).

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

(243) ##STR00145##

(244) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis(4-methoxybenzyl)-1-neopentyl-1H-pyrazole-3-sulfonamide and N-methyl-N— methylenemethanaminium iodide to afford the title compound (198 mg, 42%) as a thick colourless oil.

(245) .sup.1H NMR (CDCl.sub.3) δ 7.14-7.06 (m, 4H), 6.83-6.75 (m, 4H), 6.68 (s, 1H), 4.36 (s, 4H), 4.13 (s, 2H), 3.80 (s, 6H), 3.76 (s, 2H), 2.42 (s, 6H), 0.97 (s, 9H).

(246) LCMS; m/z 515.3 (M+H).sup.+ (ES.sup.+); 513.5 (M−H).sup.− (ES.sup.−).

Step C: 5-((Dimethylamino)methyl)-1-neopentyl-1H-pyrazole-3-sulfonamide

(247) ##STR00146##

(248) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-neopentyl-1H-pyrazole-3-sulfonamide to afford the title compound (94 mg, 90%) as a colourless oil.

(249) .sup.1H NMR (CDCl.sub.3) δ 6.60 (s, 1H), 4.95 (s, 2H), 4.07 (s, 2H), 3.45 (s, 2H), 2.23 (s, 6H), 0.99 (s, 9H).

(250) LCMS; m/z 275.3 (M+H).sup.+ (ES.sup.+).

Intermediate P20: 5-(1-(Dimethylamino)cyclopropyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-N,N-dimethyl-1H-pyrazole-5-carboxamide

(251) ##STR00147##

(252) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P8, Step A) and carbamoyl chloride to afford the title compound (0.6 g, 50%) as a yellow gum.

(253) .sup.1H NMR (DMSO-d.sub.6) δ 7.09-6.98 (m, 4H), 6.88 (s, 1H), 6.85-6.77 (m, 4H), 4.69 (sept, J=6.6 Hz, 1H), 4.24 (s, 4H), 3.72 (s, 6H), 3.01 (s, 3H), 2.95 (s, 3H), 1.39 (d, J=6.6 Hz, 6H).

(254) LCMS; m/z 523.4 (M+Na)+(ES.sup.+).

Step B: 5-(1-(Dimethylamino)cyclopropyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(255) ##STR00148##

(256) 1 M Ethylmagnesium bromide in THF (2.0 mL, 2.000 mmol) was added dropwise over seconds to a stirred solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-N,N-dimethyl-1H-pyrazole-5-carboxamide (0.5 g, 0.999 mmol) and 1 M triisopropoxy(methyl)titanium (1.2 mL, 1.200 mmol) in THF (15 mL) at room temperature. The mixture was then left to stir at room temperature for 23 hours. The reaction mixture was quenched with water (5 mL) and the reaction mixture filtered. The filtrate was partitioned between EtOAc (30 mL) and brine (50 mL) and the organic layer separated. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO.sub.4), filtered and evaporated to dryness. The crude product was loaded onto a column of SCX (3 g) in 9:1 DCM:MeOH. The column was washed with MeOH:DCM (1:9) and then the product was eluted with 0.7 M ammonia in MeOH:DCM (1:9). The resultant mixture was concentrated in vacuo to afford the title compound (0.37 g, 52%) as a pale yellow solid.

(257) .sup.1H NMR (DMSO-d.sub.6) δ 7.07-6.95 (m, 4H), 6.82-6.73 (m, 4H), 6.47 (s, 1H), 4.92 (sept, J=6.0 Hz, 1H), 4.22 (s, 4H), 3.71 (s, 6H), 2.15 (s, 6H), 1.38 (d, J=6.5 Hz, 6H), 1.06-0.97 (m, 2H), 0.86-0.77 (m, 2H).

(258) LCMS; m/z 513.3 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-(Dimethylamino)cyclopropyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(259) ##STR00149##

(260) 5-(1-(Dimethylamino)cyclopropyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.37 g, 0.520 mmol) was dissolved in TFA (5 mL) and stirred at room temperature for 17 hours. The mixture was evaporated to dryness, dissolved in 9:1 DCM:MeOH and loaded onto SCX (2 g). The column was washed with 9:1 DCM:MeOH (20 mL), then the product was eluted with 0.7 NH.sub.3 in 1:9 MeOH:DCM (20 mL). The resultant mixture was concentrated in vacuo to afford crude product as a pale yellow solid. The crude product was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (79 mg, 55%) as a white solid.

(261) .sup.1H NMR (DMSO-d.sub.6) δ 7.36 (s, 2H), 6.43 (s, 1H), 4.92 (sept, J=6.5 Hz, 1H), 2.17 (s, 6H), 1.40 (d, J=6.5 Hz, 6H), 1.10-0.96 (m, 2H), 0.86-0.73 (m, 2H).

(262) LCMS; m/z 273.3 (M+H).sup.+ (ES.sup.+).

Intermediate P21: 5-(2-(Dimethylamino)ethyl)-1-isopropyl-H-pyrazole-3-sulfonamide

Step A: 5-(2-Hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(263) ##STR00150##

(264) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P8, Step A) and oxirane (2.5 M in THF) to afford the title compound (1.33 g, 56%) as a yellow oil.

(265) .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).

(266) LCMS; m/z 496.4 (M+Na)+(ES.sup.+).

Step B: 5-(2-(Dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(267) ##STR00151##

(268) Dess-Martin periodinane (220 mg, 0.492 mmol) was added to a solution of 5-(2-hydroxyethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (212 mg, 0.448 mmol) in anhydrous DCM (4 mL) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Then dimethylamine (2 M in THF) (671 μL, 1.343 mmol) was added and the reaction mixture stirred for 20 minutes, before NaBH(OAc).sub.3 (142 mg, 0.671 mmol) was added. The reaction mixture was stirred for 48 hours. The crude product was loaded onto a column of SCX (1 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The MeOH fraction was concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford the title compound (162 mg, 61%) as a colourless oil.

(269) .sup.1H NMR (DMSO-d.sub.6) δ 7.05-6.97 (m, 4H), 6.86-6.77 (m, 4H), 6.48 (s, 1H), 4.65 (sept, J=6.7 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 2.84 (t, J=7.4 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.24 (s, 6H), 1.39 (d, J=6.5 Hz, 6H).

(270) LCMS m/z 501.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(2-(Dimethylamino)ethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(271) ##STR00152##

(272) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(2-(dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (55 mg, 84%) as a colourless oil.

(273) .sup.1H NMR (DMSO-d.sub.6) δ 7.31 (s, 2H), 6.41 (s, 1H), 4.61 (sept, J=6.5 Hz, 1H), 2.81 (t, J=7.3 Hz, 2H), 2.19 (s, 6H), 1.38 (d, J=6.5 Hz, 6H). CH.sub.2 triplet cannot be observed, under DMSO.

(274) LCMS; m/z 261.3 (M+H).sup.+ (ES.sup.+).

Intermediate P22: 5-(2-(Dimethylamino)propan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate

(275) ##STR00153##

(276) Prepared according to the general procedure of N,N-bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P9, Step A) from ethyl 3-(chlorosulfonyl)-1-methyl-1H-pyrazole-5-carboxylate to afford the title compound (15.9 g, 91%) as a white solid.

(277) .sup.1H NMR (DMSO-d.sub.6) δ 7.19-7.00 (m, 5H), 6.85-6.77 (m, 4H), 4.33 (q, J=7.1 Hz, 2H), 4.25 (s, 4H), 4.15 (s, 3H), 3.71 (s, 6H), 1.33 (t, J=7.1 Hz, 3H).

(278) LCMS; m/z 496.4 (M+Na)+(ES.sup.+).

Step B: 5-(2-Hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(279) ##STR00154##

(280) Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (2 g, 3.67 mmol) was dissolved in dry THF (70 mL) under nitrogen atmosphere and cooled to −78° C. (bath temperature). Methylmagnesium chloride (3 M in THF) (6.2 mL, 18.60 mmol) was added via syringe over the course of 5 minutes and the mixture was warmed to room temperature and stirred over the weekend. The yellow reaction mixture was cooled in an ice bath and quenched by cautious addition of saturated aqueous ammonium chloride (20 mL). Water (20 mL) and EtOAc (80 mL) were added and the phases separated. The aqueous layer was extracted with EtOAc (2×80 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give a pale yellow oil. The crude product was loaded onto silica and purified by chromatography on SiO.sub.2 (40 g column, 0-70% EtOAc/isohexane) to afford the title compound (1.56 g, 87%) as a clear colourless crystalline solid after drying in the desiccator overnight.

(281) .sup.1H NMR (DMSO-d.sub.6) δ 7.05 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.41 (s, 1H), 5.48 (s, 1H), 4.21 (s, 4H), 4.03 (s, 3H), 3.72 (s, 6H), 1.49 (s, 6H).

(282) LCMS; m/z 482.1 (M+Na)+(ES.sup.+).

Step C: 5-(2-Aminopropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(283) ##STR00155##

(284) To a mixture of 5-(2-hydroxypropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (1 g, 2.176 mmol) and azidotrimethylsilane (0.58 mL, 4.37 mmol) in toluene (5 mL) was added BF.sub.3.OEt.sub.2 (4 mL, 15.07 mmol) via syringe. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with aqueous NaHCO.sub.3 (30 mL) and extracted with DCM (3×30 mL). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo to give a brown oil. The residue was dissolved in EtOH (45 mL) and hydrogenated using an H-Cube (10% Pd/C at 35° C., 1 cycle). After evaporation of the solvent, the residue was loaded onto SCX with MeOH, washed with MeOH and the product was eluted with 0.7 M NH.sub.3 in MeOH to afford the title compound (322 mg, 29%) as a clear colourless oil.

(285) .sup.1H NMR (DMSO-d.sub.6) δ 7.05 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.36 (s, 1H), 4.21 (s, 4H), 4.12 (s, 3H), 3.72 (s, 6H), 2.00 (s, 2H), 1.42 (s, 6H).

(286) LCMS; m/z 459.2 (M+H).sup.+ (ES.sup.+).

Step D: 5-(2-(Dimethylamino)propan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(287) ##STR00156##

(288) A mixture of 5-(2-aminopropan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (320 mg, 0.698 mmol), formaldehyde (37% in H.sub.2O, 10% MeOH) (1.1 mL, 14.77 mmol) and formic acid (0.54 mL, 14.08 mmol) was stirred at 60° C. overnight. Upon cooling to room temperature, the mixture was diluted with EtOAc (15 mL), basified with 2 M aqueous NaOH (2 mL) and diluted with H.sub.2O (5 mL). The layers were separated and the aqueous layer extracted with EtOAc (2×15 mL). The combined organic extracts were passed through a phase separator and the solvent was removed in vacuo. To the residue was added SCX and the mixture was stirred for 30 minutes before being transferred into a cartridge. The suspension was washed with MeOH and the product subsequently eluted with 0.7 M NH.sub.3 in MeOH. The solvent was evaporated to afford the title compound (275 mg, 75%) as a pale yellow oil.

(289) .sup.1H NMR (DMSO-d.sub.6) δ 7.06 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.36 (s, 1H), 4.21 (s, 4H), 4.06 (s, 3H), 3.71 (s, 6H), 2.08 (s, 6H), 1.31 (s, 6H).

(290) LCMS; m/z 487.6 (M+H).sup.+ (ES.sup.+).

Step E: 5-(2-(Dimethylamino)propan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide

(291) ##STR00157##

(292) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(2-(dimethylamino)propan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (135 mg, 78%) as a sticky yellow oil.

(293) .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (s, 2H), 6.40 (s, 1H), 4.05 (s, 3H), 2.10 (s, 6H), 1.34 (s, 6H).

(294) LCMS; m/z 247.4 (M+H).sup.+ (ES.sup.+).

Intermediate P23: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

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

(295) ##STR00158##

(296) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P6, Step D) and N-methyl-N-methylenemethanaminium iodide to afford the title compound (9 g, 82%) as a yellow oil.

(297) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-6.98 (m, 4H), 6.85-6.77 (m, 4H), 6.57 (s, 1H), 4.20 (s, 4H), 3.80 (tt, J=6.6, 4.5 Hz, 1H), 3.73 (s, 6H), 3.57 (s, 2H), 2.20 (s, 6H), 1.10-1.00 (m, 4H).

(298) LCMS m/z 485.5 (M+H).sup.+ (ES.sup.+).

Step B: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

(299) ##STR00159##

(300) To a solution 1-cyclopropyl-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (9 g, 18.57 mmol, 1 eq) in DCM (30 mL) was added TFA (154.0 g, 1.35 mol, 100 mL, 72.73 eq). The reaction mixture was stirred at 25° C. for 12 hours and then concentrated under reduced pressure. The residue was treated with MeOH (300 mL) and a solid formed. The mixture was filtered and the filtrate was collected. The pH of the filtrate was adjusted to 8-9 with ion exchange resin (Amberlyst® A-21). The mixture was filtered and the filtrate was concentrated. The residue was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (3.97 g, 88%) as a white solid.

(301) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (br s, 2H), 6.48 (s, 1H), 3.78-3.74 (m, 1H), 3.56 (s, 2H), 2.20 (s, 6H), 1.11-1.02 (m, 4H).

(302) LCMS m/z 245.2 (M+H).sup.+ (ES.sup.+).

Intermediate P24: 1-(tert-Butyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

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

(303) ##STR00160##

(304) To a solution of 1-(tert-butyl)-1H-pyrazole-3-sulfonyl chloride (40 g, 179.6 mmol) in THF (400 mL) was added TEA (54.53 g, 538.9 mmol, 75.00 mL) and bis(4-methoxybenzyl)amine (13.87 g, 53.9 mmol). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into H.sub.2O (1 L) and extracted with EtOAc (3×1 L). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30:1 to 2:1 petroleum ether/EtOAc) and then purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O/CH.sub.3CN) to give the title compound (15 g, 19%) as a yellow oil.

(305) .sup.1H NMR (CDCl.sub.3) δ 7.54 (d, 1H), 7.07 (d, 4H), 6.77 (d, 4H), 6.66 (d, 1H), 4.32 (s, 4H), 3.79 (s, 6H), and 1.60 (s, 9H).

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

(306) ##STR00161##

(307) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-(tert-butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and N-methyl-N— methylenemethanaminium iodide to afford the title compound (266 mg, 23%).

(308) .sup.1H NMR (DMSO-d.sub.6) δ 7.05-7.00 (m, 4H), 6.83-6.78 (m, 4H), 6.60 (s, 1H), 4.22 (s, 4H), 3.72 (s, 6H), 3.52 (s, 2H), 2.17 (s, 6H), 1.60 (s, 9H).

(309) LCMS; m/z 501.6 (M+H).sup.+ (ES.sup.+).

Step C: 1-(tert-Butyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

(310) ##STR00162##

(311) 1-(tert-Butyl)-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (266 mg, 0.531 mmol) was dissolved in DCM (1.5 mL) and TFA (1.5 mL) was added. The solution was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude product was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The crude product was purified by chromatography on SiO.sub.2 (12 g column, 0-10% MeOH/DCM) to afford the title compound (30 mg, 19%) as a white solid.

(312) .sup.1H NMR (DMSO-d.sub.6) δ 7.42 (s, 2H), 6.62 (s, 1H), 3.61 (s, 2H), 2.26 (s, 6H), 1.71 (s, 9H).

(313) LCMS; m/z 261.3 (M+H).sup.+ (ES.sup.+).

Intermediate P25: 5-(Azetidin-1-ylmethyl)-1-(tert-butyl)-1H-pyrazole-3-sulfonamide

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

(314) ##STR00163##

(315) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-(tert-butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P24, Step A) and morpholine-4-carbaldehyde to afford the title compound (713 mg, 31%) as a colourless oil.

(316) .sup.1H NMR (DMSO-d.sub.6) δ 9.97 (s, 1H), 7.54 (s, 1H), 7.14-7.03 (m, 4H), 6.91-6.75 (m, 4H), 4.29 (s, 4H), 3.72 (s, 6H), 1.61 (s, 9H).

(317) LCMS; m/z 494.5 (M+Na)+(ES.sup.+).

Step B: 5-(Azetidin-1-ylmethyl)-1-(tert-butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(318) ##STR00164##

(319) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 1-(tert-butyl)-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and azetidine hydrochloride to afford the title compound (690 mg, 73%) as a white oil.

(320) .sup.1H NMR (DMSO-d.sub.6) δ 7.05-6.99 (m, 4H), 6.84-6.78 (m, 4H), 6.57 (s, 1H), 4.20 (s, 4H), 3.72 (s, 6H), 3.70 (s, 2H), 3.16 (t, J=7.0 Hz, 4H), 2.01 (p, J=7.0 Hz, 2H), 1.59 (s, 9H).

(321) LCMS; m/z 513.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(Azetidin-1-ylmethyl)-1-(tert-butyl)-1H-pyrazole-3-sulfonamide

(322) ##STR00165##

(323) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(azetidin-1-ylmethyl)-1-(tert-butyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (284 mg, 63%).

(324) .sup.1H NMR (DMSO-d.sub.6) δ 7.31 (s, 2H), 6.51 (s, 1H), 3.70 (s, 2H), 3.18 (t, J=7.0 Hz, 4H), 2.01 (p, J=7.0 Hz, 2H), 1.60 (s, 9H).

(325) LCMS; m/z 273.4 (M+H).sup.+ (ES.sup.+).

Intermediate P26: 5-((Dimethylamino)methyl)-1-isopropyl-H-pyrazole-3-sulfonamide

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

(326) ##STR00166##

(327) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P8, Step A) and N-methyl-N-methylenemethanaminium iodide to afford the title compound (2.43 g, 69%) as a white solid.

(328) .sup.1H NMR (CDCl.sub.3) δ 7.13-7.04 (m, 4H), 6.83-6.76 (m, 4H), 6.58 (s, 1H), 4.86 (sept, J=6.5 Hz, 1H), 4.34 (s, 4H), 3.81 (s, 6H), 3.51 (s, 2H) 2.38 (s, 6H), 1.51 (d, J=6.5 Hz, 6H).

(329) LCMS; m/z 487 (M+H).sup.+ (ES.sup.+); 485 (M−H).sup.− (ES.sup.−).

Step B: 5-((Dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(330) ##STR00167##

(331) 5-((Dimethylamino)methyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2.43 g, 4.84 mmol) was dissolved in DCM (20 mL) and TFA (10 mL, 130 mmol) was added. The mixture was stirred over the weekend at room temperature. The reaction solvent was removed in vacuo. DCM (50 mL) and MeOH (50 mL) were added along with SCX (25 g, ˜3 eq). The mixture was stirred for 2 hours at room temperature. The SCX was filtered and washed with MeOH (3×100 mL). The product was then eluted with 0.7 M ammonia in MeOH (3×100 mL). Concentration of the ammoniacal washings in vacuo gave a pale yellow semi-solid. This residue was dissolved in a minimum amount of DCM/MeOH (9:1, ˜10 mL). Then the product was precipitated by adding an excess of iso-hexanes (100 mL). After filtration, the title compound (1.04 g, 86%) was isolated as a colourless solid that was dried in vacuo and used without further purification.

(332) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.46 (s, 1H), 4.78 (sept, J=6.6 Hz, 1H), 3.47 (s, 2H), 2.16 (s, 6H), 1.38 (d, J=6.6 Hz, 6H).

(333) LCMS; m/z 247 (M+H).sup.+ (ES.sup.+); 245 (M−H).sup.− (ES.sup.−).

Intermediate P27: N,N,N-Trimethyl-1-(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methanaminium 2,2,2-trifluoroacetate

Step A: 1-(3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazol-5-yl)-N,N,N-trimethylmethanaminium iodide

(334) ##STR00168##

(335) MeI (0.136 mL, 2.181 mmol) was added to a stirred solution of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P16, Step A) (500 mg, 1.090 mmol) in MTBE (5 mL). The reaction mixture was stirred at room temperature 16 hours. Additional MeI (0.136 mL, 2.181 mmol) was added and the reaction mixture stirred for 48 hours. The precipitate was filtered and washed with MTBE (10 mL) to afford the title compound (490 mg, 69%).

(336) .sup.1H NMR (DMSO-d.sub.6) δ 7.12-7.03 (m, 5H), 6.87-6.78 (m, 4H), 4.74 (s, 2H), 4.26 (s, 4H), 4.04 (s, 3H), 3.73 (s, 6H), 3.09 (s, 9H).

(337) LCMS; m/z 473.3 (M)+(ES.sup.+).

Step B: N,N,N-Trimethyl-1-(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methanaminium 2,2,2-trifluoroacetate

(338) ##STR00169##

(339) Prepared according to the general procedure of 1-(1-isopropyl-3-sulfamoyl-H-pyrazol-5-yl)-N,N,N-trimethylethan-1-aminium 2,2,2-trifluoroacetate (Intermediate P8, Step E) from 1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazol-5-yl)-N,N,N-trimethylmethanaminium iodide to afford the title compound (182 mg, 47%) as a brown solid.

(340) .sup.1H NMR (DMSO-d.sub.6) δ 7.61 (s, 2H), 7.01 (s, 1H), 4.81 (s, 2H), 4.08 (s, 3H), 3.18 (s, 9H).

(341) LCMS; m/z 233.0 (M)+(ES.sup.+).

Intermediate P28: 5-(Azetidin-1-ylmethyl)-1-ethyl-1H-pyrazole-3-sulfonamide

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

(342) ##STR00170##

(343) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P7, Step A) and morpholine-4-carbaldehyde to afford the title compound (960 mg, 45%) as a white solid.

(344) .sup.1H NMR (DMSO-d.sub.6) δ 9.90 (s, 1H), 7.44 (s, 1H), 7.10-7.04 (m, 4H), 6.85-6.79 (m, 4H), 4.54 (q, J=7.2 Hz, 2H), 4.26 (s, 4H), 3.72 (s, 6H), 1.36 (t, J=7.2 Hz, 3H).

(345) LCMS; m/z 466.3 (M+Na)+(ES.sup.+).

Step B: 5-(Azetidin-1-ylmethyl)-1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(346) ##STR00171##

(347) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 1-ethyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and azetidine hydrochloride to afford the title compound (555 mg, 49%) as a white oil.

(348) .sup.1H NMR (DMSO-d.sub.6) δ 7.04-6.99 (m, 4H), 6.84-6.78 (m, 4H), 6.53 (s, 1H), 4.23-4.15 (m, 6H), 3.72 (s, 6H), 3.60 (s, 2H), 3.14 (t, J=7.0 Hz, 4H), 1.99 (p, J=7.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

(349) LCMS; m/z 485.3 (M+H).sup.+ (ES.sup.+).

Step C: 5-(Azetidin-1-ylmethyl)-1-ethyl-1H-pyrazole-3-sulfonamide

(350) ##STR00172##

(351) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(azetidin-1-ylmethyl)-1-ethyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (255 mg, 98%).

(352) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.45 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.60 (s, 2H), 3.21-3.10 (m, 4H), 2.00 (p, J=7.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

(353) LCMS; m/z 245.4 (M+H).sup.+ (ES.sup.+).

Intermediate P29: 2,2,2-Trifluoro-N-((1-isopropyl-3-sulfamoyl-H-pyrazol-5-yl)methyl)-N-methylacetamide

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

(354) ##STR00173##

(355) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P8, Step A) and morpholine-4-carbaldehyde to afford the title compound (3.45 g, 80%) as a white solid.

(356) .sup.1H NMR (DMSO-d.sub.6) δ 9.90 (s, 1H), 7.44 (s, 1H), 7.10-7.03 (m, 4H), 6.86-6.80 (m, 4H), 5.34 (sept, J=6.6 Hz, 1H), 4.26 (s, 4H), 3.72 (s, 6H), 1.42 (d, J=6.5 Hz, 6H).

(357) LCMS; m/z 480.3 (M+Na)+(ES.sup.+).

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

(358) ##STR00174##

(359) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide and methylamine (2 M in THF) to afford the title compound (388 mg, 68%) as a yellow oil.

(360) .sup.1H NMR (DMSO-d.sub.6) δ 7.05-6.98 (m, 4H), 6.84-6.78 (m, 4H), 6.56 (s, 1H), 4.78 (sept, J=6.6 Hz, 1H), 4.19 (s, 4H), 3.73 (s, 2H), 3.72 (s, 6H), 3.32 (br s, 1H), 2.27 (s, 3H), 1.39 (d, J=6.6 Hz, 6H).

(361) LCMS; m/z 473.3 (M+H).sup.+ (ES.sup.+).

Step C: N-((3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-2,2,2-trifluoro-N-methylacetamide

(362) ##STR00175##

(363) To a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide (388 mg, 0.739 mmol) in DCM (2.5 mL) was added pyridine (0.131 mL, 1.626 mmol) and the mixture was cooled to 0° C. Trifluoroacetic anhydride (0.157 mL, 1.108 mmol) was added dropwise and the resultant mixture was stirred at 0° C. for 15 minutes before warming to room temperature for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (5 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×10 mL) and EtOAc (10 mL) and the combined organics were dried with MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by chromatography on SiO.sub.2 (24 g column, 0-100% EtOAc/isohexane) to afford the title compound (366 mg, 86%) as a white solid.

(364) .sup.1H NMR (DMSO-d.sub.6) δ 7.02 (d, J=8.7 Hz, 4H), 6.85-6.79 (m, 4H), 6.73 (s, 1H), 4.81 (s, 2H), 4.70-4.62 (m, 1H), 4.22 (s, 4H), 3.72 (s, 6H), 3.11-3.07 (m, 3H), 1.36 (d, J=6.5 Hz, 6H).

(365) LCMS; m/z 591.3 (M+Na)+(ES.sup.+).

Step D: 2,2,2-Trifluoro-N-((1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

(366) ##STR00176##

(367) N-((3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-2,2,2-trifluoro-N-methylacetamide (366 mg, 0.644 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred for 16 hours, concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude product was purified by chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford the title compound (186 mg, 85%) as a brown solid.

(368) .sup.1H NMR (DMSO-d.sub.6) δ 7.42 (br s, 2H), 6.57 (s, 1H), 4.80 (s, 2H), 4.70-4.56 (m, 1H), 3.13-3.10 (m, 3H), 1.38 (d, J=6.5 Hz, 6H).

(369) LCMS m/z 329.6 (M+H).sup.+ (ES.sup.+).

Intermediate P30: 5-(Azetidin-1-ylmethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

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

(370) ##STR00177##

(371) A suspension of 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) (500 mg, 1.093 mmol) in MeOH (11 mL) was treated with NaBH.sub.4 (70.3 mg, 1.858 mmol). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo. The crude product was redissolved in EtOAc (10 mL) and washed with brine (5 mL). The organic phase was dried (MgSO.sub.4) and evaporated in vacuo to afford the title compound (514 mg, 98%).

(372) .sup.1H NMR (DMSO-d.sub.6) δ 7.04-7.00 (m, 4H), 6.83-6.79 (m, 4H), 6.60 (s, 1H), 5.48 (d, J=5.3 Hz, 1H), 4.73 (sept, J=6.4 Hz, 1H), 4.57 (d, J=5.0 Hz, 2H), 4.19 (s, 4H), 3.72 (s, 6H), 1.41 (d, J=6.6 Hz, 6H).

(373) LCMS; m/z 482.3 (M+Na)+(ES.sup.+).

Step B: 5-(Azetidin-1-ylmethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(374) ##STR00178##

(375) MsCl (62.0 μL, 0.796 mmol) was added to a solution of 5-(hydroxymethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (305 mg, 0.663 mmol) and DIPEA (151 μL, 0.862 mmol) in anhydrous DCM (3 mL) at 0° C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (10 mL) and saturated aqueous NaHCO.sub.3 solution was added (10 mL). The phases were separated and the aqueous phase was extracted with a further portion of DCM (10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo to give crude intermediate as a brown oil. The crude intermediate was redissolved in anhydrous THF (3 mL) and azetidine (303 mg, 5.30 mmol) was added. The mixture was heated to 60° C. and stirred for 1 hour. The solvent was removed in vacuo. The crude product was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The crude product was purified by chromatography on SiO.sub.2 (12 g column, 0-10% MeOH/DCM) to afford the title compound (212 mg, 55%) as a white solid.

(376) .sup.1H NMR (DMSO-d.sub.6) δ 7.03-6.98 (m, 4H), 6.84-6.79 (m, 4H), 6.53 (s, 1H), 4.74 (sept, J=6.6 Hz, 1H), 4.19 (s, 4H), 3.72 (s, 6H), 3.61 (s, 2H), 3.13 (t, J=7.0 Hz, 4H), 1.99 (p, J=7.0 Hz, 2H), 1.39 (d, J=6.6 Hz, 6H).

(377) LCMS; m/z 499.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(Azetidin-1-ylmethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(378) ##STR00179##

(379) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(azetidin-1-ylmethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (91 mg, 94%) as a white solid.

(380) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.43 (s, 1H), 4.71 (sept, J=6.6 Hz, 1H), 3.60 (s, 2H), 3.14 (t, J=7.0 Hz, 4H), 1.99 (p, J=7.0 Hz, 2H), 1.38 (d, J=6.6 Hz, 6H).

(381) LCMS; m/z 259.4 (M+H).sup.+ (ES.sup.+).

Intermediate P31:5-(((2,2-Difluoroethyl)(methyl)amino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 5-(((2,2-Difluoroethyl)(methyl)amino)methyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(382) ##STR00180##

(383) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) and 2,2-difluoro-N-methylethanamine hydrochloride to afford the title compound (374 mg, 60%) as a colourless oil.

(384) .sup.1H NMR (DMSO-d.sub.6) δ 7.03-6.97 (m, 4H), 6.85-6.78 (m, 4H), 6.62 (s, 1H), 6.16 (tt, J=55.6, 4.2 Hz, 1H), 4.80 (sept, J=6.5 Hz, 1H), 4.20 (s, 4H), 3.72 (s, 8H), 2.83 (td, J=15.6, 4.2 Hz, 2H), 2.26 (s, 3H), 1.39 (d, J=6.6 Hz, 6H).

(385) LCMS; m/z 57.5 (M+H).sup.+ (ES.sup.+).

Step B: 5-(((2,2-Difluoroethyl)(methyl)amino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(386) ##STR00181##

(387) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (145 mg, 81%) as a white solid.

(388) .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (s, 2H), 6.50 (s, 1H), 6.15 (tt, J=55.7, 4.3 Hz, 1H), 4.76 (sept, J=6.6 Hz, 1H), 3.71 (s, 2H), 2.81 (td, J=15.6, 4.3 Hz, 2H), 2.27 (s, 3H), 1.38 (d, J=6.6 Hz, 6H).

(389) LCMS; m/z 297.3 (M+H).sup.+ (ES.sup.+).

Intermediate P32: 5-(((2-Fluoroethyl)(methyl)amino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: 5-(((2-Fluoroethyl)(methyl)amino)methyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(390) ##STR00182##

(391) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) and 2-fluoro-N-methylethanamine hydrochloride to afford the title compound (279 mg, 48%) as a colourless oil.

(392) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-6.97 (m, 4H), 6.86-6.77 (m, 4H), 6.59 (s, 1H), 4.83 (sept, J=6.5 Hz, 1H), 4.55 (dt, J=47.8, 4.8 Hz, 2H), 4.20 (s, 4H), 3.72 (s, 6H), 3.65 (s, 2H), 2.68 (dt, J=28.4, 4.9 Hz, 2H), 2.21 (s, 3H), 1.39 (d, J=6.6 Hz, 6H).

(393) LCMS; m/z 519.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(((2-Fluoroethyl)(methyl)amino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(394) ##STR00183##

(395) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(((2-fluoroethyl)(methyl)amino)methyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (129 mg, 100%).

(396) .sup.1H NMR (DMSO-d.sub.6) δ 7.36 (s, 2H), 6.48 (s, 1H), 4.79 (sept, J=6.6 Hz, 1H), 4.54 (dt, J=47.8, 4.9 Hz, 2H), 3.63 (s, 2H), 2.68 (dt, J=28.3, 4.9 Hz, 2H), 2.22 (s, 3H), 1.38 (d, J=6.6 Hz, 6H).

(397) LCMS; m/z 279.4 (M+H).sup.+ (ES.sup.+).

Intermediate P33: 5-(1-(Dimethylamino)cyclopropyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

(398) ##STR00184##

(399) Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate (Intermediate P22, Step A) (2 g, 4.22 mmol) was suspended in EtOH (20 mL) and THF (5 mL) and 2 M aqueous NaOH (4.22 mL, 8.45 mmol). The reaction was left to stir at room temperature for 20.5 hours. The reaction was then evaporated to dryness under reduced pressure to give a white solid. The solid obtained was suspended in THF (25 mL) to which T3P, 50 wt % in EtOAc (4.8 mL, 8.06 mmol), 2 M dimethylamine in THF (2.5 mL, 5.00 mmol) and DIPEA (1.4 mL, 8.02 mmol) were added. The reaction mixture was stirred at room temperature for 90 minutes. A gel was obtained, so further THF (10 mL) was added and the mixture stirred for a further 17 hours. Further T3P, 50 wt % in EtOAc (4.8 mL, 8.06 mmol), DIPEA (1.4 mL, 8.02 mmol) and 2 M dimethylamine in THF (2.5 mL, 5.00 mmol) were added and the mixture was stirred for a further 24 hours at room temperature. The mixture was quenched with 1 M aqueous HCl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with 1 M aqueous HCl (50 mL), dried (MgSO.sub.4), filtered and concentrated to dryness to give a yellow oil. The yellow oil was dissolved in THF (25 mL) and 2 M dimethylamine in THF (2.5 mL, 5.00 mmol), DIPEA (1.4 mL, 8.02 mmol) and T3P, 50 wt % in EtOAc (4.8 mL, 8.06 mmol) were added sequentially. The mixture was stirred at room temperature for a further 1 hour. The mixture was quenched with 1 M aqueous HCl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with 1 M aqueous HCl (50 mL), 2 M aqueous NaOH and then dried (MgSO.sub.4), filtered and concentrated to dryness to give an orange oil. The crude product was purified by chromatography on SiO.sub.2 (40 g column, 0-100% EtOAc/isohexane) to afford the title compound (1.64 g, 85%) as a beige solid.

(400) .sup.1H NMR (DMSO-d.sub.6) δ 7.20-7.01 (m, 4H), 6.95 (s, 1H), 6.88-6.70 (m, 4H), 4.23 (s, 4H), 3.91 (s, 3H), 3.71 (s, 6H), 3.01 (s, 3H), 3.00 (s, 3H).

(401) LCMS; m/z 495.2 (M+Na)+(ES.sup.+).

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

(402) ##STR00185##

(403) Prepared according to the general procedure 5-(1-(dimethylamino)cyclopropyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P20, Step B) from 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide to afford the title compound (345 mg, 48.3%) as a white solid.

(404) .sup.1H NMR (DMSO-d.sub.6) δ 7.08-6.97 (m, 4H), 6.85-6.74 (m, 4H), 6.49 (s, 1H), 4.22 (s, 4H), 3.94 (s, 3H), 3.72 (s, 6H), 2.15 (s, 6H), 1.04-0.95 (m, 2H), 0.88-0.80 (m, 2H).

(405) LCMS; m/z 485.6 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-(Dimethylamino)cyclopropyl)-1-methyl-1H-pyrazole-3-sulfonamide

(406) ##STR00186##

(407) Prepared according to the general procedure of 5-(1-(dimethylamino)cyclopropyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P20, Step C) from 5-(1-(dimethylamino)cyclopropyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (140 mg, 68%) as a white solid.

(408) .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (br s, 2H), 6.47 (s, 1H), 3.93 (s, 3H), 2.18 (s, 6H), 1.07-0.95 (m, 2H), 0.93-0.71 (m, 2H).

(409) LCMS; m/z 245.4 (M+H).sup.+ (ES.sup.+).

Intermediate P34: 5-(2-(Dimethylamino)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(410) ##STR00187##

(411) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P9, Step A) and oxirane (2.5 M in THF) to afford the title compound (0.55 g, 25%) as a yellow oil.

(412) .sup.1H NMR (CDCl.sub.3) δ 7.10-7.05 (m, 4H), 6.80-6.74 (m, 4H), 6.41 (d, J=0.6 Hz, 1H), 4.30 (s, 4H), 3.88 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 3.78 (s, 6H), 2.87 (t, J=6.3 Hz, 2H).

(413) OH signal not observed.

(414) LCMS; m/z 468.4 (M+Na)+(ES.sup.+).

Step B: 5-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(415) ##STR00188##

(416) Dess-Martin periodinane 0.540 g, 1.210 mmol) was added to a solution of 5-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.50 g, 1.100 mmol) in anhydrous DCM (8 mL) at room temperature. The mixture was stirred for 2.5 hours at room temperature and then quenched by addition of a 5% aqueous NaS.sub.2O.sub.3 solution (3 mL), followed by a saturated aqueous NaHCO.sub.3 solution (5 mL). This mixture was then stirred for 15 minutes and extracted with EtOAc (3×25 mL). The combined organic phases were washed with saturated aqueous NaHCO.sub.3 solution (2×10 mL), H.sub.2O (10 mL), and brine (10 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give a yellow oil. NaCNBH.sub.3 (0.086 g, 1.299 mmol) was added to a pre-stirred solution (10 minutes at room temperature) of this oil and dimethylamine (2 M in THF) (2.71 mL, 5.41 mmol) in anhydrous MeOH (5 mL) at room temperature. The mixture was stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure, redissolved in MeOH (3 mL) and loaded onto SCX (ca. 5 g), which was then rinsed with MeOH (15 mL) and eluted with 0.7 M NH.sub.3/MeOH (15 mL). The eluent was concentrated in vacuo to give a pale yellow oil. The residue was re-dissolved in anhydrous MeOH (5 mL), NaBH.sub.4 (0.082 g, 2.165 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with 14% w/v aqueous NaOH (0.928 mL, 3.25 mmol) and stirred for 20 minutes at room temperature before being concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and brine (10 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phases were washed with brine (2×10 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on SiO.sub.2 (12 g column, 0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (0.24 g, 43%) as a very pale yellow oil.

(417) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-7.00 (m, 4H), 6.84-6.77 (m, 4H), 6.48 (s, 1H), 4.18 (s, 4H), 3.84 (s, 3H), 3.71 (s, 6H), 2.79 (t, J=7.4 Hz, 2H), 2.20 (s, 6H). 2H triplet directly underneath DMSO peak.

(418) LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(2-(Dimethylamino)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide

(419) ##STR00189##

(420) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.07 g, 85%) as a colourless oil.

(421) LCMS; m/z 233.4 (M+H).sup.+ (ES.sup.+).

Intermediate P35: 4-(Dimethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide

Step A: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-5-carboxylate

(422) ##STR00190##

(423) Prepared according to the general procedure of N,N-bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P9, Step A) from ethyl 3-(chlorosulfonyl)-1H-pyrazole-5-carboxylate to afford the title compound (5.7 g, 81%) as a white solid.

(424) .sup.1H NMR (DMSO-d.sub.6) δ 14.87 (s, 1H), 7.28-6.98 (m, 5H), 6.98-6.47 (m, 4H), 4.35 (q, J=7.1 Hz, 2H), 4.24 (br s, 4H), 3.71 (s, 6H), 1.33 (t, J=7.1 Hz, 3H).

(425) LCMS; m/z 482.1 (M+Na)+(ES.sup.+).

Step B: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(4-methoxy-4-oxobutyl)-1H-pyrazole-5-carboxylate

(426) ##STR00191##

(427) A mixture of ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-5-carboxylate (1 g, 2.176 mmol), ethyl 4-bromobutanoate (0.509 g, 2.61 mmol) and K.sub.2CO.sub.3 (600 mg, 4.34 mmol) in DMF (10 mL) was stirred at room temperature for 72 hours. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the organic layer washed with water (100 mL), dried (MgSO.sub.4), filtered and evaporated to afford the title compound (1.09 g, 85%) as an oil.

(428) .sup.1H NMR (CDCl.sub.3) δ 7.14 (s, 1H), 7.13-7.09 (m, 4H), 6.82-6.78 (m, 4H), 4.67 (t, J=6.9 Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 4.34 (s, 4H), 3.80 (s, 6H), 3.70 (s, 3H), 2.35 (t, J=7.2 Hz, 2H), 2.24-2.16 (m, 2H), 1.42 (t, J=7.1 Hz, 3H).

(429) LCMS; m/z 582 (M+Na)+(ES.sup.+).

Step C: Methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate and ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate

(430) ##STR00192##

(431) Toluene (15 mL) was added to ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(4-methoxy-4-oxobutyl)-1H-pyrazole-5-carboxylate (1.06 g, 1.894 mmol) and the solution evaporated under reduced pressure. A solution of sodium tert-butoxide (1 mL, 2.000 mmol) (2 M in THF) was added to a solution of ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(4-methoxy-4-oxobutyl)-1H-pyrazole-5-carboxylate (1.06 g, 1.894 mmol) in toluene (15 mL). The reaction mixture was stirred at room temperature for 10 minutes and then heated at 80° C. for 3 hours. The mixture was cooled, and partitioned between EtOAc (80 mL) and 1 M aqueous HCl (50 mL). The organic layer was washed with water (40 mL), dried (MgSO.sub.4), filtered and evaporated. The residue was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (510 mg, 45%) and ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (264 mg, 24%) as solids.

(432) Methyl ester: .sup.1H NMR (CDCl.sub.3) δ 11.93 (s, 1H), 7.13-709 (m, 4H), 6.92 (s, 1H), 6.82-6.78 (m, 4H), 4.35 (s, 4H), 4.28 (t, J=7.5 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 6H), 2.93 (t, J=7.4 Hz, 2H).

(433) LCMS; m/z 514 (M+H).sup.+ (ES.sup.+); 512 (M−H).sup.− (ES.sup.−).

(434) Ethyl ester: LCMS; m/z 528 (M+H).sup.+ (ES.sup.+); 526 (M−H).sup.− (ES.sup.−).

Step D: N,N-Bis(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide

(435) ##STR00193##

(436) A mixture of methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (450 mg, 0.876 mmol), ethyl 2-(N,N— bis(4-methoxybenzyl)sulfamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (260 mg, 0.493 mmol) and LiCl (120 mg, 2.83 mmol) in DMSO (10 mL) and water (1 mL) was heated at 120° C. for 3 hours. The mixture was partitioned between EtOAc (80 mL) and 10% brine (50 mL), the organic layer separated, dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by chromatography on silica gel (40 g column, 0-70% EtOAc/isohexane) to afford the title compound (525 mg, 80%) as a solid.

(437) .sup.1H NMR (CDCl.sub.3) δ 7.13-7.10 (m, 5H), 6.81-6.77 (m, 4H), 4.42-4.39 (m, 2H), 4.36 (s, 4H), 3.80 (s, 6H), 2.77-2.73 (m, 2H), 2.45-2.39 (m, 2H).

(438) LCMS; m/z 478 (M+Na)+(ES.sup.+); 454.3 (M−H).sup.− (ES.sup.−).

Step E: 4-(Dimethylamino)-N,N-bis(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide

(439) ##STR00194##

(440) To a mixture of N,N-bis(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide (200 mg, 0.439 mmol), dimethylamine (2 M in THF) (280 μL, 0.560 mmol) and triethylamine (200 μL, 1.435 mmol) in DCM (4 mL) at 0° C. was added titanium(IV) chloride (1 M in DCM) (220 μL, 0.220 mmol) slowly via syringe. The resulting mixture was warmed to room temperature and stirred overnight. NaBH(OAc).sub.3 (240 mg, 1.132 mmol) and MeOH (1 mL) were added and stirring was continued over the weekend. The reaction was quenched with H.sub.2O (5 mL) and brine (10 mL) and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (15 mL), passed through a phase separator and the solvent was removed under reduced pressure. The residue was loaded onto a SCX column with MeOH and the product eluted with 0.7 M NH.sub.3 in MeOH to afford the title compound (133 mg, 59%) as a yellow oil.

(441) .sup.1H NMR (DMSO-d.sub.6) δ 7.03 (d, J=8.7 Hz, 4H), 6.81 (d, J=8.7 Hz, 4H), 6.44 (d, J=0.9 Hz, 1H), 4.28-4.11 (m, 5H), 4.12-3.96 (m, 1H), 3.94-3.85 (m, 1H), 3.71 (s, 6H), 2.21 (s, 6H), 2.21-2.11 (m, 1H), 2.03-1.82 (m, 2H), 1.76-1.61 (m, 1H).

(442) LCMS; m/z 485.2 (M+H).sup.+ (ES.sup.+).

Step F: 4-(Dimethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide

(443) ##STR00195##

(444) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 4-(dimethylamino)-N,N-bis(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide to afford the title compound (58 mg, 81%) as a beige solid.

(445) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.42 (s, 1H), 4.18-4.07 (m, 1H), 4.07-3.94 (m, 1H), 3.93-3.85 (m, 1H), 2.23 (s, 6H), 2.19-2.08 (m, 1H), 1.99-1.80 (m, 2H), 1.75-1.60 (m, 1H).

(446) LCMS; m/z 245.4 (M+H).sup.+ (ES.sup.+).

Intermediate P36: 5-(1-(Dimethylamino)propyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

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

(447) ##STR00196##

(448) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P8, Step A) and propionaldehyde to afford the title compound (1.79 g, 77%) as a very pale yellow oil.

(449) LCMS; m/z 488.3 (M+H).sup.+ (ES.sup.+).

Step B: 5-(1-(Dimethylamino)propyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(450) ##STR00197##

(451) MsCl (0.158 mL, 2.026 mmol) was added to a solution of 5-(1-hydroxypropyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.84 g, 1.688 mmol) and DIPEA (0.413 mL, 2.364 mmol) in anhydrous DCM (8 mL) at 0° C. After 20 minutes, the solution was allowed to warm to room temperature and stirred overnight. Dimethylamine (2 M in THF) (5.06 mL, 10.13 mmol) was added and the mixture was heated to 40° C. for 23 hours. The mixture was concentrated under reduced pressure and the flask was recharged with dimethylamine (2 M in THF) (5.06 mL, 10.13 mmol) and heated to 50° C. overnight. After a further 24 hours, the reaction mixture was transferred to a microwave vial, dimethylamine (2 M in THF) (1.688 mL, 3.38 mmol) was added, and the vessel was sealed and heated at 40° C. over the weekend. To the reaction mixture was added saturated aqueous NaHCO.sub.3 (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (30 mL), passed through a phase separator and the solvent was removed in vacuo to give a brown oil. The residue was loaded onto a SCX column with MeOH and the column was washed with further MeOH (15 mL). The product was eluted with 0.7 M NH.sub.3 in MeOH (˜20 mL) and the solvent was removed in vacuo to afford the title compound (428 mg, 48%) as a light brown oil.

(452) .sup.1H NMR (DMSO-d.sub.6) δ 6.99 (d, J=8.7 Hz, 4H), 6.80 (d, J=8.7 Hz, 4H), 6.53 (s, 1H), 4.89-4.80 (m, 1H), 4.21 (s, 2H), 4.20 (s, 2H), 3.71 (s, 6H), 3.70-3.65 (m, 1H), 2.10 (s, 6H), 1.88-1.76 (m, 1H), 1.72-1.61 (m, 1H), 1.40 (d, J=6.5 Hz, 3H), 1.33 (d, J=6.5 Hz, 3H), 0.76 (t, J=7.3 Hz, 3H).

(453) LCMS; m/z 515.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-(Dimethylamino)propyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(454) ##STR00198##

(455) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(1-(dimethylamino)propyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide to afford the title compound (202 mg, 91%) as a light tan solid.

(456) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.43 (s, 1H), 4.88-4.75 (m, 1H), 3.66 (dd, J=4.8, 9.8 Hz, 1H), 2.12 (s, 6H), 1.91-1.78 (m, 1H), 1.71-1.59 (m, 1H), 1.40 (d, J=6.5 Hz, 3H), 1.35 (d, J=6.5 Hz, 3H), 0.79 (t, J=7.3 Hz, 3H).

(457) LCMS; m/z 275.1 (M+H).sup.+ (ES.sup.+).

Intermediate P37:5-(1-(Dimethylamino)propyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(458) ##STR00199##

(459) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P9, Step A) and propionaldehyde to afford the title compound (3.4 g, 84%) as a viscous colourless oil.

(460) .sup.1H NMR (DMSO-d.sub.6) δ 7.08-7.02 (m, 4H), 6.84-6.80 (m, 4H), 6.53 (s, 1H), 5.50 (d, J=5.8 Hz, 1H), 4.60 (q, J=6.4 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.72 (s, 6H), 1.73 (td, J=7.7, 6.5 Hz, 2H), 0.95-0.81 (m, 3H).

(461) LCMS; m/z 460 (M+H).sup.+ (ES.sup.+).

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

(462) ##STR00200##

(463) MsCl (0.094 mL, 1.200 mmol) was added to a solution of 5-(1-hydroxypropyl)-N,N— bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.484 g, 1.000 mmol) and DIPEA (0.245 mL, 1.400 mmol) in anhydrous DCM (5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2.5 hours. Then the pale yellow solution was cooled to 0° C. and dimethylamine (2 M in THF) (12.50 mL, 25.00 mmol) was added. The reaction mixture was warmed to 40° C. and stirred for 17 hours. A further portion of dimethylamine (2 M in THF) (1.0 mL, 2.000 mmol) was added and the reaction was stirred at 40° C. for a further 2 hours. The mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in EtOAc (50 mL) and saturated aqueous NaHCO.sub.3 solution (10 mL), the layers were separated, and the aqueous phase was extracted with further portions of EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaHCO.sub.3 solution (10 mL) and brine (2×10 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give crude product as a yellow oil. The crude product was re-dissolved in MeOH (3 mL) and loaded onto SCX (ca. 4 g), which was then washed with MeOH (15 mL) and eluted with 0.7 M NH.sub.3/MeOH (15 mL) and concentrated in vacuo to afford the title compound (0.27 g, 48%) as a pale yellow oil.

(464) LCMS; m/z 487.5 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-(Dimethylamino)propyl)-1-methyl-1H-pyrazole-3-sulfonamide

(465) ##STR00201##

(466) TFA (1.412 mL, 18.45 mmol) was added to a solution of 5-(1-(dimethylamino)propyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.630 g, 1.230 mmol) in anhydrous DCM (4 mL) at room temperature. The mixture was stirred at room temperature for 19 hours. A second portion of TFA (0.471 mL, 6.15 mmol) was added and the reaction was stirred for a further 2 hours at room temperature. The reaction mixture was concentrated in vacuo and co-evaporated with portions of MeCN (2×10 mL). The residue was then redissolved in MeOH (3 mL) and loaded onto SCX (ca. 5 g), which was rinsed with MeOH (15 mL) and eluted with 0.7 M NH.sub.3/MeOH (15 mL) to give a yellow solid after concentration in vacuo. This material was pre-adsorbed onto silica and purified by chromatography on SiO.sub.2 (12 g column, 0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (0.14 g, 45%) as an off-white solid.

(467) LCMS; m/z 247.4 (M+H).sup.+ (ES.sup.+).

Intermediate P38: 2,2,2-Trifluoro-N-methyl-N-((1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)acetamide

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

(468) ##STR00202##

(469) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis-(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P9, Step A) and DMF to afford the title compound (4 g, 93%) as a white solid.

(470) .sup.1H NMR (DMSO-d.sub.6) δ 9.90 (s, 1H), 7.41 (s, 1H), 7.11-7.02 (m, 4H), 6.87-6.78 (m, 4H), 4.25 (s, 4H), 4.17 (s, 3H), 3.72 (s, 6H).

(471) LCMS; m/z 452.4 (M+Na)+(ES.sup.+).

Step B: N,N-Bis(4-methoxybenzyl)-1-methyl-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide

(472) ##STR00203##

(473) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide and methylamine (2 M in THF) to afford the title compound (251 mg, 44%).

(474) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-7.01 (m, 4H), 6.83-6.78 (m, 4H), 6.59 (s, 1H), 4.19 (s, 4H), 3.90 (s, 3H), 3.72 (s, 8H), 3.34 (br s, 1H), 2.27 (s, 3H).

(475) LCMS; m/z 445771 (M+H).sup.+ (ES.sup.+).

Step C: 1-Methyl-5-((methylamino)methyl)-1-H-pyrazole-3-sulfonamide

(476) ##STR00204##

(477) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from N,N-bis(4-methoxybenzyl)-1-methyl-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (110 mg, 91%) as a tan solid.

(478) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (br s, 2H), 6.47 (s, 1H), 3.84 (s, 3H), 3.69 (s, 2H), 2.27 (s, 3H). N—H not observed.

(479) LCMS; m/z 205.3 (M+H).sup.+ (ES.sup.+).

Step D: 2,2,2-Trifluoro-N-methyl-N-((1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)acetamide

(480) ##STR00205##

(481) Prepared according to the general procedure of N-((3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-2,2,2-trifluoro-N— methylacetamide (Intermediate P29, Step C) from 1-methyl-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (27 mg, 21%) as a white solid.

(482) .sup.1H NMR (DMSO-d.sub.6) δ 7.42 (br s, 2H), 6.56 (s, 1H), 4.75 (s, 2H), 3.86 (s, 3H), 3.18-3.07 (m, 3H).

(483) LCMS; m/z 301.2 (M+H).sup.+ (ES.sup.+).

Intermediate P39: 5-(1-(Dimethylamino)ethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(484) ##STR00206##

(485) 5-(1-(Dimethylamino)ethyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P8, Step C) (88 mg, 0.176 mmol) was dissolved in TFA (5 mL) and stirred for 16 hours. The reaction mixture was concentrated and the crude product was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (38 mg, 76%) as a tan solid.

(486) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.45 (s, 1H), 4.86 (sept, J=6.6 Hz, 1H), 3.94 (q, J=6.8 Hz, 1H), 2.14 (s, 6H), 1.38 (app t, J=6.2 Hz, 6H), 1.25 (d, J=6.8 Hz, 3H).

(487) LCMS; m/z 261.5 (M+H).sup.+ (ES.sup.+).

Intermediate P40: 5-(3-Hydroxy-1-methylazetidin-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: Benzyl 3-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazol-5-yl)-3-hydroxyazetidine-1-carboxylate

(488) ##STR00207##

(489) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P9, Step A) and benzyl 3-oxoazetidine-1-carboxylate to afford the title compound (4.20 g, 83%) as a pale yellow oil.

(490) .sup.1H NMR (DMSO-d.sub.6) δ 7.39-7.35 (m, 4H), 7.07-7.02 (m, 4H), 6.91 (s, 1H), 6.82-6.79 (m, 5H), 5.07 (s, 2H), 4.42 (br d, J=9.4 Hz, 2H), 4.22 (s, 4H), 4.15 (br d, J=9.4 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 1H), 3.70 (s, 6H).

(491) LCMS; m/z 607.0 (M+H).sup.+ (ES.sup.+).

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

(492) ##STR00208##

(493) A slurry of Pd/C (J&M Type 39, 50% paste with water) (0.631 g, 2.97 mmol) in EtOH (2 mL) was added to a solution of benzyl 3-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazol-5-yl)-3-hydroxyazetidine-1-carboxylate (2.00 g, 2.97 mmol) in EtOH (18 mL). The vessel was charged with hydrogen (5 bar) and stirred at room temperature for 17 hours. The mixture was filtered through a plug of Celite® (ca. 6 g), rinsed with further portions of EtOH (3×20 mL), and concentrated in vacuo to give a pale yellow oil. The residue was redissolved in MeOH (5 mL) and loaded onto SCX (ca. 5 g), which was washed with MeOH (15 mL) and then eluted with 0.7 M NH.sub.3/MeOH (15 mL) and concentrated in vacuo to give a colourless oil, which solidified upon standing to afford the title compound (0.61 g, 41%) as a white solid.

(494) .sup.1H NMR (DMSO-d.sub.6) δ 7.18-6.97 (m, 4H), 6.84-6.78 (m, 4H), 6.77 (s, 1H), 6.34 (br s, 1H), 4.22 (br s, 4H), 3.84 (s, 3H), 3.75 (br s, 3H), 3.71 (s, 6H), 3.17 (s, 2H).

(495) LCMS; m/z 473.0 (M+H).sup.+ (ES.sup.+).

Step C: 5-(3-Hydroxy-1-methylazetidin-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(496) ##STR00209##

(497) NaCNBH.sub.3 (0.160 g, 2.54 mmol) was added to a mixture of 5-(3-hydroxyazetidin-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.60 g, 1.270 mmol) and formaldehyde (37% aqueous solution) (0.473 mL, 6.35 mmol) in anhydrous DCM (8 mL) at room temperature. The reaction mixture was stirred for 4 days at room temperature. The mixture was diluted with MeOH (˜2 mL) and the flask was rinsed with DCM (˜2 mL). The product was loaded onto SCX (ca. 6 g), which was washed with MeOH (18 mL) and eluted with 0.7 M NH.sub.3/MeOH (18 mL) and then concentrated in vacuo to give an opaque viscous oil. The crude product was purified by chromatography on SiO.sub.2 (24 g column, 0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (0.18 g, 25%) as a viscous colourless oil.

(498) LCMS; m/z 487.4 (M+H).sup.+ (ES.sup.+).

Step D: 5-(3-Hydroxy-1-methylazetidin-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

(499) ##STR00210##

(500) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(3-hydroxy-1-methylazetidin-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.09 g, 107%) as a white solid.

(501) LCMS; m/z 247.3 (M+H).sup.+ (ES.sup.+).

Intermediate P41: 5-(1-(Azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(1-(Azetidin-1-yl)ethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(502) ##STR00211##

(503) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-isopropyl N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P30, Step B) from 5-(1-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P9, Step B) and azetidine to afford the title compound (0.58 g, 55%) as a yellow oil.

(504) LCMS; m/z 485.1 (M+H).sup.+ (ES.sup.+).

Step B: 5-(˜(Azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide

(505) ##STR00212##

(506) Prepared according to the general procedure of 1-cyclopropyl-5-(˜(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(1-(azetidin-1-yl)ethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.26 g, 89%) as a cream coloured solid.

(507) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.40 (s, 1H), 3.89 (s, 3H), 3.65-3.56 (m, 1H), 3.18-2.98 (m, 4H), 1.97-1.89 (m, 2H), 1.12 (d, J=6.6 Hz, 3H).

(508) LCMS; m/z 245.1 (M+H).sup.+ (ES.sup.+).

Intermediate P42: 5-(1-(Dimethylamino)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide

(509) ##STR00213##

(510) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(1-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P9, Step C) to afford the title compound (0.17 g, 83%) as a cream coloured solid.

(511) .sup.1H NMR (MeOH-d.sub.4) δ 6.51 (s, 1H), 3.84 (s, 3H), 3.83 (q, J=6.8 Hz, 1H), 2.16 (s, 6H), 1.27 (d, J=6.8 Hz, 3H). NH.sub.2 signal not observed.

(512) LCMS; m/z 233.1 (M+H).sup.+ (ES.sup.+).

Intermediate P43: 1-Methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide

(513) ##STR00214##

(514) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and pyrrolidine to afford the title compound (211 mg, 46%) as a clear colourless gum.

(515) .sup.1H NMR (DMSO-d.sub.6) δ 7.10-6.95 (m, 4H), 6.87-6.73 (m, 4H), 6.56 (s, 1H), 4.19 (s, 4H), 3.88 (s, 3H), 3.71 (s, 6H), 3.65 (s, 2H), 2.45-2.35 (m, 4H), 1.77-1.62 (m, 4H).

(516) LCMS; m/z 485.2 (M+H).sup.+ (ES.sup.+).

Step B: 1-Methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide

(517) ##STR00215##

(518) Prepared according to the general procedure of 5-(1-(dimethylamino)ethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P39) from N,N-bis(4-methoxybenzyl)-1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide to afford the title compound (100 mg, 84%) as a waxy orange solid.

(519) .sup.1H NMR (DMSO-d.sub.6) δ 7.31 (s, 2H), 6.46 (s, 1H), 3.84 (s, 3H), 3.64 (s, 2H), 2.47-2.40 (m, 4H), 1.73-1.64 (m, 4H).

(520) LCMS; m/z 245.1 (M+H).sup.+ (ES.sup.+).

Intermediate P44: 5-((3-Fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(521) ##STR00216##

(522) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and 3-fluoroazetidine hydrochloride to afford the title compound (0.34 g, 73%) as a colourless gum.

(523) .sup.1H NMR (DMSO-d.sub.6) δ 7.10-6.97 (m, 4H), 6.85-6.75 (m, 4H), 6.57 (s, 1H), 5.30-5.04 (m, 1H), 4.18 (s, 4H), 3.85 (s, 3H), 3.71 (s, 8H), 3.65-3.49 (m, 2H), 3.25-3.11 (m, 2H).

(524) LCMS; m/z 489.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-((3-Fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(525) ##STR00217##

(526) 5-((3-Fluoroazetidin-1-yl)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.34 g, 0.696 mmol) was dissolved in TFA (5 mL, 64.9 mmol) and stirred for 4 hours. The solution was diluted with toluene (20 mL) and evaporated in vacuo to afford a colourless gum. The gum was dissolved in THF, absorbed onto SCX and eluted with THF/MeOH/DCM (1:1:3) followed by (1 M NH.sub.3/MeOH)/THF/DCM (1:1:3). The solvent was evaporated in vacuo to afford the title compound (0.17 g, 95%) as a white solid.

(527) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.49 (s, 1H), 5.32-5.04 (m, 1H), 3.82 (s, 3H), 3.71 (s, 2H), 3.57 (m, 2H), 3.21 (m, 2H).

(528) LCMS; m/z 249.1 (M+H).sup.+ (ES.sup.+).

Intermediate P45: 5-((Diethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(529) ##STR00218##

(530) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and diethylamine to afford the title compound (0.35 g, 72%) as a colourless oil.

(531) .sup.1H NMR (DMSO-d.sub.6) δ 7.08-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.59 (s, 1H), 4.20 (s, 4H), 3.90 (s, 3H), 3.72 (s, 6H), 3.61 (s, 2H), 2.47 (q, J=7.1 Hz, 4H), 0.98 (t, J=7.1 Hz, 6H).

(532) LCMS; m/z 487.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-((Diethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(533) ##STR00219##

(534) Prepared according to the general procedure of 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P44, Step B) from 5-((diethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.17 g, 94%) as a white solid.

(535) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.49 (s, 1H), 3.86 (s, 3H), 3.59 (s, 2H), 2.47 (q, J=7.1 Hz, 4H), 0.98 (t, J=7.1 Hz, 6H).

(536) LCMS; m/z 247.1 (M+H).sup.+ (ES.sup.+).

Intermediate P46:5-((Ethyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(537) ##STR00220##

(538) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and N-methylethanamine to afford the title compound (0.42 g, 76%) as a colourless gum.

(539) .sup.1H NMR (DMSO-d.sub.6) δ 7.03 (m, 4H), 6.81 (m, 4H), 6.58 (s, 1H), 4.20 (s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.53 (s, 2H), 2.40 (q, J=7.1 Hz, 2H), 2.11 (s, 3H), 1.03 (t, J=7.1 Hz, 3H).

(540) LCMS; m/z 473.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-((Ethyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(541) ##STR00221##

(542) Prepared according to the general procedure of 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P44, Step B) from 5-((ethyl(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.23 g, 103%) as a white solid.

(543) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.48 (s, 1H), 3.85 (s, 3H), 3.52 (s, 2H), 2.40 (q, J=7.1 Hz, 2H), 2.12 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).

(544) LCMS; m/z 233.1 (M+H).sup.+ (ES.sup.+).

Intermediate P47: 5-((Cyclopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(545) ##STR00222##

(546) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and N-methylcyclopropanamine hydrochloride to afford the title compound (0.42 g, 72%) as a colourless gum.

(547) .sup.1H NMR (DMSO-d.sub.6) δ 7.10-7.00 (m, 4H), 6.85-6.77 (m, 4H), 6.59 (s, 1H), 4.19 (s, 4H), 3.85 (s, 3H), 3.72 (s, 6H), 3.71 (m, 2H), 2.20 (s, 3H), 1.72 (tt, J=3.6, 6.6 Hz, 1H), 0.44 (m, 2H), 0.31 (m, 2H).

(548) LCMS; m/z 485.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-((Cyclopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(549) ##STR00223##

(550) Prepared according to the general procedure of 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P44, Step B) from 5-((cyclopropyl(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (200 mg, 94%) as a colourless gum.

(551) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.48 (s, 1H), 3.80 (s, 3H), 3.70 (s, 2H), 2.21 (s, 3H), 1.73 (tt, J=3.6, 6.7 Hz, 1H), 0.45 (m, 2H), 0.31 (m, 2H).

(552) LCMS; m/z 245.1 (M+H).sup.+ (ES.sup.+).

Intermediate P48: 5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(553) ##STR00224##

(554) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and azetidine hydrochloride to afford the title compound (0.46 g, 84%) as a colourless gum.

(555) .sup.1H NMR (DMSO-d.sub.6) δ 7.08-6.98 (m, 4H), 6.85-6.77 (m, 4H), 6.54 (s, 1H), 4.19 (s, 4H), 3.86 (s, 3H), 3.72 (s, 6H), 3.59 (s, 2H), 3.15 (t, J=7.0 Hz, 4H), 1.99 (p, J=7.0 Hz, 2H).

(556) LCMS; m/z 471.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazole-3-sulfonamide

(557) ##STR00225##

(558) Prepared according to the general procedure of 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P44, Step B) from 5-(azetidin-1-ylmethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (220 mg, 98%) as a white solid.

(559) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.44 (s, 1H), 3.82 (s, 3H), 3.58 (s, 2H), 3.15 (t, J=7.0 Hz, 4H), 1.99 (p, J=7.0 Hz, 2H).

(560) LCMS; m/z 231.0 (M+H).sup.+ (ES.sup.+).

Intermediate P49: 5-((Isopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(561) ##STR00226##

(562) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and N-methylpropan-2-amine to afford the title compound (0.46 g, 88%) as a colourless gum.

(563) .sup.1H NMR (DMSO-d.sub.6) δ 7.03 (m, 4H), 6.81 (m, 4H), 6.57 (s, 1H), 4.20 (s, 4H), 3.89 (s, 3H), 3.72 (s, 6H), 3.57 (s, 2H), 2.84 (sept, J=6.6 Hz, 1H), 2.05 (s, 3H), 1.02 (d, J=6.5 Hz, 6H).

(564) LCMS; m/z 487.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-((Isopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(565) ##STR00227##

(566) Prepared according to the general procedure of 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P44, Step B) from 5-((isopropyl(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.24 g, 104%) as a white solid.

(567) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 2H), 6.47 (s, 1H), 3.85 (s, 3H), 3.56 (s, 2H), 2.83 (sept, J=6.6 Hz, 1H), 2.07 (s, 3H), 1.01 (d, J=6.6 Hz, 6H).

(568) LCMS; m/z 247.1 (M+H).sup.+ (ES.sup.+).

Intermediate P50: N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

Step A: 1-Methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic acid, Sodium Salt

(569) ##STR00228##

(570) To a suspension of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (3 g, 12.86 mmol) in ethanol (60 mL) was added a solution of sodium hydroxide (2.0 M, 13.5 mL) and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off, washed with ethanol and dried to afford the title compound (2.92 g, 99%) as a white solid.

(571) .sup.1H NMR (D.sub.2O) δ 6.79 (s, 1H), 4.01 (s, 3H). NH.sub.2 not observed.

Step B: N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

(572) ##STR00229##

(573) To a mixture of 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic acid, sodium salt (2.38 g, 10.48 mmol) was added T3P (50% in EtOAc, 12.47 mL, 20.95 mmol) and DIPEA (Hunig's Base, 3.66 mL, 20.95 mmol) in THF (50 mL). A solution of 2.0 M dimethylamine in THF (15.71 mL, 31.4 mmol) was added and the reaction stirred for 20 hours, before being quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (magnesium sulfate), filtered and evaporated in vacuo to afford a yellow gum. The crude product was triturated in DCM (20 mL) and filtered to obtain the title compound (900 mg) as a white solid. The mother layers were evaporated, dissolved in DCM/MeOH and purified by chromatography (Companion apparatus, 40 g column, 0-10% MeOH/DCM with product eluting at ˜5% MeOH) to afford a further batch of the title compound (457 mg) as a white solid. The solids were combined to afford the title compound (1.36 g, 55%).

(574) .sup.1H NMR (DMSO-d.sub.6) δ 7.50 (s, 2H), 6.82 (s, 1H), 3.90 (s, 3H), 3.03 (s, 3H) and 3.01 (s, 3H).

(575) LCMS; m/z 233.0 (M+H).sup.+ (ES.sup.+).

Intermediate P51: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid

(576) ##STR00230##

(577) Triphosgene (170 mg, 0.573 mmol) was added to a mixture of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (165 mg, 0.952 mmol) and triethylamine (0.36 mL, 2.58 mmol) in THF (8 mL) and stirred for 15 hours. The reaction mixture was evaporated in vacuo and azeotroped with toluene (3×1 mL). THF (8 mL) was added and the reaction mixture was filtered. The filtrate was added to a mixture of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (200 mg, 0.857 mmol) and sodium hydride (86 mg, 2.150 mmol) in THF (8 mL) and stirred for 20 hours. The reaction was quenched with aqueous Na.sub.2CO.sub.3 (3.5 mL, 1.295 mmol), and evaporated in vacuo to remove the THF. The residual aqueous was washed with MTBE (2×5 mL). The solid that precipitated from the aqueous was filtered off and dried to afford ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium (100 mg) as a solid. The filtrate was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (180 mg) as a white solid. The solids were combined and dissolved in MeOH (3 mL). Aq. NaOH (0.25 mL, 0.500 mmol) was added and the reaction mixture was stirred for 20 hours. The MeOH was evaporated in vacuo. The remaining aqueous was adjusted to pH 8 with NaH.sub.2PO.sub.4 and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (140 mg, 39%) as a white solid.

(578) .sup.1H NMR (DMSO-d.sub.6) δ 7.65 (s, 2H), 6.31 (s, 1H), 6.15 (s, 1H), 3.41 (s, 3H), 2.05 (t, J=7.4 Hz, 4H), 1.90 (t, J=7.3 Hz, 4H), 1.24 (quin, J=7.4 Hz, 4H). One exchangeable proton not observed.

(579) LCMS; m/z 405.0 (M+H).sup.+ (ES.sup.+).

Intermediate P52: 1-Methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide

(580) ##STR00231##

(581) Prepared according to the general procedure for N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P50, Step B) from 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylic acid, sodium salt (Intermediate P50, Step A) and pyrrolidine to afford the title compound (204 mg, 54%) as a cream solid.

(582) LCMS; m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate P53: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, disodium Salt

Step A: Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt

(583) ##STR00232##

(584) 2 M Sodium tert-butoxide in THF (1.005 mL, 2.009 mmol) was added to a solution of ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (0.5 g, 1-914 mmol) in THF (15 mL) and stirred at room temperature for 1 hour to give a white suspension. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.419 g, 2.105 mmol) in THF (5 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washing with THF (4 mL), and dried in vacuo to afford the title compound (930 mg, 91%) as a colourless solid.

(585) .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (s, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.3 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H), 1.30 (t, J=7.1 Hz, 3H).

(586) LCMS; m/z 433.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, disodium Salt

(587) ##STR00233##

(588) Ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (3.15 g, 6.24 mmol) was dissolved in MeOH (20 mL), 2 M aqueous NaOH (3.12 mL, 6.24 mmol) was added and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.80 g, 99%) as a colourless solid.

(589) .sup.1H NMR (DMSO-d.sub.6) δ 7.57 (s, 1H), 6.76 (s, 1H), 6.44 (s, 1H), 4.02 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.89 (p, J=7.4 Hz, 4H).

(590) LCMS; m/z 405.4 (M+H).sup.+ (ES.sup.+).

Intermediate P54: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-1-carboxylic Acid, disodium Salt

Step A: Ethyl 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

(591) ##STR00234##

(592) Ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (2 g, 7.65 mmol) was dissolved in THF (80 mL, 986 mmol). Sodium hydride (0.367 g, 9.18 mmol) was added and stirred at room temperature for 30 minutes to give a white suspension. Then 2-isocyanato-1,3-diisopropylbenzene (Intermediate A19) (1.712 g, 8.42 mmol) in THF (20 mL) was added and stirred at room temperature overnight. The resultant colourless precipitate was collected by filtration, washing with THF (2×20 mL), and dried in vacuo to afford the title compound (2.16 g, 60%) as a colourless solid.

(593) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 1H), 7.15-7.05 (m, 1H), 7.05-6.95 (m, 2H), 6.93 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.20-3.02 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.9 Hz, 12H).

(594) LCMS; m/z 437.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, disodium Salt

(595) ##STR00235##

(596) Prepared according to the general procedure for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53, Step B) from ethyl 3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (2.0 g, 99%) as a colourless solid.

(597) .sup.1H NMR (DMSO-d.sub.6) δ 7.44 (s, 1H), 7.13-7.05 (m, 1H), 7.05-6.94 (m, 2H), 6.42 (s, 1H), 4.00 (s, 3H), 3.16-3.03 (m, 2H), 1.01 (d, J=6.8 Hz, 12H).

(598) LCMS; m/z 409.4 (M+H).sup.+ (ES.sup.+).

Intermediate P55: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, disodium Salt

Step A: Ethyl 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

(599) ##STR00236##

(600) Prepared according to the general procedure for ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (Intermediate P53, Step A) from ethyl 1-methyl-3-sulfamoyl-H-pyrazole-5-carboxylate and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (1.7 g, 92%) as a colourless solid.

(601) .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (s, 1H), 6.93 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.21-2.94 (m, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.8 Hz, 12H).

(602) LCMS; m/z 455.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, disodium Salt

(603) ##STR00237##

(604) Prepared according to the general procedure for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53, Step B) from ethyl 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt to afford the title compound (1.65 g, 98%) as a colourless solid.

(605) .sup.1H NMR (DMSO-d.sub.6) δ 7.41 (s, 1H), 6.77 (d, J=10.1 Hz, 2H), 6.45 (s, 1H), 4.01 (s, 3H), 3.15-3.02 (m, 2H), 1.10-0.93 (m, 12H).

(606) LCMS; m/z 427.4 (M+H).sup.+ (ES.sup.+).

Intermediate P56: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

Step A: Ethyl 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, Sodium Salt

(607) ##STR00238##

(608) Prepared according to the general procedure for ethyl 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (Intermediate P53, Step A) from ethyl 1-methyl-3-sulfamoyl-H-pyrazole-5-carboxylate and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A22) to afford the title compound (1.32 g, 92%) as a colourless solid.

(609) .sup.1H NMR (DMSO-d.sub.6); δ 7.41 (s, 1H), 7.01 (s, 2H), 6.92 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 3.13 (br s, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.04 (d, J=6.8 Hz, 12H).

(610) LCMS; m/z 471.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid, Disodium Salt

(611) ##STR00239##

(612) Prepared according to the general procedure for 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53, Step B) from ethyl 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate, sodium salt (Intermediate P56, Step A) to afford the title compound (1.0 g, 77%) as a colourless solid.

(613) .sup.1H NMR (DMSO-d.sub.6) δ 7.49 (s, 1H), 7.00 (s, 2H), 6.42 (s, 1H), 4.01 (s, 3H), 3.09 (br s, 2H), 1.02 (d, J=6.8 Hz, 12H).

(614) LCMS; m/z 443.4 (M+H).sup.+ (ES.sup.+).

Intermediate P57: 5-(Azetidine-1-carbonyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

Step A: Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylate

(615) ##STR00240##

(616) Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazole-5-carboxylate (Intermediate P35, Step A) (1 g, 2.176 mmol), K.sub.2CO.sub.3 (0.391 g, 2.83 mmol) and 2-iodopropane (0.26 mL, 2.61 mmol) were stirred in DMF (10 mL) under a nitrogen atmosphere for 18 hours. The reaction was poured onto brine (100 mL) and EtOAc (50 mL). The aqueous layer was discarded and the organic layer washed with brine (2×100 mL), dried (MgSO.sub.4), filtered and concentrated to dryness to give a yellow oil which was purified by chromatography on silica gel (80 g column, 0-40% EtOAc/isohexane) to afford the title compound (1.0 g, 85%) as a clear colourless oil which solidified on standing.

(617) .sup.1H NMR (DMSO-d.sub.6) δ 7.22-6.93 (m, 5H), 6.93-6.68 (m, 4H), 5.45 (sept, J=6.6 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 4.25 (s, 4H), 3.71 (s, 6H), 1.42 (d, J=6.6 Hz, 6H), 1.32 (t, J=7.1 Hz, 3H).

(618) LCMS; m/z 524.2 (M+Na)+(ES.sup.+).

Step B: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylic Acid, Sodium Salt

(619) ##STR00241##

(620) Ethyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylate (1 g, 1.994 mmol) was suspended in EtOH (10 mL) and 2 M aqueous sodium hydroxide (1.994 ml, 3.99 mmol). The reaction was left to stir at room temperature for 17 hours, then evaporated to dryness under reduced pressure to afford the title compound as a colourless foam which was used without further purification.

(621) LCMS; m/z 496.1 (M+Na)+(ES.sup.+).

Step C: 5-(Azetidine-1-carbonyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(622) ##STR00242##

(623) T3P (50 wt % in EtOAc) (2.28 mL, 3.83 mmol) was added to a mixture of sodium 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazole-5-carboxylate (0.99 g, 1.913 mmol) and azetidine hydrochloride (0.215 g, 2.296 mmol) in THF (10 mL). DIPEA (0.67 mL, 3.84 mmol) was added and the reaction stirred at room temperature for 5 hours. Additional T3P (50 wt % in EtOAc) (2.28 mL, 3.83 mmol), DIPEA (0.67 mL, 3.84 mmol) and azetidine hydrochloride (0.215 g, 2.296 mmol) were added and the reaction was stirred at room temperature for a further 2 days. The reaction mixture was diluted with EtOAc (20 mL) and washed with 2 M aqueous NaOH (2×20 mL) followed by 1 M aqueous H C1 (20 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated to dryness to give crude product still containing starting acid. The mixture was subjected to the reaction procedure above, stirred for 2 days, then diluted with EtOAc (20 mL) and washed with water (2×30 mL) followed by 1 M aqueous HCl (20 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated to dryness to afford the title compound (786 mg, 75%) as an orange oil which was used without further purification in the next step.

(624) .sup.1H NMR (CDCl.sub.3) δ 7.17-6.99 (m, 4H), 6.85-6.73 (m, 4H), 6.70 (s, 1H), 5.46 (sept, J=6.6 Hz, 1H), 4.37-4.24 (m, 6H), 4.20 (t, J=7.8 Hz, 2H), 3.78 (s, 6H), 2.50-2.29 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).

(625) LCMS; m/z 513.2 (M+H).sup.+ (ES.sup.+).

Step D: 5-(Azetidine-1-carbonyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(626) ##STR00243##

(627) 5-(Azetidine-1-carbonyl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (0.79 g, 1.54 mmol) was dissolved in DCM:TFA (5:1.12 mL) and stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the purple residue obtained was purified by chromatography on silica gel (24 g column, 0-5% MeOH/DCM) to afford the title compound (201 mg, 47%) as a colourless foam.

(628) .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (s, 2H), 6.85 (s, 1H), 5.28 (sept, J=6.6 Hz, 1H), 4.30 (t, J=7.7 Hz, 2H), 4.04 (t, J=7.8 Hz, 2H), 2.27 (p, J=7.8 Hz, 2H), 1.40 (d, J=6.6 Hz, 6H).

(629) LCMS; m/z 273.1 (M+H).sup.+ (ES.sup.+).

Intermediate P58: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide

(630) ##STR00244##

(631) A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P50) (459 mg, 1.976 mmol) in MeCN (2.3 mL) was treated with N,N-dimethylpyridin-4-amine (483 mg, 3.95 mmol) and the reaction mixture was stirred at room temperature until the sulfonamide had dissolved. Diphenyl carbonate (466 mg, 2.174 mmol) was added and the reaction mixture was left for 16 hours at room temperature. The resulting precipitate was separated by filtration, washed with MeCN and dried to afford the title compound (578 mg, 77%) which was used in the next step without further purification.

(632) .sup.1H NMR (DMSO-d.sub.6) δ 8.77-8.73 (m, 2H), 7.02-6.98 (m, 2H), 6.83 (s, 1H), 3.85 (s, 3H), 3.26 (s, 6H), 3.05 (s, 3H), 3.00 (s, 3H).

Intermediate P59:5-(1-(Dimethylamino)-2,2,2-trifluoroethyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-methyl-5-(2,2,2-trifluoroacetyl)-1H-pyrazole-3-sulfonamide

(633) ##STR00245##

(634) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P9, Step A) and ethyl 2,2,2-trifluoroacetate to afford the title compound (1.23 g, 53%) as a colourless solid.

(635) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-7.00 (m, 4H), 6.83-6.79 (m, 4H), 6.74 (s, 1H), 4.22 (s, 4H), 4.01 (s, 3H), 3.72 (s, 6H).

(636) LCMS; m/z not found, no ionisation.

Step B: N,N-Bis(4-methoxybenzyl)-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole-3-sulfonamide

(637) ##STR00246##

(638) A solution of N,N-bis(4-methoxybenzyl)-1-methyl-5-(2,2,2-trifluoroacetyl)-1H-pyrazole-3-sulfonamide (0.6 g, 1.206 mmol) in MeOH (5 mL) was stirred at 0° C. under nitrogen. NaBH.sub.4 (0.046 g, 1.206 mmol) was added in small portions over 5 minutes, then the reaction was left at 0° C. for 1 hour. After concentration under reduced pressure, the residue was treated with a concentrated solution of aqueous ammonium chloride, taken up in EtOAc (50 mL), dried over MgSO.sub.4, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) to afford the title compound (510 mg, 82%) as a sticky colourless gum.

(639) .sup.1H NMR (DMSO-d.sub.6) δ 7.32 (d, J=6.6 Hz, 1H), 7.07-6.98 (m, 4H), 6.87-6.77 (m, 4H), 6.74 (s, 1H), 5.71-5.53 (m, 1H), 4.28-4.16 (m, 4H), 3.97 (s, 3H), 3.72 (s, 6H).

(640) LCMS; m/z 522.4 (M+H).sup.+ (ES.sup.+).

Step C: 5-(1-(Dimethylamino)-2,2,2-trifluoroethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(641) ##STR00247##

(642) Triflic anhydride (1 M in DCM) (2 mL, 2.000 mmol) was added to a solution of N,N— bis(4-methoxybenzyl)-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole-3-sulfonamide (500 mg, 1.001 mmol) and 2,6-dimethylpyridine (0.233 mL, 2.002 mmol) in anhydrous DCM (5 mL) at 0° C. The reaction was allowed to warm to room temperature, stirred for 2 hour and then cooled to 0° C. A solution of dimethylamine (5 mL, 10.00 mmol) was added and the mixture was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in EtOAc (50 mL) and saturated aqueous NaHCO.sub.3 solution (10 mL), the layers were separated, and the aqueous phase was extracted with further portions of EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaHCO.sub.3 solution (10 mL) and brine (2×10 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo to give crude product as a yellow oil. The crude product was re-dissolved in MeOH (3 mL) and loaded onto SCX (ca. 4 g), which was then washed with MeOH (15 mL) and eluted with 0.7 M NH.sub.3/MeOH (15 mL) and concentrated in vacuo to give the title compound (200 mg, 32%) as a pale yellow solid.

(643) .sup.1H NMR (DMSO-d.sub.6) δ 7.10-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.59 (s, 1H), 5.15 (q, J=8.5 Hz, 1H), 4.24 (s, 4H), 3.95 (s, 3H), 3.72 (s, 6H), 2.36 (s, 6H).

(644) LCMS; m/z 549.4 (M+Na)+(ES.sup.+).

Step D: 5-(1-(Dimethylamino)-2,2,2-trifluoroethyl)-1-methyl-1H-pyrazole-3-sulfonamide

(645) ##STR00248##

(646) 5-(1-(Dimethylamino)-2,2,2-trifluoroethyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (200 mg, 0.304 mmol) was dissolved in TFA (5 mL) and stirred for 16 hours. The reaction mixture was concentrated and the crude product was loaded onto a column of SCX (2 g) in MeOH. The column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (85 mg, 98%) as a yellow oil.

(647) LCMS; m/z 287.5 (M+H).sup.+ (ES.sup.+).

Intermediate P60: 1-Isopropyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

Step A: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

(648) ##STR00249##

(649) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) and 2,2,2-trifluoro-N-methylethanamine (114 mg, 1.005 mmol) and sodium triacetoxyborohydride to afford the title compound (170 mg, 60%) as a colourless oil.

(650) .sup.1H NMR (DMSO-d.sub.6) 7.04-6.99 (m, 4H), 6.84-6.78 (m, 4H), 6.64 (s, 1H), 4.78 (sept, J=6.6 Hz, 1H), 4.20 (s, 4H), 3.82 (s, 2H), 3.72 (s, 6H), 3.37-3.25 (m, 2H), 2.31 (s, 3H), 1.39 (d, J=6.6 Hz, 6H).

(651) LCMS; m/z 577.9 (M+Na)+(ES.sup.+).

Step B: 1-Isopropyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

(652) ##STR00250##

(653) 1-Isopropyl-N,N-bis(4-methoxybenzyl)-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide (168 mg, 0.303 mmol) was dissolved in DCM (0.4 mL) and TFA (0.6 mL) was added. The reaction mixture was stirred for 16 hours, concentrated in vacuo, suspended in toluene (5 mL) and concentrated again. The crude product was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (15 mg, 14%) as a white solid.

(654) .sup.1H NMR (DMSO-d.sub.6) δ 7.38 (bs, 2H), 6.53 (s, 1H), 4.74 (sept, J=6.6 Hz, 1H), 3.81 (s, 2H), 3.32-3.25 (m, 2H), 2.33 (s, 3H), 1.39 (d, J=6.6 Hz, 6H).

(655) LCMS m/z 315.1 (M+H).sup.+ (ES.sup.+).

Intermediate P61: 1-Methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

(656) ##STR00251##

(657) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and 2,2,2-trifluoro-N-methylethanamine to afford the title compound (148 mg, 50%) as a colourless oil.

(658) .sup.1H NMR (DMSO-d.sub.6) δ 7.06-7.00 (m, 4H), 6.84-6.78 (m, 4H), 6.66 (s, 1H), 4.20 (s, 4H), 3.89 (s, 3H), 3.82 (s, 2H), 3.72 (s, 6H), 3.30 (q, J=10.1 Hz, 2H), 2.34 (s, 3H).

(659) LCMS; m/z 549.4 (M+Na)+(ES.sup.+).

Step B: 1-Methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

(660) ##STR00252##

(661) Prepared according to the general procedure of 1-isopropyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P60, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide to afford the title compound (74 mg, 39%) as a white solid.

(662) .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (bs, 2H), 6.55 (s, 1H), 3.85 (s, 3H), 3.80 (s, 2H), 3.30-3.24 (m, 2H), 2.35 (s, 3H).

(663) LCMS; m/z 287.2 (M+H).sup.+ (ES.sup.+).

Intermediate P62: 5-(3-(Dimethylamino)oxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

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

(664) ##STR00253##

(665) A solution of n-BuLi (2.5 M in hexanes; 0.70 mL, 1.750 mmol) was added dropwise to a stirred solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P9, Step A) (0.70 g, 1.74 mmol) in THF (15 mL) at −78° C. The reaction was stirred for 1 hour, then a solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (0.40 g, 2.28 mmol) in THF (5 mL) was added. The reaction mixture was left at −78° C. for 5 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with DCM (3×20 mL). The organic extracts were dried (MgSO.sub.4), filtered and concentrated in vacuo. The resultant orange gum was dissolved in MeOH (18 mL) and HCl (3.7 M in 1,4-dioxane, 1.7 mL, 6.29 mmol) was added. The solution was stirred for 16 hours and then concentrated in vacuo. The crude product was loaded onto a column (SCX; 5 g) in MeOH and the column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo to afford the title compound (0.25 g, 41%) as a thick brown gum.

(666) .sup.1H NMR (DMSO-d.sub.6) δ 7.09-7.04 (m, 4H), 6.86-6.80 (m, 4H), 6.79 (s, 1H), 4.87 (d, J=6.4 Hz, 2H), 4.65 (d, J=6.4 Hz, 2H), 4.22 (s, 4H), 3.84 (s, 3H), 3.71 (s, 6H), 3.16 (s, 2H).

(667) LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

Step B: 5-(3-(Dimethylamino)oxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(668) ##STR00254##

(669) Prepared according to the general procedure of 5-(2-(dimethylamino)propan-2-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P22, Step D) from 5-(3-aminooxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (0.17 g, 61%) as an orange oil.

(670) .sup.1H NMR (DMSO-d.sub.6) δ 7.11-7.03 (m, 4H), 6.86-6.78 (m, 4H), 6.77 (s, 1H), 4.93 (d, J=7.2 Hz, 2H), 4.74 (d, J=7.2 Hz, 2H), 4.23 (s, 4H), 3.75 (s, 3H), 3.72 (s, 6H), 2.19 (s, 6H).

(671) LCMS; m/z 501.4 (M+H).sup.+ (ES.sup.+).

Step C: 5-(3-(Dimethylamino)oxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

(672) ##STR00255##

(673) 5-(3-(Dimethylamino)oxetan-3-yl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (0.17 g, 0.25 mmol) was dissolved in TFA (3 mL) and stirred at room temperature for 23 hours. Additional TFA (3 mL) was added and the mixture was stirred for a further 3 hours at room temperature. The mixture was then evaporated to dryness and purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford an orange solid. The product was further purified by precipitation on addition of isohexane to a solution of the product in 19:1 DCM:MeOH.

(674) The product was collected by filtration to afford the title compound (65 mg, 84%) as an orange solid.

(675) .sup.1H NMR (DMSO-d.sub.6) δ 7.46 (s, 2H), 6.79 (s, 1H), 5.00 (d, J=7.6 Hz, 2H), 4.85 (d, J=7.6 Hz, 2H), 3.76 (s, 3H), 2.38 (br s, 6H).

(676) LCMS; m/z 261.1 (M+H).sup.+ (ES.sup.+).

Intermediate P63: 5-(((2-Hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: 5-(((2-Hydroxyethyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(677) ##STR00256##

(678) 2-(Methylamino)ethanol (112 μL, 1.40 mmol) was added to a solution of 5-formyl-N,N— bis(4-methoxybenzyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P38, Step A) (0.40 g, 0.93 mmol) in dry THF (20 mL) containing 4 Å molecular sieves and stirred for 1 hour. Sodium triacetoxyborohydride (0.30 g, 1.42 mmol) and acetic acid (6 μL, 0.1 mmol) were added and the reaction was stirred at room temperature for 3 days. An additional portion of acetic acid (54 μL, 0.94 mmol) was added and the reaction mixture stirred for 20 hours at 60° C. Then 2-(methylamino)ethanol (112 μL, 1.39 mmol) and more sodium triacetoxyborohydride (0.30 g, 1.42 mmol) were added and the reaction was heated at 60° C. for another 20 hours. The reaction was quenched with water (1 mL) and loaded onto a column (SCX). The column was washed with 20% MeOH in DCM and then the crude product was eluted with 0.7M ammonia in DCM:MeOH (9:1, 50 mL). The resultant mixture was concentrated in vacuo and the crude product was further purified by chromatography on silica gel (12 g column, 0-20% (0.7M ammonia in MeOH)/DCM) to afford the title compound (0.19 g, 41%) as a colourless gum.

(679) .sup.1H NMR (DMSO-d.sub.6) δ 7.07-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.61 (s, 1H), 4.49 (t, J=5.3 Hz, 1H), 4.20 (s, 4H), 3.91 (s, 3H), 3.72 (s, 6H), 3.60 (s, 2H), 3.54 (td, J=5.2, 6.1 Hz, 2H), 2.47 (t, J=6.1 Hz, 2H), 2.17 (s, 3H).

(680) LCMS; m/z 489.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(((2-Hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(681) ##STR00257##

(682) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from 5-(((2-hydroxyethyl)(methyl)amino) methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide to afford the title compound (95 mg, 95%) as a colourless gum.

(683) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.49 (s, 1H), 4.47 (t, J=5.3 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 2H), 3.56-3.48 (m, 2H), 2.45 (t, J=6.1 Hz, 2H), 2.17 (s, 3H).

(684) LCMS; m/z 249.1 (M+H).sup.+ (ES.sup.+).

Intermediate P64: 5-(((2-Methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-5-(((2-methoxyethyl)(methyl)amino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(685) ##STR00258##

(686) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and 2-methoxy-N-methylethanamine to afford the title compound (0.41 g, 86%) as a pale colourless oil.

(687) .sup.1H NMR (DMSO-d.sub.6) δ 7.08-6.99 (m, 4H), 6.86-6.77 (m, 4H), 6.59 (s, 1H), 4.20 (s, 4H), 3.90 (s, 3H), 3.72 (s, 6H), 3.60 (s, 2H), 3.46 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.55 (t, J=5.7 Hz, 2H), 2.17 (s, 3H).

(688) LCMS; m/z 503.4 (M+H).sup.+ (ES.sup.+).

Step B: 5-(((2-Methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(689) ##STR00259##

(690) Prepared according to the general procedure of 1-cyclopropyl-5-(1-(dimethylamino) ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10, Step C) from N,N-bis(4-methoxybenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-H-pyrazole-3-sulfonamide to afford the title compound (0.20 g, 91%) as a white solid.

(691) .sup.1H NMR (DMSO-d.sub.6) δ 7.34 (s, 2H), 6.49 (s, 1H), 3.86 (s, 3H), 3.58 (s, 2H), 3.45 (t, J=5.8 Hz, 2H), 3.24 (s, 3H), 2.54 (t, J=5.8 Hz, 2H), 2.18 (s, 3H).

(692) LCMS; m/z 263.1 (M+H).sup.+ (ES.sup.+).

Intermediate P65: 1-Methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

Step A: 5-(Hydroxymethyl)-1-methyl-1H-pyrazole-3-sulfonamide

(693) ##STR00260##

(694) A solution of LiBH.sub.4 (2 M in THF; 4.3 mL, 8.6 mmol) was added dropwise over 5 minutes to a stirred solution of ethyl 1-methyl-3-sulfamoyl-H-pyrazole-5-carboxylate (1.00 g, 4.29 mmol) in THF (10 mL) at 0° C. The reaction was allowed to warm to room temperature, stirred for 3 hours and then heated at 40° C. for 20 hours. The reaction was cooled to 0° C. LiAlH.sub.4 (2 M in THF; 0.55 mL, 1.10 mmol) was added and the reaction was stirred for a further 2 days at 40° C. The reaction was cooled to 0° C. and aqueous saturated ammonium chloride (10 mL) was cautiously added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and EtOAc (30 mL) was added. The reaction mixture was stirred vigorously for 10 minutes and then filtered through a pad of Celite®. The layers were separated and the aqueous layer was saturated with NaCl and extracted further with EtOAc (5×20 mL). The combined organic extracts were dried (MgSO.sub.4), filtered and evaporated in vacuo to afford the title compound (0.67 g, 78%) as a white solid.

(695) .sup.1H NMR (DMSO-d.sub.6) δ 5.70 (s, 1H), 3.73 (s, 2H), 3.02 (s, 3H). Three exchangeable protons not observed.

(696) LCMS; m/z 192.0 (M+H).sup.+ (ES.sup.+).

Step B: 5-Formyl-1-methyl-1H-pyrazole-3-sulfonamide

(697) ##STR00261##

(698) Manganese(IV) oxide (1.00 g, 11.5 mmol) was added to a solution of 5-(hydroxymethyl)-1-methyl-H-pyrazole-3-sulfonamide (0.55 g, 2.88 mmol) in 1,2-dimethoxyethane (30 mL). The reaction mixture was stirred for 20 hours at room temperature and then at 40° C. for a further 6 hours. Further manganese(IV) oxide (0.50 g, 5.75 mmol) was added and the reaction was heated at 40° C. for 2 days. The mixture was cooled to room temperature and filtered through a pad of Celite®, washing with 1,2-dimethoxyethane. The filtrate was concentrated in vacuo to afford the title compound (0.29 g, 52%), as a yellow gum.

(699) .sup.1H NMR (DMSO-d.sub.6) δ 9.92 (s, 1H), 7.64 (s, 2H), 7.31 (s, 1H), 4.16 (s, 3H).

(700) LCMS; m/z 189.9 (M+H).sup.+ (ES.sup.+).

Step C: 1-Methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

(701) ##STR00262##

(702) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-1-methyl-1H-pyrazole-3-sulfonamide and morpholine to afford the title (73 mg, 25%) as a colourless gum.

(703) .sup.1H NMR (DMSO-d.sub.6) δ 7.36 (s, 2H), 6.50 (s, 1H), 3.87 (s, 3H), 3.57 (m, 4H), 3.56 (s, 2H), 2.37 (m, 4H).

(704) LCMS; m/z 261.0 (M+H).sup.+ (ES.sup.+).

Intermediate P66: 2-((Dimethylamino)methyl)-1-methyl-1H-imidazole-4-sulfonamide, and

Intermediate P67: 5-((Dimethylamino)methyl)-1-methyl-1H-imidazole-4-sulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-methyl-1H-imidazole-4-sulfonamide

(705) ##STR00263##

(706) 1-Methyl-1H-imidazole-4-sulfonyl chloride (4 g, 22.15 mmol) was added portionwise to a solution of bis(4-methoxybenzyl)amine (5.98 g, 23.25 mmol) and triethylamine (6.17 ml, 44.3 mmol) in DCM (100 mL) cooled in an ice bath. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for 16 hours. The mixture was washed with water (2×50 mL), aq 1 M HCl (50 mL), water (50 mL), and brine (50 mL), then dried over MgSO.sub.4, filtered and evaporated to dryness to give crude product as a cream coloured solid. The crude product was dissolved in a minimum amount of DCM to load, then purified by column chromatography on silica gel (220 g column, 0-80% EtOAc/isohexane) to afford the title compound (5-1, 55%) as a white solid.

(707) .sup.1H NMR (DMSO-d.sub.6) δ 7.87-7.78 (m, 2H), 7.09-6.99 (m, 4H), 6.91-6.73 (m, 4H), 4.19 (s, 4H), 3.72 (s, 6H), 3.33 (s, 3H).

(708) LCMS; m/z 402.3 (M+H).sup.+ (ES.sup.+).

Step B: 2-((Dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-imidazole-4-sulfonamide and 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-imidazole-4-sulfonamide

(709) ##STR00264##

(710) Prepared according to the general procedure of 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7, Step B) from N,N-bis(4-methoxybenzyl)-1-methyl-1H-imidazole-4-sulfonamide and N-methyl-N— methylenemethanaminium iodide to afford the title compounds as a 85:15 mixture (374 mg, 28%) as a yellow oil.

(711) .sup.1H NMR (major product) (DMSO-d.sub.6) δ 7.83 (s, 1H), 7.05-6.98 (m, 4H), 6.83-6.74 (m, 4H), 4.24 (s, 4H), 3.71 (s, 6H), 3.70 (s, 3H), 3.68 (s, 2H), 2.16 (s, 6H).

(712) LCMS; m/z 459.4 (M+H).sup.+ (ES.sup.+).

Step C: 2-((Dimethylamino)methyl)-1-methyl-1H-imidazole-4-sulfonamide and 5-((dimethylamino)methyl)-1-methyl-1H-imidazole-4-sulfonamide

(713) ##STR00265##

(714) A 85:15 mixture of 2-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-imidazole-4-sulfonamide and 5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1-methyl-1H-imidazole-4-sulfonamide (552 mg, 1.204 mmol) was dissolved in TFA (5 ml, 1.204 mmol) and stirred overnight. Additional TFA (2 mL) was added and stirred for a further 24 hours at room temperature. The mixture was concentrated in vacuo and the residue was suspended in a mixture of MeOH (50 mL) and DCM (1 mL). SCX (3 eq.) was added and the suspension was stirred at room temperature for 1 hour. The SCX was filtered and washed with MeOH (50 mL) and the product was then eluted with 0.7% ammonia in MeOH (50 mL). After concentration in vacuo, a 85:15 mixture of 2-((dimethylamino)methyl)-1-methyl-H-imidazole-4-sulfonamide and 5-((dimethylamino)methyl)-1-methyl-H-imidazole-4-sulfonamide (222 mg, 84%) was isolated as a pale yellow oil.

(715) .sup.1H NMR (major product) (DMSO-d.sub.6) δ 7.72 (s, 1H), 7.10 (s, 2H), 3.66 (s, 3H), 3.65 (s, 2H), 2.15 (s, 6H).

Intermediate P68: N-((1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N— methylacetamide

Step A: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide, acetic Acid Salt

(716) ##STR00266##

(717) Acetic acid (10 μL, 0.175 mmol) was added to a stirred suspension of 5-formyl-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P29, Step A) (400 mg, 0.874 mmol), methylamine (2 M in THF) (874 μL, 1.748 mmol) and sodium triacetoxyborohydride (278 mg, 1.311 mmol) in THF (14 mL). The reaction mixture was left to stir at room temperature for 16 hours. Water (1 mL) was added and volatiles were evaporated. The crude product was purified by chromatography on SiO.sub.2 (24 g column, 0-10% MeOH/DCM) to afford the title compound (130 mg, 24%) as a colourless oil.

(718) .sup.1H NMR (DMSO-d.sub.6) δ 7.05-6.98 (m, 4H), 6.85-6.79 (m, 4H), 6.57 (s, 1H), 4.77 (sept, J=6.5 Hz, 1H), 4.19 (s, 4H), 3.74 (s, 2H), 3.72 (s, 6H), 3.37 (bs, 1H), 2.27 (s, 3H), 1.90 (s, 3H), 1.39 (d, J=6.5 Hz, 6H). OH not observed.

(719) LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+).

Step B: N-((3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

(720) ##STR00267##

(721) To a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide, acetic acid salt (130 mg, 0.248 mmol) in DCM (1 mL) was added pyridine (45 μL, 0.556 mmol) and the mixture was cooled to 0° C. Trifluoroacetic anhydride (53 μL, 0.375 mmol) was added dropwise and the resultant mixture was stirred at 0° C. for 15 minutes, before warming to room temperature for 16 hours. Additional pyridine (45 μL, 0.556 mmol) and trifluoroacetic anhydride (53 μL, 0.375 mmol) were added and the mixture was stir for another 16 hours. The mixture was quenched with saturated sodium bicarbonate (5 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×10 mL) and EtOAc (10 mL) and the combined organic phases were dried with magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by chromatography on SiO.sub.2 (12 g column, 0-10% MeOH/DCM) to afford the title compound (88 mg, 57%) as a brown oil.

(722) .sup.1H NMR (DMSO-d.sub.6); rotamers: δ 7.05-6.99 (m, 4H), 6.85-6.79 (m, 4H), 6.63 (s, 1H), 4.75-4.66 (m, 1H), 4.63 (s, 2H), 4.21 (s, 4H), 3.73 (s, 6H), 3.32 (s, 3H), 2.07 (s, 3H), 1.35 (d, J=6.5 Hz, 6H).

(723) LCMS; m/z 537.1 (M+Na)+(ES.sup.+).

Step C: N-((1-Isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N— methylacetamide

(724) ##STR00268##

(725) Prepared according to the general procedure of 1-isopropyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P60, Step B) from N-((3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide to afford the title compound (30 mg, 78%) as a white solid.

(726) .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (bs, 2H), 6.51 (s, 1H), 4.73-4.66 (m, 1H), 4.61 (s, 2H), 2.95 (s, 3H), 2.06 (s, 3H), 1.35 (d, J=6.5 Hz, 6H).

(727) LCMS; m/z 275.2 (M+H).sup.+ (ES.sup.+).

Intermediate P69: 1-Methyl-5-((methyl(1-methylazetidin-3-yl)amino) methyl)-1H-pyrazole-3-sulfonamide

Step A: N,N-bis(4-Methoxybenzyl)-1-methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide

(728) ##STR00269##

(729) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (Intermediate P18, Step B) from 5-formyl-N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P38, Step A) and N,1-dimethylazetidin-3-amine to afford the title compound (195 mg, 38%) as a colourless oil.

(730) .sup.1H NMR (DMSO-d.sub.6) δ 7.08-7.00 (m, 4H), 6.86-6.77 (m, 4H), 6.60 (s, 1H), 4.20 (s, 4H), 3.93 (s, 3H), 3.72 (s, 6H), 3.43 (s, 2H), 3.37 (m, 2H), 2.97 (p, J=6.5 Hz, 1H), 2.72 (m 2H), 2.21 (s, 3H), 1.96 (s, 3H).

(731) LCMS; m/z 514.2 (M+H).sup.+ (ES.sup.+).

Step B: 1-Methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide

(732) ##STR00270##

(733) N,N-bis(4-Methoxybenzyl)-1-methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide (190 mg, 0.370 mmol) was dissolved in TFA (5 ml, 64.9 mmol) and stirred for 4 hours. The solution was diluted with toluene (20 ml) and evaporated in vacuo to afford a colourless gum. The gum was dissolved in THF, absorbed onto SCX and eluted with THF/MeOH/DCM (1:1:3) followed by (1M NH.sub.3/MeOH)/THF/DCM (1:1:3). The NH.sub.3/THF/DCM was evaporated in vacuo to afford the title compound (96 mg, 93%) as a white solid.

(734) .sup.1H NMR (DMSO-d.sub.6) δ 7.35 (s, 2H), 6.49 (s, 1H), 3.88 (s, 3H), 3.41 (s, 2H), 3.35 (m, 2H), 2.96 (p, J=6.6 Hz, 1H), 2.68 (m, 2H), 2.20 (s, 3H), 1.97 (s, 3H).

(735) LCMS; m/z 274.1 (M+H).sup.+ (ES.sup.+).

Intermediate P70: N,N-Bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

Step A: 1-Methyl-1H-pyrazole-3-sulfonyl chloride

(736) ##STR00271##

(737) A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 mL) at 0° C. was treated with concentrated HCl (60 mL) and H.sub.2O (60 mL). Then an aqueous solution of NaNO.sub.2 (21-31 g, 308.90 mmol, 1.2 eq) in H.sub.2O (60 mL) was added slowly. The resulting mixture was stirred at 0° C. for 40 minutes. AcOH (6 mL), CuCl.sub.2 (17-31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 307.78 μL, 0.05 eq) were added, then SO.sub.2 gas (15 psi) was bubbled into the mixture for 15 minutes at 0° C. The reaction mixture was concentrated in vacuo to remove most of the MeCN. Then the reaction mixture was treated with H.sub.2O (2.5 L) and extracted with EtOAc (2×1.2 L). The combined organic layers were washed with brine (3×2 L), dried over anhydrous Na.sub.2SO.sub.4 filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=15:1 to 5:1) to give the title compound (19 g, 41%) as a yellow oil.

(738) .sup.1H NMR (CDCl.sub.3): δ 7.52 (d, 1H), 6.89 (d, 1H) and 4.07 (s, 3H).

Step B: N,N-Bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

(739) ##STR00272##

(740) To a solution of bis(4-methoxybenzyl)amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 118.68 mL, 2 eq), followed by 1-methyl-1H-pyrazole-3-sulfonyl chloride (77 g, 426.33 mmol, 1 eq). Then the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated in vacuo to remove most of the THF. The reaction mixture was quenched by addition of aqueous HCl (1 M, 500 mL) and then extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 mL, v:v=5:1) to give the title compound (138 g, 81%) as a white solid.

(741) .sup.1H NMR (CDCl.sub.3): δ 7.40 (d, 1H), 7.08 (d, 4H), 6.78 (d, 4H), 6.65-6.63 (m, 1H), 4.32 (s, 4H), 3.98 (s, 3H) and 3.79 (s, 6H).

(742) LCMS: m/z 402.2 (M+H).sup.+ (ES.sup.+).

Step C: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic Acid

(743) ##STR00273##

(744) A solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) was cooled to −70° C. Then n-BuLi (2.5 M, 104.61 mL, 1.05 eq) was added dropwise. The reaction mixture was stirred at −70° C. for 1 hour, then CO.sub.2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at −70° C. for another 1 hour. The reaction mixture was quenched with H.sub.2O (1.2 L) and adjusted with aqueous HCl (1 M) to pH=3. Then the mixture was extracted with EtOAc (2×1). The combined organic layers were washed with brine (2×1 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 mL, v:v=1:1) to give the title compound (94 g, 84% yield, 99% purity on LCMS) as a white solid.

(745) .sup.1H NMR (DMSO-d.sub.6): δ 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

(746) LCMS: m/z 468.2 (M+Na)+(ES.sup.+).

Step D: 3-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

(747) ##STR00274##

(748) To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (8 g, 17.96 mmol, 1 eq) in DMF (100 mL) was added with HATU (10.24 g, 26.94 mmol, 1.5 eq), DIPEA (6.96 g, 53.87 mmol, 3 eq) and bis(2-methoxyethyl)amine (2.87 g, 21.55 mmol, 1.2 eq). The reaction mixture was stirred at 25° C. for 1 hour. Then the reaction mixture was diluted with EtOAc (50 mL), washed with saturated aqueous NH.sub.4C solution (3×50 mL) and brine (3×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O-MeCN) to give the title compound (8 g, 79%) as a red oil.

(749) .sup.1H NMR (CD.sub.3OD): δ 7.05 (d, 4H), 6.81-6.77 (m, 5H), 4.29 (s, 4H), 3.90 (s, 3H), 3.79-3.72 (m, 8H), 3.68-3.57 (m, 4H), 3.48-3.46 (m, 2H), 3.38 (s, 3H) and 3.27 (s, 3H).

(750) LCMS: m/z 561.3 (M+H).sup.+ (ES.sup.+).

Step E: N,N-Bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

(751) ##STR00275##

(752) To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (8 g, 14.27 mmol, 1 eq) in DCM (50 mL) was added TFA (56 g, 491.13 mmol, 34.42 eq). The reaction mixture was stirred at 25° C. for 12 hours and then concentrated in vacuo. The residue was triturated with a mixture of EtOAc and PE (50 mL, v:v=3:2) to give the title compound (4.0 g, 88%) as a white solid.

(753) .sup.1H NMR (DMSO-d.sub.6): δ 7.50 (s, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 3.63 (t, 4H), 3.43-3.40 (m, 4H), 3.28 (s, 3H) and 3.18 (s, 3H).

Intermediate A1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

(754) ##STR00276##

(755) To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in EtOAc (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in EtOAc (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification.

(756) .sup.1H NMR (CDCl.sub.3) δ 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A2: 5-Fluoro-2-isocyanato-1,3-diisopropylbenzene

(757) ##STR00277##

(758) 4-Fluoro-2,6-diisopropylaniline (1 g, 5.12 mmol) and triethylamine (0.785 mL, 5.63 mmol) were dissolved in THF (10 mL) and cooled to 0° C. Triphosgene (0.760 g, 2.56 mmol) was added to the mixture portionwise and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo. Isohexane (so mL) was added and the suspension filtered through silica (3 g). The filtrate was dried under reduced pressure to afford the title compound (900 mg, 75%) as a colourless oil.

(759) .sup.1H NMR (DMSO-d.sub.6) δ 6.8 (d, J=9.4 Hz, 2H), 3.27-3.12 (m, 2H), 1.23 (d, J=6.8 Hz, 12H).

Intermediate A3: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

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

(760) ##STR00278##

(761) N-Bromosuccinimide (5.64 g, 31.7 mmol) was added portionwise to 4-fluoro-2-isopropylaniline (4.62 g, 30.2 mmol) in DCM (72 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour and then left to warm to room temperature over 21 hours. The reaction mixture was washed with a solution of aqueous sodium hydroxide (2 M, 2×50 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give a brown residue. The crude product was then filtered through a plug of silica (50 g) and washed through with 50% DCM in iso-hexane (500 mL). The red filtrate was concentrated to dryness and the crude product was purified by chromatography on silica gel (120 g column, 0-10% DCM/iso-hexane) to afford the title compound (4.99 g, 70%) as a red oil.

(762) .sup.1H NMR (CDCl.sub.3) δ 7.07 (dd, 1H), 6.86 (dd, 1H), 4.14 (s, 2H), 2.93 (sept, 1H) and 1.25 (d, 6H). NH.sub.2 not observed.

(763) LCMS; m/z 232.2/234.3 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropyl-6-(pyridin-3-yl)aniline

(764) ##STR00279##

(765) To a stirred, nitrogen-degassed mixture of 2-bromo-4-fluoro-6-isopropylaniline (1.00 g, 4.27 mmol) was added pyridin-3-ylboronic acid (0.577 g, 4.69 mmol), Pd(dppf)Cl.sub.2 (0.156 g, 0.213 mmol) and potassium carbonate (1.769 g, 12.80 mmol) in a 10:1 mixture of 14-dioxane:water (33 mL). The reaction mixture was then heated to 80° C. under a nitrogen atmosphere for 2 days, left to cool to room temperature, filtered through a pad of Celite® (10 g) and the filter cake washed with EtOAc (2×30 mL). The filtrate was poured onto water (50 mL) and the organic layer collected. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to dryness. The crude product was purified by chromatography on silica gel (80 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (273 mg, 27%) as a brown gum.

(766) .sup.1H NMR (CDCl.sub.3) δ 8.70 (dd, 1H), 8.63 (dd, 1H), 7.82 (ddd, 1H), 7.48-7.34 (m, 1H), 6.94 (dd, 1H), 6.70 (dd, 1H), 2.93 (sept, 1H), 3.98-2.44 (br s, 2H) and 1.29 (d, 6H).

(767) LCMS; m/z 231.1 (M+H).sup.+ (ES.sup.+).

(768) The following intermediates were synthesised following the general procedure for Intermediate A3:

(769) TABLE-US-00001 Intermediate Structure Analytical data A4 0 .sup.1H NMR (CDCl.sub.3) δ 7.50-7.32 (m, 5H), 6.90 (dd, 1 H), 6.74 (dd, 1H), 4.11 (br s, 2H), 3.15-2.80 (m, 1H) and 1.29 (d, 6H). LCMS; m/z 230.1 (M + H).sup.+ (ES.sup.+). (161 mg, 82%) A5 .sup.1H NMR (CDCl.sub.3) δ 7.82-7.74 (m, 1H), 7.73- 7.66 (m, 1H), 7.66-7.60 (m, 1H), 7.59-7.49 (m, 1H), 6.96 (dd, 1H), 6.69 (dd, 1 H), 3.10- 2.84 (m, 1H), and 1.29 (d, 6H). LCMS; m/z 255.1 (M + H).sup.+ (ES.sup.+). (182 mg, 81%) A6 .sup.1H NMR (CDCl.sub.3) δ 6.95 (dd, 1H), 6.68 (dd, 1H), 6.09 (s, 1H), 3.69 (s, 3H), 2.98-2.81 (m, 1H), 2.33 (s, 3H) and 1.28 (d, 6H). LCMS; m/z 248.1 (M + H).sup.+ (ES.sup.+). (72 mg, 34%) A7 .sup.1H NMR (CDCl.sub.3) δ 8.25 (d, 1H), 7.00 (d, 1H), 6.93 (dd, 1H), 6.85 (s, 1H), 6.71 (dd, 1H), 4.01 (s, 3H), 2.92 (sept, 1H) and 1.28 (d, 6H). Exchangeable NH.sub.2 observed as broad signal from 4.5-0.5 ppm. LCMS; m/z 261.1 (M + H).sup.+ (ES.sup.+). (174 mg, 78%) A8 .sup.1H NMR (CDCl.sub.3) δ 9.23 (s, 1H), 8.86 (s, 2H), 6.98 (dd, 1H), 6.69 (dd, 1H), 3.55 (br s, 2H), 2.92 (sept, 1H) and 1.29 (d, 6H). (126 mg, 60%) A9 .sup.1H NMR (CDCl.sub.3) δ 8.78 (dd, 1H), 7.86 (dd, 1H), 7.65 (dd, 1H), 6.99 (dd, 1H), 6.69 (dd, 1H), 3.49 (br s, 2H), 2.93 (sept, 1H) and 1.29 (d, 6H). LCMS; m/z 256.5 (M + H).sup.+ (ES.sup.+). (89 mg, 29%)  A10 .sup.1H NMR (CDCl.sub.3) δ 7.68 (d, 1 H), 7.58 (d, 1 H), 6.86 (dd, 1 H), 6.78 (dd, 1 H), 3.99 (s, 3 H), 3.74 (br s, 2 H), 2.94 (sept, 1 H) and 1.29 (d, 6 H). (85 mg, 22%)

Intermediate A11: 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

Step A: N-(7-Fluoro-2,3-dihydro-1H-inden-4-yl)pivalamide

(770) ##STR00287##

(771) To an ice-cooled solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (2.5 g, 11.50 mmol) in dry DCM (50 mL) was added pyridine hydrofluoride (9 mL, 69.9 mmol). The pale yellow mixture was stirred for 30 minutes at 0° C. A solution of bis(tert-butylcarbonyloxy)iodobenzene (7.5 g, 17.91 mmol) in DCM (10 mL) was then slowly added over 10 minutes. The reaction was slowly allowed to reach room temperature and stirred overnight. It was then quenched with triethylamine (0.5 mL, 3.58 mmol) and the mixture was absorbed onto silica gel and purified by chromatography on silica gel (120 g column, 0-30% EtOAc/isohexane) to afford the title compound (0.64 g, 22%) as a yellow crystalline solid.

(772) .sup.1H NMR (CDCl.sub.3) δ 7.68 (dd, J=8.8, 4.5 Hz, 1H), 7.14 (s, 1H), 6.87 (t, J=8.6 Hz, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.18 (p, J=7.5 Hz, 2H), 1.34 (s, 9H).

(773) LCMS; m/z 236.3 (M+H).sup.+ (ES.sup.+); 234.2 (M−H).sup.− (ES.sup.−).

Step B: 7-Fluoro-2,3-dihydro-1H-inden-4-amine

(774) ##STR00288##

(775) N-(7-Fluoro-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.69 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H.sub.2SO.sub.4 (95% aqueous) (5 mL, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100° C. (bath temperature) over the weekend. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and then basified with 2 M aqueous NaOH. The mixture was extracted with DCM (3×100 mL). The combined organic phases were washed, dried by passing through a hydrophobic frit and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g column, 0-30% EtOAc/isohexane) to afford the title compound (350 mg, 82%) as a pale pink oil that solidified on standing.

(776) .sup.1H NMR (CDCl.sub.3) δ 6.71 (dd, J=9.0, 8.2 Hz, 1H), 6.46 (dd, J=8.5, 3.9 Hz, 1H), 3.45 (s, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.16 (p, J=7.6 Hz, 2H).

(777) LCMS; m/z 152.3 (M+H).sup.+ (ES.sup.+).

Step C: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine

(778) ##STR00289##

(779) 7-Fluoro-2,3-dihydro-1H-inden-4-amine (345 mg, 2.282 mmol) was dissolved in DCM (1 mL). NBS (450 mg, 2.53 mmol) was added at room temperature in a single portion. The mixture turned dark brown immediately and was stirred for 15 minutes at room temperature. The reaction mixture was partitioned between DCM (20 mL) and 1 M aqueous NaOH (20 mL) and stirred for 15 minutes. The organic phase was separated and washed with brine (10 mL), and then dried by passing through a hydrophobic frit. The solvent was removed in vacuo to give a dark brown oil. The crude product was purified by chromatography on silica gel (24 g column, 0-20% EtOAc/isohexane) to afford the title compound (323 mg, 82%) as a dark purple oil.

(780) .sup.1H NMR (CDCl.sub.3) δ 7.08 (d, J=7.8 Hz, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.20 (p, J=7.6 Hz, 2H). NH.sub.2 not observed.

Step D: 7-Fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

(781) ##STR00290##

(782) Prepared according to the general procedure of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A14) from 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine and (2-methoxypyridin-4-yl)boronic acid to afford the title compound (0.19 g, 49%) as a pale brown oil that crystallized on standing.

(783) .sup.1H NMR (CDCl.sub.3) δ 8.27 (d, J=5.4 Hz, 1H), 7.06 (d, J=5.3 Hz, 1H), 6.95 (s, 1H), 6.73 (d, J=9.0 Hz, 1H), 4.03 (s, 3H), 3.00 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.23 (p, J=7.5 Hz, 2H). NH.sub.2 not observed.

(784) LCMS; m/z 259.3 (M+H).sup.+ (ES.sup.+).

Intermediate A12: 7-Fluoro-5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-amine

(785) ##STR00291##

(786) Prepared according to the general procedure of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A14) from 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (Intermediate A11, Step C) and pyridin-3-ylboronic acid to afford the title compound (0.32 g, 68%) as a green crystalline solid.

(787) .sup.1H NMR (CDCl.sub.3) δ 8.79 (s, 1H), 8.65 (s, 1H), 8.00 (d, J=7.1 Hz, 1H), 7.56 (s, 1H), 6.71 (d, J=8.9 Hz, 1H), 3.04 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.24 (p, J=7.5 Hz, 2H). NH.sub.2 not observed.

(788) LCMS; m/z 229.3 (M+H).sup.+ (ES.sup.+).

Intermediate A13: 5-Bromo-2,3-dihydro-1H-inden-4-amine

Step A: N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)pivalamide

(789) ##STR00292##

(790) N-(2,3-dihydro-1H-inden-4-yl)pivalamide (1 g, 4.60 mmol), p-toluenesulfonic acid monohydrate (0.45 g, 2.366 mmol), Pd(OAc).sub.2 (0.05 g, 0.223 mmol), and NBS (0.9 g, 5.06 mmol) were suspended in toluene (20 mL) and stirred under air for 16 hours. The dark green mixture was diluted with EtOAc (20 mL), and then washed with saturated aqueous NaHCO.sub.3 (2×10 mL), water (2×10 mL) and brine (10 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a dark green amorphous solid. The crude product was purified by chromatography on silica gel (40 g column, 0-30% EtOAc/isohexane) to afford the title compound (1.662 g, 100%) as a colourless crystalline solid that was contaminated with a small amount of reaction byproducts.

(791) LCMS; m/z 296.3/298.3 (M+H).sup.+ (ES.sup.+).

Step B: 5-Bromo-2,3-dihydro-1H-inden-4-amine

(792) ##STR00293##

(793) N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)pivalamide (0.632 g, 2.134 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature. H.sub.2SO.sub.4 (95% aqueous) (5 mL, 89 mmol) was slowly added to water (5 mL) and this mixture was then added to the reaction mixture. The slurry was heated to 100° C. (bath temperature) at which point the mixture became homogeneous and it was stirred at this temperature over the weekend. The mixture was cooled to room temperature and then basified with 2 M aqueous NaOH. The mixture was extracted with DCM (3×20 mL). The organic phases were dried by passing through a hydrophobic frit, and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.14 g, 29%).

(794) .sup.1H NMR (CDCl.sub.3) δ 7.23 (d, J=7.9 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.92 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.15 (p, J=7.5 Hz, 2H).

Intermediate A14: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

(795) ##STR00294##

(796) 5-Bromo-2,3-dihydro-H-inden-4-amine (Intermediate A13) (280 mg, 1.320 mmol) was dissolved in dioxane (5 mL). A solution of potassium carbonate (600 mg, 4.34 mmol) in water (1 mL) and (2-methoxypyridin-4-yl)boronic acid (250 mg, 1.635 mmol) were added. The mixture was degassed with nitrogen for 15 minutes, before Pd(dppf)Cl.sub.2.DCM (60 mg, 0.073 mmol) was added. The reaction mixture was heated to 80° C. (bath temperature) for 2 hours. The mixture was cooled to room temperature and partitioned between DCM (30 mL) and water (20 mL). The organic phase was dried by passing through a hydrophobic frit and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc/isohexane) to afford the title compound (0.29 g, 87%) as a pale yellow crystalline solid.

(797) .sup.1H NMR (CDCl.sub.3) δ 8.26 (d, J=5.4 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.97 (s, 1H), 6.80 (d, J=7.6 Hz, 1H), 4.06 (s, 3H), 2.98 (t, J=7.6 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.19 (p, J=7.5 Hz, 2H). NH.sub.2 not observed.

(798) LCMS; m/z 241.3 (M+H).sup.+ (ES.sup.+).

Intermediate A15: 4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl) aniline

Step A: 2-Bromo-4-fluoro-6-(prop-1-en-2-yl)aniline

(799) ##STR00295##

(800) Nitrogen gas was bubbled through a mixture of 2,6-dibromo-4-fluoroaniline (5 g, 18.59 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.2 mL, 22.34 mmol) and potassium triphosphate (7.9 g, 37.2 mmol) in dioxane (50 mL) and water (8 mL) for 15 minutes. Then (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate [XPhos G3 Pd cat (500 mg, 0.591 mmol)] was added. The mixture was heated at 90° C. for 8 hours and then partitioned between hexane (200 mL) and water (100 mL). The organic layer was dried (magnesium sulfate), filtered, evaporated in vacuo and the residue purified by chromatography on silica gel (120 g column, 0-2% EtOAc/iso-hexane) to afford the title compound (1.95 g, 43%) as an oil.

(801) .sup.1H NMR (CDCl.sub.3) δ 7.13 (dd, 1H), 6.77 (dd, 1H), 5.37-5.35 (m, 1H), 5.12-5.10 (m, 1H), 3.52 (br s, 2H) and 2.08-2.06 (m, 3H).

(802) LCMS; m/z 230.2 (M+H).sup.+ (ES.sup.+).

Step B: 2-(3,6-Dihydro-2H-pyran-4-yl)-4-fluoro-6-(prop-1-en-2-yl)aniline

(803) ##STR00296##

(804) 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (457 mg, 2.176 mmol), tetrakis(triphenylphosphine)palladium(0) (251 mg, 0.218 mmol), sodium carbonate (923 mg, 8.70 mmol) and water (4 mL) were added to a sealed vial containing a solution of 2-bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (500 mg, 2.173 mmol) in DMF (22 mL). The reaction mixture was heated under nitrogen at 100° C. overnight and then allowed to cool. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by chromatography on silica (40 g column, 0-20% EtOAc/iso-hexanes) to afford the title compound (355 mg, 65%) as a brownish oil.

(805) .sup.1H NMR (CDCl.sub.3) δ 6.71 (dd, 1H), 6.67 (dd, 1H), 5.88 (m, 1H), 5.35-5.31 (m, 1H), 5.09 (m, 1H), 4.32 (m, 2H), 3.95 (t, J=5.4 Hz, 2H), 3.82 (br s, 2H), 2.42 (m, 2H) and 2.09-2.07 (m, 3H).

Step C: 4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)aniline

(806) ##STR00297##

(807) A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-6-(prop-1-en-2-yl)aniline (355 mg, 1.522 mmol) and 5% palladium on carbon (156 mg, 0.03 mmol; type 87L (58.5% moisture)) in EtOAc (3.8 mL) was hydrogenated at 5 bar for 1 hour. The mixture was filtered through Celite® and evaporated to afford the title compound (340 mg, 91%).

(808) .sup.1H NMR (CDCl.sub.3) δ 6.80 (dd, 1H), 6.75 (dd, 1H), 4.16-4.14 (m, 1H), 4.13-4.10 (m, 1H), 3.65-3.51 (m, 4H), 3.01-2.89 (m, 1H), 2.85-2.74 (m, 1H), 1.86-1.78 (m, 4H) and 1.28 (d, 6H).

(809) LCMS; m/z 238.1 (M+H).sup.+ (ES.sup.+).

Intermediate A16: 2-Isopropyl-5-(1-methyl-1H-pyrazol-4-yl)aniline

(810) ##STR00298##

(811) To a sealed vial was added 5-bromo-2-isopropylaniline (250 mg, 1.168 mmol) in DMF (11 mL), followed by the addition of (1-methyl-1H-pyrazol-4-yl)boronic acid (147 mg, 1.168 mmol), Pd(PPh.sub.3).sub.4 (135 mg, 0.117 mmol) and aqueous 2 M Na.sub.2CO.sub.3 (2.335 mL, 4.67 mmol). The reaction mixture is heated under Argon at 100° C. overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated, and then purified by chromatography on silica gel (40 g column, 0-60% EtOAc/iso-hexane) to afford the title compound (90 mg, 36%) as a white solid.

(812) .sup.1H NMR (CDCl.sub.3) δ 7.70 (d, J=0.9 Hz, 1H), 7.54 (s, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.90 (dd, J=7.9, 1.8 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 3.93 (s, 3H), 3.69 (bs, 2H), 2.90 (sept, J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H).

Intermediate A17: 2-Isopropyl-5-(pyrimidin-5-yl)aniline

(813) ##STR00299##

(814) Prepared according to the general procedure for 2-isopropyl-5-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A16) from 5-bromo-2-isopropylaniline and pyrimidin-5-ylboronic acid to afford the title compound (130 mg, 51%) as a white solid.

(815) .sup.1H NMR (CDCl.sub.3) δ 9.16 (s, 1H), 8.91 (s, 2H), 7.28 (d, J=7.9 Hz, 1H), 6.98 (dd, J=8.0, 1.9 Hz, 1H), 6.87 (d, J=1.9 Hz, 1H), 3.84 (bs, 2H), 2.95 (sept, J=6.8 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H).

Intermediate A18: 2,5-Diisopropylaniline

Step A: 2-Isopropyl-5-(prop-1-en-2-yl)aniline

(816) ##STR00300##

(817) Nitrogen was bubbled through a mixture of 5-bromo-2-isopropylaniline (500 mg, 2.335 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.527 mL, 2.80 mmol) and Cs.sub.2CO.sub.3 (7609 mg, 23.35 mmol) in toluene (20 mL) and water (10 mL) for 15 minutes. Then palladium (II) acetate (157 mg, 0.701 mmol) and tricyclohexylphosphine (327 mg, 1.168 mmol) were added. The mixture was heated at 100° C. for 4 hours and then partitioned between hexane (50 mL) and water (20 mL). The organic layer was dried (MgSO.sub.4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-30% EtOAc/iso-hexane) to afford the title compound (227 mg, 53%) as an oil.

(818) .sup.1H NMR (CDCl.sub.3) δ 7.13 (d, J=8.0 Hz, 1H), 6.94 (dd, J=8.0, 1.9 Hz, 1H), 6.83 (d, J=1.9 Hz, 1H), 5.37-5.30 (m, 1H), 5.03 (p, J=1.6 Hz, 1H), 3.69 (bs, 2H), 2.93 (sept, J=6.8 Hz, 1H), 2.17-2.11 (m, 3H), 1.29 (d, J=6.8 Hz, 6H).

Step B: 2,5-Diisopropylaniline

(819) ##STR00301##

(820) A mixture of 2-isopropyl-5-(prop-1-en-2-yl)aniline (227 mg, 1.295 mmol) and 5% Pd/C (0.133 g, 0.026 mmol) (Type 87 μL, 58-5% moisture) in EtOAc (3 mL) was hydrogenated at 5 bar for 16 hours. The mixture was filtered through Celite® and evaporated to afford the title compound (209 mg, 88%).

(821) .sup.1H NMR (CDCl.sub.3) δ 7.06 (d, J=7.9 Hz, 1H), 6.66 (dd, J=7.9, 1.9 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 3.71 (bs, 2H), 2.88 (sept, J=7.0 Hz, 1H), 2.78 (sept, J=7.0 Hz, 1H), 1.25 (d, J=7.1 Hz, 6H), 1.21 (d, J=6.9 Hz, 6H).

Intermediate A19: 2-Isocyanato-1,3-diisopropylbenzene

(822) ##STR00302##

(823) 2,6-Diisopropylaniline (3.07 g, 17-14 mmol) was dissolved in dry THF (40 mL) and Et.sub.3N (3 mL, 21.52 mmol) was added. A solution of triphosgene (4.26 g, 14.35 mmol) in dry THF (12 mL) was added over 5 minutes, resulting in the formation of a thick colourless precipitate. The reaction mixture was stirred at room temperature overnight.

(824) The THF was removed in vacuo and toluene (50 mL) was added. The mixture was filtered through a short silica plug eluting with toluene (150 mL). The filtrate was concentrated in vacuo to afford the title compound (2.76 g, 92%) as a colourless oil.

(825) .sup.1H NMR (CDCl.sub.3) δ 7.20-7.10 (m, 3H), 3.22 (hept, J=6.9 Hz, 2H), 1.26 (d, J=6.8 Hz, 12H).

Intermediate A20:4-(4-Isocyanato-2,3-dihydro-H-inden-5-yl)-2-methoxypyridine

Step A: 4-Nitro-2,3-dihydro-1H-indene

(826) ##STR00303##

(827) To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated H.sub.2SO.sub.4 (50 mL) dropwise at 0° C. over a period of 3.5 hours. The reaction mixture was stirred at 0° C. for 0.5 hour. Then the reaction mixture was poured into ice water (600 mL) and extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2×500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, 66%) as a colourless oil.

(828) .sup.1H NMR (CDCl.sub.3): δ 7.98 (d, 1H), 7.51 (d, 1H), 7.30 (t, 1H), 3.41 (t, 2H), 302 (t, 2H) and 2.22-2.20 (m, 2H).

Step B: 2,3-Dihydro-1H-inden-4-amine

(829) ##STR00304##

(830) To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The reaction mixture was stirred under H.sub.2 (50 psi) at 20° C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.39% purity on LCMS) as a brown oil.

(831) .sup.1H NMR (CDCl.sub.3): δ 7.01 (t, 1H), 6.71 (d, 1H), 6.51 (d, 1H), 3.57 (br s, 2H), 2.93 (t, 2H), 2.75 (t, 2H) and 2.16-2.08 (m, 2H).

(832) LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).

Step C: N-(2,3-Dihydro-1H-inden-4-yl)acetamide

(833) ##STR00305##

(834) To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) over 6 minutes at 0° C. Then the reaction mixture was warmed to 16° C. and stirred for 1.4 hours. The mixture was poured into water (500 mL) and extracted with DCM (2×300 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.69% purity on LCMS) as a white solid.

(835) .sup.1H NMR (CDCl.sub.3): δ 7.70 (d, 1H), 7.15 (t, 1H), 7.02 (d, 1H), 2.95 (t, 2H), 2.81 (t, 2H), 2.18 (s, 3H) and 2.15-2.08 (m, 2H).

(836) LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+)

Step D: N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)acetamide

(837) ##STR00306##

(838) N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), p-toluenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and stirred at 20° C. for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. Then the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

(839) .sup.1H NMR (CDCl.sub.3): δ 7.33 (d, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 2.92-2.83 (m, 4H), 2.21 (s, 3H) and 2.10-2.02 (m, 2H).

(840) LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).

Step E: 5-Bromo-2,3-dihydro-1H-inden-4-amine

(841) ##STR00307##

(842) A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt % in water) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to 0° C. in an ice bath and some solid precipitated. The suspension was filtered. The filter cake was washed with ice water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.08% purity on LCMS, HCl salt) as a grey solid.

(843) .sup.1H NMR (DMSO-d.sub.6): δ 7.67 (br S, 2H), 7.24 (d, 1H), 6.69 (d, 1H), 2.85 (t, 2H), 2.79 (t, 2H) and 2.04-1.96 (m, 2H).

(844) LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).

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

(845) ##STR00308##

(846) A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437-74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80° C. for 12 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×700 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 10:1) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

(847) .sup.1H NMR (CDCl.sub.3): δ 8.22 (d, 1H), 7.03-7.00 (m, 1H), 6.99 (d, 1H), 6.87 (s, 1H), 6.77 (d, 1H), 3.99 (s, 3H), 3.77 (br s, 2H), 2.97 (t, 2H), 2.77 (t, 2H) and 2.21-2.13 (m, 2H).

(848) LCMS: m/z 241.2 (M+H).sup.+ (ES.sup.+).

Step G: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

(849) ##STR00309##

(850) To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50-35 mmol, 1.1 eq) in THF (275 mL) was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) in portions at 0° C. Then the reaction mixture was stirred at 16° C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

(851) .sup.1H NMR (CDCl.sub.3): δ 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m 4H) and 2.23-2.15 (m, 2H).

Intermediate A21: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine

Step A: 4-Fluoro-2-(prop-1-en-2-yl)aniline

(852) ##STR00310##

(853) To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)Cl.sub.2 (7.51 g, 10.26 mmol, 0.05 eq) under N.sub.2 atmosphere. Then the reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

(854) .sup.1H NMR (CDCl.sub.3): δ 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

(855) LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

(856) ##STR00311##

(857) To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59 mmol, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The reaction mixture was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

(858) .sup.1H NMR (CDCl.sub.3): δ 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

(859) LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

Step C: 2-Bromo-4-fluoro-6-isopropylaniline

(860) ##STR00312##

(861) To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130-55 mmol, 1 eq) at 25° C. The reaction mixture was stirred at 25° C. for 10 minutes. Then the reaction mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc (2×250 mL). The organic phases were washed with brine (2×400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting only by using petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

(862) .sup.1H NMR (CDCl.sub.3): δ 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

(863) LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step D: 4-Bromo-2-isopropoxypyridine

(864) ##STR00313##

(865) To a solution of 4-bromo-2-chloropyridine (20 g, 103.93 mmol, 1 eq) in THF (400 mL) was added NaH (6.24 g, 155.89 mmol, 60% purity, 1.5 eq) at 0° C. Then the mixture was stirred for 0.5 hour. Propan-2-ol (6.87 g, 114.32 mmol, 8.75 mL, 1.1 eq) was added and the resulting mixture was warmed to 50° C. and stirred for 12 hours. The reaction mixture was quenched with H.sub.2O (1 L) at 25° C. and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 40:1) to give the title compound (22 g, 98%) as a light yellow oil.

(866) .sup.1H NMR (CDCl.sub.3): δ 7.96 (d, 1H), 6.98 (dd, 1H), 6.89 (d, 1H), 5.44-5.24 (m, 1H) and 1.34 (d, 6H).

Step E: 2-Isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

(867) ##STR00314##

(868) To a solution of 4-bromo-2-isopropoxypyridine (19 g, 87.93 mmol, 1 eq) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (22.33 g, 87.93 mmol, 1 eq) in 1,4-dioxane (300 mL) was added KOAc (25.89 g, 263.80 mmol, 3 eq) followed by Pd(dppf)Cl.sub.2 (1.93 g, 2.64 mmol, 0.03 eq) under nitrogen. Then the reaction mixture was heated to 80° C. and stirred for 12 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (22 g, 95%) as a light yellow oil.

(869) .sup.1H NMR (CDCl.sub.3): δ 8.16 (d, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 5.32-5.24 (m, 1H), 1.34 (s, 12H) and 1.27 (s, 6H).

(870) LCMS: m/z 264.2 (M+H).sup.+ (ES.sup.+).

Step F: 4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylaniline

(871) ##STR00315##

(872) To a solution of 2-bromo-4-fluoro-6-isopropylaniline (10.94 g, 47.12 mmol, 1 eq) and 2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12.4 g, 47.12 mmol, 1 eq) in 1,4-dioxane (200 mL) and H.sub.2O (20 mL) was added Pd(dppf)Cl.sub.2 (1.72 g, 2.36 mmol, 0.05 eq) followed by K.sub.2CO.sub.3 (19.54 g, 141-37 mmol, 3 eq) at 25° C. Then the reaction mixture was heated to 80° C. and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=50:1 to 20:1) to give the title compound (10.3 g, 69% yield, 91% purity on LCMS) as a brown oil.

(873) .sup.1H NMR (CDCl.sub.3): δ 8.21 (d, 1H), 6.94-6.91 (m, 2H), 6.76 (s, 1H), 6.72 (dd, 1H), 5.38-5.29 (m, 1H), 3.64 (br s, 2H), 2.98-2.89 (m, 1H), 1.38 (d, 6H) and 1.30-1.27 (m, 6H).

(874) LCMS: m/z 289.2 (M+H).sup.+ (ES.sup.+).

Step G: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine

(875) ##STR00316##

(876) To a solution of 4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylaniline (4 g, 13.87 mmol, 1 eq) in THF (80 mL) was added TEA (2.81 g, 27.74 mmol, 3.86 mL, 2 eq). The mixture was cooled to 0° C. and then triphosgene (1.65 g, 5.55 mmol, 0.4 eq) was added to the mixture. The resulting mixture was heated to 70° C. and stirred for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate=100:1 to 30:1) to give the title compound (1.9 g, 44% yield) as a yellow oil, which was used directly in the next step.

Intermediate A22: 5-Chloro-2-isocyanato-1,3-diisopropylbenzene

(877) ##STR00317##

(878) To a solution of 4-chloro-2,6-diisopropylaniline (0.105 g, 0.496 mmol) in toluene (1 mL) was added a phosgene solution (0.65 mL, 20 wt % in toluene, 1.22 mmol) and the reaction mixture was refluxed for 1 hour. Upon cooling, the mixture was concentrated in vacuo to afford the title compound as an orange oil (0.111 g, 94%).

(879) .sup.1H NMR (CDCl.sub.3) δ 7.07 (d, 2H), 3.17 (h, 2H), 1.24 (d, 12H).

PREPARATION OF EXAMPLES

Example 1: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide, Sodium Salt

(880) ##STR00318##

(881) 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (Intermediate P1) (59.8 mg, 0.26 mmol) was dissolved in THF:DMF (1:1) (4 mL) and sodium tert-butoxide (2M in THF) (0.136 ml, 0.273 mmol) was added. After stirring for 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (54-3 mg, 0.273 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. Ethyl acetate (6 mL) was added and the suspension stirred for hours. The resultant precipitate was collected by filtration, washed with ethyl acetate (2 mL), triturated with ethyl acetate (5 mL) for 1 hour, filtered, and dried under reduced pressure to afford the title compound (73 mg, 60%) as a white solid.

(882) .sup.1H NMR (DMSO-d.sub.6) δ 7.47 (s, 1H), 6.79-6.74 (m, 2H), 4.38-4.32 (m, 2H), 3.80-372 (m, 2H), 3.00 (s, 3H), 2.79-2.71 (m, 4H), 2.67 (t, J=7.2 Hz, 4H), 1.95-1.86 (m, 4H).

(883) LCMS; m/z 430 (M+H).sup.+ (ES.sup.+).

Example 2: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-(2-(methylamino)ethyl)-1H-pyrazole-5-carboxylic Acid

(884) ##STR00319##

(885) 5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (Intermediate P1) (80.5 mg, 0.350 mmol) was dissolved in THF (10 mL) and sodium tert-butoxide (2M in THF) (0.184 ml, 0.367 mmol) was added. After stirring for 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (69.7 mg, 0.350 mmol) was added and the reaction mixture stirred at room temperature for 15 hours. The resultant precipitate was collected by filtration, washed with THF (1 mL), triturated with ethyl acetate (5 mL) for 1 hour, filtered, and purified by chromatography on silica gel (RP Flash C18) (13 g column, 0-50% acetonitrile/10 mM ammonium bicarbonate). The compound obtained was triturated with TBME (2 mL) for 2 hours, filtered and dried under reduced pressure to afford the title compound (91 mg, 56%) as a white solid. Ring opening occurred on purification.

(886) .sup.1H NMR (DMSO-d.sub.6) δ 7.58 (s, 1H), 6.77 (s, 1H), 6.44 (s, 1H), 4.72-4.56 (m, 2H), 3.57-3.38 (m, 2H), 2.83-2.58 (m, 11H), 1.98-1.82 (m, 4H). Three exchangeable protons not visible.

(887) LCMS; m/z 448 (M+H).sup.+ (ES.sup.+).

Example 3: 1-(2-(Dimethylamino)ethyl)-5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(888) ##STR00320##

(889) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-(2-(methylamino)ethyl)-1H-pyrazole-5-carboxylic acid (Example 2) from 1-(2-(dimethylamino)ethyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P2) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (40.1 mg, 46%) as a white solid.

(890) .sup.1H NMR (DMSO-d.sub.6) δ 7.92 (s, 1H), 6.89 (s, 1H), 6.60 (s, 1H), 4.31 (t, J=6.8 Hz, 2H), 3.51 (s, 2H), 2.83-2.71 (m, 6H), 2.59 (t, J=7.4 Hz, 4H), 2.26 (s, 6H), 2.18 (s, 6H), 1.98-1.85 (m, 4H). One exchangeable proton not visible.

(891) LCMS; m/z 475 (M+H).sup.+ (ES.sup.+); 473 (M−H).sup.− (ES.sup.−).

Example 4: 1-(2-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

(892) ##STR00321##

(893) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-(2-(methylamino)ethyl)-1H-pyrazole-5-carboxylic acid (Example 2) from 1-(2-(dimethylamino)ethyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide (Intermediate P3) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (23.7 mg, 27%) as a white solid.

(894) .sup.1H NMR (DMSO-d.sub.6) δ 7.93 (s, 1H), 6.90 (s, 1H), 6.48 (s, 1H), 4.53 (t, J=7.2 Hz, 2H), 2.85 (t, J=7.1 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.3 Hz, 4H), 2.27 (s, 6H), 2.00-1.83 (m, 4H), 1.51 (s, 6H). Two exchangeable protons not visible.

(895) LCMS; m/z 476 (M+H).sup.+ (ES.sup.+); 474 (M−H).sup.− (ES.sup.−).

Example 5: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide

(896) ##STR00322##

(897) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-(2-(methylamino)ethyl)-1H-pyrazole-5-carboxylic acid (Example 2) from 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (Intermediate P4) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (16 mg, 26%) as a colourless solid.

(898) .sup.1H NMR (DMSO-d.sub.6) δ 10.78 (s, 1H), 7.94 (s, 1H), 6.92 (s, 1H), 6.49 (s, 1H), 4.15 (t, J=5.6 Hz, 2H), 3.60 (s, 2H), 2.88 (t, J=5.7 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.39 (s, 3H), 2.05-1.86 (m, 4H).

(899) LCMS; m/z 416 (M+H).sup.+ (ES.sup.+).

Example 6: 1-(2-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-isopropyl-1H-pyrazole-3-sulfonamide

(900) ##STR00323##

(901) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-(2-(methylamino)ethyl)-1H-pyrazole-5-carboxylic acid (Example 2) from 1-(2-(dimethylamino)ethyl)-5-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P5) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (47 mg, 39%) as a white solid.

(902) .sup.1H NMR (DMSO-d.sub.6) δ 11.28-9.98 (br s, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.52 (s, 1H), 4.20 (t, J=6.8 Hz, 2H), 3.09 (sept, J=6.8 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.70 (t, J=6.8 Hz, 2H), 2.60 (t, J=7.4 Hz, 4H), 2.20 (s, 6H), 1.93 (p, J=7.4 Hz, 4H), 1.21 (d, J=6.8 Hz, 6H).

(903) LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.3 (M−H).sup.− (ES.sup.−).

Example 7: 1-Cyclopropyl-5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(904) ##STR00324##

(905) To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P6) (4.5 g, 18.42 mmol, 1 eq) in THF (50 mL) was added t-BuONa (1.86 g, 19.34 mmol, 1.05 eq). Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (3.67 g, 18.42 mmol, 1 eq) was added. The reaction mixture was stirred at 70° C. for 10 minutes and then concentrated in vacuo. The residue was purified by reversed phase prep-HPLC (column: Synergi Max-R.sup.β; 250 mm*50 mm*10 μm; mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-MeCN]; B %: 5%-35%, 20 minutes) to give the title compound (5.1 g, 61.8% yield, 99% HPLC purity, free acid) as a white solid.

(906) .sup.1H NMR (DMSO-d.sub.6) δ 8.00 (s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3.82-3.78 (m, 1H), 3.61 (s, 2H), 2.80-2.76 (m, 4H), 2.59-2.55 (m, 4H), 2.21 (s, 6H), 1.97-1.89 (m, 4H) and 1.11-1.04 (m, 4H).

(907) LCMS: m/z 444.2 (M+H).sup.+ (ES.sup.+).

Example 7B: 1-Cyclopropyl-5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(908) ##STR00325##

(909) To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 7) (3.7 g, 8.34 mmol, 1 eq) in THF (50 mL) was added t-BuONa (801 mg, 8.34 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was triturated with TBME (25 mL). Then the mixture was filtered to give the title compound. The title compound combined with another batch (3.7 g) obtained in parallel was redissolved in H.sub.2O (300 mL) and lyophilized to give the title compound (6.8 g, 87.36% yield, 100% HPLC purity, sodium salt) as a white solid.

(910) .sup.1H NMR (DMSO-d.sub.6) δ 7.53 (s, 1H), 6.76 (s, 1H), 6.31 (s, 1H), 3.65-3.61 (m, 1H), 3.49 (s, 2H), 2.76-2.72 (m, 4H), 2.65-2.60 (m, 4H), 2.18 (s, 6H), 1.92-1.86 (m, 4H), 1.08-1.05 (m, 2H), 0.95-0.93 (m, 2H).

(911) LCMS: m/z 444.2 (M+H).sup.+ (ES.sup.+).

Example 8: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(912) ##STR00326##

(913) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide, sodium salt (Example 1) from 1-methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P69) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (13 mg, 23%) as a white solid.

(914) .sup.1H NMR (DMSO-d.sub.6) δ 7.51 (s, 1H), 6.76 (s, 1H), 6.29 (s, 1H), 3.79 (s, 3H), 3.34 (m, 2H), 3.33 (s, 2H), 2.93 (p, J=6.5 Hz, 1H), 2.75 (t, J=7.4 Hz, 4H), 2.71-2.63 (m, 6H), 2.18 (s, 3H), 1.94 (s, 3H), 1.89 (p, J=7.4 Hz, 4H). NH not observed.

(915) LCMS; m/z 473.5 (M+H).sup.+ (ES.sup.+); 471.4 (M−H).sup.− (ES.sup.−).

Example 9: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(916) ##STR00327##

(917) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide, sodium salt (Example 1) from 1-methyl-5-((methyl(1-methylazetidin-3-yl)amino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P69) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (31 mg, 54%) as a white solid.

(918) .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.28 (s, 1H), 3.78 (s, 3H), 3.38-3.33 (m, 2H), 3.14 (m, 2H), 2.93 (p, J=6.6 Hz, 1H), 2.69 (t, J=7.2 Hz, 2H), 2.20 (s, 3H), 1.94 (s, 3H), 1.03 (d, J=6.8 Hz, 12H). 2H under solvent.

(919) LCMS; m/z 495.5 (M+H).sup.+ (ES.sup.+); 493.3 (M−H).sup.− (ES.sup.−).

Example 10: N-(3-(Dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(920) ##STR00328##

(921) N1,N1,N3-Trimethylpropane-1,3-diamine (28 μl, 0.19 mmol), sodium bicarbonate (16 mg, 0.19 mmol) and HATU (72 mg, 0.19 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred at room temperature for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound as a white solid (34 mg, 43%).

(922) .sup.1H NMR (DMSO-d.sub.6) (rotamers) δ 7.77 (s, 1H), 6.83 (s, 1H), 6.80 & 6.72 (2×s, 1H), 3.85 &3.81 (2×s, 3H), 3.47 & 3.30 (t, J=6.9 & 7.3 Hz, 2H), 3.01 & 2.96 (2×s, 3H), 2.84 & 2.76 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.64 (t, J=6.1 Hz, 4H), 2.60 & 2.32 (2×s, 6H), 1.89 (quin, J=7.2 Hz, 4H), 1.90 & 1.77 (2×m, 2H). NH not observed.

(923) LCMS; m/z 503.5 (M+H).sup.+ (ES.sup.+); 501.3 (M−H).sup.− (ES.sup.−).

Example 11: N-Cyclobutyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(924) ##STR00329##

(925) Prepared according to the general procedure of N-(3-(dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 10) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methylcyclobutanamine, HCl salt to afford the title compound (40 mg, 54%) as a white solid.

(926) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.74 (s, 1H), 7.39 (br s, 1H), 6.83 (s, 1H), 6.80-6.32 (m, 1H), 5.00-4.14 (m, 1H), 3.83 (s, 3H), 2.98 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.36-2.12 (m, 2H), 2.13-1.85 (m, 6H), 1.81-1.24 (m, 2H).

(927) LCMS; m/z 472.5 (M+H).sup.+ (ES.sup.+); 470.3 (M−H).sup.− (ES.sup.−).

Example 12: N-Cyclobutyl-3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(928) ##STR00330##

(929) HATU (68.5 mg, 0.180 mmol) was added to a solution of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) (67.9 mg, 0.150 mmol) and N-methylcyclobutanamine, HCl (20.07 mg, 0.165 mmol) in DMF (1 mL). Triethylamine (23.01 μL, 0.165 mmol) was added and the mixture stirred for 20 hours. Water (1 mL) was slowly added and the suspension stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was purified by chromatography on RP Flash C18 (13 g column, 0-50% MeCN/10 mM ammonium bicarbonate) and triturated with TBME (2 mL) for 1 hour to afford the title compound (30 mg, 40%) as a white solid.

(930) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.09 (s, 1H), 7.90 (s, 1H), 7.28-7.20 (m, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.03-6.86 (2×m, 1H), 4.78-4.24 (2×m, 1H), 3.91 (s, 3H), 3.02-2.91 (m, 5H), 2.27-1.91 (m, 4H), 1.72-1.36 (m, 2H), 1.17-0.94 (m, 12H).

(931) LCMS; m/z 476 (M+H).sup.+ (ES.sup.+).

Example 13: N-(2-Cyanoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(932) ##STR00331##

(933) HATU (77 mg, 0.201 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (75.2 mg, 0.168 mmol) and 3-(methylamino)propanenitrile (18.83 μL, 0.201 mmol) in DMF (1 mL) and the mixture stirred at room temperature for hours. Water (1 mL) was slowly added and the suspension stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (25 mg, 31%) as a white solid.

(934) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.96 (s, 1H), 8.09 (s, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 3.95-3.92 (2×s, 3H), 3.80-3.65 (m, 2H), 3.07-2.87 (2×s, 3H), 2.88 (t, J=6.6 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.5 Hz, 4H), 1.99-1.92 (m, 4H).

(935) LCMS: m/z 471 (M+H).sup.+ (ES.sup.+).

Example 14: N-(2-(Dimethylamino)ethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(936) ##STR00332##

(937) N1,N1,N2-Trimethylethane-1,2-diamine (29 μL, 0.223 mmol) and HATU (83 mg, 0.219 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (34 mg, 44%) as a white solid.

(938) .sup.1H NMR (DMSO-d.sub.6), rotamers; 610.36 (s, 1H), 7.87 & 7.80 (2×s, 1H), 6.91-6.80 (m, 2H), 3.88 & 3.83 (2×s, 3H), 3.70-3.62 & 3.48-3.40 (2×m, 2H), 3.04 & 2.96 (2×s, 3H), 2.86 & 2.40 (2×m, 2H), 2.77 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 2.01-1.85 (m, 7H). CH.sub.3 not visible.

(939) LCMS; m/z 489.4 (M+H).sup.+ (ES.sup.+); 487.3 (M−H).sup.− (ES.sup.−).

Example 15: N-Cyclopentyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, sodium Salt

(940) ##STR00333##

(941) N-Methylcyclopentanamine (0.012 mL, 0.102 mmol) and HATU (39 mg, 0.103 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (60 mg, 0.134 mmol) in DMF (1 mL) and stirred for 20 hours. TBME (5 mL) was added and the resulting solid filtered off. The filtrate was treated with NaHCO.sub.3 (5-7 mg, 0.068 mmol) and the solution purified by reversed phase chromatography (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the crude product as a white solid. This material (33 mg) was dissolved in MeOH (3 mL), 0.1 M aqueous NaHCO.sub.3 (0.68 mL, 0.068 mmol) and water (1 mL), sonicated for 10 minutes, evaporated in vacuo and dried to afford the title compound (29 mg, 83%) as a white solid.

(942) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.51 (s, 1H), 6.76 (s, 1H), 6.53 (br s, 1H), 4.31-414 (m, 1H), 3.78 (s, 3H), 2.86 (s, 3H), 2.74 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.5 Hz, 4H), 1.89 (p, J=7.5 Hz, 4H), 1.82-1.47 (m, 8H).

(943) LCMS; m/z 486.5 (M+H).sup.+ (ES.sup.+); 484.3 (M−H).sup.− (ES.sup.−).

Example 16: N-((5-Bromo-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide

(944) ##STR00334##

(945) 5-Bromo-2,3-dihydro-H-inden-4-amine (Intermediate A13) (45 mg, 0.212 mmol) was dissolved in THF (2 mL). Triethylamine (35 μL, 0.251 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (62 mg, 0.209 mmol) in THF (1 mL). The slurry was stirred at room temperature for 1 hour, before being concentrated in vacuo. The solid was washed with THF (5 mL) and DCM (mL. Then the filtrate was concentrated in vacuo to give 5-bromo-4-isocyanato-2,3-dihydro-1H-indene as a pale yellow solid that was used without further purification. The isocyanate was dissolved in dry DMF (1 mL). A solution of 5-((dimethylamino)methyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7) (50 mg, 0.215 mmol) in dry THF (2 mL) was treated with sodium tert-butoxide (2 M in THF) (110 μL, 0.220 mmol) and stirred at room temperature for 1 hour. The solution of 5-bromo-4-isocyanato-2,3-dihydro-1H-indene in DMF was added and the mixture was stirred overnight. The THF was removed in vacuo and DMSO (1 mL) was added. The mixture was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (24 mg, 24%) as a colourless powder.

(946) .sup.1H NMR (DMSO-d.sub.6) δ 11.00 (s, 1H), 8.09 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 6.65 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.52 (s, 2H), 2.83 (t, J=7.4 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.18 (s, 6H), 1.92 (p, J=7.6 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

(947) LCMS m/z 470.3/472.3 (M+H).sup.+ (ES.sup.+); 468.4/470.2 (M−H).sup.− (ES.sup.−).

Example 17: 5-((Dimethylamino)methyl)-1-ethyl-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(948) ##STR00335##

(949) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7) and 5-(2-methoxypyridin-4-yl)-2,3-dihydro-H-inden-4-amine (Intermediate A14) to afford the title compound (29 mg, 28%) as a colourless powder.

(950) .sup.1H NMR (DMSO-d.sub.6) δ 10.81 (s, 1H), 8.13 (dd, J=5.3, 0.7 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (dd, J=5.3, 1.5 Hz, 1H), 6.73-6.71 (m, 1H), 6.56 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.89 (s, 3H), 3.50 (s, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.17 (s, 6H), 1.96 (p, J=7.5 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).

(951) LCMS; m/z 499.4 (M+H).sup.+ (ES.sup.+); 497.3 (M−H).sup.− (ES.sup.−).

Example 18: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide

(952) ##STR00336##

(953) Sodium tert-butoxide (2 M in THF) (0.24 mL, 0.480 mmol) was added to a solution of 1-(1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)-N,N,N-trimethylethanaminium trifluoroacetate (Intermediate P8) (90 mg, 0.233 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (51.1 mg, 0.256 mmol) was added and stirred at room temperature overnight. Additional 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (51.1 mg, 0.256 mmol) was added and the mixture stirred for 24 hours. Volatiles were evaporated and the residue was dissolved in DMSO (2 mL), filtered and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (35 mg, 31%) as a white solid.

(954) .sup.1H NMR (DMSO-d.sub.6) δ 7.44 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 5.07 (q, J=6.8 Hz, 1H), 4.97-4.85 (m, 1H), 3.01 (s, 9H), 2.75 (t, J=7.4 Hz, 4H), 2.67-2.57 (m, 4H), 1.96-1.81 (m, 4H), 1.69 (d, J=6.8 Hz, 3H), 1.50 (d, J=6.4 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H).

(955) LCMS; m/z 474.5 (M+H).sup.+ (ES.sup.+).

Example 19: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((1-methyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide

(956) ##STR00337##

(957) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from N,N,N-trimethyl-1-(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)ethan-1-aminium 2,2,2-trifluoroacetate (Intermediate P9) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (27 mg, 37%) as a white solid.

(958) .sup.1H NMR (DMSO-d.sub.6) δ 7.45 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 4.99 (q, J=6.8 Hz, 1H), 3.93 (s, 3H), 3.01 (s, 9H), 2.75 (t, J=7.4 Hz, 4H), 2.72-2.57 (m, 4H), 1.98-1.80 (m, 4H), 1.68 (d, J=6.8 Hz, 3H).

(959) LCMS; m/z 446.5 (M+H).sup.+ (ES.sup.+).

Example 20: 5-((Dimethylamino)methyl)-1-ethyl-N-((7-fluoro-5-(pyridin-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(960) ##STR00338##

(961) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7) and 7-fluoro-5-(pyridin-3-yl)-2,3-dihydro-H-inden-4-amine (Intermediate A12) to afford the title compound (5 mg, 6%) as a colourless powder.

(962) .sup.1H NMR (DMSO-d.sub.6) δ 10.83 (s, 1H), 8.56 (dd, J=4.8, 1.6 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 7.90 (s, 1H), 7.72-7.68 (m, 1H), 7.43-7.39 (m, 1H), 7.03 (d, J=9.2 Hz, 1H), 6.54 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.51 (s, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 2.18 (s, 6H), 2.03 (p, J=7.6 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).

(963) LCMS; m/z 487.5 (M+H).sup.+ (ES.sup.+); 485.3 (M−H).sup.− (ES.sup.−).

Example 21: 5-((Dimethylamino)methyl)-1-ethyl-N-((7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(964) ##STR00339##

(965) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7) and 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate A11) to afford the title compound (5 mg, 7%) as a colourless powder.

(966) .sup.1H NMR (DMSO-d.sub.6) δ 1.85 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.90 (s, 1H), 7.02 (d, J=9.2 Hz, 1H), 6.89 (dd, J=5.3, 1.5 Hz, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.89 (s, 3H), 3.51 (s, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.66 (t, J=7.1 Hz, 2H), 2.18 (s, 6H), 2.02 (p, J=7.6 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

(967) LCMS; m/z 517.4 (M+H).sup.+ (ES.sup.+); 515.3 (M−H).sup.− (ES.sup.−).

Example 22: 1-Cyclopropyl-5-(1-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(968) ##STR00340##

(969) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 1-cyclopropyl-5-(1-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P10) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (83 mg, 52%) as a white solid.

(970) .sup.1H NMR (DMSO-d.sub.6) δ 10.76 (s, 1H), 8.00 (s, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 4.09 (q, J=6.8 Hz, 1H), 3.92-3.84 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.4 Hz, 4H), 2.17 (s, 6H), 1.93 (p, J=7.4 Hz, 4H), 1.29 (d, J=6.8 Hz, 3H), 1.22-1.14 (m, 1H), 1.08-0.97 (m, 3H).

(971) LCMS; m/z 458.5 (M+H).sup.+ (ES.sup.+).

Example 23: 5-(1-(Azetidin-1-yl)propyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(972) ##STR00341##

(973) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-(1-(azetidin-1-yl)propyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P11) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (42 mg, 36%) as a white solid.

(974) .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (s, 1H), 7.98 (s, 1H), 6.91 (s, 1H), 6.58 (s, 1H), 3.96-3.87 (m, 1H), 3.81-3.73 (m, 1H), 3.16 (q, J=6.9 Hz, 2H), 3.09 (q, J=6.9 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.4 Hz, 4H), 2.00-1.87 (m, 6H), 1.77-1.63 (m, 1H), 1.63-1.49 (m, 1H), 1.20-1.12 (m, 1H), 1.12-1.01 (m, 3H), 0.69 (t, J=7.4 Hz, 3H).

(975) LCMS; m/z 484.5 (M+H).sup.+ (ES.sup.+).

Example 24: 1-Cyclopropyl-5-(1-(dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(976) ##STR00342##

(977) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 1-cyclopropyl-5-(1-(dimethylamino)propyl)-1H-pyrazole-3-sulfonamide (Intermediate P12) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (40 mg, 31%) as a white solid.

(978) .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (s, 1H), 7.99 (s, 1H), 6.92 (s, 1H), 6.66 (s, 1H), 3.90 (dd, J=9.3, 5.3 Hz, 1H), 3.87-3.79 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.55 (t, J=7.4 Hz, 4H), 2.16 (s, 6H), 1.92 (p, J=7.4 Hz, 4H), 1.88-1.78 (m, 1H), 1.77-1.63 (m, 1H), 1.20-0.98 (m, 4H), 0.78 (t, J=7.3 Hz, 3H).

(979) LCMS; m/z 472.4 (M+H).sup.+ (ES.sup.+).

Example 2t: 5-(˜(Azetidin-1-yl)ethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(980) ##STR00343##

(981) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-(1-(azetidin-1-yl)ethyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P13) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (11 mg, 12%) as a white solid.

(982) .sup.1H NMR (DMSO-d.sub.6) δ 1.8 (s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.55 (s, 1H), 3.92-3.79 (m, 2H), 3.24-3.05 (m, 4H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.01-1.87 (m, 6H), 1.19 (d, J=6.5 Hz, 3H), 1.15-1.02 (m, 4H).

(983) LCMS; m/z 470.4 (M+H).sup.+ (ES.sup.+).

Example 26: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt (Enantiomer 1)

(984) ##STR00344##

Step A: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Enantiomer 1)

(985) ##STR00345##

(986) To a solution of 5-(1-(azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide, enantiomer B (Intermediate P15) (3.4 g, 13.92 mmol, 1 eq.) in THF (100 ml) and DMF (13 mL) was added t-BuONa (2 M, 6.96 mL, 1 eq) and the reaction mixture was stirred for 20 minutes. Then a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (2.77 g, 13.92 mmol, 1 eq) in THF (20 mL) was added. The mixture was stirred at 25° C. for 20 minutes. LCMS showed the starting material was consumed completely and the desired mass was detected. The reaction mixture was concentrated in vacuo. The residue was triturated with MTBE (150 mL) and a solid was formed. The mixture was filtered. The filter cake was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (2.77 g, 43%) as a white solid.

(987) .sup.1H NMR (DMSO-d.sub.6) δ 8.03 (s, 1H), 6.93 (s, 1H), 6.61 (s, 1H), 3.93 (s, 3H), 3.78-374 (m, 1H), 3.23-3.13 (m, 4H), 2.81-2.77 (t, 4H), 2.61-2.57 (m, 4H), 1.98-1.92 (m, 6H), 1.16 (d, 3H).

(988) LCMS m/z 444.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(989) ##STR00346##

(990) To a solution of 5-(1-(azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Enantiomer 1) (3.5 g, 7.89 mmol, 1 eq, free acid) in THF (20 mL) was added a solution of t-BuONa in THF (2 M, 3.95 mL, 1 eq). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was triturated with MBTE (100 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was combined with another batch of product (350 mg, crude) and re-dissolved in H.sub.2O and lyophilised to give the title compound (2.96 g, 69%) as a light yellow solid.

(991) .sup.1H NMR (DMSO-d.sub.6) δ 7.58 (s, 1H), 6.77 (s, 1H), 6.24 (s, 1H), 3.80 (s, 3H), 3.56-3.50 (m, 1H), 3.09-3.00 (m, 4H), 2.75-2.71 (m, 4H), 2.63-2.60 (m, 4H), 1.91-1.86 (m, 6H), 1.09 (d, J=6.0 Hz, 3H).

(992) LCMS; m/z 444.2 (M+H).sup.+ (ES.sup.+).

Example 27: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt (Enantiomer 2)

(993) ##STR00347##

Step A: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Enantiomer 2)

(994) ##STR00348##

(995) A solution of sodium tert-butoxide in THF (2 M, 3.27 mL) was added to a solution of 5-(1-(azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide, enantiomer A (Intermediate P14) (1.6 g, 6.55 mmol) in THF (20 mL) and DMF (20 mL) at 20° C. The reaction was stirred for 10 minutes at 20° C., before a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (913 mg, 4.58 mmol, 0.7 eq) in THF (12 mL) was added dropwise. The resulting mixture was stirred at 20° C. for 1 hour. The reaction mixture was diluted with MTBE (96 mL) and the solid was filtered and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (581 mg, 20%) as a white solid.

(996) .sup.1H NMR (DMSO-d.sub.6) δ 8.03 (s, 1H), 6.93 (s, 1H), 6.61 (s, 1H), 3.93 (s, 3H), 3.78-3.74 (m, 1H), 3.23-3.13 (m, 4H), 2.81-2.77 (t, 4H), 2.61-2.57 (m, 4H), 1.98-1.92 (m, 6H), 1.16 (d, 3H).

(997) LCMS: m/z 444.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(˜(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt (Enantiomer 2)

(998) ##STR00349##

(999) To a solution of 5-(1-(azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Enantiomer 2) (950 mg, 2.10 mmol) in THF (20 mL) was added a solution of t-BuONa in THF (2 M, 1.05 mL). The mixture was stirred at 20° C. for 1 hour and then concentrated in vacuo. The residue was triturated with MTBE (30 mL) and the solid was filtered. The filter cake was re-dissolved in THF (20 mL) and the resulting solution was added dropwise into 60 mL of MTBE. Some precipitate formed at the same time. The suspension was filtered to give the title compound (760 mg) as an off-white solid. The product combined with another batch of product (200 mg) was re-dissolved in deionized water (40 mL) and then lyophilized to give the title compound (841 mg, 78%).

(1000) .sup.1H NMR (DMSO-d.sub.6) δ 7.57 (s, 1H), 6.77 (s, 1H), 6.25 (s, 1H), 3.81 (s, 3H), 3.55-3.52 (m, 1), 3.11-3.01 (m, 4H), 2.76-2.73 (m, 4H), 2.64-2.61 (m, 4H), 1.93-1.86 (m, 6H), 1.10 (d, J=6.4 Hz, 3H).

(1001) LCMS m/z 444.2 (M+H).sup.+ (ES.sup.+).

Example 28: 4-(2-(3-((5-((Dimethylamino)methyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)ureido)-5-fluoro-3-isopropylphenyl)picolinamide

(1002) ##STR00350##

(1003) 4-(2-Amino-5-fluoro-3-isopropylphenyl)picolinonitrile (Intermediate A9) (0.05 g, 0.196 mmol) was dissolved in dry THF (2 mL). Triethylamine (0.030 mL, 0.215 mmol) and a solution of bis(trichloromethyl) carbonate (0.058 g, 0.196 mmol) in THF (1 mL) was added. The thick, opaque mixture was stirred for two hours. The THF was removed in vacuo and the mixture was suspended in toluene (10 mL) and filtered through a phase separator cartridge washing with toluene (10 mL). After concentration in vacuo, 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile was isolated as a yellow oil that was used without further purification. The isocyanate was dissolved in dry THF (2 mL).

(1004) A suspension of 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) (0.043 g, 0.196 mmol) in dry THF (2 mL) was treated with sodium hydride (10 mg, 0.250 mmol), which had been previously washed with iso-hexanes (5 mL) to remove silicone oil. The suspension was stirred at room temperature for 30 minutes, before the previously prepared solution of 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile was added in a single portion. The reaction mixture was stirred at room temperature overnight. The THF was removed in vacuo and the residue was dissolved in DMSO (2 mL) and then purified by reversed phase prep-HPLC (General Methods, basic prep). After concentration of product containing fractions, the title compound (16 mg, 15%) was isolated as a colourless powder. Hydrolysis of the nitrile occurred during the reaction.

(1005) .sup.1H NMR (DMSO-d.sub.6) δ 10.86 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.96 (s, 2H), 7.69 (s, 1H), 7.49 (dd, J=5.1, 1.8 Hz, 1H), 7.25 (dd, J=10.1, 3.0 Hz, 1H), 7.10 (dd, J=8.8, 2.9 Hz, 1H), 6.41 (s, 1H), 3.86 (s, 3H), 3.47 (s, 2H), 3.17-2.96 (m, 1H), 2.16 (s, 6H), 1.11 (br s, 6H).

(1006) LCMS; m/z 518.4 (M+H).sup.+ (ES.sup.+); 516.3 (M−H).sup.− (ES.sup.−).

Example 29: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(1-(3-methylazetidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide

(1007) ##STR00351##

(1008) To a solution of 1-methyl-5-(1-(3-methylazetidin-1-yl)ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P17) (75 mg, 0.290 mmol) in THF (2 mL) was added sodium tert-butoxide (2 M in THF) (0.15 mL, 0.300 mmol) and the mixture was stirred at room temperature for 1 hour. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (58 mg, 0.291 mmol) in THF (2 mL) was added and stirring was continued overnight. The mixture was diluted with EtOAc (6 mL) and extracted twice with H.sub.2O (2 mL) containing a few drops of 2 M NaOH. The combined aqueous extracts were loaded onto a reversed phase column and purified by chromatography on RP Flash C18 (13 g column, 5-75% MeCN/10 mM ammonium bicarbonate) to afford a clear colourless solid. The product was further purified by preparative HPLC to afford the title compound (72 mg, 54%) as a clear colourless solid.

(1009) .sup.1H NMR (DMSO-d.sub.6) δ 10.71 (s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.56 (s, 1H), 3.91 (s, 3H), 3.75-3.62 (m, 1H), 3.39 (d, J=6.0 Hz, 1H), 3.24 (t, J=6.9 Hz, 1H), 2.78 (t, J=7.5 Hz, 4H), 2.75-2.64 (m, 2H), 2.58 (t, J=7.5 Hz, 4H), 2.47-2.33 (m, 1H), 1.93 (p, J=7.5 Hz, 4H), 1.14 (d, J=6.6 Hz, 3H), 1.09 (d, J=6.7 Hz, 3H).

(1010) LCMS; m/z 458.5 (M+H).sup.+ (ES.sup.+).

Example 30:5-(Azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(1011) ##STR00352##

(1012) To a solution of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P8) (75 mg, 0.293 mmol) in THF (1.5 mL) was added sodium tert-butoxide (2 M in THF) (0.16 mL, 0.320 mmol) and the mixture was stirred at room temperature for 1 hour. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (61 mg, 0.306 mmol) in THF (1.5 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (6 mL) and extracted twice with H.sub.2O (2 mL) containing a few drops of 2 M aqueous NaOH. The combined aqueous extracts were loaded onto a reversed phase column and purified by reversed phase chromatography (13 g column, 5-75% MeCN/10 mM ammonium bicarbonate) to afford the title compound (72 mg, 49%) as a clear colourless solid.

(1013) .sup.1H NMR (DMSO-d.sub.6) δ 10.78 (s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.59 (s, 1H), 3.79 (s, 2H), 3.76-3.68 (m, 1H), 3.28 (t, J=7.1 Hz, 4H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.03 (p, J=7.1 Hz, 2H), 1.93 (p, J=7.4 Hz, 4H), 1.10-0.98 (m, 4H).

(1014) LCMS; m/z 456.4 (M+H).sup.+ (ES.sup.+).

Example 31: 5-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-neopentyl-1H-pyrazole-3-sulfonamide

(1015) ##STR00353##

(1016) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-((dimethylamino)methyl)-1-neopentyl-1H-pyrazole-3-sulfonamide (Intermediate P19) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (16 mg, 28%) as a colourless powder.

(1017) .sup.1H NMR (DMSO-d.sub.6) δ 1.81 (s, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 4.03 (s, 2H), 3.51 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.3 Hz, 4H), 2.17 (s, 6H), 1.92 (p, J=7.4 Hz, 4H), 0.92 (s, 9H).

(1018) LCMS; m/z 474.2 (M+H).sup.+ (ES.sup.+); 472.4 (M−H).sup.− (ES.sup.−).

Example 32: 5-(1-(Dimethylamino)cyclopropyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1019) ##STR00354##

(1020) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-(1-(dimethylamino)cyclopropyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P20) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (22 mg, 25%) as a white solid.

(1021) .sup.1H NMR (DMSO-d.sub.6) δ 10.84 (s, 1H), 8.03 (s, 1H), 6.93 (s, 1H), 6.62 (s, 1H), 4.96 (sept, J=6.5 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.58-2.52 (m, 4H), 2.16 (s, 6H), 1.91 (p, J=7.5 Hz, 4H), 1.40 (d, J=6.5 Hz, 6H), 1.07-1.00 (m, 2H), 0.85-0.78 (m, 2H).

(1022) LCMS; m/z 472.5 (M+H).sup.+ (ES.sup.+); 470.3 (M−H).sup.− (ES.sup.−).

Example 33: 5-(2-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1023) ##STR00355##

(1024) Sodium tert-butoxide (2 M in THF) (0.103 mL, 0.206 mmol) was added to a solution of 5-(2-(dimethylamino)ethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P21) (51 mg, 0.196 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (43 mg, 0.216 mmol) was added and stirred at room temperature overnight. The suspension was filtered and the collected solid washed with THF (2 mL) and MTBE (4 mL). The solid was dissolved in MeCN and evaporated under vacuum to afford the title compound (63 mg, 64%).

(1025) .sup.1H NMR (DMSO-d.sub.6) δ 7.58 (s, 1H), 6.77 (s, 1H), 6.23 (s, 1H), 4.51 (sept, J=6.5 Hz, 1H), 2.79-2.70 (m, 6H), 2.64 (t, J=7.4 Hz, 4H), 2.47 (t, J=7.5 Hz, 2H), 2.19 (s, 6H), 1.89 (p, J=7.4 Hz, 4H), 1.36 (d, J=6.5 Hz, 6H).

(1026) LCMS; m/z 460.6 (M+H).sup.+ (ES.sup.+).

Example 14: 5-(2-(Dimethylamino)propan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1027) ##STR00356##

(1028) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(2-(dimethylamino)propan-2-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P22) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (4.8 mg, 4%) as a clear colourless solid.

(1029) .sup.1H NMR (DMSO-d.sub.6) δ 7.60 (s, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 3.98 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.10 (s, 6H), 1.89 (p, J=7.4 Hz, 4H), 1.32 (s, 6H). NH not resolved.

(1030) LCMS; m/z 446.5 (M+H).sup.+ (ES.sup.+).

Example 35: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide

(1031) ##STR00357##

(1032) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P7) and 4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (Intermediate A9) to afford the title compound (7 mg, 6%) as a colourless powder.

(1033) .sup.1H NMR (DMSO-d.sub.6) δ 11.02 (br s, 1H), 8.65 (d, J=5.0 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.97 (s, 1H), 7.73-7.65 (m, 1H), 7.26 (dd, J=10.0, 3.0 Hz, 1H), 7.15 (dd, J=8.8, 3.0 Hz, 1H), 6.29 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.46 (s, 2H), 3.21-3.02 (m, 1H), 2.16 (s, 6H), 1.33 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.8 Hz, 6H).

(1034) LCMS; m/z 514.6 (M+H).sup.+ (ES.sup.+); 512.4 (M−H).sup.− (ES.sup.−).

Example 16: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1035) ##STR00358##

(1036) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (Intermediate Aq) to afford the title compound (8 mg, 7%) as a colourless powder.

(1037) .sup.1H NMR (DMSO-d.sub.6) δ 10.91 (s, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.07-7.97 (m, 2H), 7.73-7.61 (m, 1H), 7.27 (dd, J=9.9, 3.0 Hz, 1H), 7.15 (dd, J=8.8, 2.9 Hz, 1H), 6.33 (s, 1H), 3.86 (s, 3H), 3.48 (s, 2H), 3.12 (sept, J=6.5 Hz, 1H), 2.17 (s, 6H), 1.12 (d, J=6.8 Hz, 6H).

(1038) LCMS; m/z 500.5 (M+H).sup.+ (ES.sup.+); 498.4 (M−H).sup.− (ES.sup.−).

Example 37: 1-(tert-Butyl)-5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(1039) ##STR00359##

(1040) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 1-(tert-butyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P24) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (15 mg, 28%) as a white solid.

(1041) .sup.1H NMR (DMSO-d.sub.6) δ 10.78 (bs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.68 (s, 1H), 3.53 (s, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.17 (s, 6H), 1.93 (p, J=7.4 Hz, 4H), 1.62 (s, 9H).

(1042) LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+).

Example 38: 5-(Azetidin-1-ylmethyl)-1-(tert-butyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(1043) ##STR00360##

(1044) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(azetidin-1-ylmethyl)-1-(tert-butyl)-1H-pyrazole-3-sulfonamide (Intermediate P25) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (4 mg, 31%) as a white solid.

(1045) .sup.1H NMR (DMSO-d.sub.6) δ 10.78 (bs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3.76 (s, 2H), 3.22 (t, J=7.0 Hz, 4H), 2.79 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.02 (p, J=7.1 Hz, 2H), 1.93 (p, J=7.4 Hz, 4H), 1.60 (s, 9H).

(1046) LCMS; m/z 472.8 (M+H).sup.+ (ES.sup.+).

Example 39: 5-((Dimethylamino)methyl)-N-((5-fluoro-3-isopropyl-[1,1′-biphenyl]-2-yl)carbamoyl)-1-isopropyl-1-H-pyrazole-3-sulfonamide

(1047) ##STR00361##

(1048) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P26) and 5-fluoro-3-isopropyl-[1,1′-biphenyl]-2-amine (Intermediate A4) to afford the title compound (36 mg, 32%) as a colourless powder.

(1049) .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (s, 1H), 7.70 (s, 1H), 7.39-7.27 (m, 5H), 7.16 (dd, J=10.1, 3.0 Hz, 1H), 6.97 (dd, J=8.9, 3.0 Hz, 1H), 6.51 (s, 1H), 4.83 (sept, J=6.6 Hz, 1H), 3.50 (s, 2H), 2.95 (sept, J=7.9 Hz, 1H), 2.17 (s, 6H), 1.39 (d, J=6.5 Hz, 6H), 1.09 (d, J=6.8 Hz, 6H).

(1050) LCMS; m/z 502 (M+H).sup.+ (ES.sup.+); 500 (M−H).sup.− (ES.sup.−).

Example 40: N-((2-(1,3-Dimethyl-1H-pyrazol-5-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1051) ##STR00362##

(1052) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 2-(1,3-dimethyl-H-pyrazol-5-yl)-4-fluoro-6-isopropylaniline (Intermediate A6) to afford the title compound (16 mg, 22%) as a colourless powder.

(1053) .sup.1H NMR (DMSO-d.sub.6) δ 10.84 (s, 1H), 7.68 (s, 1H), 7.24 (dd, J=10.1, 3.0 Hz, 1H), 7.04 (dd, J=8.7, 3.0 Hz, 1H), 6.52 (s, 1H), 5.93 (s, 1H), 3.89 (s, 3H), 3.50 (s, 2H), 3.45 (s, 3H), 3.08-2.92 (m, 1H), 2.17 (s, 6H), 2.14 (s, 3H), 1.09 (d, J=6.8 Hz, 6H).

(1054) LCMS; m/z 492 (M+H).sup.+ (ES.sup.+); 490 (M−H).sup.− (ES.sup.−).

Example 41: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1055) ##STR00363##

(1056) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A3) to afford the title compound (36 mg, 34%) as a colourless powder.

(1057) .sup.1H NMR (DMSO-d.sub.6) δ 10.84 (s, 1H), 8.57-8.52 (m, 1H), 8.49 (s, 1H), 7.83 (s, 1H), 7.73-7.67 (m, 1H), 7.35 (dd, J=8.0, 4.9 Hz, 1H), 7.21 (dd, J=10.1, 3.0 Hz, 1H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 6.47 (s, 1H), 3.89 (s, 3H), 3.49 (s, 2H), 3.04 (sept, J=6.4 Hz, 1H), 2.17 (s, 6H), 1.10 (d, J=6.6 Hz, 6H).

(1058) LCMS; m/z 475 (M+H).sup.+ (ES.sup.+); 473 (M−H).sup.− (ES.sup.−).

Example 42: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1059) ##STR00364##

(1060) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-isopropyl-H-pyrazole-3-sulfonamide (Intermediate P26) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A8) to afford the title compound (17 mg, 12%) as a colourless powder.

(1061) .sup.1H NMR (DMSO-d.sub.6) δ 11.02 (s, 1H), 9.13 (s, 1H), 8.76 (s, 2H), 8.04 (s, 1H), 7.26 (dd, J=10.0, 3.0 Hz, 1H), 7.20 (dd, J=8.8, 3.0 Hz, 1H), 6.44 (s, 1H), 4.81 (sept, J=6.6 Hz, 1H), 3.51 (s, 2H), 3.03 (sept, J=7.0 Hz, 1H), 2.17 (s, 6H), 1.38 (d, J=6.6 Hz, 6H), 1.10 (d, J=6.8 Hz, 6H).

(1062) LCMS; m/z 504 (M+H).sup.+ (ES.sup.+); 502 (M−H).sup.− (ES.sup.−).

Example 4: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1063) ##STR00365##

(1064) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A8) to afford the title compound (14 mg, 10%) as a colourless powder.

(1065) .sup.1H NMR (DMSO-d.sub.6) δ 10.93 (s, 1H), 9.15 (s, 1H), 8.73 (s, 2H), 8.02 (s, 1H), 7.27 (dd, J=10.0, 3.0 Hz, 1H), 7.19 (dd, J=8.8, 3.0 Hz, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 3.53 (s, 2H), 3.06 (sept, J=6.9 Hz, 1H), 2.19 (s, 6H), 1.11 (d, J=6.7 Hz, 6H).

(1066) LCMS; m/z 476 (M+H).sup.+ (ES.sup.+); 474 (M−H).sup.− (ES.sup.−).

Example 44: ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((1-methyl-5-((trimethylammonio)methyl)-1H-pyrazol-3-yl)sulfonyl)amide

(1067) ##STR00366##

(1068) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from N,N,N-trimethyl-1-(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methanaminium 2,2,2-trifluoroacetate (Intermediate P27) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (22 mg, 25%) as a white powder.

(1069) .sup.1H NMR (DMSO-d.sub.6) δ 7.45 (s, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 4.66 (s, 2H), 3.90 (s, 3H), 3.05 (s, 9H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.90 (p, J=7.4 Hz, 4H).

(1070) LCMS; m/z 432.5 (M)+(ES.sup.+).

Example 45: N-((3′-Cyano-5-fluoro-3-isopropyl-[1,1′-biphenyl]-2-yl)carbamoyl)-5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1071) ##STR00367##

(1072) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-isopropyl-H-pyrazole-3-sulfonamide (Intermediate P26) and 2′-amino-5′-fluoro-3′-isopropyl-[1,1′-biphenyl]-3-carbonitrile (Intermediate A5) to afford the title compound (28 mg, 24%) as a colourless powder.

(1073) .sup.1H NMR (DMSO-d.sub.6) δ 10.92 (s, 1H), 7.93 (s, 1H), 7.85-7.79 (m, 2H), 7.68-7.63 (m, 1H), 7.57-7.51 (m, 1H), 7.21 (dd, J=10.0, 3.0 Hz, 1H), 7.07 (dd, J=8.9, 3.0 Hz, 1H), 6.42 (s, 1H), 4.79 (sept, J=6.6 Hz, 1H), 3.48 (s, 2H), 3.00 (sept, J=6.9 Hz, 1H), 2.15 (s, 6H), 1.37 (d, J=6.6 Hz, 6H), 1.09 (s, 6H).

(1074) LCMS; m/z 527 (M+H).sup.+ (ES.sup.+); 525 (M−H).sup.− (ES.sup.−).

Example 46: N-((3′-Cyano-5-fluoro-3-isopropyl-[1,1′-biphenyl]-2-yl)carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1075) ##STR00368##

(1076) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 2′-amino-5′-fluoro-3′-isopropyl-[1,1′-biphenyl]-3-carbonitrile (Intermediate A5) to afford the title compound (37 mg, 34%) as a colourless powder.

(1077) .sup.1H NMR (DMSO-d.sub.6) δ 1.86 (s, 1H), 7.90 (s, 1H), 7.84-7.78 (m, 2H), 7.65-7.60 (m, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.21 (dd, J=10.0, 3.0 Hz, 1H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 6.45 (s, 1H), 3.87 (s, 3H), 3.49 (s, 2H), 3.04 (sept, J=7.0 Hz, 1H), 2.17 (s, 6H), 1.10 (br s, 6H).

(1078) LCMS; m/z 499 (M+H).sup.+ (ES.sup.+); 497 (M−H).sup.− (ES.sup.−).

Example 47: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1079) ##STR00369##

(1080) Prepare according to the general procedure of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P26) and 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A7) to afford the title compound (44 mg, 43%) as a colourless powder.

(1081) .sup.1H NMR (DMSO-d.sub.6) δ 10.92 (s, 1H), 8.09 (dd, J=5.3, 0.7 Hz, 1H), 7.87 (s, 1H), 7.22 (dd, J=10.0, 3.0 Hz, 1H), 7.04 (dd, J=8.9, 3.0 Hz, 1H), 6.92 (dd, J=5.2, 1.5 Hz, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 4.81 (sept, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.48 (s, 2H), 2.98 (sept, J=6.9 Hz, 1H), 2.15 (s, 6H), 1.37 (d, J=6.6 Hz, 6H), 1.08 (d, J=6.8 Hz, 6H).

(1082) LCMS; m/z 533 (M+H).sup.+ (ES.sup.+); 531 (M−H).sup.− (ES.sup.−).

Example 48: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1083) ##STR00370##

(1084) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (Intermediate A7) to afford the title compound (15 mg, 16%) as a colourless powder.

(1085) .sup.1H NMR (DMSO-d.sub.6) δ 10.87 (s, 1H), 8.09 (dd, J=5.3, 0.7 Hz, 1H), 7.85 (s, 1H), 7.22 (dd, J=10.0, 3.0 Hz, 1H), 7.04 (dd, J=8.8, 3.0 Hz, 1H), 6.89 (dd, J=5.3, 1.4 Hz, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 3.88 (s, 6H), 3.49 (s, 2H), 3.02 (sept, J=7.2 Hz, 1H), 2.17 (s, 6H), 1.09 (d, J=6.8 Hz, 6H).

(1086) LCMS; m/z 505 (M+H).sup.+ (ES.sup.+); 503 (M−H).sup.− (ES.sup.−).

Example 4A: 5-(Azetidin-1-ylmethyl)-1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(1087) ##STR00371##

(1088) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(azetidin-1-ylmethyl)-1-ethyl-H-pyrazole-3-sulfonamide (Intermediate P28) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (52 mg, 40%) as a white solid.

(1089) .sup.1H NMR (DMSO-d.sub.6) δ 10.85 (br s, 1H), 7.99 (s, 1H), 6.92 (s, 1H), 6.61 (s, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.68 (s, 2H), 3.22 (t, J=7.1 Hz, 4H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.01 (p, J=7.1 Hz, 2H), 1.94 (p, J=7.4 Hz, 4H), 1.35 (t, J=7.2 Hz, 3H).

(1090) LCMS; m/z 444.4 (M+H).sup.+ (ES.sup.+).

Example 50: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide

(1091) ##STR00372##

(1092) Sodium tert-butoxide (2 M in THF) (0.152 mL, 0.305 mmol) was added to a solution of 2,2,2-trifluoro-N-((1-isopropyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)-N— methylacetamide (Intermediate P29) (100 mg, 0.305 mmol) in THF (6 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (67 mg, 0.336 mmol) was added and stirred at room temperature overnight. The volatiles were evaporated. MeOH (0.3 mL) and K.sub.2CO.sub.3 (44 mg, 0.318 mmol) were added and stirred for 16 hours. Another equivalent of K.sub.2CO.sub.3 (44 mg, 0.318 mmol) was added and stirred for further 16 hours. The volatiles were evaporated and the crude product was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (23 mg, 17%) as a white solid.

(1093) .sup.1H NMR (DMSO-d.sub.6) δ 7.83 (s, 1H), 6.86 (s, 1H), 6.59 (s, 1H), 4.70 (sept, J=6.4 Hz, 1H), 3.96 (s, 2H), 3.33 (bs, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 2.42 (s, 3H), 1.92 (p, J=7.5 Hz, 4H), 1.35 (d, J=6.5 Hz, 6H). One exchangeable proton missing.

(1094) LCMS; m/z 432.5 (M+H).sup.+ (ES.sup.+).

Example 51: 5-((Dimethylamino)methyl)-1-ethyl-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1H-pyrazole-3-sulfonamide

(1095) ##STR00373##

(1096) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 1-(2-(dimethylamino)ethyl)-5-((dimethylamino)methyl)-H-pyrazole-3-sulfonamide (Intermediate P7) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (53 mg, 45%).

(1097) .sup.1H NMR (DMSO-d.sub.6) δ 10.96 (br s, 1H), 7.76 (s, 1H), 6.91 (d, J=9.9 Hz, 2H), 6.58 (s, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.46 (s, 2H), 3.04-2.91 (m, 2H), 2.14 (s, 6H), 1.36 (t, J=7.2 Hz, 3H), 1.14-0.93 (m 12H).

(1098) LCMS; m/z 454.5 (M+H).sup.+ (ES.sup.+).

Example 52: 5-((Dimethylamino)methyl)-1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

(1099) ##STR00374##

(1100) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 1-(2-(dimethylamino)ethyl)-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P7) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (44 mg, 39%).

(1101) .sup.1H NMR (DMSO-d.sub.6) δ 10.79 (br s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.48 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.16 (s, 6H), 1.93 (p, J=7.4 Hz, 4H), 1.35 (t, J=7.2 Hz, 3H).

(1102) LCMS; m/z 432.4 (M+H).sup.+ (ES.sup.+).

Example 53: 5-(Azetidin-1-ylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1103) ##STR00375##

(1104) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-(azetidin-1-ylmethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P30) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (88 mg, 54%) as a white solid.

(1105) .sup.1H NMR (DMSO-d.sub.6) δ 10.78 (br s, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.60 (s, 1H), 4.74 (sept, J=6.5 Hz, 1H), 3.66 (s, 2H), 3.18 (t, J=7.1 Hz, 4H), 2.79 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.3 Hz, 4H), 2.03-1.97 (m, 2H), 1.96-1.90 (m, 4H), 1.38 (d, J=6.5 Hz, 6H).

(1106) LCMS; m/z 458.4 (M+H).sup.+ (ES.sup.+).

Example 54: 5-((Dimethylamino)methyl)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1107) ##STR00376##

(1108) 5-((Dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P26; 0.020 g, 0.081 mmol) and N,N-dimethylaminopyridine (0.030 g, 0.244 mmol) were dissolved in dry MeCN (1 mL) at room temperature and stirred for 10 minutes, after which time the mixture had become homogeneous. Diphenyl carbonate (0.019 g, 0.089 mmol) was then added as a solid and the slightly turbid reaction mixture was stirred at room temperature overnight. This was repeated 4 times at different temperatures. The crude reaction mixtures were combined and added to 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A3) (36.4 mg, 0.158 mmol). The mixture was then heated to 70° C. for 2 hours, evaporated to dryness in vacuo and the brown residue obtained triturated with 1:4 EtOAc:DCM (4 mL). The filtrate was then purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (26 mg, 30%) as a white solid.

(1109) .sup.1H NMR (DMSO-d.sub.6) δ 10.91 (br s, 1H), 8.60-8.39 (m, 2H), 7.86 (s, 1H), 7.73 (dt, 1H), 7.36 (ddd, 1H), 7.21 (dd, 1H), 7.07 (dd, 1H), 6.44 (s, 1H), 4.80 (sept, 1H), 3.48 (s, 2H), 3.04-2.93 (m, 1H), 2.15 (s, 6H), 1.38 (d, 6H) and 1.09 (d, 6H).

(1110) LCMS; m/z 503.6 (M+H).sup.+ (ES.sup.+); 501.4 (M−H).sup.− (ES.sup.−).

Example 55: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1111) ##STR00377##

(1112) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-((dimethylamino)methyl)-1-isopropyl-H-pyrazole-3-sulfonamide (Intermediate P26) and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A22) to afford the title compound (n mg, 11%) as a white solid.

(1113) .sup.1H NMR (DMSO-d.sub.6) δ 11.06 (s, 1H), 7.87 (s, 1H), 7.13 (s, 2H), 6.59 (s, 1H), 4.82 (sept, J=6.6 Hz, 1H), 3.48 (s, 2H), 2.95 (sept, J=6.9 Hz, 2H), 2.14 (s, 6H), 1.39 (d, J=6.6 Hz, 6H), 1.05 (br s, 12H).

(1114) LCMS; m/z 484/486 (M+H).sup.+ (ES.sup.+); 482/484 (M−H).sup.− (ES.sup.−).

Example 56: 5-(((2,2-Difluoroethyl)(methyl)amino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1115) ##STR00378##

(1116) Prepare according to the general procedure of 5-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 33) from 5-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P31) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (70 mg, 55%).

(1117) .sup.1H NMR (DMSO-d.sub.6) δ 7.55 (s, 1H), 6.76 (s, 1H), 6.32 (s, 1H), 6.12 (tt, J=55.7, 4.3 Hz, 1H), 4.67 (sept, J=6.7 Hz, 1H), 3.63 (s, 2H), 2.84-2.72 (m, 6H), 2.63 (t, J=7.3 Hz, 4H), 2.25 (s, 3H), 1.88 (p, J=7.4 Hz, 4H), 1.36 (d, J=6.6 Hz, 6H).

(1118) LCMS; m/z 496.5 (M+H).sup.+ (ES.sup.+).

Example 57: 5-(((2-Fluoroethyl)(methyl)amino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1119) ##STR00379##

(1120) Prepared according to the general procedure of 5-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 33) from 5-(((2-fluoroethyl)(methyl)amino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P32) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (42 mg, 33%).

(1121) .sup.1H NMR (DMSO-d.sub.6) δ 7.57 (s, 1H), 6.77 (s, 1H), 6.31 (s, 1H), 4.74-4.65 (m, 1H), 4.52 (dt, J=47.8, 4.8 Hz, 2H), 3.55 (s, 2H), 2.75 (t, J=7.5 Hz, 4H), 2.71-2.60 (m, 6H), 2.19 (s, 3H), 1.89 (p, J=7.4 Hz, 4H), 1.35 (d, J=6.6 Hz, 6H).

(1122) LCMS; m/z 478.5 (M+H).sup.+ (ES.sup.+).

Example 58: 5-(1-(Dimethylamino)cyclopropyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1123) ##STR00380##

(1124) Prepared according to the general procedure of 5-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 33) from 5-(1-(dimethylamino)cyclopropyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P33) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (64 mg, 65%) as a white solid.

(1125) .sup.1H NMR (DMSO-d.sub.6) δ 7.55 (s, 1H), 6.76 (s, 1H), 6.29 (s, 1H), 3.84 (s, 3H), 2.74 (t, J=7.5 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 2.16 (s, 6H), 1.88 (p, J=7.4 Hz, 4H), 1.01-0.92 (m, 2H), 0.88-0.71 (m, 2H).

(1126) LCMS; m/z 444.5 (M+H).sup.+ (ES.sup.+); 442.1 (M−H).sup.− (ES.sup.−).

Example 59: 5-(2-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1127) ##STR00381##

(1128) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(2-(dimethylamino)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P34) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (70 mg, 57%) as a clear glass, which gave a white solid after scratching.

(1129) .sup.1H NMR (DMSO-d.sub.6) δ 7.94 (s, 1H), 6.90 (s, 1H), 6.51 (s, 1H), 3.79 (s, 3H), 2.85 (t, J=7.5 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.71 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.4 Hz, 4H), 2.36 (s, 6H), 1.95 (p, J=7.4 Hz, 4H). NH not observed.

(1130) LCMS; m/z 432.5 (M+H).sup.+ (ES.sup.+).

Example 60: 4-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide

(1131) ##STR00382##

(1132) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 4-(dimethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-sulfonamide (Intermediate P35) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (57 mg, 64%) as a pale tan solid.

(1133) .sup.1H NMR (DMSO-d.sub.6) δ 10.75 (s, 1H), 8.03 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 4.20-4.12 (m, 1H), 4.08-3.98 (m, 1H), 3.93 (dd, J=9.9, 5.3 Hz, 1H), 2.79 (t, J=7.5 Hz, 4H), 2.59 (t, J=7.5, 4H), 2.24 (s, 6H), 2.20-2.11 (m, 1H), 2.02-1.82 (m, 6H), 1.74-1.61 (m, 1H).

(1134) LCMS; m/z 444.5 (M+H).sup.+ (ES.sup.+).

Example 61: 5-((Dimethylamino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1135) ##STR00383##

(1136) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P26) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (35 mg, 36%) as a colourless powder.

(1137) .sup.1H NMR (DMSO-d.sub.6) δ 11.01 (s, 1H), 7.79 (s, 1H), 6.92 (d, J=9.9 Hz, 2H), 6.60 (s, 1H), 4.83 (sept, J=6.5 Hz, 1H), 3.48 (s, 2H), 2.95 (sept, J=7.1 Hz, 2H), 2.14 (s, 6H), 1.39 (d, J=6.5 Hz, 6H), 1.05 (br s, 12H).

(1138) LCMS; m/z 468 (M+H).sup.+ (ES.sup.+); 466 (M−H).sup.− (ES.sup.−).

Example 62: 5-(1-(Dimethylamino)propyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1139) ##STR00384##

(1140) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)propyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P36) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (17 mg, 19%) as a clear colourless crystalline solid.

(1141) .sup.1H NMR (DMSO-d.sub.6) δ 11.00 (s, 1H), 7.77 (s, 1H), 6.91 (d, J=9.9 Hz, 2H), 6.57 (s, 1H), 4.91-4.80 (m, 1H), 3.68 (dd, J=10.0, 4.7 Hz, 1H), 3.03-2.91 (m, 2H), 2.11 (s, 6H), 1.86-1.77 (m, 1H), 1.68-1.59 (m, 1H), 1.41 (d, J=6.5 Hz, 3H), 1.35 (d, J=6.5 Hz, 3H), 1.04 (br s, 12H), 0.75 (t, J=7.3 Hz, 3H).

(1142) LCMS; m/z 496.6 (M+H).sup.+ (ES.sup.+).

Example 63: 5-(1-(Dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1143) ##STR00385##

(1144) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)propyl)-1-isopropyl-H-pyrazole-3-sulfonamide (Intermediate P36) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (11 mg, 13%) as a clear colourless crystalline solid.

(1145) .sup.1H NMR (DMSO-d.sub.6) δ 10.84 (s, 1H), 7.86 (s, 1H), 6.86 (s, 1H), 6.49 (s, 1H), 4.87-4.76 (m, 1H), 3.64 (dd, J=9.8, 4.7 Hz, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.11 (s, 6H), 1.94-1.78 (m, 5H), 1.71-1.56 (m, 1H), 1.39 (d, J=6.5 Hz, 3H), 1.33 (d, J=6.5 Hz, 3H), 0.77 (t, J=7.3 Hz, 3H).

(1146) LCMS; m/z 474.5 (M+H).sup.+ (ES.sup.+).

Example 64: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-5-(1-(dimethylamino)propyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1147) ##STR00386##

(1148) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)propyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P37) and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A22) to afford the title compound (15 mg, 25%) as a colourless glass, which gave a white solid after scratching.

(1149) .sup.1H NMR (DMSO-d.sub.6) δ 10.99 (br s, 1H), 7.85 (s, 1H), 7.12 (s, 2H), 6.58 (s, 1H), 3.88 (s, 3H), 3.65 (dd, J=9.5, 5.1 Hz, 1H), 3.05-2.94 (m, 2H), 2.10 (s, 6H), 1.87-1.74 (m, 1H), 1.69-1.54 (m, 1H), 1.04 (d, J=6.6 Hz, 12H), 0.77 (t, J=7.3 Hz, 3H).

(1150) LCMS; m/z 484.5/486.5 (M+H).sup.+ (ES.sup.+).

Example 65: 5-(1-(Dimethylamino)propyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1151) ##STR00387##

(1152) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)propyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P37) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (18 mg, 32%) as a colourless glass, which gave a white solid after scratching.

(1153) .sup.1H NMR (DMSO-d.sub.6) δ 10-95 (br s, 1H), 7.80 (s, 1H), 6.91 (d, J=9.9 Hz, 2H), 6.59 (s, 1H), 3.89 (s, 3H), 3.65 (dd, J=9.5, 5.1 Hz, 1H), 3.03-2.94 (m, 2H), 2.10 (s, 6H), 1.87-1.75 (m, 1H), 1.69-1.56 (m, 1H), 1.04 (app. br s, 12H), 0.77 (t, J=7.3 Hz, 3H).

(1154) LCMS; m/z 468.5 (M+H).sup.+ (ES.sup.+).

Example 66: 5-((Dimethylamino)methyl)-N-((5-fluoro-3-isopropyl-[1,1′-biphenyl]-2-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1155) ##STR00388##

(1156) Prepared according to the general procedure of N-((5-bromo-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5-((dimethylamino)methyl)-1-ethyl-1H-pyrazole-3-sulfonamide (Example 16) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A4) to afford the title compound (14 mg, 14%) as a colourless solid.

(1157) .sup.1H NMR (DMSO-d.sub.6) δ 10.73 (s, 1H), 7.68 (s, 1H), 7.42-7.30 (m, 3H), 7.31-7.24 (m, 2H), 7.16 (dd, J=10.0, 3.0 Hz, 1H), 6.96 (dd, J=9.0, 3.0 Hz, 1H), 6.54 (s, 1H), 3.90 (s, 3H), 3.50 (s, 2H), 2.99 (sept, J=7.6 Hz, 1H), 2.17 (s, 6H), 1.09 (d, J=6.8 Hz, 6H).

(1158) LCMS; m/z 474 (M+H).sup.+ (ES.sup.+); 472 (M−H).sup.− (ES.sup.−).

Example 67: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methylamino)methyl)-1H-pyrazole-3-sulfonamide

(1159) ##STR00389##

(1160) 2 M sodium tert-butoxide in THF (47.2 μL, 0.094 mmol) was added to a solution of 2,2,2-trifluoro-N-methyl-N-((1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl)acetamide (Intermediate P38) (27 mg, 0.090 mmol) in THF (2 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A11 (20 mg, 0.100 mmol) was added and stirred at room temperature overnight. The volatiles were evaporated. MeOH (0.1 mL) and K.sub.2CO.sub.3 (13 mg, 0.094 mmol) were added and stirred for 16 hours. Volatiles were evaporated and the crude product was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (15 mg, 39%) as a white solid.

(1161) .sup.1H NMR (DMSO-d.sub.6) δ 7.74 (s, 1H), 6.84 (s, 1H), 6.57 (s, 1H), 3.94 (s, 2H), 3.82 (s, 3H), 2.77 (t, J=7.2 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 2.41 (s, 3H), 1.92 (p, J=7.3 Hz, 4H).

(1162) Two exchangeable protons not observed.

(1163) LCMS; m/z 404.5 (M+H).sup.+ (ES.sup.+).

Example 68: 5-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1164) ##STR00390##

(1165) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P26) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (5 mg, 7%) as a white solid.

(1166) .sup.1H NMR (DMSO-d.sub.6) δ 10.90 (s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.59 (s, 1H), 4.85-4.75 (m, 1H), 3.48 (s, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.15 (s, 6H), 1.92 (p, J=7.5 Hz, 4H), 1.38 (d, J=6.5 Hz, 6H).

(1167) LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+).

Example 6A: 5-(1-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Enantiomer 1

(1168) ##STR00391##

(1169) Prepared by chiral separation of 5-(1-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 77) (142.3 mg, 0.330 mmol) by SFC (AmyC (20 mm×250 mm, 5 μm) column, 40° C., 50 mL/min flow rate at 100 BarG isocratic 20:80 MeOH:CO.sub.2 with 90.2 v/v NH.sub.3, monitoring at 210 nm) to give the title compound (35 mg, 24%).

(1170) .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (br s, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.64 (s, 1H), 3.94 (q, J=6.8 Hz, 1H), 3.89 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.13 (s, 6H), 2.01-1.85 (m, 4H), 1.24 (d, J=6.8 Hz, 3H).

(1171) LCMS; m/z 432.5 (M+H).sup.+ (ES.sup.+); 430.4 (M−H).sup.− (ES.sup.−).

Example 70: 5-(1-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Enantiomer 2

(1172) ##STR00392##

(1173) Prepared by chiral separation of 5-(1-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 77) (142.3 mg, 0.330 mmol) by SFC (AmyC (20 mm×250 mm, 5 μm) column, 40° C., 50 mL/min flow rate at 100 BarG isocratic 20:80 MeOH:CO.sub.2 with 90.2 v/v NH.sub.3, monitoring at 210 nm) to give the title compound (29 mg, 20%).

(1174) .sup.1H NMR (DMSO-d.sub.6) δ 10.73 (br s, 1H), 8.01 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 3.95 (q, J=6.8 Hz, 1H), 3.89 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.13 (s, 6H), 2.05-1.83 (m, 4H), 1.25 (d, J=6.8 Hz, 3H).

(1175) LCMS; m/z 432.4 (M+H).sup.+ (ES.sup.+); 430.4 (M−H).sup.− (ES.sup.−).

Example 71: 5-(1-(Dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Enantiomer 1

(1176) ##STR00393##

(1177) Prepared by chiral separation of 5-(1-(dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 74) (68.8 mg, 0.330 mmol) by SFC (AmyC (20 mm×250 mm, 5 μm) column, 40° C., 50 mL/min flow rate at 100 BarG isocratic 20:80 MeOH:CO2 with 90.2 v/v NH.sub.3, monitoring at 210 nm) to give the title compound (20 mg, 29%).

(1178) .sup.1H NMR (DMSO-d.sub.6) δ 10.73 (br s, 1H), 8.02 (s, 1H), 6.92 (s, 1H), 6.66 (s, 1H), 3.90 (s, 3H), 3.70 (dd, J=9.5, 5.1 Hz, 1H), 2.77 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.4 Hz, 4H), 2.13 (s, 6H), 2.00-1.87 (m, 4H), 1.87-1.75 (m, 1H), 1.75-1.53 (m, 1H), 0.78 (t, J=7.3 Hz, 3H).

(1179) LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+); 444.4 (M−H).sup.− (ES.sup.−).

Example 72: 5-(1-(Dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Enantiomer 2

(1180) ##STR00394##

(1181) Prepared by chiral separation of 5-(1-(dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide (Example 74) (68.8 mg, 0.330 mmol) by SFC (AmyC (20 mm×250 mm, 5 μm) column, 40° C., 50 mL/min flow rate at 100 BarG isocratic 20:80 MeOH:CO.sub.2 with 90.2 v/v NH.sub.3, monitoring at 210 nm) to give the title compound (20 mg, 29%).

(1182) .sup.1H NMR (DMSO-d.sub.6) δ 10.73 (br s, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.64 (s, 1H), 3.89 (s, 3H), 0.68 (dd, J=9.4, 5.1 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.12 (s, 6H), 1.99-1.87 (m, 4H), 1.87-1.76 (m, 1H), 1.73-1.58 (m, 1H), 0.78 (t, J=7.3 Hz, 3H).

(1183) LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+); 444.4 (M−H).sup.− (ES.sup.−).

Example 73: 5-(1-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

(1184) ##STR00395##

(1185) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)ethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P39) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (34 mg, 50%) as a colourless solid.

(1186) .sup.1H NMR (DMSO-d.sub.6) δ 10.79 (s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.62 (s, 1H), 4.97-4.82 (m, 1H), 3.99 (q, J=6.7 Hz, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.14 (s, 6H), 1.98-1.85 (m, 4H), 1.43-1.33 (m, 6H), 1.26 (d, J=6.7 Hz, 3H).

(1187) LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+).

Example 74: 5-(1-(Dimethylamino)propyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1188) ##STR00396##

(1189) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)propyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P37) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (77 mg, 62%) as a white solid.

(1190) .sup.1H NMR (DMSO-d.sub.6) δ 10.73 (br s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3.90 (s, 3H), 3.69 (dd, J=9.5, 5.1 Hz, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.13 (s, 6H), 1.98-1.88 (m, 4H), 1.88-1.78 (m, 1H), 1.72-1.59 (m, 1H), 0.78 (t, J=7.3 Hz, 3H).

(1191) LCMS; m/z 446.5 (M+H).sup.+ (ES.sup.+).

Example 75: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-hydroxy-1-methylazetidin-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide

(1192) ##STR00397##

(1193) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(3-hydroxy-1-methylazetidin-3-yl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P40) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (66 mg, 40%) as a white solid.

(1194) .sup.1H NMR (DMSO-d.sub.6) δ 10.75 (br s, 1H), 7.93 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6.43 (s, 1H), 3.87 (d, J=8.1 Hz, 2H), 3.81 (s, 3H), 3.39 (d, J=8.1 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 2.38 (s, 3H), 1.99-1.90 (m, 4H).

(1195) LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+).

Example 76: 5-(1-(Azetidin-1-yl)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1196) ##STR00398##

(1197) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(azetidin-1-yl)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P41) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (40 mg, 10%) as a white solid.

(1198) .sup.1H NMR (DMSO-d.sub.6) δ 10.76 (br s, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.58 (s, 1H), 3.92 (s, 3H), 3.73-3.66 (m, 1H), 3.22-3.05 (m, 6H), 2.78 (t, J=7.5 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 1.98-1.89 (m, 4H), 1.14 (d, J=6.5 Hz, 3H).

(1199) LCMS; m/z 444.5 (M+H).sup.+ (ES.sup.+).

Example 77: 5-(1-(Dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1200) ##STR00399##

(1201) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(1-(dimethylamino)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P42) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (222 mg, 77%) as a white solid.

(1202) .sup.1H NMR (DMSO-d.sub.6) δ 10.73 (br s, 1H), 8.01 (s, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 3.96 (q, J=6.7 Hz, 1H), 3.90 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.14 (s, 6H), 1.93 (p, J=7.4 Hz, 4H), 1.25 (d, J=6.8 Hz, 3H).

(1203) LCMS; m/z 432.5 (M+H).sup.+ (ES.sup.+).

Example 78: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(1204) ##STR00400##

(1205) 1-Methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P43) (35 mg, 0.143 mmol) was dissolved in 2-MeTHF (0.5 mL) and DMF (0.5 mL), and 2 M sodium tert-butoxide in THF (0.079 mL, 0.158 mmol) was added. After 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (31.4 mg, 0.158 mmol) followed by 2-MeTHF (1 mL) was added and the mixture stirred at room temperature for 2 days. EtOAc (3 mL) was added and the mixture stirred for 1 hour. The solvent was removed under reduced pressure and the residue obtained was purified by chromatography on RP Flash C18 (13 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford a white solid (30 mg). The white solid obtained was suspended in EtOAc (1 mL) and 1 molar equivalent of 2 M sodium tert-butoxide in THF was added. The solvent was removed under reduced pressure to give a pale yellow glass. A 1:1 mixture of MTBE: MeCN was added (2 mL) and the reaction mixture was left to settle for 2 hours. The soluble portion was decanted and concentrated to dryness to give the title compound (23 mg, 32%) as a white solid.

(1206) .sup.1H NMR (DMSO-d.sub.6) δ 7.50 (s, 1H), 6.75 (s, 1H), 6.27 (s, 1H), 3.75 (s, 3H), 3.57 (s, 2H), 2.74 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.44-2.37 (i, 4H), 2.02-1.76 (m, 4H), 1.76-1.58 (m, 4H).

(1207) LCMS; m/z 444.5 (M+H).sup.+ (ES.sup.+); 442.3 (M−H).sup.− (ES.sup.−).

Example 79: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1208) ##STR00401##

(1209) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P44) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (28 mg, 40%) as a white solid.

(1210) .sup.1H NMR (DMSO-d.sub.6) δ 10.96 (br s, 1H), 7.82 (s, 1H), 6.92 (d, J=9.9 Hz, 2H), 6.63 (s, 1H), 5.16 (dp, J=5.0, 57.6 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 2H), 3.55 (m, 2H), 3.19 (m, 2H), 2.96 (m, 2H), 1.06 (d, J=12.0 Hz, 12H).

(1211) LCMS; m/z 470.5 (M+H).sup.+ (ES.sup.+); 468.4 (M−H).sup.− (ES.sup.−).

Example 80: 5-((3-Fluoroazetidin-1-yl)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1212) ##STR00402##

(1213) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-((3-fluoroazetidin-1-yl)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P44) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (25 mg, 38%) as a white solid.

(1214) .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (br s, 1H), 8.02 (s, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 5.17 (dp, J=5.0, 57.6 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 2H), 3.55 (m, 2H), 3.20 (m, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.3 Hz, 4H), 1.95 (p, J=7.4 Hz, 4H).

(1215) LCMS; m/z 448.5 (M+H).sup.+ (ES.sup.+); 446.3 (M−H).sup.− (ES.sup.−).

Example 81: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide

(1216) ##STR00403##

(1217) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate P43) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (18 mg, 26%) as a white solid.

(1218) .sup.1H NMR (DMSO-d.sub.6) δ 10.93 (s, 1H), 7.78 (s, 1H), 6.91 (d, J=9.9 Hz, 2H), 6.60 (s, 1H), 3.87 (s, 3H), 3.66 (s, 2H), 3.00-2.92 (m, 2H), 2.44 (br s, 4H), 1.68 (br s, 4H), 1.04 (br s, 12H).

(1219) LCMS; m/z 466.5 (M+H).sup.+ (ES.sup.+); 464.4 (M−H).sup.− (ES.sup.−).

Example 82: 5-((Diethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1220) ##STR00404##

(1221) Sodium tert-butoxide, 2 M in THF (78 μL, 0.156 mmol) was added to a solution of 5-((diethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P45) (35 mg, 0.142 mmol) in 2-MeTHF (2 mL) and stirred for 30 minutes. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (31 mg, 0.156 mmol) was added and the reaction stirred for a further 2 days. The resulting solid was filtered off, washed with EtOAc and dried to afford the title compound (26 mg, 38%) as a white solid.

(1222) .sup.1H NMR (DMSO-d.sub.6) δ 7.52 (s, 1H), 6.77 (s, 1H), 6.29 (s, 1H), 3.77 (s, 3H), 3.52 (s, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.45 (q, J=7.1 Hz, 4H), 1.89 (p, J=7.3 Hz, 4H), 0.97 (t, J=7.1 Hz, 6H).

(1223) LCMS; m/z 446.5 (M+H).sup.+ (ES.sup.+); 444.4 (M−H).sup.− (ES.sup.−).

Example 83: 5-((Diethylamino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium Salt

(1224) ##STR00405##

(1225) Prepared according to the general procedure of 5-((diethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 82) from 5-((diethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P45) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (53 mg, 75%) as a white solid.

(1226) .sup.1H NMR (DMSO-d.sub.6) δ 7.39 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.28 (s, 1H), 3.76 (s, 3H), 3.51 (s, 2H), 3.13 (m, 2H), 2.45 (q, J=7.1 Hz, 4H), 1.03 (d, J=6.8 Hz, 12H), 0.97 (t, J=7.1 Hz, 6H).

(1227) LCMS; m/z m/z 468.5 (M+H).sup.+ (ES.sup.+); 466.3 (M−H).sup.− (ES.sup.−).

Example 84: 5-((Ethyl(methyl)amino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1228) ##STR00406##

(1229) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-((ethyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P46) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (32 mg, 48%) as a white powder.

(1230) .sup.1H NMR (DMSO-d.sub.6) δ 10.75 (s, 1H), 8.01 (s, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 3.88 (s, 3H), 3.56 (s, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.42 (q, J=7.1 Hz, 2H), 2.13 (s, 3H), 1.94 (p, J=7.5 Hz, 4H), 1.02 (t, J=7.1 Hz, 3H).

(1231) LCMS; m/z 432.5 (M+H).sup.+ (ES.sup.+); 430.4 (M−H).sup.− (ES.sup.−).

Example 8t: 5-((Cyclopropyl(methyl)amino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1232) ##STR00407##

(1233) Sodium tert-butoxide, 2 M in THF (79 μL, 0.158 mmol) was added to a solution of 5-((cyclopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P47) (35 mg, 0.143 mmol) in THF (2 mL) and stirred for 30 minutes. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (32 mg, 0.161 mmol) was added and the reaction stirred for a further 2 days. The THF was evaporated in vacuo, the residue dissolved in a mixture of DMF/water/THF and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford a white solid. This solid (32 mg) was dissolved in THF (1 mL), treated with sodium tert-butoxide, 2 M in THF (38 μL, 0.076 mmol) and stirred for 1 hour. The resulting solid was filtered off, washed with EtOAc and dried to afford the title compound (17 mg, 25%) as a white solid.

(1234) .sup.1H NMR (DMSO-d.sub.6) δ 7.52 (s, 1H), 6.76 (s, 1H), 6.30 (s, 1H), 3.72 (s, 3H), 3.63 (s, 2H), 2.75 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.18 (s, 3H), 1.89 (p, J=7.5 Hz, 4H), 1.74-1.68 (m, 1H), 0.44 (m, 2H), 0.32 (m, 2H).

(1235) LCMS; m/z 444.4 (M+H).sup.+ (ES.sup.+); 442.1 (M−H).sup.− (ES.sup.−).

Example 86: 5-(Azetidin-1-ylmethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1236) ##STR00408##

(1237) Prepared according to the general procedure of 5-((cyclopropyl(methyl)amino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 85) from 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P48) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (15 mg, 21%) as a white powder.

(1238) .sup.1H NMR (DMSO-d.sub.6) δ 7.52 (s, 1H), 6.77 (s, 1H), 6.26 (s, 1H), 3.73 (s, 3H), 3.50 (s, 2H), 3.12 (t, J=7.0 Hz, 4H), 2.75 (t, J=7.3 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.97 (m, 2H), 1.90 (p, J=7.4 Hz, 4H).

(1239) LCMS; m/z 430.5 (M+H).sup.+ (ES.sup.+); 428.0 (M−H).sup.− (ES.sup.−).

Example 87: 5-((Cyclopropyl(methyl)amino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium Salt

(1240) ##STR00409##

(1241) Sodium tert-butoxide, 2 M in THF (79 μL, 0.158 mmol) was added to a solution of 5-((cyclopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P47) (35 mg, 0.143 mmol) in THF (2 mL) and stirred for 30 minutes. Then 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) (35 mg, 0.158 mmol) was added and the reaction stirred for a further 2 days. The resulting solid was filtered off, washed with EtOAc and dried to afford the title compound (47 mg, 67%) as a white solid.

(1242) .sup.1H NMR (DMSO-d.sub.6) δ 7.38 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.28 (s, 1H), 3.70 (s, 3H), 3.63 (s, 2H), 3.13 (m, 2H), 2.18 (s, 3H), 1.74-1.69 (m, 1H), 1.03 (d, J=6.8 Hz, 12H), 0.45 (m, 2H), 0.33 (m, 2H).

(1243) LCMS; m/z m/z 466.5 (M+H).sup.+ (ES.sup.+); 464.4 (M−H).sup.− (ES.sup.−).

Example 88: 5-(Azetidin-1-ylmethyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1244) ##STR00410##

(1245) Prepared according to the general procedure of 5-((cyclopropyl(methyl)amino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 87) from 5-(azetidin-1-ylmethyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P48) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (46 mg, 63%) as a white solid.

(1246) .sup.1H NMR (DMSO-d.sub.6) δ 7.38 (s, 1H), 6.79 (d, J=10.2 Hz, 2H), 6.25 (s, 1H), 3.72 (s, 3H), 3.50 (s, 2H), 3.14 (m, 2H), 3.12 (t, J=7.0 Hz, 4H), 2.03-1.91 (m, 2H), 1.03 (d, J=6.8 Hz, 12H).

(1247) LCMS; m/z 452.5 (M+H).sup.+ (ES.sup.+); 450.4 (M−H).sup.− (ES.sup.−).

Example 89: 5-((Ethyl(methyl)amino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium Salt

(1248) ##STR00411##

(1249) Prepare according to the general procedure of 5-((cyclopropyl(methyl)amino)methyl-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 87) from 5-((ethyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P46) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (39 mg, 54%) as a white solid.

(1250) .sup.1H NMR (DMSO-d.sub.6) δ 7.39 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.27 (s, 1H), 3.75 (s, 3H), 3.44 (s, 2H), 3.13 (m, 2H), 2.38 (q, J=7.2 Hz, 2H), 2.11 (s, 3H), 1.11-0.95 (m, 15H).

(1251) LCMS; m/z 454.5 (M+H).sup.+ (ES.sup.+); 452.4 (M−H).sup.− (ES.sup.−).

Example 90: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-((isopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium Salt

(1252) ##STR00412##

(1253) Prepared according to the general procedure of 5-((cyclopropyl(methyl)amino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 87) from 5-((isopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P49) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (45 mg, 64%) as a white solid.

(1254) .sup.1H NMR (DMSO-d.sub.6) δ 7.39 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.27 (s, 1H), 3.75 (s, 3H), 3.48 (s, 2H), 3.13 (m, 2H), 2.83 (sept, J=6.6 Hz, 1H), 2.05 (s, 3H), 1.03 (d, J=6.8 Hz, 12H), 1.00 (d, J=6.6 Hz, 6H).

(1255) LCMS; m/z 468.5 (M+H).sup.+ (ES.sup.+); 466.4 (M−H).sup.− (ES.sup.−).

Example 1: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-((isopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1256) ##STR00413##

(1257) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from 5-((isopropyl(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P49) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (33 mg, 51%) as a white solid.

(1258) .sup.1H NMR (DMSO-d.sub.6) δ 10.65 (bs, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.62 (s, 1H), 3.86 (s, 3H), 3.58 (s, 2H), 2.85 (m, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 2.06 (s, 3H), 1.94 (p, J=7.5 Hz, 4H), 1.01 (d, J=6.6 Hz, 6H).

(1259) LCMS; m/z 446.5 (M+H).sup.+ (ES.sup.+); 444.4 (M−H).sup.− (ES.sup.−).

Example 92: 5-((Dimethylamino)methyl)-N-((4-fluoro-2,6-diisopropyl-phenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1260) ##STR00414##

(1261) Prepared according to the general procedure of 5-((cyclopropyl(methyl)amino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 87) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (41 mg, 55%) as a white solid.

(1262) .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (s, 1H), 6.78 (d, J=10.1 Hz, 2H), 6.26 (s, 1H), 3.74 (s, 3H), 3.37 (s, 2H), 3.12 (m, 2H), 2.13 (s, 6H), 1.01 (d, J=6.9 Hz, 12H).

(1263) LCMS; m/z 440.4 (M+H).sup.+ (ES.sup.+); 438.4 (M−H).sup.− (ES.sup.−).

Example 93: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-5-((dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1264) ##STR00415##

(1265) Prepared according to the general procedure of 5-((cyclopropyl(methyl)amino)methyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 87) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A22) to afford the title compound (43 mg, 64%) as a white solid.

(1266) .sup.1H NMR (DMSO-d.sub.6) δ 7.46 (s, 1H), 7.01 (s, 2H), 6.27 (s, 1H), 3.75 (s, 3H), 3.38 (s, 2H), 3.13 (m, 2H), 2.14 (s, 6H), 1.03 (d, J=6.8 Hz, 12H).

(1267) LCMS; m/z 456.4/458.4 (M+H).sup.+ (ES.sup.+); 454.3/456.3 (M−H).sup.− (ES.sup.−).

Example 94: 5-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1268) ##STR00416##

(1269) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P16) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (38 mg, 66%) as a white solid.

(1270) .sup.1H NMR (DMSO-d.sub.6) δ 10.74 (br s, 1H), 7.99 (s, 1H), 6.93 (s, 1H), 6.65 (s, 1H), 3.88 (s, 3H), 3.49 (s, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.17 (s, 6H), 1.94 (quin, J=7.4 Hz, 4H).

(1271) LCMS; m/z 418.45 (M+H).sup.+ (ES.sup.+); 416.36 (M−H).sup.− (ES.sup.−).

Example 95: 5-(˜(Dimethylamino)-2,2,2-trifluoroethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1272) ##STR00417##

(1273) Sodium tert-butoxide, 2 M in THF (0.147 mL, 0.293 mmol) was added to a solution of 5-(1-(dimethylamino)-2,2,2-trifluoroethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P59) (80 mg, 0.279 mmol) in THF (1 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (61.2 mg, 0.307 mmol) in THF (1 mL) was added and stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate), followed by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (9 mg, 7%) as a colourless solid.

(1274) .sup.1H NMR (DMSO-d.sub.6) δ 10.87 (s, 1H), 8.02 (s, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 5.14 (q, J=8.4 Hz, 1H), 3.92 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.55 (t, J=7.4 Hz, 4H), 2.34 (s, 6H), 1.99-1.83 (m, 4H).

(1275) LCMS; m/z 486.3 (M+H).sup.+ (ES.sup.+).

Example 96: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide

(1276) ##STR00418##

(1277) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 1-isopropyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P60) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (17 mg, 76%) as a white solid.

(1278) .sup.1H NMR (DMSO-d.sub.6) δ 1.86 (s, 1H), 8.00 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 4.81-4.75 (m, 1H), 3.82 (s, 2H), 3.31-3.26 (m, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.57 (t, J=7.4 Hz, 4H), 2.30 (s, 3H), 1.92 (p, J=7.5 Hz, 4H), 1.39 (d, J=6.5 Hz, 6H).

(1279) LCMS; m/z 514.4 (M+H).sup.+ (ES.sup.+).

Example 97: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(1280) ##STR00419##

(1281) Sodium tert-butoxide, 2 M in THF (136 μL, 0.271 mmol) was added to a solution of 1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P61) (74 mg, 0.258 mmol) in THF (5 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (57 mg, 0.286 mmol) was added and stirred at room temperature overnight. The suspension was filtered and the collected solid washed with EtOAc (2 mL). The solid was dissolved in MeCN and then dried under vacuum to afford the title compound (110 mg, 83%).

(1282) .sup.1H NMR (DMSO-d.sub.6) δ 7.54 (s, 1H), 6.77 (s, 1H), 6.36 (s, 1H), 3.77 (s, 3H), 3.73 (s, 2H), 3.25 (q, J=10.1 Hz, 2H), 2.75 (t, J=7.3 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 2.32 (s, 3H), 1.89 (p, J=7.4 Hz, 4H).

(1283) LCMS; m/z 486.5 (M+H).sup.+ (ES.sup.+).

Example 98: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(2-(N-methylacetamido)ethyl)-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1284) ##STR00420##

(1285) Prepared according to the general procedure of N-(3-(dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 10) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methyl-N-(2-(methylamino)ethyl)acetamide to afford the title compound (38 mg, 47%) as a white solid.

(1286) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.98 (br s, 1H), 7.90 (br s, 1H), 6.94-6.74 (m, 2H), 3.92-3.77 (m, 3H), 3.65-3.37 (m, 4H), 3.08-2.51 (m, 14H), 2.04-1.76 (m, 7H).

(1287) LCMS; m/z 517.4 (M+H).sup.+ (ES.sup.+); 515.3 (M−H).sup.− (ES.sup.−).

Example 99: N-(2-Acetamidoethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1288) ##STR00421##

(1289) Prepared according to the general procedure of N-(3-(dimethylamino)propyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 10) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-(2-(methylamino)ethyl)acetamide, HCl (34 mg, 0.223 mmol) to afford the title compound (26 mg, 33%) as a white solid.

(1290) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.94 (br s, 1H), 8.32-7.69 (m, 2H), 6.94-6.74 (m, 2H), 3.92-3.78 (m, 3H), 3.54-3.36 (m, 2H), 3.31-3.12 (m, 2H), 3.08-2.93 (m, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.5 Hz, 4H), 1.81-1.62 (m, 3H).

(1291) LCMS; m/z 503.5 (M+H).sup.+ (ES.sup.+); 501.3 (M−H).sup.− (ES.sup.−).

Example 100: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide, sodium salt

(1292) ##STR00422##

(1293) HATU (49.3 mg, 0.130 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (67.3 mg, 0.150 mmol) and N-methyltetrahydro-2H-pyran-4-amine (14.93 mg, 0.130 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxamide. The solid was dissolved in THF (2 mL) and 2 M sodium tert-butoxide in THF (54.0 μL, 0.108 mmol) was added. The suspension was stirred at room temperature for 2 hours and filtered. The collected solid was washed with EtOAc (2 mL) and dried under reduced pressure for 6 hours to afford the title compound (46 mg, 80%) as a white solid.

(1294) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.47 (s, 1H), 6.77 (s, 1H), 6.58 (s, 1H), 4.53-4.49 (m, 0.6H), 3.94-3.90 (m, 2.4H), 3.80 (s, 3H), 3.43-3.41 (m, 1H), 3.16-3.12 (m, 1H), 2.89 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.66 (t, J=7.6 Hz, 4H), 1.93-1.80 (m, 6H), 1.59-1.55 (m, 2H).

(1295) LCMS; m/z 502 (M+H).sup.+ (ES.sup.+).

Example 101: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1296) ##STR00423##

(1297) HATU (67.9 mg, 0.178 mmol) was added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (66.7 mg, 0.149 mmol) and 2,2′-azanediylbis(ethan-1-ol) (17.11 μL, 0.178 mmol) in DMF (1 mL) and the reaction mixture was stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the reaction mixture was stirred for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (32 mg, 42%) as a white solid.

(1298) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.60 (d, J=10.0 Hz, 1H), 7.24 (br s, 1H), 6.80 (s, 1H), 6.69 (s, 1H), 4.95-4.77 (m, 2H), 3.78 (s, 3H), 3.78-3.52 (m, 8H), 2.76 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.6 Hz, 4H), 1.95-1.88 (m, 4H).

(1299) LCMS; m/z 492 (M+H).sup.+ (ES.sup.+).

Example 102: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1300) ##STR00424##

(1301) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 101) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and 2-((2-methoxyethyl)amino)ethan-1-ol to afford the title compound as a white solid (7 mg, 9%).

(1302) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.61 (s, 1H), 7.11 (br s, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 4.89-4.82 (m, 1H), 3.78 (s, 3H), 3.67-3.36 (m, 8H), 3.28-3.15 (2×2s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.95-1.88 (m, 4H).

(1303) LCMS; m/z 506 (M+H).sup.+ (ES.sup.+).

Example 103: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(oxetan-3-yl)-1H-pyrazole-5-carboxamide

(1304) ##STR00425##

(1305) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,N-bis(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 101) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and N-methyloxetan-3-amine to afford the title compound (27 mg, 36%) as a white solid.

(1306) .sup.1H NMR (DMSO-d.sub.6) rotamers: δ 10.95 (br s, 1H), 8.09 (s, 1H), 7.11 (s, 0.5H), 6.95 (s, 1H), 6.89 (s, 0.5H), 5.25-5.22 (m, 0.5H), 5.06-5.03 (m, 0.5H), 4.69-4.60 (m, 4H), 3.92 (s, 3H), 3.19-3.06 (m, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.5 Hz, 4H), 2.00-1.92 (m, 4H).

(1307) LCMS; m/z 474 (M+H).sup.+ (ES.sup.+).

Example 104: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1308) ##STR00426##

(1309) 3-(Methylamino)propan-1-ol (19 μL, 0.195 mmol), NaHCO.sub.3 (16 mg, 0.190 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 2 days. The reaction was quenched with water (1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (37 mg, 48%) as a white solid.

(1310) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.81 (s, 1H), 7.61-6.99 (br s, 1H), 6.85 (s, 1H), 6.82-6.71 (m, 1H), 4.48 (br s, 1H), 3.94-3.78 (m, 3H), 3.59-3.13 (m, 4H), 3.07-2.90 (m, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.4 Hz, 4H), 1.92 (p, J=7.4 Hz, 4H), 1.79-1.57 (m, 2H).

(1311) LCMS; m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.4 (M−H).sup.− (ES.sup.−).

Example 105: N-(2,3-Dihydroxypropyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1312) ##STR00427##

(1313) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 104) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and 3-(methylamino)propane-1,2-diol to afford the title compound (43 mg, 54%) as a white solid.

(1314) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.83-7.64 (m, 1H), 7.61-7.01 (m, 1H), 6.87-6.80 (m, 1H), 6.78-6.71 (m, 1H), 5.13-4.99 (m, 1H), 4.96-4.84 (m, 1H), 4.62 (s, 1H), 3.90-3.73 (m, 3H), 3.71-3.09 (m, 5H), 3.07 (s, 1H), 2.98 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 2.07-1.79 (m, 4H).

(1315) LCMS; m/z 492.4 (M+H).sup.+ (ES.sup.+); 490.2 (M−H).sup.− (ES.sup.−).

Example 106: N-Ethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1316) ##STR00428##

(1317) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 104) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and 2-(ethylamino)ethan-1-ol to afford the title compound (39 mg, 52%) as a white solid.

(1318) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 8.16-6.99 (br s, 1H), 7.82 & 7.80 (2×s, 1H), 6.86 (s, 1H), 6.79 & 6.74 (2×s, 1H), 4.93 & 4.82 (2×m, 1H), 3.82 (s, 3H), 3.65-3.33 (m, 6H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.93 (quin, J=7.4 Hz, 4H), 1.15 & 1.08 (2×t, J=7.1 Hz, 3H).

(1319) LCMS; m/z 476.5 (M+H).sup.+ (ES.sup.+); 474.3 (M−H).sup.− (ES.sup.−).

Example 107: N-((2,6-Diisopropylphenyl)carbamoyl)-1-methyl-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide

(1320) ##STR00429##

(1321) Morpholine (19 μL, 0.220 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (41 mg, 53%) as a white solid.

(1322) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (br s, 1H), 7.79 (s, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.7 Hz, 2H), 6.91 (s, 1H), 3.93 (s, 3H), 3.72-3.39 (m, 8H), 2.98 (sept, J=6.9 Hz, 2H), 1.05 (d, J=6.8 Hz, 12H).

(1323) LCMS; m/z 478.4 (M+H).sup.+ (ES.sup.+); 476.4 (M−H).sup.− (ES.sup.−).

Example 108: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1324) ##STR00430##

(1325) HATU (66.5 mg, 0.175 mmol) was added to a solution of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) (65.9 mg, 0.146 mmol) and 2-methoxy-N-methylethanamine (19.00 μL, 0.175 mmol) in DMF (1 mL) and the mixture stirred at room temperature for hours. Water (1 mL) was slowly added and the reaction mixture was stirred at room temperature for 1 hour. The suspension was filtered and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered and the collected solid was washed with water (0.5 mL) and TBME (1 mL). The solid was dried under reduced pressure for 6 hours to afford the title compound (18 mg, 25%) as a white solid.

(1326) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (s, 1H), 8.00-7.72 (m, 1H), 7.28-7.20 (m, 1H), 7.15-7.09 (m, 2H), 7.02-6.86 (m, 1H), 3.93 (s, 1H), 3.86 (s, 2H), 3.66-3.57 (m, 1H), 3.57-3.45 (m, 2H), 3.44-3.37 (m, 1H), 3.27 (s, 1H), 3.16 (s, 2H), 3.03-2.87 (m, 4H), 1.17-0.77 (m, 12H).

(1327) LCMS; m/z 480 (M+H).sup.+ (ES.sup.+).

Example 100: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N— bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

(1328) ##STR00431##

(1329) Prepared according to the general procedure of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 108) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and bis(2-methoxyethyl)amine to afford the title compound (22 mg, 23%) as a white solid.

(1330) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (s, 1H), 7.91 (s, 1H), 7.31-7.18 (m, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 3.86 (s, 3H), 3.66-3.58 (m, 2H), 3.56-3.47 (m, 4H), 3.43-3.35 (m, 2H), 3.27 (s, 3H), 3.14 (s, 3H), 2.94 (sept, J=6.8 Hz, 2H), 1.18-0.87 (m, 12H).

(1331) LCMS; m/z 524 (M+H).sup.+ (ES.sup.+).

Example 110: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(4-hydroxypiperidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, Partial ammonium Salt

(1332) ##STR00432##

(1333) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 104) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and piperidin-4-ol to afford the title compound (44 mg, 57%) as a white solid.

(1334) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.88 (s, 1H), 7.48-6.92 (m, 1H), 6.88 (s, 1H), 6.78 (s, 1H), 4.83 (d, J=3.9 Hz, 1H), 3.96 (m, 1H), 3.87 (s, 3H), 3.77 (m, 1H), 3.63 (m, 1H), 3.32 (m, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (quin, J=7.5 Hz, 4H), 1.77 (m, 2H), 1.39 m, 2H).

(1335) LCMS; m/z 488.4 (M+H).sup.+ (ES.sup.+); 486.3 (M−H).sup.− (ES.sup.−).

Example 11: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, Partial ammonium Salt

(1336) ##STR00433##

(1337) 3-Methoxypyrrolidine (19 mg, 0.188 mmol) and HATU (72 mg, 0.189 mmol) were successively added to a suspension of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) (70 mg, 0.156 mmol) in DMF (1 mL) and stirred for 20 hours. The solution was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (25 mg, 32%) as a white solid.

(1338) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.82 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=2.6 Hz, 1H), 6.86 (s, 1H), 4.07-3.90 (m, 4H), 3.75-3.67 (m, 1H), 3.64-3.39 (m, 4H), 3.26 (s, 1H), 3.19 (s, 1H), 2.76 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.06-1.84 (m, 6H).

(1339) LCMS; m/z 488.43 (M+H).sup.+ (ES.sup.+); 48635 (M−H).sup.− (ES.sup.−).

Example 112: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1340) ##STR00434##

(1341) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(3-methoxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, partial ammonium salt (Example 111) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and bis(2-methoxyethyl)amine to afford the title compound (36 mg, 44%) as a white solid.

(1342) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.79 (s, 1H), 7.10 (br s, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.63 (t, J=5.8 Hz, 2H), 3.58-3.49 (m, 4H), 3.39 (t, J=5.0 Hz, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.3 Hz, 4H), 1.92 (quin, J=7.5 Hz, 4H).

(1343) LCMS; m/z 520.44 (M+H).sup.+ (ES.sup.+); 518.30 (M−H).sup.− (ES.sup.−).

Example 113: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, sodium Salt

(1344) ##STR00435##

(1345) 2-Methoxy-N-methylethanamine (19 μL, 0.173 mmol), HATU (71 mg, 0.187 mmol) and Hunig's base (65 μL, 0.372 mmol) were successively added to a solution of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P51) (50 mg, 0.124 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (1 mL) and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford crude product. 18 mg of the crude product were partitioned between TBME (1 mL) and 0.1 M aqueous NaHCO.sub.3 (340 μL, 0.034 mmol). The layers were separated and the aqueous layer washed with further TBME (2×1 mL). The aqueous layer was evaporated in vacuo and dried to afford the title compound (17 mg, 27%) as a white solid.

(1346) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.52 (s, 1H), 6.77 (s, 1H), 6.6 & 6.55 (2×s, 1H), 3.81 & 3.76 (2×s, 3H), 3.61 (m, 1H), 3.56 (m, 2H), 3.4 (m, 1H), 3.28 & 3.16 (2×s, 3H), 3.05 & 2.97 (2×s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.89 (quin, J=7.5 Hz, 4H).

(1347) LCMS; m/z 476.4 (M+H).sup.+ (ES.sup.+); 474.3 (M−H).sup.− (ES.sup.−).

Example 14: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(morpholine-4-carbonyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(1348) ##STR00436##

(1349) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 113) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid disodium salt (Intermediate P53) and morpholine to afford the title compound (12 mg, 16%) as a white solid.

(1350) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.54 (s, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.76-3.43 (m, 8H), 2.75 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.3 Hz, 4H), 1.90 (quin, J=7.5 Hz, 4H).

(1351) LCMS; m/z 474.4 (M+H).sup.+ (ES.sup.+); 472.3 (M−H).sup.− (ES.sup.−).

Example 115: 5-(3-(Dimethylamino)oxetan-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1352) ##STR00437##

(1353) 5-(3-(Dimethylamino)oxetan-3-yl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P62) (65 mg, 0.21 mmol) was dissolved in 4:1 THF:DMF (2.5 mL) and sodium tert-butoxide (2 M in THF; 0.117 mL, 0.233 mmol) was added. After 1 hour, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (46.5 mg, 0.233 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on reversed phase flash chromatography C18 (12 g column, 10-40% MeCN/10 mM ammonium bicarbonate) to afford the title compound (20 mg, 20%) as a white solid.

(1354) .sup.1H NMR (DMSO-d.sub.6) δ 1.82 (br s, 1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 4.95 (d, J=7.2 Hz, 2H), 4.76 (d, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.58 (t, J=7.4 Hz, 4H), 2.21 (s, 6H), 1.93 (p, J=7.4 Hz, 4H).

(1355) LCMS; m/z 460.3 (M+H).sup.+ (ES.sup.+); 458.2 (M−H).sup.− (ES.sup.−).

Example 16: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1356) ##STR00438##

(1357) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P63) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (28 mg, 32%) as a white solid.

(1358) .sup.1H NMR (DMSO-d.sub.6) δ 10.97 (br s, 1H), 7.82 (s, 1H), 6.93 (d, J=9.9 Hz, 2H), 6.64 (s, 1H), 4.48 (t, J=5.3 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.97 (m, 2H), 2.46 (t, J=6.1 Hz, 2H), 2.15 (s, 3H), 1.06 (br s, 12H).

(1359) LCMS; m/z 470.5 (M+H).sup.+ (ES.sup.+); 468.2 (M−H).sup.− (ES.sup.−).

Example 17: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1360) ##STR00439##

(1361) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(((2-hydroxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P63) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (22 mg, 27%) as a white solid.

(1362) .sup.1H NMR (DMSO-d.sub.6) δ 10.71 (br s, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.61 (s, 1H), 4.47 (t, J=5.3 Hz, 1H), 3.88 (s, 3H), 3.59 (s, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.46 (t, J=6.1 Hz, 2H), 2.15 (s, 3H), 1.94 (p, J=7.5 Hz, 4H).

(1363) LCMS; m/z 448.5 (M+H).sup.+ (ES.sup.+); 446.1 (M−H).sup.− (ES.sup.−).

Example 118: N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1364) ##STR00440##

(1365) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 97) from 5-(((2-methoxyethyl)(methyl)amino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P64) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (22 mg, 39%) as a white solid.

(1366) .sup.1H NMR (DMSO-d.sub.6) δ 7.37 (s, 1H), 6.79 (d, J=10.0 Hz, 2H), 6.27 (s, 1H), 3.76 (s, 3H), 3.50 (s, 2H), 3.45 (t, J=5.8 Hz, 2H), 3.23 (s, 3H), 3.14 (m, 2H), 2.51 (t, J=5.8 Hz, 2H), 2.15 (s, 3H), 1.03 (d, J=6.8 Hz, 12H).

(1367) LCMS; m/z 484.5 (M+H).sup.+ (ES.sup.+); 482.3 (M−H).sup.− (ES.sup.−).

Example 119: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1368) ##STR00441##

(1369) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 97) from 5-(((2-methoxyethyl)(methyl)amino) methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P64) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (32 mg, 47%) as a white solid.

(1370) .sup.1H NMR (DMSO-d.sub.6) δ 7.59 (m, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.79 (s, 3H), 3.52 (s, 2H), 3.44 (t, J=5.8 Hz, 2H), 3.23 (s, 3H), 2.75 (t, J=7.3 Hz, 4H), 2.64 (t, J=7.4 Hz, 4H), 2.51 (t, J=5.8 Hz, 2H), 2.16 (s, 3H), 1.90 (p, J=7.5 Hz, 4H).

(1371) LCMS; m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.4 (M−H).sup.− (ES.sup.−).

Example 120: N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl)-1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

(1372) ##STR00442##

(1373) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 97) from 1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide (Intermediate P65) and 5-chloro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A22) to afford the title compound (38 mg, 53%) as a white solid.

(1374) .sup.1H NMR (DMSO-d.sub.6) δ 7.45 (s, 1H), 7.01 (s, 2H), 6.28 (s, 1H), 3.77 (s, 3H), 3.56 (t, J=4.6 Hz, 4H), 3.48 (s, 2H), 3.13 (m, 2H), 2.36 (t, J=4.6 Hz, 4H), 1.03 (d, J=6.8 Hz, 12H).

(1375) LCMS; m/z 498.4/500.5 (M+H).sup.+ (ES.sup.+); 496.3/498.4 (M−H).sup.− (ES.sup.−).

Example 121: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide

(1376) ##STR00443##

(1377) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 97) from 1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-sulfonamide (Intermediate P65) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (12 mg, 18%) as a white solid.

(1378) .sup.1H NMR (DMSO-d.sub.6) δ 10.81 (br s, 1H), 7.96 (s, 1H), 6.91 (s, 1H), 6.62 (s, 1H), 3.88 (s, 3H), 3.56 (s, 2H), 3.56 (m, 4H), 2.78 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 2.36 (m, 4H), 1.93 (p, J=7.5 Hz, 4H).

(1379) LCMS; m/z 460.4 (M+H).sup.+ (ES.sup.+); 458.4 (M−H).sup.− (ES.sup.−).

Example 122: N-((3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-isopropyl-1H-pyrazol-5-yl)methyl)-N-methylacetamide

(1380) ##STR00444##

(1381) Prepared according to the general procedure of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((1-isopropyl-5-(1-(trimethylammonio)ethyl)-1H-pyrazol-3-yl)sulfonyl)amide (Example 18) from N-((1-isopropyl-3-sulfamoyl-H-pyrazol-5-yl)methyl)-N-methylacetamide (Intermediate P68) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (20 mg, 38%) as a white solid.

(1382) .sup.1H NMR (DMSO-d.sub.6) δ 10.77 (br s, 1H), 7.93 (s, 1H), 6.88 (s, 1H), 6.62 (s, 1H), 4.75-4.61 (m, 1H), 4.59 (s, 2H), 2.90 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.56 (t, J=7.3 Hz, 4H), 2.02 (s, 3H), 1.90 (p, J=7.6 Hz, 4H), 1.31 (d, J=6.5 Hz, 6H).

(1383) LCMS; m/z 474.5 (M+H).sup.+ (ES.sup.+)

Example 123: 5-(Azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1384) ##STR00445##

(1385) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-((methyl(2,2,2-trifluoroethyl)amino)methyl)-1H-pyrazole-3-sulfonamide, sodium salt (Example 97) from 5-(azetidine-1-carbonyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate P57) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (46 mg, 48%) as a white solid.

(1386) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.65 (s, 1H), 5.26 (sept, J=6.7 Hz, 1H), 4.25 (t, J=7.7 Hz, 2H), 4.02 (t, J=7.8 Hz, 2H), 3.22-2.93 (m, 2H), 2.26 (app. pent, J=7.7 Hz, 2H), 1.37 (d, J=6.6 Hz, 6H), 1.03 (d, J=6.8 Hz, 12H).

(1387) LCMS; m/z 494.4 (M+H).sup.+ (ES.sup.+); 492.3 (M−H).sup.− (ES.sup.−)

Example 124: 5-(Azetidine-1-carbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, Partial ammonium Salt

(1388) ##STR00446##

(1389) Prepared according to the general procedure of 5-(azetidin-1-ylmethyl)-1-cyclopropyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide (Example 30) from 5-(azetidine-1-carbonyl)-1-isopropyl-H-pyrazole-3-sulfonamide (Intermediate P57) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (47 mg, 53%) as a white solid.

(1390) .sup.1H NMR (DMSO-d.sub.6) δ 7.77 (s, 1H), 6.92-6.68 (m, 2H), 5.28 (sept, J=6.5 Hz, 1H), 4.27 (t, J=7.7 Hz, 2H), 4.03 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.3 Hz, 4H), 2.31-2.19 (m, 2H), 1.90 (p, J=7.4 Hz, 4H), 1.38 (d, J=6.6 Hz, 6H).

(1391) LCMS; m/z 472.5 (M+H).sup.+ (ES.sup.+); 470.3 (M−H).sup.− (ES.sup.−).

Example 125: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1392) ##STR00447##

(1393) HATU (68.8 mg, 0.181 mmol) was added to a solution of 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P56) (73.4 mg, 0.151 mmol) and methylamine (83 μL, 0.166 mmol) in DMF (1 mL). TEA (21 μL, 0.151 mmol) was added and the mixture stirred at room temperature for 20 hours. Water (1 mL) was slowly added and the mixture stirred for 1 hour, filtered, and the collected solid triturated in water (3 mL) for 0.5 hour. The suspension was filtered, the solid washed with water (0.5 mL) and MTBE (1 mL), and then purified by chromatography on RP Flash C18 (13 g column, 0-50% MeCN/10 mM ammonium bicarbonate). The product was triturated with MTBE (2 mL) for 1 hour, filtered and dried under vacuum for 15 hours to afford the title compound (7 mg, 10%) as a white solid.

(1394) .sup.1H NMR (DMSO-d.sub.6) δ 11.21 (s, 1H), 8.64 (s, 1H), 7.89 (s, 1H), 7.31 (s, 1H), 7.12 (s, 2H), 4.13 (s, 3H), 3.00-2.90 (m, 2H), 2.74 (d, J=4.5 Hz, 3H), 1.05-1.01 (m, 12H).

(1395) LCMS; m/z 456.4 and 458.4 (M+H).sup.+ (ES.sup.+).

Example 126: 3-(N-((4-Fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1396) ##STR00448##

(1397) A mixture of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) (70 mg, 0.184 mmol) and 4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)aniline (Intermediate A15) (40 mg, 0.167 mmol) in MeCN (1 mL) was stirred at 50° C. for 1 hour. The crude product was purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the desired carboxamide as a white solid (21 mg). To a solution of the carboxamide (21 mg) in THF (0.5 mL), a solution of 2.0 M NaO.sup.tBu in THF (1.0 eq) was added. The mixture was stirred for 1 hour, the solvent evaporated and the solid triturated with THF/MTBE. The precipitate was collected by filtration, washing with ether, and dried in vacuo to afford the title compound (5 mg, 6%) as a white solid.

(1398) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.39 (s, 1H), 6.81 (td, J=10.6, 2.9 Hz, 2H), 6.61 (s, 1H), 3.90-3.81 (m, 5H), 3.28-3.11 (m, 3H), 3.04-2.97 (m, 7H), 1.57-1.43 (m, 4H), 1.04 (d, J=6.8 Hz, 6H).

(1399) LCMS; m/z 496.5 (M+H).sup.+ (ES.sup.+); 494.3 (M−H).sup.− (ES.sup.−).

Example 127: 3-(N-((2-Isopropyl-5-(pyrimidin-5-yl)phenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1400) ##STR00449##

(1401) Prepare according to the general procedure or 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 126) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) and 2-isopropyl-5-(pyrimidin-5-yl)aniline (Intermediate A17) to afford the title compound (27 mg, 23%) as a white solid.

(1402) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 9.15 (s, 1H), 9.01 (s, 2H), 8.14 (s, 1H), 7.77 (s, 1H), 7.31 (s, 2H), 6.63 (s, 1H), 3.82 (s, 3H), 3.19 (sept, J=6.8 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1.17 (d, J=6.8 Hz, 6H).

(1403) LCMS; m/z 472.4 (M+H).sup.+ (ES.sup.+); 470.4 (M−H).sup.− (ES.sup.−).

Example 128: 3-(N-((4-Fluoro-2-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1404) ##STR00450##

(1405) Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 126) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) and 4-fluoro-2-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A10) to afford the title compound (40 mg, 20%) as a white solid.

(1406) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.95 (s, 1H), 7.76 (s, 1H), 7.25 (s, 1H), 7.10 (dd, J=9.9, 3.0 Hz, 1H), 6.86 (dd, J=9.8, 2.9 Hz, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.20 (m, 1H), 2.99 (s, 6H), 1.06 (d, J=6.8 Hz, 6H).

(1407) LCMS; m/z 492.4 (M+H).sup.+ (ES.sup.+); 490.3 (M−H).sup.− (ES.sup.−).

Example 120: 3-(N-((2-Isopropyl-5-(1-methyl-1H-pyrazol-4-yl)phenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1408) ##STR00451##

(1409) Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 126) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) and 2-isopropyl-5-(1-methyl-1H-pyrazol-4-yl)aniline (Intermediate A16) to afford the title compound (6 mg, 5%) as a white solid.

(1410) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.94 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.10-7.05 (m, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.09 (sept, J=6.8 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1.14 (d, J=6.8 Hz, 6H).

(1411) LCMS; m/z 474.5 (M+H).sup.+ (ES.sup.+); 472.3 (M−H).sup.− (ES.sup.−).

Example 130: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N-(cyanomethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1412) ##STR00452##

(1413) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P56) and 2-(methylamino)acetonitrile, HCl to afford the title compound (26 mg, 42%).

(1414) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.25 (s, 1H), 7.99 (s, 1H), 7.14 (s, 3H), 4.58 (s, 2H), 3.97 (s, 3H), 3.12 (s, 3H), 2.98-2.85 (m, 2H), 1.05 (br s, 12H),

(1415) LCMS; m/z 495.5 and 497.5 (M+H).sup.+ (ES.sup.+).

Example 13: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N— isopropyl-1-methyl-1H-pyrazole-5-carboxamide

(1416) ##STR00453##

(1417) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and isopropylamine to afford the title compound (28 mg, 45%) as a white solid.

(1418) .sup.1H NMR (DMSO-d.sub.6) δ 11.06 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.47 (s, 1H), 7.27-7.20 (m, 1H), 7.11 (d, J=7.6 Hz, 2H), 4.15 (s, 3H), 4.09-3.99 (m, 1H), 2.90-2.86 (m, 2H), 1.13 (d, J=6.6 Hz, 6H), 1.05-1.03 (m, 12H).

(1419) LCMS; m/z 450 (M+H).sup.+ (ES.sup.+).

Example 132: N-((2,6-Diisopropylphenyl)carbamoyl)-5-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1420) ##STR00454##

(1421) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and 3-fluoroazetidine, HCl. The sodium salt was generated by dissolving the free acid (19 mg, 0.041 mmol) in THF (1 mL) and adding 2 M solution of sodium tert-butoxide (20.50 μL, 0.041 mmol) in THF. The suspension was stirred for 2 hours and filtered. The collected solid was washed with EtOAc (2 mL) and dried under reduced pressure for 6 hours to afford the title compound (6 mg, 8%) as a white solid.

(1422) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.32 (s, 1H), 7.11-7.10 (m, 1H), 7.01 (d, J=7.3 Hz, 2H), 6.71 (s, 1H), 5.51-5.33 (m, 1H), 4.63-4.59 (m, 1H), 4.40-4.32 (m, 2H), 4.11-4.01 (m, 1H), 3.98 (s, 3H), 3.16-3.12 (m, 2H), 1.04 (d, J=6.8 Hz, 12H).

(1423) LCMS; m/z 466 (M+H).sup.+ (ES.sup.+).

Example 133: N-(Cyanomethyl)-3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1424) ##STR00455##

(1425) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and 2-(methylamino)acetonitrile, HCl to afford the title compound (25 mg, 33%) as a white solid.

(1426) .sup.1H NMR (DMSO-d.sub.6) δ 7.59 (s, 1H), 7.20-7.12 (m, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.91 (s, 1H), 4.57 (s, 2H), 3.91 (s, 3H), 3.13 (s, 3H), 3.08-3.05 (m, 2H), 1.05 (d, J=6.9 Hz, 12H). Acidic NH not observed.

(1427) LCMS; m/z 461 (M+H).sup.+ (ES.sup.+).

Example 134: 3-(N-((4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium Salt

(1428) ##STR00456##

(1429) Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 126) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) and 4-fluoro-2-isopropyl-6-(pyridin-3-yl)aniline (Intermediate A3) to afford the title compound (23 mg, 9%) as a white solid.

(1430) .sup.1H NMR (DMSO-d.sub.6, 70° C.) δ 8.55 (m, 1H), 8.45 (dd, J=4.8, 1.7 Hz, 1H), 7.77 (dt, J=7.8, 2.0 Hz, 1H), 7.25 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 7.06 (dd, J=10.2, 3.0 Hz, 1H), 6.91 (dd, J=9.1, 3.0 Hz, 1H), 6.44 (s, 1H), 3.84 (s, 3H), 3.26 (sept, J=6.9 Hz, 1H), 3.04 (s, 6H), 1.13 (d, J=6.9 Hz, 6H). NH not observed.

(1431) LCMS; m/z 489.4 (M+H).sup.+ (ES.sup.+).

Example 135: 3-(N-((4-Fluoro-2-isopropyl-6-(pyrimidin-5-yl)phenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium Salt

(1432) ##STR00457##

(1433) Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 126) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) and 4-fluoro-2-isopropyl-6-(pyrimidin-5-yl)aniline (Intermediate A8) to afford the title compound (44 mg, 16%) as a white solid.

(1434) .sup.1H NMR (DMSO-d.sub.6, 70° C.) δ 9.03 (s, 1H), 8.76 (s, 2H), 7.30 (bs, 1H), 7.11 (dd, J=10.2, 3.0 Hz, 1H), 7.03 (dd, J=9.0, 3.0 Hz, 1H), 6.43 (s, 1H), 3.85 (s, 3H), 3.26 (sept, J=6.8 Hz, 1H), 3.04 (s, 6H), 1.14 (d, J=6.8 Hz, 6H).

(1435) LCMS; m/z 490.4 (M+H).sup.+ (ES.sup.+).

Example 16: N-Cyclopropyl-3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1436) ##STR00458##

(1437) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and N— methylcyclopropanamine, HCl to afford the title compound (45 mg, 55%) as a white solid.

(1438) .sup.1H NMR (DMSO-d.sub.6), rotamers; 611.04 (s, 1H), 7.96-7.86 (2×s, 1H), 7.26-7.23 (m, 1H), 7.16-7.11 (m, 3H), 3.95 (s, 3H), 3.09-2.84 (m, 6H), 1.18-1.14 (m, 12H), 0.55-0.52 (m, 4H).

(1439) LCMS; m/z 462 (M+H).sup.+ (ES.sup.+).

Example 137: 3-(N-((2,5-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1440) ##STR00459##

(1441) Prepared according to the general procedure for 3-(N-((4-fluoro-2-isopropyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 126) from (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)amide (Intermediate P58) and 2,5-diisopropylaniline (Intermediate A18) to afford the title compound (8 mg, 7%) as a white solid.

(1442) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.51-7.47 (m, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.80 (dd, J=8.0, 2.0 Hz, 1H), 6.62 (s, 1H), 3.83 (s, 3H), 3.04 (m, 4H), 2.99 (s, 3H), 2.75 (sept, J=6.9 Hz, 1H), 1.15 (d, J=6.9 Hz, 6H), 1.10 (d, J=6.8 Hz, 6H).

(1443) LCMS; m/z 436.5 (M+H).sup.+ (ES.sup.+).

Example 138: 5-(Azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Sodium Salt

(1444) ##STR00460##

(1445) Azetidine hydrochloride (17 mg, 0.182 mmol), NaHCO.sub.3 (30 mg, 0.357 mmol) and HATU (68 mg, 0.179 mmol) were successively added to a solution of 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P55) (70 mg, 0.149 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (1 mL) and purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the free acid (s mg, 84%) as a white solid. The sodium salt was generated by dissolving the free acid (55 mg, 0.12 mmol) in THF (3 mL) and adding a 2 M solution of sodium tert-butoxide (63 μL, 0.126 mmol) in THF. The suspension was stirred for 30 minutes and filtered. The collected solid was washed with EtOAc (2 mL), slurried in MeCN (3 mL), filtered and dried under vacuum to afford the title compound (29 mg, 40%) as a white solid.

(1446) .sup.1H NMR (DMSO-d.sub.6) δ 7.33 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.67 (s, 1H), 4.29 (t, J=7.7 Hz, 2H), 4.03 (t, J=7.7 Hz, 2H), 3.98 (s, 3H), 3.11 (m, 2H), 2.27 (p, J=7.7 Hz, 2H), 1.02 (d, J=7.7 Hz, 12H).

(1447) LCMS; m/z 466.4 (M+H).sup.+ (ES.sup.+); 464.3 (M−H).sup.− (ES.sup.−).

Example 139: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-isopropyl-1-methyl-1H-pyrazole-5-carboxamide

(1448) ##STR00461##

(1449) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and isopropylamine to afford the title compound (14 mg, 24%) as a white solid.

(1450) .sup.1H NMR (DMSO-d.sub.6) δ 10.94 (s, 1H), 8.50 (d, J=7.8 Hz, 1H), 8.02 (s, 1H), 7.46 (s, 1H), 6.94 (s, 1H), 4.13 (s, 3H), 4.09-3.98 (m, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.98-1.91 (m, 4H), 1.14 (d, J=6.6 Hz, 6H).

(1451) LCMS; m/z 446 (M+H).sup.+ (ES.sup.+).

Example 140: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N-isopropyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1452) ##STR00462##

(1453) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P55) and N— methylpropan-2-amine to afford the title compound (33 mg, 45%) as a white solid.

(1454) .sup.1H NMR (DMSO-d.sub.6), rotamers; 611.18 (bs, 1H), 7.82 (s, 1H), 6.92 & 6.80 (2×s, 1H), 6.90 (d, J=10.0 Hz, 2H), 4.67 & 3.96 (2×m, 1H), 3.89 & 3.87 (2×s, 3H), 2.99 (m, 2H), 2.85 & 2.82 (2×s, 3H), 1.14 (d, J=6.7 Hz, 6H), 1.04 (bs, 12H).

(1455) LCMS; m/z 482.4 (M+H).sup.+ (ES.sup.+); 480.3 (M−H).sup.− (ES.sup.−).

Example 141: N,N-Diethyl-3-(N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1456) ##STR00463##

(1457) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P55) and diethylamine to afford the title compound (26 mg, 34%) as a white solid.

(1458) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.35 (s, 1H), 6.79 (d, J=10.0 Hz, 2H), 6.51 (s, 1H), 3.77 (s, 3H), 3.50-3.28 (m, 4H), 3.14 (m, 2H), 1.12 (bs, 6H), 1.03 (d, J=6.8 Hz, 12H).

(1459) LCMS; m/z 482.4 (M+H).sup.+ (ES.sup.+); 480.4 (M−H).sup.− (ES.sup.−).

Example 142: N-Ethyl-3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1460) ##STR00464##

(1461) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P55) and N— methylethanamine to afford the title compound (24 mg, 33%) as a white solid.

(1462) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.34 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.58 & 6.52 (2×s, 1H), 3.80 (s, 3H), 3.52-3.35 (m, 2H), 3.14 (m, 2H), 3.0 & 2.96 (2×s, 3H), 1.12 (t, J=7.1 Hz, 3H), 1.03 (d, J=6.9 Hz, 12H).

(1463) LCMS; m/z 468.4 (M+H).sup.+ (ES.sup.+); 466.3 (M−H).sup.− (ES.sup.−).

Example 14-: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1464) ##STR00465##

(1465) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P55) and methylamine to afford the title compound (26 mg, 39%) as a white solid.

(1466) .sup.1H NMR (DMSO-d.sub.6) δ 11.16 (bs, 1H), 8.62 (q, J=4.6 Hz, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 6.89 (d, J=10.0 Hz, 2H), 4.12 (s, 3H), 2.95 (sept, J=6.4 Hz, 2H), 2.74 (d, J=4.6 Hz, 3H), 1.02 (bs, 12H).

(1467) LCMS; m/z 440.4 (M+H).sup.+ (ES.sup.+); 438.4 (M−H).sup.− (ES.sup.−).

Example 144: 5-(Azetidine-1-carbonyl)-N-((2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1468) ##STR00466##

(1469) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and azetidine, HCl to afford the title compound (6 mg, 8%) as a white solid.

(1470) .sup.1H NMR (DMSO-d.sub.6) δ 7.38 (s, 1H), 7.11 (dd, J=8.4, 6.8 Hz, 1H), 7.06-6.99 (m, 2H), 6.71 (s, 1H), 4.29 (t, J=7.7 Hz, 2H), 4.07-3.97 (m, 5H), 3.12-3.08 (m, 2H), 2.31-2.22 (m, 2H), 1.04 (d, J=6.8 Hz, 12H). Acidic NH not observed.

(1471) LCMS; m/z 448 (M+H).sup.+ (ES.sup.+).

Example 145: N-Cyclopropyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1472) ##STR00467##

(1473) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methylcyclopropanamine, HCl to afford the title compound (28 mg, 34%) as a white solid.

(1474) .sup.1H NMR (DMSO-d.sub.6) δ 10.90 (br s, 1H), 8.06 (s, 1H), 7.16 (br s, 1H), 6.95 (s, 1H), 3.94 (s, 3H), 2.99 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.59 (t, J=7.4 Hz, 4H), 1.99-1.91 (m, 4H), 0.60-0.50 (m, 4H). One exchangeable proton not observed.

(1475) LCMS; m/z 458 (M+H).sup.+ (ES.sup.+).

Example 146: N-(Cyanomethyl)-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1476) ##STR00468##

(1477) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and 2-(methylamino)acetonitrile, HCl to afford the title compound (33 mg, 46%) as a white solid.

(1478) .sup.1H NMR (DMSO-d.sub.6) δ 7.75 (s, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.14 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 1.92 (quin, J=7.4 Hz, 4H).

(1479) LCMS; m/z 457.4 (M+H).sup.+ (ES.sup.+); 455.3 (M−H).sup.− (ES.sup.−).

Example 147: 5-(Azetidine-1-carbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide

(1480) ##STR00469##

(1481) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and azetidine, HCl to afford the title compound (40 mg, 55%) as a white solid.

(1482) .sup.1H NMR (DMSO-d.sub.6) δ 10.93 (bs, 1H), 8.09 (s, 1H), 7.06 (s, 1H), 6.95 (s, 1H), 4.34 (t, J=7.7 Hz, 2H), 4.08 (s, 3H), 4.05 (t, J=7.7 Hz, 2H), 2.79 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.3 Hz, 4H), 2.33-2.20 (m, 2H), 1.95 (quin, J=7.4 Hz, 4H).

(1483) LCMS; m/z 444.5 (M+H).sup.+ (ES.sup.+); 442.3 (M−H).sup.− (ES.sup.−).

Example 148: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1484) ##STR00470##

(1485) Methylamine in THF (108 μL, 0.217 mmol) and HATU (82 mg, 0.217 mmol) were successively added to a solution of 3-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) (70 mg, 0.155 mmol) in DMF (1 mL) and stirred for 20 hours. The reaction was quenched with water (0.1 mL) and purified by reversed phase prep-HPLC (General Methods, basic prep) to afford the title compound (26 mg, 40%) as a white solid.

(1486) .sup.1H NMR (DMSO-d.sub.6) δ 11.07 (bs, 1H), 8.62 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.28 (s, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.7 Hz, 2H), 4.13 (s, 3H), 2.96 (m, 2H), 2.73 (d, J=4.5 Hz, 3H), 1.06-1.00 (m, 12H).

(1487) LCMS; m/z 422.4 (M+H).sup.+ (ES.sup.+); 420.4 (M−H).sup.− (ES.sup.−).

Example 149: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-ethyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1488) ##STR00471##

(1489) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 148) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and N-methylethanamine to afford the title (10 mg, 14%) as a white solid.

(1490) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.09 (bs, 1H), 7.81 (s, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.11 (d, J=7.6 Hz, 2H), 6.96 & 6.87 (2×s, 1H), 3.92 & 3.90 (2×s, 3H), 3.46 & 3.31 (2×q, J=7.1 Hz, 2H), 2.98 (brs, 5H), 1.16-1.0 (m, 15H).

(1491) LCMS; m/z 450.5 (M+H).sup.+ (ES.sup.+); 448.4 (M−H).sup.− (ES.sup.−).

Example 150: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N— diethyl-1-methyl-1H-pyrazole-5-carboxamide

(1492) ##STR00472##

(1493) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 148) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and diethylamine to afford the title compound (33 mg, 45%) as a white solid.

(1494) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.09 (bs, 1H), 7.83 (s, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.11 (d, J=7.7 Hz, 2H), 6.87 (s, 1H), 3.88 (s, 3H), 3.45 (m, 2H), 3.31 (m, 2H), 2.98 (sept, J=6.8 Hz, 2H), 1.20-0.95 (m, 18H).

(1495) LCMS; m/z 464.5 (M+H).sup.+ (ES.sup.+); 462.4 (M−H).sup.− (ES.sup.−).

Example 151: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N— isopropyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1496) ##STR00473##

(1497) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 148) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and N-methylpropan-2-amine to afford the title compound (47 mg, 58%) as a white solid.

(1498) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.13 (br s, 1H), 7.91 (s, 1H), 7.30-7.19 (m, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.02 (s, o5H), 6.90 (s, o5H), 4.74-4.57 (m, 1H), 3.92-3.78 (m, 3H), 2.95-2.93 (m, 2H), 2.85-2.82 (m, 3H), 1.11-1.08 (m, 18H).

(1499) LCMS; m/z 464 (M+H).sup.+ (ES.sup.+).

Example 152: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide

(1500) ##STR00474##

(1501) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 123) from 1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide (Intermediate P52) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1). The crude product was purified by chromatography on RP Flash C18 (13 g column, 0-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (25 mg, 28%) as a white solid.

(1502) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.9 (br s, 1H), 7.99 (s, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 3.98 (s, 3H), 3.52 and 3.47 (2×t, J=6.2 Hz, 4H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 2.02-1.75 (m, 8H).

(1503) LCMS; m/z 458 (M+H).sup.+ (ES.sup.+).

Example 153: 3-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1504) ##STR00475##

(1505) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 123) from N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P50) and 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (Intermediate A2) to afford the title compound (55 mg, 67%) as a white solid.

(1506) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.35 (s, 1H), 6.79 (d, J=10.1 Hz, 2H), 6.59 (s, 1H), 3.81 (s, 3H), 3.18-3.07 (m, 2H), 3.03 (s, 3H), 2.98 (s, 3H), 1.02 (d, J=6.9 Hz, 12H).

(1507) LCMS; m/z 454 (M+H).sup.+ (ES.sup.+).

Example 154: 5-(3-Fluoroazetidine-1-carbonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, Partial ammonium Salt

(1508) ##STR00476##

(1509) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and 3-fluoroazetidine, HCl to afford the title compound (36 mg, 50%) as a white solid.

(1510) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.74 (s, 1H), 6.87 (s, 1H), 6.78 (s, 1H), 5.45-5.26 (m, 1H), 4.61-4.47 (m, 1H), 4.44-4.22 (m, 2H), 4.08-3.95 (m, 1H), 3.95 (s, 3H), 2.70 (t, J=7.4 Hz, 4H), 2.55 (t, J=7.4 Hz, 4H), 1.85 (quin, J=7.5 Hz, 4H).

(1511) LCMS; m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.4 (M−H).sup.− (ES.sup.−).

Example 155: N-Ethyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1512) ##STR00477##

(1513) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl) carbamoyl)-1-methyl-1H-pyrazole-3-sulfonamide, sodium salt (Example 138) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methylethanamine to afford the title (31 mg, 44%) as a white solid.

(1514) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.98 (s, 1H), 8.00 (s, 1H), 6.96-6.87 (m, 2H), 3.90 & 3.88 (2×s, 3H), 3.47 and 3.33 (2×q, J=7.0 Hz, 2H), 3.00 and 2.97 (2×s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.94 (p, J=7.4 Hz, 4H), 1.15-1.08 (m, 3H).

(1515) LCMS; m/z 446.4 (M+H).sup.+ (ES.sup.+); 444.4 (M−H).sup.− (ES.sup.−).

Example 156: N-((2,6-Diisopropylphenyl)carbamoyl)-1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide

(1516) ##STR00478##

(1517) Prepared according to the general procedure for 5-(azetidine-1-carbonyl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (Example 123) from 1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide (Intermediate P52) and 2-isocyanato-1,3-diisopropylbenzene (Intermediate A19). The crude product was purified by chromatography on RP Flash C18 (12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (40 mg, 43%) as a colourless solid.

(1518) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.11 (s, 1H), 7.89 (s, 1H), 7.30-7.18 (m, 1H), 7.16-7.07 (m, 3H), 4.01 (s, 3H), 3.57-3.40 (m, 4H), 3.03-2.85 (m, 2H), 1.91-1.78 (m, 4H), 1.04 (br s, 12H).

(1519) LCMS; m/z 462.5 (M+H).sup.+ (ES.sup.+).

Example 157: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-isopropyl-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1520) ##STR00479##

(1521) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P51) and N— methylpropan-2-amine to afford the title compound (25 mg, 42%) as a white solid.

(1522) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.74 (s, 1H), 6.85 (s, 1H), 6.78 & 6.67 (2×s, 1H), 4.68 & 4.03 (s, 1H), 3.83 (s, 3H), 2.85 (s, 3H), 2.77 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.4 Hz, 4H), 1.92 (quin, J=7.4 Hz, 4H), 1.15 (d, J=6.7 Hz, 6H). Acidic proton not observed.

(1523) LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.3 (M−H).sup.− (ES.sup.−).

Example 158: N,N-diethyl-3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide

(1524) ##STR00480##

(1525) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-H-pyrazole-5-carboxylic acid (Intermediate P51) and diethylamine to afford the title compound (35 mg, 8%) as a white solid.

(1526) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 10.96 (s, 1H), 7.92 (s, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 3.86 (s, 3H), 3.45 & 3.30 (2×m, 4H), 2.78 (t, J=7.3 Hz, 4H), 2.61 (t, J=7.4 Hz, 4H), 1.94 (quin, J=7.4 Hz, 4H), 1.18-1.05 (m, 6H).

(1527) LCMS; m/z 460.5 (M+H).sup.+ (ES.sup.+); 458.4 (M−H).sup.− (ES.sup.−).

Example 159: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1528) ##STR00481##

(1529) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate P51) and methylamine to afford the title compound (18 mg, 35%) as a white solid.

(1530) .sup.1H NMR (DMSO-d.sub.6) δ 10.88 (s, 1H), 8.61 (q, J=4.6 Hz, 1H), 7.97 (s, 1H), 7.28 (s, 1H), 6.87 (s, 1H), 4.07 (s, 3H), 2.71 (t, J=7.4 Hz, 4H), 2.67 (d, J=4.6 Hz, 3H), 2.52 (t, J=7.4 Hz, 4H), 1.87 (quin, J=7.5 Hz, 4H).

(1531) LCMS; m/z 418.4 (M+H).sup.+ (ES.sup.+); 416.3 (M−H).sup.− (ES.sup.−).

Example 160: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1532) ##STR00482##

(1533) N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P50) (105 mg, 0.452 mmol) was dissolved in THF (5 mL) and 2 M sodium tert-butoxide in THF (0.237 mL, 0.475 mmol) added. After 1 hour, 2-isocyanato-1,3-diisopropylbenzene (Intermediate A19) (92 mg, 0.452 mmol) was added and the mixture stirred at room temperature for 15 hours. The suspension was filtered and washed with THF (1 mL). The collected solid was triturated with EtOAc (5 mL) for 1 hour, filtered, and dried under vacuum to afford the title compound (137 mg, 64%) as a white solid.

(1534) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.37 (br s, 1H), 7.14-7.05 (m, 1H), 7.01 (d, J=7.5 Hz, 2H), 6.61 (s, 1H), 3.81 (s, 3H), 3.15-3.13 (m, 2H), 3.03 (s, 3H), 2.99 (s, 3H), 1.03 (d, J=6.8 Hz, 12H).

(1535) LCMS; m/z 436 (M+H).sup.+ (ES.sup.+).

Example 161: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

(1536) ##STR00483##

(1537) 4-Chloro-2,6-diisopropylaniline, HCl (51.9 mg, 0.209 mmol) and triethylamine (0.064 ml, 0.460 mmol) were dissolved in dry THF (5 mL). Triphosgene (49.6 mg, 0.167 mmol) was added to the mixture at room temperature and stirred for 5 hours. The mixture was concentrated in vacuo and dried azeotropically with toluene (1 mL×3). Dry THF (2 mL) was added to the residue and N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P50) (48.6 mg, 0.209 mmol) added to the mixture. After 30 minutes, 60% sodium hydride (20.91 mg, 0.523 mmol) was added and the mixture heated at 60° C. for 15 hours. After cooling to room temperature, saturated aqueous ammonium chloride (10 mL) was added and the mixture extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (5 mL), dried over MgSO.sub.4, concentrated in vacuo and the residue purified by chromatography on silica gel (25 g column, 5-100% EtOAc/isohexane) to afford the title compound (17 mg, 17%) as a white solid.

(1538) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.24 (s, 1H), 7.98 (s, 1H), 7.14 (s, 2H), 7.01 (s, 1H), 3.93 (s, 3H), 3.00 (s, 3H), 2.99 (s, 3H), 2.98-2.91 (m, 2H), 1.17-0.93 (br d, 12H).

(1539) LCMS; m/z 469 and 471 (M+H).sup.+ (ES.sup.+).

Example 162: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1540) ##STR00484##

(1541) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt (Example 160) from N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P50) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (235 mg, 64%) as a white solid.

(1542) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.51 (s, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 3.82 (s, 3H), 3.04 (s, 3H), 2.99 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.65 (t, J=7.4 Hz, 4H), 1.93-1.86 (m, 4H).

(1543) LCMS; m/z 432 (M+H).sup.+ (ES.sup.+).

Example 163: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(thiazol-2-ylmethyl)-1H-pyrazole-5-carboxamide

(1544) ##STR00485##

(1545) Prepared according to the general procedure of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 108) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methyl-1-(thiazol-2-yl)methanamine to afford the title compound (18 mg, 26%) as a white solid.

(1546) .sup.1H NMR (DMSO-d.sub.6), rotamers; 610.95 (br s, 1H), 8.09-8.07 (2×s, 1H), 7.89-7.65 (m, 2H), 7.11-7.08 (2×s, 1H), 6.94 (s, 1H), 4.97-4.92 (2×s, 2H), 3.97-3.95 (2×s, 3H), 3.12-3.01 (2×s, 3H), 2.78 (t, J=7.6 Hz, 4H), 2.64-2.53 (m, 4H), 1.94-1.92 (m, 4H).

(1547) LCMS; m/z 515 (M+H).sup.+ (ES.sup.+).

Example 164: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-5-carboxamide

(1548) ##STR00486##

(1549) Prepared according to the general procedure of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 108) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methyl-1-(1-methyl-1H-imidazol-2-yl)methanamine to afford the title compound (11 mg, 14%) as a white solid.

(1550) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.71 (s, 1H), 7.20 (s, 0.4H), 7.14 (s, 0.6H), 7.05 (s, 0.6H), 6.93 (s, 0.4H), 6.85-6.83 (m, 2H), 4.73-4.17 (m, 2H), 3.89 (s, 3H), 3.64-3.45 (2×s, 3H), 2.98-2.94 (2×s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.63-2.59 (m, 4H), 1.94-1.87 (m, 4H). NH not observed.

(1551) LCMS; m/z 512 (M+H).sup.+ (ES.sup.+).

Example 165: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-(thiazol-2-yl)-1H-pyrazole-5-carboxamide

(1552) ##STR00487##

(1553) Prepared according to the general procedure of 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N-(2-methoxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 108) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methylthiazol-2-amine to afford the title compound (4 mg, 7%) as a white solid.

(1554) .sup.1H NMR (DMSO-d.sub.6) δ 11.03 (br s, 1H), 8.11 (br s, 1H), 7.66 (d, J=3.6 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 4.05 (s, 3H), 3.72 (s, 3H), 2.79 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 1.99-1.92 (m, 4H).

(1555) LCMS; m/z 501 (M+H).sup.+ (ES.sup.+).

Example 166: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N,1-dimethyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1556) ##STR00488##

(1557) Prepared according to the general procedure of 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-N-(3-hydroxypropyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, partial ammonium salt (Example 104) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and N-methyl-1-(1-methyl-H-pyrazol-5-yl)methanamine to afford the title compound (14 mg, 17%) as a white solid.

(1558) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.65 & 7.58 (2×s, 1H), 7.50-7.00 (br s, 1H), 7.36 (d, J=1.9 Hz, 1H), 6.81 (s, 1H), 6.81 & 6.60 (2×s, 1H), 6.27 & 6.14 (2×s, 1H), 4.76 & 4.70 (2×s, 2H), 3.87 & 3.80 (2×s, 3H), 3.80 & 3.58 (2×s, 3H), 2.99 (s, 3H), 2.75 (t, J=7.4 Hz, 4H), 2.63 (t, J=7.5 Hz, 4H), 1.89 (p, J=7.5 Hz, 4H).

(1559) LCMS; m/z 512.4 (M+H).sup.+ (ES.sup.+); 510.3 (M−H).sup.− (ES.sup.−).

Example 167: 2-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-imidazole-4-sulfonamide

(1560) ##STR00489##

(1561) Sodium tert-butoxide, 2 M in THF (0.120 mL, 0.241 mmol) was added to a solution of a mixture of 2-((dimethylamino)methyl)-1-methyl-1H-imidazole-4-sulfonamide and 5-((dimethylamino)methyl)-1-methyl-1H-imidazole-4-sulfonamide (Intermediates P66 and P67) (50 mg, 0.229 mmol) in THF (1 mL) and stirred at room temperature for 1 hour. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (47.9 mg, 0.241 mmol) in THF (1 mL) was added and the reaction stirred at room temperature over the weekend. The reaction mixture was concentrated and the crude product was purified by chromatography (Companion apparatus, RP Flash C18, 12 g column, 5-50% MeCN/10 mM ammonium bicarbonate) to afford 2-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-imidazole-4-sulfonamide (Example 167) (44 mg, 46%) and 5-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-methyl-1H-imidazole-4-sulfonamide (3 mg, 3%), both as colourless solids.

(1562) Example 167: .sup.1H NMR (DMSO-d.sub.6) δ 7.91 (s, 1H), 7.77 (s, 1H), 6.83 (s, 1H), 4.26 (s, 2H), 3.67 (s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.66-2.53 (m, 10H), 1.96-1.84 (m, 4H) (1 exchangeable NH not observed).

(1563) LCMS; m/z 418.3 (M+H).sup.+ (ES.sup.+).

Example 168: 3-(N-((4-Chloro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1564) ##STR00490##

(1565) Prepared according to the general procedure for 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 125) from 3-(N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P56) and 2-(methylamino)ethanol to afford the title compound (10 mg, 18%) as a white solid.

(1566) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 11.18 (s, 1H), 7.95 (s, 1H), 7.14 (s, 2H), 6.98 (s, 1H), 4.96-4.79 (m, 1H), 3.93-3.86 (m, 3H), 3.64-3.41 (m, 4H), 3.06-2.88 (m, 5H), 1.08 (br s, 12H).

(1567) LCMS; m/z 500.4/502.4 (M+H).sup.+ (ES.sup.+).

Example 16A: 3-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide

(1568) ##STR00491##

(1569) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 148) from 3-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P54) and 2-(methylamino)ethanol to afford the title compound (8 mg, 11%) as a white solid.

(1570) .sup.1H NMR (DMSO-d.sub.6), rotamers; 611.07 (s, 1H), 7.88 (s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.12 (d, J=7.7 Hz, 2H), 7.02 & 7.0 (2×s, 1H), 4.96 & 4.81 (t, J=5.0 & 5.7 Hz, 1H), 3.94& 3.89 (2×s, 3H), 3.59 & 3.40 (2×t, J=5.6 & 5.1 Hz, 2H), 3.50 (2×t, J=5.6 & 5.2 Hz, 2H), 3.03 & 2.98 (2×s, 3H), 2.95 (m, 2H), 1.06 (br s, 12H).

(1571) LCMS; m/z 466.5 (M+H).sup.+ (ES.sup.+); 464.4 (M−H).sup.− (ES.sup.−).

Example 170: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1572) ##STR00492##

(1573) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 148) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and ethanolamine to afford the title compound (18 mg, 25%) as a white solid.

(1574) .sup.1H NMR (DMSO-d.sub.6) δ 8.61 (t, J=5.7 Hz, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 6.88 (s, 1H), 4.73 (t, J=5.7 Hz, 1H), 4.10 (s, 3H), 3.48 (app q, J=6.0 Hz, 2H), 3.27 (app q, J=6.0 Hz, 2H), 2.78 (t, J=7.4 Hz, 4H), 2.60 (t, J=7.4 Hz, 4H), 1.93 (p, J=7.4 Hz, 4H). One exchangeable proton not seen.

(1575) LCMS; m/z 448.4 (M+H).sup.+ (ES.sup.+); 446.4 (M−H).sup.− (ES.sup.−).

Example 171: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1576) ##STR00493##

(1577) Prepared according to the general procedure for 3-(N-((2,6-diisopropylphenyl) carbamoyl)sulfamoyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide (Example 148) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and 2-methoxyethan-1-amine to afford the title compound (37 mg, 51%) as a colourless solid.

(1578) .sup.1H NMR (DMSO-d.sub.6) δ 10.93 (br s, 1H), 8.74 (t, J=5.5 Hz, 1H), 7.90 (s, 1H), 7.36 (s, 1H), 6.90 (s, 1H), 4.11 (s, 3H), 3.44 (t, J=5.5 Hz, 2H), 3.39 (t, J=5.5 Hz, 2H), 3.26 (s, 3H), 2.78 (t, J=7.4 Hz, 4H), 2.61 (t, J=7.3 Hz, 4H), 1.94 (p, J=7.5 Hz, 4H).

(1579) LCMS; m/z 462.4 (M+H).sup.+ (ES.sup.+); 460.3 (M−H).sup.− (ES.sup.−).

Example 172: 3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-N-(2-hydroxyethyl)-N,1-dimethyl-1H-pyrazole-5-carboxamide, Partial ammonium Salt

(1580) ##STR00494##

(1581) Prepared according to the general procedure for N-((2,6-diisopropylphenyl) carbamoyl)-1-methyl-5-(pyrrolidine-1-carbonyl)-1H-pyrazole-3-sulfonamide (Example 156) from 3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid, disodium salt (Intermediate P53) and 2-(methylamino)ethanol to afford the title compound (39 mg, 54%) as a white solid.

(1582) .sup.1H NMR (DMSO-d.sub.6), rotamers; δ 7.69 (s, 1H), 7.10 (s, 1H), 7.10 & 6.74 (2×s, 1H), 6.82 (s, 1H), 4.96 & 4.84 (2×t, J=5.5 Hz, 1H), 3.84 & 3.80 (2×s, 3H), 3.59 (m, 1H), 3.55-3.41 (m, 3H), 3.06 & 2.97 (2×s, 3H), 2.76 (t, J=7.4 Hz, 4H), 2.64 (t, J=7.5 Hz, 4H), 1.92 (p, J=7.5 Hz, 4H).

(1583) LCMS; m/z 462.42 (M+H).sup.+ (ES.sup.+); 460.30 (M−H).sup.− (ES.sup.−).

(1584) The compound of example 173 was synthesised by methods analogous to those outlined above and below.

(1585) TABLE-US-00002 TABLE 1 .sup.1H NMR and MS data Ex Structure and Name .sup.1H NMR spectrum MS MW 173 .sup.1H NMR (DMSO-d.sub.6) δ 10.82 (s, 1H), 7.94 (s, 1H), 7.82-7.79 (m, 1H), 7.73-7.72 (m, 1H), 7.63-7.53 (m, 2H), 7.23 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.49 (s, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.17 (s, 6H), 1.98 (p, J = 7.5 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). m/z 493.0 (M + H).sup.+ (ES.sup.+); 491.3 (M − H).sup.− (ES.sup.−). 492.6

Example 174: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropyl-phenyl)carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, sodium salt

Step A: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

(1586) ##STR00496##

(1587) A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P70) (2.2 g, 6.87 mmol, 1 eq), 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine (Intermediate A21) (2.16 g, 6.87 mmol, 1 eq) and t-BuONa (659 mg, 6.87 mmol, 1 eq) in THF (100 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 μm, mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 0%-30%, 35 min) to give the title compound (2.5 g, 6% yield, 98% purity on LCMS) as a white solid.

(1588) .sup.1H NMR (DMSO-d.sub.6): δ 11.10 (br s, 1H), 8.06 (d, 1H), 7.79 (br s, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.83-6.72 (m, 2H), 6.70 (s, 1H), 5.29-5.23 (m, 1H), 3.83 (s, 3H), 3.64-3.61 (m, 2H), 3.55-3.50 (m, 4H), 3.45-3.40 (m, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 3.03-300 (m, 1H), 1.30 (d, 6H) and 1.09-1.05 (m, 6H).

(1589) LCMS: m/z 635.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl) sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1590) ##STR00497##

(1591) To a solution of 3-(N-((4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl) carbamoyl)sulfamoyl)-N,N-bis(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (2.5 g, 3-94 mmol, 1 eq, free form) in THF (100 mL) was added with t-BuONa (378 mg, 3.94 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 mL) to give the title compound (2.2 g, 85% yield, 99% purity on LCMS, sodium salt) as a white solid.

(1592) .sup.1H NMR (DMSO-d.sub.6): 7.99-7.88 (m, 1H), 7.53-7.40 (m, 1H), 7.15-7.08 (m, 1H), 6.94-6.82 (m, 2H), 6.68 (s, 1H), 6.51-6.44 (m, 1H), 5.28-5.22 (m, 1H), 3.75 (s, 3H), 3.74-3.56 (m, 6H), 3.45-3.38 (m, 2H), 3.29 (s, 3H), 3.17 (s, 3H), 3.12-307 (m, 1H), 1.29 (d, 6H) and 1.20-1.04 (m, 6H).

(1593) LCMS: m/z 635.1 (M+H).sup.+ (ES.sup.+).

Example 175: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

Step A: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide

(1594) ##STR00498##

(1595) A solution of N,N-bis(2-methoxyethyl)-1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P70) (2.56 g, 7.99 mmol, 1 eq) and t-BuONa (768 mg, 7.99 mmol, 1 eq) in THF (200 mL) was stirred at 25° C. for 30 minutes. Then 4 (4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A20) (3.34 g, 8.79 mmol, 1.1 eq) was added. The reaction mixture was stirred at 70° C. for 2 hours and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 μm, mobile phase: [A: water (0.05% ammonium hydroxide); B: MeCN]; B %: 0%-30%, 35 min) to give the title compound (1.35 g, 29% yield, 99% purity on LCMS) as a white solid.

(1596) .sup.1H NMR (DMSO-d.sub.6): δ 8.08 (d, 1H), 7.14-7.11 (m, 1H), 7.07-7.05 (m, 1H), 6.91 (d, 1H), 6.74 (s, 1H), 6.60 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.64-3.62 (m, 2H), 3.56-354 (m, 4H), 3.39-3.37 (m, 2H), 3.28 (s, 3H), 3.14 (s, 3H), 2.89 (t, 2H), 2.71 (t, 2H) and 1.99-1.94 (m, 2H).

(1597) LCMS: m/z 587.3 (M+H).sup.+ (ES.sup.+).

Step B: N,N-Bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1598) ##STR00499##

(1599) To a solution of N,N-bis(2-methoxyethyl)-3-(N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxamide (1.35 g, 2.30 mmol, 1 eq, free form) in THF (20 mL) was added with t-BuONa (221 mg, 2.30 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour and then concentrated in vacuo. The residue was triturated with isopropyl ether (20 mL) to give the title compound (1.2 g, 85% yield, 99% purity on HPLC) as a white solid.

(1600) .sup.1H NMR (DMSO-d.sub.6): δ 8.05 (d, 1H), 7.30 (br s, 1H), 7.04 (dd, 2H), 6.92 (d, 1H), 6.76 (s, 1H), 6.48 (d, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.64-3.62 (m, 2H), 3.56-3.53 (m, 4 H), 3.39-3.37 (m, 2H), 3.29 (s, 3H), 3.15 (s, 3H), 2.87 (t, 2H), 2.73-2.70 (m, 2H) and 1.98-1.91 (m, 2H).

(1601) LCMS: m/z 587.1 (M+H).sup.+ (ES.sup.+).

Example 176: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropyl-phenyl)carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium salt

Step A: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl)carbamoyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

(1602) ##STR00500##

(1603) To a solution of N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P50) (1.7 g, 7.32 mmol, 1 eq) in THF (20 mL) was added t-BuONa (703 mg, 7.32 mmol, 1 eq) at 25° C. and stirred for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-isopropoxypyridine (Intermediate A21) (2.30 g, 7.32 mmol, 1 eq) was added and the resulting mixture was stirred for 0.5 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Ultimate XB_C18, 41 mm*235 mm*20/40 μm; mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 0%-30%, 35 min) to give the title compound (2.34 g, 59% yield, 98% purity on HPLC) as a white solid.

(1604) .sup.1H NMR (DMSO-d.sub.6): δ 8.03 (d, 1H), 7.65 (br s, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.85 (d, 1H), 6.74 (s, 1H), 6.70 (s, 1H), 5.30-5.21 (m, 1H), 3.89 (s, 3H), 3.09-3.03 (m, 1H), 3.00 (s, 6H), 1.30 (d, 6H) and 1.07 (d, 6H).

(1605) LCMS: m/z 547.4 (M+H).sup.+ (ES.sup.+).

Step B: 3-(N-((4-Fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, Sodium Salt

(1606) ##STR00501##

(1607) To a solution of 3-(N-((4-fluoro-2-(2-isopropoxypyridin-4-yl)-6-isopropylphenyl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (1.71 g, 3.13 mmol, 1 eq, free form) in THF (40 mL) was added t-BuONa (300 mg, 3.13 mmol, 1 eq) at 25° C. Then the mixture was stirred for 1 hour. The mixture was concentrated in vacuo. The residue was triturated with MTBE (100 mL). The solid was dissolved in water (100 mL) and then lyophilized to give the title compound (1.60 g, 90% yield, 99.9% purity on HPLC) as a white solid.

(1608) .sup.1H NMR (DMSO-d.sub.6): δ 7.95 (d, 1H), 7.37 (br s, 1H), 7.09 (d, 1H), 6.93-6.90 (m, 2H), 6.69 (s, 1H), 6.53 (s, 1H), 5.29-5.22 (m, 1H), 3.83 (s, 3H), 3.15-3.09 (m, 1H), 3.01 (d, 6H), 1.29 (d, 6H) and 1.05 (d, 6H).

(1609) LCMS: m/z 547.3 (M+H).sup.+ (ES.sup.+).

Example 177: 3-(N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, sodium Salt

(1610) ##STR00502##

(1611) A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate-P50) (6.59 g, 28.39 mmol, 0.9 eq) and t-BuONa (3.33 g, 34.70 mmol, 1.1 eq) in THF (200 mL) was stirred at 16° C. for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (Intermediate A20) (8.4 g, 31-54 mmol, 1 eq) was added. The reaction mixture was stirred at 16° C. for 0.5 hour and then filtered. The filter cake was washed with MeCN (125 mL). Then the solid was dissolved in H.sub.2O (100 mL) and filtered. The filtrate was lyophilized to give the title compound (8.02 g, 49% yield, 99.54% purity on LCMS, Na salt) as a white solid.

(1612) .sup.1H NMR (DMSO-d.sub.6): δ 8.02 (d, 1H), 7.42 (br s, 7.10-7.02 (m, 2H), 6.89 (dd, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 3.84 (d, 6H), 3.02 (d, 6H), 2.87 (t, 2H), 2.72 (t, 2H) and 1.97-1.90 (m, 2H).

(1613) LCMS: m/z 499.3 (M+H).sup.− (ES.sup.+).

(1614) The compounds of examples 178-187 were synthesised by methods analogous to those outlined above.

(1615) TABLE-US-00003 TABLE 2 .sup.1H NMR and MS data Ex Structure and Name .sup.1H NMR spectrum MS MW 178 03 .sup.1H NMR (DMSO-d.sub.6) δ 8.07-8.04 (m, 1H), 7.36 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.96- 6.92 (m, 1H), 6.76 (s, 1H), 6.28-6.24 (m, 1H), 3.86 (s, 3H), 3.78- 3.74 (m, 2H), 3.63- 3.57 (m, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.30 (d, J = 6.2 Hz, 3H), 2.08- 1.99 (m, 1H), 1.94 (p, J = 7.5 Hz, 2H), 1.10- 1.04 (m, 2H), 0.97- 0.92 (m, 2H). m/z 497.2 (M + H).sup.+ (ES.sup.+); 495.0 (M − H).sup.− (ES.sup.−). 496.6 179 04 .sup.1H NMR (DMSO-d.sub.6) δ 8.06 (d, J = 5.3 Hz, 1H), 7.45 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H), 6.78 (s, 1H), 6.24 (s, 1H), 4.75 (sept, J = 6.7 Hz, 1H), 3.87 (s, 3H), 3.14-3.08 (m, 1H), 2.86 (t, J = 7.4 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.25-2.19 (m, 2H), 2.17 (s, 3H), 1.89 (p, J = 7.4 Hz, 2H), 1.85-1.58 (m, 4H), 1.38 (d, J = 6.6 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H). m/z 539.3 (M + H).sup.+ (ES.sup.+); 537.1 (M − H).sup.− (ES.sup.−). 538.7 180 05 .sup.1H NMR (DMSO-d.sub.6) δ 10.84 (s, 1H), 8.15 (dd, J = 5.2, 0.6 Hz, 1H), 7.90 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.4 Hz, 1H), 6.72 (d, J = 1.4 Hz, 1H), 6.57 (s, 1H), 4.86 (sept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.75- 3.67 (m, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.14 (s, 6H), 1.92 (p, J = 7.4 Hz, 2H), 1.89- 1.80 (m, 1H), 1.71-1.60 (m, 1H), 1.41 (d, J = 6.5 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H). m/z 541.3 (M + H).sup.+ (ES.sup.+); 539.3 (M − H).sup.− (ES.sup.−). 540.7 181 06 .sup.1H NMR (DMSO-d.sub.6) δ 10.85 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.73- 6.71 (m, 1H), 6.55 (s, 1H), 4.81 (sept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.50 (s, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.4 Hz, 2H), 2.16 (s, 6H), 1.95 (p, J = 7.6 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H). m/z 513.3 (M + H).sup.+ (ES.sup.+); 511.3 (M − H).sup.− (ES.sup.−). 512.6 182 07 .sup.1H NMR (DMSO-d.sub.6) δ 10.74 (s, 1H), 7.79 (s, 1H), 7.33-7.28 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.95-6.91 (m, 1H), 6.87-6.79 (m, 2H), 6.61 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 3.51 (s, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.18 (s, 6H), 1.95 (p, J = 7.5 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). m/z 498.4 (M + H).sup.+ (ES.sup.+); 496.1 (M − H).sup.− (ES.sup.−). 497.6 183 08 .sup.1H NMR (DMSO-d.sub.6) δ 7.75 (s, 1H), 6.85 (s, 1H), 6.61 (s, 1H), 4.05 (s, 2H), 3.68 (s, 1H), 2.77 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.3 Hz, 4H), 2.46 (s, 3H), 1.93 (p, J = 7.4 Hz, 4H), 1.09-0.96 (m, 4H). Amine NH and acidic NH are not resolved. m/z 430.3 (M + H).sup.+ (ES.sup.+); 428.4 (M − H).sup.− (ES.sup.−). 429.5 184 09 .sup.1H NMR (DMSO-d.sub.6) δ 7.68 (s, 1H), 6.31 (s, 1H), 6.29 (s, 1H), 4.37 (t, J = 8.6 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.39 (s, 2H), 2.95 (t, J = 8.6 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 2.14 (s, 6H), 1.89 (p, J = 7.4 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). m/z 434.2 (M + H).sup.+ (ES.sup.+). 433.5 185 0 .sup.1H NMR (DMSO-d.sub.6) δ 7.19 (s, 1H), 6.76 (s, 1H), 6.29 (s, 1H), 4.43 (t, J = 8.6 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.38 (s, 2H), 3.07 (t, J = 8.7 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.60 (t, J = 7.4 Hz, 2H), 2.14 (s, 6H), 1.86 (p, J = 7.4 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). m/z 434.4 (M + H).sup.+ (ES.sup.+). 433.5 186 .sup.1H NMR(DMS0-d.sub.6)δ 7.59 (s, 1H), 6.76 (s, 1H), 6.26 (s, 1H), 4.72 (pent., J = 6.5 Hz, 1H), 3.12-3.06 (m, 1H), 2.75 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.3 Hz, 4H), 2.23-2.17 (m, 2H), 2.16 (s, 3H), 1.88 (p, J = 7.5 Hz, 4H), 1.84 -1.72 (m, 2H), 1.66-1.57 (m, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H). One NH not observed. m/z 472.3 (M + H).sup.+ (ES.sup.+); 470.2 (M − H).sup.− (ES.sup.−). 471.6 187 .sup.1H NMR (DMSO-d.sub.6)δ 11.21 (s, 1H), 8.01 (s, 1H), 6.90 (s, 1H), 4.89 (sept, J = 6.6 Hz, 1H), 3.67 (s, 2H), 2.77 (t, J = 7.4 Hz, 4H), 2.61 (t,J = 7.2 Hz, 4H), 2.19 (s, 6H), 1.92 (p, J = 7.4 Hz, 4H), 1.39 (d, J = 6.6 Hz, 6H). m/z 447.3 (M + H).sup.+ (ES.sup.+); 445.2 (M − H).sup.− (ES.sup.−). 446.6

Examples—Biological Studies

(1616) NLRP and Pyroptosis

(1617) 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), 1691-171; 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.

(1618) THP-1 Cells: Culture and Preparation

(1619) 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.

(1620) THP-1 Cells Pyroptosis Assay

(1621) The following method step-by-step assay was followed for compound screening. 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) 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 3. Incubate for 3 hrs at 37° C. in 5% CO.sub.2 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells 5. Incubate for 1 hr at 37° C. and 5% CO.sub.2 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant 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 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

(1622) 96-Well Plate Map

(1623) TABLE-US-00004 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

(1624) The results of the pyroptosis assay performed are summarised in Table 3 below as THP IC.sub.50.

(1625) Human Whole Blood IL1β Release Assay

(1626) 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.

(1627) Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) 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 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 4. Add 10 μl Nigericin (Sigma #N7143) (10 μM FAC) to all wells 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date) 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1β Kit AL220F-5000) 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

(1628) The results of the human whole blood assay are summarised in Table 3 below as HWB IC.sub.50.

(1629) TABLE-US-00005 TABLE 3 Example No THP IC.sub.50 HWB IC.sub.50 1 + ND 2 + ND 3 +++++ ***** 4 ++++ **** 5 +++ ** 6 +++ *** 7 +++++ **** 8 +++ ND 9 + ND 10 + ND 11 +++ * 12 ++ ND 13 +++ ND 14 ++ ND 15 ++ ND 16 ++ ND 17 +++++ ***** 18 ++ ND 19 ++ ND 20 +++++ ***** 21 +++++ ***** 22 +++++ **** 23 +++++ ***** 24 +++++ ***** 25 +++++ ***** 26 ++++ ***** 27 ++++ ***** 28 ++ ND 29 ++++ **** 30 ++++ **** 31 ++++ **** 32 ++++ **** 33 +++ **** 34 ++++ **** 35 ++++ ***** 36 ++++ ***** 37 +++++ * 38 ++++ ** 39 ++ ** 40 +++ **** 41 ++++ ***** 42 ++ ND 43 ++ ND 44 ++ ***** 45 +++ *** 46 ++++ ***** 47 ++++ ***** 48 +++++ ***** 49 ++++ ***** 50 ++++ **** 51 +++ ***** 52 +++++ ***** 53 +++++ **** 54 +++ **** 55 ++++ ** 56 ++++ * 57 +++++ ** 58 ++++ *** 59 +++ *** 60 +++++ **** 61 +++ ND 62 +++ **** 63 +++++ ***** 64 +++++ *** 65 +++++ ***** 66 +++ **** 67 ++++ **** 68 +++++ **** 69 +++++ ***** 70 +++++ ***** 71 +++++ ***** 72 +++++ ***** 73 +++++ ***** 74 +++++ ***** 75 +++ *** 76 ++++ ***** 77 +++++ ***** 78 ++++ **** 79 ++ *** 80 +++ ** 81 +++ ***** 82 ++++ *** 83 ++ **** 84 ++++ **** 85 +++ ND 86 +++ *** 87 ++ ND 88 +++ ***** 89 +++ ***** 90 +++ ***** 91 +++ **** 92 +++ ***** 93 ++++ *** 94 +++++ ***** 95 +++++ *** 96 ++++ * 97 +++ ND 98 + ND 99 + ND 100 + ND 101 +++ ***** 102 ++++ **** 103 ++ ND 104 +++ ** 105 ++ ND 106 +++ *** 107 ++ ND 108 + ND 109 + ND 110 + ND 111 + ND 112 ++++ **** 113 ++++ **** 114 ++ ND 115 +++ *** 116 +++ ***** 117 ++++ ***** 118 ++ ND 119 +++ ** 120 ++ ND 121 ++ ND 122 ++++ **** 123 +++ ND 124 ++++ *** 125 +++ ** 126 ++ **** 127 ++ ND 128 ++ ***** 129 ++ ND 130 ++ ND 131 + ND 132 ++ *** 133 + ND 134 ++++ ***** 135 +++ ***** 136 ++++ *** 137 +++ * 138 ++++ ***** 139 + ND 140 ++++ **** 141 +++ ND 142 +++ **** 143 +++ ***** 144 +++ ***** 145 ++++ **** 146 +++ *** 147 ++++ ** 148 +++ **** 149 ++ ** 150 ++ ND 151 +++ **** 152 ++ ND 153 +++ ***** 154 ++ ND 155 ++++ **** 156 ++ ND 157 ++++ ** 158 ++++ *** 159 ++ ND 160 +++ ***** 161 ++++ ** 162 ++++ ***** 163 +++ ** 164 ++++ *** 165 +++ ND 166 ++ ND 167 + ND 168 ++++ *** 169 ++ ND 170 + ND 171 + ND 172 ++++ ***** 173 ++++ **** 174 + * 175 +++ ***** 176 +++ ** 177 +++++ ***** 178 ++++ ***** 179 ++++ *** 180 ++++ ***** 181 +++++ ***** 182 ++ ND 183 ++++ **** 184 +++++ **** 185 +++ ** 186 +++++ **** 187 +++++ *** NLRP3 inhibitory activity [THP IC.sub.50 (≤0.04 μM = +++++, ≤0.16 μM = ++++, ≤0.64 μM = +++, ≤2.56 μM = ++, ≤10 μM = +, not determined = ND)] [HWB IC.sub.50 (≤0.4 μM = *****, ≤0.8 μM = ****, ≤1.6 μM = ***, ≤3.2 μM = **, ≤10 μM = *, not determined = ND)]

(1630) PK Protocol

(1631) Pharmacokinetic parameters were determined in male Sprague Dawley rats (Charles River, UK, 250-350 g; or Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were individually housed during the study and maintained under a 12 h light/dark cycle. Animals had free access to food and water except that some orally dosed animals were food deprived overnight prior to the study.

(1632) For intravenous administration, compounds were formulated as a solution in water or DMSO:PBS [1:90] in 2 mL/kg dosing volume and administered via tail vein. For oral administration, compounds were formulated as a solution in water or DMSO:water [10:90] in 5 mL/kg dosing volume and administered orally.

(1633) Serial blood samples (about 120-300 μL) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h) or at each of 12 time-points post dose (0.03, 0.1, 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h) or pre-dose and at each of 9 time-points post dose (0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h). Samples were held on ice for no longer than 30 minutes before centrifugation (10,000 rpm (8,385 g) for 3 minutes; or 5,696 rpm (3,0009 for 15 minutes) for plasma generation. Plasma was frozen on dry ice prior to boanalysis. PK parameters were generated from LC-MS/MS data using Dotmatics or Phoenix WinNonlin 6.3 software.

(1634) TABLE-US-00006 TABLE 4 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng .Math. hr/mL) (hr) (L/kg) (mL/min/kg) 3 2.5 1126.5 1.3 1.32 37.0 4 1 3777.3 1.6 0.12 4.4 7 1 3475.8 1.2 0.36 4.9 17 1.7 2710.4 3.8 1.23 10.5 24 1 1278.8 1.0 0.84 13.0 25 1.64 3457.0 1 0.58 10.0 27 1 3895.2 1.1 0.33 4.3 30 1 6210.6 2.8 0.53 2.7 40 1 259.1 0.5 0.98 65.6 41 1 259.0 0.5 0.75 64.9 44 1 3118.7 1.2 0.21 5.3 46 1 375.4 1.2 1.14 51.5 47 1 247.8 0.3 1.32 67.2 48 1 356.0 0.5 0.8 47.6 49 1 6626.6 2.2 0.34 2.7 50 1 11371 3.5 0.39 1.5 52 1.65 7969.2 1.5 0.39 3.5 63 1 4007.3 0.8 0.25 4.2 72 1.4 2777.5 2.4 0.51 8.5 73 1 4252.9 3.5 0.51 4.3 76 1.65 4896.0 3.2 0.66 5.8 77 1 4439.1 3.5 0.38 3.8 84 1 2492.6 1.0 0.47 6.7 86 1 4399.1 3.2 0.48 3.8 88 1 1496.3 4.3 1.64 11.2 89 1 1022.7 1.4 1.4 16.3 91 1 2619.9 4.3 1.03 6.9 92 1 1278.5 3.2 2.19 13.1 93 2.2 4229.8 3.3 1.71 10.8 94 1 4698.7 1.1 0.27 3.8 112 2.88 329.7 0.2 1.84 149.3 113 1 1162.1 2.9 2.24 14.4 117 1 2067.0 14.2 1.9 8.1 124 1 302.7 1.6 1.66 55.3 126 1 182.5 2.3 2.72 91.3 128 1 661.2 12.1 3.03 25.2 134 1 274.4 6.3 3.95 60.7 138 1 415.0 6.4 7.96 40.3 153 1 283.3 3.3 4.08 59.2 155 2.46 1723.1 0.1 0.24 25.0 160 0.83 333.7 0.5 0.99 48.7 161 3.34 353.3 1.3 10.55 160.9 162 5.05 3389.9 25.3 17.78 24.8 172 2.41 786.6 0.3 2.37 114.1

(1635) TABLE-US-00007 TABLE 5 PK data (oral administration) Example Dose C.sub.max AUC T.sub.max T.sub.1/2 Cl/F No (mg/kg) (ng/mL) (ng .Math. hr/mL) (hr) (hr) (mL/min/kg) Bioavailability 7 3 6688.6 21246.8 1.0 2.2 2.4 203.8 50 2 2411 19053 1.3 3.3 1.8 84 69 4.2 7465.0 17003.1 0.38 1.2 4.2 ND 70 3.87 5665.0 11115.9 0.5 1.1 6.0 ND 76 4.17 2340.0 5646.9 0.5 2.9 12.3 45.6 93 5.5 1095.2 3309.1 0.36 ND 18.0 31.3 94 3 7178.7 12914.8 0.58 1.5 4.1 91.6 113 3 700.6 2415.2 0.08 4.9 21.5 67 153 5 494.7 769.7 0.17 9.7 109.8 54.3 162 3 599.6 1052.0 0.25 3.4 49.5 62.0 (ND = not determined)

(1636) As is evident from the results presented in Table 3, 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.

(1637) As is evident from the results presented in Tables 4 and 5, the compounds of the invention show advantageous pharmacokinetic properties, for example half-life T.sub.1/2, area under the curve AUC, clearance Cl and/or bioavailability, compared to the prior art compounds.

(1638) 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.