NOVEL SULFONEUREA COMPOUNDS

Abstract

The present invention relates to compounds of formula (I): wherein A, B, X, Y, R.sup.1, R.sup.4 and R.sup.7 are as defined in the specification. 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.

##STR00001##

Claims

1. A compound of formula (I): ##STR00168## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: A is a phenyl or 5- or 6-membered heteroaryl group, wherein A is substituted in the a position with B, in the β position with R.sup.7 and in the α′ position with R.sup.4, and wherein A is optionally further substituted; B is a phenyl, 5- or 6-membered heteroaryl, or 4- to 6-membered saturated heterocyclic group, wherein B is optionally substituted; X is O, NH or N(CN); Y is O or S; R.sup.1 is a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, or —R.sup.20—R.sup.21 group, all optionally halo-substituted; either R.sup.4 is monovalent, and attached to A in the α′ position, and selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl and phenyl, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C.sub.1-C.sub.4 alkyl) and —O(C.sub.1-C.sub.4 haloalkyl); or R.sup.4 is divalent, and attached to A in the α′ and β′ positions, and selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O—, —OCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2—and —CH═CH—CH═CH—, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C.sub.1-C.sub.4 alkyl) and —O(C.sub.1-C.sub.4 haloalkyl); R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl) or halogen; R.sup.20 is a bond, —NH—, —NMe—, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.21 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.4 alkyl), —R.sup.22—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—NH.sub.2, —R.sup.22—NH(C.sub.1-C.sub.4 alkyl), —R.sup.22—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.22—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 haloalkyl).sub.2 and —R.sup.22—R.sup.23; R.sup.22 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein B is a pyridinyl group which is optionally substituted.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is of formula (IA): ##STR00169## wherein: A is a phenyl or 5- or 6-membered heteroaryl group, wherein A is substituted in the a position with B, in the β position with R.sup.7 and in the α′ position with R.sup.4, and wherein A is optionally further substituted; B is a phenyl, 5- or 6-membered heteroaryl, or 4- to 6-membered saturated heterocyclic group, wherein B is substituted with R.sup.2, and wherein B is optionally further substituted; X is O, NH or N(CN); Y is O or S; R.sup.1 is a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, or —R.sup.20—R.sup.21 group, all optionally halo-substituted; R.sup.2 is hydrogen, halo, cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, —R.sup.8—OH, —R.sup.8—O(C.sub.1-C.sub.4 alkyl), —R.sup.8—O(C.sub.1-C.sub.4 haloalkyl), —O—R.sup.10—OH, —O—R.sup.10—O(C.sub.1-C.sub.4 alkyl), —O—R.sup.10—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.8—NH.sub.2, —R.sup.8—NH(C.sub.1-C.sub.4 alkyl), —R.sup.8—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.8—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.8—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.8—N(C.sub.1-C.sub.4 haloalkyl).sub.2, —R.sup.11, —OR.sup.11 or —O—R.sup.10—R.sup.11; either R.sup.4 is monovalent, and attached to A in the α′ position, and selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl and phenyl, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C.sub.1-C.sub.4 alkyl) and —O(C.sub.1-C.sub.4 haloalkyl); or R.sup.4 is divalent, and attached to A in the α′ and β′ positions, and selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O—, —OCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2— and —CH═CH—CH═CH—, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C.sub.1-C.sub.4 alkyl) and —O(C.sub.1-C.sub.4 haloalkyl); R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl) or halogen; R.sup.8 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.10 is C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.11 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halo-substituted and/or optionally substituted with one, two or three substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 cycloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, phenyl, benzyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —NH(C.sub.1-C.sub.4 haloalkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl) and —N(C.sub.1-C.sub.4 haloalkyl).sub.2; R.sup.20 is a bond, —NH—, —NMe-, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.21 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.4 alkyl), —R.sup.22—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—NH.sub.2, —R.sup.22—NH(C.sub.1-C.sub.4 alkyl), —R.sup.22—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.22—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 haloalkyl).sub.2 and —R.sup.22—R.sup.23; R.sup.22 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein B is a pyridinyl group, substituted with R.sup.2, and optionally further substituted.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein A is a phenyl or imidazolyl group, wherein A is substituted in the a position with B, in the β position with R.sup.7 and in the α′ position with R.sup.4, and wherein A is optionally further substituted.

6. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein Y is O.

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein either R.sup.4 is monovalent, and attached to A in the α′ position, and selected from isopropyl, cyclopentyl, cyclohexyl and phenyl; or R.sup.4 is divalent, and attached to A in the α′ and β′ positions, and selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2O—and —OCH.sub.2CH.sub.2—.

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is of formula (II): ##STR00170## wherein: X is O, NH or N(CN); R.sup.1 is a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, or —R.sup.20—R.sup.21 group, all optionally halo-substituted; R.sup.2a is hydrogen, halo, cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —O-(alkoxyalkyl), —OR.sup.9 or —OCH.sub.2—R.sup.9; R.sup.3 is hydrogen or methyl; R.sup.4a is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl or phenyl, all optionally halo-substituted; R.sup.5 is hydrogen; or R.sup.4a and R.sup.5 together form —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2O—or —OCH.sub.2CH.sub.2—, all optionally halo-substituted; R.sup.6 is hydrogen, halogen or cyano; R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl or halogen; R.sup.9 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halo-substituted and/or optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, phenyl, benzyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH(C.sub.1-C.sub.4 alkyl) and —N(C.sub.1-C.sub.4 alkyl).sub.2; R.sup.20 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.21 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.4 alkyl), —R.sup.22—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—NH.sub.2, —R.sup.22—NH(C.sub.1-C.sub.4 alkyl), —R.sup.22—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.22—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 haloalkyl).sub.2 and —R.sup.22—R.sup.23; R.sup.22 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted.

9. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 8, wherein: either R.sup.5 is hydrogen and R.sup.4a is isopropyl, cyclopentyl, cyclohexyl or phenyl; or R.sup.4a and R.sup.5 together form —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2O— or —OCH.sub.2CH.sub.2—.

10. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 8, wherein R.sup.6 is hydrogen or fluoro.

11. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is of formula (III): ##STR00171## wherein: X is O, NH or N(CN); R.sup.1 is a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, or —R.sup.20—R.sup.21 group, all optionally halo-substituted; R.sup.2b is hydrogen, halo, cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, —O(C.sub.1-C.sub.4 alkyl) or —O(C.sub.1-C.sub.4 haloalkyl); R.sup.3 is hydrogen or methyl; R.sup.4b is C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl; R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl or halogen; R.sup.20 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.21 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.4 alkyl), —R.sup.22—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—NH.sub.2, —R.sup.22—NH(C.sub.1-C.sub.4 alkyl), —R.sup.22—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.22—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 haloalkyl).sub.2 and —R.sup.22—R.sup.23; R.sup.22 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted.

12. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 11, wherein R.sup.4b is isopropyl, sec-butyl, isobutyl or t-butyl, all optionally halo-substituted.

13. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein X is O.

14. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NHMe, —NMe.sub.2, —NHEt, —NEt.sub.2 or —NMeEt, all optionally halo-substituted; or R.sup.1 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thiophenyl, pyrazolyl or imidazolyl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from C.sub.1-C.sub.3 alkyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.3 alkyl), —R.sup.22—NH(C.sub.1-C.sub.3 alkyl), —R.sup.22—N(C.sub.1-C.sub.3 alkyl).sub.2 and —R.sup.22—R.sup.23; wherein R.sup.22 is a bond or C.sub.1-C.sub.4 alkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl group.

15. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 3, wherein R.sup.2 is hydrogen, halo, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.8—OH, —R.sup.8—O(C.sub.1-C.sub.3 alkyl), —R.sup.8—O(C.sub.1-C.sub.3 haloalkyl), —O—R.sub.10—O(C.sub.1-C.sub.3 alkyl), —OR.sup.11 or —O—R.sup.10—R.sup.11; wherein R.sup.8 is a bond or —CH.sub.2—; R.sup.10 is C.sub.1-C.sub.3 alkylene; and R.sup.11 is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl group, all optionally substituted with one or two substituents independently selected from fluoro, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, phenyl, benzyl, —OH, —O(C.sub.1-C.sub.3 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl) and —N(C.sub.1-C.sub.3 alkyl).sub.2.

16. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.7 is methyl, ethyl, cyclopropyl or fluoro.

17. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, selected from the group consisting of: ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182##

18. (canceled)

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

20. The pharmaceutical composition as claimed in claim 19, wherein the pharmaceutical composition is an oral or topical pharmaceutical composition.

21. (canceled)

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

23. The method as claimed in claim 22, 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.

24. The method as claimed in claim 22, 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).

25. (canceled)

26. The method as claimed in claim 22, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

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

28. 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 a pharmaceutically acceptable salt, solvate or prodrug 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.

Description

EXAMPLES

Compound Synthesis

[0421] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

[0422] Abbreviations

[0423] 2-MeTHF 2-methyltetrahydrofuran

[0424] Ac.sub.2O acetic anhydride

[0425] AcOH acetic acid

[0426] aq aqueous

[0427] B.sub.2Pin.sub.2 bis(pinacolato)diboron, also called 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′- bi(1,3,2-dioxaborolane)

[0428] Boc tert-butyloxycarbonyl

[0429] br broad

[0430] Cbz carboxybenzyl

[0431] CDI 1,1-carbonyl-diimidazole

[0432] conc concentrated

[0433] d doublet

[0434] DABCO 1,4-diazabicyclo[2.2.2]octane

[0435] DCE 1,2-dichloroethane, also called ethylene dichloride

[0436] DCM dichloromethane

[0437] DIPEA N,N-diisopropylethylamine, also called Hiinig's base

[0438] DMA dimethylacetamide

[0439] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine

[0440] DME dimethoxyethane

[0441] DMF N,N-dimethylformamide

[0442] DMSO dimethyl sulfoxide

[0443] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0444] eq or equiv equivalent

[0445] (ES.sup.+) electrospray ionization, positive mode

[0446] Et ethyl

[0447] EtOAc ethyl acetate

[0448] EtOH ethanol

[0449] h hour(s)

[0450] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0451] HPLC high performance liquid chromatography

[0452] LC liquid chromatography

[0453] m multiplet

[0454] m-CPBA .sub.3-chloroperoxybenzoic acid

[0455] Me methyl

[0456] MeCN acetonitrile

[0457] MeOH methanol

[0458] (M+H).sup.+ protonated molecular ion

[0459] MHz megahertz

[0460] min minute(s)

[0461] MS mass spectrometry

[0462] Ms mesyl, also called methanesulfonyl

[0463] MsCl mesyl chloride, also called methanesulfonyl chloride

[0464] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether

[0465] m/z mass-to-charge ratio

[0466] NaOtBu sodium tert-butoxide

[0467] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide

[0468] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide

[0469] NMP N-methylpyrrolidine

[0470] NMR nuclear magnetic resonance (spectroscopy)

[0471] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o)

[0472] PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), also called Pd(dppf)Cl.sub.2

[0473] PE petroleum ether

[0474] Ph phenyl

[0475] PMB p-methoxybenzyl, also called 4-methoxybenzyl

[0476] prep HPLC preparative high performance liquid chromatography

[0477] prep-TLC preparative thin layer chromatography

[0478] PTSA p-toluenesulfonic acid

[0479] q quartet

[0480] RP reversed phase

[0481] RT room temperature

[0482] s singlet

[0483] sat saturated

[0484] SCX solid supported cation exchange (resin)

[0485] sept septuplet

[0486] t triplet

[0487] T3P propylphosphonic anhydride

[0488] TBME tert-butyl methyl ether, also called methyl tert-butyl ether

[0489] TEA triethylamine

[0490] TFA 2,2,2-trifluoroacetic acid

[0491] THF tetrahydrofuran

[0492] TLC thin layer chromatography

[0493] wt % weight percent or percent by weight

[0494] Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0495] Experimental Methods

[0496] Nuclear Magnetic Resonance

[0497] 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: [0498] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0499] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0500] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0501] 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 [0502] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

[0503] LC-MS

[0504] 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.

[0505] Preparative Reversed Phase HPLC General Methods

[0506] Acidic prep HPLC (x-y% MeCN in water): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, x % MeCN; 0.2-5.5 min, ramped from x % MeCN to y % MeCN; 5.5-5.6 min, ramped from y % MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0507] Acidic prep HPLC (x-y % MeOH in water): Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM aq formic acid-gradient over 7.5 min using UV detection at 254 nm. Gradient information: 0.0-1.5 min, x % MeOH; 1.5-6.8 min, ramped from x % MeOH to y % MeOH; 6.8-6.9 min, ramped from y % MeOH to 95% MeOH; 6.9-7.5 min, held at 95% MeOH.

[0508] Basic prep HPLC (x-y % MeCN in water): Waters X-Bridge Prep column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 minl x % MeCN; 0.2-5.5 min, ramped from x % MeCN to y % MeCN; 5.5-5.6 min, ramped from y % MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

Synthesis of Intermediates

Intermediate L1: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)(methylsulfonyl)amide

[0509] ##STR00022##

[0510] A solution of methanesulfonamide (1.7 g, 17.87 mmol) and DMAP (4.37 g, 35.7 mmol) in MeCN (25 mL) was stirred at room temperature for 10 minutes. Diphenyl carbonate (4.21 g, 19.66 mmol) was then added and the reaction was stirred at room temperature for 5 days. The precipitate was filtered off, washed with MTBE and dried in vacuo to afford the title compound (1.67 g, 38%) as a white solid.

[0511] 1H NMR (CDCl.sub.3) δ 9.07 (d, J=7.4 Hz, 2H), 6.74 (d, J=7.5 Hz, 2H), 3.35 (s, 6H), 3.20 (s, 3H).

[0512] The following intermediates were prepared according to the general procedure of Intermediate L1:

TABLE-US-00001 Int. Structure and name Characterisation and procedure L2 [00023] .sup.1H NMR (CDCl.sub.3) δ 9.08 (d, J = 7.4 Hz, 2H), 6.72 (d, J = 7.5 Hz, 2H), 3.34 (s, 6H), 3.03 (tt, J = 8.1, 4.9 Hz, 1H), 1.36-1.29 (m, 2H), 0.99-0.90 (m, 2H). From cyclopropanesulfonamide L3 [00024] From (N-methyl-N- aminosulfoamino)methane L4 [00025] From ethanesulfonamide L5 [00026] From benzenesulfonamide L6 [00027] .sup.1H NMR (CDCl.sub.3) δ 8.24 (s, 2H), 6.55 (s, 2H), 3.06 (s, 6H), 1.48 (s, 9H). From 2-methyl-2-propanesulfonamide

Intermediate L7: 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

Step A: Ethyl furan-3-carboxylate

[0513] ##STR00028##

[0514] To a mixture of furan-3-carboxylic acid (50 g, 446.10 mmol, 1 eq) in EtOH (500 mL) was added dropwise H.sub.2SO.sub.4 (89.29 g, 892.20 mmol, 98% purity in solution, 2 eq) at 25° C. Then the reaction mixture was heated to 75° C. and stirred for 2.5 hours. The mixture was poured into ice water (200 mL) and extracted with EtOAc (.sub.3×200 mL). The organic phases were washed with 20% aqueous NaHCO.sub.3 solution (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (50 g, 80%) as a yellow oil.

[0515] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.01 (d, 1H), 7.43 (t, 1H), 6.75 (t, 1H), 4.3.sup.1 (q, 2H) and 1.35 (S, 3H).

Step B: 4-(Ethoxycarbonyl)furan-2-sulfonic acid

[0516] ##STR00029##

[0517] To a mixture of ethyl furan-3-carboxylate (45 g, 321.12 mmol, 1 eq) in DCM (500 mL) at −10° C. was added dropwise sulfurochloridic acid (46.77 g, 401.39 mmol, 1.25 eq) under N.sub.2. After 15 minutes, the reaction mixture was stirred at 20° C. for 24 hours. Then the reaction mixture was filtered and the filter cake was dried in vacuo to give the title compound (55 g, 78%) as a white solid.

[0518] 1H NMR (400 MHz, D.sub.2O) δ 8.19 (s, 1H), 7.10 (s, 1H), 4.27 (q, 2H) and 1.27 (t, 3H).

Step C: Ethyl 5-(chlorosulfonyl)furan-3-carboxylate

[0519] ##STR00030##

[0520] To a mixture of 4-(ethoxycarbonyl)furan-2-sulfonic acid (55 g, 249.77 mmol, 1 eq) in DCM (350 mL) at −10° C. was added dropwise pyridine (20.74 g, 262.26 mmol, 1.05 eq) under N.sub.2. After 15 minutes, PCl.sub.5 (54.61 g, 262.26 mmol, 1.05 eq) was added and the resulting mixture was stirred for another 15 minutes. Then the reaction mixture was warmed to 20° C. and stirred for 12 hours. The mixture was quenched with water (200 mL) and extracted with DCM (2×200 mL). Then the combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (35 g, 59%) as a yellow oil, which was used directly in the next step without further purification.

Step D: Ethyl 5-sulfamoylfuran-3-carboxylate

[0521] ##STR00031##

[0522] NH.sub.3 (15 psi) was bubbled into a solution of ethyl 5-(chlorosulfonyl)furan-3-carboxylate (35 g, 146.66 mmol, 1 eq) in DCM (300 mL) at 0° C. for 15 minutes. Then the reaction mixture was stirred at 20° C. for 45 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by trituration with DCM (200 mL).The mixture was filtered and the filter cake was dried in vacuo to give the title compound (24 g, 75%) as a white solid.

[0523] 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.63 (s, 1H), 7.93 (s, 2H), 7.12 (s, 1H), 4.27 (q, 2H) and 1.28 (t, 3H).

Step E: 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

[0524] ##STR00032##

[0525] To a mixture of ethyl 5-sulfamoylfuran-3-carboxylate (24 g, 109.48 mmol, 1 eq) in THF (500 mL) was added dropwise over a period of 3o minutes MeMgBr (3 M, 164.22 mL, 4.5 eq) at −10° C. under N.sub.2. The mixture was stirred at 0° C. for 30 minutes, then warmed to 20° C. and stirred for 12 hours. The mixture was poured slowly into ice-water (300 mL) and extracted with EtOAc (2×300 mL).The organic phases were washed with brine (loo mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by trituration with a mixture of n-hexane: EtOAc (v:v 20:1, 300 mL). The mixture was filtered and the filter cake was dried in vacuo to give the title compound (22 g, 97% yield, 99.3% purity on LCMS) as a white solid.

[0526] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.68 (s, 1H), 7.65 (br s, 2H), 6.94 (s, 1H), and 1.38 (s, 6H).

Intermediate L8: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

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

[0527] ##STR00033##

[0528] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in DCE (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol, 1.57 eq) at 25° C. The mixture was stirred at 25° C. for 30 minutes. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol, 1 eq) was added, and the reaction mixture was heated to 70° C. and stirred for 15.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 30:1 to 3:1) to give impure product (26.7 g). The impure product was dissolved in pyrrolidine (10 mL), and the resulting mixture was stirred at 70° C. for 2 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 1M aqueous HCl solution. The mixture was extracted with EtOAc (.sub.3×50 mL). The combined organic layers were washed with brine (2×33 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as a yellow oil.

[0529] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H) and 1.13-1.07 (m, 2H).

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

[0530] ##STR00034##

[0531] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 5 eq) in H.sub.2O (150 mL). Then the reaction mixture was heated to 60° C. and iron powder (39.38 g, 705.24 mmol, 3 eq) was added in portions. The reaction mixture was stirred at 60° C. for 16 hours. Then the reaction mixture was concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL), and the mixture was 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%) as a yellow oil.

[0532] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H) and 0.90-0.87 (m, 2H).

[0533] LCMS: m/z 124.2 (M+H).sup.+(ES.sup.+).

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

[0534] ##STR00035##

[0535] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in MeCN (500 mL) and H.sub.2O (50 mL) at 0° C. was added concentrated HCl solution (50 mL, 36 wt % aqueous solution). Then a 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. Then SO.sub.2 gas (15 psi) was bubbled into the resulting mixture at 0° C. for 20 minutes. The resulting reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was 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, 1:0 to 1:1) to give the title compound (14 g, 44%) as a yellow oil.

[0536] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H) and 1.16-1.12 (m, 2H).

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

[0537] ##STR00036##

[0538] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (.sub.300 mL) was added TEA (27.42 g, 270.99 mmol, 2 eq) and bis(4-methoxybenzyl)amine (34.87 g, 135.49 mmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour, diluted with H.sub.2O (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (0.5% NH.sub.3.H.sub.2O-MeCN) and the collected eluting solution was concentrated under reduced pressure to remove most of MeCN. Then the mixture was extracted with EtOAc (3×1 L). 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, 52% yield, 99.8% purity on HPLC).

[0539] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.49 (d, 1H), 7.08-7.06 (m, 4H), 6.79-6.77 (m, 4H), 6.62 (d, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 3.68-3.64 (m, 1H), 1.15-1.13 (m, 2H) and 1.09-1.06 (m, 2H).

[0540] LCMS: m/z 428.2 (M+H).sup.+(ES.sup.+).

Step E: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

[0541] ##STR00037##

[0542] To a mixture of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide g, 2.34 mmol, 1 eq) in DCM (10 mL) was added TFA (15.40 g, 135.06 mmol, 57.74 eq). The mixture was stirred at 25° C. for 12 hours. Most of the solvent was evaporated, and the residue was re-dissolved in MeOH (30 mL). Solids were formed and the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was triturated with a mixture of petroleum ether and EtOAc (30 mL, 20:1) to give the title compound (430 mg, 88% yield, 90% purity on LCMS) as a white solid.

[0543] .sup.1H NMR (DMSO-d.sub.6) δ 7.92 (s, 1H), 7.38 (br s, 2H), 6.55 (s, 1H), 3.84-3.78 (m, 1H) and 1.10-0.98 (m, 4H).

Intermediate L9: 1-Methyl-3-[methyl(sulfamoyl)amino]pyrrolidine

[0544] ##STR00038##

[0545] To a solution of N,1-dimethylpyrrolidin-3-amine (4 g, 35.03 mmol, 1 eq) in 1,2-dimethoxyethane (80 mL) was added sulfuric diamide (4.04 g, 42.04 mmol, 1.2 eq) in one portion. The reaction mixture was heated to 90° C. and stirred for 12 hours under N.sub.2. Then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, EtOAc: EtOH, 20:1 to 5:1) to give the title compound (3.5 g, 43% yield, 83% purity on LCMS) as a brown oil.

[0546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.65 (s, 2H), 4.31-4.23 (m, 1H), 2.62 (s, 3H), 2.61-2.56 (m, 2H), 2.41-2.36 (m, 1H), 2.20 (s, 3H), 2.18-2.12 (m, 1H), 2.05-1.98 (m, 1H) and 1.78-1.71 (m, 1H).

[0547] LCMS: m/z 194.0 (M+H).sup.+(ES.sup.+).

Intermediate L10: Benzenesulfinamide

[0548] ##STR00039##

[0549] To a solution of methyl benzenesulfinate (500 mg, 3.20 mmol, 1 eq) in THF (10 mL) was added with LiHMDS (1M, 4.80 mL, 1.5 eq) at −78° C. The reaction mixture was stirred at −78° C. for 2 hours. Then a solution of NH.sub.4Cl (342 mg, 6.40 mmol, 2 eq) in H.sub.2O (5 mL) was added, and the resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with water (20 mL), and extracted with ethyl acetate (3×20 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (400 mg, 89%) as a white solid.

[0550] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78-7.74 (m, 2H), 7.54-7.51 (m, 3H) and 4.36 (br s, 2H).

[0551] LCMS: m/z 141.9 (M+H).sup.+(ES.sup.+).

Intermediate L11: Methanesulfinamide

[0552] ##STR00040##

[0553] Ammonia gas (15 psi) was bubbled into THF (10 mL) at −78° C. for 10 minutes. Oxalyl chloride (39.18 mmol, 3.4 mL, 2 eq) was added into a solution of sodium methanesulfinate (2 g, 19.59 mmol, 1 eq) in THF (20 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hour. Then the mixture was dropped into the above NH.sub.3/THF solution at 0° C. The resulting mixture was stirred at 20° C. for 12 hours. A solid formed. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound (0.9 g, crude) as a yellow solid.

[0554] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.30 (br s, 2H) and 2.66 (s, 3H).

Intermediate R1: 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-amine

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

[0555] ##STR00041##

[0556] Nitric acid (150 mL, 2350 mmol) was slowly added to sulfuric acid (150 mL) cooled to 0° C., while keeping the temperature below 20° C. The mixture was stirred for 10 minutes and added dropwise to a stirred mixture of N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide (58 g, 228 mmol) in AcOH (300 mL) and sulfuric acid (150 mL), keeping the temperature below 30° C. The reaction mixture was stirred at room temperature for 4 hours and then poured onto ice/water (4.5 L total volume, 2.5 kg ice) and left to stand at room temperature for 18 hours. The solid was filtered, washed with water (2.5 L), and dried to afford the title compound (55 g, 80%) as an ochre powder.

[0557] .sup.1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.85 (s, 1H), 3.01-2.88 (m, 4H), 2.07 (p, J=7.5 Hz, 2H), 2.00 (s, 3H).

LCMS m/z 299.0/301.0 (M+H).SUP.+.(ES.SUP.+.).

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

[0558] ##STR00042##

[0559] A mixture of N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (30 g, 100 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.02 mL, 100 mmol) and K.sub.2CO.sub.3 (34.7 g, 251 mmol) in dioxane (500 mL) and H.sub.2O (140 mL) was degassed with N.sub.2 for 15 minutes. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (4.10 g, 5.01 mmol) was added. The reaction mixture was heated at 100° C. for 16 hours, diluted with brine (300 mL), and extracted with EtOAc (2×800 mL). The organic layers were dried (MgSO.sub.4) and evaporated. The residue was triturated with EtOAc/isohexane (1:1 mixture, 400 mL) and the resultant solid was filtered, rinsing with hexanes, and dried in vacuo to afford the title compound (15.33 g, 56%) as a brown solid.

[0560] .sup.1H NMR (DMSO-d6) δ 9.65 (s, 1H), 7.41 (s, 1H), 2.98-2.87 (m, 4H), 2.20 (s, 3H), 2.07-2.03 (m, 2H), 1.99 (s, 3H).

[0561] LCMS m/z 235.2 (M+H).sup.+(ES.sup.+).

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

[0562] ##STR00043##

[0563] N-(6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (15.33 g, 65.4 mmol) was suspended in a mixture of EtOH (126 mL) and concentrated aq HCl (126 mL). The mixture was heated to reflux overnight and concentrated in vacuo. The residue was basified by portionwise addition of 2M aq NaOH (500 mL). The aqueous layer was extracted with DCM (5×200 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (15.18 g, 84%) as a brown solid.

[0564] .sup.1H NMR (DMSO-d6) δ 7.21 (s, 1H), 6.61 (s, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.16 (s, 3H), 2.00-1.94 (m, 2H).

[0565] LCMS m/z 193.4 (M+H).sup.+(ES.sup.+).

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

[0566] ##STR00044##

[0567] A solution of 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine (4.9 g, 20.39 mmol) and isopentyl nitrite (3 mL, 22.33 mmol) in MeCN (400 mL) was heated to 55° C., whereupon CuBr.sub.2 (4.56 g, 20.39 mmol) was added. The reaction mixture was heated to 70° C. and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature and 1M HCl (200 mL) was added. The reaction mixture was extracted with DCM (3×200 mL). The organic phases were concentrated in vacuo and the crude product was purified by flash chromatography (0-20% EtOAc/isohexane) to afford the title compound (3.2 g, 60%) as a pale yellow solid.

[0568] .sup.1H NMR (DMSO-d6) δ 7.50 (s, 1H), 2.94-2.86 (m, 4H), 2.41 (s, 3H), 2.09 (p, J=7.6 Hz, 2H).

[0569] LCMS m/z 279.2 (M+Na).sup.+(ES.sup.+).

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

[0570] ##STR00045##

[0571] A stirred mixture of 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (8.42 g, 32.9 mmol), saturated aq NH.sub.4Cl (50 mL) and iron powder (7.34 g, 132 mmol) in EtOH/water (3:2, 80 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc (20 mL), and filtered through a pad of Celite®. The filtrate was diluted with water (10 mL). The layers were separated and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/isohexane) to afford the title compound (6.52 g, 75%) as a pink solid.

[0572] .sup.1H NMR (DMSO-d6) δ 6.48 (s, 1H), 4.94 (br s, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.24 (s, 3H), 2.02-1.95 (m, 2H).

[0573] LCMS m/z 226/228 (M+H).sup.+(ES.sup.+).

Intermediate R2: 2-Bromo-5-cyclopropyl-4-fluoroaniline

Step A: 3-Cyclopropyl-4-fluoroaniline

[0574] ##STR00046##

[0575] A mixture of 3-bromo-4-fluoroaniline (5 g, 26.3 mmol), cyclopropylboronic acid (2.7 g, 31.4 mmol) and K.sub.2CO.sub.3 (11 g, 80 mmol) in dioxane (100 mL) and water (20 ml) was degassed with N.sub.2 for 10 minutes. PdCl.sub.2(dppf) (0.96 g, 1.312 mmol) was added and the reaction mixture heated at 80° C. for 16 hours. Additional cyclopropylboronic acid (2.7 g, 26.3 mmol) and additional PdCl.sub.2(dppf) (0.96 g, 26.3 mmol) were added and the reaction mixture heated at 80° C. for 48 hours. Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was washed with saturated brine (2×100 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc/isohexane) to afford the title compound (1.87 g, 42%) as a brown solid.

[0576] .sup.1H NMR (DMSO-d.sub.6) δ 6.79-6.71 (m, 1H), 6.35-6.28 (m, 1H), 6.12 (dd, J=7.0, 2.7 Hz, 1H), 4.78 (s, 2H), 1.96-1.88 (m, 1H), 0.94-0.86 (m, 2H), 0.61- 0.55 (m, 2H).

[0577] LCMS m/z 152.1 (M+H)+(ES+).

Step B: 2-Bromo-5-cyclopropyl-4-fluoroaniline

[0578] ##STR00047##

[0579] 3-Cyclopropyl-4-fluoroaniline (1.37 g, 8.07 mmol) and NBS (1.4 g, 7.87 mmol) in MeCN (20 mL) were stirred at room temperature for 16 hours. Then the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (0-40% EtOAc/hexanes) to afford the title compound (1.04 g, 52%) as a pale tan solid.

[0580] .sup.1H NMR (DMSO-d.sub.6) δ 7.18 (d, J=9.7 Hz, 1H), 6.40 (d, J=7.4 Hz, 1H), 5.00 (s, 2H), 1.91 (tt, J=8.5, 5.2 Hz, 1H), 0.97-0.90 (m, 2H), 0.63-0.58 (m, 2H).

[0581] LCMS m/z 229.9/231.9 (M+H)+(ES+).

Intermediate R3: 2-Bromo-4-fluoro-5-(trifluoromethoxy)aniline

[0582] ##STR00048##

[0583] 4-Fluoro-3-(trifluoromethoxy)aniline (1 g, 5.13 mmol) and NBS (1 g, 5.62 mmol) in MeCN (50 mL) were stirred at room temperature for 3 hours. Volatiles were evaporated. The crude product was diluted with DCM (50 mL), washed with water (100 mL) and saturated aq Na.sub.2S.sub.2O.sub.3 (100 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc/isohexane) to afford the title compound (1.25 g, 88%) as a brown oil.

[0584] .sup.1H NMR (DMSO-d.sub.6) δ 7.62 (d, J=9.9 Hz, 1H), 6.94-6.87 (m, 1H), 5.53 (s, 2H).

[0585] LCMS m/z 273/275 (M+H).sup.+(ES.sup.+).

Intermediate R4: 2-Bromo-5-ethyl-4-fluoroaniline

[0586] ##STR00049##

[0587] 3-Ethyl-4-fluoroaniline (1.06 g, 7.62 mmol) and NBS (1.4 g, 7.87 mmol) in MeCN (25 mL) were stirred at room temperature for 3 hours. Volatiles were evaporated. The crude product was diluted with DCM (50 mL), washed with water (loo mL) and saturated aq Na.sub.2S.sub.2O.sub.3 (100 mL), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-40% EtOAc/isohexane), followed by another flash chromatography on silica gel (0-50% EtOAc/isohexane) to afford the title compound (1.39 g, 75%) as a brown oil.

[0588] .sup.1H NMR (DMSO-d.sub.6) δ 7.19 (d, J=9.4 Hz, 1H), 6.70 (d, J=7.3 Hz, 1H), 5.12 (s, 2H), 2.47 (q, J=7.4 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H).

[0589] LCMS m/z 218/220 (M+H).sup.+(ES.sup.+).

Intermediate R5: 4-Bromo-3-methyl-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0590] ##STR00050##

1-Methylpiperidin-4-ol (0.67 g, 5.79 mmol) was added to a mixture of KO.SUP.t.Bu (0.89 g,

[0591] 7.89 mmol) in THF (5 mL) at room temperature. The reaction mixture was stirred for 1 hour, and then cooled in an ice bath. A solution of 4-bromo-2-fluoro-3-methylpyridine (1 g, 5.26 mmol) in THF (5 mL) was added. The mixture was warmed to room temperature, stirred for 2 days, and then partitioned between EtOAc (20 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The organic phases were combined, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/)/DCM) to afford the title compound (1.30 g, 86%) as a colourless oil.

[0592] .sup.1H NMR (DMSO-d6) δ 7.85 (dd, J=5.4, 0.8 Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 5.02 (tt, J=8.1, 4.0 Hz, 1H), 2.59-2.52 (m, 2H), 2.26-2.20 (m, 5H), 2.17 (s, 3H), 1.97-1.86 (m, 2H), 1.74-1.62 (m, 2H).

[0593] LCMS m/z 285.1/287.1 (M+H).sup.+(ES.sup.+).

[0594] The following intermediate was prepared according to the general procedure of Intermediate R5:

TABLE-US-00002 Int. Structure and name Characterisation and procedure R6 [00051] .sup.1H NMR (DMSO-d6) δ 8.05 (d, J = 5.5 Hz, 1H), 7.18 (dd, J = 5.5, 1.7 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 4.92-4.85 (m, 1H), 2.23- 2.12 (m, 7H), 2.11-2.01 (m, 2H), 1.88-1.75 (m, 2H), 1.46-1.24 (m, 4H). LCMS m/z 299.1/301.1 (M + H).sup.+ (ES.sup.+).

Intermediate R7: 5-Bromo-6-cyclopropyl-2,3-dihydro-1H-inden-4-amine

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

[0595] ##STR00052##

[0596] N.sub.2 was bubbled through a stirred mixture of N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate R1, step A) (1 g, 3.34 mmol), cyclopropylboronic acid (0.35 g, 4.01 mmol) and K.sub.2CO.sub.3 (1.39 g, 10.03 mmol) in dioxane (35 ml) and water (10 ml) for 10 minutes. PdCl.sub.2(dppf) (0.122 g, 0.167 mmol) was added. Then the reaction mixture was heated at 80° C. for 4 hours, cooled to room temperature, and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was dried (MgSO.sub.4) and evaporated. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/isohexane) to afford the title compound (120 mg, 13%) as a yellow solid.

[0597] .sup.1H NMR (DMSO-d6) δ 9.76 (s, 1H), 7.09 (s, 1H), 2.98-2.88 (m, 4H), 2.09-1.94 (m, 6H), 1.00-0.89 (m, 2H), 0.68-0.60 (m, 2H).

[0598] LCMS m/z 261.2 (M+H).sup.+(ES.sup.+).

Step B: 6-Cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-amine

[0599] ##STR00053##

[0600] N-(6-Cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (120 mg, 0.461 mmol) was suspended in H.sub.2O (2 mL). Concentrated HCl (2 mL) was added slowly, whilst the reaction mixture was cooled in an ice bath. Then reaction mixture was stirred at 110° C. for 16 hours and cooled to 0° C. on ice. The reaction mixture was basified by portionwise addition of 50 wt % aqueous NaOH (˜50 mL by 10 mL increments). The aqueous mixture was extracted with DCM (5×200 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (107 mg, 51%) as a brown solid.

[0601] .sup.1H NMR (DMSO-d6) δ 7.14 (s, 1H), 6.76 (s, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 1.97 (p, J=7.4 Hz, 2H), 1.76-1.65 (m, 1H), 0.96-0.90 (m, 2H), 0.59-0.47 (m, 2H).

[0602] LCMS m/z 219.4 M+H).sup.+(ES.sup.+).

Step C: 5-Bromo-6-cyclopropyl-4-nitro-2,3-dihydro-1H-indene

[0603] ##STR00054##

[0604] A solution of 6-cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-amine (106 mg, 0.487 mmol) and isopentyl nitrite (72 μL, 0.536 mmol) in MeCN (7 mL) was heated to 55° C. Then CuBr.sub.2 (109 mg, 0.487 mmol) was added, and the reaction mixture was heated to 70° C. and stirred for 1 hour. Then the reaction mixture was allowed to cool to room temperature. 1M HCl (10 mL) was added and the reaction mixture was extracted with DCM (3×20 mL). The combined organic phases were concentrated in vacuo to afford the title compound which was used crude in the next step.

Step D: 5-Bromo-6-cyclopropyl-2,3-dihydro-1H-inden-4-amine

[0605] ##STR00055##

[0606] A stirred mixture of 5-bromo-6-cyclopropyl-4-nitro-2,3-dihydro-1H-indene (104 mg, 0.369 mmol), saturated aqueous ammonium chloride (0.5 mL) and iron powder (82 mg, 1.474 mmol) in EtOH:water (3:2, 1 mL) was stirred at 80° C. for 2 hours. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and filtered through a pad of Celite®. The filtrate was diluted with water (10 mL) and the organic layer was collected, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc/isohexane) to afford the title compound (17 mg, 11%) as a pink solid.

[0607] LCMS m/z 252/254 (M+H).sup.+(ES.sup.+).

Intermediate R8: 6-Methyl-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0608] ##STR00056##

[0609] N.sub.2 was bubbled through a stirred mixture of 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R1) (200 mg, 0.885 mmol), pyridin-4-ylboronic acid (120 mg, 0.973 mmol) and K.sub.2CO.sub.3 (367 mg, 2.65 mmol) in dioxane (30 mL) and water (5 mL) for 5 minutes. PdCl.sub.2(dppf) (32.4 mg, 0.044 mmol) was added, and the reaction mixture was heated at 80° C. for 20 hours. Then the reaction mixture was cooled to room temperature, and partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was dried (MgSO.sub.4), evaporated and the residue was purified by flash chromatography on silica gel (0-40% EtOAc/isohexane) to afford the title compound (40 mg, 20%) as a yellow oil.

[0610] .sup.1H NMR (DMSO-d6) δ 8.67-8.62 (m, 2H), 7.21-7.17 (m, 2H), 6.47 (s, 1H), 4.14 (s, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.65 (t, J=7.3 Hz, 2H), 2.00 (p, J=7.4 Hz, 2H), 1.87 (s, 3H).

[0611] LCMS m/z 225.1 (M+H).sup.+(ES.sup.+).

[0612] The following intermediates were prepared according to the general procedure of Intermediate R8:

TABLE-US-00003 Int. Structure and name Characterisation and procedure R9 [00057] .sup.1H NMR (DMSO-d6) δ 8.51 (d, J = 5.1 Hz, 1H), 7.05 (s, 1H), 6.98 (dd, J = 5.0, 1.6 Hz, 1H), 6.46 (s, 1H), 4.11 (s, 2H), 3.33 (s, 3H), 2.79 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.4 Hz, 2H), 2.00 (p, J = 7.4 Hz, 2H), 1.87 (s, 3H). LCMS m/z 239.2 (M + H).sup.+ (ES.sup.+). From Intermediate R.sub.1 R10 [00058] .sup.1H NMR (DMSO-d6) δ 8.80-8.77 (m, 1H), 7.85 (s, 1H), 7.54 (dd, J = 5.0, 1.7 Hz, 1H), 6.47 (s, 1H), 4.40 (s, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.00 (p, J = 7.4 Hz, 2H), 1.86 (s, 3H). LCMS m/z 250.4 (M + H).sup.+ (ES.sup.+). From Intermediate R.sub.1 R11 [00059] .sup.1H NMR (DMSO-d6) δ 8.82 (d, J = 4.9 Hz, 1H), 7.65 (s, 1H), 7.53 (dd, J = 4.9, 1.5 Hz, 1H), 6.48 (s, 1H), 4.36 (s, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 2.04-1.96 (m, 2H), 1.86 (s, 3H). LCMS m/z 293.5 (M + H).sup.+ (ES.sup.+). From Intermediate R.sub.1 R12 [00060] .sup.1H NMR (DMSO-d6) δ 7.42-7.36 (m, 1H), 6.93 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.71 (dt, J = 7.5, 1.3 Hz, 1H), 6.68 (dd, J = 2.6, 1.4 Hz, 1H), 6.45 (s, 1H), 3.96 (s, 2H), 3.77 (s, 3H), 2.79 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.00 (p, J = 7.4 Hz, 2H), 1.88 (s, 3H). LCMS m/z 254.2 (M + H).sup.+ (ES.sup.+). From Intermediate R.sub.1

Intermediate R13: 5-(2-Cyclopropoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

Step A: 4-Bromo-2-cyclopropoxypyridine

[0613] ##STR00061##

[0614] To a mixture of cyclopropanol (1 g, 17.22 mmol) and 4-bromo-2-fluoropyridine (1.2 ml, 11.68 mmol) in NMP (13 mL) was added potassium tert-butoxide (1.9 g, 16.93 mmol) portionwise. The resultant mixture was stirred at room temperature for 30 minutes under nitrogen. Then the reaction mixture was diluted with EtOAc (50 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (2.27 g, 83%) as a brown oil.

[0615] .sup.1H NMR (DMSO-d6) δ 8.12 (d, J=5.4 Hz, 1H), 7.28 (dd, J=5.4, 1.7 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.21 (tt, J=6.2, 3.0 Hz, 1H), 0.80-0.74 (m, 2H), 0.70-0.66 (m, 2H).

[0616] LCMS m/z 214/216 (M+H).sup.+(ES.sup.+).

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

[0617] ##STR00062##

[0618] To a solution of 4-bromo-2-cyclopropoxypyridine (189 mg, 0.885 mmol) in dioxane (5 mL) was added B.sub.2Pin.sub.2 (247 mg, 0.973 mmol), followed by potassium acetate (347 mg, 3.54 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (36 mg, 0.044 mmol). The reaction was degassed (N.sub.2, 5 minutes), evacuated and backfilled with N.sub.2 (×3) and stirred at 90° C. for 2 hours. Then the reaction mixture was cooled to room temperature. A solution of 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R1) (200 mg, 0.885 mmol) in dioxane (3 mL) was added, followed by a solution of potassium carbonate (367 mg, 2.65 mmol) in water (1.5 mL). The reaction mixture was stirred at 90° C. for 16 hours, diluted with brine (io mL), and extracted with DCM (2×20 mL). The organic layer was dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by flash chromatography (0-60% EtOAc/isohexane) to afford the title compound (135 mg, 52%) as a yellow oil.

[0619] .sup.1H NMR (DMSO-d6) δ 8.26 (d, J=5.1 Hz, 1H), 6.81 (dd, J=5.1, 1.3 Hz, 1H), 6.63 (d, J=1.2 Hz, 1H), 6.45 (s, 1H), 4.22 (tt, J=6.3, 3.1 Hz, 1H), 4.16 (s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.02-1.95 (m, 2H), 1.88 (s, 3H), 0.81- 0.68 (m, 4H).

[0620] LCMS m/z 281.2 (M+H)+(ES+).

[0621] The following intermediates were prepared according to the general procedure of Intermediate R13:

TABLE-US-00004 Int. Structure and name Characterisation and procedure R14 [00063] LCMS m/z 281.2 (M + H).sup.+ (ES.sup.+). From Intermediate R7 R15 [00064] .sup.1H NMR (DMSO-d6) δ 8.32 (d, J = 5.1 Hz, 1H), 7.76 (t, J = 72.9 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 6.87 (s, 1H), 6.46 (s, 1H), 4.27 (s, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.04-1.96 (m, 2H), 1.89 (s, 3H). LCMS m/z 291.1 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R16 [00065] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J = 5.1 Hz, 1H), 6.77 (dd, J = 5.2, 1.2 Hz, 1H), 6.58 (t, J = 1.1 Hz, 1H), 6.45 (s, 1H), 4.16 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.01-1.93 (m, 2H), 1.88 (s, 3H). LCMS m/z 258.3 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R17 [00066] .sup.1H NMR (DMSO-d6) δ 8.28 (d, J = 5.1 Hz, 1H), 6.88 (d, J = 11.3 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 6.65 (s, 1H), 4.01 (s, 2H), 3.04-2.95 (m, 1H), 1.79 (d, J = 2.1 Hz, 3H), 1.15 (d, J = 6.7 Hz, 6H). LCMS m/z 278.1 (M + H).sup.+ (ES.sup.+). From Intermediate R33, step C R18 [00067] .sup.1H NMR (DMSO-d6) δ 8.22 (d, J = 5.2 Hz, 1H), 6.77 (dd, J = 5.2, 1.4 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.57-5.52 (m, 1H), 4.16 (s, 2H), 3.96-3.92 (m, 1H), 3.89-3.80 (m, 2H), 3.80-3.74 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.30- 2.21 (m, 1H), 2.09-1.96 (m, 3H), 1.88 (s, 3H). LCMS m/z 311.2 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R19 [00068] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.1 Hz, 1H), 6.74 (d, J = 5.2 Hz, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 5.35 (s, 1H), 4.14 (s, 2H), 3.59- 3.53 (m, 1H), 3.50-3.45 (m, 1H), 3.30 (s, 3H), 2.78 (t, J = 7.4 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.04-1.93 (m, 2H), 1.88 (s, 3H), 1.30-1.26 (m, 3H). LCMS m/z 313.2 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R20 [00069] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.2 Hz, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 5.27-5.15 (m, 1H), 4.14 (s, 2H), 3.93-3.80 (m, 4H), 2.78 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.11-1.93 (m, 4H), 1.88 (s, 3H), 1.72-1.56 (m, 2H). LCMS m/z 325.2 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R21 [00070] .sup.1H NMR (DMSO-d6) δ 8.20 (d, J = 5.2 Hz, 1H), 6.72 (dd, J = 5.1, 1.4 Hz, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 5.11-5.04 (m, 1H), 4.47 (d, J = 3.9 Hz, 1H), 4.14 (s, 2H), 3.67- 3.62 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.68- 2.61 (m, 2H), 2.00 (q, J = 7.6 Hz, 2H), 1.94-1.85 (m, 5H), 1.73-1.66 (m, 2H), 1.64-1.58 (m, 4H). LCMS m/z 339.1 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R22 [00071] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.1 Hz, 1H), 6.75 (dd, J = 5.1, 1.4 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 2.89-2.81 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.18 (s, 3H), 2.08-1.95 (m, 4H), 1.96- 1.90 (m, 1H), 1.88 (s, 3H), 1.86-1.77 (m, 2H), 1.77-1.69 (m, 2H), 1.69-1.60 (m, 2H), 1.56-1.44 (m, 2H). LCMS m/z 352.6 (M + H).sup.+ (ES.sup.+). From Intermediate R1 R23 [00072] LCMS m/z 352.2 (M + H).sup.+ (ES.sup.+). From Intermediate R1 + Intermediate R5 R24 [00073] .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J = 5.1 Hz, 1H), 6.71 (dd, J = 5.1, 1.4 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.98-4.87 (m, 1H), 4.12 (s, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.25-2.05 (m, 9H), 1.98 (p, J = 7.5 Hz, 2H), 1.90-1.77 (m, 5H), 1.49- 1.26 (m, 4H). LCMS m/z 366.6 (M + H).sup.+ (ES.sup.+). From Intermediate R1 + Intermediate R6

Intermediate R25: 5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

Step A: 2-Methoxy-4-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)pyridine

[0622] ##STR00074##

[0623] A mixture of 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (Intermediate R1, Step D) (218 mg, 0.851 mmol), (2-methoxypyridin-4-yl)boronic acid (156 mg, 1.021 mmol) in dioxane (2.5 ml) and K.sub.2CO.sub.3 (353 mg, 2.55 mmol) in water (0.5 mL) was degassed with N.sub.2 for 15 minutes. Then Pd(dppf)Cl.sub.2. DCM (35 mg, 0.043 mmol) was added. The reaction mixture was heated to 80° C. for 2 hours, cooled to room temperature and partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO.sub.4) and evaporated to afford the title compound (186 mg, 63%) which was used in the next step without purification.

[0624] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J=5.2 Hz, 1H), 7.50 (s, 1H), 6.88-6.81 (m, 1H), 6.67 (d, J=2.0 Hz, 1H), 3.89 (s, 3H), 3.03-2.92 (m, 4H), 2.18-2.03 (m, 5H).

[0625] LCMS m/z 285.0 (M+H).sup.+(ES.sup.+).

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

[0626] ##STR00075##

[0627] A mixture of 2-methoxy-4-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)pyridine (186 mg, 0.536 mmol) and 5% Pd/C (Type 87L, 58.5% moisture) (55 mg, 10.72 mol) in EtOH (2 mL) was hydrogenated at 1 bar for 6 hours. Then the reaction mixture was filtered through Celite® and evaporated to afford the title compound (120 mg, 77%) which was used without purification.

[0628] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J=5.2 Hz, 1H), 6.77 (dd, J=5.2, 1.5 Hz, 1H), 6.58 (s, 1H), 6.45 (s, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.4 Hz, 2H), 1.99 (p, J=7.4 Hz, 2H), 1.88 (s, 3H).

[0629] LCMS m/z 255.1 (M+H).sup.+(ES.sup.+).

[0630] The following intermediate was prepared according to the general procedure of Intermediate R25:

TABLE-US-00005 Int. Structure and name Characterisation and procedure R26 [00076] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.1 Hz, 1H), 6.73 (dd, J = 5.2, 1.4 Hz, 1H), 6.55- 6.47 (m, 1H), 6.45 (s, 1H), 5.01 (tt, J = 8.8, 4.2 Hz, 1H), 4.14 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.74-2.58 (m, 4H), 2.27-2.09 (m, 5H), 2.06-1.93 (m, 4H), 1.88 (s, 3H), 1.76-1.63 (m, 2H). LCMS m/z 338.2 (M + H).sup.+ (ES.sup.+). From Intermediate R1, step D

Intermediate R27: 4-(4-Isocyanato-6-methyl-2,3-dihydro-1H-inden-5-yl)-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0631] ##STR00077##

[0632] Triphosgene (0.077 g, 0.260 mmol) in THF (1 mL) was added dropwise to an ice-cooled solution of 6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R26) (0.129 g, 0.4 mmol) and Et.sub.3N (0.112 mL, 0.800 mmol) in THF (5 mL), and stirred at room temperature for 3 hours. The reaction mixture was filtered, washed with THF, concentrated in vacuo and dried azeotropically with toluene (3×1 mL). The crude product was used without further purification.

[0633] The following intermediate was prepared according to the general procedure of Intermediate R27:

TABLE-US-00006 Int. Structure and name Characterisation and procedure R28 [00078] From Intermediate R25

Intermediate R29: 5-(2-Ethoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

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

[0634] ##STR00079##

[0635] A solution of 4-bromo-2-fluoropyridine (1.170 g, 6.65 mmol), KOAc (2.60 g, 26.5 mmol), B.sub.2Pin.sub.2 (1.685 g, 6.63 mmol) and PdCl.sub.2(dppe-CH.sub.2Cl.sub.2 adduct (0.271 g, 0.332 mmol) in 1,4-dioxane (20 mL) was heated at 100° C. for 2 hours under N.sub.2. Then the reaction mixture was cooled to room temperature and a solution 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R1) (1.5 g, 6.63 mmol) in 1,4-dioxane (5 mL) was added, followed by a solution of K.sub.2CO.sub.3 (3.67 g, 26.5 mmol) in water (2.5 mL). The reaction mixture was heated at 100° C. for 2 hours, diluted with EtOAc (75 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was separated, dried (MgSO.sub.4) and evaporated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc/isohexane) to afford the title compound (940 mg, 55%) as a white solid.

[0636] .sup.1H NMR (CDCl.sub.3) δ 8.32 (d, J=5.0 Hz, 1H), 7.12 (dt, J=5.2, 1.6 Hz, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 3.36 (s, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.14 (p, J=7.5 Hz, 2H), 2.00 (s, 3H).

[0637] LCMS m/z 243.2 (M+H).sup.+(ES.sup.+).

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

[0638] ##STR00080##

[0639] 5-(2-Fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (100 mg, 0.413 mmol) was dissolved in THF (2 mL). EtONa (42 mg, 0.617 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. Additional EtONa (42 mg, 0.617 mmol) was added and the reaction mixture stirred for 4 hours. Then the reaction mixture was partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was separated, washed with water (10 mL), dried (phase separator) and concentrated in vacuo to afford the title compound (121 mg, quantitative yield).

[0640] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J=5.2 Hz, 1H), 6.74 (dd, J=5.2, 1.4 Hz, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 4.14 (s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 1.99 (p, J=7.5 Hz, 2H), 1.88 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).

[0641] LCMS m/z 269.2 (M+H)+(ES+).

[0642] The following intermediate was prepared according to the general procedure of Intermediate R29:

TABLE-US-00007 Int. Structure and name Characterisation and procedure R30 [00081] .sup.1H NMR (DMSO-d6) δ 8.19 (dd, J = 5.1, 0.7 Hz, 1H), 6.70 (dd, J = 5.1, 1.4 Hz, 1H), 6.45 (s, 1H), 6.42 (dd, J = 1.4, 0.7 Hz, 1H), 4.11 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.03-1.96 (m, 2H), 1.88 (s, 3H), 1.58 (s, 9H). LCMS m/z 297.3 (M + H).sup.+ (ES.sup.+). From Intermediate R29, step A

Intermediate R31: 5-(2-(Cyclohexyloxy)pyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

[0643] ##STR00082##

[0644] KO.sup.tBu (0.132 g, 1.176 mmol) was added to cyclohexanol (0.163 mL, 1.568 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0° C. 5-(2-Fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R29, step A) (0.200 g, 0.784 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. Then the reaction mixture was partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography (0-25% EtOAc/isohexane) to afford the title compound (0.177 g, 61%) as a thick colourless oil.

[0645] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J=5.1 Hz, 1H), 6.71 (dd, J=5.1, 1.4 Hz, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04-4.96 (m, 1H), 4.12 (s, .sup.2H), 2.77 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.04-1.94 (m, 4H), 1.88 (s, 3H), 1.78-1.69 (m, 2H), 1.59-1.52 (m, 1H), 1.51-1.33 (m, 4H), 1.30-1.22 (m, 1H).

[0646] LCMS m/z 323.3 (M+H).sup.+(ES.sup.+).

[0647] The following intermediate was prepared according to the general procedure of Intermediate R31:

TABLE-US-00008 Int. Structure and name Characterisation and procedure R32 [00083] .sup.1H NMR (DMSO-d6) δ 8.20 (t, J = 4.8 Hz, 1H), 6.73-6.71 (m, 1H), 6.51-6.50 (m, 1H), 6.45 (s, 1H), 5.12-5.06 (m, 0.5H), 5.05-4.98 (m, 0.5H), 4.13 (s, 2H), 3.25 (s, 1.5H), 3.24 (s, 1.5H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.13- 2.04 (m, 1H), 2.05-1.94 (m, 4H), 1.88 (d, J = 3.0 Hz, 3H) 1.84-1.69 (m, 3H), 1.69- 1.58 (m, 1H), 1.54-1.44 (m, 1H), 1.41- 1.30 (m, 1H). 50:50 mixture of cis/trans ring. LCMS m/z 353.3 (M + H).sup.+ (ES.sup.+). From Intermediate R29, step A

Intermediate R33: 4-Fluoro-6-isopropyl-2-(2-methoxypyridin-4-yl)-3-methylaniline

Step A: 4-Fluoro-5-methyl-2-(prop-1-en-2-yl)aniline

[0648] ##STR00084##

[0649] A mixture of 2-bromo-4-fluoro-5-methylaniline (10.00 g, 49.0 mmol), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (11 mL, 58.8 mmol), Pd(OAc).sub.2 (440 mg, 1.960 mmol), tricyclohexylphosphine (21.2 g, 76 mmol) and K.sub.3PO.sub.4 (28.1 g, 132 mmol) in dioxane (120 mL) and water (30 mL) was degassed with N.sub.2. Then the reaction mixture was heated at 100° C. for 18 hours. Solvent was evaporated and the io residue partitioned between isohexane (500 mL) and water (300 mL). The organic layer was washed with water (200 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-40% EtOAc/isohexane) to afford the title compound (9.09 g, 99%) as a brown oil.

[0650] .sup.1H NMR (DMSO-d.sub.6) δ 6.70 (d, J=10.6 Hz, 1H), 6.52 (d, J=7.3 Hz, 1H), 5.24-5.20 (m, 1H), 5.01-4.98 (m, 1H), 4.59 (br s, 2H), 2.09 (s, 3H), 1.98 (s, 3H).

Step B: 4-Fluoro-2-isopropyl-5-methylaniline

[0651] ##STR00085##

[0652] A mixture of 4-fluoro-5-methyl-2-(prop-1-en-2-yl)aniline (13.33 g, 81 mmol) and 5% Pd/C (Type 87L, 58.5% moisture) (1.66 g, 0.324 mmol) in EtOAc (145 mL) was hydrogenated at 3 bar for 16 hours. Then the reaction mixture was filtered through Celite® and concentrated in vacuo to afford the title compound (11.95 g, 79%) as a dark green oil.

[0653] .sup.1H NMR (DMSO-d.sub.6) δ 6.74 (d, J=11.4 Hz, 1H), 6.50 (d, J=7.3 Hz, 1H), 5.07 (s, 2H), 2.92 (hept, J=6.7 Hz, 1H), 2.08 (s, 3H), 1.11 (d, J=6.8 Hz, 6H).

[0654] LCMS m/z 168.1 (M+H)+(ES+).

Step C: 2-Bromo-4-fluoro-6-isopropyl-3-methylaniline

[0655] ##STR00086##

[0656] NBS (12.08 g, 67.9 mmol) was added to a solution of 4-fluoro-2-isopropyl-5-methylaniline (11.95 g, 67.9 mmol) in DCM (180 mL). The reaction mixture was stirred at room temperature for 20 minutes, then washed with water (200 mL) and io% aqueous Na.sub.2S.sub.2O.sub.3 (200 mL), dried (phase separator) and concentrated in vacuo to afford crude product (14.6 g). 5 g of the crude product was purified by flash chromatography on silica gel (0-20% EtOAc/isohexane) to afford the title compound (3.26 g, 19%) as a red-orange oil.

[0657] .sup.1H NMR (DMSO-d.sub.6) δ 6.89 (d, J=11.0 Hz, 1H), 4.87 (s, 2H), 3.06 (sept, J=6.7 Hz, 1H), 2.20 (d, J=2.4 Hz, 3H), 1.14 (d, J=6.7 Hz, 6H).

[0658] LCMS m/z 246.1/248.1 (M+H).sup.+(ES.sup.+).

Step D: 4-Fluoro-6-isopropyl-2-(2-methoxypyridin-4-yl)-3-methylaniline

[0659] ##STR00087##

[0660] (2-Methoxypyridin-4-yl)boronic acid (200 mg, 1.308 mmol), 2-bromo-4-fluoro-6-isopropyl-3-methylaniline (322 mg, 1.308 mmol), potassium carbonate (723 mg, 5.23 mmol) and PdCl.sub.2(dppf). DCM (53 mg, 0.065 mmol) were dissolved in 1,4-dioxane (6 mL) and water (3 mL). The reaction mixture was degassed (N.sub.2, 5 minutes) and evacuated and backfilled with N.sub.2 (×.sub.3). Then the reaction mixture was stirred at 100° C. for 3 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (2×20 mL). The organic extract was dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/isohexane) to afford the title compound (276 mg, 73%) as a brown oil.

[0661] .sup.1H NMR (DMSO-d.sub.6) δ 8.28 (d, J=5.1 Hz, 1H), 6.88 (d, J=11.3 Hz, 1H), 6.81 (dd, J=5.2, 1.4 Hz, 1H), 6.65 (s, 1H), 3.99 (s, 2H), 3.90 (s, 3H), 3.03-2.96 (m, 1H), 1.79 (d, J=2.1 Hz, 3H), 1.15 (d, J=6.7 Hz, 6H).

[0662] LCMS (m/z 275.1 (M+H)+(ES+).

[0663] The following intermediates were prepared according to the general procedure of Intermediate R33:

TABLE-US-00009 Int. Structure and name Characterisation and procedure R34 [00088] .sup.1H NMR (DMSO-d6) δ 8.28 (d, J = 5.3 Hz, 1H), 7.11 (dd, J = 12.3, 9.0 Hz, 1H), 6.97- 6.92 (m, 1H), 6.80 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.02 (sept, J = 6.8 Hz, 1H), 1.16 (d, J = 6.8 Hz, 6H). LCMS m/z 279.2 (M + H).sup.+ (ES.sup.+). R35 [00089] .sup.1H NMR (DMSO-d6) δ 8.26 (d, J = 5.1 Hz, 1H), 6.88 (dd, J = 5.2, 1.3 Hz, 1H), 6.82 (d, J = 12.7 Hz, 1H), 6.70 (s, 1H), 3.89 (s, 3H), 4.01 (s, 2H), 2.98 (app p, J = 6.7 Hz, 1H), 1.43-1.33 (m, 1H), 1.15 (d, J = 6.7 Hz, 6H), 0.57-0.41 (m, 4H). LCMS m/z 301.1 (M + H).sup.+ (ES.sup.+). From Intermediate R2 R36 [00090] LCMS m/z 329.1 (M + H).sup.+ (ES.sup.+). R37 [00091] .sup.1H NMR (DMSO-d6) δ 8.29 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 12.0 Hz, 1H), 6.89 (dd, J = 5.2, 1.4 Hz, 1H), 6.73 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.05 (sept, J = 6.8 Hz, 1H), 1.18 (d, J = 6.7 Hz, 6H). LCMS m/z 345.2 (M + H).sup.+ (ES.sup.+). From Intermediate R3 R38 [00092] .sup.1H NMR (DMSO-d6) δ 8.28 (d, J = 5.1 Hz, 1H), 6.88 (d, J = 11.6 Hz, 1H), 6.83 (dd, J = 5.2, 1.4 Hz, 1H), 6.66 (t, J = 1.1 Hz, 1H), 3.97 (s, 2H), 3.91 (s, 3H), 2.98 (hept, J = 6.6 Hz, 1H), 2.26-2.13 (m, 2H), 1.16 (dd, J = 6.8, 2.0 Hz, 6H), 0.90 (t, J = 7.5 Hz, 3H). LCMS m/z 289.1 (M + H).sup.+ (ES.sup.+). From Intermediate R4

Intermediate R39: 4-Isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine

Step A: 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0664] ##STR00093##

[0665] To a solution of NaH (9.74 g, 243.59 mmol, 60 wt % in mineral oil, 1 eq) in DMF (200 mL) was added in portions 2-methyl-1H-imidazole (20 g, .sup.243.59 mmol, 1 eq) at 0° C. The reaction mixture was stirred at 0° C. for 3o minutes. Then (2-(chloromethoxy)ethyl) trimethylsilane (48.73 g, 292.31 mmol, 1.2 eq) was added. The resulting mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched with ice-water (300 mL), diluted with ethyl acetate (1 L), and washed with saturated aqueous NH.sub.4Cl solution (3×300 mL) and brine (3×300 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 1:1) to give the title compound (40 g, 76% yield, 98% purity on LCMS) as a yellow oil.

[0666] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.90 (s, 2H), 5.18 (s, 2H), 3.47 (t, 2H), 2.43 (s, 3H), 0.89 (t, 2H) and 0.01 (s, 9H).

[0667] LCMS: m/z 213.0 (M+H).sup.+(ES.sup.+).

Step B: 4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0668] ##STR00094##

[0669] To a solution of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (20 g, 94.18 mmol, 1 eq) in DMF (200 mL) was added NBS (16.76 g, 94.18 mmol, 1 eq) at −20° C. Then the reaction mixture was stirred at −20° C. for 2 hours. The reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.3solution (100 mL), diluted with EtOAc (200 mL), and washed with saturated aqueous NH.sub.4Cl solution (3×100 mL) and brine (3×100 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 10:1 to 5:1) to give the title compound (13.5 g, 41% yield, 84% purity on LCMS) as a yellow oil.

[0670] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.88 (s, 1H), 5.25 (s, 2H), 3.55 (t, 2H), 2.42 (s, 3H), 0.91 (t, 2H) and 0.02 (s, 9H).

[0671] LCMS: m/z 292.9 (M+H).sup.+(ES.sup.+).

Step C: 2-Methyl-4-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0672] ##STR00095##

[0673] A solution of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (10 g, 28.84 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.33 g, 31.72 mmol, 1.1 eq), Pd(dppf)Cl.sub.2 (1.06 g, 1.44 mmol, 0.05 eq) and Na.sub.2CO.sub.3 (6.11 g, 57.68 mmol, 2 eq) in dioxane (100 mL) and H.sub.2O (20 mL) was stirred at 100° C. for 12 hours under N.sub.2. The reaction mixture was diluted with water (100 mL), and then is extracted with ethyl acetate (3×100 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 1:1) to give the title compound (7 g, 96%) as a yellow oil.

[0674] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.88 (s, 1H), 5.23 (s, 2H), 5.20 (s, 1H), 5.14 (s, 1H), 3.52 (t, 2H), 2.48 (s, 3H), 2.08 (s, 3H), 0.93 (t, 2H) and 0.01 (s, 9H).

[0675] LCMS: m/z 253.0 (M+H).sup.+(ES.sup.+).

Step D: 4-Isopropyl-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0676] ##STR00096##

[0677] To a solution of 2-Methyl-4-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (7.18 g, 28.44 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (700 mg, 10 wt % loading on activated carbon) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The mixture was stirred at 25° C. for 12 hours under H.sub.2 (15 psi). Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (8 g, 99% yield, 90% purity on LCMS) as a yellow oil.

[0678] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.66 (s, 1H), 5.15 (s, 2H), 3.49 (t, 2H), 2.95-2.84 (m, 1H), 2.43 (s, 3H), 1.26 (d, 6H), 0.91 (t, 2H) and 0.02 (s, 9H).

[0679] LCMS: m/z 255.2 (M+H).sup.+(ES.sup.+).

Step E: 4-Isopropyl-2-methyl-1H-imidazole

[0680] ##STR00097##

[0681] To a solution of 4-isopropyl-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (8 g, .sub.31.44 mmol, 1 eq) in DCM (8o mL) was added TFA (123.20 g, 1.08 mol, 34.37 eq) at 25° C. Then the mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched with ice-water (io mL) and saturated aqueous NaHCO.sub.3 solution (300 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, ethyl acetate: methanol, 1:0 to 20:1) to give the title compound (3.7 g, 95%) as a yellow oil.

[0682] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.71 (s, 1H), 2.99-2.93 (m, 1H), 2.53 (s, 3H) and 1.27 (d, 6H).

[0683] LCMS: m/z 125.3 (M+H).sup.+(ES.sup.+).

Step F: 4-(4-Isopropyl-2-methyl-1H-imidazol-1-yl)pyridine

[0684] ##STR00098##

[0685] To a solution of 4-isopropyl-2-methyl-1H-imidazole (1.4 g, 11.27 mmol, 1 eq) and 4-iodopyridine (1.85 g, 9.02 mmol, 0.8 eq) in DMF (14 mL) was added with Cu.sub.2O (81 mg, 563.68 μmol, 0.05 eq) and Cs.sub.2CO.sub.3 (7.35 g, 22.55 mmol, 2 eq). The reaction mixture was stirred at 100° C. for 15 hours. Then the reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated aqueous NH.sub.4Cl solution (3×30 mL) and brine (3×30 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 0:1) to give the title compound (600 mg, 26% yield, 97% purity on LCMS) as a yellow solid.

[0686] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.73 (dd, 2H), 7.27 (dd, 2H), 6.77 (s, 1H), 2.93-2.86 (m, 1H), 2.48 (s, 3H) and 1.29 (d, 6H).

[0687] LCMS: m/z 202.0 (M+H).sup.+(ES.sup.+).

Step G: 4-(4-Isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl)pyridine

[0688] ##STR00099##

[0689] To a solution of 4-(4-isopropyl-2-methyl-1H-imidazol-1-yl)pyridine (400 mg, 1.93 mmol, 1 eq) in H.sub.2SO.sub.4 (71.33 mmol, 3.88 mL, 98% purity in solution, 37 eq) was added with HNO.sub.3 (5.78 mmol, 400 μL, 65% purity in aqueous solution, 3 eq) at 0° C. Then the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched with ice-water (20 mL), and adjusted to pH=8˜9 with saturated aqueous NaHCO.sub.3 solution. The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The yellow solid was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 2:1 to 1:1) to give the title compound (400 mg, 84%) as a yellow solid.

[0690] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.83 (d, 2H), 7.22 (d, 2H), 3.75-3.69 (m, 1H), 2.25 (s, 3H) and 1.36 (d, 6H).

[0691] LCMS: m/z 247.1 (M+H).sup.+(ES.sup.+).

Step H: 4-Isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine

[0692] ##STR00100##

[0693] A mixture of 4-(4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl)pyridine (400 mg, 1.62 mmol, 1 eq) and Pd/C (40 mg, 10 wt % loading on activated carbon) in MeOH (20 mL) was hydrogenated at 20° C. for 1 hour under H.sub.2 (15 psi). Then the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in THF (10 mL), and adjusted to pH−3˜4 with 4M HCl/dioxane. The resulting mixture was concentrated in vacuo to give the title compound (400 mg, 97%, HCl salt) as a yellow solid, which was used in the next step without further purification.

[0694] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 15.02 (s, 1H), 8.99 (d, 2H), 7.90 (d, 2H), 3.25-3.15 (m, 1H), 2.45 (s, 3H) and 1.27 (d, 6H).

[0695] LCMS: m/z 217.1 (M+H).sup.+(ES.sup.+).

Intermediate R40: 4-Isopropyl-1-(2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-5-amine

Step A: 4-(4-Isopropyl-2-methyl-1H-imidazol-1-yl)-2-methoxypyridine

[0696] ##STR00101##

[0697] A reaction mixture of 4-isopropyl-2-methyl-1H-imidazole (Intermediate R39, step E) (1 g, 6.44 mmol, 1 eq), 4-iodo-2-methoxypyridine (1.51 g, 6.44 mmol, 1 eq), Cu.sub.2O (922 mg, 6.44 mmol, 1 eq) and Cs.sub.2CO.sub.3 (4.20 g, 12.88 mmol, 2 eq) in DMF (10 mL) was stirred at 100° C. for 12 hours. Then the reaction mixture was filtered. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 1:1) to give the title compound (700 mg, 47%) as a yellow oil.

[0698] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.25 (d, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.84 (s, 1H), 3.96 (s, 3H), 2.87-2.80 (m, 1H), 2.46 (s, 3H) and 1.26 (d, 6H).

[0699] LCMS: m/z 232.2 (M+H).sup.+(ES.sup.+).

Step B: 4-(4-Isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl)-2-methoxypyridine

[0700] ##STR00102##

[0701] To a solution of 4-(4-isopropyl-2-methyl-1H-imidazol-1-yl)-2-methoxypyridine (0.7 g, 3.03 mmol, 1 eq) in H.sub.2SO.sub.4 (12.88 g, 98 wt % in aqueous solution, 131.32 mmol, 43.39 eq) was added with HNO.sub.3 (829 mg, 9.08 mmol, 69 wt % in aqueous solution, 3 eq) at 0° C. Then the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into ice-water (40 mL), and adjust to pH=8˜9 with NaOH solid. Then the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to 3:1) to give the title compound (600 mg, 67% yield, 94% purity on LCMS) as a yellow solid.

[0702] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.33 (d, 1H), 6.99 (dd, 1H), 6.90 (d, 1H), 4.00 (s, 3H), 3.76-3.68 (m, 1H), 2.25 (s, 3H) and 1.34 (d, 6H).

[0703] LCMS: m/z 277.0 (M+H).sup.+(ES.sup.+).

Step C: 4-Isopropyl-1-(2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-5-amine

[0704] ##STR00103##

[0705] To a solution of 4-(4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl)-2-methoxypyridine (200 mg, 723.88 μmol, 1 eq) in MeOH (5 mL) was added Pd/C (20 mg, 10 wt % loading on the activated carbon) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The mixture was stirred at 25° C. for 2 hours under H.sub.2 (15 psi). Then the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (178 mg, 100%) as a yellow oil, which was used directly in the next step.

[0706] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.30 (d, 1H), 6.81 (dd, 1H), 6.65 (d, 1H), 4.01 (s, 3H), 3.65-3.57 (m, 1H), 2.26 (s, 3H) and 1.37 (d, 6H).

Intermediate R41

Phenyl (6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate

Step A: 4-Bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0707] ##STR00104##

[0708] To a solution of KOtBu (41.13 g, 366.51 mmol, 1.5 eq) in THF (500 mL) was added 1-methylpiperidin-4-ol (33.77 g, 293.20 mmol, 1.2 eq) at 20° C. The reaction mixture was stirred for 1 hour. Then 4-bromo-2-fluoropyridine (43 g, 244.34 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred at 20° C. for 12 hours, and then poured into water (500 mL). The aqueous phase was 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 column chromatography (SiO.sub.2, with 0.1% NH.sub.3.H.sub.2O, DCM: methanol 1:0 to 10:1) to give the title is compound (61 g, 92%) as a yellow solid.

[0709] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (d, 1H), 7.18 (dd, 1H), 7.06 (s, 1H), 4.98-4.93 (m, 1H), 2.62-2.59 (m, 2H), 2.16-2.11 (m, 5H) 1.94-1.91 (m, 2H) and 1.66-1.62 (m, 2H)

[0710] LCMS: m/z 273.0 (M+H).sup.+(ES.sup.+).

Step B: 2-((1-Methylpiperidin-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0711] ##STR00105##

[0712] To a mixture of 4-bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine (20 g, 73.76 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (24.35 g, 95.89 mmol, 1.3 eq) in dioxane (200 mL) was added PdCl.sub.2(dppf) (3.24 g, 4.43 mmol, 0.06 eq) and KOAc (34.24 g, 348.88 mmol, 4.73 eq) in one portion under N.sub.2. Then the reaction mixture was heated to 100° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reserved phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (22.5 g, 96%) as a brown oil.

[0713] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17-8.12 (m, 1H), 7.08-7.03 (m, 1H), 6.93-6.88 (m, 1H), 5.05-4.90 (m, 1H), 3.92-3.86 (m, 2H), 2.73-2.66 (m, 2H), 2.22 (s, 3H), 1.95-1.90 (m, 2H), 1.69-1.63 (m, 2H) and 1.06 (s, 12H).

[0714] LCMS: m/z 319.0 (M+H).sup.+(ES.sup.+).

Step C

6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0715] ##STR00106##

[0716] To a mixture of 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R1) (40 g, 176.90 mmol, 1 eq) and 2-((1-methylpiperidin-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78.81 g, 247.66 mmol, 1.4 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was added K.sub.2CO.sub.3 (73.35 g, 530.71 mmol, 3 eq) and PdCl.sub.2(dppf) (7.77 g, 10.61 mmol, 0.06 eq) in one portion under N.sub.2. Then the reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was diluted with DCM (300 mL) and extracted with HCl (3×100 mL, 3 M). The combined aqueous phases were adjusted to pH 8 with saturated aqueous Na.sub.2CO.sub.3solution, and then extracted with DCM (3×200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE: EtOAc 1:0 to 5:1, then DCM: MeOH 1:0 to 10:1 with 0.1% NH.sub.3.H.sub.2O) to give the title compound (50 g, 80% yield, 95.6% purity on HPLC) as a brown gum.

[0717] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (d, 1H), 6.72 (dd, 1H), 6.50 (s, 1H), 6.44 (s, 1H), 5.02-4.97 (m, 1H), 4.13 (s, 2H), 2.77 (t, 2H), 2.67-2.61 (m, 4H), 2.17 (s, 3H), 2.16-2.11 (m, 2H), 2.02-1.94 (m, 4H), 1.87 (s, 3H) and 1.72-1.64 (m, 2H).

[0718] LCMS: m/z 338.2 (M+H).sup.+(ES.sup.+).

Step D

Phenyl (6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate

[0719] ##STR00107##

[0720] To a solution of 6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (1 g, 2.96 mmol, 1 eq) and phenyl carbonochloridate (463 mg, 2.96 mmol, 1 eq) in DCM (20 mL) was added TEA (300 mg, 2.96 mmol, 1 eq) at 0° C. Then the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash io chromatography (0.1% TFA in water-MeCN) to give the title compound (350 mg, 20% yield, 95% purity on LCMS, TFA salt) as a yellow solid.

[0721] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.70-9.60 (m, 1H), 9.19 (s, 1H), 8.25 (t, 1H), 7.36-7.34 (m, 2H), 7.23-7.16 (m, 2H), 6.90-6.81 (m, 3H), 6.68-6.62 (m, 1H), 5.36-5.19 (m, 1H), 3.39-3.14 (m, 4H), 2.97-2.91 (m, 2H), 2.87-2.79 (m, 5H), 2.38-2.33 (m, 1H), 2.27-2.16 (m, 1H), 2.06 (d, 6H) and 1.90-1.78 (m, 1H).

[0722] LCMS: m/z 458.1 (M+H).sup.+(ES.sup.+).

Preparation of Examples

Example 1

N-((6-Methyl-5-(2-methylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonamide

[0723] ##STR00108##

[0724] 6-Methyl-5-(2-methylpyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R9) (35 mg, 0.147 mmol) was added to a suspension of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(methylsulfonyl)amide (Intermediate L1) (36 mg, 0.148 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at 60° C. for 1 hour. Volatiles were evaporated, and the crude product dissolved in DMSO (1 mL) and filtered. The crude product was purified by basic prep HPLC (10-40% MeCN in water) to afford the title compound (7 mg, 13%) as a white solid.

[0725] .sup.1H NMR (DMSO-d6) δ 8.48 (d, J=5.1 Hz, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 6.96 (d, J=5.1 Hz, 1H), 3.30 (s, 3H), 3.02 (s, 3H), 2.91 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.3 Hz, 2H), 2.04-1.97 (m, 5H). Two exchangeable protons not observed.

[0726] LCMS m/z 360.2 (M+H).sup.+(ES.sup.+).

[0727] The following examples were prepared according to the general procedure of Example 1:

TABLE-US-00010 Ex. Structure and name Characterisation and procedure  2 [00109] .sup.1H NMR (DMSO-d6) δ 8.66-8.59 (m, 2H), 7.50 (s, 1H), 7.23-7.15 (m, 2H), 7.12 (s, 1H), 2.99 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.05-1.96 (m, 5H). One exchangeable proton not observed. LCMS m/z 346.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R8  3 [00110] .sup.1H NMR (DMSO-d6) δ 8.29 (d, J = 5.1 Hz, 1H), 7.77 (t, J = 72.9 Hz, 1H), 7.50 (s, 1H), 7.11 (s, 1H), 7.05 (dd, J = 5.1, 1.4 Hz, 1H), 6.88 (s, 1H), 2.95 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.81-2.72 (m, 2H), 2.05-1.95 (m, 5H). One exchangeable proton not observed. LCMS m/z 412.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R15  4 [00111] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J = 5.1 Hz, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.79 (dd, J = 5.2, 1.4 Hz, 1H), 6.63 (d, J = 1.2 Hz, 1H), 4.21 (tt, J = 6.3, 3.1 Hz, 1H), 3.02 (s, 3H), 2.90 (t, J = 7.5 Hz, 2H), 2.78-2.71 (m, 2H), 2.05-1.95 (m, 5H), 0.80-0.64 (m, 4H). One exchangeable proton not observed. LCMS m/z 402.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R13  5 [00112] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.1 Hz, 1H), 7.47 (s, 1H), 7.10 (s, 1H), 6.75-6.70 (m, 1H), 6.56 (s, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.04 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.78-2.70 (m, 2H), 2.05-1.94 (m, 5H), 1.34 (t, J = 7.1 Hz, 3H). One exchangeable proton not observed. LCMS m/z 390.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R29  6 [00113] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 6.74-6.68 (m, 1H), 6.52 (s, 1H), 5.05 (tt, J = 7.1, 3.4 Hz, 1H), 4.47 (d, J = 3.9 Hz, 1H), 3.68- 3.60 (m, 1H), 3.17 (d, J = 3.3 Hz, 1H), 2.92- 2.84 (m, 4H), 2.76 (s, 1H), 2.03-1.94 (m, 5H), 1.92-1.83 (m, 2H), 1.72-1.64 (m, 3H), 1.60 (dd, J = 7.7, 4.1 Hz, 4H). One exchangeable proton not observed. LCMS m/z 460.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R21  7 [00114] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.60 (s, 1H), 7.13 (d, J = 11.1 Hz, 1H), 6.79 (s, 1H), 6.64 (s, 1H), 3.87 (s, 3H), 3.16-3.09 (m, 1H), 2.74 (s, 3H), 1.88 (s, 3H), 1.14 (d, J = 6.9 Hz, 6H). One exchangeable proton not observed. LCMS m/z 396.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R33  8 [00115] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.2 Hz, 1H), 7.40 (s, 1H), 7.16 (d, J = 11.0 Hz, 1H), 6.88-6.74 (m, 1H), 6.64 (s, 1H), 3.16- 3.05 (m, 1H), 2.82 (s, 3H), 1.89 (s, 3H), 1.15 (d, J = 5.2 Hz, 6H). One exchangeable proton not observed. LCMS m/z 399.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R17  9 [00116] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.10 (s, 1H), 6.68 (dd, J = 5.2, 1.5 Hz, 1H), 6.43 (s, 1H), 3.04 (s, 3H), 2.90 (t, J = 7.5 Hz, 2H), 2.78-2.71 (m, 2H), 2.05-1.98 (m, 5H), 1.57 (s, 9H). One exchangeable proton not observed. LCMS m/z 362.6 (M-tBu + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R30 10 [00117] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.11 (s, 1H), 6.75 (d, J = 5.2 Hz, 1H), 6.59 (s, 1H), 3.05 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.78-2.71 (m, 2H), 2.03-1.97 (m, 5H). One exchangeable proton not observed. LCMS m/z 379.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R16 11 [00118] .sup.1H NMR (DMSO-d6) δ 10.62 (s, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.83-7.76 (m, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 7.46 (s, 1H), 7.06 (s, 1H), 6.54 (d, J = 4.8 Hz, 1H), 6.49 (s, 1H), 3.89 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 1.97-1.87 (m, 5H). Two protons under solvent. LCMS m/z 438.6 (M + H).sup.+ (ES.sup.+). Intermediate L5 + Intermediate R25 12 [00119] .sup.1H NMR (DMSO-d6) δ 8.22 (d, J = 5.2 Hz, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.60 (s, 1H), 3.89 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.80-2.70 (m, 3H), 2.05-1.97 (m, 5H), 1.00-0.93 (m, 4H). One exchangeable proton not observed. LCMS m/z 402.5 (M + H).sup.+ (ES.sup.+). Intermediate L2 + Intermediate R25 13 [00120] .sup.1H NMR (DMSO-d6) δ 9.66 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.46 (s, 1H), 7.11 (s, 1H), 6.75 (dd, J = 5.3, 1.4 Hz, 1H), 6.59 (s, 1H), 3.89 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.76-2.70 (m, 2H), 2.66 (s, 6H), 2.05- 1.96 (m, 5H). LCMS m/z 405.2 (M + H).sup.+ (ES.sup.+). Intermediate L3 + Intermediate R25 14 [00121] .sup.1H NMR (DMSO-d6) δ 8.30-8.04 (m, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.54-6.49 (m, 1H), 5.02- 4.95 (m, 1H), 3.25 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.80-2.73 (m, 2H), 2.72-2.62 (m, 3H), 2.11-2.03 (m, 2H), 2.02-1.92 (m, 7H), 1.82-1.69 (m, 1H), 1.63 (s, 1H), 1.52-1.43 (m, 2H), 1.39-1.31 (m, 1H). One exchangeable proton not observed. LCMS m/z 474.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R32 15 [00122] .sup.1H NMR (DMSO-d6) δ 8.14 (dd, J = 5.1, 1.8 Hz, 1H), 7.02 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (d, J = 1.4 Hz, 1H), 5.06 (s, 1H), 3.24 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.84-2.72 (m, 5H), 2.03-1.94 (m, 5H), 1.83-1.69 (m, 5H), 1.67-1.59 (m, 2H). Two protons masked by water, two exchangeable protons not observed. LCMS m/z 474.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R32 16 [00123] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.50 (s, 1H), 5.05-4.96 (m, 1H), 2.96 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.79-2.72 (m, 2H), 2.05-1.96 (m, 7H), 1.78-1.71 (m, 2H), 1.60-1.53 (m, 1H), 1.51-1.32 (m, 4H), 1.31-1.20 (m, 1H). One exchangeable proton not observed. LCMS m/z 444.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R31 17 [00124] .sup.1H NMR (DMSO-d6) δ 8.20 (d, J = 5.1 Hz, 1H), 7.65 (s, 1H), 7.10 (s, 1H), 6.74 (dd, J = 5.1, 1.3 Hz, 1H), 6.56 (s, 1H), 3.88 (s, 3H), 2.89 (t, J = 7.4 Hz, 2H), 2.75-2.69 (m, 2H), 1.99 (d, J = 4.8 Hz, 5H), 1.18 (s, 9H). One exchangeable proton not observed. LCMS m/z 418.2 (M + H).sup.+ (ES.sup.+). Intermediate L6 + Intermediate R25 18 [00125] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.71 (s, 1H), 7.09 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (d, J = 1.2 Hz, 1H), 5.01 (tt, J = 8.8, 4.1 Hz, 1H), 2.89 (t, J = 7.5 Hz, 2H), 2.80-2.68 (m, 4H), 2.36- 2.20 (m, 5H), 2.07-1.88 (m, 7H), 1.76- 1.65 (m, 2H), 1.17 (s, 9H). One exchangeable proton not observed. LCMS m/z 501.3 (M + H).sup.+ (ES.sup.+). Intermediate L6 + Intermediate R26 19 [00126] .sup.1H NMR (DMSO-d6) δ 8.10 (d, J = 5.2 Hz, 1H), 7.74-7.69 (m, 2H), 7.55-7.50 (m, 1H), 7.48 (dd, J = 8.2, 6.5 Hz, 2H), 7.26- 7.17 (m, 1H), 7.00 (s, 1H), 6.61 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (s, 1H), 5.13-5.09 (m, 1H), 3.08-3.00 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.78-2.67 (m, 2H), 2.14- 2.04 (m, 2H), 1.96 (s, 3H), 1.94-1.87 (m, 2H), 1.87-1.80 (m, 2H). Five protons under DMSO. One exchangeable proton not observed. LCMS m/z 521.2 (M + H).sup.+ (ES.sup.+). Intermediate L5 + Intermediate R26 20 [00127] .sup.1H NMR (DMSO-d6) δ 8.00 (d, J = 5.0 Hz, 1H), 7.07 (s, 2H), 6.59 (d, J = 5.2 Hz, 1H), 5.15-5.06 (m, 1H), 2.95-2.88 (m, 5H), 2.82-2.68 (m, 4H), 2.45-2.37 (m, 2H), 2.30 (s, 3H), 2.05-1.96 (m, 4H), 1.88 (s, 3H), 1.80-1.71 (m, 5H). One exchangeable proton not observed. LCMS m/z 473.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R23 21 [00128] .sup.1H NMR (DMSO-d6) δ 9.94 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.46 (s, 1H), 7.09 (s, 1H), 6.73 (dd, J = 5.2, 1.4 Hz, 1H), 6.54 (s, 1H), 5.02 (tt, J = 8.7, 4.1 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.83-2.69 (m, 5H), 2.37- 2.24 (m, 5H), 2.07-1.97 (m, 7H), 1.77- 1.66 (m, 2H), 0.97-0.86 (m, 4H). LCMS m/z 485.1 (M + H).sup.+ (ES.sup.+). Intermediate L2 + Intermediate R26 22 [00129] .sup.1H NMR (DMSO-d6) δ 8.18 (d, J = 5.2 Hz, 1H), 7.38 (s, 1H), 7.09 (s, 1H), 6.73 (dd, J = 5.2, 1.4 Hz, 1H), 6.56 (d, J = 1.4 Hz, 1H), 5.25-5.16 (m, 1H), 3.93-3.83 (m, 2H), 3.54-3.46 (m, 2H), 2.97 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.81-2.68 (m, 2H), 2.09- 1.96 (m, 7H), 1.72-1.59 (m, 2H). One exchangeable proton not observed. LCMS m/z 446.2 (M + H).sup.+ (ES.sup.+); m/z 444.2 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R20 23 [00130] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.1 Hz, 1H), 7.25 (s, 1H), 7.07 (s, 1H), 6.75 (d, J = 5.2 Hz, 1H), 6.59 (s, 1H), 4.33-4.01 (m, 2H), 3.08-2.97 (m, 1H), 2.95-2.82 (m, 6H), 2.76 (t, J = 7.6 Hz, 2H), 2.42-2.30 (m, 3H), 2.26-2.04 (1H, 2H), 2.04-1.93 (m, 6H), 1.78-1.66 (m, 2H), 1.63-1.50 (m, 1H), 1.16-1.04 (m, 1H). One exchangeable proton not observed. LCMS m/z 473.0 (M + H).sup.+ (ES.sup.+); m/z 471.2 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R22 24 [00131] .sup.1H NMR (DMSO-d6) δ 8.18 (d, J = 5.2 Hz, 1H), 7.37 (s, 1H), 7.08 (s, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.58 (s, 1H), 5.56-5.49 (m, 1H), 3.96-3.89 (m, 1H), 3.89-3.83 (m, 1H), 3.83-3.73 (m, 2H), 2.96 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.80-2.70 (m, 2H), 2.29-2.20 (m, 1H), 2.07-1.95 (m, 6H). One exchangeable proton not observed. LCMS m/z 432.2 (M + H).sup.+ (ES.sup.+); m/z 430.1 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R18 25 [00132] .sup.1H NMR (DMSO-d6) δ 10.11 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.55 (s, 1H), 7.12 (s, 1H), 6.72 (d, J = 5.3 Hz, 1H), 6.52 (s, 1H), 5.38-5.31 (m, 1H), 3.58-3.51 (m, 1H), 3.49-3.44 (m, 1H), 3.29 (s, 3H), 3.07 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.78-2.70 (m, 2H), 2.05-1.97 (m, 5H), 1.27 (d, J = 6.4 Hz, 3H). LCMS m/z 434.2 (M + H).sup.+ (ES.sup.+); m/z 432.2 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R19 26 [00133] .sup.1H NMR (DMSO-d.sub.6) δ 8.19 (d, J = 5.2 Hz, 1H), 7.46 (bs, 1H), 7.10 (s, 1H), 6.72 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (s, 1H), 5.04-4.95 (m, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.77- 2.69 (m, 4H), 2.64 (s, 6H), 2.28-2.16 (m, 5H), 2.09-1.94 (m, 7H), 1.73-1.64 (m, 2H). One exchangeable proton not observed. LCMS m/z 488.4 (M + H).sup.+ (ES.sup.+); m/z 486.3 (M − H).sup.− (ES.sup.−). Intermediate L3 + Intermediate R26 27 [00134] .sup.1H NMR (DMSO-d.sub.6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.17 (bs, 1H), 7.04 (s, 1H), 6.71 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (s, 1H), 4.97-4.88 (m, 1H), 2.95-2.82 (m, 5H), 2.79-2.72 (m, 2H), 2.66-2.59 (m, 1H), 2.42 (s, 6H), 2.21- 2.15 (m, 2H), 2.04-1.87 (m, 7H), 1.53-1.38 (m, 4H). One exchangeable proton not observed. LCMS m/z 487.4 (M + H).sup.+ (ES.sup.+); m/z 485.3 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R24 28 [00135] .sup.1H NMR (DMSO-d6) δ 8.17 (t, J = 5.7 Hz, 1H), 7.35 (s, 1H), 7.08 (d, J = 5.1 Hz, 1H), 6.74-6.71 (m, 1H), 6.55-6.54 (m, 1H), 5.06-5.00 (m, 1H), 3.00-2.94 (m, 3H), 2.92-2.87 (m, 2H), 2.84-2.78 (m, 2H), 2.76-2.72 (m, 2H), 2.42-2.35 (m, 2H) 2.34-2.28 (m, 3H), 2.08-1.93 (m, 7H), 1.78-1.64 (m, 2H). One exchangeable proton not observed. LCMS m/z 459.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R26 29 [00136] .sup.1H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.92 (s, 1H), 7.48 (s, 1H), 7.14 (d, J = 11.0 Hz, 1H), 6.81-6.35 (m, 3H), 3.89 (s, 3H), 3.87-3.83 (m, 1H), 2.95-2.84 (m, 1H), 1.85 (s, 3H), 1.10-1.03 (m, 10H). One exchangeable proton not observed. LCMS m/z 488.3 (M + H).sup.+ (ES.sup.+). Intermediate R33 + known sulfonamide 30 [00137] .sup.1H NMR (DMSO-d6) δ 8.23 (d, J = 5.3 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J = 11.7 Hz, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 3.88 (s, 3H), 3.21-3.10 (m, 1H), 2.90 (s, 3H), 1.18 (d, J = 6.9 Hz, 6H). One exchangeable proton not observed. LCMS m/z 466.1 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R37 31 [00138] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.2 Hz, 1H), 7.47 (s, 1H), 7.14 (d, J = 12.2 Hz, 1H), 6.85 (s, 1H), 6.69 (s, 1H), 3.88 (s, 3H), 3.11-3.01 (m, 1H), 2.93 (s, 3H), 1.56-1.47 (m, 1H), 1.18-1.09 (m, 6H), 0.62-0.54 (m, 2H), 0.50-0.41 (m, 2H). One exchangeable proton not observed. LCMS m/z 422.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R35 32 [00139] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 13.2 Hz, 2H), 6.81 (s, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.19-3.07 (m, 1H), 2.90 (s, 3H), 1.24-1.11 (m, 6H). One exchangeable proton not observed. LCMS m/z 450.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R36 33 [00140] .sup.1H NMR (DMSO-d6) δ 8.23 (d, J = 5.2 Hz, 1H), 7.84 (s, 1H), 7.48 (t, J = 10.4 Hz, 1H), 6.99-6.89 (m, 1H), 6.81 (s, 1H), 3.88 (s, 3H), 3.18-3.06 (m, 1H), 2.90 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H). One exchangeable proton not observed. LCMS m/z 400.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R34 34 [00141] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 6.83-6.79 (m, 1H), 6.67-6.62 (m, 2H), 6.54 (s, 1H), 3.87 (s, 3H), 2.84 (t, J = 7.4 Hz, 2H), 2.80-2.75 (m, 2H), 1.98- 1.91 (m, 2H), 1.48-1.41 (m, 1H), 0.68- 0.63 (m, 2H), 0.57-0.52 (m, 2H). One exchangeable proton not observed. Three protons under DMSO. LCMS m/z 402.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R14 35 [00142] .sup.1H NMR (DMSO-d6) δ 10.67 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.65 (d, J = 5.2 Hz, 1H), 6.61-6.47 (m, 2H), 3.93- 3.83 (m, 4H), 2.87 (t, J = 7.5 Hz, 2H), 2.61- 2.52 (m, 2H), 2.02-1.88 (m, 5H), 1.11- 0.98 (M, 4H). LCMS m/z 468.3 (M + H).sup.+ (ES.sup.+). Intermediate R25 + known sulfonamide 36 [00143] .sup.1H NMR (DMSO-d6) δ 8.80-8.76 (m, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.53 (dd, J = 5.0, 1.7 Hz, 1H), 7.15 (s, 1H), 2.99-2.89 (m, 5H), 2.77 (t, J = 7.7 Hz, 2H), 2.04- 1.98 (m, 5H). Acidic NH not observed. LCMS m/z 371.1 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R10 37 [00144] .sup.1H NMR (DMSO-d6) δ 8.81 (d, J = 4.9 Hz, 1H), 7.77-7.68 (m, 1H), 7.67 (s, 1H), 7.52 (dd, J = 4.9, 1.5 Hz, 1H), 7.16 (s, 1H), 2.97- 2.88 (m, 5H), 2.78 (t, J = 7.4 Hz, 2H), 2.07-1.98 (m, 5H). Acidic NH not observed. LCMS m/z 414.1 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R11 38 [00145] .sup.1H NMR (DMSO-d6) δ 10.06 (s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.52 (s, 1H), 7.21 (d, J = 11.4 Hz, 1H), 6.80 (s, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.10-3.00 (m, 1H), 2.96 (s, 3H), 2.33-2.25 (m, 2H), 1.24-1.09 (m, 6H), 0.94 (t, J = 7.5 Hz, 3H). LCMS m/z 410.2 (M + H).sup.+ (ES). Intermediate L1 + Intermediate R38 39 [00146] .sup.1H NMR (DMSO-d6) δ 7.36 (t, J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 6.97-6.89 (m, 1H), 6.73-6.63 (m, 2H), 3.76 (s, 3H), 3.04 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.05-1.93 (m, 5H). Acidic NH not observed. LCMS m/z 375.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R12

Example 40

N-((5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonamide, sodium salt

[0728] ##STR00147##

[0729] 5-(2-Methoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R25) (148 mg, 0.582 mmol) was added to a suspension of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(methylsulfonyl)amide (Intermediate L1) (142 mg, 0.582 mmol) in MeCN (2 mL). The reaction mixture was stirred at 60° C. for 1 hour. Volatiles were evaporated, and the crude product was dissolved in DMSO (2 mL) and filtered. The crude product was purified by basic prep HPLC to afford the free acid, which was treated with 0.5 M NaOH (474 μL, 0.237 mmol) and freeze dried to afford the title compound (83 mg, 87%) as a white solid.

[0730] .sup.1H NMR (DMSO-d6) δ 8.15 (dd, J=5.2, 0.7 Hz, 1H), 6.95 (s, 1H), 6.75 (dd, J=5.2, 1.4 Hz, 1H), 6.63-6.54 (m, .sup.2H), 3.87 (s, 3H), 2.86 (t, J=7.4 Hz, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.58 (s, 3H), 2.04-1.89 (m, 5H).

[0731] LCMS m/z 376.2 (M+H).sup.+(ES.sup.+).

Example 41

1-(2-(Dimethylamino)ethyl)-N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[0732] ##STR00148##

[0733] To a stirred solution of 1-(2-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide (22 mg, 0.1 mmol) in THF (2 mL) at room temperature was added 2M sodium tert-butoxide in THF (0.055 mL, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. Then a solution of 4-(4-isocyanato-6-methyl-2,3-dihydro-1H-inden-5-yl)-2-((1-methylpiperidin-4-yl)oxy)pyridine (Intermediate R27) (36.3 mg, 0.1 mmol) in THF (1 mL) was added and the reaction mixture stirred at room temperature overnight. Volatiles were evaporated, and the crude product dissolved in DMSO (1 mL) and purified by basic prep HPLC (10-40% MeCN in water) to afford the title compound (5 mg, 9%) as a solid.

[0734] .sup.1H NMR (DMSO-d6) δ 8.13 (d, J=5.3 Hz, 1H), 7.79 (s, 1H), 7.25 (s, 1H), 7.02 (s, 1H), 6.67 (d, J=5.3 Hz, 1H), 6.53 (s, 1H), 6.47-6.40 (m, 1H), 5.13-5.04 (m, 1H), 4.23 (t, J=6.6 Hz, 2H), 2.96-2.89 (m, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.66 (t, J=6.6 Hz, 2H), 2.62-2.56 (m, 4H), 2.41 (s, 3H), 2.19 (s, 6H), 2.10-2.03 (m, 2H), 1.98 (s, 3H), 1.96-1.90 (m, 2H), 1.87-1.73 (m, 2H). One exchangeable proton not observed.

[0735] LCMS m/z 582.3 (M+H).sup.+(ES.sup.+).

[0736] The following examples were prepared according to the general procedure of Example 41:

TABLE-US-00011 Ex. Structure and name Characterisation and procedure 42 [00149] .sup.1H NMR (DMSO-d6) δ 8.20 (d, J = 5.2 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 6.75 (d, J = 5.2 Hz, 1H), 6.59 (s, 1H), 3.88 (s, 3H), 3.15 (q, J = 7.3 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.79 -2.69 (m, 2H), 2.05-1.94 (m, 5H), 1.08 (t, J = 7.3 Hz, 3H). One exchangeable proton not observed. LCMS m/z 390.2 (M + H).sup.+ (ES.sup.+). Intermediate L4 + Intermediate R28 43 [00150] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 7.37-7.22 (m, 1H), 7.06 (s, 1H), 6.74- 6.67 (m, 1H), 6.52 (s, 1H), 5.07-4.95 (m, 1H), 3.22-3.17 (m, 1H), 3.08-2.98 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.82-2.70 (m, 4H), 2.26 (s, 5H), 2.07-1.94 (m, 9H), 1.85-1.66 (m, 5H), 1.62-1.52 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H). One exchangeable proton not observed, one proton under DMSO. LCMS m/z 556.3 (M + H).sup.+ (ES.sup.+). Intermediate R27 + known sulfonamide 44 [00151] .sup.1H NMR (DMSO-d6) δ 8.16-8.10 (m, 1H), 7.86-7.80 (m, 1H), 7.30 (s, 1H), 7.02 (s, 1H), 6.67 (dd, J = 5.2, 1.6 Hz, 1H), 6.53 (s, 1H), 6.46 (d, J = 2.3 Hz, 1H), 5.11-5.04 (m, 1H), 4.59-4.50 (m, 1H), 3.00-2.89 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.59- 2.53 (m, 4H), 2.42 (s, 3H), 2.11-2.03 (m, 2H), 1.97 (s, 3H), 1.91 (p, J = 7.7 Hz, 2H), 1.86-1.75 (m, 2H), 1.42 (d, J = 6.6 Hz, 6H). One exchangeable proton not observed. LCMS m/z 553.3 (M + H).sup.+ (ES). Intermediate R27 + known sulfonamide 45 [00152] .sup.1H NMR (DMSO-d6) δ 9.69 (bs, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.44 (s, 1H), 7.14- 6.99 (m, 1H), 6.98 (s, 1H), 6.72 (d, J = 5.1 Hz, 1H), 6.67-6.55 (m, 2H), 5.22-5.12 (m, 1H), 4.95 (s, 1H), 3.22 (s, 2H), 3.11 2.94 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.72- 2.61 (m, 5H), 2.17-2.07 (m, 2H), 2.00- 1.88 (m, 7H), 1.37 (s, 6H). LCMS m/z 569.3 (M + H).sup.+ (ES). Intermediate R27 + known sulfonamide

Example 46

4-(2-Hydroxypropan-2-yl)-N-((4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-yl)carbamoyl)furan-2-sulfonamide, ammonium salt

Step A: ((4-(2-Hydroxypropan-2-yl)furan-2-yl)sulfonyl)(4-isopropylpyridin-1-ium-1-carbonyl)amide

[0737] ##STR00153##

[0738] A solution of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (Intermediate L.sub.7) (100 mg, 487.26 μmol, 1 eq) and N,N-dimethylpyridin-4-amine (119 mg, 974.51 μmol, 2 eq) in MeCN (2 mL) was stirred at 25° C. for 30 minutes. Then diphenyl carbonate (115 mg, 535.98 μmol, 1.1 eq) was added. The reaction mixture was stirred at 25° C. for 12 hours.

[0739] The reaction mixture, a red solution (theoretical amount: 172.19 mg, in 2 mL MeCN), was used directly in the next step.

Step B

4-(2-Hydroxypropan-2-yl)-N-((4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-yl)carbamoyl)furan-2-sulfonamide, ammonium salt

[0740] ##STR00154##

[0741] To a solution of 4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine (Intermediate R39) (100 mg, 395.66 μmol, 1 eq, HCl salt) in MeCN (1 mL) was added a solution of ((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)(4-isopropylpyridin-1-ium-1-carbonyl)amide in MeCN (theoretical amount: 140 mg, 1.6 mL, 395.66 μmol, 1 eq). The reaction mixture was stirred at 70° C. for 1 hour. Then the reaction mixture was purified by reversed phase prep HPLC (column: Waters XBridge C18, 150 mm×25 mm×5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 1%-20%, 10 min) to give the title compound (9.52 mg, 5% yield over two steps, 99% purity on LCMS, ammonium salt) as a white solid.

[0742] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) δ 8.71 (s, 2H), 7.51-7.40 (m, 3H), 6.72-6.65 (s, 1H), 2.85-2.81 (m, 1H), 2.33 (s, 3H), 1.37 (s, 6H) and 1.17 (s, 6H).

[0743] LCMS: m/z 448.1 (M+H).sup.+(ES.sup.+).

Example 47

1-Cyclopropyl-N-((4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

Step A: ((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide

[0744] ##STR00155##

[0745] A mixture of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate L8) (150 mg, 801.20 μmol, 1 eq) and N,N-dimethylpyridin-4-amine (196 mg, 1.60 mmol, 2 eq) in MeCN (3 mL) was stirred at 25° C. for 30 minutes. Then diphenyl carbonate (189 mg, 881.32 μmol, 1.1 eq) was added. The resulting mixture was stirred at 25° C. for 12 hours. The reaction mixture became turbid and some solid precipitated out. The suspension io was filtered, and the filter cake was collected to give the title compound (95 mg, 35%) as an off-white solid.

[0746] .sup.1H NMR (DMSO-d.sub.6) δ 8.10 (d, 2H), 7.92 (d, .sup.1H), 6.59-6.56 (m, 3H), 3.84-3.75 (m, 1H), 2.95 (s, 6H) and 1.07-0.99 (m, 4H).

Step B

1-Cyclopropyl-N-((4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-yl)carbamoyl)-1H-pyrazole-3-sulfonamide

[0747] ##STR00156##

[0748] To a solution of 4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine (Intermediate R39) (107 mg, 424.89 μmol, 1.5 eq, HCl salt) in MeCN (4 mL) was added ((1-cyclopropyl-1H-pyrazol-3-yl)sulfonyl)(4-(dimethylamino)pyridin-1-ium-1-carbonyl)amide (95 mg, 283.26 μmol, 1 eq). The reaction mixture was stirred at 70° C. for 45 minutes under N.sub.2. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) and then purified by reversed phase prep HPLC (column: Waters XBridge, 150 mm×25 mm×5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 1%-20%, 10 min) to give the title compound (11.61 mg, 9% yield over two steps, 98% purity on HPLC) as a white solid.

[0749] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65-8.62 (m, 2H), 7.89 (s, 1H), 7.79 (d, 1H), 7.34-7.31(m, .sup.2H), 6.47 (s, 1H), 3.83-3.81 (m, 1H), 2.67-2.64 (m, 1H), 2.20 (s, 3H) and 1.10-1.02 (m, 10H).

[0750] LCMS: m/z 430.1 (M+H).sup.+(ES.sup.+).

Example 48

4-(2-Hydroxypropan-2-yl)-N-((4-isopropyl-1-(2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-5-yl)carbamoyl)furan-2-sulfonamide

[0751] ##STR00157##

[0752] A mixture of 4-isopropyl-1-(2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-5-amine (Intermediate R40) (178 mg, 722.67 μmol, 1 eq) and ((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)(4-isopropylpyridin-1-ium-1-carbonyl)amide (Example 46, step A) (255 mg, 722.67 μmol, 1 eq) in MeCN (.sub.5 mL) was stirred at 70° C. for 2 hours under N.sub.2. The reaction mixture was purified directly by reversed phase flash is chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) and then further purified by reversed phase prep HPLC (column: Xtimate C18, 150 mm×25 mm×5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 0%-24%, 10 min) to give the title compound (24.92 mg, 7% yield over two steps, 100% purity on LCMS) as a white solid.

[0753] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27-8.19 (m, 1H), 7.68-7.45 (m, 1H), 7.39 (s, 1H), 7.04-6.77 (m, 2H), 6.65-6.53 (m, 1H), 4.93 (s, 1H), 3.87 (s, 3H), 2.80-2.69 (m, 1H), 2.22 (s, 3H), 1.33 (s, 6H) and 1.10 (s, 6H).

[0754] LCMS: m/z 478.3 (M+H).sup.+(ES.sup.+).

Example 49

1-(5-Isopropyl-2-methyl-3-(4-pyridyl)imidazol-4-yl)-3-(methyl-(1-methylpyrrolidin-3-yl)sulfamoyl)urea

Step A: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)amide

[0755] ##STR00158##

[0756] A solution of N,N-dimethylpyridin-4-amine (366 mg, 3.00 mmol, 2 eq) and 1-methyl-3-[methyl(sulfamoyl)amino]pyrrolidine (Intermediate L9) (0.29 g, 1.50 mmol, 1 eq) in MeCN (8 mL) was stirred at 20° C. for 30 minutes. Then diphenyl carbonate (353 mg, 1.65 mmol, 1.1 eq) was added. The resulting mixture was stirred at 20° C. for 12 hours. The mixture (theoretical amount: 0.53 g, crude) was used directly in the next step.

Step B: 1-(5-Isopropyl-2-methyl-3-(4-pyridyl)imidazol-4-yl)-3-(methyl-(1-methylpyrrolidin-3-yl)sulfamoyl)urea

[0757] ##STR00159##

[0758] To a mixture of 4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine (Intermediate R39) (0.2 g, 791.32 μmol, 1 eq, HCl salt) in MeCN (1 mL) was added a solution of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)amide (the reaction mixture of step A) in MeCN (8 mL). The resulting mixture was heated to 70° C. and stirred for 30 minutes under N.sub.2. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) and then further purified by prep HPLC (column: Waters XBridge C18, 150 mm×25mm×5 μm; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 1%-15%, 10 minutes) to give the title compound (25.13 mg, 7% yield over two steps, 100% purity on LCMS) as a white solid.

[0759] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.70 (d, J=6.0 Hz, 2H), 7.50-7.48 (m, 2H), 4.48-4.44 (m, 1H), 3.30-2.92 (m, 5H), 2.74(s, 3H), 2.63 (s, 3H), 2.29 (s, 3H), 2.15-1.98 (m, 2H), 1.27 (d, J=6.8 Hz, 6H). 2 ×NH were missing.

[0760] LCMS: m/z 436.1 (M+H).sup.+(ES.sup.+).

Example 50

N-((4-Isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-yl)carbamoyl)benzenesulfonamide

Step A: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)(phenylsulfonyl)amide

[0761] ##STR00160##

[0762] A solution of benzenesulfonamide (125 mg, 795.22 μmol, 1 eq) and N,N-dimethylpyridin-4-amine (194 mg, 1.59 mmol, 2 eq) in MeCN (3 mL) was stirred at 25° C. for 3o minutes. Then diphenyl carbonate (187 mg, 874.74 μmol, 1.1 eq) was added. The resulting mixture was stirred at 25° C. for 12 hours. The reaction mixture (theoretical amount: 242 mg, crude) was used directly in the next step.

Step B: N-((4-Isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-yl)carbamoyl)benzenesulfonamide

[0763] ##STR00161##

[0764] To a solution of 4-isopropyl-2-methyl-1-(pyridin-4-yl)-1H-imidazol-5-amine (197 mg, 780.00 μmol, 1 eq, HCl salt) (Intermediate R39) in MeCN (2 mL) was added a solution of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(phenylsulfonyl)amide (the reaction mixture of step A) in MeCN (3 mL). The resulting mixture was stirred at 70° C. for 45 minutes under N.sub.2. Then the reaction mixture was concentrated and the residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) and then further purified by prep HPLC (column: Xtimate C18, 150 mm×25 mm×5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 0%-30%, 10 minutes) to give the title compound (17.42 mg, 6% yield over two steps, 99.8% purity on HPLC) as a white solid.

[0765] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.60-8.45 (m, 2H), 7.70-7.47 (m, 6H), 7.26-6.90 (m, 2H), 2.68-2.65 (m, 1H), 2.19 (s, 3H) and 1.09 (d, 6H). 1×NH was missing.

[0766] LCMS: m/z 400.1 (M+H).sup.+(ES.sup.+).

Example 51

N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonimidamide

Step A

N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfinamide

[0767] ##STR00162##

[0768] To a solution of benzenesulfinamide (Intermediate L10) (50 mg, 354.13 μmol, 1 eq) in THF (1 mL) was added with t-BuONa (102 mg, 1.06 mmol, 3 eq) at 25° C. The reaction mixture was stirred at 25° C. for 30 minutes. Then phenyl (6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (Intermediate R41) (202 mg, 354.13 μmol, 1 eq, TFA salt) was added. The resulting mixture was stirred at 25° C. for 5 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (120 mg, 59% yield, 88% purity on LCMS) as a white solid.

[0769] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57-9.27 (m, 1H), 8.31-8.17 (m, 1H), 7.71-7.42 (m, 5H), 7.24-7.07 (m, 1H), 6.82-6.65 (m, 1H), 6.51 (s, 1H), 5.11-4.93 (m, 1H), 3.48-3.41 (m, 2H), 2.99-2.68 (m, 5H), 2.24-1.96 (m, 11H) and 1.89-1.61 (m, 2H). 1×NH was missing.

[0770] LCMS: m/z 505.3 (M+H).sup.+(ES.sup.+).

Step B

N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonimidamide

[0771] ##STR00163##

[0772] To a solution of N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfinamide (0.1 g, 198.16 μmol, 1 eq) in THF (1 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (27 mg, 178.34 μmol, 0.9 eq). The reaction mixture was stirred at 25° C. for 30 minutes. Then the reaction mixture was added into a solution of NH.sub.3/THF (5 mL) at −70° C.; NH.sub.3 was bubbled into THF for 5 minutes to afford the NH.sub.3/THF solution. After addition, the mixture was stirred at −70° C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, DCM:methanol, 10:1) and then further purified by prep HPLC (column: Phenomenex luna C18, 150 mm×25 mm×10 μm; mobile phase [A: water (0.1% TFA); B: MeCN]; B%: 22%-42%, 10 minutes) to give the title compound (21.45 mg, 17% yield, 100% purity on LCMS, TFA salt) as a white solid.

[0773] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.22-8.10 (m, 1H), 8.02-7.80 (m, 2H), 7.68-7.46 (m, 3H), 7.10 (d, 1H), 6.83-6.62 (m, 2H), 5.45-5.21 (m, 1H), 3.93-3.40 (m, 2H), 3.38-3.01 (m, 2H), 3.00-2.71 (m, 7H), 2.49-2.19 (m, 4H) and 2.17-1.96 (m, 5H). 3×NHs were missing.

[0774] LCMS: m/z 520.1 (M+H).sup.+(ES.sup.+).

Example 52

N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonimidamide

Step A: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfinamide

[0775] ##STR00164##

[0776] Sodium tert-butoxide (134 mg, 1.40 mmol, 1.6 eq) was added into a mixture of methanesulfinamide (Intermediate L11) (103 mg, 1.31 mmol, 1.5 eq) in THF (2 mL) at 20° C. The reaction mixture was stirred at 20° C. for 30 minutes. Then phenyl (6-methyl-5-(2-(((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (Intermediate R41) (400 mg, 874.20 μmol, 1 eq) was added at 20° C. and the resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was poured into ice-water (30 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to afford the title compound (150 mg, 26% yield, 68% purity on LCMS) as a white solid.

[0777] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (d, 1H), 7.14 (d, 1H), 6.71-6.65 (m, 1H), 6.54 (d, 1H), 5.08-5.04 (m, 1H), 2.97 (t, 2H), 2.87 (t, 2H), 2.75-2.73 (m, 2H), 2.64 (s, 3H), 2.33-2.27 (m, 5H), 2.15-2.07 (m, 7H) and 1.86-1.73 (m, 2H). 2×NHs were missing.

[0778] LCMS: m/z 443.4 (M+H).sup.+(ES.sup.+).

Step B: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3 -dihydro-1H-inden-4-yl)carbamoyl)methanesulfonimidamide

[0779] ##STR00165##

[0780] To a solution of N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfinamide (250 mg, 564.88 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (78 mg, 508.39 μmol, 0.9 eq) at 20° C. The reaction mixture was stirred for 30 minutes at 20° C. Then the reaction mixture was added into a solution of NH.sub.3/THF at −78° C.; NH.sub.3 gas (15 psi) was bubbled into THF (5 mL) for 5 minutes to afford the NH.sub.3/THF solution. The resulting mixture was stirred at −78° C. for 20 minutes, and then warmed to 20° C. and stirred for 2 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep HPLC (column: Xtimate C18, 150 mm×40 mm×10 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 19%-49%, 10 minutes) to afford the title compound (2.19 mg, 1% yield, 99.8% purity on LCMS) as a yellow solid.

[0781] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.12 (d, 1H), 7.09 (s, 1H), 6.82 (d, 1H), 6.69 (s, 1H), 5.14-5.12 (m, 1H), 3.21 (s, 3H), 3.03-3.01 (m, 2H), 2.95 (t, 2H), 2.88 (t, 2H), 2.83-2.57 (m, 2H), 2.55 (s, 3H) and 2.14-1.92 (m, 9H). 3×NHs were missing.

[0782] LCMS: m/z 458.3 (M+H).sup.+(ES.sup.+).

Example 53

1-(N-Cyano-S-methyl-sulfonimidoyl)-3-(6-methyl-5-(2-((1-methyl-4-piperidyl)oxy)-4-pyridyl)indan-4-yl)urea

[0783] ##STR00166##

[0784] To a mixture of N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonimidamide (Example 52) (30 mg, 65.56 μmol, 1 eq) and triethylamine (27 mg, 262.24 μmol, 4 eq) in DMF (1 mL) was added cyanic bromide (14 mg, 131.12 μmol, 2 eq) at 25° C. The reaction mixture was stirred at 25° C. for 12 hours, and then quenched with water (0.5 mL) and concentrated in vacuo. The residue was purified by prep HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 μm; mobile phase [A: water (0.1% TFA), B: MeCN]; B %: 20%-30%, 7 minutes) to afford the title compound (21.8 mg, 54% yield, 97.6% purity on HPLC, TFA salt) as yellow oil.

[0785] .sup.1H NMR (400 MHz, DMSO-d6+D.sub.2O) δ 8.16 (t, 1H), 7.09 (s, 1H), 6.79 (t, 1H), 6.63 (d, 1H), 5.27-5.13 (m, 1H), 3.48-3.45 (m, 1H), 3.35-3.32 (m, 1H), 3.27-3.12 (m, 5H), 2.88 (t, 2H), 2.81-2.75 (m, 5H), 2.34-2.30 (m, 1H), 2.18-2.13 (m, 1H), 3.05-1.96 (m, 6H) and 1.83-1.75 (m, 1H). 2×NHs were missing.

[0786] LCMS: m/z 483.2 (M+H).sup.+(ES.sup.+).

Examples

Biological Studies

[0787] NLRP3 and Pyroptosis

[0788] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 6o-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.

[0789] THP-1 Cells: Culture and Preparation

[0790] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with imM 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 μg/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

[0791] THP-1 Cells Pyroptosis Assay

[0792] The following method step-by-step assay was followed for compound screening. [0793] 1. Seed THP-1 cells (25,000cells/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) [0794] 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 [0795] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [0796] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [0797] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [0798] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [0799] 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 [0800] 8. Nates were read in an Envision reader at Ex 560 nm and Em 590 nm [0801] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[0802] 96-well Nate Map

TABLE-US-00012 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

[0803] The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

[0804] Human Whole Blood IL-1β Release Assay

[0805] 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.

[0806] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [0807] 1. Nate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [0808] 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 [0809] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [0810] 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells [0811] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [0812] 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) [0813] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [0814] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[0815] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

[0816] For comparison, three compounds outside the scope of the claims are included in Table 1:

##STR00167##

TABLE-US-00013 TABLE 1 NLRP3 inhibitory activity Example No THP IC.sub.50 HWB IC.sub.50  1 ++++ ++++  2 ++++++ +++++  3 ++++++ ++++  4 ++++++ +++++  5 ++++++ +++++  6 ++++++ ++++++  7 +++++ ++++  8 +++++ ++++ 10 ++++++ +++++ 11 ++++++ +++ 12 ++++++ ++++ 13 ++++++ ++++ 14 ++++++ ++++ 15 ++++++ ++++ 16 ++++++ +++ 18 ++++++ ++ 19 ++++++ ++++ 20 +++++ +++++ 21 ++++++ ++++++ 22 ++++++ ++++++ 23 ++++++ ++++++ 24 ++++++ +++++ 25 ++++++ +++++ 26 ++++++ ++++++ 27 ++++++ ++++++ 28 ++++++ ++++++ 29 ++++++ +++ 31 ++++ +++ 33 ++++ +++ 34 ++++++ +++ 35 ++++++ ++++ 36 ++++ ++++ 38 +++++ +++ 40 ++++++ +++++ 42 ++++++ +++++ 44 ++++++ +++++ 45 ++++++ ++++ 46 ++++++ ++++++ 47 +++++ +++++ 48 +++++ +++++ 49 + ND 51 ++++++ +++ 52 ++++++ ++++ comp ex 1 +++ inactive comp ex 2 ++ ND comp ex 3 ++ ND (≤0.25 μM = ‘++++++’, ≤0.5 μM = ‘+++++’, ≤1 μM = ‘++++’, ≤2 μM = ‘+++’, ≤5 μM = ‘++’, ≤10 μM = ‘+’, >10 μM = ‘inactive’, not determined = ‘ND’).

[0817] As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in particular in the human whole blood assay.

[0818] 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.