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6-SUBSTITUTED NAPHTHALENE-1,3-DISULFONIC ACID DERIVATIVES AS MODULATORS OF THE EXTRACELLULAR NICOTINAMIDE PHOSPHORIBOSYL TRANSFERASE (ENAMPT) FOR THE TREATMENT OF E.G. DIABETES

20240300968 · 2024-09-12

    Inventors

    Cpc classification

    International classification

    Abstract

    This invention relates to therapeutic 6-substituted naphthalene-1,3-disulfonic acid derivatives of formula (I) (Formula (I)). More specifically, the invention relates to compounds of formula (I) useful as modulators of extracellular nicotinamide phosphoribosyl transferase (eNAMPT) that stabilize the protein in its dimeric form. In addition the invention contemplates pharmaceutical compositions comprising the compounds, processes to prepare the compounds and the compounds for use in methods of medical treatment of e.g. (i) diabetes; (ii) cardiovascular disease; (iii) inflammatory bowel condition; (iv) cancer; (v) liver disease; (vi) inflammatory skin conditions; (vii) lung conditions; (viii) arthritis; (ix) kidney disease (e.g. chronic kidney disease); or (x) sepsis. An exemplary compound is e.g. 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl) phenyl) ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (example 1).

    ##STR00001##

    Claims

    1. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below: ##STR00092## wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00093## wherein: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; each R.sub.2 group, when present, is selected from: halo, nitro, cyano, R.sub.2a, [CH.sub.2].sub.qNR.sub.2aR.sub.2b, [CH.sub.2].sub.qOR.sub.2a, [CH.sub.2].sub.qC(O)R.sub.2a, [CH.sub.2].sub.qC(O)OR.sub.2a, [CH.sub.2].sub.qOC(O)R.sub.2a, [CH.sub.2].sub.qC(O)N(R.sub.2b)R.sub.2a, [CH.sub.2].sub.qN(R.sub.2b)C(O)R.sub.2a, [CH.sub.2].sub.qN(R.sub.2c)C(O)N(R.sub.2b)R.sub.2a, [CH.sub.2].sub.qS(O).sub.pR.sub.2a (where p is 0, 1 or 2), [CH.sub.2].sub.qSO.sub.2N(R.sub.2)R.sub.2a, [CH.sub.2].sub.qN(R.sub.2b)SO.sub.2R.sub.2a; wherein q is 0, 1, 2 or 3; R.sub.2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.2b and R.sub.2c are hydrogen or (1-2C)alkyl; R.sub.N is selected from hydrogen or methyl; or a R.sub.2 group and R.sub.N are linked so as to form a 5- or 6-membered heterocyclic ring fused to Ring A, the fused 5- or 6-membered heterocyclic ring comprising one or two N atoms and being optionally substituted by halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W.sub.1 is: ##STR00094## wherein A.sub.1, A.sub.2, A.sub.3 or A.sub.4 are selected from CH, N or CF, with the provisos that: only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be N; and only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be CF; X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from O, S, SO, SO.sub.2, N(R.sub.x1a), C(O), C(O)O, OC(O), C(O)N(R.sub.x1a), N(R.sub.x1a)C(O), N(R.sub.x1b)C(O)N(R.sub.x1a), N(R.sub.x1a)C(O)O, OC(O)N(R.sub.x1a), S(O).sub.2N(R.sub.x1a), N(R.sub.x1a)SO.sub.2, or C(O)N(R.sub.x1a)SO.sub.2, or SO.sub.2N(R.sub.x1a)C(O); and wherein R.sub.x1a and R.sub.x1b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.1 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y1a, [CH.sub.2].sub.rNR.sub.y1aR.sub.y1b, [CH.sub.2].sub.rOR.sub.y1a, [CH.sub.2].sub.rC(O)R.sub.y1a, [CH.sub.2].sub.rC(O)OR.sub.y1a, [CH.sub.2].sub.rOC(O)R.sub.y1a, [CH.sub.2].sub.rC(O)N(R.sub.y1b)R.sub.y1a, [CH.sub.2].sub.rN(R.sub.y1b)C(O)R.sub.y1a, [CH.sub.2].sub.rN(R.sub.y1c)C(O)N(R.sub.y1b)R.sub.y1a, [CH.sub.2].sub.rS(O).sub.pR.sub.y1a (where p is 0, 1 or 2), [CH.sub.2].sub.rSO.sub.2N(R.sub.y1b)R.sub.y1a, or [CH.sub.2].sub.rN(R.sub.y1b)SO.sub.2R.sub.y1a; wherein r is 0, 1, 2 or 3; R.sub.y1 is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y1b and R.sub.y1c are hydrogen or (1-2C)alkyl; (ii) a group of the formula III: ##STR00095## wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1 or 2; each R.sub.3 group, when present, is selected from: halo, nitro, cyano, R.sub.3a, [CH.sub.2].sub.q1NR.sub.3aR.sub.3b, [CH.sub.2].sub.q1OR.sub.3a, [CH.sub.2].sub.q1C(O)R.sub.3a, [CH.sub.2].sub.q1C(O)OR.sub.3a, [CH.sub.2].sub.q1OC(O)R.sub.3a, [CH.sub.2].sub.q1C(O)N(R.sub.3b)R.sub.3a, [CH.sub.2].sub.q1N(R.sub.3b)C(O)R.sub.3a, [CH.sub.2].sub.q1N(R.sub.3c)C(O)N(R.sub.3b)R.sub.3a, [CH.sub.2].sub.q1S(O).sub.pR.sub.3a (where p is 0, 1 or 2), [CH.sub.2].sub.q1SO.sub.2N(R.sub.3b)R.sub.3a, [CH.sub.2].sub.q1N(R.sub.3b)SO.sub.2R.sub.3a; wherein q1 is 0, 1, 2 or 3; R.sub.3a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.3b and R.sub.3c are hydrogen or (1-2C)alkyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each independently selected from hydrogen or methyl or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms; W.sub.2 is a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.w2a, [CH.sub.2].sub.sNR.sub.w2aR.sub.w2b, [CH.sub.2].sub.sOR.sub.w2a, [CH.sub.2].sub.sC(O)R.sub.w2a, [CH.sub.2].sub.sC(O)OR.sub.w2a, [CH.sub.2].sub.sOC(O)R.sub.w2a, [CH.sub.2].sub.sC(O)N(R.sub.w2b)R.sub.w2a, [CH.sub.2].sub.sN(R.sub.w2b)C(O)R.sub.w2a, [CH.sub.2].sub.sN(R.sub.w2c)C(O)N(R.sub.w2b)R.sub.w2a, [CH.sub.2].sub.sS(O).sub.pR.sub.w2a (where p is 0, 1 or 2), [CH.sub.2].sub.sSO.sub.2N(R.sub.w2b)R.sub.w2a, or [CH.sub.2].sub.sN(R.sub.w2b)SO.sub.2R.sub.w2a; wherein s is 0, 1, 2 or 3; R.sub.w2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.w2b and R.sub.w2e are hydrogen or (1-2C)alkyl; X.sub.2 is a linker group of the formula:
    [CH.sub.2].sub.m1-L.sub.2-[CH.sub.2].sub.m2 wherein m1 and m2 are selected from 0 or 1; L.sub.2 is selected from O, S, SO, SO.sub.2, N(R.sub.x2a), C(O), C(O)O, OC(O), C(O)N(R.sub.x2a), N(R.sub.x2a)C(O), N(R.sub.x2b)C(O)N(R.sub.x2a), N(R.sub.x2a)C(O)O, OC(O)N(R.sub.x2a), S(O).sub.2N(R.sub.x2a), N(R.sub.x2a)SO.sub.2, or C(O)N(R.sub.x2a)SO.sub.2, or SO.sub.2N(R.sub.x2a)C(O); and wherein R.sub.x2a and R.sub.x2b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.2 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y2a, [CH.sub.2].sub.tNR.sub.y2aR.sub.y2b, [CH.sub.2].sub.tOR.sub.y2a, [CH.sub.2].sub.tC(O)R.sub.y2a, [CH.sub.2].sub.tC(O)OR.sub.y2a, [CH.sub.2].sub.tOC(O)R.sub.y2a, [CH.sub.2].sub.tC(O)N(R.sub.y2b)R.sub.y2a, [CH.sub.2].sub.tN(R.sub.y2b)C(O)R.sub.y2a, [CH.sub.2].sub.tN(R.sub.y2c)C(O)N(R.sub.y2b)R.sub.y2a, [CH.sub.2].sub.tS(O).sub.pR.sub.y2a (where p is 0, 1 or 2), [CH.sub.2].sub.tSO.sub.2N(R.sub.y2b)R.sub.y2a, or [CH.sub.2].sub.tN(R.sub.y2b)SO.sub.2R.sub.y2a; wherein t is 0, 1, 2 or 3; R.sub.y2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y2b and R.sub.y2 are hydrogen or (1-2C)alkyl; (iii) a group of the formula IV: ##STR00096## wherein: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1 or 2; each R.sub.4 group, when present, is selected from: halo, nitro, cyano, R.sub.4a, [CH.sub.2].sub.q2NR.sub.4aR.sub.4b, [CH.sub.2].sub.q2OR.sub.4a, [CH.sub.2].sub.q2C(O)R.sub.4a, [CH.sub.2].sub.q2C(O)OR.sub.4a, [CH.sub.2].sub.q2OC(O)R.sub.4a, [CH.sub.2].sub.q2C(O)N(R.sub.4b)R.sub.4a, [CH.sub.2].sub.q2N(R.sub.4b)C(O)R.sub.4a, [CH.sub.2].sub.q2N(R.sub.4c)C(O)N(R.sub.4b)R.sub.4a, [CH.sub.2].sub.q2S(O).sub.pR.sub.4a (where p is 0, 1 or 2), [CH.sub.2].sub.q2SO.sub.2N(R.sub.4b)R.sub.4a, [CH.sub.2].sub.q2N(R.sub.4b)SO.sub.2R.sub.4a; wherein q2 is 0, 1, 2 or 3; R.sub.4a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.4b and R.sub.4c are hydrogen or (1-2C)alkyl; L is a 6C alkylene linker which is optionally substituted by one or more fluoro atoms; X is selected from O, CR.sub.xaR.sub.xb, S, SO, SO.sub.2, N(R.sub.xa), C(O); and wherein R.sub.xa and R.sub.xb are each independently selected from hydrogen or methyl; A.sub.30 and A.sub.31 are selected from CH, N or CF; A.sub.32 and A.sub.33 are selected from CH or N; with the proviso that only one or two of A.sub.30, A.sub.31, A.sub.32 and A.sub.33 can be N; A.sub.34 and A.sub.35 are selected from CH, N or CR.sub.30; A.sub.36, A.sub.37 and A.sub.38 are selected from CH or N; with the proviso that only one or two of A.sub.34, A.sub.35, A.sub.36, A.sub.37 and A.sub.38 can be N; and wherein R.sub.30 is selected from halo, nitro, cyano, R.sub.30a, [CH.sub.2].sub.tNR.sub.30aR.sub.30b, [CH.sub.2].sub.tOR.sub.30a, [CH.sub.2].sub.tC(O)R.sub.30a, [CH.sub.2].sub.tC(O)OR.sub.30a, [CH.sub.2].sub.tOC(O)R.sub.30a, [CH.sub.2].sub.tC(O)N(R.sub.30b)R.sub.30a, [CH.sub.2].sub.tN(R.sub.30b)C(O)R.sub.30a, [CH.sub.2].sub.tN(R.sub.30c)C(O)N(R.sub.30b)R.sub.30a, [CH.sub.2].sub.tS(O).sub.pR.sub.30a (where p is 0, 1 or 2), [CH.sub.2].sub.tSO.sub.2N(R.sub.30b)R.sub.30a, or [CH.sub.2].sub.tN(R.sub.30b)SO.sub.2R.sub.30a; wherein t is 0, 1, 2 or 3; R.sub.30a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.30b and R.sub.30c are hydrogen or (1-2C)alkyl; (iv) a group of the formula V or VI: ##STR00097## wherein: A.sub.40 is selected from NH, NMe or O; A.sub.42, A.sub.43, A.sub.44 and A.sub.46 are each independently selected from CH, N or CR.sub.2; A.sub.41 and A.sub.45 are each independently selected from C or N; with the proviso that: (iv) only up to three of A.sub.40, A.sub.41, A.sub.42, A.sub.43, A.sub.44, A.sub.45 and A.sub.46 are N; (v) A.sub.41 and A.sub.45 cannot both be N; (vi) only one or two of A.sub.40, A.sub.42, A.sub.43, A.sub.44 and A.sub.46 can be CR.sub.2; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; A.sub.50, A.sub.53, A.sub.54 and A.sub.55 are each independently selected from CH, N or CR.sub.2; A.sub.52 and A.sub.56 are each independently selected from C or N; with the proviso that: (iv) only up to three of A.sub.50, A.sub.51, A.sub.52, A.sub.53, A.sub.54, A.sub.55 and A.sub.56 are N; (v) A.sub.52 and A.sub.56 cannot both be N; (vi) only one or two of A.sub.50, A.sub.51, A.sub.53, A.sub.54 and A.sub.55 can be CR.sub.2; wherein R.sub.2 is as defined above; W.sub.4 is: ##STR00098## wherein A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d are selected from CH, N or CF, with the provisos that: only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be N; and only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be CF; X.sub.4 is a linker group of the formula:
    [CH.sub.2].sub.j1-L.sub.4-[CH.sub.2].sub.j2 wherein j1 and j2 are selected from 0 or 1; L.sub.4 is selected from O, S, SO, SO.sub.2, N(R.sub.x4a), C(O), C(O)O, OC(O), C(O)N(R.sub.x4a), N(R.sub.x4a)C(O), N(R.sub.x4b)C(O)N(R.sub.x4a), N(R.sub.x4a)C(O)O, OC(O)N(R.sub.x4a), S(O).sub.2N(R.sub.x4a), N(R.sub.x4a)SO.sub.2, or C(O)N(R.sub.x4a)SO.sub.2, or SO.sub.2N(R.sub.x4a)C(O); and wherein R.sub.x4a and R.sub.x4b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.4 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y4a, [CH.sub.2].sub.uNR.sub.y4aR.sub.y4b, [CH.sub.2]OR.sub.y4a, [CH.sub.2].sub.uC(O)R.sub.y4a, [CH.sub.2].sub.uC(O)OR.sub.y4a, [CH.sub.2].sub.uOC(O)R.sub.y4a, [CH.sub.2].sub.uC(O)N(R.sub.y4b)R.sub.y4a, [CH.sub.2].sub.uN(R.sub.y4b)C(O)R.sub.y4a, [CH.sub.2].sub.uN(R.sub.y4c)C(O)N(R.sub.y4b)R.sub.y4a, [CH.sub.2].sub.uS(O).sub.pR.sub.y4a (where p is 0, 1 or 2), [CH.sub.2].sub.uSO.sub.2N(R.sub.y4b)R.sub.y4a, or [CH.sub.2].sub.uN(R.sub.y4b)SO.sub.2R.sub.y4a; wherein u is 0, 1, 2 or 3; R.sub.y4 is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y4b and R.sub.y4c are hydrogen or (1-2C)alkyl.

    2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00099## wherein: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; each R.sub.2 group, when present, is selected from: halo, nitro, cyano, R.sub.2a, [CH.sub.2].sub.qNR.sub.2aR.sub.2b, [CH.sub.2].sub.qOR.sub.2a, [CH.sub.2].sub.qC(O)R.sub.2a, [CH.sub.2].sub.qC(O)OR.sub.2a, [CH.sub.2].sub.qOC(O)R.sub.2a, [CH.sub.2].sub.qC(O)N(R.sub.2b)R.sub.2a, [CH.sub.2].sub.qN(R.sub.2b)C(O)R.sub.2a, [CH.sub.2].sub.qN(R.sub.2c)C(O)N(R.sub.2b)R.sub.2a; wherein q is 0, 1 or 2; R.sub.2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.2b and R.sub.2c are hydrogen or (1-2C)alkyl; R.sub.N is selected from hydrogen or methyl; or a R.sub.2 group and R.sub.N are linked so as to form a 5- or 6-membered heterocyclic ring fused to Ring A, the fused 5- or 6-membered heterocyclic ring comprising one or two N atoms and being optionally substituted by halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W.sub.1 is: ##STR00100## wherein A.sub.1, A.sub.2, A.sub.3 or A.sub.4 are selected from CH, N or CF, with the provisos that: only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be N; and only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be CF; X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from O, S, SO, SO.sub.2, N(R.sub.x1a), C(O), C(O)O, OC(O), C(O)N(R.sub.x1a), N(R.sub.x1a)C(O), N(R.sub.x1b)C(O)N(R.sub.x1a), N(R.sub.x1a)C(O)O or OC(O)N(R.sub.x1a); and wherein R.sub.x1a and R.sub.x1b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.1 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y1a, [CH.sub.2].sub.rNR.sub.y1aR.sub.y1b, [CH.sub.2].sub.rOR.sub.y1a, [CH.sub.2].sub.rC(O)R.sub.y1a, [CH.sub.2].sub.rC(O)OR.sub.y1a, [CH.sub.2].sub.rOC(O)R.sub.y1a, [CH.sub.2].sub.rC(O)N(R.sub.y1b)R.sub.y1a, [CH.sub.2].sub.rN(R.sub.y1b)C(O)R.sub.y1a or [CH.sub.2].sub.rN(R.sub.y1c)C(O)N(R.sub.y1b)R.sub.y1a; wherein r is 0, 1 or 2; R.sub.y1 is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y1b and R.sub.y1c are hydrogen or (1-2C)alkyl; (ii) a group of the formula III: ##STR00101## wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1 or 2; each R.sub.3 group, when present, is selected from: halo, nitro, cyano, R.sub.3a, [CH.sub.2].sub.q1NR.sub.3aR.sub.3b, [CH.sub.2].sub.q1OR.sub.3a, [CH.sub.2].sub.q1C(O)R.sub.3a, [CH.sub.2].sub.q1C(O)OR.sub.3a, [CH.sub.2].sub.q1OC(O)R.sub.3a, [CH.sub.2].sub.q1C(O)N(R.sub.3b)R.sub.3a, [CH.sub.2].sub.q1N(R.sub.3b)C(O)R.sub.3a or [CH.sub.2].sub.q1N(R.sub.3c)C(O)N(R.sub.3b)R.sub.3a; wherein q1 is 0, 1 or 2; R.sub.3a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.3b and R.sub.3c are hydrogen or (1-2C)alkyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.v2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each independently selected from hydrogen or methyl or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms; W.sub.2 is a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.w2a, [CH.sub.2].sub.sNR.sub.w2aR.sub.w2b, [CH.sub.2].sub.sOR.sub.w2a, [CH.sub.2].sub.sC(O)R.sub.w2a, [CH.sub.2].sub.sC(O)OR.sub.w2a, [CH.sub.2].sub.sOC(O)R.sub.w2a, [CH.sub.2].sub.sC(O)N(R.sub.w2b)R.sub.w2a, [CH.sub.2].sub.sN(R.sub.w2b)C(O)R.sub.w2a or [CH.sub.2].sub.sN(R.sub.w2c)C(O)N(R.sub.w2b)R.sub.w2a; wherein s is 0, 1 or 2; R.sub.w2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.w2b is hydrogen or (1-2C)alkyl; X.sub.2 is a linker group of the formula:
    [CH.sub.2].sub.m1-L.sub.2-[CH.sub.2].sub.m2 wherein m1 and m2 are selected from 0 or 1; L.sub.2 is selected from O, S, SO, SO.sub.2, N(R.sub.x2a), C(O), C(O)O, OC(O), C(O)N(R.sub.x2a), N(R.sub.x2a)C(O), N(R.sub.x2b)C(O)N(R.sub.x2a), N(R.sub.x2a)C(O)O or OC(O)N(R.sub.x2a); and wherein R.sub.x2a and R.sub.x2b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.2 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y2a, [CH.sub.2].sub.tNR.sub.y2aR.sub.y2b, [CH.sub.2].sub.tOR.sub.y2a, [CH.sub.2].sub.tC(O)R.sub.y2a, [CH.sub.2].sub.tC(O)OR.sub.y2a, [CH.sub.2].sub.tOC(O)R.sub.y2a, [CH.sub.2].sub.tC(O)N(R.sub.y2b)R.sub.y2a, [CH.sub.2].sub.tN(R.sub.y2b)C(O)R.sub.y2a or [CH.sub.2].sub.tN(R.sub.y2c)C(O)N(R.sub.y2b)R.sub.y2a; wherein t is 0, 1 or 2; R.sub.y2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y2b and R.sub.y2c are hydrogen or (1-2C)alkyl; (iii) a group of the formula IV: ##STR00102## wherein: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1 or 2; each R.sub.4 group, when present, is selected from: halo, nitro, cyano, R.sub.4a, [CH.sub.2].sub.q2NR.sub.4aR.sub.4b, [CH.sub.2].sub.q2OR.sub.4a, [CH.sub.2].sub.q2C(O)R.sub.4a, [CH.sub.2].sub.q2C(O)OR.sub.4a, [CH.sub.2].sub.q2OC(O)R.sub.4a, [CH.sub.2].sub.q2C(O)N(R.sub.4b)R.sub.4a or [CH.sub.2].sub.q2N(R.sub.4b)C(O)R.sub.4a, [CH.sub.2].sub.q2N(R.sub.4c)C(O)N(R.sub.4b)R.sub.4a; wherein q2 is 0, 1, 2 or 3; R.sub.4a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.4b and R.sub.4e are hydrogen or (1-2C)alkyl; L is a 6C alkylene linker which is optionally substituted by one or more fluoro atoms; X is selected from O, CR.sub.xaR.sub.xb, S, SO, SO.sub.2, N(R.sub.xa), C(O); and wherein R.sub.xa and R.sub.xb are each independently selected from hydrogen or methyl; A.sub.30 and A.sub.31 are selected from CH, N or CF; A.sub.32 and A.sub.33 are selected from CH or N; with the proviso that only one or two of A.sub.30, A.sub.31, A.sub.32 and A.sub.33 can be N; A.sub.34 and A.sub.35 are selected from CH, N or CR.sub.30; A.sub.36, A.sub.37 and A.sub.38 are selected from CH or N; with the proviso that only one or two of A.sub.34, A.sub.35, A.sub.36, A.sub.37 and A.sub.38 can be N; and wherein R.sub.30 is selected from halo, nitro, cyano, R.sub.30a, [CH.sub.2].sub.tNR.sub.30aR.sub.30b, [CH.sub.2].sub.tOR.sub.30a, [CH.sub.2].sub.tC(O)R.sub.30a, [CH.sub.2].sub.tC(O)OR.sub.30a, [CH.sub.2].sub.tOC(O)R.sub.30a, [CH.sub.2].sub.tC(O)N(R.sub.30b)R.sub.30a, [CH.sub.2].sub.tN(R.sub.30b)C(O)R.sub.30a or [CH.sub.2].sub.tN(R.sub.30c)C(O)N(R.sub.30b)R.sub.30a; wherein t is 0, 1 or 2; R.sub.30a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.30b and R.sub.30c are hydrogen or (1-2C)alkyl; (iv) a group of the formula V or VI: ##STR00103## wherein: A.sub.40 is selected from NH, NMe or O; A.sub.42, A.sub.43, A.sub.44 and A.sub.46 are each independently selected from CH, N or CR.sub.2; A.sub.41 and A.sub.45 are each independently selected from C or N; with the proviso that: (vii) only up to three of A.sub.40, A.sub.41, A.sub.42, A.sub.43, A.sub.44, A.sub.45 and A.sub.46 are N; (viii) A.sub.41 and A.sub.45 cannot both be N; (ix) only one or two of A.sub.40, A.sub.42, A.sub.43, A.sub.44 and A.sub.46 can be CR.sub.2; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; A.sub.50, A.sub.53, A.sub.54 and A.sub.55 are each independently selected from CH, N or CR.sub.2; A.sub.52 and A.sub.56 are each independently selected from C or N; with the proviso that: (vii) only up to three of A.sub.50, A.sub.51, A.sub.52, A.sub.53, A.sub.54, A.sub.55 and A.sub.56 are N; (viii) A.sub.52 and A.sub.56 cannot both be N; (ix) only one or two of A.sub.50, A.sub.51, A.sub.53, A.sub.54 and A.sub.55 can be C R.sub.2; wherein R.sub.2 is as defined above; W.sub.4 is: ##STR00104## wherein A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d are selected from CH, N or CF, with the provisos that: only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be N; and only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be CF; X.sub.4 is a linker group of the formula:
    [CH.sub.2].sub.j1-L.sub.4-[CH.sub.2].sub.j2 wherein j1 and j2 are selected from 0 or 1; L.sub.4 is selected from O, S, SO, SO.sub.2, N(R.sub.x4a), C(O), C(O)O, OC(O), C(O)N(R.sub.x4a), N(R.sub.x4a)C(O), N(R.sub.x4b)C(O)N(R.sub.x4a), N(R.sub.x4a)C(O)O or OC(O)N(R.sub.x4a); and wherein R.sub.x4a and R.sub.x4b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.4 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y4a, [CH.sub.2].sub.uNR.sub.y4aR.sub.y4b, [CH.sub.2].sub.uOR.sub.y4a, [CH.sub.2].sub.uC(O)R.sub.y4a, [CH.sub.2].sub.uC(O)OR.sub.y4a, [CH.sub.2].sub.uOC(O)R.sub.y4a, [CH.sub.2].sub.uC(O)N(R.sub.y4b)R.sub.y4a, [CH.sub.2].sub.uN(R.sub.y4b)C(O)R.sub.y4a or [CH.sub.2], N(R.sub.y4c)C(O)N(R.sub.y4e)R.sub.y4a; wherein u is 0, 1 or 2; R.sub.y4 is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y4b and R.sub.y4c are hydrogen or (1-2C)alkyl.

    3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00105## wherein: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; each R.sub.2 group, when present, is selected from: halo, nitro, cyano, R.sub.2a, [CH.sub.2].sub.qNR.sub.2aR.sub.2b, [CH.sub.2].sub.qOR.sub.2a, [CH.sub.2].sub.qC(O)R.sub.2a, [CH.sub.2].sub.qC(O)OR.sub.2a or [CH.sub.2].sub.qOC(O)R.sub.2a; wherein q is 0, 1 or 2; R.sub.2a is hydrogen or (1-2C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.2b is hydrogen or (1-2C)alkyl; R.sub.N is selected from hydrogen or methyl; or a R.sub.2 group and R.sub.N are linked so as to form a 5- or 6-membered heterocyclic ring fused to Ring A, the fused 5- or 6-membered heterocyclic ring comprising one or two N atoms and being optionally substituted by halo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, cyano or amino; W.sub.1 is: ##STR00106## wherein A.sub.1, A.sub.2, A.sub.3 or A.sub.4 are selected from CH, N or CF, with the provisos that: only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be N; and only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be CF; X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from O, S, SO, SO.sub.2, N(R.sub.x1a), C(O), C(O)O, OC(O), C(O)N(R.sub.x1a) or N(R.sub.x1a)C(O); and wherein R.sub.x1a and R.sub.x1b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.1 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y1a, [CH.sub.2].sub.rNR.sub.y1aR.sub.y1b, [CH.sub.2].sub.rOR.sub.y1a, [CH.sub.2].sub.rC(O)R.sub.y1a, [CH.sub.2].sub.rC(O)OR.sub.y1a or [CH.sub.2].sub.rOC(O)R.sub.y1a; wherein r is 0 or 1; R.sub.y1a is hydrogen or (1-2C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y1b and R.sub.y1c are hydrogen or (1-2C)alkyl; (ii) a group of the formula III: ##STR00107## wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1 or 2; each R.sub.3 group, when present, is selected from: halo, nitro, cyano, R.sub.3a, [CH.sub.2].sub.q1-NR.sub.3aR.sub.3b, [CH.sub.2].sub.q1-OR.sub.3a, [CH.sub.2].sub.q1-C(O)R.sub.3a, [CH.sub.2].sub.q1C(O)OR.sub.3a or [CH.sub.2].sub.q1OC(O)R.sub.3a; wherein q1 is 0, 1 or 2; R.sub.3a is hydrogen or (1-2C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.3b is hydrogen or (1-2C)alkyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each independently selected from hydrogen or methyl or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms; W.sub.2 is a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.w2a, [CH.sub.2].sub.sNR.sub.w2aR.sub.w2b, [CH.sub.2].sub.sOR.sub.w2a, [CH.sub.2].sub.sC(O)R.sub.w2a, [CH.sub.2].sub.sC(O)OR.sub.w2a or [CH.sub.2].sub.sOC(O)R.sub.w2a; wherein s is 0, 1 or 2; R.sub.w2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.w2b and R.sub.w2e are hydrogen or (1-2C)alkyl; X.sub.2 is a linker group of the formula:
    [CH.sub.2].sub.m1-L.sub.2-[CH.sub.2].sub.m2 wherein m1 and m2 are selected from 0 or 1; L.sub.2 is selected from O, S, SO, SO.sub.2, N(R.sub.x2a), C(O), C(O)O, OC(O), C(O)N(R.sub.x2a) or N(R.sub.x2a)C(O), and wherein R.sub.x2a and R.sub.x2b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.2 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y2a, [CH.sub.2].sub.tNR.sub.y2aR.sub.y2b, [CH.sub.2].sub.tOR.sub.y2a, [CH.sub.2].sub.tC(O)R.sub.y2a, [CH.sub.2].sub.tC(O)OR.sub.y2a or [CH.sub.2].sub.tOC(O)R.sub.y2a; wherein t is 0 or 1; R.sub.y2a is hydrogen or (1-2C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y2b is hydrogen or (1-2C)alkyl; (iii) a group of the formula IV: ##STR00108## wherein: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1 or 2; each R.sub.4 group, when present, is selected from: halo, nitro, cyano, R.sub.4a, [CH.sub.2].sub.q2NR.sub.4aR.sub.4b, [CH.sub.2].sub.q2OR.sub.4a, [CH.sub.2].sub.q2C(O)R.sub.4a, [CH.sub.2].sub.q2C(O)OR.sub.4a or [CH.sub.2].sub.q2OC(O)R.sub.4a; wherein q2 is 0, 1, 2 or 3; R.sub.4a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.4b is hydrogen or (1-2C)alkyl; L is a 6C alkylene linker which is optionally substituted by one or more fluoro atoms; X is selected from O, CR.sub.xaR.sub.xb, S, SO, SO.sub.2, N(R.sub.xa), C(O); and wherein R.sub.xa and R.sub.xb are each independently selected from hydrogen or methyl; A.sub.30 and A.sub.31 are selected from CH, N or CF; A.sub.32 and A.sub.33 are selected from CH or N; with the proviso that only one or two of A.sub.30, A.sub.31, A.sub.32 and A.sub.33 can be N; A.sub.34 and A.sub.35 are selected from CH, N or CR.sub.30; A.sub.36, A.sub.37 and A.sub.38 are selected from CH or N; with the proviso that only one or two of A.sub.34, A.sub.35, A.sub.36, A.sub.37 and A.sub.38 can be N; and wherein R.sub.30 is selected from halo, nitro, cyano, R.sub.30a, [CH.sub.2].sub.tNR.sub.30aR.sub.30b, [CH.sub.2].sub.tOR.sub.30a, [CH.sub.2].sub.tC(O)R.sub.30a, [CH.sub.2].sub.tC(O)OR.sub.30a or [CH.sub.2].sub.tOC(O)R.sub.30a; wherein t is 0, 1 or 2; R.sub.30a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.30b and R.sub.30c are hydrogen or (1-2C)alkyl; (iv) a group of the formula V or VI: ##STR00109## wherein: A.sub.40 is selected from NH, NMe or O; A.sub.42, A.sub.43, A.sub.44 and A.sub.46 are each independently selected from CH, N or CR.sub.2; A.sub.41 and A.sub.45 are each independently selected from C or N; with the proviso that: (i) only up to three of A.sub.40, A.sub.41, A.sub.42, A.sub.43, A.sub.44, A.sub.45 and A.sub.46 are N; (ii) A.sub.41 and A.sub.45 cannot both be N; (iii) only one or two of A.sub.40, A.sub.42, A.sub.43, A.sub.44 and A.sub.46 can be CR.sub.2; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; A.sub.50, A.sub.53, A.sub.54 and A.sub.55 are each independently selected from CH, N or CR.sub.2; A.sub.52 and A.sub.56 are each independently selected from C or N; with the proviso that: (i) only up to three of A.sub.50, A.sub.51, A.sub.52, A.sub.53, A.sub.54, A.sub.55 and A.sub.56 are N; (ii) A.sub.52 and A.sub.56 cannot both be N; (iii) only one or two of A.sub.50, A.sub.51, A.sub.53, A.sub.54 and A.sub.55 can be CR.sub.2; wherein R.sub.2 is as defined above; W.sub.4 is: ##STR00110## wherein A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d are selected from CH, N or CF, with the provisos that: only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be N; and only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be CF; X.sub.4 is a linker group of the formula:
    [CH.sub.2].sub.j1-L.sub.4-[CH.sub.2].sub.j2 wherein j1 and j2 are selected from 0 or 1; L.sub.4 is selected from O, S, SO, SO.sub.2, N(R.sub.x4a), C(O), C(O)O, OC(O), C(O)N(R.sub.x4a) or N(R.sub.x4a)C(O); and wherein R.sub.x4a and R.sub.x4b are each independently selected from hydrogen or (1-2C)alkyl; Y.sub.4 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y4a, [CH.sub.2].sub.uNR.sub.y4aR.sub.y4b, [CH.sub.2].sub.uOR.sub.y4a, [CH.sub.2].sub.uC(O)R.sub.y4a, [CH.sub.2].sub.uC(O)OR.sub.y4a or [CH.sub.2].sub.uOC(O)R.sub.y4a, wherein u is 0 or 1; R.sub.y4a is hydrogen or (1-2C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.y4b and R.sub.y4c are hydrogen or (1-2C)alkyl.

    4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00111## wherein: Ring A is selected from phenyl or a 5- or 6-membered heteroaryl; n is 0, 1 or 2; each R.sub.2 group, when present, is selected from: halo, nitro, cyano, R.sub.2a, [CH.sub.2].sub.qNR.sub.2aR.sub.2b, [CH.sub.2].sub.qOR.sub.2a, [CH.sub.2].sub.qC(O)R.sub.2a; wherein q is 0 or 1; R.sub.2a is hydrogen or methyl; and R.sub.2b is hydrogen or methyl; R.sub.N is selected from hydrogen or methyl; or a R.sub.2 group and R.sub.N are linked so as to form a 5- or 6-membered heterocyclic ring fused to Ring A, the fused 5- or 6-membered heterocyclic ring comprising one or two N atoms and being optionally substituted by halo, hydroxy, methyl, halomethyl, cyano or amino; W.sub.1 is: ##STR00112## wherein A.sub.1, A.sub.2, A.sub.3 or A.sub.4 are selected from CH or CF, with the proviso that: only one or two of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 can be CF; X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from O, S, SO, SO.sub.2, N(R.sub.x1a) or C(O); and wherein R.sub.x1a is selected from hydrogen or methyl; Y.sub.1 is selected from a phenyl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y1a, NR.sub.y1aR.sub.y1b, OR.sub.y1a or C(O)R.sub.y1a; R.sub.y1a is hydrogen or methyl; and R.sub.y1b is hydrogen or methyl; (ii) a group of the formula III: ##STR00113## wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0, 1 or 2; each R.sub.3 group, when present, is selected from: halo, nitro, cyano, R.sub.3a, [CH.sub.2].sub.q1NR.sub.3aR.sub.3b, [CH.sub.2].sub.q1OR.sub.3a or [CH.sub.2].sub.q1C(O)R.sub.3a; wherein q1 is 0 or 1; R.sub.3a is hydrogen or methyl; and R.sub.3b is hydrogen or methyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.v2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each independently selected from hydrogen or methyl or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms; W.sub.2 is a carbocyclic or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.w2a, [CH.sub.2].sub.sNR.sub.w2aR.sub.w2b, [CH.sub.2].sub.sOR.sub.w2a or [CH.sub.2].sub.sC(O)R.sub.w2a; wherein s is 0 or 1; R.sub.w2a is hydrogen or (1-2C)alkyl optionally substituted by halo, hydroxy, amino or cyano; and R.sub.w2b and R.sub.w2e are hydrogen or (1-2C)alkyl; X.sub.2 is a linker group of the formula:
    [CH.sub.2].sub.m1-L.sub.2-[CH.sub.2].sub.m2 wherein m1 and m2 are selected from 0 or 1; L.sub.2 is selected from O, S, SO, SO.sub.2, N(R.sub.x2a) or C(O) and wherein R.sub.x2a is selected from hydrogen or methyl; Y.sub.2 is selected from a phenyl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y2a, NR.sub.y2aR.sub.y2b, OR.sub.y2a or C(O)R.sub.y2a; R.sub.y2a is hydrogen or methyl; and R.sub.y2b is hydrogen or methyl; (iii) a group of the formula IV: ##STR00114## wherein: Ring C is selected from phenyl, a 5- or 6-membered heteroaryl; k is 0, 1 or 2; each R.sub.4 group, when present, is selected from: halo, nitro, cyano, R.sub.4a, [CH.sub.2].sub.q2NR.sub.4aR.sub.4b, [CH.sub.2].sub.q2OR.sub.4a, [CH.sub.2].sub.q2C(O)R.sub.4a; wherein q2 is 0 or 1; R.sub.4a is hydrogen or methyl; and R.sub.4b is hydrogen or methyl; L is a 6C alkylene linker which is optionally substituted by one or more fluoro atoms; X is selected from O, CR.sub.xaR.sub.xb, S, SO, SO.sub.2, N(R.sub.xa), C(O); and wherein R.sub.xa and R.sub.xb are each independently selected from hydrogen or methyl; A.sub.30 and A.sub.31 are selected from CH, N or CF; A.sub.32 and A.sub.33 are selected from CH or N; with the proviso that only one or two of A.sub.30, A.sub.31, A.sub.32 and A.sub.33 can be N; A.sub.34 and A.sub.35 are selected from CH, N or CR.sub.30; A.sub.36, A.sub.37 and A.sub.38 are selected from CH or N; with the proviso that only one or two of A.sub.34, A.sub.35, A.sub.36, A.sub.37 and A.sub.38 can be N; and wherein R.sub.30 is selected from halo, nitro, cyano, R.sub.30a, NR.sub.30aR.sub.30b, OR.sub.30a or C(O)R.sub.30a; wherein R.sub.30a is hydrogen or methyl; and R.sub.30b is hydrogen or methyl; (iv) a group of the formula V or VI: ##STR00115## wherein: A.sub.40 is selected from NH, NMe or O; A.sub.42, A.sub.43, A.sub.44 and A.sub.46 are each independently selected from CH, N or CR.sub.2; A.sub.41 and A.sub.45 are each independently selected from C or N; with the proviso that: (i) only up to three of A.sub.40, A.sub.41, A.sub.42, A.sub.43, A.sub.44, A.sub.45 and A.sub.46 are N; (ii) A.sub.41 and A.sub.45 cannot both be N; (iii) only one or two of A.sub.40, A.sub.42, A.sub.43, A.sub.44 and A.sub.46 can be CR.sub.2; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; A.sub.50, A.sub.53, A.sub.54 and A.sub.55 are each independently selected from CH, N or CR.sub.2; A.sub.52 and A.sub.56 are each independently selected from C or N; with the proviso that: (i) only up to three of A.sub.50, A.sub.51, A.sub.52, A.sub.53, A.sub.54, A.sub.55 and A.sub.56 are N; (ii) A.sub.52 and A.sub.56 cannot both be N; (iii) only one or two of A.sub.50, A.sub.51, A.sub.53, A.sub.54 and A.sub.55 can be CR.sub.2; wherein R.sub.2 is as defined above; W.sub.4 is: ##STR00116## wherein A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d are selected from CH or CF, with the proviso that: only one or two of A.sub.4a, A.sub.4b, A.sub.4c or A.sub.4d can be CF; X.sub.4 is a linker group of the formula:
    [CH.sub.2].sub.j1-L.sub.4-[CH.sub.2].sub.j2 wherein j1 and j2 are selected from 0 or 1; L.sub.4 is selected from O, S, SO, SO.sub.2, N(R.sub.x4a) or C(O), C(O)O, OC(O), C(O)N(R.sub.x4a) or N(R.sub.x4a)C(O); and wherein R.sub.x4a and R.sub.x4b are each independently selected from hydrogen or methyl; Y.sub.4 is selected from a phenyl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y4a, NR.sub.y4aR.sub.y4b, OR.sub.y4a or C(O)R.sub.y4a; wherein R.sub.y4a is hydrogen or methyl; and R.sub.y4b is hydrogen or methyl.

    5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00117## wherein: Ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; each R.sub.2 group, when present, is selected from: halo, nitro, cyano, R.sub.2a, NR.sub.2aR.sub.2b, OR.sub.2a, C(O)R.sub.2a; R.sub.2a is hydrogen or methyl; and R.sub.2b is hydrogen or methyl; or a R.sub.2 group and R.sub.N are linked so as to form a 5- or 6-membered heterocyclic ring fused to Ring A, the fused 5- or 6-membered heterocyclic ring comprising one or two N atoms and being optionally substituted by halo, hydroxy, methyl, halomethyl, cyano or amino; W.sub.1 is: ##STR00118## X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from O, S, SO.sub.2 or C(O); Y.sub.1 is selected from a phenyl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.y1a or OR.sub.y1a; R.sub.y1a is hydrogen or methyl; and R.sub.y1b is hydrogen or methyl; (ii) a group of the formula III: ##STR00119## wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0 or 1; each R.sub.3 group, when present, is selected from: halo, nitro, cyano, R.sub.3a, NR.sub.3aR.sub.3b, OR.sub.3a or C(O)R.sub.3a; R.sub.3a is hydrogen or methyl; and R.sub.3b is hydrogen or methyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each independently selected from hydrogen or methyl or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms; W.sub.2 is a carbocyclic or heterocyclic ring which is optionally substituted by halo, nitro, cyano, R.sub.w2a, NR.sub.w2aR.sub.w2b, OR.sub.w2a or C(O)R.sub.w2a; wherein R.sub.w2a is hydrogen or methyl; and R.sub.w2b and R.sub.w2c are hydrogen or methyl; X.sub.2 is a linker group of the formula:
    [CH.sub.2].sub.m1-L.sub.2-[CH.sub.2].sub.m2 wherein m1 and m2 are selected from 0 or 1; L.sub.2 is selected from O, S, SO.sub.2 or C(O); Y.sub.2 is selected from a phenyl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, hydrogen, methyl or OR.sub.y2a; R.sub.y2a is hydrogen or methyl; and R.sub.y2b is hydrogen or methyl; (iii) a group of the formula IV: ##STR00120## wherein: Ring C is selected from phenyl or a 6-membered heteroaryl; k is 0 or 1; each R.sub.4 group, when present, is selected from: halo, nitro, cyano, R.sub.4a, NR.sub.4aR.sub.4b, OR.sub.4a, C(O)R.sub.4a; R.sub.4a is hydrogen or methyl; and R.sub.4b is hydrogen or methyl; L is a 6C alkylene linker which is optionally substituted by one or more fluoro atoms; X is selected from O, S, SO.sub.2, or C(O); A.sub.30 and A.sub.31 are selected from CH or CF; A.sub.32 and A.sub.33 are CH; A.sub.34 and A.sub.35 are selected from CH or CR.sub.30; A.sub.36, A.sub.37 and A.sub.38 are CH; and wherein R.sub.30 is selected from halo, nitro, cyano, hydrogen, methyl, NR.sub.30aR.sub.30b, OR.sub.30a or C(O)R.sub.30a; wherein R.sub.30a is hydrogen or methyl; and R.sub.30b is hydrogen or methyl; (iv) a group of the formula V or VI: ##STR00121## wherein: A.sub.40 is selected from NH or O; A.sub.42, A.sub.43, A.sub.44 and A.sub.46 are each independently selected from CH or CR.sub.2; A.sub.41 and A.sub.45 are each C; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; A.sub.50, A.sub.53, A.sub.54 and A.sub.55 are each independently selected from CH or CR.sub.2; A.sub.52 and A.sub.56 are each C; wherein R.sub.2 is as defined above; W.sub.4 is: ##STR00122## X.sub.4 is a linker group of the formula:
    -L.sub.4- wherein L.sub.4 is selected from O, S, SO, SO.sub.2, N(R.sub.x4a) or C(O), C(O)O, OC(O), C(O)N(R.sub.x4a) or N(R.sub.x4a)C(O); and wherein R.sub.x4a and R.sub.x4b are each independently selected from hydrogen or methyl; Y.sub.4 is selected from a phenyl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano or methyl.

    6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00123## wherein: Ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; each R.sub.2 group, when present, is selected from: halo or OR.sub.2a; wherein R.sub.2a is hydrogen or methyl; and R.sub.N is hydrogen or a R.sub.2 group and R.sub.N are linked so as to form a 5- or 6-membered heterocyclic ring fused to Ring A, the fused 5- or 6-membered heterocyclic ring comprising one or two N atoms and being optionally substituted by halo, hydroxy, methyl, halomethyl, cyano or amino; W.sub.1 is: ##STR00124## X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from O, S, SO.sub.2 or C(O); Y.sub.1 is selected from a phenyl, or heterocyclic ring which is optionally substituted by halo, nitro, cyano, hydrogen, methyl, or OR.sub.y1a; R.sub.y1a is hydrogen or methyl; (ii) a group of the formula III: ##STR00125## wherein: Ring B is selected from phenyl or a 5- or 6-membered heteroaryl; m is 0 or 1; each R.sub.3 group, when present, is selected from: halo, or OR.sub.3a; wherein R.sub.3a is hydrogen or methyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.v2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each independently selected from hydrogen or methyl or R.sub.v2a and R.sub.v2 are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms; W.sub.2 is a heterocyclic ring which is optionally substituted by halo, or OR.sub.w2a; wherein R.sub.w2a is hydrogen or methyl; X.sub.2 is a linker group of the formula:
    -L.sub.2- wherein L.sub.2 is selected from O, S, SO.sub.2 or C(O); Y.sub.2 is a phenyl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, hydrogen, methyl or OR.sub.y2a; R.sub.y2a is hydrogen or methyl; (iii) a group of the formula IVa: ##STR00126## wherein: Ring C is selected from phenyl or a 6-membered heteroaryl; k is 0 or 1; each R.sub.4 group, when present, is selected from: halo, or OR.sub.4a; wherein R.sub.4a is hydrogen or methyl; L is a 6C alkylene linker which is optionally substituted by one or more fluoro atoms; X is selected from O, S, SO.sub.2, or C(O); (iv) a group of the formula Va or VIa: ##STR00127## VIa wherein: A.sub.40 is selected from NH or 0; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; wherein R.sub.2 is as defined above; W.sub.4 is: ##STR00128## X.sub.4 is a linker group of the formula:
    -L.sub.4- wherein L.sub.4 is selected from SO.sub.2, C(O)N(R.sub.x4a) or N(R.sub.x4a)C(O); and wherein R.sub.x4a is selected from hydrogen or methyl; Y.sub.4 is a phenyl or heterocyclic ring which is optionally substituted by halo, nitro, cyano or methyl.

    7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from: (i) a group of the formula II: ##STR00129## wherein: Ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; each R.sub.2 group, when present, is selected from: halo or OR.sub.2a; wherein R.sub.2a is hydrogen or methyl; and R.sub.N is hydrogen or a R.sub.2 group and R.sub.N are linked so as to form a 5-membered heterocyclic ring fused to Ring A, the fused 5-membered heterocyclic ring comprising one or two N atoms; W.sub.1 is: ##STR00130## X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from SO.sub.2; Y.sub.1 is selected from a phenyl, or heterocyclic ring which is optionally substituted by halo, or OR.sub.y1a; wherein R.sub.y1a is hydrogen or methyl; (ii) a group of the formula III: ##STR00131## wherein: Ring B is selected from phenyl or a 6-membered heteroaryl; m is 0 or 1; each R.sub.3 group, when present, is selected from: halo, or OR.sub.3a; wherein R.sub.3a is hydrogen or methyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each hydrogen, or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker; W.sub.2 is a heterocyclic ring which is optionally substituted by halo, or OR.sub.w2a; wherein R.sub.w2a is hydrogen or methyl; X.sub.2 is a linker group of the formula:
    -L.sub.2- wherein L.sub.2 is selected from C(O); Y.sub.2 is a phenyl ring which is optionally substituted by halo, or OR.sub.y2a; wherein R.sub.y2a is hydrogen or methyl; (iii) a group of the formula IVa: ##STR00132## wherein: Ring C is selected from phenyl or a 6-membered heteroaryl; k is 0 or 1; each R.sub.4 group, when present, is selected from: halo, or OR.sub.4a; wherein R.sub.4a is hydrogen or methyl; L is a 6C alkylene linker; X is O; (iv) a group of the formula Va or VIa: ##STR00133## wherein: A.sub.40 is selected from NH or O; A.sub.51 is selected from NH, NMe, CH or CR.sub.2; wherein R.sub.2 is as defined above W.sub.4 is: ##STR00134## X.sub.4 is a linker group of the formula:
    -L.sub.4- wherein L.sub.4 is selected from SO.sub.2 or C(O)N(R.sub.x4a); and wherein R.sub.x4a is independently selected from hydrogen or methyl; Y.sub.4 is a heterocyclic ring.

    8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from: (i) a group of the formula IIa or IIb: ##STR00135## ##STR00136## wherein: Ring A is selected from phenyl or a 6-membered heteroaryl; n is 0 or 1; each R.sub.2 group, when present, is selected from: halo or OR.sub.2a; wherein R.sub.2a is hydrogen or methyl; and R.sub.N is hydrogen or a R.sub.2 group and R.sub.N are linked so as to form a 5-membered heterocyclic ring fused to Ring A, the fused 5-membered heterocyclic ring comprising one or two N atoms; W.sub.1 is: ##STR00137## X.sub.1 is a linker group of the formula:
    [CH.sub.2].sub.n1-L.sub.1-[CH.sub.2].sub.n2 wherein n1 and n2 are selected from 0 or 1; L.sub.1 is selected from SO.sub.2; Y.sub.1 is selected from a phenyl, or heterocyclic ring which is optionally substituted by halo or OR.sub.y1a; wherein R.sub.y1a is hydrogen or methyl; (ii) a group of the formula IIIa: ##STR00138## wherein: m is 0 or 1; each R.sub.3 group, when present, is selected from: halo, or OR.sub.3a; wherein R.sub.3a is hydrogen or methyl; V.sub.2 is selected from C(R.sub.v2aR.sub.v2b)C(R.sub.v2cR.sub.v2d) or C(R.sub.v2a)?C(R.sub.2c), wherein R.sub.v2a, R.sub.v2b, R.sub.v2c and R.sub.v2d are each hydrogen, or R.sub.v2a and R.sub.v2c are linked to form a cyclopropyl ring; Z.sub.2 is a 4C alkylene linker; W.sub.2 is a heterocyclic ring which is optionally substituted by halo, or OR.sub.w2a; wherein R.sub.w2a is hydrogen or methyl; X.sub.2 is a linker group of the formula:
    -L.sub.2- wherein L.sub.2 is selected from C(O); Y.sub.2 is a phenyl ring which is optionally substituted by halo, or OR.sub.y2a; wherein R.sub.y2a is hydrogen or methyl; (iii) a group of the formula IVb: ##STR00139## wherein: k is 0 or 1; each R.sub.4 group, when present, is selected from: halo, or OR.sub.4a; wherein R.sub.4a is hydrogen or methyl; L is a 6C alkylene linker; X is O; (iv) a group of the formula Vb, Vc, VIb or VIc: ##STR00140## ##STR00141## wherein: W.sub.4 is: ##STR00142## X.sub.4 is a linker group of the formula:
    -L.sub.4- wherein L.sub.4 is SO.sub.2; Y.sub.4 is a 5 or 6 membered heterocyclic ring.

    9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following: 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid; (E)-6-(5-(3-((4-(1-benzoylpiperidin-4-yl)butyl)amino)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid; 6-(2-fluoro-5-((3-(4-(phenylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid; 6-(3-(1-(6-([1,1-biphenyl]-2-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid; 6-(3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid; 6-(4-fluoro-3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid; 6-(2-methoxy-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid; 6-(5-((3-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)ureido)methyl)-2-fluorophenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid; 6-(2-((4-(piperidin-1-ylsulfonyl)benzyl)carbamoyl)-1H-indol-5-yl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid; (S)-6-(2-((4-(((Tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)carbamoyl)isoindolin-5-yl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid.

    10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

    11. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use in therapy.

    12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use in the treatment of: (i) diabetes; (ii) cardiovascular disease (e.g. pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy); (iii) inflammatory bowel condition (e.g. inflammatory bowel disease (IBD), Crohn's Disease or ulcerative colitis) (iv) cancer (e.g. breast cancer, prostate cancer or chronic lymphocytic leukaemia (CLL)); (v) liver disease (e.g. non-alcoholic fatty liver disease (NAFLD), in particular Non-Alcoholic SteatoHepatitis (NASH)); (vi) inflammatory skin conditions (e.g. psoriasis); (vii) lung conditions (Acute Lung Injury (ALI), Ventilator Induced Lung Injury (VILI), Radiation-Induced Lung Injury (RILI), pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis)); (viii) arthritis (e.g. osteoarthritis or rheumatoid arthritis); (ix) kidney disease (e.g. chronic kidney disease); or (x) sepsis.

    13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use in the treatment of: (i) diabetes; (ii) pulmonary arterial hypertension, acute coronary syndrome (ACS), congestive heart failure (CHF) or left ventricular hypertrophy; (iii) inflammatory bowel disease (IBD), Crohn's Disease or ulcerative colitis; (iv) breast cancer, prostate cancer or chronic lymphocytic leukaemia (CLL) (v) non-alcoholic fatty liver disease (NAFLD), in particular Non-Alcoholic SteatoHepatitis (NASH), hepatic steatosis, fibrosis or cirrhosis); (vi) psoriasis; (vii) Acute Lung Injury (ALI), Ventilator Induced Lung Injury (VILI), Radiation-Induced Lung Injury (RILI), pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis); (viii) osteoarthritis or rheumatoid arthritis; (ix) chronic kidney disease; or (x) sepsis.

    14. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use in the treatment of non-alcoholic fatty liver disease, for example hepatic steatosis, through inflammatory non-alcoholic steatohepatitis (NASH) to fibrosis or cirrhosis.

    Description

    EXAMPLES

    [0990] Reference is made to the accompanying figures, in which:

    [0991] FIG. 1 shows native mass spectra of NAMPT alone (top), or incubated with example 1 (middle) or FK866 (bottom). The major peaks for NAMPT dimer are observed in the range 5,500 to 6,750 in all samples. The major peaks for NAMPT monomer are observed in the range 4,000 to 4,800, but are absent in the example 1 sample, indicating the absence of monomeric protein under these conditions.

    [0992] FIG. 2 shows the region from m/z 6125-6500 of the native mass spectra of NAMPT alone (top), or incubated with example 1 (middle) or FK866 (bottom). The major peak for NAMPT dimer is observed at ?6240 (18+). Under these conditions the mass for the stable 2+2 complex between NAMPT and example 1 is observed at m/z ?6320, whereas the FK866 complex dissociates resulting in detection of NAMPT only.

    [0993] FIG. 3 shows the region from m/z 2950-5200 of the native mass spectra of NAMPT alone (top), or incubated with example 1 (middle) or FK866 (bottom). The major peaks for NAMPT monomer are observed in the range 4,000 to 4,800, but are absent in the example 1 sample, indicating the absence of monomeric protein under these conditions.

    SYNTHESIS OF STARTING MATERIALS

    Warheads:

    [0994] ##STR00061##

    7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A)

    [0995] A suspension of 7-aminonaphthalene-1,3-disulfonic acid (16.5 mmol, 5.0 g) and HCl (37%, 3.6 mL) in H.sub.2O (11 mL) was cooled down to 0? C. forming a white sludge. An ice-cooled solution of NaNO.sub.2 (16.5 mmol, 1.1 g) in water (9 mL) was added dropwise via cannula. The mixture was stirred at 0? C. for 1 h. A solution of NaI (53.0 mmol, 7.9 g) and HCl (37%, 3.6 mL) in H.sub.2O (15 mL) at 0? C. was added dropwise via cannula. The resulting dark mixture was allowed to reach RT, concentrated under reduced pressure and recrystallized on boiling water. The resulting pale-brown solid was washed with ice cooled water (40 mL), Et.sub.2O (20 mL) and dried under air giving the product as a beige solid (3.1 g, 44% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.18 (d, J=1.3 Hz, 1H), 8.23 (d, J=1.7 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.78 (br. s, 2H).

    Tail Precursors:

    [0996] ##STR00062##

    (E)-3-(3-bromo-4-fluorophenyl)acrylic acid (Intermediate 1)

    [0997] A mixture of 3-bromo-4-fluorobenzaldehyde (5.03 mmol, 930 mg), malonic acid (11.05 mmol, 1150 mg), piperidine (10 mol %, 0.05 mL) and pyridine (2.5 mL) was combined in a high pressure tube and stirred at 115? C. for 3 h. The mixture was allowed to reach RT and poured into 200 mL of 2M HCl. A white precipitate was formed, isolated by filtration and dried under vacuum giving the desired product (640 mg, 52%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 12.49 (br., 1H), 8.13 (dd, J=6.8, 2.1 Hz, 1H), 7.79 (ddd, J=8.7, 4.9, 2.2 Hz, 1H), 7.57 (d, J=16.0 Hz, 1H), 7.43 (app. t, J=8.7 Hz, 1H), 6.60 (d, J=16.0 Hz, 1H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) ? 167.8, 159.5 (d, J=248.9 Hz), 141.8, 133.7, 133.2 (d, J=3.8 Hz), 130.1 (d, J=7.8 Hz), 121.1, 117.6 (d, J=22.6 Hz), 109.2 (d, J=21.5 Hz); m/z (M+H).sup.+ (ES.sup.+) 243.0, 245.0; t.sub.R=2.35 min. HPLC Method 2 (Base).

    ##STR00063##

    (4-(4-azidobutyl)piperidin-1-yl)(phenyl)methanone (Intermediate 2)

    [0998] (4-(4-Hydroxybutyl)piperidin-1-yl)(phenyl)methanone (2.22 mmol, 545 mg), was dissolved in dry DMF (6 mL), degassed, and ice-cooled. DPPA (6.67 mmol, 1.4 mL), DBU (6.67 mmol, 1.0 mL) were added, the mixture stirred for 30 min at 0? C., followed by the addition of sodium azide (2.22 mmol, 144 mg) and stirring at 100? C. for 4 h. The mixture was allowed to reach RT, diluted with Et.sub.2O (40 mL), washed with water (2?20 mL) and brine (30 mL), dried over MgSO.sub.4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% HCOOH modifier) affording the desired product as a brown oil (364 mg, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.45-7.37 (s, 5H), 4.80-4.67 (m, 1H), 3.82-3.70 (m, 1H), 3.30 (t, J=6.8 Hz, 2H), 3.03-2.90 (m, 1H), 2.82-2.69 (m, 1H), 1.90-1.78 (m, 1H), 1.76-1.49 (m, 4H), 1.47-1.38 (m, 2H), 1.36-1.01 (m, 4H); m/z (M+H).sup.+ (ES.sup.+) 287.4; t.sub.R=2.67 min. HPLC Method 2 (Base).

    ##STR00064##

    (4-(4-aminobutyl)piperidin-1-yl)(phenyl)methanone (Intermediate 3)

    [0999] (4-(4-Azidobutyl)piperidin-1-yl)(phenyl)methanone (Intermediate 2; 1.27 mmol, 364 mg) was dissolved in MeOH:DCM (1:1, 10 mL) under an inert atmosphere. Pd/C (10% w/w, 10 mol %, 80 mg) was added and H.sub.2 (1 atm) was bubbled through the solution. The mixture was stirred for 1 h, then filtered through Celite?, washed with DCM (20 mL), MeOH (20 mL) and concentrated under reduced pressure giving a colourless oil (184 mg, 55%). The crude was taken into the next step without further purification. m/z (M+H).sup.+ (ES.sup.+) 261.4, 263.4; t.sub.R=1.76 min. HPLC Method 2 (Base).

    ##STR00065##

    2-((6-azidohexyl)oxy)-1,1-biphenyl (Intermediate 4)

    [1000] 6-([1,1-biphenyl]-2-yloxy)hexan-1-01 (0.89 mmol, 240 mg), was dissolved in dry DMF (3 mL), degassed, and ice-cooled. DPPA (2.68 mmol, 0.57 mL), DBU (2.68 mmol, 0.40 mL) were added, the mixture stirred for 30 min at 0? C., followed by the addition of sodium azide (0.89 mmol, 58 mg) and stirring at 100? C. for 4 h. The mixture was allowed to reach RT, diluted with Et.sub.2O (40 mL), washed with water (2?20 mL) and brine (30 mL), dried over MgSO.sub.4, filtered, concentrated under reduced pressure and used in the next step without further purification (200 mg, 76%). m/z (M+H).sup.+ (ES.sup.+) 296.1; t.sub.R=3.16 min. HPLC Method 2 (Base).

    ##STR00066##

    1-bromo-3-ethynylbenzene (Intermediate 5)

    [1001] 1-Bromo-3-iodobenzene (2.12 mmol, 0.27 mL), TEA (8.48 mmol, 1.19 mL), and ethynyltrimethylsilane (2.40 mmol, 0.32 mL) were dissolved in anhydrous THF (12 mL) and degassed with Ar for 20 min. PdCl.sub.2(PPh.sub.3).sub.2 (0.11 mmol, 74 mg) and CuI (0.06 mmol, 12 mg) were added and the mixture stirred at RT for 4 h. The mixture was concentrated, redissolved in Et.sub.2O (30 mL) and washed with water (2?20 mL) and brine (20 mL). The organic phase was dried over MgSO.sub.4, filtered, concentrated under reduced pressure and purified by filtering through a small pad of silica (ca. 2-3 g) and eluting with Hexane:AcOEt (95:5). The solution was concentrated under reduced pressure and redissolved in MeOH (10 mL). K2CO3 (5.30 mmol, 736 mg) was added and the mixture stirred for 1 h. The mixture was concentrated, filtered through a pad of silica (ca. 2-3 g) and eluted with Hex:AcOEt (95:5) affording a colourless oil (365 mg, 95%). m/z (M+H).sup.+ (ES.sup.+) 181.3; t.sub.R=3.25 min. HPLC Method 2 (Base).

    ##STR00067##

    (3-bromo-4-methoxyphenyl)methanamine hydroformate (Intermediate 6)

    [1002] 1-Bromo-4-methoxybenzonitrile (1.0 g, 4.72 mmol) was dissolved in THF (20 mL). Borane (1M solution in THF, 14.15 mL) was added dropwise for 10 min at RT then the mixture was taken to reflux and stirred for 2 h. The mixture was cooled to 0? C. and slowly quenched with MeOH (10 mL) and concentrated under reduced pressure. The mixture was diluted with water (20 mL), extracted with CH.sub.3Cl (3?15 mL) and washed with brine (15 mL). The organic phase was dried over MgSO.sub.4, filtered, concentrated and purified by reverse phase chromatography (0.1% HCOOH modifier) affording the desired product as a white solid (443 mg, 43%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.54 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.43 (dd, J=8.5, 2.3 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 4.06 (s, 2H), 3.92 (s, 3H). m/z (M+H).sup.+ (ES.sup.+) 216.2, 218.2; t.sub.R=2.08 min. HPLC Method 2 (Base).

    ##STR00068##

    4-(Piperidin-1-ylsulfonyl)benzonitrile (Intermediate 7)

    [1003] 3-Cyanobenzenesulfonyl chloride (500 mg, 2.47 mmol) was dissolved in DCM (6 mL). Piperidine (0.37 mL, 3.71 mmol) and TEA (0.69 mL, 4.94 mmol) were added to the mixture and stirred overnight. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (0.1% HCOOH modifier) affording the desired product as a white solid (470 mg, 76%). m/z: Compound does not ionise; t.sub.R=2.39 min. HPLC Method 2 (Base).

    ##STR00069##

    (4-(Piperidin-1-ylsulfonyl)phenyl)methanamine (Intermediate 8)

    [1004] 4-(Piperidin-1-ylsulfonyl)benzonitrile (Intermediate 7; 100 g, 0.40 mmol) was dissolved in THF (20 mL). Borane (1M solution in THF, 1.2 mL) was added dropwise for 10 min at RT then the mixture was taken to reflux and stirred for 1 h. The mixture was cooled to 0? C. and slowly quenched with MeOH (10 mL) and concentrated under reduced pressure. The mixture was diluted in MeOH (1 mL) and loaded onto a SCX cartridge (washed with 2 volumes of MeOH), washed with MeOH (3 mL), eluted with NH.sub.3 in MeOH (7M, 2 mL) and concentrated under reduced pressure affording the desired product as a white solid (95 mg, 93%). m/z (M+H).sup.+ (ES.sup.+) 255.3; t.sub.R=1.68 min. HPLC Method 2 (Base).

    Tails:

    [1005] ##STR00070##

    1-(3-bromo-4-fluorobenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 9)

    [1006] 3-Bromo-4-fluorobenzylamime hydrochloride (2.30 mmol, 553 mg) and TEA (5.06 mmol, 0.35 mL) were added into a ?40? C., light protected solution of 4-(chlorosulfonyl)phenyl isocyanate (2.30 mmol, 500 mg) in THF (20 mL). The mixture was stirred for 2 h and allowed to reach RT before addition of piperidine (2.30 mmol, 0.23 mL) and TEA (5.06 mmol, 0.35 mL). The mixture was stirred for another 2 h then concentrated under reduced pressure, redissolved in DCM (ca. 30 mL) and washed with water (2?20 mL) and brine (20 mL), dried over MgSO.sub.4, filtered, concentrated and purified by flash chromatography in silica gel (1% MeOH in DCM) affording the desired product as a white solid (458 mg, 42%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.19 (s, 1H), 7.68-7.53 (m, 5H), 7.40-7.31 (m, 2H), 6.91 (t, J=6.0 Hz, 1H), 4.30 (d, J=5.9 Hz, 2H), 2.83 (t, J=5.3 Hz, 4H), 1.62-1.46 (m, 4H), 1.42-1.17 (m, 2H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) ? 157.6 (d, J=243.4 Hz), 155.2, 145.1, 139.0 (d, J=3.5 Hz), 132.4, 129.2, 129.0 (d, J=7.4 Hz), 127.3, 117.7, 117.0 (d, J=22.3 Hz), 108.1 (d, J=20.9 Hz), 47.1, 42.1, 25.1, 23.4; m/z (M+H).sup.+ (ES.sup.+) 470.2, 472.2; t.sub.R=2.62 min. HPLC Method 2 (Base).

    ##STR00071##

    1-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)-3-(3-bromo-4-fluorobenzyl)urea (Intermediate 10)

    [1007] 3-Bromo-4-fluorobenzylamime hydrochloride (0.98 mmol, 200 mg) and DIPEA (1.03 mmol, 0.18 mL) were added into a ?40? C., light protected solution of 4-(chlorosulfonyl)phenyl isocyanate (0.98 mmol, 213 mg) in MeCN (20 mL). The mixture was stirred for 2 h and allowed to reach RT before addition of 8-oxa-3-azabicyclo[3.2.1]octane (1.11 mmol, 122 mg) and DIPEA (1.03 mmol, 0.18 mL). The mixture was stirred for another 2 h then concentrated under reduced pressure, redissolved in DCM (ca. 30 mL) and washed with water (2?20 mL) and brine (20 mL), dried over MgSO.sub.4, filtered, concentrated and purified by reverse phase column chromatography (0.1% HCOOH modifier). The product co-eluted with some impurities and was taken to the next step without further purification. m/z (M+H).sup.+ (ES.sup.+) 498.1, 500.1; t.sub.R=2.50 min. HPLC Method 2 (Base).

    ##STR00072##

    (E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(3-bromo-4-fluorophenyl)acrylamide (Intermediate 11)

    [1008] A mixture of Intermediate 3 (0.77 mmol, 200 mg) and Intermediate 1 (0.77 mmol, 183 mg) were dissolved in anhydrous DMF (5 mL). HATU (1.15 mmol, 439 mg) and DIPEA (1.54 mmol, 0.26 mL) were added and the mixture stirred at RT overnight. The mixture was extracted with AcOEt (30 mL) and washed with brine (3?20 mL). The organic phase was dried over MgSO.sub.4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% HCOOH modifier) affording the desired compound as a colourless oil (300 mg, 80%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.61 (dd, J=6.6, 2.1 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 7.35-7.26 (m, 5H), 7.20 (s, 1H), 7.03 (app. t, J=8.3 Hz, 1H), 6.25 (d, J=15.5 Hz, 1H), 5.96 (t, J=5.9 Hz, 1H), 4.77-4.53 (m, 1H), 3.66 (d, J=13.4 Hz, 1H), 3.28 (app. q, J=6.7 Hz, 2H), 2.95-2.83 (m, 1H), 2.72-2.60 (m, 1H), 1.85-1.68 (m, 2H), 1.60-1.50 (m, 1H), 1.50-1.38 (m, 3H), 1.36-0.89 (m, 5H). m/z (M+H).sup.+ (ES.sup.+) 487.3, 489.3; t.sub.R=2.65 min. HPLC Method 2 (Base).

    ##STR00073##

    1-(6-([1,1-biphenyl]-2-yloxy)hexyl)-4-(3-bromophenyl)-1H-1,2,3-triazole (Intermediate 12)

    [1009] A mixture of Intermediate 4 (164 mg, 0.55 mmol), Intermediate 5 (100 mg, 0.55 mmol), copper sulfate (5 mg, 5 mol %), and sodium ascorbate (11 mg, 10 mol %) in THF:H.sub.2O (5:1, 6 mL) was stirred at room temperature for 1 h. The reaction mixture was extracted with AcOEt (30 mL) and washed with brine (2?20 mL), dried over MgSO.sub.4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% formic acid modifier) affording the desired product as a colourless oil (96 mg, 37%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.84 (app. t, J=1.8 Hz, 1H), 7.62 (app. dt, J=7.8, 1.3 Hz, 1H), 7.53 (s, 1H), 7.42-7.38 (m, 2H), 7.33 (app. dd, J=8.0, 2.1 Hz, 1H), 7.28-7.22 (m, 2H), 7.22-7.14 (m, 3H), 7.13 (s, 1H), 6.90 (app. td, J=7.5, 1.1 Hz, 1H), 6.83 (dd, J=8.2, 1.2 Hz, 1H), 4.18 (app. t, J=7.2 Hz, 2H), 3.83 (app. t, J=6.1 Hz, 2H), 1.76 (app. p, J=7.4 Hz, 2H), 1.62-1.54 (m, 2H), 1.36-1.26 (m, 2H), 1.24-1.15 (m, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) ? 155.9, 146.3, 138.7, 132.7, 131.0, 131.0, 130.9, 130.4, 129.6, 128.7, 128.6, 127.8, 126.8, 124.2, 122.9, 120.9, 119.8, 112.6, 68.1, 50.2, 30.1, 28.8, 25.9, 25.4; m/z (M+H).sup.+ (ES.sup.+) 476.3; t.sub.R=3.18 min. HPLC Method 2 (Base).

    ##STR00074##

    1-(3-bromobenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 13)

    [1010] A mixture of 3-bromobenzylamine (201 mg, 1.08 mmol), phenyl (4-(cyclohexylsulfonyl)phenyl)carbamate (300 mg, 0.83 mmol), and TEA (0.35 mL, 2.49 mmol) in dioxane (10 mL) was stirred at 60? C. for 2 h. Upon cooling down the product crashed out as a white solid. The mixture was concentrated, redissolved in AcOEt (10 mL), washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO.sub.4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% ammonia modifier) affording the desired product as a white solid (190 mg, 50%). m/z (M+H).sup.+ (ES.sup.+) 452.2, 454.4; t.sub.R=2.63 min. HPLC Method 2 (Base).

    ##STR00075##

    1-(5-bromo-2-fluorobenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 14)

    [1011] A mixture of 5-bromo-2-fluorobenzylamine (216 mg, 0.90 mmol), phenyl (4-(cyclohexylsulfonyl)phenyl)carbamate (250 mg, 0.69 mmol), and TEA (0.29 mL, 2.07 mmol) in dioxane (10 mL) was stirred at 60? C. for 4 h. Upon cooling down the product crashed out as a white solid. The mixture was concentrated, redissolved in AcOEt (10 mL), washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting white solid was triturated with Et.sub.2O (ca. 10 mL) and dried giving the pure product (400 mg, 85%). m/z (M+H).sup.+ (ES.sup.+) 470.2, 472.2; t.sub.R=2.66 min. HPLC Method 2 (Base). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.66-7.60 (m, 2H), 7.53 (dd, J=6.6, 2.5 Hz, 1H), 7.52-7.48 (m, 2H), 7.41-7.31 (m, 1H), 7.16 (br. s, 1H), 6.95 (app. t, J=9.1 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.96 (app. t, J=5.4 Hz, 4H), 1.69-1.63 (m, 4H), 1.43 (app. tq, J=8.8, 5.4, 4.4 Hz, 2H). m/z (M+H).sup.+ (ES.sup.+) 470.2, 472.2; t.sub.R=2.66 min. HPLC Method 2 (Base).

    ##STR00076##

    1-(3-bromo-4-methoxybenzyl)-3-(4-(piperidin-1-ylsulfonyl)phenyl)urea (Intermediate 15)

    [1012] A mixture of (3-bromo-4-methoxyphenyl)methanamine hydroformate (245 mg, 0.55 mmol), phenyl (4-(piperidin-1-ylsulfonyl)phenyl)carbamate (200 mg, 0.55 mmol), and TEA (0.23 mL, 1.65 mmol) in dioxane (10 mL) was stirred at 60? C. for 2 h. Upon cooling down the product crashed out as a white solid. The mixture was concentrated, redissolved in AcOEt (10 mL), washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting white solid was purified by flash chromatography in silica gel (Hexane:AcOEt 2:3) affording the desired product as a colourless oil (262 mg, 99%). m/z (M+H).sup.+ (ES.sup.+) 482.2, 484.2; t.sub.R=2.59 min. HPLC Method 2 (Acid).

    ##STR00077##

    5-bromo-N-(4-(piperidin-1-ylsulfonyl)benzyl)-1H-indole-2-carboxamide (Intermediate 16)

    [1013] A mixture of 5-bromo-1H-indole-2-carboxylic acid (60 mg, 0.37 mmol), intermediate 8 (95 mg, 0.37 mmol), HATU (200 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.74 mmol) in DMF (3 mL) was stirred at RT overnight. The mixture extracted with Et.sub.2O (20 mL), washed with water (10 mL) and brine (10 mL). The organic phase was separated, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting white solid was purified by reverse phase column chromatography (0.1% HCOOH modifier) affording the desired product as a pale yellow oil (57 mg, 32%). m/z (M+H).sup.+ (ES.sup.+) 476.2, 478.2; t.sub.R=2.70 min. HPLC Method 2 (Acid).

    ##STR00078##

    Ethyl 4-(5-bromoisoindoline-2-carboxamido)benzoate (Intermediate 17)

    [1014] 5-bromoisoindoline (387 mg, 1.51 mmol), ethyl 4-isocyanatobenzoate (339 mg, 01.77 mmol) in THF (3 mL) were combined at 0? C. and the mixture was stirred at RT overnight. The mixture concentrated under reduced pressure, suspended on ice-cooled AcOEt (5 mL) and filtered. The resulting yellow solid was washed with ice-cooled AcOEt (5 mL) and taken to the next step without further purification (418 mg, 71%). m/z (M+H).sup.+ (ES.sup.+) 389.2, 391.2; t.sub.R=2.96 min. HPLC Method 2 (Base).

    ##STR00079##

    4-(5-bromoisoindoline-2-carboxamido)benzoic acid (Intermediate 18)

    [1015] A solution of ethyl 4-(5-bromoisoindoline-2-carboxamido)benzoate (Intermediate 17; 200 mg, 0.51 mmol) in THF:MeOH:H.sub.2O (3:1:1, 5 mL) was stirred with lithium hydroxide monohydrate (2.06 mmol, 84 mg) at RT overnight. The mixture was concentrated under reduced pressure, redissolved in H.sub.2O (30 mL), washed with AcOEt (20 mL), acidified to pH 3, and extracted with AcOEt (2?30 mL). The organic phases were combined, dried on MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting yellow solid was taken to the next step without further purification (176 mg, 96%). m/z (M+H).sup.+ (ES.sup.+) 375.2, 377.2; t.sub.R=2.89 min. HPLC Method 2 (Base).

    ##STR00080##

    (S)-5-bromo-N-(4-(((tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)isoindoline-2-carboxamide (Intermediate 19)

    [1016] 4-(5-bromoisoindoline-2-carboxamido)benzoic acid (Intermediate 18; 120 mg, 0.33 mmol) was dissolved in anhydrous DMF (5 mL). HATU (0.50 mmol, 188 mg), DIPEA (1.32 mmol, 0.23 mL) and (S)-(tetrahydrofuran-3-yl)methanamine (0.40 mmol, 42 ?L) were sequentially added and the mixture was stirred at RT for 3 h. The mixture was extracted with AcOEt (30 mL) and washed with brine (3?20 mL). The organic phase was dried over MgSO.sub.4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% HCOOH modifier) affording the desired compound as a pale yellow solid (120 mg, 82%). m/z (M+H).sup.+ (ES.sup.+) 444.3, 446.3; t.sub.R=2.72 min. HPLC Method 2 (Acid).

    Synthesis of NAMPT Inhibitors:

    [1017] ##STR00081##

    [1018] General Procedure: A solution of the corresponding haloarene/heteroarene derivative (1.0 eq), bis(pinacolato)diboron (1.5 eq) and potassium acetate (1.5-3.0 eq) in dioxane (0.1 M) was degassed with N.sub.2 for 15 min. Bis(dibenzylidenacetone)palladium(0) (5 mol %) and triscyclohexylphosphine (10 mol %) were added and the mixture was stirred at 90? C. until all the starting haloderivative has been converted to the corresponding boronic ester (monitored by LCMS the formation of the boronic acid). The mixture was allowed to reach RT followed by the addition of 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 1.0-1.2 eq), bis(triphenylphosphine)palladium(II) dichloride (10 mol %), potassium carbonate (3.0 eq) and degassed water (0.3 M). The mixture was stirred at 100? C. until all the boronic este derivative has been converted to the desired product (monitored by LCMS). The mixture was allowed to reach RT, filtered, washed with MeOH (5 mL), concentrated under reduced pressure and purified by reverse phase column chromatography (5 to 100% MeCN in H.sub.2O, modifier indicated) giving the corresponding disulfonate derivative.

    ##STR00082##

    6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid (Example 1)

    [1019] Intermediate 9 (0.64 mmol, 300 mg), bis(pinacolato)diboron (0.96 mmol, 247 mg), potassium acetate (1.92 mmol, 188 mg), dioxane (4 mL), bis(dibenzylidenacetone)palladium(0) (0.06 mmol, 37 mg) and triscyclohexylphosphine (0.06 mmol, 13 mg) stirred for 2 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.70 mmol, 291 mg), bis(triphenylphosphine)palladium(II) dichloride (0.06 mmol, 45 mg), potassium carbonate (1.92 mmol, 267 mg) and degassed water (1 mL) stirred for 1 h at 100? C. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (264 mg, 61%). mp. 167-169? C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.17 (s, 1H), 8.97 (d, J=1.6 Hz, 1H), 8.29 (d, J=1.8 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.68-7.60 (m, 3H), 7.59-7.54 (m, 2H), 7.48 (dd, J=7.6, 2.3 Hz, 1H), 7.43-7.37 (m, 1H), 7.32 (dd, J=10.4, 8.4 Hz, 1H), 6.99 (t, J=5.8 Hz, 1H), 4.39 (d, J=5.8 Hz, 2H), 2.82 (app. t, J=5.4 Hz, 4H), 1.52 (app. t, J=5.9 Hz, 4H), 1.39-1.29 (m, 2H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) ? 158.7 (d, J=244.9 Hz), 155.2, 145.2, 144.8, 144.2, 137.1 (d, J=3.4 Hz), 133.5, 132.6, 130.3, 129.4-128.8 (m, 3C), 127.9, 127.2 (d, J=2.2 Hz), 127.1, 125.6, 123.8, 117.6, 117.6, 116.6, 116.4, 49.1, 47.0, 42.7, 25.1, 23.3; m/z (M+H).sup.+ (ES.sup.+) 678.2; t.sub.R=1.76 min. HPLC Method 1; HRMS (ES-TOF): m/z calcd. for C.sub.29H.sub.26FN.sub.3O.sub.9S: 337.5402, found 337.5408 [M?2H].sup.2?. .sup.1H-NMR missing 2H signals from exchangeable protons.

    ##STR00083##

    (E)-6-(5-(3-((4-(1-benzoylpiperidin-4-yl)butyl)amino)-3-oxoprop-1-en-1-yl)-2-fluorophenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid (Example 2)

    [1020] Intermediate 11 (0.15 mmol, 70 mg), bis(pinacolato)diboron (0.21 mmol, 53 mg), potassium acetate (0.21 mmol, 21 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.02 mmol, 9 mg) and triscyclohexylphosphine (0.03 mmol, 6 mg) stirred for overnight at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.15 mmol, 62 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 10 mg), potassium carbonate (0.30 mmol, 42 mg) and degassed water (0.75 mL) stirred for 2 h at 100? C. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (4.6 mg, 5%) as the diammonium salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.99 (s, 1H), 8.28 (d, J=1.7 Hz, 1H), 8.18-8.10 (m, 2H), 8.07 (d, J=8.5 Hz, 1H), 7.75-7.61 (m, 3H), 7.48 (d, J=15.8 Hz, 1H), 7.45-7.40 (m, 4H), 7.38-7.30 (m, 2H), 7.10 (s, 8H), 6.66 (d, J=15.8 Hz, 1H), 4.55-4.38 (m, 1H), 4.14-4.05 (m, 1H), 3.59-3.38 (m, 1H), 3.06-2.91 (m, 1H), 2.82-2.65 (m, 1H), 1.80-1.65 (m, 1H), 1.65-1.40 (m, 5H), 1.38-1.17 (m, 6H); m/z (M+H).sup.+ (ES.sup.+) 695.3; t.sub.R=2.21 min. HPLC Method 2 (Base).

    ##STR00084##

    6-(2-fluoro-5-((3-(4-(phenylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (Example 3)

    [1021] 1-(3-bromo-4-fluorobenzyl)-3-(4-(phenylsulfonyl)phenyl)urea (0.13 mmol, 60 mg, prepared from phenyl (4-(phenylsulfonyl)phenyl)carbamate, CAS 1439358-24-3, using an analogous method to the synthesis of intermediate 9), bis(pinacolato)diboron (0.19 mmol, 50 mg), potassium acetate (0.26 mmol, 26 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.01 mmol, 7 mg) and triscyclohexylphosphine (0.03 mmol, 6 mg) stirred for 1 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.13 mmol, 54 mg), bis(triphenylphosphine)palladium(II) dichloride (0.01 mmol, 9 mg), potassium carbonate (0.26 mmol, 36 mg) and degassed water (0.75 mL) stirred for 2 h at 100? C. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (25 mg, 29%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.21 (s, 1H), 8.97 (s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.90 (d, J=7.3 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.69-7.55 (m, 6H), 7.47 (dd, J=7.6, 2.3 Hz, 1H), 7.42-7.35 (m, 1H), 7.31 (dd, J=10.4, 8.4 Hz, 1H), 7.00 (t, J=5.9 Hz, 1H), 4.37 (d, J=5.8 Hz, 2H); .sup.13C NMR (126 MHz, DMSO-d.sub.6) ? 158.7 (d, J=245.1 Hz), 155.1, 145.9, 144.7, 144.2, 142.6, 137.0 (d, J=3.2 Hz), 133.7, 133.5, 132.6 (d, J=2.2 Hz), 130.3 (d, J=2.5 Hz), 130.1, 129.2, 129.2, 129.1, 129.0, 129.0, 128.9, 127.9, 127.4, 127.3 (d, J=2.2 Hz), 125.6, 123.8, 118.0, 116.0 (d, J=22.7 Hz), 42.7; .sup.19F NMR (471 MHz, DMSO-d.sub.6) ? ?120.53; m/z (M+H).sup.+ (ES.sup.+) 688.2; t.sub.R=1.77 min. HPLC Method 2 (Base).

    ##STR00085##

    6-(3-(1-(6-([1,1-biphenyl]-2-yloxy)hexyl)-1H-1,2,3-triazol-4-yl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (Example 4)

    [1022] Intermediate 12 (0.19 mmol, 90 mg), bis(pinacolato)diboron (0.28 mmol, 72 mg), potassium acetate (0.38 mmol, 37 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium (0) (0.01 mmol, 7 mg) and triscyclohexylphosphine (0.02 mmol, 4 mg) stirred for 1 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.19 mmol, 78 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 13 mg), potassium carbonate (0.57 mmol, 78 mg) and degassed water (0.75 mL) stirred for 1 h at 100? C. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (30 mg, 24%) as the diammonium salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.16 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93-7.86 (m, 2H), 7.69 (app. dt, J=7.7, 1.5 Hz, 1H), 7.62 (app. t, J=7.7 Hz, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.39 (app. t, J=7.6 Hz, 2H), 7.33-7.25 (m, 3H), 7.14 (br., 8H), 7.08 (d, J=8.1 Hz, 1H), 7.00 (app. td, J=7.4, 1.0 Hz, 1H), 4.39 (t, J=7.2 Hz, 2H), 3.96 (t, J=6.3 Hz, 2H), 1.92-1.81 (m, 2H), 1.69-1.60 (m, 2H), 1.42-1.36 (m, 2H), 1.34-1.24 (m, 2H); .sup.13C NMR (126 MHz, DMSO-d.sub.6) ? 155.9, 146.7, 144.5, 144.5, 144.3, 141.8, 138.7, 138.1, 132.7, 132.1, 130.9, 130.4, 130.1, 129.8, 129.7, 129.5, 129.3, 128.3, 127.2, 127.1, 125.7, 125.7, 124.8, 124.2, 123.8, 122.1, 121.2, 113.3, 68.1, 50.0, 30.0, 28.8, 25.9, 25.4; m/z (M+H).sup.+ (ES.sup.+) 684.3; t.sub.R=1.93 min. HPLC Method 2 (Base).

    ##STR00086##

    6-(3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (Example 5)

    [1023] Intermediate 13 (0.22 mmol, 100 mg), bis(pinacolato)diboron (0.33 mmol, 84 mg), potassium acetate (0.44 mmol, 43 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.02 mmol, 13 mg) and triscyclohexylphosphine (0.04 mmol, 8 mg) stirred for 1 h at 100? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.22 mmol, 83 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 13 mg), potassium carbonate (0.66 mmol, 83 mg) and degassed water (0.75 mL) stirred for 2 h at 100? C. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (70 mg, 48%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.16 (s, 1H), 9.13-9.04 (m, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.14-8.10 (m, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.82-7.77 (m, 1H), 7.69-7.59 (m, 4H), 7.56 (d, J=8.5 Hz, 2H), 7.50 (app. t, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 6.97 (t, J=5.9 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 2.82 (app. t, J=5.3 Hz, 4H), 1.52 (app. t, J=5.8 Hz, 4H), 1.33 (app. t, J=5.8 Hz, 2H); .sup.13C NMR (126 MHz, DMSO-d.sub.6) ? 155.3, 145.3, 144.6, 144.3, 141.2, 141.2, 138.2, 132.6, 129.7, 129.5, 129.5, 129.2, 129.2, 127.1, 126.9, 126.5, 126.2, 125.7, 125.5, 123.8, 117.6, 47.1, 43.4, 25.1, 23.3; m/z (M+H).sup.+ (ES.sup.+) 660.2; t.sub.R=1.77 min. HPLC Method 2 (Base).

    ##STR00087##

    6-(4-fluoro-3-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (Example 6)

    [1024] Intermediate 14 (0.21 mmol, 100 mg), bis(pinacolato)diboron (0.32 mmol, 81 mg), potassium acetate (0.63 mmol, 62 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.02 mmol, 12 mg) and triscyclohexylphosphine (0.04 mmol, 8 mg) stirred for 1 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.25 mmol, 110 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 15 mg), potassium carbonate (0.63 mmol, 87 mg) and degassed water (0.75 mL) stirred for 2 h at 100? C. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (96 mg, 67%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.24 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.24 (d, J=1.8 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.73-7.67 (m, 2H), 7.59 (app. d, J=8.7 Hz, 3H), 7.51 (d, J=8.5 Hz, 2H), 7.31 (t, J=9.2 Hz, 1H), 7.12-7.04 (m, 1H), 4.42 (d, J=5.1 Hz, 2H), 2.77 (app. t, J=5.4 Hz, 4H), 1.47 (app. t, J=5.7 Hz, 4H), 1.34-1.25 (m, 2H); .sup.19F NMR (471 MHz, DMSO-d.sub.6) ? ?121.08; m/z (M+H).sup.+ (ES.sup.+) 678.2; t.sub.R=1.68 min. HPLC Method 2 (Base).

    ##STR00088##

    6-(2-methoxy-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid (Example 7)

    [1025] Intermediate 15 (0.30 mmol, 145 mg), bis(pinacolato)diboron (0.45 mmol, 115 mg), potassium acetate (0.90 mmol, 88 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.03 mmol, 17 mg) and triscyclohexylphosphine (0.06 mmol, 12 mg) stirred for 3 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.33 mmol, 136 mg), bis(triphenylphosphine)palladium(II) dichloride (0.03 mmol, 21 mg), potassium carbonate (0.90 mmol, 125 mg) and degassed water (0.75 mL) stirred for 2 h at 100? C. After purification by two reverse phase column chromatography (first 0.1% NH.sub.4OH modifier, second 0.1 HCOOH) the desired product was isolated as a white crystalline solid (3 mg, 2%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.07 (s, 1H), 8.83 (d, J=1.7 Hz, 1H), 8.24 (d, J=1.6 Hz, 1H), 8.09 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.64-7.58 (m, 2H), 7.58-7.53 (m, 3H), 7.34 (dd, J=8.4, 2.3 Hz, 1H), 7.27 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.86 (br., 1H), 4.33 (d, J=4.2 Hz, 2H), 3.76 (s, 3H), 2.82 (app. t, J=5.5 Hz, 4H), 1.57-1.45 (m, 4H), 1.40-1.28 (m, 2H); m/z (M+H).sup.+ (ES.sup.+) 690.2; t.sub.R=1.74 min. HPLC Method 2 (Base).

    ##STR00089##

    6-(5-((3-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)phenyl)ureido)methyl)-2-fluorophenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid (Example 8)

    [1026] Intermediate 10 (0.30 mmol, 150 mg), bis(pinacolato)diboron (0.45 mmol, 115 mg), potassium acetate (0.90 mmol, 88 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.03 mmol, 17 mg) and triscyclohexylphosphine (0.06 mmol, 12 mg) stirred for 3 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.30 mmol, 124 mg), bis(triphenylphosphine)palladium(II) dichloride (0.03 mmol, 21 mg), potassium carbonate (0.90 mmol, 125 mg) and degassed water (0.75 mL) stirred for 1 h at 100? C. After purification by two reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white crystalline solid (12 mg, 6%) as the diammonium salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.19 (s, 1H), 8.98 (d, J=1.7 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.68-7.62 (m, 3H), 7.58-7.52 (m, 2H), 7.50 (dd, J=7.6, 2.3 Hz, 1H), 7.45-7.37 (m, 1H), 7.34 (dd, J=10.4, 8.4 Hz, 1H), 7.17 (s, 8H), 6.99 (t, J=5.9 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 4.33 (s, 1H), 3.27-3.14 (m, 2H), 2.43 (dd, J=11.4, 2.3 Hz, 2H), 1.86-1.71 (m, 4H); .sup.19F NMR (376 MHz, DMSO) ? ?120.51; m/z (M+H).sup.+ (ES.sup.+) 706.2; t.sub.R=1.68 min. HPLC Method 2 (Base).

    ##STR00090##

    6-(2-((4-(piperidin-1-ylsulfonyl)benzyl)carbamoyl)-1H-indol-5-yl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (Example 9)

    [1027] Intermediate 16 (0.12 mmol, 55 mg), bis(pinacolato)diboron (0.17 mmol, 44 mg), potassium acetate (0.36 mmol, 35 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.01 mmol, 7 mg) and triscyclohexylphosphine (0.01 mmol, 2 mg) stirred for 2 h at 90? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.13 mmol, 54 mg), bis(triphenylphosphine)palladium(II) dichloride (0.01 mmol, 8 mg), potassium carbonate (0.39 mmol, 54 mg) and degassed water (0.75 mL) stirred at 100? C. overnight. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a pale yellow oil (8 mg, 11%) as the diammonium salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.80 (s, 1H), 9.28 (app. t, J=6.1 Hz, 1H), 9.13 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.92-7.89 (m, 1H), 7.85-7.79 (m, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.65-7.60 (m, 3H), 7.34 (s, 1H), 4.67 (d, J=6.0 Hz, 2H), 2.89 (app. t, J=5.4 Hz, 4H), 1.60-1.49 (m, 4H), 1.43-1.34 (m, 2H); m/z (M+H).sup.+ (ES.sup.+) 684.3; t.sub.R=1.69 min. HPLC Method 2 (Base).

    ##STR00091##

    (S)-6-(2-((4-(((Tetrahydrofuran-3-yl)methyl)carbamoyl)phenyl)carbamoyl)isoindolin-5-yl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid (Example 10)

    [1028] Intermediate 19 (0.22 mmol, 96 mg), bis(pinacolato)diboron (0.32 mmol, 82 mg), potassium acetate (0.66 mmol, 65 mg), dioxane (3 mL), bis(dibenzylidenacetone)palladium(0) (0.02 mmol, 13 mg) and triscyclohexylphosphine (0.02 mmol, 4 mg) stirred for 1.5 h at 80? C. Then, 7-Iodonaphthalene-1,3-disulfonic acid (Intermediate A; 0.24 mmol, 100 mg), bis(triphenylphosphine)palladium(II) dichloride (0.02 mmol, 15 mg), potassium carbonate (0.66 mmol, 92 mg) and degassed water (0.75 mL) stirred at 100? C. for 1.5 h. After purification by reverse phase column chromatography (0.1% NH.sub.4OH modifier) the desired product was isolated as a white solid (20 mg, 14%) as the diammonium salt. .sup.1H NMR (500 MHz, DMSO) ? 9.13 (s, 1H), 8.66 (s, 1H), 8.44 (app. t, J=5.8 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.86 (dd, J=8.6, 1.9 Hz, 1H), 7.82-7.77 (m, 2H), 7.74-7.67 (m, 4H), 7.53 (d, J=7.9 Hz, 1H), 4.91 (s, 2H), 4.87 (s, 2H), 3.79-3.71 (m, 1H), 3.69 (dd, J=8.5, 6.9 Hz, 1H), 3.66-3.58 (m, 1H), 3.49 (dd, J=8.5, 5.2 Hz, 1H), 3.31-3.17 (m, 2H), 2.51-2.43 (m, 1H), 2.00-1.87 (m, 1H), 1.67-1.54 (m, 1H); .sup.13C NMR (126 MHz, DMSO) ? 166.5, 154.1, 144.5, 144.2, 143.7, 140.4, 138.2, 138.0, 136.7, 132.6, 129.8, 129.5, 128.2, 127.9, 126.9, 125.6, 125.6, 125.5, 123.9, 123.8, 121.7, 118.7, 71.0, 67.3, 42.3, 40.9, 39.4, 30.0; m/z (M+H).sup.+ (ES.sup.+) 652.3; t.sub.R=1.54 min. HPLC Method 2 (Base).

    Native Mass Spectrometry

    [1029] The protein was expressed and isolated as previously described and, on the day of analysis, the buffer was exchanged into 100 mM ammonium acetate (Fisher Scientific, Loughborough, UK) pH 6.9 using micro Bio-Spin Chromatography columns (Micro Bio-Spin 6 Columns, Bio-Rad, Watford, UK) following the instructions specified by the manufacturer. The procedure was repeated twice and diluted to give a final concentration of NAMPT (5 ?mol/l), which was incubated with compound (5 ?mol/l) for 12 hours prior to analysis. Native MS data was acquired on the Synapt G2S HDMS (Waters, Manchester, UK). NanoESI capillaries were prepared in-house from thin-walled borosilicate capillaries (inner diameter 0.9 mm, outer diameter 1.2 mm, World Precision Instruments, Stevenage, UK) using a Flaming/Brown P-1000 micropipette puller (Sutter Instrument Company, Novato, CA, USA). A positive voltage was applied to the solution via a platinum wire (Goodfellow Cambridge Ldt, Huntington, UK) inserted into the capillary. Gentle source conditions were applied to preserve the native-like structure: capillary voltage 1.2-1.5 kV, sampling cone 50-200 V, source temperature 70? C. Trap collision energy was 4 V, transfer collision energy was set to 0 V. Nitrogen was the carrier gas. External calibration of the spectra was achieved using solutions of cesium iodide (2 mg/mL in 50:50 water:isopropanol). Data were acquired and processed with MassLynx software (Waters, Manchester, UK). FIGS. 1, 2 and 3 depict the mass spectra for NAMPT alone or incubated with FK866 ((E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide, which is a known NAMPT inhibitor used for comparative purposes) or 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl)phenyl)ureido)methyl)phenyl)-4-(trioxidaneylthio)naphthalene-2-sulfonic acid (Example 1).

    Enzyme Assay

    [1030] In a 96-well opaque black plate, NAMPT (30 nMall concentrations provided as final), PRPP (50 ?M) and ATP (2 mM) with or without test compounds (11 concentrations, prepared by three-fold dilutions from final concentration of 30 mM, all in triplicate) were incubated for 20 minutes at 37? C. in TMD buffer (50 mM Tris-HCl, 10 mM MgCl.sub.2, 2 mM DTT, pH 7.5). The enzymatic reaction was initiated by the addition of NAM (25 ?M) and the plate incubated for 20 minutes at 37? C. 20 ?L of 20% acetophenone (in DMSO) and 20 ?l of 2 M KOH were added to each well and incubated to ambient temperature of 5 minutes, then 90 ?l of 100% formic acid was added to each well and the plate incubated at 37? C. for 20 minutes before reading on a Hides Sense plate reader (Ex/Em=355/460 nm). Data was processed to % control in Excel and IC.sub.50 curves fitted using GraphPad Prism. Data is reported from fitting of n=3 separate repeats.

    Tm Shift Assay

    [1031] Thermal melting experiments were carried out using an Applied Biosystem StepOnePlus qPCR instrument. NAMPT (1 ?M) was buffered in 10 mM HEPES, pH 7.5, 140 mM NaCl and assayed in a 96-well plate at a final concentration of 2 ?M in a 50 ?L volume.

    [1032] Compounds were added at a final concentration of 100 ?M and SYPRO Orange was added as a fluorescence probe at a dilution of 1:5000 (v/v). The temperature was raised with a step of 1? C. per minute from 25 to 96? C., and fluorescence readings were taken at each interval. Experiments were performed in triplicate, and the observed temperature shifts were recorded as the difference between the transition midpoints of sample and reference wells containing protein without ligand in the same plate and determined by nonlinear least-squares fit, reported in ? C. as the mean of the values obtained from 3 independent repeats.

    THP-1 WST-1 Assay

    [1033] THP-1 cells were plated at 30,000 cells per well (400,000 cells per mL) in a final volume of 150 ?L media (RPMI-1640 containing 10% v/v FBS) containing 1 ?M test compound. Samples were incubated for 48 hrs at which point 15 ?L WST-1 solution (Sigma-Aldrich) was added. Light was excluded and the samples incubated for a further 2 hrs. Absorbance of wells were read at 450 nm and 630 nm using a Hidex Sense plate reader. Metabolic inhibition was determined by the absorbance at 450 nM and transformed to % control using Excel. Data reported is an average of three replicates.

    TABLE-US-00001 NAMPT THP-1 WST-1 NAMPT Tm shift enzymatic (% inhibition Example (? C.) IC.sub.50 at 1 ?M) Comparative 2.6 1.6*** 79.6%.sup. Example: FK866.sup.1 1 10.3 511 <0% 2 9.1 8358 70.4 3 12.2 ND <0% 4 ND* ND <0% 5 10.8 ND <0% 6 9.6 ND 1.0% 7 7.5 ND <0% 8 9.7 ND <0% 9 4.2** ND <0% 10 20.5** ND ND *Comparative fluorescence prevents detection in Sypro orange channel. **Compounds effectively completely supress the melt event, Tm shift values fitted to resultant profile but with low confidence. ***Literature value; Acta Pharmacologica Sinica (2018) 39: 394-301. .sup.1FK866 is the compouond (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide, which is a known NAMPT inhibitor used for comparative purposes.