US 2024/0300968 A1 · 6-SUBSTITUTED NAPHTHALENE-1,3-DISULFONIC ACID DERIVATIVES AS MODULATORS OF THE EXTRACELLULAR NICOTINAMIDE PHOSPHORIBOSYL TRANSFERASE (ENAMPT) FOR THE TREATMENT OF E.G. DIABETES

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).

A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below:

wherein R1 is selected from:
(i) a group of the formula II:
wherein:
Ring A is selected from phenyl or a 5- or 6-membered heteroaryl;
n is 0, 1 or 2;
each R2 group, when present, is selected from:
halo, nitro, cyano, R2a, —[CH2]q—NR2aR2b, —[CH2]q—OR2a, —[CH2]q—C(O)R2a, —[CH2]q—C(O)OR2a, —[CH2]q—OC(O)R2a, —[CH2]q—C(O)N(R2b)R2a, —[CH2]q—N(R2b)C(O)R2a, —[CH2]q—N(R2c)—C(O)—N(R2b)R2a, —[CH2]q—S(O)pR2a (where p is 0, 1 or 2), —[CH2]q—SO2N(R2)R2a, —[CH2]q—N(R2b)SO2R2a;
wherein q is 0, 1, 2 or 3;
R2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
R2b and R2c are hydrogen or (1-2C)alkyl;
RN is selected from hydrogen or methyl;
or a R2 group and RN 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;
W1 is:
wherein A1, A2, A3 or A4 are selected from CH, N or C—F, with the provisos that:
only one or two of A1, A2, A3 or A4 can be N;
and
only one or two of A1, A2, A3 or A4 can be C—F;
X1 is a linker group of the formula:
—[CH2]n1-L1-[CH2]n2—
wherein
n1 and n2 are selected from 0 or 1;
L1 is selected from —O—, —S—, —SO—, —SO2—, —N(Rx1a)—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(Rx1a)—, —N(Rx1a)C(O)—, —N(Rx1b)C(O)N(Rx1a)—, —N(Rx1a)C(O)O—, —OC(O)N(Rx1a)—, —S(O)2N(Rx1a), —N(Rx1a)SO2—, or —C(O)N(Rx1a)SO2—, or —SO2N(Rx1a)C(O)—;
and wherein Rx1a and Rx1b are each independently selected from hydrogen or (1-2C)alkyl;
Y1 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, Ry1a, —[CH2]r—NRy1aRy1b, —[CH2]r—ORy1a, —[CH2]r—C(O)Ry1a, —[CH2]r—C(O)ORy1a, —[CH2]r—OC(O)Ry1a, —[CH2]r—C(O)N(Ry1b)Ry1a, —[CH2]r—N(Ry1b)C(O)Ry1a, —[CH2]r—N(Ry1c)—C(O)—N(Ry1b)Ry1a, —[CH2]r—S(O)pRy1a (where p is 0, 1 or 2), —[CH2]r—SO2N(Ry1b)Ry1a, or —[CH2]r—N(Ry1b)SO2Ry1a;
wherein r is 0, 1, 2 or 3;
Ry1 is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
Ry1b and Ry1c are hydrogen or (1-2C)alkyl;
(ii) a group of the formula III:
wherein:
Ring B is selected from phenyl or a 5- or 6-membered heteroaryl;
m is 0, 1 or 2;
each R3 group, when present, is selected from:
halo, nitro, cyano, R3a, —[CH2]q1—NR3aR3b, —[CH2]q1—OR3a, —[CH2]q1—C(O)R3a, —[CH2]q1—C(O)OR3a, —[CH2]q1—OC(O)R3a, —[CH2]q1—C(O)N(R3b)R3a, —[CH2]q1—N(R3b)C(O)R3a, —[CH2]q1—N(R3c)—C(O)—N(R3b)R3a, —[CH2]q1—S(O)pR3a (where p is 0, 1 or 2), —[CH2]q1—SO2N(R3b)R3a, —[CH2]q1—N(R3b)SO2R3a;
wherein q1 is 0, 1, 2 or 3;
R3a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
R3b and R3c are hydrogen or (1-2C)alkyl;
V2 is selected from —C(Rv2aRv2b)C(Rv2cRv2d)— or —C(Rv2a)═C(R2c)—, wherein Rv2a, Rv2b, Rv2c and Rv2d are each independently selected from hydrogen or methyl or Rv2a and Rv2c are linked to form a cyclopropyl ring;
Z2 is a 4C alkylene linker which is optionally substituted by one or more fluoro atoms;
W2 is a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, Rw2a, —[CH2]s—NRw2aRw2b, —[CH2]s—ORw2a, —[CH2]s—C(O)Rw2a, —[CH2]s—C(O)ORw2a, —[CH2]s—OC(O)Rw2a, —[CH2]s—C(O)N(Rw2b)Rw2a, —[CH2]s—N(Rw2b)C(O)Rw2a, —[CH2]s—N(Rw2c)—C(O)—N(Rw2b)Rw2a, —[CH2]s—S(O)pRw2a (where p is 0, 1 or 2), —[CH2]s—SO2N(Rw2b)Rw2a, or —[CH2]s—N(Rw2b)SO2Rw2a;
wherein
s is 0, 1, 2 or 3;
Rw2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
Rw2b and Rw2e are hydrogen or (1-2C)alkyl;
X2 is a linker group of the formula:
—[CH2]m1-L2-[CH2]m2—
wherein
m1 and m2 are selected from 0 or 1;
L2 is selected from —O—, —S—, —SO—, —SO2—, —N(Rx2a)—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(Rx2a)—, —N(Rx2a)C(O)—, —N(Rx2b)C(O)N(Rx2a)—, —N(Rx2a)C(O)O—, —OC(O)N(Rx2a)—, —S(O)2N(Rx2a), N(Rx2a)SO2, or C(O)N(Rx2a)SO2, or —SO2N(Rx2a)C(O)—;
and wherein Rx2a and Rx2b are each independently selected from hydrogen or (1-2C)alkyl;
Y2 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, Ry2a, —[CH2]t—NRy2aRy2b, —[CH2]t—ORy2a, —[CH2]t—C(O)Ry2a, —[CH2]t—C(O)ORy2a, —[CH2]t—OC(O)Ry2a, —[CH2]t—C(O)N(Ry2b)Ry2a, —[CH2]t—N(Ry2b)C(O)Ry2a, —[CH2]t—N(Ry2c)—C(O)—N(Ry2b)Ry2a, —[CH2]t—S(O)pRy2a (where p is 0, 1 or 2), —[CH2]t—SO2N(Ry2b)Ry2a, or —[CH2]t—N(Ry2b)SO2Ry2a;
wherein t is 0, 1, 2 or 3;
Ry2a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
Ry2b and Ry2 are hydrogen or (1-2C)alkyl;
(iii) a group of the formula IV:
wherein:
Ring C is selected from phenyl, a 5- or 6-membered heteroaryl;
k is 0, 1 or 2;
each R4 group, when present, is selected from:
halo, nitro, cyano, R4a, —[CH2]q2—NR4aR4b, —[CH2]q2—OR4a, —[CH2]q2—C(O)R4a, —[CH2]q2—C(O)OR4a, —[CH2]q2—OC(O)R4a, —[CH2]q2—C(O)N(R4b)R4a, —[CH2]q2—N(R4b)C(O)R4a, —[CH2]q2—N(R4c)—C(O)—N(R4b)R4a, —[CH2]q2—S(O)pR4a (where p is 0, 1 or 2), —[CH2]q2—SO2N(R4b)R4a, —[CH2]q2—N(R4b)SO2R4a;
wherein q2 is 0, 1, 2 or 3;
R4a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
R4b and R4c 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—, —CRxaRxb—, —S—, —SO—, —SO2—, —N(Rxa)—, —C(O)—;
and
wherein Rxa and Rxb are each independently selected from hydrogen or methyl;
A30 and A31 are selected from CH, N or C—F;
A32 and A33 are selected from CH or N;
with the proviso that only one or two of A30, A31, A32 and A33 can be N;
A34 and A35 are selected from CH, N or C—R30;
A36, A37 and A38 are selected from CH or N;
with the proviso that only one or two of A34, A35, A36, A37 and A38 can be N;
and wherein R30 is selected from halo, nitro, cyano, R30a, —[CH2]t—NR30aR30b, —[CH2]t—OR30a, —[CH2]t—C(O)R30a, —[CH2]t—C(O)OR30a, —[CH2]t—OC(O)R30a, —[CH2]t—C(O)N(R30b)R30a, —[CH2]t—N(R30b)C(O)R30a, —[CH2]t—N(R30c)—C(O)—N(R30b)R30a, —[CH2]t—S(O)pR30a (where p is 0, 1 or 2), —[CH2]t—SO2N(R30b)R30a, or —[CH2]t—N(R30b)SO2R30a;
wherein
t is 0, 1, 2 or 3;
R30a is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
R30b and R30c are hydrogen or (1-2C)alkyl;
(iv) a group of the formula V or VI:
wherein:
A40 is selected from NH, NMe or O;
A42, A43, A44 and A46 are each independently selected from CH, N or CR2;
A41 and A45 are each independently selected from C or N;
with the proviso that:
(iv) only up to three of A40, A41, A42, A43, A44, A45 and A46 are N;
(v) A41 and A45 cannot both be N;
(vi) only one or two of A40, A42, A43, A44 and A46 can be CR2;
A51 is selected from NH, NMe, CH or CR2;
A50, A53, A54 and A55 are each independently selected from CH, N or CR2;
A52 and A56 are each independently selected from C or N;
with the proviso that:
(iv) only up to three of A50, A51, A52, A53, A54, A55 and A56 are N;
(v) A52 and A56 cannot both be N;
(vi) only one or two of A50, A51, A53, A54 and A55 can be CR2;
wherein R2 is as defined above;
W4 is:
wherein A4a, A4b, A4c or A4d are selected from CH, N or C—F, with the provisos that:
only one or two of A4a, A4b, A4c or A4d can be N;
and
only one or two of A4a, A4b, A4c or A4d can be C—F;
X4 is a linker group of the formula:
—[CH2]j1-L4-[CH2]j2—
wherein
j1 and j2 are selected from 0 or 1;
L4 is selected from —O—, —S—, —SO—, —SO2—, —N(Rx4a)—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(Rx4a)—, —N(Rx4a)C(O)—, —N(Rx4b)C(O)N(Rx4a)—, —N(Rx4a)C(O)O—, —OC(O)N(Rx4a)—, —S(O)2N(Rx4a), —N(Rx4a)SO2—, or —C(O)N(Rx4a)SO2—, or —SO2N(Rx4a)C(O)—;
and wherein Rx4a and Rx4b are each independently selected from hydrogen or (1-2C)alkyl;
Y4 is selected from a carbocyclic, aryl, heteroaryl or heterocyclic ring which is optionally substituted by halo, nitro, cyano, Ry4a, —[CH2]u—NRy4aRy4b, —[CH2]—ORy4a, —[CH2]u—C(O)Ry4a, —[CH2]u—C(O)ORy4a, —[CH2]u—OC(O)Ry4a, —[CH2]u—C(O)N(Ry4b)Ry4a, —[CH2]u—N(Ry4b)C(O)Ry4a, —[CH2]u—N(Ry4c)—C(O)—N(Ry4b)Ry4a, —[CH2]u—S(O)pRy4a (where p is 0, 1 or 2), —[CH2]u—SO2N(Ry4b)Ry4a, or —[CH2]u—N(Ry4b)SO2Ry4a;
wherein u is 0, 1, 2 or 3;
Ry4 is hydrogen or (1-4C)alkyl optionally substituted by halo, hydroxy, amino or cyano;
and
Ry4b and Ry4c are hydrogen or (1-2C)alkyl.

114 more elements

6-substituted naphthalene-1,3-disulfonic acid derivatives as modulators of the extracellular nicotinamide phosphoribosyl transferase (enampt) for the treatment of e.g. diabetes

Life of this patent

6-substituted naphthalene-1,3-disulfonic acid derivatives as modulators of the extracellular nicotinamide phosphoribosyl transferase (enampt) for the treatment of e.g. diabetes

Life of this patent

Abstract

Claims14