A method of treating a disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a stereoisomer, enantiomer, racemic, tautomer, solvent, hydrate or pharmaceutically acceptable salt thereof,
- wherein the disease is selected from the group consisting of diabetes mellitus, Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy, cystic fibrosis, Creutzfeld-Jacob's disease, impaired glucose tolerance, hyperglycemia, hypoglycemia, glyceraldehyde-3-phosphate dehydrogenase deficiency, hyperinsulinism, impaired insulin production, impaired insulin sensitivity, metabolic syndrome, insulin resistance syndrome, obesity, lipidoses, cardiac lipidoses, dyslipidemia, fatty liver, lipodistrophy, and hypertension;
- wherein the compound of formula (I) has the structure
- wherein,
- n is an integer selected from 0, 1, 2 or 3;
- R1is selected from the group consisting of C1-6alkyl, halo, haloC1-6alkyl, and haloC1-6alkyloxy;
- R3 is selected from the group consisting of C6-12aryl, hydrogen, C1-6alkyl, C3-12cycloalkyl, heterocyclyl, heteroaryl, C6-12arylC1-6alkyl, C6-12arylC1-6alkylC6-12aryl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, haloC1-6alkyloxy, amino, —NR20R21, and cyano;
- wherein said C6-12aryl, C1-6alkyl, C3-12cycloalkyl, heterocyclyl, heteroaryl, C6-12aiylC1-6alkyl, or C6-12arylC1-6alkylC6-12aryl can be unsubstituted or substituted with one or more Z1;
- L1 is selected from the group consisting of —SO2—, —CO—,
- wherein * represents where L1 is bound to L2;
- and ** represents where L1 is bound to the azetidine ring;
- and wherein,
- A1 is S or O;
- q is an integer selected from 0, 1, 2, or 3;
- L6 is —CO— or —SO2—,
- each R2 is independently selected from the group consisting of haloC1-6alkyloxy, —OR18, halo, hydrogen, C1-6alkyl, haloC1-6alkyl, C3-12cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, SR19, cyano, amino, —NR20R21, —CO2R22, —C(O)NR20R21, —C(O)R22, —S(O)R22, —S(O)2R22, —SO2NR20R21, nitro, —NR23C(O)R22, —R24—C(O)NR20R21, —NR23S(O)2R22, and —NR23C(O)NR20R21, wherein two R2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring;
- and wherein at least one carbon atom or heteroatom of said ring, C6-12aryl, C3-8cycloalkyl, heterocyclyl, heteroaryl can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- R4 is selected from the group consisting C6-12aryl, hydrogen, C1-6alkyl, C3-12cycloalkyl, heterocyclyl, heteroaryl, C6-12arylC1-6alkyl, C6-12arylC1-6alkylC6-12aryl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, haloC1-6alkyloxy, amino, —NR20R21, and cyano;
- and wherein said C6-12aryl, C1-6alkyl, C3-12cycloalkyl, heterocyclyl, heteroaryl, C6-12arylC1-6alkyl, or C6-12arylC1-6alkylC6-12aryl can be unsubstituted or substituted with one or more Z2;
- L2 is a single bond or a group of formula (i);
- wherein the left side of the group of formula (i) is attached to R3 and the right side thereof is attached to the nitrogen atom of the azetidine ring;
- and wherein,
- m is an integer selected from 0, 1, 2, or 3;
- w is an integer selected from 0, 1, 2 or 3;
- L5 is a single bond, or is selected from the group consisting of —O—, and —NR12—;
- R8 is selected from the group consisting of hydrogen, C1-6alkyl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, and haloC1-6alkyloxy;
- R9 is selected from the group consisting of hydrogen, C1-6alkyl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, and haloC1-6alkyloxy;
- or R8 and R9 together with the carbon atom to which they are attached from a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring;
- R10 is selected from the group consisting of hydrogen, C1-6alkyl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, and haloC1-6alkyloxy;
- R11 is selected from the group consisting of hydrogen, C1-6alkyl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, and haloC1-6alkyloxy;
- or R10 and R11 together with the carbon atom to which they are attached from a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring;
- R12 is selected from the group consisting of hydrogen, and C1-6alkyl;
- L3 is selected from the group consisting of —SO2—, —PO4—, and —PO3—;
- L4 is a single bond or is selected from the group consisting of —(CR15R16)t, —O—, and —NR17—;
- wherein,
- t is an integer selected from 1, 2 or 3;
- R15 is selected from the group consisting of hydrogen, C1-6alkyl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, and haloC1-6alkyloxy;
- R16 is selected from the group consisting of hydrogen, C1-6alkyl, halo, hydroxyl, —OR18, —SR19, haloC1-6alkyl, and haloC1-6alkyloxy;
- or R15 and R16 together with the carbon atom to which they are attached form a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring;
- R17 is selected from the group consisting of hydrogen, and C1-6alkyl;
- wherein at least one of L3, L4 is not a single bond;
- and wherein when L4 is a single bond, R4 is not methyl;
- each R18 is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, and cyanoC1-6alkyl;
- wherein at least one carbon atom or heteroatom of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, or cyanoC1-6alkyl can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- each R19 is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, and cyanoC1-6alkyl;
- wherein at least one carbon atom or heteroatom of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, heteroarylC1-6alkyl, or cyanoC1-6alkyl can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- each R20 is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl;
- wherein at least one carbon atom or heteroatom of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be oxidized to form at least one CO,=C=S, N═O, N═S, S═O or S(O)2;
- each R21 is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl;
- wherein at least one carbon atom or heteroatom of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be oxidized to form at least one CO,=C=S, N═O, N═S, S═O or S(O)2;
- or wherein R20 and R21 together with the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered heterocyclyl;
- and wherein at least one carbon atom or heteroatom of said heterocyclyl can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- each R22 is independently selected from the group consisting of hydrogen, hydroxyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl;
- wherein at least one carbon atom or heteroatom of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be oxidized to form at least one CO,=C=S, N═O, N═S, S═O or S(O)2;
- each R23 is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl;
- and wherein at least one carbon atom or heteroatom of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-12aryl, C3-8cycloalkyl, C642arylC1-6alkyl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl can be oxidized to form at least one CO,=C=S, N═O, N═S, S═O or S(O)2;
- each R24 is independently selected from the group consisting of C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C6-12arylene, C3-8cycloalkylene, C6-12aryleneC1-6alkylene*, heterocyclylene, heteroarylene, heterocyclyleneC1-6alkylene*, and heteroaryleneC1-6alkylene*;
- wherein * represents where R24 is bound to CO;
- wherein at least one carbon atom or heteroatom of said C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C6-12arylene, C3-8cycloalkylene, C6-12aryleneC1-6alkylene, heterocyclylene, heteroarylene, heterocyclyleneC1-6alkylene, or heteroaryleneC1-6alkylene can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- each Z1 is independently selected from the group consisting of haloC1-6alkyloxy, —OR18, halo, hydrogen, C1-6alkyl, haloC1-6alkyl, C3-12cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, heteroaryl, heteroarylC1-6alkyl, hydroxyl, —SR19, cyano, amino, —NR20R21, —CO2R22, —C(O)NR20R21, —C(O)R22, —S(O)R22, —S(O)2R22, —SO2NR20R21, nitro, —NR23C(O)R22, —R24—C(O)NR20R21, —NR23S(O)2R22, and —NR23C(O)NR20R21;
- wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring;
- and wherein at least one carbon atom or heteroatom of said C1-6alkyl, C3-12cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, heteroaryl or heteroarylC1-6alkyl can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- and
- each Z2 is independently selected from the group consisting of haloC1-6alkyloxy, —OR18, halo, hydrogen, C1-6alkyl, haloC1-6alkyl, C3-12cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, heteroaryl, heteroarylC1-6alkyl, hydroxyl, —SR19, cyano, amino, —NR20R21, —CO2R22, —C(O)NR20R21, —C(O)R22, —S(O)R22, —S(O)2R22, —SO2NR20R21, nitro, —NR23C(O)R22, —R24C(O)NR20R21, —NR23S(O)2R22, and NR23C(O)NR20R21;
- wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring;
- and wherein at least one carbon atom or heteroatom of said C1-6alkyl, C3-12cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, heteroaryl or heteroarylC1-6alkyl can be oxidized to form at least one C═O, C═S, N═O, N═S, S═O or S(O)2;
- with the proviso that said compound is not
- N-(1-methylethyl)-7-(phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- N-(3-fluorophenyl)-7-(phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- N-phenyl-7-(phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- N-(4-methoxyphenyl)-7-(phenylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- (1H-benzotriazol-5-yl)-{7-[2-(3-chloro-phenyl)-ethanesulfonyl]-2,7-diaza-spiro[3.5]non-2-yl}-methanone,
- N-(4-methoxyphenyl)-7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- N-(3-cyanophenyl)-7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- 7-(methylsulfonyl)-N-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- N-(3-fluorophenyl)-7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide,
- or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof.