# US 9,750,745 B2 · 2,7-diazaspiro[3.5]nonane compounds

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- Number: US 9,750,745 B2
- Document ID: US9750745B2
- Status: Granted
- Kind: B2
- Application number: 15/433,164
- Filed: 2017-02-15
- Published: 2017-06-08
- Granted: 2017-09-05
- Earliest claimed: 2014-03-17
- Assignees: Remynd NV
- Applicants: Remynd NV
- Inventors: Gerard Griffioen; Bart De Taeye; Katrien Princen; Koen De Witte; Emilie Blanche; Hasane Ratni; Mark Rogers-Evans
- Web page: https://patentgrep.com/patent/US9750745B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/10: Spiro-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a compound of formula (I) or a stereoisomer, enantiomer, racemic, or tautomer thereof, Formula (I), wherein R1, R3, R4, L1, L2, L3, L4, and n, have the same meaning as that defined in the claims and the description. The present invention also relates to compositions, in particular pharmaceuticals, comprising such compounds, and to uses of such compounds and compositions for the prevention and/or treatment of metabolic disorders and/or neurodegenerative diseases, and/or protein misfolding disorders.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (IA)

### Claim 3 (depends on 1)

The method according to claim 1, wherein L1 is —SO2—.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (IB)

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (ID)

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (IC)

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (IE)

### Claim 8 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (IF)

### Claim 9 (depends on 1)

The method according to claim 1, wherein L6 is a single bond.

### Claim 10 (depends on 1)

The method according to claim 1, wherein L1 is

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of 2,7-Bis((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-((4-Fluorophenyl)sulfonyl)-7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 7-((4-Methoxyphenyl)sulfonyl)-2-((4-propoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-((4-Chlorophenyl)sulfonyl)-7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-(4-Fluorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethanone; (4-Chlorophenyl)(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (3,4-Difluorophenyl)(7-(4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (4-Fluorophenyl)(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; 1-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-phenylethanone; 1-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-phenylbutan-1-one; 4,4,4-Trifluoro-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)butan-1-one; 1-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methyl-2-phenylpropan-1-one; (7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)(1-phenylcyclopropyl)methanone; 3-(4-Fluorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-1-one; 2-(3-Methoxyphenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-1-one; 1-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methyl-2-(pyridin-3-ylmethoxy)propan-1-one; 2-Hydroxy-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(pyridin-2-yl)propan-1-one; 2-(4-Methoxyphenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-1-one; 1-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methyl-2-(o-tolyl)propan-1-one; Chroman-4-yl(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (S)-2-(4-Fluorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-methylbutan-1-one; 2-(2-Methoxyphenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-1-one; 2-(2-Methoxyphenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-1-one; (7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)(1,2,3,4-tetrahydronaphthalen-1-yl)methanone; 2-(4-Chlorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-1-one; 2-(4-Chlorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-1-one; (7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)(1-phenylcyclopentyl)methanone; 2-(3,5-Difluorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)propan-1-one; 2-(3-Chlorophenyl)-1-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-1-one; 5-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(2,2,2-trifluoroethyl)-1,2,4-thiadiazole; 3-(4-Chlorobenzyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(3,4-Difluorobenzyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-Cyclopropyl-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-Butyl-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(3-(trifluoromethyl)benzyl)-1,2,4-thiadiazole; 3-(4-Methoxyphenyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((4-Methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(pyrazin-2-yl)-1,2,4-thiadiazole; 3-(4-Chlorophenyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(1-(4-Fluorophenyl)cyclopropyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((4-(methylthio)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 7-((4-(Difluoromethoxy)phenyl)sulfonyl)-2-((4-ethoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-((4-Chlorophenyl)sulfonyl)-7-((4-(difluoromethoxy)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 7-((4-(Difluoromethoxy)phenyl)sulfonyl)-2-((4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 7-((4-(Difluoromethoxy)phenyl)sulfonyl)-2-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 7-((4-Ethoxyphenyl)sulfonyl)-2-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 7-((4-Chlorophenyl)sulfonyl)-2-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2,7-Bis((4-(difluoromethoxy)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-7-((4-ethoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 7-((4-Chlorophenyl)sulfonyl)-2-((4-(difluoromethoxy)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-7-((4-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane; 6-Chloro-2-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole; 6-Chloro-2-(7-((4-ethoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole; 6-Chloro-2-(7-((4-(difluoromethoxy)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole; 6-Chloro-2-(7-((4-(methylthio)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole; 3-(1-(4-Fluorophenyl)ethyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; N-(4-((2-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)phenyl)acetamide; 3-(4-Fluorobenzyl)-5-(7-((4-(methylsulfonyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((2,4-Difluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 5-(7-((3,4-Dimethoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((2-methoxy-5-methylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((5-Chloro-2-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((3-(trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((4-(trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-(m-tolylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((2-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((4-Ethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-(o-tolylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((4-(Tert-butyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((3-fluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((2,5-Dimethoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 5-(7-((2,5-Difluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 5-(7-((2,6-Difluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 5-(7-((3,4-Difluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((3-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((5-Fluoro-2-methylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 2-Ethoxy-5-((2-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)benzonitrile; 3-(4-Fluorobenzyl)-5-(7-((4-methoxy-3-(trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((2-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((3-Chloro-4-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((3-(methylsulfonyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((3,5-Difluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; Methyl3-((2-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)benzoate; 5-(7-((4-(Difluoromethoxy)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 5-(7-((5-Fluoro-2-methoxyphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 5-(7-((4-Ethoxy-3-methylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((4-methoxy-3-methylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-(pyridin-3-ylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 4-((2-(3-(4-Fluorobenzyl)-1,2,4-thiadiazol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl-3,5-dimethylisoxazole; 3-(4-Fluorobenzyl)-5-(7(thiophen-2-ylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((5-Chlorothiophen-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-(thiophen-3-ylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((5-methylthiophen-2-yl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 3-(4-Fluorobenzyl)-5-(7-((3,3,3-trifluoropropyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-thiadiazole; 5-(7-((Cyclohexylmethyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-(4-fluorobenzyl)-1,2,4-thiadiazole; and 4-((2-(3-(4-Fluorobenzyl)-1,2,4-thiadiazol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)sulfonyl)morpholine; or a solvate, hydrate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of 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, 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, and (1H-benzotriazol-5-yl)-{7-[2-(3-chloro-phenyl)-ethanesulfonyl]-2,7-diaza-spiro[3.5]non-2-yl}-methanone; or a solvate, hydrate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.