JPWO2012161119A1 - Novel spiropiperidine derivatives and pharmaceuticals containing the same - Google Patents

Abstract

Provided is a novel compound that has an action of promoting insulin secretion from pancreatic β cells and is useful as a preventive and / or therapeutic agent for diseases caused by hyperglycemia, such as diabetes. The following general formula (1): [wherein the A ring represents a C6-C10 aryl group or a 5-10 membered heterocyclic group; Z represents O, N—R9, S (O) m, CH2 or C R 1, R 2, R 3, R 4 are not present independently of each other, or represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a nitro group, a tetrazolyl group, etc .; R 5, R 6 , R7, independently of each other, represents a hydrogen atom, a halogen atom, a cyano group or a carboxyl group; R8 represents a C1-6 alkyl group, a C6-10 aryl group, etc., and R13 or R14 represents a hydrogen atom or a halogen atom. Or a salt thereof, or a solvate thereof.

Description

  The present invention relates to a drug having an action of promoting insulin secretion from pancreatic β cells and preventing and / or treating diseases caused by hyperglycemia such as diabetes.

  The pancreas is an endocrine / exocrine gland tissue derived from the endoderm, and is composed of endocrine cells, acinar cells, and duct cells. Pancreatic Langerhans Islet (pancreatic La Islet), which is an endocrine cell, constitutes 1% of the entire pancreas and is mainly classified into four cells. That is, α cells that secrete glucagon, β cells that secrete insulin, δ cells that synthesize and secrete somatostatin, and F cells that synthesize and secrete pancreatic polypeptides. Of these, insulin secreted from β cells has the effect of lowering blood sugar as a main physiological function, and is the only hormone that exhibits a hypoglycemic action. Insulin is secreted by sensing an increase in blood glucose in the pancreatic β cells and released into the portal vein. The released insulin suppresses gluconeogenesis and sugar release in the liver, and promotes glucose uptake in fat and muscle tissues, which are peripheral tissues, thereby maintaining the blood sugar level of the living body.

  Diabetes is a persistent hyperglycemic condition caused by insulin deficiency or by its lack of action. Diabetes mainly leads to insulin-dependent diabetes (IDDM) caused by abnormal pancreatic insulin secretion due to autoimmune diseases, etc., and persistent high insulin status due to insufficient insulin action (insulin resistance), and the insulin secretion ability due to pancreatic exhaustion associated therewith It is divided into two types of non-insulin dependent diabetes mellitus (NIDDM) caused by a decrease. Persistent hyperglycemia due to diabetes causes vascular damage and complications in multiple organs. Typical complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc., and problems such as decreased quality of life (QOL), increased medical costs, decreased survival rate, etc. Yes.

  Treatment of diabetes includes exercise therapy, diet therapy, and drug therapy. Examples of the drug used for drug therapy include a drug that promotes insulin secretion from pancreatic β cells, a drug that improves insulin resistance, a drug that suppresses sugar absorption, and a drug that promotes the use of sugar. Among them, an insulin secretagogue is expected to increase blood insulin concentration and lower blood sugar, and is therefore expected to suppress hyperglycemia and improve diabetes. A sulfonylurea preparation (SU drug), Rapid insulin secretion promoters, DPPIV inhibitors (see Non-Patent Document 1), GLP-1 analogs (see Non-Patent Document 2) and the like are actually used in the field of diabetes treatment. However, the most commonly used SU drug in Japan stimulates pancreatic β-cells and promotes endogenous insulin secretion (see Non-Patent Document 3), but may exhibit hypoglycemia as a side effect, particularly in the elderly, Care should be taken when using this product if the patient has impaired renal function or if the diet is irregular. Also, side effects such as weight gain have been reported. Furthermore, there may be a primary ineffectiveness in which no effect is seen from the initial administration, or a secondary ineffectiveness in which clinical effects are lost during the administration period (see Non-Patent Document 4), and these side effects are reduced, and the insulin secretion ability Development of an insulin secretagogue that reduces the burden on pancreatic β cells is desired.

  As compounds having a spiropiperidine skeleton, compounds having an acetyl-CoA carboxylase (ACC) inhibitory action have been reported (Patent Documents 1 to 3). However, all these compounds are characterized by a ring structure having an oxo group at the 4-position on the fused ring. In addition, a compound having a stearoyl-CoA desaturase (SCD) inhibitory action has been reported (Patent Document 4). However, all these compounds are characterized in that the substituent on the piperidine ring nitrogen atom is a heteroarylcarbamoyl group. In addition, a nitrogen-containing spirocycle compound has been reported (Patent Document 5). These compounds are disclosed as class III antiarrhythmic agents.

WO2007 / 011809 Pamphlet WO2007 / 011811 pamphlet WO2008 / 102749 pamphlet WO2010 / 112520 pamphlet JP-A-4-217960

J Clin Endocrinol Metab, May 2004, 89 (5): 2078-2084. Regul Pept, 2004, 117 (2): 77-88 The Lancet, Aug 31, 1985, 2: 474-475. The Lancet, Sep 12, 1998, 352: 837-853.

  An object of the present invention is to provide a compound having an action of promoting insulin secretion from pancreatic β cells and useful as a prophylactic / therapeutic agent for diseases caused by hyperglycemia such as diabetes.

  As part of research to find a compound having insulin secretion promoting activity, the present inventors searched for a compound that promotes insulin secretion using a hamster pancreatic β cell line HIT-T15 cell. The present inventors have found that a spiropiperidine derivative represented by (2) has an excellent effect of promoting insulin secretion from pancreatic β cells and is useful as a therapeutic agent for diabetes.

That is, this invention relates to the invention shown below.
[1] The following general formula (1):

[Where:
A ring _represents a heterocyclic group C 6 _{-C 10} aryl group or 5- to 10-membered;
Z is O, N—R ⁹ , S (O) m, CH ₂ or C═O (where R ⁹ is a hydrogen atom, a C _1-6 alkyl group, a C _1-7 alkanoyl group, or C _1-6. Represents an alkylsulfonyl group, and m represents an integer of 0 to 2);

R ¹ , R ² , R ³ and R ⁴ do not exist independently of each other, or are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a carboxy-C _1-6 alkyl group, a C _1-6 alkoxy carbonyl _{-C 1-6} alkyl group, with a heterocyclic -C _1-6 alkyl group to 4-10 membered (where the heterocycle 4-10 membered, _{C 1-6} alkyl or _{C 1-6} alkylsulfonyl Group may be substituted), C _1-6 alkoxy group, C _3-10 cycloalkyl-C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonyloxy group, C _{1- 6} alkylsulfonylamino group, hydroxyl group, cyano group, nitro group, tetrazolyl group, or the following formula (2) or formula (3):

(In the formula, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, a halogen atom or a C _1-6 alkyl group, and R ¹² represents a C _1-20 alkyl group, a C _2-6 alkenyl group, a haloC _1-6 alkyl group, C _2-7 alkanoyl group, C _6-10 aryl group, 4-10 membered heterocyclic group (the hetero ring may be substituted with a halogen atom), C _3-10 cycloalkyl- C _1-6 alkyl group, amino C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, cyano-C _1-6 alkyl group, C _1-6 alkoxy-C _1-6 alkyl group, carboxy-C _{1 -6} alkyl group, C _1-6 alkoxycarbonyl-C _1-6 alkyl group, carbamoyl-C _1-6 alkyl group, C _1-6 alkylsulfonyl-C _1-6 alkyl group, C _6-10 aryl-C _{1 -6} alkyl groups (where C _6-10 aryl may be substituted by a halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _1-6 alkylsulfonyl group or carboxyl group) or 4-10 membered hetero A ring -C _1-6 alkyl group (wherein the heterocycle may be substituted by a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group or an oxo group), l is 1 to 1 An integer of 3 and n represents an integer of 0 to 2);
R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom, a cyano group or a carboxyl group;
R ⁸ is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a halo C _1-6 alkyl group, a trialkylsilyl-C _1-6 alkyl group, a cyano C _1-6 alkyl Group, C _1-6 alkoxy-C _1-6 alkyl group, C _3-10 cycloalkyl group (wherein cycloalkyl may be substituted by a halogen atom), C _3-10 cycloalkyl-C _{1 A -6} alkyl group (wherein cycloalkyl may be substituted by a C _1-6 alkyl group), a C _6-10 aryl group (where C _6-10 aryl includes a halogen atom, a cyano group) , A halo C _1-6 alkoxy group, an amino group, a dialkylamino group, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkylthio group or a C _6-10 aryl-C _1-6 alkyloxy Even if the group is substituted There), with _{C 6-10} aryl -C _1-6 alkyl group (wherein the _{C 6-10} aryl, halogen _{atom, C 1-6} alkyl, halo _{C 1-6} alkoxy group or a halo _{C 1-6} An alkyl group may be substituted), a 4-10 membered heterocyclic-C _1-6 alkyl group (wherein the hetero ring is substituted with a C _1-6 alkyl group or a C _1-6 alkoxycarbonyl group). Or a 4-10 membered heterocyclic group,
R ¹³ or R ¹⁴ independently of each other represents a hydrogen atom or a halogen atom;

Or a salt thereof, or a solvate thereof.

[2] The ring according to [1], wherein the ring A is a group selected from a phenyl group, a pyridyl group, an indolyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a thiazolyl group, and an oxadiazolyl group, and Z is O. Compound or a salt thereof, or a solvate thereof.

[3] In general formula (1), ^one of R ¹ , R ² , R ³ and R ⁴ is a C _1-6 alkylsulfonyl group, a 4-10 membered heterocyclic-C _1-6 alkyl group (where, A 4- to 10-membered heterocycle may have the above-mentioned substituent) or a group represented by the formula (2), and there is no residue, or a hydrogen atom, a halogen atom, a cyano group, C The compound or salt thereof according to [1] or [2] above, which is a _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl-C _1-6 alkoxy group, or a solvate thereof .

[4] The group represented by the formula (2) is C _1-6 alkyl-S (O) _n CH ₂ —, C _6-10 aryl-C _1-6 alkyl-S (O) _n CH ₂ —, or 4 -10-membered heterocycle -C _1-6 alkyl-S (O) _n CH _2- (wherein the aryl or heterocycle may have the above-mentioned substituent, and n represents an integer of 0 to 2) The compound or salt thereof according to any one of [1] to [3], or a solvate thereof.

[5] The following compound group:
tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-((methylsulfonyl) methyl))) phenyl) spiro [chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 7- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 7- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-nitrophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (methylsulfonamido) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-hydroxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

tert-butyl 6- (4-((methylsulfonyl) oxy) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfinyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (6-((methylsulfonyl) methyl) pyridin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-methyl-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-methoxy-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) -3-propoxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3- (cyclopropylmethoxy) -4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

tert-butyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((1-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((2-methylsulfonyl) propan-2-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (1H-tetrazol-1-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (methylsulfonyl) methylpiperidino) spiro [chroman-2,4′-piperidine) -1′-carboxylate,
Ethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trifluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methoxyethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

Phenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-bis (trifluoromethyl) benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

Pyridin-4-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Pyridin-3-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Pyridin-2-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trichloro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Adamantan-1-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Adamantan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Oxetane-3-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Tetrahydro-2H-pyran-4-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4,4-difluorocyclohexyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

Phenyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
Neopentyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
Neopentyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trifluoroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate,

Neopentyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((pyridin-4-ylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((pyridin-4-ylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((phenylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((phenylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (4-(((5-Methyl-1,3,4-thiadiazol-2-yl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-Butyl 6- (4-(((5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-butyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((dodecylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((dodecylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((acetylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((propylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((allylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

tert-butyl 6- (4-((2-methoxyethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((cyclopropylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((cyclohexylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyridin-3-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

Cyclopropylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate,
Cyclobutylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1-methylcyclopropyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclobutyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Trimethylsilyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (6-((methylsulfonyl) methyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-((methylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7-fluoro-6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7-fluoro-6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 3-hydroxy-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) -3-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 4,4-dideuterio-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 4-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-cyano-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

tert-butyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate),
Neopentyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- [4-{(2- (isopropylsulfonyl) methyl) phenyl} spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((2-fluoroethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((cyanomethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((cyanomethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

2,2,2-trichloroethyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylates,
Neopentyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine]- 1′-carboxylate,
tert-butyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1-cyclopropylethyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoropropan-2-yl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′- Piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((3-hydroxypropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Isopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Isobutyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′- Carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
(Isopropyl-d7) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Tert-butyl-d9) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate,
(R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate ,
(R) -neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
(R) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, 4-piperidine] -1′-carboxylate,
(R) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [ Chroman-2,4-piperidine] -1′-carboxylate,
(S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate ,
(S) -neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
(S) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, 4-piperidine] -1′-carboxylate,
(S) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [ Chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4- Piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman- 2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoroisopropyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-Butyl 6- (5-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,

tert-butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoroisopropyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylates,
tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxy rate,
tert-butyl 6- (4-(((3-aminopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(S) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
(R) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
tert-Butyl 6- (4-(((3- (3,3-difluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-butyl 6- (4-(((methylsulfonyl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-((4- (1′-tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) butanoic acid,
tert-butyl 6- (4-(((4-amino-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy rate,
Ethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trifluoroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,3,4,4,4-pentafluorobutyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′- Piperidine] -1′-carboxylate,
(Ethyl-d5) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Isopropyl-d7) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Tert-butyl-d9) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Trimethylsilyl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1- (tert-butoxycarbonyl) piperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1-methylpiperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

4-isopropylbenzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) benzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((benzylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 6- (5-((benzylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((4-fluorobenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylates,
tert-butyl 6- (5-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,

tert-butyl 6- (5-(((2-methylbenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((((2-trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid,
3-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid,
2-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid,
tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Methyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Ethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Butyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isobutyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
sec-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-pentyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-methylpentan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-methylpentan-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methylbut-3-en-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

2-methylbut-3-in-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-methylpent-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Hexa-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-cyanoethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Cyclohexyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) cyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,3,5-trimethyldicyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1R, 2S, 4S) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylates,
(1S, 2R, 4R) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylates,
(3-methyloxetane-3-yl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Cyclohexylmethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Adamantan-1-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Trimethylsilyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2- Trifluoroethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,3,4,4,4-pentafluorobutyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate,
1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman -2,4'-piperidine] -1'-carboxylate,

(Methyl-d3) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Ethyl-d5) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Isopropyl-d7) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Tert-butyl-d9) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [ Chroman-2,4′-piperidine] -1′-carboxylate,
Benzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-phenylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-phenylpropyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methyl-1-phenylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methyl-4-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2- (trifluoromethoxy) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-methylbenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

4- (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-isopropylbenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,3-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,5-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-6-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-4-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dimethylbenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-bis (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Perfluorophenyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Furan-2-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

2-chlorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2- (trifluoromethoxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3- (dimethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3- (diethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-isopropylphenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-pentyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (methylthio) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,3-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

2,6-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-6-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-4-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-2-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-3-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-3-methylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluoro-3- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluoro-5- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4,6-trichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (benzyloxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Phenyl-2,3,4,5,6-d5) 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'- Carboxylate,
tert-butyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,

tert-butyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] carboxylate,
Neopentyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-((((6- (1 ′-(tert-butoxycarbonylspiro (chroman-2,4′-piperidin) -6-yl) pyridin-3-yl) methyl) sulfonyl) methyl) pyridine-1-oxide ,
tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isobutyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (5-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 '-Piperidine] -1'-carboxylate,
tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate,

1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((6-methylpyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyrazin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((((pyrazin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((thiazol-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine]- 1′-carboxylate,
tert-butyl 6- (5-((((pyrimidin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfinyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((1- (pyridin-2-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate,
tert-butyl 7-fluoro-6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (2-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((1H-imidazol-1-yl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (2-ethoxy-2-oxoethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2- (4- (1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) phenyl) acetic acid,
Isopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate and isopropyl 6 -(4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The compound according to [4] or a salt thereof, or a solvate thereof.

[6] A pharmaceutical composition comprising the compound according to the above [1] to [5] or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
[7] An insulin secretagogue comprising the compound or salt thereof according to [1] to [5] or a solvate thereof as an active ingredient.
[8] A hypoglycemic agent comprising the compound or salt thereof according to [1] to [5] or a solvate thereof as an active ingredient.
[9] A prophylactic and / or therapeutic agent for diabetes comprising the compound according to [1] to [5] or a salt thereof, or a solvate thereof as an active ingredient.

[10] A method for promoting insulin secretion, comprising administering an effective amount of the compound according to [1] to [5] or a salt thereof, or a solvate thereof.
[11] A method for lowering blood glucose, comprising administering an effective amount of the compound according to [1] to [5] or a salt thereof, or a solvate thereof.
[12] A method for the prophylaxis and / or treatment of diabetes, comprising administering an effective amount of the compound according to [1] to [5] or a salt thereof, or a solvate thereof.
[13] The compound according to the above [1] to [5] or a salt thereof, or a solvate thereof for promoting insulin secretion.
[14] The compound or a salt thereof, or a solvate thereof according to the above [1] to [5] for lowering blood glucose.
[15] The compound according to the above [1] to [5] or a salt thereof, or a solvate thereof for preventing and / or treating diabetes.
[16] Use of the compound or a salt thereof, or a solvate thereof according to the above [1] to [5] for producing an insulin secretion promoter, a hypoglycemic agent, or a preventive and / or therapeutic agent for diabetes.

  The spiropiperidine derivative of the present invention or a salt thereof, or a solvate thereof is an orally administrable low molecular weight compound having an action of potently promoting insulin secretion from pancreatic β-cells. It is useful as a prophylactic and / or therapeutic agent for diseases caused by the disease, such as diabetes.

  In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  In the present specification, examples of the “hydrogen atom” include a hydrogen atom (H) or a deuterium atom (D).

In the present specification, the “C _1-20 alkyl group” means a linear or branched alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group, n-pentyl group, n-octyl group, n-nonyl group N-decyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group, icosadecyl group, etc. Can be mentioned.

In the present specification, the “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group, isobutyl group, tert-butyl group, l-methylpropyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, neopentyl group, n-hexyl group, 1,3-dimethyl A butyl group, 3-methylpentyl group, etc. are mentioned.

In the present specification, "halo C _1-6 alkyl group", a C _1-6 alkyl group the same or different 1 to replaceable maximum halogen atoms are substituted, for example, monofluoromethyl Methyl group, difluoromethyl group, trifluoromethyl group, monochloromethyl group, dichloromethyl group, trichloromethyl group, monobromomethyl group, monoiodomethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group 2,2,2-trichloroethyl group, 1,1,1-trifluoro-2-methylpropan-2-yl group, 1,1-dimethyl-2,2,2-trifluoroethyl group, 1,1 -A dimethyl-2,2,2-trichloroethyl group, a 3,3,3-trifluoropropyl group, etc. are mentioned.

In the present specification, the “C _3-10 cycloalkyl group” is a monocyclic, polycyclic or condensed ring having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. And a cycloalkyl group of the formula. Examples of such a cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, an adamantyl group, and the like.

In this specification, examples of the “C _2-6 alkenyl group” include a vinyl group, a prop-1-en-1-yl group (propenyl group), and a prop-2-en-1-yl group (allyl group). , Isopropenyl group, but-1-en-1-yl group, but-2-en-1-yl group (crotyl group), but-3-en-1-yl group, 2-methylprop-2-ene- 1-yl group, 1-methylprop-2-en-1-yl group, penta-1-en-1-yl group, penta-2-en-1-yl group, penta-3-en-1-yl group Penta-4-en-1-yl group, 3-methylbut-2-en-1-yl group, 3-methylbut-3-en-1-yl group, hexa-1-en-1-yl group, hexa 2-ene-1-yl group, hexa-3-en-1-yl group, hexa-4-en-1-yl Group, hexa-5-en-1-yl group, 4-methylpent-3-en-1-yl group and the like.

In the present specification, examples of the “C _2-6 alkynyl group” include ethynyl group, propargyl group, 3-methyl-1-pentyn-3-yl group, 1-hexyn-3-yl group and the like.

In the present specification, examples of the “C _1-6 alkoxy group” include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. N-pentoxy group, isopentoxy group, neopentoxy group, n-hexyloxy group, isohexyloxy group and the like.

In this specification, the "halo C _1-6 alkoxy group", a C _1-6 alkoxy group the same or different 1 to replaceable maximum halogen atoms are substituted, such as mono- fluoromethoxy Group, difluoromethoxy group, trifluoromethoxy group, and trichloromethoxy group.

In the present specification, examples of the “C _1-7 alkanoyl group” include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group and the like.

In the present specification, examples of the “C _1-6 alkylsulfonyl group” include, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butyl. Sulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1-methylbutylsulfonyl group, 1-ethylpropylsulfonyl group, 2,2- Dimethylpropylsulfonyl group, n-hexylsulfonyl group, 4-methylpentylsulfonyl group, 3-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 1-methylpentylsulfonyl group, 3,3-dimethylbutylsulfonyl group, 2 , 2-dimethylbutylsulfonyl group, 1,1-dimethylbutylsulfonyl group, 1,2-dimethylbutylsulfonyl group, 1,3-dimethylbutylsulfonyl group, 2,3-dimethylbutylsulfonyl group, 1-ethylbutylsulfonyl group , 2-ethylbutylsulfonyl group and the like.

In the present specification, examples of the “C _1-6 alkylsulfonyloxy group” include a methylsulfonyloxy group, an ethylsulfonyloxy group, an n-propylsulfonyloxy group, an isopropylsulfonyloxy group, an n-butylsulfonyloxy group, and an isobutyl. Sulfonyloxy group, sec-butylsulfonyloxy group, tert-butylsulfonyloxy group, n-pentylsulfonyloxy group, isopentylsulfonyloxy group, neopentylsulfonyloxy group, 2-methylbutylsulfonyloxy group, 1-methylbutylsulfonyl Oxy group, 1-ethylpropylsulfonyloxy group, 2,2-dimethylpropylsulfonyloxy group, n-hexylsulfonyloxy group, 4-methylpentylsulfonyloxy group, 3-methylpentylsulfonyl Ruoxy group, 2-methylpentylsulfonyloxy group, 1-methylpentylsulfonyloxy group, 3,3-dimethylbutylsulfonyloxy group, 2,2-dimethylbutylsulfonyloxy group, 1,1-dimethylbutylsulfonyloxy group, 1 , 2-dimethylbutylsulfonyloxy group, 1,3-dimethylbutylsulfonyloxy group, 2,3-dimethylbutylsulfonyloxy group, 1-ethylbutylsulfonyloxy group, 2-ethylbutylsulfonyloxy group, and the like.

In the present specification, examples of the “C _1-6 alkylsulfonylamino group” include a methylsulfonylamino group, an ethylsulfonylamino group, an n-propylsulfonylamino group, an isopropylsulfonylamino group, an n-butylsulfonylamino group, and an isobutyl. Sulfonylamino group, sec-butylsulfonylamino group, tert-butylsulfonylamino group, n-pentylsulfonylamino group, isopentylsulfonylamino group, neopentylsulfonylamino group, 2-methylbutylsulfonylamino group, 1-methylbutylsulfonyl Amino group, 1-ethylpropylsulfonylamino group, 2,2-dimethylpropylsulfonylamino group, n-hexylsulfonylamino group, 4-methylpentylsulfonylamino group, 3-methylpentylsulfonyl Ruamino group, 2-methylpentylsulfonylamino group, 1-methylpentylsulfonylamino group, 3,3-dimethylbutylsulfonylamino group, 2,2-dimethylbutylsulfonylamino group, 1,1-dimethylbutylsulfonylamino group, 1 , 2-dimethylbutylsulfonylamino group, 1,3-dimethylbutylsulfonylamino group, 2,3-dimethylbutylsulfonylamino group, 1-ethylbutylsulfonylamino group, 2-ethylbutylsulfonylamino group, and the like.

In the present specification, examples of the “C _6-10 aryl group” include a phenyl group, a naphthyl group, an azulenyl group, an indanyl group, and the like.

  In the present specification, the “4-10 membered heterocyclic group” means a 4-10 membered monocyclic, polycyclic or 1 to 4 hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Fused cyclic saturated or unsaturated heterocyclic group means, for example, oxetanyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group , Isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzo Thienyl group, indolyl group, indolinyl group, isoindo Group, indazolyl group, benzimidazolyl group, benzoxazolyl group, benzoisoxazolyl group, benzothiazolyl group, benzisothiazolyl group, benzoxiadiazolyl group, benzothiadiazolyl group, benzotriazolyl group, quinolyl Group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, furopyridyl group, thienopyridyl group, pyrrolopyridyl group, oxazolopyridyl group, thiazolopyridyl group, imidazopyridyl group, etc. Can be mentioned.

In the present specification, the “C _1-6 alkoxy-C _1-6 alkyl group” includes a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an isopropoxymethyl group, a methoxyethyl group, an ethoxyethyl group, and the like. Can be mentioned.

In the present specification, as the “C _3-10 cycloalkyl-C _1-6 alkyl group”, a cyclopropylmethyl group, a 1-methylcyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, Examples thereof include a cyclohexylmethyl group and a cyclooctylmethyl group.

In the present specification, the “C _3-10 cycloalkyl-C _1-6 alkoxy group” includes a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, a cyclohexylmethoxy group, An octylmethoxy group etc. are mentioned.

In the present specification, examples of the “C _6-10 aryl-C _1-6 alkyl group” include benzyl group, phenethyl group, phenylpropyl group, naphthylmethyl group and the like.

In the present specification, the “4-10 membered heterocycle-C _1-6 alkyl group” includes an oxetanylmethyl group, a pyridylmethyl group, a pyrazinylmethyl group, an imidazolylmethyl group, a triazolylmethyl group, and a tetrazolylmethyl group. Etc.

In the present specification, a carboxy-C _1-6 alkyl group, a C _1-6 alkoxycarbonyl-C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a cyano-C _1-6 alkyl group, a carbamoyl-C ₁ C _1-6 alkyl or C _{1 in a -6} alkyl group, a C _1-6 alkylsulfonyl-C _1-6 alkyl group, a trialkylsilyl-C _1-6 alkyl group, a dialkylamino group, a C _1-6 alkylthio group and the like _{Examples of the -6} alkoxy moiety include the same groups as the aforementioned C _1-6 alkyl group or C _1-6 alkoxy group. The alkyl group in the dialkylamino group and trialkylsilyl group is also preferably a C _1-6 alkyl group.

In general formula (1), as a _C6-10 aryl group in A ring, a phenyl group and a naphthyl group are preferable, and a phenyl group is more preferable.

  In general formula (1), as the 4- to 10-membered heterocyclic group in the A ring, oxetanyl group, piperidyl group, thiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group An oxadiazolyl group, an indolinyl group, a dihydrobenzofuranyl group and the like are preferable.

In the general formula (1), the C _1-6 alkyl group for R ⁹ is preferably a C _1-4 alkyl group, and more preferably a methyl group or an ethyl group.

In the general formula (1), the C _1-7 alkanoyl group in R ⁹ is preferably a C _2-5 alkanoyl group, more preferably an acetyl group or a propionyl group.

In the general formula (1), the C _1-6 alkylsulfonyl group in R ⁹ is preferably a C _1-4 alkylsulfonyl group, and more preferably a methylsulfonyl group or an ethylsulfonyl group.

  In general formula (1), m is preferably an integer of 0 to 2, and more preferably 2.

In general formula (1), as a halogen atom in R < ¹ >, R < ² >, R < ³ >, R < ⁴ >, a fluorine atom and a chlorine atom are preferable.

In the general formula (1), the C _1-6 alkyl group in R ¹ , R ² , R ³ , R ⁴ is preferably a C _1-4 alkyl group, and more preferably a methyl group or an ethyl group.

In the general formula (1), as the 4-10 membered heterocyclic-C _1-6 alkyl group in R ¹ , R ² , R ³ , R ⁴ , a 5-10 membered heterocyclic-C _1-6 alkyl group is Preferably, a 5-6 membered heterocyclic- _C1-4 alkyl group is more preferable. Here, the 5-membered heterocycle is preferably a pyrrolyl group, an imidazolyl group, a triazolyl group, or a tetrazolyl group. Moreover, as a _C1-4 alkyl group, a methyl group and an ethyl group are preferable. Examples of the 6-membered heterocycle include a pyridyl group, piperidinyl group, pyrazinyl group, pyridazinyl group, and pyrimidinyl group. A 9-membered heterocycle includes an indolyl group. Here, the group substituted on the 4-10 membered heterocycle is preferably a _C1-4 alkyl group or a _C1-4 alkylsulfonyl group, and a methyl group, an ethyl group, a methylsulfonyl group, and an ethylsulfonyl group are preferable. Specific examples of the 4-10 membered heterocyclic C _1-6 alkyl group include imidazolylmethyl group, 1-methylimidazolylmethyl group, 1-methylsulfonylimidazolylmethyl group, triazolylmethyl group, and tetrazolylmethyl group. preferable.

In formula (1), the C _1-6 alkoxy group in R ¹ , R ² , R ³ , R ⁴ is preferably a C _1-4 alkoxy group, and is a methoxy group, ethoxy group, n-propoxy group, isopropoxy group. Groups are more preferred.

In the general formula (1), the C _3-10 cycloalkyl-C _1-6 alkoxy group in R ¹ , R ² , R ³ , R ⁴ is preferably a C _3-8 cycloalkyl-C _1-6 alkoxy group. , A C _3-6 cycloalkyl-C _1-4 alkoxy group is more preferable, and a cyclopropylmethoxy group, a cyclopropylethoxy group, a cyclopentylmethoxy group, and a cyclohexylmethoxy group are more preferable.

In the general formula (1), the C _1-6 alkylsulfonyl group in R ¹ , R ² , R ³ , R ⁴ is preferably a C _1-4 alkylsulfonyl group, and more preferably a methylsulfonyl group or an ethylsulfonyl group.

In the general formula (1), the C _1-6 alkylsulfonyloxy group in R ¹ , R ² , R ³ , R ⁴ is preferably a C _1-4 alkylsulfonyloxy group, a methylsulfonyloxy group, an ethylsulfonyloxy group. Is more preferable.

In the general formula (1), the C _1-6 alkylsulfonylamino group in R ¹ , R ² , R ³ , R ⁴ is preferably a C _1-4 alkylsulfonylamino group, a methylsulfonylamino group, an ethylsulfonylamino group Is more preferable.

In General Formula (1), examples of the carboxy-C _1-6 alkyl group in R ¹ , R ² , R ³ , and R ⁴ include a carboxymethyl group and a carboxyethyl group. Examples of the C _1-6 alkoxycarbonyl C _1-6 alkyl group include an ethoxycarbonylmethyl group and an isopropyloxycarbonylmethyl group.

In formula (2), the halogen atom in R ¹⁰ and R ¹¹ is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

In formula (2), the C _1-6 alkyl group in R ¹⁰ and R ¹¹ is preferably a C _1-4 alkyl group, and more preferably a methyl group.

In formula (2), the C _1-20 alkyl group in R ¹² is preferably a C _1-12 alkyl group, and is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-hexyl group. N-octyl group, n-decanyl group and n-dodecanyl group are more preferable.

In formula (2), the C _2-6 alkenyl group in R ¹² is preferably a C _2-4 alkenyl group, and more preferably an allyl group.

In formula (2), the halo C _1-6 alkyl group in R ¹² is preferably a halo C _1-4 alkyl group, and includes a trifluoromethyl group, a 2,2,2-trifluoroethyl group, 3, 3, 3 -A trifluoropropyl group is more preferred.

In formula (2), the C _2-7 alkanoyl group in R ¹² is preferably a C _2-5 alkanoyl group, more preferably an acetyl group or a propionyl group.

In formula (2), the C _6-10 aryl group for R ¹² is preferably a phenyl group or a naphthyl group, and more preferably a phenyl group.

In the formula (2), the 4-10 membered heterocyclic group in R ¹² is preferably a 4-6 membered heterocyclic group, and an oxetanyl group, a pyrrolidinyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a thiadiazolyl group, a pyridyl group. More preferred are a fluoropyridyl group and a difluoropyrrolidinyl group.

In formula (2), the C _3-10 cycloalkyl-C _1-6 alkyl group in R ¹² is preferably a C _3-6 cycloalkyl-C _1-4 alkyl group, and is preferably a cyclopropylmethyl group or a cyclohexylmethyl group. Is more preferable.

In formula (2), the C _1-6 alkoxy-C _1-6 alkyl group for R ¹² is preferably a C _1-4 alkoxy-C _1-4 alkyl group, more preferably a methoxyethyl group or an ethoxyethyl group.

In formula (2), examples of the hydroxy C _1-6 alkyl group include a hydroxypropyl group, a hydroxybutyl group, and a hydroxypentyl group. Examples of the cyano-C _1-6 alkyl group include a cyanomethyl group and a cyanoethyl group. Examples of the amino-C _1-6 alkyl group include an aminoethyl group and an aminopropyl group.

In formula (2), the carboxy-C _1-6 alkyl group for R ¹² is preferably a carboxy-C _1-4 alkyl group, more preferably a carboxymethyl group, a carboxyethyl group, or a carboxypropyl group.

In formula (2), the C _6-10 aryl-C _1-6 alkyl group in R ¹² is preferably a phenyl-C _1-4 alkyl group, and is a benzyl group, a 2-carboxybenzyl group, a 3-carboxybenzyl group, A 4-carboxybenzyl group, a fluorobenzyl group, a trifluorobenzyl group, a methylbenzyl group, a methoxybenzyl group, a dimethoxybenzyl group, and a metalsulfonylbenzyl group are more preferable.

In the formula ^(2), the 4-10 membered heterocyclic _{-C 1-6} alkyl group in ^{R 12,} preferably 4-6 membered heterocyclic _{-C 1-4} alkyl group, 2-pyridylmethyl group, 3-pyridyl A methyl group, 4-pyridylmethyl group, 2-pyrazinylmethyl group, methyloxetane-methyl group, tetrahydrofuran-methyl group, tetrahydropyran-methyl group, and pyrimidine-methyl group are more preferable.

  In the formula (2), l is preferably 1 or 2, and more preferably 1. Moreover, as n, the integer of 0-2 is preferable.

In general formula (1), as a halogen atom in R < ⁵ >, R < ⁶ >, R < ⁷ >, a fluorine atom and a chlorine atom are preferable.

In the general formula (1), the C _1-6 alkyl group in R ⁸ is preferably a C _1-5 alkyl group, and includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, A tert-butyl group and a neopentyl group are more preferable.

In the general formula (1), examples of the C _2-6 alkenyl group for R ⁸ include a 2-methyl-3-buten-2-yl group. Examples of the C _2-6 alkynyl group include a 2-methyl-3-butyn-2-yl group, a 3-methyl-1-pentyn-3-yl group, and a 1-hexyn-3-yl group.

In the general formula (1), the halo C _1-6 alkyl group in R ⁸ is preferably a halo C _1-4 alkyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, 2, 2,2-trichloroethyl group, 1,1,1-trifluoro-2-methylpropan-2-yl group, 1,1-dimethyl-2,2,2-trifluoroethyl group, 1,1-dimethyl- A 2,2,2-trichloroethyl group is more preferred.

In the general formula (1), examples of the trialkylsilyl-C _1-6 alkyl group represented by R ⁸ include a trimethylsilylmethyl group and a trimethylsilylethyl group. Examples of the cyano-C _1-6 alkyl group include a cyanomethyl group and a cyanoethyl group.

In the general formula (1), the _1-6 alkoxy-C _1-6 alkyl group in R ⁸ is preferably a C _1-4 alkoxy-C _1-4 alkyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group. Is more preferable.

In the general formula (1), as the C 3-10 cycloalkyl group in R 8, C 3-6 cycloalkyl group, a halogeno C 3-6 cycloalkyl group is preferred, adamantyl group, cyclohexyl group, 4,4 -Difluorocyclohexyl group, cyclopropyl group, and 1-methylcyclopropyl group are more preferable.

In the general formula (1), the C _3-10 cycloalkyl-C _1-6 alkyl group in R ⁸ is preferably a C _3-6 cycloalkyl-C _1-6 alkyl group, a cyclopropylmethyl group, 1-methyl A cyclopropylmethyl group and a cyclobutylmethyl group are more preferable.

In the general formula (1), as the C _6-10 aryl group in R ⁸ , a phenyl group, a halogenophenyl group, a halo C _1-6 alkoxyphenyl group, an aminophenyl group, a diC _1-6 alkylaminophenyl group, C _1-6 alkylphenyl group, di-C _1-6 alkylphenyl group, C _1-6 alkylthiophenyl group, benzyloxyphenyl group are preferable, phenyl group, chlorophenyl group, fluorophenyl group, dichlorophenyl group, difluorophenyl group, cyanophenyl Group, trifluoromethoxyphenyl group, dimethylaminophenyl group, diethylaminophenyl group, methylphenyl group, isopropylphenyl group, t-butylphenyl group, t-pentylphenyl group, methylthiophenyl group, dimethylphenyl group, chloro (methyl) phenyl Group, fluo A ro (trifluoromethyl) phenyl group, a trichlorophenyl group, a chloro (dimethyl) phenyl group, a benzyloxyphenyl group and the like are preferable.

In the general formula (1), the C _6-10 aryl-C _1-6 alkyl group represented by R ⁸ includes a phenyl-C _1-4 alkyl group, a halogenophenyl-C _1-4 alkyl group, and a halo C _1-6 alkyl group. Phenyl-C _1-4 alkyl group, C _1-6 alkylphenyl-C _1-6 alkyl group, halo C _1-6 alkoxyphenyl-C _1-6 alkyl group are preferable, benzyl group, chlorobenzyl group, dichlorobenzyl group , A fluorobenzyl group, a difluorobenzyl group, a trifluoromethylbenzyl group, a 3,5-bistrifluoromethylbenzyl group, a fluoro (chloro) benzyl group, and a pentafluorobenzyl group are more preferable.

In the general formula (1), the 4-10 membered heterocyclic _{-C 1-6} alkyl group in ^{R 8,} preferably 4-6 membered heterocyclic _{-C 1-4} alkyl group, oxetanylmethyl group, 2-pyridylmethyl The group, 3-pyridylmethyl group and 4-pyridylmethyl group are more preferable.

  In general formula (1), O is more preferable as Z.

In general formula (1), as a combination of R ¹ , R ² , R ³ and R ⁴ , one of them is a C _1-6 alkylsulfonyl group, a 4-10 membered heterocyclic-C _1-6 alkyl group ( Here, the heterocyclic ring may have the above-mentioned substituent) or a group represented by the formula (2), and there is no residue, or a hydrogen atom, a halogen atom, a cyano group, C _{1- It} is preferably a ₆ alkyl group, a C _1-6 alkoxy group, or a C _3-8 cycloalkyl-C _1-6 alkoxy group. The group represented by the formula (2) is more preferably R ¹² —S (O) _n (CH ₂ ) ₁ —, more preferably R ¹² S (O) _n —CH ₂ —, C _1-6 alkyl-S (O) _n CH ₂ —, C _6-10 aryl-C _1-6 alkyl-S (O) _n CH ₂ — or 4-10 membered heterocycle-C _1-6 alkyl-S (O) _n CH ₂ — (wherein the aryl or heterocycle may have the above-mentioned substituent) is further preferred, and C _1-6 alkyl SO ₂ —CH ₂ —, C _6-10 aryl —C _1-6 alkyl-SO ₂ CH ₂ — or a 4-10 membered heterocycle —C _1-6 alkyl SO ₂ —CH ₂ — (wherein the aryl or heterocycle may have a substituent) It is particularly preferred.

In the general formula (1), as a combination of R ⁵ , R ⁶ and R ⁷ , it is more preferable that two of these are hydrogen atoms and the remainder is a hydrogen atom, a halogen atom, a cyano group or a carboxyl group. .

In the general formula (1), as the R 8, C 1-6 alkyl, halo C 1-6 alkyl group, C 1-6 alkoxy -C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3 A -8 cycloalkyl-C 1-6 alkyl group is more preferred.

In general formula (1), the halogen atom for R ¹³ or R ¹⁴ is preferably a fluorine atom.

In general formula (1), the hydrogen atom contained in the substituent in R ⁸ may be substituted with a deuterium atom as long as it is chemically acceptable.

As a more preferable compound of the spiropiperidine derivative represented by the general formula (1),
tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate (Example 1),
tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 2),
tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 3),
tert-butyl 6- (3-((methylsulfonyl) methyl))) phenyl) spiro [chroman-2,4′-piperidine) -1′-carboxylate (Example 4),
tert-butyl 7- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine) -1′-carboxylate (Example 5),
tert-butyl 7- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 6),
tert-butyl 6- (4-nitrophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 7),
tert-butyl 6- (4- (methylsulfonamido) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 8),
tert-butyl 6- (4-hydroxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 9),

tert-butyl 6- (4-((methylsulfonyl) oxy) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 10),
tert-butyl 6- (2-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 11),
tert-butyl 6- (2-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 12),
tert-butyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 13),
tert-butyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 14),
tert-butyl 6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 15A),
tert-butyl 6- (5-((methylsulfinyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 15B),
tert-butyl 6- (6-((methylsulfonyl) methyl) pyridin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 16),
tert-butyl 6- (3-methyl-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 17),
tert-butyl 6- (3-methoxy-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 18),
tert-butyl 6- (4-((methylsulfonyl) methyl) -3-propoxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 19),
tert-butyl 6- (3- (cyclopropylmethoxy) -4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 20),

tert-butyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 21),
tert-butyl 6- (4-((1-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 22),
tert-butyl 6- (4-((2-methylsulfonyl) propan-2-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 23),
tert-butyl 6- (4- (1H-tetrazol-1-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 24),
tert-butyl 6- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 25),
tert-butyl 7- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 26),
tert-butyl 6- (4- (methylsulfonyl) methylpiperidino) spiro [chroman-2,4′-piperidine) -1′-carboxylate (Example 27),
Ethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 28),
2,2,2-trifluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 29),
2,2,2-trichloroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 30),
2-fluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 31),
2-methoxyethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 32),
Isopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 33),
Benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 34),

Phenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 35),
4-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 36),
3-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 37),
2-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 38),
4-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 39),
3-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 40),
2-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 41),
3,5-bis (trifluoromethyl) benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 42),

Pyridin-4-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 43),
Pyridin-3-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 44),
Pyridin-2-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 45),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 46),
1,1,1-Trichloro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 47),
Neopentyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 48),
Adamantan-1-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 49),
Adamantan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 50),
Oxetane-3-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 51),
Tetrahydro-2H-pyran-4-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 52),
4,4-difluorocyclohexyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 53),
2,2,2-trichloroethyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 54),

Phenyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 55),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate (Example 56),
Neopentyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 57),
2,2,2-trichloroethyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 58),
Phenyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 59),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate (Example 60),

Neopentyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 61),
2,2,2-trifluoroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 62) ),
2,2,2-Trichloroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 63) ,
Phenyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 64),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate (Example 65),
Neopentyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 66),
tert-butyl 6- (4-((pyridin-4-ylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 67),
tert-butyl 6- (4-((pyridin-4-ylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 68),
tert-butyl 6- (4-((phenylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 69),
tert-butyl 6- (4-((phenylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 70),
tert-Butyl 6- (4-(((5-Methyl-1,3,4-thiadiazol-2-yl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 71),
tert-Butyl 6- (4-(((5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 72),
tert-butyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 73),
tert-butyl 6- (4-((dodecylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 74),
tert-butyl 6- (4-((dodecylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 75),
tert-butyl 6- (4-((acetylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 76),
tert-butyl 6- (4-((propylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 77),
tert-butyl 6- (4-((allylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 78),
tert-butyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 79),

tert-butyl 6- (4-((2-methoxyethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 80),
tert-butyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 81),
tert-butyl 6- (4-(((cyclopropylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 82),
tert-butyl 6- (4-(((cyclohexylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 83),
tert-butyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 84),
tert-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 85),
tert-butyl 6- (4-((((pyridin-3-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 86),
tert-butyl 6- (4-((((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 87),

Cyclopropylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate (Example 88),
Cyclobutylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 89),
(1-methylcyclopropyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 90),
1-methylcyclobutyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 91),
1-methylcyclopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 92),
(Trimethylsilyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 93),
tert-butyl 6- (5-((methylsulfonyl) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 94),
tert-butyl 6- (6-((methylsulfonyl) methyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 95),
tert-butyl 6- (5-((methylsulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 96),
tert-butyl 6- (4-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 97),
tert-butyl 6- (5-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 98),
tert-butyl 6- (2-((methylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 99),
tert-Butyl 6- (5-((methylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 100),
tert-butyl 7-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 101),
tert-butyl 7-fluoro-6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 102),
tert-butyl 7-fluoro-6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 103),
tert-butyl 3-hydroxy-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 104),
tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) -3-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 105),
tert-butyl 4,4-dideuterio-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 106),
tert-butyl 4-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate (Example 107),
tert-butyl 6- (3-cyano-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 108),
2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 109),

tert-butyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 110),
2,2,2-Trichloroethyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 111) ,
Neopentyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 112),
2,2,2-trichloroethyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 113),
Neopentyl 6- [4-{(2- (isopropylsulfonyl) methyl) phenyl} spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 114),
tert-butyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 115),
2,2,2-trichloroethyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 116),
tert-butyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 117),
2,2,2-Trichloroethyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 118) ,
Neopentyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 119),
tert-butyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 120),
2,2,2-trichloroethyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 121),
Neopentyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 122),
1-methylcyclopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 123),
1,1,1-trifluoropropan-2-yl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 124),
tert-butyl 6- (4-(((2-fluoroethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 125),
tert-butyl 6- (4-(((cyanomethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 126),
tert-butyl 6- (5-(((cyanomethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 127),
2,2,2-trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 128),
tert-Butyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 129),

2,2,2-trichloroethyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylate (Example 130),
Neopentyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 131) ),
tert-Butyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 132),
2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine]- 1′-carboxylate (Example 133),
tert-Butyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 134),
Neopentyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 135) ),
1-methylcyclopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 136),
1-cyclopropylethyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 137),
1,1,1-trifluoropropan-2-yl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′- Piperidine] -1′-carboxylate (Example 138),
tert-butyl 6- (4-(((3-hydroxypropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 139),
tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 140),
Isopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 141),
Isobutyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 142),
Neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 143),
1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 144),
1-cyclopropylethyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 145),
1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′- Carboxylate (Example 146),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 147),
(Isopropyl-d7) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 148) ,
(Tert-Butyl-d9) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 149),

tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 150),
Neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate (Example 151),
1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate (Example 152),
(R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 153),
(R) -Neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Example 154),
(R) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, 4-piperidine] -1′-carboxylate (Example 155),
(R) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [ Chroman-2,4-piperidine] -1′-carboxylate (Example 156),
(S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 157),
(S) -Neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Example 158),
(S) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, 4-piperidine] -1′-carboxylate (Example 159),
(S) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [ Chroman-2,4-piperidine] -1′-carboxylate (Example 160),
tert-Butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate Example 161),
Neopentyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 162) ),
1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4- Piperidine] -1′-carboxylate (Example 163),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman- 2,4-piperidine] -1′-carboxylate (Example 164),
tert-butyl 6- (5-((((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 165),
Neopentyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 166),
1,1,1-trifluoroisopropyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 167),
tert-Butyl 6- (4-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 168) ,
tert-Butyl 6- (5-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 169),

tert-Butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 170),
Neopentyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 171) ,
1,1,1-trifluoroisopropyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ Carboxylate (Example 172),
tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxy Rate (Example 173),
tert-butyl 6- (4-(((3-aminopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 174),
(S) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate (Example 175),
(R) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate (Example 176),
tert-Butyl 6- (4-(((3- (3,3-difluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 177),
tert-butyl 6- (4-(((methylsulfonyl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 178),
tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 179),
4-((4- (1′-tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) butanoic acid (Example 180),
tert-butyl 6- (4-(((4-amino-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 181),
tert-Butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Rate (Example 182),
Ethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 183),
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 184),
Isopropyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 185),
2,2,2-trifluoroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 186),
1-cyclopropylethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 187),
3,3,4,4,4-pentafluorobutyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 188),
1,1,1-trifluoropropan-2-yl 6- [4-{(pyridin-4-ylmethyl) sulfonyl} methyl] phenyl] spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 189),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 190),
1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 191),
1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′- Piperidine] -1′-carboxylate (Example 192),
(Ethyl-d5) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 193),
(Isopropyl-d7) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 194),
(Tert-butyl-d9) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 195),
(1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 196),
(Trimethylsilyl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 197),
(1- (tert-Butoxycarbonyl) piperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 198),
(1-methylpiperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 199),

4-isopropylbenzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 200),
4- (tert-butyl) benzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 201),
2-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 202),
4-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 203),
tert-butyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 204),
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 205),
Neopentyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 206),
tert-butyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 207),
2,2,2-Trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 208) ,
tert-butyl 6- (5-((benzylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate (Example 209),
tert-Butyl 6- (5-((benzylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 210),
tert-butyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 211),
2,2,2-trichloroethyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 212),
Neopentyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 213),
tert-butyl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 214),
1,1,1-trifluoropropan-2-yl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 215),
tert-butyl 6- (5-((((4-fluorobenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 216),
tert-butyl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 217),
1,1,1-trifluoropropan-2-yl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ Carboxylate (Example 218),
tert-Butyl 6- (5-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 219) ),

tert-butyl 6- (5-(((2-methylbenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 220),
tert-Butyl 6- (5-(((2-trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 221) ),
4-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid (Example 222),
3-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid (Example 223),
2-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid (Example 224),
tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 225),
tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 226),
Methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 227),
Ethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 228),
Isopropyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 229),
Butyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 230),
Neopentyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 231),
Isobutyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 232),
1-methylcyclopropyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 233),
1-cyclopropylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 234),
sec-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 235),
tert-pentyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 236),
4-Methylpentan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 237) ,
3-Methylpentan-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 238) ,
2-Methylbut-3-en-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 239),

2-Methylbut-3-in-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 240),
3-methylpent-1-yn-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 241),
Hex-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 242) ),
2-cyanoethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 243),
Cyclohexyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 244),
4- (tert-Butyl) cyclohexyl 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 245) ,
3,3,5-Trimethyldichlorohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 246) ),
(1R, 2S, 4S) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylate (Example 247),
(1S, 2R, 4R) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ Carboxylate (Example 248),
(3-Methyloxetane-3-yl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 249),
Cyclohexylmethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 250),
Adamantane-1-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 251),
(Trimethylsilyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 252),
2,2,2-trichloroethyl 6- (4-((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 253),
2,2,2-trifluoroethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 254) ),
3,3,4,4,4-pentafluorobutyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 255),
1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 256),
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate (Example 257),
1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 258),
1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman -2,4'-piperidine] -1'-carboxylate (Example 259),

(Methyl-d3) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 260),
(Ethyl-d5) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 261),
(Isopropyl-d7) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 262),
(Tert-butyl-d9) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 263),
(1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [ Chroman-2,4′-piperidine] -1′-carboxylate (Example 264),
Benzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 265),
1-phenylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 266),
1-phenylpropyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 267),
Phenethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 268),
2-Methyl-1-phenylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 269),
2-Phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 270) ,
2-Methyl-4-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 271),
2-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 272),
3-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 273),
4-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 274),
2-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 275),
3-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 276),
4-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 277),
2- (Trifluoromethoxy) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 278) ,
4-methylbenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 279),

4- (Trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 280) ,
4-isopropylbenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 281),
4- (tert-Butyl) benzyl 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 282) ,
2,6-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 283),
2,3-dichlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 284),
2,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 285),
3,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 286),
3,5-dichlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 287),
2,6-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 288),
2,5-difluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 289),
2,4-difluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 290),
3,4-difluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 291),
3,5-difluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 292),
2-Chloro-6-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 293) ,
2-Chloro-4-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 294) ,
2,4-dimethylbenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 295),
3,5-bis (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 296),
(Perfluorophenyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 297),
Furan-2-ylmethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 298),
Phenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 299),

2-chlorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 300),
4-chlorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 301),
2-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 302),
3-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 303),
4-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 304),
2-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 305),
3-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 306),
4-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 307),
2- (Trifluoromethoxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 308) ,
3- (dimethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 309),
3- (diethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 310),
4-isopropylphenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 311),
4- (tert-Butyl) phenyl 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 312) ,
4- (tert-pentyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 313) ,
4- (methylthio) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 314),
2,6-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 315),
2,3-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 316),
2,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 317),
3,5-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 318),
3,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 319),

2,6-difluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 320),
3,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 321),
2,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 322),
2,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 323),
3,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 324),
2-Chloro-6-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 325) ,
2-Chloro-4-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 326) ,
4-Chloro-2-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 327) ,
4-chloro-3-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 328) ,
2,4-Dimethylphenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 329),
3,5-dimethylphenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 330),
4-Chloro-3-methylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 331) ,
2-Fluoro-3- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 332),
2-Fluoro-5- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 333),
2,4,6-Trichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 334) ,
4-chloro-3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 335),
4- (benzyloxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 336),
(Phenyl-2,3,4,5,6-d5) 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'- Carboxylate (Example 337),
tert-butyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 338),
2,2,2-trichloroethyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ( Example 339)

tert-Butyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 340) ),
2,2,2-Trichloroethyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] carboxylate (Examples) 341),
Neopentyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 342),
1-methylcyclopropyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 343),
tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 344),
2-((((6- (1 ′-(tert-butoxycarbonylspiro (chroman-2,4′-piperidin) -6-yl) pyridin-3-yl) methyl) sulfonyl) methyl) pyridine-1-oxide ( Example 345),
tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 346),
Neopentyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 347),
1-methylcyclopropyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 348) ),
tert-Butyl 6- (4-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 349) ),
Isobutyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 350),
Neopentyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 351),
1-methylcyclopropyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 352),
1-cyclopropylethyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 353),
1,1,1-trifluoropropan-2-yl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 354),
tert-Butyl 6- (5-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 355),
1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate (Example 356),
1,1,1-trifluoropropan-2-yl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 '-Piperidine] -1'-carboxylate (Example 357),
tert-Butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate (Examples) 358),
Neopentyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate (Example 359) ,

1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate ( Example 360),
tert-Butyl 6- (4-((((6-methylpyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 361) ),
tert-Butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 362) ),
tert-butyl 6- (4-((((pyrazin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 363),
tert-butyl 6- (5-((((pyrazin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate (Example 364),
tert-butyl 6- (4-(((thiazol-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 365),
tert-butyl 6- (4-((((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine]- 1′-carboxylate (Example 366),
tert-Butyl 6- (5-(((((pyrimidin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 367) ,
tert-Butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfinyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 368) ,
tert-Butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 369) ,
tert-Butyl 6- (4-(((1- (pyridin-2-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 370) ,
tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 371),
Neopentyl 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate (Example 372),
1,1,1-trifluoropropan-2-yl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate (Example 373),
tert-butyl 7-fluoro-6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 374),
tert-butyl 6- (4- (2-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 375),
tert-butyl 6- (4-((1H-imidazol-1-yl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 376),
tert-butyl 6- (4- (2-ethoxy-2-oxoethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 377),
2- (4- (1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) phenyl) acetic acid (Example 378),
Isopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Example 379),
Isopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate (Example 380) ), And isopropyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (Examples) 381)
A compound selected from the group consisting of:

  When geometrical isomers or optical isomers exist in the compound of the present invention, these isomers are also included in the scope of the present invention. These isomers are separated by a conventional method.

  The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. When the compound is treated as an acidic compound, for example, alkali metal salt or alkaline earth metal salt such as sodium, potassium, magnesium, calcium; trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N- And salts with organic bases such as methylmorpholine. When treating a compound as a basic compound, for example, acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, Examples include acid addition salts of organic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. It is done.

  Examples of the solvate of the compound represented by the general formula (1) or a salt thereof include, but are not limited to, hydrates and the like.

  It should be noted that all compounds that are metabolized in vivo and converted into the compound represented by the general formula (1), so-called prodrugs, are also included in the present invention. Examples of the group that forms a prodrug of the compound of the present invention include groups described in “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161. Examples include the groups described in Yodogawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163-198.

  The compound represented by the above general formula (1), a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, the reaction described below It can be manufactured according to the process. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance as necessary, and may be deprotected at an appropriate stage. The protection and deprotection conditions can be performed with reference to commonly used methods (for example, the method described in Green's Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc., 2006). Further, in each step, the reaction may be carried out by a usual method (for example, the method described in Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc; 1999), and isolation and purification are performed by crystallization and recrystallization. Ordinary methods such as chromatography may be appropriately selected or combined.

(Method for producing the compound represented by the general formula (1))
The compound represented by the general formula (1) of the present invention can be produced by the method shown in the following reaction pathway diagram 1.
[Reaction Path Diagram 1]

(In the formula, A, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ and R ¹⁵ are the same as those in the general formula (1). X ¹ represents a halogen atom, and R ¹⁶ and R ¹⁷ represent a hydrogen atom or a C _1-6 alkyl group, or R ¹⁶ and R ¹⁷ together form part of the ring. )

(A-1) Step A-1 is a step for producing compound (4) by reacting compound (2) with compound (3) in the presence of a solvent or in the presence of a secondary amine. The secondary amine used is not particularly limited, and for example, diethylamine, morpholine, piperidine, pyrrolidine and the like can be used. Pyrrolidine is preferable. The solvent to be used is not particularly limited. For example, alcohols such as isopropanol, ethanol and methanol; amides such as N, N-dimethylformamide; ethers such as diethyl ether, dioxane and tetrahydrofuran; acetonitrile and propio Nitriles such as nitriles; halogenated hydrocarbons such as methylene chloride, and the like, which can be used alone or mixed at any ratio. Alcohols are preferable, and methanol is more preferable. The reaction temperature is 30 to 150 ° C, preferably 50 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 3 hours to 24 hours. As the compound (2) or (3) used in the above reaction, those which are available can be used as they are, or can be appropriately produced by known methods, but are not limited thereto.

(A-2) Step A-2 is a step of producing compound (6) by reacting compound (4) with compound (5) by Suzuki-Miyaura coupling reaction. The metal catalyst, base and reaction conditions to be used are not particularly limited as long as they are usually reagents and conditions used for the Suzuki-Miyaura coupling reaction. For example, N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995) can be used. The metal catalyst to be used is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) Palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) Palladium complexes such as dichloride and tetrakis (triphenylphosphine) palladium (0), preferably [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium. Sodium carbonate and cesium carbonate. Although there is no restriction | limiting in particular as a solvent, For example, Ethers, such as tetrahydrofuran, 1, 4- dioxane, ethylene glycol dimethyl ether; Aromatic hydrocarbons, such as toluene; Amides, such as N, N- dimethylformamide, N-methylpyrrolidone Dimethyl sulfoxide, water and the like can be used alone or in combination. Preferred are tetrahydrofuran, ethylene glycol dimethyl ether, N, N-dimethylformamide, water, and mixed solvents thereof. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is 1 hour to 48 hours, preferably 30 minutes to 20 hours. As the compound (5) used in the above reaction, an available one may be used as it is, or it can be appropriately produced by a known method, but it is not limited thereto.

(A-3) Step A-3 is a step of producing compound (7) by reacting compound (6) with a reducing agent in the presence of a solvent. The reducing agent used is not particularly limited, and for example, sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like can be used. Preferably, it is sodium borohydride. The solvent to be used is not particularly limited, and examples thereof include alcohols such as methanol, ethanol and isopropanol; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile, and the like alone or in combination. Can be used. Alcohols are preferable, and methanol and ethanol are more preferable. The reaction temperature is -20 to 100 ° C, preferably 0 ° C to 60 ° C. The reaction time is 10 minutes to 48 hours, preferably 30 minutes to 10 hours.

(A-4) Step A-4 is a step for producing compound (1a) by reacting compound (7) with a dehydrating agent in the presence of a solvent, in the presence or absence of a base. The dehydrating agent to be used is not particularly limited, and examples thereof include methanesulfonyl chloride, p-toluenesulfonyl chloride, methyl carbamate-N- (triethylammoniumsulfonyl), and preferably methyl carbamate-N- (triethyl). Ammoniumsulfonyl). The base used is not particularly limited, and examples thereof include triethylamine, N, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the like. The solvent to be used is not particularly limited. For example, amides such as N, N-dimethylformamide; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; aromatic hydrocarbons such as toluene Class: Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, etc., which can be used alone or in combination. Preferred are ethers, and more preferred is tetrahydrofuran. The reaction temperature is 0 to 150 ° C, preferably 30 to 110 ° C. The reaction time is 1 to 48 hours, preferably 2 to 24 hours.

(A-5) In step A-5, compound (1b) is produced by a reduction reaction using a metal catalyst in the presence of a solvent, in the presence or absence of hydrogen, at normal pressure or under pressure. It is a process. Examples of the metal catalyst to be used include palladium carbon, palladium hydroxide, Lindlar catalyst, platinum oxide, rhodium tris (triphenylphosphine) chloride (Wilkinson catalyst), and preferably palladium carbon. Solvents used include alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as hexane; esters such as ethyl acetate; ethers such as tetrahydrofuran; preferably alcohols and ethers. More preferred are methanol and tetrahydrofuran. The reaction temperature is 0 to 120 ° C, preferably 20 to 80 ° C. The reaction time is 1 to 48 hours, preferably 2 to 24 hours.

A compound having a substituent other than a hydrogen atom at R ¹³ , R ¹⁴ and R ¹⁵ uses an intermediate of this reaction route diagram, for example, Bioorg. Med. Chem. Lett. 2010, 746, or WO2010 / 103381 Although it can manufacture by referring the method as described in a pamphlet etc., it is not limited to this.

Apart from the method described above, the compound represented by the general formula (1) of the present invention can also be produced by the method shown in the following reaction pathway diagram 2.
[Reaction Path Diagram 2]

(In the formula, A, X ¹ , Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ , R ¹⁵ R ¹⁶ and R ¹⁷ are As defined above, X ² represents a halogen atom, R ¹⁸ and R ¹⁹ represent a hydrogen atom or a C _1-6 alkyl group, or R ¹⁸ and R ¹⁹ together form a ring. Form)

(B-1) Step B-1 is a step of producing compound (8) by reacting compound (4) with a reducing agent in the presence of a solvent. The reducing agent used is not particularly limited, and for example, sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like can be used. Preferably, it is sodium borohydride. The solvent to be used is not particularly limited, and examples thereof include alcohols such as methanol, ethanol and isopropanol; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile, and the like alone or in combination. Can be used. Alcohols are preferable, and methanol and ethanol are more preferable. The reaction temperature is -20 to 100 ° C, preferably 0 ° C to 60 ° C. The reaction time is 10 minutes to 48 hours, preferably 30 minutes to 10 hours.

(B-2) Step B-2 is a step of producing compound (9) by reacting compound (8) with a reducing agent in the presence or absence of a solvent and in the presence of an acid. The reducing agent used is not particularly limited, but is preferably sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, diisobutylaluminum hydride, triethylsilane, phenylsilane, etc. Is triethylsilane. The acid used is not particularly limited, but is acetic acid, trifluoroacetic acid, trichloroacetic acid, trifluoroborane / diethyl ether, trimethylsilyl triflate, etc., preferably trifluoroacetic acid. The reaction temperature is -20 to 120 ° C, preferably 50 to 100 ° C. The reaction time is 10 minutes to 48 hours, preferably 1 to 24 hours.

(B-3) Step B-3 is a step for producing compound (1b) by reacting compound (9) with compound (5) by Suzuki-Miyaura coupling reaction. The metal catalyst, base and reaction conditions to be used are not particularly limited as long as they are usually reagents and conditions used for the Suzuki-Miyaura coupling reaction. For example, N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995) can be used. The metal catalyst to be used is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) Palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) Palladium complexes such as dichloride and tetrakis (triphenylphosphine) palladium (0), preferably [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium. Sodium carbonate and cesium carbonate. Although there is no restriction | limiting in particular as a solvent, For example, Ethers, such as tetrahydrofuran, 1, 4- dioxane, ethylene glycol dimethyl ether; Aromatic hydrocarbons, such as toluene; Amides, such as N, N- dimethylformamide, N-methylpyrrolidone Dimethyl sulfoxide, water and the like can be used alone or in combination. Preferred are tetrahydrofuran, ethylene glycol dimethyl ether, N, N-dimethylformamide, water, and mixed solvents thereof. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is 1 hour to 48 hours, preferably 30 minutes to 12 hours. As the compound (5) used in the above reaction, an available one may be used as it is, or it can be appropriately produced by a known method, but it is not limited thereto.

(C-1) Step C-1 is a step of producing borane compound (10) from compound (9) using a metal catalyst. The metal catalyst to be used is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) Palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) Palladium complexes such as dichloride and tetrakis (triphenylphosphine) palladium (0) are preferred, and bis (triphenylphosphine) palladium (II) dichloride is preferred. Examples of the base used include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate, and preferably potassium acetate. Although there is no restriction | limiting in particular as a solvent used, For example, Ethers, such as tetrahydrofuran and 1, 4- dioxane; Aromatic hydrocarbons, such as toluene; Amides, such as N, N- dimethylformamide, N-methylpyrrolidone Dimethyl sulfoxide, water and the like can be used alone or in combination. A mixed solvent of 1,4-dioxane and water is preferred. The reaction temperature is 0 to 200 ° C, preferably 80 to 150 ° C. The reaction time is 1 hour to 48 hours, preferably 2 hours to 24 hours.

(C-2) Step C-2 is a step for producing compound (1b) by reacting compound (10) with compound (11) by Suzuki-Miyaura coupling reaction. The metal catalyst, base and reaction conditions to be used are not particularly limited as long as they are usually reagents and conditions used for the Suzuki-Miyaura coupling reaction. For example, N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995) can be used. The metal catalyst to be used is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) Palladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), bis (triphenylphosphine) palladium (II) Palladium complexes such as dichloride and tetrakis (triphenylphosphine) palladium (0), preferably [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium ( 0). The base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium. Sodium carbonate and cesium carbonate. Although there is no restriction | limiting in particular as a solvent, For example, Ethers, such as tetrahydrofuran, 1, 4- dioxane, ethylene glycol dimethyl ether; Aromatic hydrocarbons, such as toluene; Amides, such as N, N- dimethylformamide, N-methylpyrrolidone Dimethyl sulfoxide, water and the like can be used alone or in combination. Preferred are tetrahydrofuran, ethylene glycol dimethyl ether, N, N-dimethylformamide, water, and mixed solvents thereof. The reaction temperature is 0 to 200 ° C, preferably 60 to 150 ° C. The reaction time is 1 hour to 48 hours, preferably 30 minutes to 12 hours. As the compound (11) used in the above reaction, an available compound may be used as it is, or it can be appropriately produced by a known method, but it is not limited thereto.

A compound having a substituent other than a hydrogen atom at R ¹³ , R ¹⁴ and R ¹⁵ uses an intermediate of this reaction route diagram, for example, Bioorg. Med. Chem. Lett. 2010, 746, or WO2010 / 103381 Although it can manufacture by referring the method as described in a pamphlet etc., it is not limited to this.

Moreover, the compound represented by General formula (1b) used by the said reaction can also be manufactured by the method of the following reaction pathway FIG.
[Reaction route diagram 3]

(In the formula, A, Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above, and W is Means a leaving group)

(D-1) Step D-1 is a step of producing compound (12) by deprotecting compound (1b ′) in the presence of an acid. The acid used is not particularly limited, and examples thereof include hydrochloric acid, formic acid, trifluoroacetic acid, and the like, and preferably hydrochloric acid. Although there is no restriction | limiting in particular as a solvent to be used, For example, halogenated hydrocarbons, such as chloroform, a dichloromethane, 1, 2- dichloroethane; Alcohols, such as methanol and ethanol; Diethyl ether, tetrahydrofuran, 1, 4- dioxane, etc. Ethers; aromatic hydrocarbons such as toluene can be used alone or in combination. Preferred are ethers, and more preferred is 1,4-dioxane. The reaction temperature is 0 ° C to 120 ° C, preferably 0 ° C to 50 ° C. The reaction time is 1 hour to 48 hours, preferably 2 hours to 24 hours.

(D-2) Step D-2 is a step of producing compound (1b) by reacting compound (12) with compound (13) in the presence of a base. The base to be used is not particularly limited. For example, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N, N, N-diisopropylethylamine, etc. Yes, preferably triethylamine or N, N-diisopropylethylamine. Although there is no restriction | limiting in particular as a solvent to be used, For example, halogenated hydrocarbons, such as chloroform, a dichloromethane, 1, 2- dichloroethane; Alcohols, such as methanol and ethanol; Diethyl ether, tetrahydrofuran, 1, 4- dioxane, etc. Ethers; aromatic hydrocarbons such as toluene; amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide and the like can be used alone or in combination. Preferred is dichloromethane or N, N-dimethylformamide. The reaction temperature is 0 ° C to 150 ° C, preferably 20 ° C to 80 ° C. The reaction time is 10 minutes to 48 hours, preferably 1 hour to 15 hours. Compound (13) used in the above reaction may be an available compound as it is, or can be appropriately produced by a known method, but is not limited thereto.

  Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. The racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to isomers. Moreover, a diastereomeric mixture can be divided | segmented by fractional crystallization or various chromatography, for example. An optically active compound can also be produced by using an appropriate optically active raw material.

  The obtained compound (1) can be converted into a salt by a usual method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.

  As a medicament containing the compound represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof as an active ingredient, this active ingredient may be used alone, but it is usually pharmaceutically acceptable. Used in combination with a carrier, additives and the like. The administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by known formulation methods.

  When preparing an oral solid preparation, the compound represented by the general formula (1) is mixed with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a corrigent and the like. After the addition, tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, and tartaric acid.

  When preparing an oral liquid preparation, add a corrigent, a buffer, a stabilizer, a corrigent, etc. to the compound represented by the general formula (1), and add an oral solution, syrup, elixir, etc. Can be manufactured. As the corrigent, those mentioned above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneous, muscle and Intravenous injections can be manufactured. Examples of the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a carrier for a suppository known to the compound represented by the general formula (1), such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and Tween (registered trademark) as necessary. After adding a surfactant, etc., it can be produced by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives, etc., which are usually used for the compound represented by the general formula (1) are blended as necessary, and mixed and formulated by conventional methods. It becomes. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and the like.

  In addition to the above, the compound represented by the general formula (1) can be converted into an inhalant, eye drop, or nasal drop by a conventional method.

  As shown in Examples described later, the compound represented by the general formula (1) has an effect of significantly promoting insulin secretion in the hamster pancreatic β cell line HIT-T15 cells. Therefore, the compound represented by the general formula (1), or an acid addition salt thereof, or a solvate thereof is used as a hypoglycemic agent and for prevention of diseases caused by hyperglycemia in mammals including humans such as diabetes. Or it is useful as a therapeutic agent. Here, as diabetes, non-insulin dependent diabetes mellitus (NIDDM) is mentioned in more detail.

  The compound represented by the general formula (1) of the present invention is administered by oral administration or parenteral administration. The dose of the medicament of the present invention varies depending on the weight, age, sex, symptoms, etc. of the patient, but in the case of a normal adult, it is 0.01 to 1000 mg per day as a compound represented by the general formula (1), preferably 0 It is preferable to administer 1 to 300 mg in 1 to 3 divided doses.

EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
quintet: quintet
hept: heptet
m: multiplet
br: broad
brs: broad singlet
J: Coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform d ₆ -DMSO: deuterated dimethyl sulfoxide CD ₃ OD: deuterated methanol
¹ H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum

Example 1 Production of tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6-bromo-4-oxospiro [ Preparation of chroman-2,4′-piperidine] -1′-carboxylate 5′-bromo-2′-hydroxyacetophenone (6.45 g, 30 mmol) and tert-butyl 4-oxo-1-piperidinecarboxylate (5.98 g, 30 mmol) was dissolved in methanol (150 mL), pyrrolidine (1.2 mL, 15 mmol) was added, and the mixture was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 10: 1 → 5: 1) to obtain the title compound (10.9 mg, 92%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.54-1.66 (2H, m), 1.96-2.05 (2H, m), 2.71 (2H, s), 3.12-3.28 (2H, m) , 3.75-3.99 (2H, m), 6.90 (1H, d, J = 8.8 Hz), 7.57 (1H, dd, J = 8.8, 2.7 Hz), 7.97 (2H, d, J = 2.7 Hz).

Step 2: Preparation of tert-butyl 6- (4- (methylsulfonyl) phenyl) -4-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-4-oxospiro [ Chroman-2,4′-piperidine] -1′-carboxylate (154 mg, 0.42 mmol) and (4- (methylsulfonyl) phenyl)) boronic acid (100 mg, 0.50 mmol) were added to ethylene glycol dimethyl ether (4 mL). ), An aqueous solution (4 mL) in which sodium carbonate (779 mg, 7.35 mmol) was dissolved was added, tetrakistriphenylphosphine palladium (0) (29 mg, 0.025 mmol) was added, and the mixture was stirred at 90 ° C. for 15 hours. . The reaction solution was diluted with ethyl acetate, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (218 mg, 100%) as a yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.60-1.71 (2H, m), 2.02-2.11 (2H, m), 2.78 (2H, s), 3.09 (3H, s), 3.18 -3.31 (2H, m), 3.88-4.00 (2H, m), 7.13 (1H, d, J = 8.5 Hz), 7.74-7.80 (3H, m), 8.01 (2H, d, J = 8.3 Hz), 8.14 (1H, d, J = 2.4 Hz).

Step 3: Preparation of tert-butyl 4-hydroxy-6- (4- (methylsulfonyl) phenyl)) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- ( Methylsulfonyl) phenyl))-4-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate (177 mg, 0.38 mmol) was dissolved in ethanol (5 mL) and sodium borohydride (15.6 mg) , 0.41 mmol) and stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (186 mg, 100%) as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.64-1.76 (2H, m), 1.78-1.88 (1H, m), 1.90-2.22 (3H, m), 2.16-2.25 (1H, m), 3.05-3.37 (5H, m), 3.76-4.01 (2H, m), 4.96 (1H, q, J = 7.1 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.48 (1H, dd , J = 8.6, 2.2 Hz), 7.71-7.76 (3H, m), 7.97 (2H, d, J = 8.3 Hz).

Step 4: Preparation of tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate tert-butyl 4-hydroxy-6- (4- (methyl (Sulfonyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (76 mg, 0.16 mmol) is dissolved in tetrahydrofuran (5 mL) and methyl carbamate-N- (triethylammoniumsulfonyl) ( Burgess reagent) (114 mg, 0.48 mmol) was added, and the mixture was heated to reflux for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (30.4 mg, 42%) as a white amorphous.

Example 2 Preparation of tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- (methylsulfonyl) phenyl) Spiro [chromene-2,4′-piperidine] -1′-carboxylate (56 mg, 0.12 mmol) was dissolved in tetrahydrofuran (4 mL), palladium on carbon (8 mg) was added, and 12 at 60 ° C. in a hydrogen atmosphere. Stir for hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (28.5 mg, 51%) as a white solid.

Example 3 Production of tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6-bromospiro [chroman Preparation of -2,4'-piperidine] -1'-carboxylate tert-Butyl 6-bromo-4-oxospiro [chroman-2,4'-piperidine] -1'-carboxylate (1.18 g, 3.0 mmol) It melt | dissolved in ethanol (20 mL), sodium borohydride (125 mg, 3.3 mmol) was added, and it stirred at 50 degreeC for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and tert-butyl 6-bromo-4-hydroxyspiro [chroman-2,4′-piperidine]- A crude 1'-carboxylate (1.30 g) was obtained as a white amorphous.
The obtained crude product (1.30 g) was dissolved in trifluoroacetic acid (10 mL), triethylsilane (2.0 mL, 12.8 mmol) was added, and the mixture was heated to reflux for 8 hours. The reaction mixture was cooled and concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain a crude product (0.91 g) of 6-bromospiro [chroman-2,4′-piperidine] trifluoroacetate as a white solid. . The obtained solid (200 mg, 0.52 mmol) was dissolved in acetone (5 mL), potassium carbonate (291 mg, 2.1 mmol) and di-tert-butyl dicarbonate (127 mg, 0.58 mmol) were added, and at room temperature. Stir for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound (190 mg, 94.1%) as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.57 (2H, m), 1.73-1.81 (4H, m), 2.76 (2H, t, J = 6.8 Hz), 3.09-3.30 (2H, m), 3.73-4.01 (2H, m), 6.68-6.74 (1H, m), 7.15-7.21 (2H, m).

Step 2: Preparation of tert-butyl 6- (4-((methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromospiro [chroman-2,4 '-Piperidine] -1'-carboxylate (128 mg, 0.33 mmol) and 4,4,5,5-tetramethyl-2- (4-((methylthio) methyl) phenyl) -1,3,2- Dissolve dioxaborate (106 mg, 0.40 mmol) in ethylene glycol dimethyl ether (4 mL), add an aqueous solution (4 mL) in which sodium carbonate (625 mg, 5.9 mmol) is dissolved, and add tetrakistriphenylphosphine palladium (0) (23 mg, 0.02 mmol) was added and the mixture was stirred at 90 ° C. for 18 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1), and tert-butyl 6- (4-((methylthio) methyl) phenyl) spiro [chroman-2,4 ′. -Piperidin] -1'-carboxylate (95.6 mg, 65%) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.61 (2H, m), 1.78-1.87 (4H, m), 2.03 (3H, s), 2.84 (2H, t, J = 6.7 Hz), 3.16-3.34 (2H, m), 3.70 (2H, s), 3.76-3.99 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 7.27-7.37 (3H, m), 7.48 (2H, d, J = 8.1 Hz).

Step 3: Preparation of tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6 (4-((methylthio) Methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (95.6 mg, 0.22 mmol) was dissolved in dichloromethane (3 mL) and metachloroperbenzoic acid (65%, 116) at 0 ° C. mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (chloroform: methanol = 20: 1) to give the title compound (46.3 mg, 45%) as a pale yellow amorphous product.

Example 4 Production of tert-butyl 6- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- (3- Preparation of ((methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-spiro [chroman-2, obtained in step 1 of example 3 4′-piperidine] -1′-carboxylate (50 mg, 0.13 mmol) and 4,4,5,5-tetramethyl-2- (3-((methylthio) methyl) phenyl) -1,3,2- To a mixed solution of dioxaborate (38 mg, 0.14 mmol) in 1,4-dioxane (1.3 mL) -water (1.3 mL), sodium carbonate (207 mg, 1.95 mmol) and tetrakistriphenylphosphine palladium (0) 15 mg, 0.013 mmol) was added, under an argon atmosphere and stirred for 11 hours at 95 ° C.. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the title compound (34.3 mg, 60%) as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.52-1.62 (2H, m), 1.78-1.88 (4H, m), 2.03 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.72 (2H, s), 3.76-4.00 (2H, m), 6.90 (1H, d, J = 8.8 Hz), 7.23 (1H, dd, J = 1.2 , 7.2 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.32-7.37 (2H, m), 7.42 (1H, d, J = 7.2 Hz), 7.47 (1H, s).

Step 2: Production of tert-butyl 6- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-obtained in Step 1 (3-((Methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound as a white amorphous Got as.

Example 5 Production of tert-butyl 7- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 7-bromo-4 Preparation of Oxospiro [chroman-2,4′-piperidine] -1′-carboxylate 4′-Bromo-2′-hydroxyacetophenone instead of 5′-bromo-2′-hydroxyacetophenone Reaction and treatment were conducted in the same manner as in Step 1 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.57-1.66 (2H, m), 1.99 (1H, s), 2.02 (1H, s), 2.71 (2H, s), 3.20 (2H , t, J = 11.6 Hz), 3.78-3.96 (2H, m), 7.15 (1H, dd, J = 1.6, 8.4 Hz), 7.21 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 8.4 Hz).

Step 2: Preparation of tert-butyl 7-bromospiro [chroman-2,4'-piperidine] -1'-carboxylate tert-butyl 7-bromo-4-oxospiro [chroman-2,4 'obtained in step 1 -Piperidin] -1'-carboxylate was reacted and treated in the same manner as in Step 1 of Example 3 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.58 (2H, m), 1.72-1.82 (4H, m), 2.72 (2H, t, J = 6.8 Hz), 3.10-3.28 (2H, m), 3.76-3.96 (2H, m), 6.91 (1H, d, J = 8.4 Hz), 6.96 (1H, dd, J = 8.4, 2.0 Hz), 7.01 (1H, d, J = 2.0 Hz).

Step 3: Preparation of tert-butyl 7- (4-((methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 7-bromospiro obtained in Step 2 The reaction and treatment were carried out in the same manner as in Step 2 of Example 3 using [chroman-2,4′-piperidine] -1′-carboxylate to obtain the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.54-1.60 (2H, m), 1.80-1.89 (4H, m), 2.03 (3H, s), 2.82 (2H, t, J = 6.8 Hz), 3.18-3.32 (2H, m), 3.71 (2H, s), 3.80-3.94 (2H, m), 7.08 (1H, d, J = 2.8 Hz), 7.09 (1H, d, J = 2.8 Hz), 7.11 (1H, s), 7.34 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz).

Step 4: Preparation of tert-butyl 7- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 7- obtained in Step 3 (4-((Methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound as a white amorphous Got as.

Example 6 Production of tert-butyl 7- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 7- (3- Preparation of ((methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4,4,5,5-tetramethyl-2- (4-((methylthio) methyl) phenyl ) -1,4,5,5-tetramethyl-2- (3-((methylthio) methyl) phenyl) -1,3,2-dioxaborate instead of -1,3,2-dioxaborate The reaction and treatment were conducted in the same manner as in Step 2 of 3 to give the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.53-1.60 (2H, m), 1.77-1.87 (4H, m), 2.02 (3H, s), 2.82 (2H, t, J = 6.4 Hz), 3.16-3.34 (2H, m), 3.73 (2H, s), 3.80-3.96 (2H, m), 7.06-7.15 (3H, m), 7.26-7.30 (1H, m), 7.36 (1H , dd, J = 7.2, 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.51 (1H, s).

Step 2: Preparation of tert-butyl 7- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 7- obtained in Step 1 (3-((Methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound as a white amorphous Got as.

Example 7 Preparation of tert-butyl 6- (4-nitrophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromospiro [chroman-2,4′-piperidine under argon atmosphere ] -1′-carboxylate (30 mg, 0.08 mmol) was dissolved in a mixed solvent of tetrahydrofuran (0.4 mL) and N, N-dimethylformamide (0.4 mL), and 4-nitrophenylboronic acid (20 mg, 0.12 mmol) was dissolved. ), Cesium carbonate (51 mg, 0.16 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (3 mg, 0.004 mmol) were added, and the mixture was stirred at 90 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 3: 1) to give the title compound (20 mg, 61%) as a yellow oil.

Example 8 Production of tert-butyl 6- (4- (methylsulfonamido) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- (4-aminophenyl) ) Preparation of spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-nitrophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (16 mg, 0.004 mmmol) was dissolved in methanol, palladium carbon (1.6 mg, 10% w / w) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (16 mg) as a crude product.

Step 2: Preparation of tert-butyl 6- (4- (methylsulfonamido) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-aminophenyl) spiro [ The crude product of chroman-2,4′-piperidine] -1′-carboxylate (16 mg) was dissolved in dichloromethane (2 mL), pyridine (10 μL, 0.12 mmol) and methanesulfonyl chloride (5 μL, 0.06). mmol) at 0 ° C. and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 2: 1) to give the title compound (14 mg, 74%) as a colorless oil.

Example 9 Preparation of tert-butyl 6- (4-hydroxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 4-hydroxyphenylboronic acid instead of 4-nitrophenylboronic acid Then, the reaction and treatment were conducted in the same manner as in Example 7 to obtain the title compound (16 mg, 52%) as a white amorphous.

Example 10 Preparation of tert-butyl 6- (4-((methylsulfonyl) oxy) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6 obtained in Example 9 -(4-Hydroxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (8 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (8 μL, 0.06 mmol) was dissolved. Methanesulfonyl chloride (2 μL, 0.03 mmol) was added at 0 ° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using preparative thin layer chromatography on silica gel (n-hexane: ethyl acetate = 2: 1) to give the title compound (9 mg, 82%) as a white solid. Obtained.

Example 11
tert-Butyl 6- (2-Fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate production step 1: tert-butyl 6- (4 , 4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Step 1 of Example 3. Tert-Butyl 6-bromo-spiro [chroman-2,4′-piperidine] -1′-carboxylate (2.5 g, 6.54 mmol) in 1,4-dioxane (33 mL) was added to bis (pinacolate) diborane. (2 g, 7.85 mmol), potassium acetate (1.93 g, 19.62 mmol) and bis (triphenylphosphine) palladium (II) dichloride (0.23 g, 0.327 mmol) are added, and 12 at 90 ° C. under an argon atmosphere. 5 hours and the mixture was stirred. Insoluble material was removed by filtration, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (n-hexane: ethyl acetate = 10: 1 to 5: 1) to obtain the title compound (2.02 g, 72%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.33 (12H, s), 1.46 (9H, s), 1.52-1.60 (2H, m), 1.75-1.84 (4H, m), 2.79 (2H, t, J = 6.8 Hz), 3.10-3.30 (2H, m), 3.74-3.98 (2H, m), 6.84 (1H, d, J = 8.0 Hz), 7.54-7.58 (2H, m).

Step 2: Preparation of tert-butyl 6- (2-fluoro-4-((methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-obtained in Step 1 Butyl 6- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (32.4 mg, 0.075 mmol ) And (4-bromo-3-fluorobenzyl) (methyl) sulfane (19.5 mg, 0.083 mmol) in 1,4-dioxane (0.75 mL) -water (0.75 mL) mixed solution was added sodium carbonate (119.2 mg, 1.125). mmol) and tetrakistriphenylphosphine palladium (0) (8.7 mg, 0.0075 mmol) were added, and the mixture was stirred at 95 ° C. for 11 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (n-hexane: ethyl acetate = 5: 1) to give the title compound (25.8 mg, 75%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.79-1.88 (4H, m), 2.04 (3H, s), 2.83 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.68 (2H, s), 3.76-4.00 (2H, m), 6.90 (1H, d, J = 8.4 Hz), 7.00-7.20 (2H, m), 7.25-7.38 (3H, m).

Step 3: Preparation of tert-butyl 6- (2-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 -Butyl 6- (2-fluoro-4-((methylthio) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate is used in the same manner as in Step 3 of Example 3. Treatment gave the title compound as a white solid.

Example 12 Production of tert-butyl 6- (2-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6 Preparation of — (2-chloro-4-((methylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3-fluorobenzyl) (methyl) sulfane Instead, (4-bromo-3-chlorobenzyl) (methyl) sulfane was used for the reaction and treatment in the same manner as in Step 2 of Example 11 to obtain the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.56-1.62 (2H, m), 1.78-1.88 (4H, m), 2.05 (3H, s), 2.82 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.66 (2H, s), 3.80-4.00 (2H, m), 6.88 (1H, d, J = 8.4 Hz), 7.14 (1H, d, J = 2.0 Hz), 7.16-7.28 (3H, m), 7.40 (1H, d, J = 2.0 Hz).

Step 2: Preparation of tert-butyl 6- (2-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 1 -Butyl 6- (2-chloro-4-((methylthio) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate is used in the same manner as in Step 3 of Example 3. Treatment gave the title compound as a white solid.

Example 13 Production of tert-butyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 4-bromo- Preparation of 2-fluoro-1-((methylsulfonyl) methyl) benzene 4-bromo-2-fluorobenzyl bromide (1 g, 3.73 mmol) in dimethyl sulfoxide (5.4 mL) was added sodium methanesulfinate (1.33 g, 13.06 mmol) was added and stirred at 120 ° C. for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether and the title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 2.83 (3H, s), 4.27 (2H, s), 7.33-7.40 (3H, m).

Step 2: Preparation of tert-butyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3- Using 4-bromo-2-fluoro-1-((methylsulfonyl) methyl) benzene obtained in Step 1 instead of (fluorobenzyl) (methyl) sulfane, reaction and treatment in the same manner as in Step 2 of Example 11 The title compound was obtained as a white solid.

Example 14 Production of tert-butyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 2-chloro- Preparation of 4-iodo-1-((methylsulfonyl) methyl) benzene (2-Chloro-4-iodophenyl) methanol (0.54 g, 2.01 mmol) in tetrahydrofuran (8.4 mL) was added to triethylamine (0.36 mL, 2.61 mmol). ) And methanesulfonyl chloride (0.17 mL, 2.21 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 3 hours, then at 40 ° C. for 1 hour and at 60 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Dimethyl sulfoxide (2.9 mL) and sodium methanesulfinate (0.72 g, 7.04 mmol) were added to the residue, and the mixture was stirred at 120 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether and washed to give the title compound (0.52 g, 79%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 2.82 (3H, s), 4.41 (2H, s), 7.30 (1H, d, J = 8.4 Hz), 7.69 (1H, dd, J = 8.4, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz).

Step 2: Preparation of tert-butyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2 obtained in Step 1 -Chloro-4-iodo-1-((methylsulfonyl) methyl) benzene was used instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane and reacted and treated in the same manner as in Step 2 of Example 11. The title compound was obtained as a white solid.

Example 15
tert-Butyl 6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (A) and tert-butyl 6- (5- Production process of ((methylsulfinyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (B) 1: tert-butyl 6- (5- (hydroxymethyl) Preparation of pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6-bromo-3-pyridinemethanol instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane Was used in the same manner as in Step 2 of Example 11 to give the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.78-1.90 (4H, m), 2.17 (1H, brs), 2.87 (2H, t, J = 6.8 Hz), 3.12-3.34 (2H, m), 3.78-4.00 (2H, m), 4.74 (2H, s), 6.92 (1H, d, J = 8.4 Hz), 7.65-7.80 (4H, m), 8.60 (1H, d, J = 1.2 Hz).

Step 2: Preparation of tert-butyl 6- (5- (bromomethyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-Butyl 6-obtained in Step 1 Dichloromethane of (5- (hydroxymethyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (25.3 mg, 0.062 mmol) and triphenylphosphine (19.4 mg, 0.074 mmol) A solution of carbon tetrabromide (24.5 mg, 0.074 mmol) in dichloromethane (2.4 mL) was added to the (1.2 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to give the title compound (7 mg, 24%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.61 (2H, m), 1.78-1.88 (4H, m), 2.87 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.78-4.00 (2H, m), 4.52 (2H, s), 6.92 (1H, d, J = 8.8 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.68-7.80 ( 3H, m), 8.63 (1H, d, J = 2.0 Hz).

Step 3: Preparation of tert-butyl 6- (5-((methylthio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-obtained in Step 2 Butyl 6- (5- (bromomethyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (7 mg, 0.015 mmol) in 1,4-dioxane (0.5 mL) To the mixture was added methylthiosodium (1.2 mg, 0.0165 mmol), and the mixture was stirred at 95 ° C. for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (6.6 mg, 100%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.62 (2H, m), 1.80-1.88 (4H, m), 2.03 (3H, s), 2.87 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.68 (2H, s), 3.78-4.00 (2H, m), 6.92 (1H, d, J = 8.0 Hz), 7.63 (1H, d, J = 7.6 Hz), 7.66-7.72 (2H, m), 7.77 (1H, d, J = 2.0 Hz), 8.52 (1H, d, J = 2.0 Hz).

Step 4: tert-butyl 6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (A) and tert-butyl 6- Production of (5-((methylsulfinyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (B) tert-butyl 6- (obtained in Step 3 5-((Methylthio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain a silica gel component. Purification using thin layer chromatography (chloroform: methanol = 5: 1) gave the title compound (A) as a white solid.

Further, the title compound (B) was obtained as a colorless oil.

Example 16 Preparation of tert-butyl 6- (6-((methylsulfonyl) methyl) pyridin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 5-bromo- Preparation of 2-((methylsulfonyl) methyl) pyridine To a solution of 5-bromo-2-pyridinemethanol (200 mg, 1.06 mmol) in tetrahydrofuran (4.4 mL) was added triethylamine (192 μL, 1.38 mmol) and methanesulfonyl chloride (91 μL). , 1.17 mmol) at 0 ° C. and stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give (5-bromopyridin-2-yl) methylmethanesulfonate (285 mg, 101%) as a reddish brown oil.
Sodium methanesulfinate (382 mg, 3.75 mmol) was added to a solution of the obtained (5-bromopyridin-2-yl) methylmethanesulfonate (285 mg, 1.07 mmol) in dimethylsulfoxide (1.53 mL) at 120 ° C. Stir for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether and washed to give the title compound (180.4 mg, 67%) as a brown solid.

¹ H-NMR (CDCl ₃ ) δ: 2.92 (3H, s), 4.38 (2H, s), 7.40 (1H, d, J = 8.0 Hz), 7.90 (1H, dd, J = 2.4, 8.0 Hz), 8.67 (1H, d, J = 2.4 Hz).

Step 2: Preparation of tert-butyl 6- (6-((methylsulfonyl) methyl) pyridin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 5 obtained in Step 1 Using -bromo-2-((methylsulfonyl) methyl) pyridine in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 11 to obtain the title compound. Obtained as a white solid.

Example 17 Preparation of tert-butyl 6- (3-methyl-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 4-Bromo- Preparation of 2-methyl-1-((methylsulfonyl) methyl) benzene Similar to Step 1 of Example 16 using (4-bromo-2-methylphenyl) methanol instead of 5-bromo-2-pyridinemethanol. Reaction and treatment gave the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.84 (3H, s), 4.27 (2H, s), 7.21 (1H, d, J = 8.0 Hz), 7.38 (1H, dd, J = 2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz).

Step 2: Preparation of tert-butyl 6- (3-methyl-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4 obtained in Step 1 -Bromo 2-methyl-1-((methylsulfonyl) methyl) benzene was used in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane and reacted and treated in the same manner as in Step 2 of Example 11, The title compound was obtained as a white solid.

Example 18 Preparation of tert-butyl 6- (3-methoxy-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 1: 4-bromo- Preparation of 2-methoxy-1-((methylsulfonyl) methyl) benzene Similar to Step 1 of Example 16 using (4-bromo-2-methoxyphenyl) methanol instead of 5-bromo-2-pyridinemethanol. Reaction and treatment gave the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 2.74 (3H, s), 3.89 (3H, s), 4.29 (2H, s), 7.09 (1H, d, J = 2.0 Hz), 7.17 (1H, dd, J = 2.0, 8.4 Hz), 7.30 (1H, d, J = 8.4 Hz).

Step 2: Preparation of tert-butyl 6- (3-methoxy-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4 obtained in Step 1 -Bromo-2-methoxy-1-((methylsulfonyl) methyl) benzene was used in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane and reacted and treated in the same manner as in Step 2 of Example 11. The title compound was obtained as a white solid.

Example 19 Preparation of tert-butyl 6- (4-((methylsulfonyl) methyl) -3-propoxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 4-bromo- Preparation of 1-((methylsulfonyl) methyl) -2-propoxybenzene To a solution of 4-bromo-1-methyl-2-propoxybenzene (60.2 mg, 0.263 mmol) derived from a commercially available compound in carbon tetrachloride (2.6 mL) , N-bromosuccinimide (46.8 mg, 0.263 mmol) and azobisisobutyronitrile (0.1 mg, 0.53 μmol) were added, and the mixture was stirred at 90 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-bromo-1- (bromomethyl) -2-propoxybenzene as a yellow oil (81 mg, 100%).
Sodium methanesulfinate (94 mg, 0.921 mmol) was added to a solution of the obtained 4-bromo-1- (bromomethyl) -2-propoxybenzene (81 mg, 0.263 mmol) in dimethyl sulfoxide (1 mL), and 120 ° C. For 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound (49.4 mg, 61%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.2 Hz), 1.80-1.90 (2H, m), 2.74 (3H, s), 3.98 (2H, t, J = 6.8 Hz), 4.30 (2H, s), 7.08 (1H, d, J = 2.0 Hz), 7.15 (1H, dd, J = 2.0, 8.0 Hz), 7.30 (1H, d, J = 8.0 Hz).

Step 2: Preparation of tert-butyl 6- (6-((methylsulfonyl) methyl) pyridin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4 obtained in Step 1 -Bromo-1-((methylsulfonyl) methyl) -2-propoxybenzene was used in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane and reacted and treated in the same manner as in Step 2 of Example 11. The title compound was obtained as a pale yellow oil.

Example 20 Preparation of tert-butyl 6- (3- (cyclopropylmethoxy) -4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of 4-bromo-2- (cyclopropylmethoxy) -1-((methylsulfonyl) methyl) benzene 4-bromo-2- (cyclopropylmethoxy) instead of 4-bromo-1-methyl-2-propoxybenzene The reaction and treatment were carried out in the same manner as in Step 1 of Example 19 using -1-methylbenzene to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.31-0.37 (2H, m), 0.65-0.72 (2H, m), 1.21-1.32 (1H, m), 2.78 (3H, s), 3.85 (2H, d, J = 6.8 Hz), 4.33 (2H, s), 7.03 (1H, d, J = 2.0 Hz), 7.15 (1H, dd, J = 2.0, 8.4 Hz), 7.30 (1H, d, J = 8.4 Hz) .

Step 2: Preparation of tert-butyl 6- (3- (cyclopropylmethoxy) -4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate In Step 1 The step of Example 11 using the resulting 4-bromo-2- (cyclopropylmethoxy) -1-((methylsulfonyl) methyl) benzene in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane Reaction and treatment in the same manner as in 2 gave the title compound as a white solid.

Example 21 Production process of tert-butyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 5- Preparation of bromo-1,3-difluoro-2-((methylsulfonyl) methyl) benzene 4-bromo-2,6-difluorobenzyl alcohol (1 g, 4.48 mmol) in ethyl acetate (9 mL) was added to diisopropylethylamine (9 mL). 0.78 mL, 4.48 mmol) and thionyl chloride (0.36 mL, 4.93 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water and diisopropylethylamine (0.78 mL, 4.48 mmol) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2- (chloromethyl) -1,3-difluorobenzene (1.1 g, 100%) as a reddish brown oil. Obtained as a thing.
Sodium methanesulfinate (1.6 g, 15.6 mmol) was added to a solution of the obtained 5-bromo-2- (chloromethyl) -1,3-difluorobenzene (1.1 g, 4.48 mmol) in dimethyl sulfoxide (6.4 mL). And stirred at 120 ° C. for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether and washed to give the title compound (0.54 g, 42%) as a brown solid.

¹ H-NMR (CDCl ₃ ) δ: 2.92 (3H, s), 4.35 (2H, s), 7.20-7.25 (2H, m).

Step 2: Preparation of tert-butyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Step 1 5-bromo-1,3-difluoro-2-((methylsulfonyl) methyl) benzene was used instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane as in Step 2 of Example 11. Reaction and treatment gave the title compound as a white solid.

Example 22 Preparation of tert-butyl 6- (4-((1- (methylsulfonyl) ethyl] phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate

Step 1: Preparation of tert-butyl 6- (4-acetylphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4,4,5,5-tetramethyl-2- (4- ( Using 4-acetylphenylboronic acid in place of (methylthio) methyl) phenyl) -1,3,2-dioxaborate, the reaction and treatment were conducted in the same manner as in Step 2 of Example 3 to obtain the title compound as a white solid. .

¹ H-NMR (CDCl ₃ ) δ: 1.43-1.63 (11H, m), 1.78-1.88 (4H, m), 2.62 (3H, s), 2.86 (2H, d, J = 6.8 Hz), 3.15-3.40 (2H, m), 3.78-4.00 (2H, m), 6.93 (1H, d, J = 8.6 Hz), 7.35 (2H, d, J = 2.2 Hz), 7.40 (1H, dd, J = 8.4, 2.2 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.5 Hz).

Step 2: Preparation of tert-butyl 6- (4- (1-hydroxyethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-Butyl 6- (obtained in Step 1 4-acetylphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (35 mg, 0.08 mmol) was dissolved in methanol (0.4 mL) and tetrahydrofuran (1 mL), and sodium borohydride ( 4 mg, 0.11 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. After adding 1 N dilute hydrochloric acid to the reaction solution at 0 ° C., the reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (22 mg, 63%) as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.44-1.63 (14H, m), 1.80-1.90 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.31-3.35 (2H, m), 3.75 -4.00 (2H, m), 4.88-4.98 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.33 (1H, dd, J = 8.3 , 2.0 Hz), 7.41 (2H, d, J = 8.3 Hz), 7.51 (2H, d, J = 8.0 Hz).

Step 3: Preparation of tert-butyl 6- (4- (1-methylsulfonyl) oxy] ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- (1-Hydroxyethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (22 mg, 0.05 mmol) is dissolved in dichloromethane (2.0 mL) and triethylamine (14 μL, 0.10 mmol) is dissolved. And methanesulfonyl chloride (5 μL, 0.07 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound (33 mg).

Step 4: Preparation of tert-butyl 6- (4- (1-methylthio) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-obtained in Step 3 Crude product (22 mg) of (4- (1-methylsulfonyl) oxy) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was converted to N, N-dimethylformamide (2.0 mL). ), Methylthiosodium (5 mg, 0.08 mmol) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, N, N-dimethylformamide was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the title compound (16 mg, 67%, 2 steps) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.62 (5H, m), 1.80-1.87 (4H, m), 1.94 (3H, s), 2.84 (2H, t, J = 6.8 Hz), 3.14-3.34 (2H, m), 3.80-4.00 (3H, m), 6.89 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31-7.37 ( 3H, m), 7.48 (2H, d, J = 8.3 Hz).

Step 5: Preparation of tert-butyl 6- (4-((1- (methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-obtained in Step 4 Butyl 6- (4- (1-methylthio) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3, The title compound was obtained as a colorless oil.

Example 23 Preparation of tert-butyl 6- (4-((2- (methylsulfonyl) propan-2-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate In Example 3 The resulting tert-butyl 6- (4- (methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (30 mg, 0.06 mmol) and methyl iodide (20 μL) , 0.32 mmol) was dissolved in tetrahydrofuran (0.6 mL), tert-butoxypotassium (18 mg, 0.16 mmol) was added at 0 ° C., and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (22 mg, 69%) as a white amorphous.

Example 24 Preparation of tert-butyl 6- (4- (1H-tetrazol-1-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3-fluorobenzyl ) Using 1- (4-bromophenyl) -1H-tetrazole instead of (methyl) sulfane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 11 to obtain the title compound as a white solid.

Example 25 Preparation of tert-butyl 6- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Step 1 of Example 3 To a solution of tert-butyl 6-bromospiro [chroman-2,4′-piperidine] -1′-carboxylate (20 mg, 0.052 mmol) and 5-methylsulfonylindoline (15.5 mg, 0.078 mmol) in toluene (1 mL) , Tert-butoxy sodium (7.5 mg, 0.078 mmol) and bis (tri-tert-butyl-phosphine) palladium (0) (2.7 mg, 0.0052 mmol) were added, and the mixture was stirred at 100 ° C. for 6 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (25.4 mg, 98%) as a white solid.

Example 26 Preparation of tert-butyl 7- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Obtained in Step 2 of Example 5. tert-Butyl 7-bromospiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Example 25 to obtain the title compound as a pale yellow solid.

Example 27 Preparation of tert-butyl 6- (4-((methylsulfonyl) methyl) piperidin-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate In Step 1 of Example 3 The resulting tert-butyl 6-bromospiro [chroman-2,4′-piperidine] -1′-carboxylate (25.6 mg, 0.067 mmol) and 4-((methylsulfonyl) methyl) piperidine (21.4 mg, 0.1 mmol) Tert-butoxy sodium (16 mg, 0.167 mmol) and bis (tri-tert-butyl-phosphine) palladium (0) (3.4 mg, 0.0067 mmol) were added to a toluene (1.3 mL) solution. Stir at 5 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (19.7 mg, 61%) as a brown amorphous.

Example 28 Preparation of ethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (obtained in Example 3 4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (423 mg, 0.90 mmol) was dissolved in methanol (10 mL), and 4N hydrochloric acid / 1, 4-Dioxane solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain a crude product (348 mg) of 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. The obtained crude product (20.0 mg, 0.05 mmol) was dissolved in dichloroethane (1 mL), triethylamine (20.4 μL, 0.15 mmol) and ethyl chloroformate (5.6 μL, 0.06 mmol) were added, and the mixture was stirred at room temperature for 12 hours. did. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (22.4 mg, 100%) as a white amorphous.

Example 29 Preparation of 2,2,2-trifluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6- (4- A crude product of ((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride (20.0 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N -Diisopropylethylamine (42.7 μL, 0.25 mmol) and 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate (28.5 mg, 0.15 mmol) were added, and the mixture was stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (25.2 mg, 100%) as a white amorphous.

Example 30 Preparation of 2,2,2-trichloroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of ethyl chloroformate And 2,2,2-trichloroethyl chloroformate were reacted and treated in the same manner as in Example 28 to obtain the title compound as a white amorphous.

Example 31 Preparation of 2-fluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-Fluoro instead of ethyl chloroformate The reaction and treatment were conducted in a similar manner to Example 28 using ethyl chloroformate to obtain the title compound as a white amorphous.

Example 32 Preparation of 2-methoxyethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-methoxy instead of ethyl chloroformate The reaction and treatment were conducted in a similar manner to Example 28 using ethyl chloroformate to obtain the title compound as a white amorphous.

Example 33 Preparation of Isopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using isopropyl chloroformate instead of ethyl chloroformate Then, the reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as a white solid.

Example 34 Preparation of benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Benzyl chloroformate instead of ethyl chloroformate Then, the reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as a white solid.

Example 35 Preparation of phenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using phenyl chloroformate instead of ethyl chloroformate Then, the reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as white amorphous.

Example 36 Preparation of 4-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4-chlorophenylchloro instead of ethyl chloroformate The formate was reacted and treated in the same manner as in Example 28 to obtain the title compound as a white amorphous.

Example 37 Preparation of 3-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3-chlorophenyl (instead of ethyl chloroformate ( 4-Nitrophenyl) carbonate was used for the reaction and treatment in the same manner as in Example 28 to obtain the title compound as white amorphous.

Example 38 Preparation of 2-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-chlorophenylchloro instead of ethyl chloroformate The formate was reacted and treated in the same manner as in Example 28 to obtain the title compound as a white amorphous.

Example 39 Preparation of 4-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4-chloro instead of ethyl chloroformate The reaction and treatment were conducted in the same manner as in Example 28 using benzyl (4-nitrophenyl) carbonate to obtain the title compound as a white amorphous.

Example 40 Preparation of 3-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3-chloro instead of ethyl chloroformate The reaction and treatment were conducted in the same manner as in Example 28 using benzyl (4-nitrophenyl) carbonate to obtain the title compound as a white amorphous.

Example 41 Preparation of 2-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-chloro in place of ethyl chloroformate The reaction and treatment were carried out in the same manner as in Example 28 using benzyl chloroformate to obtain the title compound as a white amorphous.

Example 42 Preparation of 3,5-bis (trifluoromethyl) benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Ethylchloroform The reaction and treatment were conducted in a similar manner to Example 28 using 3,5-bis (trifluoromethyl) benzyl (4-nitrophenyl) carbonate instead of mate, and the title compound was obtained as a white amorphous substance.

Example 43 Preparation of pyridin-4-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 4-ethyl instead of ethyl chloroformate Reaction and treatment were carried out in the same manner as in Example 28 using nitrophenyl (pyridin-4-ylmethyl) carbonate to obtain the title compound as a white solid.

Example 44 Preparation of pyridin-3-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 4-ethyl instead of ethyl chloroformate Reaction and treatment were conducted in the same manner as in Example 28 using nitrophenyl (pyridin-3-ylmethyl) carbonate to obtain the title compound as a white solid.

Example 45 Preparation of pyridin-2-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6- (4-((methylsulfonyl) ) Methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride crude (20.0 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (1 mL) and N, N-diisopropylethylamine ( 42.7 μL, 0.25 mmol) and pyridin-2-ylmethyl 1H-imidazole-1-carboxylate (19.9 mg, 0.15 mmol) were added, and the mixture was stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: acetone = 2: 1) to obtain the title compound (25.7 mg, 100%) as a white amorphous.

Example 46 1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Preparation of rate 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride crude (20.0 mg, 0.05 mmol), 1,1,1-trifluoro- 2-Methylpropan-2-yl 1H-imidazole-1-carboxylate (28.5 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1 mL) and N, N-diisopropylethylamine (42.7 μL, 0.25 mmol) was dissolved. ) And stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (25.2 mg, 100%) as a white amorphous.

Example 47 1,1,1-Trichloro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 1,1,1-trichloro-2-methylpropan-2-ylchloroformate instead of ethyl chloroformate, the reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as a white amorphous product. It was.

Example 48 Preparation of neopentyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Neopentyl chloroformate was used instead of ethyl chloroformate. And the reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as white amorphous.

Example 49 Preparation of adamantane-1-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate adamantane instead of ethyl chloroformate The reaction and treatment were conducted in a similar manner to Example 28 using 1-yl (4-nitrophenyl) carbonate to obtain the title compound as a white amorphous.

Example 50 Preparation of adamantane-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate adamantane instead of ethyl chloroformate Using 2-yl (4-nitrophenyl) carbonate, reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as white amorphous.

Example 51 Preparation of Oxetan-3-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 4-ethyl instead of ethyl chloroformate Using nitrophenyl (oxetane-3-yl) carbonate, reaction and treatment were conducted in the same manner as in Example 28 to obtain the title compound as a white amorphous.

Example 52 Preparation of tetrahydro-2H-pyran-4-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Instead, 4-nitrophenyl (tetrahydro-2H-pyran-4-yl) carbonate was used for the reaction and treatment in the same manner as in Example 28 to obtain the title compound as a white amorphous.

Example 53 Preparation of 4,4-difluorocyclohexyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 6- (4-((methyl A crude product (20.0 mg, 0.05 mmol) of sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine was dissolved. (42.7 μL, 0.25 mmol), 4,4-difluorocyclohexyl 1H-imidazole-1-carboxylate (33.8 mg, 0.15 mmol) was added, and the mixture was stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) to obtain the title compound (19.0 mg, 73%) as a white amorphous.

Example 54 Preparation of 2,2,2-trichloroethyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Tert-butyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in 13 (268 mg, 0.55 mmol) Was dissolved in methanol (5 mL), 4N hydrochloric acid / 1,4-dioxane solution (5 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated to obtain a crude product (230 mg) of 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. The obtained crude product (20.0 mg, 0.05 mmol) was dissolved in dichloroethane (1 mL), and triethylamine (19.5 μL, 0.14 mmol) and 2,2,2-trichloroethyl chloroformate (7.6 μL, 0.06 mmol) were dissolved. The mixture was further stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (22.2 mg, 84%) as a white amorphous.

Example 55 Preparation of phenyl 6- [3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in the same manner as in Example 54 using phenyl chloroformate instead of formate to obtain the title compound as a white amorphous.

Example 56 1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine]- Preparation of 1′-carboxylate 6- [3-Fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride crude product obtained in Example 54 (20.0 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (32.7 μL, 0.19 mmol), 1,1,1-trifluoro-2-methylpropan-2- Ile 1H-imidazole-1-carboxylate (15.7 mg, 0.08 mmol) was added and stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) to obtain the title compound (30.0 mg, 100%) as a white amorphous.

Example 57 Preparation of neopentyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in the same manner as in Example 54 using neopentyl chloroformate instead of formate to obtain the title compound as a white amorphous.

Example 58 Preparation of 2,2,2-trichloroethyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 14-tert-butyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate (347 mg, 0.69 mmol) Was dissolved in methanol (7 mL), 4N hydrochloric acid / 1,4-dioxane solution (7 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated to obtain a crude product (307 mg) of 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. The obtained crude product (20.0 mg, 0.05 mmol) was dissolved in dichloroethane (1 mL), and triethylamine (18.7 μL, 0.14 mmol) and 2,2,2-trichloroethyl chloroformate (7.3 μL, 0.06 mmol) were dissolved. In addition, the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (23.1 mg, 88%) as a white amorphous.

Example 59 Preparation of phenyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in the same manner as in Example 58 using phenylchloroformate instead of formate to give the title compound as a white amorphous.

Example 60 1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine]- Preparation of 1′-carboxylate 6- (3-Chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride crude product (20.0) obtained in Example 58 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (31.4 μL, 0.18 mmol), 1,1,1-trifluoro-2-methylpropan-2- IL 1H-imidazole-1-carboxylate (14.9 mg, 0.07 mmol) was added, and the mixture was stirred at 80 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: acetone = 2: 1) to obtain the title compound (12.3 mg, 49%) as a white amorphous.

Example 61 Preparation of neopentyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in the same manner as in Example 58 using neopentyl chloroformate instead of formate to obtain the title compound as a white amorphous.

Example 62 2,2,2-trifluoroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Production tert-Butyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Example 21 (53.0 mg, 0.10 mmol) was dissolved in methanol (1.5 mL), 4N hydrochloric acid / 1,4-dioxane solution (1 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated to obtain a crude product (50.8 mg) of 6- [3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. The obtained crude product (16.1 mg, 0.04 mmol) was dissolved in N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (31.4 μL, 0.18 mmol), 2,2,2-trifluoroethyl. 1H-imidazole-1-carboxylate (21.0 mg, 0.11 mmol) was added, and the mixture was stirred at 80 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (4.1 mg, 21%) as a white amorphous.

Example 63 Preparation of 2,2,2-trichloroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Crude product (14.3 mg, 0.03 mmol) of 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in Example 62 Was dissolved in dichloroethane (1 mL), triethylamine (13.3 μL, 0.10 mmol) and 2,2,2-trichloroethyl chloroformate (5.2 μL, 0.04 mmol) were added, and the mixture was stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: acetone = 2: 1) to obtain the title compound (5.5 mg, 29%) as a white amorphous.

Example 64 Preparation of phenyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2,2,2-trichloro The reaction and treatment were conducted in a similar manner to Example 63 using phenyl chloroformate instead of ethyl chloroformate, and the title compound was obtained as a white amorphous substance.

Example 65 1,1,1-trifluoro-2-methylpropan-2-yl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine Preparation of 6 ′-(3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in Example 62 The crude product (16.0 mg, 0.04 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (31.4 μL, 0.18 mmol), 1,1,1-trifluoro-2-methyl was dissolved. Propan-2-yl 1H-imidazole-1-carboxylate (24.0 mg, 0.07 mmol) was added, and the mixture was stirred at 80 ° C. for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: acetone = 2: 1) to obtain the title compound (19.0 mg, 94%) as a white amorphous.

Example 66 Preparation of neopentyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trichloro The reaction and treatment were conducted in the same manner as in Example 63 using neopentyl chloroformate instead of ethyl chloroformate, and the title compound was obtained as a white amorphous substance.

Example 67 Production of tert-butyl 6- (4-((pyridin-4-ylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- Preparation of (4- (hydroxymethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4,4,5,5-tetramethyl-2- (4-((methylthio) methyl) Using (4- (hydroxymethyl) phenyl) boronic acid in place of (phenyl) -1,3,2-dioxaborate, the reaction and treatment were carried out in the same manner as in Step 2 of Example 3 to obtain the title compound as a white solid. .

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.55 (4H, dt, J = 13.0, 4.9 Hz), 1.79-1.87 (4H, m), 2.84 (2H, t, J = 6.8 Hz ), 3.14-3.36 (2H, m), 3.75-4.02 (2H, m), 4.69-4.75 (2H, br), 6.90 (1H, d, J = 8.5 Hz), 7.29 (1H, d, J = 2.2 Hz), 7.34 (1H, dd, J = 8.3, 2.2 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz).

Step 2: Preparation of tert-butyl 6- (4- (bromomethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- (hydroxymethyl) phenyl) spiro [Chroman-2,4′-piperidine] -1′-carboxylate (200 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL), carbon tetrabromide (162 mg, 0.73 mmol) and triphenylphosphine (166 mg). , 0.63 mmol) and stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1 → 3: 1 → 2: 1) to obtain the title compound (230 mg, quant.) As a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.62 (11H, m), 1.78-1.88 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.14-3.34 (2H, m), 3.75 -4.02 (2H, m), 4.54 (2H, s), 6.90 (1H, d, J = 8.3 Hz), 7.26-7.31 (1H, br), 7-33 (1I, dd, J = 8.4, 2.2 Hz ), 7.42 (2H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.3 Hz).

Step 3: Preparation of tert-butyl 6- (4-((pyridin-4-ylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- (Bromomethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (36 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1.5 mL) and 4-pyridinethiol (10 mg, 0.09 mmol). And N, N-diisopropylethylamine (27 μL, 0.09 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (17 mg, 45%.) As a white solid.

Example 68 Preparation of tert-butyl 6- (4-((pyridin-4-ylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Obtained in Example 67 tert-Butyl 6- (4-((Pyridin-4-ylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate as in step 3 of example 3 Reaction and treatment gave the title compound as a white solid.

Example 69 Preparation of tert-butyl 6- (4-((phenylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using thiophenol instead of 4-pyridinethiol The reaction and treatment were conducted in the same manner as in Example 67, and the title compound was obtained as a white solid.

Example 70 Preparation of tert-butyl 6- (4-((phenylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate tert-Butyl 6 obtained in Example 69 -(4-((Phenylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound. Obtained as a white solid.

Example 71 tert-Butyl 6- (4-(((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate The reaction and treatment were conducted in the same manner as in Example 67 using 5-methyl-1,3,4-thiadiazole-2-thiol instead of 4-pyridinethiol to obtain the title compound as a white solid. .

Example 72 tert-butyl 6- (4-(((5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' Preparation of carboxylate tert-butyl 6- (4-(((5-methyl-1,3,4-thiadiazol-2-yl) thio) methyl) phenyl) spiro [chroman-2 obtained in Example 71 , 4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound as a white solid.

Example 73 Preparation of tert-butyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6- (4- Production of ((ethylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Reaction and treatment were carried out in the same manner as in Example 67 using ethanethiol instead of 4-pyridinethiol. The title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.42-1.61 (11H, m), 1.76-1.88 (4H, m), 2.47 (2H, q, J = 7.3 Hz ), 2.84 (2H, t, J = 6.6 Hz), 3.15-3.33 (2H, m), 3.75 (2H, s), 3.80-4.01 (2H, m), 6.90 (1H, d, J = 8.3 Hz) , 7.27-7.37 (4H, m), 7.47 (2H, d, J = 8.3 Hz).

Step 2: Preparation of tert-butyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-((ethylthio ) Methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound as a white solid.

Example 74 Preparation of tert-butyl 6- (4-((dodecylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using dodecanethiol instead of 4-pyridinethiol The reaction and treatment were conducted in the same manner as in Example 67, and the title compound was obtained as a colorless oil.

Example 75 Preparation of tert-butyl 6- (4-((dodecylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate tert-Butyl 6 obtained in Example 74 Using-(4-((dodecylthio) methyl) phenyl) spiro [chromone-2,4′-piperidine] -1′-carboxylate, the reaction and treatment were conducted in the same manner as in Step 3 of Example 3 to obtain the title compound. Obtained as a white solid.

Example 76 Preparation of tert-butyl 6- (4-((acetylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-obtained in Step 67 of Example 67 Butyl 6- (4- (bromomethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (1.0 g, 2.12 mmol) was dissolved in N, N-dimethylformamide (5 mL), S-potassium thioacetate (484 mg, 4.23 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1 → 3: 1) to obtain the title compound (827 mg, 84%) as a pale yellow solid.

Example 77 Production of tert-butyl 6- (4-((propylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- (4- Preparation of ((propylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-((acetylthio) methyl) phenyl obtained in Example 76) Spiro [chroman-2,4′-piperidine] -1′-carboxylate (30 mg, 0.06 mmol) is dissolved in methanol (0.3 mL) and tetrahydrofuran (0.3 mL), and 1-iodopropane (8 μL, 0.08 mmol) is dissolved. And 4 N aqueous sodium hydroxide solution (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 3: 1) to give the title compound (21 mg, 70%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.6 Hz), 1.47 (9H, s), 1.50-1.66 (4H, m), 1.78-1.88 (4H, m), 2.43 (2H , t, J = 7.6 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.18-3.33 (2H, m), 3.73 (2H, s), 3.79-3.99 (2H, m), 6.90 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.34 (3H, m), 7.48 (2H, d, J = 8.1 Hz).

Step 2: Preparation of tert-butyl 6- (4-((propylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-((propylthiol) ) Methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound as a white amorphous.

Example 78 Production of tert-butyl 6- (4-((allylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- (4- Preparation of ((allylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Similar to Example 77, using 1-iodoprop-2-ene instead of 1-iodopropane The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.34-1.61 (11H, m), 1.76--1.86 (4H, m), 2.76-2.86 (2H, m), 3.07 (2H, d, J = 7.1 Hz), 3.22-3.34 (2H, m), 3.69 (2H, s), 3.75-4.01 (2H, m), 5.00-5.19 (2H, m), 5.68-5.86 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.22-7.36 (4H, m), 7.47 (1H, d, J = 8.3 Hz).

Step 2: Preparation of tert-butyl 6- (4-((allylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-((allylthio) ) Methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound as a white amorphous.

Example 79 Production step 1 of tert-butyl 6- (4-((3,3,3-trifluoropropyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (4-((3,3,3-trifluoropropyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1-iodopropane Using 1-iodo-3,3,3-trifluoropropane instead of, the reaction and treatment were conducted in the same manner as in Example 77 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.63 (2H, m), 1.78-1.87 (4H, m), 2.24-2.38 (2H, m), 2.57-2.64 (2H, m), 2.85 (2H, t, J = 6.8 Hz), 3.18-3.26 (2H, m), 3.76 (2H, s), 3.80-3.96 (2H, m), 6.90 (1H, d, J = 8.3 Hz ), 7.26-7.37 (4H, m), 7.50 (1H, d, J = 8.0 Hz).

Step 2: Preparation of tert-butyl 6- (4-((3,3,3-trifluoropropyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert- The process of Example 3 using butyl 6- (4-((3,3,3-trifluoropropyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to 3 to give the title compound as a white solid.

Example 80 Production of tert-butyl 6- (4-((2-methoxyethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6 Preparation of-(4-((2-methoxyethyl) thio) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 1-bromo-2-methoxy instead of 1-iodopropane The reaction and treatment were conducted in a similar manner to Example 77 using ethane to give the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.62 (11H, m), 1.76-1.88 (4H, m), 2.64 (2H, t, J = 6.6 Hz), 2.84 (2H, t, J = 6.8 Hz ), 3.16-3.39 (5H, m), 3.53 (2H, t, J = 6.6 Hz), 3.70-4.00 (4H, m), 6.90 (1H, d, J = 8.6 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31-7.38 (3H, m), 7.48 (2H, d, J = 8.1 Hz).

Step 2: Preparation of tert-butyl 6- (4-((2-methoxyethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4 -((2-Methoxyethyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3, and the title The compound was obtained as a white solid.

Example 81 Preparation of tert-butyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6- (4- Preparation of ((Isopropylthio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Reaction similar to Example 77 using 2-iodopropane instead of 1-iodopropane Treatment gave the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.6 Hz), 1.47 (9H, s), 1.50-1.58 (2H, m), 1.77-1.87 (4H, m), 2.78-2.88 (3H, m), 3.15-3.31 (2H, m), 3.77 8 (2H, s), 3.80-4.00 (2H, m), 6.89 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.30-7.37 (3H, m), 7.47 (2H, d, J = 8.0 Hz).

Step 2: Preparation of tert-butyl 6- (4-((isopropylsulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-((isopropyl Using thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate, the reaction and treatment were carried out in the same manner as in Step 3 of Example 3 to obtain the title compound as a white solid.

Example 82
tert-Butyl 6- (4-((Cyclopropylmethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6- (4- Preparation of ((Cyclopropylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 77 was obtained using bromomethylcyclopropane instead of 1-iodopropane. The same reaction and treatment were performed to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.12-0.21 (2H, m), 0.48-0.58 (2H, m), 0.92-1.02 (1H, m), 1.47 (9H, s), 1.50-1.61 (2H, m), 1.76-1.87 (4H, m), 2.40 (2H, d, J = 7.1 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.14-3.36 (2H, m), 3.74-4.00 (4H , m), 6.90 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31-7.38 (3H, m), 7.47 (2H, d, J = 8.0 Hz).

Step 2: Preparation of tert-butyl 6- (4-((cyclopropylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- ((Cyclopropylmethyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound. Obtained as a white amorphous.

Example 83 Production of tert-butyl 6- (4-((cyclohexylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- ( Preparation of 4-((cyclohexylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 77 was obtained using bromomethylcyclohexane instead of 1-iodopropane. The same reaction and treatment were performed to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.84-0.98 (2H, m), 1.16-1.30 (3H, m), 1.36-1.73 (15H, m), 1.75-1.89 (6H, m), 2.34 (2H, d, J = 6.8 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.13-3.35 (2H, m), 3.70 (2H, s), 3.78-4.01 (2H, m), 6.90 (1H, d , J = 8.3 Hz), 7.28 (1H, d, J = 1.9 Hz), 7.30-7.36 (3H, m), 7.47 (2H, d, J = 8.1 Hz).

Step 2: Preparation of tert-butyl 6- (4-((cyclohexylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- ( (Cyclohexylmethyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound as a white amorphous Got as.

Example 84 Production of tert-butyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- (4- Production of ((benzylthio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Reaction and treatment were carried out in the same manner as in Example 77 using benzyl bromide instead of 1-iodopropane. The title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.60 (11H, m), 1.78-1.88 (4H, m), 2.85 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.60 -3.66 (4H, m), 3.75-4.00 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 7.24-7.36 (9H, m), 7.48 (2H, d, J = 8.0 Hz).

Step 2: Preparation of tert-butyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4-((benzylthio ) Methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound as a white solid.

Example 85 Production of tert-butyl 6- (4-((pyridin-2-ylmethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl Preparation of 6- (4-((pyridin-2-ylmethyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-chloromethylpyridine instead of 1-iodopropane The reaction and treatment were conducted in a similar manner to Example 77 using the hydrochloride, and the title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.60 (2H, m), 1.78-1.88 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.24-3.32 (2H, m), 3.72 (2H, s), 3.78 (2H, s), 3.82-3.98 (2H, m), 6.90 (2H, d, J = 8.3 Hz), 7.16 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 7.27 (1H, d, J = 2.2 Hz), 7.29-7.36 (4H, m), 7.46 (2H, d, J = 8.3 Hz), 7.63 (1H, dt, J = 1.9, 7.7 Hz), 8.55 (1H , d, J = 4.9 Hz).

Step 2: Preparation of tert-butyl 6- (4-((pyridin-2-ylmethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- ( 4-((Pyridin-2-ylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (22 mg, 0.04 mmol) in isopropanol (0.5 mL) and dichloromethane (0.5 In addition, sodium tungsten (VI) dihydrate (1 mg, 0.004 mmol) and 37% aqueous hydrogen peroxide (16 μL, 0.17 mmol) were added at 0 ° C. and stirred at room temperature overnight. . Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (9 mg, 39%) as a colorless oil.

Example 86 tert-Butyl 6- (4-((Pyridin-3-ylmethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl Preparation of 6- (4-((pyridin-3-ylmethyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3-Bromomethylpyridine instead of 1-iodopropane The reaction and treatment were conducted in a similar manner to Example 77 using hydrobromide, and the title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.55 (2H, ddd, J = 13.0, 12.8, 4.9 Hz), 1.81-1.86 (4H, m), 2.85 (2H, t, J = 6.8 Hz), 3.18-3.33 (2H, m), 3.60 (2H, s), 3.63 (2H, s), 3.77-3.95 (2H, m), 6.90 (1H, d, J = 8.3 Hz), 7.20- 7.36 (5H, m), 7.48 (2H, d, J = 8.3 Hz), 7.61-7.67 (1H, m), 8.47-8.51 (2H, m).

Step 2: Preparation of tert-butyl 6- (4-((pyridin-3-ylmethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- ( 4-((Pyridin-3-ylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (30 mg, 0.06 mmol) in methanol (2.0 mL) and ethyl acetate ( 0.5 mL), hexaammonium heptamolybdate tetrahydrate (1 mg, 0.004 mmol) and 37% aqueous hydrogen peroxide (0.2 mL) were added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 1: 3) to give the title compound (27 mg, 79%) as a white solid.

Example 87 Production of tert-butyl 6- (4-((pyridin-4-ylmethyl) sulfonyl) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl Preparation of 6- (4-((pyridin-4-ylmethyl) thio) methyl] phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4-bromomethylpyridine instead of 1-iodopropane The reaction and treatment were conducted in a similar manner to Example 77 using the hydrobromide, and the title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.62 (11H, m), 1.78-1.89 (4H, m), 2.85 (2H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.57 (2H, s), 3.63 (2H, s), 3.80-4.00 (2H, m), 6.91 (1H, d, J = 8.6 Hz), 7.20-7.36 (6H, m), 7.48 (2H, d, J = 8.0 Hz), 8.54 (2H, d, J = 5.9 Hz).

Step 2: Preparation of tert-butyl 6- (4-((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- ( 4-((Pyridin-4-ylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 2 of Example 86. The title compound was obtained as a white solid.

Example 88 Preparation of cyclopropylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chromene-2,4'-piperidine] -1'-carboxylate 2,2,2-trifluoroethyl 1H- The reaction and treatment were conducted in the same manner as in Example 29 using cyclopropylmethyl 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate to give the title compound as a white amorphous.

Example 89 Preparation of cyclobutylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2,2,2-trifluoroethyl 1H- The reaction and treatment were conducted in the same manner as in Example 29 using cyclobutylmethyl 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 90 Preparation of (1-methylcyclopropyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2- Using (1-methylcyclopropyl) methyl 1H-imidazole-1-carboxylate instead of trifluoroethyl 1H-imidazole-1-carboxylate, the reaction and treatment were carried out in the same manner as in Example 29 to give the title compound as a white amorphous Got as.

Example 91 Preparation of 1-methylcyclobutyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trifluoroethyl The reaction and treatment were conducted in the same manner as in Example 29 using 1-methylcyclobutyl 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 92 Preparation of 1-methylcyclopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trifluoroethyl The reaction and treatment were conducted in the same manner as in Example 29 using 1-methylcyclopropyl 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 93 Preparation of (trimethylsilyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trifluoroethyl 1H -The reaction and treatment were conducted in the same manner as in Example 29 using (trimethylsilyl) methyl 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 94 Production of tert-butyl 6- (5-((methylsulfonyl) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6 Preparation of-(5- (hydroxymethyl) pyrazin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane The reaction and treatment were conducted in a similar manner to process 2 of example 11 using (5-chloropyrazin-2-yl) methanol to obtain the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.58-1.63 (2H, m), 1.79-1.90 (4H, m), 2.89 (2H, t, J = 6.6 Hz), 3.16-3.35 (2H, m), 3.79-4.04 (2H, m), 4.85 (2H, s), 6.96 (1H, d, J = 8.3 Hz), 7.73-7.80 (2H, m), 8.60 (1H, s), 8.90 (1H, s).

Step 2: Preparation of tert-butyl 6- (5-((((methylsulfonyl) oxy) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate under argon atmosphere tert-Butyl 6- (5- (hydroxymethyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (29 mg, 0.07 mmol), triethylamine (30 μL, 0.21 mmol) Methanesulfonyl chloride (10 μL, 0.11 mmol) was slowly added dropwise at 0 ° C. to an anhydrous methylene chloride solution (1.4 mL) and stirred at the same temperature for 20 minutes. The reaction was stopped by adding water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (65 mg, crude) as a yellow amorphous.

Step 3: tert-butyl 6- (5-((methylsulfonyl) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-under argon atmosphere (5-(((Methylsulfonyl) oxy) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (35 mg, crude) in anhydrous dimethyl sulfoxide (1.4 mL ) Was added sodium methanesulfinate (28 mg, 0.28 mmol), and the mixture was stirred at 120 ° C. for 1 hour. Water was added to stop the reaction, and the mixture was extracted with diethyl ether. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 100: 1) to give the title compound (22 mg, 65% for 2 steps). Obtained as a white amorphous.

Example 95 Production of tert-butyl 6- (6-((methylsulfonyl) methyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6 Preparation of-(6- (hydroxymethyl) pyridazin-3-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane The reaction and treatment were carried out using (6-chloropyridazin-3-yl) methanol in the same manner as in Step 2 of Example 11 to obtain the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.55-1.59 (2H, m), 1.84-1.86 (4H, m), 2.89 (2H, t, J = 6.8 Hz), 3.17-3.32 (2H, m), 3.48-3.61 (1H, m), 3.80-4.01 (2H, m), 4.98 (2H, s), 6.97 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.74-7.82 (2H, m), 7.89 (1H, s).

Step 2: Preparation of tert-butyl 6- (6-(((methylsulfonyl) oxy) methyl) pyridazin-3-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in Step 1 Tert-Butyl 6- (6- (hydroxymethyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate as in Step 2 of Example 94 Reaction and treatment gave the title compound as a yellow amorphous.

Step 3: Preparation of tert-butyl 6- (6-((methylsulfonyl) methyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 Step 3 of Example 94 using 6-butyl 6- (6-(((methylsulfonyl) oxy) methyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The title compound was obtained as a yellow amorphous product.

Example 96 Preparation of tert-butyl 6- (5-((methylsulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: tert-butyl 6 Preparation of-(5- (hydroxymethyl) pyrimidin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane Using (2-chloropyrimidin-5-yl) methanol, reaction and treatment were carried out in the same manner as in Step 2 of Example 11 to obtain the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.55 (2H, td, J = 12.8, 4.6 Hz), 1.79-1.88 (4H, m), 2.88 (2H, t, J = 6.6 Hz ), 3.16-3.32 (2H, m), 3.77-4.02 (2H, m), 4.74 (2H, s), 6.93 (1H, d, J = 8.3 Hz), 8.15-8.21 (2H, m), 8.74 ( 2H, s).

Step 2: Preparation of tert-butyl 6- (5-((((methylsulfonyl) oxy) methyl) pyrimidin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in Step 1 Tert-Butyl 6- (5- (hydroxymethyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate as in step 2 of Example 94 Reaction and treatment gave the title compound as a yellow amorphous.

Step 3: Preparation of tert-butyl 6- (5-((methylsulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 Step 3 of Example 94 using 6-butyl 6- (5-(((methylsulfonyl) oxy) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The title compound was obtained as a yellow amorphous product.

Example 97 Preparation of tert-butyl 6- (4-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: tert-butyl 6 Preparation of-(4- (hydroxymethyl) thiazol-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane (4-Bromothiazol-2-yl) methanol was used for reaction and treatment in the same manner as in Step 2 of Example 11 to obtain the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.52-1.59 (2H, m), 1.78-1.87 (4H, m), 2.36-2.38 (1H, br m), 2.84 (2H, t , J = 6.8 Hz), 3.14-3.36 (2H, m), 3.80-4.04 (2H, m), 4.80 (2H, s), 6.88 (1H, d, J = 8.3 Hz), 7.09 (1H, s) , 7.63-7.71 (2H, m).

Step 2: Preparation of tert-butyl 6- (4-(((methylsulfonyl) oxy) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Step 1 Tert-Butyl 6- (4- (hydroxymethyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate as in step 94 of Example 94 Reaction and treatment gave the title compound as a yellow amorphous.

Step 3: Preparation of tert-butyl 6- (4-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 -Similar to Step 3 of Example 94 using 6- (4-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Reaction and treatment gave the title compound as a yellow amorphous.

Example 98 Production of tert-butyl 6- (5-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6 Preparation of-(5- (hydroxymethyl) thiazol-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane (2-Bromothiazol-5-yl) methanol was used for reaction and treatment in the same manner as in Step 2 of Example 11 to obtain the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.62 (11H, m), 1.75-1.89 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.16-3.24 (2H, m), 3.77 -4.02 (2H, m), 4.87 (2H, s), 6.88 (1H, d, J = 8.6 Hz), 7.58-7.71 (3H, m).

Step 2: Preparation of tert-butyl 6- (5-((((methylsulfonyl) oxy) methyl) thiazol-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in Step 1 Tert-Butyl 6- (5- (hydroxymethyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate as in Step 94 of Example 94 Reaction and treatment gave the title compound as a yellow amorphous.

Step 3: Preparation of tert-butyl 6- (5-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 -Similar to Step 3 of Example 94 using 6- (5-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Reaction and treatment gave the title compound as a white solid.

Example 99 Preparation of tert-butyl 6- (2-((methylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6 Preparation of-(2- (hydroxymethyl) thiazol-5-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane (5-Bromothiazol-2-yl) methanol was used for the reaction and treatment in the same manner as in Step 2 of Example 11 to obtain the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.78-1.87 (4H, m), 2.81 (2H, t, J = 6.6 Hz), 3.15-3.32 (2H, m), 3.80-3.98 (2H, m), 4.93 (2H, s), 6.86 (1H, d, J = 8.3 Hz), 7.21-7.31 (2H, m), 7.75 (1H, s).

Step 2: Preparation of tert-butyl 6- (2-(((methylsulfonyl) oxy) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-Butyl 6- (2- (hydroxymethyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate as in Step 2 of Example 94 Reaction and treatment gave the title compound as a yellow amorphous.

Step 3: tert-Butyl 6- (2-((Methylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 -Butyl 6- (2-(((methylsulfonyl) oxy) methyl) thiazol-5-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate and The same reaction and treatment were performed to obtain the title compound as a yellow amorphous.

Example 100 tert-butyl 6- (5-((methylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: Preparation of tert-butyl 6-cyanospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-cyanospiro (chroman-2) obtained in Example 3 under an argon atmosphere , 4′-piperidine) -1′-carboxylate (300 mg, 0.78 mmol) and zinc cyanide (184 mg, 1.57 mmol) in N-methylpyrrolidone solution (4 ml), tetrakistriphenylphosphine palladium (0) ( 91 mg, 0.078 mmol) was added, and the mixture was stirred at 140 ° C. for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound (141 mg, 55%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.52-1.64 (2H, m), 1.74-1.86 (4H, m), 2.80 (2H, t, J = 6.9 Hz), 3.11-3.27 (2H, m), 3.79-4.00 (2H, br), 6.88 (1H, d, J = 9.2 Hz), 7.37-7.41 (2H, m).

Step 2: Preparation of tert-butyl 6- (N′-hydroxycarbamimidoyl) spiro (chroman-2,4′-piperidine) -1′-carboxylate tert-butyl 6-cyanospiro obtained in Step 1 ( To a solution of chroman-2,4′-piperidine) -1′-carboxylate (165 mg, 0.50 mmol) in ethanol (6 mL) was added hydroxyamine hydrochloride (105 mg, 1.51 mmol) and sodium bicarbonate (127 mg, 1.51 mmol). ) And stirred at 75 ° C. for 4 hours. Ethanol was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (155 mg).

Step 3: Preparation of tert-butyl 6- (5- (acetoxymethyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Under cooling, tert-butyl 6- (N′-hydroxycarbamimidoyl) spiro (chroman-2,4′-piperidine) -1′-carboxylate (30 mg, 0.08 mmol) obtained in Step 2 in dichloromethane (0.8 mL) To the solution were added pyridine (20 μL, 0.25 mmol) and acetoxyacetic chloride (11 mg, 0.08 mmol), and the mixture was stirred at room temperature for 2 hours, after which the solvent was distilled off. Toluene (0.5 mL) was added to the obtained residue, and the mixture was heated to reflux for 12 hours. After toluene was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (8.8 mg, 24%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.43-1.64 (11H, m), 1.76-1.88 (4H, m), 2.82-2.88 (2H, m), 2.22 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.14-3.32 (2H, m), 3.86-4.00 (2H, m), 5.33 (2H, s), 6.92 (1H, d, J = 9.0 Hz), 7.78-7.84 (2H, m ).

Step 4: Production of tert-butyl 6- (5- (hydroxymethyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-butyl 6- (5- (acetoxymethyl) -1,2,4-oxadiazol-3-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate obtained in 3 To a solution of 34 mg, 0.08 mmol) in methanol (1.5 mL) was added potassium carbonate (106 mg, 0.77 mmol), and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, water was added to the resulting residue and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (25 mg, 81%) as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.51-1.62 (2H, m), 1.76-1.86 (4H, m), 2.80-2.86 (2H, m), 3.17-3.32 (2H, m), 3.80-3.94 (2H, m), 4.93 (2H, s), 6.91 (1H, d, J = 9.6 Hz), 7.78-7.84 (2H, m).

Step 5: tert-Butyl 6- (5-(((methylsulfonyl) oxy) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate tert-Butyl 6- (5- (hydroxymethyl) -1,2,4-oxadiazol-3-yl) spiro (chroman-2,4 ') obtained in Step 4 under ice cooling -Piperidine) -1'-carboxylate (25 mg, 0.06 mmol) in dichloromethane (2.0 mL) was added triethylamine (26 μL, 0.19 mmol) and methanesulfonyl chloride (7 μL, 0.09 mmol), and then at room temperature for 1 hour. Stir. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (30 mg).

Step 6: tert-Butyl 6- (5-((methylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-butyl 6- (5-(((methylsulfonyl) oxy) methyl) -1,2,4-oxadiazol-3-yl) spiro (chroman-2,4′-) obtained in Step 5 Using piperidine) -1′-carboxylate, the reaction and treatment were conducted in the same manner as in Step 3 of Example 94 to obtain the title compound as a white amorphous.

Example 101 Production of tert-butyl 7-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 7 -Production of fluoro-4-oxospiro (chroman-2,4'-piperidine) -1'-carboxylate Reaction was carried out in the same manner as in Step 1 of Example 1 using commercially available 4'-fluoro-2'-hydroxyacetophenone. Treatment gave the title compound as a colorless oil.

Step 2: Preparation of tert-butyl 7-fluorospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 7-fluoro-4-oxospiro [chroman-2,4 obtained in step 1 The reaction and treatment were conducted in the same manner as in Step 1 of Example 3 using '-piperidine] -1'-carboxylate to obtain the title compound as a colorless oil.

Step 3: Preparation of tert-butyl 6-bromo-7-fluorospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 7-fluorospiro (chroman-2, obtained in step 2) N-bromosuccinimide (1.1 g, 6.35 mmol) was added to a solution of 4′-piperidine) -1′-carboxylate (1.7 g, 5.29 mmol) in N, N-dimethylformamide (14 mL) at 30 ° C. for 30 minutes. Stir for minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the title compound (1.79 g, 84%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.58 (11H, m), 1.74-1.84 (4H, m), 2.73 (2H, t, J = 6.8 Hz), 3.08-3.24 (2H, m), 3.76 -3.98 (2H, m), 6.63 (1H, d, J = 10.0 Hz), 7.21 (1H, d, J = 7.6 Hz).

Step 4: Preparation of tert-butyl 7-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 3 -Butyl 6-bromo-7-fluorospiro (chroman-2,4'-piperidine) -1'-carboxylate (46 mg, 0.11 mmol) and 4,4,5,5-tetramethyl-2- (4 -((Methylsulfonyl) methyl) phenyl) -1,3,2-dioxaborane (41 mg, 0.14 mmol) dissolved in ethylene glycol dimethyl ether (2 mL) and sodium carbonate (122 mg, 1.15 mmol) in water (1 mL) was added, tetrakistriphenylphosphine palladium (0) (13 mg, 0.011 mmol) was added, and the mixture was stirred at 90 ° C. for 12 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (42 mg, 75%) as a white amorphous.

Example 102 Preparation of tert-butyl 7-fluoro-6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Example 101 Tert-butyl 6-bromo-7-fluorospiro [chroman-2,4′-piperidine] -1′-carboxylate (22 mg, 0.055 mmol) and 2- (3-fluoro- 4-((methylsulfonyl) methyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborane (21 mg, 0.066 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL) An aqueous solution (1 mL) in which sodium (58 mg, 0.55 mmol) was dissolved was added, tetrakistriphenylphosphine palladium (0) (6 mg, 0.005 mmol) was added, and the mixture was stirred at 90 ° C. for 12 hours. It was 拌. The reaction solution was diluted with ethyl acetate, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (21 mg, 75%) as a pale yellow solid.

Example 103 Preparation of tert-butyl 7-fluoro-6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 7-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Of tert-butyl 6-bromo-7-fluorospiro [chroman-2,4′-piperidine] -1′-carboxylate (235 mg, 0.59 mmol) obtained in Step 3 of Example 101, 1,4 -To dioxane (4 mL) solution, bis (pinacolato) diborane (179 mg, 0.70 mmol), potassium acetate (173 mg, 1.76 mmol) and bis (triphenylphosphine) palladium (II) dichloride (41 mg, 0.059 mmol) was added, and the mixture was stirred at 90 ° C. for 12.5 hours under an argon atmosphere. Insoluble material was removed by filtration, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the title compound (67 mg, 25%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (12H, s), 1.40-1.58 (11H, m), 1.72-1.84 (4H, m), 2.74 (2H, t, 6.4 Hz), 3.10-3.26 (2H , m), 3.76-3.96 (2H, m), 6.52 (1H, d, J = 10.4 Hz), 7.44 (1H, d, J = 6.8 Hz).

Step 2: Preparation of tert-butyl 7-fluoro-6- (5- (hydroxymethyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Step 1 tert-Butyl 7-fluoro-6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate Reaction and treatment were conducted in the same manner as in Step 1 to obtain the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.61 (2H, m), 1.75-1.85 (4H, m), 2.82 (2H, t, J = 6.8 Hz), 3.14-3.28 (2H, m), 3.78-3.98 (2H, m), 4.75 (2H, s), 6.65 (1H, d, J = 12.8 Hz), 7.55 (1H, d, J = 10.0 Hz), 7.63-7.72 ( 2H, m), 8.64 (1H, s).

Step 3: Preparation of tert-butyl 7-fluoro-6- (5-(((methylsulfonyl) oxy) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Performed using tert-butyl 7-fluoro-6- (5- (hydroxymethyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate obtained in step 2. Reaction and treatment were carried out in the same manner as in Step 2 of Example 94 to obtain a crude product.

Step 4: Preparation of tert-butyl 7-fluoro-6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate In Step 3 Using the resulting tert-butyl 7-fluoro-6- (5-(((methylsulfonyl) oxy) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Then, the reaction and treatment were carried out in the same manner as in Step 3 of Example 94 to obtain a white amorphous.

Example 104 Production of tert-butyl 3-hydroxy-6- [4-{(methylsulfonyl) methyl} phenyl] spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6 Preparation of bromo-4-hydroxyspiro (chroman-2,4′-piperidine) -1′-carboxylate tert-butyl 6-bromo-4-oxospiro [chroman-2, obtained in step 1 of Example 1 4′-piperidine] -1′-carboxylate (200 mg, 0.505 mmol) was dissolved in methanol (5 mL), sodium borohydride (24.8 mg, 0.656 mmol) was added under ice cooling, and 1 at room temperature. Stir for 5 hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (201 mg, 100%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.51-1.69 (2H, m), 1.75-1.94 (3H, m), 2.12 (1H, dd, J = 6.1, 13.6 Hz), 2.15 (1H, brs), 3.05-3.30 (2H, m), 3.75-3.90 (2H, m), 4.83 (1H, q, J = 6.9 Hz), 6.73 (1H, d, J = 8.8 Hz), 7.29 ( 1H, d, J = 2.4 Hz), 7.57 (1H, d, J = 2.4 Hz).

Step 2: Preparation of tert-butyl 6-bromo-4-chlorospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-4-hydroxyspiro [chroman-2,4′- Piperidine] -1′-carboxylate (200 mg, 0.505 mmol) was dissolved in dichloromethane (5 mL), and mesyl chloride (86.3 mg, 0.753 mmol) and triethylamine (76.2 mg, 0.753 mmol) were added under ice-cooling. For 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow amorphous.

Step 3: Preparation of tert-butyl 6-bromospiro [chromene-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-4-chlorospiro [chroman-2,4′-piperidine] -1 ′ -Carboxylate (239 mg, 0.505 mmol) was melt | dissolved in N-methylpyrrolidone (2 mL), DBU (84.1 mg, 0.552 mmol) was added, and it stirred at 100 degreeC for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (191 mg, 100%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.65 (2H, m), 1.90-2.00 (2H, m), 3.20-3.35 (2H, m), 3.80-3.90 (2H, m), 5.59 (1H, d, J = 9.8 Hz), 6.33 (1H, d, J = 9.8 Hz), 6.71 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 2.4 Hz) , 7.20 (1H, dd, J = 2.4, 8.8Hz).

Step 4: Preparation of tert-butyl 1a, 7b-dihydrospiro (oxyleno [2,3-c] chromene-2,4′-piperidine) -1′-carboxylate tert-butyl 6-bromospiro [chromene-2,4 '-Piperidin] -1'-carboxylate (70.0 mg, 0.184 mmol) was dissolved in dichloromethane (2 mL), and under ice cooling, methachloroperbenzoic acid (47.6 mg, 0.276 mmol) and sodium hydrogen carbonate (30.9 mg, 0.368 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (44.5 mg, 61%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.54-1.66 (2H, m), 1.81 (1H, dt, J = 4.9, 13.0 Hz), 2.06 (1H, dd, J = 1.7, 10.2 Hz), 2.95-3.10 (1H, m), 3.20-3.35 (1H, m), 3.43 (1H, d, J = 4.4 Hz), 3.84 (1H, d, J = 4.4 Hz), 3.90-4.10 ( 2H, m), 6.75 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 2.4, 8.6 Hz), 7.47 (1H, d, J = 2.4 Hz).

Step 5: Preparation of tert-butyl 6-bromo-3-hydroxyspiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 1a, 7b-dihydrospiro (oxyleno [2,3-c] Chromene-2,4′-piperidine) -1′-carboxylate (44.0 mg, 0.111 mmol) was dissolved in tetrahydrofuran (1 mL), and lithium aluminum hydride (4.06 mg, 0.122 mmol) was added under ice cooling. Stir at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, filtered through celite, the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (39.5 mg, 89%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.54-1.65 (3H, m), 1.95-2.30 (1H, m), 1.97 (1H, dd, J = 2.4, 13.9 Hz), 2.77 (1H, dd, J = 4.9, 17.3 Hz), 3.03 (1H, dd, J = 4.9, 17.3 Hz), 2.95-3.20 (2H, m), 3.74-3.75 (1H, m), 3.80-4.05 (2H , m), 6.77 (1H, d, J = 8.5 Hz), 7.20-7.24 (2H, m).

Step 6: Preparation of the preparation of tert-butyl 3-hydroxy-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- Instead of bromospiro [chroman-2,4′-piperidine] -1′-carboxylate, tert-butyl 6-bromo-3-hydroxyspiro (chroman-2,4′-piperidine) -1′-carboxylate is replaced with 4 , 4,5,5-tetramethyl-2- [4-((methylthio) methyl) phenyl) -1,3,2-dioxaborate instead of 4,4,5,5-tetramethyl-2- [4- Using {(methylsulfonyl) methyl} phenyl] -1,3,2-dioxaborane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 3 to obtain the title compound (14.0 mg, 33%). It was obtained as a Ilona crystal form solid.

Example 105 Production of tert-butyl 6- [4-{(methylsulfonyl) methyl} phenyl] -3-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- Preparation of bromo-3-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-3-hydroxyspiro [chroman-2,4′-piperidine] -1′-carboxylate (20.0 mg, 0.050 mmol) was dissolved in dichloromethane (0.5 mL), des Martin periodinane (31.9 mg, 0.075 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (18.4 mg, 93%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.62-1.69 (2H, m), 1.84-1.90 (2H, m), 3.10-3.30 (2H, m), 3.58 (2H, s) , 3.90-4.10 (2H, m), 6.94 (1H, d, J = 8.5 Hz), 7.25-7.26 (1H, m), 7.35 (1H, dd, J = 1.9, 8.5 Hz).

Step 2: Preparation of tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) -3-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-3 -Oxospiro [chroman-2,4'-piperidine] -1'-carboxylate was reacted and treated in the same manner as in Step 6 of Example 104 to give the title compound (6.50 mg, 29%) as a white light yellow amorphous Got as.

Example 106 Production of tert-butyl 4,4-dideuterio-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 1: tert- Preparation of butyl 6-bromo-4-deuterio-4-hydroxyspiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-4-oxospiro [chroman-2,4′-piperidine ] Sodium deuteride (11 mg, 0.27 mmol) was slowly added to a methanol solution (1.4 mL) of -1'-carboxylate (100 mg, 0.27 mmol) at room temperature. After stirring for 1 hour, water was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (108 mg,) as a pale yellow oil.

Step 2: Preparation of tert-butyl 6-bromo-4-chloro-4-deuteriospiro [chroman-2,4'-piperidine] -1'-carboxylate tert-butyl 6-bromo-4- under argon atmosphere Deuterio-4-hydroxyspiro [chroman-2,4′-piperidine] -1′-carboxylate (d1) (108 mg, Crude) in triethylamine (75 μL, 0.54 mmol) in anhydrous methylene chloride (1 mL) Methanesulfonyl chloride (46 mg, 0.41 mmol) was added slowly at 0 ° C. After stirring at room temperature for 5 hours, water was added and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a pale yellow oil.

Step 3: Preparation of tert-butyl 6-bromo-4,4-dideuteriospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-4-chloro-4-de Teriospiro [chroman-2,4′-piperidine] -1′-carboxylate (d1) (86 mg, 0.21 mmol), nickel chloride hexahydrate (73 mg, 0.31 mmol) in methanol (1 mL) Sodium deuteride borohydride (39 mg, 0.93 mmol) was added and stirred overnight at room temperature. The residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (22 mg, 28%) as a white solid.

Step 4: Preparation of tert-butyl 4,4-dideuterio-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- Bromo-4,4-dideuteriospiro [chroman-2,4′-piperidine] -1′-carboxylate (20 mg, 0.052 mmol) and 4,4,5,5-tetramethyl-2- (4 -((Methylsulfonyl) methyl) phenyl) -1,3,2-dioxaborane (23 mg, 0.078 mmol) was dissolved in 1,4-dioxane (0.8 mL) and sodium carbonate (28 mg, 0.26 mmol) was dissolved. Aqueous solution (0.2 mL) was added, tetrakistriphenylphosphine palladium (0) (6 mg, 0.005 mmol) was added, and the mixture was stirred at 90 ° C. for 18 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (chloroform: ethyl acetate = 6: 1) to give the title compound (11 mg, 44%) as a white amorphous.

Example 107 Production of tert-butyl 4-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-butyl 6- Preparation of (4-((methylsulfonyl) methyl) phenyl) -4-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6-bromo-4,4-dideteriospiro [ Example 106 using tert-butyl 6-bromo-4-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate instead of chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Step 4 to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 4-hydroxy-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- To a solution of ((methylsulfonyl) methyl) phenyl) -4-oxospiro [chroman-2,4′-piperidine] -1′-carboxylate (121 mg, 0.25 mmol) in methanol (2.5 mL), sodium borohydride (10 mg, 0.25 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the obtained residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (121 mg, quant) as a white amorphous.

Step 3: Preparation of tert-butyl 4-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 4 under argon atmosphere Dexo fluor (40 μL) was added to a solution of -hydroxy-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate (30 mg, 0.061 mmol) in methylene chloride. ) And stirred at room temperature for 10 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (22 mg, 73%) as a white amorphous.

Example 108 Preparation of tert-butyl 6- (3-cyano-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3- Using 5-bromo-2-((methylsulfonyl) methyl) benzonitrile in place of fluorobenzyl) (methyl) sulfane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 11 to give the title compound as a colorless oil Obtained.

Example 109 Preparation of 2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: S-4 -(Spiro [chroman-2,4'-piperidin] -yl) benzyl ethanethioate hydrochloride tert-butyl 6- (4-((acetylthio) methyl) phenyl) spiro [chroman-2,4 obtained in Example 76 '-Piperidine] -1'-carboxylate (49 mg, 0.10 mmol) was dissolved in dichloromethane (0.5 mL), 4N hydrochloric acid / ethyl acetate solution (0.5 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated to obtain a crude product of S-4- (spiro [chroman-2,4′-piperidin] -yl) benzyl ethanethioate hydrochloride.

Step 2: Preparation of 2,2,2-trichloroethyl 6- (4-((ethylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate S obtained in Step 1 -4- (Spiro [chroman-2,4′-piperidin] -yl) benzyl Ethanethioate hydrochloride was reacted and treated in the same manner as in Example 30 to obtain the title compound as a white solid.

Step 3: Preparation of 2,2,2-trichloroethyl 6- (4-((ethylthio) methyl) phenyl) spirochroman-2,4'-piperidine] -1'-carboxylate 2,2 obtained in Step 2 , 2-Trichloroethyl 6- (4-((ethylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (30 mg, 0.06 mmol) in methanol (0.3 mL) and tetrahydrofuran (0.3 mL), 1-iodomethane (10 μL, 0.13 mmol) and 6 N aqueous sodium hydroxide solution (0.05 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound (22 mg, 74%) as a white amorphous.

Step 4: Preparation of 2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2- To a solution of trichloroethyl 6- (4-((ethylthio) methyl) phenyl) spirochroman-2,4′-piperidine] -1′-carboxylate (21 mg, 0.040 mmol) in methylene chloride (1 mL) was added metachloroperbenzoic acid. (30 mg, 0.122 mmol) was slowly added at 0 ° C. and stirred overnight. An aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel preparative thin-layer chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (14 mg, 61%) as a white amorphous Got as.

Example 110 Preparation of tert-butyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo- Using 5-bromo-2-((ethylsulfonyl) methyl) -1,3-difluorobenzene instead of 3-fluorobenzyl) (methyl) sulfane, the reaction and treatment were carried out in the same manner as in Step 2 of Example 11, The title compound was obtained as a white amorphous.

Example 111 Preparation of 2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: Preparation of 6- (4-((Ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] hydrochloride tert-Butyl obtained in Example 110 6 (4-((Ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate is reacted and treated in the same manner as in Step 1 of Example 109. To obtain a crude hydrochloride salt.

Step 2: Preparation of 2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The crude product of 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in Step 1 was treated with 6- (3,5- Difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride was used in place of the crude product and reacted and treated in the same manner as in Example 63 to give the title compound as a white amorphous Got as.

Example 112 Preparation of neopentyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trichloro The reaction and treatment were conducted in the same manner as in Step 2 of Example 111 using neopentyl chloroformate instead of ethyl chloroformate to obtain the title compound as a white amorphous.

Example 113 Preparation of 2,2,2-trichloroethyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Step 1: 2, Preparation of 2,2-trichloroethyl 6- (4-((isopropylthio) methyl) phenyl) spirochroman-2,4'-piperidine] -1'-carboxylate Performed using 2-iodopropane instead of iodoethane The reaction and treatment were conducted in a similar manner to process 3 of example 109, and the title compound was obtained as a white amorphous.

Step 2: Preparation of 2,2,2-trichloroethyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in Step 1 2,4,2-trichloroethyl 6- (4-((isopropylthio) methyl) phenyl) spirochroman-2,4′-piperidine] -1′-carboxylate and The same reaction and treatment were performed to obtain the title compound as a yellow amorphous.

Example 114 Production of neopentyl 6- (4- (2- (isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: 6- [4-{(2 -(Isopropylsulfonyl) methyl) phenyl} spiro [chroman-2,4'-piperidine] Preparation of hydrochloride tert-butyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [Example 81] Chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain the title compound as a crude hydrochloride salt.

Step 2: Preparation of neopentyl 6- (4- (2- (isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6- (4- (2- (isopropylsulfonyl) ) Methyl) phenyl) spiro [chroman-2,4′-piperidine] The crude hydrochloride salt (10.0 mg, 0.02 mmol) was dissolved in dichloroethane (0.5 mL), triethylamine (16.0 μL, 0.11 mmol), neopentylchloro Formate (5.1 μL, 0.03 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (chloroform: acetone = 100: 1) to obtain the title compound (13.5 mg, quant.) As a white solid.

Example 115 Preparation of tert-butyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3- Using 4-bromo-2-fluoro-1-((isopropylsulfonyl) methyl) benzene in place of fluorobenzyl) (methyl) sulfane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 11, and the title compound was converted into white amorphous Got as.

Example 116 Production Process 1 of 2,2,2-trichloroethyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride tert-butyl 6- (3-fluoro obtained in Example 115 4-((Isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain the hydrochloride salt. Obtained as a crude product.

Step 2: Production of 2,2,2-trichloroethyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1 Using 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in the same manner as in Example 54, The title compound was obtained as a white amorphous.

Example 117 Preparation of tert-butyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo- Using 5-bromo-1,3-difluoro-2-((isopropylsulfonyl) methyl) benzene in place of 3-fluorobenzyl) (methyl) sulfane, the reaction and treatment were carried out in the same manner as in Step 2 of Example 11, The title compound was obtained as a white amorphous.

Example 118 Production step of 2,2,2-trichloroethyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] carboxylate 1: 6 Preparation of-(3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] hydrochloride tert-Butyl 6- (4- ( (Ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain hydrochloride. As a crude product.

Step 2: Preparation of 2,2,2-trichloroethyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The crude product of 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in Step 1 was converted to 6- (3,5- Difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride was used in place of the crude product and reacted and treated in the same manner as in Example 63 to give the title compound as a white amorphous Got as.

Example 119 Preparation of neopentyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trichloro The reaction and treatment were conducted in a similar manner to process 2 of example 118 using neopentyl chloroformate instead of ethyl chloroformate, and the title compound was obtained as a white solid.

Example 120 Production of tert-butyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate Step 1: tert-butyl 6 Preparation of-(5-((acetylthio) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate tert-Butyl obtained in Step 1 of Example 15 6- (5- (hydroxymethyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (0.28 g, 0.69 mmol) and triethylamine (0.13 mL, 0.90 mmol) in tetrahydrofuran (2.9 To the solution, methanesulfonyl chloride (48.3 μL, 0.76 mmol) was added and stirred at room temperature for 1 hour. The precipitated salt was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (3.5 mL), S-potassium thioacetate (0.12 g, 1.04 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound (0.2 g, 62%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.54-1.60 (2H, m), 1.78-1.88 (4H, m), 2.37 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.78-4.00 (2H, m), 4.12 (2H, s), 6.91 (1H, d, J = 8.8 Hz), 7.56-7.78 (4H, m), 8.55 (1H, d, J = 2.0 Hz).

Step 2: Preparation of tert-butyl 6- (5-((isopropylthio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (5 -((Acetylthio) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate (35 mg, 0.08 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) 2-iodopropane (11.2 μL, 0.11 mmol) and 1N aqueous sodium hydroxide solution (0.25 mL) were added to the solution, and the mixture was stirred at room temperature for 13.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound (15.8 mg, 45%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.4 Hz), 1.47 (9H, s), 1.50-1.60 (2H, m), 1.80-1.88 (4H, m), 2.74-2.90 (3H, m), 3.18-3.34 (2H, m), 3.75 (2H, s), 3.80-4.00 (2H, m), 6.92 (1H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 7.66-7.74 (2H, m), 7.77 (1H, d, J = 2.4 Hz), 8.54 (1H, d, J = 2.0 Hz).

Step 3: Preparation of tert-butyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (5 -((Isopropylthio) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate (15.8 mg, 0.034 mmol) in methanol (0.5 mL) and ethyl acetate (0.5 mL) ) Hexammonium hexamolybdate tetrahydrate (8.4 mg, 0.007 mmol) and 30% aqueous hydrogen peroxide (68 μL) were added to the solution, and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (5/1). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the title compound (15.5 mg, 91%) as a white solid.

Example 121 Step 1, Production of 2,2,2-trichloroethyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate : Preparation of 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride tert-Butyl obtained in Example 120 6- (5- ((Isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain the dihydrochloride salt. As a crude product.

Step 2: Preparation of 2,2,2-trichloroethyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4'-piperidine) -1'-carboxylate Step 1 The crude product of 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in 1 above was converted to 6- (3,5-difluoro-4 -((Methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] hydrochloride was used in place of the crude product and reacted and treated in the same manner as in Example 63 to obtain the title compound as a white solid. .

Example 122 Preparation of neopentyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in the same manner as in Step 2 of Example 121 using neopentyl chloroformate instead of formate to obtain the title compound as a white amorphous.

Example 123 Preparation of 1-methylcyclopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Under an argon atmosphere, 6 -(5-((Isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] hydrochloride (4 mg, 0.002 mmol), 1-methylcyclopropyl 1H-imidazole-1-carboxyl Rate (2 mg, 0.012 mmol), N, N-diisopropylethylamine (30 μL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at 80 ° C. overnight. Water was added, extracted with chloroform, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 50: 1) to give the title compound (1 mg, 23%) was obtained as a white amorphous.

Example 124 1,1,1-trifluoropropan-2-yl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxy Example 1 Using 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate instead of 1-methylcyclopropyl 1H-imidazole-1-carboxylate Example The reaction and treatment were conducted in the same manner as in 123 to give the title compound as a pale brown amorphous.

Example 125 Preparation of tert-butyl 6- (4-(((2-fluoroethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate Step 1: tert-Butyl 6 Preparation of-(4-(((2-fluoroethyl) thio) methyl) phenyl) spiro [chroman-2,4-piperidine] -1'-carboxylate 2-Fluoroethyl methanesulfonate instead of 1-iodopropane Were used and reacted in the same manner as in Step 1 of Example 77 to obtain the title compound as white amorphous.

Step 2: Preparation of tert-butyl 6- (4-(((2-fluoroethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate tert-butyl 6- (4 -(((2-Fluoroethyl) thio) methyl) phenyl) spiro [chroman-2,4-piperidine] -1'-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3, and the title The compound was obtained as a white amorphous.

Example 126 Production of tert-butyl 6- (4-(((cyanomethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6- ( Preparation of 4-(((cyanomethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step of Example 77 using bromoacetonitrile instead of 1-iodopropane The reaction and treatment were conducted in the same manner as in 1 to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (4-(((cyanomethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (4- ( ((Cyanomethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to give the title compound as a white amorphous Got as.

Example 127 Preparation of tert-butyl 6- (5-(((cyanomethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert- Preparation of 6- (5-((acetylthio) methyl) pyrimidin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate tert-Butyl obtained in Step 1 of Example 96 6- (5- (hydroxymethyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 120. The title compound was obtained as a brown solid.

Step 2: Preparation of tert-butyl 6- (5-(((cyanomethyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (5-((Acetylthio) methyl) pyrimidin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate (30 mg, 0.06 mmol) in methanol (0.15 mL) and tetrahydrofuran (0.15 mL) ) 2-Bromoacetonitrile (15 mg, 0.13 mmol) and 1N aqueous sodium hydroxide solution (0.05 mL) were added to the solution, and the mixture was stirred at room temperature for 13.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound (20 mg, 67%) as a colorless oil.

Step 3: Preparation of tert-butyl 6- (5-(((cyanomethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Step 2 Step of Example 85 using tert-butyl 6- (5-(((cyanomethyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Reaction and treatment in the same manner as in 2 gave the title compound as a yellow amorphous.

Example 128 2,2,2-Trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate production process 1: 2,2,2-trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) thio) methyl) phenyl) spirochroman-2,4'-piperidine] -1 Production of '-carboxylate Reaction was carried out in the same manner as in Step 3 of Example 109 using 1-iodo-3,3,3-trifluoropropane instead of iodoethane to obtain the title compound as a white amorphous.

Step 2: 2,2,2-Trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate 2,2,2-trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) thio) methyl) phenyl) spirochroman-2,4'-piperidine obtained in step 1 ] -1′-carboxylate was used and reacted in the same manner as in Step 4 of Example 109 to obtain the title compound as a white amorphous.

Example 129 tert-butyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Preparation of rate Using 4-bromo-2-fluoro-1-((((3,3,3-trifluoropropyl) sulfonyl) methyl) benzene in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane In the same manner as in Step 2 of Example 11, the title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.51-1.62 (2H, m), 1.79-1.88 (4H, m), 2.56-2.70 (2H, m), 2.85 (2H, t, J = 6.8 Hz), 3.10-3.16 (2H, m), 3.18-3.31 (2H, m), 3.80-3.99 (2H, m), 4.37 (2H, s), 6.93 (1H, d, J = 8.7 Hz ), 7.29-7.36 (3H, m), 7.41 (1H, dd, J = 1.8, 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz).

Example 130 2,2,2-Trichloroethyl 6- (3-Fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] Step 1: 6- (3-Fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] Preparation of hydrochloride salt tert-butyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4 'obtained in Example 129 -Piperidine] -1'-carboxylate was used for the reaction and treatment in the same manner as in Step 1 of Example 109 to obtain a crude hydrochloride salt.

Step 2: 2,2,2-Trichloroethyl 6- (3-Fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] Preparation of -1′-carboxylate 6- (3-Fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4 ′ obtained in Step 1 -Piperidine] hydrochloride crude was used in place of the crude 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] hydrochloride Reaction and treatment were conducted in the same manner as in Example 63 to obtain the title compound as a white amorphous.

Example 131 Neopentyl 6- (3-Fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation 6- (3-Fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] obtained in Step 1 of Example 130 The crude hydrochloride salt was reacted and treated in the same manner as in Step 2 of Example 114 to obtain the title compound as a white amorphous.

Example 132 tert-butyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' Preparation of carboxylate 5-Bromo-1,3-difluoro-2-(((3,3,3-trifluoropropyl) sulfonyl) methyl instead of (4-bromo-3-fluorobenzyl) (methyl) sulfane ) The reaction and treatment were carried out using benzene in the same manner as in Step 2 of Example 11 to obtain the title compound as a white amorphous.

Example 133 2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'- Step 1: Production of piperidine] -1′-carboxylate 1: 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4 Preparation of '-piperidine] hydrochloride tert-butyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro obtained in Example 132 Chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain a crude hydrochloride salt.

Step 2: 2,2,2-Trichloroethyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'- Preparation of piperidine] -1′-carboxylate 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-] obtained in step 1 The crude 2,4′-piperidine] hydrochloride is converted to the crude 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. Instead, the reaction and treatment were carried out in the same manner as in Example 63 to obtain the title compound as a white amorphous.

Example 134 tert-butyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4'-piperidine) -1'-carboxy Process for producing rate 1: tert-butyl 6- (5-(((3,3,3-trifluoropropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 Production of '-carboxylate Using 1-iodo-3,3,3-trifluoropropane instead of 2-iodopropane, the reaction and treatment were carried out in the same manner as in Step 2 of Example 120, and the title compound was converted into a white amorphous substance. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.54-1.64 (2H, m), 1.80-1.88 (4H, m), 2.28-2.42 (2H, m), 2.58-2.66 (2H, m), 2.87 (3H, t, J = 6.8 Hz), 3.16-3.32 (2H, m), 3.75 (2H, s), 3.80-3.98 (2H, m), 6.92 (1H, d, J = 8.8 Hz ), 7.62-7.72 (3H, m), 7.78 (1H, d, J = 2.0 Hz), 8.54 (1H, d, J = 1.2 Hz).

Step 2: tert-Butyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxy Production of rate Tert-butyl 6- (5-(((3,3,3-trifluoropropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine obtained in step 1 ] -1′-Carboxylate was used for reaction and treatment in the same manner as in Step 2 of Example 85 to obtain the title compound as a light brown solid.

Example 135 Neopentyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Production Step 1: Production of 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) dihydrochloride Examples Tert-butyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylate was used for reaction and treatment in the same manner as in Step 1 of Example 109 to obtain a dihydrochloride crude product.

Step 2: Neopentyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) dihydrochloride obtained in Step 1 Step 2 of Example 114 using the crude in place of the crude 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. The reaction and treatment were conducted in a similar manner to give the title compound as a white solid.

Example 136 1-methylcyclopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Preparation of carboxylate 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 obtained in Step 1 of Example 135 The crude product of '-piperidine] dihydrochloride was reacted and treated in the same manner as in Example 123 to obtain the title compound as a pale yellow oil.

Example 137 1-cyclopropylethyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate The reaction and treatment were conducted in the same manner as in Example 136 using 1-cyclopropylethyl 1H-imidazole-1-carboxylate instead of 1-methylcyclopropyl 1H-imidazole-1-carboxylate. The compound was obtained as a brown oil.

Example 138 1,1,1-trifluoropropan-2-yl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, Preparation of 4′-piperidine] -1′-carboxylate 1,1,1-trifluoropropan-2-yl 1H-imidazole-1-carboxylate instead of 1-methylcyclopropyl 1H-imidazole-1-carboxylate Was used in the same manner as in Example 136 to give the title compound as a pale yellow amorphous product.

Example 139 Preparation of tert-butyl 6- (4-(((3-hydroxypropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate Step 1: tert-butyl 6 Preparation of-(4-(((3-hydroxypropyl) thio) methyl) phenyl) spiro [chroman-2,4-piperidine] -1'-carboxylate 3-bromo-1-propanol instead of 1-iodopropane Was used in the same manner as in Step 1 of Example 77 to give the title compound as a white solid.

Step 2: Preparation of tert-butyl 6- (4-(((3-hydroxypropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate tert obtained in Step 1 -Butyl 6- (4-(((3-hydroxypropyl) thio) methyl) phenyl) spiro [chroman-2,4-piperidine] -1'-carboxylate as in step 2 of example 85 Reaction and treatment gave the title compound as a white solid.

Example 140 Preparation of tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-((((3-hydroxypropyl) thio) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate of 2-iodopropane Instead, 3-bromo-1-propanol was used and reacted and treated in the same manner as in Step 2 of Example 120 to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate tert-butyl Performed with 6- (5-(((3,3,3-trifluoropropyl) thio) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 2 of example 85, and the title compound was obtained as a white amorphous substance.

Example 141 Preparation of Isopropyl 6- (5-((((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate 1: 6- Preparation of (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride tert-Butyl obtained in Example 140 6- (5 -(((3-Hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate is reacted and treated in the same manner as in Step 1 of Example 109. And obtained as a crude product of dihydrochloride.

Step 2: Preparation of isopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate obtained in Step 1 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride (10.0 mg, 0.02 mmol) was converted to dichloroethane ( 0.5 mL) and N, N-dimethylformamide (0.5 mL), N, N-diisopropylethylamine (20 μL, 0.11 mmol) and isopropyl chloroformate (3.0 mg, 0.024 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (chloroform: methanol = 9: 1) to give the title compound (7 mg, 63%) as a white amorphous product.

Example 142 Preparation of Isobutyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate Step of Example 141 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride obtained in 1 (10.0 mg, 0.02 mmol) ) Is dissolved in N, N-dimethylformamide (0.5 mL), N, N-diisopropylethylamine (20.0 μL, 0.11 mmol), isobutyl 1H-imidazole-1-carboxylate (9.0 mg, 0.04 mmol) is added, and 80 is added. Stir at 12 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (chloroform: methanol = 9: 1) to give the title compound (5.0 mg, 45%) as a white amorphous product.

Example 143 Preparation of neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Instead, neopentyl chloroformate was used and reacted and treated in the same manner as in Step 2 of Example 141 to obtain the title compound as a white amorphous.

Example 144 Preparation of 1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Isobutyl The reaction and treatment were conducted in a similar manner to Example 142 using 1-methylcyclopropyl 1H-imidazole-1-carboxylate in place of 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 145 Preparation of 1-cyclopropylethyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Isobutyl The reaction and treatment were conducted in a similar manner to Example 142 using 1-cyclopropylethyl 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 146 1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine]- Preparation of 1′-carboxylate Similar to Example 142, using 1,1,1-trifluoropropan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate Reaction and treatment yielded the title compound as a white amorphous.

Example 147 1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 -Piperidine] -1'-carboxylate production 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 142, and the title compound was obtained as a white amorphous.

Example 148 Preparation of (Isopropyl-d7) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate The reaction and treatment were conducted in the same manner as in Example 142 using (isopropyl-d7) 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 149 (tert-Butyl-d9) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 142 using (tert-butyl-d9) 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, and the title compound was converted into a white amorphous substance. Obtained.

Example 150 Preparation of tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-((((3-hydroxypropyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate instead of 2-bromoacetonitrile The product was reacted and treated in the same manner as in Step 2 of Example 127 using 3-bromo-1-propanol to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate tert-butyl Using 6- (5-(((3-hydroxypropyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate and step 2 of Example 85; The same reaction and treatment were performed to obtain the title compound as a white amorphous.

Example 151 Production step of neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate 1: 6- ( Preparation of 5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] hydrochloride tert-Butyl obtained in Example 150 6- (5- ( ((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109. Obtained as the crude hydrochloride salt.

Step 2: Preparation of neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate obtained in Step 1 A crude product of 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] hydrochloride is converted to 6- (5-(((3- Hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride was used in place of the crude product and reacted and treated in the same manner as in Example 143 to give the title compound as a white amorphous Got as.

Example 152 Preparation of 1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1'-carboxylate 151 Using 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] hydrochloride obtained in Step 1 of 151 The title compound was obtained as a white amorphous product by reacting and treating in the same manner as described above.

Example 153 (R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1 ' -Production step of carboxylate 1: (R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4- Preparation of piperidine] -1′-carboxylate Reaction and treatment were carried out in the same manner as in Step 2 of Example 120 using (R) -3-bromo-2-methylpropan-1-ol instead of 2-iodopropane. The title compound was obtained as a white amorphous.

Step 2: (R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1 ′ Preparation of carboxylate (R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine]- Using 1′-carboxylate, reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 154 (R) -Neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxy Step of production of rate 1: (R) -2-methyl-3-(((6- (spiro [chroman-2,4′-piperidin] -6-yl) pyridin-3-yl) methyl) sulfonyl) propane- Preparation of 1-ol dihydrochloride (R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridine-2- obtained in Step 2 of Example 153 Yl) Spiro [chroman-2,4-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain a dihydrochloride crude product.

Step 2: (R) -Neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxy (R) -2-Methyl-3-(((6- (spiro [chroman-2,4′-piperidin] -6-yl) pyridin-3-yl) methyl) sulfonyl obtained in Step 1 ) Propane-1-ol dihydrochloride crude product of 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride The title compound was obtained as a white amorphous product by reacting and treating in the same manner as in Example 143 using the crude product.

Example 155 (R) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman Preparation of -2,4-piperidine] -1'-carboxylate (R) -2-Methyl-3-(((6- (spiro [chroman-2,4'-piperidin] -6-yl) pyridine-3 -Il) methyl) sulfonyl) propan-1-ol dihydrochloride was reacted and treated in the same manner as in Example 146 to obtain the title compound as a white amorphous.

Example 156 (R) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl ) Preparation of spiro [chroman-2,4-piperidine] -1'-carboxylate 1,1,1-trimethyl instead of 1,1,1-trifluoropropan-2-yl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in a similar manner to Example 155 using fluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 157 (S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1 ' -Production of carboxylate Step 1: (S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4- Preparation of piperidine] -1′-carboxylate Reaction and treatment were performed in the same manner as in Step 2 of Example 120, using (S) -3-bromo-2-methylpropan-1-ol instead of 2-iodopropane. The title compound was obtained as a white amorphous.

Step 2: (S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1 ′ Preparation of carboxylate (S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine]- Using 1′-carboxylate, reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 158 (S) -Neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxy Preparation of rate (S) -2-methyl-3-(((6- (spiro [chroman-2,4′-piperidin] -6-yl) pyridin-3-yl) methyl) sulfonyl) propan-1-ol The dihydrochloride was used for reaction and treatment in the same manner as in Example 154 to obtain the title compound as a white amorphous.

Example 159 (S) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman Preparation of -2,4-piperidine] -1'-carboxylate (S) -2-Methyl-3-(((6- (spiro [chroman-2,4'-piperidin] -6-yl) pyridine-3 -Il) methyl) sulfonyl) propan-1-ol dihydrochloride was used for reaction and treatment in the same manner as in Example 155 to obtain the title compound as a white amorphous substance.

Example 160 (S) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl ) Preparation of Spiro [chroman-2,4-piperidine] -1′-carboxylate (S) -2-Methyl-3-(((6- (Spiro [chroman-2,4′-piperidin] -6-yl ) Pyridin-3-yl) methyl) sulfonyl) propan-1-ol dihydrochloride was reacted and treated in the same manner as in Example 156 to obtain the title compound as a white amorphous.

Example 161 tert-butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxy Process for producing rate 1: tert-butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1 Production of '-carboxylate Using 3-bromo-2,2-dimethylpropan-1-ol instead of 2-iodopropane, the reaction and treatment were carried out in the same manner as in Step 2 of Example 120, and the title compound was converted into white amorphous Got as.

Step 2: tert-Butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxy Preparation of tert-butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxy Using the rate, the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 162 Neopentyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate Production step 1: 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate Preparation of hydrochloride salt tert-butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 obtained in Example 161 -Piperidine] -1'-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain a crude dihydrochloride salt.

Step 2: Neopentyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate 6- (5-(((3-Hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′- obtained in production step 1 Instead of the crude carboxylate dihydrochloride 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride The title compound was obtained as a white amorphous product in the same manner as in Example 154.

Example 163 1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2 , 4-Piperidin] -1′-carboxylate 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4- Piperidine] -1′-carboxylate dihydrochloride was reacted and treated in the same manner as in Example 155 to obtain the title compound as a white amorphous.

Example 164 1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro Preparation of [chroman-2,4-piperidine] -1′-carboxylate 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman- Using 2,4-piperidine] -1′-carboxylate dihydrochloride, the reaction and treatment were conducted in the same manner as in Example 156 to obtain the title compound as white amorphous.

Example 165 Production of tert-butyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-(((3-methoxypropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate instead of 2-iodopropane And 1-bromo-3-methoxypropane was used for the reaction and treatment in the same manner as in Step 2 of Example 120 to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate tert-butyl 6- (5-(((3-methoxypropyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate and The same reaction and treatment were performed to obtain the title compound as a white amorphous.

Example 166 Production step of neopentyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 6 Preparation of-(5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] dihydrochloride tert-Butyl obtained in Example 165 6- Similar to Step 1 of Example 109 using (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate The reaction and treatment were performed to obtain a crude hydrochloride salt.

Step 2: Preparation of neopentyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in step 1 Using 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in the same manner as in Example 143 Treatment gave the title compound as a white amorphous.

Example 167 1,1,1-trifluoroisopropyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′- Preparation of carboxylate 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in Step 1 of Example 166 The salt was used for the reaction and treatment in the same manner as in Example 146 to obtain the title compound as white amorphous.

Example 168 Preparation of tert-butyl 6- (4-((((3-methyloxetan-3-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate Step 1: Preparation of tert-butyl 6- (4-((((3-methyloxetane-3-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate Tert-Butyl 6- (4- (bromomethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (12 mg, 0.025 mmol) obtained in Step 2 of Example 67 was dissolved in methanol ( 0.3 mL) and tetrahydrofuran (0.3 mL), S-((3-methyloxetan-3-yl) ethanethioate (6 mg, 0.037 mmol) and 4 N sodium hydroxide Aqueous solution (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours.Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform.The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, The obtained residue was purified by silica gel preparative thin layer chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound (14 mg, quant.) As a white amorphous.

Step 2: Preparation of tert-butyl 6- (4-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate Tert-Butyl 6- (4-((((3-methyloxetane-3-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxy obtained in step 1 Using the rate, the reaction and treatment were conducted in the same manner as in Step 3 of Example 3 to obtain the title compound as a white amorphous.

Example 169 tert-butyl 6- (5-((((3-methyloxetan-3-yl) methyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Production step of carboxylate 1: tert-butyl 6- (5-((((3-methyloxetan-3-yl) methyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4'- Preparation of piperidine] -1′-carboxylate Using oxetane-3-ylmethyl methanesulfonate instead of 2-iodopropane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 120 to obtain the title compound as a white amorphous substance. .

Step 2: tert-Butyl 6- (5-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate tert-butyl 6- (5-((((3-methyloxetan-3-yl) methyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4'-piperidine]- Using 1′-carboxylate, reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 170 tert-butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Step 1: tert-Butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate The reaction and treatment were carried out in the same manner as in Step 2 of Example 120 using (tetrahydrofuran-3-yl) methyl methanesulfonate instead of 2-iodopropane to obtain the title compound as a white amorphous substance.

Step 2: tert-Butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Preparation of tert-butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate And the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 171 Preparation of neopentyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Step 1: Preparation of 6- (5-(((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride In Example 170 The resulting tert-butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Was used in the same manner as in Step 1 of Example 109 to obtain a dihydrochloride crude product.

Step 2: Preparation of neopentyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 6- (5-(((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in step 1 The reaction and treatment were conducted in the same manner as in Example 143, and the title compound was obtained as a white amorphous.

Example 172 1,1,1-trifluoroisopropyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] Preparation of -1′-carboxylate 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2] obtained in Step 1 of Example 171 , 4′-piperidine] dihydrochloride, followed by reaction and treatment in the same manner as in Example 146 to obtain the title compound as white amorphous.

Example 173 tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1 Production step of 1-carboxylate 1: tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4 Production of '-piperidine] -1'-carboxylate Reaction and treatment were carried out in the same manner as in Step 2 of Example 120, using (tetrahydro-2H-pyran-4-yl) methyl methanesulfonate instead of 2-iodopropane. The title compound was obtained as a white amorphous.

Step 2: tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1 Preparation of '-carboxylate tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine ] -1′-Carboxylate was used for the reaction and treatment in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 174 Preparation of tert-butyl 6- (4-(((3-aminopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl Preparation of 6- (4-(((3-bromopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-Butyl obtained in Example 139 6- (4-(((3-hydroxypropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (28 mg, 0.05 mmol), carbon tetrabromide (20 mg, 0.06) mmol) and triphenylphosphine (20 mg, 0.08 mmol) were added methylene chloride (1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (17 mg, 59%) as a white solid.

Step 2: Preparation of tert-butyl 6- (4-(((3-azidopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Under argon atmosphere, tert- Butyl 6- (4-(((3-bromopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (15 mg, 0.03 mmol), sodium azide (7 mg, 0.10 mmol) was added anhydrous N, N-dimethylformamide (0.5 mL) and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (14 mg, Crude) as a pale yellow oil.

Step 3: Preparation of tert-butyl 6- (4-(((3-aminopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- ( 4-(((3-azidopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (14 mg, Crude), triphenylphosphine (13 mg, 0.03 mmol) To the mixture were added tetrahydrofuran (1 mL) and water (0.3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to give the title compound (11 mg, 81%) as colorless crystals.

Example 175 (S) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine]- Preparation of 1′-carboxylate tert-Butyl 6- (4-(((3-bromopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] obtained in Step 1 of Example 174 -1′-carboxylate (16 mg, 0.028 mmol) in dichloromethane (2.5 mL) and triethylamine (12 μL, 0.083 mmol) and (S)-(+)-3-fluoropyrrolidine hydrochloride (5 mg, 0.041 mmol) ) And stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (6 mg, 35%) as a pale yellow solid.

Example 176 (R) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine]- Production of 1′-carboxylate (S)-(+)-3-Fluoropyrrolidine Reaction was carried out in the same manner as in Example 175 using (R)-(−)-3-fluoropyrrolidine hydrochloride instead of hydrochloride. Treatment gave the title compound as a pale yellow solid.

Example 177 tert-butyl 6- (4-(((3- (3,3-difluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate (S)-(+)-3-Fluoropyrrolidine Using 3,3-difluoropyrrolidine hydrochloride instead of hydrochloride, the reaction and treatment were carried out in the same manner as in Example 175, and the title compound was pale yellow Obtained as a solid.

Example 178 Preparation of tert-butyl 6- (4-(((methylsulfonyl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1 of Example 174 Tert-butyl 6- (4-(((3-bromopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate (10 mg, 0.017 mmol) Sodium methanesulfinate (5 mg, 0.052 mmol) was added to a dimethyl sulfoxide solution (1 mL), and the mixture was stirred at 120 ° C. for 25 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 3) to give the title compound (3 mg, 33%) as a white solid.

Example 179 Preparation of tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of 1-iodopropane And methyl 4-bromobutanoic acid in the same manner as in Step 1 of Example 77 to give the title compound as a colorless oil.

Step 2: Preparation of tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Using the resulting tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 2 of example 85, and the title compound was obtained as a white solid.

Example 180 Preparation of 4-((((4- (1'-tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) sulfonyl) butanoic acid Obtained in Example 179 tert-Butyl 6- (4-(((4-methoxy-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (17 mg, 0.03 mmol) The mixture was dissolved in methanol (1.0 mL) and tetrahydrofuran (2.0 mL), 4N aqueous sodium hydroxide solution (0.1 mL) was added, and the mixture was stirred at room temperature for 20 min. After the reaction solution was washed with diethyl ether, 1 N hydrochloric acid was added until pH 4 and extracted three times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (13 mg, quant.) As a white solid.

Example 181 Preparation of tert-butyl 6- (4-(((4-amino-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 180 Of 4-((((4- (1′-tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) butanoic acid (6 mg, 0.011 mmol) WSCD · HCl (3 mg, 0.013 mmol), aqueous ammonia (0.1 mL) and N, N-dimethyl-4-aminopyridine (catalytic amount) were added to a dichloromethane solution (1.5 mL), and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel preparative thin layer chromatography (chloroform: methanol = 10: 1) to give the title compound (1 mg, 18%) as a white solid.

Example 182 tert-butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 Production step of '-carboxylate 1: tert-butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) thio) methyl) phenyl) spiro [chroman-2,4 Production of '-piperidine] -1'-carboxylate Using ethyl 2-bromo-2-methylpropanoic acid instead of 1-iodopropane, the reaction and treatment were carried out in the same manner as in Step 1 of Example 77, and the title compound was converted. Obtained as a colorless oil.

Step 2: tert-Butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 Production of '-carboxylate tert-butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) thio) methyl) phenyl) spiro [chroman-] obtained in Step 1 2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3 to obtain the title compound as a colorless oil.

Example 183 Preparation of ethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- (obtained in Example 84 4-((Benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Example 28 to obtain the title compound as a white amorphous. .

Example 184 Preparation of 2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of ethyl chloroformate And 2,2,2-trichloroethyl chloroformate were used and treated in the same manner as in Example 183 to obtain the title compound as a white solid.

Example 185 Preparation of Isopropyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Substituting isopropyl chloroformate for ethyl chloroformate The reaction and treatment were conducted in the same manner as in Example 183, and the title compound was obtained as a white solid.

Example 186 Preparation of 2,2,2-trifluoroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6- (4- ((Benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride was used for the reaction and treatment in the same manner as in Example 29 to obtain the title compound as a white amorphous.

Example 187 Preparation of 1-cyclopropylethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trifluoroethyl The reaction and treatment were conducted in a similar manner to Example 186 using 1-cyclopropylethyl 1H-imidazole-1-carboxylate in place of 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 188 Preparation of 3,3,4,4,4-pentafluorobutyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Argon Under an atmosphere, 3,3,4,4,4-pentafluorobutanol (7.4 mg, 0.045 mmol), triphosgene (4.5 mg, 0.015 mmol) in anhydrous methylene chloride (0.2 mL) were added with N, N-diisopropylethylamine (16 μL, 0.090 mmol) was added dropwise at 0 ° C. and stirred for 30 minutes. 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] (10.0 mg, 0.021 mmol) was added at 0 ° C., and the mixture was further stirred for 30 minutes. Water was added to stop the reaction, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: ethyl acetate = 4: 1) to give the title compound (4.3 mg, 33%) as a white amorphous Got as.

Example 189 1,1,1-trifluoropropan-2-yl 6- (4-((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate Reaction and treatment were conducted in the same manner as in Example 188 using 1,1,1-trifluoropropan-2-ol in place of 3,3,4,4,4-pentafluorobutanol to give the title compound. Was obtained as a white amorphous.

Example 190 1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Production of rate 1,2,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate was used instead of 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 186, and the title compound was obtained as a white amorphous.

Example 191 1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate Reaction in the same manner as in Example 188 using 1,1,3,3,3-hexafluoropropan-2-ol instead of 3,3,4,4,4-pentafluorobutanol Treatment gave the title compound as a white amorphous.

Example 192 1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2, Preparation of 4'-piperidine] -1'-carboxylate 1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl instead of 3,3,4,4,4-pentafluorobutanol ) Propan-2-ol was used for the reaction and treatment in the same manner as in Example 188 to obtain the title compound as white amorphous.

Example 193 Preparation of (ethyl-d5) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trifluoroethyl Using (ethyl-d5) 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate, the reaction and treatment were conducted in the same manner as in Example 186 to obtain the title compound as a white amorphous.

Example 194 Preparation of (isopropyl-d7) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-trifluoroethyl The reaction and treatment were conducted in the same manner as in Example 186 using (isopropyl-d7) 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 195 Preparation of (tert-butyl-d9) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-tri Using (tert-butyl-d7) 1H-imidazole-1-carboxylate instead of fluoroethyl 1H-imidazole-1-carboxylate, the reaction and treatment were carried out in the same manner as in Example 186 to obtain the title compound as a white amorphous substance. It was.

Example 196 (1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4 ′ -Piperidine] -1'-carboxylate production using 1,1,1,3,3,3-hexafluoro-2-propanol-d1 instead of 3,3,4,4,4-pentafluorobutanol The reaction and treatment were conducted in the same manner as in Example 188, and the title compound was obtained as a white amorphous.

Example 197 Preparation of (trimethylsilyl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3,3,4,4,4- The reaction and treatment were conducted in the same manner as in Example 188 using (trimethylsilyl) methanol instead of pentafluorobutanol to obtain the title compound as a white amorphous.

Example 198 (1- (tert-Butoxycarbonyl) piperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The title compound was reacted and treated in the same manner as in Example 188 using tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate instead of 3,3,4,4,4-pentafluorobutanol. Was obtained as a white amorphous.

Example 199 Production of (1-methylpiperidin-4-yl) methyl 6- [4-{(benzylsulfonyl) methyl} phenyl] spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: Preparation of piperidin-4-ylmethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (1- (tert-butoxycarbonyl) piperidine-4 -Yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate in dichloromethane (1 mL) was added 4 N hydrochloric acid-ethyl acetate ( 1 mL) was added and stirred at room temperature overnight. Ethyl acetate was added, the precipitate was filtered, and piperidin-4-ylmethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate hydrochloride Obtained as a crude product.

Step 2: Preparation of (1-methylpiperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Under argon atmosphere Piperidin-4-ylmethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate hydrochloride (24 mg, 0.039 mmol), paraformaldehyde ( 1,2-dichloroethane (0.5 mL) and methanol (0.5 mL) were added to 12 mg, 0.39 mmol) and stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (82 mg, 0.39 mmol) was added overnight. Stir. The reaction mixture was concentrated, and the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: ammonia methanol = 30: 1) to obtain the title compound (16 mg, 66%) as a pale yellow amorphous.

Example 200 Preparation of 4-isopropylbenzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3,3,4,4,4- The reaction and treatment were conducted in the same manner as in Example 188 using 4-isopropylbenzyl alcohol in place of pentafluorobutanol to give the title compound as a white amorphous.

Example 201 Preparation of 4- (tert-butyl) benzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3,3,4, The reaction and treatment were conducted in a similar manner to Example 188 using 4- (tert-butyl) benzyl alcohol in place of 4,4-pentafluorobutanol, and the title compound was obtained as a white amorphous substance.

Example 202 Preparation of 2-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2-chlorophenylchloro instead of ethyl chloroformate The formate was reacted and treated in the same manner as in Example 183 to obtain the title compound as a white amorphous.

Example 203 Preparation of 4-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4-chlorophenylchloro instead of ethyl chloroformate The formate was reacted and treated in the same manner as in Example 183 to obtain the title compound as a white amorphous.

Example 204 Preparation of tert-butyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3- Using 1-((benzylsulfonyl) methyl) -4-bromo-2-fluorobenzene in place of fluorobenzyl) (methyl) sulfane, the reaction and treatment were conducted in the same manner as in Step 2 of Example 11, and the title compound was converted into white amorphous Got as.

Example 205 Production of 2,2,2-trichloroethyl 6- (4-((benzylsulfonyl)) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate hydrochloride tert--obtained in Example 204 Reaction as in Step 1 of Example 109 using butyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Treatment gave a crude hydrochloride salt.

Step 2: Production of 2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1 Of 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate hydrochloride (16 mg, 0.028 mmol) obtained in (1.0 mL) To the solution were added triethylamine (20 μL, 0.14 mmol) and 2,2,2-trichloroethyl chloroformate (5.0 μL, 0.034 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel chromatography (n-hexane: ethyl acetate = 1: 3) to give the title compound (9 mg, 50%) as a white amorphous.

Example 206 Preparation of neopentyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in a similar manner to Example 205 using neopentyl chloroformate instead of formate, and the title compound was obtained as a pale yellow oil.

Example 207 Preparation of tert-butyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo- Using 2-{(benzylsulfonyl) methyl} -5-bromo-1,3-difluorobenzene instead of (3-fluorobenzyl) (methyl) sulfane, the reaction and treatment were carried out in the same manner as in Step 2 of Example 11, The title compound was obtained as a white amorphous.

Example 208 Preparation of 2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] hydrochloride, the reaction and treatment were carried out in the same manner as in Example 205 to give the title compound. Obtained as a white amorphous.

Example 209 Production of tert-butyl 6- (5-((benzylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate Step 1: tert-butyl 6 Preparation of-(5-((benzylthio) methyl) pyridin-2-yl) spiro (chroman-2,4'-piperidine) -1'-carboxylate Conducted using benzyl bromide instead of 2-iodopropane Reaction and treatment were conducted in the same manner as in Step 2 of Example 120 to give the title compound as a white solid.

Step 2: Preparation of tert-butyl 6- (5-((benzylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate tert obtained in Step 1 Reaction similar to step 2 of Example 86 using -butyl 6- (5-((benzylthio) methyl) pyridin-2-yl) spiro (chroman-2,4'-piperidine) -1'-carboxylate Treatment gave the title compound as a white solid.

Example 210 tert-butyl 6- (5-((benzylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6- (5-((benzylthio) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxy Preparation of rate Tert-butyl 6- (N′-hydroxycarbamimidoyl) spiro (chroman-2,4′-piperidine) -1′-carboxylate obtained in Step 2 of Example 100 (30 mg, 0.083 mmol) in tetrahydrofuran (2.0 mL), 2- (benzylthio) acetic acid (17 mg, 0.091 mmol), N, N-diisopropylethylamine (29 μL, 0.17 mmol), WSCD · HCl (19 mg, 0.1 mmol). When 1-hydroxybenzotriazole (13 mg, 0.1 mmol) and the mixture was stirred at room temperature for 24 hours and evaporated. Toluene (0.5 mL) was added to the obtained residue, and the mixture was heated to reflux for 6 hours. After evaporating toluene, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound (21 mg, 50%) as a colorless oil.

Step 2: tert-Butyl 6- (5-((benzylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-butyl 6- (5-((benzylthio) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1 obtained in Step 1 '-Carboxylate was used for reaction and treatment in the same manner as in Step 3 of Example 3 to obtain the title compound as a white amorphous.

Example 211 Preparation of tert-butyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6 Preparation of-(2-((acetylthio) methyl) thiazol-5-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate tert obtained in step 2 of example 99 under argon atmosphere -Butyl 6- (2-(((methylsulfonyl) oxy) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (135 mg, 0.27 mmol) anhydrous N , N-dimethylformamide solution (1 mL) was added potassium thioacetate (90 mg, 0.79 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (69 mg, 44%) as a brown amorphous Got as.

Step 2: Preparation of tert-butyl 6- (2-((benzylthio) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-obtained in Step 1 Using butyl 6- (2-((acetylthio) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate, the reaction was carried out in the same manner as in Step 1 of Example 209. Treatment gave the title compound as a yellow oil.

Step 3: Preparation of tert-butyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert obtained in Step 2 Reaction as in step 2 of Example 85 using -butyl 6- (2-((benzylthio) methyl) thiazol-5-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Treatment gave the title compound as a white amorphous.

Example 212 Production Process 1 of 2,2,2-Trichloroethyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate : Preparation of 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4'-piperidine] hydrochloride tert-Butyl obtained in Example Dt 6- (2- ( (Benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain the crude hydrochloride salt. Got as a body.

Step 2: Production of 2,2,2-trichloroethyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1 Using the crude product of 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in the same manner as in Example 205, Treatment gave the title compound as a white amorphous.

Example 213 Preparation of neopentyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in the same manner as in Example 212 using neopentyl chloroformate instead of formate to obtain the title compound as a white amorphous.

Example 214 tert-Butyl 6- (4-(((4-Fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl Preparation of 6- (4-(((4-fluorobenzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1- (bromomethyl) instead of 1-iodopropane The reaction and treatment were conducted in the same manner as in Step 1 of Example 77 using -4-fluorobenzene to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert-butyl 6- ( 4-(((4-Fluorobenzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 3 of Example 3. The title compound was obtained as a white amorphous.

Example 215 1,1,1-trifluoropropan-2-yl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Production step of carboxylate 1: Production of 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride tert-butyl 6- (4- ( ((4-Fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain hydrochloride. As a crude product.

Step 2: 1,1,1-trifluoropropan-2-yl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Preparation of carboxylate The reaction and treatment were carried out in the same manner as in Example 189 using 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride. The title compound was obtained as a white amorphous.
Example 216 Production of tert-butyl 6- (5-(((4-fluorobenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-(((4-fluorobenzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate instead of 2-iodopropane And 1- (bromomethyl) -4-fluorobenzene was reacted and treated in the same manner as in Step 2 of Example 120 to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (5-(((4-fluorobenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate tert-butyl 6- (5-(((4-Fluorobenzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate and Example 85, step 2 and The same reaction and treatment were performed to obtain the title compound as a white amorphous.

Example 217 Production process 1 of tert-butyl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (4-(((4- (trifluoromethyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-iodopropane Using 1- (bromomethyl) -4- (trifluoromethyl) benzene in place of, the reaction and treatment were conducted in the same manner as in Step 1 of Example 77, and the title compound was obtained as a white amorphous substance.

Step 2: Preparation of tert-butyl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert- The process of Example 3 using butyl 6- (4-(((4- (trifluoromethyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in 3, and the title compound was obtained as a white amorphous.

Example 218 1,1,1-trifluoropropan-2-yl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] Production step of 1′-carboxylate 1: Production of 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride tert -Butyl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were performed in the same manner as in Step 1 to obtain a crude hydrochloride salt.

Step 2: 1,1,1-trifluoropropan-2-yl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] Preparation of -1′-carboxylate 6- (4-((((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride obtained in step 1 Was used in the same manner as in Example 189 to give the title compound as a white amorphous.

Example 219 tert-Butyl of 6- (5-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate Production step 1: tert-butyl 6- (5-(((4- (trifluoromethyl) benzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 2 of example 120 using 1- (bromomethyl) -4- (trifluoromethyl) benzene in place of 2-iodopropane, and the title compound was obtained as a white amorphous.

Step 2: tert-Butyl 6- (5-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation tert-Butyl 6- (5-(((4- (trifluoromethyl) benzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in step 2 of example 85, and the title compound was obtained as a white amorphous.

Example 220 Production step 1 of tert-butyl 6- (5-(((2-methylbenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-(((2-methylbenzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2-iodopropane 1- (Bromomethyl) -2-methylbenzene was used in place of and the reaction and treatment were conducted in the same manner as in Step 2 of Example 120 to obtain the title compound as a colorless oil.

Step 2: Preparation of tert-butyl 6- (5-(((2-methylbenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert- The process of Example 85 using butyl 6- (5-(((2-methylbenzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate. The reaction and treatment were conducted in the same manner as in 2 to obtain the title compound as a white amorphous.

Example 221 tert-butyl 6- (5-((((2-trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert-Butyl 6- (5-((((2-trifluoromethyl) benzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate The reaction and treatment were conducted in the same manner as in Step 2 of Example 120 using 1- (bromomethyl) -2- (trifluoromethyl) benzene in place of 2-iodopropane to give the title compound as a colorless oil. Obtained.

Step 2: tert-Butyl 6- (5-((((2-trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Preparation of tert-butyl 6- (5-((((2-trifluoromethyl) benzyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate And the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 222 4-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid 1: 4 Preparation of-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) thio) methyl) benzoic acid 4 instead of 1-iodopropane The reaction and treatment were conducted in the same manner as in Step 1 of Example 77 using methyl-(bromomethyl) benzoate to obtain the title compound as a white amorphous.

Step 2: Preparation of 4-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid 4-(( ((4-1 '-(tert-Butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) thio) methyl) benzoic acid as in step 2 of example 85 Reaction and treatment yielded the title compound as a white amorphous.

Example 223 Preparation of 3-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid 1: 3 Preparation of-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) thio) methyl) benzoic acid 3 instead of 1-iodopropane The reaction and treatment were conducted in the same manner as in Step 1 of Example 77 using methyl-(bromomethyl) benzoate to obtain the title compound as a white amorphous.

Step 2: Preparation of 3-((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid 3-(( ((4-1 '-(tert-Butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) thio) methyl) benzoic acid as in step 2 of example 85 Reaction and treatment yielded the title compound as a white amorphous.

Example 224 Preparation of 2-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid 1: 2 Preparation of-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) thio) methyl) benzoic acid 2 instead of 1-iodopropane The reaction and treatment were conducted in the same manner as in Step 1 of Example 77 using methyl-(bromomethyl) benzoate to obtain the title compound as a white amorphous.

Step 2: Preparation of 2-((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid 2-(( ((4-1 '-(tert-Butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) thio) methyl) benzoic acid as in step 2 of example 85 Reaction and treatment yielded the title compound as a white amorphous.

Example 225 Preparation of tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Propyl iodide The reaction and treatment were conducted in a similar manner to process 1 of example 77 using 1- (bromomethyl) -4- (methylsulfonyl) benzene in place of, and the title compound was obtained as a colorless oil.

Example 226 Preparation of tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Example 225 Tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in Reaction and treatment were conducted in the same manner as in Step 2 of Example 85, and the title compound was obtained as a white solid.

Example 227 Preparation of methyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: 6- (4 -(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] dihydrochloride Preparation of tert-butyl 6- (4-((pyridine 2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 1 of Example 109 to obtain the dihydrochloride salt. Obtained as a crude product.

Step 2: Preparation of methyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6 obtained in Step 1 -(4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] dihydrochloride (10.0 mg, 0.022 mmol) was dissolved in dichloroethane (0.2 mL), N, N-diisopropylethylamine (20 μL, 0.11 mmol) and methyl chloroformate (3 mg, 0.033 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: ethyl acetate = 4: 1) to obtain the title compound (9.0 mg, 83%) as a white amorphous.

Example 228 Preparation of ethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of methyl chloroformate The reaction and treatment were conducted in a similar manner to Example 227 using ethyl chloroformate to obtain the title compound as a white amorphous.

Example 229 Preparation of Isopropyl 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of methyl chloroformate The reaction and treatment were conducted in a similar manner to Example 227 using isopropyl chloroformate, to give the title compound as a white amorphous.

Example 230 Preparation of butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Butane-1 under argon atmosphere -N, N-diisopropylethylamine (40 μL, 0.22 mmol) was added dropwise at 0 ° C. to a methylene chloride solution (0.2 mL) of ol (4.0 mg, 0.066 mmol) and triphosgene (7.0 mg, 0.022 mmol) and stirred for 30 minutes. did. 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] (10.0 mg, 0.022 mmol) was added at 0 ° C., and the mixture was further stirred for 30 minutes. Water was added to stop the reaction, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: ethyl acetate = 4: 1) to give the title compound (10.1 mg, 80%) as a white amorphous Got as.

Example 231 Preparation of neopentyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of methyl chloroformate The reaction and treatment were carried out in the same manner as in Example 227 using neopentyl chloroformate to obtain the title compound as a white amorphous.

Example 232 Preparation of isobutyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6- (4-(( Dissolve crude (10.0 mg, 0.022 mmol) of (pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride in N, N-dimethylformamide (0.2 mL). , N, N-diisopropylethylamine (20.0 μL, 0.11 mmol) and isobutyl 1H-imidazole-1-carboxylate (4.0 mg, 0.022 mmol) were added, and the mixture was stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: ethyl acetate = 4: 1) to obtain the title compound (10.0 mg, 84%) as a white amorphous.

Example 233 Preparation of 1-methylcyclopropyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H— The reaction and treatment were conducted in a similar manner to Example 232 using 1-methylcyclopropyl 1H-imidazole-1-carboxylate in place of imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 234 Preparation of 1-cyclopropylethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1 The reaction and treatment were conducted in the same manner as in Example 230 using 1-cyclopropylethanol in place of ol to give the title compound as a white amorphous.

Example 235 Preparation of sec-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole- The reaction and treatment were conducted in the same manner as in Example 232 using sec-butyl 1H-imidazole-1-carboxylate in place of 1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 236 Preparation of tert-pentyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole- The reaction and treatment were conducted in a similar manner to Example 232 using tert-pentyl 1H-imidazole-1-carboxylate in place of 1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 237 Preparation of 4-methylpentan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 232 using 4-methylpentan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance. It was.

Example 238 Preparation of 3-methylpentan-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 232 using 3-methylpentan-3-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate to give the title compound as a white amorphous product It was.

Example 239 2-Methylbut-3-en-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Production of rate The reaction and treatment were conducted in the same manner as in Example 232 using 2-methylbut-3-en-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate. The compound was obtained as a white amorphous.

Example 240 2-Methylbut-3-in-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Production of rate The reaction and treatment were conducted in the same manner as in Example 232 using 2-methylbut-3-in-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate. The compound was obtained as a white amorphous.

Example 241 3-Methylpent-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Production of rate The reaction and treatment were carried out in the same manner as in Example 232 using 3-methylpent-1-in-3-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate. The compound was obtained as a white amorphous.

Example 242 Hex-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Production Isobutyl 1H-imidazole-1-carboxylate instead of hexa-1-in-3-yl 1H-imidazole-1-carboxylate was reacted and treated in the same manner as in Example 232 to give the title compound as a white amorphous Got as.

Example 243 Preparation of 2-cyanoethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butan-1-ol The reaction and treatment were conducted in the same manner as in Example 230 using 2-cyanoethanol instead of to give the title compound as a white amorphous.

Example 244 Preparation of cyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole-1- The reaction and treatment were conducted in a similar manner to Example 232 using cyclohexyl 1H-imidazole-1-carboxylate in place of carboxylate, and the title compound was obtained as a white amorphous substance.

Example 245 Preparation of 4- (tert-butyl) cyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 4- (tert-butyl) cyclohexyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, the reaction and treatment were conducted in the same manner as in Example 232 to obtain the title compound as a white amorphous substance. It was.

Example 246 3,3,5-Trimethyldicyclohexyl 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Production The reaction and treatment were conducted in the same manner as in Example 232 using 3,3,5-trimethyldichlorohexyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, and the title compound was converted into white amorphous Got as.

Example 247 (1R, 2S, 4S) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] Preparation of -1′-carboxylate Example using (1R, 2S, 4S) -2-isopropyl-4-methylcyclohexyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in H.232, and the title compound was obtained as a white amorphous.

Example 248 (1S, 2R, 4R) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] Example 1 Using (1S, 2R, 4R) -2-isopropyl-4-methylcyclohexyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in H.232, and the title compound was obtained as a white amorphous.

Example 249 (3-Methyloxetan-3-yl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxy Preparation of rate The reaction and treatment were conducted in the same manner as in Example 232 using (3-methyloxetane-3-yl) methyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate. The compound was obtained as a white amorphous.

Example 250 Preparation of cyclohexylmethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole-1 -The reaction and treatment were conducted in the same manner as in Example 232 using cyclohexylmethyl 1H-imidazole-1-carboxylate instead of carboxylate to obtain the title compound as a white amorphous.

Example 251 Preparation of adamantan-1-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H— The reaction and treatment were conducted in the same manner as in Example 232 using adamantane-1-ylmethyl 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 252 Preparation of (trimethylsilyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using (trimethylsilyl) methanol instead of oar to obtain the title compound as a white amorphous.

Example 253 Preparation of 2,2,2-trichloroethyl 6- (4-((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Methyl The reaction and treatment were conducted in the same manner as in Example 227 using 2,2,2-trichloroethyl chloroformate in place of chloroformate, and the title compound was obtained as a white amorphous substance.

Example 254 2,2,2-trifluoroethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Manufacture The reaction and treatment were conducted in the same manner as in Example 232 using 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, and the title compound was converted into white amorphous Got as.

Example 255 3,3,4,4,4-pentafluorobutyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Production of carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 3,3,4,4,4-pentafluorobutanol instead of butan-1-ol to obtain the title compound as a white amorphous.

Example 256 1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Production of carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 1,1,1-trifluoropropan-2-ol instead of butan-1-ol to obtain the title compound as a white amorphous substance.
Example 257 1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′- Preparation of piperidine] -1′-carboxylate Using 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 232, and the title compound was obtained as a white amorphous.

Example 258 1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4 ′ -Piperidine] -1'-carboxylate production Reaction and treatment in the same manner as in Example 230 except that 1,1,1,3,3,3-hexafluoro-2-propanol was used instead of butan-1-ol. The title compound was obtained as a white amorphous.

Example 259 1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) Preparation of spiro [chroman-2,4′-piperidine] -1′-carboxylate 1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propane instead of butan-1-ol Using 2-ol, the reaction and treatment were conducted in the same manner as in Example 230 to obtain the title compound as white amorphous.

Example 260 Preparation of (methyl-d3) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H— The reaction and treatment were conducted in the same manner as in Example 232 using (methyl-d3) 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 261 Preparation of (ethyl-d5) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H— The reaction and treatment were conducted in the same manner as in Example 232 using (ethyl-d5) 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate to obtain the title compound as a white amorphous.

Example 262 Preparation of (Isopropyl-d7) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Isobutyl 1H- The reaction and treatment were conducted in the same manner as in Example 232 using (isopropyl-d7) 1H-imidazole-1-carboxylate instead of imidazole-1-carboxylate to give the title compound as a white amorphous.

Example 263 (tert-Butyl-d9) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Isobutyl (Tert-Butyl-d9) 1H-imidazole-1-carboxylate was used instead of 1H-imidazole-1-carboxylate, and the reaction and treatment were carried out in the same manner as in Example 232 to obtain the title compound as a white amorphous.

Example 264 (1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl ) Preparation of spiro [chroman-2,4′-piperidine] -1′-carboxylate 1,1,1,3,3,3-hexafluoro-2-propanol-d1 was used instead of butan-1-ol Then, the reaction and treatment were conducted in the same manner as in Example 230 to obtain the title compound as white amorphous.

Example 265 Preparation of benzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate instead of methyl chloroformate The reaction and treatment were carried out in the same manner as in Example 227 using benzyl chloroformate to obtain the title compound as a white amorphous.

Example 266 Preparation of 1-phenylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Isobutyl 1H-imidazole The reaction and treatment were conducted in a similar manner to Example 232 using 1-phenylethyl 1H-imidazole-1-carboxylate in place of -1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 267 Preparation of 1-phenylpropyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole The reaction and treatment were conducted in a similar manner to Example 232 using 1-phenylpropyl 1H-imidazole-1-carboxylate in place of -1-carboxylate, and the title compound was obtained as a white amorphous substance.

Example 268 Preparation of Phenethyl 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole-1- The reaction and treatment were conducted in a similar manner to Example 232 using phenethyl 1H-imidazole-1-carboxylate in place of carboxylate, and the title compound was obtained as a white amorphous.

Example 269 2-Methyl-1-phenylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate Reaction and treatment were carried out in the same manner as in Example 232, using 2-methyl-1-phenylpropan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous.

Example 270 Preparation of 2-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 232 using 2-phenylbutan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate to obtain the title compound as a white amorphous substance. It was.

Example 271 2-Methyl-4-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate Reaction and treatment were carried out in the same manner as in Example 232 using 2-methyl-4-phenylbutan-2-yl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate. The title compound was obtained as a white amorphous.

Example 272 Preparation of 2-chlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 2-chlorobenzyl alcohol in place of oar to give the title compound as a white amorphous.

Example 273 Preparation of 3-chlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in a similar manner to Example 230 using 3-chlorobenzyl alcohol in place of oar, and the title compound was obtained as a white amorphous.

Example 274 Preparation of 4-chlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- Using 4-chlorobenzyl alcohol instead of oar, reaction and treatment were conducted in the same manner as in Example 230 to obtain the title compound as a white amorphous.

Example 275 Preparation of 2-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 2-fluorobenzyl alcohol in place of oar to give the title compound as a white amorphous.

Example 276 Preparation of 3-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 3-fluorobenzyl alcohol in place of oar to give the title compound as a white amorphous.

Example 277 Preparation of 4-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- Using 4-fluorobenzyl alcohol instead of oar, the reaction and treatment were conducted in the same manner as in Example 230 to obtain the title compound as white amorphous.

Example 278 Preparation of 2- (trifluoromethoxy) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 2- (trifluoromethoxy) benzyl alcohol in place of butan-1-ol, and the title compound was obtained as a white amorphous.

Example 279 Preparation of 4-methylbenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in a similar manner to Example 230 using 4-methylbenzyl alcohol in place of oar, and the title compound was obtained as a white amorphous.

Example 280 Preparation of 4- (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 4- (trifluoromethyl) benzyl alcohol in place of butan-1-ol, and the title compound was obtained as a white amorphous.

Example 281 Preparation of 4-isopropylbenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 4-isopropylbenzyl alcohol in place of oar to give the title compound as a white amorphous.

Example 282 Preparation of 4- (tert-butyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 4- (tert-butyl) benzyl alcohol in place of butan-1-ol, and the title compound was obtained as a white amorphous.

Example 283 Preparation of 2,6-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,6-dichlorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 284 Preparation of 2,3-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,3-dichlorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 285 Preparation of 2,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,4-dichlorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 286 Preparation of 3,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,4-dichlorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 287 Preparation of 3,5-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,5-dichlorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 288 Preparation of 2,6-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,6-difluorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 289 Preparation of 2,5-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,5-difluorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 290 Preparation of 2,4-difluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,4-difluorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 291 Preparation of 3,4-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,4-difluorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 292 Preparation of 3,5-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,5-difluorobenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 293 Preparation of 2-chloro-6-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 2-chloro-6-fluorobenzyl alcohol in place of butan-1-ol to give the title compound as a white amorphous.

Example 294 Preparation of 2-chloro-4-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 2-chloro-4-fluorobenzyl alcohol in place of butan-1-ol, and the title compound was obtained as a white amorphous.

Example 295 Preparation of 2,4-dimethylbenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,4-dimethylbenzyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 296 3,5-bis (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxy Production of rate Using 3,5-bis (trifluoromethyl) benzyl alcohol in place of butan-1-ol, the reaction and treatment were conducted in the same manner as in Example 230 to obtain the title compound as a white amorphous substance.

Example 297 Preparation of (perfluorophenyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using (perfluorophenyl) methyl alcohol in place of 1-ol to give the title compound as a white amorphous.

Example 298 Preparation of furan-2-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1 The reaction and treatment were conducted in the same manner as in Example 230 using furan-2-ylmethanol instead of ol to obtain the title compound as a white amorphous.

Example 299 Preparation of phenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate instead of methyl chloroformate The reaction and treatment were carried out using phenyl chloroformate in the same manner as in Example 227 to obtain the title compound as a white amorphous.

Example 300 Preparation of 2-chlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Instead, 2-chlorophenyl chloroformate was used and reacted and treated in the same manner as in Example 227 to obtain the title compound as a white amorphous.

Example 301 Preparation of 4-chlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Instead, 4-chlorophenyl chloroformate was used and reacted and treated in the same manner as in Example 227 to obtain the title compound as a white amorphous.

Example 302 Preparation of 2-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 2-fluorophenol instead of oar to obtain the title compound as a white amorphous product.

Example 303 Preparation of 3-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 3-fluorophenol in place of oar to obtain the title compound as a white amorphous product.

Example 304 Preparation of 4-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 4-fluorophenol in place of oar to obtain the title compound as a white amorphous product.

Example 305 Preparation of 2-cyanophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 2-cyanophenol in place of oar to obtain the title compound as a white amorphous product.

Example 306 Preparation of 3-cyanophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 3-cyanophenol in place of oar to obtain the title compound as a white amorphous product.

Example 307 Preparation of 4-cyanophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1- The reaction and treatment were conducted in the same manner as in Example 230 using 4-cyanophenol in place of oar to obtain the title compound as a white amorphous product.

Example 308 Preparation of 2- (trifluoromethoxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 2- (trifluoromethoxy) phenol in place of butan-1-ol, and the title compound was obtained as a white amorphous.

Example 309 Preparation of 3- (dimethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in a similar manner to Example 230 using 3- (dimethylamino) phenol in place of -1-ol, and the title compound was obtained as a white amorphous substance.

Example 310 Preparation of 3- (diethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in a similar manner to Example 230 using 3- (diethylamino) phenol in place of 1-ol, and the title compound was obtained as a white amorphous product.

Example 311 Preparation of 4-isopropylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl 1H-imidazole The reaction and treatment were conducted in the same manner as in Example 232 using 2-methyl-4-phenylbutan-2-yl 1H-imidazole-1-carboxylate instead of -1-carboxylate, and the title compound was obtained as a white amorphous substance. It was.

Example 312 4- (tert-Butyl) phenyl Preparation of 6- (4-(((Pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 232 using 4- (tert-butyl) phenyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, and the title compound was obtained as a white amorphous substance. It was.

Example 313 Preparation of 4- (tert-pentyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 4- (tert-pentyl) phenyl 1H-imidazole-1-carboxylate instead of isobutyl 1H-imidazole-1-carboxylate, the reaction and treatment were conducted in the same manner as in Example 232 to obtain the title compound as a white amorphous substance. It was.

Example 314 Preparation of 4- (methylthio) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane- The reaction and treatment were conducted in a similar manner to Example 230 using 4- (methylthio) phenol in place of 1-ol, and the title compound was obtained as a white amorphous product.

Example 315 Preparation of 2,6-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1 The reaction and treatment were conducted in the same manner as in Example 230 using 2,6-dichlorophenol instead of -ol to obtain the title compound as a white amorphous.

Example 316 Preparation of 2,3-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1 -The reaction and treatment were conducted in the same manner as in Example 230 using 2,3-dichlorophenol instead of ol, and the title compound was obtained as a white amorphous substance.

Example 317 Preparation of 2,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1 -The reaction and treatment were conducted in the same manner as in Example 230 using 2,4-dichlorophenol in place of ol, and the title compound was obtained as a white amorphous substance.

Example 318 Preparation of 3,5-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane-1 -The reaction and treatment were conducted in the same manner as in Example 230 using 3,5-dichlorophenol in place of ol, and the title compound was obtained as a white amorphous substance.

Example 319 Preparation of 3,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Butane-1 -The reaction and treatment were conducted in the same manner as in Example 230 using 3,4-dichlorophenol in place of ol, and the title compound was obtained as a white amorphous substance.

Example 320 Preparation of 2,6-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,6-difluorophenol in place of 1-ol to give the title compound as a white amorphous.

Example 321 Preparation of 3,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,5-difluorophenol in place of 1-ol to give the title compound as a white amorphous.

Example 322 Preparation of 2,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,5-difluorophenol in place of 1-ol to give the title compound as a white amorphous.

Example 323 Preparation of 2,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,4-difluorophenol in place of 1-ol to give the title compound as a white amorphous.

Example 324 Preparation of 3,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,4-difluorophenol in place of 1-ol to give the title compound as a white amorphous.

Example 325 Preparation of 2-chloro-6-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 2-chloro-6-fluorophenol in place of butan-1-ol to give the title compound as a white amorphous.

Example 326 Preparation of 2-chloro-4-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 2-chloro-4-fluorophenol in place of butan-1-ol to give the title compound as a white amorphous.

Example 327 Preparation of 4-chloro-2-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 4-chloro-2-fluorophenol instead of butan-1-ol, the reaction and treatment were conducted in the same manner as in Example 230 to obtain the title compound as white amorphous.

Example 328 Preparation of 4-chloro-3-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 4-chloro-3-fluorophenol in place of butan-1-ol, and the title compound was obtained as a white amorphous product.

Example 329 Preparation of 2,4-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 2,4-dimethylphenol in place of 1-ol to give the title compound as a white amorphous.

Example 330 Preparation of 3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in the same manner as in Example 230 using 3,5-dimethylphenol in place of 1-ol to give the title compound as a white amorphous.

Example 331 Preparation of 4-chloro-3-methylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to Example 230 using 4-chloro-3-methylphenol in place of butan-1-ol, and the title compound was obtained as a white amorphous.

Example 332 2-Fluoro-3- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Production of carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 2-fluoro-3- (trifluoromethyl) phenol instead of butan-1-ol to obtain the title compound as a white amorphous substance.

Example 333 2-fluoro-5- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'- Production of carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 2-fluoro-5- (trifluoromethyl) phenol instead of butan-1-ol to obtain the title compound as a white amorphous substance.

Example 334 Preparation of 2,4,6-trichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 2,4,6-trichlorophenol in place of butan-1-ol to obtain the title compound as a white amorphous.

Example 335 4-chloro-3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate The reaction and treatment were conducted in the same manner as in Example 230 using 4-chloro-3,5-dimethylphenol instead of butan-1-ol, and the title compound was obtained as a white amorphous substance.

Example 336 Preparation of 4- (benzyloxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Butane The reaction and treatment were conducted in a similar manner to Example 230 using 4- (benzyloxy) phenol in place of -1-ol, and the title compound was obtained as a white amorphous.

Example 337 (phenyl-2,3,4,5,6-d5) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine]- Production of 1′-carboxylate Using (phenol-2,3,4,5,6-d5) in place of butan-1-ol, the reaction and treatment were conducted in the same manner as in Example 230, and the title compound was converted into white amorphous Got as.

Example 338 Preparation of tert-butyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Using 2-(((4-bromo-2-fluorobenzyl) sulfonyl) methyl) pyridine in place of 4-bromo-3-fluorobenzyl) (methyl) sulfane, reaction and treatment in the same manner as in Step 2 of Example 11 The title compound was obtained as a white amorphous.

Example 339 2,2,2-trichloroethyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'- Carboxylate Production Step 1: Production of 6- (3-Fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride Example 338 Tert-butyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in 1 Then, the reaction and treatment were carried out in the same manner as in Step 1 of Example 109 to obtain a crude product of dihydrochloride.

Step 2: 2,2,2-Trichloroethyl 6- (3-Fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'- Preparation of carboxylate Crude of 6- (3-Fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in Step 1 The product was reacted in the same manner as in Example 63 using 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] hydrochloride as a crude product. Treatment gave the title compound as a white solid.

Example 340 tert-Butyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation As in Step 2 of Example 11, using 2-(((4-bromo-2,6-difluorobenzyl) sulfonyl) methyl) pyridine in place of (4-bromo-3-fluorobenzyl) (methyl) sulfane. The title compound was obtained as a white amorphous product.

Example 341 2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] carboxylate Step 1: Preparation of 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride Example 340 Tert-butyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in Was used in the same manner as in Step 1 of Example 109 to obtain a dihydrochloride crude product.

Step 2: 2,2,2-Trichloroethyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] carboxylate Similar to Example 63, using 6- (3,5-difluoro-4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride. Reaction and treatment yielded the title compound as a white amorphous.

Example 342 Preparation of neopentyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 6 Reaction as in Example 231 using-(3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride Treatment gave the title compound as a white amorphous.

Example 343 1-methylcyclopropyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Preparation of rate Example 233 with 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride The title compound was obtained as a white amorphous product by reacting and treating in the same manner as described above.

Example 344 Production of tert-butyl 6- (5-(((pyridin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: Preparation of tert-butyl 6- (5-((((pyridin-2-ylmethyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2- The reaction and treatment were conducted in a similar manner to process 2 of example 120 using 2-bromomethylpyridine bromate in place of iodopropane, and the title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.60 (2H, m), 1.80-1.88 (4H, m), 2.87 (3H, t, J = 6.8 Hz), 3.16-3.34 (2H, m), 3.70 (2H, s), 3.78 (2H, s), 3.80-4.00 (2H, m), 6.92 (1H, d, J = 8.8 Hz), 7.15-7.17 (1H, m), 7.31 (1H, d, J = 7.6 Hz), 7.56-7.78 (5H, m), 8.52-8.58 (2H, m).

Step 2: Preparation of tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate tert -Butyl 6- (5-((((pyridin-2-ylmethyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Example 120 The reaction and treatment were conducted in the same manner as in Step 3, to give the title compound as a pale yellow solid.

Example 345 2-((((6- (1 ′-(tert-butoxycarbonylspiro (chroman-2,4′-piperidin) -6-yl) pyridin-3-yl) methyl) sulfonyl) methyl) pyridine 1 -Production of oxide The reaction and treatment were carried out in the same manner as in Example 344 to obtain the title compound as a pale yellow solid.

Example 346 Production Step 1 of tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-((((pyridin-2-ylmethyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate 2-bromoacetonitrile Using 2-bromomethylpyridine bromate instead of, the reaction and treatment were conducted in the same manner as in Step 2 of Example 127 to obtain the title compound as a white amorphous.

Step 2: Preparation of tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Step 1 Using tert-butyl 6- (5-(((pyridin-2-ylmethyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate obtained in The reaction and treatment were conducted in the same manner as in step 2 of example 85, and the title compound was obtained as a white amorphous.

Example 347 Neopentyl 6- (5-(((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Step 1: 6 Preparation of-(5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride tert-Butyl obtained in Example 346 6- Similar to Step 1 of Example 109 using (5-(((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate To give a dihydrochloride crude product.

Step 2: Preparation of neopentyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate obtained in step 1 Using 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride obtained in the same manner as in Example 114 Treatment gave the title compound as a white amorphous.

Example 348 1-methylcyclopropyl 6- (5-(((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation Using 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] dihydrochloride obtained in Step 1 of Example 347 The reaction and treatment were conducted in the same manner as in Example 233, and the title compound was obtained as a white amorphous.

Example 349 tert-Butyl 6- (4-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Production step 1: tert-butyl 6- (4-((((5-fluoropyridin-2-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 1 of example 77 using (5-fluoropyridin-2-yl) methyl methanesulfonate in place of 1-iodopropane, and the title compound was obtained as a pale-yellow solid.

Step 2: tert-Butyl 6- (4-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Production of tert-butyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ obtained in Step 1 -Carboxylate was used for the reaction and treatment in the same manner as in Step 2 of Example 85 to obtain the title compound as a white solid.

Example 350 Production Process of Isobutyl 6- (4-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Preparation of 1: 6- (4-(((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in Example 349 Using tert-butyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Step 1 of Example 109 to obtain a crude dihydrochloride salt.

Step 2: Preparation of isobutyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate A crude product of 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride obtained in 1 (150 mg, 0.28 mmol) was dissolved in dichloroethane (3 mL), triethylamine (0.19 mL, 1.39 mmol) and isobutyl chloroformate (55.0 μL, 0.42 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (115 mg, 44%) as a white solid.

Example 351 Preparation of neopentyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Isobutyl The reaction and treatment were conducted in a similar manner to Example 350, using neopentyl chloroformate instead of chloroformate, and the title compound was obtained as a white solid.

Example 352 1-methylcyclopropyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Preparation of the rate 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] dihydrochloride crude (205.0 mg, 0.46 mmol) was dissolved in N, N-dimethylformamide (5 mL), N, N-diisopropylethylamine (0.39 mL, 2.32 mmol), 1-methylcyclopropyl 1H-imidazole-1-carboxylate (92.0 mg, 0.56). mmol) and stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound (130 mg, 50%) as a white amorphous.

Example 353 1-cyclopropylethyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy Preparation of rate Using 1-cyclopropylethyl 1H-imidazole-1-carboxylate in place of 1-methylcyclopropyl 1H-imidazole-1-carboxylate, the reaction and treatment were carried out in the same manner as in Example 352 to give the title compound. Obtained as a pale yellow solid.

Example 354 1,1,1-trifluoropropan-2-yl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4 ′ -Piperidine] -1'-carboxylate preparation 1,1,1-trifluoropropan-2-yl 1H-imidazole-1-carboxylate instead of 1-methylcyclopropyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in a similar manner to Example 352, and the title compound was obtained as a white solid.

Example 355 tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylate production step 1: tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4'- Preparation of piperidine] -1′-carboxylate Reaction and treatment were conducted in the same manner as in Step 2 of Example 120 using (5-fluoropyridin-2-yl) methyl methanesulfonate instead of 2-iodopropane to give the title compound. Was obtained as a light brown amorphous.

Step 2: tert-Butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1 ' -Production of carboxylate tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) thio) methyl) pyridin-2-yl) spiro [chroman-2, obtained in step 1 4′-piperidine] -1′-carboxylate was reacted and treated in the same manner as in Step 2 of Example 85 to obtain the title compound as a white solid.

Example 356 1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine]- Production step of 1′-carboxylate 1: 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine Preparation of dihydrochloride In Example 355 tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 Using “-piperidine] -1′-carboxylate, the reaction and treatment were performed in the same manner as in Step 1 of Example 109 to obtain a crude dihydrochloride salt.

Step 2: 1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine]- Preparation of 1′-carboxylate 6- (5-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 obtained in Step 1 The reaction and treatment were conducted in the same manner as in Example 352 using '-piperidine] dihydrochloride to obtain the title compound as a yellow solid.

Example 357 1,1,1-trifluoropropan-2-yl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman- Preparation of 2,4′-piperidine] -1′-carboxylate 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridine obtained in Step 1 of Example 356 -2-yl) spiro [chroman-2,4′-piperidine] dihydrochloride was reacted and treated in the same manner as in Example 354 to obtain the title compound as a white solid.

Example 358 tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1'-carboxylate The reaction and treatment were conducted in the same manner as in step 2 of example 127 using (5-fluoropyridin-2-yl) methyl methanesulfonate in place of 2-bromoacetonitrile to give the title compound as a white amorphous.

Example 359 Preparation of neopentyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1'-carboxylate Step 1: Preparation of 6- (5-(((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] hydrochloride Obtained in Example 358 Tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1'-carboxylate Were used and reacted in the same manner as in Step 1 of Example 109 to obtain a crude hydrochloride salt.

Step 2: Preparation of neopentyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1'-carboxylate The crude 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] hydrochloride obtained in step 1 is Were used and reacted in the same manner as in Example 231 to obtain the title compound as white amorphous.

Example 360 1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1'- Preparation of carboxylate 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-] obtained in Step 1 of Example 359. The crude product of piperidine] hydrochloride was reacted and treated in the same manner as in Example 233 to obtain the title compound as a white amorphous.

Example 361 tert-Butyl 6- (4-((((6-Methylpyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Production process 1: tert-butyl 6- (4-((((6-methylpyridin-2-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 1 of example 77 using 2- (bromomethyl) -6-methylpyridine in place of 1-iodopropane, and the title compound was obtained as a colorless oil.

Step 2: tert-Butyl 6- (4-((((6-methylpyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Manufacturing

  Tert-Butyl 6- (4-((((6-methylpyridin-2-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- obtained in step 1 Using carboxylate, the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as white amorphous.

Example 362 of tert-butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Production step 1: tert-butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate S-((3-methyloxetane-3-yl) ethanethioate was replaced with S-((6-methoxypyridin-2-yl) methyl) ethanethioate in the same manner as in Step 1 of Example 168. Treatment gave the title compound as a colorless oil.

Step 2: tert-Butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Production of tert-butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ obtained in Step 1 -Carboxylate was used for the reaction and treatment in the same manner as in Step 2 of Example 85 to obtain the title compound as a colorless oil.

Example 363 Production of tert-butyl 6- (4-(((pyrazin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: tert- Preparation of butyl 6- (4-((((pyrazin-2-ylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2- (Instead of 1-iodopropane (Bromomethyl) pyrazine was used for the reaction and treatment in the same manner as in Step 1 of Example 77 to obtain the title compound as a pale yellow amorphous.

Step 2: Preparation of tert-butyl 6- (4-((((pyrazin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in step 1 Step of Example 85 with tert-butyl 6- (4-((((pyrazin-2-ylmethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in 2 to obtain the title compound as a white amorphous.

Example 364 Preparation 1 of tert-butyl 6- (5-((((pyrazin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate Preparation of tert-butyl 6- (5-((((pyrazin-2-ylmethyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate 2-iodopropane Using 2- (bromomethyl) pyrazine in place of, the reaction and treatment were conducted in the same manner as in Step 2 of Example 120 to obtain the title compound as a white amorphous.

Step 2: tert-Butyl 6- (5-((((pyrazin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1'-carboxylate obtained in step 1 With tert-butyl 6- (5-(((pyrazin-2-ylmethyl) thio) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 2 of example 85, and the title compound was obtained as a white amorphous substance.

Example 365 Production of tert-butyl 6- (4-(((thiazol-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: tert- Preparation of butyl 6- (4-(((thiazol-4-ylmethyl) thia) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 4- (instead of 1-iodopropane Chloromethyl) thiazole hydrochloride was used for the reaction and treatment in the same manner as in Step 1 of Example 77 to obtain the title compound as a colorless oil.

Step 2: Preparation of tert-butyl 6- (4-(((thiazol-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate obtained in step 1 Step of Example 85 with tert-butyl 6- (4-(((thiazol-4-ylmethyl) thia) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to 2 to give the title compound as a colorless oil.

Example 366 tert-butyl 6- (4-((((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′- Step 1: Production of piperidine] -1′-carboxylate 1: tert-butyl 6- (4-((((3-isopropyl-124-oxadiazol-5-yl) methyl) thio) methyl) phenyl) spiro [chroman Preparation of -2,4'-piperidine] -1'-carboxylate The reaction was conducted in the same manner as in Step 1 of Example 77 using 5- (chloromethyl) -3-isopropyl-oxazole instead of 1-iodopropane. Treatment gave the title compound as a colorless oil.

Step 2: tert-Butyl 6- (4-((((3-Isopropyl-124-oxadiazol-5-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 Production of '-carboxylate tert-butyl 6- (4-((((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) thio) methyl) phenyl) obtained in Step 1 The reaction and treatment were conducted in a similar manner to process 2 of example 85 using spiro [chroman-2,4'-piperidine] -1'-carboxylate, to give the title compound as a colorless oil.

Example 367 Preparation of tert-butyl 6- (5-((((pyrimidin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: Preparation of tert-butyl 6- (5-((((pyrimidin-2-ylmethyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 2 of example 127 using pyrimidin-2-ylmethyl methanesulfonate in place of 2-bromoacetonitrile, and the title compound was obtained as a white amorphous substance.

Step 2: Preparation of tert-butyl 6- (5-((((pyrimidin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-Butyl 6- (5-((((pyrimidin-2-ylmethyl) thio) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxy obtained in step 1 Using the rate, the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 368 Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfinyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 1 of example 77 using 1- (pyridin-2-yl) ethyl methanesulfonate in place of 1-iodopropane, and the title compound was obtained as a colorless oil.

Step 2: Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfinyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-Butyl 6- (4-(((1- (pyridin-2-yl) ethyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy obtained in step 1 Using the rate, the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 369 Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Example 368, and the title compound was obtained as a white amorphous.

Example 370 Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Step 1: Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) propyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in a similar manner to process 1 of example 77 using 1- (pyridin-2-yl) propyl methanesulfonate in place of 1-iodopropane, and the title compound was obtained as a colorless oil.

Step 2: Preparation of tert-butyl 6- (4-(((1- (pyridin-2-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-Butyl 6- (4-(((1- (pyridin-2-yl) propyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy obtained in step 1 Using the rate, the reaction and treatment were conducted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white amorphous.

Example 371 Production of tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 1: Preparation of tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) thio) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate S- ((3-Methyloxetane-3-yl) S- (2- (pyridin-2-yl) ethyl) ethanethioate was used in place of ethanethioate for reaction and treatment in the same manner as in Step 1 of Example 168 to give the title compound Was obtained as a white solid.

Step 2: Production of tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) thio) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate obtained in 1 Were used and reacted in the same manner as in Step 2 of Example 85 to obtain the title compound as a white solid.

Example 372 Neopentyl 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate Step 1: Preparation of 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] dihydrochloride Obtained in Step 2 of Example 371 tert-Butyl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate The reaction and treatment were conducted in the same manner as in Step 1 of 109 to obtain a dihydrochloride crude product.

Step 2: Preparation of neopentyl 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate In Step 1 The same as Example 231 using the obtained 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] dihydrochloride. The title compound was obtained as a white amorphous product.

Example 373 1,1,1-trifluoropropan-2-yl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine Preparation of 1′-carboxylate 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4 obtained in Step 1 of Example 372 The reaction and treatment were conducted in the same manner as in Example 230 using '-piperidine] dihydrochloride to obtain the title compound as a white amorphous.

Example 374 Preparation of tert-butyl 7-fluoro-6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Using tert-butyl 6-bromo-7-fluorospiro (chroman-2,4′-piperidine) -1′-carboxylate obtained in Step 3 of Example 101, the reaction and treatment were carried out in the same manner as in Example 85. The title compound was obtained as a white amorphous.

Example 375 Preparation of tert-butyl 6- (4- (2-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-bromo-3-fluorobenzyl) The reaction and treatment were conducted in a similar manner to process 2 of example 11 using 1-bromo-4- (2- (methylsulfonyl) ethyl) benzene in place of (methyl) sulfane, and the title compound was obtained as a white amorphous substance.

Example 376 Preparation of tert-butyl 6- (4-((1H-imidazol-1-yl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate Imidazole (3.0 mg, 0.048 mmol) was dissolved in tetrahydrofuran (0.3 mL), 60% sodium hydride (3.0 mg, 0.064 mmol) was added under ice cooling, and the mixture was stirred for 15 minutes, and then tert-butyl 6- (4- (bromomethyl) phenyl). Spiro [chroman-2,4′-piperidine] -1′-carboxylate (15.0 mg, 0.032 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) to obtain the title compound (11.0 mg, 79%) as a white amorphous.

Example 377 Preparation of tert-butyl 6- (4- (2-ethoxy-2-oxoethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (4-Bromo-3-fluorobenzyl ) The reaction and treatment were conducted in the same manner as in step 2 of example 11 using ethyl 2- (4-bromophenyl) acetic acid in place of (methyl) sulfane to give the title compound as a colorless oil.

Example 378 Preparation of 2- (4- (1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) phenyl) acetic acid tert-butyl 6 obtained in Example 377 -(4- (2-Ethoxy-2-oxoethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate (10 mg, 0.021 mmol) in methanol (0.1 mL) and tetrahydrofuran (0.1 mL) 4N aqueous sodium hydroxide solution (0.1 mL) was added and stirred for 30 minutes. The reaction solution was neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (5 mg, 56%) as a white solid.

Example 379 Preparation of Isopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2-Trichloroethylchloro The reaction and treatment were conducted in a similar manner to process 2 of example 121 using isopropyl chloroformate instead of formate, and the title compound was obtained as a white solid.

Example 380 Isopropyl of 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4'-piperidine) -1'-carboxylate Manufacture The reaction and treatment were conducted in a similar manner to process 2 of example 135 using isopropyl chloroformate instead of neopentyl chloroformate, and the title compound was obtained as a white solid.

Example 381 Preparation of Isopropyl 6- (4-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate Isobutyl The reaction and treatment were conducted in a similar manner to Example 350 using isopropyl chloroformate instead of chloroformate, and the title compound was obtained as a white solid.

  The compounds obtained by the above examples are shown in Tables 1 to 77.

Test Example 1 Insulin Secretion Promoting Action Hamster pancreatic β cell line HIT-T15 cells were transferred using Ham's F-12K medium containing penicillin (100 units / mL), streptomycin (100 μg / mL) and 10% fetal bovine serum. Subcultured. Cells were seeded in a 24-well culture plate, cultured for 48 hours at 37 ° C., and then washed with a KRBH buffer containing 0.1% albumin. Subsequently, it left still at 37 degreeC with the same buffer for 1 hour. Glucose was added to this to a final concentration of 2 mM, and the compound of the present invention dissolved in dimethyl sulfoxide at a concentration 1000 times the concentration (from 0.0001 μM to 10 μM at a common ratio of 10) was added to the buffer. It was added under the condition of 0.1% by volume. After adding the compound of the present invention, the mixture was allowed to stand at 37 ° C. for 1 hour, and then the insulin concentration contained in the supernatant was measured with an insulin kit (Setty Medical Co., Ltd.). As the standard solution, a hamster insulin standard solution (Shiba Goat Co., Ltd.) was used. A control to which only dimethyl sulfoxide was added was used. The results are shown in Table 19 as 50% effect concentration (EC ₅₀ value, 50% effect concentration) of each test compound. The EC ₅₀ value was calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS institute Japan Co., Tokyo).

  From the above, it can be seen that the compound of the present invention has a strong insulin secretion promoting effect.

  The spiropiperidine derivative represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof has an excellent insulin secretion promoting action and is useful for the prevention and / or treatment of diabetes. Has industrial applicability.

Claims (16)

The following general formula (1):

[Where:
A ring _represents a heterocyclic group C 6 _{-C 10} aryl group or 5- to 10-membered;
Z is O, N—R ⁹ , S (O) m, CH ₂ or C═O (where R ⁹ is a hydrogen atom, a C _1-6 alkyl group, a C _1-7 alkanoyl group, or C _1-6. Represents an alkylsulfonyl group, and m represents an integer of 0 to 2);

R ¹ , R ² , R ³ and R ⁴ do not exist independently of each other, or are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a carboxy-C _1-6 alkyl group, a C _1-6 alkoxy carbonyl _{-C 1-6} alkyl group, with a heterocyclic -C _1-6 alkyl group to 4-10 membered (where the heterocycle 4-10 membered, _{C 1-6} alkyl or _{C 1-6} alkylsulfonyl Group may be substituted), C _1-6 alkoxy group, C _3-10 cycloalkyl-C _1-6 alkoxy group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonyloxy group, C _{1- 6} alkylsulfonylamino group, hydroxyl group, cyano group, nitro group, tetrazolyl group, or the following formula (2) or formula (3):

(In the formula, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, a halogen atom or a C _1-6 alkyl group, and R ¹² represents a C _1-20 alkyl group, a C _2-6 alkenyl group, a haloC _1-6 alkyl group, C _2-7 alkanoyl group, C _6-10 aryl group, 4-10 membered heterocyclic group (the hetero ring may be substituted with a halogen atom), C _3-10 cycloalkyl- C _1-6 alkyl group, amino C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, cyano-C _1-6 alkyl group, C _1-6 alkoxy-C _1-6 alkyl group, carboxy-C _{1 -6} alkyl group, C _1-6 alkoxycarbonyl-C _1-6 alkyl group, carbamoyl-C _1-6 alkyl group, C _1-6 alkylsulfonyl-C _1-6 alkyl group, C _6-10 aryl-C _{1 -6} alkyl groups (where C _6-10 aryl may be substituted by a halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _1-6 alkylsulfonyl group or carboxyl group) or 4-10 membered hetero A ring -C _1-6 alkyl group (wherein the heterocycle may be substituted by a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group or an oxo group), l is 1 to 1 An integer of 3 and n represents an integer of 0 to 2);
R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom, a cyano group or a carboxyl group;
R ⁸ is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a halo C _1-6 alkyl group, a trialkylsilyl-C _1-6 alkyl group, a cyano C _1-6 alkyl Group, C _1-6 alkoxy-C _1-6 alkyl group, C _3-10 cycloalkyl group (wherein cycloalkyl may be substituted by a halogen atom), C _3-10 cycloalkyl-C _{1 A -6} alkyl group (wherein cycloalkyl may be substituted by a C _1-6 alkyl group), a C _6-10 aryl group (where C _6-10 aryl includes a halogen atom, a cyano group) , A halo C _1-6 alkoxy group, an amino group, a dialkylamino group, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkylthio group or a C _6-10 aryl-C _1-6 alkyloxy Even if the group is substituted There), with _{C 6-10} aryl -C _1-6 alkyl group (wherein the _{C 6-10} aryl, halogen _{atom, C 1-6} alkyl, halo _{C 1-6} alkoxy group or a halo _{C 1-6} An alkyl group may be substituted), a 4-10 membered heterocyclic-C _1-6 alkyl group (wherein the hetero ring is substituted with a C _1-6 alkyl group or a C _1-6 alkoxycarbonyl group). Or a 4-10 membered heterocyclic group,
R ¹³ or R ¹⁴ independently of each other represents a hydrogen atom or a halogen atom;

Or a salt thereof, or a solvate thereof.   The compound or a salt thereof according to claim 1, wherein the ring A is a group selected from a phenyl group, a pyridyl group, an indolyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a thiazolyl group, and an oxadiazolyl group, and Z is O. Or a solvate thereof. In general formula (1), ^one of R ¹ , R ² , R ³ and R ⁴ is a C _1-6 alkylsulfonyl group, a 4-10 membered heterocyclic-C _1-6 alkyl group (wherein the heterocyclic ring is Or a group represented by the formula (2), no residue is present, or a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, C _1- The compound according to claim 1 or 2 or a salt thereof, or a solvate thereof, which is a ₆ alkoxy group or a C _3-8 cycloalkyl-C _1-6 alkoxy group. The group represented by formula (2) is C _1-6 alkyl-S (O) _n CH ₂ —, C _6-10 aryl-C _1-6 alkyl-S (O) _n CH ₂ —, or 4-10 member. Heterocycle —C _1-6 alkyl-S (O) _n CH ₂ — (wherein aryl or heterocycle may have the above-mentioned substituent, and n represents an integer of 0 to 2). The compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof. The following compound groups:
tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (methylsulfonyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-((methylsulfonyl) methyl))) phenyl) spiro [chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 7- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 7- (3-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-nitrophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (methylsulfonamido) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-hydroxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) oxy) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfinyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (6-((methylsulfonyl) methyl) pyridin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-methyl-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-methoxy-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) -3-propoxyphenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3- (cyclopropylmethoxy) -4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((1-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((2-methylsulfonyl) propan-2-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (1H-tetrazol-1-yl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7- (5- (methylsulfonyl) indoline-1-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (methylsulfonyl) methylpiperidino) spiro [chroman-2,4′-piperidine) -1′-carboxylate,
Ethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trifluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluoroethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methoxyethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorophenyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorobenzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-bis (trifluoromethyl) benzyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Pyridin-4-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Pyridin-3-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Pyridin-2-ylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trichloro-2-methylpropan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Adamantan-1-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Adamantan-2-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Oxetane-3-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Tetrahydro-2H-pyran-4-yl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4,4-difluorocyclohexyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
Neopentyl 6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
Neopentyl 6- (3-chloro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trifluoroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate,
Neopentyl 6- (3,5-difluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((pyridin-4-ylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((pyridin-4-ylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((phenylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((phenylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (4-(((5-Methyl-1,3,4-thiadiazol-2-yl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-Butyl 6- (4-(((5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-butyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((dodecylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((dodecylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((acetylthio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((propylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((allylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((2-methoxyethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((cyclopropylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((cyclohexylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyridin-3-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylatecyclopropylmethyl 6- (4-(( Methylsulfonyl) methyl) phenyl) spiro [chromene-2,4′-piperidine] -1′-carboxylate,
Cyclobutylmethyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1-methylcyclopropyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclobutyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Trimethylsilyl) methyl 6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) pyrazin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (6-((methylsulfonyl) methyl) pyridazin-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) thiazol-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-((methylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((methylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7-fluoro-6- (3-fluoro-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 7-fluoro-6- (5-((methylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 3-hydroxy-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((methylsulfonyl) methyl) phenyl) -3-oxospiro (chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 4,4-dideuterio-6- (4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 4-fluoro-6- (4-((methylsulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-cyano-4-((methylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′carboxylate),
Neopentyl 6- (4-((ethylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′carboxylate,
2,2,2-trichloroethyl 6- (4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4- (2- (isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′carboxylate,
Neopentyl 6- (3,5-difluoro-4-((isopropylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′carboxylate,
tert-butyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((2-fluoroethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((cyanomethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((cyanomethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylates,
Neopentyl 6- (3-fluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((3,3,3-trifluoropropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine]- 1′-carboxylate,
tert-butyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1-cyclopropylethyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoropropan-2-yl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′- Piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((3-hydroxypropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Isopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Isobutyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′- Carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
(Isopropyl-d7) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Tert-butyl-d9) 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-(((3-hydroxypropyl) sulfonyl) methyl) pyrimidin-2-yl) [chroman-2,4-piperidine] -1′-carboxylate,
(R) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate ,
(R) -neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
(R) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, 4-piperidine] -1′-carboxylate,
(R) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [ Chroman-2,4-piperidine] -1′-carboxylate,
(S) -tert-butyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate ,
(S) -neopentyl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
(S) -1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2, 4-piperidine] -1′-carboxylate,
(S) -1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2-methylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [ Chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4- Piperidine] -1′-carboxylate,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (5-(((3-hydroxy-2,2-dimethylpropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman- 2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoroisopropyl 6- (5-(((3-methoxypropyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-Butyl 6- (5-((((3-methyloxetane-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-butyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoroisopropyl 6- (5-((((tetrahydrofuran-3-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylates,
tert-butyl 6- (5-((((tetrahydro-2H-pyran-4-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4'-piperidine] -1'-carboxy rate,
tert-butyl 6- (4-(((3-aminopropyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(S) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
(R) -tert-butyl 6- (5-(((3- (3-fluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
tert-Butyl 6- (4-(((3- (3,3-difluoropyrrolidin-1-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
tert-butyl 6- (4-(((methylsulfonyl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4-methoxy-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-(((4- (1′-tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) butanoic acid,
tert-butyl 6- (4-(((4-amino-4-oxobutyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (4-(((1-ethoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxy rate,
Ethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trifluoroethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,3,4,4,4-pentafluorobutyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′- Piperidine] -1′-carboxylate,
(Ethyl-d5) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Isopropyl-d7) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Tert-butyl-d9) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1,1,1,3,3,3-hexafluoropropan-2-yl-2-d1) 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Trimethylsilyl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1- (tert-butoxycarbonyl) piperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1-methylpiperidin-4-yl) methyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-isopropylbenzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) benzyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorophenyl 6- (4-((benzylsulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((benzylsulfonyl) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-(((benzylsulfonyl)) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((benzylsulfonyl)) methyl) -3-fluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((benzylsulfonyl) methyl) -3,5-difluorophenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((benzylsulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate,
tert-butyl 6- (5-((benzylsulfonyl) methyl) -1,2,4-oxadiazol-3-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (2-((benzylsulfonyl) methyl) thiazol-5-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((4-fluorobenzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((4-fluorobenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylates,
tert-butyl 6- (5-(((4- (trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((2-methylbenzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-(((2-trifluoromethyl) benzyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-(((((4-1 '-(tert-butoxycarbonyl) spiro [chroman-2,4'-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid,
3-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid,
2-(((((4-1 ′-(tert-butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) benzyl) sulfonyl) methyl) benzoic acid,
tert-butyl 6- (4-((((4- (methylsulfonyl) benzyl) thio) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((4- (methylsulfonyl) benzyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Methyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Ethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Butyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isobutyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
sec-butyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-pentyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-methylpentan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-methylpentan-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methylbut-3-en-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methylbut-3-in-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-methylpent-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Hexa-1-in-3-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-cyanoethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Cyclohexyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) cyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,3,5-trimethyldicyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1R, 2S, 4S) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1 ' -Carboxylates,
(1S, 2R, 4R) -2-isopropyl-4-methylcyclohexyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 ′ -Carboxylates,
(3-methyloxetane-3-yl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Cyclohexylmethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Adamantan-1-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Trimethylsilyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (4-((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 2,2,2- Trifluoroethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,3,4,4,4-pentafluorobutyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1,1,1-trifluoro-2-methylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate,
1,1,1,3,3,3-hexafluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1,3,3,3-hexafluoro-2- (trifluoromethyl) propan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman -2,4'-piperidine] -1'-carboxylate,
(Methyl-d3) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Ethyl-d5) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Isopropyl-d7) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Tert-butyl-d9) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(1,1,1,3,3,3-hexafluoro-2-propan-2-yl-2-d1) 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [ Chroman-2,4′-piperidine] -1′-carboxylate,
Benzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-phenylethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-phenylpropyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenethyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methyl-1-phenylpropan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-methyl-4-phenylbutan-2-yl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-fluorobenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2- (trifluoromethoxy) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-methylbenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-isopropylbenzyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,3-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-dichlorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,5-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-difluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-6-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-4-fluorobenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dimethylbenzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-bis (trifluoromethyl) benzyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Perfluorophenyl) methyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Furan-2-ylmethyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Phenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chlorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chlorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-fluorophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-cyanophenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2- (trifluoromethoxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3- (dimethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3- (diethylamino) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-isopropylphenyl 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-butyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (tert-pentyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (methylthio) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,3-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate 3,5-dichlorophenyl 6- ( 4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,6-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,5-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,4-difluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-6-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-chloro-4-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-2-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-3-fluorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-3-methylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluoro-3- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-fluoro-5- (trifluoromethyl) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,4,6-trichlorophenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4-chloro-3,5-dimethylphenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
4- (benzyloxy) phenyl 6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
(Phenyl-2,3,4,5,6-d5) 6- (4-((((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'- Carboxylate,
tert-butyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3-fluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2,2,2-trichloroethyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] carboxylate,
Neopentyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (3,5-difluoro-4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
2-((((6- (1 ′-(tert-butoxycarbonylspiro (chroman-2,4′-piperidin) -6-yl) pyridin-3-yl) methyl) sulfonyl) methyl) pyridine-1-oxide ,
tert-butyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-((((pyridin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isobutyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1-cyclopropylethyl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-Butyl 6- (5-((((5-Fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate ,
1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′- Carboxylate,
1,1,1-trifluoropropan-2-yl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4 '-Piperidine] -1'-carboxylate,
tert-butyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate,
Neopentyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate,
1-methylcyclopropyl 6- (5-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) pyrimidin-2-ylspiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((6-methylpyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((6-methoxypyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((pyrazin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (5-((((pyrazin-2-ylmethyl) sulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((thiazol-4-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((((3-isopropyl-1,2,4-oxadiazol-5-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine]- 1′-carboxylate,
tert-butyl 6- (5-((((pyrimidin-2-ylmethyl) sulfonyl) methyl) pyrimidin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfinyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((1- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((1- (pyridin-2-yl) propyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Neopentyl 6- (4-(((2- (pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) [chroman-2,4′-piperidine] -1′-carboxylate,
1,1,1-trifluoropropan-2-yl 6- (4-(((2-pyridin-2-yl) ethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1 '-Carboxylate,
tert-butyl 7-fluoro-6- (4-(((pyridin-2-ylmethyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (2-methylsulfonyl) ethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4-((1H-imidazol-1-yl) methyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
tert-butyl 6- (4- (2-ethoxy-2-oxoethyl) phenyl) spiro [chroman-2,4′-piperidine] -1′-carboxylate and 2- (4- (1 ′-(tert- Butoxycarbonyl) spiro [chroman-2,4′-piperidin] -6-yl) phenyl) acetic acid,
Isopropyl 6- (5-((isopropylsulfonyl) methyl) pyridin-2-yl) spiro [chroman-2,4′-piperidine] -1′-carboxylate,
Isopropyl 6- (5-(((3,3,3-trifluoropropyl) sulfonyl) methyl) pyridin-2-yl) spiro (chroman-2,4′-piperidine) -1′-carboxylate and isopropyl 6 A compound selected from-(4-((((5-fluoropyridin-2-yl) methyl) sulfonyl) methyl) phenyl) spiro [chroman-2,4'-piperidine] -1'-carboxylate. The compound of any one of these, its salt, or those solvates.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.   The insulin secretion promoter which uses the compound of any one of Claims 1 thru | or 5, its salt, or those solvates as an active ingredient.   A hypoglycemic agent comprising the compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof as an active ingredient.   A preventive and / or therapeutic agent for diabetes comprising the compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof as an active ingredient.   A method for promoting insulin secretion, comprising administering an effective amount of the compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof.   A method for lowering blood glucose, comprising administering an effective amount of the compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof.   A method for preventing and / or treating diabetes, comprising administering an effective amount of the compound according to any one of claims 1 to 5 or a salt thereof, or a solvate thereof.   The compound according to any one of claims 1 to 5, or a salt thereof, or a solvate thereof, for promoting secretion of insulin.   The compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 5, for lowering blood glucose.   The compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 5, for the prevention and / or treatment of diabetes. Use of the compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 5, for the manufacture of an insulin secretion promoter, a hypoglycemic agent, or a preventive and / or therapeutic agent for diabetes.