Picolinamide and pyrimidine-4-carboxamide compounds, process for preparing and pharmaceutical composition comprising the same

• US 9,096,571 B2
• Filed: 05/04/2011
• Issued: 08/04/2015
• Est. Priority Date: 05/07/2010
• Status: Active Grant

• Current Assignee: SK Chemicals Co Ltd (SK Discovery Co. Ltd.)
• Original Assignee: SK Chemicals Co Ltd (SK Discovery Co. Ltd.)
• Inventors: Ryu, Je Ho, Kim, Shin Ae, Ryu, Keun Ho, Kim, Jae Sun, Kim, Nam Ho, Han, Hye Young, Kim, Yong Hyuk, Youn, Won-No, Lee, Yoon-Jung, Son, Hyun Joo, Lee, Bong-Yong, Park, Sung Hoon, Lee, Ju Young, Lee, Hyun Jung, Shin, Young Ah, Lee, Jung A, Jung, Hoe Chul, Lee, Bo Ram, Sa, Joon Ho
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US13/696,400
• Publication Number:
  US 20130210811A1
• Time in Patent Office: 1,553 Days
• Field of Search: 514/218, 514/318, 514/253.13, 514/253.09, 514/316, 514/235.5, 514/314, 514/252.14, 514/252.18, 514/252.19, 540/575, 544/130, 544/295, 544/365, 544/364, 546/167, 546/187, 546/194
• US Class Current: 1/1
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/06 : for tuberculosis
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 239/557 : with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings

Abstract

Provided are picolinamide and pyrimidine-4-carboxamide compounds, a method for preparing the same, a pharmaceutical composition containing the same, and a medical use using the compound as an agent for preventing, regulating, and treating diseases related to regulation of glucocorticoids by using selective inhibitory activity of the compound for an 11β-HSD1 enzyme. The picolinamide and pyrimidine-4-carboxamide compounds of the present invention are selective inhibitors of human-derived 11β-HSD1 enzymes, and are useful in an agent for preventing, regulating, and treating diseases related to glucocorticoid regulation in which human-derived 11β-HSD1 enzymes are involved, for example, metabolic syndromes such as, type 1 and type 2 diabetes, diabetes later complications, latent autoimmune diabetes adult (LADA), insulin tolerance syndromes, obesity, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), damaged glucose tolerance, dyslipidemia, atherosclerosis, hypertension, etc.

Claims

1. An amide compound represented by the formula 1 below, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof,

2. The amide compound, or the pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof, of claim 1,

wherein R₁ and R₂ independently represent hydrogen, (C3-C10)cycloalkyl, norbornyl, adamantyl, or noradamantyl;

L represents a single bond, —

CO—

, —

SO₂—

, —

(CR₂₁R₂₂)—

(CH₂)_c—

(c represents an integer of 0 to

     5),

3. The amide compound, or the pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof, of claim 1, selected from the group consisting of:

N-cyclohexyl-6-(piperidin-1-yl)picolinamide;

N-cyclohexyl-6-(4-methylpiperidin-1-yl)picolinamide;

N-cyclohexyl-6-(4-(4-methoxyphenyl)piperidin-1-yl)picolinamide;

N-cyclohexyl-6-(4-(4-chlorophenyl)piperidin-1-yl)picolinamide;

N-cyclohexyl-6-(4-(4-fluorophenyl)piperidin-1-yl)picolinamide;

(N-(Adamantan-2-yl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)picolinamide)(N-(adamantan-2-yl)-6-(piperidin-1-yl)picolinamide;

N-(adamantan-2-yl)-6-(4-methylpiperidin-1-yl)picolinamide;

(N-(adamantan-2-yl)-6-(4-(4-chlorophenyl)piperazin-1-yl)picolinamide;

N-(adamantan-2-yl)-6-(4-(4-fluorophenyl)piperazin-1-yl)picolinamide;

N-(adamantan-2-yl)-6-(4-methylpiperazin-1-yl)picolinamide;

N-(adamantan-2-yl)-6-(4-acetylpiperidin-1-yl)picolinamide;

(N-(adamantan-2-yl)-6-(piperazin-1-yl)picolinamide;

(N-(adamantan-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)picolinamide;

methyl 3-(4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazin-1-yl)propanoate;

3-(4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazin-1-yl)propanoic acid;

N-(adamantan-2-yl)-6-(4-(3-amino3-oxopropyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(trifluoromethyl)-4-hydroxypiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(3-(trifluoromethyl)-3-hydroxypiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-hydroxy-4-methylpiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-cyclopropyl-4-hydroxypiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-hydroxy-4-phenylpiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(hydroxymethyl)piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(methoxycarbonylmethyl)piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(methoxycarbonylethyl)piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(piperidin-1-yl)piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-morpholinopiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-phenylpiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-cyanophenyl)piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-phenylpiperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-cyanophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-hydroxyphenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-chlorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-trifluoromethyl)phenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-fluorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-p-tolylpiperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-methoxyphenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-nitrophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(3,4-dihydroquinoline-1(2H)-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(3,4-dihydroisoquinoline-2(1H)-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(2-methylpiperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-benzylpiperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(pyridin-3-ylmethyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)picolinamide;

methyl 3-(4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)propanoate;

3-(4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)propanic acid;

6-(4-(3-amino-3-oxopropyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

2-(1-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)acetic acid;

6-(4-(3-amino-3-oxopropyl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

3-(1-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)propanic acid;

6-(4-(4-carbamoylphenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-carbamoylphenyl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-aminophenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-cyano-3-fluorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(2-chloro-4-cyanophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(3,4-dimethoxyphenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-(4-(4-ethoxycarbonylmethoxyphenyl)piperazin-1-yl)picolinamide;

6-(4-(4-carbamoyl-3-fluorophenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-carbamoyl-2-chlorophenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

2-(4-(4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)phenoxy)acetic acid;

6-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-fluoropyridin-2-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-methylpyridin-2-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-carbamoylpyridin-2-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-fluorophenyl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-p-tolylpiperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-methoxyphenyl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(pyridin-2-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-fluoropyridin-2-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-methylpyridin-2-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(5-cyanopyridin-2-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(3-cyanopyridin-2-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(pyridin-3-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(6-methylpyridin-3-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(6-aminopyridin-3-yl)piperidin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(1-(4-cyanophenyl)piperidin-4-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((S)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((S)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(3-(methylsulfonyl)phenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide

6-((R)-4-(4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(3-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(3,4-dimethoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(dimethylamino)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(4-nitrophenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(5-methoxypyridin-2-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(6-methoxypyridin-3-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(6-methylpyridin-3-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(6-nitropyridin-3-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(pyridin-4-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(4-(methylsulfonyl)phenyl)-1,4-diazepan-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-(4-(2-fluoro-4-methoxyphenyl)-1,4-diazepan-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(6-aminopyridin-3-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-aminophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-acetamidophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-(methylsulfoneamido)phenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methylpiperazin-1-yl)picolinamide;

methyl 4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)benzoate;

4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)benzoic acid;

6-((R)-4-(4-carbamoylphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-(methylcarbamoyl)phenyl)piperazin-1-yl)picolinamide;

6-((R)-4-(4-(cyclopropylcarbamoyl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-4-(4-((2-hydroxyethyl)carbamoyl)phenyl)-2-methylpiperazin-1-yl)picolinamide;

methyl 4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-fluorobenzoate;

4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-fluorobenzoic acid;

6-((R)-4-(4-carbamoyl-3-fluorophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-(methylcarbamoyl)-3-fluorophenyl)piperazin-1-yl)picolinamide;

methyl 4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)3-chlorobenzoate;

4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)3-chlorobenzoic acid;

6-((R)-4-(4-carbamoyl-2-chlorophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(methylcarbamoyl)-2-chlorophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

methyl 4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-methoxybenzoate;

4-((S)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-methoxybenzoic acid;

6-((R)-4-(4-carbamoyl-3-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(methylcarbamoyl)-3-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

methyl 5-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-methoxybenzoate;

5-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-methoxybenzoic acid;

6-((R)-4-(3-carbamoyl-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(3-(methylcarbamoyl)-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

methyl 5-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-fluorobenzoate;

5-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-2-fluorobenzoic acid;

6-((R)-4-(3-(methylcarbamoyl)-4-fluorophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(6-methoxycarbonylpyridin-3-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-2-methyl-4-(6-hydroxycarbonylpyridin-3-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(6-carbamoylpyridin-3-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(6-(methylcarbamoyl)pyridin-3-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

methyl 6-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)nicotinate;

6-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)nicotinic acid;

6-((R)-4-(5-carbamoylpyridin-2-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(5-(methylcarbamoyl)pyridin-2-yl)piperazin-1-yl)picolinamide;

ethyl 6-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-5-chloronicotinate;

6-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-5-chloronicotinic acid;

6-((R)-4-(5-carbamoyl-3-chloropyridin-2-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(5-(methylcarbamoyl)-3-chloropyridin-2-yl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-sulfamoylphenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-(N-methylsulfamoyl)phenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-sulfamoyl-2-fluorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-(N-methylsulfamoyl)-2-fluorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-sulfamoyl-3-fluorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(4-(N-methylsulfamoyl)-3-fluorophenyl)piperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-4-(4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-methylpiperazin-1-yl)picolinamide;

6-((R)-4-(4-acetylphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-trifluoroacetylphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(2-cyanopropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(ethylcarbonyl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(3-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(1-hydroxycyclopropyl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(dimethylaminomethyl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-(2-methyl-2-hydroxypropoxy)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((2R)-4-(4-(1-hydroxyethyl)phenyl)-2-methylpiperazin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((2R)-2-methyl-4-(4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)piperazin-1-yl)picolinamide;

6-((R)-4-(4-(1-amino-2-methyl-1-oxopropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide

6-((R)-4-(3-chloro-4-hydroxyphenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

ethyl 2-(2-chloro-4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)phenoxy)acetate;

2-(2-chloro-4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)phenoxy)acetic acid;

6-((R)-4-(4-(2-amino-2-oxoethoxy)-3-chlorophenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl)picolinamide;

6-((R)-4-(2-hydroxy-2-methylpropyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)picolinamide;

6-((R)-4-((1-cyanocyclopropyl)methyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-((1-carbamoylcyclopropyl)methyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-cyclopropyl-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)picolinamide;

6-((R)-4-(4-hydroxy-4-methylcyclohexyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(piperidin-4-yl)piperazin-1-yl)picolinamide;

6-((R)-4-(1-acetylpiperidin-4-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)piperazin-1-yl)picolinamide;

6-((R)-4-acetyl-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-cyclopropylcarbonyl-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-methylsulfonyl-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-cyclopropylsulfonyl-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-methoxyphenylsulfonyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-trifluoromethylphenylsulfonyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-bromophenylcarbonyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-hydroxyacetyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-hydroxy-2,2-dimethylacetyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-hydroxymethyl-2,2-dimethylacetyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-dimethylaminoacetyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(2-methoxycarbonylmethylacetyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

6-((R)-4-(4-amino-4-oxobutanoyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

4-((R)-4-(6-(((E)-5-hydroxyadamantan-2-yl)carbamoyl)pyridin-2-yl)-3-methylpiperazin-1-yl)-4-oxobutanoic acid;

5-fluoro-N-((E)-5-hydroxyadamantan-2-yl)-6-((R)-2-methylpiperazin-1-yl)picolinamide;

5-fluoro-6-((R)-4-(4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

5-fluoro-6-((R)-4-(2-(2-hydroxypropan-2-yl)pyridin-5-yl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

5-fluoro-6-((R)-4-(4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-5-methyl-6-(piperidin-1-yl)picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-5-methyl-6-(piperazin-1-yl)picolinamide;

5-methyl-6-(4-(4-(2-hydroxypropan-2-yl)phenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

5-methyl-6-(4-(2-(2-hydroxypropan-2-yl)pyridin-5-yl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

5-methyl-6-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)picolinamide;

N-((E)-4-hydroxycyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-cyclopropyl-N—

((Z)-4-hydroxycyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-cyclopropyl-N-((E)-4-hydroxycyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-cyclopropyl-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-cyclopropyl-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-cyclopropyl-N-((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-cyclopropyl-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-6-(piperidin-1-yl)picolinamide;

N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-6-(piperidin-1-yl picolinamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-(((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-(4-(4-methoxyphenyl)piperazin-1-yl)pyrimidine-4-carboxamide;

2-((R)-4-benzyl-2-methylpiperazin-1-yl)-N-((E)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-(2-hydroxypropan-2-yl)pyridin-5-yl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-cyanophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-chlorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-trifluoromethylphenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-t-butylphenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-methyl-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-fluoro-4-(ethylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-chloro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2,5-difluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(3-fluoro-pyridin-4-yl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(3,5-difluoro-pyridin-4-yl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-fluoro-4-(dimethylaminomethyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2,6-difluoro-4-(dimethylaminomethyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-amino-4-fluoro-pyridin-5-yl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-amino-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-amino-2,6-difluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(3-methyl-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(3-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-(methylsulfonyl)naphthyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(2-(methylsulfonyl)-5-bromophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-(2-hydroxypropan-2-yl)-3-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-cyano-3-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-cyano-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-4-(4-cyano-2-chlorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-cyclohexyl-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-cyclohexyl-2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-cyclohexyl-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-(4,4-difluorocyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-(4,4-difluorocyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-(4,4-difluorocyclohexyl)pyrimidine-4-carboxamide;

N-(bicyclo[2.2.1]heptan-2-yl)-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-(bicyclo[2.2.1]heptan-2-yl)-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-(bicyclo[2.2.1]heptan-2-yl)-2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((2R,3as,5S,6aS)-octahydro-2,5-methanopentalen-3a-yl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((2R,3as,5S,6aS)-octahydro-2,5-methanopentalen-3a-yl)pyrimidine-4-carboxamide;

2-((R)-4-(4-cyano-2-fluorophenyl)-2-methylpiperazin-1-yl)-N-((2R,3as,5S,6aS)-octahydro-2,5-methanopentalen-3a-yl)pyrimidine-4-carboxamide;

N-(adamantan-2-yl)-2-((R)-4-(4-cyano-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-(adamantan-2-yl)-2-((R)-4-(4-methylsulfonyl-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-(adamantan-2-yl)-2-((R)-4-(4-(2-hydroxypropan-2-yl)-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-(adamantan-2-yl)-2-((R)-4-(4-methoxy-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((S)-4-(4-cyano-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((S)-4-(4-methylsulfonyl-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((S)-4-(4-(2-hydroxypropan-2-yl)-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((S)-4-(4-methoxy-2-fluorophenyl)-2-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

N-cyclopropyl-2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1s,4S)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1 r,4R)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-methoxyphenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(4-cyano-2-fluorophenyl)-2-methylpiperazin-1-yl)-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

2-((R)-4-(4-cyano-2-fluorophenyl)-2-methylpiperazin-1-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(4-nitro-2-fluorophenyl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(2,6-difluoro-4-(methylsulfonyl)phenyl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(2-fluoro-4-(3-dimethylaminopropylsulfonyl)phenyl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(3-trifluoromethylpyridin-4-yl) piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(3-trifluoromethyl-5-fluoropyridin-4-yl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(3-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(3-fluoro-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidine-4-carboxamide;

N-((E)-5-hydroxyadamantan-2-yl)-2-((R)-2-methyl-4-(3-trifluoromethyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidine-4-carboxamide.

4. A pharmaceutical composition comprising the amide compound or the pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof according to claim 1, and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition for treating diseases caused, mediated, and/or spread by the high cortisol level, the pharmaceutical composition comprising the amide compound or the pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof according to claim 1, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for treating diabetes, prediabetes, insulin tolerance, low glucose tolerance, hyperglycemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, or lipid disorders, the pharmaceutical composition comprising the amide compound or the pharmaceutically acceptable salt, solvate, hydrate, prodrug, racemate, or stereoisomer thereof according to claim 1, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition as claimed in claim 6, wherein the diabetes is non-insulin dependent diabetes.

8. The pharmaceutical composition as claimed in claim 6, wherein the lipid disorders are low HDL levels or high LDL levels.