US010399945B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 399 ,945 B2 Saitoh et al. (45 ) Date of Patent: Sep . 3, 2019

( 54 ) TETRAHYDRONAPHTHYL UREA (2018 . 01 ) ; A61P 37 / 06 (2018 .01 ); A61P 43700 DERIVATIVE ( 2018 .01 ); C07C 213 / 10 ( 2013 .01 ) ; (Continued ) (71 ) Applicant: MOCHIDA PHARMACEUTICAL ( 58 ) Field of Classification Search CO ., LTD ., Tokyo ( JP ) CPC .. . CO7D 213 /89 ; CO7D 401/ 04 ; CO7D 405 /04 (72 ) Inventors: Fumihiko Saitoh , Tokyo ( JP ); Hiroshi See application file for complete search history . Nagasue , Tokyo ( JP ) (73 ) Assignee : MOCHIDA PHARMACEUTICAL (56 ) References Cited CO ., LTD . , Tokyo ( JP ) U .S . PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this 3 , 953 ,506 A 4 / 1976 Spicer et al . patent is extended or adjusted under 35 4 ,005 , 140 A 1/ 1977 Spicer et al. U . S . C . 154 (b ) by 0 days . (Continued ) (21 ) Appl. No. : 16 /138 ,369 FOREIGN PATENT DOCUMENTS 11 - 060543 A 3 / 1999 (22 ) Filed : Sep . 21 , 2018 2002 - 187875 A 7 /2002 (65 ) Prior Publication Data (Continued ) US 2019/ 0023657 A1 Jan . 24 , 2019 OTHER PUBLICATIONS Aalto et al. , “ Nerve Growth Factor in Serum of Children with Related U . S . Application Data Systemic Lupus Erythematosus Is Correlated With Disease Activ (63 ) Continuation of application No . ity ” , Cytokine , vol. 20 , No. 3 , Nov. 7 , 2002, pp . 136 - 139 . PCT/ JP2018 /016806 , filed on Apr. 25 , 2018 . (Continued ) ( 30 ) Foreign Application Priority Data Primary Examiner - Emily A Bernhardt Apr . 27 , 2017 ( JP ) ...... 2017 - 088933 (74 ) Attorney , Agent, or Firm — Birch , Stewart , Kolasch Sep . 15, 2017 ( JP ) ...... 2017 - 177596 & Birch , LLP ( 51 ) Int . Ci. (57 ) ABSTRACT C07D 213 /89 ( 2006 .01 ) The present invention aims to provide a compound having a C07D 401/ 04 ( 2006 .01 ) TrkA inhibitory action , a pharmaceutically acceptable salt (Continued ) thereof, or a solvate thereof, a pharmaceutical composition (52 ) U . S . CI. containing the same as an active ingredient, and a preventive CPC ...... C07D 213 /75 ( 2013. 01) ; A61K 31/ 444 and / or therapeutic agent for medicinal use , in particular for ( 2013 . 01 ); A61K 31/ 4418 ( 2013 .01 ) ; A61K a disease in which TrkA in involved (pain , cancers , inflam 31/ 4433 ( 2013 .01 ) ; A61K 31 /4439 (2013 .01 ) ; mation /inflammatory diseases, allergic diseases , skin dis A61K 31 / 506 (2013 .01 ) ; A61K 45 / 00 eases , neurodegenerative diseases, infectious diseases , ( 2013 .01 ) ; A61K 45 /06 (2013 . 01 ) ; A61P 1/ 00 Sjogren ' s syndrome, endometriosis , renal diseases , osteo ( 2018 . 01) ; A61P 1 /02 ( 2018 .01 ) ; A61P 1 /04 porosis , and the like ). Specifically , the present invention ( 2018 .01 ) ; A61P 1 / 16 ( 2018 .01 ) ; A61P 1 / 18 provides a compound or an optical isomer thereof, a phar ( 2018 .01 ) ; A61P 3 /04 (2018 . 01 ) ; A61P 3 / 06 maceutically acceptable salt thereof, a solvate thereof, or the ( 2018 .01 ) ; A61P 3 / 10 ( 2018 .01 ) ; A61P 5 / 14 like , the compound represented by formula ( I ) : ( 2018 .01 ) ; A61P 7700 ( 2018 . 01 ) ; A61P 9 / 00 ( 2018 . 01) ; A61P 9 / 06 ( 2018 .01 ) ; A61P 9 / 12 ( 2018 . 01 ) ; A61P 11 /00 ( 2018 .01 ) ; A61P 11 / 02 ( 2018 . 01 ) ; A61P 11 /04 ( 2018 .01 ) ; A61P 11 / 06 ( 2018 .01 ) ; A61P 13 / 02 ( 2018 . 01 ) ; A61P 13 / 08 ( 2018 . 01 ) ; A61P 13 / 10 (2018 .01 ) ; A61P 13 / 12 ( 2018 .01 ); A61P 15 / 00 ( 2018 .01 ) ; A61P 17700 R2 ( 2018 . 01 ) ; A61P 19 /02 ( 2018 .01 ) ; A61P 19 / 10 R25 ( 2018 .01 ) ; A61P 21 /00 ( 2018 .01 ) ; A61P 21/ 02 ( 2018 .01 ) ; A61P 25 / 00 ( 2018 . 01 ) ; A61P 25 / 04 ( 2018 . 01 ) ; A61P 25 /08 ( 2018 .01 ) ; A61P 25 / 16 N ( 2018 .01 ) ; A61P 25 / 20 ( 2018 .01 ) ; A61P 25 / 24 OH ( 2018 .01 ); A61P 25 /28 ( 2018 .01 ) ; A61P 29 /00 ( 2018 . 01 ); A61P 29 /02 ( 2018 .01 ) ; A61P 31/ 00 ( 2018 .01 ) ; A61P 31 / 18 ( 2018 . 01 ) ; A61P 35 / 00 ( 2018 .01 ) ; A61P 35 / 02 ( 2018 .01 ) ; A61P 37/ 00 27 Claims, No Drawings US 10 ,399 ,945 B2 Page 2

(51 ) Int. CI. C07D 405 / 14 (2013 .01 ); C07D 413 / 12 C07D 405 /04 ( 2006 .01 ) (2013 .01 ) ; C07D 417/ 04 ( 2013 .01 ) ; COZB CO7D 413 / 04 ( 2006 .01 ) 2200 /07 (2013 .01 ) CO7D 417/ 04 ( 2006 . 01 ) A61P 17 / 06 ( 2006 .01 ) References Cited A61P 25 / 00 ( 2006 . 01 ) (56 ) A61P 35 / 00 ( 2006 .01 ) U .S . PATENT DOCUMENTS CO7D 213 / 75 ( 2006 . 01 ) A61K 31/ 4418 ( 2006 .01 ) 4 ,062 , 856 A 12 / 1977 Spicer et al . 2016 /0229850 AL 8 /2016 Cooke et al. A61K 31 /506 ( 2006 .01 ) 2016 /0280692 AL 9 / 2016 Andrews et al. A61K 31/ 4439 ( 2006 .01 ) 2016 / 0297796 A1 10 / 2016 Allen et al . A61K 31 /444 ( 2006 . 01 ) 2016 /0355521 Al 12 /2016 Allen et al . CO7D 213 /84 ( 2006 . 01 ) 2017 / 0087156 AL 3 /2017 Allen et al. A61K 31/ 4433 (2006 .01 ) C07D 405 / 14 ( 2006 . 01 ) FOREIGN PATENT DOCUMENTS C07D 213 /81 ( 2006 . 01 ) JP 2011 -098930 A 5 / 2011 C07D 413 / 12 ( 2006 .01 ) JP 50 - 108250 A 3 / 2015 A61K 45 /06 ( 2006 . 01 ) JP 2015 - 537001 A 12 / 2015 A61K 45 / 00 ( 2006 .01 ) WO WO 2014 / 078454 A1 3 / 1999 C07C 213 / 10 ( 2006 .01 ) WO WO 2014 / 078325 A1 5 / 2014 ( 2006 .01 ) WO WO 2014 / 078378 A1 5 / 2014 C07C 215 /44 Wo WO 2015 /039333 AL 3 / 2015 A61P 1 / 16 ( 2006 .01 ) WO WO 2015 / 175188 A1 11 /2015 A61P 1 /02 ( 2006 .01 ) WO WO 2017 / 125534 A1 7 / 2017 A61P 31/ 00 ( 2006 . 01 ) A61P 3 /06 ( 2006 . 01 ) A61P 3 /04 ( 2006 .01 ) OTHER PUBLICATIONS A61P 1 /00 ( 2006 . 01 ) Althaus, Hans H ., “ Remyelination in multiple sclerosis : a new role A61P 21/ 02 ( 2006 .01 ) for neurotrophins ? ” , Progress in Brain Research , vol. 146 , 2004 , pp . A61P 13 / 02 ( 2006 .01 ) 415 - 432 A61P 11 / 00 ( 2006 .01 ) Ashraf et al. , " Selective inhibition of tropomyosin -receptor -kinase A61P 37 / 06 ( 2006 .01 ) A ( TrkA ) reduces pain and joint damage in two rat models of A61P 25 /24 ( 2006 .01 ) inflammatory arthritis ” , Arthritis Research & Therapy , vol. 18 , A61P 15 /00 ( 2006 . 01 ) 2016 , pp . 1 - 11 . A61P 29 /02 ( 2006 .01 ) Brodeur, Garrett M . , “ Neuroblastoma: Biological Insights Into a A61P 13 / 10 ( 2006 . 01 ) Clinical Enigma” , Nature Reviews Cancer , vol. 3 , Mar. 2003 , pp . A61P 25 / 04 ( 2006 . 01 ) 203 - 216 . A61P 25 / 16 ( 2006 . 01 ) Carr et al. , “ Neurotrophins and asthma” , Current Opinion in Pul A61P 25 / 20 ( 2006 . 01 ) monary Medicine , vol. 7 , 2001 , pp . 1 - 7 . A61P 21/ 00 ( 2006 .01 ) Chang et al. , “ Anti- nerve growth factor in pain management : A61P 9 / 06 ( 2006 . 01 ) current evidence ” , Journal of Pain Research , vol. 9 , 2016 , pp . A61P 9 /00 ( 2006 . 01 ) 373 - 383 A61P 25 / 28 ( 2006 . 01 ) Crowley et al ., “Mice Lacking Nerve Growth Factor Display A61P 29/ 00 Perinatal Loss of Sensory and Sympathetic Neurons yet Develop ( 2006 . 01 ) Basal Forebrain Cholinergic Neurons ” , Cell, vol. 76 , Mar . 25 , 1994 , A61P 5 / 14 ( 2006 .01 ) pp . 1001 - 1011 . A61P 35 /02 ( 2006 . 01 ) D ' Arco et al ., “ Neutralization of Nerve Growth Factor Induces A61P 19 / 10 ( 2006 .01 ) Plasticity of ATP -Sensitive P2X2 Receptors ofNociceptive Trigeminal A61P 1 / 18 ( 2006 .01 ) Ganglion Neurons” , The Journal of Neuroscience, vol. 27, No. 31 , A61P 37/ 00 ( 2006 . 01 ) Aug . 1, 2007 , pp . 8190 -8201 . A61P 13 /08 ( 2006 .01 ) Database Registry [ online ] , [ retrieved on Jul. 24 , 2018 ], American A61P 31 / 18 ( 2006 .01 ) Chemical Society, Retrieved from : STN , Entered STN : Nov . 28 , A61P 11 / 04 ( 2006 .01 ) 2013, RN : 1482781 - 17 - 8 , RN : 1482929 -49 - 6 , RN : 1483091 - 97 - 9 . , A61P 17/ 00 ( 2006 . 01 ) 3 pages. A61P 13 / 12 ( 2006 . 01 ) Demir et al . , “ Nerve growth factor & TrkA as novel therapeutic A61P 11 /06 ( 2006 .01 ) targets in cancer” , Biochimica et Biophysica Acta , vol. 1866 , 2016 , A61P 11 /02 ( 2006 . 01 ) pp . 37 - 50 . A61P 1 /04 ( 2006 .01 ) DiMola et al . , “ Nerve growth factor and Trk high affinity receptor A61P 19 /02 ( 2006 .01 ) ( TrkA ) gene expression in inflammatory bowel disease ” , Gut, vol. A61P 43/ 00 ( 2006 . 01 ) 46 , 2000 , pp . 670 -678 . A61P 7700 ( 2006 .01 ) English translation of claims filed in PCT/ JP2018 / 016806 . A61P 9 / 12 ( 2006 . 01 ) Gruber- Olipitz et al. , “ Synthesis , Chaperoning, and Metabolism of A61P 25 / 08 ( 2006 .01 ) Proteins Are Regulated by NT- 3 / TrkC Signaling in the Medulloblastoma Cell Line DAOY ” , Journal of Proteome Research , vol. 7 , No. 5 , A61P 3 / 10 ( 2006 .01 ) 2008 , pp . 1932 - 1944 . (52 ) U . S . CI. Guchhait et al. , “ A reaction of 1 , 2 - diamines and aldehydes with CPC ...... C07C 215 /44 ( 2013 .01 ) ; C07D 213 /81 cyanide pronucleophile to access 2 - aminopyrazines and ( 2013 .01 ) ; C07D 213 /84 ( 2013 . 01 ) ; C07D 2 - aminoquinoxalines ” , RSC Advances , vol . 6 , 2016 , pp . 56056 401/ 04 ( 2013 .01 ); C07D 405 /04 ( 2013 .01 ) ; 56063. US 10 ,399 ,945 B2 Page 3

References Cited Patapoutian et al . , “ Trk receptors : mediators of neurotrophin action ” , ( 56 ) Current Opinion Neurobiology , vol . 11 , 2001, pp . 272 - 280 . OTHER PUBLICATIONS Prakash et al. , “ Neurotrophins in lung health and disease ” , Expert Review of Respiratory Medicine , vol. 4 , No. 3 , Jun . 2010 , 28 pages. Higashijima et al. , “ cis - 1 - Amino - 1 , 2 , 3 , 4 - tetrahydro - 2 Rapp et al. , “ Analgesia Via Blockade of NGF/ TrkA Signaling Does naphthalenol: resolution and application to the catalytic enantioselec Not Influence Fracture Healing in Mice ” , Journal of Orthopaedic tive reduction of ketones” , Tetrahedron : Asymmetry , vol . 8 , No. 18 , Research , vol . 33, Aug . 2015 , pp . 1235 - 1241. 1997, pp . 3107 - 3110 . Roblin et al. , “ Topical Trka Kinase Inhibitor CT327 is an Effective, International Search Report (PCT / ISA /210 ) issued in PCT/ JP2018 / Novel Therapy for the Treatment of Pruritus due to Psoriasis : 016806 , dated Aug. 7 , 2018 . Results from Experimental Studies, and Efficacy and Safety of Kamiya et al ., “ Prognostic value of tropomyosin -related kinases A , CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis ” , Acta B , and C in gastric cancer ” , Clinical & Translational Oncology, vol. Dermato - Venereologica , vol. 95 , 2015 , pp . 542 - 548 . 18 , 2016 , pp . 599 -607 . Sabsovich et al. , “ Effect of anti -NGF antibodies in a rat tibia Kinbara et al. , “ Probability of spontaneously resolvable conglom fracture model of complex regional pain syndrome type I” , Pain , erates for racemic acid / racemic amine salts predicted on the basis of vol. 138 , No . 1 , Aug . 15 , 2008, 24 pages. the results of diastereomeric resolutions” , Tetrahedron : Asymmetry , Vaishnavi et al ., “ TRKing down an old oncogene in a new era of vol. 12 , 2001 , pp . 2927 - 2930 . targeted therapy ” , Cancer Discovery , vol. 5 , No. 1 , Jan . 2015 , 19 Klein , Rüdliger, “ Role of neurotrophins in mouse neuronal devel pages . opment” , The FASEB Journal, vol . 8 , Jul. 1994 , pp . 738 -744 . Written Opinion (PCT / ISA /237 ) issued in PCT/ JP2018 /016806 , McKelvey et al ., “ Nerve growth factor- mediated regulation of pain dated Aug. 7 , 2018 . signalling and proposed new intervention strategies in clinical pain Zhang et al. , “ Paradoxical Effect of Trk A Inhibition in Alzheimer ' s management” , Journal of Neurochemistry. vol. 124 , 2013 , pp . Disease Models ” , Journal of Alzheimer ' s Disease , vol . 40 , No . 3 , 276 - 289 . 2014 , 20 pages. US 10 , 399 , 945 B2 TETRAHYDRONAPHTHYL UREA gastric cancer , lung cancer , breast cancer, glioma , astrocy DERIVATIVE toma, medulloblastoma, cholangiocellular carcinoma , secre tory breast carcinoma, salivary gland carcinoma , prostate CROSS REFERENCE TO RELATED cancer, pancreatic cancer, thyroid papillary carcinoma, and APPLICATIONS 5 adult myeloid leukemia due to mutations and the like including overexpression , activation , and gene fusion . It has This application is a Continuation of PCT International been shown in clinical studies and nonclinical studies that Application No . PCT/ JP2018 /016806 , filed on Apr. 25 , Trk inhibitors inhibit tumor proliferation (Non Patent Lit 2018 , which claims priority under 35 U . S . C . 119 ( a ) to Patent eratures 10 to 14 ) . Application No . 2017 -088933 , filed in Japan on Apr. 27 , 10 Also , it is reported that : the Trka receptor is also 2017 , and to Patent Application No . 2017 - 177596 , filed in expressed in inflammatory cells such as mast cells and Japan on Sep . 15 , 2017 , all of which are hereby expressly eosinophils , immunocompetent cells such as monocytes , incorporated by reference into the present application . macrophages , T cells , and B cells , central nerve cells includ 15 ing cholinergic nerves, and the like ; and the NGF / TrkA TECHNICAL FIELD pathway is also involved in diseases such as asthma, rhinitis , The present invention relates to a compound havingo a atopic dermatitis , ulcerative colitis , Crohn ' s disease , psoria tropomyosin receptor kinase A ( TrkA ) inhibitory action , in sis , multiple sclerosis , systemic lupus erythematosus , and particular a compound having a urea structure represented Alzheimer ' s disease (Non Patent Literatures 15 to 21 ) . by formula ( I ) to be described later or an optical isomer 20 For those reasons, the creation of a drug having a TrkA thereof, a pharmaceutically acceptable salt thereof, or a inhibitory activity can be expected to produce a novel type solvate thereof, and to a pharmaceutical composition con of therapeutic and /or preventive agent because the created taining the same as an active ingredient. Also , the present drug has a possibility of application to the treatment ofpain , invention relates to a method of producing a urea compound cancers , inflammatory diseases , allergic diseases , and auto represented by formula ( 1 ) to be described later, a pharma- 25 immune diseases , and the like . ceutically acceptable salt thereof, or a solvate thereof, and to Derivatives having a urea structure and exhibiting a TrkA an intermediate compound useful in the production method inhibitory action are disclosed in , for example , International Moreover , the present invention relates to a preventive Publication No. WO2015 / 175788 (Patent Literature 1 ) , and / or therapeutic agent for a disease in which TrkA is International Publication No . WO2015 /039333 (Patent Lit involved . 30 erature 2 ), International Publication No . WO2014 / 078378 ( Patent Literature 3 ) , and International Publication No . BACKGROUND ART WO2014 /078325 (Patent Literature 4 ) . However, the deriva tives disclosed in these literatures do not include a com Tropomyosin receptor kinase ( Trk ) is a neurotrophin (NT ) pound with a tetrahydronaphthyl structure which is a char receptor tyrosine kinase which has an NT- binding domain 35 acteristic structure of the present invention , and there is no extracellularly and a kinase domain intracellularly , and is disclosure or suggestion for a compound with a tetrahy classified into TrkA being a receptor for nerve growth factor dronaphthyl structure . (NGF ) , TrkB being a receptor for brain -derived neurotrophic Meanwhile , although International Publication No . factor (BDNF ) and NT- 4 /5 , or TrkC being a receptor for WO2014 /078454 (Patent Literature 5 ) discloses a derivative NT- 3 . These Trk receptors are reported to be highly 40 having a tetrahydronaphthyl structure and exhibiting a TrkA expressed in nerve tissues and be involved in neuronal inhibitory action , the patent is a urea derivative having a differentiation and maintenance, and signal transduction pyrazole ring and does not disclose a specific compound of (Non Patent Literature 1 ) . the present invention . The NGF is known to increase in concentration in painful Here, in drug development, it is required to satisfy strict diseases such as arthritis , pancreatitis , cystitis , chronic head - 45 criteria in various aspects such as absorption , distribution , ache , diabetic neuropathy , and cancers. In addition , it has metabolism , and excretion as well as the intended pharma been reported that administration of the NGF to a human or cological activities . There are requirements concerning vari a rat induces pain (Non Patent Literature 2 ) . Moreover, it is ous problems to be considered such as drug interaction , known that human loss - of- function mutation in the NGF or desensitivity or tolerance , gastrointestinal absorption by oral TrkA results in congenital analgesia (Non Patent Literature 50 administration , rate of transfer into the small intestine , 3 ) and that pain symptoms disappear in NGF or Trka absorption rate and first pass effect , organ barrier , protein knockout mice (Non Patent Literatures 4 and 5 ) . Therefore , binding , induction or inhibition of drug metabolizing it is considered that the NGF / TrkA pathway is strongly enzyme, excretion route and body clearance , and application involved in the development of pain in vivo . method (application part ,method , purpose ). It is hard to find It has been shown in clinical studies and nonclinical 55 a drug which satisfies these requirements . However, these studies that inhibitors of the NGF / TrkA pathway , namely problems seem to be always associated with medicines . anti- NGF antibodies , anti - TrkA antibodies, small molecule Trk inhibitors, and the like are able to ameliorate various CITATION LIST pain symptoms. For example , it has been reported that they are effective for pain associated with osteoarthritis , chronic 60 Patent Literatures low back pain , rheumatoid arthritis , bone fracture, intersti tial cystitis , and chronic pancreatitis , and for pain such as Patent Literature 1 : International Publication No. WO2015 / neuropathic pain , cancer pain , complex regional pain syn - 175788 drome, and migraine (Non Patent Literatures 2 and 6 to 9 ) . Patent Literature 2 : International Publication No. WO2015 / It is known that Trk receptors including TrkA are involved 65 039333 in various cancers such as neuroblastoma , ovarian cancer, Patent Literature 3 : International Publication No. WO2014 / colon and rectal cancer, melanoma, head and neck cancer, 078378 US 10 , 399 , 945 B2 Patent Literature 4 : International Publication No . WO2014 ) invention also provides a method of producing a urea 078325 compound having a TrkA inhibitory action , a pharmaceuti Patent Literature 5 : International Publication No . WO2014 ! cally acceptable salt thereof , or a solvate thereof , and an 078454 intermediate compound useful in the production method . Furthermore , although there are several reported Non Patent Literatures examples of compounds having a TrkA inhibitory action , the above -mentioned comprehensive problems in the drug Non Patent Literature 1 : Current Opinion in Neurobiology , development are always present. More specifically , there are Volume 11 , pp . 272 - 280 , 2001 problems in usefulness and safety such as a problem of poor Non Patent Literature 2 : Journal of Pain Research , Volume 10 solubility , a problem that systemic exposure by oral admin 9, pp . 373 - 383 , 2016 istration is difficult due to a low metabolic stability , a Non Patent Literature 3 : Journal of Neurochemistry , Volume problem that pharmacokinetics such as absorbability and 124 , pp . 276 - 289 , 2013 sustainability is poor, a problem of exhibiting the inhibitory Non Patent Literature 4 : Cell, Volume 76 , pp . 1001 - 1011, activity of the hERG (human ether - a - go - go -related gene ) 1994 15 channel which has a risk of causing arrhythmia , a problem Non Patent Literature 5 : The FASEB Journal, Volume 8 , pp . of exhibiting induction or inhibitory activity of a drug 738 - 744 , 1994 metabolizing enzyme ( for example , cytochrome P450 and Non Patent Literature 6 : Arthritis Research & Therapy , the like ) , and a problem of exhibiting a high protein binding Volume 18 , p . 97 , 2016 rate . It is required to find a compound which is highly Non Patent Literature 7 : Journal of Orthopaedic Research , 20 effective and which solves these problems as many as Volume 33 , pp . 1235 - 1241, 2015 possible . Non Patent Literature 8 : Pain , Volume 138 , pp . 47- 60 , 2008 Non Patent Literature 9 : The Journal of Neuroscience , Means for Solution of the Problems Volume 27 , pp . 8190 - 8201, 2007 Non Patent Literature 10 : Biochimica et Biophysica Acta , 25 The present inventors have continuously made earnest Volume 1866 , pp . 37 - 50 , 2016 studies in order to achieve the above object , specifically , to Non Patent Literature 11: Cancer discovery, Volume 5 , pp . obtain a TrkA inhibitor which is high in safety and /or which 25 - 34 , 2015 is excellent in effectiveness, and consequently found that a Non Patent Literature 12 : Clinical & Translational Oncol compound having a urea structure represented by the fol ogy , Volume 18 , pp . 599 -607 , 2016 30 lowing formula ( I) , a pharmaceutically acceptable salt Non Patent Literature 13 : Journal of Proteome Research , thereof , or a solvate thereof has a TrkA inhibitory action . Volume 7 , pp . 1932 - 1944 , 2008 Also , the present inventors have found a method of produc Non Patent Literature 14 : Nature Reviews Cancer, Volume ing the compound represented by formula (I ) , a pharmaceu 3 , pp . 203 -216 , 2003 tically acceptable salt thereof, or a solvate thereof, and an Non Patent Literature 15 : Journal of Alzheimer ' s Disease , 35 intermediate compound useful in the production method . Volume 40 , pp . 605 -617 , 2014 The compound of the present invention can have an action Non Patent Literature 16 : Expert review of Respiratory of ameliorating pain and the like because it has a TrkA Medicine , Volume 4 , pp . 395 - 411, 2010 inhibitory action . Non Patent Literature 17 : Current Opinion in Pulmonary Medicine , Volume 7 , pp . 1 -7 , 2001 40 Non Patent Literature 18 : Gut, Volume 46 , pp . 670 -678 , 2000 Non Patent Literature 19 : Acta Dermato - Venereologica , Volume 95 , 542 - 548 , 2015 Rza Non Patent Literature 20 : Cytokine, Volume 20 , pp . 136 - 45 139 , 2002 R20 Non Patent Literature 21: Progress in Brain Research , Vol ume 146 , pp . 415 -432 , 2004 NH OH SUMMARY OF INVENTION 50 The present invention has an object to provide a com - The present invention relates to a compound having a pound having a TrkA inhibitory action , a pharmaceutically tetrahydronaphthyl urea structure represented by formula ( I ) acceptable salt thereof, or a solvate thereof, a pharmaceuti or an optical isomer thereof, a pharmaceutically acceptable cal composition containing the same as an active ingredient, 55 salt thereof, or a solvate thereof, and to a pharmaceutical and a preventive and /or therapeutic agent for medicinal use , composition containing the same as an active ingredient. in particular for a disease in which Trk , is involved [for The compound of the present invention is a compound example , pain ( pain associated with osteoarthritis , rheuma - having a TrkA inhibitory action and can have an action of toid arthritis , bone fracture , interstitial cystitis , chronic pan - ameliorating various diseases such as pain in which TrkA is creatitis , and prostatitis , nociceptive pain typified by chronic 60 involved . low back pain , diabetic peripheral neuropathic pain , post - The pharmaceutical composition containing the com operative pain , pelvic pain , cancer pain , and the like, neu - pound of the present invention as an active ingredient can be ropathic pain , acute pain , chronic pain , and inflammatory administered orally and is expected as a TrkA inhibitor and pain ) , cancers , inflammation / inflammatory diseases , allergic as a preventive and / or therapeutic agent for a disease in diseases , skin diseases , neurodegenerative diseases, infec - 65 which TrkA is involved , particularly pain . In addition , it can tious diseases, Sjogren ' s syndrome, endometriosis, renal be said that the compounds of the present invention are each diseases , osteoporosis , and the like ) . In addition , the present useful as a medical drug because it has a TrkA inhibitory US 10 ,399 ,945 B2 action . The compounds of the present invention each can - continued have any of or all of the following excellent characteristics (PS - 2 ) ( i ) to ( ix ) , for example : ( i ) solubility is good ; ( ii ) oral absorbability is excellent; ( iii ) inhibitory action against CYP enzymes ( for example , CYP1A2 , CYP2C9 , CYP2C19 , 5 CYP2D6, CYP3A4 , and the like ) is weak ; (iv ) good phar macokinetics such as high bioavailability and moderate clearance is exhibited ; ( v ) metabolic stability is high ; (vi ) ( PS - 3 ) irreversible inhibitory action is not exhibited against CYP enzymes (example : CYP3A4 ) within the concentration range of the measurement conditions described in the pres 10 ent specification ; ( vii) no mutagenicity , ( viii ) cardiovascular risk is low / the inhibitory action of hERG channel is small ; and ( ix ) TrkA receptor selectivity is high . (PS - 4 ) DESCRIPTION OF EMBODIMENTS 15 The present invention is a compound having a tetrahy dronaphthyl urea structure represented by the following formula ( I ) shown in the embodiments to be described below or an optical isomer thereof, a pharmaceutically acceptable 20 (PS - 5 ) salt thereof, or a solvate thereof, a pharmaceutical compo sition containing the same as an active ingredient, and medicinal use thereof and a TrkA inhibitor . More specifi cally , exemplary embodiments of the present invention can be as [ 1 ] to [ 30 ] below . 25 [ 1 ] A compound or an optical isomer thereof , a pharma moun ceutically acceptable salt thereof, or a solvate thereof, the compound represented by the following formula ( I) : (where Re in the partial structural formula (PS - 5 ) is a 30 hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C3- 8 cycloalkyl group , a C1- 6 alkoxy C1- 6 alkyl group , a haloge nated C1- 6 alkoxy C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a hydroxy halogenated C1- 6 alkyl group , or a 35 cyanated C1- 6 alkyl group ; the ring A is the following partial structural formula (SS - 1 ) to formula (SS - 5 ) :

N NH (SS - 1 ) OH 40 D4a where p represents an integer of 0 , 1 , 2 , 3 , or 4 ; R 45 R are each independently a halogen atom , a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a C1- 6 alkoxy 45 R3 group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 ( SS - 2 ) alkyl group , a mono -/ di - C2- 7 alkanoyl amino group , a car TProD 4a boxamide group , or a C1- 6 alkoxy carbonyl group ; R24 and R26 are each independently a hydrogen atom , a ( hydroxyl group , a halogen atom , a C1- 6 alkyl group , a 50 halogenated C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , or a ( SS - 3 ) R4 RAN - C1- 6 alkyl group (the R4c and Rd are each inde pendently a hydrogen atom , a C1- 6 alkyl group , a hydroxy 55 C1- 6 alkyl group , or a halogenated C1- 6 alkyl group ) ; R46 moreover, R2a and R25 are capable of bonding to each other to form a ring arbitrarily selected from the following partial structural formula (PS - 1 ) to formula (PS - 5 ) : 60 (SS - 4 ) 40 ( PS - 1 ) RA

R3 US 10 , 399 , 945 B2

-continued heterocyclic group ( the non - aromatic heterocyclic group ( SS - 5 ) may have each 1 to 3 substituent groups arbitrarily selected R4a from a hydroxyl group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy R46 5 C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C1- 6 alkoxy carbonyl group , a C2- 6 alkanoyl R3 group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a - NRØR group , a CONRORP group ( the Ra and Rp are where R3 in the partial structural formula (SS - 1 ) to 10 each independently a hydrogen atom , a C1- 6 alkyl group , a formula (SS - 5 ) is a hydrogen atom , a halogen atom , a C1- 6 halogenated C1- 6 alkyl group , or a C3- 8 cycloalkyl group ), a alkyl group , a Cz. g cycloalkyl group , a halogenated C , . . carboxy group , and a carboxamide group ), a — NR * R alkyl group, a hydroxy C1- 6 alkyl group , a C6- 10 aryl group , group , a CONR44R4 group (the R4e and R4 are each a 5 - or 6 -membered heteroaryl group , or a non - aromatic 15 independently a hydrogen atom , a C1- 6 alkyl group , a heterocyclic group ( the C6- 10 aryl group , the 5 - or 6 -mem hydroxy C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a bered heteroaryl group , and the non - aromatic heterocyclic hydroxy halogenated C1- 6 alkyl group , a C3- 8 cycloalkyl group may each have 1 to 3 substituent groups arbitrarily group , or a 5 - or 6 -membered heteroaryl C1- 6 alkyl group selected from a halogen atom and a C1- 6 alkyl group ); ( the 5 - or 6 -membered heteroaryl in the 5 - or 6 -membered R4a is a hydrogen atom , a halogen atom , a cyano group , a 20 heteroaryl C1- 6 alkyl group may have 1 to 3 substituent C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy groups arbitrarily selected from a halogen atom and a C1- 6 C1- 6 alkyl group , a C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy alkyl group )) , a RCR N C1- alkoxy group ( the R4c and group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 R4d are each independently a hydrogen atom , a C1- 6 alkyl alkyl group , a C1- 6 alkoxy C1- 6 alkoxy group , a C1- 6 alkoxy group , a hydroxy C1- 6 alkyl group , or a halogenated C1- 6 carbonyl group , a _ NR4CR 4d group , a _ CONR4CR4d group . 25 alkyl group ) , a halogenated mono - /di - C2 - 7 alkanoyl amino a R4CRAdN - C1- 6 alkoxy group (the R4C and R4d are each group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , independently a hydrogen atom , a C1- 6 alkyl group , a and a halogenated C1- 6 alkylsulfonyl group ) . hydroxy C1- 6 alkyl group , and a halogenated C1- 6 alkyl [ 2 ] The compound or the optical isomer thereof, the group ), a carboxamide group , a halogenated mono - / di- C2 - 7 pharmaceutically acceptable salt thereof, and the solvate alkanoyl amino group , or a C1- 6 alkylthio group ; and 30 thereof according to [ 1 ] described above, the compound R4 is a group arbitrarily selected from a hydrogen atom , a being the following formula ( I - a ): halogen atom , a hydroxyl group , a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy haloge nated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C1- 6 ( I - a ) alkoxy group , a hydroxy C1- 6 alkoxy group , a halogenated 35 C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C1- 6 Rla alkoxy C1- 6 alkoxy group , a halogenated C1- 6 alkoxy C1- 6 R4a alkyl group , a hydroxy C1- 6 alkoxy C1- 6 alkoxy group , a hydroxy halogenated C1- 6 alkoxy group , a C1-6 alkoxy car RAB bonyl group , a C1- 6 alkoxy carbonyl C1- 6 alkyl group , a 40 carboxy group , a carboxamide group , a C3- 8 cycloalkyl group ( the C3- 8 cycloalkyl group may have 1 to 3 substituent ZI NH groups arbitrarily selected from a hydroxyl group , a halogen R3 OH atom , a C1- 6 alkyl group , a C1-6 alkoxy group , and a C1- 6 alkoxy Cl- alkyl group ) , a C6 - 10 aryl group (may have 1 to 45 3 substituent groups arbitrarily selected from a hydroxyl where the substituents Rla , R1b , R24 , R26 , R3, R40, R4b , and group , a cvano group , a halogen atom . a alkyl group . a X represent the same groups as the groups defined in halogenated C1-6 alkyl group , a hydroxy C1- 6 alkyl group , a Embodiment 2 of the present invention to be described later. C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a halogenated [ 3 ] The compound or the optical isomer thereof, the C , alkoxy group , a C , alkoxy C , alkyl group , a C , 50 pharmaceutically acceptable salt thereof, and the solvate alkoxy carbonyl group , a C2- 6 alkanoyl group , a C1- 6 alky thereof according to [ 1 ] described above , the compound Ithio group , a C1- 6 alkylsulfonyl group , a - NR RP group , being the following formula (1 - a -1 ): a CONR “ RP group (the Rº and RP are each independently a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a C3 -8 cycloalkyl group ) , a carboxy group , 55 ( I - a - 1 ) and a carboxamide group ) , a 5 - or 6 -membered heteroaryl Rib group ( the 5 - or 6 -membered heteroaryl group may have 1 to 3 substituent groups arbitrarily selected from a hydroxyl Rla group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a 60 ( R et) B CH3 C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a halogenated - CH3 C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C2- 6 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a - NRØRP group , a CONRØRP group (the R™ and NH N RP are each independently a hydrogen atom , a C1- 6 alkyl 65 R3 OH group , a halogenated C1-6 alkyl group , or a C3- 8 cycloalkyl) , a carboxy group , and a carboxamide group ), a non -aromatic US 10 , 399 , 945 B2 10 where the substituents Rla , R15 , R ", and R " , the ring B , and tion is used in combination with a preventive and /or thera q represent the same groups as the groups defined in peutic drug for a disease selected from pain , cancers , inflam Embodiment 3 of the present invention to be described later. mation / inflammatory diseases , allergic diseases, skin 141 The compound or the optical isomer thereof the diseases , neurodegenerative diseases , infectious diseases , pharmaceuticall? acceptable salt thereof and the solvate 5 Sjogren ' s syndrome, endometriosis, renal diseases , and osteoporosis . thereof according to [ 1] described above, the compound [ 12 ] A method of treating a disease selected from pain , being the following formula (l -a - 2) : cancers , inflammation / inflammatory diseases , allergic dis eases , skin diseases, neurodegenerative diseases, infectious diseases , Sjogren 's syndrome, endometriosis , renal diseases , (I - a -2 ) 10 and osteoporosis , the method comprising: administering at - R16 least one of the compound or the optical isomer thereof, the Rla pharmaceutically acceptable salt thereof, and the solvate CH3 thereof according to any one of [ 1 ] to [ 5 ] described above to a subject in need of treatment of the disease . R4g 15 [ 14 ] A compound , a salt thereof, or a solvate thereof, the CH3 compound represented by the following formula (AM - 3 ) :

(AM - 3 ) OH 20 R 42 where the substituents Rla , R15 , R ?, and R4 represent the same groups as the groups defined in Embodiment 4 of the present invention to be described later. [5 ] A compound or an optical isomer thereof, a pharma 25 NH2 ceutically acceptable salt thereof, or a solvate thereof, the R3a compound being listed in Embodiment 5 of the present invention to be described later. where the substituents R34 , R4a , R45 , and X1 represent the [ 6 ] A pharmaceutical composition comprising : at least one 30 same groups as the groups defined in Embodiment 14 of the of the compound or the optical isomer thereof, the pharma present invention to be described later. ceutically acceptable salt thereof, and the solvate thereof [ 15 ] A compound , a salt thereof, or a solvate thereof, the according to any one of [ 1 ] to [5 ] described above as an compound represented by the following formula (AM - 3 - a ): active ingredient. [ 7 ] A preventive and / or therapeutic agent for a disease in 35 which Trka is involved , comprising : at least one of the (AM - 3 - a ) compound or the optical isomer thereof, the pharmaceuti CH3 cally acceptable salt thereof, and the solvate thereof accord (R50 , - B ing to any one of [ 1 ] to [5 ] described above as an active ingredient. 40 [ 8 ] A preventive and /or therapeutic agent for a disease IV selected from pain , cancers, inflammation / inflammatory dis NH2 eases , allergic diseases , skin diseases, neurodegenerative R32 diseases, infectious diseases, Sjogren ' s syndrome, endo metriosis , renal diseases , and osteoporosis , the agent com - 45 prising : at least one of the compound or the optical isomer where the ring B , q , and the substituents R3a and R5a thereof, the pharmaceutically acceptable salt thereof, and the represent the same groups as the groups defined in Embodi solvate thereof according to any one of [ 1 ] to [ 5 ] described ment 15 of the present invention to be described later . above as an active ingredient . [ 16 ] A compound , a salt thereof, or a solvate thereof, the 191 A TrkA inhibitor comprising : one or more of the 50 compound represented by the following formula (AM - 3 - b ) : compound or the optical isomer thereof, the pharmaceuti cally acceptable salt thereof, and the solvate thereof accord ( AM - 3 - b ) ing to any one of [ 1 ] to [5 ] described above . CH [ 10 ] A pharmaceutical composition comprising : one or more of the compound or the optical isomer thereof, the 55 pharmaceutically acceptable salt thereof, and the solvate thereof according to any one of [ 1 ] to [ 5 ] described above ; N and one or more types of preventive and /or therapeutic drugs Y NH2 for a disease selected from pain , cancers , inflammation / inflammatory diseases , allergic diseases , skin diseases, neu - 60 R3a rodegenerative diseases, infectious diseases, Sjogren ' s syn drome, endometriosis , renal diseases, and osteoporosis . where the substituents R $ a and R4a represent the same [ 11 ] A pharmaceutical composition comprising : at least groups as the groups defined in Embodiment 16 of the one of the compound or the optical isomer thereof, the present invention to be described later . pharmaceutically acceptable salt thereof, and the solvate 65 [ 17 ] A compound , a salt thereof, or a solvate thereof, the thereof according to any one of [ 1 ] to [ 5 ] described above as compound being listed in Embodiments 17 , 17a , and 17b of an active ingredient, wherein the pharmaceutical composi - the present invention to be described later. US 10 , 399 , 945 B2 11 12 [ 18 ] A compound , a salt thereof, or a solvate thereof, the [ 22 ] A compound , a pharmaceutically acceptable salt compound being listed in Embodiment 18 of the present thereof, or a solvate thereof, the compound represented by invention to be described later . the following formula (AM -2a -SS )• (L - TA ): [ 19 ] A compound , a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound represented by the following formula (AM - 2 -RR ) * ( D - TA ) : ( AM - 2a - SS ) • ( L - TA ) (AM -2 - RR )• ( D - TA ) 10 Pla (R !) OH – Rºb : HOOC COOH . H20

COOH 4 R20 . HOOC •H2O 15 HNY HN" OH OTI OH where the substituents Rla, R16 , R20 , and R26 represent the same groups as the groups defined in Embodiment 20 of the where the substituents R1, R20 , and R25 and p represent the present invention to be described later . same groups as the groups defined in Embodiment 19 of the [ 23 ] A method of producing a compound represented by present invention to be described later. the following formula (AM -2 -RR )* (D - TA ): [ 20 ] A compound , a pharmaceutically acceptable salt 25 thereof, or a solvate thereof, the compound represented by the following formula (AM -2a - RR ) • (D - TA ): ( AM - 2 - RR ) • ( D - TA ) (R ') ; ( AM -2a - RR )• (D - TA ) 30 OH RI – R2b • HOOC COOH .HO Rla (R ) OH OH 35 H2N ! ! Yo( R ) R2b • HO?C COOH .HO OH ( R ) HNH OH 40 OH where the substituents R1, R20 , and R2b and p represent the same groups as the groups defined in Embodiment 23 of the present invention to be described later. where the substituents R ' , R15 , R24 and R2b represent the [24 ] A method of producing a compound represented by same groups as the groups defined in Embodiment 20 of the 43 the following formula (AM - 2a -RR ) * ( D - TA ) : present invention to be described later. [21 ] A compound , a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound represented by (AM -2a -RR ) • ( D - TA ) the following formula (AM - 2 -SS ) • ( L - TA ) : 50 Rio Rla OH ( AM - 2 -SS )• ( L - TA ) COOH . H ,0 (R ' p V 55 – R2b • HO?C OH H2N " ( R ) R20 HOOC COOH .H20 OH H?NYs ÕH 60 SH where the substituents Rla , Rlb , R20 , and R26 represent the same groups as the groups defined in Embodiment 24 of the where the substituents R ', R20 , and R25 and p represent the 65 present invention to be described later same groups as the groups defined in Embodiment 21 of the [25 ] A method of producing a compound represented by present invention to be described later. the following formula ( AM - 2 - SS ) * ( L - TA ) : US 10 ,399 ,945 B2 13 14

( I -RR - 1 ) ( AM - 2 - SS ) • ( L - TA ) Rlb (R ' p Rla OH 5 R2a R2b • HO?C COOH . 1 ,0 HAN Y 10 NH ON OH

15 where the ring A and the substituents Rla , Rlb , R20 , and R25 where the substituents R1, R20 , and R25 and p represent the represent the same groups as the groups defined in Embodi same groups as the groups defined in Embodiment 25 of the ment 30 of the present invention to be described later . present invention to be described later . [26 ] A method of producing a compound representeded by byao Embodiments of Present Invention the following formula (AM -2a - SS )• (L - TA ): More specifically , the present invention includes Embodi ments [ 1 ] to [30 ] described below . (AM -2a - SS )• ( L - TA ) [ 1 ] Embodiment 1 of the present invention is a compound or 25 an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound represented by Rla the following formula (1 ) : R20 Rºb• HOOC COOH .HO H ,0 ) 3030

HN R20 35 ZI where the substituents R14 , R15 , R24 , and R2b represent the OH same groups as the groups defined in Embodiment 26 of the 40 present invention to be described later . where p represents an integer of 0 , 1 , 2 , 3 , or 4 ; R are each [27 ] A compound listed in Embodiment 27 of the present independently a halogen atom , a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl invention to be described later. group , a cyanated C1- 6 alkyl group , a C1- 6 alkoxy group , a [ 28 ] A compound listed in Embodiment 28 of the present 45 halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl invention to be described later. group , a mono - di- C2- 7 alkanoyl amino group , a carboxam [29 ] A method of producing a compound represented by ide group , or a C1- 6 alkoxy carbonyl group; the following formula ( I -RR ) : R2a and R25 are each independently a hydrogen atom , a 50 hydroxyl group , a halogen atom , a C1- 6 alkyl group , a halogenated C1-6 alkyl group , a C1- 6 alkoxy C1- 6 alkyl group , ( I -RR ) a hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , or a R4R4dN - C1- , alkyl group ( the R4c and R4d are each inde 55 pendently a hydrogen atom , a C1- 6 alkyl group , a hydroxy 6 C1- 6 alkyl group, or a halogenated C1- 6 alkyl group ) ; ( R ) moreover , R2a and R2b are capable of bonding to each other n ZZ (R ) to form a ring arbitrarily selected from the following partial structural formula (PS - 1 ) to formula ( PS - 5 ) : OH 60 where the ring A , p , and the substituents R ' , R24 , and R26 (PS - 1 ) represent the same groups as the groups defined in Embodi ment 29 of the present invention to be described later. inn [30 ] A method of producing a compound represented by the following formula ( I- RR - 1 ) : US 10 , 399 ,945 B2 15 16 -continued -continued (PS - 2 ) RUE ( SS - 5 ) mun R46 (PS - 3 )

10 where R3 in the partial structural formula (SS - 1 ) to formula (SS -5 ) is a hydrogen atom , a halogen atom , a C1- 6 alkyl ma group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl ( PS - 4 ) group , a hydroxy C1- 6 alkyl group , a C6- 10 aryl group , a 5 15 or 6 -membered heteroaryl group , or a non -aromatic hetero cyclic group ( the C6- 10 aryl group , the 5 - or 6 -membered heteroaryl group , and the non -aromatic heterocyclic group Ni may each have 1 to 3 substituent groups arbitrarily selected (PS - 5 ) from a halogen atom and a C1- 6 alkyl group ) ; 20 R4a is a hydrogen atom , a halogen atom , a cyano group , a Z C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy group , a halogenated C - , alkoxy group , a C1- 6 alkoxy C1 - 6 alkyl group , a C1- 6 alkoxy C1- 6 alkoxy group, a C1- 6 alkoxy 25 carbonyl group , a NR4R4d group , a — CONR + R4d group , mu a R4CR4dN - C1- 6 alkoxy group ( the R4C and R4d are each independently a hydrogen atom , a C1- 6 alkyl group , a where Re in the partial structural formula ( PS - 5 ) is a hydro - hydroxy C1- 6 alkyl group , and a halogenated C1- 6 alkyl group ), a carboxamide group , a halogenated mono -/ di- C2- 7 gen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkylcycloalkví group , 30 alkanoyl amino group , or a C1- 6 alkylthio group ; and a C3- 8 cycloalkyl group , a halogenated C3- 8 cycloalkyl 30 R4 is a group arbitrarily selected from a hydrogen atom , a group , a C1- 6 alkoxy C1- 6 alkyl group , a halogenated C1- 6 halogen atom , a hydroxyl group , a cyano group , a C1- 6 alkyl alkoxy C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a group , a halogenated C1- 6 alkyl group , a hydroxy haloge hydroxy halogenated C1- 6 alkyl group , or a cyanated C1- 6 nated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkyl group ; the ring A is the following partial structural 35 alkoxy group , a hydroxy C1- 6 alkoxy group , a halogenated formula (SS - 1 ) to formula (SS - 5 ) : C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 alkoxy group , a halogenated C1- 6 alkoxy C1- 6 alkyl group , a hydroxy C1- 6 alkoxy C1- 6 alkoxy group , a ( SS - 1) hydroxy halogenated C1- 6 alkoxy group , a C1- 6 alkoxy car R4a 40 bonyl group , a C1- 6 alkoxy carbonyl C1- 6 alkyl group , a carboxy group , a carboxamide group , a C3- 8 cycloalkyl R46 group (the C3- 8 cycloalkyl group may have 1 to 3 substituent groups arbitrarily selected from a hydroxyl group , a halogen atom , a C1- 6 alkyl group , a C1- 6 alkoxy group , and a C1- 6 R3 45 alkoxy C1- 6 alkyl group ), a C6 - 10 aryl group (the C6 -10 aryl (SS - 2 ) group may have 1 to 3 substituent groups arbitrarily selected from a hydroxyl group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy 50 group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C1- 6 alkoxy carbonyl group , a C2- 6 alkanoyl mir group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a (SS - 3 ) - NR “ RP group , a CONR RP group (the Rº and Rp are each independently a hydrogen atom , a C1- 6 alkyl group , a 55 halogenated C1- 6 alkyl group , or a C3- 8 cycloalkyl group ) , a carboxy group , and a carboxamide group ) , a 5 - or 6 -mem bered heteroaryl group ( the 5 - or 6 -membered heteroaryl group may have 1 to 3 substituent groups arbitrarily selected from a hydroxyl group , a cyano group , a halogen atom , a ( SS -4 ) 60 C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C2- 6 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a - NR RP group , a CONR RP 65 group ( the R? and Rp are each independently a hydrogen mm atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a C3- 8 cycloalkyl ), a carboxy group , and a carboxamide US 10 , 399 , 945 B2 18 group ) , a non - aromatic heterocyclic group ( the non - aromatic In the present specification , unless otherwise noted , a heterocyclic group may have each 1 to 3 substituent groups " cyanated C - alkyl group ” means a group in which the arbitrarily selected from a hydroxyl group , a cyano group, a “ C1- 6 alkyl” is arbitrarily substituted with several and pref halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl e rably 1 to 5 cyano groups , and includes groups of, for group , a hydroxy C1- 6 alkyl group , a C3- 8 cycloalkyl group , 5 example , cyanomethyl , 1 - cyanoethyl, and 2 -cyanoethyl . a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , a C1- 6 In the present specification , unless otherwise noted , a alkoxy C1- 6 alkyl group , a C1- 6 alkoxy carbonyl group , a “ hydroxy halogenated C1- 6 alkyl group ” means a group in C2- 6 alkanoyl group , a C1- 6 alkylthio group , a Cl- , alkylsul which the “ halogenated C1- 6 alkyl” is arbitrarily substituted fonyl group , a NR RP group , a CONR RP group (the with several and preferably 1 to 5 hydroxyl groups , and Rº and RP are each independently a hydrogen atom , a C1- 6 " includes groups of, for example , 2 , 2 , 2 -trifluoro - 1 -hydroxy alkyl group , a halogenated C1- 6 alkyl group , or a C3- 8 ethyl and 2- hydroxy - 1, 1 -difluoroethyl . cycloalkyl group ), a carboxy group , and a carboxamide In the present specification , unless otherwise noted , a group ) , a - NR4eRº group , a CONR4 R4 group (the R4e “ C1- 6 alkoxy group ” represents an alkoxy in which the “ C1- 6 and Rºare each independently a hydrogen atom , a C1- 6 alkyl 15 alkyl” is bound to an oxygen atom , and includes groups of, group , a hydroxy C1-6 alkyl group , a halogenated C1- 6 alkyl for example , methoxy , ethoxy, propoxy , isopropoxy, butoxy , group , a hydroxy halogenated C1- 6 alkyl group , a C3- 8 isobutoxy , sec -butoxy , tert- butoxy , pentyloxy, and hexyloxy . cycloalkyl group , or a 5 - or 6 -membered heteroaryl C1- 6 In the present specification , unless otherwise noted , a alkyl group (the 5 - or 6 -membered heteroaryl in the 5 - or “ halogenated C1- 6 alkoxy group ” represents a halogenated 6 -membered heteroaryl C1- 6 alkyl group may have 1 to 3 20 alkoxy in which the “ halogenated C1- 6 alkyl” is bound to an substituent groups arbitrarily selected from a halogen atom oxygen atom , and includes groups of, for example , fluo and a C1- 6 alkyl group ) ), a R4R4dN - C1- 6 alkoxy group ( the romethoxy, difluoromethoxy, trifluoromethoxy, 2, 2 ,2 -trif R4C and R4d are each independently a hydrogen atom , a C1- 6 luoroethoxy , 1 , 1 , 2 , 2 - tetrafluoroethoxy, and pentafluoroeth alkyl group , a hydroxy C1- 6 alkyl group , or a halogenated oxy . C1- 6 alkyl group ) , a halogenated mono - /di - C2 - 7 alkanoyl 25 In the present specification , unless otherwise noted , a amino group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl “ hydroxy C alkoxy group ” means a group in which the group , and a halogenated C1- 6 alkylsulfonyl group ) . “ C1- 6 alkoxy group ” is arbitrarily substituted with several Hereinafter , a detailed description is provided for the and preferably 1 to 5 hydroxyl groups , and includes groups groups in the above formula (I ) of the present invention and in formula ( I - a ) and the like being more specific embodi - 30 of, for example , hydroxyethoxy and 3 -hydroxypropoxy . ments of formula ( I ) . In the present specification , unless otherwise noted , a In the explanation of the compounds of the present “ hydroxy halogenated Cl- , alkoxy group ” means a group in invention , for example , " C _ 6 " indicates that the number of which the “ halogenated C1- 6 alkoxy group ” is arbitrarily constituent carbon atoms is 1 to 6 and represents the total substituted with several and preferably 1 to 5 hydroxyl number of carbon atoms of a linear, branched , or cyclic 3536 groups , and includes groups of, for example , 1 - fluoro - 1 group unless otherwise noted . It means the " total number of hydroxyethoxy, 1 , 1 - difluoro - 1 -hydroxyethoxy , and 2 - hy carbon atoms in the chains and the rings” for a group droxy - 1 , 1 , 1 - trifluoroethoxy . including linear groups and cyclic groups . In the present specification , unless otherwise noted , a In the present specification , unless otherwise noted , a “ halogenated C1- 6 alkoxy C1- 6 alkyl group ” means a group “ halogen atom ” includes, for example , a fluorine atom , a 40 in which the “ halogenated C1- 6 alkoxy group ” is substituted chlorine atom , a bromine atom , and an iodine atom . with the “ C1- 6 alkyl group ," and includes groups of, for In the present specification , unless otherwise noted , the example , fluoromethoxy methyl, difluoromethoxy methyl, " halogenated ” in a " halogenated C1- 6 alkyl group ” and the trifluoromethoxy methyl, 2 ,2 , 2 -trifluoroethoxy methyl , 1 ,1 , like means that several and preferably 1 to 5 of the “ halogen 2 , 2 - tetrafluoroethoxy methyl, and pentafluoroethoxy ethyl . atoms” may be included as substituents . 45 In the present specification , unless otherwise noted , a In the present specification , unless otherwise noted , the “ C1- 6 alkoxy C1- 6 alkyl group ” means a group in which the " cyanated ” in a “ cyanated C - alkyl” and the likemeans that “ C , - alkoxy ” is substituted with the " C . alkyl. ” In the that several and preferably 1 to 5 of the “ cyano groups” may present specification , unless otherwise noted , the “ C1- 6 be included as substituents . alkoxy C1- 6 alkyl ” includes groups of, for example, methoxy In the present specification , unless otherwise noted , a 50 methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, 1 , 1 “ C1- 6 alkyl group ” includes groups of, for example , methyl, dimethoxy methyl, and 1 , 1 - diethoxy ethyl . ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl , tert - butyl, In the present specification , unless otherwise noted , a pentyl , isopentyl , neopentyl, and hexyl. “ C1- 6 alkoxy C1- 6 alkoxy group ” means a group in which the In the present specification , unless otherwise noted , a “ C1- 6 alkoxy ” is substituted with the “ C1- 6 alkoxy, " and “ halogenated C1- 6 alkyl group ” means a group in which the 55 includes groups of, for example , methoxymethoxy, “ C1- 6 alkyl” is arbitrarily substituted with several and pref methoxyethoxy, ethoxymethoxy , ethoxyethoxy, 1 , 1 -dime erably 1 to 5 halogen atoms, and includes groups of, for thoxymethoxy , and 1 , 1 -diethoxyethoxy . example , fluoromethyl, difluoromethyl, trifluoromethyl, 2 , 2 , In the present specification , unless otherwise noted , a 2 -trifluoroethyl , 1 , 1, 2 , 2 - tetrafluoroethyl, and pentafluoro - “ hydroxy C1- 6 alkoxy C1- 6 alkoxy group ” means a group in ethyl. 60 which the " C , - alkoxy Cl- , alkoxy group ” is arbitrarily In the present specification , unless otherwise noted , a substituted with several and preferably 1 to 5 hydroxyl “ hydroxy C1- 6 alkyl group ” means a group in which the groups, and includes groups of, for example , hydroxy “ C1-6 alkyl” is arbitrarily substituted with several and pref ethoxymethoxy , hydroxyethoxyethoxy, and 3 -hydroxy erably 1 to 5 hydroxyl groups, and includes groups of, for propoxymethoxy. example , hydroxymethyl , 2 -hydroxyethyl , 3- hydroxypro - 65 In the present specification , unless otherwise noted , a pyl, and 2 , 2 - dimethyl- 2 - hydroxyethyl ( = 2 - hydroxy - 2 -meth “ C3- 8 cycloalkyl group ” includes monocyclic or polycyclic ylpropyl) . and saturated or unsaturated cycloalkyl groups having 3 to US 10 , 399 , 945 B2 19 20 8 carbon atoms, and includes groups of, for example , In the present specification , unless otherwise noted , a cyclopropyl , cyclobutyl, cyclopentyl , cyclohexyl, cyclohep - “ 6 -membered heteroaryl group ” is a 6 -membered heteroaryl tyl, and cyclooctyl . ring containing 1 to 4 hetero atoms selected from nitrogen In the present specification , unless otherwise noted , a atoms, sulfur atoms, and oxygen atoms, and the “ 6 -mem “ halogenated Cz. & cycloalkyl group ” means a group in 5 bered heteroaryl group ” means, unless otherwise noted , a which the “ C3- 8 cycloalkyl” is arbitrarily substituted with monovalent group formed by removing arbitrary hydrogen several and preferably 1 to 5 halogen atoms, and includes atoms from the heteroaryl ring , and includes groups of, for groups of, for example , fluorocyclopropyl , fluorocyclobutyl, example , pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 , 2 , fluorocyclopentyl, fluorocyclohexyl, fluorocycloheptyl, and 3 - triazinyl, 1, 2 ,4 - triazinyl, 1, 3 ,5 - triazinyl, 2H - 1 ,2 , 3 - thiadi fluorocyclooctyl. 10 azinyl, 4H - 1 , 2 , 4 - thiadiazinyl, 6H - 1 , 3 , 4 - thiadiazinyl, In the present specification , unless otherwise noted , a pyridazin - 3 (2H ) -one , pyrimidin - 2 ( 1H ) -one , pyrazin - 2 ( 1H ) “ halogenated C1- 6 alkoxy C1- 6 alkyl group ” means a group one, and pyridin - 2 ( 1H ) - one . in which the “ halogenated C1- 6 alkoxy ” is substituted with In the present specification , unless otherwise noted , a “ 5 the “ C1- 6 alkyl, ” and includes groups of, for example , or 6 -membered heteroaryl C1- 6 alkyl group ” means a group fluoromethoxy methyl, difluoromethoxy methyl, trifluo - 15 in which the “ 5 - or 6 -membered heteroaryl group ” is sub romethoxy methyl, 2 , 2 , 2 - trifluoroethoxy methyl, 1 , 1 , 2 , 2 - stituted with the “ C1- 6 alkyl group ,” and includes groups of, tetrafluoroethoxy methyl, and pentafluoroethoxy methyl. for example , pyrrolylmethyl, furylmethyl, thienylmethyl, In the present specification , unless otherwise noted , a imidazolylmethyl, pyrazolylmethyl, oxazolylmethyl, isox “ C6- 10 aryl group ” includes groups of, for example, phenyl, azolylmethyl, thiazolylmethyl, isothiazolylmethyl, 1 , 2 , 3 - tri 1 - naphthyl, 2 -naphthyl , indanyl , indenyl, and 1 , 2 ,3 , 4 - tetra - 20 azolylmethyl, 1 , 2 ,4 - triazolylmethyl, 1 , 2 , 3 - oxadiazolylm hydronaphthyl . ethyl, 1, 2 ,4 -oxadiazolylmethyl , 1, 3 ,4 -oxadiazolylmethyl , In the present specification , unless otherwise noted , a furazanylmethyl , 1 , 2 , 3 - thiadiazolylmethyl, 1 , 2 , 4 - thiadiaz “ heteroaryl group ” means a monocyclic , polycyclic , or fused olylmethyl, 1 , 3 ,4 -thiadiazolylmethyl , tetrazolylmethyl, cyclic (which may partially be hydrogenated if polycyclic or pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl, fused cyclic ) 5 - to 14 -membered , preferably 5 - to 8 -mem - 25 pyrazinylmethyl, 1 ,2 , 3 - triazinylmethyl, 1 , 2 , 4 - triazinylm bered , and more preferably 5 - to 7 -membered heteroaryl ring ethyl , 1, 3 ,5 - triazinylmethyl, 2H - 1, 2 ,3 - thiadiazinylmethyl , containing 1 to 5 and preferably 1 to 3 hetero atoms selected 4H - 1 , 2 , 4 -thiadiazinylmethyl , and 6H - 1 , 3 , 4 - thiadiazinylm from the group consisting of nitrogen atoms, sulfur atoms, ethyl. and oxygen atoms. In the present specification , unless otherwise noted , a In the present specification , unless otherwise noted , the 30 “ non -aromatic heterocyclic group ” means a “ 3 - to 14 -mem " heteroaryl group ” includes, for example , a “ monocyclic bered saturated or unsaturated non - aromatic heterocyclic heteroaryl group ," a " fused cyclic heteroaryl group , " and a group . ” " partially hydrogenated fused cyclic heteroaryl group . ” In the present specification , unless otherwise noted , the In the present specification , unless otherwise noted , the “ 3 - to 14 -membered saturated or unsaturated non -aromatic " monocyclic heteroaryl group ” is a monocyclic one among 35 heterocyclic group ” means a monovalent group formed by the heteroaryl rings, having 5 to 8 and further preferably 5 removing arbitrary hydrogen atoms from a 3 - to 14 -mem or 6 ring members (“ 5 - or 6 -membered heteroaryl group ” ) . bered saturated or unsaturated heterocycle containing 1 to 4 In the present specification , unless otherwise noted , the hetero atoms selected from nitrogen atoms, sulfur atoms, “ 5 - or 6 -membered heteroaryl group ” is a 5 - or 6 -membered and oxygen atoms. heteroaryl ring containing 1 to 4 hetero atoms selected from 40 In the present specification , unless otherwise noted , the nitrogen atoms, sulfur atoms, and oxygen atoms, and the “ 5 - " non -aromatic heterocyclic group ” includes groups of, for or 6 -membered heteroaryl group ” means , unless otherwise example , aziridinyl, azetidinyl, oxiranyl, thiiranyl, oxetanyl, noted , a monovalent group formed by removing arbitrary thietanyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl , thiola hydrogen atoms from the heteroaryl ring . nyl , pyrazolinyl, pyrazolidinyl, imidazolidinyl, piperidinyl , In the present specification , unless otherwise noted , the 45 dihydropyranyl, tetrahydropyranyl ( 2 -tetrahydro - 2H - pyra “ 5 - or 6 -membered heteroaryl group ” includes groups of, for nyl , 3 - tetrahydro -2H -pyranyl , 4 - tetrahydro -2H -pyranyl example , pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, ( 4 -tetrahydro - 2H - pyran - 4 - yl group ) ), tetrahydrothiopyranyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2 ,3 - triazolyl, piperazinyl, dioxanyl, oxazolidinyl, isoxazolinyl, 1 ,3 -oxazo 1 , 2 , 4 -triazolyl , 1 , 2 , 3 - oxadiazolyl, 1 , 2 , 4 - oxadiazolyl, 1 , 3 ,4 - lidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, 1 , 3 -thi oxadiazolyl , furazanyl, 1 , 2 , 3 -thiadiazolyl , 1 , 2 , 4 - thiadiaz - 50 azolidinyl, isothiazolidinyl, oxadiazolinyl, 1 , 3 , 4 - oxadiazo olyl, 1 , 3 ,4 - thiadiazolyl, tetrazolyl , pyridyl, pyridazinyl, lidinyl , morpholinyl, thiomorpholinyl , quinuclidinyl , pyrimidinyl , pyrazinyl, 1 , 2 , 3 -triazinyl , 1 , 2 , 4 - triazinyl, 1, 3 , azepanyl, diazepinyl, and oxepanyl . 5 - triazinyl, 2H - 1, 2 ,3 - thiadiazinyl, 4H - 1, 2 ,4 - thiadiazinyl, In the present specification , unless otherwise noted , a 6H - 1 , 3 , 4 - thiadiazinyl, pyridazin - 3 ( 2H ) - one , pyrimidin - 2 " C2- 7 alkanoyl group ” means a “ C1- 6 alkyl carbonyl group " ( 1H )- one, pyrazin - 2 ( 1H )- one , and pyridin - 2 ( 1H )- one . 55 in which a carbonyl group is bound to the “ C1- 6 alkyl group ,” In the present specification , unless otherwise noted , a and includes groups of, for example , acetyl, propionyl , “ 5 -membered heteroaryl group ” is a 5 -membered heteroaryl butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl , ring containing 1 to 4 hetero atoms selected from nitrogen heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclo atoms, sulfur atoms, and oxygen atoms, and the “ 5 -mem - pentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcar bered heteroaryl group ” means, unless otherwise noted , a 60 bonyl, and 2 -methylcyclopropylcarbonyl . monovalent group formed by removing arbitrary hydrogen In the present specification , unless otherwise noted , a atoms from the heteroaryl ring , and includes groups of, for “ mono - di- C2- 7 alkanoyl amino group ” means an “ amino example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, group ” in which one or two hydrogen atoms on the nitrogen oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 , 2 , 3 - triazolyl, atom of the amino group are substituted with the “ C24 1 , 2 , 4 -triazolyl , 1 , 2 , 3 - oxadiazolyl, 1 , 2 , 4 - oxadiazolyl, 1 , 3 ,4 - 65 alkanoyl group ,” and includes groups of, for example , oxadiazolyl, furazanyl, 1 , 2 , 3 - thiadiazolyl, 1 , 2 , 4 - thiadiaz acetamide, propionamide , butylamide, isobutylamide, val olyl, 1 , 3 , 4 - thiadiazolyl, and tetrazolyl. eramide, isovaleramide, pivalamide, hexanamide , heptana US 10 , 399 , 945 B2 21 22 mide , cyclopropanecarboxamide, cyclobutanecarboxamide , pendently a hydrogen atom , a C1- 6 alkyl group , a haloge cyclopentanecarboxamide , cyclohexanecarboxamide, nated C1- 6 alkyl group , or a C3- 8 cycloalkyl group . 2 -methylcyclopropanecarboxamide , and diacetamide. In the present specification , unless otherwise noted , a In the present specification , unless otherwise noted , a “ R4CR4dN - C , alkoxy group ” means a group in which the “ halogenated mono - /di - C2 - 7 alkanoyl amino group ” meansas “ _ NR4CR4d group ” is substituted with the “ C , alkoxy group in which the “ C1- 6 alkyl group ” of the “ mono - di- C2- 7 group, " and includes groups of, for example, N , N - dimeth alkanoyl amino group ” is arbitrarily substituted with several ylaminomethoxy , N -methylaminomethoxy , N - ethylamin and preferably 1 to 5 halogen atoms, and includes groups of, omethoxy, N , N -dimethylaminoethoxy , N -methylaminoeth for example , trifluoroacetamide, 3 , 3 , 3 - trifluoropropana mide , and trifluoroacetyltrifluoroacetamide . 10 oxy, and N - ethylaminoethoxy. The definitions of R4C and In the present specification , unless otherwise noted , a R4d are as described above. “ C1- 6 alkoxy carbonyl group ” means a group in which the In the present specification , unless otherwise noted , a hydrogen atom of the “ carboxy group ( COOH ) ” is sub “ R4CR4N - C1- 6 alkyl group ” means a group in which the stituted with the “ C1- 6 alkyl group, ” i. e . an “ ester group , ” “ — NR4CR4d group ” is substituted with the “ C1- 6 alkyl and includes groups of, for example , methoxycarbonyl group ," and includes groups of, for example , aminomethyl, (methyl ester ), ethoxycarbonyl ( ethyl ester ) , and tert - bu N , N - dimethylaminomethyl, N -methylaminomethyl , N - eth toxycarbonyl ( tert -butyl ester) . ylaminomethyl, aminoethyl, N , N -dimethylaminoethyl , In the present specification , unless otherwise noted , a N -methylaminoethyl , and N - ethylaminoethyl . The defini “ C1- 6 alkoxy carbonyl C1-6 alkyl group ” means a group in 20 tions of R4C and R4d are as described above. which the “ C1- 6 alkoxy carbonyl group ” is substituted with In the present specification , unless otherwise noted , a the “ C1- 6 alkyl group, " and includes groups of, for example , “ _ CONR4R4d group ” means an amide group having the methoxycarbonylmethyl, ethoxycarbonylmethyl, and tert “ _ NR4CR4d group ” described above , a “ _ CONR4R44 butoxycarbonylmethyl. group ” means an amide group having the “ — NR4R44 In the present specification , unless otherwise noted , a 25s gogroup ” described above, and a “ _ CONRORP group ” means “ C1- 6 alkylthio group ” means a group in which the hydrogen an amide group having the “ _ NR RP group ” described atom of the “ thiol group ( SH )” is substituted with the above. The definitions of R4c, R4d , R4 , R4f, Ra , and RB are “ C1-6 alkyl group, ” and includes groups of, for example , as described above . methylthio , ethylthio , propylthio , and isopropylthio . [ 1 - 1 ] In the compound of the above formula (I ) of In addition , the “ alkylthio group ” can be rephrased as an 30 Embodiment [ 1 ] described above , p is an integer of prefer “ alkylsulfanyl group ,” in other words the “ C1- 6 alkylthio ably 0 , 1 , 2 , or 3 ; and an integer ofmore preferably 0 , 1 , or group ” means the same group as the “ C1- 6 alkylsulfanyl 2 . group .” [ 1 - 2 ] In the compound of the above formula ( 1) of In the present specification , unless otherwise noted , a Embodiment [ 1 ] described above, R ' is preferably a halogen " C1- 6 alkylsulfonyl group ” means a group in which the 35 atom , a hydroxy C ., alkyl group , a C . alkoxy group , a " sulfonyl group : — S02 — ” is substituted with the “ C1- 6 C alkoxy C alkyl group , a carboxamide group , or a C , alkyl group ," and includes groups of, for example , methyl- alkoxy carbonyl group ; more preferably a halogen atom or sulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfo - a C . alkoxy C . alkyl group ; and further preferably a nyl. In the present specification , unless otherwise noted , a 40 fluorine atom , a bromine atom , or a methoxy methyl group . " halogenated C1. 6 alkylsulfonyl group ” means a group in [ 1 - 3 ] In the compound of the above formula ( I ) of which the “ C , alkyl group” of the “ C , alkylsulfonyl Embodiment [1 ] described above , R2a or R25 is preferably a group ” is arbitrarily substituted with several and preferably hydrogen atom , a halogen atom , or a C1- 6 alkyl group ; is 1 to 5 halogen atoms, and includes groups of, for example , further a ring arbitrarily selected from the following partial trifluoromethanesulfonyl. 45 stystructural formula (PS - 2 ) or formula (PS - 3 ): In the present specification , unless otherwise noted , a “ — NR4CR4d group ” means a group in which two hydrogen atoms on the nitrogen atom of the “ amino group ” are (PS - 2 ) substituted with R4C and R4d , a " — NR4R44 group ” means a group in which two hydrogen atoms on the nitrogen atom 50 of the “ amino group ” are substituted with — R4e and — R4 , and a “ — NR RP group ” means a group in which two min hydrogen atoms on the nitrogen atom of the “ amino group " ( PS - 3 ) are substituted with — Rº and — RP . In the present specification , unless otherwise noted , R4C 55 and R4d are each independently a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , and a halogenated C1- 6 alkyl group . In the present specification , unless other wise noted , R4e and R44 are each independently a hydrogen mm atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a 60 halogenated C1-6 alkyl group , a hydroxy halogenated C1- 6 which are formed when R2a and R26 bond to each other; alkyl group , a Cae cycloalkyl group , or a 5 - or 6 -membered more preferably a C1- 6 alkyl group ; and further preferably a heteroaryl C . , alkyl group ( the 5 - or 6 -membered heteroaryl methyl group . in the 5 - or 6 -membered heteroaryl C1- 6 alkyl group may [ 1 -4 ] In the compound of the above formula (1 ) of have 1 to 3 substituent groups arbitrarily selected from a 65 Embodiment [ 1 ] described above, the ring A is preferably halogen atom and a C1- 6 alkyl group ) . In the present speci- the following partial structural formula ( SS - 1 ) or formula fication , unless otherwise noted , R? and RP are each inde (SS -3 ): US 10 , 399 , 945 B2 24 23 C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy (SS - 1 ) C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy R 45 group , a halogenated C1- 6 alkoxy group , a C2- 6 alkanoyl group , and a C1- 6 alkylsulfonyl group ) , a 5 - or 6 -membered heteroaryl group ( the 5 - or 6 -membered heteroaryl group may have 1 to 3 arbitrary substituent groups selected from a hydroxyl group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 (SS - 3) alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a 10 halogenated C1- 6 alkoxy group , a C2- 6 alkanoyl group , a C1- 6 alkylthio group , and a C1- 6 alkylsulfonyl group ), a C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy group , a C1-6 alkoxy zar C1- 6 alkoxy group , a — NR4R4 group , a — CONR4eR4 group [ the R4e and R4 are each independently an arbitrary 15 group selected from a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy halogenated C1- 6 alkyl group , and a 5 - or 6 -mem where R3, R4a , and R4C are the same as the definitions in bered heteroaryl C1- 6 alkyl group (the 5 - or 6 -membered Embodiment [ 1 ] described above; and is more preferably the heteroaryl of the 5 - or 6 -membered heteroaryl C1- 6 alkyl following partial structural formula (SS - 1 ) : 20 group may have 1 to 3 substituent halogens or C1- 6 alkyl groups )] , or a di- C1 -6 alkylamino C1- 6 alkoxy group ; more preferably a hydrogen atom , a C1- 6 alkyl group , a hydroxy ( SS -1 ) C - 6 alkyl group , a C6 - 10 aryl group (the C6 - 10 aryl group may have 1 to 3 arbitrary substituent groups selected from 25 a cyano group and a hydroxy C1- 6 alkyl group ), a 6 -mem bered heteroaryl group ( the 6 -membered heteroaryl group may have 1 to 3 arbitrary substituent groups selected from a hydroxyl group , a cyano group , a C1- 6 alkyl group , a R3 halogenated C1- 6 alkyl group , a hydroxy C1 -6 alkyl group , 30 and a C1- 6 alkylsulfonyl group ) , or a CONR4R4 group [ the R4e and R ^ are each independently a hydrogen atom , a where R3, R4a, and R46 are the same as the definitions in hydroxy C1- 6 alkyl group , or a 5 - or 6 -membered heteroaryl Embodiment [ 1 ] described above. C1- 6 alkyl group ( the 5 - or 6 -membered heteroaryl of the 5 [ 1 -5 ] In the compound of the above formula (I ) of or 6 -membered heteroaryl C1- 6 alkyl group may have 1 to 3 Embodiment [ 1 ] described above or the compound of thethe z35 substituent C1- 6 alkyl groups) ] ; further preferably a hydro partial structural formula (SS - 1 ) or formula (SS - 3 ) of gen atom , a methyl group , a hydroxymethyl group , a cya Embodiment [ 1 - 4 ] described above, the substituent R of the nophenyl group , a hydroxymethylphenyl group , a hydroxy ring A is preferably a C1-6 alkyl group , a C6- 10 aryl group , or pyridyl group , a cyanopyridyl group , a methylpyridyl group , a non - aromatic heterocyclic group ( the C6 - 10 aryl group and a hydroxymethyl pyridyl group , a trifluoromethyl pyridyl the non - aromatic heterocyclic group may each have 1 to 3 40 group , a methanesulfonyl pyridyl group , a methylpyrimidi substituent groups arbitrarily selected from a halogen atom nyl group , a trifluoromethyl pyrimidinyl group , a ( 2 -hy and a C1- 6 alkyl group ); more preferably a C6- 10 aryl group droxypropan - 2 -yl ) pyrimidinyl group , a methylpyridazinyl or a non - aromatic heterocyclic group ( the C6- 10 aryl group group , a 1H -pyrazolyl group , a 1 - methyl- 1H - pyrazolyl and the non -aromatic heterocyclic group may each have 1 to group , a methylthiazolyl group , a carboxamide group , an 3 substituent groups arbitrarily selected from a halogen atom 45 N - ( 2 -hydroxy - 2 -methylpropyl ) aminocarbonyl group , or an and a C1- 6 alkyl group ); and further preferably a phenyl N -( ( 5 -methyl - 1 ,3 , 4 -oxazol - 2 -yl ) methyl ) aminocarbonyl group or a 4 -tetrahydro - 2H -pyranyl group . group ; and particularly preferably a hydrogen atom , a [ 1 -6 ] In the compound of the above formula ( I ) of methyl group , a hydroxymethyl group , a 3 - cyanophenyl Embodiment [1 ] described above or the compound of the group , a 4 -cyanophenyl group , a 3 - (hydroxymethyl ) phenyl partial structural formula (SS - 1 ) or formula (SS -3 ) of 50 group, a 4 -( hydroxymethyl ) phenyl group , a 2- hydroxypyri Embodiment [ 1 - 4 ] described above , the substituent R?a of din - 5 - yl group , a 2 - cyanopyridin - 5 - yl group , a 2 -methyl the ring A is preferably a hydrogen atom , a C1- 6 alkyl group , pyridin - 5 -yl group , a 2 -hydroxymethylpyridin -4 -yl group , a a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy group , a 2 -hydroxymethylpyridin - 5 -yl group , a 2 -trifluoromethyl - NR4CR4d group , or a CONR4CR4d group (the R4C and pyridin - 4 - yl group , a 3 - trifluoromethylpyridin -5 -yl group , a R4d are each independently a hydrogen atom , a C1- 6 alkyl 55 2 -methanesulfonylpyridin - 5 - yl group , a 2 -methylpyrimidin group , a hydroxy C1- 6 alkyl group , or a halogenated C1- 6 5 -yl group , a 2 - trifluoromethylpyrimidin - 5 -yl group , a alkyl group ) ; more preferably a hydrogen atom or a C1- 6 ( 2 - hydroxypropan - 2 - yl) pyrimidin - 5 -yl group , a 6 -methyl alkyl group ; and further preferably a hydrogen atom or a pyridazin - 4 - yl group , a 1H -pyrazol - 4 - yl group , a 1 -methyl methyl group . 1H -pyrazol - 4 -yl group , a 2 -methylthiazol - 5 -yl group , a car [ 1 - 7 ] In the compound of the above formula ( I ) of 60 boxamide group , an N -( 2 -hydroxy - 2 -methylpropyl ) Embodiment [ 1 ] described above or the compound of the aminocarbonyl group , or an N - (( 5 -methyl - 1, 3 , 4 - oxazol - 2 partial structural formula (SS - 1 ) or formula (SS - 3 ) of yl) methyl ) aminocarbonyl group . Embodiment [ 1 - 4 ] described above , the substituent Rob of [ 1 - 8 ] In the compound of the above formula (1 ) of the ring A is preferably a hydrogen atom , a C1- 6 alkyl group , Embodiment [ 1 ] described above , preferably , p is an integer a hydroxy C1- 6 alkyl group , a C6- 10 aryl group ( the C6- 10 aryl 65 of 0 , 1, or 2 ; R is a halogen atom or a Cl- alkoxy C1- 6 alkyl group may have 1 to 3 arbitrary substituent groups selected group (more specifically , a hydrogen atom , a fluorine atom , from a hydroxyl group , a cyano group , a halogen atom , a a bromine atom , or a methoxy methyl group ); R24 and R25 US 10 , 399 , 945 B2 25 26 are each a C1- 6 alkyl group (more specifically , a methyl a hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a group ); the ring A is the following partial structural formula C 1- 6 alkoxy group , or a halogenated C1- 6 alkoxy group ; (SS - 1 ) : X is a nitrogen atom , a C - H , or a C - C1- 6 alkyl group; R * is a hydrogen atom , a halogen atom , a C1- 6 alkyl group , a 5 C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a (SS - 1 ) hydroxy C1- 6 alkyl group , a C6- 10 aryl group , a 5 - or D45 6 -membered heteroaryl group , or a non -aromatic heterocy clic group ( the C6- 10 aryl group , the 5 - or 6 -membered R4a heteroaryl group , and the non - aromatic heterocyclic group ZAS 10 may each have 1 to 3 substituent groups arbitrarily selected AN from a halogen atom and a C1- 6 alkyl group ); P3 R4a is a hydrogen atom , a halogen atom , a cyano group , a C1- 6 alkyl group , a halogenated C1-6 alkyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy the substituent R3 of the ring A is a phenyl group or a 15 group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 4 - tetrahydro -2H -pyranyl group ; the substituent R4a of the alkyl group , a C1-6 alkoxy C1- 6 alkoxy group , a C1-6 alkoxy ring A is a hydrogen atom or a C1- 6 alkyl group (more carbonyl group , a - NR + R4d group , a CONRCR4d group , specifically , a hydrogen atom or a methyl group ) ; and the a R4R4N C1- 6 alkoxy group (the R4C and R4d are each substituent RT of the ring A is a hydrogen atom , a methyl independently a hydrogen atom , a Cialkyl group , a group , a hydroxymethyl group , a 3 -cyanophenyl group , a 20 hydroxy C . alkyl group , or a halogenated C - alkyl 4 - cyanophenyl group , a 3 -( hydroxymethyl) phenyl group , a group ) , a carboxamide group , a halogenated mono - / di- C2 - 7 4 - hydroxymethyl) phenyl group , a 2 -hydroxypyridin - 5 - ylalkanoyl amino group , or a C1- 6 alkylthio group ; and group , a 2 - cyanopyridin - 5 - yl group , a 2 -methylpyridin - 5 - yl R46 is a hydrogen atom , a halogen atom , a hydroxyl group , group , a 2 - hydroxymethylpyridin - 4 - yl group , a 2 - hy - a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl droxymethylpyridin - 5 - yl group , a 2 - trifluoromethylpyridin - 25 group , a hydroxy halogenated C1- 6 alkyl group , a hydroxy 4 - yl group , a 3 -trifluoromethylpyridin - 5 - yl group , a 2 -meth C1- 6 alkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 anesulfonylpyridin - 5 - yl group , a 2 -methylpyrimidin - 5 - y1 alkoxy group , a hydroxy C1- 6 alkoxy group , a hydroxy group , a 2 - trifluoromethylpyrimidin - 5 -yl group , a ( 2 -hy - halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl droxypropan - 2- yl ) pyrimidin -5 -yl group , a 6 -methyl group , a halogenated C1- 6 alkoxy C1- 6 alkyl group , a C1- 6 pyridazin - 4 - yl, a 1H - pyrazol- 4 - yl group , a 1 -methyl - 1H - 30 alkoxy C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy C1- 6 pyrazol- 4 - yl group , a 2 -methylthiazol - 5 - yl group , a alkoxy group , a C1- 6 alkoxy carbonyl group , a C1- 6 alkoxy carbonyl C1- 6 alkyl group , a carboxy group , a carboxamide carboxamide group , an N -( 2 -hydroxy - 2 -methylpropyl ) group , a C2- 8 cycloalkyl group ( the C3- 8 cycloalkyl group aminocarbonyl group , or an N - (( 5 -methyl -1 ,3 ,4 -oxazol -2 may have 1 to 3 arbitrary substituent groups selected from yl)methyl ) aminocarbonyl group . 35 a hydroxyl group , a halogen atom , a C1- 6 alkyl group , a C1- 6 [2 ] Embodiment 2 of the present invention is a preferable alkoxy group , and a C1- 6 alkoxy C1- 6 alkyl group ), a C6- 10 embodiment of the compound or the optical isomer thereof, aryl group (the C6- 10 aryl group may have 1 to 3 arbitrary the pharmaceutically acceptable salt thereof, or the solvate substituent groups selected from a hydroxyl group , a cyano thereof according to the above formula ( I ) of Embodiment group , a halogen atom , a C1- 6 alkyl group , a halogenated [ 1 ] described above , and is specifically a compound or an 40 C , alkyl group , a hydroxy C alkyl group , a Cze optical isomer thereof, a pharmaceutically acceptable salt cycloalkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 thereof, or a solvate thereof, the compound represented by alkoxy group , a C1- alkoxy C1- 6 alkyl group , a C1- 6 alkoxy the following formula (I - a ): carbonyl group , a C2- 6 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a — NRØRP group , a 45 CONRØR group (the Rº and R? are each independently ( I- a ) a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 R16 alkyl group , or a C3- 8 cycloalkyl group ) , a carboxy group , Rla and a carboxamide group ) , a 5 - or 6 - membered heteroaryl group ( the 5 - or 6 -membered heteroaryl group may have 1 50 to 3 arbitrary substituent groups selected from a hydroxyl R46 group , a cyano group , a halogen atom , a C1- 6 alkyl group , a R26 halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1-6 alkoxy group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a C2- 6 N 55 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl R3 OH group , a — NRØRP group , a — CONRØRP group (the R™ and RP are each independently a hydrogen atom , a C1- 6 alkyl where Rla and Rib are each independently a hydrogen atom , group , a halogenated C1- 6 alkyl group , or a C3 -8 cycloalkyl a halogen atom , a cyano group , a C1- 6 alkyl group, a group ), a carboxy group , and a carboxamide group ) , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a 60 NR4eRº group , a CONR4eRº group (the R4e and R4 cyanated C1- 6 alkyl group , a Cl. alkoxy group , a haloge - are each independently a hydrogen atom , a C1- 6 alkyl group , nated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a a hydroxy C1- 6 alkyl group , a halogenated C1- 6 alkyl group , mono -/ di- C2 - 7 alkanoyl amino group , a carboxamide group , a hydroxy halogenated C1- 6 alkyl group , a C3- 8 cycloalkyl or a Cl- , alkoxy carbonyl group ; group , or a 5 - or 6 -membered heteroaryl C1-6 alkyl group R2a and R26 are each independently a hydrogen atom , a 65 (the 5 - or 6 -membered heteroaryl in the 5 - or 6 -membered hydroxyl group, a halogen atom , a C1- 6 alkyl group , a heteroaryl C1- 6 alkyl group may have 1 to 3 substituent halogenated C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 alkyl group , halogen atoms or C1- 6 alkyl groups )) , a R4R4dN - C1- 6 US 10 , 399 , 945 B2 27 28 alkoxy group ( the R4C and R4d are each independently a C1- 6 alkyl group may have 1 to 3 substituent halogens or C1- 6 hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl alkyl groups )) , or a di- C1 - 6 alkylamino C1-6 alkoxy group ; group , or a halogenated C1- 6 alkyl group ) , a halogenated more preferably a hydrogen atom , a C1- 6 alkyl group , a mono - /di - C2- 7 alkanoyl amino group , a C1- 6 alkylthio group , hydroxy C1- 6 alkyl group , a C6- 10 aryl group (the C6 - 10 aryl a C1- 6 alkylsulfonyl group , or a halogenated C1- 6 alkylsul - 5 group may have 1 to 3 substituent cyano groups or hydroxy fonyl group . C1- 6 alkyl groups ) , a 6 -membered heteroaryl group ( the [2 -1 ] In the compound of the above formula ( I- a ) of 6 -membered heteroaryl group may have 1 to 3 arbitrary Embodiment [ 2 ] described above , preferably , Rla and R16 substituent groups selected from a hydroxyl group , a cyano are each a hydrogen atom , a halogen atom , a hydroxy C1- 6 group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a alkyl group , a C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl 10 hydroxy C1- 6 alkyl group , and a C1- 6 alkylsulfonyl group ), or group , a carboxamide group , or a C1- 6 alkoxy carbonyl a CONR4R + group ( the R4e and R4 are each indepen group ; more preferably , Rla is a hydrogen atom , a halogen dently a hydrogen atom , a hydroxy C1-6 alkyl group , or a 5 atom , or a C1- 6 alkoxy C1- 6 alkyl group , and R15 is a or 6 -membered heteroaryl C1- 6 alkyl group ( the 5 - or hydrogen atom or a halogen atom ; and further preferably , 6 -membered heteroaryl of the 5 - or 6 -membered heteroaryl Rla is a hydrogen atom , a fluorine atom , a bromine atom , or 15 C1- 6 alkyl group may have 1 to 3 substituent C1- 6 alkyl a methoxy methyl group , and R16 is a hydrogen atom , a groups ) ); further preferably a hydrogen atom , a methyl fluorine atom , or a bromine atom . group , a hydroxymethyl group , a cyanophenyl group , a [2 - 2 ] In the compound of the above formula (I - a ) of hydroxymethylphenyl group, a hydroxypyridyl group , a Embodiment [ 2 ] described above , preferably , R2a and R25 cyanopyridyl group , a methylpyridyl group , a hydroxym are each a hydrogen atom , a halogen atom , or a C1- 6 alkyl 20 ethyl pyridyl group , a trifluoromethyl pyridyl group , a group ; more preferably a Cl. alkyl group ; and further methanesulfonyl pyridyl group , a hydroxypyrimidinyl preferably a methyl group . group , a methylpyrimidinyl group , a trifluoromethyl pyrim [ 2 - 3 ] In the compound of the above formula ( I - a ) of idinyl group , a (2 -hydroxypropan -2 -yl ) pyrimidinyl group , a Embodiment [ 2 ] described above , preferably , X is a nitro - methylpyridazinyl group , a 1H - pyrazolyl group , a 1- methyl gen atom , a C - H , or a C — CHz; and more preferably a 25 1H -pyrazolyl group , a methylthiazolyl group , a carboxam C - H or a C — CHZ. ide group , an N - ( 2 -hydroxy - 2 -methylpropyl ) aminocarbonyl [ 2 - 4 ] In the compound of the above formula (I - a ) of group , or an N - ( ( 5 -methyl - 1 , 3 ,4 - oxazol - 2 - yl) methyl ) amin Embodiment [2 ] described above , preferably , R * is a C1- 6 ocarbonyl group ; and particularly preferably a hydrogen alkyl group , a C6 - 10 aryl group , or a non - aromatic hetero - atom , a methyl group , a hydroxymethyl group , a 3 -cyano cyclic group ( the Co- 10 aryl group and the non -aromatic 30 phenyl group , a 4 -cyanophenyl group , a 3 - hydroxymethyl) heterocyclic group may each have 1 to 3 substituent halogen phenyl group , a 4 - hydroxymethyl) phenyl group , a 2 -hy atoms or C1- 6 alkyl groups ); more preferably a phenyl group droxypyridin - 5 -yl group , a 2 -cyanopyridin - 5 -yl group , a or a tetrahydro - 2H - pyranyl group ( the phenyl group and the 2 -methylpyridin - 5 - yl group , a 2 -hydroxymethylpyridin - 4 - yl tetrahydro - 2H -pyranyl group may each have 1 to 3 substitu group , a 2 -hydroxymethylpyridin - 5 - yl group , a 2 - trifluo ent halogen atoms or C1- 6 alkyl groups) ; and further pref- 35 romethylpyridin - 4 - yl group , a 3 -trifluoromethylpyridin - 5 - yl erably a phenyl group or a 4 - tetrahydro - 2H -pyranyl group group , a 2 -methanesulfonylpyridin -5 -yl group , a 2 -hydroxy (tetrahydro - 2H -pyran - 4 -yl group ) . pyrimidin -5 -yl group , a 2 -methylpyrimidin -5 -yl group , a [ 2 - 5 ] In the compound of the above formula ( I - a ) of 2 - trifluoromethylpyrimidin - 5 - yl group , a ( 2 -hydroxypro Embodiment [ 2 ] described above, preferably ,R4a is a hydro - pan - 2 -yl ) pyrimidin - 5 -yl group , a 6 -methylpyridazin - 4 -yl , a gen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , or 40 1H -pyrazol - 4 - yl group , a 1 -methyl - 1H -pyrazol - 4 - yl group , a a C1- 6 alkoxy group ; more preferably a hydrogen atom or a 2 -methylthiazol - 5 -yl group , a carboxamide group , an N - (2 C1- 6 alkyl group ; and further preferably a hydrogen atom or hydroxy - 2 -methylpropyl ) aminocarbonyl group, or an N - ( ( 5 a methyl group . methyl- 1 , 3 ,4 - oxazol- 2 - yl) methyl ) aminocarbonyl group . [2 -6 ] In the compound of the above formula (I - a ) of [ 2 - 7 ] In the compound of the above formula (I - a ) of Embodiment [2 ] described above , preferably , Rob is a 45 Embodiment [2 ] described above , preferably, Rla is a hydro hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl gen atom , a halogen atom , or a C1- 6 alkoxy C1-6 alkyl group group , a C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy group , a (more specifically , a hydrogen atom , a fluorine atom , a C1- 6 alkoxy C1- 6 alkoxy group , a C6- 10 aryl group ( the C6 - 10 bromine atom , or a methoxy methyl group ) ; R is a hydro aryl group may have 1 to 3 arbitrary substituent groups gen atom or a halogen atom (more specifically , a hydrogen selected from a hydroxyl group , a cyano group , a halogen 50 atom , a fluorine atom , or a bromine atom ) ; R2a and R25 are atom , a C1- 6 alkyl group , a halogenated C1-6 alkyl group , a each a C1- 6 alkyl group (more specifically , a methyl group ); hydroxy C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 X is a C - H or a C — CH3; R * is a phenyl group or a alkoxy group , a halogenated C1-6 alkoxy group , a C2- 6 4 - tetrahydro -2H -pyranyl group ( tetrahydro -2H -pyran - 4 -yl alkanoyl group , and a C1- 6 alkylsulfonyl group ) , a 5 - or group ) ; R4a is a hydrogen atom or a C1- alkyl group (more 6 -membered heteroaryl group ( the 5 - or 6 -membered het- 55 specifically, a hydrogen atom or a methyl group ); and R4h is eroaryl group may have 1 to 3 arbitrary substituent groups a hydrogen atom , a methyl group , a hydroxymethyl group , selected from a hydroxyl group , a cyano group , a halogen a 3 -cyanophenyl group , a 4 -cyanophenyl group , a 3 - (hy atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a droxymethyl) phenyl group , a 4 - hydroxymethyl) phenyl hydroxy C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 group , a 2 - hydroxypyridin - 5 - yl group , a 2 - cyanopyridin - 5 alkoxy group , a halogenated C1- 6 alkoxy group , a C2- 6 60 yl group , a 2 -methylpyridin - 5 - yl group , a 2 -hydroxymeth alkanoyl group , a C - , alkylthio group , and a C - , alkylsul- ylpyridin - 4 -yl group , a 2 - hydroxymethylpyridin - 5 -yl group , fonyl group ), a - NR4R4 group , a CONR4R4 group a 2 - trifluoromethylpyridin - 4 -yl group , a 3 - trifluoromethyl (the R4e and R44 are each independently a hydrogen atom , a pyridin - 5 -yl group , a 2 -methanesulfonylpyridin - 5 - yl group , C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a halogenated a 2 -hydroxypyrimidin - 5 -yl group , a 2 -methylpyrimidin - 5 -yl C1- 6 alkyl group , a hydroxy halogenated C1- 6 alkyl group , or 65 group , a 2 -trifluoromethylpyrimidin -5 -yl group , a (2 -hy a 5 - or 6 -membered heteroaryl C - , alkyl group ( the 5 - or d roxypropan - 2 -yl ) pyrimidin - 5 - yl group , a 6 -methyl 6 -membered heteroaryl of the 5 - or 6 -membered heteroarylp yridazin - 4 - yl, a 1H -pyrazol - 4 - yl group , a 1 -methyl - 1H US 10 , 399 , 945 B2 29 30 pyrazol- 4 -yl group , a 2 -methylthiazol - 5 -yl group , a cyclic group ( the C6- 10 aryl group and the non -aromatic carboxamide group , an N -( 2 -hydroxy - 2 -methylpropyl ) heterocyclic group may each have 1 to 3 substituent groups aminocarbonyl group , or an N - ( ( 5 -methyl - 1 , 3 , 4 -oxazol - 2 arbitrarily selected from a halogen atom or a C1- 6 alkyl yl) methyl ) aminocarbonyl group . group ) ; more preferably a phenyl group or a tetrahydro - 2H [ 3 ] Embodiment 3 of the present invention is a preferable 5 pyranyl group (the phenyl group and the tetrahydro - 2H embodiment of the compound or the optical isomer thereof, pyranyl group may each have 1 to 3 substituent groups the pharmaceutically acceptable salt thereof , or the solvate arbitrarily selected from a halogen atom or a C1- 6 alkyl thereof according to the above formula ( I - a ) of Embodiment group ) ; and further preferably a phenyl group or a 4 - tetra [ 2 ] described above, and is specifically a compound or an hydro -2H -pyranyl group ( tetrahydro - 2H -pyran - 4 -yl group ) . optical isomer thereof, a pharmaceutically acceptable salt 10 [3 -3 ] In the compound of the above formula (I - a -1 ) of thereof, or a solvate thereof, the compound represented by Embodiment [ 3 ] described above, preferably , the ring B is a the following formula (I - a - 1 ): group arbitrarily selected from the following partial struc tural formulas : ( I- a - 1 ) 15

( TS - 1 ) R la CH3 (RS ) q - B CH3 20 + CH3 ( TS - 2 ) N N 25 R3 OH where Rla and Rlb are each independently a hydrogen atom , a halogen atom , a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a 30 ( TS - 3 ) cyanated C1- 6 alkyl group , a C1- 6 alkoxy group , a haloge nated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a Za mono - /di - C2 - 2 alkanoyl amino group , a carboxamide group , or a C1- 6 alkoxy carbonyl group ; R is a hydrogen atom , a halogen atom , a C1- 6 alkyl group , 35 a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a ( TS - 4 ) hydroxy C1- 6 alkyl group , a C6- 10 aryl group , a 5 - or 6 -membered heteroaryl group , or a non - aromatic heterocy EZ clic group (the C6- 10 aryl group , the 5 - or 6 -membered heteroaryl group , and the non - aromatic heterocyclic group 40 min may each have 1 to 3 substituent groups arbitrarily selected from a halogen atom and a C1- 6 alkyl group ); ( TS - 5 ) the ring B is a C6- 10 aryl group or a 5 - or 6 -membered heteroaryl group ; = q is an integer of 0 , 1 , 2 , or 3 ; and 45 Z R® is a hydrogen atom , a hydroxyl group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1-6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , a C2- 6 ( TS - 6 ) alkanoyl group , a C1- 6 alkylsulfonyl group , a CONRØRP 50 group ( the Ra and RP are each independently a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a C3- 8 cycloalkyl group ) , or a carboxamide group . [3 - 1 ] In the compound of the above formula (I - a - 1 ) of Embodiment [ 3 ] described above , preferably , Rla and R16 55 ( TS - 7 ) are each a hydrogen atom , a halogen atom , a hydroxy C1- 6 Z alkyl group , a C1- 6 alkoxy group , a C1-6 alkoxy C1- 6 alkyl - group , a carboxamide group , or a C1- 6 alkoxy carbonyl group ; more preferably , Rla is a hydrogen atom , a halogen atom , or a C1- 6 alkoxy C1- 6 alkyl group , and R ! " is a 60 hydrogen atom or a halogen atom ; and further preferably, ( TS - 8 ) Rla is a hydrogen atom , a fluorine atom , a bromine atom , or a methoxymethyl group , and R16 is a hydrogen atom , a fluorine atom , or a bromine atom . [ 3 - 2 ] In the compound of the above formula ( I - a - 1 ) of 65 Embodiment [ 3 ] described above, preferably, R3 is a C1- 6 alkyl group , a C6- 10 aryl group , or a non - aromatic hetero US 10 . 399 , 945 B2 31 32 -continued - continued ( TS - 9 ) ( TS- 17) RIN www ( TS -18 ) 10 ( TS -10 ) *Rw ( TS- 19 )

( TS- 11 1 )) 20? Rw ( TS - 20 )

25

Rw ( TS -12 )

—N where R " is a hydrogen atom, a Cire alkyl group , a haloge 30 nated C1-6 alkyl group , or a hydroxy C1- 6 alkyl group ; more preferably a group arbitrarily selected from the following partial structural formulas:

135 (TS -13 ) ( TS -1 )

RW t 41 us ( TS - 2 ) ( TS- 14 ) 45 RW ( TS- 3 )

50

Wu

( TS - 15 ) 55 ( TS- 4)

Z RW - N =|

60 ( TS -16 ) ( TS - 5 )

L1 65 ELL US 10 . 399 , 945 B2 33 us 10. 9 5% 34 -continued -continued ( TS - 6 ) ( TS - 20)

( TS- 7 ) 10 where R " is a hydrogen atom or a C1- 6 alkyl group ; and further preferably a group arbitrarily selected from the following partial structural formulas :

( TS - 8115 ) ( TS -1 )

s ( TS- 9 ) 20 RW ( TS- 2 )

25 SAS (TS - 3 ) (TS - 12 ) RW 30

( TS - 4 )

35

(TS - 15 ) ( TS- 5 ) RW - N 41 ?mm ( TS- 16) ( TS- 9 ) 45 Rw

( TS(- 11 17)

( TS - 12) ( TS- 18 )55

160 (TS - 19 ) ( TS - 15 ) RW — N 65 num US 10 ,399 ,945 B2 35 36 - continued - continued ( TS - 18 ) RIN (US - 9 ) where R " is a hydrogen atom or a methyl group . minn 10 (US - 12 ) [ 3 - 4 ] In the compound of the above formula ( I - a - 1 ) of Rw Embodiment [ 3 ] described above , q is an integer of prefer - ably 0 , 1 , or 2 ; and an integer of more preferably 0 or 1 . ? [ 3 - 5 ] In the compound of the above formula ( I - a - 1 ) of Embodiment [ 3 ] described above , preferably , R is a hydro - 13 gen atom , a hydroxyl group , a cyano group , a C1- 6 alkyl group , a halogenated C1-6 alkyl group , a hydroxy C1- 6 alkyl group , or a C1- 6 alkylsulfonyl group ; and more preferably a (US -15 ) hydrogen atom , a hydroxyl group , a cyano group , a methyl 20 group , a trifluoromethyl group , a hydroxymethyl group , a RW - N 2 - hydroxypropan - 2 - yl group , or a methanesulfonyl group . PS [ 3 - 6 ] In the compound of the above formula ( I- a - 1 ) of Embodiment [ 3 ] described above, the following partial (US -18 ) structural formula (US ) : 25 R ) (US ) mir 30

where R is a hydroxyl group , a cyano group , a C1- 6 alkyl is preferably a group arbitrarily selected from the following group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl partial structural formulas: 35 group , a C1- 6 alkylsulfonyl group , or a carboxamide group ; and R " is a hydrogen atom or a C1- 6 alkyl group ; more preferably a group arbitrarily selected from the following (US - 1) partial structural formulas :

40 (US - 1 - 1 ) RS (US - 2 ) 45 min monen (US - 1 - 2 ) (US - 5 ) 50

nnn RSR $ (US - 2 - 1 ) (US - 4 ) 55 RS RS

n

60 min (US - 5 ) (US - 2 - 2)

inn 65 US 10 ,399 , 945 B2 37 38 -continued - continued (US - 3 - 1 ) H3C NC

(US - 4 - 1 ) HO

10

(US - 5 -1 ) HO RS 15

mm w

Rw (US - 9 -1 ) 20 Fzc

?? . 2525 F3C (US -12 - 1 ) Rw

30 min (US - 15 - 1 ) 35

RW - N HO N

40 (US - 18 - 1 ) RS m HO . 45 ! ma m where R is a hydroxyl group , a cyano group , a methyl group , a trifluoromethyl group , a hydroxymethyl group , a H3C — H3C - N 2 -hydroxypropan - 2 - yl group , a methanesulfonyl group , or a 50 in carboxamide group ; and R " is a hydrogen atom or a methyl group ; and further preferably a group arbitrarily selected m from the groups represented by the following partial struc tural formulas: 55

HO

?? . [ 3 - 7 ] In the compound of the above formula (I -a - 1) of Embodiment [ 3 ] described above, preferably , Rla is a hydro gen atom , a halogen atom , or a C1- 6 alkoxy C1- 6 alkyl group minn mm (more specifically , a hydrogen atom , a fluorine atom , a bromine atom , or a methoxy methyl group ) ; Rlb is a hydrogen atom or a halogen atom (more specifically , NC 65 a hydrogen atom , a fluorine atom , or a bromine atom ) ; min R3 is a phenyl group or a 4 - tetrahydro -2H -pyranyl group ( tetrahydro - 2H -pyran - 4 - yl group ) ; US 10 , 399 , 945 B2 39 40 the ring B is the following partial structural formulas : group , a hydroxymethyl group, a 2 -hydroxypropan - 2 - yl group , a methanesulfonyl group , or a carboxamide group ) . [3 - 7 - 1 ] In Embodiment [ 3 -7 ] described above, more pref (TS - 1 ) erably , the following partial structural formula (US ):

(US ) (R ) , + B tot (TS - 2 ) 10 min is a group arbitrarily selected from the following partial structural formulas : (TS -3 ) 15 HO

HO 20 mu (TS - 4 ) NG

25 mun NC ( TS - 5 ) NC

30

nh ( TS - 9 ) RW HO 35

HO (TS -12 ) 40 mi NS 45 F30 ( TS - 15 ) HO . R " — N 50 FzC munun ( TS - 18 ) 55 H

60 where RW is a hydrogen atom or a methyl group ) ; q is an integer of 0 or 1 ; and N R is a hydrogen atom , a hydroxyl group , a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkylsulfonyl group or a carboxam - 65 ??? ide group (more specifically , a hydrogen atom , a hydroxyl group , a cyano group , a methyl group, a trifluoromethyl men US 10 , 399 ,945 B2 42 - continued group , a halogenated C1- 6 alkyl group , a hydroxy haloge nated C1- 6 alkyl group , a C3- 8 cycloalkyl group , or a 5 - or N 6 -membered heteroaryl C - alkyl group ( the 5 - or 6 -mem HO . bered heteroaryl in the 5 - or 6 -membered heteroaryl C1- 6 5 alkyl group may have 1 to 3 substituent groups arbitrarily selected from a halogen atom and a C - , alkyl group ) ), a mm N mm R4CR4dN C1- 6 alkoxy group (the R4C and R4d are each independently a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , or a halogenated C1- 6 alkyl 10 group ), a carboxamide group , a halogenated mono - di- C2- 7 alkanoyl amino group , a C1- 6 alkylthio group , a C1-6 alkyl nam sulfonyl group , or a halogenated C1- 6 alkylsulfonyl group . HN [ 4 - 1 ] In the compound of the above formula (l - a - 2 ) of Embodiment [ 4 ] described above, preferably , Ria and Rib 15 are each a hydrogen atom , a halogen atom , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy group , a C1-6 alkoxy C1- 6 alkyl group , a carboxamide group , or a C1-6 alkoxy carbonyl group ; more preferably , Rla is a hydrogen atom , a halogen [ 4 ] Embodiment 4 of the present invention is a preferable atom , or a C1-6 alkoxy C1- 6 alkyl group , and R ! " is a embodiment of the compound or the optical isomer thereofCol; , 20a hydrogen atom or a halogen atom ; and further preferably , the pharmaceutically acceptable salt thereof, or the solvate Rla is a hydrogen atom , a fluorine atom , a bromine atom , or thereof according to the above formula (1 - a ) of Embodiment a methoxy methyl group , and R15 is a hydrogen atom , a [ 2 ] described above , and is specifically a compound or an fluorine atom , or a bromine atom . optical isomer thereof, a pharmaceutically acceptable salt 14 - 2 ] In the compound of the above formula ( l -a - 2 ) of thereof, or a solvate thereof, the compound represented by 25 Embodiment [ 4 ] described above, preferably, R * is a C . the following formula (I - a - 2 ): alkyl group , a C6- 10 aryl group , or a non - aromatic hetero cyclic group ( the C6 - 10 aryl group and the non -aromatic heterocyclic group may each have 1 to 3 substituent groups ( I- a - 2 ) arbitrarily selected from a halogen atom or a C1- , alkyl 30 group ); more preferably a phenyl group or a tetrahydro - 2H R la pyranyl group ( the phenyl group and the tetrahydro - 2H CH ; pyranyl group may each have 1 to 3 substituent groups CH3 arbitrarily selected from a halogen atom or a C . , alkyl R4g group ) ; and further preferably a phenyl group or a 4 - tetra - CH3 35 hydro -2H - pyranyl group ( tetrahydro - 2H -pyran - 4 -yl group ) . [ 4 - 3 ] In the compound of the above formula ( I - a - 2 ) of Embodiment [ 4 ] described above, preferably , R48 is a hydro ZE N gen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a OH C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy group , a C1- 6 40 alkoxy C alkoxy group , a — NR4R4 group , a where Rla and R16 are each independently a hydrogen atom , CONR + R4 group [the R4e and R * are each independently a halogen atom , a cyano group , a C1- 6 alkyl group , a a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a group , a halogenated C -, alkyl group , a hydroxy haloge cyanated C1-6 alkyl group , a C1- 6 alkoxy group , a haloge - nated C1- 6 alkyl group , or a 5 - or 6 -membered heteroaryl nated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a 45 C1- 6 alkyl group ( the 5 - or 6 -membered heteroaryl in the 5 mono - /di - C2- 7 alkanoyl amino group , a carboxamide group , or 6 -membered heteroaryl C1- 6 alkyl group may have 1 to 3 or a Cl- , alkoxy carbonyl group ; substituent groups arbitrarily selected from a halogen atom R is a hydrogen atom , a halogen atom , a C1- 6 alkyl group , and a C1- 6 alkyl group )] , a RCR40N - C1-6 alkoxy group (the a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a R4C and R4d are each independently a hydrogen atom , a C1- 6 hydroxy C1- 6 alkyl group , a C6- 10 aryl group , a 5 - or 50 alkyl group , a hydroxy C1- 6 alkyl group , or a halogenated 6 -membered heteroaryl group , or a non -aromatic heterocy C1- 6 alkyl group ) ; more preferably a hydrogen atom , a clic group ( the C6- 10 aryl group , the 5 - or 6 -membered hydroxy C1- 6 alkyl group , a CONR40R4 group [the R4e heteroaryl group , and the non - aromatic heterocyclic group and R ^ are each independently a hydrogen atom , a hydroxy may each have 1 to 3 substituent groups arbitrarily selected C1-6 alkyl group , or a 5 - or 6 -membered heteroaryl C1- 6 alkyl from a halogen atom and a C1- 6 alkyl group ); and 55 group (the 5 - or 6 -membered heteroaryl in the 5 - or 6 -mem R49 is a hydrogen atom , a halogen atom , a hydroxyl group , bered heteroaryl C1- 6 alkyl group may have 1 to 3 substituent a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl C1- 6 alkyl groups) ]; and further preferably a hydrogen atom , group , a hydroxy C1- 6 alkyl group , a hydroxy halogenated a hydroxymethyl group , a carboxamide group , an N - ( 2 C1- 6 alkyl group, a C1- 6 alkoxy group , a halogenated C1- 6 hydroxy - 2 -methylpropyl ) aminocarbonyl group , or an N - ( ( 5 alkoxy group , a hydroxy C1- 4 alkoxy group , a C1- 6 alkoxy 60 methyl - 1 , 3 , 4 -oxazol - 2 - yl) methyl ) aminocarbonyl group . C1- 6 alkyl group, a halogenated C - alkoxy C1- 6 alkyl group , [ 4 -4 ] In the compound of the above formula ( I - a - 2 ) of a C1- 6 alkoxy C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy C1- 6 Embodiment [ 4 ] described above, preferably , Rla is a hydro alkoxy group , a hydroxy halogenated C1- 6 alkoxy group , a gen atom , a halogen atom , or a C1- 6 alkoxy C1- 6 alkyl group C1- 6 alkoxy carbonyl group , a C1- 6 alkoxy carbonyl C1- 6 (more specifically , a hydrogen atom , a fluorine atom , a alkyl group , a carboxy group , a - NR4 R4 group , a 65 bromine atom , or a methoxy methyl group ) ; R15 is a hydro - CONR + R4 group ( the R4e and R * are each independently gen atom or a halogen atom (more specifically , a hydrogen a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl a tom , a fluorine atom , or a bromine atom ) ; R is a phenyl US 10 , 399 , 945 B2 43 44 group or a 4 - tetrahydro -2H -pyranyl group (tetrahydro - 2H - 1 - (6 - ( 4 -cyanophenyl ) - 5 - methyl - 2 - phenylpyridin - 3 - yl) - 3 pyran -4 - yl group ); and R4S is a hydrogen atom , a hydroxym - ( ( 1R ,2R )- 2 -hydroxy -4 , 4 -dimethyl - 1 , 2 ,3 ,4 -tetrahy ethyl group , a carboxamide group , an N - ( 2 -hydroxy - 2 dronaphthalen - 1 - yl) urea ; methylpropyl) aminocarbonyl group , or an N -( (5 -methyl - 1, 1 -( (1R ,2R )- 2- hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , 4 -tetrahy 3 ,4 -oxazol - 2 - yl)methyl ) aminocarbonyl group . dronaphthalen - 1 -yl ) - 3 -( 3 -methyl -6 -phenyl - 2 - (trifluo As described above, it is possible to form a preferable romethyl ) - [ 2 , 4 '- bipyridin ) - 5 - yl) urea ; embodiment of the compound represented by the above 1 - (( 1R ,2R )- 2 -hydroxy -4 ,4 -dimethyl - 1 , 2, 3 ,4 -tetrahy formula (I ) of Embodiment [1 ] described above as desired dronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 -phenyl - 6 - ( 1H -pyra by appropriately combining Embodiments [ 1 ] to [ 4 ] of the zol- 4 - yl) pyridin - 3 -yl ) urea ; present invention , preferable embodiments thereof, and 1 -( (1R ,2R )- 2- hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , 4 -tetrahy moreover the definitions of the substituents . dronaphthalen - 1 -yl ) - 3 -( 6 - (2 -hydroxypyrimidin -5 -yl ) - 5 In Embodiments [ 1 ] to [ 4 ] described above and sub methyl- 2 -phenylpyridin - 3 -yl ) urea ; embodiments thereof, more preferable substituents or com - 1 - (6 -hydroxy - 3 - methyl -6 - phenyl- [ 2 , 3 -bipyridin ) -5 - yl) - 3 binations thereof in the above formula ( 1) follow the expla - 15. (( 1R ,2R ) - 2 -hydroxy -4 , 4 - dimethyl- 1 , 2 , 3 , 4 -tetrahy nation described in Embodiment 1 . dronaphthalen - 1 -yl ) urea ; [5 ] Embodiment 5 of the present invention is a preferable 1- ( (1R ,2R ) - 2 -hydroxy -4 , 4 -dimethyl - 1, 2 ,3 ,4 - tetrahy compound in the compound of the above formula (I ) of dronaphthalen - 1 -yl ) - 3 - (6 - ( 2 - (2 -hydroxypropan - 2 -yl ) py Embodiment [ 1 ] described above, and is specifically a rimidin - 5 - yl ) - 5 -methyl - 2 - phenylpyridin - 3 - yl ) urea ; compound , a pharmaceutically acceptable salt thereof, or a 20 1 -( (1R 2R )- 6 - bromo- 2 -hydroxy - 4 ,4 -dimethyl - 1 , 2, 3 ,4 - tetra solvate thereof listed below , or the compound of the above hydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 -phenylpyridin - 3 formula ( I ) , a salt thereof, or an optical isomer of a solvate y l) urea ; thereof. 5 -( 3 - (( 1R , 2R ) -6 -bromo - 2 -hydroxy -4 ,4 -dimethyl - 1 ,2 , 3, 4 1 - (( 1R ,2R )- 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 ,4 - tetrahy tetrahydronaphthalen -1 -yl ) ureido )- 3 -methyl - 6 -phenylpi dronaphthalen - 1 -yl ) -3 - (2 -phenylpyridin - 3 -yl ) urea ; 25 colinamide ; 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy 5 - ( 3 - (( 1R ,2R ) - 2 -hydroxy - 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahy dronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 - phenylpyridin - 3 -yl ) dronaphthalen - 1 - yl) ureido ) - 3 -methyl - 6 - phenylpicolina urea ; 1 - ( ( 1R , 2R ) - 2 -hydroxy -4 , 4 -dimethyl - 1 , 2 , 3 , 4 -tetrahy mide ; dronaphthalen - 1 -yl ) - 3 - ( 5 -methyl -6 - ( 2 -methylpyrimidin - 30 N -( 2 -hydroxy -2 -methylpropyl ) -5 -( 3 -( ( 1R 2R )- 2 -hydroxy - 4 , 5 - yl) - 2 - phenylpyridin - 3 - yl) urea ; 4 - dimethyl- 1 ,2 ,3 ,4 - tetrahydronaphthalen - 1 -yl ) ureido ) -3 1 -( ( 1R ,2R ) -2 -hydroxy -4 , 4 -dimethyl - 1, 2 ,3 ,4 -tetrahy methyl- 6 -phenylpicolinamide ; dronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 6 - ( 1 -methyl - 1H - pyra 1- ( (1R ,2R ) - 2 -hydroxy -4 , 4 -dimethyl - 1, 2 ,3 ,4 - tetrahy zol- 4 -yl ) - 2 -phenylpyridin - 3 -yl ) urea ; dronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 2 - ( tetrahydro - 2H 1 -( (1R 2R )- 2- hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahy 35 pyran - 4 -yl ) pyridin - 3 -yl ) urea ; dronaphthalen -1 -yl ) - 3 -( 5 -methyl -2 -phenyl - 6 -( 1H -pyra 5 - ( 3 - (( 1R , 2R ) - 2 - hydroxy - 4 ,4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy zol- 4 - yl) pyridin - 3 - yl) urea ; dronaphthalen - 1 -yl ) ureido ) - 3 -methyl - 6 - (tetrahydro - 2H 1 -( 6 -hydroxy -3 -methyl - 6 -phenyl -[ 2 ,3 '- bipyridin )- 5 -yl ) - 3 pyran -4 -yl ) picolinamide; ( 1R , 2R ) - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy 1 -( ( 1R ,2R )- 2 -hydroxy -4 ,4 -dimethyl - 1, 2, 3 ,4 - tetrahy dronaphthalen - 1 -yl ) urea ; 40 dronaphthalen - 1 - yl) - 3 - ( 5 -methyl -6 - ( 2 -methylpyrimidin 1 -( 1R ,2R )- 2- hydroxy -4 ,4 -dimethyl -1 ,2 ,3 ,4 - tetrahy 5 - yl) - 2 - (tetrahydro - 2H -pyran - 4 -yl ) pyridin - 3 -yl ) urea ; dronaphthalen - 1 - yl) - 3 - (5 -methyl - 2 -phenylpyridin - 3 -yl ) 1 - (( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahy urea ; dronaphthalen - 1 - yl) - 3 - ( 5 -methyl -6 - ( 1 -methyl - 1H - pyra 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 -tetrahy zol - 4 - yl) - 2 - ( tetrahydro - 2H -pyran -4 -yl )pyridin - 3 - yl )urea ; dronaphthalen - 1 -yl ) -3 - (6 - (hydroxymethyl )- 5 -methyl - 2 - 45 1 -( ( 1R 2R )- 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahy phenylpyridin - 3 - yl) urea ; dronaphthalen - 1 - yl) - 3 - ( 5 -methyl -6 - ( 1H - pyrazol - 4 - yl ) - 2 1 - ( ( 1R . 2R ) - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy ( tetrahydro - 2H -pyran - 4 -yl ) pyridin - 3 -yl ) urea ; dronaphthalen - 1 -yl ) - 3 - ( 5 -methyl -6 - ( 2 -methylpyrimidin 1 - ( 6 -hydroxy - 3 -methyl - 6 - ( tetrahydro -2H -pyran - 4 -yl ) - [ 2 , 3 ' 5 - yl )- 2 - phenylpyridin -3 - yl) urea ; bipyridin ) - 5 -yl ) - 3 - ( ( 1R 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahy - 50 3 , 4 - tetrahydronaphthalen - 1 - yl) urea ; dronaphthalen - 1 - yl) - 3 - ( 5 -methyl -6 - ( 1 -methyl - 1H -pyra - 1 - ( ( 1R ,2R ) - 7 - bromo - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetra zol- 4 - yl) -2 -phenylpyridin - 3 - yl )urea ; hydronaphthalen -1 -yl ) - 3 -( 5 -methyl - 2 -phenylpyridin -3 1 -( (1R , 2R )- 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahy yl) urea ; dronaphthalen - 1 - yl) - 3 - ( 3 -methyl - 6 -phenyl - 5 '- ( trifluo 1 - ( ( 1R , 2R ) - 2 - hydroxy - 7 - (methoxymethyl ) - 4 , 4 -dimethyl - 1 , romethyl) - [ 2 ,3 '- bipyridin )- 5 -yl ) urea ; 55 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 2 - (tetra 1 - ( 3 , 6 '- dimethyl- 6 - phenyl- [ 2 , 3 -bipyridin ) - 5 -yl ) - 3 - ( ( 1R , hydro - 2H -pyran - 4 - yl) pyridin - 3 -yl ) urea ; 2R ) - 2 -hydroxy -4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphtha - 1 - ( ( 1R ,2R ) - 7 - fluoro - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 2 ,3 , 4 - tetra len - 1 - yl )urea ; hydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 6 - ( 2 -methylpyrimi 1 - ( 6 - cyano - 3 -methyl - 6 -phenyl - [ 2 , 3 '- bipyridin ) - 5 -yl ) - 3 din - 5 - yl) - 2 -phenylpyridin - 3 - yl) urea ; ( (1R ,2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 -tetrahy 60 1 - ( (1R 2R ) -6 - fluoro - 2 - hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 ,4 - tetra dronaphthalen - 1 -yl ) urea ; hydronaphthalen - 1 - yl) - 3 - ( 5 -methyl -6 - ( 2 -methylpyrimi 1 - ( ( 1R . 2R ) - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy din - 5 -yl ) - 2 -phenylpyridin - 3 -yl ) urea ; dronaphthalen - 1 -yl ) - 3 -( 3 -methyl -6 '- (methylsulfonyl ) -6 - 1- ( (1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 phenyl- [ 2 , 3 ' -bipyridin ) - 5 - yl) urea ; tetrahydronaphthalen - 1 - yl) - 3 - ( 2 - phenylpyridin - 3 - yl) urea ; 1 - (( 1R ,2R )- 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahy 65 1 - ( (1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 ,4 dronaphthalen - 1 -yl ) - 3 -( 5 -methyl - 2- phenyl- 6 -( 2- (trifluo tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 -phenylpyridin romethyl ) pyrimidin - 5 - yl) pyridin - 3 - yl )urea ; 3 - yl) urea ; US 10 , 399 , 945 B2 45 46 1 -( ( 1R ,2R )- 6 , 7 -difluoro -2 -hydroxy -4 ,4 - dimethyl- 1, 2 ,3 , 4 - 1 -( (1R , 2R )- 6 ,7 - difluoro - 2 -hydroxy -4 ,4 -dimethyl - 1 ,2 , 3 ,4 tetrahydronaphthalen - 1 - yl) - 3 - ( 4 -methyl - 2 - phenylpyridin tetrahydronaphthalen - 1 - yl) - 3 - ( 6 - ( 2 - ( 2 -hydroxypropan - 2 3 - yl) urea ; yl) pyrimidin - 5 - yl) - 5 -methyl - 2 - phenylpyridin - 3 - yl) urea ; 1 - ( (1R , 2R ) - 6 , 7 -difluoro - 2 -hydroxy -4 , 4 - dimethyl- 1 , 2 , 3 , 4 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 ,4 tetrahydronaphthalen - 1 -yl ) - 3 - ( 6 -methyl - 2 -phenylpyridin - 5 tetrahydronaphthalen - 1 -yl ) - 3 - ( 6 - (hydroxymethyl ) - 3 3 -yl ) urea ; methyl- 6 -phenyl - [ 2 , 3 ' - bipyridin ) - 5 - yl) urea ; 5 - ( 3 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 ,4 - dimethyl- 1 , 2 , 3 , 1 - ( ( 1R , 2R ) -6 , 7 - difluoro - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 ,4 4 - tetrahydronaphthalen -1 -yl ) ureido ) -3 -methyl - 6 -phe tetrahydronaphthalen - 1 - yl) - 3 - ( 2 '- (hydroxymethyl ) - 3 nylpicolinamide ; methyl -6 - phenyl- [ 2 , 4 ' - bipyridin ) - 5 - yl) urea ; 5 -( 3 - (( 1R , 2R ) -6 ,7 - difluoro - 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , 10 1 -( (1R , 2R ) -6 , 7 - difluoro - 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , 4 4 - tetrahydronaphthalen - 1 - yl) ureido ) - 3 -methyl - N - ( (5 tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 - ( tetrahydro methyl - 1, 3 , 4 -oxadiazol - 2 -yl ) methyl ) -6 -phenylpicolina 2H -pyran - 4 -yl )pyridin - 3 - yl )urea ; mide; 5 -( 3 -( ( 1R 2R ) -6 , 7 -difluoro - 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , 5 - ( 3 - ( ( 1R 2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 15 4 - tetrahydronaphthalen - 1 - yl) ureido ) - 3 -methyl - 6 - ( tetra 4 - tetrahydronaphthalen - 1 -yl ) ureido )- N - (2 -hydroxy -2 hydro -2H - pyran - 4 - yl) picolinamide ; methylpropyl) - 3 -methyl - 6 - phenylpicolinamide ; 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 ,4 -dimethyl - 1 , 2 , 3 , 4 1 - ( ( 1R 2R ) - 6 , 7 -difluoro - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 tetrahydronaphthalen - 1 -yl ) - 3 -( 5 -methyl - 6 -( 2 -methylpy tetrahydronaphthalen - 1 - yl) - 3 - (6 - ( hydroxymethyl ) - 5 rimidin - 5 - yl) - 2 -( tetrahydro - 2H - pyran - 4 - yl) pyridin - 3 - yl) methyl- 2 - phenylpyridin - 3 - yl) urea ; 20 urea ; 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 ,4 - dimethyl- 1 , 2 , 3 ,4 5 - ( 3 - ( ( 1R 2R ) - 6 , 7 -difluoro - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl -6 - ( 2 -methylpy 4 - tetrahydronaphthalen - 1 -yl ) ureido ) - N - ( 2 -hydroxy - 2 rimidin - 5 -yl ) - 2 - phenylpyridin - 3 -yl ) urea ; methylpropyl) - 3 - methyl- 6 - ( tetrahydro - 2H -pyran - 4 -yl ) pi 1 - (( 1R ,2R )- 6 , 7 -difluoro -2 -hydroxy -4 ,4 -dimethyl - 1, 2 ,3 ,4 colinamide ; tetrahydronaphthalen - 1 -yl ) - 3 - (6 - (4 - hydroxymethyl) phe - 25 1- ( (1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 nyl) - 5 -methyl - 2 - phenylpyridin - 3 - yl) urea ; tetrahydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 6 - ( 1H -pyrazol 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - 4 - yl) - 2 - ( tetrahydro - 2H -pyran - 4 - yl )pyridin - 3 -yl ) urea ; and tetrahydronaphthalen - 1 -yl ) - 3 - (6 -( 3 -( hydroxymethyl ) phe - 1 -( ( 1R ,2R )- 6 , 7 -difluoro -2 -hydroxy -4 ,4 -dimethyl - 1, 2 ,3 ,4 nyl) - 5 -methyl - 2 -phenylpyridin - 3 - yl) urea ; tetrahydronaphthalen - 1 - yl ) -3 -( 6 -( 2 - hydroxypyrimidin -5 1 - (6 - ( 3 - cyanophenyl) - 5 -methyl - 2 - phenylpyridin - 3 - yl) - 3 - 30 yl) - 5 -methyl - 2 - ( tetrahydro - 2H -pyran - 4 -yl ) pyridin - 3 - yl) ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 urea . tetrahydronaphthalen - 1 -yl ) urea ; The compound of the present invention can have several 1 - ( 1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 types of tautomers as exemplified by the following formulas . tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 6 - ( 1- methyl - 1H These tautomers are also included in the scope of the pyrazol- 3 - yl) - 2 - phenylpyridin - 3 -yl ) urea ; 35 compound of the present invention . The abundance ratio of 1 - ( (1R , 2R ) -6 , 7 -difluoro - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 these tautomers can vary depending on whether the com tetrahydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 6 - ( 6 -methyl pound is in the solid state or in the state of dissolution in a pyridazin - 4 -yl ) - 2 - phenylpyridin - 3 - yl) urea; liquid .

P15 Rb HON Rla CZ R la R4a R4a R26 N IZ NH OH K2 OH ( I - a - x ) (I - a - y )

1 -( ( 1R , 2R ) -6 , 7 - difluoro - 2 -hydroxy -4 ,4 -dimethyl - 1, 2 ,3 , 4 Note that the description of a certain particular tautomer tetrahydronaphthalen - 1- yl) -3 - (5 -methyl - 6 -( 2 -methylthi - in any structural formula in the present specification is not azol- 5 -yl ) - 2 -phenylpyridin - 3 -yl ) urea ; intended to be limited to its type but is intended to represent 1 -( (1R , 2R )- 6 ,7 - difluoro - 2 -hydroxy -4 ,4 -dimethyl - 1 ,2 , 3 ,4 the total set of tautomers . tetrahydronaphthalen - 1 - yl) - 3 - ( 5 - methyl- 6 - ( 1 -methyl - 1H For example , in the compound of Example 20 to be pyrazol- 4 - yl) - 2 - phenylpyridin - 3 - yl) urea ; 60 described later , when the compound name is described as 1 - ( 6 '- hydroxy - 3 -methyl - 6 - phenyl- [ 2 , 3 ' -bipyridin ) - 5 -yl ) - 3 1 -( 6 -( 4 -cyanophenyl ) - 5 -methyl - 2 -phenylpyridin - 3 -yl ) - 3 ( 1R , 2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaph ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 thalen - 1 -yl ) urea , one of its tautomers 1 -( ( 1R ,2R )- 2 -hy tetrahydronaphthalen - 1 - yl) urea ; droxy - 4 , 4 - dimethyl- 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 - yl) - 3 1 -( ( 1R ,2R )- 6 , 7 -difluoro - 2- hydroxy -4 ,4 -dimethyl -1 ,2 ,3 ,4 - 65 (3 -methyl - 6 '- oxo -6 -phenyl - 1' , 6 '- dihydro - [2 , 3' - bipyridin ]- 5 tetrahydronaphthalen - 1 -yl ) - 3 -( 5 -methyl - 2 -phenyl - 6 - (1H yl) urea is also a compound included in the compound of pyrazol - 4 - yl) pyridin - 3 - yl ) urea ; Example 20 . US 10 , 399 , 945 B2 48 In the present specification , unless otherwise noted , the stone , sore throat, fibromyalgia , chronic pain syndrome, case where a cyclic group has a variable substituent means thalamic pain syndrome, pain from a stroke, phantom limb that the variable substituent is not bound to a particular pain , sunburn , radiculopathy, complex regional pain syn carbon atom of the cyclic group . This means, for example , drome, HIV sensory neuropathy , central nervous disorder that the variable substituent R * in the following formula A 5 pain syndrome, multiple sclerosis pain , Parkinson 's disease can be substituted for any of the carbon atoms i , ii , and iii pain , spinal cord injury pain ,menstrual pain , toothache, pain from bone metastasis , pain from endometriosis , pain from in the formula A and that the variable substituent Ry in the uterine fibroids, nociceptive pain , hyperalgesia , and tem following formula B can be substituted for any of the carbon poromandibular joint pain . atoms iv and v in the formula B . 10 According to the definition of the International Associa tion for the Study of Pain , the “ acute pain " is attributed to Formula A diseases , inflammation , or damage to tissues . Generally , this type of pain occurs suddenly after , for example , an external injury or an operation , can be accompanied by anxiety or stress , and is limited to a certain duration and severity . In some cases , acute pain can be chronic . According to the definition of the International Associa tion for the Study of Pain , the " chronic pain ” is widely Formula B believed to indicate a disease itself . 20 Chronic pain can be exacerbated by environmental and psychological factors . Chronic pain generally lasts longer than acute pain over a period of three months or longer and is resistant to most internal medical therapies . Chronic pain iv v can cause serious problems for patients and thus causes serious problems in many cases . Chronic pain includes [ 6 ] Embodiment 6 of the present invention is a pharma cancer pain (pain arising from tumor ), visceral pain ( for ceutical composition comprising : at least one of the com - example , visceral pain resulting from pancreatic cancer pound represented by the above formula ( 1 ) or the optical and / or metastasis in the abdomen ) , and somatic pain ( for isomer thereof, the pharmaceutically acceptable salt thereof, example , somatic pain resulting from one or more of bone and the solvate thereof as an active ingredient. 30 cancer, metastasis in bone , postoperative pain , sarcoma, [ 7 ] Embodiment 7 of the present invention is a preventive connective tissue cancer, bone tissue cancer , bone marrow and / or therapeutic agent for a disease in which TrkA is hematopoietic cell cancer ,multiple myeloma, leukemia , and involved , comprising : at least one of the compound repre - primary or secondary bone cancer ) sented by the above formula ( I ) or the optical isomer thereof, The “ inflammatory pain ” means pain resulting from the pharmaceutically acceptable salt thereof , and the solvate 35 inflammation . Inflammatory pain manifests often as thereof as an active ingredient. increased sensitivity to mechanical stimuli (mechanical For example , the “ disease in which TrkA is involved ” hyperalgesia or tenderness ) . For example , inflammatory includes, but is not limited to , pain (pain associated with pain is attributed to a condition selected from the group osteoarthritis , rheumatoid arthritis , bone fracture , interstitial consisting of the following : burn , sunburn , arthritis , large cystitis , chronic pancreatitis , and prostatitis , nociceptive 40 intestine inflammation , carditis, dermatitis , myositis , neuri pain typified by chronic low back pain , diabetic peripheral tis , mucositis , urethritis , cystitis , gastritis , pneumonia , col neuropathic pain , postoperative pain , pelvic pain , cancer lagen vascular disease , etc . pain , and the like, and pain such as neuropathic pain , acute The “ neuropathic pain ” means pain resulting from a pain , chronic pain , and inflammatory pain ), cancers, inflam - condition or an event which causes nerve damage . The mation / inflammatory diseases, allergic diseases, skin dis - 45 “ neuropathic ” means a disease process which causes dam eases, neurodegenerative diseases, infectious diseases , age to nerves. The " causalgia ” means the state of chronic Sjogren ' s syndrome, endometriosis, renal diseases, and pain after nerve damage . “ Allodynia” usually means a state osteoporosis . in which a person feels pain in response to a painless [ 7 - 1 ] Embodiment 7 - 1 of the present invention is the stimulus , for example a gentle touch . compound represented by the above formula ( I) or the 50 For example , the “ neuropathic pain ” is attributed to a optical isomer thereof, the pharmaceutically acceptable salt condition selected from , for example , causalgia , diabetes , thereof, or the solvate thereof for prevention and /or treat- collagen vascular disease, trigeminal neuralgia , spinal cord ment of a disease in which TrkA is involved . injury , brain stem injury , thalamic pain syndrome, complex “ Pain ” is a characteristic of a number of external injuries regional pain syndrome type I/ reflex sympathetic dystrophy , and disease states . When substantial damage to body tissues 55 Fabry syndrome, small fiber neuropathy , cancer , cancer involving a disease or an external injury occurs , the noci - chemotherapy , chronic alcohol intoxication , stroke , abscess , ceptor activation characteristics change , which leads to demyelinating disease , viral infection , antiviral therapy, hypersensitivity at the site of damage and nearby normal AIDS, and AIDS therapy . tissues . Specific pain includes , but is not limited to , osteoar The “ neuropathic pain ” is attributed to a causal factor thritis pain , arthralgia , neuropathic pain , postoperative pain , 60 selected from , for example , external injury , operation , ampu lower back pain , diabetic neuropathy, intraoperative pain , tation , toxin , and chemotherapy . cancer pain , chemotherapy - induced pain , headache ( includ - The “ nociceptive pain ” is induced by tissue damage or a ing cluster headache , tension headache , migraine pain ) , severe stimulus which can cause damage . Pain afferent nerve trigeminal neuralgia , herpes zoster pain , post herpetic neu fibers are activated by the transmission of stimuli performed ralgia , carpal tunnel syndrome, inflammatory pain , pain 65 by nociceptors at the damaged site and sensitize the spinal from rheumatoid arthritis , colitis , interstitial cystitis pain , cord at their terminal positions. These are then relayed up in visceral pain , pain from the kidney stones , pain from gall - the spinal tract to the brain where pain is perceived . Acti US 10 ,399 ,945 B2 49 50 vation of nociceptors activates two types of afferent nerve neuropathic pain , postoperative pain , pelvic pain , cancer fibers . Myelinated A - 8 fibers transmit quickly and are pain , and the like , and pain such as neuropathic pain , acute responsible for a sharp and stabbing pain sensation , while pain , chronic pain , and inflammatory pain ) , cancers, inflam unmyelinated C fibers transmit at a slower rate and convey mation / inflammatory diseases , allergic diseases, skin dis dull or aching pain . Moderate to severe acute nociceptive 5 eases , neurodegenerative diseases, infectious diseases , pain is a significant characteristic of, but is not limited to , Sjogren ' s syndrome, endometriosis , renal diseases, and pain from contusion /sprain , postoperative pain (pain after osteoporosis, the agent comprising: any type of surgical operation ) , pain after external injury , at least one of the compound represented by the above burn , myocardial infarction , acute pancreatitis , and renal colic . In general, cancer- related acute pain syndrome is also 10 formula (I ) or the optical isomer thereof, the pharmaceuti attributed to therapeutic interactions such as chemotherapy cally acceptable salt thereof, and the solvate thereof as an toxicity , immunotherapy , hormonal therapy, and radiation active ingredient. therapy. Preferably , Embodiment 8 of the present invention is a Moderate to severe acute nociceptive pain is a significant prepreventive and /or therapeutic agent for pain (pain associated characteristic of, but is not limited to , cancer pain (for 15 with osteoarthritis , rheumatoid arthritis , bone fracture , inter example , bone pain , headache, facial pain , and visceral stitial cystitis, chronic pancreatitis, and prostatitis, nocicep pain ), cancer pain which can be pain associated with cancer tive pain typified by chronic low back pain , diabetic periph therapy ( for example , postchemotherapy syndrome, chronic eral neuropathic pain , postoperative pain , pelvic pain , cancer postoperative pain syndrome, and post -radiation syndrome ), pain , and the like , and pain such as neuropathic pain , acute and back section pain which may be attributed to an abnor- 20 pain , chronic pain , and inflammatory pain ), the agent com mality in the herniated or fractured intervertebral disc , the prising: lumbar facet joint, the sacroiliac joint, the paraspinal at least one of the compound represented by the above muscles, or the posterior longitudinal ligament. formula (I ) or the optical isomer thereof, the pharmaceuti The “ cancer ” means or represents a physiological condi - cally acceptable salt thereof, and the solvate thereof as an tion in a mammal , typically characterized by disordered cell 25 active ingredient. proliferation . Specific examples of the “ cancer” include, but 18 - 1 ] Embodiment 8 - 1 of the present invention is the are not limited to , neuroblastoma, ovarian cancer , endome compound represented by the above formula ( I ) or the trial cancer, pleomorphic glioblastoma, cervical cancer , pan optical isomer thereof, the pharmaceutically acceptable salt creatic cancer , colon cancer , rectal cancer , prostate cancer , melanoma, myeloma, thyroid cancer , lung cancer ( small cell 30 thereof, or the solvate thereof for prevention and /or treat lung cancer , non - small cell lung cancer ) , brain tumor, ment of e. g . pain (pain associated with osteoarthritis , rheu esophageal cancer , kidney cancer , osteoma and blood can matoid arthritis, bone fracture , interstitial cystitis , chronic cers ( chronic myelogenous leukemia , acute lymphoblastic pancreatitis , and prostatitis , nociceptive pain typified by leukemia, Philadelphia chromosome positive acute lympho chronic low back pain , diabetic peripheral neuropathic pain , blastic leukemia (Ph + ALL ) , acute myelogenous leukemia 35 postoperative pain , pelvic pain , cancer pain , and the like , (AML ) , and chronic lymphocytic leukemia (CML ) ) , and pain such as neuropathic pain , acute pain , chronic pain , squamous cell carcinoma, glioma, gastrointestinal cancer, and inflammatory pain ) , cancers , inflammation /inflamma ovarian cancer , liver cancer , gastric cancer , bladder cancer , tory diseases , allergic diseases , skin diseases, neurodegen hepatoma , breast cancer, head and neck cancer , germ cell erative diseases , infectious diseases , Sjogren ' s syndrome, tumor, pediatric sarcoma, paranasal sinus natural killer, 40 endometriosis , renal diseases , and osteoporosis . multiple myeloma. Preferably, Embodiment 8 - 1 of the present invention is Specific examples of the “ inflammation / inflammatory dis - the compound represented by the above formula ( I ) or the eases ” include, butare not limited to , interstitial cystitis (IC ), optical isomer thereof, the pharmaceutically acceptable salt painful bladder syndrome (PBS ), urinary incontinence , thereof, or the solvate thereof for prevention and / or treat inflammatory cystitis , inflammatory bowel disease , ulcer - 45 ment of pain (pain associated with osteoarthritis , rheumatoid ative colitis , Crohn ' s disease , rheumatoid arthritis , joint arthritis , bone fracture , interstitial cystitis , chronic pancrea swelling, asthma, atopic dermatitis , psoriasis , psoriatic titis , and prostatitis , nociceptive pain typified by chronic low arthritis , and systemic lupus erythematosus . back pain , diabetic peripheral neuropathic pain , postopera Specific examples of the “ allergic diseases” include , but tive pain , pelvic pain , cancer pain , and the like, and pain are not limited to , asthma, atopic dermatitis , and rhinitis . 50 such as neuropathic pain , acute pain , chronic pain , and Specific examples of the “ skin diseases ” include , but are inflammatory pain ) . not limited to , pruritus ( including systemic cutaneous pru - [ 9 ] Embodiment 9 of the present invention is a TrkA ritus , localized cutaneous pruritus , and diffuse cutaneous inhibitor comprising / composed of: one or more of the com pruritus ) . pound represented by the above formula ( I ) or the optical Specific examples of the “ renal diseases” include, but are 55 isomer thereof, the pharmaceutically acceptable salt thereof, not limited to , diabetic nephropathy, kidney fibrosis , and and the solvate thereof. chronic kidney disease . 9 - 1 ] Embodiment 9 - 1 of the present invention is the Specific examples of the “ particular infectious diseases” compound represented by the above formula (I ) or the include , but are not limited to , cruzi trypanosoma infection . optical isomer thereof, the pharmaceutically acceptable salt Specific examples of the “ neurodegenerative diseases” 60 thereof, or the solvate thereof for TrkA inhibition . include , but are not limited to , multiple sclerosis , Parkin - [ 10 ] Embodiment 10 of the present invention is use of at son ' s disease , and Alzheimer ' s disease . least one of the compound represented by the above formula [8 ] Embodiment 8 of the present invention is a preventive (I ) or the optical isomer thereof, the pharmaceutically and / or therapeutic agent for e . g . pain ( pain associated with acceptable salt thereof, and the solvate thereof as a phar osteoarthritis , rheumatoid arthritis , bone fracture , interstitial 65 maceutical composition . cystitis , chronic pancreatitis, and prostatitis , nociceptive [ 10 - 1 ] Embodiment 10 - 1 of the present invention is use of pain typified by chronic low back pain , diabetic peripheral the compound represented by the above formula (I ) or the US 10 , 399 , 945 B2 51 52 optical isomer thereof, the pharmaceutically acceptable salt visceral pain , pain from the kidney stones, pain from gall thereof, or the solvate thereof for the production of a stone , sore throat , fibromyalgia , chronic pain syndrome , pharmaceutical composition . thalamic pain syndrome, pain from a stroke , phantom limb [ 11 ] Embodiment 11 of the present invention is use of at pain , sunburn , radiculopathy, complex regional pain syn least one of the compound represented by the above formula 5 drome, HIV sensory neuropathy, central nervous disorder ( I ) or the optical isomer thereof, the pharmaceutically pain syndrome, multiple sclerosis pain , Parkinson 's disease acceptable salt thereof, and the solvate thereof as TrkA pain , spinal cord injury pain , menstrual pain , toothache , pain inhibition . from bone metastasis , pain from endometriosis , pain from [ 11 - 1 ] Embodiment 11- 1 of the present invention is use of uterine fibroids , nociceptive pain , hyperalgesia , temporo the compound represented by the above formula (I ) or the 10 mandibular joint pain , neuroblastoma, ovarian cancer, endo optical isomer thereof, the pharmaceutically acceptable salt metrial cancer , pleomorphic glioblastoma, cervical cancer, thereof, or the solvate thereof for the production of a TrkA pancreatic cancer, colon cancer, rectal cancer , prostate can inhibitor . cer , melanoma, myeloma, thyroid cancer, lung cancer (small [ 12 ] Embodiment 12 of the present invention is a method cell lung cancer , non - small cell lung cancer ) , brain tumor, of treating a disease selected from pain (pain associated with 15 esophageal cancer, kidney cancer , osteoma and blood can osteoarthritis , rheumatoid arthritis , bone fracture, interstitial cers ( chronic myelogenous leukemia , acute lymphoblastic cystitis , chronic pancreatitis, and prostatitis , nociceptive leukemia , Philadelphia chromosome positive acute lympho pain typified by chronic low back pain , diabetic peripheral blastic leukemia (PH + ALL ) , acute myelogenous leukemia neuropathic pain , postoperative pain , pelvic pain , cancer ( AML) , and chronic lymphocytic leukemia (CML ) ) , pain , and the like, and pain such as neuropathic pain , acute 20 squamous cell carcinoma, glioma, gastrointestinal cancer, pain , chronic pain , and inflammatory pain ) , cancers , inflam ovarian cancer , liver cancer , gastric cancer , bladder cancer, mation /inflammatory diseases, allergic diseases , skin dis hepatoma, breast cancer , head and neck cancer, germ cell eases , neurodegenerative diseases, infectious diseases, tumor , pediatric sarcoma, paranasal sinus natural killer, Sjogren ' s syndrome, endometriosis , renal diseases, and multiple myeloma, interstitial cystitis ( IC ) , painful bladder osteoporosis , the method comprising : 25 administering at least one of the compound represented by syndrome (PBS ) , urinary incontinence , inflammatory cysti the above formula ( I ) or the optical isomer thereof, the tis , inflammatory bowel disease , ulcerative colitis , Crohn ' s pharmaceutically acceptable salt thereof, and the solvate disease , systemic lupus erythematosus rheumatoid arthritis , thereof to a subject in need of treatment of the disease . joint swelling, asthma, atopic dermatitis , psoriasis , psoriatic Preferably, Embodiment 12 of the present invention is a 30 arthritis , rhinitis , systemic cutaneous pruritus, localized method of treating pain (pain associated with osteoarthritis , cutaneous pruritus, diffuse cutaneous pruritus ,multiple scle rheumatoid arthritis , bone fracture , interstitial cystitis , rosis , Parkinson ' s disease , Alzheimer ' s disease , cruzi try chronic pancreatitis , and prostatitis , nociceptive pain typi panosoma infection , Sjogren 's syndrome, endometriosis , fied by chronic low back pain , diabetic peripheral neuro diabetic nephropathy , kidney fibrosis , chronic kidney dis pathic pain , postoperative pain , pelvic pain , cancer pain , and 35 ease , and osteoporosis . the like , and pain such as neuropathic pain , acute pain , [ 14 ] The Embodiment 14 of the present invention is an chronic pain , and inflammatory pain ) , the method compris intermediate compound , a salt thereof, or a solvate thereof, ing: the intermediate compound being the following formula administering at least one of the compound represented by (AM - 3 ) : the above formula (I ) or the optical isomer thereof, the 40 pharmaceutically acceptable salt thereof, and the solvate (AM - 3 ) thereof to a subject in need of treatment of the disease , and R4a is more preferably a method of treating pain (pain associated with osteoarthritis , rheumatoid arthritis , bone fracture , inter R46 stitial cystitis , chronic pancreatitis , and prostatitis , nocicep - 45 tive pain typified by chronic low back pain , diabetic periph eral neuropathic pain , postoperative pain , pelvic pain , cancer Y NH pain , and the like, and pain such as neuropathic pain , acute pain , chronic pain , and inflammatory pain ) . R3a Here , the “ subject ” includes humans as well as nonhuman 50 mammals such as dogs , cats , rats , mice, monkeys, cows , where Xl is C - H or N ; horses, pigs , and sheep . Rla is a phenyl group or a tetrahydro -2H -pyranyl group (the In the present specification , unless otherwise noted , the phenyl group and the tetrahydro -2H -pyranyl group may " treatment" as in the " treatment of a disease” means recov each have 1 to 3 substituent halogen atoms or C1- 6 alkyl ery from one or more “ diseases , " or moderation or inhibition 55 groups ) ; of the progression of a “ disease . ” R4a is a C - alkyl group ; and [ 13 ] Embodiment 13 of the present invention is the R4 is a hydrogen atom , a halogen atom , a hydroxyl group , preventive and /or therapeutic agent according to Embodi- a cyano group , a C - alkyl group , a halogenated C - alkyl ment [8 ] or the method according to Embodiment [ 12] , group , a hydroxy halogenated C1- 6 alkyl group , a hydroxy wherein the disease is selected from the group of osteoar - 60 C1- 6 alkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 thritis pain , arthralgia , neuropathic pain , postoperative pain , alkoxy group , a hydroxy C1- 6 alkoxy group , a hydroxy lower back pain , diabetic neuropathy, intraoperative pain , halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl cancer pain , chemotherapy - induced pain , headache ( includ group , a halogenated C1- 6 alkoxy C1- 6 alkyl group , a C1- 6 ing cluster headache , tension headache , migraine pain ), alkoxy C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy C1- 6 trigeminal neuralgia , herpes zoster pain , post herpetic neu - 65 alkoxy group , a C1- 6 alkoxy carbonyl group , a C1- 6 alkoxy ralgia , carpal tunnel syndrome, inflammatory pain , pain carbonyl C1- 6 alkyl group , a carboxy group , a carboxamide from rheumatoid arthritis , colitis , interstitial cystitis pain , group, a C3- 8 cycloalkyl group (the C3- 8 cycloalkyl group US 10 , 399 , 945 B2 53 54 may have 1 to 3 arbitrary substituent groups which may be group , a halogen atom , a C1 - 6 alkyl group , a halogenated selected from a hydroxyl group , a halogen atom , a C1- 6 alkyl C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a C3- 8 group , a C1- 6 alkoxy group , and a C1- 6 alkoxy C1- 6 alkyl cycloalkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 group ) , a C6 - 10 aryl group (the C6 - 10 aryl group may have 1 alkoxy group , a C1- 6 alkoxy carbonyl group , a C2- 6 alkanoyl to 3 arbitrary substituent groups which may be selected from 5 group , a C1- 6 alkylthio group , and a C1- 6 alkylsulfonyl a hydroxyl group , a cyano group , a halogen atom , a C1- 6 group ) , a - NR4eRº group , a CONRER4 group ( the R4e alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 andR are each independently a hydrogen atom , a C1- 6 alkyl alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a group , a hydroxy C1- 6 alkyl group , a halogenated C1- 6 alkyl halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a hydroxy halogenated C1- 6 alkyl group , or a 5 - or group , a C1- 6 alkoxy carbonyl group , a C2- 6 alkanoyl group , 10 6 -membered heteroaryl C1- 6 alkyl group (the 5 - or 6 -mem a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a bered heteroaryl of the 5 - or 6 -membered heteroaryl C1- 6 - NR RP group , a CONR RP group (the RQ and Rß are alkyl group may have 1 to 3 substituent halogens or C1- 6 each independently a hydrogen atom , a C1- 6 alkyl group , a alkyl groups ) ), or a di- C1 - 6 alkylamino C1- 6 alkoxy group ; halogenated C1-6 alkyl group , or a C3 -8 cycloalkyl group ), a more preferably , a hydrogen atom , a C1- 6 alkyl group , a carboxy group , and a carboxamide group ) , a 5 - or 6 - mem - 15 hydroxy C1- 6 alkyl group , a C6- 10 aryl group ( the C6- 10 aryl bered heteroaryl group ( the 5 - or 6 -membered heteroaryl group may have 1 to 3 substituent cyano groups or hydroxy group may have 1 to 3 arbitrary substituent groups which C1- 6 alkyl groups ), a 6 -membered heteroaryl group (the may be selected from a hydroxyl group , a ( 4 -methoxyben 6 -membered heteroaryl group may have 1 to 3 arbitrary zyl) oxy group , a cyano group, a halogen atom , a C1- 6 alkyl substituent groups which may be selected from a hydroxyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl 20 group , a cyano group , a C1- 6 alkyl group , a halogenated C1- 6 group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a alkyl group , a hydroxy C1- 6 alkyl group , and a C1- 6 alkyl halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl sulfonyl group ), or a CONR *' R “ group ( the R4e and R ^ group , a C1- 6 alkoxy carbonyl group , a C2- 6 alkanoyl group , are each independently a hydrogen atom , a hydroxy C1- 6 a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a alkyl group , or a 5 - or 6 -membered heteroaryl C1- 6 alkyl - NR RP group , a — CONR RP group (the R and Rp are 25 group ( the 5 - or 6 -membered heteroaryl of the 5 - or 6 -mem each independently a hydrogen atom , a C1- 6 alkyl group , a bered heteroarylC1 - 6 alkyl groupmay have 1 to 3 substituent halogenated C1- 6 alkyl group , or a C3- 8 cycloalkyl group ) , a C1- 6 alkyl groups) ) ; carboxy group , and a carboxamide group ) , a — NR4R44 further preferably a hydrogen atom , a bromine atom , a cyano group , a CONR4eRº group (the R4e and R are each group, a hydroxymethyl group , a ethoxycarbonyl group , a independently a hydrogen atom , a Cl. alkyl group , a 30 cyanophenyl group , a hydroxypyridyl group , a cyanopyridyl hydroxy C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a group , a methylpyridyl group , a hydroxymethyl pyridyl hydroxy halogenated C1- 6 alkyl group , a C3- 8 cycloalkyl group , a trifluoromethyl pyridyl group , a methanesulfonyl group , or a 5 - or 6 -membered heteroaryl C - alkyl group pyridyl group , a methoxycarbonylpyridyl group , a 2 - ( ( 4 ( the 5 - or 6 -membered heteroaryl in the 5 - or 6 -membered methoxybenzyl )oxy ) pyridinyl group , a hydroxypyrimidinyl heteroaryl C1- 6 alkyl group may have 1 to 3 substituent 35 group , a methylpyrimidinyl group , a trifluoromethyl pyrim halogen atoms or C1- 6 alkyl groups )) , a R4R4N C1- 6 idinyl group , a (2 -hydroxypropan - 2 -yl ) pyrimidinyl group , a alkoxy group (the R4C and R4d are each independently a 2 - ( ( 4 -methoxybenzyl ) oxy ) pyrimidinyl group , a methyl hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl p yridazinyl group , a 1H -pyrazolyl group , a 1 -methyl - 1H group , or a halogenated C1- 6 alkyl group ), a halogenated pyrazolyl group , a 1 - tert -butoxycarbonyl - 1H -pyrazolyl mono -/ di - C2 - 7 alkanoyl amino group , a C1- 6 alkylthio group , 40 group , a methylthiazolyl group , a carboxyl group , a carbox a C1-6 alkylsulfonyl group , or a halogenated C1- 6 alkylsul- amide group , an N -( 2 - hydroxy - 2 -methylpropyl ) aminocar fonyl group (note that if Rla is a phenyl group , R46 is not a bonyl group , or an N -( (5 -methyl - 1, 3 ,4 -oxazol - 2 -yl )methyl ) hydrogen atom ) . aminocarbonyl group ; and particularly preferably a [14 - 1 ] In the compound of the above formula (AM -3 ) of hydrogen atom , a bromine atom , a cyano group , a Embodiment [14 ] described above , X ' is preferably a C - H . 45 hydroxymethyl group , a ethoxycarbonyl group , a 4 - cyano [ 14 - 2 ] In the compound of the above formula (AM - 3 ) of phenyl group , a 2 -hydroxypyridin - 5 - yl group , a 2 - cyano Embodiment [14 ] described above , R3a is preferably a pyridin - 5 - yl group , a 2 -methylpyridin - 5 - yl group , a 2 - hy phenyl group or a 4 -tetrahydro - 2H - pyranyl group (tetra - droxymethylpyridin - 5 - yl group , a 2 -trifluoromethylpyridin hydro -2H -pyran - 4 -yl group ) . 4 - yl group , a 3 - trifluoromethylpyridin - 5 - yl group , a [ 14 - 3 ] In the compound of the above formula ( AM - 3 ) of 50 2 -methanesulfonylpyridin - 5 -yl group , a 2 -methoxycarbo Embodiment [ 14 ] described above, R4a is preferably a nylpyridin -4 -yl group , a 2 -( (4 -methoxybenzyl ) oxy )pyridin methyl group . 5 -yl group , a 2 -hydroxypyrimidin - 5 -yl group , a 2 -methyl [ 14 - 4 ] In the compound of the above formula ( AM - 3 ) of pyrimidin - 5 - yl group , a 2 - trifluoromethylpyrimidin - 5 - yl Embodiment [ 14 ] described above, R45 is preferably a group, a ( 2 -hydroxypropan - 2 - yl) pyrimidin - 5 - yl group , a hydrogen atom , a halogen atom , a cyano group , a C1- 6 alkyl 55 2 - ( ( 4 -methoxybenzyl ) oxy )pyrimidin - 5 - yl group , a 1H -pyra group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy group , a zol- 4 - yl group , a 1 -methyl - 1H -pyrazol - 4 - yl group , a 1 -tert hydroxy C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkoxy group , butoxycarbonyl- 1H -pyrazol - 4 -yl group , a carboxyl group , a a C6- 10 aryl group ( the C6- 10 aryl group may have 1 to 3 carboxamide group , an N - ( 2 -hydroxy - 2 -methylpropyl ) arbitrary substituent groups which may be selected from a aminocarbonyl group , or an N - (( 5 -methyl - 1 ,3 ,4 -oxazol -2 hydroxyl group , a cyano group , a halogen atom , a C1- 6 alkyl 60 yl) methyl ) aminocarbonyl group ( note that if R3a is a phenyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , R * is not a hydrogen atom ) . group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a [ 14 - 5 ] In the compound of the above formula ( AM - 3 ) of halogenated C1- 6 alkoxy group , a C2- 6 alkanoyl group , and a Embodiment [ 14 ] described above, R46 is preferably a C1- 6 alkylsulfonyl group ), a 5 - or 6 -membered heteroaryl cyanophenyl group , a hydroxymethylphenyl group , a group ( the 5 - or 6 -membered heteroaryl group may have 1 65 hydroxymethyl pyridyl group , a methylpyridazinyl group , or to 3 arbitrary substituent groups which may be selected from a methylthiazolyl group ; and more preferably a 3 -cyanophe a hydroxyl group , a (4 -methoxybenzyl ) oxy group , a cyano nyl group , a 3- hydroxymethyl ) phenyl group , a 4 - hy US 10 , 399 , 945 B2 55 56 droxymethyl) phenyl group , a 2 -hydroxymethylpyridin - 4 -yl -continued group , a 6 -methylpyridazin -4 -yl , or a 2 -methylthiazol - 5 - yl group . ( TS - 4 ) [15 ] Embodiment 15 of the present invention is a prefer N able embodiment of the compound , the salt thereof, or the 5 solvate thereof according to the above formula ( AM - 3 ) of Embodiment [ 14 ] described above , and is specifically an intermediate compound , a salt thereof, or a solvate thereof, the intermediate compound being the following formula ( TS - 5 ) ( AM - 3 - a ) : 10 ZE ( AM - 3 - a ) CH3 (R ) - B ) 15 ( TS - 6 )

NH2

R3a 20 ( TS - 7 ) where R3a is a phenyl group or a tetrahydro - 2H - pyranyl group ( the phenyl group and the tetrahydro - 2H -pyranyl group may each have 1 to 3 substituent halogen atoms or 8x C1- 6 alkyl groups) ; 25 the ring B is a C6- 10 aryl group or a 5 - or 6 -membered heteroaryl group ; ( TS - 8 ) q is an integer of 0 to 3 ; and R $ a is a hydrogen atom , a hydroxyl group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a ( 4 -methoxybenzyl ) oxy A group , a C3- 8 cycloalkyl group , a C1- 6 alkoxy group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy carbonyl group , a C2- 6 alkanoyl group , a C1- 6 alkylsulfonyl group , a ( TS - 9 ) - CONR RP group ( the R? and Rp are each independently a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a C3- 8 cycloalkyl group ), or a carboxamide group . [15 - 1] In the compound of the above formula (AM -3 -a ) of Embodiment [15 ] described above , R3a is preferably a 40 phenyl group or a 4 - tetrahydro - 2H -pyranyl group ( tetra hydro -2H -pyran - 4 -yl group ) . ( TS -10 ) [ 15 - 2 ] In the compound of the above formula ( AM -3 -a ) of Embodiment [15 ] described above , the ring B is preferably a group which may be arbitrarily selected from the following 45 partial structural formulas:

(TS - 1 ) 50 ( TS - 11 )

(TS -2 ) 55 L ( TS - 12 ) Rw (TS -3 ) US 10 . 399 , 945 B2 57 58 -continued ( TS- 13 ) ( TS -1 )

Rw

www ( TS - 2 ) (TS - 14 ) 10

Rw 11 Z?? ( TS - 3 ) NI

( TS -15 ) 20 ( TS - 4 )

N=

(TS -16 ) 25 ( TS - 5 )

RW ( TS -17 ) 30

( TS - 6 )

35

( TS -18 ) ( TS- 7 ) 40

45 (TS - 8 ) (TS - 19 )

50 ( TS- 9 )

R—N

(TS - 20 ) 55

( TS - 10) 6 ) R—N where RW is a group which may be arbitrarily selected from a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a 4 -methoxybenzyl group (PMB group ), a C1- 6 alkoxy carbonyl group , and a hydroxy C1- 6 alkyl group ; 65 more preferably a group which may be arbitrarily selected from???????? the following partial structural formulas : ????????? US 10 . 399 , 945 B2 59 60 -continued - continued ( TS -11 ) ( TS - 20) RW

10 where RW is a group which may be arbitrarily selected from Rw ( TS- 12 ) 1 a hydrogen atom , a Cl. alkyl group , a 4 -methoxybenzyl group (PMB group ) , and a C1- 6 alkoxy carbonyl group ; and further preferably a group which may be arbitrarily selected from the following partial structural formulas : 15

( TS- 1 ) (TS - 13 ) 20 Rw ( TS - 2 )

25

( TS - 14 ) wis

Rw 30 (TS - 3)

?

35 ( TS -5 ) *???? (TS - 15 ) tppt RW

. 40 (TS - 9 ) ( TS -16 ) RW

—N

45 m Rw (TS - 17 ) ( TS -12 ) Rw up 50 A :

. ( TS -18 ) 55

( TS - 15 ) RW - N ( TS - 19 ) 60 ?? eNe

65 where R " is a group which may be arbitrarily selected from a hydrogen atom , a methyl group , a 4 -methoxybenzyl group (PMB group ), and a tert- butoxycarbonyl group . US 10 , 399 , 945 B2 62 [ 15 - 3 ] In the compound of the above formula ( AM - 3 - a ) of - continued Embodiment [ 15 ] described above , the ring B is preferably (US - 4a ) a group which may be arbitrarily selected from the following partial structural formulas:

( TS - 4 ) (US -5a ) ns 10 RS

m ( TS -18 )

15 (US -9a ) Inn KIN R Sa [ 15 - 4 ] In the compound of the above formula ( AM - 3 - a ) of 20 Embodiment [ 15 ] described above, q is an integer preferably of 0 to 2 ; and an integer of more preferably 0 or 1 . (US - 12a ) [ 15 - 5 ] In the compound of the above formula (AM - 3 -a ) of RW Embodiment [ 15 ] described above, RSa is preferably a hydrogen atom , a hydroxyl group, a cyano group , a C1- 6 25 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a ( 4 -methoxybenzyl ) oxy group , a C1- 6 alkoxy carbonyl group , or a C1- 6 alkylsulfonyl group ; and more preferably a hydrogen atom , a hydroxyl group , a cyano min group , a methyl group , a trifluoromethyl group , a hydroxym - 30 (US - 15a ) ethyl group , a 2 -hydroxypropan - 2 - yl group , a ( 4 -methoxy benzyl ) oxy group , a methoxycarbonyl group , or a meth RW - N . anesulfonyl group . [15 - 6 ] In the compound of the above formula (AM - 3 -a ) of Embodiment [15 ] described above, the following partial > structural formula (US - a ): (US - 18a )

RW (US - a ) 40 (R52 ) where R $a is a hydroxyl group , a cyano group , a C1- 6 alkyl 45 group, a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl is preferably a group which may be arbitrarily selected from group , a (4 -methoxybenzyl ) oxy group , a C1- 6 alkoxy car following partial structural formulas : bonyl group , a C1- 6 alkylsulfonyl group , or a carboxamide group ; and RW is a hydrogen atom , a C1- 6 alkyl group , a 4 -methoxybenzyl group (PMB group ) , or a tert -butoxycar (US - 1a ) 50 bonyl group ; more preferably a group which may be arbi Sa trarily selected from the following partial structural formu las:

(US - 2a ) 55 (US - 1 - 1 ) A RS R5a

60 mann (US - 3a ) (US - 1 - 2 ) min 65 US 10 , 399 ,945 B2 63 64 - continued may be arbitrarily selected from the groups represented by (US - 2- 1 ) the following partial structural formulas:

NC . (US - 2 - 2 )

10

RS HO . N HO (US - 3 - 1 ) 15

( US- 4 - 1 ) 20 mnmann FC HzCN - 2525 (US - 5 - 1 )

IZ 30

(US - 9 - 1 ) Rw mm 35 HO mon F3C (US - 12 -1 ) 40 n RW H3C PMB

45

PMB (US -15 - 1 ) H3C - N RW - N 50 ? Boc - N HN (US - 18 - 1 ) Rw 55 min NC . H3CO where R a is a hydroxyl group , a cyano group , a methyl 60 group , a trifluoromethyl group, a hydroxymethyl group , a 2 -hydroxypropan -2 -yl group , a methoxycarbonyl group , a ( 4 -methoxybenzyl ) oxy group , a methanesulfonyl group , or a carboxamide group ; and RW is a hydrogen atom , a methyl 65 [ 15 - 7 ] In the compound of the above formula (AM - 3 - a ) of group , a 4 -methoxybenzyl group (PMB group ) , or a tert - Embodiment [ 15 ] described above , the following partial butoxycarbonyl group ; and further preferably a group which structural formula (US - a ) : US 10 , 399 , 945 B2 65 66 bered heteroaryl in the 5 - or 6 -membered heteroaryl C1- 6 (US - a ) alkyl group may have 1 to 3 substituent groups arbitrarily selected from a halogen atom and a C1- 6 alkyl group )) , a (R5 ), B R4CR N - C1- 6 alkoxy group (the R4C and R4d are each 5 independently a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , or a halogenated C1- 6 alkyl group ) , a carboxamide group , a halogenated mono - / di- C2- 7 is preferably a group which may be arbitrarily selected from alkanoyl amino group , a C1- 6 alkylthio group , a C1- 6 alkyl the groups represented by the following partial structural sulfonyl group, or a halogenated C1- 6 alkylsulfonyl group formulas : ( note that if R3a is a phenyl group , Rth is not a hydrogen atom ) . [ 16 - 1 ] In the compound of the above formula (AM - 3 - b ) of HO Embodiment [ 16 ] described above, R3a is preferably a 15 phenyl group or a 4 - tetrahydro - 2H -pyranyl group ( tetra hydro - 2H - pyran - 4 - yl group ). NC [16 - 2 ] In the compound of the above formula ( AM - 3 -b ) of Embodiment [ 16 ] described above , R4h is preferably a hydrogen atom , a halogen atom , a cyano group , a C1- 6 alkyl H3C 20 group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy group , a HO . hydroxy C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkoxy group , nnnnn a C1- 6 alkoxy carbonyl group , a carboxy group , a - NR4R4 group , a CONR4R4 group ( the Rte and R4 are each independently a hydrogen atom , a C1- 6 alkyl group , a HO 25 hydroxy C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a HC hydroxy halogenated C1- 6 alkyl group , or a 5 - or 6 -mem bered heteroaryl C1- 6 alkyl group ( the 5 - or 6 -membered mino heteroaryl in the 5 - or 6 -membered heteroaryl C1- 6 alkyl group may have 1 to 3 substituent groups arbitrarily selected [16 ] Embodiment 16 of the present invention is a prefer - 30 from a halogen atom and a C1- 6 alkyl group ) ] , a R4CR4dN able embodiment of the compound , the salt thereof, or the C1- 6 alkoxy group ( the R4C and R4d are each independently solvate thereof according to the above formula ( AM -3 ) of a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl Embodiment [ 14 ] described above , and is specifically an group , or a halogenated C1-6 alkyl group ) ; more preferably intermediate compound, a salt thereof , or a solvate thereof , a hydrogen atom , a halogen atom , a cyano group , a hydroxy the intermediate compound represented by the following 35 C1- 6 alkyl group , a C1- 6 alkoxy carbonyl group , a carboxy group , a — CONR4R4 group [ the R4e and R4 are each formula (AM - 3 -b ): independently a hydrogen atom , a hydroxy C1-6 alkyl group , or a 5 - or 6 -membered heteroaryl C1-6 alkyl group (the 5 - or (AM - 3 - b ) 6 -membered heteroaryl in the 5 - or 6 -membered heteroaryl 40 C1- 6 alkyl group may have 1 to 3 substituent C1- 6 alkyl groups) ]; and further preferably a hydrogen atom , a bromine R4h atom , a cyano group , a hydroxymethyl group , a ethoxycar bonyl group , a carboxy group , a carboxamide group , an N - ( 2 -hydroxy - 2 -methylpropyl ) aminocarbonyl group , or an Y NH2 45 N - ( ( 5 -methyl - 1 , 3 , 4 -oxazole - 2 -yl ) methyl ) aminocarbonyl R3? group ( note that if R3a is a phenyl group , Rth is not a hydrogen atom ). As described above , it is possible to form a preferable where R is a phenyl group or a tetrahydro - 2H -pyranyl embodiment of the compound represented by the above group ( the phenyl group and the tetrahydro - 2H - pyranyl 50 formula ( AM - 3 ) of Embodiment [ 14 ] described above as group may each have 1 to 3 substituent halogen atoms or desired by appropriately combining Embodiments [ 14 ] to C1- 6 alkyl groups ); and [ 16 ] of the present invention , preferable embodiments R *^ is a hydrogen atom , a halogen atom , a hydroxyl group , thereof, and moreover the definitions of the substituents . a cyano group, a C1- 6 alkyl group , a halogenated C1- 6 alkyl In Embodiments [ 14 ] to [ 16 ] described above and sub group , a hydroxy C1- 6 alkyl group , a hydroxy halogenated 55 embodiments thereof , more preferable substituents or com C1- 6 alkyl group , a C1- 6 alkoxy group , a halogenated C1. 6 binations thereof in the above formula ( AM -3 ) follow the alkoxy group , a hydroxy C1- 4 alkoxy group , a C1- 6 alkoxy explanation described in Embodiment 14 . C1- 6 alkyl group , a halogenated C1-6 alkoxy C1-6 alkyl group , [ 17 ] Embodiment 17 of the present invention is a prefer a C1- 6 alkoxy C1- 6 alkoxy group , a hydroxy C1- 6 alkoxy C1- 6 able compound in the compound of the above formula alkoxy group , a hydroxy halogenated C1- 6 alkoxy group , a 60 (AM - 3) of Embodiment [14 ] described above, and is spe C1- 6 alkoxy carbonyl group , a C1- 6 alkoxy carbonyl C1- 6 cifically an intermediate compound , a salt thereof, or a alkyl group , a carboxy group , a — NR4R4 group , a solvate thereof listed below . - CONR4R4 group ( the R4e and R4f are each independently 5 - amino - 3 -methyl - 6 - phenyl - [ 2 , 3 -bipyridin ] - 6 '- ol; a hydrogen atom , a C1- 6 alkyl group , a hydroxy C1- 6 alkyl 5 -methyl - 6 -( 2 -methylpyrimidin -5 - yl) -2 -phenylpyridin - 3 group , a halogenated C1- 6 alkyl group , a hydroxy haloge - 65 amine; nated C1- 6 alkyl group , a C3- 8 cycloalkyl group , or a 5 - or 5 -methyl - 6 - ( 1 -methyl - 1H - pyrazol - 4 - yl) - 2 - phenylpyridin - 3 6 -membered heteroaryl C1- 6 alkyl group ( the 5 - or 6 -mem amine ; US 10 , 399 , 945 B2 68 3 -methyl - 6 -phenyl - 5 '- (trifluoromethyl ) - [2 , 3' - bipyridin )- 5 5 - amino - N - ( 2 - hydroxy - 2 -methylpropyl ) - 3 -methyl - 6 - ( tetra amine ; hydro - 2H -pyran - 4 -yl ) picolinamide . 3 , 6 '- dimethyl- 6 -phenyl - [ 2 , 3 '- bipyridin ) - 5 - amine ; [ 18 ] Embodiment 18 of the present invention is a prefer 5 -amino - 3 -methyl - 6 -phenyl - [ 2 , 3 - bipyridine ] - 6 -carboni able compound in the compound of the above formula trile ; 5 ( AM - 3 ) of Embodiment [ 14 ] described above, and is spe 3 -methyl - 6 -( methylsulfonyl )- 6 -phenyl -[ 2 ,3 ' - bipyridin )- 5 cifically an intermediate compound , a salt thereof, or a amine ; solvate thereof listed below . 5 -methyl -2 - phenyl -6 - (2 -( trifluoromethyl ) pyrimidin - 5 - yl ) 5 -methyl - 6 - ( 1 -methyl - 1H -pyrazol - 4 - yl ) - 2 - ( tetrahydro - 2H pyridin - 3 - amine ; pyran - 4 - yl) pyridin - 3 - amine; 4 - ( 5 - amino - 3 -methyl - 6 -phenylpyridin - 2 - yl) benzonitrile ; 10 5 -methyl - 6 - ( 1H -pyrazol - 4 - yl) - 2 - ( tetrahydro -2H -pyran - 4 - yl) 3 -methyl - 6 -phenyl - 2 -( trifluoromethyl) -[ 2 ,4 ' - bipyridin )- 5 pyridin - 3 -amine ; amine ; 5 -amino -3 -methyl - 6 - (tetrahydro -2H -pyran -4 -yl ) - [2 , 3' - bi tert -butyl 4 - ( 5 - amino - 3 -methyl - 6 - phenylpyridin - 2 - yl) - 1H - pyridin ) -6 - ol; pyrazole - 1 - carboxylate ; 15 (4 - (5 -amino -3 -methyl - 6 - phenylpyridin - 2 -yl ) phenyl )metha 6 -( 2 -[ (4 -methoxybenzyl ) oxy )pyrimidin -5 -yl ) - 5 -methyl - 2 - nol; phenylpyridin - 3 -amine ; (3 -( 5 -amino -3 -methyl - 6 -phenylpyridin - 2 - yl )phenyl ) metha 6 - ( (4 -methoxybenzyl ) oxy )- 3 -methyl - 6 -phenyl - [ 2 , 3 - bipyri nol; din ) - 5 -amine ; 3 -( 5 -amino -3 -methyl - 6 -phenylpyridin - 2 -yl ) benzonitrile ; 2 - ( 5 - ( 5 - amino - 3 -methyl - 6 -phenylpyridin - 2 - yl) pyrimidin - 2 - 20 5 -methyl - 6 - ( 1 -methyl - 1H - pyrazol - 3 - yl) - 2 - phenylpyridin - 3 yl) propan - 2 -ol ; amine; 5 -methyl - 6 - ( 2 -methylpyrimidin - 5 -yl ) - 2 - ( tetrahydro - 2H 5 -methyl - 6 - ( 6 -methylpyridazin -4 - yl) - 2 -phenylpyridin - 3 pyran - 4 - yl) pyridin - 3 - amine ; amine ; ( 5 -amino - 3 -methyl - 6 -phenyl - [ 2 , 3 '- bipyridin ) -6 - yl) metha 5 -methyl - 6 - ( 2 -methylthiazol - 5 - yl )- 2 -phenylpyridin -3 nol; 25 amine ; methyl 5 -amino - 3 -methyl - 6 - phenyl- [ 2, 4 '- bipyridine ] -2 '- car - 5 -methyl - 6 - ( 1 -methyl - 1H - pyrazol -4 - yl) -2 -phenylpyridin - 3 boxylate ; amine; tert- butyl 4 - ( 5 - amino - 3 -methyl - 6 - ( tetrahydro - 2H - pyran - 4 - 4 - ( 5 - amino - 3 -methyl - 6 -phenylpyridin - 2 - ylbenzonitrile : yl) pyridin - 2 - yl) - 1H -pyrazole - 1 - carboxylate ; and 6 - ( 2 - ( ( 4 -methoxybenzyl ) oxy ) pyrimidin - 5 - yl) - 5 -methyl - 2 - 30 ( 5 .and ( tetrahydro - 2H -pyran - 4 - yl) pyridin - 3 - amine . 1 - 2 - 30 ( 5 - amino - 3 -methyl - 6 - phenyl- [ 2 , 4 '- bipyridin ) - 2 -yl )metha [17a ] Embodiment 17a of the present invention is a nol. preferable compound in the compound of the above formula [ 19 ] Embodiment 19 of the present invention is an inter (AM -3 ) of Embodiment [14 ] described above, and is spe mediate compound , a pharmaceutically acceptable salt cifically an intermediate compound , a salt thereof, or a 35 thereof, or a solvate thereof, the intermediate compound solvate thereof listed below . represented by the following formula (AM - 2- RR ) *( D - TA ): 5 -methyl - 2 -phenyl - 6 - ( 1H - pyrazol - 4 - yl) pyridin - 3 - amine ; 5 -( 5 -amino -3 -methyl - 6 -phenylpyridin - 2 -yl ) pyrimidin - 2 -ol ; 5 -methyl - 6 - ( 1H - pyrazol- 4 -yl ) - 2 - ( tetrahydro - 2H - pyran - 4 - yl) ( AM -2 -RR )• ( D - TA ) pyridin - 3 -amine ; and 40 ( T 5 -( 5 -amino -3 -methyl - 6 -( tetrahydro -2H -pyran -4 -yl ) pyridin 2 - yl) pyrimidin - 2 -ol . OH [ 176 ] Embodiment 17b of the present invention is a COOH preferable compound in the compound of the above formula – R2b • HO?C • H2O (AM - 3 ) of Embodiment [ 14 ] described above, and is spe - 45 cifically an intermediate compound , a salt thereof, or a HN OH solvate thereof listed below . 6 -bromo - 5 -methyl - 2 -phenylpyridin - 3 -amine ; OH 5 - amino - 3 -methyl - 6 -phenylpicolinonitrile ; ethyl 5 -amino -3 -methyl - 6 -phenyl picolinate ; 50 where ( 5 - amino - 3 -methyl - 6 - phenylpyridin - 2 - yl) methanol ; p represents an integer of 0 to 4 ; 5 - amino - N - ( 2 - hydroxy - 2 -methylpropyl ) - 3 -methyl - 6 -phe R ? each independently represent a halogen atom , a cyano nylpicolinamide ; group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a 5 -methyl - 2 - ( tetrahydro - 2H -pyran - 4 - yl ) pyridin - 3 - amine; hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a 6 - bromo- 5 -methyl - 2 -( tetrahydro -2H -pyran - 4 - yl) pyridin - 3 - 55 halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl amine ; group , a mono -/ di - C2- 7 alkanoyl amino group , a carboxam 5 -amino - 3 -methyl - 6 - ( tetrahydro - 2H -pyran - 4 - yl ) picolinoni ide group , or a C1- 6 alkoxy carbonyl group ; and trile ; R24 and R25 each independently represent a C1- 6 alkyl group . 5 - amino - 3 -methyl - 6 - ( tetrahydro - 2H -pyran - 4 - yl ) picolina [ 19 - 1 ] In the compound of the above formula mide; 60 (AM - 2 -RR ) • ( D - TA ) of Embodiment [ 19 ] described above , p 5 - amino - 3 -methyl - 6 - phenyl picolinic acid ; is an integer of preferably 0 to 3 ; an integer of more 5 -amino - 3 -methyl - N -( (5 -methyl - 1, 3 ,4 -oxadiazol - 2 -yl ) preferably 0 to 2 ; and further preferably 0 . methyl) -6 -phenylpicolinamide ; [ 19 - 2 ] In the compound of the above formula ethyl 5 - amino - 3 -methyl - 6 - ( tetrahydro - 2H -pyran - 4 - yl) pico - (AM - 2 - RR ) • ( D - TA ) of Embodiment [ 19 ] described above , linate ; 65 R is preferably a halogen atom , a hydroxy C1- 6 alkyl group , 5 - amino - 3 -methyl - 6 - ( tetrahydro - 2H -pyran - 4 - yl) picolinica C1- 6 alkoxy C1- 6 alkyl group , a carboxamide group , or a acid ; and C1- 6 alkoxy carbonyl group ; more preferably , a halogen US 10 , 399 ,945 B2 69 70 atom , or a C1- 6 alkoxy C1-6 alkyl group ; and further prefer ably, the combinations of Ria and Rib are (Rla , Rib ) = ably, a fluorine atom , a bromine atom , or a methoxy methyl (hydrogen atom , hydrogen atom ), (hydrogen atom , bromine group . atom ), (bromine atom , hydrogen atom ) , (methoxy methyl [ 19 - 31 In the compound of the above formula group , hydrogen atom ) , ( fluorine atom , hydrogen atom ) , ( AM - 2 -RR )* ( D - TA ) of Embodiment [19 ] described above , 5 (hydrogen atom , fluorine atom ) , and ( fluorine atom , fluorine R24 or R25 is preferably a methyl group . atom ); and R2a or R25 is a methyl group . [ 19 -4 ] In the compound of the above formula [ 20 -4 ] In the compound of the above formula ( AM -2a (AM - 2 -RR ) • ( D - TA ) of Embodiment [ 19 ] described above , RR ) • ( D - TA ) of Embodiment [ 20 ] described above , prefer preferably , p is an integer of 0 to 2 ; R ' is a fluorine atom , a ably , Rla and Rlb are each a hydrogen atom ; and R20 or R25 bromine atom , or a methoxy methyl group ; and Ra or R is a methyl group . is a methyl group . [20 -5 ] The compound of the above formula [ 19 - 5 ] In the compound of the above formula (AM - 2a - RR ) • ( D - TA ) of Embodiment [ 20 ] described above ( AM - 2 - RR ) * ( D - TA ) of Embodiment [ 19 ] described above, is preferably a ( 1R ,2R ) - 1 -amino - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetra preferably , p is 0 ; and R2a or R25 is a methyl group . hydronaphthalen - 2 - ol ( 2S ,3S ) - 2 , 3 - dihydroxy succinate [19 -6 ] The compound of the above formula monohydrate . ( AM - 2 -RR ) - ( D - TA ) of Embodiment [ 19 ] described above is 15 [ 21 ] Embodiment 21 of the present invention is an inter preferably a ( 1R , 2R ) - 1 - amino - 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahy - mediate compound , a pharmaceutically acceptable salt dronaphthalen - 2 -ol (2S , 3S )- 2 ,3 - dihydroxy succinate mono thereof, or a solvate thereof, the intermediate compound hydrate . represented by the following formula ( AM - 2 - SS ) • ( L - TA ) : [ 20 ] Embodiment 20 of the present invention is an inter mediate compound , a pharmaceutically acceptable salt 20 thereof, or a solvate thereof, the intermediate compound (AM -2 - SS )• ( L - TA ) represented by the following formula ( AM - 2a -RR )• ( D - TA ):

(AM -2a - RR )• (D - TA ) 25 OH COOH RIO R25 HOOC . H20 Rla OH HN 30 - R2b HOOC wonCOOH . H2O

OH where p represents an integer of 0 to 4 ; HN11111 * * R each independently represent a halogen atom , a cyano 35 group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a halogenated C1 -6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl where Rla and Rlb each independently represent a hydrogen group , a mono - / di- C2- 7 alkanoyl amino group , a carboxam atom , a halogen atom , a cyano group , a C1-6 alkyl group , a ide group , or a C1- 6 alkoxy carbonyl group ; and halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a 40 R20 and R25 each independently represent a C1- 6 alkyl group . cyanated C1- 6 alkyl group , a halogenated C1- 6 alkoxy group , [21 - 1 ] In the compound of the above formula a C1- 6 alkoxy C1- 6 alkyl group , a mono -/ di - C2 - 7 alkanoyl ( AM - 2 - SS ) • ( L - TA ) of Embodiment [21 ] described above , p amino group , a carboxamide group , or a C - , alkoxy carbo - is an integer of preferably 0 to 3 ; an integer of more nyl group ; and R20 and R25 each independently represent a preferably 0 to 2 ; and further preferably 0 . C1- 6 alkyl group . 45 [ 21- 2 ] In the compound of the above formula [ 20 - 1 ] In the compound of the above formula ( AM -2a - (AM - 2 - SS ) • ( L - TA ) of Embodiment [21 ] described above , RR ) •( D - TA ) of Embodiment [ 20 ] described above , prefer - R ' is preferably a halogen atom , a hydroxy C1- 6 alkyl group , ably , Rla and Rls are each a hydrogen atom , a halogen atom , a C1- 6 alkoxy C1- 6 alkyl group , a carboxamide group , or a a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 alkyl group , C1- 6 alkoxy carbonyl group ; more preferably a halogen a carboxamide group , or a C1- 6 alkoxy carbonyl group ; more 50 atom , or a C1-6 alkoxy C1- 6 alkyl group ; and further prefer preferably , Rla is a hydrogen atom , a halogen atom , or a C1- 6 ably a fluorine atom , a bromine atom , or a methoxy methyl alkoxy C1- 6 alkyl group , and R15 is a hydrogen atom or a group . halogen atom ; further preferably , Ria is a hydrogen atom , a [21 -3 ] In the compound of the above formula fluorine atom , a bromine atom , or a methoxy methyl group , (AM - 2 -SS ) • ( L - TA ) of Embodiment [21 ] described above , and R16 is a hydrogen atom , a fluorine atom , or a bromine 55 R20 or R26 is preferably a methyl group . atom , and specifically the combination of Rla and Rlb is [ 21 - 4 ] In the compound of the above formula (R14 , R15 ) = (hydrogen atom , hydrogen atom ), (hydrogen (AM - 2 - SS )• (L - TA ) of Embodiment [21 ] described above, atom , bromine atom ) , ( bromine atom , hydrogen atom ) , preferably , p is an integer of 0 to 2 ; R ' is a fluorine atom , a (methoxy methyl group , hydrogen atom ), ( fluorine atom , bromine atom , or a methoxy methyl group ; and R20 or R25 hydrogen atom ) , (hydrogen atom , fluorine atom ) , ( fluorine 60 is a methyl group . atom , fluorine atom ); and particularly preferably, Rla and [ 21 - 5 ] In the compound of the above formula Rl' are each a hydrogen atom . (AM - 2 - SS ) • ( L - TA ) of Embodiment [21 ] described above , [20 - 2 ] In the compound of the above formula ( AM -2a - preferably , p is 0 ; and R20 or R25 is a methyl group . RR ) • ( D - TA ) of Embodiment [ 20 ] described above, R2a or [21 - 6 ] The compound of the above formula ( AM - 2 - SS ) . R25 is preferably a methyl group . 65 ( L - TA ) of Embodiment [ 21 ] described above is preferably a [20 - 3 ] In the compound of the above formula (AM - 2a - (15 , 2S )- 1 - amino - 4 ,4 -dimethyl - 1, 2 ,3 , 4 -tetrahydronaphtha RR )• ( D - TA ) of Embodiment [20 ] described above, prefer - len - 2 -ol (2R ,3R )- 2, 3 -dihydroxy succinate monohydrate . US 10 , 399 , 945 B2 71 72 [ 22 ] Embodiment 22 of the present invention is an inter mediate compound , a pharmaceutically acceptable salt ( AM - 2 - RR ) • ( D - TA ) thereof, or a solvate thereof, the intermediate compound represented by the following formula (AM - 2a - SS ) • ( L - TA ) : (R1 ). OH (AM -2a -SS ) • ( L -TA ) — R2b • H000 COOH RID OH Rla 10 HN D ( R ) . OH OH COOH – R2b • HOOCM • H2O where p, R ' , R20, and R25 are the same as the definitions of 15 Embodiment [ 19 ] described above , the method comprising HN adding D - tartaric acid and a compound which is a racemate

?? represented by the following formula (AM - 2 -RC ) : where Rla and R15 each independently represent a hydrogen 20 ( AM - 2 - RC ) atom , a halogen atom , a cyano group , a C1- 6 alkyl group , a (R ') p , halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group, a cyanated C1- 6 alkyl group , a halogenated C1- 6 alkoxy group , a C1- 6 alkoxy C1- 6 alkyl group , a mono - / di- C2- 7 alkanoyl amino group , a carboxamide group , or a C1- 6 alkoxy carbo - 25 nyl group ; and R2a and R25 each independently represent a C1- 6 alkyl group . HA11 [ 22 - 1 ] In the compound of the above formula ( AM - 2a SS ) • ( L - TA ) of Embodiment [ 22 ] described above, prefer OH ably , Rla and Rib are each a hydrogen atom , a halogen atom , 30 a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 alkyl group , where p , R1, R20, and R25 are the same as the definitions of a carboxamide group , or a C1- 6 alkoxy carbonyl group ; more thethe above formula ((AM - 2 -1RR )* ( D - TA ) ( a general method of preferably , Ria is a hydrogen atom , a halogen atom , or a C , producing formula ( AM - 2 - RC ) follows [ Production Method alkoxy C1- alkyl group , and Rlb is a hydrogen atom or a A ] to be described later ) , into a mixture solvent of water and halogen atom ; further preferably , Rla is a hydrogen atom , a 35 a solvent which may be arbitrarily selected from acetonitrile , fluorine atom , a bromine atom , or a methoxy methyl group , acetone, 1 , 2 - dimethoxyethane , and the like, and Rib is a hydrogen atom , a fluorine atom , or a bromine causing reaction by stirring ( optionally heating ) the atom , and specifically the combination of Rla and R16 is obtained mixture solution in a range of room temperature to (R14 , R15 ) = (hydrogen atom , hydrogen atom ), (hydrogen a reflux temperature of the mixture solution , and atom , bromine atom ) , (bromine atom , hydrogen atom ) , 40 obtaining the intermediate compound represented by the ( methoxy methyl group , hydrogen atom ), ( fluorine atom , formula ( AM - 2 -RR )• ( D - TA ) by allowing the reaction solu hydrogen atom ), (hydrogen atom , fluorine atom ), ( fluorine tion after the reaction to stand at room temperature or to cool atom , fluorine atom ); and particularly preferably , Ria and to room temperature . Rl' are each a hydrogen atom . [ 23 - 1 ] In the method of producing the compound of the [ 22 - 2 ] In the compound of the above formula (AM - 2a - 45 above formula (AM - 2 -RR )• ( D - TA ) of Embodiment [23 ] SS ) •( L - TA ) of Embodiment [ 22 ] described above, R2a or described above , p is an integer of preferably 0 to 3 ; an R2b is preferably a methyl group . integer of more preferably 0 to 2 ; and further preferably 0 . [22 - 3 ] In the compound of the above formula (AM - 2a - [ 23 - 2 ] In the method of producing the compound of the SS ) • ( L - TA ) of Embodiment [22 ] described above , prefer above formula (AM - 2 - RR )* ( D - TA ) of Embodiment [23 ] ably , the combinations of Rla and R16 are (R14 , Rib ) = 50 described above , R ' is preferably a halogen atom , a hydroxy (hydrogen atom , hydrogen atom ), (hydrogen atom , bromine C1- 6 alkyl group , a C1- 6 alkoxy C1-6 alkyl group , a carbox atom ), (bromine atom , hydrogen atom ), (methoxy methylamide group , or a C1- 6 alkoxy carbonyl group ;more pref group , hydrogen atom ) , ( fluorine atom , hydrogen atom ) , erably a halogen atom , or a C1- 6 alkoxy C1- 6 alkyl group ; and (hydrogen atom , fluorine atom ), and ( fluorine atom , fluorine further preferably a fluorine atom , a bromine atom , or a atom ) ; and R2a or R25 is a methyl group . 55 methoxy methyl group . [22 - 4 ] In the compound of the above formula ( AM -2a - [ 23 - 3 ] In the method of producing the compound of the SS )• ( L - TA ) of Embodiment [22 ] described above, prefer - above formula ( AM -2 -RR ) •( D - TA ) of Embodiment [23 ] ably , Rla and Rib are each a hydrogen atom ; and R2a or R25 described above, R2a or R26 is preferably a methyl group . is a methyl group . [ 23 - 4 ] In the method of producing the compound of the [22 - 5 ] The compound of the above formula 60 above formula ( AM - 2 - RR ) * ( D - TA ) of Embodiment [ 24 ] ( AM - 2a - SS ) • ( L - TA ) of Embodiment [22 ] described above is described above , preferably, the solvent is acetonitrile. preferably a ( 15 ,2S ) - 1 - amino - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy [23 - 5 ] In the method of producing the compound of the dronaphthalen -2 - ol (2R ,3R ) -2 , 3 -dihydroxy succinate mono - above formula ( AM -2 -RR )* ( D - TA ) of Embodiment [ 23 ] hydrate . described above , preferably , the ratio of the solvent and the [ 23 ] Embodiment 23 of the present invention is a method 65 water in the mixture solvent is 5 to 30 times ( mL ) for the of producing an intermediate compound being the following solvent and 0 . 1 to 10 times (mL ) for the water; more formula (AM - 2 -RR )• ( D - TA ): preferably 10 to 25 times (mL ) for the solvent and 0 . 5 to 6 US 10 , 399 , 945 B2 73 74 times (mL ) for the water ; further preferably 15 to 20 times where the definitions of Ria , Rlb , R20 , and R2b are the same (mL ) for the solvent and 1 to 3 times (mL ) for the water , and as the definitions of the above formula ( AM -2a -RR ) • ( D - TA ) particularly preferably 18 times (mL ) for the solvent and 2 (a general method of producing formula (AM -2a -RC ) fol times (mL ) for the water relative to theweight ( g ) of formula lows [ Production Method A ] to be described later ), into a ( AM - 2 -RC ) . mixture solvent of water and a solvent which may be [ 23 -6 ] In the method of producing the compound of the arbitrarily selected from acetonitrile , acetone , 1 , 2 - dime above formula (AM - 2 -RR )• ( D - TA ) of Embodiment [23 ] thoxyethane , and the like, described above , preferably , the ratio of D - tartaric acid is 1 . 0 causing reaction by stirring ( optionally heating ) the to 1 . 3 equivalents relative to the number of moles of the compound of formula ( AM - 2 - RC ) ; and more preferably the obtained mixture solution in a range of room temperature to ratio of D - tartaric acid is 1 . 0 to 1 . 05 equivalents relative to 10 a reflux temperature of the mixture solution , and the number of moles of the compound of formula (AM - 2 obtaining the intermediate compound represented by the RC ) . formula ( AM - 2a -RR ) • ( D - TA ) by allowing the reaction solu [ 23 - 7 ] In the method of producing the compound of the tion after the reaction to stand at room temperature or to cool above formula ( AM - 2 -RR ) • ( D - TA ) of Embodiment [23 ] to room temperature . described above , preferably, p is an integer of 0 to 2 ; R1 is 15 [ 24 - 1 ] In the method of producing the compound of the a fluorine atom , a bromine atom , or a methoxy methyl group ; above formula (AM - 2a - RR ) • ( D - TA ) of Embodiment [24 ] R2a or R25 is a methyl group ; the ratio of acetonitrile and described above, preferably , Rla and R16 are each a hydro water in the mixture solvent is 18 times (mL ) for the gen atom , a halogen atom , a hydroxy C1- 6 alkyl group , a C1- 6 acetonitrile and 2 times (mL ) for the water relative to the weight ( g ) of formula (AM - 2 -RC ) ; and the ratio of D -tartaric alkoxy C1- 6 alkyl group , a carboxamide group , or a C1- 6 acid is 1 . 0 to 1 . 05 equivalents relative to the number of 20 alkoxy carbonyl group ; more preferably , R is a hydrogen moles of the compound of formula ( AM - 2 -RC ) . atom , a halogen atom , or a C , . , alkoxy C - alkyl group , and [ 23 - 8 ] In the method of producing the compound of the R ' ' is a hydrogen atom or a halogen atom ; further prefer above formula ( AM - 2 - RR ) • ( D - TA ) of Embodiment [ 23 ] ably, Ria is a hydrogen atom , a fluorine atom , a bromine described above, preferably , p is 0 ; R20 or R2b is a methyl atom , or a methoxy methyl group , and Rib is a hydrogen group ; the ratio of acetonitrile and water in the mixture 25 atom , a fluorine atom , or a bromine atom , and specifically solvent is 18 times (mL ) for the acetonitrile and 2 times the combination of Rla and Rlb is (R14 , R1b ) = ( hydrogen (mL ) for the water relative to the weight ( g ) of formula atom , hydrogen atom ) , (hydrogen atom , bromine atom ) , ( AM - 2 -RC ) ; and the ratio of D - tartaric acid is 1 . 0 to 1 . 05 (bromine atom , hydrogen atom ), (methoxy methyl group , equivalents relative to the number ofmoles of the compound hydrogen atom ), ( fluorine atom , hydrogen atom ), (hydrogen of formula (AM - 2 - RC ). 30 atom , fluorine atom ) , ( fluorine atom , fluorine atom ) ; and [24 ] Embodiment 24 of the present invention is a method particularly preferably, Rla and R 16 are each a hydrogen of producing an intermediate compound being the following atom . formula (AM -2a - RR )• (D - TA ): [ 24 - 2 ] In the method of producing the compound of the above formula (AM - 2a -RR )• ( D - TA ) of Embodiment [24 ] 35 described above, R24 or R25 is preferably a methyl group. (AM -2a - RR )• ( D - TA ) [ 24 - 3 ] In the method of producing the compound of the above formula (AM - 2a - RR ) • ( D - TA ) of Embodiment [ 24 ] R16 described above, preferably , Rla and R15 are each a hydro Ria gen atom ; and R2a or R25 is a methyl group . OH 40 [ 24 - 4 ] In the method of producing the compound of the above formula ( AM - 2a -RR ) • ( D - TA ) of Embodiment [ 24 ] – R25 • HO?C COOH H ,O described above, preferably , the solvent is acetonitrile . ( R ) [24 - 5 ] In the method of producing the compound of the OH above formula (AM - 2a -RR ) • ( D - TA ) of Embodiment [ 24 ] HINT Y (R ) 45 described above , preferably , the ratio of the solvent and the ?? water in the mixture solvent is 5 to 30 times (mL ) for the solvent and 0 . 1 to 10 times (mL ) for the water; more preferably 10 to 25 times (mL ) for the solvent and 0 . 5 to 6 where the definitions of Rla , R1 , R20, and R25 are the same times (mL ) for the water ; further preferably 15 to 20 times as the definitions of Embodiment [20 ] described above , the 50 (mL ) for the solvent and 1 to 3 times (mL ) for the water: and method comprising particularly preferably 18 times (mL ) for the solvent and 2 adding D - tartaric acid and a compound which is a race times (mL ) for the water relative to the weight ( g ) of formula mate represented by the following formula ( AM -2a -RC ) : ( AM - 2a -RC ) . [ 24 - 6 ] In the method of producing the compound of the 55 above formula ( AM - 2a -RR ) • ( D - TA ) of Embodiment [ 24 ] ( AM - 2a - RC ) described above , preferably , the ratio of D - tartaric acid is 1 . 0 Rio to 1 . 3 equivalents relative to the number of moles of the Rla compound of formula ( AM -2a - RC ) ; and more preferably the ratio of D - tartaric acid is 1 . 0 to 1 . 05 equivalents relative to 60 the number of moles of the compound of formula (AM - 2a RC ). [ 24 -7 ] In the method of producing the compound of the above formula ( AM -2a - RR )* ( D - TA ) of Embodiment [24 ] H2NH described above , preferably , the combinations of definitions OH 65 of Rla and R16 are (R14 , R1b ) = (hydrogen atom , hydrogen atom ), (hydrogen atom , bromine atom ), (bromine atom , hydrogen atom ), (methoxy methyl group , hydrogen atom ), US 10 , 399 , 945 B2 75 76 ( fluorine atom , hydrogen atom ), (hydrogen atom , fluorine described above , p is an integer of preferably 0 to 3 ; an atom ), and ( fluorine atom , fluorine atom ) ; R20 or R25 is a integer of more preferably 0 to 2 , and further preferably 0 . methyl group ; the ratio of acetonitrile and water in the [25 - 2 ] In the method of producing the compound of the mixture solvent is 18 times (mL ) for the acetonitrile and 2 above formula ( AM - 2 -SS ) • ( L - TA ) of Embodiment [ 25 ] times (mL ) for the water relative to the weight ( g ) of formula 5 described above, R ' is preferably a halogen atom , a hydroxy ( AM -2a -RC ); and the ratio of D - tartaric acid is 1. 0 to 1. 05 C1- 6 alkyl group, a C1- 6 alkoxy C1- 6 alkyl group, a carbox equivalents relative to the number of moles of the compound amide group , or a C1- 6 alkoxy carbonyl group ; more pref of formula ( AM - 2a - RC ) . erably a halogen atom or a C1- 6 alkoxy C1- 6 alkyl group ; and [ 24 - 8 ] In the method of producing the compound of the further preferably a fluorine atom , a bromine atom , or a above formula ( AM - 2a -RR )• ( D - TA ) of Embodiment [24 ] 10 methoxy methyl group . described above , preferably , Rla and Rib are each a hydro [ 25 - 3 ] In the method of producing the compound of the gen atom ; R20 or R25 is a methyl group ; the ratio of above formula ( AM - 2 - SS ) • ( L - TA ) of Embodiment [25 ] acetonitrile and water in the mixture solvent is 18 times described above , Rza or R25 is preferably a methyl group . (mL ) for the acetonitrile and 2 times (mL ) for the water 15 [ 25 - 4 ] In the method of producing the compound of the relative to the weight ( g ) of formula (AM -2a -RC ); and the above formula ( AM -2 - SS )• (L - TA ) of Embodiment [25 ] ratio of D -tartaric acid is 1. 0 to 1 .05 equivalents relative to described above, preferably , the solvent is acetonitrile . the number of moles of the compound of formula (AM - 2a - [ 25 - 5 ] In the method of producing the compound of the RC ) . above formula ( AM - 2 - SS ) • ( L - TA ) of Embodiment [ 25 ] [ 25 ] Embodiment 25 of the present invention is a method 20 described above , preferably , the ratio of the solvent and the of producing an intermediate compound being the following water in the mixture solvent is 5 to 30 times (mL ) for the formula (AM - 2 - SS )- (L - TA ) : solvent and 0 . 1 to 10 times (mL ) for the water ; more preferably 10 to 25 times (mL ) for the solvent and 0 .5 to 6 times (mL ) for the water ; further preferably 12 to 20 times (AM -2 - SS )• ( L - TA ) 25 (mL ) for the solvent and 1 to 3 times (mL ) for the water ; and particularly preferably 18 times (mL ) for the solvent and 2 times (mL ) for the water relative to the weight ( g ) of formula OH ( AM - 2 -RC ) . [25 - 6 ] In the method of producing the compound of the COOH . H , 0 30 above formula (AM -2 -SS )• (L - TA ) of Embodiment [25 ] - R2b HOOC described above , preferably , the ratio of L - tartaric acid is 1 . 0 110 to 1 . 3 equivalents relative to the number of moles of the HN compound of formula (AM - 2 -RC ) ; and more preferably the ratio of L -tartaric acid is 1. 0 to 1 .05 equivalents relative to 35 the number of moles of the compound of formula (AM - 2 RC ) . where p , R1, R24 , and R25 are the same as the definitions of [ 25 - 7 ] In the method of producing the compound of the Embodiment |21 | described above , the method comprising above formula ( AM - 2 - SS ) • ( L - TA ) of Embodiment 1251 adding L - tartaric acid and a compound which is a racemate described above , preferably , p is an integer of 0 to 2 ; R ' is represented by the following formula (AM - 2 -RC ): 40 a fluorine atom , a bromine atom , or a methoxy methyl group ; R2a or R25 is a methyl group ; the ratio of acetonitrile and water in the mixture solvent is 12 to 20 times (mL ) for the ( AM - 2 - RC ) acetonitrile and 1 to 3 times (mL ) for the water relative to the (RI ). weight ( g ) of formula (AM - 2 -RC ) ; and the ratio of L - tartaric 45 acid is 1 . 0 to 1 .05 equivalents relative to the number of moles of the compound of formula ( AM - 2 - RC ) . [25 - 7 - 1 ] In Embodiment [ 25 - 7 ] described above, more preferably , the ratio of acetonitrile and water in the mixture solvent is 18 times (mL ) for the acetonitrile and 2 times 50 mL ) for the water relative to the weight ( g ) of formula ?? (AM - 2 -RC ) . [ 25 - 8 ] In the method of producing the compound of the above formula (AM - 2 - SS )• ( L - TA ) of Embodiment [ 25 ] where p , R1, R20 , and R25 are the same as the definitions of described above, preferably , p is 0 ; R20 or R25 is a methyl the above formula ( AM - 2 - SS ) * ( L - TA ) , into a mixture sol- 55 group : the ratio of acetonitrile and water in the mixture vent of water and a solvent which may be arbitrarily selected solvent is 12 to 20 times (mL ) for the acetonitrile and 1 to from acetonitrile , acetone , 1 , 2 - dimethoxyethane , and the 3 times (mL ) for the water relative to the weight ( g ) of like, formula ( AM - 2 - RC ) ; and the ratio of L -tartaric acid is 1 . 0 to causing reaction by stirring (optionally heating ) the 1. 05 equivalents relative to the number of moles of the obtained mixture solution in a range of room temperature to 60 compound of formula ( AM - 2 -RC ) . a reflux temperature of the mixture solution , and [25 - 8 - 1 ] In Embodiment [25 - 8 ] described above, more obtaining the intermediate compound represented by the preferably, the ratio of acetonitrile and water in the mixture formula (AM - 2 -SS ) • ( L - TA ) by allowing the reaction solu - solvent is 18 times for the acetonitrile and 2 times for the tion after the reaction to stand at room temperature or to cool water relative to the weight ( g ) of formula ( AM - 2 -RC ) . to room temperature . 65 [ 26 ] Embodiment 26 of the present invention is a method [ 25 - 1 ] In the method of producing the compound of the of producing an intermediate compound being the following above formula (AM - 2 - SS ) • (L - TA ) of Embodiment [25 ] formula (AM - 2a - SS )• ( L - TA ): US 10 , 399 , 945 B2 78 [ 26 - 3 ] In the method of producing the compound of the ( AM - 2a - SS ) •( L - TA ) above formula (AM - 2a -SS ) * ( L - TA ) of Embodiment [ 26 ] described above , preferably , the solvent is acetonitrile . [ 26 - 4 ] In the method of producing the compound of the Rla 5 above formula (AM - 2a - SS ) • ( L - TA ) of Embodiment [ 26 ] OH described above, preferably , the ratio of the solvent and the R2a water in the mixture solvent is 5 to 30 times (mL ) for the R2b . HOOC COOH solvent and 0 . 1 to 10 times (mL ) for the water ; more •H20 preferably 10 to 25 times (mL ) for the solvent and 0 . 5 to 6 ÕH 10 times (mL ) for the water ; further preferably 12 to 20 times HN : ( S ) (mL ) for the solvent and 1 to 3 times (mL ) for the water ; and ?? particularly preferably 18 times (mL ) for the solvent and 2 times (mL ) for the water relative to the weight ( g ) of formula where Rla , R16 , R20 , and R25 are the same as the definitions 15 (AM - 2a -RC ) . of Embodiment [22 ] described above , the method compris [ 26 - 5 ] In the method of producing the compound of the ing above formula (AM -2a - SS ) • ( L - TA ) of Embodiment [ 26 ] adding L -tartaric acid and a compound which is a race described above , preferably, the ratio of L -tartaric acid is 1 . 0 mate represented by the following formula (AM -2a -RC ) : to 1 . 3 equivalents relative to the number of moles of the 20 compound of formula (AM -2a - RC ) ; and more preferably the ratio of L -tartaric acid is 1 . 0 to 1 .05 equivalents relative to ( AM - 2a -RC ) the number ofmoles of the compound of formula ( AM -2a - Rib RC ) . Rla [ 26 - 6 ] In the method of producing the compound of the 25 above formula (AM - 2a -SS )• ( L - TA ) of Embodiment [26 ] described above , preferably , p is an integer of 0 to 2 ; Rl is R 26 a fluorine atom , a bromine atom , or a methoxy methyl group ; R2a or R25 is a methyl group ; the ratio of acetonitrile and water in the mixture solvent is 12 to 20 times (mL ) for the HN 30 acetonitrile and 1 to 3 times (mL ) for the water relative to the OH weight ( g ) of formula (AM - 2a - RC ) ; and the ratio of L - tar taric acid is 1 . 0 to 1 .05 equivalents relative to the number of where Ria , R15 , R20 , and R26 are the same as the definitions moles of the compound of formula ( AM -2a - RC ) . of the above formula (AM - 2a- SS ) • ( L - TA ) , into a mixture 35 [ 26 -6 - 1 ] In Embodiment [ 26 -6 ] described above, more solvent of water and a solvent which may be arbitrarily preferably , the ratio of acetonitrile and water in the mixture selected from acetonitrile , acetone , 1 , 2 - dimethoxyethane, solvent is 18 times (mL ) for the acetonitrile and 2 times and the like , (mL ) for the water relative to the weight ( g ) of formula causing reaction by stirring ( optionally heating) the (AM - 2a - RC ) . obtained mixture solution in a range of room temperature to 4040 [26 - 7 ] In the method of producing the compound of the above formula ( AM - 2a -SS ) ( L - TA ) of Embodiment [ 26 ] a reflux temperature of the mixture solution , and described above , preferably , p is 0 ; R2a or R25 is a methyl obtaining the intermediate compound represented by the group ; the ratio of acetonitrile and water in the mixture formula ( AM - 2a -SS ) • ( L - TA ) by allowing the reaction solu solvent is 12 to 20 times (ml ) for the acetonitrile and 1 to tion after the reaction to stand at room temperature or toPod cool 45 3 times (mL ) for the water relative to the weight ( g ) of to room temperature . formula ( AM - 2a -RC ) ; and the ratio of L -tartaric acid is 1 . 0 [ 26 - 1 ] In the method of producing the compound of the to 1 . 05 equivalents relative to the number of moles of the above formula ( AM - 2a - SS ) • ( L - TA ) of Embodiment [ 26 ] compound of formula (AM - 2a -RC ) . described above, preferably , Rla and Rib are each a hydro [ 26 - 7 - 1 ] In Embodiment [ 26 - 7 ] described above , more gen atom , a halogen atom , a hydroxy C1- 6 alkyl group , a C1- 6 50 preferably , the ratio of acetonitrile and water in the mixture alkoxy C1- 6 alkyl group , a carboxamide group , or a C1- 6 solvent is 18 times (mL ) for the acetonitrile and 2 times alkoxy carbonyl group ; more preferably , R?a is a hydrogen (mL ) for the water relative to the weight ( g ) of formula atom , a halogen atom , or a C1- 6 alkoxy C1- 6 alkyl group , and (AM -2a - RC ) . Rlb is a hydrogen atom or a halogen atom ; further prefer - [ 27 ] Embodiment 27 of the resent invention is a prefer ably , Rla is a hydrogen atom , a fluorine atom , a bromine 55 able compound in the compound of the above formula atom , or a methoxy methyl group , and R16 is a hydrogen ( AM - 2 -RR )* ( D - TA ) of Embodiment [ 19 ] described above or atom , a fluorine atom , or a bromine atom , and specifically in the compound of the above formula (AM - 2a -RR )• ( D - TA ) the combination of Rla and Rlb is (Rla , R15 ) = (hydrogen of Embodiment [20 ] described above, and is specifically a atom , hydrogen atom ), (hydrogen atom , bromine atom ), compound listed below . (bromine atom , hydrogen atom ), (methoxy methyl group , 60 ( 1R , 2R )- 1 -amino - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 -tetrahydronaphtha hydrogen atom ) , ( fluorine atom , hydrogen atom ) , (hydrogen len - 2 - ol ( 2S ,3S ) - 2 , 3 - dihydroxy succinate monohydrate ; atom , fluorine atom ) , ( fluorine atom , fluorine atom ) ; and ( 1R , 2R ) - 1 -amino - 6 - fluoro - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahy particularly preferably , Rla and R15 are each a hydrogen dronaphthalen - 2 - ol (2S ,3S ) - 2 , 3 - dihydroxy succinate atom . monohydrate ; [ 26 - 2 ] In the method of producing the compound of the 65 ( 1R ,2R ) - 1 - amino - 7 - fluoro - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy above formula (AM - 2a -SS )• ( L - TA ) of Embodiment [ 26 ] dronaphthalen - 2 -ol ( 2S ,3S ) - 2 , 3 - dihydroxy succinate described above, R24 or R26 is preferably a methyl group . monohydrate ; US 10 , 399 , 945 B2 79 80 (1R 2R ) - 1 - amino -6 , 7 -difluoro - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetra hydronaphthalen - 2 - ol (2S , 3S )- 2 , 3 - dihydroxy succinate monohydrate ; (AM - 1 ) ( 1R ,2R ) - 1 -amino -6 -bromo - 4 ,4 -dimethyl - 1 , 2, 3, 4 - tetrahy dronaphthalen - 2 -ol ( 2S , 3S ) - 2 , 3 - dihydroxy succinate 5 " NH2 monohydrate ; ( 1R . 2R ) - 1 - amino - 7 - bromo- 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy dronaphthalen - 2- ol (2S ,3S ) - 2, 3 -dihydroxy succinate where the ring A has the same definition as that in the monohydrate ; formula (I - RR ), and a urea forming agent which may be ( 1R 2R )- 1- amino - 7 - (methoxymethyl ) -4 ,4 -dimethyl - 1 ,2 , 3, 10 arbitrarily selected from trichloroethyl chloroformate , phe 4 - tetrahydronaphthalen - 2 -ol (2S ,3S ) -2 ,3 -dihydroxy suc nyl chloroformate , p - nitrophenyl chloroformate , p - tolyl cinate monohydrate . chloroformate , N , N ' -carbonyldiimidazole , N , N -disuccinim [ 27 - 1 ] In the compound of Embodiment [ 27 ] described idyl carbonate , and the like to a solvent which may be above, a more preferable compound is a ( 1R 2R ) - 1 -amino arbitrarily selected from acetonitrile , diethyl ether, tetrahy 4 ,4 -dimethyl - 1, 2 , 3 ,4 - tetrahydronaphthalen -2 - ol (2S ,3S )- 2 , 15 drofuran , dimethoxyethane , 1 , 4 - dioxane , dichloromethane , 3 -dihydroxy succinate monohydrate . chloroform , 1 , 2 - dichloroethane, N -methylpyrrolidone , mix [ 28 ] Embodiment 28 of the present invention is a prefer ture solvents thereof, and the like in the presence or absence able compound in the compound of the above formula of a base which may be arbitrarily selected from organic ( AM - 2 - SS ) • ( L - TA ) of Embodiment [ 21 ] described above or 20 bases and the like such as pyridine, triethylamine , and in the compound of the above formula (AM - 2a - SS )• ( L - TA ) 20 N , N - diisopropylethylamine and inorganic bases and the like of Embodiment [ 22 ] described above , and is specifically a such as sodium hydrogen atom carbonate , sodium carbonate , compound listed below . and potassium carbonate , ( 18 ,2S ) - 1 - amino - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 -tetrahydronaphtha obtaining a compound represented by formula (CB - 1) : len - 2 - ol ( 2R , 3R ) - 2 , 3 - dihydroxy succinate monohydrate ; 25 ( 15 ,2S ) - 1 - amino -6 - fluoro - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy dronaphthalen - 2 - ol ( 2R ,3R ) - 2 , 3 -dihydroxy succinate monohydrate ; (CB - 1 ) (15 ,2S )- 1- amino -7 - fluoro -4 ,4 -dimethyl - 1, 2, 3 ,4 - tetrahy dronaphthalen - 2 -ol ( 2R , 3R ) - 2 , 3 - dihydroxy succinate 30 monohydrate ; ( 18 , 2S ) - 1 - amino -6 , 7 - difluoro - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy dronaphthalen - 2 -ol ( 2R , 3R ) - 2 , 3 - dihydroxy succinate monohydrate ; where the ring A has the same definition as that in the ( 18 , 2S ) - 1 - amino - 6 - bromo- 4 , 4 - dimethyl- 1 , 2 , 3 ,4 - tetrahy - 35 formulatorr (I - RR ), and E represents a group which may be dronaphthalen - 2 -ol (2R ,3R ) - 2 , 3 -dihydroxy succinate arbitrarily selected from groups represented by the following monohydrate ; partial structural formulas : ( 18 ,2S ) - 1 - amino - 7 - bromo - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy dronaphthalen - 2 -ol ( 2R , 3R ) - 2 ,3 - dihydroxy succinate monohydrate ; 40 (CS - 1 ) ( 18 ,2S )- 1 -amino - 7 - methoxy methyl) -4 ,4 -dimethyl - 1 ,2 ,3 ,4 tetrahydronaphthalen - 2 -ol ( 2R , 3R ) - 2 , 3 - dihydroxy succi nate monohydrate . [28 - 1 ] In the compound of Embodiment [28 ] described above, a more preferable compound is a (15 ,2S ) - 1 -amino - 45 4 , 4 -dimethyl - 1 , 2 , 3 , 4 -tetrahydronaphthalen - 2 - ol ( 2R , 3R ) - 2 , (CS - 2 ) 3 - dihydroxy succinate monohydrate . CH [ 29 ] Embodiment 29 of the present invention is a method of producing a compound represented by the following formula ( I- RR ) ( subconcept of the above formula (1 ) ) : 50 (CS - 3 ) ( I -RR )

55 ( CS - 4 ) NO2

EZ ( R ) 60 ?? (CS - 5 ) where the ring A , p , R ' , R20, and R26 have the same definitions as those in Embodiment [ 1 ], the method com - 65 mi prising adding an intermediate compound represented by formula (AM - 1 ) : US 10 ,399 ,945 B2 87 82 -continued ( CS - 6 ) (AM - 1 - [ 2 ])

R 45

NO NH Rz by causing reaction in the obtained mixture solution A in a 10 (AM - 1 - [ 3 ] range of 0° C . to a reflux temperature of the mixture solution CH3 A ( Stage [ 29 ] - 1 ) , (R™ ) a subsequently adding the compound represented by the T above formula (CB - 1 ) and an intermediate compound rep resented by the following formula (AM - 2- RR ) •( D - TA ): 15 Y NH R3 ( AM - 1 - [ 4 ] ) ( AM -2 -RR )• ( D - TA ) CH2 (R ) 20 R 4g OH

OOH – R2b . HOOC Y •H2O NH2 ?? 25 ( AM -3 ) OH R 46 where p , R1, R24 and R2b have the same definitions as those 30 in Embodiment [ 19 ] , to a inert solvent and which may be arbitrarily selected from aprotic polar solvents such as NH2 dimethylformamide , dimethylacetamide, dimethyl sulfox ide, N -methylpyrrolidone , and acetonitrile , ether - based sol R3a vents such as diethyl ether, tetrahydrofuran , dimethoxy - 35 ( AM - 3 - a ) ethane , and 1 , 4 - dioxane , ester -based solvents such as ethyl acetate and propyl acetate , chlorinated solvents such as ( R $) a + B dichloromethane , chloroform , and 1 , 2 - dichloroethane , a mixture solvent of these , and the like in the presence of a base which may be arbitrarily selected from organic bases 40 NH2 such as pyridine , triethylamine, N , N -diisopropylethylamine , R3a and 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 -ene (DBU ) , inorganic (AM - 3 - b ) bases such as sodium hydrogen atom carbonate , sodium CH carbonate , and potassium carbonate, metal alkoxides such as potassium tert -butoxide and sodium tert -butoxide , metal 45 R4h hydride compounds such as sodium hydride , potassium hydride, and calcium hydride , alkyl lithiums such as meth yllithium and butyllithium , lithium amides such as lithium hexamethyldisilazide and lithium diisopropylamide , these NH2 basic mixtures , and the like , and 50 R3a obtaining the compound represented by the formula ( I- RR ) by reacting the obtained mixture solution B at 0° C . (the definitions of the substituents in formula (AM - 1 -[ 2 ] ) are to a reflux temperature of the mixture solution B (Stage the same as the definitions of the substituents in Embodi [ 29 ] - 2 ). ment [ 2 ] ; the definitions of the substituents in formula [29 - 1 ] In the method of producing the compound of the 55 ( AM - 1 - [ 3 ] ) are the same as the definitions of the substituents above formula ( I- RR ) of Embodiment [ 29 ] described above , in Embodiment [ 3 ] ; the definitions of the substituents in preferably , an intermediate compound represented by for formula (AM - 1 - [ 4 ]) are the same as the definitions of the mula (AM - 1 ) : substituents in Embodiment [4 ]; the definitions of the sub stituents in formula (AM - 3 ) are the same as the definitions 60 of the substituents in Embodiment [ 14 ] ; the definitions of the ( AM - 1 ) substituents in formula ( AM - 3 - a ) are the same as the defi nitions of the substituents in Embodiment [ 15 ] ; and the definitions of the substituents in formula ( AM - 3 - b ) are the NH2 same as the definitions of the substituents in Embodiment 65 [ 16 ] . Note that formula (AM - 1 - [ 2 ]) , formula ( AM - 1 - [ 3 ]) , is an amine which may be arbitrarily selected from amines and formula (AM - 1 -[ 4 ]) also include their subconcepts represented by the following formulas : formula ( AM - 1 - a ), formula ( AM - 1 - b ) , formula ( AM - 1 - c ) , US 10 , 399 , 945 B2 83 84 formula ( AM - 1 - d ), formula (AM - 1 - e ), formula (AM - 1 - f ), formula ( AM - 1 - g ), formula (AM - 1 - h ) , formula ( AM - 1 - i ), (AM -2a - RR ) • ( D - TA ) formula (AM - 1 -j ), formula (AM - 1 - A ), formula ( AM - 1 - B ), formula ( AM - 1 - C ), formula ( AM - 1 - D ), formula ( AM - 1 - E ), R la formula (AM - 1- F ), formula (AM -1 -G ) , formula (AM - 1 -H ), OH formula (AM - 1 -I ) , and formula (AM - 1- 1 ) to be described COOH later . Y _ R2b . HO?C [29 - 2 ] In the method of producing the compound of the •H20 above formula (I - RR ) of Embodiment [29 ] described above , OH more preferably , the amine of the above formula (AM - 1 ) is HUNT ( R ) an amine which may be arbitrarily selected from the amines OH described in Embodiment [ 17 ]. [ 29 - 3 ] In the method of producing the compound of the 15 where the definitions of Ra, R15, R24 , and R2b are the same above formula (I - RR ) of Embodiment [29 ] described above , as the definitions of Embodiment [20 ] described above . more preferably , the amine of the above formula ( AM - 1 ) is [ 29 - 11 - 1 ] In the method of producing the compound of an amine which may be arbitrarily selected from the amines the above formula (I -RR ) of Embodiment [ 29 ] described above , the above formula ( AM - 2 - RR ) • ( D - TA ) is preferably described in Embodiment [ 172 ]. 20 a ( 1R , 2R ) - 1 - amino - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaph [ 29 - 4 ] In the method of producing the compound of the thalen - 2 -ol ( 2S ,3S ) - 2 , 3 - dihydroxy succinate monohydrate . above formula (I - RR ) of Embodiment [ 29 ] described above , [ 29 - 12 ] In the method of producing the compound of the more preferably , the amine of the above formula (AM - 1 ) is above formula (I -RR ) of Embodiment [29 ] described above , an amine which may be arbitrarily selected from the amines the urea forming agent used in (Stage [ 29 ] - 1 ) is preferably described in Embodiment [ 17b ] . 25 trichloroethyl chloroformate or p - nitrophenyl chlorofor [ 29 - 5 ] In the method of producing the compound of the mate ; and more preferably trichloroethyl chloroformate . above formula (I -RR ) of Embodiment [ 29 ] described above, [ 29 - 13 ] In the method of producing the compound of the more preferably , the amine of the above formula (AM - 1 ) is above formula (I -RR ) of Embodiment [ 29 ] described above, an amine which may be arbitrarily selected from the amines the base used in (Stage [29 ]- 1 ) is preferably pyridine , described in Embodiment [ 18 ]. 30 triethylamine, N ,N -diisopropylethylamine , or the absence of [29 -6 ] In the compound of the above formula (AM -2 -RR ) a base; and more preferably pyridine or the absence of a • ( D - TA ) in the method of producing the compound of the [29 - 14 ] In the method of producing the compound of the above formula (I -RR ) of Embodiment [ 29 ] described above, above formula (I - RR ) of Embodiment [29 ] described above , ger of more 35 the solvent used in (Stage [29 ]- 1) is preferably N -methyl p is an integer of preferably 0 to 3; an integer of more 35 pyrrolidone, diethyl ether , tetrahydrofuran , 1 , 4 - dioxane , preferably 0 to 2 ; and further preferably 0 . dichloromethane, or 1 , 2 -dichloroethane ; and more prefer [ 29 - 7 ] In the compound of the above formula ably N -methylpyrrolidone , tetrahydrofuran , or 1 ,2 -dichlo (AM - 2 -RR )• ( D - TA ) in the method of producing the com - roethane . pound of the above formula (I - RR ) of Embodiment [ 29 ] 40 [29 - 15 ] In the method of producing the compound of the above formula ( I - RR ) of Embodiment [ 29 ] described above , described above, R ' is preferably a halogen atom , a hydroxy the reaction temperature of ( Stage [ 29 ]- 1) ( temperature of C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 alkyl group , a carbox the mixture solution A ) is preferably 0° C . to 80° C .; more amide group , or a C1- 6 alkoxy carbonyl group ; more pref preferably 0 to 50° C .: and further preferably 0° C . to room erably a halogen atom or a C1- 6 alkoxy C1- 6 alkyl group ; and 45 temperature . further preferably a fluorine atom , a bromine atom , or a * [ 29 - 16 ] In the method of producing the compound of the methoxy methyl group . above formula ( I - RR ) of Embodiment [ 29 ] described above , [29 - 8 ] In the compound of the above formula E in formula (CB - 1 ) : (AM - 2 -RR ) • (D - TA ) in the method of producing the com pound of the above formula ( I- RR ) of Embodiment [ 29 ] 50 described above , R2a or R25 is preferably a methyl group . (CB - 1 ) [29 - 9 ] In the compound of the above formula ( AM - 2 - RR ) * ( D - TA ) in the method of producing the com pound of the above formula ( I - RR ) of Embodiment [29 ] EZ described above, preferably , p is an integer of 0 to 2 ; R ' is a fluorine atom , a bromine atom , or a methoxy methyl group ; where the ring A is the same as the definition in the above and R2a or R2b is a methyl group . formula (I - RR ), is preferably the following partial structural [29 - 10 ] In the compound of the above formula (AM -2 formula : RR )• (D - TA ) in the method of producing the compound of the above formula ( I - RR ) of Embodiment [29 ] described above, preferably , p is 0 ; and R2a or R25 is a methyl group . (CS - 1 ) [ 29 - 11 ] In the method of producing the compound of the above formula (I - RR ) of Embodiment [ 29 ] described above, the above formula (AM - 2 -RR )• (D - TA ) is preferably an 65 intermediate compound represented by the following for mula (AM - 2a - RR ) * ( D - TA ) : US 10 , 399 , 945 B2 85 86 - continued { in formula ( I -RR - 1 ) , the ring A is the following partial (CS - 2 ) structural formula (AM - 3 -aps ) : CH3; (AM -3 -aps ) CH3 (R $a ) ? and more preferably is the following partial structural for mula : 10

R3a ( CS - 1 ) [ in formula (AM - 3 - aps ) , the definitions of the ring B , q , R3a , 15 and R5a are the same as the definitions in Embodiment [ 15 ] min described above ), and the definitions of Ria , R15 , R20 , and CI R26 are the same as the definitions of Embodiment [ 20 ] described above ) , the method comprising [ 29 -17 ] In the method of producing the compound of the adding an intermediate compound represented by formula above formula ( I -RR ) of Embodiment [ 29 ] described above , 20 (AM - 3 - a ): the base used in (Stage [29 ]- 2 ) is preferably pyridine, triethylamine , N , N - diisopropylethylamine , 1 , 8 - diazabicyclo [ 5 . 4 .0jundec - 7 - ene (DBU ) , sodium carbonate , or potassium (AM - 3 - a ) potassium carbonate ; more preferably pyridine , triethylam CH3 ine , N ,N -diisopropylethylamine , 1 , 8 -diazabicyclo [ 5 .4 . 0 ]un - 25 (R50g dec - 7 - ene (DBU ) , or potassium carbonate ; and further pref erably 1, 8 -diazabicyclo [ 5 .4 . 0 ]undec - 7 -ene (DBU ) . [ 29 - 18 ] In the method of producing the compound of the above formula ( I - RR ) of Embodiment [ 29 ] described above , NH2 the equivalent amount of the base used in (Stage [ 29 ] - 2 ) is zo preferably 1 to 5 equivalents ; more preferably 1 . 5 to 3 . 5 30 R 3a equivalents : and further preferably 2 to 3 equivalents . [29 - 19 ] In the method of producing the compound of the where the definitions of the ring B , q , R3a , and R5a are the above formula ( I - RR ) of Embodiment [ 29 ] described above , same as the definitions in the above formula ( AM - 3 -aps ) , the solvent used in (Stage [29 ] - 2 ) is preferably dimethyl and a urea forming agent which may be arbitrarily selected formamide , dimethylacetamide , dimethyl sulfoxide, 35 from trichloroethyl chloroformate , p - tolyl chloroformate , N -methylpyrrolidone , acetonitrile , tetrahydrofuran , dichlo and the like to a solvent which may be arbitrarily selected romethane , or 1 ,2 - dichloroethane ; more preferably , dim from acetonitrile , diethyl ether , tetrahydrofuran , dimethoxy ethyl sulfoxide , N -methylpyrrolidone , or acetonitrile ; and further preferably dimethyl sulfoxide. ethane , 1 , 4 -dioxane , dichloromethane , chloroform , 1 , 2 - di [29 -20 ] In the method of producing the compound of the 40 chloroethanether , N -methylpyrrolidone , mixture solvents above formula ( I - RR ) of Embodiment [ 29 ] described above , thereof, and the like in the presence or absence of a base the amount of the solvent used in (Stage [ 29 ] - 2 ) is preferably such as pyridine, 5 to 15 times ; more preferably 5 to 10 times : and further obtaining a compound represented by formula (CB - 1 - a ) : preferably 5 times relative to formula (CB - 1 ) . [ 29 - 21 ] In the method of producing the compound of the 45 (CB - 1 - a ) above formula ( I- RR ) of Embodiment [ 29 ] described above , CH3 the reaction temperature of ( Stage [ 29 ] - 2 ) (temperature of the mixture solution B ) is 0° C . to 80° C . ; more preferably (R5 ) , fB+ B ) 0 to 50° C . : and further preferably 0° C . to room tempera ture . [ 30 ] Embodiment 30 of the present invention is a method 50 of producing a compound represented by the following N ? formula ( I -RR - 1 ) : R3a 55 where the definitions of the ring B , q , R34 , and RSa are the ( I- RR -1 ) same as the definitions in above formula ( AM - 3 - aps ) , and E RIO represents a group which may be arbitrarily selected from R la groups represented by the following partial structural for mulas : 60

(CS - 1 ) NH ( R ) OH 65 US 10 , 399 , 945 B2 87 88 - continued fluorine atom , or a bromine atom , and more specifically the ( CS - 2 ) combination of Rla and Rib is (R14 , R1b ) = (hydrogen atom , CH3, hydrogen atom ), ( hydrogen atom , bromine atom ) , (bromine atom , hydrogen atom ) , (methoxy methyl group , hydrogen 5 atom ), ( fluorine atom , hydrogen atom ), (hydrogen atom , fluorine atom ) , ( fluorine atom , fluorine atom ); and particu mu larly preferably , Ria and Rib are each independently a by causing reaction in the obtained mixture solution A in a hydrogen atom . range of 0° C . to a reflux temperature of the mixture solution 10 [30 - 5 ] In the compound of the above formula (AM -2a A (Stage [30 ] -1 ), RR ) (D - TA ) in the method of producing the compound of subsequently adding the compound represented by the the above formula ( I- RR - 1 ) of Embodiment [ 30 ] described above formula (CB - 1 - a ) and an intermediate compound above , preferably, R24 or R25 is a methyl group . represented by the following formula ( AM - 2a -RR )* ( D - TA ): [ 30 -6 ] In the method of producing the compound of the 15 above formula (I - RR - 1 ) of Embodiment [30 ] described above , the urea forming agent used in (Stage [ 30 ] - 1 ) is (AM -2a -RR )• ( D -TA ) preferably trichloroethyl chloroformate . [30 - 7 ] In the method of producing the compound of the R10 above formula (I - RR - 1) of Embodiment [ 30 ] described Rla 20 above , the base used in (Stage [30 ]- 1) is preferably pyridine OH or the absence of a base . R2A [ 30 - 8 ] In the method of producing the compound of the – R25 HO?C COOH •H , O above formula (I - RR - 1) of Embodiment [ 30 ] described above , the solvent used in (Stage [ 30 ] - 1 ) is preferably OH N -methylpyrrolidone , diethyl ether , tetrahydrofuran , 1 , 4 Y (R ) dioxane, dichloromethane, or 1 , 2 - dichloroethane ; and more OH preferably N -methylpyrrolidone , tetrahydrofuran , or 1 , 2 dichloroethane. [ 30 - 9 ] In the method of producing the compound of the where the definitions of Rla , R15 , R20, and R26 are thehe same 30 above formula (I -RR - 1 ) of Embodiment [ 30 ] described as the definitions in the above formula ( I- RR - 1 ) , to a inert above, the reaction temperature of ( Stage [ 30 ] - 1 ) (tempera solvent and which may be arbitrarily selected from dimethyl ture of the mixture solution A ) is preferably 0° C . to 80° C .; sulfoxide, N -methylpyrrolidone , acetonitrile , and the like in more preferably 0 to 50° C . : and further preferably 0° C . to the presence of a base which may be arbitrarily selected room temperature . from pyridine, triethylamine, N ,N -diisopropylethylamine , 35 [ 30 - 10 ] In the method of producing the compound of the 1 ,8 -diazabicyclo [ 5 .4 .0 ]undec - 7 -ene (DBU ), potassium car - above formula (I - RR - 1) of Embodiment [30 ] described bonate , and the like , and above , E in formula (CB - 1 - a ): obtaining the compound represented by the formula ( I - RR - 1 ) by reacting the obtained mixture solution B at 0° C . to a reflux temperature of the mixture solution B (Stage 40 (CB - 1 - a ) [ 30 ] - 2 ) . CH3 [30 - 1 ] In the method of producing the compound of the ( R $ at) B above formula (I - RR - 1) of Embodiment [ 30 ] described above, more preferably, the amine of the above formula ( AM - 3 - a ) is an amine which may be arbitrarily selected 45 from the amines described in Embodiment [ 17 ] . N [ 30 - 2 ] In the method of producing the compound of the R3a above formula ( I -RR - 1 ) of Embodiment [ 30 ] described above , more preferably , the amine of the above formula ( AM - 3 - a ) is an amine which may be arbitrarily selected 50 where the definitions of the ring B , q, R3a , and Rsa are the from the amines described in Embodiment [ 17a ) . same as the definitions in the above formula (AM -3 - aps ), is [30 - 3 ] In the method of producing the compound of the preferably the following partial structural formula : above formula ( I -RR - 1 ) of Embodiment [ 30 ] described above, more preferably, the amine of the above formula ( AM - 3 - a ) is an amine which may be arbitrarily selected 55 ( CS - 1 ) from the amines described in Embodiment [ 18 ] . [ 30 - 4 ] In the compound of the above formula ( AM - 2a RR )* ( D - TA ) in the method of producing the compound of the above formula ( I- RR - 1 ) of Embodiment [ 30 ] described above , preferably , Rla and Rib are each a hydrogen atom , a 60 halogen atom , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxy C1- 6 [30 - 11 ] In the method of producing the compound of the alkyl group , a carboxamide group , or a C1- 6 alkoxy carbonyl above formula ( I -RR - 1 ) of Embodiment [ 30 ] described group ; more preferably , Rla is a hydrogen atom , a halogen above , thebase used in ( Stage [ 30 ] - 2 ) is preferably pyridine , atom , or a C1- 6 alkoxy C1- 6 alkyl group , and R15 is a triethylamine, N , N - diisopropylethylamine , 1 , 8 - diazabicyclo hydrogen atom or a halogen atom ; further preferably , Ria is 65 [5 . 4 . 0 ] undec - 7 - ene (DBU ), or potassium carbonate ; and a hydrogen atom , a fluorine atom , a bromine atom , or a more preferably 1 , 8 - diazabicyclo [ 5 .4 .0jundec -7 - ene methoxy methyl group , and Rlb is a hydrogen atom , a (DBU ) . US 10 , 399 , 945 B2 89 90 [ 30 - 12 ] In the method of producing the compound of the hydroiodic acid , nitric acid , sulfuric acid , phosphoric acid , above formula (I -RR - 1 ) of Embodiment [30 ] described and the like . Preferable examples of the salt with an organic above, the base used in (Stage [30 ] -2 ) is preferably 1 to 5 acid include, for example , salts with aliphatic monocarbox equivalents ; more preferably 1. 5 to 3 .5 equivalents : and ylic acids such as formic acid , acetic acid , trifluoroacetic further preferably 2 to 3 equivalents . 5 acid , propionic acid , butyric acid , valeric acid , enanthic acid , [ 30 - 13 ] In the method of producing the compound of the capric acid , myristic acid , palmitic acid , stearic acid , lactic above formula (I - RR - 1) of Embodiment [30 ] described acid , sorbic acid , and mandelic acid , salts with aliphatic above, the solvent used in ( Stage [30 ]- 2 ) is preferably dicarboxylic acids such as oxalic acid , malonic acid , suc dimethyl sulfoxide, N -methylpyrrolidone , or acetonitrile ; cinic acid , fumaric acid , maleic acid , malic acid , and tartaric and more preferably dimethyl sulfoxide . 10 acid , salts with aliphatic tricarboxylic acids such as citric [ 30 - 14 ] In the method of producing the compound of the acid , salts with aromatic monocarboxylic acids such as above formula (I -RR - 1 ) of Embodiment [30 ] described benzoic acid and salicylic acid , salts of aromatic dicarbox above, the amount of the solvent used in (Stage [ 30 ]- 2 ) is ylic acids such as phthalic acid , salts with organic carboxylic preferably 5 to 15 times ; more preferably 5 to 10 times: and acids such as cinnamic acid , glycolic acid , pyruvic acid , further preferably 5 times relative to formula ( CB - 1 - a ) . 15 oxylic acid , salicylic acid , and N -acetylcysteine , salts with [ 30 - 15 ] In the method of producing the compound of the organic sulfonic acids such as methanesulfonic acid , benze above formula ( I -RR - 1 ) of Embodiment [ 30 ] described nesulfonic acid , and p - toluenesulfonic acid , and acid addi above, the reaction temperature of (Stage [ 30 ] - 2 ) ( tempera - tion salts with acidic amino acids such as aspartic acid and ture of the mixture solution B ) is preferably ( ° C . to 80° C .; glutamic acid . Preferable examples of the salt with a basic more preferably 0 to 50° C .: and further preferably 0° C . to 20 amino acid include , for example , salts with arginine , lysine , room temperature . ornithine , and the like , and preferable examples of the salt In an embodiment concerning the above - described pro with an acidic amino acid include , for example , salts with duction method ( for example , Embodiment [ 23 ] , [ 24 ] , [ 25 ] , aspartic acid , glutamic acid , and the like . Among these , [ 26 ], [ 29 ] , or [ 30 ] ) , the meaning of “ room temperature to a pharmaceutically acceptable salts are preferable . Examples reflux temperature of the mixture solution ” means any 25 include inorganic salts such as alkali metal salts ( for temperature in a range from room temperature to the tem - example , sodium salts , potassium salts , and the like ) and perature at which the mixture solution (solvent ) refluxes . In alkaline earth metal salts (for example , calcium salts , mag addition , the meanings of " 0° C . to a reflux temperature of nesium salts , barium salts , and the like ) , ammonium salts , the mixture solution A ” and “ 0° C . to a reflux temperature and the like if the compound has an acidic functional group of the mixture solution B ” mean any temperature in a range 30 therein , and examples include salts with inorganic acids such from 0° C . to the temperature at which the mixture solution as hydrochloric acid , hydrobromic acid , nitric acid , sulfuric A or B ( solvent) refluxes, respectively . acid , and phosphoric acid or salts with organic acids such as In all the embodiments described above, when the phrase acetic acid , phthalic acid , fumaric acid , oxalic acid , tartaric " compound ” is used , it also refers to a " pharmaceutically acid , maleic acid , citric acid , succinic acid , methanesulfonic acceptable salt thereof. " 35 acid , and p - toluenesulfonic acid if the compound has a basic In addition , in the present specification , unless otherwise functional group therein . noted , a description such as the “ compound of formula (I )” The salts can be obtained in a usual manner, for example , and the " compound represented by formula ( I ) ” also refers by mixing the compound of the present invention with a to compounds corresponding to subconcepts of the " com - solution containing an appropriate amount of acid or base to pound of formula ( I ) " such as the " compound of formula 40 form the intended salt , followed by fractional filtration or ( I - a ), ” the " compound of formula ( l - a - 1 ) ,” and the " com distillation of the mixture solvent. In addition , the compound pound of formula ( I - a - 2 ). ” of the present invention or a salt thereof can form a solvate The compound of the present invention may form an acid with a solvent such as water , ethanol, and glycerol. addition salt or form a salt with a base depending on the As a review on salts , Handbook of Pharmaceutical Salts : substituent type . Although no particular limitation is 45 Properties , Selection , and Use , Stahl & Wermuth (Wiley imposed as long as those salts are a pharmaceutically VCH , 2002 ) has been published and a detailed description is acceptable salt , they include , for example , a metal salt, an provided in this book . ammonium salt , salt with an organic base , a salt with an A " prodrug ” of the compound of the present invention is inorganic acid , a salt with an organic acid , a salt with a basic also included in the compound of the present invention . or acidic amino acid , and the like . Preferable examples of the 50 Regarding the “ prodrug, " for example consider a case where metal salt include , for example , alkali metal salts such as when a certain type of derivative of the compound of the lithium salts , sodium salts , potassium salts , and cesium salts , present invention , which has a possibility of exhibiting no or alkaline earth metal salts such as calcium salts, magnesium almost no intended pharmacological activity , is administered salts, and barium salts , aluminum salts, and the like ( includ - in or on the body , the derivative is converted to the com ing , for example , monosalts as well as disodium salts and 55 pound of the present invention having the intended pharma dipotassium salts ) . Preferable examples of the salt with an cological activity due to e . g . hydrolysis . In this case , the organic base include , for example , salts with methylamine , compound before administration is referred to as the " pro ethylamine, t- butylamine , t- octylamine , diethylamine , trim drug. ” ethylamine, triethylamine , cyclohexylamine, dicyclohex Regarding the “ prodrug” of the compound of the present ylamine , dibenzylamine , ethanolamine , diethanolamine , tri- 60 invention , for example , an appropriate functional group ethanolamine , piperidine , morpholine , pyridine , picoline , present in the compound of the present invention can be lysine , arginine, ornithine, ethylenediamine , N -methylglu - produced in accordance with a method known in the litera camine , glucosamine , phenylglycine alkyl ester , guanidine , ture, for example , the method described in Design of Pro 2 , 6 -lutidine , ethanolamine , diethanolamine , trietha drugs , H . Bundgaard (Elsevier , 1985 ) . nolamine, N , N -dibenzylethylenediamine , and the like . Pref - 65 The compound of the present invention can exist in an erable examples of the salt with an inorganic acid include , unsolvated form or a solvated form . In the present specifi for example , salts with hydrochloric acid , hydrobromic acid , cation , a “ solvate ” means a molecular complex containing US 10 , 399 , 945 B2 91 92 the compound of the present invention and one or more -continued pharmaceutically acceptable solvent molecules ( for ( TN - 2 ) example , water, ethanol, and the like ) . It is referred to as a “ hydrate ” in particular if the solventmolecule is water. Hereinafter, descriptions on the compound of the present 5 invention include descriptions on its salts and solvates , and solvates of the salts . If the compound of the present invention has isomers such ZI as a geometric isomer , a configurational isomer , a tautomer , ?? an optical isomer , a stereoisomer , a positional isomer , and a rotational isomer, the other isomer and the mixture are (15 ,2S ) included in the compound of the present invention . More ( TN - 3 ) over, if the compound of the present invention has an optical isomer , the optical isomer separated from the racemate is also included in the compound of the present invention . 15 When the compound of the present invention has one or more asymmetric carbon atoms, two or more types of stereoisomers can exist . In addition , tautomerism may also occur when the structural isomers are interconvertible by low energy barriers. The tautomerism includes , for example , 20 ÕH a form of a proton tautomerism in a compound having an ( 1R ,2S ) imino , keto , or oxime group . ( TN - 4 ) An optical isomer can exist in the partial structural formula ( TN ) [ note that in formula ( TN ) , the C ( O ) group is not included in the 1 - amino - 2 -hydroxy - 1, 2 ,3 ,4 tetrahydronaphthalene skeleton ): NH (TN ) 30 OH ( 15 ,2R ) If a geometric isomer, a configurational isomer, a stereoi somer, a conformer , and the like exist in the compound of the present invention or an intermediate compound , it is pos sible to isolate them by a known means. OH If the compound of the present invention or an interme diate compound is an optically active compound , it can be corresponding to the l -amino -2 -hydroxy - 1 ,2 ,3 ,4 -tetrahy tetrahy . 40 separated into the ( + ) form or ( - ) form [D form or L form ] dronaphthalene skeleton in formula (I ) of the compound of from the corresponding racemate by ordinary optical reso the present invention . In the present specification , unless lution means. otherwise noted , formula ( TN ) means that it includes iso If an optical isomer , a stereoisomer, a positional isomer, mers represented by ( 1R 2R ) form ( formula ( TN - 1 ) ) , (1S , a rotational isomer , and a tautomer exist in the compound of 2S ) form ( formula ( TN - 2 )) , ( 1R ,2S ) form ( formula ( TN - 3 ))) , 45 the present invention or an intermediate compound , each of and (15 ,2R ) form (formula ( TN -4 )) . the isomers can be obtained as a single compound by a per se known synthesis method or separation method . The separation method includes , for example , optical resolution (TN ) methods such as a fractional recrystallization method , a 50 diastereomer method , and a chiral column method . Herein after , a description is provided in detail for the separation methods . The fractional recrystallization method : is a method in inn which an optical resolution agent is ionically bonded to a N 55 racemate to obtain a crystalline diastereomer, thereafter the OH : crystalline diastereomer is separated by the fractional recrys ( TN - 1 ) tallization method , followed by a step of removing the optical resolution agent as desired to obtain an optically pure compound . The optical resolution agent includes , for 60 example , ( + ) -mandelic acid , ( - ) -mandelic acid , ( + ) - tartaric acid , ( - ) - tartaric acid , ( + ) - 1 -phenethylamine , ( - ) - 1 -pheneth ylamine, cinchonine , ( - ) - cinchonidine , brucine , and the like . The diastereomer method : is a method in which an optical resolution agent is covalently bonded to a mixture of race OH 65 mates to obtain a mixture of diastereomers , which is then (1R ,2R ) separated by ordinary separation means (for example , frac tional recrystallization , silica gel column chromatography, US 10 , 399 , 945 B2 93 94 HPLC , and the like ) to an optically pure diastereomer , composed of two ormore unique solids at room temperature , followed by a step of removing the optical resolution agent each having different physical properties ( for example , by a chemical reaction (hydrolysis reaction or the like ) to structure , melting point, heat of fusion , hygroscopicity , obtain an optically pure optical isomer . solubility , stability , and the like ) . Co - crystals or co - crystal For example , if the compound of the present invention or 5 salts can be produced according to a per se known co an intermediate compound has a hydroxyl group or an amino crystallization method . group (primary , secondary ) , a diastereomer of an ester or an The compound of the present invention also includes amide is obtained therefrom by condensation reaction of the compound of the present invention or the intermediate compounds labeled or substituted by isotope elements ( for compound with an optically active organic acid (for 10 example , isotopes of hydrogen : 2H , SH , and the like ; iso example , A -methoxy - a - ( trifluoromethyl) phenyl acetate , topes of carbon : " 1c , 13C , 14C , and the like; isotopes of ( - )- menthoxyacetic acid , and the like ). In addition , if the chlorine : 36C1 and the like ; isotopes of fluorine: 18F and the compound of the present invention has a carboxy group , a like ; isotopes of iodine : 1231 , 1251, and the like; isotopes of diastereomer of an amide or an ester can be obtained nitrogen : 13N , 15N , and the like ; isotopes of oxygen : 150 , therefrom by a condensation reaction of the compound of 15 170 , 180 , and the like ; isotopes of phosphorus: 32P and the the present invention with an optically active amine or an like ; and isotopes of sulfur: 35S and the like ). optically active alcohol. When the diastereomers obtained Among the compounds of the present invention , com by the condensation reaction are separated and each diaste - pounds labeled or substituted by certain types of isotope reomer is subjected to a hydrolysis reaction by an acid or a elements ( for example , positron emitting isotope elements base, they are converted to optically pure optical isomers of 20 such as " c , 18F , 150 , and 13N ) can be used as tracers for use the original compound . in , for example , positron emission tomography (PET ) (PET The chiral column method : is a method of direct optical tracers ) , and are useful in the field of medical diagnosis and resolution by subjecting a racemate or a salt thereof to the like . chromatography on a chiral column ( column for optical In addition , among the compounds of the present inven isomer separation ) . 25 tion , compounds labeled or substituted by certain types of For example , in the case of high performance liquid isotope elements are useful in tissue distribution studies of chromatography (HPLC ) , it is possible to separate optical drugs and /or substrates . For example, PH and 14C are useful isomers by adding a mixture of optical isomers to a chiral for the research purpose, because labeling or substitution by column ( for example , the CHIRAL series and the like use of them is easy and the detection means is easy . manufactured by Daicel ) , followed by development by use 30 Among the compounds of the present invention , com of an elution solvent (water , various buffer solutions ( for pounds labeled or substituted by H (or which may be example , phosphate buffer solution ) , single solvents such as denoted as D or deuterium . ) ( D compounds , deuterated organic solvents ( for example , ethanol, methanol, isopropa - compounds ) are expected to have high stability and are nol, acetonitrile , trifluoroacetic acid , diethylamine , and the useful as an active compound itself . For example , it is like ) , or a mixture solvent thereof) . In addition , in the case 35 possible to list a compound in which a hydrogen atom at a of gas chromatography , for example , it is possible to sepa - position to be metabolized is substituted with 2H , making it rate optical isomers using a chiral column ( for example , possible to decrease the metabolic reaction rate almost CP - Chirasil- DeX CB (manufactured by GL Sciences Inc .) ) . without affecting the properties of the compound . In addi Moreover , for example , in the case of supercritical fluid tion , a compound in which ? H is substituted for a position chromatography (SFC ) , it is possible to separate optical 40 which irreversibly binds to a metabolic enzyme can suppress isomers by adding a mixture of optical isomers to a chiral inhibition of the action of the metabolic enzyme, making it column ( for example , the CHIRAL series and the like possible to reduce the drug interaction when combined . manufactured by Daicel) and using carbon dioxide and an Among the compounds of the present invention , isotopi appropriate organic solvent ( for example , methanol, ethanol, cally labeled compounds can be obtained by ordinary tech isopropanol, trifluoroacetic acid , diethylamine , and the like ) 45 niques known to those skilled in the art or by methods as an elution solvent. analogous to the synthetic methods described in Examples to If the compound of the present invention or an interme - be described later. Also , instead of unlabelled compounds , diate compound is an optically active compound , it can be the obtained isotopically labeled compounds can be used in synthesized by asymmetric synthesis in which one of the pharmacological experiments . optical isomers is selectively synthesized . An optically 50 [Method of Producing Compound of Present Invention ] active compound can be synthesized by ( 1 ) asymmetric Hereinafter , a description is provided for a method of synthesis reaction of enantioselectively reacting a racemic producing the compound of the present invention repre compound to an optically active compound and ( 2 ) a method sented by formula ( I ) . With a commercially available com of diastereoselectively synthesizing from a naturally occur pound or a compound which can easily be obtained from a ring optically active compound (sugar , amino acids, and the 55 commercially available compound by production methods like ) . known in the literature as a starting material or an interme The compound of the present invention may be crystalline diate compound , the compound represented by formula (1 ) in some cases . The case of a crystal is also included in the being the compound of the present invention , a salt thereof, compound of the present invention whether or not the and a solvate thereof can easily be produced by combining crystalline form is single or a crystalline form mixture . 60 known general chemical production methods , and can be Additionally , in the case where the crystal of the compound produced in accordance with the representative production of the present invention has crystal polymorphism , any methods shown below . Moreover , the present invention is crystal form is included in the compound of the present not limited at all to the production methods described below . invention . Unless otherwise noted , the definitions of p , q , the ring A , The compound of the present invention may be pharma- 65 the ring B , R ' , R20 , R25 , R ’ , R4a , R45 , R4C, R40 , RS, and the ceutically acceptable co - crystals or co - crystal salts . Here , a like in the formulas of each of the production methods co -crystal or a co - crystal salt means a crystalline substance described below are the same as the definitions of the US 10 , 399 , 945 B2 95 96 formulas such as general formula ( I ) and formula ( Ia - 1 ) 1 . 5 hours , 2 hours , 3 hours, 4 hours , 5 hours , 10 hours, 12 described in the above embodiments . hours, 18 hours, 24 hours, 36 hours , 48 hours , 60 hours, and xl in the production methods described below is , unless 72 hours or a time range having these as the lower limit otherwise noted , a nitrogen atom , a C - H , or a C1- 6 alkyl value and the upper limit value, preferably 0 . 5 to 48 hours, group ( specifically a C - CHZ) ; X is , unless otherwise 5 and more preferably 1 to 36 hours . noted , a halogen atom ( specifically a fluorine atom , a The “ temperature range from – 78° C . to the reflux tem chlorine atom , a bromine atom , or an iodine atom ); and RA perature of the solvent” in the reaction temperature is , unless otherwise noted , a C1- 6 alkyl group , C6 - 10 aryl described above means a temperature in a range from - 78° group , or a benzyl group , and [ B ] is boric acid , boronate C . to the temperature at which the solvent (or the mixture ester, boronic acid N -methyliminodiacetic acid (MIDA ) 10 solvent ) used in the reaction refluxes . For example , in the ester , or the like . case where methanol is used as the solvent, " at the tempera The formulas in each step of the production method of the ture from - 78° C . to the reflux temperature of the solvent” present invention may form a salt , and the salt includes the means a temperature in a range from - 78° C . to the same ones as the salts of the above - described formula ( I ) . temperature at which methanol refluxes . In addition , simi The raw material compound in each step of the production 15 larly , " at the temperature from – 78° C . to the reflux tem method of the present invention can be used in the next perature of the reaction solution ” means any temperature in reaction as a reaction solution as it is or as a crude product. a range from - 78° C . to the temperature at which the In addition , the raw material compound can be isolated from reaction solution refluxes . the reaction mixture in accordance with a usual manner and The “ temperature from 0° C . to the reflux temperature of can be purified easily by per se known methods, for 20 the mixture solution ” is the same and means a temperature example , separation methods such as extraction , concentra - in a range from 0° C . to the temperature atwhich the mixture tion , neutralization , filtration , distillation , recrystallization , solution refluxes . The lower limit value of the temperature and chromatography . is , for example , - 78° C . and 0° C . as described above , but If the formulas in each step of the production method of may be other temperatures of 20° C ., 23° C . , 25° C . , 40° C . , the present invention contain a convertible functional group 25 50° C ., 70° C ., 80° C ., 90° C ., and 100° C . or + 1° C ., + 2° ( a carboxy group , an amino group , a hydroxyl group , a C . , + 3° C ., + 4° C ., and + 5° C . shifted from the temperatures . carbonyl group , a mercapto group , a C - 6 alkoxy carbonyl In the production method of the present specification , group , a - C ( O ) - 0 - C6- 10 aryl group , a - C ( O ) - 0 - unless otherwise noted , the “ room temperature ” means a C7- 20 aralkyl group in the present specification , unless temperature of an experimental room , a laboratory , and the otherwise noted , the “ C7- 20 aralkyl group ” includes groups 30 like, and the “ room temperature ” in Examples of the present of, for example , a benzyl group , a phenethyl group , a specification shall indicate a temperature of usually about 1° diphenylmethyl group , a trityl group , a biphenylmethyl C . to about 30° C . , preferably usually about 5° C . to about group , a naphthylmethyl group , an indanylmethyl group , a 30° C ., more preferably usually about 15° C . to about 25° C . , 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 -ylmethyl group , and the and further preferably 20 + 3° C . like ) , a sulfo group , a halogen atom , and the like ) , it is 35 The reaction in each step of the production method of the possible to produce various compounds by converting these present invention can be carried out without a solvent or by functional groups by a per se known method or a method dissolving or suspending , before the reaction , the raw mate analogous thereto . rial compound in an appropriate solvent which will not be In the above conversion reaction , if a compound is involved in reaction . obtained in a free form , it may be converted into a salt in 40 The above - described solvent which will not be involved accordance with a usual manner, and if a compound is in reaction includes , for example , water, cyclohexane , obtained as a salt , it can be converted into a free form or hexane , benzene , chlorobenzene , toluene , xylene , methanol, another salt in accordance with a usual manner . ethanol, 1 -propanol , 2 - propanol, tert -butyl alcohol, N , N Conversion of these functional groups can be carried out dimethylformamide (DMF ) , N , N -dimethylacetamide , by following the method and the like described in the book 45 N -methylpyrrolidone (NMP ) , hexamethylphosphoric tri of Larock (Richard C . Larock ) et al . , Comprehensive amide, 1 , 3 - dimethyl- 2 - imidazolidinone , dimethyl sulfoxide , Organic Transformations, Second Edition , published in acetonitrile , propionitrile , diethyl ether, diisopropyl ether, October 1999 , Wiley - VCH , for example . diphenyl ether , methyltert - butyl ether (MTBE ) , tetrahydro If there is a reactive group such as a hydroxyl group , an furan , 2 -methyltetrahydrofuran , 1 , 4 - dioxane , 1 , 2 -dime amino group , a carboxy group , or a thiol group as a 50 thoxyethane , methyl acetate , ethyl acetate , butyl acetate , substituent in the formulas in each step of the production acetone ,methyl ethyl ketone , dichloromethane , chloroform , method of the present invention , it is possible to suitably carbon tetrachloride , 1 , 2 -dichloroethane , triethylamine , protect these groups in each reaction step and to remove the N , N - diisopropylethylamine , pyridine , lutidine , acetic anhy protecting group at an appropriate stage . dride , formic acid , acetic acid , propionic acid , trifluoroacetic The method of introducing and removing a protecting 55 acid ,methanesulfonic acid , hydrochloric acid , sulfuric acid , group is appropriately carried out depending on the type of and the like . These solvents can be used singly , or two or the protected group or the protecting group , and can be more kinds of the solvents can appropriately be selected carried out by , for example , the method described in the depending on the reaction conditions and used as a mixture book of Greene et al. , " Protective Groups in Organic Syn - in an appropriate ratio . These solvents are appropriately thesis, Fourth Edition , 2007 , John Wiley & Sons. ” 60 selected depending on reaction conditions . Unless otherwise noted , the reaction temperature in each In the production method of the present specification , step of the production method of the present invention is not unless otherwise noted , if described as a “ solvent which will limited as long as it is in a temperature range from - 78° C . not be involved in reaction ” or a " non - reactive solvent, ” the to the reflux temperature of the solvent . In addition , unless solvent to be used means that one solvent may be used otherwise noted , the reaction time is not limited as long as 65 singly , or two or more kinds of the solvents may appropri the reaction sufficiently proceeds . The reaction timemay be ately be selected depending on the reaction conditions and a time period of, for example , 0 . 1 hours , 0 .5 hours , 1 hour, used as a mixture in an appropriate ratio .

US 10 ,399 ,945 B2 99 100 -continued p( R ? R20 R26

NH NH OH 20 R20 R26 ( IM - 2 ) PR1) R26 25 R22 - Step 4 > 1 = N - R25 NH2 o = OH (AM - 1) (IC - 2 ) 30 ( IM - 3 ) R2a "attaisikiti LR26 35 p( R1 ) NH NH OH R26 < Step 5 40 Hereinafter , a method of producing the amine derivative represented by formula ( AM - 2 ) ; the amine derivatives rep ( IM - 4 ) resented by formula (AM - 1 - a ), ( AM - 1 - b ), ( AM - 1 - c ) , ( AM 1 - d ), (AM - 1 - e ), ( AM - 1 - f ) , ( AM - 1 - g ) , ( AM - 1 - h ), ( AM - 1 - i ), formula (AM - 1 - i) , formula ( AM - 1 - A ) , ( AM - 1 - B ) , (AM - 1 ?- 445 . C ) , (AM - 1 - D ) , ( AM - 1 - E ), ( AM - 1 - F ) , ( AM - 1 - G ) , (AM - 1 p( R ! H ) , (AM - 1 - 1 ) , and formula ( AM - 1 - J ) , which are subformu las of formula ( AM - 1 ) ; and the compounds represented by R2a formula (I - b - 1a ), formula (I - b -2a ) , formula ( I- b - 3a ), formula < Step 6 > ( 1- b - 1A ) , formula (I -b - 2A ), and formula ( I- b -3A ), which are > - R26 subformulas of formula ( I) . [Production Method A ] A method of synthesizing the HO amine derivative represented by formula (AM - 2 ) : (IM - 5 ) 55 p( R ?) PR1 R2a - R26 < Step 7 > LOH

( IM - 6 ) (SM - 1 ) US 10 , 399 , 945 B2 101 102 - continued such as 1, 3- dicyclohexylcarbodiimide (DCC ), 1 -ethyl - 3 -( 3 p( R !) dimethylaminopropyl) carbodiimide hydrochloride (WSC .HCI ) , 1- hydroxybenzotriazole (HOBT ) , benzotriaz ole- 1 -yloxytris (dimethylamino ) phosphonium hexafluoro < Step 8 > phosphate (BOP reagent) , bis ( 2 -oxo -3 -oxazolidinyl ) phos - R26 phinic chloride (BOP -CI ) , 2 - chloro - 1 , 3 dimethylimidazolinium hexafluorophosphate (CIP ) , 4 - ( 4 , 6 dimethoxy - 1 , 3 , 5 -triazine - 2 - yl) - 4 -methylmorpholinium chloride (DMTMM ), polyphosphoric acid (PPA ), 2 - ( 1H - 7 ( IM - 7 ) 10 azabenzotriazole - 1 - yl) - 1 , 1 , 3 , 3 -tetramethyluronium p( R ! ) hexafluorophosphate methane aluminum (HATU ) , and ( 1 - cyano - 2 - ethoxy - 2 -oxo ethylidene aminooxy ) dimethyl amino -morpholino - carbenium hexafluorophosphate (COMU ) and in the presence or absence of a base such as triethylamine and pyridine in accordance with a method known in the literature , for example the method described in H2N Y " Jikken Kagaku Koza , Fourth Edition , 22 , Organic Synthe OH sis IV , Acid , Amino Acid , and Peptide , pp . 191- 309, 1992 , 20 Maruzen .” (AM - 2 ) In addition , it is possible to produce the compound represented by formula (IM - 1 ) in the same manner by : converting the compound represented by formula (SM - 1 ) to < Step 1 > It is possible to produce the compound repre an acid halide by use of a halogenation agent such as thionyl sented by formula ( IM - 1 ) by using the compound repre 25 chloride , oxalyl chloride , phosphoryl chloride , sulfuryl chlo sented by formula (SM - 1 ) [ the compound of formula (SM - 1 ) ride , phosphorus trichloride , phosphorus pentachloride , and is a commercially available compound or a compound which phosphorus tribromide, a non - reactive solvent such as 1 ,4 can be produced by the production method known in the dioxane, tetrahydrofuran , 1 , 2 - dimethoxyethane , benzene , literature from a commercially available compound ] and toluene , dichloromethane , 1 , 2 - dichloroethane, and chloro using a solvent such as methanol, ethanol, and 2 -propanol , 30 form , or a mixture solvent thereof , followed by reaction at followed by reaction at 0° C . to the reflux temperature of the 0° C . to the reflux temperature of the solvent in the presence solvent in the presence of an acidic reagent such as hydro - or absence of a base such as triethylamine , N . N - diisopro chloric acid , sulfuric acid , thionyl chloride , and acetyl pylethylamine , and N , N - dimethylaminopyridine in accor chloride in accordance with a method known in the litera dance with a method known in the literature, for example the ture , for example the method described in “ Jikken Kagaku 35 method described in " Journal of the American Chemical Koza , Fourth Edition , 22 , Organic Synthesis IV , Acid , Society ) , 109 ( 24 ), p 7488 - 7494 , 1987” ; and using an Amino Acid , and Peptide , pp . 1 -82 , 1992 , Maruzen .” alcohol ( for example , methanol, ethanol, benzyl alcohol, and In addition , it possible to produce the compound repre - the like ) by use of a inert solvent such as dichloromethane, sented by formula ( IM - 1 ) by using the compound repre chloroform , 1 ,2 -dichloroethane , diethyl ether , tetrahydro sented by formula (SM - 1 ) and using a polar solvent such as 40 furan , 1 , 4 - dioxane, 1 , 2 -dimethoxyethane , toluene, benzene , N , N -dimethylformamide , dimethyl sulfoxide , and N -meth - N , N - dimethylformamide , and N -methylpyrrolidone or a ylpyrrolidone , followed by reaction at 0° C . to the reflux mixture solvent thereof, followed by reaction at 0° C . to the temperature of the solvent in the presence of an alkyl halide reflux temperature of the solvent in the presence of a base agent ( for example , methyl iodide , ethyl iodide, and the like ) such as triethylamine, N , N - diisopropylethylamine , pyridine , and in the presence of a base such as potassium carbonate , 45 and 4 - dimethylaminopyridine in accordance with a method sodium carbonate , potassium hydroxide , and sodium known in the literature , for example the method described in hydroxide in accordance with a method known in the “ Jikken Kagaku Koza , Fourth Edition , 22 , Organic Synthe literature , for example the method described in “ Synthetic sis IV , Acid , Amino Acid , and Peptide, pp . 144 - 146 , 1992 , Communications, 31 ( 14 ) , pp . 2177 -2183 , 2001. " Maruzen . ” In addition , it is possible to produce the compound 50 (Case where none of R24 and R25 is a hydrogen represented by formula (IM - 1 ) by using the compound atom ) It is possible to produce the compound represented by represented by formula (SM - 1 ) , followed by reaction at 0° formula ( IM - 2 ) by using the compound represented by C . to room temperature in a methylation agent such as formula ( IM - 1 ) obtained in [Production Method A ] < Step 1 > diazomethane and trimethylsilyl diazomethane , a inert sol- and using a non -reactive solvent such as diethyl ether, vent such as ether and methanol, or a mixture solvent thereof 55 1 , 4 - dioxane , tetrahydrofuran , 2 -methyltetrahydrofuran , 1 , 2 in accordance with a method known in the literature , for d imethoxyethane , benzene , toluene , and xylene or a mixture example the method described in “ Chemical & Pharmaceu solvent thereof, followed by reaction at - 78° C . to the reflux tical Bulletin , 29 (5 ), pp . 1475 - 1478 , 1981. " temperature of the solvent in the presence of a Grignard In addition , it is possible to produce the compound reagent ( for example , methylmagnesium chloride, methyl represented by formula (IM - 1 ) by using the compound 60 magnesium bromide , ethylmagnesium bromide , allylmag represented by formula (SM - 1 ) and an alcohol (for example , nesium bromide , and the like ) or an alkyl metal reagent ( for methanol, ethanol, benzyl alcohol, and the like ) and using a example , methyllithium , phenyllithium , and the like ) in inert solvent such as dichloromethane , chloroform , diethyl accordance with a method known in the literature, for ether, tetrahydrofuran , toluene , benzene, N , N - dimethylfor - example the method described in “ Jikken Kagaku Koza, mamide , and N -methylpyrrolidone or a mixture solvent 65 Fourth Edition , 25 , Organic Synthesis VII , Synthesis by thereof, followed by reaction at 0° C . to the reflux tempera - Organic Metal Reagent, pp . 13 - 19 , pp . 59 -72 , 1992 , Maru ture of the solvent in the presence of a condensation agent zen . ” US 10 , 399 , 945 B2 103 104 (Case where both of R2a and R25 are a hydrogen atom ) It reagent such as p - toluenesulfonic acid as an acid in accor is possible to produce the compound represented by formula dance with a method known in the literature , for example the ( IM - 2 ) by using the compound represented by formula method described in “ International Publication No. WO ( IM - 1 ) obtained in [ Production Method A ] < Step 1 > and 2014 /078454 . " using a inert solvent such as diethyl ether, tetrahydrofuran , 5 1 , 2 -dimethoxyethane , and 1 , 4 -dioxane or a mixture solvent < Step 7 > It is possible to produce the compound repre thereof, followed by reaction at 0° C . to the reflux tempera sented by formula ( IM - 7 ) by using the compound repre ture of the solvent in the presence of a reducing agent such sented by formula (IM -6 ) obtained in [Production Method as diisobutylaluminum hydride (DIBAH ) , lithium aluminum A ] < Step 6 > in a inert solvent such as dichloromethane , hydride (LAH ) , lithium borohydride , and lithium triethoxy - 10 chloroform , toluene , benzene , acetonitrile , acetone , and aluminum hydride in accordance with a method known in water or a mixture solvent thereof, followed by reaction at the literature , for example the method described in " Jikken 0° C . to the reflux temperature of the solvent in the presence Kagaku Koza , Fourth Edition , 26 , Organic Synthesis VIII , of a peracid or a peroxide such as hydrogen peroxide water Asymmetric Synthesis , Reduction , Saccharide, and Labeled (H2O2 ) , m -chloroperoxybenzoic acid (MCPBA ) , trifluorop Compound , pp . 234 -245 , 1992, Maruzen .” 15 eroxyacetic acid (CF , COOOH ) , Oxone ( registered trade < Step 3 > It is possible to produce the compound repre mark ) (DuPont ) , and tert - butyl hydroperoxide ( TBHP ) in sented by formula (IM - 3 ) by using the compound repre accordance with a method known in the literature , for sented by formula ( IM -2 ) obtained in [Production Method example the method described in " Jikken Kagaku Koza , A ] < Step 2 > and using a non - reactive solvent such as Fourth Edition , 20 , Organic Synthesis V , Oxidation Reac dichloromethane , chloroform , cyclohexane , benzene , tolu - 20 tion . pp . 276 - 280 , 1992 . Maruzen . ” ene, xylene , diethyl ether , 2 - propanol, and water or a mix ture solvent thereof, followed by reaction at 0° C . to the < Step 8 > It is possible to produce the compound repre reflux temperature of the solvent in the presence of an acidic sented by formula (AM - 2 ) by using the compound repre reagent such as trifluoromethanesulfonic acid , diphosphorus sented by formula (IM - 7 ) obtained in [ Production Method pentoxide. phosphorus pentachloride , sulfuric acid , phos - 25 A ] < Step 7 > and using aqueous ammonia solution , followed phoric acid , and bismuth ( III ) trifluoromethane sulfonate as by reaction at 0° C . to the reflux temperature of the solvent an acid in accordance with a method known in the literature , in accordance with a method known in the literature , for for example the method described in “ Tetrahedron Letters , example the method described in “ Journal of the Chemical 54 (32 ), p 4330 - 4332, 2013 .” Society, Perkin Transactions 1 : Organic and Bio -Organic < Step 4 > It is possible to produce the compound repre- 30 Chemistry , (1972 -1999 ) , (11 ) , p 2807 -2810 , 1983 .” The sented by formula ( IM -4 ) by using the compound repre obtained formula ( AM - 2 ) can be separated into a chiral sented by formula (IM - 3 ) obtained in [ Production Method compound by the optical resolution method described A ] < Step 3 > and using a non -reactive solvent such as above . dichloromethane , chloroform , carbon tetrachloride , ben zene , acetonitrile , tert- butyl alcohol, and water or a mixture 35 [Production Method B ] A method of synthesizing various solvent thereof, followed by reaction at 0° C . to the reflux types of amine derivatives represented by formula ( AM - 1 - a ) temperature of the solvent in the presence of an oxidizing to formula ( AM - 1 - h ), which are subformulas of the above agent such as Oxone ( registered trademark ) (DuPont ) , tert formula (AM - 1 ) : butyl hydroperoxide ( TBHP ) , potassium permanganate , manganese dioxide , and chromic acid in accordance with a 40 TABLE A method known in the literature , for example the method described in “ Chemistry Letters , 70 ( 10 ) , p 1042 - 1043 , Posi 2013 ." Position tion Position < Step 5 > It is possible to produce the compound repre - Formula Ring A 2 ( * ) 5 (* ) 6( * ) sented by formula ( IM - 5 ) by using the compound repre - 45 – sented by formula (IM - 4 ) obtained in [ Production Method ( AM - 1 -a ) 3 - Pyridinyl Group, Phenyl Group (# ) R40 H A ] < Step 4 > and using a inert solvent such as diethyl ether, 3 -Pyrazinyl Group tetrahydrofuran , 1 , 2 - dimethoxyethane , 1 , 4 -dioxane , metha (AM - 1 - b ) 3 -Pyridinyl Group , Phenyl Group( # ) R40 Br nol, ethanol, and 2 - propanol or a mixture solvent thereof , 3 - Pyrazinyl Group followed by reaction at 0° C . to the reflux temperature of the 50 ( AM - 1 -c ) 3 - Pyridinyl Group, Phenyl Group (# ) R40 CN solvent in the presence of a reducing agent such as sodium 3 - Pyrazinyl Group borohydride , lithium borohydride , diisobutylaluminum (AM - 1 - d ) 3 -Pyridinyl Group , Phenyl Group( # ) R40 CONH , hydride (DIBAH ), lithium aluminum hydride ( LAH ) , 3 - Pyrazinyl Group borane - tetrahydrofuran ( BHZ. THF ) , and borane - dimethyl (AM - 1 - e ) 3 -Pyridinyl Group , Phenyl Group (# ) R4 COOR4 sulfide (BHz . Me , S ) in accordance with a method known in 55 3 -Pyrazinyl Group the literature , for example the method described in “ Jikken Kagaku Koza , Fourth Edition , 26 , Organic Synthesis VIII , ( AM - 1 - f) 3 - Pyridinyl Group , Phenyl Group (# ) R1a CONR4R5 Asymmetric Synthesis , Reduction , Saccharide, and Labeled 3 -Pyrazinyl Group Compound , pp . 234 - 245 , 1992 , Maruzen .” (AM - 1 - g ) 3 -Pyridinyl Group , Phenyl Group # ) R4a COOH < Step 6 > It is possible to produce the compound repre - 60 3 - Pyrazinyl Group sented by formula ( IM - 6 ) by using the compound repre - (AM - 1 - h ) 3 - Pyridinyl Group , Phenyl Group( * ) R40 CH OH sented by formula ( IM - 5 ) obtained in [Production Method 3- Pyrazinyl Group A ] < Step 5 > and using a non - reactive solvent such as dichloromethane , 1 , 2 -dichloroethane , chloroform , benzene , ( * ) The substitution position of the ring A obeys the numbering of the following formula ( SM - 2 ). toluene , xylene , and 1 , 2 -dimethoxyethane or a mixture 65 (# The phenyl group may have 1 to 3 substituent groups arbitrarily selected from a halogen solvent thereof, followed by reaction at 0° C . to the reflux atom and a C1- 6 alkyl group . temperature of the solvent in the presence of an acidic 2 US 10 ,399 ,945 B2 105 106

[ B ] R4a R4a R4a position 5 position 6 ( RG - 1 ) NBS Zn (CN ) 2 position 2 NH , < Step 1 > - NH2 < Step 2> - NH2 < Step 3> X2 ( SM - 2 )

( AM - 1 - a ) ( AM - 1 - b ) R4a O Ria - A Raa NC R4C H2N N . Rad NH , < Step 4 > 2NH2 Y NH2

R46 HN - R40 R 40 (RG - 3 ) ( AM - 1 - c ) (AM - 1 - d ) HN - ( AM - 1 - f ) < Step 9 > < Step 5 (RG -3 ) < Step 6 > R4a R4a ???? . RAO

NH2 < Step 7 > NH

( AM - 1 - e ) ( AM - 1 - g ) < Step 10 > < Step 8 > R4a HOHOY

( AM - 1 - h )

< Step 1 > It is possible to produce the compound repre- N ,N - dimethylformamide, N , N -dimethylacetamide , N -meth sented by formula (AM - 1 - a ) by using the compound of ylpyrrolidone , 1 , 2 - dimethoxyethane, acetonitrile ( acetoni formula (SM - 2 ) [ the compound of formula (SM - 2 ) is a trile/ water ) , 1 , 4 -dioxane ( 1 , 4 - dioxane /water ) , and tetrahy commercially available compound or a compound which 60 drofuran (tetrahydrofuran /water ) or a mixture solvent can be produced by the production method known in the thereof, followed by reaction at 0° C . to the reflux tempera literature from a commercially available compound ) and the ture of the solvent in the presence of a palladium catalyst compound of formula (RG - 1 ) [ the compound of formula such as palladium ( II ) acetate (Pd ( OAC ) 2 ), tetrakis triphenyl (RG - 1 ) is a commercially available compound or a com phosphine palladium (Pd (PPhz ) 4 ), bis ( triphenylphosphine ) pound which can be produced by the production method 65 palladium ( II ) chloride ( Pd (PPhz ) 2C12) , tris ( dibenzylide known in the literature from a commercially available neacetone )dipalladium (Pd , (dba ) ), bis (dibenzylideneac compound ] and using a inert solvent such as toluene , xylene , etone )palladium (Pd ( dba ) 2 ) , and [ 1 , 1 '- bis ( diphenylphos US 10 , 399 , 945 B2 107 108 phino ) ferrocene ] dichloropalladium ( II) (PdCl? (dppf ) ) , a compound which can be produced by the production method phosphine -based reagent such as triphenylphosphine, tris known in the literature from a commercially available ( tert - butyl) phosphine , tris ( o - tolyl) phosphine, 2 - dicyclohex compound ), followed by reaction at a temperature of 0° C . ylphosphino - 2 ' ,6 ' -dimethoxybiphenyl , and 2 - dicyclohexyl to 150° C . in accordance with a method known in the phosphino - 2 ', 4 ', 6 ' -triisopropylbiphenyl , and an organic or 5 literature , for example the method described in “ Bioorganic inorganic base such as triethylamine, N , N - diisopropylethyl- & Medicinal Chemistry , 22 (9 ) , p 2783 - 2790 , 2014 . " amine , potassium phosphate , sodium carbonate , potassium < Step 7 > It is possible to produce the compound repre carbonate , and cesium carbonate in accordance with a sented by formula (AM - 1 - g ) by using the compound of method known in the literature , for example the methods formula (AM - 1 - e ) obtained in [ Production Method B ] < Step described in “ Jikken Kagaku Koza , Fifth Edition , 18 , Syn - 10 5 > and using a non -reactive solvent such as water, methanol , thesis of Organic Compound , VI, Organic Synthesis Using ethanol, 2 - propanol, N , N - dimethylformamide , N -methyl Metal- , pp . 327 - 352 , 2004 , Maruzen ” and “ Journal of pyrrolidone , 1 , 4 - dioxane, and tetrahydrofuran or a mixture Medicinal Chemistry , 48 ( 20 ), p 6326 -6339 , 2005 .” Alter solvent thereof, followed by reaction at 0° C . to the reflux natively , production is possible in a similar manner by use temperature of the solvent in the presence of a base such as of tetramethylammonium chloride , tetrabutylammonium 15 lithium hydroxide , sodium hydroxide, potassium hydroxide , chloride , or the like instead of the phosphine - based reagent. lithium carbonate , sodium carbonate , and potassium carbon < Step 2 > It is possible to produce the compound repre - ate in accordance with a method known in the literature, for sented by formula ( AM - 1 - b ) by using the compound of example the method described in “ Jikken Kagaku Koza , formula (AM - 1 - a ) obtained in [ Production Method B ] < Step Fourth Edition , 22 , Organic Synthesis IV , Acid , Amino Acid , 1 > and N -bromosuccinimide (NBS ) and using a inert solvent 20 and Peptide, pp . 1 - 43 , 1992 , Maruzen .” ( Case where R4 is a such as N -methylpyrrolidone , dimethylformamide , N , N - tert - butyl group ) It is possible to produce the compound dimethylformamide , N , N - dimethylacetamide , and acetoni- represented by formula (AM - 1 - g ) by using the compound of trile or a mixture solvent thereof, followed by reaction at 0° formula ( AM - 1 - e ) obtained in [Production Method B ] < Step C . to the reflux temperature of the solvent in accordance 5 > and using an acid such as hydrochloric acid , sulfuric acid , with a method known in the literature , for example the 25 acetic acid , and trifluoroacetic acid , followed by reaction at method described in “ International Publication No . Wo 0° C . to the reflux temperature of the solvent in accordance 2009 / 088103 . " with a method known in the literature, for example the < Step 3 > It is possible to produce the compound repre - deprotection method described in the book ofGreene et al . , sented by formula ( AM - 1 - c ) by using the compound of “ Protective Groups in Organic Synthesis , Fourth Edition , formula (AM - 1 - b ) obtained in [ Production Method B ] < Step 30 2007 , John Wiley & Sons .” 2 > and using a inert solvent such as toluene, xylene , < Step 8 > It is possible to produce the compound repre N , N -dimethylformamide , N , N -dimethylacetamide , and sented by formula ( AM - 1 - h ) by using the compound of N -methylpyrrolidone , followed by reaction at 0° C . to the formula ( AM - 1 - e ) obtained in [Production Method B ] < Step reflux temperature of the solvent in the presence of a 5 > and using a inert solvent such as diethyl ether , tetrahy cyanation agent ( for example , zinc cyanide ( Zn (CN ) , ) and 35 drofuran , 1 , 2 - dimethoxyethane , and 1 , 4 - dioxane or a mix the like ) and in the presence of a palladium catalyst such as ture solvent thereof, followed by reaction at 0° C . to the tetrakis triphenylphosphine palladium in accordance with a reflux temperature of the solvent in the presence of a method known in the literature , for example the method reducing agent such as diisobutylaluminum hydride described in “ International Publication No. WO 2014 ) (DIBAH ) , lithium aluminum hydride (LAH ) , lithium boro 139150 . " 40 hydride , and lithium triethoxyaluminum hydride in accor < Step 4 > It is possible to produce the compound repre - dance with a method known in the literature , for example the sented by formula (AM -1 - d ) by using the compound of method described in “ Jikken Kagaku Koza, Fourth Edition , formula (AM - 1 -c ) obtained in [Production Method B ] < Step 26 , Organic Synthesis VIII , Asymmetric Synthesis , Reduc 3 > and using hydrogen peroxide water and a inert solvent tion , Saccharide , and Labeled Compound , pp . 234 - 245 , such as dimethyl sulfoxide , followed by reaction at a tem - 45 1992 , Maruzen ." perature of 0° C . to 50° C . in the presence of a base such as < Step 9 > It is possible to produce the compound repre potassium carbonate in accordance with a method known in sented by formula ( AM - 1 - f ) by using the compound of the literature , for example the methods described in “ Yuki formula ( AM - 1 - g ) obtained in [Production Method B ] < Step Gosei Kagaku , 21 ( 11 ) , p 870 - 887 , 1963 ” and “ Synthesis , 7 > and the compound of formula ( RG - 3 ) in a inert solvent 12 , p 949 - 950 , 1989 .” 50 such as dichloromethane, chloroform , diethyl ether , tetrahy < Step 5 > It is possible to produce the compound repre - drofuran , toluene , benzene , N , N - dimethylformamide , sented by formula (AM - 1 - e ) by using the compound of N -methylpyrrolidone , methanol, ethanol , and 2 -propanol , formula (AM - 1 - c ) obtained in [Production Method B ] < Step followed by reaction at 0° C . to the reflux temperature of the 3 > , using an acid (hydrochloric acid , sulfuric acid , and the solvent in the presence of a condensation agent such as like ) or a base ( sodium hydroxide ), and using an alcohol- 55 1 ,3 -dicyclohexylcarbodiimide (DCC ), 1 -ethyl - 3 - ( 3 dimeth based solvent such as methanol and ethanol, followed by ylaminopropyl ) carbodiimide hydrochloride (WSC .HCl ) , reaction at 0° C . to the reflux temperature of the solvent in 1 -hydroxybenzotriazole (HOBT ), benzotriazole - 1 -yloxytris accordance with a method known in the literature , for (dimethylamino ) phosphonium hexafluorophosphate (BOP example themethod described in " Journal of Organic Chem - reagent) , bis ( 2 -oxo -3 - oxazolidinyl) phosphinic chloride istry , 55 ( 2 ) , p 738 - 741, 1990 , ” “ Journal of American 60 (BOP - C1) , 2 - chloro - 1 , 3 - dimethylimidazolinium hexafluoro Chemical Society , 134 (47 ), p 19366 - 19369 , 2012 ,” or phosphate (CIP ) , 4 -( 4 ,6 -dimethoxy - 1 ,3 , 5 -triazine - 2 -yl ) - 4 “ Tetrahedron Letters, 37 (21 ) , p 3617 - 3618 , 1996 .” methylmorpholinium chloride (DMTMM ) , polyphosphoric < Step 6 > It is possible to produce the compound repre - acid (PPA ), 2 -( 1H - 7- azabenzotriazole - 1 - yl) - 1 , 1, 3 ,3 - tetram sented by formula (AM - 1 - f ) by using the compound of ethyluronium hexafluorophosphate methane aluminum formula ( AM - 1 - e ) obtained in [ Production Method B ] and the compound of formula (RG - 3 ) [ the compound of nooxy ) dimethylamino -morpholino -carbenium hexafluoro formula (RG -3 ) is a commercially available compound or a phosphate (COMU ) and in the presence or absence of a base US 10 , 399 , 945 B2 109 110 such as triethylamine, N , N -diisopropylethylamine , and pyri It is possible to produce the compound of formula (AM dine in accordance with a method known in the literature , for 1 - i ) by using the compound of formula (AM - 1 - b ) obtained example the method described in “ Jikken Kagaku Koza , in [ Production Method B ] < Step 2 > and the compound of Fourth Edition , 22 , Organic Synthesis IV , Acid , Amino Acid , and Peptide, pp . 191 -309 , 1992 , Maruzen . " formula (RG - 2 ) [ the compound of formula (RG - 2 ) is a In addition , it is possible to produce the compound commercially available compound or a compound which represented by formula ( AM - 1 - f ) in the same manner by : can be produced by the production method known in the converting the compound represented by formula (AM - 1 - g ) literature from a commercially available compound ], fol to an acid halide by use of a halogenation agent such as lowed by reaction in accordance with [Production Method thionyl chloride , oxalyl chloride, phosphoryl chloride , sul- B ] < Step 1 > . Note that the substituent R on the ring B can furyl chloride, phosphorus trichloride , phosphorus pen appropriately be subjected to functional group conversion as tachloride, and phosphorus tribromide, a non -reactive sol necessary . vent such as dioxane , tetrahydrofuran , 1, 2 - dimethoxyethane , benzene , toluene , dichloromethane , 1 , 2 - dichloroethane , and [Production Method D ] A method of synthesizing the chloroform , or a mixture solvent thereof, followed by reac amine derivative represented by formula ( AM - 1- j ), which is tion at 0° C . to the reflux temperature of the solvent in the 15 a subformula of the above formula (AM - 1 ) ( case where R™ presence or absence of a base such as triethylamine , N , N - is already introduced ; R * " zhalogen atom ; and after conver diisopropylethylamine , and N , N -dimethylaminopyridine in sion to formula (AM - 1 - j ) , R46 can appropriately be sub accordance with a method known in the literature , for jected to functional group conversion ) example the method described in “ Journal of the American Chemical Society , 109 (24 ) , p 7488 -7494 , 1987 " ; and using 20 the compound represented by formula (RG - 3 ) in a inert B ] solvent such as dichloromethane, chloroform , 1 , 2 -dichlo R4a roethane , diethyl ether, tetrahydrofuran , 1 , 2 - dimethoxy Position 5 ethane , 1 , 4 - dioxane, toluene , benzene, N , N - dimethylforma R 45 mide, and N -methylpyrrolidone , followed by reaction at 0° 25 Position " 6 C . to the reflux temperature of the solvent in the presence of (RG - 1 ) a base such as triethylamine , N ,N -diisopropylethylamine , N pyridine , and 4 -dimethylaminopyridine in accordance with , Position 2 12 for example , the method described in “ Jikken Kagaku Koza , X2 Fourth Edition , 22 , Organic Synthesis IV , Acid , Amino Acid , and Peptide , pp . 144 - 146 , 1992 , Maruzen .” 30 (SM - 3 ) < Step 10 > It is possible to produce the compound repre sented by formula (AM - 1 - h ) by using the compound of formula (AM - 1 - g ) obtained in [Production Method B ] < Step 7 > , followed by reaction in accordance with [Production R4a Method B ] < Step 8 > . 35 [Production Method C ] A method of synthesizing the RAB amine derivative represented by formula ( AM - 1 - i ) , which is a subformula of the above formula ( AM - 1 ) (case where R45 is a partial structural formula (US ) ) : NH2

R4a Î PositionPosition ( RS) , Br B2 [ B ] Position 6 (RG - 2 ) ( AM - 1 - 1) Position 2 z NH ,

It is possible to produce the compound of formula (AM (AM - 1 - b ) 1 - j ) by using the compound of formula ( SM - 3 ) [ the com R 4a pound of formula ( SM - 3 ) is a commercially available com ( R ) - B 55 pound or a compound which can be produced by the X ! production method known in the literature from a commer cially available compound ] and the compound of formula (RG - 1 ) , followed by reaction in accordance with [ Produc NH tion Method B ] < Step 1 > . [Production Method E ] A method of synthesizing various types of amine derivatives represented by formula ( AM - 1 A ) to formula ( AM - 1 - H ) , which are subformulas of the above formula ( AM - 1 ) (particularly in the case where R4h is (AM - 1 - 1 ) 65 a bromine atom , a cyano group , a carboxamide group , a COOR4, a — CONR + R ” , a carboxy group , or a hydroxym ethyl group ): US 10 , 399 , 945 B2 111 112 TABLE B

Formula Ring A Position 2 (* * ) Position 5 ( * * ) Position 6 ( * * ) ( AM - 1- A ) 3- Pyridinyl Group , 4- Tetrahydro -2H - Pyranyl Group ($ ) R4a 3 -Pyrazinyl Group ( AM - 1- B ) 3- Pyridinyl Group , 4- Tetrahydro -2H -Pyranyl Group (s ) R4a Br 3 -Pyrazinyl Group (AM - 1 - C ) 3 - PyridinylGroup , 4 - Tetrahydro - 2H - Pyranyl Group( $) R4a - CN 3 - Pyrazinyl Group ( AM - 1- D ) 3- Pyridinyl Group, 4 -Tetrahydro - 2H -Pyranyl Group ( $ ) R4a CONH2 3 - Pyrazinyl Group (AM - 1 - E ) 3- Pyridinyl Group , 4 - Tetrahydro -2H -Pyranyl Group ($ ) R4a - COOR 3 -Pyrazinyl Group (AM -1 - F ) 3- Pyridinyl Group, 4 - Tetrahydro -2H -Pyranyl Group( s ) R4a CONR4R5 3 - Pyrazinyl Group (AM - 1 - G ) 3- Pyridinyl Group , 4 - Tetrahydro -2H -Pyranyl Group ( $) R4a – COOH 3 -Pyrazinyl Group ( AM - 1- H ) 3- Pyridinyl Group , 4- Tetrahydro -2H -Pyranyl Group ($ ) R4a CH OH 3 - Pyrazinyl Group ( * * ) The substitution position of the ring A obeys the numbering of the following formula ( SM - 2 ) . The 4 - tetrahydro - 2H - pyranyl group may have 1 to 3 substituent groups arbitrarily selected from a halogen atom and a C16 alkyl group

V [ B ] R4a R4a R4a position 5 O H . position 6 (RG - 4 ) NH2 NBS Zn (CN )2 N . NH position 2 NH2 < Step 1 > < Step 2 > < Step 3 > < Step 4 > X2 (SM - 2 ) ( IM - 8 ) ( AM - 1 - A ( AM - 1 - B )

R4a R4a o Rua

NO R 40 H2N Z R4d N Z NH < Step 5 > NH2 NH2 R4c HN - R40 R 40 (RG -3 ) ( AM - 1 - C ) ( AM - 1 - D ) HNR 4d (AM - 1 - F ) < Step 10 > (RG - 3) < Step 6 > < Step 7 > US 10 ,399 , 945 B2 113 114 - continued R4a R4a HOOC R40

NH2 < Step 8 > NH2

O (AM - 1 - E ) ( AM - 1 - G < Step 11 > < Step > R4a HO

NH2

( AM - 1 - H )

< Step 1 > It is possible to produce the compound of 30 < Step 6 > It is possible to produce the compound of formula ( IM - 8 ) by using the compounds of formula ( SM - 2 ) formula (AM - 1 - E ) by using the compound of formula and formula (RG - 4 ) [the compound of formula (RG - 4 ) is a commercially available compound or a compound which (AM - 1 - C ) obtained in [Production Method E ] < Step 4 > , can be produced by the production method known in the followed by reaction in accordance with [Production literature from a commercially available compound ) , fol- Method B ] < Step 5 > . lowed by reaction in accordance with [ Production Method 33 B ] < Step 1 > . < Step 7 > It is possible to produce the compound of < Step 2> It is possible to produce the compound repre formula (AM - 1 - F ) by using the compound of formula (AM sented by formula ( AM - 1 - A ) by using the compound of 1 - E ) obtained in [Production Method E ] < Step 6 ) , followed formula ( IM -8 ) obtained in [Production Method E ] < Step 1 > by reaction in accordance with [Production Method B ] and using a inert solvent such as methanol, ethanol, 2 - pro - 40 < Step 6 ) . panol, diethyl ether, tetrahydrofuran , 1 , 2 - dimethoxyethane , It is possible to produce the compound of 1 , 4 -dioxane , ethyl acetate , and methyl acetate or a mixture formula (AM - 1 - G ) by using the compound of formula solvent thereof , followed by reaction at 0° C . to the reflux temperature of the solvent under a hydrogen gas atmosphere ( AM - 1- E ) obtained in [Production Method E ] < Step 6 ) , in the presence of a catalyst such as palladium - carbon 45 followed by reaction in accordance with [ Production ( PdC ) , Raney nickel (Raney - Ni) , platinum oxide (Pto , ) , Method B ] . and dichlorotri triphenylphosphine ruthenium in accordance < Step 9 > It is possible to produce the compound of with a method known in the literature , for example the formula (AM - 1 -H ) by using the compound of formula method described in “ Jikken Kagaku Koza , Fourth Edition , ( AM -1 - E ) obtained in [ Production Method E ] < Step 6 > , 26 , Organic Synthesis VIII , Asymmetric Synthesis , Reduc - 50 followed by reaction in accordance with [ Production tion , Saccharide, and Labeled Compound , pp . 159- 266 , Me 1992 , Maruzen . " < Step 3 > It is possible to produce the compound of < Step 10 > It is possible to produce the compound of formula (AM - 1 - B ) by using the compound of formula formula ( AM - 1 - F ) by using the compound of formula (AM (AM - 1 - A ) obtained in [Production Method E ] < Step 2 > and 55 1 - G ) obtained in [ Production Method E ] < Step 8 > , followed N -bromosuccinimide (NBS ), followed by reaction in accor- by reaction in accordance with [Production Method B ] dance with [Production Method B ] < Step 2 > . < Step 9 > It is possible to produce the compound of formula (AM - 1 - C ) by using the compound of formula < Step 11 > It is possible to produce the compound of ( AM - 1- B ) obtained in [Production Method E ] < Step 3 > , 60 formula ( AM - 1 - H ) by using the compound of formula followed by reaction in accordance with [Production ( AM - 1 -G ) obtained in [Production Method E ] < Step 8 > , Method B ] < Step 3 > . followed by reaction in accordance with [Production < Step 5 > It is possible to produce the compound of Method B ] < Step 10 % . formula ( AM - 1 - D ) by using the compound of formula [ Production Method F ] A method of synthesizing the ( AM - 1 - C ) obtained in [Production Method E ] < Step 4 > , 65 amine derivative represented by formula (AM - 1 - 1 ) , which is followed by reaction in accordance with [Production a subformula of the above formula ( AM - 1 ) (case where R45 Method B ] < Step 4 > . is a partial structural formula (US ) ) : US 10 , 399 ,945 B2 115 116 [B ] Rta Position Br (R )a B L T IBI R 46 Position 5 Position 6 (RG -2 ) Position 6 T (RG -4 ) Position 2 NH Position 2 NH2 < Step 1 > > XP 10 (SM - 3 )

( AM - 1 - B ) R4a R46 R46

20 R4a NH < Step 2 > > NH2 (R ) - B

NH, 25 ( IM - 9 ) ( AM - 1 - 1 ) < Step 1 > It is possible to produce the compound of s formula ( IM - 9 ) by using the compound of formula (SM - 3 ) and the compound of formula (RG -4 ), followed by reaction ( AM - 1 - 1) in accordance with [ Production Method B ] < Step 1 > . < Step 2 > It is possible to produce the compound of formula ( AM - 1 - J ) by using the compound of formula ( IM - 9 ) It is possible to produce the compound of formula (AM 35 obtained in [ Production Method G ] < Step 1 > , followed by 1 -I ) by using the compound of formula (AM - 1- B ) obtained reaction in accordance with [ Production Method E ] < Step in [Production Method E ] < Step 3 > and the compound of 2 > formula (RG - 2 ), followed by reaction in accordance with [Production Method H ] A method of synthesizing the [Production Method C ] .Note that the substituent Rs on the compounds represented by formula ( 1 - b - la ) , formula ( 1 - b ring B can appropriately be subjected to functional group 40 2a ), formula (? - b -3a ), formula (I -b -1A ), formula (I - b -2A ), conversion as necessary . and formula ( 1- b - 3A ) , which are subformulas of formula (I ) : it is possible to produce the compound of formula ( 1 - b - 2a ) , [Production Method G ] A method of synthesizing the formula (1 - b - 3a ) , formula ( I - b -2A ) , or formula ( 1 - b -3A ) by amine derivative represented by formula (AM - 1 - J) , which is using the above formula (AM - 1 - b ) or formula (AM - 1 - B ) a subformula of the above formula ( AM - 1 ) (case where R45 us and subjecting the compound of formula ( 1- b - 1a ) or formula is already introduced ; R46 = halogen atom ; and after conver ( 1 - b - 1A ) , obtained by urea formation reaction with formula sion to formula (AM - 1 - J ) , R4h can appropriately be sub ( AM - 2 ) , to the methods described in [Production Method B ] jected to functional group conversion ) to [ Production Method G ) .

R4a Br

R20 Urea IV Formation NH2 - R26 Reaction H2N OH ( AM - 1 - b ) (AM - 2 ) US 10 , 399, 945 B2 117 118 - continued

yl O 25

Functional R4a Group Conversion Br OH R20 NH OH ( 1 -b - 2a ) (R ) tBIBI ( I - b - la ) ( RG - 2 )

R4a (R ?) + B X O

IZ Zir OH

( I - b -3a ) R4a

Br

Urea " Formation NH2 - R26 Reaction + H?N

OH ( AM - 2 ) ( AM - 1 - B )

R46 O Functional ?4a Group N R2Q Conversion Br OH R 26 N NH go OH ( I - b - 2A )

(R ), B2 [B ] ( I - b - 1A ) (RG - 2 ) US 10 ,399 ,945 B2 119 120 - continued 120

R4a (R ), fB o

OH

( I - b - 3A )

[Concomitant Agent Containing Compound of Present (A5 ) COX - 2 selective inhibitors [ specifically , celecoxib , Invention ] rofecoxib , parecoxib , valdecoxib , deracoxib , etoricoxib , The compound and the pharmaceutical composition of the 20 lumiracoxib , and the like ) ; present invention can be used in combination with other ( A6 ) peripheral neuropathic pain / fibromyalgia drugs [ spe pharmaceutical preparations or drugs by a common method cifically , pregabalin and the like ) ; carried out in the medical field . The drug which can be (A7 ) descending pain modulatory drugs [ specifically , dulox blended or used in combination with the compound of the etine , neutropin , and the like ); in addition , the following present invention includes , for example , ( A ) a pain remedy - drugs diverted to neuropathic pain for prescription drug , (B ) a drug for treating a disease with which pain is (A8 ) antiepileptics [specifically , gabapentin , phenytoin , car likely to occur, and the like . bamazepine , sodium valproate, clonazepam , zonisamide , Thus, another embodiment of the present invention pro - and the like ) ; vides a pharmaceutical composition which contains one or 20 (A9 ) antidepressants [ specifically , selective serotonin more of the compound represented by the above formula (I ), reuptake inhibitors (SSRI ) such as escitalopram , citalopram , the pharmaceutically acceptable salt thereof, and the solvate desmethylcitalopram , escitalopram , paroxetine , sertraline , thereof and one or more types of other pharmaceutical demethylsertraline, fluvoxamine, fluoxetine , and norfluox preparations and drugs such as ( A ) a pain remedy drug and etine, selective serotonin /noradrenaline reuptake inhibitors ( B ) a preventive and /or therapeutic drug for a disease with 35 (SNRI ) such as milnacipran , duloxetine , venlafaxine , and which pain is likely to occur. nefazodone , selective noradrenaline /dopamine reuptake Still another embodiment of the present invention pro - inhibitors (NDRI ) such as bubropin , noradrenergic and vides a pharmaceutical composition which contains at least specific serotonergic antidepressants ( NaSSA ) such as mir one of the compound represented by the above formula (1 ), tazapine , triazolopyridine antidepressants (SARI ) such as the pharmaceutically acceptable salt thereof, and the solvate 40 trazodone, selective noradrenaline reuptake inhibitors such thereof as an active ingredient, the pharmaceutical compo - as ( S , S )- reboxetine , dual serotonin - noradrenaline reuptake sition used in combination with other pharmaceutical prepa - inhibitors such as venlafaxine, O -desmethylvenlafaxine , rations and drugs such as ( A ) a pain remedy drug and ( B ) a clomipramine , desmethylclomipramine, duloxetine , mil preventive and / or therapeutic drug for a disease with which nacipran , and imipramine , norepinephrine reuptake inhibi pain is likely to occur . tors such as maprotiline, lofepramine, mirtazepine, oxapro For example , the drug of ( A ) includes the following . tiline , fezolamine , tomoxetine , mianserin , buproprion , (A1 ) opioid agonists [ specifically , morphine, oxycodone , hydroxybuproprion , nomifensine, and viloxazine , tetracy fentanyl, remifentanil, codeine, pethidine , meperidine , clic antidepressants such as setiptiline , mianserin , and buprenorphine, pentazocine , tramadol, heroin , hydromor- s maprotiline, tricyclic antidepressants such as amitriptyline , phone, oxymorphone , levorphanol, levallorphan , metha - trimipramine , imipramine, nortriptyline , desipramine , clo done , cocaine , dihydrocodeine, hydrocodone, propoxy - mipramine , lofepramine, amoxapine , and dosulepin , and the phene , nalmefene, nalorphine, naloxone , naltrexone , like] ; butorphanol, nalbuphine , and the like ); (A10 ) antiarrhythmics [ specifically , lidocaine , mexiletine , ( A2 ) pyrin -based antipyretics and analgesics [specifically , 55 flecainide , and the like ); sulpyrine and the like ) ; (A11 ) NMDA receptor antagonists [ specifically , ketamine ( A3 ) non -pyrin -based antipyretics and analgesics [ specifi- hydrochloride(ATI ) , dextromethorphan , dextrorphan , memantine , cally , acetaminophen (paracetamol ) and the like ) ; pyrroloquinoline quinine, cis - 4 - (phosphonomethyl ) - 2 - pip ( A4 ) nonsteroidal anti - inflammatory drugs (NSAIDs ) [ spe - eridinecarboxylic acid , budipine , MorphiDex ( registered cifically , aspirin , mefenamic acid , diclofenac, sulindac , fel- 60 trademark ) , complex preparation of morphine and dex binac, etodolac , indomethacin , ibuprofen , ketoprofen , flur- tromethorphan , topiramate , neramexane , perzinfotel , ifen biprofen , naproxen , pranoprofen , loxoprofen , zaltoprofen , prodil, and the like ); piroxicam , lornoxicam , meloxicam , epirizole , tiaramide , (A12 ) bisphosphonates [specifically , zoledronic acid hydrate diflusinal , fenbufen , fenoprofen , flufenisal , flurbiprofen , and the like ) ; ketorolac, meclofenamic acid , nabumetone, nimesulide, 65 (A13 ) vanilloid receptor agonists [specifically , resinifera nitroflurbiprofen , olsalazine , oxaprozin , phenylbutazone , toxin or antagonists ( for example , capsazepine and the sulfasalazine, tolmetin , zomepirac , and the like) ; like ) ]; US 10 , 399 , 945 B2 121 122 ( A14 ) sodium channel modulators [ specifically , Nav 1 . 7 Y (NPY ) receptor antagonists [ specifically , S - 2367 and the channel modulator, Nav 1 . 3 modulator, Nav 1 . 8 modulator, like ] , (iv ) feeding inhibitors [monoamine reuptake inhibitors and the likel; [specifically , sibutramine ,mazindol , and the like ]] , (v ) lipase (A15 ) fatty acid amide hydrolase (FAAH ) inhibitory active inhibitors [ specifically, orlistat, cetilistat, and the like ) , ( vi) compounds ; 5 peptide YY (PYY ) receptor antagonists, and the like ); (A16 ) barbiturate sedatives [specifically , amobarbital , apro (B3 ) antihyperlipidemic agents such as cholesterol lowering barbital, butabarbital, butabital, mephobarbital , metharbital, drugs ( i ) w3 fatty acids [ specifically , ethyl icosapentate methohexital, pentobarbital, phenobartital, secobarbital, ( EPA - E formulation , for example, product name: Epadel talbutal, theamylal, thiopental , and the like) ; ( registered trademark ) and the like ) , docosahexaenoic acid (A17 ) benzodiazepines having a sedative action [specifi - 10 (DHA ) , mixed preparations of ethyl icosapentate and ethyl cally , chlordiazepoxide, clorazepate , diazepam , flurazepam , docosahexaenoate ( for example , product name: LovazaTM , lorazepam , oxazepam , temazepam , triazolam , and the like) ; Omacor ( registered trademark ), and the like ), and the like ) , (A18 ) H1 antagonists [ specifically , diphenhydramine , pyri- ( ii ) HMG - CoA reductase inhibitors [ specifically , atorvasta lamine , promethazine , chlorpheniramine, chlorcyclizine , tin , simvastatin , pitavastatin , itavastatin , fluvastatin , lovas and the like ) ; 15 tatin , pravastatin , rivastatin , rosuvastatin , and the like ] ( iii ) ( A19 ) 5 -HT receptor agonists or antagonists [ specifically , HMG -CoA synthase inhibitors , ( iv ) cholesterol absorption eletriptan , sumatriptan , naratriptan , and the like ) ; inhibitors [specifically , ezetimibe ] , ( v ) acyl- CoA / cholesterol ( A20 ) microsomal prostaglandin E synthase type 1 acyltransferase (ACAT ) inhibitors , (vi ) CETP inhibitors , (mPGES - 1 ) inhibitors ; ( vii ) squalene synthase inhibitors, ( viii ) antioxidants [ spe ( A21 ) leukotriene B4 antagonists [ specifically , CP - 105696 , 20 cifically , probucol and the like ], ( ix ) PPARa agonists [ spe ONO -4057 , DPC - 11870 , and the like ) ; cifically , clofibrate , etofibrate , fenofibrate , bezafibrate, cip ( A22 ) a2- 8 ligands [specifically , methyl- octanoic acid , (3S , rofibrate , gemfibrozil , KRP - 101, and the like ) , ( x ) PPARS 5R ) - 3 - amino - 5 -methyl - nonanoic acid , (3S ,5R )- 3 - amino - 5 - agonists , (xi ) LXR agonists , ( xii ) FXR agonists [ specifically , methyl - octanoic acid , ( 3R , 4R ,5R ) - 3 - amino - 4 , 5 - dimethyl INT- 747 and the like ], (xiii ) MTTP inhibitors, (xiv ) heptanoic acid , ( 3R , 4R ,5R ) - 3 - amino - 4 , 5 - dimethyl- octanoic 25 Squalene epoxidase inhibitor, and the like ) ; acid , and the like ) ; (B4 ) antihypertensive agents ( ( i ) diuretics [ specifically, ( A23 ) metabotropic glutamate subtype 1 receptor (mGluR1 ) trichlormethiazide , hydrochlorothiazide , mefruside , indap antagonists ; and amide, meticrane, chlorthalidone , tripamide , furosemide , ( A24 ) prostaglandin E2 subtype 4 ( EP 4 ) antagonists . torasemide , bumetanide , ethacrynic acid , spironolactone , In addition , for example , the drug of ( B ) includes the 30 triamterene , eplerenone, and the like ] , ( ii ) calcium receptor following drugs having activities against the TrkA pathway antagonists [ specifically , amlodipine , felodipine, nicar other than the compound of the present invention of formula dipine, nifedipine , nimodipine , nitrendipine, nilvadipine, ( I ) , the drug including aranidipine , azelnidipine, manidipine , barnidipine, efo ( B1 ) diabetes treatment drugs ( i) PPARy agonists (agonists nidipine, cilnidipine , benidipine , diltiazem , and the like) , and inhibitors ) [specifically , pioglitazone, rosiglitazone , tro - 35 ( iii ) angiotensin converting enzyme inhibitors (ACEI ) [ spe glitazone, ciglitazone , darglitazone , englitazone , netoglita - cifically , captopril, lisinopril, enalapril , delapril, perindopril, zone , and the like ), ( ii ) insulin secretagogues [ (a ) sulfony benazepril, trandolapril , quinapril, alacepril, imidapril , lurea agents (specifically , tolbutamide , acetohexamide , temocapril, cilazapril , and the like ) , ( iv ) angiotensin II chlorpropamide , glibenclamide , gliclazide, glipizide , receptor blockers ( ARB ) [specifically , losartan , olmesartan , glimepiride , glypentide , gliquidone, glysolamide , tolaz - 40 telmisartan , valsartan , candesartan cilexetil , irbesartan , and amide , and the like ), ( b ) non -sulfonylurea agents and the the like ) , ( v ) direct renin inhibitors [ specifically , aliskiren like ], ( iii ) rapid -acting insulin secretagogues (specifically , and the like ), ( vi ) a -receptor blockers [specifically , tolazo nateglinide, mitiglinide, repaglinide, and the like ), (iv ) line , phentolamine , doxazosin , prazosin , bunazosin , tera a - glucosidase inhibitors [specifically , acarbose, voglibose , zosin , urapidil , and the like ], ( vii ) B - receptor blockers [ spe miglitol, camiglibose , adiposine, emiglitate , pradimicin - Q , 45 cifically , bopindolol, pindolol, timolol, dichloroisoprenaline , salbostatin , and the like ], ( v ) insulin sensitizers [specifically , alprenolol, carteolol, indenolol, bunitrolol, penbutolol, pro ( a ) PPARy agonists , ( b ) PTP - 1B inhibitors , ( c ) DPP - 4 inhibi - pranolol, nadolol, nipradilol, tilisolol, acebutolol, celiprolol, tors [specifically , sitagliptin , vildagliptin , alogliptin , saxa metoprolol, atenolol, bisoprolol , betaxolol, practolol, bev gliptin , NVP - DPP -728 , and the like ) , ( d ) GLP - 1 and GLP - 1 antolol, butoxamine , carvedilol, amosulalol, arotinolol , agonists [ specifically , exenatide , liraglutide, and the like ], 50 labetalol, and the like ) , ( viii ) aiß blockers [ specifically , ( e ) 11B -HSD inhibitors and the like , ( f ) GPR40 agonists , ( g ) carvedilol, labetalol, arotinolol, bevantolol, and the like ) , GPR119 agonists , and (h ) GPR120 agonists ] , ( vi) hepatic (ix ) A2 receptor stimulants [ specifically, clonidine , methyl gluconeogenesis inhibitors [specifically , glucagon antago - dopa , guanfacine, and the like] ) ; nists and the like ], ( vii ) biguanide agents [ specifically , (B5 ) disease modifying anti- rheumatic drugs (DMARDs ) metformin , buformin , phenformin , and the like ], ( viii) insu - 55 [ specifically , adalimumab , abatacept, infliximab , etanercept, lin or insulin derivatives ( specifically , insulin zinc suspen - tocilizumab , methotrexate , salazosulfapyridine, tacrolimus , sion , insulin lispro , insulin aspart, regular insulin , NPH bucillamine , and the like ) ; insulin , insulin glargine, insulin detemir, mixed type insulin , (B6 ) anti -cytokine drugs [ specifically , ustekinumab , secuki and the like ), ( ix ) a2- antagonists [ specifically , midaglizole , numab , ixekizumab , brodalumab , TNF inhibitors, MAP isaglidol, deriglidole , idazoxan , efaroxane , and the like ]) , 60 kinase inhibitors , and the like ), and ( x ) SGLT2 inhibitors [ specifically, ipragliflozin , dapa (B7 ) sexual hormones or derivatives thereof [ specifically , gliflozin , luseogliflozin , tofogliflozin , canagliflozin , empa progesterone , estradiol, estradiol benzoate , and the like ) ; gliflozin , and the like ) ; (B8 ) parathyroid hormone (PTH ) ; (B2 ) anti - obesity drugs ( i ) adrenaline B3 receptor agonists (B9 ) GABA , receptor agonists [ specifically , baclofen and [specifically , KRP -204 , TRK - 380 , TAC - 301, and the like] , 65 the like ) ; ( ii) CB - 1 receptor antagonists [specifically , rimonabant, (B10 ) steroid drugs [specifically , dexamethasone , hexestrol, SR - 147778 , BAY- 65 - 2520 , and the like) , (iii ) neuropeptide cortisone acetate , fluticasone, and the like ); US 10 ,399 ,945 B2 123 124 (B11 ) A -adrenergic agonists [ specifically , tamsulosin , clo - (B34 ) apoptosis regulators and signal transduction pathway nidine , guanfacine , dexmetatomidine, modafinil, and the inhibitors [specifically , everolimus, perifosine , rapamycin , like ] ; sorafenib , temsirolimus , trametinib , vemurafenib , obataclax , ( B12 ) a2 - adrenergic receptor agonists [ specifically , tizani and the like ) ; dine , clonidine, and the like ] ; 5 (B35 ) cytotoxic chemotherapeutic drugs [ specifically , arse ( B13) sedatives [specifically , dichloralphenazone , glute nic trioxide , bleomycin , cabazitaxel, capecitabine, carbopla thimide, meprobamate , methaqualone, and the like ) ; tin , cisplatin , cyclophosphamide, cytarabine , dacarbazine , (B14 ) skeletal muscle relaxants [specifically , baclofen , cari daunorubicin , docetaxel , doxorubicin , etoposide, fluoroura soprodol, chlorzoxazone , cyclobenzaprine , methocarbamol, cil, gemcitabine, irinotecan , lomustine , methotrexate , mito orphrenadine , and the like ) ; mycin C , oxaliplatin , paclitaxel, pemetrexed , temozolomide , ( B15 ) anticonvulsant drugs [ specifically , carbamazepine , vincristine , and the like ); lamotrigine , topiramate, valproate , and the like ); (B36 ) angiogenesis targeted therapeutic drugs [ specifically , (B16 ) tachykinin (NK ) antagonists (NK 3 , NK - 2 , or NK - 1 aflibercept, bevacizumab , and the like ]; antagonists ) [ specifically , TAK -635 , MK - 869 , aprepitant, 15 (B37 ) immune targeted drugs [ specifically , aldes leukin , ipi lanepitant, dapitant, and the like ]; limumab , interferon alfa - 2b , lambrolizumab , nivolumab , (B17 ) muscarinic antagonists [ specifically , oxybutynin , tolt - prednisone , sipuleucel - T , and the like ) ; erodine, propiverine, trospium chloride, darifenacin , solif (B38 ) NGF targeted biopharmaceuticals [ specifically , NGF enacin , temiverine , ipratropium , and the like ) ; antibodies, tanezumab , and the like ) ; and (B18 ) coal tar analgesics [ specifically , paracetamol and the 20 (B39 ) pan - Trk inhibitors ( for example , 1 - ( (3S , 4R ) -4 - ( 3 like] ; fluorophenyl) - 1 - ( 2 -methoxy ethyl) pyrrolidine - 3 -yl ) - 3 - ( 4 ( B19 ) neuroleptics [ specifically , droperidol , chlorpromaz methyl - 3 - ( 2 -methylpyrimidin - 5 - yl) - 1 - phenyl- 1H - pyrazol ine , haloperidol, perphenazine , thioridazine , mesoridazine , 5 - yl) urea , ARRY- 954 , and the like ) . trifluoperazine , fluphenazine , clozapine , olanzapine, risperi - Use in combination with existing drugs against the dis done , ziprasidone, quetiapine , sertindole , aripiprazole , 25 eases described abovemakes it possible to lower the dosage sonepiprazole , blonanserin , iloperidone, perospirone, raclo of the existing drugs and to reduce side effects of the existing pride , zotepine , bifeprunox , asenapine , lurasidone, amisul drugs. It goes without saying that the combined use method pride , balaperidone , parin , dre , eplivanserin , osanetant, using the drugs is not limited to the diseases described rimonabant, meclinertant , Miraxion ( registered trademark ), above, and the drugs used in combination are not limited to sarizotan , and the like ) ; the compounds exemplified above . (B20 ) T2A receptor antagonists ; In the case of using the compound of the present invention (B21 ) 5 -HT3 antagonists [specifically , ondansetron and the and a drug used in combination , they may be separate like ] ; preparations ( or a kit containing them ) or a combined ( B22 ) cholinergic (nicotinic ) analgesics [specifically , 36 preparation . Also , in separate preparations, it is possible to ispronicline ( TC - 1734 ) , RJR -2403 , ABT- 594 , nicotine , and take both at the same time or to administer asynchronously . the like) ; The compound of the present invention can be adminis ( B23 ) PDEV inhibitors ; tered singly or in combination with a pharmaceutically (B24 ) nitric oxide synthase ( ?NOS ) inhibitors [ specifically , acceptable carrier , either in single or multiple doses . The guanidinoethyl disulfide and the like) ; 40 suitable pharmaceutical carrier includes inert solid diluents, (B25 ) acetylcholinesterase inhibitors [ specifically, donepezil fillers, sterile aqueous solutions, and various organic sol and the like ) ; vents . The pharmaceutical composition formed thereby can (B26 ) 5 - lipoxygenase inhibitors [ specifically , zileuton , then be readily administered in a variety of dosage forms ZD - 2138 , CV -6504 , and the like ) ; such as tablets , powders, lozenges, liquid preparations , ( B27 ) anti - TNF therapy [ specifically , monoclonal antibodies 45 syrups, and injectable solutions . These pharmaceutical com such as infliximab (Remicade ) , adalimumab (Humira ) , cer - positions may optionally contain additional ingredients such tolizumab pegol (Cimzia ), golimumab (Simponi ) and blood as flavoring agents , binders , and excipients . Accordingly , the receptor fusion proteins such as etanercept (Enbrel ) ] ; compound of the present invention can be formulated in a (B28 ) antimetabolites and antifolates ( specifically , metho trexate and the like ) ; form suitable for oral, buccal , nasal , parenteral ( for example , (B29 ) targeted kinase inhibitors [ specifically , JAK family intravenous, intramuscular, or subcutaneous) , transdermal inhibitors (ruxolitinib , tofacitinib , CYT387, lestaurtinib , ( for example , patch ) , or rectal administration or for admin pacritinib , TG101348 , and the like ) and the like ] ; istration by inhalations or insufflations. (B30 ) anticonvulsant agents (specifically , pregabalin , gaba [Dosage Form of Concomitant or Combination Drug/ pentin , and the like ); 55 Combination Agent] ( B31) calcitonin gene -related peptide receptor (CGRP ) The dosage form of the concomitant drug and the com antagonists ; pound of the present invention is not particularly limited and ( B32 ) tyrosine kinase targeted therapeutic agents [specifi may be such that, at the time of administration , the con cally , afatinib , cetuximab , dabrafenib , panitumumab , cabo comitant drug and the compound of the present invention are zantinib , crizotinib , erlotinib , gefitinib , imatinib , lapatinib , 60 combined . Such dosage form used includes, for example , nilotinib , pazopanib , pertuzumab , regorafenib , sunitinib , ( 1 ) administration of a single preparation obtained by simul trastuzumab , and the like ) ; taneously formulating the concomitant drug and the com (B33 ) Ras -Raf - MEK - ERK pathway inhibitors [ specifically , pound of the present invention sorafenib , trametinib , vemurafenib , and the like ] ; ( 2 ) simultaneous administration of two types of preparations ( B34 ) PI3K -Akt - mTOR - S6K pathway inhibitors [specifi - 65 obtained by separately formulating the concomitant drug cally , everolimus , rapamycin , perifosine , temsirolimus, and and the compound of the present invention in the same the like ) ; administration route US 10 , 399 , 945 B2 125 126 ( 3 ) asynchronous administration of two types of prepara present invention , the same as used in the above -described tions obtained by separately formulating the concomitant pharmaceutical composition of the present invention can be drug and the compound of the present invention in the same used . administration route The blend ratio of the concomitant drug and the com ( 4 ) simultaneous administration of two types of preparations 5 pound of the present invention in the concomitant agent of obtained by separately formulating the concomitant drug the present invention can appropriately be selected depend and the compound of the present invention in different ing on the administration target, administration route , dis ease , and the like . administration routes Two or more of the above - described concomitant drugs ( 5 ) asynchronous administration of two types of prepara+ 10 may be used in combination at an appropriate ratio . tions obtained by separately formulating the concomitant The dosage of the concomitant drug can appropriately be drug and the compound of the present invention in different selected based on the clinically used dose . In addition , the administration routes ( for example , administration in the blend ratio of the concomitant drug and the compound of the order of compound - > concomitant drug of the present inven present invention can appropriately be selected depending tion and administration in the reverse order ) . Hereinafterreinanter, 15 on the administration target, administration route , target these dosage forms are collectively referred to as the con disease , symptom , combination , and the like . For example, comitant agent of the present invention . when the administration target is a human , 0 .01 to 100 parts When administering the concomitant agent of the present by mass of the concomitant drug may be used per 1 part by invention , although the concomitantdrug and the compound mass of the compound of the present invention . of the present invention may be administered at the same 20 For example , although the content of the compound of the time, the compound of the present invention may be admin present invention in the concomitant agent of the present istered after the administration of the concomitant drug , or invention varies depending on the form of the preparation , the concomitant drug may be administered after the admin - it is generally in a range of about 0 .01 to 99 . 9 % by mass , istration of the compound of the present invention . In the preferably in a range of about 0 . 1 to 50 % by mass , and case of asynchronous administration , the time difference 25 further preferably in a range of about 0 .5 to 20 % by mass varies depending on the active ingredient to be administered , relative to the total preparation . Note that the upper limit the dosage form , and the administration method . For values and the lower limit values of these numerical ranges example , when the concomitant drug is administered first, a may be a numerical range by arbitrarily combining the values . method can be mentioned of administering the compound of? 30 Although the content of the concomitant drug in the the present invention within 1 minute to 3 days , preferably 30 concomitant agent of the present invention varies depending within 10 minutes to 1 day, and more preferably within 15 on the form of the preparation , it is generally in a range of minutes to 1 hour after the administration of the concomitant about 0 . 01 to 99. 9 % by mass, preferably in a range of about drug . When the compound of the present invention is 0 . 1 to about 50 % by mass, and further preferably in a range administered first , a method can be mentioned of adminisMinis - 35 of about 0 . 5 to about 20 % by mass relative to the total tering the concomitant drug within 1 minute to 1 day, preparation . Note that the upper limit values and the lower preferably within 10 minutes to 6 hours , anda more preferably limit values of these numerical ranges may be a numerical within 15 minutes to 1 hour after the administration of the range by arbitrarily combining the values . compound of the present invention . Although the content of the additive such as a carrier in The dosage of the concomitant drug can be set in any 40 the concomitant agent of the present invention varies amount as long as the side effect is not a problem and can depending on the form of the preparation , it is generally in appropriately be selected on based on the clinically used a range of about 1 to 99. 99 % by mass and preferably in a dose as a standard . In addition , the blend ratio of the range of about 10 to about 90 % by mass relative to the total compound of the present invention and the concomitant drug preparation . Note that the upper limit values and the lower can appropriately be selected depending on the administra - 45 limit values of these numerical ranges may be a numerical tion target , administration route , target disease , symptom , range by arbitrarily combining the values . combination , and the like . When the compound of the The content may be the same when the compound of the present invention is used in combination with a concomitant present invention and the concomitant drug are formulated drug , the amount of each agent can be reduced within a safe separately. range in consideration of the opposite effects of these agents . 50 Since the dosage varies under various conditions as For example , when the administration target is a human , described above , the dosage may be sufficient in an amount 0 .01 to 100 parts by weight of the concomitant drug may be smaller than the above -described dosage or may need to be used per 1 part by weight of the compound of the present administered beyond the range . invention . [ Formulation of Preventive/ Therapeutic Agent of Present The concomitant agent of the present invention has low 55 Invention ] toxicity . For example , in accordance with a known method , The medicament of the present invention is administered the compound of the present invention or (and ) the con - in the form of a pharmaceutical composition . comitant drug described above can be mixed with a phar The pharmaceutical composition of the present invention maceutically acceptable carrier to form a pharmaceutical may contain at least one of the compound represented by composition , for example , a tablet ( including a sugar -coated 60 formula ( I) of the present invention or the optical isomer tablet and a film -coated tablet ) , a powder, a granule , a thereof , the pharmaceutically acceptable salt thereof, and the capsule ( including a soft capsule ), a solution , an injection , a solvate thereof, and is made optionally in combination with suppository, a sustained release agent, and the like, which a pharmaceutically acceptable additive . More specifically , can be safely administered orally or parenterally ( for various dosage forms can be obtained by appropriately example , topically , rectally , intravenously , and the like ). 65 combining the compound of the present invention or the like As the pharmaceutically acceptable carrier which may be with excipients ( examples : glucose , lactose (monohydrates , used in the production of the concomitant agent of the spray - dried monohydrates , anhydrides , and the like) , US 10 , 399 , 945 B2 127 128 sucrose , white sugar, mannitol , mannite , xylitol, sorbitol, directly from the mouth . Preparations suitable for oral crystalline cellulose , microcrystalline cellulose , silicic acid , administration include , for example , tablets; capsules con starch , maize starch , potato starch , dicalcium phosphate taining microparticles , liquids , or powders; lozenges ( in dehydrate , and the like ), binders [examples : celluloses (hy - cluding liquid -containing ones ) and chews ( chewable tab droxypropyl cellulose (HPC ) , hydroxypropyl methylcellu - 5 lets ) ; multiparticulates and nanoparticulates; and solid lose (HPMC ) ) , crystalline cellulose , microcrystalline cellu preparations and liquid preparations such as gels , solid lose , gelatin , sugars (lactose , mannite , white sugar, sorbitol, erythritol, and xylitol ) , starches (maize starch and potato solutions, liposomes, films (including mucoadhesive starch ), pregelatinized starch , dextrin , polyvinylpyrrolidone agents ) , vaginal suppositories , and sprays . (PVP ) , macrogol, polyvinyl alcohol (PVA ), polyethylene 10 The liquid preparations include, for example , suspen glycol, natural rubber , synthetic rubber, and the like ), lubri sions , solutions, syrups , elixirs , and the like . The preparation cants ( examples : magnesium stearate , calcium stearate , zinc can be used as a filler for soft or hard capsules , in particular stearate , sodium stearyl fumarate , a mixture of magnesium it contains a carrier ( for example , water, ethanol, polyeth stearate and sodium lauryl sulfate , talc , carboxymethyl cel ylene glycol, propylene glycol, methyl cellulose , suitable lulose, and the like ) , disintegrants [ examplesamples : starches 1515 oilOll , and the like ) and one or more types of emulsifying (maize starch , potato starch , starch , and pregelatinized agents and / or suspending agents . The liquid preparations starch ) , sodium carboxymethyl starch , carmellose , carmel- can also be prepared by reconstitution from solid , for lose calcium , sodium croscarmellose , crospovidone , sodium example sachets ( packs or bags for granules ) . starch glycolate , sodium carboxymethyl cellulose , calcium The medicament of the present invention can be directly carboxymethyl cellulose , polyvinylpyrrolidone, methyl cel - 20 administered by injection , including using a catheter tech lulose , microcrystalline cellulose , lower alkyl substituted nique or infusion , in the blood stream , muscle , or viscera . hydroxypropyl cellulose, sodium alginate , and the like) , The injection includes intravenous administration , intraar surfactants (sodium lauryl sulfate , polysorbate 80 , and the terial administration , intraperitoneal administration , intrath like ), glidants ( silicon dioxide, talc , and the like ) coating ecal administration , intraventricular administration , intrau agents examples: celluloses (hydroxypropyl cellulose 25 rethral administration , intrasternal injection , intracranial (HPC ) , hydroxypropyl methylcellulose (HPMC ) , amino administration , intramuscular administration , subcutaneous alkylmethacrylate copolymer E , and methacrylic acid copo administration , and the like . For injections , devices such as lymer LD ], plasticizers ( examples : triethyl citrate and mac needle syringes , needle - free syringes , and the like are used . rogol) , masking agents ( examples: titanium oxide ), Direct administration by injection also includes , for colorants , flavoring agents , antiseptics (examples : benzalko - 30 example , pharmaceutical techniques such as preparation of nium chloride and paraoxybenzoic acid ester ) , isotonizing injectable preparations by freeze -drying . agents ( examples : glycerin , sodium chloride, calcium chlo - The injectable preparations can be provided in unit dosage ride , mannitol, and glucose ) , pH adjusters (examples : buffer form , for example in ampoules or in multi - dose containers , solutions such as sodium hydroxide , potassium hydroxide , with the addition of preservatives. These preparations can sodium carbonate , hydrochloric acid , sulfuric acid , and 35 take the form of a suspension , a solution , an emulsion , or the phosphate buffer solution ) , stabilizers ( examples: sugar, like in oily or aqueous medium and can contain a formula sugar alcohol, and xanthan gum ) , dispersants , antioxidants tion agent such as a suspending agent, a stabilizer, and /or a ( examples: ascorbic acid , butylhydroxyanisole (BHA ) , pro - dispersant. Alternatively , the active component may be of pyl gallate , and dl- a - tocopherol ) , buffers , preservatives ( ex - powder form for reconstitution with a suitable medium amples : paraben , benzyl alcohol, and benzalkonium chlo - 40 before use , for example sterile pyrogen - free water. ride) , aromatics (examples : vanillin , 1 -menthol , and rose When a product solution is required , the product solution oil ) , solubilizers ( examples: polyoxyethylene hardened cas - can be prepared by dissolving an isolation and inclusion tor oil, polysorbate 80 , polyethylene glycol, phospholipid complex in water (or other aqueous medium ) in an amount cholesterol, and triethanolamine ) , absorption promoters ( ex sufficient to produce a solution of the strength required for amples : sodium glycolate , sodium edetate , sodium caprate , 45 oral or parenteral administration to the patient. These com acylcarnitines , and limonene ) gelling agents , suspending pounds can be formulated in a fast dispersing dosage form agents , emulsifying agents , or commonly used suitable (fddf ) , which is designed to release the active component in additives or solvents . the oral cavity . These preparations are often formulated The various dosage forms include, for example , a tablet , using matrices based on rapidly dissolving gelatin . These a capsule , a granule , a powder, a pill , an aerosol, an inhalant, 50 dosage forms are well known and can be used to deliver a an ointment , a patch , a suppository , an injection , a troche , a wide range of drugs. Most fast dispersing dosage forms solution , a spirit , a suspension , an extract , an elixir , and the utilize gelatin as a carrier or a structure - forming agent. like . In addition , the medicament of the present invention Typically, gelatin is used to impart sufficient strength to the can be administered to a patient by , for example , oral dosage form in order to prevent breakage at the time of administration , subcutaneous administration , intramuscular 55 removal from the package , but once in the mouth , gelatin administration , intranasal administration , transdermal allows its dosage form to decompose instantaneously. Alter administration , intravenous administration , intraarterial natively , various starches are used to obtain the same effect . administration , perineural administration , epidural adminis - The medicament of the present invention can be admin tration , intrathecal administration , intraventricular adminis - istered topically to the skin or mucosa , i . e . dermally or tration , intrarectal administration , inhalation , and the like . 60 transdermally . Typical formulations of these include gels , The medicament of the present invention is preferably hydrogels , lotions , solutions, creams, ointments , dusting suitable for oral administration . powders , dressings , foams, films, skin patches, wafers , The medicament of the present invention can be admin - implants , sponges , fibers, bandages , and microemulsion istered orally . Oral administration is to take swallowing from agents . Liposomes can also be used . the mouth so that the compound enters the gastrointestinal 65 The medicament of the present invention can be admin tract , or it can be buccal administration or sublingual admin - istered rectally or vaginally , for example , in the form of a istration in which the compound enters the bloodstream suppository , pessary , or enema. As a suppository base , it is US 10 , 399 , 945 B2 129 130 possible to formulate in rectal compositions such as sup - invention is not limited by them at all. Pharmacological positories or retention enemas , for example using cocoa Examples 1 to 12 to be described later provide a method of butter or other glycerides . testing the effectiveness the compound of the present inven The medicament of the present invention can also be administered directly to the eye or the ear in the form of 5 tion . drops of micronized suspension or solution in isotonic and ( Pharmacological Experimental Example 1 ) : pH adjusted sterile saline . Other preparations suitable for ophthalmic and otic administration include ointments , bio Evaluation of Binding Activity for Human TrkA degradable ( for example , absorbent gel sponges and colla Protein gens ) and nonbiodegradable ( for example , silicone ) implants , wafers , lenses , fine particle preparations such as 10 Measurement was carried out using Trka LanthaScreen niosomes or liposomes, vesicles, and the like. ( registered trademark ) Eu Kinase Binding Assay ( Thermo The medicament of the present invention can also be Fisher SCIENTIFIC ). To a 384 well plate (Corning ), 2 .5 uL administered intranasally or by inhalation , for example in of the test compound having various concentrations and the form of a solution or suspension , in the form of a dry diluted with Kinase buffer ( ThermoFisher SCIENTIFIC ) powder from a dry powder inhaler, or as an aerosol spray . In 15 and 2 . 5 uL of 15 nM TrkA enzyme ( Thermo Fisher SCIEN the form of a solution or a suspension , a pump spray TIFIC ) were added . Moreover, uL of 3 nM Eu -anti -His Tag container is used which is squeezed by the patient or pumped antibody ( Thermo Fisher SCIENTIFIC ) and 5 uL of 30 nM out. For aerosol sprays , pressurized containers , pumps, Kinase ( registered trademark ) Tracer 236 ( ThermoFisher sprays , atomizers , nebulizers, or the like are used with ( or SCIENTIFIC ) were added , followed by reaction at room without ) the use of suitable propellants or other suitable 20 temperature for 60 minutes . After the reaction , the fluores gases . In the case of dry powder inhalers and aerosols , the cence intensity of Europium (Emission wavelength 615 nm ) dosage unit is determined by prefilled capsules , blisters , or pockets or by a system utilizing a dosing chamber supplied and TR -FRET (Emission wavelength 665 nm ) with an gravimetrically . The units according to the present invention excitation wavelength of 340 nm were measured with En Vi are typically arranged to administer an amount containing 1 2 sion 2100 (PerkinElmer ) to calculate the fluorescence ratio to 5000 ug of compound or salt, in other words a “ puff. ” The 25 as the amount of the test compound and the TrkA enzyme total daily dosage is typically in the range of 1 ug to 20 mg bonded . The inhibitory activity ( IC50 value ) of each test and can be administered in a single dose or in divided doses. compound was calculated with the fluorescence ratio of the For administration to a human patient, the total daily well to which a solvent was added instead of the test dosage of the medicament of the present invention is deter compound being 0 % and the fluorescence ratio of the well mined according to the administration method and is in the 30 without addition of the TrkA protein being 100 % . range of 0 .005 mg to 200 mg, preferably in the range of 0 .01 The TrkA inhibitory activity of the test compound can be mg to 100 mg, and more preferably in the range of 0 . 1 mg evaluated by IC50 value, and Table 1 shows the compounds to 50 mg. Total daily dosage can be administered in single having an IC50 value of 50 nmol/ L or less as A ( activity is dose or divided doses . These doses are calculated based on very high ) , the compounds having an IC50 value of more the average human patient having a body weight of about 65 35 than 50 nmol/ L and 1000 nmol/ L or less as B ( activity is kg to 70 kg . The doctor can separately determine the dosage high ) , and the compounds having an IC o value ofmore than to subjects such as infants and elderly people whose body 1000 nmol/ L as C (activity is low ). In Table 1, Compounds weights are outside the above range . 1 to respectively mean Compounds 1 to 62 synthesized in The dose administered in the therapeutic use described accordance with Examples 1 to 62 described later. above varies depending on the compound or salt used , the 40 mode of administration , the treatment desired , and the TABLE 1 disorder indicated . The dosage of the pharmaceutical com position of the present invention is desirably set in consid IC50 eration of the patient ' s age , body weight, type and extent of Compound Value the disease , administration route , and the like , and usually 45 will be in the range of 0 . 05 to 100 mg/ kg / day and preferably of 0 . 1 to 10 mg/ kg / day in the case of oral administration . In the case of parenteral administration , the dosage varies widely depending on the administration route , but it will usually be in the range of 0 . 005 to 10 mg/ kg /day and 50 preferably 0 .01 to 1 mg/ kg / day . It is possible to administer it once ( single dose ) to several divided times ( divided doses ) mtinosa a day . Note that the upper limit values and the lower limit values of these numerical ranges may be a numerical range by arbitrarily combining the values. EXAMPLES 15 Hereinafter, the present invention is specifically described with reference to experimental examples, but the present 60 invention is not limited by them at all. PHARMACOLOGICAL EXPERIMENTAL EXAMPLES OS Hereinafter, the present invention is specifically described with reference to experimental examples , but the present US 10 , 399 , 945 B2 131 132 TABLE 1 -continued mM HEPES /HBSS containing 0. 1 % BSA was added (DMSO final concentration : 0 . 1 % ) and set in an intracellular Compound IC 50 calcium concentration measurement system (FDSS 7000 , Value Hamamatsu Photonics ) . NGF - B (Sigma - Aldrich Japan ) was 28 5 added ( final concentration : 30 ng /mL ) 5 minutes after the 29 addition of the test compound , and intracellular calcium concentration was measured as a fluorescence signal. The ????? inhibitory activity (IC50 value ) of each test compound was calculated with the fluorescence signal of the well to which 34a 34b 10 a solvent was added instead of the test compound being 0 % 35a and the fluorescence signal of the well without addition of 35b the NGF- ß being 100 % . 36 37 (Pharmacological Experimental Example 3 ) : 37a 37b Inhibitory Action Against Rat NGF- Induced 38 Vascular Hyperpermeability 39 40 41 The inhibitory activity against TrkA in vivo was evalu 41a ated . A compound dissolved or suspended using a solvent 41b 20 was orally administered (amount dissolved or suspended : 5 42 mL /kg ) to a male Sprague - Dawley rat (CD (SD ) IGS rat, 43 Charles River Japan ) which had been shaved at the back . A 44 44a solvent was orally administered to the solvent control group . 44b From 1 to 24 hours after the administration , 1 % Evans Blue 45 25 (Nacalai Tesque ) was administered intravenously via tail vein ( amount dissolved or suspended : 3 mL /kg ) under 47 48 isoflurane anesthesia , and immediately afterwards, a 300 48a ng /mL NGF (mouse 2 . 5 s , Alomone ) solution diluted with 48b isotonic sodium chloride solution was administered intrad 49 30 ermally at two sites on the back and isotonic sodium chloride solution at 2 sites on the back (amount dissolved or sus 51 pended : 50 uL / site ) . Ten minutes after the intradermal administration , the administration sites ( 4 places ) of the dorsal skin were cut off and each of the skin samples was nminDN 35 transferred to the wells of a 24 -well plate (Nikkei Products ). innininin Formamide (Wako Pure Chemical Industries ) was added to 58 the plate at 1 . 5 mL /well each , and the plate was covered and 59 incubated at 37° C . overnight. Then , 200 uL of formamide 60 61 extract was transferred to a 96 -well plate (nunc ) , and the 61a 40 absorbance of Evans Blue extracted into formamide (wave 61b length : 620 nm ) was measured using SpectraMax (Molecu 62 lar Devices) . At the same time, the absorbance of the Evans Blue standard product diluted with formamide was also measured (Pharmacological Experimental Example 2 ) : 45 and a calibration curve was created . The Evans Blue con Inhibitory Activity Evaluation Using Human TrkA centration of each sample was calculated from the calibra Expressing Cells tion curve and the absorbance of each sample . Among the four skin samples taken from the same indi The inhibitory activity against TrkA kinase in the cell line vidual, the value of the individual was taken as the value was carried out with the increase in ligand -dependent intrafra 50 obtained by subtracting the average value of the two sites cellular calcium concentration using CHO -K1 cells administered with isotonic sodium chloride solution from (CellSenser ( registered trademark ) TrkA -NFAT - bla CHO the average value of the two sites administered with NGF. K1 cells , ThermoFisher SCIENTIFIC ) stably expressing The inhibitory rate of rat NGF - induced vascular hyperper human TrkA as an index . meability was calculated assuming that Evans Blue concen On the day before the assay , cells were suspended in 55 tration of the solvent control group was 0 % . Opti- MEM ( registered trademark ) 1 Reduced Serum (Pharmacological Experimental Example 4 ): Medium ( Thermo Fisher SCIENTIFIC ) with assay medium Analgesic Effect on Complete Freund ' s Adjuvant ( 0 . 5 % inactivated Dialyzed FBS ( ThermoFisher SCIEN (CFA ) - Induced Model Rat TIFIC ) , NEAA ( Thermo Fisher SCIENTIFIC ), 1 mM 60 Sodium Pyruvate ( ThermoFisher SCIENTIFIC ) ) and seeded The analgesic effect of the test compound was evaluated in a 96 -well clear bottom plate (Greiner ) at a density of using a CFA - induced model rat. 4 .0x104 cells / 100 uL /well . On the day of the assay , 100 ul ( 1 ) Preparation of CFA - Induced Model Rat of loading buffer containing 2 .5 mM probenecid (FLIPR An emulsion was prepared by mixing equal amounts of Calcium assay kit, Molecular Devices ) was added , followed 65 CFA (Sigma - Aldrich Japan ) and isotonic sodium chloride by incubation for 1 hour under the conditions of 37° C . and solution , and 100 uL of the emulsion was administered to the 5 % CO2. The test compound preliminarily diluted with 20 footpad of the right limb of the rat using a 26 G injection US 10 , 399 , 945 B2 133 134 needle under isoflurane anesthesia . The normal control rat , mouse , dog , or monkey ; XenoTech ) and an NADPH group was administered with 100 uL of isotonic sodium production solution (water containing B -NADP , Glucose - 6 chloride solution . Phosphate , G - 6 -PDH ( Y ) , and MgCl2 ) to a final concentra ( 2 ) Administration of Test Compound and Anti -NGF Anti body tion of 1 uM . The solution was incubated at 37° C . for a The test compound was dissolved or suspended in 0 . 5 % 5 predetermined time and then quenched with acetonitrile . methyl cellulose (Wako Pure Chemical Industries ) (amount Centrifuge filtration was carried out on the reaction solution dissolved or suspended : 5 mL /kg ) . The anti -NGF antibody with a filter plate (MultiScreen gts -HV plate (Merck Milli as a positive control was dissolved and diluted with isotonic pore )) and measurement was carried out on the test com sodium chloride solution to prepare a 2 mL /kg solution . The pound in the filtrate using high performance liquid chro test compound - administered group was orallylly administered 10 matogram /mass spectrometry . Likewise , the sample with a repeatedly for 7 days twice a day from the administration reaction time of 0 min was measured as a control and the day of CFA . The anti- NGF antibody was intraperitoneally residual rate ( % ) at each time point was calculated , thereby administered on the same day as CFA administration . calculating the metabolic rate ( % ) from 100 - residual rate ( 3 ) Measurement of 50 % Threshold ( g ) ( % ) . Measurement was carried out 7 days after CFA adminis - 15 tration . Following acclimation of the animal to the measure (Pharmacological Experimental Example 7 ) : hERG ment environment for 1 hour or more , the footpad was Inhibition Test by Patch Clamp Method stimulated using von Frey filaments in accordance with the Dixon up - down method ( Journal of Neuroscience Methods , The action on the hERG ( human ether - a - go - go related Volume 53 , pp . 55 -63 , 1994 ) , and the 50 % threshold ( g ) was 20 gene ) channel was measured using a fully automated patch calculated by the following formula . Note that the measure clamp system ( CytoPatchTM2 or 4 ( Cytocentrics ) ) . In order ment was carried out in a blinded fashion . to check the hERG IK ,, current of the cells ( CHO HERG DUO 50 % threshold ( g ) = ( 10 ^ [ xf+ kd ]/ 10000 ) ( B ’ SYS ) ) , the membrane potential was maintained at - 80 Xf: value of the last used filament mV, and the following pulses were applied once every 15 k : tabular value 25 seconds: depolarization pulses of – 50 mV with duration 0 . 11 d : average difference between used filaments ( = 0 .224 ) seconds and of 20 mV with duration 4 seconds , followed by a repolarization pulse of - 50 mV with duration 2 seconds. (Pharmacological Experimental Example 5 ) : The action of the test compound on the hERG channel was Solubility Test checked by the change in the tail current induced by the 30 repolarization pulse. The measurement was carried out at (1 ) DMSO Precipitation Solubility (Kinetic Solubility ) room temperature . The hERG channel inhibition rate was A 10 mM DMSO solution of the compound of the present calculated as the reduction rate ( inhibition rate ) of the tail invention was added to a 50 mM phosphate buffer solution current after addition of the test compound to the tail current (pH 7 . 4 ) to a final concentration of 100 uM . The solution peak value before addition . was incubated at room temperature for 1. 5 hours with 35 Calculation of this inhibition rate shows the possibility of stirring at 600 rpm and then filtered through a filter plate inducing QT prolongation by drug followed by fatal side (MultiScreenHts - PCF filter plate (Merck Millipore )) , and the effects (such as ventricular tachycardia and sudden death ). absorbance of the filtrate was measured at the maximum absorption wavelength using a plate reader (Powerscan HT ( Pharmacological Experimental Example 8 ) : ( Dainippon Pharmaceutical ) ) . At the same time, measure - 40 Pharmacokinetics (PK ) Test ment was carried out on the absorbance of each standard solution with DMSO solutions added with known concen - ( 1 ) Rat Cassette PK Test trations (1 , 3, 10 , 30 , 100 UM ) of the test compound as To a male Crl : CD (SD ) rat of 6 to 10 weeks of age , the standard solutions for calibration curve , thereby creating a compound of the present invention was intravenously calibration curve . The solubility (UM ) of the compound was 45 administered at 0 . 3 mg/kg (the solvent administered was calculated from the absorbance values of the filtrate and the DMSO : Dimethylacetamide : PEG 400 : physiological standard solutions . saline = 1 . 2 : 2 . 8 : 4 : 2 , 1 mL /kg ) , and after 0 . 083 , 0 .25 , 0 . 5 , 1 , 2 , ( 2 ) Solubility ( Thermodynamic Solubility ) 4 , and 6 hours , blood was collected from the jugular vein , or The compound of the present invention was added to a the compound of the present invention was orally adminis solvent ( for example , water and a buffer solution ) to 1 50 tered singly at 1 mg/ kg ( the solvent administered was mg/ mL . The solution was incubated at 25° C . or 37° C . for DMSO : Tween 80 :distilled water = 1 : 1 : 8 , 10 mL /kg ) , and 24 hours with stirring at 1000 rpm and then filtered through after 0 . 5 , 1 , 2 , and 4 hours , blood was collected from the a filter plate . The filtrate was analyzed by HPLC , the peak jugular vein . Using plasma obtained by centrifuging the was detected at the maximum absorption wavelength , and blood ( 3000 rpm , 15 minutes, 4° C .) , the test compound in the peak area was measured . Likewise , solutions added with 55 the plasma was measured by high performance liquid chro known concentrations ( for example , 0 .01 , 0 .03 , 0 . 1, 0 .3 , 1 , matogram /mass spectrometry . Similarly , measurement was 3 , 10 ug /mL ) of the test compound ( for example , DMSO carried out on the standard solutions added with the known solution , 1 , 4 - dioxane solution , and methanol solution ) were concentrations of the test compound , calculation was carried used as standard solutions for calibration curve to measure out on the plasma concentration ( ug /mL ) from the created the peak areas , and the solubility (ug /mL ) of the compound 60 calibration curve , and the maximum plasma concentration was calculated from the peak areas of the calibration curve . was set as Cmax (ug / mL ) . ( 2 ) PK Test (Pharmacological Experimental Example 6 ) : To the animals ( a male Crl : CD (SD ) rat of about 6 to 8 Metabolic Stability Test weeks of age , a male beagle dog of about 1 to 3 years of age , 65 or a male cynomolgus monkey of about 1 to 3 years of age ) , A 10 mM DMSO solution of the compound of the present the compound of the present invention was intravenously invention was added to a liver microsome solution (human , administered at 0 . 3 to 1 mg /kg ( the solvent administered was US 10 , 399 , 945 B2 135 136 Dimethylacetamide: PEG 400 :distilled water = 4 : 4 : 2 , 0 . 1 to 1 invention was orally administered to a mouse or a rat in a mL /kg ), followed by passage of time of 0 .083 , 0 .25 , 0 . 5 , 1 , single dose , no death case was observed or no marked 2 , 4 , 8 , and 24 hours , or the compound of the present behavioral abnormality was observed . invention was orally administered at 0 . 5 to 3 mg/ kg ( the From the above results , it was shown that the compound solvent administered was 0 . 5 % MC , 2 to 5 mL /kg ) , followed 5 of the present invention had an excellent TrkA inhibitory by passage of time of 0 .25 , 0 . 5 , 1 , 2 , 4 , 8 , and 24 hours . After that, blood was collected from the jugular vein for the rat and action . from the cephalic vein of the upper arm for the dog and the In addition , no abnormality was observed in the safety monkey . Using plasma obtained by centrifuging the blood test, showing the low toxicity of the present invention . ( 3000 rpm , 15 minutes, 4° C . ) , the test compound in the Moreover, the above test showed that the compound of the plasma was measured by high performance liquid chromato 10 present invention was satisfactory in one of the viewpoints gram /mass spectrometry . Similarly , measurement was car of solubility , metabolic stability , pharmacokinetics , avoid ried out on the standard solutions added with the known ance of hERG channel inhibitory action , etc . concentrations of the test compound , calculation was carried Thus, the compound of the present invention is expected out on the plasma concentration (ug /mL ) from the created to be used as a TrkA inhibitor in a preventive and / or calibration curve, and the maximum plasma concentration 15 therapeutic agent for a disease in which TrkA is involved , was set as Cmax ( ug /mL ) . the disease including , for example , pain (pain associated with osteoarthritis , rheumatoid arthritis , bone fracture , inter (Pharmacological Experimental Example 9 ): Protein stitial cystitis , chronic pancreatitis , and prostatitis , nocicep Binding Test tive pain typified by chronic low back pain , diabetic periph 20 eral neuropathic pain , postoperative pain , pelvic pain , cancer A 10 mM DMSO solution of the compound of the present pain , and the like, and pain such as neuropathic pain , acute invention was added to normal plasma (human , rat, dog , and monkey ) to a final concentration of 10 uM . After dialysis at pain , chronic pain , and inflammatory pain ), cancers, inflam 37° C . for 4 hours with a simple equilibrium dialyzer mation / inflammatory diseases , allergic diseases , skin dis (HTD96b Complete Unit (HTDialysis )) , the concentration 25 eases, neurodegenerative diseases, infectious diseases, of the test compound in the inner side (plasma side ) solution 25 Sjogren ' s syndrome, endometriosis , renal diseases, and and the outer side ( PBS side ) solution of the dialysis osteoporosis . membrane was measured using high performance liquid The compound of the present invention is expected to chromatogram /mass spectrometry . The unbound fraction exhibit promising preventive or therapeutic effects against ( % ) was calculated from the ratio between the PBS side and various diseases in which TrkA is involved . the plasma side, and the protein binding rate ( % ) was 30 calculated from 100 - unbound fraction ( % ) . Examples ( Pharmacological Experimental Example 10 ) : Next, examples and test examples will be provided in Calculation of Various Parameters in order to explain the present invention in further detail, but Pharmacokinetics Test 35 these examples are merely implementations, and do not limit the present invention and may be varied without departing Model- independent analysis was carried out on the time from the scope of the present invention . course of the plasma concentration obtained by the PK test J EOL JNM - ECX 400 FT- NMR ( JEOL ) , JEOL JNM - ECX ( Pharmacological Experimental Example 6 described 300 FT- NMR ( JEOL ), and Bruker Avance III 400 MHz above ) in the animal species of rat , dog , and monkey to 40 NMR ( Bruker) were used for nuclear magnetic resonance calculate the total body clearance CLtot ( L /hr /kg ) , the dis - spectrum (NMR )measurement . The liquid chromatography tribution volume Vdss (L /kg ) at steady state , the area under mass spectrometry spectrum (LC -Mass ) was measured by the plasma concentration - time curve AUC ( ug / hr/ mL ) , and the following method . [UPLC ] [Method A ] A Waters the half life T1/ 2 (hr ) . In addition , bioavailability was AQUITY UPLC system and a CAPCELL Pak columns ( 2 . 0 calculated by comparing the AUC at the time of intravenous 45 mmx50 mm , 3 um ) ( Shiseido ) were used , and mobile phase administration and the AUC at the time of oral administra and gradient conditions of methanol: 0 .05 % trifluoroacetic tion . acid aqueous solution = 5 : 95 ( 0 min ) to 95 : 5 ( 1 . 0 min ) to 95 : 5 ( 1 .6 min ) to 5 : 95 ( 2 . 0 min ) were used . (Pharmacological Experimental Example 11 ): [LCMS ] [Method B ] A Waters FractionLynx MS system Prediction of Pharmacokinetic Parameters in 50 ( Waters) and SunFire columns ( 4 .6 mmx5 cm , 5 um ) (Wa Humans ters ) were used , and mobile phase and gradient conditions of acetonitrile : 0 .05 % acetic acid aqueous solution = 10 : 90 ( 0 Pharmacokinetic parameters in humans were predicted by min ) to 100 : 0 ( 5 . 0 min ) to 100 : 0 (6 . 0 min ) to 10 : 90 ( 7 . 0 min ) a method known to those skilled in the art such as the or [Method C ] acetonitrile : 0 .05 % trifluoroacetic acid aque method by allometric scaling or the IVIVE ( in vitro / in vivo 55 ous solution = 10 : 90 ( 0 min ) to 100 : 0 ( 5 . 0 min ) to 100 : 0 (6 . 0 extrapolation ) method , using various parameters in the ani- min ) to 10 : 90 ( 7 . 0 min ) were used . Gradient conditions mal pharmacokinetics test or parameters such as the meta appropriately changed depending on the compound were bolic stability and the protein binding rate in the in vitro test, used for the preparative system . The optical resolution by which had been obtained by the above methods described in supercritical fluid liquid chromatography ( SFC ) was carried Pharmacological Experimental Example 6 , 8 , 9 , 10 , or the 60 out using Waters SFC Prep 15 System , SFC 800 System , and like . the corresponding chiral columns . The optical purity analy sis was carried out using Waters SFC UPC2 and the corre ( Pharmacological Experimental Example 12 ) : sponding chiral column . Safety Test In the " H -NMR data , in the pattern of NMR signal , s 65 means singlet , d doublet , t triplet, 4 quartet , m multiplet , br Safety of the compound of the present invention was broad , J coupling constant, Hz Hertz , CDC13 deuterated demonstrated because when the compound of the present chloroform , DMSO - D6 heavy dimethyl sulfoxide , and US 10 , 399 , 945 B2 137 138 CD3OD heavy methanol . In the ' H -NMR data , signals Step 2 which cannot be confirmed because they are a broadband , such as hydroxyl group (OH ) , amino group (NH2 ) , proton of Synthesis of 1 , 1 -dimethyl - 1 , 2 - dihydronaphthalene carboxyl group (COOH ) , are not described in the data . In the LC -Mass data , M means the molecular weight, RT 5 A toluene ( 10 mL ) solution of the compound ( 1 . 0 g ) the retention time, [ M + H ] * and [ M + Na ] * each a molecular obtained in (Example 1 ) < Step 1> and p - toluenesulfonic ion peak . Also , A , B , and C in the tables mean “ UPLC acid monohydrate ( 0 . 05 g ) was stirred at 90° C . for 1 . 5 [Method A ], ” “ LCMS [Method B ], ” and “ LCMS [method hours . After cooling to room temperature , ethyl acetate ( 40 C ], ” respectively . mL ) and a saturated aqueous solution of sodium hydrogen The optical purity of the compound obtained in (Example carbonate ( 30 mL ) were added for partitioning . The organic 7 ) < Step 2 > was measured under the measurement condi- layer was washed with brine , dried over sodium sulfate , and tions of ( system ) Shimadzu Prominence , ( column ) CHI- concentrated under reduced pressure to obtain the title RALPAK IG (Daicel ) 4 .6x150 mm , (solvent ) 95 % hexane compound (0 . 86 g ) as a yellow oily material . 5 % ethanol- 0 .10 diethylamine, and (measurement 15 wavelength ) 254 nm . Step 3 The optical purity of each of the compounds obtained in ( Example 7a ) to (Example 7i) was measured under the measurement conditions of the SFC method [ ( system ) Synthesis of 3 , 3 - dimethyl- 1a , 2 , 3 , 7b - tetrahydronaph Waters SFC UPC2 , (column ) CHIRALCEL ODH (Daicel ) 20 tho [ 1, 2 -b ]oxirene 4 .6x150 mm , ( solvent) 90 % supercritical carbon dioxide 10 % methanol- 0 . 10 diethylamine , (column temperature ) 40° An aqueous solution ( 0 .60 mL ) of potassium peroxy C . , ( flow rate ) 3 mL /min , and (measurement wavelength ) monosulfate ( 0 . 15 g ) was added under ice cooling to an 220 nm ) or the HPLC method [ ( system ) Shimadzu Promi acetone ( 0 .60 mL ) suspension of the compound (30 mg) nence, (column ) CHIRALPAK IG (Daicel ) 4. 6x150 mm , 25 . obtainedobtain in ( Example 1 ) < Step 2 > and sodium hydrogen ( solvent) 90 % hexane - 10 % ethanol- 0 . 10 diethylamine, ( col carbonate (80 mg) . The reaction solution was stirred at the umn temperature ) 40° C ., ( flow rate ) 0 . 5 mL /min , and same temperature for 1 hour and then at room temperature (measurement wavelength ) 220 nm ) . for 16 hours . Ethyl acetate and a saturated aqueous solution The optical purity of the compound obtained in ( Example of sodium hydrogen carbonate were added to the reaction 63 ) was measured under the measurement conditions off 30 solution for partitioning . The organic layer was washed (system ) Shimadzu Prominence , ( column ) CHIRALPAK IG successively with an aqueous solution of sodium thiosulfate (Daicel ) 4 .6x150 mm , ( solvent) 95 % hexane - 5 % ethanol and brine , and dried over sodium sulfate . The solvent was 0 . 1 % diethylamine , and (measurement wavelength ) 254 nm . distilled off under reduced pressure , and the obtained residue The “ room temperature” in the examples shall generally was purified by silica gel column chromatography (mobile indicate a temperature of about 1° C . to about 30° C . 35 Pphase : heptane/ ethyl acetate = 100 : 0 to 90 : 10 ) to obtain the In the example compound names, a compound denoted as title compound (24 mg) as a colorless oily material . Rac - ( 1R , 2R ) also includes its mirror image ( 18 , 2S ). Spe cifically , rac - 1 - ( ( 1R , 2R ) - 2 - hydroxy - 4 ,4 -dimethyl - 1 , 2 , 3 , 4 Step 4 tetrahydronaphthalen - 1- yl) - 3 -( 2 -phenylpyridin - 3 -yl ) urea of ( Example 1 ) includes 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl - 40 1 , 2 , 3 ,4 -tetrahydronaphthalen - 1 - yl) - 3 -( 2 - phenylpyridin - 3 Synthesis of rac - ( 1R ,2R ) - 1 -amino - 4 , 4 -dimethyl - 1 , 2 , yl) urea and 1 - ( ( 15 , 2S ) - 2 - hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tet 3 , 4 -tetrahydronaphthalen - 2 - ol rahydronaphthalen - 1 - yl) - 3 - ( 2 - phenylpyridin - 3 - yl) urea . To an ethanol (0 .070 mL ) solution of the compound (30 Example 1 45 mg) obtained in ( Example 1 ) < Step 3 > , 25 % aqueous ammonia solution ( 1 . 0 mL ) was added . The reaction solu Synthesis of rac - 1 -( 1R , 2R ) -2 -hydroxy -4 ,4 -dim tion was stirred in a sealed tube at 90° C . for 1 hour. After ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 2 - phe cooling , water was added to the reaction solution , and the nylpyridin - 3 - yl) urea precipitated solid was collected by filtration and dried under 50 reduced pressure to obtain the title compound ( 14 mg) . Step 1 Step 5 Synthesis of 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - ol 55 Synthesis of rac- 1 -( ( 1R , 2R ) -2 -hydroxy -4 ,4 -dim Sodium borohydride ( 0 . 24 g ) was added in two portions ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 2 -phe to a methanol ( 10 mL ) solution of commercially available nylpyridin -3 -yl ) urea 4 , 4 - dimethyl- 3 , 4 -dihydronaphthalene - 1 ( 2H ) - one (CAS number 2979 -69 - 3 ) ( 1 . 0 g ) under ice water cooling , fol- To an acetonitrile (0 . 50 mL ) solution of commercially lowed by stirring for 1 hour at room temperature. Methanol 60 available 2 - phenyl- 3 -pyridineamine (CAS number 101601 was removed under reduced pressure, and 1 N sodium 80 - 3 ) (25 mg) , p -tolyl chloroformate ( 25 mg) was added . hydroxide aqueous solution ( 30 mL ) and ethyl acetate (40 After stirring the reaction solution at room temperature for mL ) were added to the obtained residue for partitioning . The 1 hour, triethylamine (0 . 061 mL ) and the compound (31 mg) organic layer was washed with brine (25 mL ) , dried over obtained in ( Example 1 ) < Step 4 > were added to the reaction sodium sulfate , and then concentrated under reduced pres- 65 solution , followed by stirring at 40° C . for 3 hours . The sure to obtain the title compound ( 1 . 0 g ) as a pale yellow oily reaction solution was purified by preparative LC -Mass to material. obtain the title compound ( 26 mg) . US 10 , 399 ,945 B2 139 140 Example 2 room temperature for 2 hours. Water ( 2 . 0 mL ) was added to the reaction solution , and the mixture was extracted twice Synthesis of rac - 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 -dim with tert- butylmethyl ether , then the organic layer was ethyl- 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 washed with water . The solvent was distilled off under 5 reduced pressure , and the obtained residue was purified by methyl- 2 -phenylpyridin - 3 -yl ) urea silica gel column chromatography ( stationary phase : amino silica gel , mobile phase : heptanelethyl acetate = 90 : 10 to Step 1 30 : 10 ) to obtain the title compound ( 0 . 20 g ) as a brown Synthesis of 5 -methyl - 2 - phenylpyridin - 3 - amine solid . 10 Step 2 Commercially available 2 - chloro -5 -methyl -3 -pyri dineamine (CAS number 34552 - 13 - 1 ) ( 1 . 0 g ), phenylbo Synthesis of p -tolyl ronic acid ( 0 . 86 g ) , and tetrakis triphenylphosphine palla ( 6 -bromo - 5 -methyl - 2 -phenylpyridin - 3 -yl ) carbamate dium ( 0 .81 g ) were added to a mixture solvent of ethanol ( 15 mL ), toluene (35 mL ), and a 2 N aqueous solution of 15 To a tetrahydrofuran (7 .5 mL ) solution of the compound potassium carbonate ( 11 mL ) , followed by stirring under a (500 mg) obtained in ( Example 3 ) < Step 1 > , p - tolyl chlo nitrogen atmosphere at 100° C . for 18 hours . After cooling , roformate ( 0 . 55 mL ) was added , followed by stirring at 40° ethyl acetate and water were added to the reaction solution C . for 3 hours . The reaction solution was concentrated under for partitioning , and the organic layer was washed with brine reduced pressure , and the obtained residue was suspended in and dried over sodium sulfate . The solvent was distilled off 20 heptane and the precipitate was collected by filtration to under reduced pressure , and the obtained residue was puri obtain the title compound ( 0 .71 g ) as a white solid . fied by silica gel column chromatography (mobile phase : heptane / ethyl acetate = 70 :30 -65 :35 -60 :40 ) to obtain the title Step 3 compound ( 1 . 2 g ) as a colorless solid . Synthesis of rac - 1 - ( 6 -bromo - 5 - methyl- 2 -phenylpyri 25 din - 3 -yl ) - 3 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , Step 2 4 - tetrahydronaphthalen - 1 -yl ) urea Synthesis of p - tolyl ( 5 -methyl - 2 - phenylpyridin - 3 - yl) The compound (0 . 12 g ) obtained in (Example 1 ) < Step 4 > carbamate and N , N -diisopropylethylamine ( 0 .20 mL ) were added to a 30 tetrahydrofuran ( 3 . 0 mL ) solution of the compound ( 0 . 11 g ) To a tetrahydrofuran ( 1 mL ) solution of the compound (43 obtained in (Example 3 ) < Step 2 > at room temperature , and mg) obtained in (Example 2 ) < Step 1 > , p -tolyl chlorofor the reaction solution was stirred at 70° C . for 1 hour. Water mate ( 0 .051 mL ) was added , and the reaction solution was was added to the reaction solution , and the mixture was stirred at 70° C . for 18 hours . After completion of the extracted with ethyl acetate . The organic layer was washed reaction , the solvent was distilled off under reduced pres- 35 successively with water and brine, and dried over sodium sure . The obtained residue was suspended in heptane and the sulfate . The solvent was distilled off under reduced pressure , precipitate was collected by filtration to obtain the title and the obtained residue was purified by silica gel column compound (70 mg) as a colorless solid . chromatography ( stationary phase : amino - silica gel, mobile phase : heptane / ethyl acetate = 1 : 1 ) to obtain the title com Step 3 40 pound ( 95 mg) as a white solid . Synthesis of rac - 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dim Step 4 ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 methyl- 2 -phenylpyridin - 3 -yl ) urea Synthesis of rac - 1 - (( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dim 45 ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 The compound ( 26 mg) obtained in ( Example 1 ) < Step 4A > methyl- 6 - ( 2 -methylpyrimidin - 5 - yl) - 2 - phenylpyridin and triethylamine ( 0 .052 mL ) were added to an N -methyl 3 - yl) urea pyrrolidone ( 0 .40 mL) solution of the compound ( 40 mg) obtained in (Example 2 ) < Step 2 > , followed by stirring at To a mixture solution of water ( 0 . 10 mL ) and 1 , 2 40° C . for 1 . 5 hours . The reaction solution was purified by 50 dimethoxyethane ( 1 . 0 mL ) of the compound (30 mg) preparative LC -Mass to obtain the title compound (12 mg) . obtained in ( Example 3 ) < Step 3 > , 2 -methyl - 5 - (4 , 4 , 5 , 5 tetramethyl- 1 , 3 , 2 -dioxaborolan - 2 -yl ) pyrimidine (41 mg) , Example 3 cesium carbonate (61 mg ) , and bis ( triphenylphosphine ) pal ladium ( II) chloride ( 4 . 4 mg) were added , followed by stir Synthesis of rac - 1 - ( (1R ,2R ) - 2 -hydroxy - 4 , 4 - dim 55 ring at 100° C . for 16 . 5 hours . The reaction solution was ethyl- 1 , 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) - 3 - ( 5 purified by preparative LC -Mass to obtain the title com methyl - 6 - ( 2 -methylpyrimidin - 5 -yl ) - 2 -phenylpyridin pound (8 .4 mg) as a white solid . 3 - yl) urea Example 4 Step 1 60 Synthesis of rac - 1 -( ( 1R ,2R ) -2 -hydroxy -4 ,4 -dim Synthesis of ethyl- 1, 2 ,3 , 4 -tetrahydronaphthalen - 1- yl) - 3 -( 5 6 -bromo - 5 -methyl - 2 -phenylpyridin - 3 - amine methyl - 6 - ( 1 -methyl - 1H - pyrazol- 4 - yl) - 2 - phenylpyri din -3 -yl ) urea N -bromosuccinimide (0 .21 g ) was added to an N -meth - 65 ylpyrrolidone ( 2 . 0 mL ) solution of the compound ( 0 . 19 g ) By the samemethod as in (Example 3 ) < Step 4 > , the title obtained in ( Example 2 ) < Step 1 > , followed by stirring at compound (22 mg) was obtained as a white solid using US 10 , 399 , 945 B2 141 142 1 -methyl - 4 - ( 4 , 4 ,5 , 5 - tetramethyl- 1 , 3 , 2 - dioxaborolan - 2 - yl ) compound (40 mg) obtained in (Example 2 ) < Step 2 > and 1H -pyrazole (39 mg) instead of 2 -methyl - 5 - ( 4 , 4 , 5 , 5 -tetram the compound (47 mg ) obtained in ( Example 7 ) < Step 1 > . ethyl- 1 , 3 , 2 - dioxaborolan - 2 - yl) pyrimidine . The below - described ( Example 7a ) to (Example 7i ) describe the synthesis of (1R , 2R )- 1 - amino - 4, 4 -dimethyl - 1 , Example 5 5 2 , 3 , 4 -tetrahydronaphthalen - 2 - ol ( 2S ,3S ) - 2 , 3 - dihydroxy suc Synthesis of rac - 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 - dim cinate monohydrate . ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 methyl- 6 - (1H -pyrazol - 4 -yl ) -2 -phenylpyridin -3 - yl) Example 7a urea 10 To a mixture solution of water ( 0 .6 mL ) and 1 , 2 - dime By the samemethod as in ( Example 3 ) < Step 4 > , the title thoxyethane ( 11 . 4 mL ) of rac - ( 1R ,2R ) - 1 -amino - 4 , 4 - dim compound ( 18 mg) was obtained as a white solid using ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 -ol ( 1 . 0 g ) obtained in tert- butyl 4 - ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 - dioxaborolan - 2 - yl) - (Example 1 ) < Step 4 > , D - ( - ) - tartaric acid ( 0 .78 g ) was 1H -pyrazole - 1 - carboxylate (55 mg ) instead of 2 -methyl - 5 added at room temperature . The reaction solution was stirred ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 -dioxaborolan - 2 - yl) pyrimidine . 15 at 100° C . for 1 hour, allowed to cool to room temperature , and then stirred at the same temperature for 2 hours and 30 Example 6 minutes . The precipitated crystal was collected by filtration , and the crystal was washed with a mixture solvent of Synthesis of rac- 1 -( 6 '- hydroxy - 3 -methyl - 6 - phenyl 1 , 2 -dimethoxyethane -water ( 19 : 1 ) and dried under reduced [ 2 , 3 - bipyridin ) - 5 - yl) - 3 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 20 pressure to obtain the title compound (0 . 86 g ) as a white dimethyl- 1, 2 , 3 ,4 - tetrahydronaphthalen - 1 - yl) urea solid . The optical purity of the obtained title compound was By the samemethod as in (Example 3 ) < Step 4 > , the title 98 . 1 % (HPLC , retention time 10 .58 minutes ). compound ( 11 mg ) was obtained as a pale yellow solid using 5 - ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 - dioxaborolan - 2 - yl) pyridin - 2 -ol 25 Example 7b (41 mg) instead of 2 -methyl - 5 - (4 , 4 ,5 ,5 -tetramethyl - 1 , 3, 2 To a mixture solution of water (2 .0 mL ) and 1, 2 -dime dioxaborolan - 2 -yl ) pyrimidine . thoxyethane ( 18 . 0 mL ) of rac - ( 1R , 2R ) - 1 -amino - 4 , 4 -dim Example 7 ethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 - ol ( 1 . 0 g ) obtained in ( Example 1 ) < Step 4 > , D - ( - ) - tartaric acid ( 0 .78 g ) was Synthesis of 1 -( ( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dimethyl - 1 , 30 added at room temperature . The reaction solution was heated 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 2 and refluxed at 110° C . for dissolution , then allowed to cool phenylpyridin - 3 - yl) urea to room temperature , and stirred at the same temperature for hours and 20 minutes . The precipitated crystal was collected Step 1 by filtration , and the crystal was washed with a mixture 35 solvent of 1, 2 - dimethoxyethane - water (9 : 1) and dried under Synthesis of (1R ,2R ) - 1 -amino - 4 , 4 -dimethyl - 1 ,2 , 3, 4 reduced pressure to obtain the title compound ( 0 .78 g ) as a tetrahydronaphthalen - 2 - ol (2S ,3S )- 2, 3 -dihydroxy white solid . The optical purity of the obtained title com succinate monohydrate pound was 99 . 4 % (HPLC , retention time 10 . 30 minutes ) . To a mixture solution of water ( 19 mL ) and acetonitrile 40 Example 7c ( 74 mL ) of the compound ( 3. 4 g ) obtained in ( Example 1 ) < Step 4 > , D - ( - ) - tartaric acid (2 . 7 g) was added at room To a mixture solution of water (0 .2 mL ) and 1, 2 -dime temperature . The reaction solution was stirred at 100° C . for thoxyethane ( 1 . 9 mL ) of rac - ( 1R ,2R ) - 1 - amino - 4 , 4 - dim 5 minutes, allowed to cool to room temperature, and allowed ethyl- 1 , 2, 3 ,4 - tetrahydronaphthalen - 2 -ol ( 100 mg) obtained to stand at the same temperature for 2 hours . The precipi- 45 in ( Example 1 ) < Step 4 > , D - ( - )- tartaric acid (78 mg) was tated crystal was collected by filtration , and the crystal was added at room temperature . The reaction solution was heated washed with a pre - cooled acetonitrile -water ( 4 : 1 ) mixture to 90° C . for dissolution , then allowed to cool to room solvent and dried under reduced pressure to obtain a product temperature , and stirred at the same temperature for 30 ( 2 . 0 g ) . Acetonitrile -water ( 4 : 1 ) (25 mL ) was added to this minutes . The precipitated crystal was collected by filtration , product, and the mixture was stirred at 100° C . for 10 50 and the crystal was washed with a mixture solvent of minutes, allowed to cool to room temperature , and allowed 1 , 2 - dimethoxyethane -water ( 23 : 2 ) and dried under reduced to stand at the same temperature for 1 hour for recrystalli - pressure to obtain the title compound (78 mg ) as a white zation . The precipitated crystal was collected by filtration , solid . The optical purity of the obtained title compound was and the crystal was washed with a pre - cooled acetonitrile - 96 . 4 % (HPLC , retention time 10 .60 minutes ) . water (4 : 1) mixture solvent and dried under reduced pres - 55 sure to obtain the title compound ( 1 . 4 g ) as a colorless solid . Example 7d The optical purity of the obtained title compound was more than 99 % (HPLC , retention time was 11 .75 minutes ). To a mixture solution of water (0 . 2 mL ) and 1 , 2 - dime thoxyethane ( 1 . 9 mL ) of rac - (1R 2R ) - 1 -amino - 4 , 4 - dim Step 2 60 ethyl- 1 ,2 , 3 , 4 - tetrahydronaphthalen - 2 - ol ( 100 mg) obtained in (Example 1 ) < Step 4 > , D - ( - ) - tartaric acid ( 78 mg) was Synthesis of 1 -( ( 1R 2R ) - 2 -hydroxy - 4 ,4 -dimethyl - 1 , added at room temperature . The reaction solution was heated 2, 3 , 4 - tetrahydronaphthalen - 1- yl ) - 3 -( 5 -methyl - 2 to 90° C . for dissolution , then allowed to cool to room phenylpyridin -3 -yl ) urea temperature , and stirred at the same temperature for 22 hours 65 and 30 minutes . The precipitated crystal was collected by By the samemethod as in (Example 2 ) < Step 3 > , the title filtration , and the crystal was washed with a mixture solvent compound ( 12 mg ) was obtained as a white solid from the of 1 , 2 - dimethoxyethane -water ( 23 : 2 ) and dried under US 10 , 399 , 945 B2 143 144 reduced pressure to obtain the title compound ( 79 mg) as a Example 7i white solid . The optical purity of the obtained title com pound was 96 . 4 % (HPLC , retention time 10 .54 minutes ). To a mixture solution of water ( 167 mL ) and acetonitrile ( 1503 mL ) of rac - ( 1R , 2R ) - 1 -amino - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 Example 7e 5 tetrahydronaphthalen - 2 -ol (83 . 5 g ) obtained in (Example 1 ) < Step 4 > , D - ( - ) - tartaric acid (65 . 5 g ) was added at room To a mixture solution of water (0 . 2 mL ) and 1, 2 -dime - temperature . The reaction solution was stirred at 75° C . for thoxyethane ( 1. 0 mL ) of rac - ( 1R ,2R ) - 1 -amino - 4 , 4 -dim - 1 hour , allowed to cool to room temperature , and stirred at ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 - ol ( 100 mg) obtained the same temperature for 16 hours . The precipitated crystal in (Example 1 ) < Step 4 > , D - ( - ) -tartaric acid (78 mg) was 10 was collected by filtration , and the crystal was washed with added at room temperature . The reaction solution was heated a mixture solvent of acetonitrile -water ( 20 : 1 ) and dried to 90° C . for dissolution , then allowed to cool to room under reduced pressure to obtain the title compound ( 59. 5 g ) temperature , and stirred at the same temperature for 30 as a white solid . The optical purity of the obtained title minutes. The precipitated crystal was collected by filtration , compound was 98 . 4 % (SFC , retention time 2 .05 minutes ). and the crystal was washed with a mixture solvent of Note that the (1R ,2R ) - 1 -amino -4 ,4 -dimethyl - 1, 2 ,3 ,4 -tet 1 , 2 -dimethoxyethane -water ( 4 : 1 ) and dried under reduced rahydronaphthalen - 2 - ol (2S , 3S ) - 2 , 3 - dihydroxy succinate pressure to obtain the title compound ( 70 mg) as a white monohydrate obtained in (Example 7a ) to (Example 7i) described above each exhibited the same 1H -NMR and solid . The optical purity of the obtained title compound was LC -Mass data as that of the compound obtained in ( Example 96 . 3 % (HPLC , retention time 10 . 50 minutes ) . 20 7 ) < Step 1 > ( Table 2 and Table 3 ) . Note that regarding the ( 1R ,2R ) - 1 - amino - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 -tetrahydronaphtha Example 7f len - 2 - ol ( 2S , 3S ) - 2 , 3 - dihydroxy succinate monohydrate obtained in ( Example 7 ) < Step 1 > and (Example 7a ) to To a mixture solution of water (0 .12 mL ) and acetone ( Example 7i) , the absolute configuration was determined by ( 1 . 08 mL) of rac - ( 1R . 2R ) - 1 -amino - 4 , 4 - dimethyl- 1, 2 , 3 , 4 -tet - 25 X -ray crystal structure analysis . Note that the crystal struc rahydronaphthalen - 2 - ol ( 100 mg) obtained in (Example 1 ) ture analysis by X - ray was carried out under the measure < Step 4 > , D - ( - ) - tartaric acid ( 78 mg) was added at room ment conditions described in FIG . 1 ( see FIG . 1 ). temperature . The reaction solution was heated and refluxed at 90° C . for dissolution , then allowed to cool to room Example 8 temperature , and stirred at the same temperature for 30 30 minutes. The precipitated crystal was collected by filtration , Synthesis of 1 - ( 1R ,2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , and the crystal was washed with a mixture solvent of 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) - 3 - (6 - ( hydroxym acetone - water ( 9 : 1 ) and dried under reduced pressure to ethyl ) - 5 -methyl - 2 -phenylpyridin - 3 -yl ) urea obtain the title compound ( 82 mg) as a white solid . The optical purity of the obtained title compound was 94 . 2 % 35 Step 1 (HPLC , retention time 10 .56 minutes ) . Synthesis of Example 7g 5 - amino - 3 -methyl - 6 - phenylpicolinonitrile To a mixture solution of water ( 0 . 2 mL ) and acetone ( 1 . 0 40 A mixture of the compound ( 13 g ) obtained in (Example mL ) of rac - ( 1R 2R ) - 1 - amino - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahy 3 ) < Step 1 > , zinc cyanide (6 .3 g ), and tetrakis triphenyl dronaphthalen - 2 - ol ( 100 mg) obtained in (Example 1 ) < Step phosphine palladium ( 5 . 7 g ) in N , N - dimethylformamide 4 > , D - ( - ) - tartaric acid ( 78 mg) was added at room tempera - ( 130 mL ) was stirred under a nitrogen atmosphere at 110° C . ture . The reaction solution was heated to 90° C . for disso - for 3 . 5 hours . The reaction solution was allowed to cool to lution , then allowed to cool to room temperature , and stirred 45 room temperature and partitioned by addition of ethyl at the same temperature for 30 minutes. The precipitated acetate and a saturated aqueous solution of sodium hydrogen crystal was collected by filtration , and the crystal was carbonate , and the mixture was filtered through a pad of washed with a mixture solvent of acetone -water ( 4 : 1 ) and Celite . After separating the ethyl acetate layer , the organic dried under reduced pressure to obtain the title compound layer was washed successively with water and brine, and ( 72 mg) as a white solid . The optical purity of the obtained 50 dried over sodium sulfate . Ethyl acetate -heptane ( 1 : 1 ) was title compound was 96 . 0 % (HPLC , retention time 10 . 51 added to the residue obtained by distilling off the solvent minutes ) . under reduced pressure , followed by triturating to obtain the title compound ( 8 . 4 g ) as a yellow solid . Example 7h 55 Step 2 To a mixture solution of water (42 mL) and acetonitrile ( 378 mL ) of rac - ( 1R , 2R ) - 1 - amino - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 -tet Synthesis of ethyl rahydronaphthalen - 2 -ol (21 . 0 g ) obtained in ( Example 1 ) 5 - amino - 3 -methyl - 6 - phenylpicolinate < Step 4 > , D - ( - ) - tartaric acid ( 16 . 5 g ) was added at room temperature . The reaction solution was stirred at 70° C . for 60 The compound ( 2 .0 g ) obtained in ( Example 8 ) < Step 1 > 1 hour, allowed to cool to room temperature , and stirred at was heated at 90° C . for 72 hours in sulfuric acid (8 .0 mL ) . the same temperature for 16 hours. The precipitated crystal Subsequently , the reaction solution was poured into ethanol was collected by filtration , and the crystal was washed with ( 16 mL ) and stirred at 90° C . for 5 hours . After cooling , the a mixture solvent of acetonitrile - water ( 9 : 1 ) and dried under reaction solution was added to ice water and neutralized reduced pressure to obtain the title compound ( 16 . 0 g ) as a 65 with 25 % aqueous ammonia solution under ice cooling . A white solid . The optical purity of the obtained title com - saturated aqueous solution of sodium hydrogen carbonate pound was 98 . 7 % (SFC , retention time 2 . 01 minutes ) . was added to the mixture , and the mixture was extracted US 10 , 399 , 945 B2 145 146 with ethyl acetate . The organic layer was washed with brine ( 1 .5 g ) , and dichloro [ 1 , 1 bis ( diphenylphosphino ) ferrocene ] and dried over sodium sulfate . The solvent was distilled off palladium dichloromethane adduct ( 0 . 12 g ) were added , under reduced pressure , and the obtained residue was puri followed by stirring at 80° C . for 4 hours . After cooling , fied by silica gel column chromatography (mobile phase : water was added to the reaction solution . Insolubles were heptane/ ethyl acetate = 90 : 10 to 60 :40 ) to obtain the title 5 filtered off with a pad of Celite and washed with ethyl compound (1 . 2 g ) as a pale yellow solid . acetate , and the organic layer was separated from the filtrate , washed successively with water and brine , and dried over Step 3 sodium sulfate . The solvent was distilled off under reduced pressure , and the obtained residue was purified by silica gel Synthesis of 10 column chromatography ( stationary phase : amino -silica gel, ( 5 -amino - 3 -methyl - 6 -phenylpyridin - 2 - yl ) methanol mobile phase : heptane /ethyl acetate = 100 :0 to 50 :50 ) to obtain the title compound ( 0 . 31 g ) . To a tetrahydrofuran (10 mL ) solution of the compound (0 . 90 g ) obtained in ( Example 8 ) < Step 2 > , a 3 molar lithium Step 2 borohydride- tetrahydrofuran solution ( 1. 8 mL ) was added 15 under ice cooling . The reaction solution was stirred at room Synthesis of 2 , 2 , 2 - trichloroethyl ( 5 -methyl - 6 - ( 2 temperature for 2 hours . The reaction was quenched by methylpyrimidin - 5 - yl ) - 2 - phenylpyridin - 3 - yl ) carbam adding brine to the reaction solution under ice cooling , and ate the mixture was extracted with ethyl acetate . The organic layer was dried over sodium sulfate , and the solvent was 20 Pyridine ( 0 .22 mL ) and 2 , 2 , 2 -trichloroethyl chlorofor distilled off under reduced pressure . Heptane - ethyl acetate mate ( 0 . 36 mL ) were added to a 1 , 2 - dichloroethane ( 100 ( 1 : 1 ) was added to the obtained residue , followed by trit - mL ) solution of the compound ( 0 .30 g ) obtained in ( Ex uraing to obtain the title compound ( 0 .64 g ) as a white solid ample 9 ) < Step 1 > at room temperature , followed by stirring at the same temperature for 1 hour. An aqueous solution of Step 4 25 sodium hydrogen carbonate was added to the reaction solu tion and the mixture was extracted with ethyl acetate. The Synthesis of p - tolyl (6 -( hydroxymethyl ) -5 -methyl organic layer was washed successively with water and brine , 2 -phenylpyridin -3 - yl) carbamate and dried over sodium sulfate . The solvent was distilled off under reduced pressure, and the obtained residue was puri To a tetrahydrofuran ( 12 mL ) solution of the compound 30 fied by silica gel column chromatography ( stationary phase : (0 . 54 g ) obtained in ( Example 8 ) < Step 3 > , p - tolyl chloro - amino - silica gel, mobile phase : heptane/ ethyl acetate = 2 : 1 ) formate ( 0 .72 mL ) was added , and the reaction solution was to obtain the title compound ( 0 .41 g ) as a white solid . stirred at 70° C . for 2 hours . Ethyl acetate ( 35 mL ) and 1 N sodium hydroxide aqueous solution (6 . 0 mL ) were added to Step 3 the reaction solution , and the mixture was stirred at room 35 temperature for 40 minutes. The ethyl acetate layer was Synthesis of 1 - ( 1R , 2R )- 2 -hydroxy - 4 ,4 -dimethyl - 1, separated and dried over sodium sulfate. The solvent was 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl )- 3 -( 5 -methyl - 6 - ( 2 distilled off under reduced pressure , and the obtained residue methylpyrimidin - 5 -yl ) - 2 -phenylpyridin - 3 - yl) urea was triturated with heptane - ethyl acetate ( 1 : 1 ) to obtain the title compound ( 0 .38 g ) as a white solid . 40 The compound ( 76 mg) obtained in (Example 7 ) < Step 1 > and triethylamine ( 0 .093 mL ) were added to an N -methyl Step 5 pyrrolidone ( 0 . 50 mL ) solution of the compound ( 0 . 10 g ) obtained in (Example 9 ) < Step 2 > , followed by stirring at Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl - 1 , 40° C . for 18 . 5 hours. Water ( 3 . 0 mL ) was added to the 2, 3 ,4 - tetrahydronaphthalen - 1 -yl ) -3 - (6 - (hydroxym 45 reaction solution , and the resulting precipitate was collected ethyl) - 5 -methyl - 2 -phenylpyridin - 3 - yl) urea by filtration , then washed with water. The crude product collected by filtration was suspended in a mixture solvent of By the samemethod as in ( Example 2 ) < Step 3 > , the title heptane - isopropanol ( 9 : 1 ) , and triturated , collected by fil compound ( 33 mg ) was obtained as a white solid from the tration , washed with heptane - isopropanol ( 9 : 1 ) , and dried compound (44 mg) obtained in (Example 8 ) < Step 4 > and 50 under reduced pressure to obtain the title compound (82 the compound (47 mg) obtained in (Example 7 ) < Step 1 > . mg) . The below - described ( Example 9a ) to (Example 9j) Example 9 describe the synthesis of 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 -dim ethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 -( 5 -methyl - 6 - ( 2 Synthesis of 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , 55 methylpyrimidin - 5 -yl ) - 2 -phenylpyridin - 3 -yl ) urea . 2 ,3 , 4 -tetrahydronaphthalen -1 -yl ) - 3- ( 5 -methyl - 6 -( 2 methylpyrimidin - 5 -yl ) - 2 -phenylpyridin - 3 -yl ) urea Examples 9a to 9j Step 1 Synthesis of 1 - ( ( 1R , 2R ) - 2 - hydroxy - 4 , 4 - dimethyl- 1 , 60 2 ,3 , 4 - tetrahydronaphthalen - 1- yl) - 3 - (5 -methyl - 6 -( 2 Synthesis of 5 -methyl - 6 - ( 2 -methylpyrimidin - 5 - yl) methylpyrimidin - 5 - yl) - 2 - phenylpyridin - 3 - yl) urea 2 - phenylpyridin - 3 - amine Example 9a To a mixture solution of water ( 2 . 0 mL ) and 1 , 2 - dime thoxyethane ( 10 mL ) of the compound ( 0 .40 g ) obtained in 65 The compound ( 80 mg) obtained in ( Example 7 ) < Step 1 > ( Example 3 ) < Step 1 > , 2 -methyl - 5 -( 4 ,4 ,5 , 5 - tetramethyl- 1 , 3 , and triethylamine (0 .093 mL ) were added to an N -methyl 2 -dioxaborolan -2 -yl ) pyrimidine ( 0 .44 g ), cesium carbonate pyrrolidone (0 .5 mL ) solution of the compound ( 0 . 1 g ) US 10 , 399 , 945 B2 147 148 obtained in (Example 9 ) < Step 2 ) , followed by stirring at sulfoxide (0 . 5 mL ) solution of the compound (0 . 1 g ) 50° C . for 2 hours to obtain the title compound ( 78 % yield ) . obtained in ( Example 9 ) < Step 2 > , followed by stirring at room temperature for 26 hours to obtain the title compound Example 9b (92 % yield ) and 5 -methyl - 6 -( 2 -methylpyrimidin - 5 -yl ) - 2 5 phenylpyridin - 3 - amine ( 3 % yield ) . The compound (2 .08 g ) obtained in (Example 7) < Step 1 > and triethylamine ( 2 .42 mL ) were added to an N -methyl Example 9i pyrrolidone (26 mL ) solution of the compound ( 2 . 6 g ) obtained in (Example 9 ) < Step 2 , followed by stirring at The compound (80 mg) obtained in ( Example 7 ) < Step 1 > 50° C . for 3 . 5 hours to obtain the title compound ( about 70 % and 1 , 8 - diazabicyclo [ 5 . 4 .0jundec - 7 - ene (DBU ) ( 0 .07 mL ) yield ) and 5 -methyl - 6 -( 2 -methylpyrimidin -5 -yl ) -2 - phe were added to a dimethyl sulfoxide ( 0 . 5 mL ) solution of the nylpyridin - 3 - amine ( 10 % yield ) . compound ( 0 . 1 g ) obtained in (Example 9 ) < Step 2 > , followed by stirring at room temperature for 3 . 25 hours to Example 9c obtain the title compound (92 % yield ) and 5 -methyl - 6 - ( 2 methylpyrimidin - 5 - yl) - 2 - phenylpyridin - 3 - amine ( 1 . 2 % The compound (80 mg) obtained in ( Example 7 ) < Step 1 > yield ). and N , N - diisopropylethylamine ( 0 . 11 mL ) were added to a dimethyl sulfoxide ( 0 . 5 mL ) solution of the compound ( 0 . 1 Example 9j g ) obtained in ( Example 9 ) < Step 2 > , followed by stirring at The compound (80 mg) obtained in (Example 7 ) < Step 1 > 50° C . for 3 .25 hours to obtain the title compound (89 % 20 and 1 , 8 - diazabicyclo [ 5 .4 . 0 ] undec - 7 -ene (DBU ) ( 0 . 1 mL ) yield ) and 5 -methyl - 6 -( 2 -methylpyrimidin -5 -yl ) -2 - phe were added to a dimethyl sulfoxide ( 0 . 5 mL ) solution of the nylpyridin - 3 -amine (8 % yield ) . compound ( 0 . 1 g ) obtained in (Example 9 ) < Step 2 > , followed by stirring at room temperature for 2 hours to Example 9d obtain the title compound ( 92 % yield ) and 5 -methyl - 6 - ( 2 25 methylpyrimidin - 5 - yl) - 2 - phenylpyridin - 3 - amine ( 0 .7 % The compound ( 80 mg) obtained in (Example 7 ) < Step 1 > yield ) . and N , N - diisopropylethylamine ( 0 . 11 mL ) were added to an Note that the 1 - ( ( 1R .2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , acetonitrile ( 1 . 5 mL ) solution of the compound ( 0 . 1 g ) 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 6 -( 2 -methylpy obtained in (Example 9 ) < Step 2 > , followed by stirring at rimidin - 5 -yl ) - 2 -phenylpyridin - 3 -yl ) urea and 5 -methyl - 6 - ( 2 50° C . for 3 .25 hours and further at 70° C . for 2 .75 hours to methylpyrimidin -5 -yl ) - 2 - phenylpyridin - 3 - amine obtained obtain the title compound ( 58 % yield ) and 5 -methyl - 6 - ( 2 - 30 in ( Example 9a ) to (Example 9j ) described above each methylpyrimidin -5 - yl) - 2 -phenylpyridin - 3 - amine (2 % exhibited the same 1H -NMR and LC -Mass data as that of yield ) . the compound obtained in (Example 9 ) < Step 3 > and ( Example 9 ) < Step 1 > ( Table 2 and Table 3 ). Example 9e 35 Example 10 The compound ( 80 mg) obtained in (Example 7 ) < Step 1 > and N , N - diisopropylethylamine ( 0 . 11 mL ) were added to a Synthesis of 1 -( (1R ,2R ) - 2 -hydroxy - 4 ,4 -dimethyl - 1 , dimethyl sulfoxide ( 0 . 5 mL ) solution of the compound ( 0 . 1 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 6 - ( 1 g ) obtained in (Example 9 ) < Step 2 > , followed by stirring at methyl -1H -pyrazol - 4 -yl ) - 2 -phenylpyridin -3 -yl )urea 50° C . for 3 hours to obtain the title compound (88 % yield ) 40 and 5 -methyl - 6 - ( 2 -methylpyrimidin - 5 - yl) - 2 - phenylpyridin Step 1 3 - amine ( 8 % yield ) . Synthesis of 5 -methyl - 6 - ( 1 -methyl - 1H -pyrazol - 4 Example 9f yl) - 2 -phenylpyridin - 3 -amine 45 The compound (80 mg) obtained in (Example 7 ) < Step 1 > To a mixture solution of water (6 . 0 mL ) and 1 , 2 -dime and pyridine ( 0 . 053 mL ) were added to a dimethyl sulfoxide thoxyethane (30 mL ) of the compound ( 1 g ) obtained in (0 . 5 mL ) solution of the compound ( 0 .1 g ) obtained in (Example 3 ) , 1 -methyl - 4 - ( tetramethyl- 1 , 3 , 2 -di ( Example 9 ) < Step 2 > , followed by stirring at 50° C . for 1 oxaborolan - 2 - yl ) - 1H -pyrazole ( 0 .95 g ) , cesium carbonate hour and further at 80° C . for 2 hours to obtain the title 50 ( 3 . 7 g ) , and dichloro [ 1 , 1 '- bis (diphenylphosphino ) ferrocene ] compound (70 % yield ) and 5 -methyl - 6 - ( 2 -methylpyrimidin palladium dichloromethane adduct ( 0 . 31 g ) were added , 5 - yl) - 2 - phenylpyridin - 3 - amine ( 20 % yield ) . followed by stirring at 80° C . for 1 hour . After cooling , water was added to the reaction solution and the mixture was Example 9g extracted with ethyl acetate . The organic layer was washed SS successively with water and brine and dried over sodium The compound (80 mg) obtained in ( Example 7 ) < Step 1 > sulfate . The solvent was distilled off under reduced pressure , and potassium carbonate ( 46 mg) were added to a dimethyl and the obtained residue was purified by silica gel column sulfoxide (0 . 5 mL ) solution of the compound ( 0 . 1 g ) chromatography (mobile phase : heptane / ethyl acetate = 2 : 1 ) obtained in (Example 9 ) < Step 2 > , followed by stirring at to obtain the title compound (0 . 65 g ) as a pale red solid . 50° C . for 1 hour and further at 80° C . for 2 hours to obtain 60 the title compound ( 81 % yield ) and 5 -methyl - 6 - 2 -methyl Step 2 pyrimidin -5 -yl ) - 2- phenylpyridin - 3 -amine ( 16 % yield ). Synthesis of p - tolyl ( 5 -methyl - 6 - ( 1 -methyl - 1H Example 9h pyrazol- 4 - yl) - 2 - phenylpyridin - 3 - yl) carbamate 65 The compound (80 mg ) obtained in ( Example 7 ) < Step 1 > To a tetrahydrofuran (20 mL ) solution of the compound and triethylamine (0 . 11 mL ) were added to a dimethyl (0 .63 g ) obtained in ( Example 10 ) < Step 1 > , p - tolyl chlo US 10 ,399 ,945 B2 149 150 roformate (0 .44 mL ) was added at room temperature , fol- the compound ( 30 mg) obtained in ( Example 7 ) < Step 1 > lowed by stirring at 70° C . for 1 hour. Water was added to and purifying the reaction solution by preparative LC -Mass . the reaction solution , and the mixture was extracted with ethyl acetate. The organic layer was washed successively Example 12 with water and brine , and dried over sodium sulfate . The 5 solvent was distilled off under reduced pressure , and heptane Synthesis of 1 - ( 3 , 6 '- dimethyl- 6 -phenyl - [ 2 , 3 - bipyri was added to the obtained residue , followed by trituraing to din )- 5 -yl ) - 3 - (( 1R ,2R )- 2 -hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , obtain the title compound ( 0 .68 g ) as a white solid . 4 - tetrahydronaphthalen - 1 -yl ) urea Step 1 Step 3 10 Synthesis of 3 ,6 '- dimethyl- 6 - phenyl- [ 2 , 3 '- bipyridin ) Synthesis of 1 - (( 1R ,2R )- 2 -hydroxy - 4, 4 -dimethyl - 1, 5 - amine 2 ,3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 -( 5 -methyl - 6 -( 1 In accordance with the method described in (Example 10 ) methyl- 1H - pyrazol - 4 - yl) - 2 - phenylpyridin - 3 - yl) urea 15 < Step 1 > , the title compound (0 .24 g ) was obtained as a yellow amorphous using 6 -methylpyridine - 3 -boronic acid Triethylamine (0 .037 mL ) was added to an N -methylpyr - (0 . 31 g ) instead of 1 -methyl - 4 -( tetramethyl - 1, 3 ,2 - dioxa rolidone ( 0 . 15 mL ) solution of the compound ( 35 mg ) borolan - 2 - yl ) - 1H -pyrazole . obtained in ( Example 10 ) < Step 2 > and the compound ( 30 mg) obtained in (Example 7 ) < Step 1 > , followed by stirring 20 Step 2 at 40° C . for 1 hour. The reaction solution was purified by preparative LC -Mass to obtain the title compound (29 mg) Synthesis of p - tolyl ( 3 ,6 -dimethyl - 6 -phenyl - [ 2 , 3 ' as a white solid . bipyridin )- 5 -yl ) carbamate Example 11 25 In accordance with the method described in (Example 10 ) < Step 2 > , the title compound ( 0 . 28 g ) was obtained as a white solid using the compound ( 0 . 24 g ) obtained in ( Ex Synthesis of 1 -( ( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dimethyl - 1 , ample 12 ) < Step 1 > instead of 5 -methyl - 6 - ( 1 -methyl - 1H 2 ,3 ,4 - tetrahydronaphthalen - 1- yl) -3 - ( 3 -methyl - 6 pyrazol- 4 - yl) - 2 -phenylpyridin - 3 - amine . phenyl- 5 - ( trifluoromethyl) - [ 2 , 3 -bipyridin ) - 5 -yl ) urea 30 Step 3 Step 1 Synthesis of 1 -( 3 ,6 '- dimethyl - 6 -phenyl - [ 2 ,3 '- bipyri din ) - 5 - yl) - 3 - ( ( 1R 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , Synthesis of 3 -methyl - 6 -phenyl - 5' - (trifluoromethyl ) - 35 4 - tetrahydronaphthalen - 1 - yl) urea [ 2 , 3 '- bipyridin ) - 5 -amine In accordance with themethod described in (Example 10 ) In accordance with the method described in (Example 10 ) < Step 3 > , the title compound (23 mg) was obtained as a < Step 1 > , the title compound ( 0 . 53 g ) was obtained as a white solid by carrying out urea formation by use of the yellow solid using 5 - trifluoromethylpyridin - 3 -boronic acid 40 compound (36 mg) obtained in (Example 12 ) < Step 2 > and pinacol ester ( 0 .62 g ) instead of 1 -methyl - 4 - (tetramethyl - 1 , the compound (30 mg) obtained in ( Example 7 ) < Step 1 > 3 , 2 -dioxaborolan - 2 - yl) - 1H - pyrazole . and purifying the reaction solution by preparative LC -Mass . Example 13 Step 2 45 Synthesis of 1 - ( 6 -cyano - 3 -methyl - 6 - phenyl- [ 2 , 3 ' Synthesis of p - tolyl ( 3 -methyl - 6 - phenyl- 5 - ( trifluo bipyridin ) - 5 - yl) - 3 - ( (1R ,2R ) - 2 -hydroxy - 4 , 4 - dimethyl romethyl ) - [ 2 , 3 ' -bipyridin ) - 5 - yl) carbamate 1 , 2, 3, 4 -tetrahydronaphthalen - 1 -yl ) urea In accordance with the method described in ( Example 10 ) 50 Step 1 < Step 2 > , the title compound ( 0 .65 g ) was obtained as a white solid using the compound (0 .53 g ) obtained in (Ex Synthesis of 5 - amino - 3 -methyl - 6 -phenyl - [2 ,3 ' - bi ample 11 ) < Step 1 > instead of 5 -methyl - 6 -( 1 -methyl - 1H pyridin ) -6 ' - carbonitrile pyrazol- 4 - yl) - 2 -phenylpyridin - 3 - amine . 55 In accordance with themethod described in (Example 10 ) < Step 1 > , the title compound ( 0 .52 g ) was obtained as a Step 3 yellow solid using 2 - cyanopyridin - 5 -boronic acid pinacol ester ( 0 .52 g ) instead of 1 -methyl - 4 - ( tetramethyl- 1 , 3 , 2 - di oxaborolan - 2 -yl ) - 1H -pyrazole . Synthesis of 1 -( ( 1R ,2R ) - 2 -hydroxy - 4 ,4 - dimethyl- 1 , 60 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 3 -methyl - 6 Step 2 phenyl- 5 ' - ( trifluoromethyl) - [ 2 , 3 - bipyridin ) - 5 - yl) urea Synthesis of p - tolyl (6 - cyano - 3 -methyl -6 - phenyl- [ 2 , In accordance with the method described in ( Example 10 ) 3 '- bipyridin ) -5 -yl ) carbamate < Step 3 > , the title compound (29 mg) was obtained as a 65 white solid by carrying out urea formation by use of the In accordance with the method described in (Example 10 ) compound (41 mg) obtained in (Example 11) < Step 2 > and < Step 2 > , the title compound (0 .49 g ) was obtained as a US 10 , 399 , 945 B2 151 152 yellow solid using the compound ( 0 .52 g ) obtained in yellow solid using ( 2 - ( trifluoromethylpyrimidin ) - 5 - yl) ( Example 13 ) < Step 1 > instead of 5 -methyl - 6 -( 1 -methyl - boronic acid ( 0 .44 g ) instead of 1- methyl - 4 - ( tetramethyl- 1, 1H -pyrazol - 4 - yl) - 2 - phenylpyridin - 3 - amine. 3 , 2 - dioxaborolan - 2 -yl ) - 1H - pyrazole Step 3 Step 2 Synthesis of 1 - ( 6 - cyano - 3 -methyl - 6 - phenyl- [ 2 , 3 ' bipyridin )- 5 -yl ) - 3- ( 1R ,2R )- 2 -hydroxy - 4, 4 -dimethyl Synthesis of p -tolyl ( 5 -methyl - 2 - phenyl- 6 - ( 2 - ( trif 1 , 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) urea luoromethyl) pyrimidin - 5 -yl ) pyridin - 3 - yl) carbamate In accordance with the method described in ( Example 10 ) 10 In accordance with the method described in (Example 10 ). < Step 3 > , the title compound ( 31 mg ) was obtained as a white solid by carrying out urea formation by use of the < Step 2 > , the title compound ( 0 .63 g ) was obtained as a compound (37 mg) obtained in ( Example 13 ) < Step 2 > and yellow solid using the compound (0 . 46 g ) obtained in the compound ( 30 mg) obtained in ( Example 7 ) < Step 1 > (Example 15 ) < Step 1 > instead of 5 -methyl - 6 - ( 1 -methyl and purifying the reaction solution by preparative LC -Mass . 15 TH1H -pyrazol -4 -yl ) - 2 -phenylpyridin - 3 -amine . Example 14 Step 3 Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl - 1 , Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 3 -methyl - 6 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 -methyl - 2 (methylsulfonyl ) -6 - phenyl- [ 2 , 3 ' -bipyridin ) - 5 - yl) urea 20 phenyl- 6 - ( 2 - ( trifluoromethyl) pyrimidin - 5 - yl) pyridin Step 1 3 - yl) urea In accordance with the method described in ( Example 10 ) Synthesis of 3 -methyl -6 '- ( methylsulfonyl ) - 6 -phenyl < Step 3 > , the title compound ( 30 mg) was obtained as a [ 2 , 3 - bipyridin ) - 5 - amine 25 white solid by carrying out urea formation by use of the In accordance with the method described in (Example 10 ) compoundcompound (41 mg) obtained in ( Example 15 ) < Step 2> and < Step 1 > , the title compound ( 0 . 55 g ) was obtained as a the amine ( 30 mg) obtained in ( Example 7 ) < Step 1 > and yellow amorphous using 6 -( methylsulfonyl )pyridine - 3 -bo - purifying the reaction solution by preparative LC -Mass . ronic acid pinacol ester ( 0 .65 g ) instead of 1 -methyl - 4 ( tetramethyl- 1 , 3, 2- dioxaborolan -2 - yl) - 1H -pyrazole . 30 Example 16 Step 2 Synthesis of 1 -( 6 - (4 -cyanophenyl ) - 5 -methyl - 2 - phe nylpyridin - 3 - yl) - 3 - ( (1R ,2R ) - 2 -hydroxy -4 , 4 -dim Synthesis of p - tolyl ( 3 -methyl -6 - (methylsulfonyl ) ethyl - 1, 2 ,3 , 4 -tetrahydronaphthalen - 1 -yl ) urea 6 -phenyl - [2 ,3² - bipyridin ) -5 -yl ) carbamate 35 In accordance with the method described in (Example 10 ) Step 1 < Step 2 > , the title compound (0 .71 g ) was obtained as a white solid using the compound ( 0 .55 g ) obtained in ( Ex Synthesis of 4 -( 5 - amino - 3 -methyl -6 -phenylpyridin ample 14 ) < Step 1 > instead of 5 -methyl -6 - ( 1 -methyl - 1H 2 -yl ) benzonitrile pyrazol - 4 -yl ) - 2 - phenylpyridin - 3 -amine . In accordance with the method described in ( Example 10 ) Step 3 < Step 1 > , the title compound (0 . 30 g ) was obtained as a Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl - 1 , brown solid using 4 -cyanophenylboronic acid ( 0 .34 g ) 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) - 3 - ( 3 -methyl - 6 instead of l -methyl - 4 - (tetramethyl - 1 ,3 , 2 - dioxaborolan - 2 (methylsulfonyl ) -6 -phenyl - [ 2 ,3 -bipyridin )- 5 -yl ) urea 45 yl) - 1H - pyrazole . In accordance with the method described in (Example 10 ) Step 2 < Step 3 > , the title compound ( 30 mg ) was obtained as a white solid by carrying out urea formation by use of the Synthesis of p - tolyl (6 -( 4 -cyanophenyl ) - 5 -methyl - 2 compound (42 mg) obtained in ( Example 14 ) < Step 2 > and phenylpyridin - 3 - yl) carbamate the compound (30 mg) obtained in (Example 7 ) < Step 1 > In accordance with the method described in ( Example 10 ) and purifying the reaction solution by preparative LC -Mass . < Step 2 > , the title compound ( 0 . 33 g ) was obtained as a Example 15 white solid using the compound ( 0 . 30 g ) obtained in (Ex 55 ample 16 ) < Step 1 > instead of 5 -methyl - 6 - ( 1 -methyl - 1H Synthesis of 1 - ( (1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , pyrazol- 4 - yl) - 2 -phenylpyridin - 3 -amine . 2 , 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 -( 5 -methyl -2 phenyl- 6 -( 2 -( trifluoromethyl ) pyrimidin - 5 -yl ) pyridin Step 3 3 - yl) urea 60 Synthesis of 1 -( 6 - (4 -cyanophenyl ) - 5 -methyl - 2 -phe Step 1 nylpyridin - 3 -yl ) - 3 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 - dim ethyl - 1, 2 ,3 ,4 - tetrahydronaphthalen - 1 -yl ) urea Synthesis of 5 -methyl - 2 -phenyl - 6 - ( 2 - ( trifluorom ethyl) pyrimidin - 5 -yl ) pyridin -3 -amine In accordance with the method described in ( Example 10 ) 65 < Step 3 > , the title compound ( 27 mg) was obtained as a In accordance with the method described in (Example 10 ) white solid by carrying out urea formation by use of the < Step 1 > , the title compound ( 0 .46 g ) was obtained as a compound (37 mg) obtained in (Example 16 ) < Step 2 > and US 10 , 399 , 945 B2 153 154 the compound ( 30 mg) obtained in (Example 7 ) < Step 1 > 3 , 2 -dioxaborolan - 2 - yl) - 1H -pyrazole - 1 - carboxylate (0 . 13 g ) and purifying the reaction solution by preparative LC -Mass . instead of 1 -methyl -4 - ( tetramethyl- 1 ,3 ,2 -dioxaborolan - 2 yl) - 1H - pyrazole . Example 17 Step 2 Synthesis of 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , Synthesis of tert- butyl 4 -( 3 -methyl - 6 -phenyl -5 - (( ( p 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 3 -methyl - 6 tolyloxy ) carbonyl) amino )pyridin - 2 -yl ) - 1H -pyra phenyl -2 ' - ( trifluoromethyl) - [ 2 ,4 ' - bipyridin )- 5 -yl )urea zole - l - carboxylate 10 In accordance with the method described in ( Example 10 ) Step 1 < Step 2 > , the title compound ( 0 . 082 g ) was obtained as a pale yellow amorphous using the compound ( 0 . 11 g ) Synthesis of 3 -methyl -6 -phenyl - 2 '- ( trifluoromethyl) obtained in (Example 18 ) < Step 1 > instead of 5 -methyl - 6 [ 2, 4 '- bipyridin )- 5 - amine 15 ( 1 -methyl -1H - pyrazol- 4 - yl) - 2 - phenylpyridin - 3 - amine . In accordance with themethod described in (Example 10 ) Step 3 < Step 1 > , the title compound (0 .45 g ) was obtained as a yellow solid using 4 -( 4 , 4 , 5 , 5 -tetramethyl - 1 , 3 , 2 - dioxaboro Synthesis of 1 -( ( 1R ,2R ) - 2 -hydroxy -4 , 4 -dimethyl -1 , lan - 2 - yl) - 2 - (trifluoromethyl ) pyridine (0 .62 g ) instead of 20 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 1 -methyl - 4 - (tetramethyl - 1 , 3 , 2 -dioxaborolan - 2 -yl ) - 1H - pyra phenyl- 6 - ( 1H -pyrazol - 4 - yl )pyridin - 3 - yl )urea zole . In accordance with the method described in ( Example 10 ) < Step 3 > , the title compound ( 13 mg ) was obtained as a Step 2 25 white solid by carrying out urea formation by use of the compound (43 mg) obtained in (Example 18 ) < Step 2 > and Synthesis of p - tolyl ( 3 -methyl - 6 - phenyl- 2 - ( trifluo the amine ( 30 mg) obtained in ( Example 7 ) < Step 1 > and romethyl )- [2 , 4 ' -bipyridin )- 5 - yl )carbamate purifying the reaction solution by preparative LC -Mass . 30 Example 19 In accordance with the method described in ( Example 10 ) < Step 2 > , the title compound (0 .52 g ) was obtained as a Synthesis of 1 - ( ( 1R ,2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , white amorphous using the compound ( 0 . 45 g ) obtained in 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 6 - ( 2 -hydroxypy (Example 17 ) < Step 1 > instead of 5 -methyl - 6 - ( 1 -methyl rimidin - 5 - yl) - 5 -methyl - 2 - phenylpyridin - 3 - yl) urea 1H -pyrazol - 4 -yl ) - 2- phenylpyridin - 3 - amine . 35 Step 1 Step 3 Synthesis of 2 -( ( 4 -methoxybenzyl ) oxy )- 5 -( 4 ,4 ,5 ,5 tetramethyl- 1 ,3 ,2 - dioxaborolan -2 - yl) pyrimidine Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl - 1 , 40 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 3 -methyl - 6 To a 1, 2 -dimethoxyethane ( 100 mL ) solution of commer phenyl- 2 - (trifluoromethyl ) - [2 , 4 '- bipyridin )- 5 -yl ) urea cially available 5 -bromo - 2 - (( 4 -methoxybenzyl ) oxy ) pyrimi dine (CAS number 1159000 -88 - 0 ) ( 4 . 6 g ) , 4 , 4 , 4 ' , 4 ' , 5 , 5 , 5 ' , 5 ' In accordance with the method described in (Example 10 ) octamethyl- 2 , 2 -bi ( 1, 3 ,2 - dioxaborolane ) ( 5 . 2 g ), dichloro [ 1 , < Step 3 > , the title compound (33 mg) was obtained as a 45 1 -bis ( diphenylphosphino ) ferrocene palladium white solid by carrying out urea formation by use of the dichloromethane adduct ( 1 . 3 g ), and potassium acetate ( 4 .6 compound (41 mg ) obtained in ( Example 17 ) < Step 2 > and g ) were added . The reaction solution was stirred at 90° C . for the compound ( 30 mg) obtained in ( Example 7 ) < Step 1 > 4 hours under a nitrogen atmosphere. After cooling , ethyl and purifying the reaction solution by preparative LC -Mass . , acetate , water, and a saturated aqueous solution of sodium 50 hydrogen carbonate were added to the reaction solution for partitioning , and the ethyl acetate layer was separated , Example 18 followed by drying over sodium sulfate . The solvent was distilled off under reduced pressure , and the obtained residue Synthesis of 1 -( ( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dimethyl - 1 , was triturated with a mixture solvent of heptane -ethyl 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 -methyl - 2 55 acetate ( 1 : 1 ) , then the precipitate was removed by filtration . The obtained filtrate was concentrated to obtain the crude phenyl- 6 - ( 1H -pyrazol - 4 -yl ) pyridin - 3 -yl ) urea title compound ( 9 . 1 g ) as a dark brown solid . Step 1 Step 2 60 Synthesis of tert -butyl 4 - (5 -amino -3 -methyl - 6 -phe Synthesis of 6 - ( 2 - ( ( 4 -methoxybenzyl ) oxy ) pyrimi nylpyridin -2 -yl ) - 1H -pyrazole - 1 -carboxylate din -5 - yl) -5 -methyl - 2 -phenylpyridin -3 -amine The compound ( 4 .6 g ) obtained in ( Example 19 ) < Step In accordance with the method described in ( Example 10 ) 65 1 > , cesium carbonate (6 . 3 g ) , and dichloro [ 1 , 1 ' -bis ( diphe < Step 1 > , the title compound ( 0 . 12 g ) was obtained as a pale nylphosphino ) ferrocene ] palladium dichloromethane adduct yellow amorphous using tert - butyl 4 - ( 4 , 4 , 5 , 5 -tetramethyl - 1 , (0 . 53 g ) were added to a mixture solution of water ( 8 mL ) US 10 , 399 , 945 B2 155 156 and 1 , 2 -dimethoxyethane (40 mL ) of the compound ( 1. 7 g ) (CAS number 663955 - 79 -1 ) (25 g ) instead of 5 -bromo -2 obtained in (Example 3 ) < Step 1 > , followed by stirring (( 4 -methoxybenzyl ) oxy )pyrimidine . under a nitrogen atmosphere at 90° C . for 3 hours . After cooling , ethyl acetate and water were added to the reaction Step 2 solution for partitioning , and the separated ethyl acetate 5 layer was dried over sodium sulfate . The residue obtained by Synthesis of 6 '- ( ( 4 -methoxybenzyl ) oxy ) - 3 -methyl - 6 distilling off the solvent under reduced pressure was purified phenyl- [ 2 ,3 ' - bipyridin )- 5 - amine by silica gel column chromatography (mobile phase : hep tanelethyl acetate = 80 : 20 to 50 : 50 to 0 : 100 , ethyl acetate ! In accordance with the method described in ( Example 19 ) methanol= 90 : 10 ) , and the fraction containing the desired 10 < Step 2 > , the title compound ( 0 . 92 g ) was obtained as a pale product was concentrated , then the obtained residue was yellow solid using the compound ( 1. 0 g ) obtained in ( Ex triturated with heptane - ethyl acetate ( 3 : 2 ) to obtain the title ample 20 ) < Step 1 > instead of the compound obtained in compound (1 .8 g ) as an gray brown solid . (Example 19 ) < Step 1 > . Step 3 15 Step 3 Synthesis of p -tolyl (6 -( 2 -( ( 4 -methoxybenzyl ) oxy ) Synthesis of p - tolyl ( 6 '- ( ( 4 -methoxybenzyl ) oxy ) - 3 pyrimidin - 5 - yl ) - 5 -methyl - 2 -phenylpyridin - 3 - yl ) car methyl- 6 - phenyl- [ 2 , 3 '- bipyridin ) - 5 - yl) carbamate bamate 20 In accordance with the method described in (Example 19) , the title compound ( 0 .84 g ) was obtained as a pale To a tetrahydrofuran ( 170 mL ) solution of the compound yellow amorphous using the compound ( 0 .70 g ) obtained in (1 . 7 g ) obtained in (Example 19 ) < Step 2 > , p - tolyl chloro - (Example 20 ) < Step 2 > instead of the amine obtained in formate ( 1 . 2 mL ) was added at room temperature , followed (Example 19 ) < Step 2 > . by stirring at 50° C . for 2 hours . Heptane ( 150 mL ) was 25 added to the reaction solution , and the reaction solution was Step 4 concentrated under reduced pressure until the volume reached about a half volume. After repeating the above Synthesis of 1 - (6 -hydroxy - 3 -methyl - 6 -phenyl - [ 2 , 3 ' operation twice , heptane (100 mL ) was added for trituraing , bipyridin ) - 5 - yl) - 3 - ( (1R 2R ) - 2 -hydroxy - 4 , 4 - dimethyl and the precipitate was collected by filtration to obtain the 30 1, 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) urea crude title compound ( 2 . 2 g ) as a yellow solid . In accordance with the method described in (Example 19 ) , the title compound ( 14 mg ) was obtained as a Step 4 white solid by carrying out urea formation and deprotection 35 by use of the compound (41 mg) obtained in (Example 20 ) Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 -dimethyl - 1 , < Step 3 > and the compound ( 30 mg ) obtained in (Example 2 ,3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 -( 6 - (2 -hydroxypy 7 ) < Step 1 > and purifying the reaction solution by prepara rimidin - 5 - yl ) - 5 -methyl - 2 - phenylpyridin - 3 - yl) urea tive LC -Mass . The compound (30 mg ) obtained in ( Example 7 ) < Step 1 > 40* Example 21 and triethylamine ( 0 . 037 mL ) were added to an N -methyl pyrrolidone ( 0 . 20 mL ) solution of the compound (47 mg) Synthesis of 1 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1 , obtained in ( Example 19 ) < Step 3 > , followed by stirring at 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - (6 - ( 2 - ( 2 -hy 40° C . for 1 hour. Subsequently , hydrogen chloride ( 4 N droxypropan - 2 -yl ) pyrimidin - 5 - yl) - 5 -methyl - 2 - phe ethyl acetate solution ) (0 .20 mL ) was added to the reaction 45 nylpyridin - 3 - yl) urea solution , followed by stirring at room temperature for 1 hour. The reaction solution was purified by preparative Step 1 LC -Mass to obtain the title compound ( 13 mg) as a white solid . Synthesis of 2 -( 5 -( 5 -amino - 3 -methyl - 6 -phenylpyri 50 din - 2 - yl) pyrimidin - 2 - yl) propan - 2 -ol Example 20 In accordance with the method described in ( Example 10 ) < Step 1 > , the title compound ( 0 .54 g ) was obtained as a Synthesis of 1 - ( 6 -hydroxy - 3 -methyl - 6 - phenyl- [ 2 , 3 ' yellow solid using 2 - ( 5 - ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 - dioxa bipyridin )- 5 -yl ) -3 -( ( 1R 2R )- 2 -hydroxy -4 , 4 - dimethyl 55 borolan -2 - yl) pyrimidin -2 - yl) propan -2 - ol (0 .76 g ) instead of 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 - yl) urea 1 -methyl - 4 - (tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl) - 1H - pyra zole . Step 1 Step 2 60 Synthesis of p - tolyl (6 -( 2 -( 2- hydroxypropan - 2- yl ) Synthesis of 2 - ( ( 4 -methoxybenzyl )oxy ) -5 - ( 4 ,4 , 5 , 5 pyrimidin - 5 - yl) - 5 -methyl - 2 - phenylpyridin - 3 - yl) car tetramethyl - 1 ,3 , 2 - dioxaborolan - 2 - yl) pyridine bamate In accordance with the method described in ( Example 19 ) 65 In accordance with the method described in (Example 10 ) < Step 1 > , the title compound (19 g ) was obtained as a brown < Step 2 > , the title compound ( 0 . 18 g ) was obtained as a solid using 5 -bromo - 2- ( (4 -methoxybenzyl ) oxy )pyridine white amorphous using the compound (0 .25 g ) obtained in US 10 , 399 , 945 B2 157 158 ( Example 21 ) < Step 1 > instead of 5 -methyl - 6 - ( 1 -methyl formate ( 1 . 3 mL ) was added at room temperature , followed 1H -pyrazol - 4 - yl) - 2 - phenylpyridin - 3 - amine . by stirring at room temperature for 16 hours and subsequent stirring at 50° C . for 2 hours . The reaction solution was Step 3 concentrated under reduced pressure , and heptane was 5 added to the residue for trituraing to obtain the title com Synthesis of 1 - (( 1R , 2R )- 2 -hydroxy - 4, 4 -dimethyl - 1, pound (1 .5 g) as a pale yellow solid . 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 6 - ( 2 - ( 2 - hy droxypropan - 2 - yl) pyrimidin - 5 - yl) -5 -methyl - 2 - phe Step 2 nylpyridin - 3 -yl ) urea 10 Synthesis of rac - 1 - ( ( 1R ,2R ) - 6 - bromo- 2 -hydroxy - 4 , In accordance with the method described in (Example 10 ) 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 6 < Step 3 > , the title compound ( 22 mg ) was obtained as a cyano -5 -methyl - 2 -phenylpyridin -3 -yl ) urea white solid by carrying out urea formation by use of the compound (40 mg) obtained in ( Example 21 ) < Step 2 > and The compound ( 0 . 10 g ) obtained in (Example 22 ) < Step the compound ( 30 mg) obtained in ( Example 7 ) < Step 1 > 15 2 > and N , N -diisopropylethylamine (0 .013 mL ) were added to a tetrahydrofuran ( 2 . 0 mL ) solution of the compound and purifying the reaction solution by preparative LC -Mass . ( 0 . 13 g ) obtained in ( Example 23 ) < Step 1 > , followed by Example 22 stirring at 60° C . for 2 hours. Ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added Synthesis of rac- 1 - ( ( 1R , 2R ) -6 - bromo - 2 - hydroxy - 4 , 20 to the reaction solution for partitioning , and the separated 4 -dimethyl -1 , 2, 3 ,4 -tetrahydronaphthalen - 1 -yl ) - 3 -( 5 ethyl acetate layer was dried over sodium sulfate . The methyl- 2 -phenylpyridin - 3 - yl) urea solvent was distilled off under reduced pressure , and the obtained residue was purified by silica gel column chroma Step 1 tography (mobile phase : heptane /ethyl acetate = 75 :25 to 25 50 :50 ) to obtain the title compound (0 . 18 g ) as a white Synthesis of 6 -bromo - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy amorphous. dronaphthalen - 1 -ol Step 3 In accordance with the method described in (Example 1 ) < Step 1 > , the title compound ( 10 g ) was obtained as a 30 Synthesis of rac - 5 - ( 3 - ( ( 1R ,2R ) - 6 -bromo - 2 -hydroxy yellow liquid from 6 -bromo - 4 , 4 - dimethyl- 3 , 4 - dihydronaph 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) thalen - 1 ( 2H ) - one (CAS number 98453 -60 - 2 ) ( 10 g ) . ureido )- 3 -methyl - 6 - phenylpicolinamide Step 2 Potassium carbonate (0 .093 g) and hydrogen peroxide 35 (0 .13 g, 30 % aqueous solution ) were added to a dimethyl Synthesis of rac- ( 1R , 2R ) - 1 - amino - 6 - bromo- 4 , 4 sulfoxide ( 2 . 0 mL ) solution of the compound ( 0 . 17 g ) dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 -ol obtained in ( Example 23 ) < Step 2 > at room temperature . The mixture was stirred at room temperature for 19 hours , The title compound ( 3 . 2 g ) was obtained as a gray white followed by stirring at 40° C . for 2 hours and at 50° C . for solid from the compound ( 10 g ) obtained in ( Example 22 ) 40 2 hours . Ethyl acetate and water were added to the reaction < Step 1 > in the same method as in (Example 1) < Step 2 > , solution for partitioning , and the separated ethyl acetate < Step 3 > , and < Step 4 > . layer was washed successively with an aqueous solution of sodium thiosulfate , water, and brine , followed by drying Step 3 over sodium sulfate . The solvent was distilled off under 45 reduced pressure to obtain the title compound ( 0 . 16 g ) as a Synthesis of rac -1 - (( 1R , 2R ) - 6 -bromo - 2 -hydroxy -4 , white amorphous. 4 - dimethyl- 1 , 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) - 3 - ( 5 methyl- 2 -phenylpyridin - 3 - yl ) urea Example 24 The title compound ( 26 mg) was obtained from the 50 Synthesis of rac - 5 -( 3 - (( 1R ,2R )- 2 -hydroxy -4 ,4 -dim compound (29 mg) obtained in (Example 2 ) < Step 2 > and ethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl ) ureido )- 3 the compound ( 27 mg) obtained ( Example 22 ) < Step 2 > in methyl- 6 -phenylpicolinamide the same method as in ( Example 2 ) < Step 3 > . Triethylamine ( 0 .080 mL ) and a small amount of 10 % Example 23 55 palladium - carbon suspended in water was added to an ethanol ( 5 . 0 mL ) solution of the compound ( 0 . 15 g ) obtained Synthesis of rac- 5 - (3 - ( (1R ,2R ) -6 -bromo - 2 -hydroxy in (Example 23 ) < Step 3 > , followed by stirring under a 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) hydrogen atmosphere at room temperature for 75 minutes . ureido ) - 3 -methyl - 6 - phenylpicolinamide After completion of the reaction , the reaction solution was 60 filtered through a pad of Celite to remove the insolubles . The Step 1 filtrate was concentrated under reduced pressure , and ethyl acetate and a saturated aqueous solution of sodium hydrogen Synthesis of p - tolyl carbonate were added to the obtained residue for partition ( 6 -cyano -5 -methyl - 2 -phenylpyridin - 3 -yl ) carbamate ing . The separated ethyl acetate layer was washed with brine 65 and dried over sodium sulfate . The solvent was distilled off To a tetrahydrofuran ( 15 mL ) solution of the compound under reduced pressure to obtain the title compound ( 0 . 12 g ) ( 0 .91 g ) obtained in (Example 8 ) < Step 1 > , p - tolyl chloro - as a white amorphous. US 10 , 399 ,945 B2 159 160 Example 25 Example 26 Synthesis of rac - N - (2 -hydroxy -2 -methylpropyl ) - 5 Synthesis of rac- 1- ( ( 1R ,2R )- 2 -hydroxy -4 ,4 -dim ( 3 -( ( 1R ,2R ) - 2 -hydroxy -4 ,4 -dimethyl - 1 , 2, 3 ,4 - tetrahy ethyl- 1, 2 ,3 ,4 - tetrahydronaphthalen - 1- yl) - 3 -( 5 dronaphthalen - 1 - yl) ureido ) - 3 -methyl - 6 -phenylpico 5 methyl- 2 -( tetrahydro -2H -pyran -4 -yl ) pyridin -3 - yl) linamide urea Step 1 Step 1 10 Synthesis of 2 - ( 3 ,6 - dihydro - 2H -pyran - 4 - yl) - 5 -meth ylpyridin - 3 - amine Synthesis of 5 - amino - N - ( 2 -hydroxy - 2 -methylpro pyl) - 3- methyl -6 -phenylpicolinamide To a mixture solution of water ( 20 mL ) and 1 , 2 - dime thoxyethane ( 100 mL ) of commercially available 2 -chloro 15 5 -methylpyridin -3 -amine (CAS number 34552 - 13 - 1 ) (5 .0 To the compound ( 2. 0 g ) obtained in (Example 8 ) < Step g ) , 2 - ( 3 , 6 - dihydro - 2H -pyran - 4 - yl) - 4 , 4 , 5 , 5 -tetramethyl - 1 , 3 , 2 > , 1- amino - 2 -methyl - 2 -propanol ( 2 .2 mL ) was added , and 2 -dioxaborolan ( 8 . 8 g ) , potassium carbonate ( 15 g ) , and the reaction solution was stirred at 150° C . for 20 hours . The dichloro [ 1 , 1 '- bis ( diphenylphosphino ) ferrocene ]palladium reaction solution was cooled to around 50° C . and methanol ( 2 .6 g ) were added , followed by stirring at 100° C . for 5 ( 6 mL ) was added . Subsequently , 1 N sodium hydroxide 2020 hours. After cooling, ethyl acetate and water were added to aqueous solution ( 1 . 5 mL ) was added , and the reaction the reaction solution , and the mixture was filtered through a solution was stirred at room temperature for 1 hour and at pad of Celite to remove the insolubles. After separating the 60° C . for 1 hour. After cooling , ethyl acetate and a saturated ethyl acetate layer, the aqueous layer was extracted with aqueous solution of sodium hydrogen carbonate were added ethylethyl acetate , and thethe cocombined organic layer was washed for partitioning . The separated ethyl acetate layer was 25 with brine and dried over sodium sulfate . The residue washed with brine , and then the solvent was distilled off obtained by distilling off the solvent under reduced pressure under reduced pressure to obtain the title compound ( 2 . 4 g ) was purified by silica gel column chromatography (mobile as yellow amorphous. phase :heptanelethyl acetate = 50 : 50 to 0 : 100 ) and then tritu rated with heptanelethyl acetate = 50 : 50 to obtain the title Step 2 30 compound (4 . 5 g ) as a brown solid . Step 2 Synthesis of p - tolyl ( 6 - ( ( 2 -hydroxy - 2 -methylpropyl ) carbamoyl) - 5 -methyl - 2 - phenylpyridin - 3 - yl) carbam Synthesis of 5 -methyl - 2 - ( tetrahydro -2H - pyran - 4 -yl ) ate 35 pyridin -3 -amine To a methanol (86 mL ) solution of the compound ( 4 .3 g ) In accordance with the method described in (Example 10 ) obtained in (Example 26 ) < Step 1 > , 10 % palladium -carbon < Step 2 > , the title compound (0 .33 g ) was obtained as a ( 2 . 4 g ) was added , followed by stirring under a hydrogen white solid using the compound (0 .23 g ) obtained in (Ex - 404 atmosphere at room temperature for 1 .5 hours . The reaction ample 25 ) < Step 1> instead of 5 -methyl - 6 -( 1 -methyl - 1H solution was filtered through a pad of Celite , and the filtrate pyrazol - 4 -yl ) -2 -phenylpyridin -3 -amine . was concentrated to obtain the title compound ( 4 . 4 g ) as a white solid . Step 3 45 Step 3 Synthesis of rac - N - (2 -hydroxy - 2 -methylpropyl ) - 5 ( 3 - ( (1R ,2R ) - 2 -hydroxy -4 , 4 -dimethyl - 1, 2 ,3 ,4 - tetrahy Synthesis of p - tolyl ( 5 -methyl - 2 - ( tetrahydro - 2H dronaphthalen - 1- yl ) ureido )- 3 -methyl - 6 -phenylpico pyran - 4 -yl )pyridin - 3 -yl ) carbamate linamide 50 In accordance with the method described in ( Example 2 ) < Step 2 > , the title compound ( 0 .91 g ) was obtained as a N , N -diisopropylethylamine ( 0 . 10 mL ) and 10 % palla white solid using the compound ( 0 .50 g ) obtained in (Ex dium - carbon ( 5 . 0 mg) were added to an ethanol ( 2 . 5 mL ) ample 26 ) < Step 2 > instead of 5 -methyl - 2 - phenylpyridin - 3 solution of the amine (50 mg) obtained in (Example 22 ) amine. < Step 2 > , followed by stirring under a hydrogen atmosphere 55 at room temperature for 15 hours . The reaction solution was Step 4 filtered through a pad of Celite to remove the insolubles , and the filtrate was concentrated under reduced pressure . Tetra Synthesis of rac - 1 -( ( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dim hydrofuran ( 2 mL ) , 2 , 6 - lutidine ( 0 . 11 mL ) , and the com ethyl- 1, 2, 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 pound (32 mg ) obtained in (Example 25 ) < Step 2 > were 60 methyl- 2 - (tetrahydro - 2H -pyran -4 -yl ) pyridin - 3 -yl ) added to the obtained residue , and the reaction solution was urea stirred at 100° C . for 4 hours . After cooling, the reaction solution was filtered to remove the insolubles , and the filtrate N , N -diisopropylethylamine ( 0 .12 mL ) and 10 % palla was concentrated . The obtained residue was purified by dium - carbon ( 6 . 0 mg) were added to an ethanol ( 3 . 0 mL ) silica gel column chromatography (mobile phase: heptane/ 65 solution of the compound (60 mg) obtained in (Example 22 ) ethyl acetate = 50 : 50 to 0 : 100 to ethyl acetate /methanol = 90 : < Step 2 > , followed by stirring under a hydrogen atmosphere 10 ) to obtain the title compound ( 10 mg) . at room temperature for 1 hour. Subsequently , the compound US 10 , 399 , 945 B2 161 162 ( 76 mg) obtained in ( Example 26 ) < Step 3 > was added to the ample 27 ) < Step 4 > and the compound (37 mg) obtained in reaction solution , followed by stirring at 50° C . for 1 hour. (Example 22 ) < Step 2 > in the same method as in (Example After cooling , the insolubles were filtered off with a pad of 2 ) < Step 3 > . Celite, and the filtrate was concentrated and purified by preparative LC -Mass to obtain the title compound ( 54 mg) . 5 Step 6 Example 27 Synthesis of rac - 5 - ( 3 - ( ( 1R , 2R ) - 2 -hydroxy - 4 , 4 -dim ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) ureido ) - 3 methyl -6 - ( tetrahydro - 2H - pyran - 4 - yl) picolinamide Synthesis of rac - 5 - ( 3 - ( ( 1R , 2R )- 2 - hydroxy - 4 , 4 -dim 10 ethyl- 1 , 2 ,3 , 4 - tetrahydronaphthalen - 1 - yl) ureido ) - 3 The title compound ( 45 mg) was obtained as a white methyl - 6 - ( tetrahydro - 2H -pyran - 4 - yl) picolinamide amorphous from the compound (58 mg) obtained in (Ex ample 27 ) < Step 5 > in the samemethod as in ( Example 24 ) . Step 1 15 Example 28 Synthesis of 6 - bromo- 5 -methyl - 2 -( tetrahydro -2H Synthesis of rac - 1 -( ( 1R ,2R ) - 2 -hydroxy - 4 ,4 -dim pyran - 4 - yl) pyridin - 3 - amine ethyl- 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 methyl- 6 - ( 2 -methylpyrimidin - 5 - yl) - 2 - ( tetrahydro In accordance with the method described in (Example 3 ) 20 2H -pyran - 4 - yl) pyridin - 3 - yl) urea < Step 1 > , the title compound ( 2 . 4 g ) was obtained as a yellow solid from the compound ( 3 . 0 g ) obtained in (Ex ample 26 ) < Step 2 > . Step 1 25 Synthesis of 5 -methyl - 6 -( 2 -methylpyrimidin -5 - yl ) Step 2 2 -( tetrahydro - 2H -pyran - 4 -yl ) pyridin -3 -amine In accordance with the method described in (Example 9 ) Synthesis of 5 -amino - 3 -methyl - 6 - (tetrahydro - 2H < Step 1 > , the title compound ( 0 .59 g ) was obtained as a pyran -4 - yl) picolinonitrile 30 brown solid using the compound (0 .55 g ) obtained in In accordance with the method described in (Example 8 ) (Example 27 ) < Step 1 > instead of the compound obtained in < Step 1 > , the title compound ( 0 .62 g ) was obtained as a (Example 3 ) < Step 1 > and using sodium carbonate ( 0 .64 g ) white solid from the compound (900 mg) obtained in instead of cesium carbonate . ( Example 27 ) < Step 1 > . 35 Step 2 Step 3 Synthesis of p - tolyl (5 -methyl - 6 -( 2 -methylpyrimi din - 5 - yl) - 2 - ( tetrahydro -2H -pyran - 4 - yl) pyridin - 3 - yl) Synthesis of 5 -amino - 3- methyl -6 - ( tetrahydro -2H - 40 carbamate pyran - 4 - yl) picolinamide In accordance with the method described in (Example 10 ) , the title compound ( 0 . 15 g ) was obtained as a The title compound ( 0 .60 g ) was obtained as a pale yellow white solid using the compound (0 .34 g ) obtained in (Ex solid from the compound ( 0 .63 g ) obtained in ( Example 27 ) ample 28 ) < Step 1 > instead of 5 -methyl - 6 - ( 1 -methyl - 1H in the same method as in (Example 23) < Step 3 > . 45 pyrazol- 4 - yl ) -2 -phenylpyridin -3 - amine. Step 4 Step 3 Synthesis of rac- 1 - ( ( 1R , 2R ) - 2 - hydroxy - 4 ,4 - dim Synthesis of p - tolyl ( 6 - carbamoyl- 5 -methyl - 2 -- ( letra tetra - 50 ethyl- 1, 2 ,3 , 4 -tetrahydronaphthalen - 1- yl) - 3 -( 5 hydro - 2H -pyran - 4 -yl ) pyridin - 3 - yl) carbamate methyl- 6 - ( 2 -methylpyrimidin - 5 - yl) - 2 - ( tetrahydro 2H -pyran - 4 -yl ) pyridin - 3 - yl) urea The title compound ( 0 . 74 g ) was obtained as a pale yellow Triethylamine (0 .020 mL ) and 10 % palladium -carbon (50 solid from the compound ( 0 .45 g ) obtained in (Example 27) 555 mg) were added to an ethanol ( 1 . 0 mL ) solution of the < Step 3 > in the same method as in ( Example 2 ) < Step 2 > . compound (19 mg) obtained in (Example 22 ) < Step 2 > , followed by stirring under a hydrogen atmosphere at room Step 5 temperature for 1 . 5 hours . Subsequently , the compound (25 mg) obtained in (Example 28 ) < Step 2 > was added to the 60 reaction solution under a nitrogen atmosphere , followed by Synthesis of rac - 5 - ( 3 - ( (1R , 2R ) - 6 - bromo - 2 -hydroxy stirring at 50° C . for 2 hours . After cooling , the insolubles 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) were filtered off with a pad of Celite , and ethyl acetate and ureido )- 3 -methyl - 6 - ( tetrahydro - 2H -pyran - 4 -yl ) pico a saturated aqueous solution of sodium hydrogen carbonate linamide were added to the filtrate for partitioning . The separated 65 ethyl acetate layer was washed with brine and dried over The title compound (62 mg) was obtained as a pale yellow sodium sulfate . The solvent was distilled off under reduced andrphousamorphous feromfrom thethe compound (50 so mgmnige) obtainedobtained in (Ex lex pressure , and heptane -MTBE - ethyl acetate was added to the US 10 , 399 , 945 B2 163 164 obtained residue , followed by trituraing to obtain the title temperature for 2 hours for deprotection to obtain the title compound ( 20 mg) as a white solid . compound ( 5 . 6 mg ) as a white solid . Example 29 Example 31 Synthesis of rac - 1 -( (1R , 2R ) - 2- hydroxy -4 ,4 - dim Synthesis of rac - 1 - (6 -hydroxy - 3 -methyl - 6 - ( tetra ethyl- 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 hydro - 2H -pyran - 4 - yl) - [ 2 , 3 '- bipyridin ) - 5 -yl ) - 3 - ( ( 1R , methyl- 6 - ( 1 - methyl- 1H -pyrazol - 4 -yl ) - 2 - ( tetrahydro 2R ) - 2 -hydroxy - 4 , 4 - dimethyl- 1, 2 , 3 ,4 - tetrahydronaph 2H - pyran - 4 - yl) pyridin - 3 - yl) urea thalen - 1 - yl) urea 10 Step 1 In accordance with the method described in ( Example 29 ) < Step 3 > , the title compound (17 mg ) was obtained as a pale Synthesis of p - tolyl ( 6 -bromo - 5 -methyl - 2 - ( tetra yellow solid by carrying out the Suzuki reaction by use of hydro - 2H - pyran - 4 -yl ) pyridin - 3 - yl) carbamate 5 - ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 -dioxaborolan - 2 -yl ) pyridin - 2 - ol (41 mg) instead of 1 -methyl -4 - (4 , 4 ,5 , 5 - tetramethyl- 1 ,3 , 2 In accordance with the method described in (Example 2 ) dioxaborolan - 2 -yl ) - 1H -pyrazole and purifying the reaction < Step 2 > , the title compound ( 1 . 1 g ) was obtained as a white solution by preparative LC -Mass . solid using the compound ( 0 .80 g ) obtained in ( Example 27 ) < Step 1 > instead of 5 -methyl - 2 -phenylpyridin - 3 - amine. Example 32 20 Step 2 Synthesis of rac- 1 - ( ( 1R , 2R ) - 7 - bromo - 2 - hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 Synthesis of rac - 1 - (6 - bromo- 5 -methyl - 2 - ( tetra methyl- 2 - phenylpyridin - 3 - yl) urea hydro -2H - pyran - 4 - yl) pyridin - 3 - yl) - 3 - ( ( 1R , 2R ) - 2 hydroxy - 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 25 Step 1 1 - yl) urea Synthesis of 7 -bromo - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahy In accordance with the method described in (Example 28 ) dronaphthalen - 1 -ol < Step 3 > , the title compound (0 .83 g ) was obtained as a pale brown amorphous using the compound (0 .83 g ) obtained in 30 The title compound ( 12 g) was obtained as a colorless ( Example 29 ) < Step 1 > instead of the compound obtained in liquid from 7 - bromo - 4 , 4 - dimethyl- 3 , 4 - dihydronaphthalen - 1 (Example 28 ) < Step 2 > . ( 2H ) - one (CAS number 166978 - 46 - 7 ) (12 g ) in the same Step 3 method as in (Example 1 ) < Step 1 > . 35 Step 2 Synthesis of rac - 1 -( ( 1R , 2R ) - 2- hydroxy -4 ,4 -dim ethyl- 1, 2 ,3 ,4 -tetrahydronaphthalen - 1- yl ) - 3 -( 5 Synthesis of rac - (1R ,2R ) - 1 -amino -7 -bromo - 4, 4 methyl - 6 - ( 1 -methyl - 1H - pyrazol - 4 - yl) - 2 - ( tetrahydro dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 -ol 2H -pyran -4 - yl) pyridin -3 -yl ) urea 40 In accordance with the method described in (Example 1 ) In accordance with the method described in ( Example 3 ) < Step 2 > , < Step 3 > , and < Step 4 > , the title compound ( 3 . 2 < Step 4 > , the title compound (25 mg ) was obtained as a pale g ) was obtained as a gray white solid from the compound ( 13 yellow amorphous by carrying out the Suzuki reaction by g ) obtained in ( Example 32 ) < Step 1 > . use of the compound (30 mg ) obtained in (Example 29 ) < Step 2 > instead of the compound obtained in ( Example 3 ) 45 Step 3 < Step 3 > and 1 - methyl- 4 - ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 - dioxa borolan - 2 -yl ) - 1H -pyrazole ( 39 mg) instead of 2 -methyl - 5 Synthesis of rac - 1 -( 1R , 2R ) -7 -bromo - 2 -hydroxy - 4 , ( 4 , 4 , 5 , 5 - tetramethyl- 1 , 3 , 2 - dioxaborolan - 2 -yl ) pyrimidine, 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 and purifying the reaction solution by preparative LC -Mass . methyl- 2 -phenylpyridin - 3 - yl) urea 50 Example 30 The title compound (21 mg ) was obtained from the compound (29 mg) obtained in (Example 2 ) < Step 2 > and Synthesis of rac - 1 -( 1R ,2R )- 2- hydroxy -4 , 4 -dim the compound (27 mg) obtained in (Example 32 ) < Step 2 > ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 in the same method as in (Example 2 ) < Step 3 > . methyl- 6 - ( 1H -pyrazol - 4 - yl) - 2 - ( tetrahydro - 2H -pyran - 55 4 - yl) pyridin - 3 - yl) urea Example 33 In accordance with the method described in ( Example 29 ) Synthesis of rac - 1- ( (1R ,2R ) - 2 -hydroxy - 7 -( methoxy < Step 3 > , the Suzuki reaction was carried out by use of methyl) - 4 , 4 -dimethyl - 1 , 2 ,3 , 4 -tetrahydronaphthalen tert- butyl 4 - ( 4 , 4 , 5 , 5 -tetramethyl - 1 , 3 , 2 -dioxaborolan - 2 - yl) - 60 1 - yl) - 3 - ( 5 -methyl - 2 - ( tetrahydro - 2H -pyran - 4 - yl) pyri 1H -pyrazole - 1 - carboxylate (54 mg) instead of 1 -methyl - 4 din - 3 -yl ) urea ( 4 , 4 ,5 , 5 - tetramethyl- 1 ,3 , 2 - dioxaborolan - 2 - yl ) - 1H -pyrazole . The reaction mixture was purified by preparative LC -Mass A crude product ( 82 mg) of rac - 1 - ( ( 1R , 2R )- 7 - bromo- 2 and the fraction was concentrated , then an N - trifluoroacety - hydroxy - 4 ,4 -dimethyl - 1, 2 ,3 , 4 -tetrahydronaphthalen - 1- yl) lamide product was formed . So the residue was dissolved in 65 3 - ( 5 -methyl - 2 - ( tetrahydro - 2H -pyran - 4 - yl) pyridin - 3 - yl) urea ethyl acetate ( 1 . 0 mL ) and 1 N sodium hydroxide aqueous was obtained from the compound (63 mg) obtained in solution ( 1. 0 mL ) was added , followed by stirring at room ( Example 26 ) < Step 3 > and the compound (50 mg ) obtained US 10 , 399 , 945 B2 165 166 in ( Example 32 ) < Step 2 > in the same method as in Step 3 (Example 2 ) < Step 3 > . Tris (dibenzylideneacetone )dipalla dium (0 ) ( 34 mg ), 2 -dicyclohexylphosphino - 2' , 6 '- diiso Synthesis of 6 - fluoro -3 ,3 - dimethyl- 1a, 2, 3 ,7b - tetra propoxy - 1 , 1 '- biphenyl ( 35 mg) , potassium (methoxymethyl ) hydronaphtho [ 1 , 2 - b ] oxirene trifluoroborate (0 .14 g) , cesium carbonate ( 0. 24 g ), 1, 4 - 5 dioxane ( 1 . 0 mL ) , and water ( 0 . 25 mL ) were added to this The title compound ( 0 . 19 g ) was obtained as an orange crude product (82 mg) , and after purging with nitrogen by liquid from the compound (0 .21 g ) obtained in (Example 34 ) degassing under reduced pressure , the mixture was stirred at < Step 2 > in the same method as in (Example 1 ) < Step 3 > . 110° C . for 15 hours . The reaction solution was filtered , and the filtrate was purified by preparative LC -Mass to obtain Step 4 the title compound ( 12 mg ). Synthesis of rac- ( 1R , 2R ) - 1 - amino - 7 - fluoro - 4 , 4 - dim Example 34 ethyl- 1 , 2 ,3 , 4 -tetrahydronaphthalen -2 -ol Synthesis of rac - 1 -( ( 1R ,2R )- 7 - fluoro - 2 -hydroxy -4 ,4 15 The title compound (90 mg) was obtained as an orange dimethyl- 1 , 2, 3 ,4 - tetrahydronaphthalen - 1 -yl ) -3 - (5 solid from the compound (0 . 19 g ) obtained in (Example 34 ) methyl- 6 - (2 -methylpyrimidin - 5 - yl) - 2 -phenylpyridin < Step 3 > in the same method as in ( Example 1 ) < Step 4 > . 3 - yl )urea Step 5 20 Step 1 Synthesis of rac - 1 - ( ( 1R ,2R ) - 7 - fluoro - 2 -hydroxy - 4 , 4 dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 Synthesis of 7 - fluoro -4 ,4 -dimethyl - 1, 2 ,3 , 4 -tetrahy methyl- 6 - (2 -methylpyrimidin - 5 -yl ) - 2 -phenylpyridin dronaphthalen - 1 - ol ( 34 - 1a ) and 6 - fluoro - 4 , 4 -dim 3 -yl ) urea ethyl- 1 , 2, 3 ,4 - tetrahydronaphthalen - 1 -ol (34 - 1b ) 25 The title compound (0 .16 g ) was obtained as a white solid To a fluorobenzene ( 1 . 2 g ) suspension of aluminum from the compound ( 0 . 16 g ) obtained in (Example 9 ) < Step chloride ( 2 .3 g ) , a fluorobenzene ( 1. 2 g ) solution of 5 ,5 - 2 > and the compound (85 mg) obtained in (Example 34 ) dimethyldihydrofuran - 2 (3H ) -one (CAS number 3123 - 97 - 5 ) < Step 4 > in the same method as in ( Example 2 ) < Step 3 > . ( 1 . 0 g ) was slowly added under ice cooling . The reaction 30 solution was heated at 75° C . for 30 minutes and then heated (Example 34a ) (Example 34b ) at 100° C . for 1 hour with a Dean - Stark apparatus. The reaction solution was cooled to 50° C . and diluted with Optical Resolution of rac - 1 - ( ( 1R , 2R ) - 7 - fluoro - 2 - hy droxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 toluene ( 5 .0 mL ) , and then water ( 20 mL ) was added undernd 35 ( 5 -methyl -6 - ( 2 -methylpyrimidin - 5 - yl) - 2 -phenylpyridin - 3 ice cooling . The mixture was filtered through Celite and ylyurea subsequently the Celite cake was washed with MTBE ( 10 By subjecting the compound ( 0 . 16 g ) obtained in (Ex mL ) , and the filtrate was extracted twice with MTBE ( 20 ample 34 ) < Step 5 > to optical resolution using SFC ( col mL ) . The organic layer was combined and the solvent was umn: CHIRALPAK ICQ20x250 mm manufactured by distilled off under reduced pressure . The residue wasas puri -- 40 DaicelDaic Corporation , mobile phase : 20 % ethanol/ CO2 , flow fied by silica gel column chromatography (mobile phase : rate : 15 mL /min , temperature : 30° C . ) , each of enantiomer heptane/ ethyl acetate = 100 : 0 to 90 : 10 ) . The fraction contain of the title compound was obtained as a first fraction ing the product was concentrated and the residue was (Example 34a : 54 mg, > 99 . 9 % ee ) and a second fraction dissolved in methanol (5 . 0 mL ) , and then sodium borohy - (Example 34b : 37 mg, > 99. 9 % ee ) . The optical purity was dride ( 100 mg ) was added under ice cooling . After stirring 45 measured by SFC ( column: CHIRALPAK IC 04 .6x150 mm at room temperature for 1 hour, it was concentrated under manufactured by Daicel Corporation , mobile phase : 15 % reduced pressure and water (20 mL ) was added . It was ethanol/ C02, flow rate : 3 . 0 mL/ min , temperature : 30° C . ) extracted twice with ethyl acetate ( 20 mL ) , and the organic (retention time: the first fraction 4 . 0 minutes , the second layer was combined , followed by drying over sodium sul- fraction 8 . 4 minutes ) . fate . The solvent was distilled off under reduced pressure , 50 and the residue was purified by silica gel column chroma Example 35 tography (mobile phase : heptanelethyl acetate = 100 : 0 to 80 :20 ) to obtain the title 7 - fluoro - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tet Synthesis of rac- 1 - ( 1R , 2R ) -6 - fluoro - 2 - hydroxy - 4 , 4 rahydronaphthalen - 1 - ol (Example 34 - la : mg) and 6 - fluoro dimethyl- 1 , 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) - 3 - ( 5 4, 4 -dimethyl - 1, 2, 3, 4 - tetrahydronaphthalen - 1 -ol (Example 55 methyl- 6 -( 2 -methylpyrimidin -5 -yl ) - 2 - phenylpyridin 34 - 1b : 0 . 19 g ) . 3 - yl) urea Step 2 Step 1

Synthesis of 60 Synthesis of 6 - fluoro - 1 ,1 -dimethyl - 1, 2 -dihydronaphthalene 7 - fluoro - 1 , 1 -dimethyl - 1 , 2 - dihydronaphthalene The title compound ( 0 .21 g ) was obtained as an orange The title compound ( 0 . 60 g ) was obtained as a yellow oily oily material from 7 - fluoro - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy - material from 6 - fluoro - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahy dronaphthalen - 1 - ol (Example 34 - 1a : 0 .29 g ) obtained in 65 dronaphthalen - 1 - ol ( Example 34 - 1b : 0 .70 g ) obtained in ( Example 34 ) < Step 1 > in the same method as in (Example (Example 34 ) < Step 1 > in the same method as in (Example 1 ) < Step 2 > 1 ) < Step 2 > . US 10 , 399 ,945 B2 167 168 Step 2 a saturated aqueous solution of sodium hydrogen carbonate and water and dried over sodium sulfate , and then the Synthesis of 7 - fluoro - 3 ,3 - dimethyl- 1a , 2 , 3 ,7b - tetra solvent was distilled off under reduced pressure . The residue hydronaphtho [ 1 , 2 - b ] oxirene was purified by silica gel column chromatography (mobile 5 phase : hexane /dichloromethane = 100 : 0 to 80 : 20 ) to obtain The title compound ( 0 .49 g ) was obtained as a yellow the title compound ( 8 . 5 g ) as a pale brown solid . liquid from the compound (0 .59 g ) obtained in (Example 35 ) < Step 1 > in the same method as in (Example 1 ) < Step 3 > , Step 2 Step 3 10 Synthesis of 6 , 7 -difluoro - 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetra hydronaphthalen - 1 - ol Synthesis of rac- (1R ,2R )- 1 - amino -6 - fluoro - 4 ,4 -dim ethyl- 1 , 2 , 3 ,4 - tetrahydronaphthalen - 2 - ol The title compound ( 3 .2 g ) was obtained as a pale yellow gum - like material from the compound (3 . 2 g ) obtained in The title compound (0 .36 g ) was obtained as a white solid 15 ( Example 36 ) < Step 1 > in the same method as in (Example from the compound ( 0 .48 g ) obtained in (Example 35 ) < Step 1 ) < Ster 1 > 2 > in the same method as in (Example 1 ) < Step 4 > . Step 4 Step 3 20 Synthesis of rac - 1 - ( ( 1R ,2R ) - 6 - fluoro - 2 -hydroxy - 4 , 4 Synthesis of rac - 1R ,2R ) - 1 -amino -6 ,7 -difluoro -4 , 4 dimethyl - 1, 2 ,3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 -( 5 dimethyl- 1, 2, 3 ,4 -tetrahydronaphthalen - 2 -ol methyl- 6 - (2 -methylpyrimidin - 5 - yl )- 2 -phenylpyridin In accordance with the method described in (Example 1 ) 3 - yl) urea 25 < Step 2 > , < Step 3 > , and < Step 4 > , the title compound ( 1 . 5 The title compound (0 .27 g ) was obtained as a white solid g ) was obtained as a gray white solid from the compound from the compound (0 .32 g ) obtained in ( Example 9 ) < Step (8 .5 g ) obtained in ( Example 36 ) < Step 2 > . 2 > and the compound ( 0 .18 g ) obtained in (Example 35 ) < Step 3 > in the same method as in (Example 2 ) < Step 3 > . Step 4 30 ( Example 35a ) ( Example 35b ) Synthesis of rac - 1- ( ( 1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 Optical Resolution of rac - 1 - ( ( 1R , 2R ) - 6 - fluoro - 2 -hy ( 2 -phenylpyridin - 3 - yl) urea droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 (5 -methyl - 6 -( 2 -methylpyrimidin - 5 -yl ) -2 -phenylpyridin -3 - 35 The title compound (9 .8 mg ) was obtained from 2 -phe yl) urea nylpyridin - 3 -amine (CAS number 101601 -80 - 3 ) (25 mg ) By subjecting the compound ( 0 . 27 g ) obtained in (Ex - and the compound (44 mg) obtained in (Example 36 ) < Step ample 35 ) < Step 4 > to optical resolution using SFC ( col- 3 > in the samemethod as in (Example 1) < Step 5 > . umn : CHIRALPAK IC 020x250 mm manufactured by Daicel Corporation , mobile phase : 20 % ethanol/ CO , , flow 40 Example 37 rate : 15 mL /min , temperature : 30° C . ) , each enantiomer of the title compound was obtained as a first fraction ( Example Synthesis of rac - 1 - ( ( 1R ,2R ) -6 , 7 - difluoro - 2 - hydroxy 35a: 0 .12 g , > 99 . 9 % ee ) and a second fraction (Example 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 35b : 0 . 11 g , > 99 . 9 % ee ) . The optical purity was measured by (5 -methyl - 2- phenylpyridin -3 -yl ) urea SFC ( column : CHIRALPAK IC 04 .6x150 mm manufac - 45 tured by Daicel Corporation , mobile phase : 15 % ethanol/ The title compound (18 mg) was obtained as a colorless CO2, flow rate : 3 . 0 mL /min , temperature : 30° C . ) ( retention amorphous from the compound ( 73 mg) obtained in (Ex time: the first fraction 3 . 7 minutes , the second fraction 3 . 9 ample 2 ) < Step 2 > and the compound (52 mg) obtained in minutes ). (Example 36 ) < Step 3 > in the samemethod as in ( Example 50 2 ) < Step 3 > . Example 36 ( Example 37a ) ( Example 37b ) Synthesis of rac- 1 -( ( 1R , 2R ) -6 , 7 -difluoro - 2 -hydroxy 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 Optical Resolution of rac - 1 - ( (1R , 2R ) - 6 , 7 -difluoro - 2 - hy ( 2 - phenylpyridin - 3 - yl) urea 55 droxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 ( 5 -methyl - 2 -phenylpyridin - 3 -yl ) urea By subjecting the Step 1 compound ( 37 mg) obtained in (Example 37) to optical resolution using SFC (column : CHIRALPAK IA Ø20x250 Synthesis of 6 , 7 - difluoro - 4 , 4 - dimethyl- 3 , 4 -dihy mm manufactured by Daicel Corporation , mobile phase : dronaphthalen - 1 (2H ) -one 60 20 % methanol/ 0 . 1 % diethylamine /CO , , flow rate : 15 mL /min , temperature : 30° C . ), each enantiomer of the title Aluminum chloride (21 g ) was added under ice cooling to compound was obtained as a first fraction ( Example 37a : 13 a mixture of 1, 2 -difluorobenzene ( 15 g ) and 5 ,5 -dimethyl - mg, > 99 . 9 % ee ) and a second fraction (Example 37b : 16 mg, dihydrofuran - 2 (3H ) -one (CAS number 3123 - 97 -5 ) ( 15 g ) , > 99 . 9 % ee ). The optical purity was measured by SFC followed by stirring in a sealed tube at 100° C . for 16 hours . 65 (column : CHIRALPAK IA 04 .6x150 mm manufactured by Ethyl acetate and water were added at room temperature for Daicel Corporation , mobile phase : 20 % methanol/ 0 . 1 % separation . The organic layer was washed successively with diethylamine/ CO2, flow rate : 3 . 0 mL/ min , temperature : 30° US 10 , 399 , 945 B2 169 170 C . ) ( retention time: the first fraction 0 .59 minutes, the Step 4 second fraction 0 .77 minutes ). The compounds of Example 38 to Example 39 below Synthesis of rac - 5 - ( 3 - ( ( 1R , 2R )- 6 , 7 - difluoro - 2 -hy were synthesized by the same method as in (Example 2 ) droxy -4 ,4 -dimethyl - 1 , 2, 3 ,4 - tetrahydronaphthalen - 1 < Step 3 > or a method analogous to this . yl) ureido ) -3 -methyl - 6 -phenylpicolinamide Example 38 The title compound ( 15 mg) was obtained as a white solid from the compound ( 23 mg) obtained in (Example 40 ) < Step rac - 1 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 - hydroxy - 4 , 4 - dim 1310 > in the same method as in (Example 23 ) < Step 3 > , ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 4 methyl - 2 - phenylpyridin - 3 -yl ) urea Example 41 Synthesis of rac - 5 - ( 3 - ( ( 1R , 2R ) -6 , 7 - difluoro - 2 -hy Example 39 15 droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 yl) ureido ) - 3 -methyl - N -( ( 5 -methyl - 1 , 3 , 4 - oxadiazol- 2 rac - 1 - (( 1R , 2R )- 6 , 7 -difluoro - 2 -hydroxy - 4 ,4 -dim yl )methyl ) - 6 -phenylpicolinamide ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 6 methyl- 2 -phenylpyridin - 3 -yl ) urea 20 Step 1 Example 40 Synthesis of 5 - amino - 3 -methyl - 6 -phenyl picolinic acid Synthesis of rac- 5 -( 3 - (( 1R ,2R ) -6 , 7 -difluoro - 2 -hy droxy -4 , 4 - dimethyl- 1 , 2 , 3 , 4 -tetrahydronaphthalen - 1 - 25 To a mixture solution of methanol (10 mL )/ tetrahydro yl) ureido ) - 3 -methyl - 6 - phenylpicolinamide furan (10 mL ) of the compound (1 .4 g ) obtained in (Example 8 ) < Step 2 > , 1 N sodium hydroxide aqueous solution (11 mL ) was added at room temperature , followed by stirring at Step 1 60° C . for 75 minutes . The organic solvent was distilled off 30 under reduced pressure , and the aqueous layer was washed Synthesis of rac- tert -butyl ( 1R ,2R ) - 6 , 7 - difluoro - 2 with tert -butylmethyl ether, then concentrated hydrochloric hydroxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen acid was added to the aqueous layer to adjust the pH to about 1 - yl) carbamate pH 5 . After stirring at room temperature for 15 minutes, the precipitate was collected by filtration and washed with water Di- tert- butyl dicarbonate and N , N -diisopropylethylamine 35 to obtain the title compound ( 1 . 1 g ) as a pale green solid . were added to a methylene chloride solution of the com pound ( 0 .30 g ) obtained in ( Example 36 ) < Step 3 > , followed Step 2 by stirring at room temperature for 16 hours to obtain the title compound ( 0 . 17 g ) as a crude product. 40 Synthesis of 5 -amino - 3 -methyl - N -( (5 -methyl - 1 ,3 , 4 oxadiazol- 2 - yl) methyl ) -6 -phenylpicolinamide Step 2 To an N , N - dimethylformamide ( 12 mL ) solution of the Synthesis of rac - ( 1R , 2R ) - 1- amino -6 ,7 -difluoro -4 , 4 compound (0 .60 g ) obtained in ( Example 41 ) < Step 1 > , dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 - ol hydro 45 (5 -methyl - 1 ,3 , 4 -oxadiazol - 2 - yl)methaneamine hydrochlo ride (CAS number 1172088 - 56 - 0 ) ( 0 .47 g ) , 4 - ( 4 , 6 -dime chloride thoxy - 1 , 3 , 5 - triazin - 2 -yl ) - 4 -methylmorpholinium chloride ( 1 . 1 g ) , and N , N -diisopropylethylamine ( 1 . 2 mL ) were Hydrogen chloride ( 4 N ethyl acetate solution ) (29 mL ) added , followed by stirring at room temperature for 40 was added to the compound ( 3 . 7 g ) obtained in (Examples 50 minutes . Water and ethyl acetate were added for extraction , 40 ) < Step 1 > , and the mixture was stirred at room tempera and the organic layer was washed with water and brine , ture for 5 hours , then the solvent was distilled off under followed by drying over sodium sulfate . The solvent was reduced pressure . The residue was washed with heptane : distilled off under reduced pressure, and the residue was ethyl acetate = 1: 1 to obtain the title compound (2 .5 g ) as a purified by silica gel column chromatography (NH -silica white solid . 55 gel , mobile phase: ethyl acetate /heptane = 2 : 1 ) to obtain the title compound ( 0 .72 g ) as a white amorphous. Step 3 Step 3 Synthesis of rac - 1- ( 6 -cyano -5 -methyl - 2 -phenylpyri 60 din - 3 -yl ) - 3 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 Synthesis of p -tolyl (5 -methyl - 6 -( (( 5 -methyl - 1 , 3 ,4 dimethyl- 1, 2, 3, 4 -tetrahydronaphthalen - 1 -yl ) urea oxadiazol - 2 - yl) methyl ) carbamoyl) - 2 -phenylpyridin 3 -yl ) carbamate The title compound ( 26 mg) was obtained as a white solid from the compound ( 50 mg) obtained in (Example 23 ) < Step 65 The title compound (0 .49 g ) was obtained as a white solid 1 > and the compound ( 33 mg) obtained in (Example 40 ) from the compound ( 0 .45 g ) obtained in ( Example 41 ) < Step < Step 2 > in the same method as in (Example 2 ) < Step 3 > . 2 > in the same method as in (Example 2 ) < Step 2 > . US 10 , 399 , 945 B2 171 172 Step 4 < Step 1 > and phenyl chloroformate ( 6 .6 g ) in the same method as in (Example 2 ) < Step 2 > . Synthesis of rac - 5 - ( 3 - ( ( 1R 2R ) -6 , 7 - difluoro - 2 -hy droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 yl) ureido )- 3 -methyl -N -( ( 5 -methyl - 1 ,3 ,4 -oxadiazol - 2 - 5 Step 2 yl) methyl ) - 6 -phenylpicolinamide The title compound (32 mg) was obtained as a white solid Synthesis of rac- 1 - (6 - bromo- 5 -methyl - 2 - phenylpyri from the compound (50 mg) obtained in (Example 41) < Step din - 3 -yl ) - 3 -( ( 1R ,2R ) -6 , 7 -difluoro -2 -hydroxy -4 , 4 3 > and the compound (25 mg) obtained in (Example 40 ) dimethyl- 1 , 2 ,3 , 4 - tetrahydronaphthalen - 1 - yl ) urea < Step 2 > in the same method as in ( Example 2 ) < Step 3 > . (Example 41a ) ( Example 41b ) The title compound (3 .0 g ) was obtained as a pale yellow amorphous from the compound ( 2 . 5 g ) obtained in (Example Optical Resolution of rac - 5 - (3 -( ( 1R ,2R ) - 6 , 7 - difluoro - 2 hydroxy - 4 , 4 - dimethyl- 1 , 2 ,3 , 4 - tetrahydronaphthalen - 1 - yl) 15 44 ) and the compound ( 1. 7 g ) obtained in (Ex ureido ) - 3 -methyl - N - ( ( 5 -methyl - 1 , 3 , 4 - oxadiazol- 2 - yl) ample 40 ) < Step 2 > in the same method as in (Example 2 ) methyl) - 6 -phenylpicolinamide By subjecting the compound (28 mg) obtained in ( Ex < Step 3 > . ample 41) < Step 4 > to optical resolution using SFC ( col umn : CHIRALPAK IB 020x250 mm manufactured by 20 Daicel Corporation , mobile phase : 20 % methanol/ 0 . 1 % Step 3 diethylamine/ CO , , flow rate : 15 mL /min , temperature : 30° C . ) , each enantiomer of the title compound was obtained as a first fraction ( Example 41a : 11 mg, > 99 . 9 % ee ) and a Synthesis of rac - 1 - ( ( 1R , 2R ) - 6 , 7 -difluoro - 2 - hydroxy second fraction (Example 41b : 12 mg , > 99 . 9 % ee ) . The 25 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 optical purity was measured by SFC ( column : CHIRALPAK ( 5 -methyl - 6 -( 2 -methylpyrimidin - 5 -yl ) - 2 -phenylpyri IB 04 .6x150 mm manufactured by Daicel Corporation , din - 3- yl )urea mobile phase : 20 % methanol/ 0 . 1 % diethylamine/ CO2, flow rate : 3 . 0 mL /min , temperature : 30° C . ) ( retention time : the The title compound ( 4 . 3 mg) was obtained as a brown first fraction 0 . 97 minutes , the second fraction 1. 1 minutes ). 30 solid from 2 -methylpyrimidine - 5 -boronic acid pinacol ester Example 42 (CAS number 1052686 -67 - 5 ) ( 13 mg) and the compound Synthesis of rac - 5 - ( 3 - ( 1R 2R ) -6 , 7 - difluoro - 2 -hy (30 mg) obtained in (Example 44 ) < Step 2 > in the same droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 yl) ureido ) -N -( 2 -hydroxy - 2- methylpropyl ) -3 -methyl - 35 method as in (Example 3 ) < Step 4 > . 6 -phenylpicolinamide The title compound ( 25 mg) was obtained from the (Example 44a ) (Example 44b ) compound ( 20 mg) obtained in (Example 25 ) < Step 2 > and the compound ( 12 mg ) obtained in (Example 40 ) < Step 2 > 40 Optical Resolution of rac -1 -( (1R ,2R )- 6 ,7 -difluoro -2 -hy in the same method as in (Example 2 ) < Step 3 > . droxy - 4 ,4 -dimethyl - 1, 2 ,3 ,4 - tetrahydronaphthalen -1 -yl ) - 3 Example 43 (5 -methyl -6 -( 2- methylpyrimidin -5 - yl) -2 - phenylpyridin -3 Synthesis of rac - 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy yl) urea 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 45 By subjecting the compound ( 0 . 10 g ) obtained in (Ex ( 6 - (hydroxymethyl ) - 5 - methyl- 2 -phenylpyridin - 3 - yl) urea ample 44 ) < Step 3 > to optical resolution using SFC ( col umn: CHIRALPAK IC 020x250 mm manufactured by Dai The title compound ( 29 mg) was obtained from the compound (44 mg) obtained in ( Example 8 ) < Step 4 > and 50 cel Corporation , mobile phase : 3 to 60 % methanol/ CO2 , the compound ( 36 mg) obtained in (Example 40 ) flow rate: 15 mL /min , temperature : 30° C . ), each enantiomer in the same method as in ( Example 2 ) < Step 3 > . of the title compound was obtained as a first fraction Example 44 (Example 44a : 29 mg, > 99. 9 % ee ) and a second fraction 55 (Example 44b : 20 mg, > 99. 9 % ee ). The optical purity was Synthesis of rac- 1 -( ( 1R , 2R ) -6 , 7 - difluoro - 2 -hydroxy 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 measured by SFC ( column : CHIRALPAK IC 04 .6x150 mm ( 5 -methyl - 6 -( 2 -methylpyrimidin -5 -yl ) - 2 -phenylpyri manufactured by Daicel Corporation , mobile phase : 3 to din - 3 -yl ) urea 80 % methanol/ C02 , flow rate : 3 . 0 mL /min , temperature : 30° 60 C . ) ( retention time: the first fraction 2 . 5 minutes, the second Step 1 fraction 2 .8 minutes ). Synthesis of phenyl The compounds of Example 45 to Example 52 below (6 -bromo - 5 -methyl - 2 - phenylpyridin - 3 -yl ) carbamate were synthesized using the compound obtained in (Example The title compound (6 . 6 g ) was obtained as a pale brown 65 44 ) < Step 2 > by the samemethod as in (Example 3 ) < Step solid from the compound (5 .0 g ) obtained in (Example 3) 4 > or a method analogous to this . US 10 , 399 , 945 B2 173 174 Example 45 > 99 . 9 % ee ). The optical purity was measured by SFC ( column : CHIRALCEL OD 04 .6x150 mm manufactured by rac - 1 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 - hydroxy - 4 , 4 - dim Daicel Corporation , mobile phase : 3 - 80 % methanol/ CO2 , ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 6 - ( 4 flow rate: 3 .0 mL /min , temperature: 30° C .) ( retention time: (hydroxymethyl )phenyl )- 5 -methyl - 2- phenylpyridin 5 the first fraction 2 . 1 minutes , the second fraction 2 . 3 min 3 - yl) urea utes ) . Example 46 Example 53 rac -1 - (( 1R , 2R )- 6 ,7 -difluoro - 2 -hydroxy -4 , 4 -dim 10 Synthesis of rac- 1 - (( 1R 2R )- 6 ,7 - difluoro - 2 -hydroxy ethyl- 1 , 2 ,3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - (6 - ( 3 4 ,4 -dimethyl - 1, 2 ,3 , 4 -tetrahydronaphthalen - 1 -yl ) -3 (hydroxymethyl ) phenyl) - 5 -methyl - 2 - phenylpyridin ( 5 -methyl - 2 -phenyl - 6 - ( 1H -pyrazol - 4 - yl) pyridin - 3 - yl) 3 - yl) urea urea Example 47 Step 1 rac - 1 - ( 6 - ( 3 - cyanophenyl ) - 5 -methyl - 2 - phenylpyridin Synthesis of p - tolyl (5 -methyl -2 -phenyl - 6 -( 1H -pyra 3 - yl) - 3 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 -dim ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) urea zol- 4 - yl) pyridin - 3 - yl ) carbamate 20 To the compound ( 1. 5 g ) obtained in (Example 18 ) < Step Example 48 2 > , 20 mL of hydrogen chloride ( 4 N ethyl acetate solution ) was added under ice cooling , followed by stirring at room rac -1 - (( 1R 2R )- 6 ,7 - difluoro - 2 -hydroxy -4 , 4 -dim temperature for 3 hours . The solvent was distilled off under ethyl- 1, 2 ,3 ,4 - tetrahydronaphthalen - 1- yl ) - 3 -( 5 reduced pressure to obtain the title compound (1 .4 g ) as a methyl- 6 - ( 1 -methyl - 1H -pyrazol - 3 - yl) - 2 - phenylpyri - 25 yellow solid . din - 3 -yl ) urea Example 49 Step 2 Synthesis of rac - 1- ( ( 1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy rac - 1 - (( 1R ,2R )- 6 ,7 -difluoro - 2 -hydroxy -4 , 4 - dim 30 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 ethyl- 1 , 2 , 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 - ( 5 ( 5 -methyl - 2 - phenyl- 6 - ( 1H - pyrazol - 4 - yl) pyridin - 3 - yl) methyl- 6 -( 6 -methylpyridazin -4 -yl ) - 2 -phenylpyridin 3 - yl) urea urea The title compound ( 12 mg) was obtained as a white solid Example 50 35 from the compound ( 50 mg) obtained in (Example 53 ) < Step 1 > and the compound ( 38 mg) obtained in (Example 40 ) rac - 1 - ( ( 1R , 2R )- 6 , 7 - difluoro - 2 - hydroxy - 4 ,4 - dim < Step 2 > in the same method as in (Example 2 ) < Step 3 > . ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 - ( 5 methyl- 6 -( 2 -methylthiazol - 5 - yl) - 2 -phenylpyridin - 3 Example 54 ylyurea 40 Synthesis of rac - 1- ( ( 1R ,2R ) -6 , 7 -difluoro - 2 -hydroxy Example 51 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 ( 6 - ( 2 - ( 2 -hydroxypropan - 2 - yl) pyrimidin - 5 - yl) - 5 rac - 1 - (( 1R ,2R )- 6 ,7 -difluoro - 2 -hydroxy -4 , 4 - dim methyl- 2 -phenylpyridin - 3 -yl ) urea ethyl- 1 ,2 , 3, 4 -tetrahydronaphthalen - 1 -yl ) - 3 -( 5 45 methyl- 6 -( 1 -methyl - 1H -pyrazol - 4 -yl ) -2 -phenylpyri The title compound ( 18 mg) was obtained as a white solid din - 3 - yl) urea from the compound ( 50 mg) obtained in (Example 21 ) < Step 2 > and the compound ( 29 mg) obtained in (Example 40 ) Example 52 < Step 2 > in the same method as in (Example 2 ) < Step 3 > . 50 rac - 1 - ( 6 - ( 4 - cyanophenyl) - 5 -methyl - 2 - phenylpyridin Example 55 3 - yl) - 3 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 -hydroxy - 4 , 4 -dim ethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) urea Synthesis of rac -1 -( 1R ,2R )- 6 ,7 - difluoro - 2- hydroxy 4 ,4 -dimethyl - 1, 2 , 3 ,4 - tetrahydronaphthalen - 1 -yl ) -3 (Example 48a ) (Example 48b ) 55 ( 6 - (hydroxymethyl ) - 3 -methyl - 6 -phenyl - [ 2 , 3 -bipyri din )- 5 - yl) urea Optical Resolution of rac - 1 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 - hy droxy -4 , 4 -dimethyl - 1, 2, 3 ,4 - tetrahydronaphthalen - 1 -yl ) - 3 Step 1 ( 5 -methyl -6 - ( 1 -methyl - 1H -pyrazol - 3 - yl) - 2 - phenylpyridin 3 - yl) urea 60 Synthesis of ( 5 - amino - 3 -methyl - 6 - phenyl- [ 2 , 3 ' -bi By subjecting the compound (27 mg) obtained in (Ex pyridin ) - 6 '- yl) methanol ample 48 ) to optical resolution using SFC (column : CHI RALCEL OD 020x250 mm manufactured by Daicel Cor - The title compound ( 0 . 91 g ) was obtained as a yellow poration , mobile phase: 3 - 40 % methanol/ CO2 , flow rate : 15 solid from (6 -( hydroxymethyl ) pyridin -3 -yl ) boronic acid mL /min , temperature : 30° C .) , each enantiomer of the title 65 (CAS number 913835 - 98 - 0 ) ( 0 .70 g ) and the compound ( 1 . 0 compound was obtained as a first fraction (Example 48a : 10 g ) obtained in (Example 3 ) < Step 1 > in the same method as mg, > 99. 9 % ee ) and a second fraction (Example 48b : 10 mg, in (Example 3 ) < Step 4 > , US 10 , 399 , 945 B2 175 176 Step 2 < Step 2 > and the compound ( 23 mg) obtained in (Example 40 ) < Step 2 > in the same method as in (Example 2 ) < Step Synthesis of p - tolyl (3 -methyl -6 -phenyl - 6 - ( (( ( p 3 > . tolyloxy ) carbonyl) oxy )methyl ) -[ 2 ,3 ' - bipyridin ) -5 yl ) carbamate Step 4 The title compound ( 0 . 17 g ) was obtained as a white Synthesis of rac- 1 -( ( 1R , 2R ) -6 , 7 - difluoro - 2 -hydroxy amorphous from the compound ( 0 .40 g ) obtained in (Ex 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 ample 55 ) < Step 1> by a method in accordance with 10 ( 2 - (hydroxymethyl ) - 3 -methyl - 6 -phenyl - [ 2 , 4 '- bipyri (Example 2 ) < Step 2 > . din ) - 5 - yl) urea Sodium borohydride ( 4 . 0 mg) was added to a methanol Step 3 ( 1 . 0 mL ) solution of the compound (30 mg) obtained in (Example 56 ) < Step 3 > , followed by stirring at room tem Synthesis of rac - 1 - ( (1R , 2R ) - 6 , 7 -difluoro - 2 -hydroxy perature for 1 .5 hours and at 40° C . for 2 hours. Sodium 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 borohydride ( 5 . 9 mg ) was added at room temperature , ( 6 '- ( hydroxymethyl ) - 3 -methyl - 6 - phenyl- [ 2 , 3 - bipyri followed by stirring at 40° C . for 1 . 5 hours . Sodium boro din ) - 5 -yl ) urea hydride ( 5 . 9 mg ) was added at room temperature , followed 20 byOy stirring at 40° C . for 16 hours . Sodium borohydride ( 9 .9 The title compound (11 mg) was obtained from the mg) was added at room temperature, followed by stirring at compound (50 mg) obtained in ( Example 55 ) < Step 2 > and 40° C . for 1 hour. A crude purified title product ( 34 mg) was the compound ( 24 mg) obtained in ( Example 40 ) < Step 2 > obtained by addition of 1 N hydrochloric acid ( 0 . 5 mL ) by a method in accordance with (Example 2 ) < Step 3 > . followed by purification by preparative LC -Mass . A satu 25 rated aqueous solution of sodium hydrogen carbonate and Example 56 ethyl acetate were added to this crude purified product for extraction . The organic layer was washed successively with water and brine and dried over sodium sulfate . The solvent Synthesis of rac - 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy was distilled off under reduced pressure to obtain the title 4 , 4 -dimethyl - 1 , 2 , 3 , 4 -tetrahydronaphthalen - 1 - yl) - 3 - 30 compound ( 12 mg ) as a white solid . ( 2 - (hydroxymethyl ) - 3 -methyl - 6 -phenyl - [ 2 , 4 -bipyri din ) - 5 -yl ) urea Example 57 Step 1 Synthesis of rac - 1 - ( ( 1R , 2R ) - 6 , 7 -difluoro - 2 - hydroxy 35 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 Synthesis of methyl 5 -amino - 3 -methyl -6 - phenyl- [2 , ( 5 -methyl - 2 - ( tetrahydro - 2H -pyran - 4 - yl) pyridin - 3 - yl) 4' - bipyridine ] -2 ' - carboxylate urea The title compound ( 13 mg) was obtained as a white solid The title compound ( 90 mg ) was obtained as an orange * from the compound (50 mg ) obtained in ( Example 26 < Step solid from 2 - methoxycarbonyl) - 4 -pyridineboronic acid 3 > and the compound (40 mg) obtained in (Example 40 ) pinacol ester (CAS number 957062- 72 - 5 ) (0 .99 g ) and the compound ( 0 . 50 g ) obtained in (Example 3 ) < Step 1 > in the < Step 2 > in the same method as in (Example 2 ) < Step 3 > .

samemethod as in (Example 3 ) < Step 4 > . 45 Example 58 Step 2 Synthesis of rac - 5 - ( 3 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 -hy droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 Synthesis ofmethyl 3 -methyl - 6 - phenyl- 5 - ( ( (p -toly yl) ureido ) - 3 -methyl - 6 - (tetrahydro - 2H -pyran - 4 - yl) loxy ) carbonyl) amino ) - [ 2 , 4 - bipyridin ) - 2' - carboxy 50 picolinamide late The title compound ( 29 mg) was obtained from the The title compound (84 mg) was obtained as an orange compound (50 mg) obtained in (Example 27) < Step 4 > and solid from the compound ( 85 mg) obtained in (Example 56 ) the compound (36 mg) obtained in ( Example 40 ) < Step 2 > < Step 1 > in the same method as in (Example 2 ) < Step 2 > . 55 in the same method as in (Example 2) < Step 3> . Example 59 Step 3 Synthesis of rac - 1 - ( ( 1R , 2R ) -6 , 7 - difluoro - 2 -hydroxy 60 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 Synthesis of rac -methyl 5 - ( 3 - ( (1R ,2R ) - 6 , 7 - difluoro ( 5 -methyl - 6 - ( 2 -methylpyrimidin - 5 - yl) - 2 - tetrahydro 2 -hydroxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 -tetrahydronaphtha len - 1- yl) ureido )- 3 -methyl - 6 -phenyl - [ 2 , 4 - bipyri 2H -pyran -4 -yl ) pyridin - 3 - yl ) urea dine ) - 2 ' - carboxylate The title compound (27 mg) was obtained as a white solid 65 from the compound ( 25 mg) obtained in ( Example 28 ) < Step The title compound (30 mg) was obtained as a yellow 2 > and the compound (17 mg) obtained in (Example 40 ) solid from the compound ( 40 mg) obtained in (Example 56 ) < Step 2 > in the same method as in ( Example 2 ) < Step 3 > . US 10 , 399 ,945 B2 177 178 Example 60 Step 7 Synthesis of rac - 5 - ( 3 - ( (1R 2R ) -6 , 7 - difluoro - 2 -hy Synthesis of rac - 5 - ( 3 - ( (1R ,2R ) - 6 , 7 - difluoro - 2 -hy droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 droxy - 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 yl) ureido )- N -( 2 -hydroxy - 2- methylpropyl ) -3 -methyl oth 5 yl) ureido ) - N - ( 2 - hydroxy - 2 -methylpropyl ) - 3 -methyl 6 - ( tetrahydro - 2H - pyran - 4 - yl) picolinamide 6 - ( tetrahydro -2H - pyran - 4 - yl) picolinamide The title compound ( 25 mg ) was obtained from the Step 1 . compound (20 mg) obtained in ( Example 60 ) < Step 6 > and the compound ( 12 mg ) obtained in ( Example 40 ) < Step 2 > Synthesis of ethyl 5 - amino - 6 - bromo- 3 -methyl in the same method as in ( Example 2 ) < Step 3 > . picolinate Example 61 The title compound ( 1. 3 g ) was obtained as a white solid Synthesis of rac - 1 - ( ( 1R ,2R ) - 6 , 7 - difluoro - 2 -hydroxy from ethyl 5 -amino - 3 -methylpicolinate (CAS number 15 4 ,4 -dimethyl - 1 ,2 ,3 , 4 -tetrahydronaphthalen - 1 -yl ) - 3 1805595 - 78 - 1 ) ( 1 . 1 g ) in the samemethod as in ( Example 3 ) ( 5 -methyl -6 - ( 1H -pyrazol - 4 - yl) - 2 -( tetrahydro - 2H < Step 1 > . pyran - 4 -yl ) pyridin - 3 - yl) urea Step 2 Step 1 20 Synthesis of ethyl 5 -amino - 6 - ( 3 , 6 -dihydro - 2H Synthesis of tert- butyl 4 - ( 5 - amino - 3 -methyl -6 - (tet pyran - 4 -yl ) - 3 -methylpicolinate rahydro - 2H -pyran -4 -yl ) pyridin - 2 -yl ) - 1H -pyrazol - 1 carboxylate The title compound ( 0 . 84 g ) was obtained as a white solid from the compound ( 1 . 3 g ) obtained in ( Example 60 ) < Step 25 The title compound ( 1 . 8 g ) was obtained as a pale brown 1 > in the same method as in (Example 26 ) < Step 1 > . solid from 1 - tert - butoxycarbonyl -pyrazole - 4 -boronic acid pinacol ester (CAS number 552846 - 17 - 0 ) ( 2 . 2 g ) and the Step 3 compound ( 1 . 7 g ) obtained in (Example 27 ) < Step 1 > in the 30 same method as in (Example 3 ) < Step 4 > . Synthesis of ethyl 5 -amino - 3 -methyl - 6 -( tetrahydro 2H - pyran - 4 - yl) picolinate Step 2 Synthesis of tert- butyl 4 - ( 3 -methyl - 6 - (tetrahydro The title compound ( 0 . 83 g ) was obtained as a white solid 2H -pyran -4 -yl ) -5 -( (( p - tolyloxy ) carbonyl) amino ) from the compound (0 .84 g ) obtained in (Example 60 ) < Step 35 pyridin - 2 - yl) - 1H - pyrazole - 1 - carboxylate 2 > in the samemethod as in ( Example 26 ) . The title compound (2 .2 g ) was obtained as a pale yellow Step 4 solid from the compound ( 1 . 5 g ) obtained in ( Example 61) < Step 1 > in the same method as in ( Example 2 ) < Step 2 > . Synthesis of 5 - amino -3 -methyl - 6 -( tetrahydro -2H 40 pyran - 4 - yl) picolinic acid Step 3 The title compound ( 0 .61 g ) was obtained as a white solid Synthesis of p - tolyl ( 5 -methyl - 6 - ( 1H -pyrazol - 4 -yl ) from the compound ( 0 . 83 g ) obtained in (Example 60 ) < Step 45 2 - (tetrahydro - 2H - pyran - 4 - yl) pyridin - 3 - yl) carbamate 3 > in the same method as in (Example 41) < Step 1 > . The title compound ( 0 . 38 g ) was obtained as a white solid from the compound ( 0 . 50 g ) obtained in (Example 61 ) < Step Step 5 2 > in the same method as in ( Example 53 ) < Step 1 > . Synthesis of 5 -amino - N - ( 2 -hydroxy - 2 -methylpro - 50 Step 4 pyl) -3 -methyl - 6 - ( tetrahydro -2H -pyran - 4 - yl) picolina mide Synthesis of rac - 1 - ( ( 1R , 2R ) - 6 , 7 -difluoro - 2 - hydroxy 4 , 4 - dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 The title compound (0 .54 g ) was obtained as a white solid ( 5 -methyl -6 - ( 1H -pyrazol - 4 - yl) - 2 - ( tetrahydro - 2H from the compound ( 0 .48 g ) obtained in (Example 60 ) < Step 35 pyran - 4 -yl ) pyridin - 3 - yl )urea 4 > by a method in accordance with (Example 41) < Step 2 > . The title compound (31 mg) was obtained from the compound (50 mg) obtained in (Example 61) < Step 3 > and Step 6 the compound (29 mg) obtained in (Example 40 ) < Step 2 > Synthesis of p -tolyl ( 6 - ( 2 - hydroxy - 2 -methylpropyl ) 60 in the same method as in (Example 2 ) < Step 3 > . carbamoyl) - 5 -methyl - 2 - ( tetrahydro - 2H -pyran - 4 - yl) (Example 61a ) ( Example 61b ) pyridin - 3 -yl )carbamate Optical Resolution of rac - 1 - ( (1R ,2R ) -6 , 7 -difluoro - 2 -hy The title compound ( 0 . 12 g ) was obtained as a white solid 65 droxy - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 from the compound ( 0 . 10 g ) obtained in (Example 60 ) < Step ( 5 -methyl - 6 - ( 1H - pyrazol- 4 - yl) - 2 - ( tetrahydro - 2H - pyran - 4 5 > in the same method as in (Example 2 ) < Step 2 > . yl) pyridin - 3 - yl) urea US 10 , 399 , 945 B2 179 180 By subjecting the compound ( 33 mg) obtained in (Ex - (12 . 0 mL ) of the rac - ( 1R ,2R ) -1 -amino -4 ,4 -dimethyl - 1 ,2 , 3 , ample 61) < Step 4 > to optical resolution using SFC ( col 4 - tetrahydronaphthalen - 2 - ol ( 1 . 0 g ) obtained in (Example 1 ) umn : CHIRALPAK IA 020x250 mm manufactured by < Step 4 > . The reaction solution was heated to 100° C . for Daicel Corporation , mobile phase : 25 % methanol/ CO , , flow dissolution and then allowed to cool to room temperature . rate: 15 mL /min , temperature : 30° C . ) , each enantiomer of 5 T the title compound was obtained as a first fraction (Example 5 The precipitated crystal was collected by filtration , and the 61a : 8 . 7 mg, > 99 . 9 % ee ) and a second fraction (Example crystal was washed with a mixture solvent of acetonitrile 61b : 16 mg, > 99 . 9 % ee ) . The optical purity was measured by water ( 4 : 1 ) and dried under reduced pressure to obtain the SFC ( column: CHIRALPAK IA 04. 6x150 mm manufac title compound ( 0 . 58 g ) as a white solid . The optical purity tured by Daicel Corporation ,mobile phase: 20 % methanol / of the obtained title compound was more than 99 % (HPLC , CO , , flow rate : 3 . 0 mL /min , temperature : 30° C . ) ( retention retention time was 9 . 03 minutes ) . Chem . 1 to Chem . 4 below time: the first fraction 1 . 4 minutes , the second fraction 1 . 8 show the structures of the final compounds synthesized in minutes ) . ( Example 1 ) to (Example 63 ) described above ( respectively corresponding to Compound 1 to Compound 63 ) . Note that Example 62 in the structural formulas of the final example compounds, Synthesis of rac - 1 - ( ( 1R , 2R ) - 6 , 7 - difluoro - 2 - hydroxy the compound marked with ( R ) or ( S ) at position 1 or 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 -yl ) - 3 position 2 in the 1 , 2 , 3 , 4 -tetrahydronaphthalene ring indi (6 - ( 2 -hydroxypyrimidin - 5 - yl) - 5 -methyl - 2 - ( tetra cates that it is a single optically active compound . Tables hydro - 2H -pyran - 4 -yl ) pyridin - 3 - yl) urea below ( Tables 2 to 5 ) show 1H -NMR data ( no symbol: 400 20 MHz NMR , * symbol: 300 MHz NMR ) and LC -Mass data Step 1 of these final example compounds . In addition , Chem . 5 to Chem . 9 below show the struc Synthesis of 6 - ( 2 - ( ( 4 -methoxybenzyl )oxy )pyrimi tures of the intermediate compounds and the reference din -5 -yl ) - 5 -methyl -2 -( tetrahydro -2H -pyran -4 -yl ) example compounds synthesized in the examples . Note that pyridin -3 -amine 25 in the intermediate structural formulas , the compound The title compound ( 0 .49 g ) was obtained as a pale brownun marked with (R ) at position 1 or position 2 in the 1 , 2 , 3 , 4 solid from the compound ( 0 .70 g ) obtained in (Example 19 ) tetrahydronaphthalene ring indicates that it is a single opti < Step 1 > and the compound ( 0 . 30 g ) obtained in (Example cally active compound . Tables 6 to 10 below show 1H -NMR 27 ) < Step 1 > in the samemethod as in (Example 3 ) < Step data (no symbol: 400 MHz NMR , * symbol: 300 MHz 4 > . 30 NMR ) and LC -Mass data of these intermediate compounds and reference example compounds . Step 2 Note that for the intermediate compounds, for example , the compound obtained in (Example 1 ) is repre Synthesis of p -tolyl (6 - ( 2 - ( ( 4 -methoxybenzyl ) oxy ) sented as in (Example 1 - 1 ) . pyrimidin - 5 - yl ) - 5 -methyl - 2 - (tetrahydro - 2H -pyran - 4 - 35M oreover , FIG . 1 below show the X -ray crystal analysis yl) pyridin -3 -yl ) carbamate data of ( 1R , 2R ) - 1 - amino - 4 , 4 - dimethyl- 1 , 2 , 3 , 4 - tetrahy The title compound ( 0 .57 g ) was obtained as a yellow dronaphthalen -2 -ol ( 2S, 3S )- 2 ,3 - dihydroxy succinate mono amorphous from the compound ( 0 . 48 g ) obtained in ( Ex hydrate obtained in (Example 7 ) < Step 2 > and ( Example 7a ) ample 62 ) < Step 1 > in the samemethod as in (Example 2 ) 40 to (Example 7i) described above. < Step 2 > . Step 3 Chem . 1 ] (Example 1) Synthesis of rac- 1 - ( ( 1R , 2R ) -6 , 7 - difluoro - 2 -hydroxy 4 , 4 -dimethyl - 1 , 2 , 3 , 4 - tetrahydronaphthalen - 1 - yl) - 3 45 (6 - ( 2 -hydroxypyrimidin - 5 - yl) - 5 -methyl - 2 - (tetra hydro - 2H -pyran - 4 -yl ) pyridin - 3 - yl) urea In accordance with the method described in (Example 2 ) < Step 3 > , urea formation reaction was carried out by use of 50 N the compound (50 mg) obtained in (Example 62 ) < Step 2 > OH and the compound (21 mg) obtained in (Example 40 ) < Step 2 > . After the reaction , the solvent was distilled off under reduced pressure , and hydrogen chloride ( 4 N ethyl acetate solution ) ( 1 .0 mL ) was added to the obtained residue . The 55 ( Example 2 ) mixture was stirred at room temperature for 3 hours , and then the reaction solution was purified by preparative LC Mass to obtain the title compound (25 mg ) . Example 63 60 Synthesis of ( 18 ,2S ) -1 -amino - 4 ,4 - dimethyl- 1, 2 ,3 , 4 tetrahydronaphthalen - 2 -ol (2R , 3R )- 2 ,3 - dihydroxy OH succinate monohydrate 65 L - ( + ) -tartaric acid ( 0 .78 g ) was added at room tempera ture to a mixture solution of water (3 .0 mL ) and acetonitrile US 10 ,399 ,945 B2 181 182 - continued - continued (Example 3 ) ( Example 8 )

N . HO

N 10 N OH OH

( Example 4 ) 15 ( Example 9 )

20 (R ) ( R )

OH OH gepas25 open ( Example 5 ) ( Example 9a )- ( Example 9j) mples) (Example 10 ) 30 HN

35 OH ÕH

40 (Example 6 ) (Example 11 ) ?? . su au

45 F3C UITO A10 OH IZ 50 OH

(Example 7) (Example 12 ) 55

TZ A10111 OH N ÕH US 10 ,399 ,945 B2 183 184 -continued -continued (Example 13 ) ( Example 18) NC N 5 HN

N NIC N ZI 10 OH OH

(Example 14 ) 15 MS [ Chem . 2 ]

20 (Example 19 ) ?? , NH OH 25 ( R ) ( R ) N W01 (Example 15 ) OH F C 30

NH 35 OH (Example 20 ) ?? , 40 (Example 16 ) NC .

45 NH OH N OH 50

(Example 21) ( Example 17 ) 55

F?C

A 111111 OH NH OH US 10 ,399 ,945 B2 185 186 - continued -continued (Example 22 ) Br (Example 27)

HN

10 N OH OH

( Example 23) 15 (Example 28 ) Br

20

HN AUDIO OH N 25 OH (Example 29 ) (Example 24 ) 30

HN 35 N NH NHW 01111 OH OH

40 (Example 30 ) (ExampleExample 25 23 ) HN 45

NH Vis OH ZH 50 OH OH

(Example 31) (Example 26 ) 55 the ??sea ,

N NH OH OH US 10 ,399 ,945 B2 187 188 - continued -continued ( Example 32) (Example 36 ) Br

U1

OH 10 A101 NH N OH

15 ( Example 33) Chem . 31 Me01 (Example 37 )

20

N

OH 25 NH OH

30 (Example 34 ) (Example 37a ) : Optically Active idoicoltoco(Example 37b ) : Optically Active (Example 38 ) N OH

( Example 34a ): Optically Active N N (Example 34b) : Optically Active HH OH

(Example 35) 50

(Example 39 ) 55 NE

OH

(Example 35a ): Optically Active (Example 35b ) : Optically Active US 10 ,399 , 945 B2 189 190 - continued - continued ( Example 40 ) ( Example 44 )

? , N " 10 N N ?? ??

15 (Example 41 ) ( Example 44a ) : Optically Active (Example 44b ) : Optically Active ?? ???(Example 45 ) 20

HN " | HO

25 N ? 25 ?? N 30 ?? ( Example 41a ): Optically Active (Example 41b ) : Optically Active

35 ???????( Example 42 ) (Example 46 )

40

HN

?? 45 ?? ?? ?? ?? 50 ?????? (Example 43) (Example 47)

55

?? NC ZI ?? US 10 ,399 , 945 B2 191 192 -continued 191 - continued ( Example 48 ) [ Chem . 4 ] (Example 52 )

- N NC

N ??

OH

( Example 48a ) : Optically Active ( Example 48b ) : Optically Active (Example 49 ) (Example 53 )

25

N N ?? ??

(Example 50 ) (Example 54 ) ??????E ????? HO 40 ????

45 IZ? I ??

50

(Example 51 ) (Example 55 ) ??? F ????? 55 HO

??

?? ???? ???? ???? US 10 ,399 ,945 B2 193 194 -continued -continued (Example 56 ) (Example 60)

?? . HN AI1011 10 OH OH OH

15 (Example 57 ) (Example 61)

20 HN

25 VHU NH N IZ H OH OH

(Example 62a ): Optically Active (Example 63b ): Optically Active (Example 62) ( Example 58 )

HO

HO NH NH OH OH

(Example 63 )

50 OH (Example 59 ) (R ) CO2H F HO2C (R ) C 55 H?N om

TABLE 2 nn Example NMR Data ( 8 : ppm ) < * 300 MHz> (CDC13 ) d : 8 . 46 - 8 .40 ( 2H , m ) , 7 .64 - 7 .59 ( 2H , m ) , 7 .55 - 7 .42 (3H , m ) , 7 . 38 - 7 .16 (5H , m ) , 6 .79 ( 1H , br s ) , 4 .88 - 4 .78 ( 2H , m ), 3 .93 - 3 .84 ( 1H , m ), 3 .20 ( 1H , br s ), 1 . 95 (1H , dd , J = 13 , 4 Hz) , 65 1 .79 ( 1H , dd , J = 13 , 13 Hz ), 1 .37 ( 3H , s ) , 1 . 29 ( 3H ,