MAIMUUTTUNTUU US009777000B2 TUNAAMINI (12 ) United States Patent (10 ) Patent No. : US 9 ,777 ,000 B2 Okano et al. (45 ) Date of Patent: Oct . 3 , 2017

(54 ) PYRAZOLE DERIVATIVE 8 , 980 , 889 B2 3 / 2015 Okano et al. 2003 /0032579 AL 2 /2003 Lebel et al . (71 ) Applicant: MOCHIDA PHARMACEUTICAL 2004 /0249148 A1 12 / 2004 Erguden et al. CO ., LTD . , Tokyo ( JP ) 2011/ 0071128 A1 3 /2011 Alberati et al. 2011 /0237564 AL 9 / 2011 Alvarez Sanchez et al. ( 72 ) Inventors : Akihiro Okano, Tokyo ( JP ) ; Kouki 2012 /0142665 A1 6 /2012 Flohr et al . Ogawa , Tokyo ( JP ) 2015 / 0133448 AL 5 / 2015 Okano et al . @( 73 ) Assignee : MOCHIDA PHARMACEUTICAL FOREIGN PATENT DOCUMENTS CO ., LTD ., Tokyo ( JP ) DE 10 2004 054 666 A1 11/ 2004 1250923 A2 10 /2002 ( * ) Notice : Subject to any disclaimer , the term of this 2008 - 528468 A 7 / 2008 patent is extended or adjusted under 35 2013 -505911 A1 6 / 2012 U . S . C . 154 (b ) by 0 days . 2013 -523673 A 6 / 2013 ( 21 ) Appl. No. : 15 /234 ,730 ( Continued ) (22 ) Filed : Aug. 11 , 2016 OTHER PUBLICATIONS Castner et al. , “ Reversal of Antipsychotic - Induced Working (65 ) Prior Publication Data Memory Deficits by Short - Term Dopamine Di Receptor Stimula US 2016 / 0347751 A1 Dec . 1 , 2016 tion ,” Science , vol. 287 , Mar. 17 , 2000 , pp . 2020 -2022 . Related U .S . Application Data (Continued ) (63 ) Continuation of application No . 14 /631 , 345, filed on Feb . 25 , 2015 , now Pat . No. 9 ,453 ,015 , which is a continuation of application No . PCT/ JP2014 /054773 , Primary Examiner — Heidi Reese filed on Feb . 26 , 2014 . (74 ) Attorney, Agent, or Firm — Birch , Stewart, Kolasch & Birch , LLP ( 30 ) Foreign Application Priority Data Feb . 27 , 2013 ( JP ) ...... 2013 -038030 (57 ) ABSTRACT (51 ) Int . CI. It has been desired to develop a pharmaceutical composi C070 471/ 04 ( 2006 . 01 ) tion , which is used in agents for preventing and /or treating CO7D 401 /04 ( 2006 .01 ) various diseases related to PDE10 ( e . g . mental disorder and CO7D 417 /04 ( 2006 . 01 ) neurodegenerative disorder ) . The present invention pro A61K 31/ 437 ( 2006 .01 ) vides : compounds having PDE10 inhibitory effect , in par A61K 31/ 444 ( 2006 .01 ) ticular, compounds having a 4 -heteroarylpyrazole - 5 - carbox A61K 31 /497 ( 2006 . 01 ) ylic acid amide structure represented by the following A61K 31 /501 ( 2006 .01 ) formula ( 1 ), or their pharmaceutically acceptable salts , or A61K 31 /506 ( 2006 .01 ) their solvates ; pharmaceutical compositions comprising , as A61K 31/ 5377 ( 2006 .01 ) active ingredients , the compounds, or their pharmaceutically A61K 45 / 06 ( 2006 .01 ) acceptable salts , or their solvates ; and medical use of the C07D 403 /04 (2006 .01 ) compounds, or their pharmaceutically acceptable salts , or (52 ) U . S . CI. their solvates . CPC ...... C070 471/ 04 ( 2013 . 01 ) ; A61K 31 /437 (2013 .01 ) ; A61K 31/ 444 (2013 .01 ) ; A61K 31 /497 ( 2013 . 01 ) ; A6IK 31 / 501 ( 2013 .01 ) ; A61K 31/ 506 (2013 .01 ) ; A61K 31/ 5377 R2 (2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; C07D Py 401/ 04 (2013 .01 ) ; C07D 403 /04 (2013 .01 ); N - N C07D 417/ 04 (2013 .01 ) N ( 58 ) Field of Classification Search None a( R See application file for complete search history . 1I? A (56 ) References Cited U . S. PATENT DOCUMENTS 8 , 349 ,824 B2 1 /2013 Flohr et al . 8 ,410 , 117 B2 * 4 /2013 Alvarez Sanchez . CO7D 487/ 04 514 /259 . 1 9 Claims, No Drawings US 9 , 777 ,000 B2 Page 2

References Cited International Search Report ( Form PCT / ISA / 210 ) for International (56 ) Application No. PCT/ JP2014 /054773 , dated Apr. 8 , 2014 , with an English translation . FOREIGN PATENT DOCUMENTS Japan Office Action for Appl. No. 2014 - 530451 dated Sep . 9 , 2014 ( w / English translation ) . JP 2013 -544859 Al 12 / 2013 Japanese Office Action issued in Japanese Patent Application No . WO WO 03 / 000693 AL 1 / 2003 2014 - 218099 on Jul. 14 , 2015 . WO WO 2005 /082883 A2 9 /2005 Kostowski et al ., “ Papaverine , Drug -Induced Stereotypy and Cata WO WO 2006 /072828 A2 7 / 2006 lepsy and Biogenic Amines in the Brain of the Rat, ” Pharmacology WO WO 2006 /077424 Al 7 / 2006 Biochemistry and Behavior, vol. 5 , 1976 , pp . 15 - 17 . wo WO 2011 /004323 A1 1 / 2011 Lapiz et al. , “ Influence of Postweaning Social Isolation in the Rat WO WO 2011 /036127 A1 3 / 2011 on Brain Development, Conditioned Behavior, and Neurotransmis WO WO 2011/ 117264 Al 3 / 2011 sion , ” Neuroscience and Behavioral Physiology, vol. 33 , No. 1 , WO WO 2011 / 154327 A1 12 / 2011 2003 , pp . 13 - 29 ( First Published in Rossiiskii Fiziologicheskii WO WO 2012 /009009 A2 1 / 2012 Zhurnal . . . , vol . 87 , No. 6 , Jun . 2001, pp . 730 -751 ) . WO WO 2012 /076430 A1 6 / 2012 Loughney et al. , “ Isolation and characterization of PDE10A , a novel WO WO 2012 / 133607 Al 10 /2012 human 3 ', 5 ' -cyclic nucleotide phosphodiesterase, ” Gene , vol. 234 , WO W O 2012009009 A3 * 4 /2014 ...... C07D 417 / 14 1999 , pp . 109 - 117 . Menniti et al ., “ Phosphodiesterase 10A inhibitors: A novel approach OTHER PUBLICATIONS to the treatment of the symptoms of schizophrenia , " Current Opin ion in Investigational Drugs , vol. 8 , No. 1 , 2007 , pp . 54 - 59 . Chappie et al. , “ Current Landscape of Phosphodiesterase 10A Menniti et al. , “ Phosphodiesterases in the CNS : targets for drug ( PDE10A ) Inhibition ,” Journal ofMedicinal Chemistry, vol . 55 , Jul. development ,” Nature, vol. 5 , Aug . 2006 , pp . 660 -670 . Mutschler et al . , “ Mutschler Drug Reactions, " Textbook of Phar 26 , 2012, pp . 7299 -7331 . macology and Toxicology, 8th Ed ., 2001, pp . 147 - 153 , 158 , 311 Essayan , “ Cyclic nucleotide phosphodiesterases , ” Journal of 313 , with an English translation . Allergy and Clinical Immunology , vol . 108 (Series : Molecular Registry (STN online ) , Aug . 24 , 2012 , RN1392274 - 35 - 9 . mechanisms in allergy and clinical immunology ) , 2001 , pp . 671 Registry (STN online ) , Mar. 21 , 2011, RN12692 - 23 - 46 - 2 . 1 . 680 . Registry File [STN online ], Apr. 15 , 2012 , RN 1368131 -71 -8 . Francis et al ., “ Cyclic Nucleotide Phosphodiesterases: Relating Sawaguchi, “ The role of D1- dopamine receptors in working Structure and Function , " Progress in Nucleic Acid Research and memory - guided movements mediated by frontal cortical areas, " Molecular Biology , vol. 65 , 2001 , pp . 1 - 52 . Parkinsonism and Related Disorders , vol. 7 , 2001 , pp . 9 - 19 . Fujishige et al. , “ Cloning and Characterization of a Novel Human Seeger et al. , “ Immunohistochemical localization of PDE10A in the Phosphodiesterase That Hydrolyzes Both CAMP and CGMP rat brain ,” Brain Research , vol. 985 , 2003 , pp . 113 - 126 . ( PDE10A ), ” The Journal of Biological Chemistry, vol. 274 , No. 26 , Soderling et al. , “ Isolation and characterization of a dual -substrate Jun . 25 , 1999 , pp . 18438 - 18445 . phosphodiesterase gene family : PDE10A , ” Proceedings of the Fujishige et al. , " Striatum - and testis - specific phosphodiesterase National Academy of Sciences of the United States of America , vol. PDE10A Isolation and Characterization of a rat PDE10A , ” Euro 96 , Jun . 1999 , pp . 7071- 7076 . pean Journal of Biochemistry , vol. 266 , 1999 , pp . 1118 - 1127 . Xie et al ., “ Cellular and Subcellular Localization of PDE10A , A Houslay et al. , " CAMP -Specific Phosphodiesterase - 4 Enzymes in Striatum - Enriched Phosphodiesterase , " Neuroscience , vol. 139 , the Cardiovascular System A Molecular Toolbox for Generating 2006 , pp . 597 -607 . Compartmentalized cAMP Signaling, ” Circulation Research , vol . 100 , 2007 , pp . 950 - 966 . * cited by examiner US 9 ,777 ,000 B2 PYRAZOLE DERIVATIVE response to extracellular signals , and are regulated based on the balance between enzymes involved in the synthesis of CROSS REFERENCE TO RELATED CAMP and CGMP ( adenyl cyclase (AC ) and guanyl cyclase APPLICATIONS (GC ) ) , and PDEs involved in the hydrolysis of these 5 enzymes (Non Patent Literature 6 ) . This application is a Continuation of Ser. No. 14 /631 . 345 . The presence of PDE10 in humans, mice , and rats was filed on Feb . 25 , 2015 , which is a Continuation of PCT reported in 1999 (Non Patent Literatures 7 and 8 ). PDE 10 is International Application No. PCT/ JP2014 /054773 , filed on mainly expressed in the brain , testis , thyroid gland , and the Feb . 26 , 2014 , which claims priority under 35 U . S . C . 119 ( a ) like in humans . In particular, PDE10 is highly expressed in to Patent Application No. 2013 - 038030 , filed in Japan on 10 medium -sized spiny neurons (MSNs ) in the corpus striatum Feb . 27 , 2013 , all of which are hereby expressly incorpo of the brain , and is moderately expressed in the thalamus, rated by reference into the present application . hippocampus, frontal cortex , and olfactory tubercle ( Non Patent Literatures 9 and 10 ) . In addition , PDE10 is highly TECHNICAL FIELD expressed in the brain and testis also in mice and rats (Non 15 Patent Literature 11 ). Since the brain sites where PDE10 is The present invention relates to a compound having expressed play an important role in the pathological mecha phosphodiesterase 10 (hereinafter referred to as “ PDE10 " ) nism of mental diseases, it has been suggested that PDE10 inhibitory effect, in particular, a compound having a 4 -het - is involved in the pathological mechanism of mental disor eroarylpyrazole - 5 -carboxylic acid amide structure repre - ders , neurodegenerative disorders , and the like (Non Patent sented by the following formula ( I) , or a pharmaceutically 20 Literature 12 ). acceptable thereof, or a solvate thereof; and a pharmaceu There are two types of MSN , namely , MSN that mainly tical composition comprising , as an active ingredient, the expresses D1 dopamine receptors and forms a nigrostriatal compound , or a pharmaceutically acceptable salt thereof, or pathway (direct pathway ) and MSN that mainly expresses a solvate thereof; or an agent for preventing and /or treating D2 dopamine receptors and forms a striatum - globus pallidus various diseases related to PDE10 ( e .g .mental disorders and 25 pathway ( indirect pathway ) . The direct pathway is involved neurodegenerative disorders ) . in the functions of motor execution and reward learning , and the indirect pathway is involved in the suppression of BACKGROUND ART movement . For example , deterioration of movements in Parkinson ' s disease is caused by excessive action of the Phosphodiesterase (PDE , cyclic nucleotide phosphodies - 30 indirect pathway, and excessive movements observed in terase ) is a superfamily of enzymes encoded by 21 different disorders such as Huntington ' s disease are caused by exces genes . To date , eleven phosphodiesterases have been iden - sive action of the direct pathway . The activity of the output tified in mammals , based on structural/ functional character- nucleus of the basal ganglia is regulated by the balance istics such as amino acid sequence homology , biochemical between antagonistic inputs from these two types of path properties , and characterization using inhibitors (Non Patent 35 ways . Since PDE10 is expressed in MSNs in both pathways , Literatures 1 and 2 ) . both pathways are considered to be activated by inhibition of The role of the PDE in cell signaling cascade is to PDE10 (Non Patent Literature 13 ) . hydrolyze the phosphodiester bond of cyclic nucleotides , The existing antipsychotic agents are mainly D2 receptor adenosine 3 , 5 ' - cyclic monophosphate (CAMP ) and /or blocking agents, and are mainly mediated by activation of guanosine 3 , 5 -cyclic monophosphate ( cGMP) , that is to 40 the indirect pathway. On the other hand , PDE10 is expressed say, to selectively catalyze the hydrolysis of a 3 ' - ester bond in both MSNs in the direct pathway and the indirect path so as to form inactive 5 '- monophosphoric acid so as to way, and thus, a PDE10 inhibitor is expected to have the metabolically inactivate the cyclic nucleotides . same antipsychotic action as that of the existing agents . The eleven PDE families are classified into three groups , Since the direct pathway is involved in motor execution , the namely, CAMP - specific PDEs (PDE 4 , 7 , and 8 ) , cGMP - 45 direct pathway is considered to antagonistically act against specific PDEs (PDE 5 , 6 , and 9 ) , and double substrate PDEs extrapyramidal disorder caused by excessive activation of ( PDE 1 , 2 , 3 , 10 , and 11 ) (Non Patent Literatures 3 and 4 ) the indirect pathway . Moreover, it can also be expected that based on substrate specificity . the direct pathway has action to reinforce the output from the Since cAMP and CGMP are important second messengers corpus striatum - thalamus circuit and to promote cognitive in intracellular signaling via G protein coupled receptors 50 function such as reward learning or problem solving . (GPCR ) , PDEs are involved in a wide range of physiological As a result of an increase in the intracellular CAMP level mechanisms and play an important role in the homeostasis by activation of the D , receptor, a series of neurites involved of organisms. Specifically , PDEs are related to various in working memory in the prefrontal cortex are likely to be physiological processes such as generation of proinflamma regulated (Non Patent Literature 14 ). Furthermore, it has tory mediators and the action thereof , ion channel function , 55 been reported that working memory deficits of schizophre muscle relaxation , learning and memory formation , differ nia patients may be improved by activation of the D . entiation , apoptosis , lipogenesis , glycogenolysis , and gluco receptor (Non Patent Literature 15 ) . Accordingly, it can be neogenesis . Particularly , in nerve cells , PDEs play an impornor anticipated that the cognitive symptoms of schizophrenia tant role in the differentiation and survival of nerve cells and will be improved by activation of the D , receptor. the regulation of neurotransmission (Non Patent Literature 60 Potential antipsychotic action of a PDE10 inhibitor has 5 ) . been attested by the study of Kostowski et al. (Non Patent Regulation of these processes by cAMP and CGMP is Literature 16 ) . According to U . S . Patent Application No. related to activation of protein kinase A (PKA ) and protein 2003 / 0032579 , papaverine a PDE10 inhibitor having a mod kinase G ( PKG ) , and thus , various substrates that regulate erate selectivity decreases apomorphine - induced stereotypy various physiological processes, such as transcriptional fac - 65 in rats which is an animalmodel of psychosis , and increases tors , ion channels, and receptors , are phosphorylated . The haloperidol- induced catalepsy in rat, and at the same time, intracellular levels of cAMP and CGMP are fluctuated in papaverine also decreases the dopamine level in the rat brain US 9 ,777 , 000 B2 and has conventional action as an antipsychotic agent. hypoglycemia - induced neurodegeneration , ( 7 ) neurodegen Further, the antipsychotic action of papaverine has been also eration associated with epileptic seizure , ( 8 ) neurodegenera proved by the application thereof to patients , and papaverine tion associated with neurotoxic addiction , (9 ) multiple sys has been established as a PDE10 inhibitor for the treatment tem atrophy, and ( 10 ) neurodegeneration of striatalmedium of psychosis (Patent Literature 1 ). 5 sized spiny neurons) ; and the like . With regard to compounds having PDE10 inhibitory International Publication No . WO2006 /0072828 (Patent effect ( PDE10 inhibitors ) , there are the following reports . Literature 5 ) discloses , as a PDE 10 inhibitors, compounds For instance , International Publication No . WO2005 /082883 ( Patent Literature 2 ) and European Patent Application No . having a 1 -methyl - 4 -heteroarylpyrazole structure as a partial 1250923 (Patent Literature 3 ) disclose , as PDE10 inhibitors , 10 structure thereof . However , this structure is different from papaverine ( isoquinoline alkaloid contained in Papaver the structure of the compound in the present invention . plants) and various types of aromatic heterocyclic com International Publication No. WO2011/ 036127 (Patent pounds ( quinazoline and isoquinazoline compounds, etc . ) . Literature 6 ), International Publication No. WO2011/ In addition , it has also been disclosed that the PDE10 154327 (Patent Literature 7 ) , and International Publication inhibitor is useful for treating or preventing diseases or 15 NoNO .. WO2012 /076430 (Patent Literature 8 ) disclose com symptoms, such as mental disorder ( e . g . schizophrenia , pounds having a pyrazole - 5 - carboxylic acid amide structure schizophreniform disorder. paranoid disorder. substance as a PDE10 inhibitors. However, the structures of the induced psychosis, paranoic personality disorder , and compounds of Patent Literatures 6 , 7 , and 8 are all different schizophrenic personality disorder) , anxiety disorder ( e . g . from the structure of the compound in the present invention panic disorder , agoraphobia , specific phobias, anthropopho - 20 in that the compounds of Patent Literatures 6 and 8 have a bia , obsessive - compulsive disorder, posttraumatic stress dis - dicarboxylic acid amide structure and in that the compound order, acute stress disorder, and generalized anxiety disor of Patent Literature 7 is a carboxylic acid amide of 7 - ami der) , motor disorder ( e. g. Huntington ' s disease , dyskinesia noimidazo [ 1 ,2 - a] pyrimidine . associated with dopamine agonist therapy, Parkinson ' s dis ease , and restless legs syndrome ), drug dependence ( e . g . 25 PRIOR ART DOCUMENTS alcohol, amphetamine , cocaine or opiate addiction ) , diseases attended with the symptoms of cognitive disorder ( e . g . Patent Documents dementia ( Alzheimer ' s disease , multi- infarct dementia , etc . ), delirium , amnestic defect, posttraumatic stress disor- Patent Literature 1: U .S . Patent Application No . 2003/ der, mental retardation , learning disorder , attention -deficit 30 0032579 hyperactivity disorder (ADHD ), and age -related cognitive Patent Literature 2 : International Publication No. WO2005 / function reduction ), and mood disorder (e .g . major depres- 082883 sive disorder, dysthymic disorder, minor depressive disor - Patent Literature 3 : European Patent Application No . der, and bipolar disorder (bipolar disorder type I and bipolar 1250923 disorder type II ) , and cyclothymic disorder ), or mood symp- 35 Patent Literature 4 : International Publication No. WO2003/ toms ( e . g . major depressive episode , manic or mixed affec - 000693 tive episode, and hypomanic episode ). Moreover, it has also Patent Literature 5 : International Publication No . WO2006 / been disclosed that the PDE10 inhibitor is useful for treating 072828 or preventing neurodegenerative disease ( e . g . Parkinson ' s Patent Literature 6 : International Publication No. WO2011 / disease and Huntington ' s disease ) . 40 036127 The publication of Menniti et al . reports that the PDE10 Patent Literature 7: International Publication No . WO2011/ inhibitor has a potential as an antipsychotic agent and also 154327 has a potential for improving cognitive function disorder in Patent Literature 8 : International Publication No. WO2012 / schizophrenia (Non Patent Literature 17 ) . 076430 International Publication No . WO2003 /000693 discloses 45 an imidazotriazine compound as a PDE10 inhibitor , and that Non -Patent Documents the PDE10 inhibitor is useful for treating or preventing neurodegenerative diseases ( in particular , Parkinson ' s dis - Non Patent Literature 1 : Essayan D M ., J Allergy Clin ease ) ( Patent Literature 4 ) . Immunol, 108 , p671 - 680 , 2001. As described above, it is anticipated that the PDE10 50 Non Patent Literature 2 : Francis S H ., Prog Nucleic Acid inhibitor can be a therapeutic agent with reduced adverse Res Mol Biol. , 65 ,p1 -52 , 2001 . drug reactions , which is useful for treating and /or preventing Non Patent Literature 3 : Soderling S H . , Proc Natl Acad mental disorders related to PDE10 ( e. g . ( 1) paranoid , dis - USA , 96 ( 12) , p7071 -' 70 '76 , 1999 . organized , catatonic, undifferentiated , or residual schizo . Non Patent Literature 4 : Chappie T A . , Journal of Medicinal phrenia , ( 2 ) schizophreniform disorder , ( 3 ) paranoid or 55 Chemistry , 55 , p7299 -7331 , 2012 . depressive schizoaffective disorder, (4 ) paranoid disorder, Non Patent Literature 5 : Menniti F S ., Nat Rev Drug Discov, ( 5 ) substance- induced mental disorder , for example , psy - 5 (8 ) , p660 -6 '70 , 2006 . chosis induced by alcohol, amphetamine , cannabis , cocaine , Non Patent Literature 6 : Houslay M D ., Cir Res, 100 (7 ), a hallucinatory drug , an inhalant, opioid , or phencyclidine , p950 - 966 , 2007 . ( 6 ) paranoic personality disorder , and ( 7 ) schizotypal per - 60 Non Patent Literature 7 : Omori K . , J Biol Chem , 274 ( 26 ) , sonality disorder ); neurodegenerative disorders related to p18438 - 18445 , 1999 . PDE 10 ( e. g . ( 1) Parkinson ' s disease , ( 2 ) Huntington 's dis - Non Patent Literature 8 : Loughney K ., Gene, 234 ( 1) , p109 ease , ( 3 ) dementia , such as Alzheimer 's disease , multi - 117, 1999 . infarct dementia , AIDS- related dementia , and frontotempo - Non Patent Literature 9 : Omori K ., Eur J Biochem , 266 ( 3 ), ral dementia , ( 4 ) neurodegeneration associated with brain 65 p1118 - 1127 , 1999 . damage, ( 5 ) neurodegeneration associated with stroke and Non Patent Literature 10 : Menniti F S ., Brain Res, 985 (2 ) , neurodegeneration associated with cerebral infarction , (6 ) p113 - 126 , 2003 . US 9 ,777 ,000 B2 5 Non Patent Literature 11: Xie Z ., Neuroscience ., 139( 2 ), (hERG ) channel, which may have a risk of causing arrhyth p597 -607 , 2006 . mia , that a compound exhibits an activity of inducing or Non Patent Literature 12 : Lapiz et al ., Neurosci Behav inhibiting drug metabolizing enzyme ( e . g . cytochrome Physiol, 33 ( 1 ) , p13 -29 , 2003 . P450 ) , and that a compound exhibits a high protein - binding Non Patent Literature 13 : Mutschler. , Arzneimittelwirkun - 5 rate . It has been desired to discover a compound that solves gen . gth ed . Stuttgart : Wissenschaftliche Verlagsgesell as many of these problems as possible and has high effec schaft mbH , 2001 . tiveness . Non Patent Literature 14 : Sawaguchi. , Parkinsonism Relat Disord. , 7 ( 1 ), p 9 - 19 , 2000 . Non Patent Literature 15 : Castner SA . , Science ., 287 (5460 ) , 10 Means for Solving the Problems p2020 - 2022 , 2000 . Non Patent Literature 16 : Kostowski W ., Pharmacol Bio The present inventors have conducted intensive studies chem Behav. , 5 ( 1 ), p15 - 17 , 1976 . directed towards solving the aforementioned problems and Non Patent Literature 17 : Menniti F S . , Curr Opin Investig obtaining a PDE10 inhibitor that is highly safe and /or is Drugs. , 8 ( 1 ) , p54 -59 , 2007 . 15 excellent in effectiveness. As a result , the inventors have discovered that a compound having a 4 -heteroarylpyrazole SUMMARY OF THE INVENTION 5 - carboxylic acid amide structure represented by a formula (1 ), or a pharmaceutically acceptable salt thereof, or a Problems to be Solved by the Invention solvate thereof has PDE10 inhibitory effect. The compounds At present, various antipsychotic agents can be used in in the present invention have PDE10 inhibitory effect and drug therapy for schizophrenia . However, such antipsy also have effect to improve various diseases related to chotic agents have a low level of satisfaction in treatment. PDE10 ( e . g . mental disorder and neurodegenerative disor Conventional antipsychotic agents having high affinity for der ). dopamine D , receptors , such as haloperidol, exhibit strong 25 adverse effects including extra pyramidal symptom (EPS ) and do not improve the negative symptoms of schizophre Effects of the Invention nia , thus the agents cannot get patients back to daily life . Clozapine , which had been developed as standard therapy for improving the positive , negative , and cognitive symp- 30 Formula u . toms of schizophrenia and which has not exhibited EPS , has been placed on the market as a benchmark for treating and recovering the positive , negative, and cognitive symptoms R2 of schizophrenia . However , this clozapine causes granulo NN cytopenia as a severe potentially lethal adverse drug reaction 35 (Capuano B . , Curr Med Chem , 9 ( 5 ), pp . 521 -548 , 2002 ) . Moreover , many therapy -resistant cases are still present (Lindenmayer J P ., J Clin Psychiatry , 63 ( 10 ), pp . 931- 935 , 2002 ) . In conclusion , it has been desired to develop a novel antipsychotic agent for improving the positive , negative , and 40 NA cognitive symptoms of psychosis and having a better adverse effect profile . VROP Moreover, in the development of pharmaceutical prod ucts , it is required to satisfy strict criteria , not only in terms The present invention is a compound having a 4 -het of pharmacological activities of interest , but also in termsof 45 eroarylpyrazole -5 -carboxylic acid amide structure repre various aspects such as absorption , distribution , metabolism , sented by the formula ( 1 ), or a pharmaceutically acceptable and excretion . For example , pharmaceutical products are salt thereof, or a solvate thereof; and a pharmaceutical required to overcome various problems regarding drug inter composition comprising, as an active ingredient, the com action , desensitization or tolerance , gastrointestinal absorp tion upon oral administration , rate of transferring into the 50 pound , or a pharmaceutically acceptable salt thereof, or a small intestine, absorption rate and first pass effect, organ solvate thereof. barriers , protein binding , induction or inhibition of drug The compound in the present invention is a compound metabolizing enzymes , excretion pathway and inner clear- having PDE10 inhibitory effect. This compound has action ance , application methods (application site , method , and to inhibit the hydrolysis of a phosphodiester bond of CAMP purpose ), and the like . It is difficult to discover a pharma - 55 in striatal GABA neurons and increase nerve ignition by ceutical product that satisfies these requirements . inhibiting PDE10 , and to improve various diseases related to There have been several reports regarding a compound PDE10 ( e . g . mental disorders and neurodegenerative disor having inhibitory effect on the PDE10 receptor. However, ders ) by promoting the activation of the corpus striatum . the above -mentioned general problems have always remained unsolved during the development of pharmaceu - 60 A pharmaceutical composition comprising , as an active tical products, and thus, such a compound has not yet been ingredient, the compound in the present invention can be placed on the market. More specifically , regarding useful preferably administered by oral administration , and it is ness and safety , there are problems such as poor solubility , expected to be an agent for preventing and / or treating low metabolic stability and difficult systemic exposure by diseases related to PDE10 . oral administration , poor drug pharmacokinetics such as 65 Moreover , a group of the compounds of the present absorbability and persistence , that a compound exhibits invention is highly useful because these compounds have at inhibitory activity on human ether - a - go -go related gene least one characteristic of good solubility , high metabolic US 9 ,777 ,000 B2 stability , excellent oral absorbability , and having only small group , a mono - / di- halogenated C1- 6 alkylsulfamoyl group , a action to inhibit the hERG channel. mono - di- C3- 8 cycloalkylsulfamoyl group , a mono -/ di - C6 - 14 arylsulfamoyl group , a mono -/ di - C7 - 20 aralkylsulfamoyl EMBODIMENTS FOR CARRYING OUT THE group , and a mono -/ di - heterocyclic sulfamoyl group ; R2 INVENTION 5 represents a hydrogen atom , a C1- 6 alkyl group , a haloge nated C1- 6 alkyl group, a hydroxy C1- 6 alkyl group , or a C1- 6 The present invention is a compound having a 4 -het alkoxyl C1- 6 alkyl group ; R each independently represents eroarylpyrazole - 5 -carboxylic acid amide structure repre a halogen atom , a cyano group , a C1- 6 alkyl group , a sented by the following formula (I ) , or a pharmaceutically halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a acceptable salt thereof, or a solvate thereof: a pharmaceu - 10 C1- 6 alkoxyl group , a halogenated C1- 6 alkoxyl group , or a C1- 6 alkoxyl C1- 6 alkyl group ; R * represents a halogen atom , tical composition comprising , as an active ingredient , the a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a C3 -8 compound , a pharmaceutically acceptable salt thereof, or a cycloalkyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl solvate thereof; and a PDE10 inhibitor as medicinal use of group , a halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 the compounds, a pharmaceutically acceptable salt thereof1 , 15 alkyl group, a CL- 6 alkylthio group , a C1- 6 alkylsulfonyl or a solvate thereof, which are described in the following group, a CONR 'R® group , an - NR ' R $ group wherein R ? embodiments . and R8 in the — NR R8 group and the CONR7R8 group The present invention includes the following embodi have the same definitions as those of R7 and R8 in the above ments [ 1 ] to [ 17 ] . R ' , a C6 - 14 aryl group , a 3 - to 14 -membered non -aromatic A first embodiment of the present invention is 20 heterocyclic group , or a 5 - to 7 -membered monocyclic [ 1 ] a compound represented by the following formula ( I ) , or heteroaryl group , wherein the Cz . , cycloalkyl group , the a pharmaceutically acceptable salt thereof, or a solvate C6- 14 aryl group , the 3 - to 14 -membered non - aromatic thereof: heterocyclic group , and the 5 - to 7 -membered monocyclic heteroaryl group , which are represented by R * , are option 25 ally substituted with one to three groups selected from [ Formula 2 ] among a hydroxyl group , a nitro group , a cyano group , a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl 2 group , a hydroxy C1- 6 alkyl group, a C1- 6 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl N - N 30 group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a CONR ' R $ group , an - NR ' R $ group wherein R7 and R8 - in the - NR R8 group and the CONR /R8 group have the 3 same definitions as those of R7 and R8 in the above R ', a C6- 14 aryl group , a 3 - to 14 -membered non - aromatic hetero 35 cyclic group , and a 5 - to 7- membered monocyclic heteroaryl group ; Rrepresents a hydrogen atom , a halogen atom , a (R ' ) p C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 alkoxyl group , or a C1- 6 wherein p represents an integer of 0 to 4 ; q represents an alkoxyl C1- 6 alkyl group ; integer of 0 to 4 ; Z represents N or CRS ; R each indepen - 40 ring A represented by the following partial structural dently represents a halogen atom , a hydroxyl group , a nitro formula (11 ) : group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C - , alkoxyl group , a halogenated C . , alkoxyl group , a [Formula 3 ] C1- 6 alkoxylcarbonyl group, a hydroxy C1- 6 alkyl group , a 45 C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfinyl group , a C1- 6 alkylsul fonyl group , an - NR ' R8 group , or a CONR ’ R8 group wherein R7 and R8 in the NR7R8 group and the CONR ’R® group each independently represent a substitu - 50 ent selected from among a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl represents a 5 - to 7 -membered monocyclic heteroaryl group group , a cyanated C1- 6 alkyl group , a C2 -6 alkenyl group , a which has a structure in which position 4 of a pyrazole ring C2- 6 alkynyl group , a C3- 8 cycloalkyl group , a C6 -14 aryl directly binds to position a to a nitrogen atom of the 5 - to group , a C7 - 20 aralkyl group , a heterocyclic group , a C2- 7 55 7 -membered monocyclic heteroaryl group , and is selected alkanoyl group , a hydroxy C2 - 7 alkanoyl group , a haloge - from the group of the heteroaryls consisting of the follow nated C2- 7 alkanoyl group , a C3- 8 cycloalkylcarbonyl group , ing: a C6- 14 arylcarbonyl group , a C7- 20 aralkylcarbonyl group , a heterocyclic carbonyl group , a mono - / di- C1 - 6 alkylcarbam oyl group , a mono -/ di - halogenated C1- 6 alkylcarbamoyl 60 (Formula 41 group , a mono -/ di- C3 - 8 cycloalkylcarbamoyl group , a mono - di- C6- 14 arylcarbamoyl group , a mono -/ di - C7 - 20 ( II - 1 ) aralkylcarbamoyl group , a mono - di- heterocyclic carbamoyl group , a C1- 6 alkylsulfonyl group , a halogenated C1- 6 alkyl sulfonyl group , a C3- 8 cycloalkylsulfonyl group , a C6- 14 65 arylsulfonyl group , a C7- 20 aralkylsulfonyl group , a hetero cyclic sulfonyl group , a mono -/ di - C1 - 6 alkylsulfamoyl US 9, 777 , 000 B2 10 - continued -continued (II - 2) (II - 12 ) ? ??????? (I - 3 ) 10 (II - 13 )

NS ? JN 15 (II - 14 ) (II - 4 )

0N 20 (II - 15 ) (II - 5 )

25

??? (II - 16 ) (II - 6 ) 30 ]N? ( II- 17 ) ??P6& 35 ( I -7 )

N (II -18 )

-3 40 ( II- 8 ) NYNYV?R6

(II -19 ) 45

(II - 9 )

50 ( II- 20 ) N !N??

/6 (II - 10) 55 ? ???????? ( II- 21 ) N ??? ? - 3 (II - 11 ) ?88 (II - 22 ) ? US 9, 777 , 000 B2 n 12 - continued -continued (II - 23 ) ( II- 33 )

W .

(I -24 ) 10 ( II- 34 )

N "

= N?N ? 15 (II -35 ) (II - 25 ) 2?)

20 NA - ( II- 36) (II - 26)

25 N

=N N (II - 27 ) (II -37 ) 30

|

(II - 28 ) 35 ( II -38 )

NYNN?

4=W ? 40 (II - 29 ) (II -39 )

| 45 (II - 30 ) ??????????) (II - 40 )

50 )NYNN ?NA!? WIN

(II -31 ) (II - 41 ) 55 NIN NIN 60 (II -32 ) (II - 42)

Z

Z 6 US 9 ,777 ,000 B2 13 14 - continued “ straight chain or branched chain , the number of constituent ( II -43 ) carbon atoms of which is 1 to 6 . ” On the other hand , the cyclic group means a “ cyclic group in which the number of carbon atoms that constitute a ring is 1 to 6 .” A group N 5 comprising a chain group and a cyclic group means a “ group , the total number of carbon atoms of which is 1 to 6 . " NEN: In the present specification , unless otherwise specified , examples of the " halogen atom ” include a fluorine atom , a chlorine atom , a bromine atom , and an iodine atom . Rº represents a hydrogen atom , a C1- 6 alkyl group , a halo - 10 In the present specification , unless otherwise specified , genated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group ; and the term “ halogenated ” means that a group optionally has fused ring B represented by the following partial struc one to five of the above described “ halogen atoms” as tural formula ( III ) : substituents . In addition , the term " halogenated ” can be 15 restated as “ optionally halogenated ” or “ halogeno .” [Formula 5 ] In the present specification , unless otherwise specified , the term “ cyanated ” means that a group optionally has one (III ) to five of the above described “ cyano groups” as substitu ents . In addition , the term “ cyanated ” can be restated as 20 “ optionally cyanated .” min In the present specification , unless otherwise specified , q (R ) w examples of the “ alkyl group ” include a “ C1- 6 alkyl group. ” Fused Ring B In the present specification , unless otherwise specified , examples of the “ C1- 6 alkyl group ” include methylethyl, 25 propyl, isopropyl, butyl, isobutyl , sec -butyl , tert -butyl , pen is selected from the group consisting of the following : tyl, isopentyl, neopentyl, tert -penty13 -methylbutyl , 1 ,2 -dim ethylpropyl, 1 - ethylpropyl, hexyl, isohexyl, 1 -methylpentyl , 2 -methylpentyl , 3 -methylpentyl , 1, 1 -dimethylbutyl , 1 , 2 -di [Formula 6 ] methylbutyl, 2 , 2 -dimethylbutyl , 1 , 3 - dimethylbutyl, 2 , 3 - di (U - 1 ) 30 methylbutyl, 3 , 3 -dimethylbutyl , 1 - ethylbutyl, 2 - ethylbutyl, R4 1 , 1 , 2 - trimethylpropyl, 1 , 2 , 2 - trimethylpropyl, 1 - ethyl- 1 methylpropyl, l - ethyl- 2 -methylpropyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1 - cyclopropylethyl, RS q( R3 ) 35 2 - cyclopropylethyl, 2 -cyclobutylethyl , and 2 -methylcyclo (III - 2 ) propyl. Px ? In the present specification , unless otherwise specified , the term “ halogenated C1- 6 alkyl group ” means a group in which the above described “ C1- 6 alkyl group ” is optionally 40 substituted with one to five halogen atoms . Examples of the halogenated C1- 6 alkyl group include fluoromethyl, difluo romethyl, trifluoromethyl, 2 , 2 , 2 - trifluoroethyl, 1 , 1 , 2 , 2 -tetra Ry (III - 3 ) fluoroethyl, and pentafluoroethyl. In the present specification , unless otherwise specified , 45 the term “ hydroxy C1- 6 alkyl group ” means a group in which the above described “ C1- 6 alkyl group ” is optionally substi tuted with one to five hydroxyl groups . Examples of the ( III - 4 ) hydroxy C1- 6 alkyl group include hydroxymethyl, hydroxy R4 ? ethyl ( specifically , 1 -hydroxyethyl and 2 - hydroxyethyl ) , 50 hydroxypropyl ( specifically, 1 - hydroxypropyl, 2 - hydroxy vin propyl, 3 -hydroxypropyl , etc .) , and 2 -hydroxy - 2 -methyl ethyl . q( R3 ) In the present specification , unless otherwise specified , the term “ cyanated C1- 6 alkyl group ” means a group in 55 which the above described “ C1- 6 alkyl group ” is optionally Hereinafter, individual groups in the above formula (I ) of substituted with one to five cyano groups. Examples of the the embodiment [1 ] will be specifically described . cyanated C1- 6 alkyl group include cyanomethyl, 1 -cyano In explanation regarding the compound in the present ethyl, and 2 - cyanoethyl. invention , for example , the term “C1 - 6 " indicates that the In the present specification , unless otherwise specified , number of constituent carbon atoms is 1 to 6 , and it indicates 60 examples of the “ alkenyl group ” include a “ C2- 6 alkenyl the number of carbon atoms in a straight -chain , branched group. ” chain , or cyclic group , unless otherwise specified . The In the present specification , unless otherwise specified , number of constituent carbon atoms includes the total num examples of the “ C2- 6 alkenyl group ” include vinyl, allyl, ber of carbon atoms of groups including straight- chain or isopropenyl, 1 -propen - 1 - yl , 2 -methylallyl , butenyl, pente branched - chain groups substituted with cyclic groups, or 65 nyl, isopentenyl, hexenyl, 1 - cyclopropen - 1 -yl , 2 - cyclopro cyclic groups substituted with straight- chain or branched pen - 1 - yl , 1 - cyclobuten - 1 - yl, 1 - cyclopenten - 1 - yl, 2 - cyclo chain groups . Accordingly , the chain group means a penten - 1 - yl , 3 - cyclopenten - 1 - yl, 1 - cyclohexen - 1 - yl, US 9 ,777 ,000 B2 15 16 2 -cyclohexen - 1 - yl, 3 -cyclohexen - 1 - yl, 2 ,4 - cyclopentadien group, " a " partially hydrogenated fused -ring heteroaryl 1 - yl, and 2 , 5 -cyclohexadien - 1 - yl. group , " and a " non - aromatic heterocyclic group .” In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , examples of the “ alkynyl group ” include a “ C2- 6 alkynyl the term " heterocyclic group ” can be restated as a “ hetero group . " 5 ring group , " the term " heteroaryl group ” can be restated as In the present specification , unless otherwise specified , an " aromatic heterocyclic group, " and the term “ non - aro matic heterocyclic group ” can be restated as a “ non - aromatic examples of the “ C2- 6 alkynyl group ” include ethynyl, hetero ring group .” 1 -propynyl , 2- propynyl , butynyl, pentynyl, and hexynyl. In the present specification , unless otherwise specified , In the present specification , unless otherwise specified“ ;, 10 the above described “ heteroaryl group ” means a 5 - to examples of the “ aryl group ” include a “ C6- 14 aryl group ." + 14 -membered heteroaryl ring group having one to five In the present specification , unless otherwise specified , heteroatoms selected from among a nitrogen atom , a sulfur the “ C6- 14 aryl group ” includes a “ monocyclic aryl group ,” atom , and an oxygen atom . a “ fused - ring aryl group ( including bicyclic or tricyclicche In the present specification , unless otherwise specified , groups ) , " and a partially hydrogenated fused -ring aryl 15 examples of the above described " heteroaryl group ” include group ( including bicyclic or tricyclic groups) . ” a " monocyclic heteroaryl group ” and a “ fused - ring het In the present specification , unless otherwise specified , eroaryl group .” examples of the “ C6- 14 aryl group ” include phenyl, 1- naph In the present specification , unless otherwise specified , thyl, 2 -naphthyl , 2 -, 3 -, or 4 -biphenylanthryl , phenanthryl, the above described “ monocyclic heteroaryl group ” is pref and acenaphthyl. 20 erably a group having five to seven ring members . That is to In the present specification , unless otherwise specified , say , examples of the “ 5 - to 7 -membered monocyclic het the term " partially hydrogenated fused - ring aryl group" eroaryl group " include pyrrolyl, furyl, thienyl, thiazolyl, means a monovalent group formed by removing any given oxazolyl, 1H - imidazolyl, isothiazolyl, isoxazolyl, 1H -pyra hydrogen atom from a partially hydrogenated fused ring in zolyl , 1 , 2 , 4 - thiadiazolyl , 1 , 2 , 4 - oxadiazolyl, 1H - 1 , 2 , 4 - triaz the above described “ fused -ring aryl group ." Either a hydro - 25 olyl, 1 , 2 , 5 - thiadiazolyl , 1 , 2 , 5 - oxadiazolyl( furazanyl) , 2H - 1 , gen atom in the aromatic ring portion of the fused ring or a 2 , 3 - triazolyl, 1 , 3 , 4 - thiadiazolyl , 1 , 3 , 4 -oxadiazolyl , 4H - 1 , 2 , hydrogen atom in the hydrogenated portion thereof may be 4 -triazolyl , 1 ,2 ,4 -thiadiazolyl , 1 ,2 ,4 -oxadiazolyl , 1H -1 ,2 ,4 removed . triazolyl, 1 , 2 , 3 - thiadiazolyl, 1 , 2 , 3 - oxadiazolyl, 1H - 1 , 2 , 3 In the present specification , unless otherwise specified , triazolyl , 1 , 2 , 3 , 4 - thiatriazolyl, 1 , 2 , 3 , 4 - oxatriazolyl, 1 , 2 , 3 , 5 examples of the “ partially hydrogenated fused - ring aryl 30 thiatriazolyl, 1 ,2 , 3 ,5 -oxatriazolyl , 1H -tetrazolyl , group ” include indanyl, indenyl, and 1 ,2 ,3 ,4 -tetrahy - 2H -tetrazolyl , pyridinyl, pyridazinyl, pyrimidinyl, pyrazi dronaphthyl. nyl, 1 , 2 , 3 - triazinyl, 1 , 2 , 4 - triazinyl, 1 , 3 , 5 -triazinyl , 1 , 2 , 4 , 5 The “ aryl group ” may be restated as an " aromatic hydro - tetrazinyl, 1, 2 ,3 ,4 - tetrazinyl , 1, 2, 3 ,5 - tetrazinyl, 2H - 1, 2 ,3 carbon group .” That is to say , the “ C6- 14 aryl group ” means thiadiazinyl, 4H -1 , 2 ,4 - thiadiazinyl, 6H - 1 ,3 ,4 -thiadiazinyl , the same group as a “ C6. 14 aromatic hydrocarbon group .” 35 1 , 4 - diazepinyl, and 1 , 4 - oxazepinyl. In the present specification , unless otherwise specified . In the present specification , unless otherwise specified , the term “ aralkyl group ” means a group in which the above the above described “ fused - ring heteroaryl group ” means a described “ aryl group ” is substituted with the above monovalent group formed by removing any given hydrogen described “ alkyl group .” atom from a fused ring that is formed by condensation of a In the present specification , unless otherwise specified , 40 “ heterocyclic group ” and an “ aryl group ,” or of a “ hetero examples of the “ aralkyl group ” include a “ C7- 20 aralkyl cyclic group ” and a “monocyclic heteroaryl group .” The any group. ” given hydrogen atom may be removed from any of the fused In the present specification , unless otherwise specified , rings. examples of the “ C7- 20 aralkyl group ” include benzyl, phen - In the present specification , unless otherwise specified , ethyl, diphenylmethyl, 2 ,2 -diphenylethyl , 3 -phenylpropyl , 45 the above described “ fused - ring heteroaryl group ” is pref 4 -phenylbutyl , 5 -phenylpentyl , 2 -biphenylmethyl , 3 - biphe - erably a group having 8 to 12 ring members. That is to say , nylmethyl, 4 - biphenylmethyl, 1 - naphthylmethyl, 2 -naphth examples of the “ 8 - to 12 -membered fused - ring heteroaryl ylmethyl, 2 - ( 1 -naphthyl ) ethyl , 2 - ( 2 -naphthyl ) ethyl , 1 - inda - group ” include indolyl, isoindolyl, benzofuranyl, isobenzo nylmethyl, 2 - indanylmethyl, 1 , 2 , 3 , 4 - tetrahydronaphthalen - furanyl, benzothienyl , isobenzothienyl, benzoxazolyl, 1 , 2 1 - ylmethyl, and 1 , 2 , 3 , 4 - tetrahydronaphthalen - 2 - ylmethyl . 50 benzoisoxazolyl, benzothiazolyl, 1 , 2 - benzisothiazolyl, In the present specification , unless otherwise specified , 1H -benzimidazolyl , 1H -indazolyl , 1H - benzotriazolyl, 2 , 1 , 3 examples of the “ non - aromatic hydrocarbon group” include benzothiadiazinyl, chromenyl, isochromenyl, 4H - 1 , 4 -ben a non -aromatic hydrocarbon ring containing three to eight zoxazinyl, 4H - 1 , 4 -benzothiazinyl , quinolyl, isoquinolyl, carbon atoms, such as a “ C3- 8 cycloalkyl group .” cinnolinyl , quinazolinyl, quinoxalinyl , phthalazinyl, benzo In the present specification , unless otherwise specified , 55 xazepinyl , benzazepinyl, benzodiazepinyl, naphthyridinyl , examples of the “ C3-8 cycloalkyl group ” include cyclopro - purinyl, pteridinyl, carbazolyl , carbolinyl, acridinyl, phe pyl, cyclobutyl , cyclopentyl , cyclohexyl, cycloheptyl and noxazinyl , phenothiazinyl, phenazinyl, phenoxathiinyl , thi cyclooctyl. anthrenyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, In the present specification , unless otherwise specified , indolizinyl , thieno [ 3 , 2 - c ]pyridyl , thiazolo [5 ,4 -c ]pyridyl , the term " heterocyclic group ” means a monovalent group 60 pyrrolo?1 , 2 - b ]pyridazinyl , pyrazolo 1 , 5 - a ]pyridyl , imidazo formed by removing any given hydrogen atom from a 3 - to [ 1 , 2 - a ] pyridyl , imidazo [ 1, 5 - a ]pyridyl , imidazo [ 1 , 2 - b ] 14 -membered monocyclic or fused ring containing one to pyridazinyl , imidazo [ 1 , 5 - a ]pyrimidinyl , 1 , 2 , 4 - triazolo [ 4 , 3 five heteroatoms that are of at least one optionally selected a ]pyridyl , 1 ,2 , 4 -triazolo [4 , 3 -b ]pyridazinyl , 1H -pyrazolo [3 , from among a nitrogen atom , a sulfur atom , and an oxygen 4 -b ]pyridyl , and 1, 2 ,4 - triazolo [ 1 ,5 - a ]pyrimidinyl . atom . 65 In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , the term " partially hydrogenated fused -ring heteroaryl examples of the “ heterocyclic group ” include a " heteroaryl group ” means a monovalent group formed by removing any US 9 ,777 , 000 B2 17 18 given hydrogen atom from a partially hydrogenated fused and examples of the alkoxyl group include a “ C1- 6 alkoxyl ring in a fused ring that is formed by condensation of a group .” The alkoxyl group is generally represented by RO " heterocyclic group ” and an “ aryl group, ” or of a “ hetero ( R = alkyl group ) . cyclic group ” and a “ heteroaryl group .” As the any given in the present specification , unless otherwise specified , hydrogen atom , either a hydrogen atom in any ring portions 5 examples of the “ C1- 6 alkoxyl group ” include methoxy, of the “ heterocyclic group ," the “ aryl group ," and the ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec - butoxy, tert -butoxy , pentyloxy, isopentyloxy , neopentyloxy , tert " heteroaryl group ” in the fused ring , or a hydrogen atom in pentyloxy , 1 -methylbutoxy , 2 -methylbutoxy , 1 , 2 - dimethyl the hydrogenated ring portion , may be removed . For propoxy, 1 - ethylpropoxy, hexyloxy , isohexyloxy , 1 -methyl example , if quinoline is partially hydrogenated tetrahydro 10 pentyloxy, 2 -methylpentyloxy , 3 -methylpentyloxy , 1 , 1 quinolyl , examples of the partially hydrogenated fused - ring dimethylbutyloxy, 1 , 2 - dimethylbutyloxy , 2 , 2 heteroaryl group include 5 ,6 , 7 , 8 - tetrahydroquinolyl and 1 , 2 , dimethylbutyloxy, 1, 3 - dimethylbutyloxy, 2 , 3 3 , 4 - tetrahydroquinolyl. Depending on the position from dimethylbutyloxy, 3 ,3 -dimethylbutoxy , 1- ethylbutyloxy, which any given hydrogen atom is removed , examples of the 2 -ethylbutyloxy , 1, 1, 2 -trimethylpropyloxy , 1, 2 ,2 - trimethyl 5 ,6 , 7 , 8 -tetrahydroquinolyl include groups with suffixesyes 15 propyloxy, l - ethyl- 1- methylpropyloxy , l -ethyl - 2 -methyl - 2 - yl, - 3 -yl , - 4 - yl, - 5 - yl, -6 -yl , - 7 - yl, and - 8 - yl, and examples propyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy , of the 1 ,2 , 3 ,4 - tetrahydroquinolyl include groups with suf cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy , fixes - 1- yl, - 2 -yl , - 3 -yl , - 4 -yl , - 5 -yl , -6 -yl , - 7 -yl , and - 8 -yl . cyclopentylmethoxy, 1 - cyclopropylethoxy, 2 -cyclopropyl In the present specification , unless otherwise specified , ethoxy, 2 -cyclobutylethoxy , and 2 -methylcyclopropyloxy . the “ partially hydrogenated fused - ring heteroaryl group ” is 20 In the present specification , unless otherwise specified , preferably a group having 8 to 12 ring members. That is to the term “ aryloxy group ” means a group in which the above say , examples of the “ partially hydrogenated 8 - to 12 -mem described “ aryl group ” is substituted with an oxygen atom , bered fused -ring heteroaryl group ” include indolinyl, 4 , 5 ,6 , and examples of the aryloxy group include a “ C6- 14 aryloxy 7 - tetrahydro - 1H - indonyl, 2 , 3 -dihydrobenzofuranyl , 4 , 5 , 6 , 7 group. ” tetrahydro - benzofuranyl, 2 , 3 - dihydrobenzo [ d ] oxazolyl, 2 , 3 - 25 In the present specification , unless otherwise specified , dihydrobenzo [ d ]thiazolyl , chromanyl , 2H - chromenyl, examples of the “ C6- 14 aryloxy group ” include phenoxy, 4H -chromenyl , isochromanyl , 1H - isochromenyl, 3, 4 -di 1 -naphthyloxy , 2 - naphthyloxy, 2 -anthryloxy , and phenan hydro -2H - 1 , 4 - benzoxazinyl, 3 , 4 - dihydro - 2H - 1 , 4 -benzothi - thryloxy . azinyl, 5 ,6 , 7, 8 - tetrahydroquinolyl, 1 ,2 , 3 ,4 - tetrahydroqui In the present specification , unless otherwise specified , nolyl, 1 , 2 - dihydroquinolyl, 1 , 2 , 3 , 4 -tetrahydroquinazolyl , 30 the term “ aralkyloxy group ” means a group in which the 1 , 2 - dihydroquinazolyl, 2 , 4 -dihydro - 1H -benzo [ d ] [ 1 , 3 ] oxazi - above described “ aralkyl group ” is substituted with an nyl, 2 ,4 - dihydro - 1H -benzo [ d ] [ 1 , 3 ]thiazinyl , 5 , 6 , 7 , 8 - tetrahy - oxygen atom , and examples of the aralkyloxy group include droisoquinolyl, 1 , 2 - dihydroisoquinolyl, 1 , 2 , 3 , 4 -tetrahy - a “ C7- 20 aralkyloxy group. ” droisoquinolyl, 1 , 2 - dihydroquinoxalinyl, 1 , 4 - In the present specification , unless otherwise specified , dihydroquinoxalinyl, 1, 2 ,3 ,4 - tetrahydroquinoxalinyl, 35 examples of the “ C7- 20 aralkyloxy group ” include benzy 4H -benzo [ d ][ 1 , 3 ]dioxanyl , 2 , 3 - dihydrobenzo [b ] [ 1 , 4 ] dioxa - loxy, phenethyloxy, 3 -phenylpropoxy , 1 - naphthylmethoxy , nyl, 1 , 3 -benzodioxolyl , 2 , 3 , 4 , 5 - tetrahydrobenzo [ b ] [ 1 , 4 ] ox 2 -naphthylmethoxy , 2 -( 1- naphthyl ) ethoxy, 2 -( 2 -naphthyl ) azepinyl, 2 , 3 , 4 , 5 - tetrahydro - 1H -benzo [ b ]azepinyl , 2 , 3 , 4 , 5 - ethoxy , 1 - indanylmethoxy , 2 - indanylmethoxy , 1 , 2 , 3 , 4 - tetra tetrahydro - 1H -benzo [b ] oxepinyl, 2 , 3 , 4 , 5 - tetrahydro - 1H hydronaphthalen - 1 -ylmethoxy , and 1 , 2 , 3 ,4 - tetrahydronaph benzo [b ]thiepinyl , and 6 , 7, 8 ,9 - tetrahydro -5H -cyclohept [ b ] 40 thalen - 2 -ylmethoxy . pyridyl. In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , the term “ C1- 6 alkoxyl Cl- 6 alkyl group ” means a group in the term “ non -aromatic heterocyclic group ” means a “ 3 - to which the above described “ C1- alkoxyl group ” is substi 14 -membered saturated or unsaturated non -aromatic hetero tuted with the above described “ C1- 6 alkyl group .” In the cyclic group .” 45 present specification , unless otherwise specified , examples In the present specification , unless otherwise specified , of the “C1 - 6 alkoxyl C1- 6 alkyl group ” include methoxym the term “ 3 - to 14 -membered saturated or unsaturated non etethyl , methoxyethyl, ethoxymethyl, ethoxyethyl, 1 ,1 -dime aromatic heterocyclic group ” means a monovalent group thoxymethyl, and 1 , 1 - diethoxyethyl. formed by removing any given hydrogen atom from a 3 - to In the present specification , unless otherwise specified , 14 -membered saturated or unsaturated heterocyclic ring 50 the term “ C1-6 alkoxyl C2- 6 alkenyl group ” means a group in containing one to four heteroatoms selected from among an which the above described “ C1- 6 alkoxyl group ” is substi oxygen atom , a sulfur atom , and a nitrogen atom . tuted with the above described “ C2- 6 alkenyl group. ” In the In the present specification , unless otherwise specified , present specification , unless otherwise specified , examples examples of the “ 3 - to 14 -membered non - aromatic hetero of the “C1 - 6 alkoxyl C2- 6 alkenyl group ” include cyclic group ” include aziridinyl, azetidinyl, oxiranyl, thii - 55 2 -methoxyvinyl , 2 - ethoxyvinyl, 2 - propoxyvinyl , ranyl , oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, 3 -methoxyallyl , 3 - ethoxyallyl, and 3 -ethoxyallyl . dihydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, imidazo - In the present specification , unless otherwise specified , lidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl( oxa the term “ halogenated C1- 6 alkoxyl group ” means a group in nyl) , tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazo? which a “C1 - 6 alkyl group " portion of the above described lidinyl, isoxazolynyl, 1 , 3 - oxazolidinyl, isoxazolidinyl, 60 " C - alkoxyl group ” is optionally substituted with one to thiazolinyl, isothiazolinyl, 1 , 3 - thiazolidinyl, isothiazolidi five halogen atoms. Examples of the halogenated C1- 6 nyl, oxadiazolinyl, 1 , 3 , 4 - oxadiazolidinyl, morpholinyl, thio - alkoxyl group include fluoromethoxy, difluoromethoxy , tri morpholinyl, quinuclidinyl, azepanyl, diazepinyl, and fluoromethoxy, 2, 2, 2- trifluoroethoxy, 1 , 1, 2 ,2 - tetrafluoroeth oxepanyl. oxy , and pentafluoroethoxy. In the present specification , unless otherwise specified , 65 In the present specification , unless otherwise specified , the term “ alkoxyl group ” means a group in which the above the term “ alkanoyl group ” means an “ alkylcarbonyl group ” described “ alkyl group ” is substituted with an oxygen atom , in which a carbonyl group binds to the above described US 9 ,777 , 000 B2 19 20 " alkyl group . ” Examples of the alkanoyl group include a described “ alkyl group . ” Examples of the alkylsulfonyl “ C2- 7 alkanoyl group .” The alkanoyl group is generally group include a “ C1- 6 alkylsulfonyl group ." The alkylsulfo represented by R - CO ( R = alkyl group ) . nyl group is generally represented by — SOR ( R = alkyl In the present specification , unless otherwise specified , group ) . examples of the “ C2- 7 alkanoyl group ” include acetyl, pro - 5 In the present specification , unless otherwise specified , pionyl, butyryl, isobutyryl , valeryl, isovaleryl, pivaloyl, examples of the “ C1- 6 alkylsulfonyl group ” include methyl hexanoyl , heptanoyl, cyclopropylcarbonyl , cyclobutylcar sulfonyl, ethyl sulfonyl, propyl sulfonyl, and isopropylsul bonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopro fonyl. pylmethylcarbonyl, and 2 -methylcyclopropylcarbonyl . In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , 10 the term “ C3. 8 cycloalkylsulfonyl group ” means a group in the term “ halogenated C2- 7 alkanoyl group ” means a group which a “ sulfonyl group ( S02 - ) ” is substituted with the in which a “ C1- 6 alkyl group ” portion of the above described above described “ C3- 8 cycloalkyl group. ” Examples of the “ C2-7 alkanoyl group ” is optionally substituted with one to C3- 8 cycloalkylsulfonyl group include cyclopropylsulfonyl, fivealkanoyl halogen group atoms include. Examples trifluoroacetyl of the and halogenated 33 3 - trifluoros C2- 7 15 cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfo propionyl. nyl , cycloheptylsulfonyl, and cyclooctylsulfonyl. In the present specification , unless otherwise specified . In the present specification , unless otherwise specified , the term “ hydroxy Co. , alkanoyl group ” means a group in the term “ halogenated C1- 6 alkylsulfonyl group ” means a which the above described “ C2 , alkanoyl group ” is option group in which an “ alkyl group " portion of the above ally substituted with one to five hydroxyl groups. Examples 20 described “ C1- 6 alkylsulfonyl group ” is optionally substi of the hydroxy C2- 7 alkanoyl group include hydroxyacetyl tuted with one to five halogen atoms. Examples of the and 3 -hydroxypropionyl . halogenated C1- 6 alkylsulfonyl group include trifluorometh In the present specification , unless otherwise specified , anesulfonyl. the term “ C3- 8 cycloalkylcarbonyl group ” means a group in In the present specification , unless otherwise specified , which a carbonyl group binds to the above described “ C3- 8 25 the term “ arylsulfonyl group ” means a group in which a cycloalkyl group .” Examples of the C3- 8 cycloalkylcarbonyl “ sulfonyl group ( S02 – )” is substituted with the above group include cyclopropylcarbonyl , cyclobutylcarbonyl, described “ aryl group .” Examples of the arylsulfonyl group cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcar - include a “ C6- 14 arylsulfonyl group . ” bonyl, and cyclooctylcarbonyl. In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , 30 examples of the “ C6- 14 arylsulfonyl group ” include phenyl the term “ alkylthio group ” means a group in which a sulfonyl, 1- naphthyl sulfonyl, 2 - naphthylsulfonyl, indan - 4 hydrogen atom of a " thiol group ( SH )” is substituted with sulfonyl, indene - 4 - sulfonyl , and 5 , 6 , 7 , 8 - tetrahydronaphthyl the above described “ alkyl group . ” Examples of the alkyl - 1 - sulfonyl. thio group include a “ C1- 6 alkylthio group .” The alkylthio In the present specification , unless otherwise specified , group is generally represented by — SR ( R = alkyl group ) . 35 the term “ aralkylsulfonyl group ” means a group in which a In the present specification , unless otherwise specified , " sulfonyl group ( S0 , - )” is substituted with the above examples of the “ C1- 6 alkylthio group ” include methylthio , described “ aralkyl group .” Examples of the aralkylsulfonyl ethylthio , propylthio , isopropylthio , butylthio , isobutylthio , group include a “ C7- 20 aralkylsulfonyl group .” sec -butylthio , tert- butylthio , pentylthio , isopentylthio , neo - In the present specification , unless otherwise specified , pentylthio , tert- pentylthio , 1- methylbutylthio , 2 -methylbu - 40 examples of the “ C7- 20 aralkylsulfonyl group ” include ben tylthio , 1 , 2 -dimethylpropylthio , 1 - ethylpropylthio , hexyl zylsulfonyl and phenethylsulfonyl. thio , isohexylthio , 1 -methylpentylthio , 2 -methylpentylthio , In the present specification , unless otherwise specified , 3 -methylpentylthio , 1, 1 -dimethylbutylthio , 1 ,2 -dimethylbu - the term " heterocyclic sulfonyl group ” means a group in tylthio , 2 , 2 - dimethylbutylthio , 1 ,3 -dimethylbutylthio , 2 ,3 - which the above described " heterocyclic group ” is substi dimethylbutylthio , 3, 3 -dimethylbutylthio , 1 - ethylbutylthio , 45 tuted with a “ sulfonyl group ( S02 — ). ” Examples of a 2 - ethylbutylthio , 1 , 1 , 2 - trimethylpropylthio , 1 , 2 , 2 -trimethyl - " heterocyclic ring” portion of the " heterocyclic sulfonyl propylthio , 1 - ethyl- 1 -methylpropylthio , and 1 - ethyl- 2 -meth group” include a " heteroaryl group, ” a “ partially hydroge ylpropylthio . In addition , the “ alkylthio group ” can be nated fused - ring heteroaryl group , " and a " non - aromatic restated as an “ alkylsulfanyl group .” That is to say, the “ C1- 6 heterocyclic group ,” which are exemplified in the above alkylthio group ” means the same group as a “ C1- 6 alkylsul- 50 described “ heterocyclic group .” fanyl group .” In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , examples of the “ heterocyclic sulfonyl group ” include a examples of the “ C3- 8 cycloalkylthio group ” include cyclo " heteroarylsulfonyl group ,” a “ partially hydrogenated fused propylthio , cyclobutylthio , cyclopentylthio , and cyclohex ring heteroarylsulfonyl group ," and a “ non - aromatic hetero ylthio . 55 cyclic sulfonyl group .” In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , the term “ alkylsulfinyl group ” means a group in which a examples of the " heteroarylsulfonyl group ” include pyridyl " sulfinyl group ( S (0 ) — )” is substituted with the above sulfonyl, furanylsulfonyl, and indonyl sulfonyl. described “ alkyl group .” Examples of the alkylsulfiny1 In the present specification , unless otherwise specified , group include a " C - , alkylsulfinyl group . ” The alkylsulfinyl 60 examples of the " partially hydrogenated fused - ring heteroar group is generally represented by - S ( O ) R ( R = alkyl group ). ylsulfonyl group” include indolinylsulfonyl, chromanylsul In the present specification , unless otherwise specified , fonyl, 5 ,6 , 7 , 8 - tetrahydroquinolylsulfonyl, 1 , 2 , 3 , 4 - tetrahyd examples of the “ C1- 6 alkylsulfinyl group ” include methyl roquinolyloxycarbonyloxy, 1, 2 , 3, 4 sulfinyl, ethylsulfinyl, propylsulfinyl, and isopropylsulfinyl. tetrahydroisoquinolylsulfonyl, and 2 ,3 - dihydrobenzo [ b ][ 1 , In the present specification , unless otherwise specified , 65 4 ]dioxanylsulfonyl . the term “ alkylsulfonyl group ” means a group in which a In the present specification , unless otherwise specified , " sulfonyl group ( S02 ) ” is substituted with the above examples of the “ non -aromatic heterocyclic sulfonyl group " US 9 ,777 ,000 B2 21 22 include pyrrolidinylsulfonyl, piperidinylsulfonyl, piperazi- 1H - indazolylcarbonyl, 1H -benzotriazolylcarbonyl , 2, 1, 3 nylsulfonyl, and morpholinylsulfonyl. benzothiadiazinylcarbonyl, quinolylcarbonyl , isoquinolyl In the present specification , unless otherwise specified , carbonyl, cinnolinylcarbonyl, quinazolinylcarbonyl, qui the term “ C1- 6 alkoxylcarbonyl group ” means a group in noxalinylcarbonyl, phthalazinylcarbonyl, which a hydrogen atom of a “ carboxy group ( COOH )” is 5 benzoxazepinylcarbonyl , benzazepinylcarbonyl, benzodiaz substituted with the above described “ C1- 6 alkyl group ,” epinylcarbonyl , naphthyridinylcarbonyl, purinylcarbonyl, namely , it means an “ ester group .” The C1- 6 alkoxylcarbonyl pteridinylcarbonyl, carbazolylcarbonyl, carbolinylcarbonyl, group is generally represented by “ the group : — COOC1- 6 acridinylcarbonyl , phenoxazinylcarbonyl, phenothiazinyl alkyl. ” carbonyl, phenazinylcarbonyl , phenoxathiinylcarbonyl, thi In the present specification , unless otherwise specified , 10 anthrenylcarbonyl, phenanthridinyl carbonyl, phenanthroli examples of the “ C1- 6 alkoxylcarbonyl group ” include nyl carbonyl, indolizinylcarbonyl, thieno [ 3, 2 -c ] methyl ester (methoxycarbonyl ) , ethyl ester ( ethoxycarbo - pyridylcarbonyl, thiazolo [ 5 , 4 - c ]pyridylcarbonyl , pyrrolo [ 1 , nyl) , and tert- butyl ester ( tert -butoxycarbonyl ) . 2 - b ]pyridazinylcarbonyl , pyrazolo [ 1 , 5 - a ]pyridylcarbonyl , In the present specification , unless otherwise specified , imidazo [ 1 , 2 - a ]pyridylcarbonyl , imidazo [ 1 , 5 - a ]pyridylcar the term “ arylcarbonyl group ” means a group in which a 15 bonyl, imidazo [ 1 ,2 - b ]pyridazinylcarbonyl , imidazo [ 1, 5 -a ] carbonyl group binds to the above described “ aryl group .” pyrimidinylcarbonyl, 1 , 2 , 4 - triazolo [ 4 , 3 - a ]pyridylcarbonyl , Examples of the arylcarbonyl group include a “ C6- 14 aryl 1 , 2 , 4 - triazolo [ 4 , 3 - b ]pyridazinylcarbonyl , 1H -pyrazolo [ 3 , 4 carbonyl group .” b ]pyridylcarbonyl , and 1 , 2 , 4 - triazolo [ 1 , 5 - a ]pyrimidinylcar In the present specification , unless otherwise specified , bonyl. examples of the “ C6- 14 arylcarbonyl group ” include benzoyl, 20 In the present specification , unless otherwise specified , 1 -naphthoyl ( 1 -naphthylcarbonyl ) , 2 -naphthoyl ( 2 -naphth - examples of the " partially hydrogenated fused - ring het ylcarbonyl) , indan - 4 - carbonyl, indene - 4 - carbonyl, and 5 , 6 , eroarylcarbonyl group ” include indolinylcarbonyl , 4 , 5 ,6 , 7 7 , 8 -tetrahydronaphthyl - 1 - carbonyl. tetrahydro - 1H - indonylcarbonyl, 2 , 3 -dihydrobenzofuranyl In the present specification , unless otherwise specified , carbonyl, 4 , 5 ,6 ,7 - tetrahydro - benzofuranylcarbonyl, 2 , 3 the term “ aralkylcarbonyl group ” means a group in which a 25 dihydrobenzo [ d ]oxazolylcarbonyl , 2, 3 -dihydrobenzo [d ] carbonyl group binds to the above described " aralkyl thiazolylcarbonyl , chromanylcarbonyl, group .” Examples of the aralkylcarbonyl group include a 2H - chromenylcarbonyl, 4H -chromenylcarbonyl , isochro “ C7- 20 aralkylcarbonyl group .” manylcarbonyl, 1H - isochromenylcarbonyl , 3 , 4 - dihydro -2H In the present specification , unless otherwise specified , 1 , 4 -benzoxazinylcarbonyl , 3 , 4 - dihydro -2H - 1 , 4 -benzothiazi examples of the “ C7- 20 aralkylcarbonyl group ” include phe - 30 nylcarbonyl , 5 , 6 ,7 , 8 - tetrahydroquinolylcarbonyl, 1 , 2 , 3 , 4 nylacetyl and 3 -phenylpropionyl . tetrahydroquinolylcarbonyl , 1 , 2 - dihydroquinolylcarbonyl, In the present specification , unless otherwise specified , 1 , 2 , 3 , 4 -tetrahydroquinazolylcarbonyl , 1 , 2 -dihydroqui the term “ heterocyclic carbonyl group ” means a group in nazolylcarbonyl, 2 ,4 -dihydro - 1H -benzo [ d ][ 1 , 3 ]oxazinylcar which a carbonyl group binds to the above described “ het - bonyl, 2 , 4 -dihydro -1H -benzo [d ][ 1 , 3 ] thiazinylcarbonyl, 5 ,6 , erocyclic group .” Examples of a “ heterocyclic ring ” portion 35 7 ,8 - tetrahydroisoquinolylcarbonyl, 1 , 2 of the " heterocyclic carbonyl group ” include a " heteroaryl dihydroisoquinolylcarbonyl , 1 , 2 , 3 , 4 group ,” a “ partially hydrogenated fused - ring heteroaryl tetrahydroisoquinolylcarbonyl, 1 ,2 group , " and a “ non - aromatic heterocyclic group ,” which are dihydroquinoxalinylcarbonyl, 1 , 4 exemplified in the above described “ heterocyclic group . ” dihydroquinoxalinylcarbonyl, 1 , 2 , 3 , 4 In the present specification , unless otherwise specified , 40 tetrahydroquinoxalinylcarbonyl, 4H -benzo [ d ][ 1 , 3 ] examples of the “ heterocyclic carbonyl group ” include a dioxanylcarbonyl, 2 , 3 - dihydrobenzo [ b ][ 1 , 4 ] " heteroarylcarbonyl group ,” a “ partially hydrogenated dioxanylcarbonyl, 1, 3 -benzodioxolylcarbonyl , fused - ring heteroarylcarbonyl group ," and a " non -aromatic tetrahydrobenzo [b ][ 1 ,4 ]oxazepinylcarbonyl , 2 , 3 ,4 ,5 - tetra heterocyclic carbonyl group .” hydro - 1H -benzo [ b ] azepinylcarbonyl, 2 , 3 , 4 , 5 - tetrahydro In the present specification , unless otherwise specified , 45 1H -benzo [ b ]oxepinylcarbonyl , 2 ,3 ,4 , 5 -tetrahydro - 1H examples of the " heteroarylcarbonyl group , ” in which the benzo [b ] thiepinylcarbonyl, and 6 ,7 , 8 , 9 -tetrahydro - 5H " heteroaryl group ” portion is a “ monocyclic heteroaryl cyclohept[ b ]pyridylcarbonyl . group , ” include pyrrolylcarbonyl , furylcarbonyl, thienylcar - In the present specification , unless otherwise specified , bonyl, imidazolylcarbonyl, pyrazolylcarbonyl, oxazolylcar - examples of the “ non -aromatic heterocyclic carbonyl group " bonyl, isoxazolylcarbonyl , thiazolylcarbonyl , isothiazolyl - 50 include aziridinylcarbonyl, azetidinylcarbonyl, pyrrolidinyl carbonyl, 1 , 2 , 3 - triazolylcarbonyl, 1 , 2 , 4 -triazolylcarbonyl , carbonyl , tetrahydrofurylcarbonyl, piperidinylcarbonyl, tet 1 , 2 , 3 - oxadiazolylcarbonyl, 1 , 2 , 4 - oxadiazolylcarbonyl, 1 , 3 , rahydropyranylcarbonyl, piperazinylcarbonyl, and mor 4 -oxadiazolylcarbonyl , furazanylcarbonyl, 1 , 2, 3 -thiadiaz - pholinylcarbonyl. olylcarbonyl, 1 , 2 , 4 - thiadiazolylcarbonyl, 1 , 3 ,4 - thiadiazolyl- In the present specification , unless otherwise specified , carbonyl, tetrazolylcarbonyl, pyridylcarbonyl, 55 the term “ amino group ” means a substituent wherein , in the pyridazinylcarbonyl, pyrimidinylcarbonyl , pyrazinylcarbo “ _ NR7R8 group, ” R7 and R8 are each a hydrogen atom . nyl, 1 ,2 , 3 - triazinylcarbonyl, 1 , 2, 4 - triazinylcarbonyl, 1 , 3, 5 - In the present specification , unless otherwise specified , triazinylcarbonyl, 2H - 1, 2 ,3 - thiadiazinylcarbonyl, 4H - 1 ,2 , 4 the term “mono - /di - alkylcarbamoyl group ” means a carbam thiadiazinylcarbonyl, 6H - 1 , 3 , 4 -thiadiazinylcarbonyl , 1 , 4 oyl group in which one or two hydrogen atoms on a nitrogen diazepinylcarbonyl, and 1 , 4 -oxazepinylcarbonyl . 60 atom of the above described " carbamoyl group ” (or R ' and Moreover , examples of the " heteroarylcarbonyl group ,” in R8 in “ the group : CONR /R8 ” ) are substituted with the which the “ heteroaryl group " portion is a " fused -ring het - above described “ alkyl groups .” Examples of the mono - di eroaryl group , " include indolylcarbonyl, isoindolylcarbonyl, alkylcarbamoyl group include a “ mono - / di- C1- 6 alkylcar benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothie - bamoyl group . ” nylcarbonyl, isobenzothienylcarbonyl , benzoxazolylcarbo - 65 In the present specification , unless otherwise specified , nyl, 1 , 2 -benzisoxazolylcarbonyl , benzothiazolylcarbonyl, examples of the “mono - di- C1 - 6 alkylcarbamoyl group ” 1 , 2 -benzisothiazolylcarbonyl , 1H -benzimidazolylcarbonyl , include methylcarbamoyl, ethylcarbamoyl , propylcarbam US 9 ,777 ,000 B2 23 24 oyl , isopropylcarbamoyl, butylcarbamoyl, isobutylcarbam In the present specification , unless otherwise specified , oyl, pentylcarbamoyl, isopentylcarbamoyl, hexylcarbamoyl , examples of the “ mono - /di - heteroarylcarbamoyl group ,” the isohexylcarbamoyl, dimethylcarbamoyl , diethylcarbamoyl, “ mono - / di- partially hydrogenated fused -ring heteroarylcar dipropylcarbamoyl, diisopropylcarbamoyl , dibutylcarbam bamoyl group ,” and the “ mono - / di- non - aromatic heterocy oyl, dipentylcarbamoyl, ethylmethylcarbamoyl, methylpro - 5 clic carbamoyl group ” include pyridylcarbamoyl , indolyl pylcarbamoyl, ethylpropylcarbamoyl, butylmethylcarbam - carbamoyl , tetrahydropyranylcarbamoyl, oyl, butylethylcarbamoyl , and butylpropylcarbamoyl. dipyridylcarbamoyl, benzofuranylpyridylcarbamoyl, fura In the present specification , unless otherwise specified , nylpiperidinylcarbamoyl, 3 ,4 - dihydro - 2H -benzo [b ][ 1 ,4 ]ox the term “mono - di- cycloalkylcarbamoyl group ” means a azinylcarbamoyl, and ditetrahydroquinolylcarbamoyl. carbamoyl group in which one or two hydrogen atoms on a 10 In the present specification , unless otherwise specified , nitrogen atom of the above described “ carbamoyl group ” ( or the term "mono - di -alkylsulfamoyl group ” means a sulfa R ’ and Rin “ the group : - CONR ’RS " ) are substituted with moyl group in which one or two hydrogen atoms of the the above described “ cycloalkyl groups. ” Examples of the above described " sulfamoyl group ” (or R7 and R8 in “ the mono -/ di - cycloalkylcarbamoyl group include a “mono -/ di group : SONR R8" ) are substituted with the above C3- 8 cycloalkylcarbamoyl group .” 15 described “ alkyl groups. ” Examples of the mono -/ di - alkyl In the present specification , unless otherwise specified , sulfamoyl group include a “mono -/ di - C1 - 6 alkylsulfamoyl examples of the “mono - /di - C3- 8 cycloalkylcarbamoyl group. ” group ” include cyclopropylcarbamoyl, cyclobutylcarbam - In the present specification , unless otherwise specified , oyl, cyclopentylcarbamoyl, and cyclohexylcarbamoyl. examples of the “ mono - / di- C1- 6 alkylsulfamoyl group " In the present specification , unless otherwise specified , 20 include methylsulfamoyl, ethylsulfamoyl , propylsulfamoyl, the term “ mono - /di - halogenated C - , alkylcarbamoyl group ” isopropylsulfamoyl, butylsulfamoyl, isobutylsulfamoyl , means a substituent in which a “ C1- 6 alkyl group ” portion of pentylsulfamoyl, isopentylsulfamoyl, hexylsulfamoyl , iso the above described “ mono -/ di - Cl - , alkylcarbamoyl group ” hexylsulfamoyl , dimethylsulfamoyl, diethylsulfamoyl, is optionally substituted with one to five halogen atoms. dipropylsulfamoyl, diisopropylsulfamoyl, dibutylsulfamoyl, Examples of the mono -/ di - halogenated C1- 6 alkylcarbamoyl 25 dipentylsulfamoyl, ethylmethylsulfamoyl, methylpropylsul group include trifluoromethylcarbamoyl, 1 , 1 , 1 - trifluoroeth - famoyl, ethylpropylsulfamoyl, butylmethylsulfamoyl , buty ylcarbamoyl, and ditrifluoromethylcarbamoyl. lethylsulfamoyl , and butylpropylsulfamoyl . In the present specification , unless otherwise specified . In the present specification , unless otherwise specified , the term “ mono - di- arylcarbamoyl group ” means a carbam - the term “mono - di -cycloalkylsulfamoyl group ” means a oyl group in which one or two hydrogen atoms on a nitrogen 30 sulfamoyl group in which one or two hydrogen atoms of the atom of the above described " carbamoyl group ” (or R ’ and above described “ sulfamoyl group ” (or R7 and R8 in the R $ in " the group : _ CONR ' R ) are substituted with the group : SO NR ' R $ " ) are substituted with the above above described " aryl groups. ” Examples of the mono -/ di described " cycloalkyl groups .” Examples of the mono -/ di arylcarbamoyl group include a “ mono -/ di - C6 - 14 arylcarbam cycloalkylsulfamoyl group include a “mono - di- C3 - 8 oyl group . " 35 cycloalkylsulfamoyl group . ” In the present specification , unless otherwise specified . In the present specification , unless otherwise specified , specific examples of the “mono -/ di - C6 -14 arylcarbamoyl examples of the “mono - /di - C3- 8 cycloalkylsulfamoyl group " group ” include phenylcarbamoyl, 2 -naphthylcarbamoyl , include cyclopropylsulfamoyl, cyclobutylsulfamoyl, cyclo diphenylcarbamoyl, and 2 -naphthylphenylcarbamoyl . pentylsulfamoyl, and cyclohexylsulfamoyl. In the present specification , unless otherwise specified , 40 In the present specification , unless otherwise specified , the term “mono - di- aralkylcarbamoyl group ” means a car- the term “ mono - / di -halogenated C - 6 alkylsulfamoyl group ” bamoyl group in which one or two hydrogen atoms on a means a substituent in which a “ C1- 6 alkyl group " portion of nitrogen atom of the above described " carbamoyl group ” (or the above described “mono -/ di - C1 - 6 alkylsulfamoyl group ” R7 and R8 in “ the group : - CONR ' RS ) are substituted with is optionally substituted with one to five halogen atoms. the above described “ aralkyl groups. ” Examples of the 45 Examples of the mono - di- halogenated C1- 6 alkylsulfamoyl mono -/ di- aralkylcarbamoyl group include a "mono -/ di- group include trifluoromethylsulfamoyl, 1 , 1 , 1 - trifluoroeth C7 - 20 aralkylcarbamoyl group .” ylsulfamoyl, and ditrifluoromethylsulfamoyl. In the present specification , unless otherwise specified . In the present specification , unless otherwise specified , specific examples of the “ mono - di- C7 - 20 aralkylcarbamoyl the term “ mono - /di - arylsulfamoyl group ” means a sulfa group ” include benzylcarbamoyl and dibenzylcarbamoyl. 50 moyl group in which one or two hydrogen atoms of the In the present specification , unless otherwise specified , above described " sulfamoyl group ” (or R7 and R8 in " the the term “ mono - /di - heterocyclic carbamoyl group ” means a group : — SO NR RS ) are substituted with the above carbamoyl group in which one or two hydrogen atoms on a described “ aryl groups .” Examples of the mono - / di- arylsul nitrogen atom of the above described " carbamoyl group ” ( or famoyl group include a " mono - /di - C6- 14 arylsulfamoyl R7 and R8 in the group : — CONR ?R8 " ) are substituted with 55 group . ” the above described “ heterocyclic groups. ” Examples of a In the present specification , unless otherwise specified , " heterocyclic ring” portion of the " mono - /di - heterocyclic examples of the “ mono -/ di - C6 - 14 arylsulfamoyl group ” carbamoyl group ” include a " heteroaryl group ,” a “ partially include phenylsulfamoyl, 2 - naphthylsulfamoyl, diphenyl hydrogenated fused -ring heteroaryl group ," and a “ non - sulfamoyl, and 2 -naphthylphenylsulfamoyl . aromatic heterocyclic group ,” which are exemplified in the 60 In the present specification , unless otherwise specified , above described “ heterocyclic group .” the term “ mono - / di- aralkylsulfamoyl group ” means a sulfa In the present specification , unless otherwise specified , moyl group in which one or two hydrogen atoms of the examples of the “ mono - di- heterocyclic carbamoyl group ” above described “ sulfamoyl group ” (or R7 and R8 in “ the include a “mono - /di - heteroarylcarbamoyl group ,” a “ mono - group : _ SO NR²R8" ) are substituted with the above di- partially hydrogenated fused - ring heteroarylcarbamoyl 65 described " aralkyl groups . ” Examples of the mono - / di group , " and a “ mono - / di- non - aromatic heterocyclic carbam aralkylsulfamoyl group include a “ mono - di- C7- 20 aralkyl oyl group .” sulfamoyl group . US 9 ,777 ,000 B2 25 26 In the present specification , unless otherwise specified , alkylsulfonyl group , and a halogenated C1- 6 alkylsulfonyl examples of the “ mono - /di - C7 - 20 aralkylsulfamoyl group ” group , or a pharmaceutically acceptable salt thereof, or a include benzylsulfamoyl and dibenzyl sulfamoyl. solvate thereof. In the present specification , unless otherwise specified , [ 1 - 1- 2 -2 ] the term “mono - /di -heterocyclic sulfamoyl group ” means a 5 Even more preferably, the compound of the above sulfamoyl group in which one or two hydrogen atoms of the embodiment [ 1 ] is a compound represented by the above formula ( I) wherein the definition of p , q , Z , R2, R3, R4, RS, above described " sulfamoyl group ” (or R7 and R8 in “ the R®, R7, RS , ring A , and fused ring B in the formula (I ) have group : SO , NR R8” ) are substituted with the above the same definitions as those described in the above embodi described “ heterocyclic groups. ” Examples of a “ heterocy 10 ment [ 1 - 1 - 2 ) ; and R each independently represents a C2- 7 clic ring ” portion of the “ mono - / di- heterocyclic sulfamoyl ” alkanoyl group , and has the same definitions as those group ” include a “ heteroaryl group , ” a “ partially hydroge described in the above embodiment [ 1 - 1 - 2 ] , or a pharma nated fused -ring heteroaryl group, " and a “ non - aromatic ceutically acceptable salt thereof, or a solvate thereof. heterocyclic group ,” which are exemplified in the above [ 1 - 1 - 3 ] described “ heterocyclic group .” 15 Further preferably, the compound of the above embodi In the present specification , unless otherwise specified , ment [suisa 1 ] is a compoundcon represented by the above formula (1 ) examples of the “mono - /di - heterocyclic sulfamoyl group ” wherein the definition of p , q, Z , R², R3, R4, RS, R , R7, R8, include a “ mono - /di - heteroarylsulfamoyl group ,” a “ mono - ring A , and fused ring B in the formula (I ) have the same di- partially hydrogenated fused - ring heteroarylsulfamoyl definitions as those described in the above embodiment [ 1 ] ; group ,” and a “ mono -/ di - non -aromatic heterocyclic sulfa - 20 p is an integer of 1 to 3 ; and R ! each independently moyl group ." represents a halogen atom , a cyano group , a Ci , alkyl In the present specification , unless otherwise specified , group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl examples of the “mono - / di- heteroarylsulfamoyl group , ” the group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halo “ mono -/ di - partially hydrogenated fused -ring heteroarylsul genated C1- 6 alkoxyl group , a hydroxy C1- 6 alkyl group , a famoyl group , " and the “ mono - di -non - aromatic heterocy - 25 C1- 6 alkoxyl C1- 6 alkyl group , a C1- 6 alkylthio group , or a clic sulfamoyl group ” include pyridylsulfamoyl, indolylsul- C1- 6 alkylsulfonyl group , or a pharmaceutically acceptable famoyl, tetrahydropyranylsulfamoyl, dipyridylsulfamoyl, salt thereof, or a solvate thereof. benzofuranylpyridylsulfamoyl, furanylpiperidinylsulfa - [ 1 - 1 - 3 - 2 ] moyl, 3 , 4 -dihydro - 2H -benzo [ b ] [ 1 , 4 ] oxazinylsulfamoyl, and Still further preferably , the compound of the above ditetrahydroquinolylsulfamoyl. 30 embodiment [ 1 ] is a compound represented by the above [ 1 - 1 ] formula (I ) wherein the definition of p , q , Z , R2, RS, R4, RS, A preferred compound of the above embodiment [ 1 ] is a R " , R " , Rº , ring A , and fused ring B in the formula (1 ) have compound represented by the formula (1 ) wherein the defi the same definitions as those described in the above embodi nition of p , q , Z , R2, R3, R4, RS, R " , R7, R , ring A , and fused ment [ 1 - 1 - 3 ) ; p is an integer of 0 to 3 ; and R each ring B in the formula ( 1) have the same definitions as those 35 independently represents a C2- 2 alkanoyl group , and has the described in the above embodiment [ 1 ] ; and Reach inde - same definitions as those described in the above embodi pendently represents a halogen atom , a hydroxyl group , a ment [ 1 - 1 - 3 ] , or a pharmaceutically acceptable salt thereof, nitro group , a cyano group , a C1- 6 alkyl group , a C3 - 8 or a solvate thereof. cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 [ 1 - 1 - 4 ] alkenyl group, a C1- 6 alkoxyl group, a halogenated C1- aao6 40 Particularly preferably , the compound of the above alkoxyl group , a C1- 6 alkoxylcarbonyl group , a hydroxy C1- 6 embodiment [ 1 ] is a compound represented by the above alkyl group , a C1- 6 alkoxyl Cl- alkyl group , a C2- 7 alkanoyl formula ( I ) wherein the definition of p , q , Z , R2, R , R4, R ” , group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , an R ', R , Rº, ring A , and fused ring B in the formula (1 ) have - NR 'R group , or a CONR 'R® group wherein Rand R8 the same definitions as those described in the above embodi in the NR R8 group and the CONRÖR8 group have the 45 ment [ 1 ]; p is an integer of 1 or 2 ; and R each independently same definitions as those described in the above embodi represents a halogen atom , a cyano group , a C1- 6 alkyl ment [ 1 ] , or a pharmaceutically acceptable salt thereof, or a group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl solvate thereof. group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , or a C1- 6 [ 1 - 1 - 2 ] alkoxyl C1- 6 alkyl group , and more specifically , R ' repre More preferably , the compound of the above embodiment 50 sents fluorine , chlorine , bromine, a cyano group , a methyl [ 1 ] is a compound represented by the above formula (1 ) group , an ethyl group , an isopropyl group , a cyclopropyl wherein the definition of q , Z , R ? , R " , R4, RS, Rº, R " , RS, group, a difluoromethyl group , a trifluoromethyl group , a ring A , and fused ring B in the formula ( I ) have the same vinyl group , a methoxy group , an ethoxyethyl group , or the definitions as those described in the above embodiment [ 1 ] ; like, or a pharmaceutically acceptable salt thereof, or a p is an integer of 0 to 3 ; and R ! each independently 55 solvate thereof. represents a halogen atom , a cyano group , a C1- 6 alkyl [1 - 1 -4 - 2 ] group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl More particularly preferably , the compound of the above group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halo - embodiment [ 1 ] is a compound represented by the above genated C1- 6 alkoxyl group , a hydroxy C1- 6 alkyl group , a formula ( 1) wherein the definition of p , q , Z , R2, R3, R4, RS , C1- 6 alkoxyl C1- 6 alkyl group , a C1- 6 alkylthio group , a C1- 6 60 RO, R ? , Rº, ring A , and fused ring B in the formula ( I) have alkylsulfonyl group , an — NR 74R84 group , or a the same definitions as those described in the above embodi - CONR ARSA group wherein R A and RSA in the ment [ 1 - 1 - 41; p is an integer of 0 to 3 ; and R each - NR74R8A group and the group each independently repre - independently represents a hydroxy C1- 6 alkyl group or a sent a substituent selected from among a hydrogen atom , a C2- 7 alkanoyl group , and has the same definitions as those C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy65 described in the above embodiment [ 1 - 1 - 4 ] , and more spe C1- 6 alkyl group , a C2- 7 alkanoyl group , a hydroxy C2- 7 cifically , R ' represents fluorine , chlorine , bromine , a cyano alkanoyl group, a halogenated C2- 7 alkanoyl group , a C1- 6 group , a methyl group , an ethyl group , an isopropyl group , US 9 ,777 ,000 B2 27 28 a tert -butyl group , a cyclopropyl group , a difluoromethyl formula ( I ) wherein the definition of p , q , Z , R ' , R², R4, R ” , group , a trifluoromethyl group , a 1 -hydroxyethyl group , a R , R , R®, ring A , and fused ring B in the formula ( I) have vinyl group , an acetyl group , a methoxy group , an ethoxy the same definitions as those described in the above embodi ethyl group , or the like, or a pharmaceutically acceptable salt ment [ 1 ] ; q represents an integer of 0 to 2 ; and R each thereof, or a solvate thereof. 5 independently represents a halogen atom , a cyano group , a [ 1 - 2 ] C1- 6 alkyl group , or a C1- 6 alkoxyl group , or a pharmaceu Preferably , the compound of the above embodiment [ 1 ] is tically acceptable salt thereof, or a solvate thereof. a compound represented by the formula ( I ) wherein the [ 1 - 3 - 4 ] definition of p , q , Z , R1, R², R3, R4, RS, R " , R7, R8, ring A , Particularly preferably , the compound of the above and fused ring B in the formula ( I ) have the same definitions 10 embodiment [ 1 ] is a compound represented by the above as those described in the above embodiment [ 1 ] ; and R2 formula ( I) wherein the definition of p , q , Z , R1, R2, R4, RS , represents a hydrogen atom , a C1- 6 alkyl group , a haloge R ' , R , R?, ring A , and fused ring B in the formula ( I ) have nated C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 alkyl group , or the same definitions as those described in the above embodi a pharmaceutically acceptable salt thereof, or a solvate ment [ 1 ]; q represents an integer of 0 or 1 ; and R3 each thereof. 15 independently represents a hydrogen atom , a halogen atom , [ 1 - 2 - 2 ] or a cyano group , and more specifically , R represents More preferably , the compound of the above embodiment fluorine, chlorine , a cyano group , or the like, or a pharma [ 1 ] is a compound represented by the above formula (1 ) ceutically acceptable salt thereof, or a solvate thereof. wherein the definition of p , q , Z , R1, R2 , R3, R4, RS , R " , R ?, [ 1 -3 -5 ] R®, ring A , and fused ring B in the formula (I ) have the same 20 More particularly preferably , the compound of the above definitions as those described in the above embodiment [ 1 ] ; embodiment [ 1 ] is a compound represented by the above and R ? represents a hydrogen atom , a C1- 6 alkyl group , or a formula ( I ) wherein the definition of p , q , Z , RP , R , R4, R ' , halogenated C1- 6 alkyl group , or a pharmaceutically accept R ” , R ? , Rº, ring A , and fused ring B in the formula ( I ) have able salt thereof, or a solvate thereof. the same definitions as those described in the above embodi [ 1 - 2 - 3 ] 25 ment [ 1 ] ; q represents an integer of 0 or 1 ; and R represents Even more preferably , the compound of the above a halogen atom , and more specifically , R3 represents fluo embodiment [ 1 ] is a compound represented by the above rine, chlorine , or the like, or a pharmaceutically acceptable formula ( I ) wherein the definition of p , q , Z , R ? , R , R4, R , salt thereof, or a solvate thereof. Rº, R7, R? , ring A , and fused ring B in the formula (I ) have [ 1 - 4 ] the same definitions as those described in the above embodi - 30 Preferably , the compound of the above embodiment [ 1 ] is ment [ 1 ]; and R ? represents a hydrogen atom or a C1- 6 alkyl a compound represented by the formula ( I) wherein the group, and more specifically , R ? represents a hydrogen atom , definition of p , q , Z , R ' , R², R ", R " , R " , R " , R? , ring A , and a methyl group , or the like, or a pharmaceutically acceptable fused ring B in the formula ( I ) have the same definitions as salt thereof, or a solvate thereof. those described in the above embodiment [1 ] ; and R + [ 1 - 2 -4 ] 35 represents a halogen atom , a C1- 6 alkyl group , a halogenated Particularly preferably, the compound of the above C1- 6 alkyl group , a C3- 8 cycloalkyl group , a C1- 6 alkoxyl embodiment [ 1 ] is a compound represented by the above group , a halogenated C - alkoxyl group , a C - 6 alkylthio formula (I ) wherein the definition of p , q , Z , R ' , R ", R4, R ', group , a C1- 6 alkylsulfonyl group , a CONR ' R $ group , an R , R7, R8, ring A , and fused ring B in the formula ( I ) have — NR ’ R group wherein R7 and R8 in the — NR ' R® group the same definitions as those described in the above embodi- 40 and the — CONR R8 group have the same definitions as ment [ 1 ] ; and R ’ represents a C1- 6 alkyl group , and more those described in the above embodiment [ 1 ] , a C6- 14 aryl specifically , R2 represents a methyl group , or a pharmaceu - group , a 3 - to 14 -membered non - aromatic heterocyclic tically acceptable salt thereof, or a solvate thereof. group , or a 5 - to 7 -membered monocyclic heteroaryl group [ 1 - 31 wherein the C3- 8 cycloalkyl group , the C6- 14 aryl group , the Preferably , the compound of the above embodiment [ 1 ] is 45 3 - to 14 -membered non - aromatic heterocyclic group , and a compound represented by the formula ( I ) wherein the the 5 - to 7 -membered monocyclic heteroaryl group , which definition of p , q , Z , R ? , R , R4, R " , Rº, R " , Rº, ring A , and are represented by RC , are optionally substituted with one to fused ring B in the formula ( I ) have the same definitions as three groups selected from among a hydroxyl group , a nitro those described in the above embodiment [ 1 ]; and R3 each group , a cyano group , a halogen atom , a C1- 6 alkyl group , a independently represents a halogen atom , a cyano group , a 50 halogenated C1- 6 alkyl group, a hydroxy C1- 6 alkyl group , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a C1- 6 C1-6 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl group , or a halogenated C1- 6 alkoxyl group , or a alkoxyl C1- 6 alkyl group , a C1- 6 alkylthio group , a C1- 6 pharmaceutically acceptable salt thereof, or a solvate alkylsulfonyl group , a CONR R8 group , an - NR ' RS thereof. group wherein R7 and R8 in the NR ' R group and the [ 1 - 3 - 2 ] 55 CONR ' R $ group have the same definitions as those More preferably , the compound of the above embodiment described in the above embodiment [ 1 ] , a C6- 14 aryl group , [ 1 ] is a compound represented by the above formula ( I ) a 3 - to 14 -membered non - aromatic heterocyclic group , and wherein the definition of p , q , Z , R1, R2, R4, RS , R " , R ? , RS, a 5 - to 7 -membered monocyclic heteroaryl group , or a ring A , and fused ring B in the formula ( I ) have the same pharmaceutically acceptable salt thereof, or a solvate definitions as those described in the above embodiment [ 1 ] ; 60 thereof . q represents an integer of 0 to 3 ; and R3 each independently [ 1- 4 - 2] represents a halogen atom , a cyano group , a C1- 6 alkyl More preferably , the compound of the above embodiment group , or a C1- 6 alkoxyl group , or a pharmaceutically accept - [ 1 ] is a compound represented by the above formula ( 1 ) able salt thereof, or a solvate thereof. wherein the definition of p , q, Z , R ', R2, R3, RS, R ", R7, R8, [ 1 - 3 - 3 ] 65 ring A , and fused ring B in the formula (1 ) have the same Even more preferably, the compound of the above definitions as those described in the above embodiment [ 1 ] ; embodiment [ 1 ] is a compound represented by the above and R * represents a halogen atom , a C1- 6 alkyl group , a C3- 8 US 9 , 777 ,000 B2 29 30 cycloalkyl group , a C1- 6 alkoxyl group , a C1- 6 alkylthio optionally substituted with one or two groups selected from group , a C1- 6 alkylsulfonyl group , an — NR 4R8A group among fluorine , a methyl group , a methoxy group , and a wherein R74 and R84 in the - NR74R8A group have the same methoxymethyl group , and more specifically , R4 represents definitions as those of R74 and R84 in the above embodiment chlorine , bromine , phenyl, 2 - fluorophenyl , 3 - fluorophenyl, [ 1- 1 -2 ], a C6- 14 aryl group , a 3- to 14 -membered non - 5 4 - fluorophenyl, 2 ,3 - difluorophenyl, 2 ,4 -difluorophenyl , 2 ,5 aromatic heterocyclic group , or a 5 - to 7 -membered mono difluorophenyl, 2 ,6 - difluorophenyl , 2 -methylphenyl , cyclic heteroaryl group wherein the C3- 8 cycloalkyl group , 3 -methylphenyl , 4 -methylphenyl , 2 -methoxyphenyl , the C6- 14 aryl group , the 3 - to 14 - membered non - aromatic 3 -methoxyphenyl , 4 -methoxyphenyl , 2 -methoxymethylphe heterocyclic group , and the 5 - to 7 -membered monocyclic nyl , 3 -methoxymethylphenyl , 4 -methoxymethylphenyl , pyr heteroaryl group , which are represented by R4, are option - 10 rolidinyl, 2 - fluoropyrrolidinyl, 3 -fluoropyrrolidinyl , 2 -meth ally substituted with one to three groups selected from ylpyrrolidinyl, 3 -methylpyrrolidinyl , among a hydroxyl group , a nitro group , a cyano group , a 2 - trifluoromethylpyrrolidinyl , 3- trifluoromethylpyrrolidi halogen atom , a C1- 6 alkyl group , a halogenated C - 6 alkyl nyl , 2 -methoxypyrrolidinyl , 3 -methoxypyrrolidinyl , group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl group , a 2 -methoxymethylpyrrolidinyl , 3- methoxymethylpyrrolidi halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl 15 nyl , 2 - fluoromorpholinyl , 3 - fluoromorpholinyl, 3 ,5 -difluo group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , a romorpholinyl, 2 ,6 - difluoromorpholinyl , 2 -methylmorpholi - CONR74R8A group , an - NR74R8A group wherein R 74 nyl, 3 -methylmorpholinyl , 3, 5 - dimethylmorpholinyl, 2 ,6 and R84 in the NR 74R8A group and the CONR74R84 dimethylmorpholinyl, 2 -methoxymethylmorpholinyl , group have the same definitions as those of R7A and R & A in 3 - methoxymethylmorpholinyl, 3 , 5 - di( methoxymethyl ) mor the above embodiment [ 1 - 1 -2 ], a C6- 14 aryl group , a 3 - to 20 pholinyl, 2 ,6 -di (methoxymethyl ) morpholinyl , or the like , or 14 -membered non -aromatic heterocyclic group , and a 5 - to a pharmaceutically acceptable salt thereof, or a solvate 7 -membered monocyclic heteroaryl group , or a pharmaceu - thereof . tically acceptable salt thereof, or a solvate thereof. [ 1 - 4 - 4 - 2 ] [ 1 - 4 - 3 ] More particularly preferably , the compound of the above Even more preferably , the compound of the above 25 embodiment [ 1 ] is a compound represented by the above embodiment [ 1 ] is a compound represented by the above formula ( I ) wherein the definition of p , q , Z , R1, R1, R2, R ? , formula ( I ) wherein the definition of p , q , Z , R , R2 , Rº, R " , R ' , RO , R ' , R , ring A , and fused ring B in the formula ( 1 ) RÓ, R " , R?, ring A , and fused ring B in the formula ( I) have have the same definitions as those described in the above the same definitions as those described in the above embodi - embodiment ( 1 - 4 - 4 ] ; and Rº represents a halogen atom , a ment [ 1 ] ; and R4 represents a halogen atom , a C - alkyl 30 C6. 14 aryl group , a 3 - to 14 -membered non - aromatic hetero group , a C3- 8 cycloalkyl group , a C1- 6 alkoxyl group , a C1- 6 cyclic group , or a 5 - to 7 -membered monocyclic heteroaryl alkylsulfonyl group , a C6- 14 aryl group , a 3 - to 14 -membered group wherein the C6 - 14 aryl group , the 3 - to 14 -membered non - aromatic heterocyclic group , or a 5 - to 7 -membered non - aromatic heterocyclic group , and the 5 - to 7 -membered monocyclic heteroaryl group wherein the C3- 8 cycloalkyl monocyclic heteroaryl group , which are represented by R4, group , the C6 .14 aryl group , the 3 - to 14 -membered non - 35 are optionally substituted with one or two groups selected aromatic heterocyclic group , and the 5 - to 7 -membered from among a halogen atom , a C1-6 alkyl group , a haloge monocyclic heteroaryl group , which are represented by R " , nated C1- 6 alkyl group , a C1- 6 alkoxyl group , and a C1- 6 are optionally substituted with one to three groups selected alkoxyl C1- 6 alkyl group , and specifically, R * represents from among a hydroxyl group , a nitro group , a cyano group , chlorine , bromine , a phenyl group , a pyridinyl group , a a halogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl 40 pyrrolidinyl group , or a morpholinyl group wherein the group , a hydroxy C1- 6 alkyl group, a C1- 6 alkoxyl group , a phenyl group , the pyridinyl group , the pyrrolidinyl group , halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl and the morpholinyl group are each optionally substituted group , a C - 6 alkylthio group , a C - alkylsulfonyl group , a with one or two groups selected from among fluorine , a - CONR74R8A group , an - NR74R8A group wherein R74 methyl group , a methoxy group , and a methoxymethyl and R & A in the — NR74R8A group and the — CONR74R8A 45 group , and more specifically , R4 represents chlorine , bro group have the same definitions as those of R7A and R & A in mine , phenyl, 2 - pyridinyl, 3 - pyridinyl, 4 - pyridinyl, 2 - fluo the above embodiment [ 1 - 1 - 2 ] , a C6- 14 aryl group , a 3 - to rophenyl, 3 - fluorophenyl , 4 - fluorophenyl , 2 , 3 - difluorophe 14 -membered non -aromatic heterocyclic group , and a 5 - to nyl, 2 ,4 -difluorophenyl , 2 , 5 -difluorophenyl , 2 ,6 7 -membered monocyclic heteroaryl group , or a pharmaceu - difluorophenyl, 2 -methylphenyl , 3 -methylphenyl , tically acceptable salt thereof, or a solvate thereof. 50 4 -methylphenyl , 2 -methoxyphenyl , 3 -methoxyphenyl , [ 1 -4 - 4 ] 4 -methoxyphenyl , 2 -methoxymethylphenyl , 3 -methoxym Particularly preferably , the compound of the above ethylphenyl , 4 -methoxymethylphenyl , pyrrolidinyl, 2 - fluo embodiment [ 1 ] is a compound represented by the above ropyrrolidinyl , 3- fluoropyrrolidinyl, 2 -methylpyrrolidinyl , formula ( I ) wherein the definition of p , q , Z , R ' , R² , R3, R ” , 3 -methylpyrrolidinyl , 2 - trifluoromethylpyrrolidinyl, 3 -trif R®, R , R8, ring A , and fused ring B in the formula (I ) have 55 luoromethylpyrrolidinyl, 2 -methoxypyrrolidinyl , the same definitions as those described in the above embodi 3 -methoxypyrrolidinyl , 2 -methoxymethylpyrrolidinyl , ment [ 1 ] ; and R * represents a halogen atom , a C6- 14 aryl 3 -methoxymethylpyrrolidinyl , 2 - fluoromorpholinyl, 3 - fluo group , or a 3 - to 14 -membered non -aromatic heterocyclic romorpholinyl, 3 , 5 -difluoromorpholinyl , 2 , 6 - difluoromor group wherein the C6- 14 aryl group and the 3 - to 14 -mem - pholinyl, 2 - methylmorpholinyl, 3 -methylmorpholinyl , 3 , 5 bered non -aromatic heterocyclic group , which are repre - 60 dimethylmorpholinyl, 2 , 6 - dimethylmorpholinyl, sented by R4 , are optionally substituted with one or two 2 -methoxymethylmorpholinyl , 3 -methoxymethylmorpholi groups selected from among a halogen atom , a C - alkyl nyl, 3 , 5 - di (methoxymethyl ) morpholinyl , 2 , 6 - di( methoxym group , a halogenated C1- 6 alkyl group , a C1- 6 alkoxyl group , ethyl) morpholinyl , or the like , or a pharmaceutically accept and a C1- 6 alkoxyl C1- 6 alkyl group , and specifically , R + able salt thereof, or a solvate thereof. represents chlorine , bromine , a phenyl group , a pyrrolidinyl 65 [ 1 -4 - 5 ] group , or a morpholinyl group wherein the phenyl group , the Even more particularly preferably , the compound of the pyrrolidinyl group , and the morpholinyl group are each above embodiment [ 1 ] is a compound represented by the US 9 ,777 ,000 B2 above formula (I ) wherein the definition of p , q , Z , R1, R2, R ' , R " , RO, R " , Rº, ring A , and fused ring B in the formula ( I ) have the same definitions as those described in the above [Formula 7 ] embodiment [ 1] ; and R * represents a C6- 14 aryl group , a 3 (II ) to 14 -membered non - aromatic heterocyclic group , or a 5 - to 5 7 -membered monocyclic heteroaryl group wherein the C6- 14 aryl group , the 3 - to 14 -membered non - aromatic heterocy clic group , and the 5 - to 7 -membered monocyclic heteroaryl group , which are represented by R4, are optionally substi tuted with one or two groups selected from among a halogen 10 atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a C1- 6 alkoxyl group , and a C1- 6 alkoxyl C1- 6 alkyl group , and is selected from the group of the heteroaryls consisting of the specifically , R4 represents phenyl, 2 -pyridinyl , 2 - fluorophe - following: nyl, 3 -fluorophenyl , 4 - fluorophenyl, 2 ,5 - difluorophenyl, 2 -methylphenyl , 2- methoxyphenyl , pyrrolidinyl, 3 - fluoro - 15 pyrrolidinyl, 2 -methylpyrrolidinyl , 2 - trifluoromethylpyrro - [Formula 8 ] lidinyl, 2 -methoxymethylpyrrolidinyl , or 2 ,6 -dimethylmor pholinyl , or a pharmaceutically acceptable salt thereof, or a ( II - 1 ) solvate thereof. [ 1 - 5 ] 20 Preferably, the compound of the above embodiment [ 1 ] is a compound represented by the formula ( I ) wherein the definition of p , q, Z , R1, R2, R3, R4 , R " , R ?, R8, ring A , and ( II - 3 ) fused ring B in the formula ( I) have the same definitions as those described in the above embodiment [ 1 ] ; and R $ 25 represents a hydrogen atom , a halogen atom , a Ci alkyl RO group , a halogenated C1- 6 alkyl group , a C1- 6 alkoxyl group , or a halogenated C1- 6 alkoxyl group , or a pharmaceutically acceptable salt thereof, or a solvate thereof. ( II - 4 ) [ 1 - 5 - 2 ] 30 More preferably , the compound of the above embodiment [ 1 ] is a compound represented by the above formula (1 ) wherein the definition of p , q, Z , R1, R², R3, R4, R ", R7, R8, ring A , and fused ring B in the formula ( 1 ) have the same ( II - 6 ) definitions as those described in the above embodiment [ 1 ] ; 35 and R represents a hydrogen atom , a halogen atom , a C1- 6 alkyl group , or a C . , alkoxyl group , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 5 - 31 Even more preferably , the compound of the above 40 embodiment [ 1 ] is a compound represented by above the formula (I ) wherein the definition of p , q , Z , R1, R2 , R3, R4, ( II - 7 ) R®, R ? , R8, ring A , and fused ring B in the formula ( I) have the same definitions as those described in the above embodi ment [ 1 ] ; and R represents a hydrogen atom , a halogen 45 atom , or a C1- 6 alkyl group , and more specifically , Rº represents a hydrogen atom , fluorine , a methyl group , or the ( II - 9 ) like , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 5 - 41 50 Particularly preferably , the compound of the above N embodiment [ 1 ] is a compound represented by the above formula ( I) wherein the definition of p , q , Z , R1, R2, R3, R4, R R®, R7, R8, ring A , and fused ring B in the formula ( I) have ( II - 10 ) the same definitions as those described in the above embodi- 55 ment [ 1 ] ; and R represents a hydrogen atom or a halogen atom , and more specifically , R represents a hydrogen atom , fluorine, or the like , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 6 ] ( II - 12 ) Preferably, the compound of the above embodiment [1 ] is a compound represented by the formula ( I ) wherein the definition of p , q , Z , R1, R2, R " , R4, R " , R7, R®, and fused N N ring B in the formula ( I ) have the same definitions as those described in the above embodiment [ 1 ] ; 65 ring A represented by the following partial structural Pok formula (II ) : US 9, 777 , 000 B2 33 34 -continued -continued (II - 13 ) (II - 30)

| ? s N? (II - 15 ) NIN (II -31 ) ? 10

? N N R6 (II - 16 ) 15 (II - 32 )

?? (II - 18 ) 20 ? (II - 33 ) y - R6 25 WA (II - 19 )

( II- 34 ) 30 (II -21 ) ? V R6 35 (II -35 )

(II - 22 ) ? N S 40 N?? *122?) (II - 36) (II - 24 )

45 w = N - N (II - 37)

( II- 25 ) 50

N? NEN (II -38 ) ( I- 27 ) ???? N?N (II - 39 ) NA (II - 29 )

? N NSSN 88 ??? US 9, 777 ,000 B2 35 36 -continued -continued ( II -40 ) ( II ~ 4 )

(II - 41 ) ( II ~ 6 ) 10 N N ZN (II - 42 ) 15 R ( II ~ 7 )

VEM 20 ( II -43 ) NS ( II ~ 9 ) IN Z-7 25 Z v= and Rº represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , ( II ~ 10 ) or a pharmaceutically acceptable salt thereof, or a solvate 30 thereof. [ 1 - 6 - 2 ] More preferably , the compound of the above embodiment î [ 1 ] is a compound represented by the above formula ( 1 ) wherein the definition of p , q , Z , R ' , R2, RS, R4 , R " , R ? , R8, 35 ( II ~ 12 ) and fused ring B in the formula ( I ) have the same definitions as those described in the above embodiment [ 1 ]; ring A represented by the following partial structural formula (II ) : B Hvor [Formula 9 ] ( II - 13 )

À

N ? A ( II - 15 ) is selected from the group of the heteroaryls consisting of the 50 following : - [Formula 10 ] Pour 55 ( II - 16 ) ( II - 1 )

( II ~ 3 ) . ( II - 18 ) N RO Ro US 9, 777 , 000 B2 37 38 - continued -continued | ( II ~ 19 ) (II ~35 )

( II ~ 21 ) (II ~ 36 ) 10

(II ~ LL) 15 (II ~ 37) ?WIN

(II ~24 ) 20 ( II ~ 38 )

N " N? 25 ??? (II ~ 39) (II ~ 27 )

30

A? ??? (II ~ 40) (II ~ 30 ) ? 35 N ' 2 ?-N? ? ?N (II ~ 41 ) N 40 ( II ~ 31 ) )??)1?)2? NIN ZZ? 45 ( II ~ 42 ) (II ~ 32 ) Z

- 50 Z (II ~ 43 )

(II ~ 33 ) 55 NSNNIN

and R° represents a hydrogen atom, a CL- 6 alkyl group , a (II ~ 34( ) 60 andhalogenated C . , alkyl group , orahydroxy C , s allkyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 6- 3 ] 65 Even more preferably, the compound of the above embodiment [ 1 ] is a compound represented by the above ????????) formula (1 ) wherein the definition of p , g , Z , RL, RP , RS, RS , US 9 . 777 ,000 B2 40 RT, RT, RS, andfused ring Bin the formula (I ) have the same -continued definitions as those described in the above embodiment [ 1 ] ; ( II -12 ) ring A represented by the following partial structural formula ( II ) : NA, [ Formula11] ?? (II ) 10 ( II-13 )

N A Wis is selected from the group of the heteroaryls consisting of the ( II -15 ) following :

[ Formula12 ]

(II - 1 ) ( II- 16)

( II- 3 ) ( II- 18 ) P6

(II - 4 ) 35 ( II - 19 )

( 640 ( II- 21 )

R6 AIN ( II - 7 ) ( II-22 )

? MIN ? ( II- 9 ) ( II- 24 )

?? NIN ????? ( I -31 ) ( I - 10 )

?) ssssssss JJJJJJ) Mus s8 US 9 ,777 , 000 B2 41 - continued ( II -32 ) [Formula 13 ] (II ) 5

(II -33 ) A 10 is selected from the group of the heteroaryls consisting of the following: ( II -34 ) 15 [Formula 14 ] ( II - 1 )

20 ( II -35 )

NN ( II - 4 ) 25 (II - 36 ) ( II - 6 ) 30

(II -37 ) 35 R6 ( II- 16 )

( II- 39 ) 40

( II -19 )

M V= 45 ( II -42 ) ( II -31 )

50 N . V = N and Rº represents a hydrogen atom , a C1- 6 alkyl group , ass ( II - 32 ) halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 6 - 4 ] ??? Particularly preferably , the compound of the above 60 ( II - 33 ) embodiment [ 1 ] is a compound represented by the above formula (I ) wherein the definition of p , q, Z , R ' ,R2 , R ’ ,R4 , RS, R7, RS , and fused ring B in the formula ( I) have the same definitions as those described in the above embodiment [1 ]; 65 ring A represented by the following partial structural formula ( II) : US 9 ,777 ,000 B2 43 44 - continued 2 -yl group , a 4 , 6 -dimethylpyridin - 2 -yl group , a 4 - fluoro ( II - 34 ) pyridin - 2 - yl group , a 4 -methylpyridin - 2 - yl group , a 4 -meth ylpyridin - 2 - yl group , a 4 -methoxypyridin - 2 -yl group , a 4 -methoxy -pyridin - 2 - yl group , a 5 -cyanopyridin - 2 - yl group , 5 a 5 - fluoropyridin -2 - yl group , a 5 -methylpyridin -2 -yl group , a 5 -methylpyridin - 2 -yl group , a 6 -( trifluoromethyl) pyridin 2 -yl group , a 6 -cyano -pyridin - 2 -yl group , a 6 -methylpyri ( II -35 ) din -2 - yl group , a 6 -methoxypyridin -2 - yl group , a 3 ,6 -dim ethylpyrazin - 2 -yl group , a 3 ,6 -dimethyl - pyrazin - 2 -yl group , 10 a 3 -methylpyrazin - 2 - yl group , a 3 -methoxypyrazin - 2 - yl N ; group , a 5 -methylpyrazin - 2 - yl group , a 6 -methylpyrazin - 2 yl group , or a 6 -methoxypyrazin - 2 -yl group , or a pharma ceutically acceptable salt thereof, or a solvate thereof. and Rº represents a hydrogen atom or a 41C1-- 6 6 alkyl group , , and 15 [ 1 - 71 more specifically , Rº represents a hydrogen atom , a methyl Preferably , the compound of the above embodiment [ 1 ] is group , or the like , or a pharmaceutically acceptable salt a compound represented by the formula ( I) wherein the thereof, or a solvate thereof. definition of p , Z , R1, R2, R3, R4 , RS , R " , R ?, RS, and ring [ 1 - 6 - 5 ] A in the formula (1 ) have the same definitions as those More particularly preferably , the compound of the above 20 described in the above embodiment [1 ]; q is an integer embodiment [ 1 ] is a compound represented by the above represented by 0 to 3 ; and fused ring B represented by the formula ( I ) wherein the definition of p , q , Z , R1, R², R9, R4 , following partial structural formula ( III ) : R® , R , R®, and fused ring B in the formula (I ) have the same definitions as those described in the above embodiment [ 1 ] ; 25 ring A and R have the same definitions as those described - [Formula 15 ] in the above embodiment [ 1 -6 - 4 ] ; and a specific ring A ( III) group , in which the definitions of the above described p , R ', R4 M and ring A are combined , represents a 1 -methyl - 1H - imida zol- 4 -yl group , a 4 - ( difluoromethyl) -5 - ethylthiazol- 2 -yl 30 group , a 4 - ( difluoromethyl) - 5 - vinylthiazol- 2 - yl group , a 4 -( difluoromethyl ) - 5 -methylthiazol - 2 -yl group , a 4 - (difluo q( R3 ) romethyl) - 5 -methylthiazol - 2 - yl group , a 4 - ( difluoromethyl) Fused Ring B thiazol- 2 -yl group , a 4 - (difluoromethyl ) thiazol - 2 -yl group , a 4 -( trifluoromethyl ) thiazol- 2 - yl group , a 4 - (trifluoromethyl ) 35 thiazol- 2 -yl group , a 4 ,5 -dimethylthiazol - 2 -yl group, a is selected from the group consisting of the following : 4 - tert -butylthiazol - 2 -yl group , a 4 -ethylthiazol - 2 -yl group , a 4 - cyanothiazol- 2 - yl group , a 4 -methylthiazol - 2 - yl group , a 4 -methylthiazol - 2 - yl group , a 5 - ( 2 - ethoxyethyl) - 4 -methyl - [Formula 16 ] thiazol- 2 - yl group , a 5 - chloro - 4 - ( difluoromethyl) thiazol- 2 - 40 yl group , a 5 - chloro - 4 - ( difluoromethyl )thiazol - 2 - yl group , a (III - 1 - 1 ) 5 -cyclopropyl - 4 - (difluoromethyl ) thiazol- 2 -yl group , a 5 -cy R4 clopropyl- 4 - methylthiazol- 2 - yl group , a 5 -bromo - 4 -methyl thiazol- 2 - yl group , a 5 -methylthiazol - 2 - yl group , a thiazol 2 - yl group , a 2 , 5 - dimethyl- thiazol- 4 -yl group , a 45 2 -methylthiazol - 4 -yl group , a 5 - (1 -hydroxyethyl ) - 2 -methyl RS (R3 ) thiazol- 4 - yl group , a 5 - acetyl- 2 -methylthiazol - 4 - yl group , a ( III - 2 - 1 ) 5 - bromo - 2 -methylthiazol - 4 - yl group , a thiazol- 4 - yl group , a 3 - isopropyl - 1 , 2 , 4 - thiadiazol- 5 - yl group , a 3 -methyl - 1 , 2 , 4 thiadiazol- 5 -yl group , a 5 - ethyl- 1 , 3 ,4 - thiadiazol- 2 - yl group , 50 a 5 -methyl - 1 , 3 , 4 -thiadiazol - 2 - yl group , a 4 -methylpyrimi RS (R3 ) din -2 -yl group , a 4 ,6 -dimethylpyrimidin - 2 - yl group , a 4 -methylpyrimidin - 2 - yl group , a 2 , 5 , 6 -trimethylpyrimidin (III - 3 - 1 ) 4 - yl group , a 2 , 5 - dimethylpyrimidin - 4 - yl group , a 2 , 6 - dim R4 ethylpyrimidin - 4 - yl group , a 2 , 6 -dimethoxypyrimidin - 4 -yl 55 group , a 2 -methylpyrimidin - 4 - yl group , a 2 -methoxypyrimi NN din -4 - yl group , a 5, 6 -dimethylpyrimidin - 4 -yl group , a 5 - chloro -2 -methylpyrimidin -4 - yl group , a 5 - chloropyrimi din -4 - yl group , a 5 - fluoro - 2 -methylpyrimidin -4 -yl group , a ( III - 4 - 1 ) 5 - fluoro - 2 -methoxypyrimidin - 4 - yl group , a 5 - fluoro - 6 - 60 P methylpyrimidin - 4 - yl group , a 5 -methylpyrimidin - 4 - yl group , a 5 -methoxypyrimidin - 4 - yl group , a 6 -methylpyrimi din - 4 - yl group , a 6 -methoxy - 5 -methylpyrimidin - 4 - yl group , q( R3 ; a 4 -methylpyridazin -3 -yl group , a 5 -methylpyridazin -3 -yl group , a 6 -methylpyridazin - 3 - yl group , a pyridazin - 3 - yl 65 group , a 3 -cyanopyridin - 2 -yl group , a 3 -cyano -pyridin -2 -yl or a pharmaceutically acceptable salt thereof, or a solvate group , a 3 -methylpyridin - 2 - yl group , a 3 -methoxypyridin - thereof . US 9 ,777 ,000 B2 45 46 [ 1 - 7 - 2 ] More preferably , the compound of the above embodiment Formula 19 ] [ 1 ] is a compound represented by the above formula ( 1 ) Fort wherein the definition of p , Z , R , R2, R3, R R4$ , R RS$ , formula RÓ, R7, RS em, Fused Ring B (III ) and ring A in the formula ( I) have the same definitions as 4 those described in the above embodiment [ 1 ] ; q is an integer represented by 0 to 2 ; and fusedel cinering estB represented by thethe ZN following partial structural formula (III ) : q (Rº ) 10 is selected from the group consisting of the following : [Formula 17 ] Fused Ring B ( III) 15 [Formula 20 ] ( III - 1 - 1 ) R4 20

is selected from the group consisting of the following : R5 g( R3 ) 25 23 ( III - 2 - 1 ) [Formula 187 RxR4 ( III- 1 - 1 ) 30 RR (III - 3 - 1 ) RS (R3 ) 35 ( III- 2 - 1 ) N - N N Vyt R4 (R3 ) ( III - 4 - 1 ) m 40 RK? $ g( R3)

Ry ( III- 3 - 1 ) (R3 ) 45 or a pharmaceutically acceptable salt thereof, or a solvate thereof. ( III -4 - 1) [ 1 - 7 - 4 ] R4 50 Particularly preferably , the compound of the above embodiment [ 1 ] is a compound represented by the above formula (I ) wherein the definition of p , Z , R , R², R3, R4, RS, R " , R ? , R8, and ring A in the formula (1 ) have the same q (R3 ) definitions as those described in the above embodiment [ 1 ]; 55 q is an integer represented by 0 or 1 ; and fused ring B or a pharmaceutically acceptable salt thereof, or a solvate represented by the following partial structural formula ( III ) : thereof. [ 1 -7 - 3 ] [Formula 21 ] Even more preferably , the compound of the above Fused Ring B (III ) embodiment [ 1 ] is a compound represented by the above R4 formula (I ) wherein the definition of p , Z , R1, R², R3, R4, RS , R®, R ?, R8, and ring A in the formula (1 ) have the same definitions as those described in the above embodiment [1 ]; 65 mm q is an integer represented by 0 or 1 ; and fused ring B (R3 ) represented by the following partial structural formula ( III ) : US 9 ,777 ,000 B2 47 48 is selected from the group consisting of the following : a Cl- , alkoxyl Cl- , alkyl group ; R has the same definitions as those described in the above embodiment [ 1 - 3 ] ; R * has the same definitions as those described in the above embodi [Formula 22 ] ment [ 1 - 4 ]; R has the same definitions as those described in (III - 1 -2 ) 5 the above embodiment [ 1 - 5 ) ; ring A represented by the R4 partial structural formula ( II ) and R have the same defini tions as those described in the above embodiment [ 1 - 6 ] ; and fused ring B represented by the partial structural formula ( III) has the same definitions as those described in the above embodiment [ 1 - 7 ], or a pharmaceutically acceptable salt ( III- 2 - 2 ) thereof, or a solvate thereof . R4 [ 1a - 1 - 2 ] More preferably , the compound of the above embodiment 15 [ 1 ] is a compound represented by the above formula (1 ) wherein p represents an integer of 0 to 3 ; q represents an integer of 0 to 2 ; Z represents N or CR® ; R ' has the same ( III- 3 - 2 ) definitions as those described in the above embodiment R4 N [ 1 -1 - 2 -2 ]; R² represents a C1- 6 alkyl group or a halogenated 20 C1- 6 alkyl group ; R3 has the same definitions as those N - N described in the above embodiment [ 1 - 3 - 2 ]; R has the same definitions as those described in the above embodiment [ 1 - 4 - 2 ]; R has the same definitions as those described in the ( 111- 4 - 2 ) above embodiment [ 1 - 5 - 2 ) ; ring A represented by the partial 24 25 structural formula ( II ) and R have the same definitions as those described in the above embodiment [ 1 - 6 - 2 ] ; and fused NN ring B represented by the partial structural formula ( III ) has the same definitions as those described in the above embodi (R3 ) ment [ 1 - 7 - 2 ) , or a pharmaceutically acceptable salt thereof, 30U or a solvate thereof. [ 1a - 1 -3 ] or a pharmaceutically acceptable salt thereof, or a solvate Even more preferably , the compound of the above thereof. embodiment [ 1 ] is a compound represented by the above [ la ] formula ( I) wherein p represents an integer of 0 to 3 ; q The compound of the above embodiment [ 1 ] is a com represents an integer of 0 or 1 ; Z represents N or CRS ; R has pound represented by the following formula ( I) : the same definitions as those described in the above embodi ment [ 1 - 1- 3 -2 ]; R2 represents a C1- 6 alkyl group ; R has the same definitions as those described in the above embodi [Formula 23 ] 40 ment [ 1 -3 - 3 ]; R4has the same definitions as those described (1 ) in the above embodiment [ 1 - 4 - 3 ) ; R has the same defini tions as those described in the above embodiment [ 1 - 5 - 3 ] ; N - N ring A represented by the partial structural formula ( II ) and Rº have the same definitions as those described in the above 45 embodiment [ 1 - 6 - 3 ) ; and fused ring B represented by the partial structural formula (III ) has the same definitions as those described in the above embodiment [ 1 -7 - 3 ), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 50 [1a - 1 - 4 ] (R ' )p ; Particularly preferably , the compound of the above embodiment [ 1 ] is a compound represented by the above wherein the definition of p , q , Z , R1, R " , R4, R ' , R ' , ring A formula ( I ) wherein p represents an integer of 0 to 3 ; q represented by the partial structural formula (II ) , and fused represents an integer of 0 or 1 ; Z represents N or CR " ; R has ring B represented by the partial structural formula ( III ) in 55 the same definitions as those described in the above embodi the formula ( I ) have the same definitions as those described ment [ 1 - 1 - 4 - 2 ] ; R ? represents a C1- 6 alkyl group ; R has the in the above embodiment [ 1 ]; and R² represents a C1- 6 alkyl same definitions as those described in the above embodi group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl ment [ 1 - 3 - 4 ); R * has the same definitions as those described group , or a C1- 6 alkoxyl C1- 6 alkyl group , or a pharmaceu - in the above embodiment [ 1 - 4 - 4 - 2 ]; R $ has the same defi tically acceptable salt thereof , or a solvate thereof. 60 nitions as those described in the above embodiment ( 1 - 5 - 41; ?la - 1 ] ring A represented by the partial structural formula ( II ) and Preferably , the compound of the above embodiment [ 1 ] is R have the same definitions as those described in the above a compound represented by the above formula (I ) whereinp e mbodiment [ 1 -6 -4 ) ; and fused ring B represented by the represents an integer of 0 to 4 ; q represents an integer of O partial structural formula (III ) has the same definitions as to 3 ; Z represents N or CR ' ; R has the same definitions as 65 those described in the above embodiment [ 1 - 7 - 4 ) , or a those described in the above embodiment [ 1 - 1 ]; R² repre - pharmaceutically acceptable salt thereof, or a solvate sents a C1-6 alkyl group , a halogenated C1- 6 alkyl group , or thereof. US 9 ,777 ,000 B2 49 50 [ 1a - 1 - 5 ] More particularly preferably, the compound of the above [ Formula 24 ] embodiment [ 1 ] is a compound represented by the above ( I- a ) formula ( I) wherein the definition of p , q , Z , R1, R2, R3, R4, R? R ” , R , ring A represented by the partial structural formula 5 ( II ) , and fused ring B represented by the partial structural R N - N formula (III ) in the formula ( I ) have the same definitions as those described in the above embodiment [ 1a - 1 -4 ] ; and a specific ring A group , in which the definitions of the above q( R3 ) described p , R ' , and ring A are combined , represents a 1 -methyl - 1H - imidazol- 4 -yl group , a 4 -( difluoromethyl ) - 5 A - ethylthiazol- 2 - yl group , a 4 - (difluoromethyl ) -5 - vinylthi (R ') pi azol- 2 -yl group , a 4 -( difluoromethyl ) - 5 -methylthiazol - 2 -yl group , a 4 - ( difluoromethyl) - 5 -methylthiazol - 2 - yl group , a wherein the definition of q , Z , R ? , R " , R4, and RS in the 15 formula (I - a ) have the same definitions as those described in 4 -( difluoromethyl) thiazol - 2 -yl group, a 4 -( difluoromethyl ) the above embodiment [ 1 ] ; p represents an integer of 0 to 2 ; thiazol- 2 - yl group , a 4 - ( trifluoromethyl) thiazol- 2 - yl group , a R each independently represents a halogen atom , a 4 -( trifluoromethyl ) thiazol- 2 -yl group , a 4 ,5 -dimethylthi hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl azol- 2 -yl group , a 4 - tert- butylthiazol - 2 - yl group , a 4 -ethyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl thiazol- 2 -yl group , a 4 -cyanothiazol - 2 - yl group , a 4 -meth - 20 group , a C2 - 0 alkenyl group , a C1- 6 alkoxyl group , a halo ylthiazol- 2 - yl group , a 4 -methylthiazol - 2 - yl group , a 5 - ( 2 genated C1- 6 alkoxyl group , a C1- 6 alkoxylcarbonyl group , a ethoxyethyl) -4 -methylthiazol -2 -yl group , a 5 - chloro -4 - hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1-6 alkyl group , a ( difluoromethyl) thiazol- 2 - yl group , a 5 - chloro - 4 C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkyl ( difluoromethyl) thiazol- 2 - yl group , a 5 - cyclopropyl - 4 - sulfinyl group , a C1 - 6 alkylsulfonyl group , an — NR 'Rº ( difluoromethyl) thiazol- 2 - yl group . a 5 - cyclopropyl - 4 - 25 group , or a — CONR R' group wherein R ' and R * in the methylthiazol- 2 - yl group , a 5 - bromo- 4 -methylthiazol - 2 - yl — NR ' Rº group and the — CONR 'Rº group have the same group , a 5 -methylthiazol - 2 - yl group , a thiazol- 2 - yl group , a definitions as those described in the above embodiment [ 1 ] ; 2 ,5 -dimethyl - thiazol - 4 -yl group , a 2 -methylthiazol - 4 -y1 r ing A represented by the following partial structura group , a 5 - ( 1 -hydroxyethyl ) - 2 -methylthiazol - 4 - yl group , a formula (11 ): 5 - acetyl- 2 -methylthiazol - 4 - yl group , a 5 - bromo- 2 -methyl - 30 thiazol- 4 - yl group , a thiazol- 4 -yl group , a 3 - isopropyl- 1 , 2 , 4 -thiadiazol - 5 -yl group , a 3 -methyl - 1, 2 ,4 - thiadiazol- 5 -y1 [Formula 25 ] group , a 5 - ethyl- 1 , 3 ,4 - thiadiazol - 2 -yl group , a 5 -methyl - 1 , 3 ,4 -thiadiazol -2 - yl group , a 4 -methylpyrimidin -2 -yl group , ( II ) a 4 ,6 -dimethylpyrimidin - 2 - yl group , a 4 -methylpyrimidin - 35 2 -yl group , a 2 , 5 ,6 - trimethylpyrimidin -4 -yl group , a 2, 5 dimethylpyrimidin - 4 -yl group , a 2 ,6 -dimethylpyrimidin - 4 A yl group , a 2 , 6 -dimethoxypyrimidin - 4 - yl group , a 2 -methylpyrimidin - 4 - yl group , a 2 -methoxypyrimidin - 4 - yl group , a 5 ,6 -dimethylpyrimidin - 4 -yl group, a 5 - chloro - 2 - 40 is selected from the group ofthe heteroaryls consisting of the methylpyrimidin - 4 -yl group , a 5 - chloropyrimidin - 4 -y1 following: group , a 5 - fluoro - 2 -methylpyrimidin - 4 - yl group , a 5 - fluoro 2 -methoxypyrimidin - 4 - yl group , a 5 - fluoro -6 -methylpy rimidin - 4 - yl group , a 5 -methylpyrimidin - 4 - yl group , a [ Formula 26] 5 -methoxypyrimidin -4 -yl group , a 6 -methylpyrimidin - 4 -yl 45 group , a 6 -methoxy -5 -methylpyrimidin -4 - yl group , a ( II - 1 ) 4 -methylpyridazin - 3 - yl group , a 5 -methylpyridazin - 3 -yl group , a 6 -methylpyridazin - 3 - yl group , a pyridazin - 3 - yl group , a 3 - cyanopyridin - 2 - yl group , a 3 - cyano - pyridin - 2 - yl group , a 3 -methylpyridin -2 -yl group , a 3 -methoxypyridin - 50 2 -yl group , a 4 ,6 -dimethylpyridin - 2 -yl group , a 4 - fluoro ( II - 2 ) pyridin - 2 - yl group , a 4 -methylpyridin - 2 -yl group , a 4 -meth ylpyridin - 2 - yl group , a 4 - methoxypyridin - 2 -yl group , a 4 -methoxy -pyridin - 2 -yl group , a 5 - cyanopyridin - 2 - yl group , -] a 5 - fluoropyridin - 2 - yl group , a 5 -methylpyridin - 2 -yl group , 55 a 5 -methylpyridin - 2 - yl group , a 6 -( trifluoromethyl) pyridin 2 - yl group , a 6 - cyano - pyridin - 2 - yl group , a 6 -methylpyri ( II - 3 ) din - 2 - yl group , a 6 -methoxypyridin - 2 - yl group , a 3 ,6 - dim ethylpyrazin - 2 - yl group , a 3 , 6 -dimethyl - pyrazin - 2 - yl group , a 3 -methylpyrazin - 2 - yl group , a 3 -methoxypyrazin - 2 -yl 60 group , a 5 -methylpyrazin -2 - yl group , a 6 -methylpyrazin - 2 yl group , or a 6 -methoxypyrazin - 2 - yl group , or a pharma ( II - 4 ) ceutically acceptable salt thereof , or a solvate thereof. [ 1 - 8 ] The compound of the above embodiment [ 1 ] represented 65 by the above formula ( I ) is preferably a compound repre sented by the following formula ( I - a ) : US 9, 777 , 000 B2 51 2 -continued -continued (II - 5 ) ( I- 15 )

? ??? ( I- 16 ) (II - 6 ) 10

15 ( I- 1 ) (II - 7 ) V

Z 20 N ( I- 18 )

? ? (II - 8 )

25 z?? (I - 19 ) (I - 9 ) 30 ( I- 20 ) ? ?4? 35 (II - 10 ) (II - 21 )

40

(I - 11 ) ??????????? ( II -22 )

45 ??N ( I- 12 ) ( II- 23 ) 50 NT

?? MA (II - 24 ) (I - 13 ) SS ? NS MIN ??? ( I- 14 ) 88 ( II - 25 ) US 9 ,777 ,000 B2 53 54 -continued ( II- 26 ) [Formula 28 ] ( II ~ 1 ) 5

NE (II -27 )

10 ( II ~ 3 ) N NR 1N = N ( II -28 ) NVRVRO 15 ( II ~ 4 )

( II- 29 ) 20 ( II ~ 6 ) N N - K (II - 30 ) 25

N - K ( II ~ 7 ) RO 30 and Rº represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , or a pharmaceutically acceptable salt thereof, or a solvate 35 ( II ~ 9 ) thereof . [ 1 - 8 - 2 ] Preferably , the compound of the above embodiment [ 1 -8 ] is a compound represented by the above formula (I - a ) wherein the definition of q , Z , R² , R3, R4 , and R in the 40 P formula ( I - a ) have the same definitions as those described in the above embodiment [1 ] ; p represents an integer of 0 to 2; ( II ~ 10 ) R each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl 45 group , a C2-6 alkenyl group , a C1- 6 alkoxyl group , a halo genated C1- 6 alkoxyl group , a C1- 6 alkoxylcarbonyl group , a hydroxy C1- 6 alkyl group , a Cl. alkoxyl C1- 6 alkyl group , a ( II ~ 12 ) C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsul fonyl group , an — NR ’ R® group , or a - CONR ' R group 50 N wherein R7 and R8 in the NR ’ RS group and the - CONR R8 group have the same definitions as those described in the above embodiment [ 1 ]; Pa ring A ' represented by the following partial structural ( II ~ 13 ) formula ( II ') : 55

[Formula 27 ] (ID ) 60 ( II ~ 15 )

Ž 65 is selected from the group of the heteroaryls consisting of the following : KA US 9 ,777 ,000 B2 55 56 -continued [1 -8 -3 ] (II ~ 16 ) More preferably , the compound of the above embodiment [ 1 - 8 ] is a compound represented by the above formula ( I - a ) wherein the definition of q , Z , R², R3, R4 , and Rs in the Z formula (I - a ) have the same definitions as those described in the above embodiment [ 1 ] ; p represents an integer of 0 to 2 ; R each independently represents a halogen atom , a (II - 18 ) hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl ?? 10 group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halo genated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl group , NE a C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkyl (II – 19) sulfonyl group , a CONR74R84 group , or an - NR 74R84 15 group wherein R74 and R & A in the — NR74R8A group and the - CONR74R8A group have the same definitions as those of R74 and R84 in the above embodiment [ 1- 1 -2 ] ; ring A ' represented by the following partial structural (II -21 ) 20 formula ( II' ) : - Ro [Formula 29 ] (II ~ 22 ) 25 ( II ) NA N - S (II - 24 ) 30 is selected from the group of the heteroaryls consisting of the following:

7=z - 35 N [Formula 301 Ro ( II ~ 25 ) ( II - 1 )

40

= (II ~ 27) ( II - 3 ) NPRO 45 NRO ( II - 4 ) (II ~- 29 29) ) 50

( II -6 ) ( II ~ 30 ) 55

60 GHZ ( II - 7 ) and Rº represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C -6 alkyl group , or a hydroxy C1- 6 alkyl group , 65 V or a pharmaceutically acceptable salt thereof, or a solvate thereof. US 9 ,777 , 000 B2 57 58 -continued -continued ( II- 9 ) ( II - 24 )

IN NN RO ( II -27 ) (II - 10 ) 10 RO N ?

N = N (II - 30 ) (11 - 12 ) 15

7=Z

20

( II- 13) and Rº represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , 25 or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 8 - 3 - 2 ] (11 -15 ) Even more preferably , the compound of the above 30 embodiment [ 1 - 8 ] is a compound represented by the above formula (I - a ) wherein the definition of p , q, Z , R², R3, R4, R®, R , and ring A ' represented by the partial structural formula ( II' ) in the formula ( I - a ) have the same definitions as N - N those described in the above embodiment [ 1 -8 -3 ]; and RI Po 35 each independently represents a hydroxy C1- 6 alkyl group , ( II - 16 ) and has the same definitions as those described in the above embodiment [ 1 - 8 - 3 ], or a pharmaceutically acceptable salt thereof, or a solvate thereof. 40 [ 1 -8 - 4 ] Z Further preferably , the compound of the above embodi ( II- 18 ) ment [ 1 - 8 ] is a compound represented by the above formula ( I- a ) wherein the definition of q, Z , R ?, R " ,R4 , and R in the Ro formula ( I - a ) have the same definitions as those described in N 45 the above embodiment [ 1 ] ; p represents an integer of 1 or 2 ; R ! each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl ( II- 19 ) group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halo 50 genated Ci- alkoxyl group , a C1 - alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group , or a C1- 6 alkylsulfonyl group ; ring A ' represented by the following partial structural (II -21 ) 55, "formula ( II ') : N VRO [Formula 31 ] 7 ( II' ) (II - 22 ) 60

A

65 is selected from the group of the heteroaryls consisting of the following: US 9 ,777 , 000 B2 59 60 -continued [Formula 32 ] ( II –19 ) ( II - 1 ) 5

( II - 21) (II ~ 3 ) 10 VRO Po - ( II ~ 22 ) ([ [ ~ 4) 15

N — S ( II ~ 24 ) 20 ( II - 6 ) ?=Z

25 RO ( II - 27) R6 ( II~ 7 ) NRO: 30 NEN

Z and R? represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , ( II ~ 9 ) 35 or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1 - 8 - 4 - 2 ] Still further preferably , the compound of the above 40 embodiment [ 1- 8 ] is a compound represented by the above formula (I - a ) wherein the definition of q , Z , R², R3 , R4, RS , ( II - 13 ) R ", and ring A ' represented by the partial structural formula ( II ') in the formula (1 - a ) have the same definitions as those described in the above embodiment [ 1 - 8 - 4 ) ; p represents an 45 integer of 0 to 2; and R ' each independently represents a hydroxy C1- 6 alkyl group , and has the same definitions as CS those described in the above embodiment [ 1 - 8 - 4 ], or a ( II ~ 15 ) pharmaceutically acceptable salt thereof, or a solvate thereof . [ 1- 8 -5 ] Particularly preferably , the compound of the above N embodiment [ 1 - 8 ] is a compound represented by the above Powe formula ( I - a ) wherein the definition of q , Z , R2, R3 , R4, and (II ~ 16 ) » RS in the formula ( I - a ) have the same definitions as those described in the above embodiment [1 ]; p represents an integer of 1 or 2 ; and R ? each independently represents a halogen atom , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 60 alkenyl group , or a C1- 6 alkoxyl C1- 6 alkyl group , and more ( II - 18 ) specifically , R ' represents chlorine, bromine , a cyano group , a methyl group , an ethyl group , an isopropyl group , a cyclopropyl group , a vinyl group , a difluoromethyl group , a NRO 65 trifluoromethyl group , an ethoxyethyl group , or the like; ring A ' represented by the following partial structural formula ( II' ) ; US 9 ,777 , 000 B2 61 62 acetyl group , or the like , or a pharmaceutically acceptable [Formula 33 ] salt thereof, or a solvate thereof. [ 1 - 8 - 6 ] ( II ) Even more particularly preferably, the compound of the 5 above embodiment [ 1 - 8 ] is a compound represented by the N above formula ( I - a ) wherein the definition of p , q , Z , R ' , R², # A ' R3 , R4 , RS, R , and ring A ' in the formula ( I - a ) have the same definitions as those described in the above embodiment [ 1 - 8 - 5 - 2 ] ; and a specific ring A ' group , in which the defini is selected from the group of the heteroaryls consisting of the 10 tions of the above described p , R ', and ring A ' are combined , following: represents a 1 -methyl - 1H -imidazol -4 - yl group , a 4 - (difluo romethyl) - 5 - ethylthiazol- 2 -yl group , a 4 -( difluoromethyl ) 5 - vinylthiazol- 2 - yl group , a 4 - ( difluoromethyl) - 5 -methyl [ Formula 34 ] thiazol- 2 - yl group , a 4 - ( difluoromethyl )thiazol - 2 - yl group , a 15 4A - (trifluoromethyl ) thiazol- 2 - yl group , a 4 , 5 -dimethylthi ( II - 1 ) azol- 2 -yl group , a 4 -tert -butylthiazol - 2 -yl group , a 4 -cyan othiazol- 2 -yl group , a 4 -methylthiazol - 2 - yl group , a 5 - ( 2 ethoxyethyl) - 4 -methylthiazol - 2 -yl group , a 5 - chloro - 4 ( difluoromethyl )thiazol - 2 - yl group , a 5 - cyclopropyl- 4 111 20 (difluoromethyl ) thiazol- 2 - yl group , a 5 - cyclopropyl- 4 methylthiazol- 2 -yl group , a 5 -bromo - 4 -methylthiazol - 2 -yl (II - 4 ) group , a 5 -methylthiazol - 2 - yl group , a thiazol- 2 - yl group , a 2 , 5 -dimethyl - thiazol - 4 - yl group , a 2 - methylthiazol- 4 - yl group , a 5 - ( 1 -hydroxyethyl ) - 2 -methylthiazol -4 - yl group , a 5 -acetyl -2 -methylthiazol - 4 -yl group , a 5 -bromo -2 -methyl thiazol- 4 -yl group , a thiazol- 4 -yl group , a 3 - isopropyl- 1 , 2 , (II - 6 ) 4 - thiadiazol - 5 -yl group , a 3 -methyl - 1 , 2 , 4 - thiadiazol- 5 -yl group , a 5 - ethyl- 1 , 3 , 4 - thiadiazol - 2 -yl group , or a 5 -methyl 1 ,3 , 4 -thiadiazol - 2 -yl group , or a pharmaceutically accept 30 able salt thereof, or a solvate thereof. [ 1 - 8a ] The compound of the above embodiment [ 1] represented by the above formula (I ) is preferably a compound repre ( II- 16 ) 35 sented by the following formula ( I- a ) : [Formula 35 ] Z ' S ( I - a ) 40 ( II- 19) RA N — N

45 9(R321 N A ' (R ') p , and Rº represents a hydrogen atom or a C1- 6 alkyl group , and more specifically , Rº represents a hydrogen atom , a 50 wherein the definition of q , Z , R ’ , R4, RS, and R in the methyl group , or the like , or a pharmaceutically acceptable formula ( I- a ) have the same definitions as those described in salt thereof, or a solvate thereof. the above embodiment [ 1 ]; p , Rº, and ring A ' represented by [ 1 -8 -5 - 2 ] the partial structural formula ( II' ) have the same definitions More particularly preferably , the compound of the above as those described in the above embodiment [ 1- 8 ]; and R ? embodiment [ 1 - 8 ] is a compound represented by the above 55 represents a C1- 6 alkyl group , a halogenated C1- 6 alkyl formula ( I - a ) wherein the definition of q , Z , R2 , R3, R4, RS, group , a hydroxy C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 Rº, and ring A ' represented by the partial structuralal formula alkyl group , or a pharmaceutically acceptable salt thereof, or ( II' ) in the formula ( I- a ) have the same definitions as those a solvate thereof. described in the above embodiment [ 1 - 8 - 5 ) ; p represents an [ 1 - 8a - 21 integer of 0 to 2 ; and R each independently represents a 60 Preferably , the compound of the above embodiment hydroxy C1- 6 alkyl group or a C2- 7 alkanoyl group , and has [ 1- 8a ] is a compound represented by the above formula (I - a ) the same definitions as those described in the above embodi - wherein R has the same definitions as those described in the ment [ 1 - 8 - 5 ] , and more specifically , R ' represents chlorine , above embodiment [ 1 - 3 ]; R + has the same definitions as bromine, a cyano group , a methyl group , an ethyl group , an those described in the above embodiment [ 1- 4 ]; Z and Rº isopropyl group , a tert -butyl group , a cyclopropyl group , a 65 have the same definitions as those described in the above vinyl group , a difluoromethyl group , a trifluoromethyl embodiment [ 1- 5 ); q has the same definitions as those group , a 1 -hydroxyethyl group , an ethoxyethyl group , an described in the above embodiment [ 1 -7 ]; p , Rº, and ring A ' US 9 ,777 , 000 B2 63 64 represented by the partial structural formula ( II' ) have the [ 1 - 8a -6 ] same definitions as those described in the above embodi More particularly preferably , the compound of the above ment [1 - 8 -2 ] ; and R² represents a C1- 6 alkyl group , a halo embodiment [ 1 - 8a ] is a compound represented by the above genated C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 alkyl group , formula ( I - a ) wherein p , q , Z , R ' , R ? , R , R4, RS , R " , and or a pharmaceutically acceptable salt thereof, or a solvate 5 ring A ' have the same definitions as those described in the thereof. above embodiment [ 1 - 8a - 5 ); and a specific ring A ' group , in [ 1 - 8a - 31 which the definitions of the above described p , R ' , and ring More preferably , the compound of the above embodiment A ' are combined , represents a 1 -methyl - 1H - imidazol- 4 -yl [ 1 - 8a ] is a compound represented by the above formula ( I - a ) 10 group , a 4 - (difluoromethyl ) - 5 - ethylthiazol- 2 - yl group , a wherein R3 has the same definitions as those described in the 11 4 - ( difluoromethyl) - 5 - vinylthiazol- 2 - yl group , a 4 - ( difluo above embodiment ( 1 - 3 - 2 ) ; R4 has the same definitions as romethyl) -5 -methylthiazol - 2 -yl group , a 4 -( difluoromethyl ) those described in the above embodiment [1 -4 - 2 ]; Z and RS thiazol- 2 - yl group , a 4 - ( trifluoromethyl )thiazol - 2 - yl group , a have the same definitions as those described in the above 4 . 5 - dimethylthiazol- 2 - yl group . a 4 - tert- butylthiazol - 2 -yl embodiment [ 1- 5 - 2 ]; q has the same definitions asas thosethose 15 group , a 4 - cyanothiazol- 2 -yl group , a 4 -methylthiazol - 2 - yl described in the above embodiment [ 1 -7 - 2 ]; p , R ', Rº, and group , a 5 - ( 2 - ethoxyethyl) - 4 -methylthiazol - 2 - yl group , a ring A 'represented by the partial structural formula (II ' ) have 5 -chloro -4 - (difluoromethyl ) thiazol- 2 - yl group , a 5 - cyclo the same definitions as those described in the above embodi propyl -4 - ( difluoromethyl) thiazol- 2 - yl group , a 5 - cyclopro ment [1 - 8- 3 - 2 ]; and R represents a C1- 6 alkyl group or a pyl- 4 -methylthiazol - 2 - yl group , a 5 - bromo- 4 -methylthiazol halogenated C1-6 alkyl group , or a pharmaceutically accept - 20 2 -yl group , a 5 -methylthiazol - 2 - yl group , a thiazol- 2 - yl able salt thereof, or a solvate thereof. group , a 2, 5 -dimethyl - thiazol- 4 -yl group , a 2 -methylthiazol [ 1 - 8a - 41 4 - yl group , a 5 - ( 1 - hydroxyethyl) - 2 -methylthiazol - 4 -yl Even more preferably , the compound of the above group , a 5 - acetyl- 2 -methylthiazol - 4 - yl group , a 5 - bromo- 2 embodiment [ 1 -8a ] is a compound represented by the above methylthiazol- 4 - yl group, a thiazol- 4 - yl group , a 3 - isopro formula (I - a ) wherein R has the same definitions as those 25 pyl- 1, 2 ,4 - thiadiazol- 5 -yl group , a 3 -methyl - 1, 2 ,4 - thiadi described in the above embodiment [ 1 - 3 - 3 ) ; R * has the same azol - 5 - yl group , a 5 - ethyl- 1 , 3 , 4 - thiadiazol- 2 - yl group , or a definitions as those described in the above embodiment 5 -methyl - 1 , 3 , 4 - thiadiazol - 2 - yl group , or a pharmaceutically [ 1 - 4 - 3 ] ; Z and Rs have the same definitions as those acceptable salt thereof, or a solvate thereof. described in the above embodiment ( 1 - 5 - 3 ); q has the same definitions as those described in the above embodiment 30 ( 1- 3 [ 1 - 7 - 3 ) ; p , R ' , Rº, and ring A ' represented by the partial The compound of the above embodiment [ 1 ] represented structural formula ( II' ) have the same definitions as those by the above formula ( I) is preferably a compound repre described in the above embodiment [ 1 - 8 - 4 - 2 ] ; and R² rep - sented by the following formula ( 1 - b ) : resents a C1-6 alkyl group , or a pharmaceutically acceptable salt thereof, or a solvate thereof. 35 [ 1 - 8a - 51 Particularly preferably , the compound of the above [Formula 36 ] embodiment [ 1 - 8a ] is a compound represented by the above ( I- b ) R2 formula ( I - a ) wherein Rº has the same definitions as those 40 described in the above embodiment [ 1 - 3 - 4 ]; Z and R have R4 N the same definitions as those described in the above embodi ment [1 - 5 - 4 ]; q has the same definitions as those described in the above embodiment [ 1 - 7 - 41; p , R ? , R " , and ring A ' 9( R3 represented by the partial structural formula ( II' ) have the 45 same definitions as those described in the above embodi ment [ 1 - 8 - 5 - 2 ) ; R² represents a C1- 6 alkyl group , and more NAR' p? specifically , R ? represents a methyl group or the like; and R + represents a C6- 14 aryl group or a 3 - to 14 -membered 50 wherein the definition of Z , R2, R3, R4 , and RS in the formula non - aromatic heterocyclic group wherein the C6- 14 aryl ( 1 -b ) have the same definitions as those described in the group and the 3 - to 14 -membered non - aromatic heterocyclic above embodiment [ 1 ] ; p represents an integer of 0 to 2 ; 9 group , which are represented by R4, are optionally substi represents an integer of 0 to 3 ; R each independently tuted with one or two groups selected from among a halogen represents a halogen atom , a hydroxyl group , a nitro group , atom , a C1- 6 alkoxyl group , and a C1- 6 alkoxyl C1- 6 alkyl 55 a cyano group , a C . alkyl group , a Cze cycloalkyl group ,

group , and specifically , R * represents phenyl, 2 - fluorophe - a halogenated C - , alkyl group , a C2 , alkenyl group , a C -a 6

nyl, 3 - fluorophenyl, 4 - fluorophenyl, 2 ,5 -difluorophenyl , alkoxyl group , a halogenated C . alkoxyl group , a C .a 2 -methoxyphenyl , 3 -methoxyphenyl , 4 -methoxyphenyl , alkoxylcarbonyl group , a hydroxy C1- 6 alkyl group , a C1- 6

pyrrolidinyl , 2 - fluoropyrrolidinyl, 3- fluoropyrrolidinyl, alkoxyl C1- 6 alkyl group, a C2- 7 alkanoyl group , a C1- a6 2 -methoxypyrrolidinyl , 3 -methoxypyrrolidinyl , 00 alkylthio group , a C1- 6 alkylsulfinyl group , a C1- 6 alkylsul 2 -methoxymethylpyrrolidinyl , 3 -methoxymethylpyrrolidi - fonyl group , an — NR 'R group , or a CONR ’R8 group nyl, or the like , and preferably represents phenyl, 2 - fluoro - wherein R ' and Rºin the — NR 'Rº group and the phenyl, 3 - fluorophenyl, 4 - fluorophenyl, 2 ,5 - difluorophenyl, CONR 'R® group have the same definitions as those 2 -methoxyphenyl , pyrrolidinyl, or 2 -methoxymethylpyrro - 65 described in the above embodiment [ 1 ] ; lidinyl, or a pharmaceutically acceptable salt thereof, or a ring A ' represented by the following partial structural solvate thereof. formula ( II ) : ?

US 9 . 777 , 000 B2 65 66 -continued [ Formula 37] ( II ~ 9 )

(1 ) 5 ?N Hi4 10 ( II ~ 10) is selected from the group of the heteroaryls consisting of the following :

Formula38 ] Mis ( II ~ 11) ( II ~ 1 ) 20 Nic (II ~ 12 ) ( I~ 2 ) 25 ?? ( 3) 30 ( II ~13 )

35 S - N ( II ~ 4 ) ( II ~14 )

40 ????????) ( 11 ~ 3 ) (II ~ 15 )

45 N 4+vt / (II ~ 6 ) /6 ( II ~16 ) 50

?JJJJJ?R6 NIN (IN7 ) 55 ( II ~ 17 ) Mis (II ~ 8 ) ( II ~ 18 ) 88 NiN ??6 US 9 ,777 ,000 B2 67 68 -continued -continued ( II ~ 19 ) ( II ~ 30 )

5 N ' N ; N - N ( II ~ 20 ) and Ro represents a hydrogen atom , a C1- 6 alkyl group , a N halogenated C1- 6 alkyl group , or a hydroxy C1 - 6 alkyl group , or a pharmaceutically acceptable salt thereof, or a solvate ( II~ 21 ) thereof. 15 [ 1 -9 - 2 ] - Ro Preferably , the compound of the above embodiment [ 1 - 9 ] is a compound represented by the above formula (1 - b ) wherein the definition of Z , R2 , R , R4, and R in the formula ( I - b ) have the same definitions as those described in the (II ~ 22 ) 20 above embodiment [ 1 ] ; p represents an integer of 0 to 2 ; q represents an integer of 0 to 3 ; R ' each independently represents a halogen atom , a hydroxyl group , a nitro group , Z=2 a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 ( II ~ 23) 25 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 alkoxylcarbonyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C - 6 alkylthio group , a C1- 6 alkylsulfonyl group , an — NR ' RS 2=Z group , or a CONR7R8 group wherein R7 and R8 in the 30 — NR ' R $ group and the CONR ' R $ group have the same ( II ~ 24 ) definitions as those described in the above embodiment [ 1 ] ; ring A ' represented by the following partial structural formula ( II' ): ?=Z Ro [Formula 39 ] (II ~ 25) ( II )

40

2-

2 ( II ~ 26 ) 45 is selected from the group of the heteroaryls consisting of the following : N O N = N (II ~ 27) 50 [Formula 40 ] ( II - 1 ) Na Ro N = EN (II ~ 28 ) 55 ( II - 3 ) Ro 60 ( II ~ 29 ) ( II - 4 )

65 O - K US 9 ,777 , 000 B2 69 70 -continued -continued ( II - 6 ) ( II -21 ) DRO ( II -22 ) (II -7 ) 10

( II - 24 ) (II - 9 ) 15 ?=z N RO 20 ( II - 25 ) PA (II - 10 ) - NEN 25 ( II - 27 )

- Ro ( II - 12 ) Na 30 ( II -29 )

Z po 35 ( II- 13 ) ( II - 30 )

??? 40 N 7=Ž N - (II - 15 ) 45 and R? represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1-6 alkyl group , or a pharmaceutically acceptable salt thereof, or a solvate thereof . [ 1 - 9 - 3 ] ( II -16 ) 50 More preferably , the compound of the above embodiment [ 1 - 9 ] is a compound represented by the above formula ( I - ) wherein the definition of Z , R2 , R , Rº , and R in the formula ( I- b ) have the same definitions as those described in the above embodiment [ 1 ] ; p represents an integer of 0 to 2 ; 9 1855 represents an integer of 0 to 2 ; R ' each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , RO a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 60 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 22 alkylthio group , a C - 6 alkylsulfonyl group , a ( II - 19 ) _ CONR74R8A group , or an - NR74R8A group wherein R74 and R8A in the NR74R8A group and the CONR74R84 group have the same definitions as those of R74 and R84 in 65 the above embodiment [ 1 - 1 -2 ]) ; ring A ' represented by the following partial structural formula ( II' ) ; ?

US 9, 777 , 000 B2 ? 72 -continued [ Formula 41 ] ( II ~13 )

(1 ) 5 (II - 15 )

10 is selected from the group of the heteroaryls consisting of the ??? following: WA ( II ~ 16 ) [ Formula 42] (II ~ )

( II ~ 18)

(II ~ 3 ) ? ??R6 ??R6 NA ( II ~ 19 )

( II ~ 4 ) ? ?3%8395 (II ~ 21) R6 (II ~ 6)

(II ~ 22 )

???? (II ~ 7 ) ? N - S ???? ( II ~ 24 ) ??? ( II ~ 9 ) MIW ??? ( II ~ 27

N

/6. NYN* (II ~ 10 ) NEN (II ~ 30)

NYN: VS ? N?N (II ~ 12 ) 60 R6

N ? and R° represents a hydrogen atom, a CL- 6 alkyl group , a NA? 65 halogenated C , s alkyl group, ora hydroxy Cis alkyl group , ?4? or a pharmaceutically acceptable salt thereof, or a solvate thereof . US 9 ,777 ,000 B2 74 [ 1 - 9 - 4 ] -continued Even more preferably , the compound of the above ( II - 9 ) embodiment [ 1 - 9 ] is a compound represented by the above formula ( I - b ) wherein the definition of Z , R2, R3, R1, and RS in the formula ( 1- b ) have the same definitions as those 5 described in the above embodiment [ 1 ]; p represents an integer of 1 or 2 ; q represents an integer of 0 to 2 ; R each independently represents a halogen atom , a hydroxyl group , Po a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 10 ( II - 13 ) cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 2 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl group, a C2- 7 alkanoyl group , a C1- 6 alkylthio group , or a C1- 6 alkylsul S — N fonyl group ; 1515 ( II -15 ) ring A ' represented by the following partial structural

formula ( II ') ; Z

20 [Formula 43 ] ( II -16 ) (II )

25 1 A . ( II - 18 ) is selected from the group of the heteroaryls consisting of the 30 Ro following: N ( II- 19 ) [Formula 44 ] (II - 1)

( II -21 )

$ ( II - 3 ) NRO Z ( II- 22 )

( II- 4 ) N - S ya ( II - 24 )

( II- 6 ) z=2 ja ( II -27 ) – 6. 60 Na (II -7 NEN

and Rº represents a hydrogen atom , a C1- 6 alkyl group , a 65 halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , or a pharmaceutically acceptable salt thereof, or a solvate thereof. US 9 ,777 ,000 B2 75 76 [ 1 -9 - 4 -2 ] -continued Further preferably , the compound of the above embodi ( II - 19 ) ment [ 1 - 9 ] is a compound represented by the above formula ( 1 - b ) wherein the definition of q , Z , R1, R2, R3, R4, RS , RO , and ring A ' represented by the partial structural formula ( II' ) in the formula ( 1 - b ) have the same definitions as those described in the above embodiment [ 1 - 9 - 4 ] ; and p represents an integer of 0 to 2 , or a pharmaceutically acceptable salt and R? represents a hydrogen atom or a C1- 6 alkyl group , and thereof, or a solvate thereof. more specifically , Rº represents a hydrogen atom , a methyl [ 1 - 9 - 5 ] group , or the like , or a pharmaceutically acceptable salt Particularly preferably , the compound of the above thereof, or a solvate thereof. embodiment [ 1 - 9 ] is a compound represented by above the [ 1 - 9 - 5 - 2 ] formula ( I - b ) wherein the definition of Z , R , R , R4, and RS - More particularly preferably, the compound of the above in the formula ( 1 - b ) have the same definitions as those embodiment ( 1 - 9 ) is a compound represented by the above described in the above embodiment [1 ] ; p represents an formula (1 - b ) wherein the definition of q, Z , R1, R2, R3, R4, integer of 1 or 2 ; q represents an integer of 0 or 1 ;R each and R in the formula ( I - b ) have the same definitions as those independently represents a halogen atom , a C1- alkyl group , described in the above embodiment [ 1 - 9 - 5 ) ; p represents an or a halogenated C1- 6 alkyl group , and more specifically , R ? 20 integer of 0 to 2 ; ring A ' represented by the following partial represents chlorine , a methyl group , an ethyl group , a structural formula ( II' ) : difluoromethyl group , a trifluoromethyl group , or the like; ring A ' represented by the following partial structural ( Formula 47] formula ( II' ): 25 ( II ) [Formula 45 ] ( II ) A 30 is selected from the group of the heteroaryls consisting of the A following :

35 is selected from the group of the heteroaryls consisting of the [ Formula 481 following : ( II - 1 )

[Formula 46 ] ( II- 1 ) ( II - 6 )

( 11- 4 )

and Rº represents a hydrogen atom or a C1- 6 alkyl group , and more specifically, Rº represents a hydrogen atom , a methyl ( II- 6 ) group , or the like , or a pharmaceutically acceptable salt 55 thereof, or a solvate thereof. [ 1 - 9 -6 ] Even more particularly preferably , the compound of the above embodiment ( 1 - 9 ] is a compound represented by the above formula ( 1 - b ) wherein the definition of p , q , ZR , R , of 60 R3, R4, RS , R ", and ring A ' in the formula ( I- b ) have the same ( II- 16 ) definitions as those described in the above embodiment [ 1 - 9 - 5 - 2 ) ; and a specific ring A ' group , in which the defini tions of the above described p , R ' , and ring A ' are combined , represents a 1 -methyl - 1H - imidazol- 4 -yl group, a 4 - (difluo 2 65 romethyl) - 5 -methylthiazol - 2 - yl group , a 4 - (difluoromethyl ) thiazol- 2 - yl group , a 4 - ( trifluoromethyl) thiazol- 2 - yl group , a 4 - ethylthiazol- 2 - yl group , a 4 -methylthiazol - 2 - yl group , a US 9 ,777 ,000 B2 77 78 5 -chloro - 4 - (difluoromethyl ) thiazol- 2 -yl group , or a pharma [ 1 - 4 - 3 ] ; Z and R have the same definitions as those ceutically acceptable salt thereof, or a solvate thereof . described in the above embodiment [ 1 - 5 - 3 ) ; q has the same [ 1 - 9a ] definitions as those described in the above embodiment The compound of the above embodiment [ 1 ] represented 11 - 7 - 31: p . RI . R6 , and ring A ' represented by the partial by the above formula ( I ) is preferably a compound repre- 5 structural formula ( II' ) have the same definitions as those sented by the following formula ( I - b ) : described in the above embodiment [ 1- 9 -4 -2 ]; and R2 rep resents a C1- 6 alkyl group , or a pharmaceutically acceptable [Formula 49 ] salt thereof, or a solvate thereof. (I - b ) 10 [1 - 9a -5 ] Particularly preferably , the compound of the above R4 embodiment [ 1 - 9a ] is a compound represented by the above formula ( I- b ) wherein R3 has the same definitions as those 15 described in the above embodiment [1 -3 -4 ] ; Z and R have (R3 , the same definitions as those described in the above embodi ment ( 1 - 5 - 4 ] ; q has the same definitions as those described NA in the above embodiment [ 1 - 7 - 4 ) ; p , R ', Rº, and ring A ' E - -- (R ') p ? 20 represented by the partial structural formula (II ' ) have the same definitions as those described in the above embodi wherein the definition of q , Z , R3, R4 , RS, and R? in the ment 11- 9 - 5 - 21: R2 represents a C . alkyl group , and more formula (1 - b ) have the same definitions as those described in the above embodiment [ 1 ]; p , R?, and ring A ' represented by specifically , R ? represents a methyl group or the like ; and R the partial structural formula (II ' ) have the same definitions 25 represents a C6- 14 aryl group , or a 3 - to 14 -membered as those described in the above embodiment [ 1 - 9 ] ; and R2 non -aromatic heterocyclic group wherein the C6- 14 aryl represents a C1- 6 alkyl group , a halogenated C1- 6 alkyl group and the 3 - to 14 -membered non - aromatic heterocyclic group , a hydroxy C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 group, which are represented by R4, are each optionally alkyl group, or a pharmaceutically acceptable salt thereof , or substituted with one or two groups selected from among a a solvate thereof. 30 halogen atom , a C1- 6 alkyl group, and a C1- 6 alkoxyl group , [ 1 - 9a - 2 ] and specifically , Rº represents phenyl, 2- fluorophenyl , Preferably , the compound of the above embodiment 3 - fluorophenyl, 4 - fluorophenyl, 2 ,5 - difluorophenyl, 2 -meth [ 1 - 9a ] is a compound represented by the above formula (1 - b ) wherein R3 has the same definitions as those described in the ylphenyl, 3 -methylphenyl , 4 -methylphenyl , 2 ,5 -dimethyl above embodiment 11 - 31: R4 has the same definitions as 35 phenyl , 2 , 6 - dimethylphenyl, 3 , 5 - dimethylphenyl, those described in the above embodiment [ 1 - 4 ] ; Z and R5 2 -methoxyphenyl , 3 -methoxyphenyl , 4 -methoxyphenyl , have the same definitions as those described in the above pyrrolidinyl, 2 - fluoropyrrolidinyl, 3 - fluoropyrrolidinyl, embodiment [1 - 5 ); q has the same definitions as those 2 -methoxypyrrolidinyl , 3- methoxypyrrolidinyl , 2 -methyl described in the above embodiment [ 1 - 71; p , Rº , and ring A ' pyrrolidinyl , 3 -methylpyrrolidinyl , morpholinyl, 2 -methyl represented by the partial structural formula ( II' ) have the 40 morpholinyl, 3- methylmorpholinyl , 2 ,6 -dimethylmorpholi same definitions as those described in the above embodi ment [ 1 - 9 - 2 ]; and R ? represents a C1- 6 alkyl group , a halo nyl, 3 ,5 -dimethylmorpholinyl , or the like , and R + preferably genated C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 alkyl group , represents phenyl , 3 - fluorophenyl, 2 -methoxyphenyl , pyrro or a pharmaceutically acceptable salt thereof, or a solvate lidinyl, 3 - fluoropyrrolidinyl, 2 -methylpyrrolidinyl , or 2 ,6 thereof. 45 dimethylmorpholinyl , or a pharmaceutically acceptable salt [ 1 - 9a - 3 ] thereof, or a solvate thereof. More preferably , the compound of the above embodiment [ 1 - 9a ] is a compound represented by the above formula ( I -b ) [1 -92 -6 ] wherein R has the same definitions as those described in the More particularly preferably , the compound of the above above embodiment [ 1 - 3 - 2 ] ; R has the same definitions as 50 embodiment [ 1 - 9a] is a compound represented by the above those described in the above embodiment [ 1 - 4 - 2 ]; Z and RS formula ( I- b ) wherein p , q , Z , R ' , R2, R3, R4, RS, R?, and have the same definitions as those described in the above ring A ' have the same definitions as those described in the embodiment [1 -5 - 2 ); q has the same definitions as those above embodiment [ 1 - 9a - 5 ); and a specific ring A ' group , in described in the above embodiment [ 1 - 7 - 2 ) ; p , RIR1, ROR ' , andand 55se whichW . the definitions of the above described p , R ' , and ring ring A ' represented by the partial structural formula ( II' ) have A ' are combined , represents a 1 -methyl - 1H - imidazol- 4 -yl the same definitions as those described in the above embodi group , a 4 - ( difluoromethyl ) - 5 -methylthiazol - 2 - yl group , a ment [ 1- 9 -3 ) ; and R2 represents a C1- 6 alkyl group or a 4 - (difluoromethyl ) thiazol- 2 -yl group , a 4 - ( trifluoromethyl) halogenated C1- 6 alkyl group , or a pharmaceutically accept thiazol- 2 - yl group , a 4 -ethylthiazol - 2 -yl group , a 4 -methyl able salt thereof, or a solvate thereof. 60 thiazol- 2 -yl group , or a 5 - chloro -4 - (difluoromethyl ) thiazol [ 1 -9a - 4 ] 2 - yl group , or a pharmaceutically acceptable salt thereof, or Even more preferably , the compound of the above a solvate thereof. embodiment [ 1 - 9a ) is a compound represented by the above [ 1 - 10 ] formula ( 1 - b ) wherein R has the same definitions as those 65 The compound of the above embodiment [ 1 ] represented described in the above embodiment [ 1 - 3 - 3 ); R * has the same by the above formula ( I ) is preferably a compound repre definitions as those described in the above embodiment sented by the following formula (I - c ): US 9 ,777 , 000 B2 19 80 -continued [Formula 50 ] ( II -33 )

(1- C ) 5 R4 ZIHN N - N ( II -34 ) R32 10

(R ) ? ( II - 35 ) wherein the definition of q, Z , R², R3, R4, and RS in the formula ( I - c ) have the same definitions as those described in N N the above embodiment [ 1 ]; p represents an integer of 0 to 4 ; R ? each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl ( II -36 ) group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halo genated C1- 6 alkoxyl group , a C1- 6 alkoxylcarbonyl group , a 25 z= hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a z C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkyl sulfinyl group , a C1- 6 alkylsulfonyl group, an - NR RS ( II -37 ) group , or a CONR ’R8 group wherein R7 and R8 in the - NR 'R $ group and the CONR ' R $ group have the same 30 definitions as those described in the above embodiment [ 1 ] ; and ring A " represented by the following partial structural formula ( II " ) : 35 ( II - 38 )

[Formula 51 ] Z= (II ") 40 ( II -39 )

45 is selected from the group of the heteroaryls consisting of the ( II -40 ) following : 50

[Formula 52 ] (11 - 31 ) 55 ( II -41 )

Z

-

4 60 ( II- 32 ) ( II - 42 )

Z ZEZ 65 = US 9 ,777 ,000 B2 87 82 -continued -continued ( II -43 ) ( II - 34 )

Z NEN: ( II - 35) or a pharmaceutically acceptable salt thereof, or a solvate 10 thereof. N N [ 1 - 10 - 2 ] Preferably , the compound of the above embodiment [ 1 - 10 ] is a compound represented by the above formula ( I -c ) ( II -36 ) wherein the definition of q , Z , R2, R " , Rº , and RS in the 15 formula ( I - c ) have the same definitions as those described in the above embodiment [ 1 ] ; p represents an integer of 0 to 4 ; N R each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3 -8 cycloalkyl group , a halogenated C1- 6 alkyl 20 ( II - 37 ) group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halo genated C - alkoxyl group , a Cl. alkoxylcarbonyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsul fonyl group , an - NR /R8 group , or a CONR /R8 group EZ wherein R7 and R8 in the NR ' R ' group and the ( II - 38 ) - CONR ' R8 group have the same definitions as those described in the above embodiment [ 1 ] ; and NN ring A " represented by the following partial structural 3020 formula ( II " ) : = ( II - 39 ) [Formula 53 ] (II " ) 35

A " (II - 40 ) 40

N is selected from the group of the heteroaryls consisting of the following : 45 ( II -41 ) [Formula 54 ] N N ( II -31 ) = 50 ( II- 42 ) (II - 32 ) 55 ZZ

000toz= ( II -43 ) 60 (II - 33 ) NIN

V= 65 or a pharmaceutically acceptable salt thereof, or a solvate thereof . US 9 ,777 ,000 B2 83 84 [ 1 - 10 - 2- 2 ] -continued More preferably , the compound of the above embodiment ( II ~ 34 ) [ 1 - 10 ] is a compound represented by the above formula ( I -c ) wherein the definition of p , Z , R², R3, R4, R ” , and ring A " represented by the partial structural formula ( II " ) in the formula (1 - c) have the same definitions as those described in the above embodiment [ 1 - 10 - 2 ]; and q represents an integer of 0 to 3 , or a pharmaceutically acceptable salt thereof, or a ( II ~ 35 ) solvate thereof. 10 [ 1 - 10 - 3 ] Even more preferably , the compound of the above embodiment [ 1 - 10 ] is a compound represented by the above formula ( I - c ) wherein the definition of q , Z , R2, R3, R4, and ( II ~ 36 ) R $ in the formula ( I -c ) have the same definitions as those 15 described in the above embodiment [ 1 ] ; p represents an integer of 0 to 3; R ' each independently represents a halogen N atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 20 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a ( II ~ 37) halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a Cl- , alkylthio group , a C1- 6 alkylsulfonyl group , a CONR74R84 group , or an z= - NR74R8A group wherein R74 and R84 in the — NR74R84 25 group and the — CONR74R8A group have the same defini tions as those of R74 and R84 in the above embodiment ( II ~ 39 ) [ 1 - 1 - 2 ] ; and ring A " represented by the following partial structural formula ( II " ): 30

Wall ( II ~ 42 ) [ Formula 55 ] ( II" ) 35 NN

= N NEN: or a pharmaceutically acceptable salt thereof, or a solvate thereof. is selected from the group of the heteroaryls consisting of the [ 1- 10 - 3- 2 ] following : Further preferably , the compound of the above embodi 45 ment [ 1 - 10 ] is a compound represented by the above for mula (I - c ) wherein the definition of p , Z ,R1 , R2, R3, R4, RS, [Formula 56 ] and ring A " represented by the partial structural formula ( II" ) in the formula ( 1 - c ) have the same definitions as those ( II ~ 31 ) described in the above embodiment [ 1 - 10 - 3 ) ; and q repre 50 sents an integer of 0 to 2 , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 1- 10 -4 ] Still further preferably , the compound of the above ( II ~ 32 ) 55 embodiment [ 1 - 10 ] is a compound represented by the above formula ( I - c ) wherein the definition of q , Z , R², Rº , R4, and R in the formula ( I- c ) have the same definitions as those described in the above embodiment [ 1 ] ; p represents an integer of 1 to 3; R ' each independently represents a halogen 60 atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 ( II ~ 33 ) alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group, or a 65 C1- 6 alkylsulfonyl group ; and ring A " represented by the following partial structural formula ( II " ) : US 9 ,777 , 000 B2 85 86 represents a C1- 6 alkyl group or a C1- 6 alkoxyl group , and [Formula 571 more specifically , R ' represents a methyl group , a methoxy group , or the like ; and (II " ) ring A " represented by the following partial structural 5 formula (II " );

[Formula 59 ]

10 ( II" ) is selected from the group of the heteroaryls consisting of the following : A " [Formula 58 ] 15 (II - 31 ) is selected from the group of the heteroaryls consisting of the following:

20 [Formula 60 ] ( II -32 ) (II - 31 )

25

( II - 33 ) ( II - 34 ) 30

( II- 34 ) 35 ( II -35 )

N N :

40 ( II - 35 ) or a pharmaceutically acceptable salt thereof, or a solvate thereof. N ; 45 [ 1 - 10 -5 - 2 ] More particularly preferably , the compound of the above embodiment [ 1 - 10 ] is a compound represented by the above formula (1 -c ) wherein the definition of Z , R ? , R3, R4, RS, RS, or a pharmaceutically acceptable salt thereof , or a solvate and ring A " represented by the partial structural formula ( II " ) thereof. 50 in the formula ( 1 - c ) have the same definitions as those described in the above embodiment [ 1 - 10 - 5 ) ; p represents an [ 1 - 10 - 4 - 2 ] integer of 0 to 3 ; q represents an integer of 0 or 1 ; Reach Still further preferably , the compound of the above independently represents a halogen atom , a C1- 6 alkyl group , embodiment [ 1 - 10 ] is a compound represented by the above a cyano group , a halogenated C1- 6 alkyl group , or a C1- 6 formula ( I - c ) wherein the definition of Z , R1, R2, R ’ , R4, RS| , 55 alkoxyl group , and more specifically , R ' represents fluorine , and ring A " represented by the partial structural formula ( II " ) » a cyano group , a methyl group , a trifluoromethyl group , a in the formula 000000( 1 - c ) have the same definitions as those methoxy group , or the like , or a pharmaceutically acceptable described in the above embodiment [ 1 - 10 - 4 ); p represents an salt thereof, or a solvate thereof. integer of 0 to 3 ; and q represents an integer of 0 or 1 , or a [ 1- 10 -6 ] pharmaceutically acceptable salt thereof, or a solvate 60 Even more particularly preferably , the compound of the thereof. above embodiment [ 1 - 10 ] is a compound represented by the [ 1 - 10 - 5 ] above formula ( I- c ) wherein the definition of p , q , Z , R ' , R² , Particularly preferably , the compound of the above R ’ , R4, R™, and ring A " in the formula ( I - c ) have the same embodiment [ 1 - 10 ] is a compound represented by the above definitions as those described in the above embodiment formula ( I - c ) wherein q , Z , R², R " , R4, and R have the same 65 [ 1 - 10 - 5 - 2 ) ; and a specific ring A " group , in which the definitions as those described in the above embodiment [ 1 ] ; definitions of the above described p , R ' , and ring A " are p represents an integer of 1 or 2 ; R ' each independently combined , represents a 4 -methylpyrimidin -2 - yl group , a US 9 ,777 , 000 B2 87 88 3 -cyano - pyridin - 2 -yl group , a 3 -methylpyridin - 2 - yl group , a have the same definitions as those described in the above 4 - fluoropyridin - 2 - yl group , a 4 - methylpyridin - 2 - yl group , a embodiment [ 1 - 10 - 3 - 2 ); and R² represents a C1- 6 alkyl group 4 -methoxy -pyridin - 2 - yl group , a 5 - fluoropyridin - 2 - yl group , or a halogenated C1- 6 alkyl group , or a pharmaceutically a 5 -methylpyridin - 2 - yl group , a 6 - cyano -pyridin - 2 - yl group , a 6 -methylpyridin - 2 - yl group , a 6 -methoxypyridin group - 2 - yl5; acceptable salt thereof, or a solvate thereof. group , a 3 ,6 -dimethylpyrazin - 2 -yl group , or a 6 -methyl pyrazin - 2 -yl group , or a pharmaceutically acceptable salt Even more preferably , the compound of the above thereof, or a solvate thereof. embodiment [1 - 10a ] is a compound represented by the [ 1 - 10a ] above formula ( I - c ) wherein R3 has the same definitions as The compound of the above embodiment [ 1 ] represented those described in the above embodiment [ 1 - 3 - 3 ) ; R4 has the by the above formula (I ) is preferably a compound repre same definitions as those described in the above embodi sented by the following formula (I - c ): ment [ 1 - 4 - 3 ] ; Z and R have the same definitions as those described in the above embodiment [1 - 5 -3 ); q has the same 15 definitions as those described in the above embodiment [ Formula 61 ] [ 1 - 7 - 3 ) ; p , R1, and ring A " represented by the partial ( I - c ) structural formula ( II" ) have the same definitions as those R2 described in the above embodiment [ 1 - 10 - 4 - 2 ]; and R ? N - N 20 represents a C1- 6 alkyl group , or a pharmaceutically accept N able salt thereof, or a solvate thereof. [ 1- 10a- 5 ] Oh Particularly preferably , the compound of the above 25 embodiment [ 1 - 10a ] is a compound represented by the above formula ( 1 - c ) wherein R3 has the same definitions as those described in the above embodiment ( 1 - 3 - 41; Z and RS ( R ) , have the same definitions as those described in the above embodiment [ 1 - 5 - 4 ] ; q has the same definitions as those 30 described in the above embodiment ( 1 -7 - 41; p , R ' , and ring A " represented by the partial structural formula ( II " ) have wherein the definition of q , Z , Rº, R4, and R in the formula the same definitions as those described in the above embodi ( 1- c ) have the same definitions as those described in the ment [ 1 - 10 - 5 -2 ]; R2 represents a C1- 6 alkyl group , and more above embodiment [ 1 ] ; p , R1, RC , and ring A " represented by specifically, R2 represents a methyl group or the like; and R4 the partial structural formula ( II" ) have the same definitions » represents a C6- 14 aryl group or a 3 - to 14 -membered as those described in the above embodiment [ 1 - 10 ]; and R2 non - aromatic heterocyclic group wherein the C6- 14 aryl represents aC alkyl group , a halogenated Cialkyl group and the 3 - to 14 -membered non -aromatic heterocyclic group , a hydroxy C1- 6 alkyl group , or a C1- 6 alkoxyl C1 -6 group , which are represented by R4, are each optionally alkyl group, or a pharmaceutically acceptable salt thereof, or in40 Ssubstituted with one or two halogen atoms, and specifically , a solvate thereof. R represents phenyl, 2 - fluorophenyl, 3 - fluorophenyl, [ 1- 10a -2 ] 4 - fluorophenyl, 2 , 5 -difluorophenyl , pyrrolidinyl, 2 - fluoro Preferably , the compound of the above embodiment pyrrolidinyl, 3 - fluoropyrrolidinyl, or the like , and R4 pref [ 1 - 10a ] is a compound represented by the above formula erably represents phenyl, 3 - fluorophenyl, or pyrrolidinyl, or ( l- c ) wherein R3 has the same definitions as those described 45 a pharmaceutically acceptable salt thereof, or a solvate in the above embodiment [ 1 - 3 ] ; R * has the same definitions thereof. as those described in the above embodiment [ 1 -4 ]; Z and RS [ 1- 10a- 6 ] have the same definitions as those described in the above More particularly preferably , the compound of the above embodiment ( 1 - 5 ) ; q has the same definitions as those embodiment [ 1 - 10al is a compound represented by the described in the above embodiment [ 1 - 7 ] ; p , R ' , and ring A " 30 above formula ( I - c ) wherein p , q , Z , R ' , R2, R3, R4, R², and represented by the partial structural formula ( II " ) have the ring A " have the same definitions as those described in the same definitions as those described in the above embodi above embodiment [ 1 - 10a - 5 ) ; and a specific ring A " group , ment [ 1 - 10 - 2 - 2 ] ; and R represents a C1- 6 alkyl group , a in which the definitions of the above described p , R ' , and halogenated C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 alkyl ring A " are combined , represents a 4 -methylpyrimidin - 2 -yl group , or a pharmaceutically acceptable salt thereof, or a 55 group , a 3 -cyano -pyridin - 2- yl group, a 3- methylpyridin - 2 -yl solvate thereof. group, a 4 - fluoropyridin - 2 -yl group , a 4 -methylpyridin -2 -yl [ 1 - 10a - 31 group , a 4 -methoxy -pyridin - 2 -yl group , a 5 - fluoropyridin More preferably , the compound of the above embodiment 2 -yl group , a 5 -methylpyridin -2 - yl group , a 6 -cyano -pyri [ 1 - 10a ] is a compound represented by the above formula din - 2 -yl group , a 6 -methylpyridin - 2 - yl group , a 6 -methoxy ( I - c ) wherein R has the same definitions as those described ou pyridin - 2 -yl group , a 3 ,6 -dimethylpyrazin - 2 - yl group , or a in the above embodiment [ 1 - 3 - 2 ] ; R4 has the same defini - 6 -methylpyrazin - 2 -yl group , or a pharmaceutically accept tions as those described in the above embodiment [ 1- 4 - 2 ); Z able salt thereof, or a solvate thereof. and Rhave the same definitions as those described in the [1 - 11 ] above embodiment [ 1 -5 - 2 ] ; q has the same definitions as 65 The compound of the above embodiment [ 1 ] represented those described in the above embodiment [ 1- 7 - 2 ); p , R ' , and by the above formula (I ) is preferably a compound repre ring A " represented by the partial structural formula ( II" ) sented by the following formula (1 - d ) : US 9 ,777 , 000 B2 89 90 -continued [Formula 62 ] ( II -33 ) (1- 0 ) R2 5 N N — N ( II -34 ) 9R3-17 10

- - A " (R ') p ? ( II - 35 ) wherein the definition of Z , R², R3, R4, and RS in the formula ( 1 - d ) have the same definitions as those described in the N N above embodiment [ 1 ]; p represents an integer of 0 to 4 ; q represents an integer of itions0 to ants3 ; R an ' integeach independentupindependently, represents a halogen atom , a hydroxyl group , a nitro group , ( II -36 ) a cyano group , a C1-byl 6 alkylgroup groupoup , ,a a cC3, Broup - 8 cycloalkyl,a niependenti group, , 20 a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 25 z=

alkoxylcarbonylalkyl groupCup ,, aa byddhydroxy Coalkenyle C1- 6 alkyl ;group , a C1- 6 z alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfinyl group , a C1- 6 alkylsul fonkylthiofonyl group , an - NR 'R8 group , or a CONR ' R $ group ( II -37 ) wherein R7 and R8 in the NRÖR8 group and the 30 _ CONR ' R8 group have the same definitions as those described in the above embodiment [ 1 ]; and ring A " represented by the following partial structural formula ( II" ) : 35 ( II - 38 )

[Formula 63 ]

Z= (II " ) 40 ( II -39 )

A "

45 V is selected from the group of the heteroaryls consisting of the ( II -40 ) following : 50 N [Formula 64 ]

( II- 31 ) ( II -41 ) 55

N N =

Z

(II - 32 ) 60 ( II -42 )

z=

z 65 US 9 ,777 ,000 B2 91 92 -continued - continued ( II -43 ) ( II - 34 )

N N = N ( II - 35) or a pharmaceutically acceptable salt thereof, or a solvate 10 thereof. N N [ 1 - 11 - 2 ] Preferably , the compound of the above embodiment [ 1- 11 ] is a compound represented by the above formula (1 - d ) ( II - 36 ) wherein the definition of Z , R2, R3, R4, and R in the formula 15 ( I - d ) have the same definitions as those described in the above embodiment [ 1 ] ; p represents an integer of 0 to 4 ; q . represents an integer of 0 to 3 ; R ' each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , 20 a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 ( II -37 ) alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 alkoxylcarbonyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , an - NR ' R $ 25 group , or a CONR7R8 group wherein R7 and R8 in the - NR 'R8 group and the CONRR8 group have the same ( II - 38 ) definitions as those described in the above embodiment [ 1 ] ; and ring A " represented by the following partial structural 30 formula ( II" ) : ( II - 39 ) [Formula 65 ] (11 ) 35

A " ( II -40 ) 40

is selected from the group of the heteroaryls consisting of the following : 45 ( II -41 ) [ Formula 66 ]

Z ( II -31 ) z=

Z- 50 z ( II -42 )

(II - 32 ) 55 V = z= ( II -43 )

z 60 (II - 33 ) N IN NEN 65 or a pharmaceutically acceptable salt thereof, or a solvate thereof . US 9 ,777 , 000 B2 93 94 [ 1 - 11 - 3 ] More preferably , the compound of the above embodiment - continued [ 1 - 11 ] is a compound represented by the above formula (I - d ) ( II - 36 ) wherein the definition of Z , R2, R3, R4, and R in the formula ( 1 - d ) have the same definitions as those described in the 5 above embodiment [ 1 ] ; p represents an integer of 0 to 3 ; 4 represents an integer of 0 to 2 ; R ? each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 10 alkoxyl group , a halogenated C1- 6 alkoxyl group , a C1- 6 ( II - 37) alkoxyl C1- 6 alkyl group , a C2 -7 alkanoyl group , a C1- 6 alkylthio group , a C16 alkylsulfonyl group , a ZN '

CONR74R8A group , or an - NR74R8A group wherein R74 = and R8A in the NR74R8A group and the - CONR74R84 15 group have the same definitions as those of R74 and R84 in the above embodiment [1 - 1 -2 ] ; ring A " represented by the following partial structural ( II - 39 ) formula ( II" ): 20 [Formula 67 ] ( II " ) 25 ( II -42 )

A "

LO =z 30 ? ?? is selected from the group of the heteroaryls consisting of the following : or a pharmaceutically acceptable salt thereof, or a solvate [Formula 68 ] 35 thereof. (II - 31 ) [1 - 11 - 4 ] Even more preferably , the compound of the above embodiment [ 1 - 11 ] is a compound represented by the above 40 formula ( I- d ) wherein the definition of Z , R2, R3, R4, and R in the formula ( I - d ) have the same definitions as those described in the above embodiment [ 1 ] ; p represents an (II -32 ) integer of 1 to 3 ; q represents an integer of 0 to 2 ;R each independently represents a halogen atom , a hydroxyl group , 45 a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 ZEZ alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 ( II- 33 ) alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 alkylthio group , or a C1- 6 alkylsul fonyl group ; and ring A " represented by the following partial structural formula ( II " ): (II - 34 ) 55 [Formula 69 ] ( II" )

60 ( II- 35 ) Z

-

65 is selected from the group of the heteroaryls consisting of the following : US 9 ,777 , 000 B2 95 96

[ Formula 70 ] [ Formula 71 ] ( II" ) ( II -31 ) 5

10 is selected from the group of the heteroaryls consisting of the (II -32 ) following :

15 [Formula 72] ( II -31 )

(11 - 33 ) 20

( II - 32 )

25 ( II -34 )

( II - 33) 30 1600oaie ( II- 35 ) N ; 35 ( II - 34 ) or a pharmaceutically acceptable salt thereof , or a solvate 40 thereof. ( II -35 ) [1 - 11 -4 - 2] Further preferably , the compound of the above embodi NN: ment [ 1 - 11 ] is a compound represented by the above formula 45 (I -d ) wherein the definition of Z ,R2 , R }, R4, R™, and ring A " represented by the partial structural formula ( II" ) in the formula ( I - d ) have the same definitions as those described in the above embodiment [ 1 - 11 - 41; p represents an integer of o or a pharmaceutically acceptable salt thereof, or a solvate to 3 ; and q represents an integer of 0 or 1 , or a pharmaceu - 30 [ 1 - 11 - 5 - 2 ] tically acceptable salt thereof, or a solvate thereof. More particularly preferably, the compound of the above [ 1 -11 -5 ] embodiment [ 1 - 11 ] is a compound represented by the above Particularly preferably , the compound of the above formula ( I - d ) wherein the definition of Z , R2 , R3, R4, RS, and embodiment [ 1 - 11 ] is a compound represented by the above 55 ring A " represented by the partial structural formula ( II" ) in formula ( I - d ) wherein the definition of Z , R2, R " , R4, and RS the formula ( 1 - d ) have the same definitions as those in the formula (1 - d ) have the same definitions as those described in the above embodiment ( 1 -11 - 41 ; p represents an described in the above embodiment [ 1 ]; p represents an integer of 0 to 3 ; and q represents an integer of 0 or 1 , or a integer of 1 to 3 : a represents an integer of 0 or 1 : Rl each pharmaceutically acceptable salt thereof, or a solvate independently represents a halogen atom , a cyano group , a ou [1 - 11 -6 ] C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a C1- 6 Even more particularly preferably , the compound of the alkoxyl group , and more specifically , R ' represents fluorine , above embodiment [ 1 - 11 ] is a compound represented by the chlorine , a cyano group , a methyl group , a trifluoromethyl above formula (1 - d ) wherein the definition of p , q , Z , R1, R², group , a methoxy group , or the like ; 65 R3, R4, RS, and ring A " in the formula ( I- d ) have the same ring A " represented by the following partial structural definitions as those described in the above embodiment formula (II " ) : [ 1 - 11 - 5 - 2 ]; and a specific ring A " group , in which the US 9 ,777 , 000 B2 97 98 definitions of the above described p , R ' , and ring A " are ment [ 1- 11 - 2 ); and R² represents a C1- 6 alkyl group , a combined , represents a 4 , 6 - dimethylpyrimidin - 2 - yl group , a halogenated C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 alkyl 4 -methylpyrimidin - 2 - yl group , a 2 , 5 ,6 -trimethylpyrimidin group , or a pharmaceutically acceptable salt thereof, or a 4 - yl group , a 2 , 5 -dimethylpyrimidin - 4 -yl group , a 2 , 6 - dim - solvate thereof. ethylpyrimidin - 4 -yl group , a 2 ,6 -dimethoxypyrimidin - 4 - yl 5 [ 1 - 11a - 3 ] group , a 2 -methylpyrimidin - 4 - yl group , a 2 -methoxypyrimi - More preferably , the compound of the above embodiment din - 4 - yl group , a 5 ,6 - dimethylpyrimidin - 4 - yl group , a [ 1 - 11a ] is a compound represented by the above formula 5 -chloro - 2 -methylpyrimidin - 4 - yl group , a 5 - chloropyrimi ( I - d ) wherein Rº has the same definitions as those described in the above embodiment [ 1 - 3 - 2 ] ; R4 has the same defini din - 4 - yl group, a 5 - fluoro - 2 -methylpyrimidin - 4 - yl group , a 10 tions as those described in the above embodiment [ 1 - 4 - 2 ] ; Z 5 - fluoro - 2 -methoxypyrimidin - 4 - yl group , a 5 - fluoro -6 and R have the same definitions as those described in the methylpyrimidin - 4 -yl group , a 5 -methylpyrimidin - 4 -yl above embodiment [ 1 - 5 - 2 ] ; q has the same definitions as group , a 5 -methoxypyrimidin - 4 -yl group , a 6 -methylpyrimi those described in the above embodiment [1 - 7 - 2 ); p , R ' , and din - 4 - yl group , a 6 -methoxy - 5 -methylpyrimidin - 4 - yl group , ring A " represented by the partial structural formula ( II " ) a 4 -methylpyridazin - 3 - yl group , a 5 -methylpyridazin - 3 - yl 15 have the same definitions as those described in the above group , a 6 -methylpyridazin - 3 - yl group , a pyridazin - 3 - yl embodiment [ 1 - 11- 3 ]; and R² represents a C1- 6 alkyl group group , a 3 - cyanopyridin - 2 - yl group , a 3 -methoxypyridin - 2 - or a halogenated C . alkyl group , or a pharmaceutically yl group , a 4 , 6 - dimethylpyridin - 2 - yl group , a 4 - fluoropyri acceptable salt thereof, or a solvate thereof. din - 2- yl group , a 4 -methylpyridin - 2 - yl group , a 4 -methoxy - [ 1- 11a -4 ] pyridin -2 - yl group , a 5 -cyanopyridin - 2 -yl group , a 20 Even more preferably , the compound of the above 5 - fluoropyridin - 2 -yl group , a 5 -methylpyridin - 2 -yl group , a embodiment [ 1 - 11a ] is a compound represented by the 6 - ( trifluoromethyl) pyridin - 2 - yl group , a 6 -methylpyridin - 2 - above formula ( I - d ) wherein R has the same definitions as yl group , a 3, 6 -dimethyl - pyrazin - 2- yl group , a 3- methyl - those described in the above embodiment [ 1 -3 - 3 ); R + has the pyrazin - 2 - yl group , a 3 -methoxypyrazin - 2 - yl group , a same definitions as those described in the above embodi 5 -methylpyrazin - 2 -yl group , a 6 -methylpyrazin - 2 - yl group , 25 ment [ 1 -4 -3 ]; Z and R have the same definitions as those or a 6 -methoxypyrazin - 2 - yl group , or a pharmaceutically described in the above embodiment ( 1 - 5 - 3 ) ; q has the same acceptable salt thereof, or a solvate thereof. definitions as those described in the above embodiment [ 1 - 11a ] [ 1 - 7 - 3 ); p , R ', and ring A " represented by the partial The compound of the above embodiment [ 1 ] represented structural formula (II " ) have the same definitions as those by the above formula (I ) is preferably a compound repre - 30 described in the above embodiment [ 1 - 11 -4 -2 ) ; and R ? sented by the following formula ( I - d ) : represents a C1- 6 alkyl group , or a pharmaceutically accept able salt thereof, or a solvate thereof. [ 1 - 11a - 5 ] [Formula 73 ] Particularly preferably , the compound of the above ( - d ) 35 embodiment [ 1 - 11a ] is a compound represented by the above formula ( I - d ) wherein R has the same definitions as those described in the above embodiment ( 1 - 3 - 41; Z and R R4 N — N have the same definitions as those described in the above N embodiment ( 1 - 5 -41 ; q has the same definitions as those 40 described in the above embodiment [ 1 - 7 - 4 ) ; p , R ' , and ring 9R317 A " represented by the partial structural formula ( II " ) have the same definitions as those described in the above embodi ment [ 1 - 11 - 5 - 2 ] ; R² represents a C - alkyl group , and more A " specifically , R ? represents a methyl group or the like ; and R4 45 represents a C6 - 14 aryl group , a 3 - to 14 -membered non ( R ) , aromatic heterocyclic group , or a 5 - to 7 -membered mono cyclic heteroaryl group wherein the C6- 14 aryl group , the 3 wherein the definition of q , Z , Rº, R4 , and R in the formula to 14 -membered non -aromatic heterocyclic group , and the ( I- d ) have the same definitions as those described in the 5 - to 7 -membered monocyclic heteroaryl group, which are above embodiment [ 1 ]; p , Rº, and ring A " represented by the 50 represented by R + , are each optionally substituted with one partial structural formula (II " ) have the same definitions as or two halogen atoms, C - , alkyl groups, or halogenated C1 - 6 those described in the above embodiment [ 1 - 11 ] ; and R alkyl groups, and specifically, R + represents phenyl, 2 -meth represents a C1- 6 alkyl group , a halogenated C1- 6 alkyl ylphenyl, 3 -methylphenyl , 4 -methylphenyl , 2 ,5 - dimethyl group , a hydroxy C1- 6 alkyl group , or a C1- 6 alkoxyl C1- 6 phenyl , 2 - fluorophenyl, 3 - fluorophenyl, 4 - fluorophenyl, 2 ,5 alkyl group , or a pharmaceutically acceptable salt thereof, or 55 difluorophenyl, pyrrolidinyl, 2 -fluoropyrrolidinyl , a solvate thereof. 3 - fluoropyrrolidinyl, 2 -methylpyrrolidinyl , 3 -methylpyrro [ 1 - 11a - 2 ] lidinyl , 2 - trifluoromethylpyrrolidinyl , 3 - trifluoromethylpyr Preferably , the compound of the above embodiment rolidinyl, 2 -pyridinyl , 3 - pyridinyl, 2 - pyridinyl, or the like , [ 1 - 11a) is a compound represented by the above formula and R4 preferably represents phenyl, 2 -methylphenyl , ( 1 - d ) wherein R has the same definitions as those described 60 4 - fluorophenyl, pyrrolidinyl, 2 -methylpyrrolidinyl , 3 - fluo in the above embodiment [1 - 3] ; R4 has the same definitions ropyrrolidinyl, 2- trifluoromethylpyrrolidinyl, or 3 -pyridinyl , as those described in the above embodiment [ 1 -4 ]; Z and RS or a pharmaceutically acceptable salt thereof, or a solvate have the same definitions as those described in the above thereof. embodiment [ 1- 5 ]; q has the same definitions as those [1 - 11a -6 ] described in the above embodiment [ 1 - 7 ); p , R ', and ring A " 65 More particularly preferably , the compound of the above represented by the partial structural formula ( II" ) have the embodiment [ 1 - 11a ] is a compound represented by the same definitions as those described in the above embodi- above formula ( I - d ) wherein the definition of p , q , Z , R1, R2, US 9 ,777 , 000 B2 99 100 R3, R4, RS, and ring A " in the formula ( I - d ) have the same 6 - ( trifluoromethyl) pyridin - 2 -yl group , a 6 -methylpyridin - 2 definitions as those described in the above embodiment yl group , a 3 ,6 - dimethyl- pyrazin - 2 - yl group , a 3 -methyl [ 1 - 11a - 5 ) ; and a specific ring A " group , in which the pyrazin - 2 - yl group , a 3 -methoxypyrazin - 2 - yl group , a definitions of the above described p , and ring A " are com - 5 -methylpyrazin - 2 -yl group , a 6 -methylpyrazin -2 -yl group , bined , represents a 4 , 6 - dimethylpyrimidin - 2 - yl group , a 5 or a 6 -methoxypyrazin - 2 - yl group , or a pharmaceutically 4 -methylpyrimidin - 2 - yl group , a 2 , 5 , 6 - trimethylpyrimidin acceptable salt thereof, or a solvate thereof. 4 - yl group , a 2 , 5 - dimethylpyrimidin - 4 - yl group , a 2 ,6 - dim - [ 1 - 12 ] ethylpyrimidin - 4 - yl group, a 2 ,6 - dimethoxypyrimidin - 4 - yl As described above, the embodiments [ 1 - 1 ] to [ 1 - 11a - 6 ] group , a 2 -methylpyrimidin - 4 -yl group , a 2 -methoxypyrimi - of the present invention , the preferred embodiments thereof, din - 4 - yl group , a 5 ,6 - dimethylpyrimidin - 4 - yl group , a 10 and further, definitions of substituents are appropriately 5 - chloro - 2 -methylpyrimidin - 4 -yl group , a 5 - chloropyrimi- combined , so that preferred embodiments of the compound din -4 -yl group , a 5 - fluoro - 2 -methylpyrimidin -4 -yl group , a of the above embodiment [ 1 ] represented by the above 5 - fluoro - 2 -methoxypyrimidin -4 -yl group , a 5 - fluoro -6 - formula (1 ) can be arbitrarily formed . methylpyrimidin - 4 -yl group , a 5 -methylpyrimidin - 4 -yl [ 2 ] group , a 5 -methoxypyrimidin - 4 -yl group , a 6 -methylpyrimi - 15 A second embodiment of the present invention is illus din -4 - yl group , a 6 -methoxy - 5 -methylpyrimidin - 4 - yl group , trated , by way of example , with the below - listed compounds a 4 -methylpyridazin - 3 - yl group , a 5 -methylpyridazin - 3 - yl that are preferable as the compounds of the above embodi group , a 6 -methylpyridazin - 3 - yl group , a pyridazin - 3 - yl ment [ 1 ] represented by the above formula ( I ) , or pharma group , a 3 - cyanopyridin - 2 - yl group , a 3 -methoxypyridin - 2 ceutically acceptable salts thereof, or their solvates, or their yl group , a 4 , 6 -dimethylpyridin - 2 - yl group , a 4 - fluoropyri - 20 optical isomers . It is to be noted that the following com din - 2 - yl group , a 4 -methylpyridin - 2 - yl group , a 4 -methoxy - pound names are based on English names obtained in pyridin - 2 - yl group , a 5 -cyanopyridin - 2 -yl group , a accordance with the chemical nomenclature program of 5 - fluoropyridin - 2 -yl group , a 5 -methylpyridin - 2 -yl group , a Cambridge Soft Chem BioDraw Ultra 12 . 0 . 2 .1076 . TABLE 1 Compound name Example No. 1 -methyl - 4 - ( 5 -methylpyridin - 2 - yl ) - N - ( 2 - phenylimidazo [ 1 , 2 - a ]pyridin 1 . 1 7 -yl ) - 1 H -pyrazole - 5 - carboxamide J 1 -methyl - 4 - ( 4 -methylthiazol - 2 -yl ) - N - ( 2- phenylimidazo [ 1 , 2 -a ]pyridin 1 . 2 7 -yl )- 1H -pyrazole - 5 -carboxamide ? 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl) - 1 -methyl - N - ( 2 -phenylimidazo [ 1 , 2 1 . 3 a ]pyridin - 7 -yl ) - 1H - pyrazole - 5 -carboxamide 4 - ( 4 - (difluoromethyl ) -5 -methylthiazol - 2 - yl) - 1 -methyl - N - ( 2 1 . 4 phenylimidazo [ 1 , 2 - a ]pyridin - 7 - yl ) - 1H -pyrazole - 5 - carboxamide 1 -methyl - N - ( 2 - phenylimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 4 - ( 4 1 . 5 ( trifluoromethyl ) thiazol- 2 - yl) - 1H -pyrazole - 5 - carboxamide 1 -methyl - N - ( 2 -phenylimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 4 - ( 6 1 . 6 (trifluoromethyl )pyridin - 2 - yl) - 1H -pyrazole - 5 - carboxamide 4 - ( 5 - chloro - 4 - (difluoromethyl ) thiazol- 2 - yl) - 1 -methyl - N - ( 2 1 . 7 phenylimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H - pyrazole - 5 - carboxamide 1 -methyl - 4 - ( 4 -methylthiazol - 2 - yl) - N - ( 2 - phenyl - 5 , 6 , 7 , 8 2 . 1 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 -carboxamide 4 - ( 4 , 5 - dimethylthiazol- 2 - yl) - 1 -methyl - N - ( 2 - phenyl- 5 ,6 , 7 , 8 2. 2 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 -carboxamide 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) & 4 - ( 4 - ( trifluoromethyl) thiazol - 2 - yl) - 1 H -pyrazole - 5 - carboxamide 4 - ( 4 - ( difluoromethyl) thiazol- 2 - yl) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 4 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 - carboxamide 4 - ( 5 -chloro - 4 - (difluoromethyl ) thiazol- 2 - yl ) - 1 -methyl - N - ( 2 -phenyl 2 . 5 5 ,6 , 7 ,8 - tetrahydroimidazo [ 1 ,2 - a ]pyridin - 7 -yl ) -1H -pyrazole -5 carboxamide 4 - ( 4 - (difluoromethyl ) - 5 -methylthiazol - 2 - yl) - 1 -methyl - N - ( 2 -phenyl 2 . 6 5 ,6 ,7 ,8 -tetrahydroimidazo [1 ,2 -a ]pyridin - 7 - yl )- 1H -pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) - 5 -methylthiazol - 2 - yl) - N - ( 2 - ( 3 - fluorophenyl) 2 . 7 5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1 -methyl - 1 H -pyrazole 5 - carboxamide N - ( 2 - ( 3 - fluorophenyl) - 5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) 2 . 8 1 -methyl - 4 - ( 4 - ( trifluoromethyl) thiazol- 2 -yl ) -1H -pyrazole - 5 carboxamide 1 -methyl - 4 - ( 6 -methylpyridin - 2 -yl ) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 9 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 -carboxamide 1 -methyl - 4 - ( 5 -methyl - 1 , 3 , 4 - thiadiazol- 2 -yl ) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 10 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 - carboxamide 4 - ( 6 -methoxypyridin - 2 -yl ) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 11 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl )- 1H -pyrazole - 5 -carboxamide 1 -methyl - 4 - ( 2 -methylthiazol - 4 -yl )- N -( 2 -phenyl - 5 ,6 , 7 , 8 2 . 12 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 -carboxamide 1 -methyl - 4 - ( 6 -methylpyrazin - 2- yl) - N - ( 2 -phenyl -5 , 6, 7 ,8 2 . 13 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1 H -pyrazole - 5 - carboxamide 4 - ( 3- isopropyl- 1 ,2 , 4 -thiadiazol - 5 -yl ) - 1 -methyl - N - ( 2- phenyl - 5 ,6 , 7 , 8 2 .14 tetrahydroimidazo [ 1 ,2 - a ]pyridin - 7 -yl ) - 1 H -pyrazole -5 - carboxamide 1 -methyl - 4 - ( 5 -methylthiazol - 2 - yl) - N - ( 2 - phenyl - 5 , 6 , 7 , 8 2 . 15 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1H -pyrazole - 5 -carboxamide US 9 ,777 ,000 B2 101 102 TABLE 1 - continued Compound name Example No. 1 -methyl - 4 - ( 4 -methylpyrimidin - 2 - yl) - N - ( 2 - phenyl - 5 , 6 , 7 , 8 2 . 16 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 -carboxamide 1 -methyl - 4 - ( 1 -methyl - 1H - imidazol- 4 - yl ) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 17 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 -carboxamide N - ( 2 - ( 2 , 5 -difluorophenyl ) -5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 ,2 - a ]pyridin - 7 2 . 18 yl) - 1 -methyl - 4- ( 5 -methyl - 1 , 3 , 4 - thiadiazol- 2 -yl ) - 1 H -pyrazole - 5 carboxamide N - ( 3 - fluoro - 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1 2 . 19 methyl - 4 - ( 4 - ( trifluoromethyl) thiazol- 2 -yl ) - 1H -pyrazole - 5 -carboxamide 4 -( 4 -( difluoromethyl ) thiazol- 2 -yl ) - N -( 2 -( 3 - fluorophenyl )- 5 , 6 ,7 ,8 2 .20 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide 1 -methyl - 4 - ( 5 -methylpyridin - 2 - yl) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 21 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl ) - 1H -pyrazole - 5 -carboxamide 1 -methyl - 4 - ( 4 -methylpyridin - 2 - yl) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 2 . 22 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H - pyrazole - 5 -carboxamide N - ( 2 -( 3 - fluorophenyl) - 5 , 6 , 7 , 8 -tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl ) 2 .23 1 -methyl - 4 - (4 -methylpyrimidin - 2 - yl ) - 1H - pyrazole - 5 - carboxamide N -( 2 -( 3 - fluorophenyl) - 5 , 6, 7 , 8 -tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl ) 2 . 24 1 -methyl - 4 - ( 6 -methylpyrazin - 2 - yl) - 1H - pyrazole - 5 - carboxamide 1 -methyl - N - ( 2 - phenyl- 5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) 2 . 25 4 - ( thiazol - 4 - yl) - 1H -pyrazole - 5 - carboxamide 1 -methyl - N - ( 2 - phenyl -5 ,6 , 7 , 8 - tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) 2 . 26 4 - ( thiazol - 2 - yl) - 1 H - pyrazole - 5 - carboxamide 4 - ( 4 - ( tert- butyl )thiazol - 2 - yl) - 1 -methyl - N - ( 2 - phenyl- 5 , 6 , 7 , 8 2 . 27 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 - yl) - 1H - pyrazole - 5 -carboxamide 4 -( 4 - (difluoromethyl ) thiazol- 2 - yl) - N -( 2 -( 4 - fluorophenyl) - 5 ,6 , 7 ,8 2 . 28 tetrahydroimidazo [ 1 , 2 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide N - ( 2 - ( 4 - fluorophenyl) - 5 , 6 , 7 , 8 - tetrahydroimidazo [ 1 ,2 - a ]pyridin - 7 -yl ) 2 . 29 1 -methyl - 4 - (4 - ( trifluoromethyl) thiazol - 2 - yl )- 1H -pyrazole - 5 carboxamide N - (6 - fluoro - 2 -phenyl - [1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 1 ( 3 -methylpyridin - 2 -yl ) - 1H -pyrazole - 5 -carboxamide N - ( 6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 2 ( 5 -methylpyrazin - 2 - yl) - 1 H -pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 3 (6 -methylpyridin - 2 - yl ) - 1H - pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl )- 4 - ( 4 3 . 4 fluoropyridin - 2 - yl) - 1 -methyl - 1 H - pyrazole - 5 - carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3 . 5 (4 -methylpyridin - 2 -yl ) - 1H -pyrazole -5 -carboxamide N - ( 6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 una3 .6 ( 4 - ( trifluoromethyl) thiazol- 2 -yl ) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 4 - ( 3 3 . 7 methoxypyridin - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 - carboxamide N - ( 6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 4 - ( 5 3 . 8 fluoropyridin - 2 - yl ) - 1 -methyl - 1 H -pyrazole - 5 - carboxamide N - ( 6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 9 ( 6 -methylpyrazin - 2 - yl) - 1H -pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3 . 10 ( 6 - (trifluoromethyl ) pyridin - 2 -yl ) - 1H -pyrazole - 5 -carboxamide 4 - ( 4 , 6 -dimethylpyridin - 2 -yl ) - N - ( 6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ] triazolo [ 1 , 5 3 . 11 a ]pyridin - 7 - yl) - 1 -methyl - 1H -pyrazole - 5 - carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 -yl ) - N - (6 - fluoro - 2 -phenyl 3 . 12 [ 1 , 2, 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 methyl- - 1H - pyrazole - 5 carboxamide 4 - ( 3 - cyanopyridin - 2 - yl) - N - 6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 3 . 13 a ]pyridin - 7 - yl )- 1 -methyl - 1H -pyrazole -5 - carboxamide 4 - ( 3 , 6 - dimethyl- pyrazin - 2 - yl ) - N - ( 6 - fluoro - 2 -phenyl 3 . 14 [ 1, 2 ,4 ] triazolo [ 1 ,5 - a )pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl ) - 1 -methyl - N - ( 2 -phenyl 3 . 15 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1H -pyrazole - 5 -carboxamide 4 - (4 - (difluoromethyl ) thiazol- 2 - yl )- N - (2 - ( 2 -methoxyphenyl ) 3 . 16 [ 1 , 2 , 4 ]triazolo [ 1 , 5 -a ]pyridin - 7 - yl )- 1 -methyl - 1H - pyrazole - 5 carboxamide 4- ( 4 - (difluoromethyl ) thiazol- 2 - yl )- N - ( 2 - (3 - fluorophenyl ) 3 . 17 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 4 - ethylthiazol- 2- yl ) - 1 -methyl - N -( 2 -phenyl - [ 1 ,2 ,4 ] triazolo [ 1 ,5 3 . 18 a ]pyridin - 7 -yl ) - 1H -pyrazole -5 -carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl) - N - ( 2 - ( ( 2S ,6R ) - 2 , 6 3 . 19 dimethylmorpholino )- [1 ,2 ,4 ] triazolo [ 1, 5 - a ]pyridin - 7- yl ) -1 -methyl - 1 H pyrazole - 5 -carboxamide 4 - ( 5 - chloro - 4 - ( difluoromethyl) thiazol- 2 - yl) - 1 -methyl - N - ( 2 - phenyl 3 . 20 [ 1 , 2, 4 ]triazolo [ 1, 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole - 5 -carboxamide US 9 ,777 ,000 B2 103 104 TABLE 1- continued Compound name Example No . N - (5 - chloro - 2 - ( 2 -methoxyphenyl ) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) 3 . 21 4 - ( 5 -chloro - 4 - (difluoromethyl ) thiazol- 2 -yl )- 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 2 , 5 -dimethylpyrimidin - 4 -yl ) - N - ( 6 - fluoro - 2 -phenyl 3 .22 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H - pyrazole - 5 carboxamide 4 - (5 - cyanopyridin - 2 - yl) - N - ( 6 -fluoro - 2 -phenyl - [1 , 2 , 4 ]triazolo [ 1 , 5 3 . 23 a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 -carboxamide N - (6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ]triazolo [ 1 , 5 -a ) pyridin - 7 - yl) - 1 -methyl - 4 3 . 24 ( 4 -methylpyridazin - 3 - yl) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl ) - 1 -methyl - 4 3 . 25 ( 2 -methylpyrimidin - 4 - yl) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 4 - ( 2 3 . 26 methoxypyrimidin -4 -yl ) - 1 -methyl - 1 H -pyrazole - 5 - carboxamide 4 - ( 5 - fluoro - 2 -methoxypyrimidin - 4 - yl ) - N - ( 6 - fluoro - 2 -phenyl 3 . 27 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H -pyrazole - 5 carboxamide N - ( 6 - fluoro - 2 -phenyl - [ 1 , 2 ,4 ] triazolo [ 1 ,5 - a ) pyridin - 7 - yl) - 4 -( 3 3 . 28 methoxypyrazin - 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 - carboxamide 4 - ( 5 -chloropyrimidin - 4 - yl) - N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 3 .29 a ]pyridin - 7 - yl ) - 1 -methyl - 1H -pyrazole - 5 - carboxamide 4 - ( 2 , 6 - dimethylpyrimidin - 4 -yl ) - N - ( 6 - fluoro - 2 - phenyl 3 . 30 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H -pyrazole - 5 carboxamide N - ( 6 - fluoro - 2 -phenyl - [ 1 , 2, 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 4 - ( 6 -methoxy 3 . 31 5 -methylpyrimidin -4 - yl) -1 -methyl - 1H -pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3 . 32 ( 3 -methylpyrazin - 2 - yl ) - 1 H -pyrazole - 5 -carboxamide N -( 6 - fluoro - 2- phenyl - [ 1 , 2, 4 ]triazolo [1 ,5 -a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 33 ( 5 -methylpyrimidin - 4 - yl) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro- 2- phenyl- [ 1, 2 ,4 ]triazolo [1 , 5 -a ]pyridin - 7 - yl) - 4 -( 5 3 . 34 methoxypyrimidin - 4 - yl) - 1 -methyl - 1 H -pyrazole - 5 -carboxamide 4 - ( 5 , 6 -dimethylpyrimidin - 4 -yl ) - N - (6 - fluoro - 2 -phenyl 3 . 35 [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole -5 carboxamide 4 - ( 5 - fluoro - 2 -methylpyrimidin - 4 -yl ) - N - ( 6 - fluoro - 2 - phenyl 3 . 36 [1 , 2 ,4 ]triazolo [ 1 , 5- a ]pyridin - 7 - yl )- 1 -methyl - 1H -pyrazole - 5 carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3 . 37 ( 2 , 5 , 6 - trimethylpyrimidin - 4 - yl) - 1 H -pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 4 - ( 5 - fluoro - 6 3 .38 methylpyrimidin - 4 -yl ) - 1 -methyl - 1 H -pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 39 ( 6 -methylpyrimidin - 4 - yl) - 1H -pyrazole - 5 - carboxamide 4 - ( 2 , 6 -dimethoxypyrimidin - 4 - yl) - N - ( 6 - fluoro - 2 -phenyl 3 . 40 [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 5 - chloro - 2 -methylpyrimidin - 4 - yl) - N - ( 6 - fluoro - 2 -phenyl 3 .41 [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 4 - ( 6 3 . 42 methoxypyrazin - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 - carboxamide N - ( 6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 4 3 . 43 (4 -methylpyrimidin -2 -yl ) - 1H -pyrazole -5 -carboxamide 4 - ( 4 , 6 -dimethylpyrimidin - 2 -yl ) - N - ( 6 - fluoro - 2 -phenyl 3 .44 [ 1 , 2, 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 methyl- - 1H - pyrazole - 5 carboxamide N - (6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ] pyridin - 7 - yl) - 1 -methyl - 4 3 .45 ( 6 -methylpyridazin - 3 - yl) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro - 2 - phenyl- [ 1 , 2 , 4 ]triazolo [ 1 , 5 -a ) pyridin - 7 - yl) - 1 -methyl - 4 3 . 46 ( 5 -methylpyridazin - 3 - yl) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3 .47 (pyridazin - 3 - yl) - 1H -pyrazole - 5 - carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ] triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3 . 48 ( 1 - methyl- 1H - imidazol- 4 - yl) - 1H -pyrazole - 5 - carboxamide 4 - ( 2 ,5 - dimethylpyrimidin - 4 - yl) - N - ( 6 - fluoro - 2 - (pyridin - 3 - yl) 3 . 49 [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a )pyridin - 7 -yl ) - 1 -methyl -1H -pyrazole - 5 carboxamide 4 - ( 2 , 5 -dimethylpyrimidin - 4 -yl ) - N - ( 6 - fluoro - 2 - ( o - tolyl) 3 . 50 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H -pyrazole - 5 carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 3. 51 ( 5 -methylpyridin - 2 - yl) - 1H - pyrazole - 5 -carboxamide N - (6 - fluoro - 2 -phenyl - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 4 - ( 4 3 .52 methoxypyridin - 2 - yl) - 1 -methyl - 1H - pyrazole - 5 -carboxamide 4 - (4 ,6 -dimethylpyridin - 2 -yl ) - N -( 6 - fluoro - 2 - phenyl- [1 ,2 ,4 ]triazolo [ 1, 5 3 .53 a )pyridin - 7 - yl ) - 1 -methyl - 1H -pyrazole - 5 - carboxamide US 9 ,777 ,000 B2 105 106 TABLE 1 - continued Compound name Example No . 4 - ( 4 ,6 - dimethylpyridin - 2 - yl ) - N - ( 6 - fluoro - 2 - ( 4 - fluorophenyl) 3 . 54 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H - pyrazole - 5 carboxamide ( S ) -4 - ( 4 - ( difluoromethyl )thiazol - 2 -yl ) - 1 -methyl - N - ( 2 - ( 2 methylpyrrolidin - 1- yl) - [ 1 , 2 , 4 ] triazolo [1 , 5 -a ]pyridin -7 - yl ) - 1 H -pyrazole 5 -carboxamide ( S ) - 4 - ( 5 - chloro - 4 - (difluoromethyl ) thiazol- 2 - yl) - 1 -methyl - N - ( 2 - ( 2 4 . 2 methylpyrrolidin - 1 -yl ) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole 5 -carboxamide ( S ) - 1 -methyl - N - ( 2 - ( 2 -methylpyrrolidin - 1 - yl ) - [ 1 , 2 , 4 ]triazolo [ 1 , 5 4 . 3 a ]pyridin - 7 - yl )- 4 - ( 6 - ( trifluoromethyl) pyridin - 2 - yl )- 1H -pyrazole - 5 carboxamide (S )- 1 -methyl - 4 - (4 -methylpyridin - 2 -yl )- N - (2 - (2 - methylpyrrolidin - 1 -yl ) 4 . 4 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 - carboxamide ( S ) - 4 - ( 4 -methoxypyridin - 2 -yl ) - 1 -methyl - N - ( 2 - ( 2 -methylpyrrolidin - 1 45 yl) - [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl ) - 1 H -pyrazole - 5 -carboxamide ( S ) - 1 -methyl - 4 - ( 6 -methylpyrazin - 2 - yl) - N - ( 2 - ( 2 -methylpyrrolidin - 1 4 . 6 yl) - [ 1 , 2 ,4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 - carboxamide ( S ) - 1- methyl - 4 -( 6 -methylpyridin - 2 -yl ) - N -( 2 - ( 2 -methylpyrrolidin - 1- yl ) 4 . 7 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 -carboxamide ( S ) - 4 - ( 4 , 6 - dimethylpyridin - 2 - yl) - 1 -methyl - N - ( 2 - ( 2 -methylpyrrolidin - 1 4 . 8 yl) - [ 1 , 2 , 4 ] triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 - carboxamide ( S ) - 4 - ( 4 - (difluoromethyl ) - 5 -methylthiazol - 2 - yl) - 1 -methyl - N - ( 2 - ( 2 4 . 9 methylpyrrolidin - 1 - yl) - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole 5 -carboxamide ( S )- 1 -methyl - N -( 2 - ( 2- methylpyrrolidin - 1 - yl )- [ 1, 2 ,4 ]triazolo [ 1 ,5 4 . 10 a ]pyridin -7 - yl) -4 - ( 4 - ( trifluoromethyl )thiazol - 2 - yl) - 1H -pyrazole - 5 carboxamide ( R ) - N - ( 6 - fluoro - 2 - (2trifluoromethyl ) pyrrolidin - 1 -yl ) 4 . 11 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 4 - ( 6 -methylpyridin - 2 - yl) 1 H -pyrazole - 5 - carboxamide ( R ) - 4 - ( 4 -( difluoromethyl )thiazol - 2 -yl ) - N -( 2 -( 3 - fluoropyrrolidin- 1 -yl ) 4 . 12 [ 1 , 2, 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 methyl- - 1H - pyrazole - 5 carboxamide ( R ) - N -( 2 - (3 - fluoropyrrolidin - 1 - yl )- [ 1, 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) 4 . 13 1 -methyl - 4 - ( 4 - ( trifluoromethyl) thiazol - 2 -yl ) - 1H -pyrazole - 5 carboxamide ( R ) - 4 - ( 4 - (difluoromethyl ) - 5 -methylthiazol - 2 - yl) - N - ( 2 - ( 3 4 . 14 fluoropyrrolidin - 1 -yl ) - [ 1, 2 ,4 ] triazolo [ 1 ,5 -a ]pyridin - 7 -yl ) - 1 -methyl - 1H pyrazole - 5 -carboxamide ( S ) - 4 - ( 4 - (difluoromethyl ) thiazol - 2 -yl ) - N - ( 2 - ( 3- fluoropyrrolidin - 1 - yl ) 4 . 15 [1 , 2 , 4 ]triazolo [1 ,5 -a ] pyridin - 7- yl ) - 1- methyl - 1H -pyrazole -5 carboxamide ( S ) - N - ( 2 - ( 3 - fluoropyrrolidin - 1 - yl) - [ 1 , 2 , 4 ] triazolo [ 1 ,5 - a ] pyridin - 7 - yl ) 4 . 16 1 -methyl - 4 - (6 - ( trifluoromethyl) pyridin - 2 -yl ) - 1H - pyrazole - 5 carboxamide ( S ) - N - ( 2 -( 3 - fluoropyrrolidin - 1 -yl ) - [ 1 , 2 , 4 ] triazolo [ 1 ,5 - a ]pyridin - 7 - yl) 4 . 17 1 -methyl - 4 - ( 4 -methylpyridin - 2 - yl) - 1H - pyrazole - 5 -carboxamide ( S ) - N - ( 2 - ( 3 - fluoropyrrolidin - 1 -yl ) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) 4 . 18 4 - ( 4 -methoxypyridin - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 -carboxamide ( S ) - N - ( 2 - ( 3 - fluoropyrrolidin - 1 - yl) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) 4 . 19 1 -methyl - 4 - ( 6 -methylpyrazin - 2 - yl) - 1 H -pyrazole - 5 - carboxamide ( S ) - 4 - ( 4 , 6 -dimethylpyridin - 2 - yl) - N - ( 2 - ( 3 - fluoropyrrolidin - 1 -yl ) 4 . 20 [ 1 ,2 ,4 ]triazolo [1 , 5 - a ]pyridin -7 - yl )- 1 -methyl - 1H -pyrazole - 5 carboxamide (S )- N - ( 2 - (3 - fluoropyrrolidin - 1- yl )- [ 1 ,2 ,4 ] triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) 4 . 21 1 -methyl - 4 - ( 6 -methylpyridin - 2 - yl) - 1H -pyrazole - 5 - carboxamide ( S ) - N - ( 2 - ( 3 - fluoropyrrolidin - 1 -yl ) - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) 4 . 22 1 -methyl - 4 - ( 4 - ( trifluoromethyl) thiazol - 2 - yl) - 1H -pyrazole - 5 carboxamide ( S ) - 4 - ( 4 - (difluoromethyl ) - 5 -methylthiazol - 2 - yl) - N - ( 2 - ( 3 4 . 23 fluoropyrrolidin - 1- yl ) - [ 1 , 2 ,4 ] triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) - 1- methyl -1H pyrazole - 5 -carboxamide ( S ) - 4 - ( 4 ,6dimethylpyridin - 2 - yl) - N - ( 6 - fluoro - 2 - ( 3 - fluoropyrrolidin - 1 4 . 24 yl ) - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl )- 1 -methyl -1H - pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl) - 1 -methyl - N - ( 2 - (pyrrolidin - 1 - yl ) 4 . 25 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1H -pyrazole -5 -carboxamide 4 - ( 5 - chloro - 4 - ( difluoromethyl) thiazol- 2 -yl ) - 1 -methyl - N - ( 2 - (pyrrolidin 4 . 26 1 - yl) - [ 1 , 2 , 4 ] triazolo [ 1 ,5 - a ]pyridin - 7 - yl ) - 1 H -pyrazole - 5 -carboxamide 1 -methyl - N - ( 2 - (pyrrolidin - 1 - yl) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 4 4 . 27 ( 6 - ( trifluoromethyl) pyridin - 2 - yl) - 1H - pyrazole - 5 - carboxamide 4 - ( 4 -methoxypyridin - 2 -yl ) - 1 -methyl - N - ( 2 - (pyrrolidin - 1 - yl ) 4 .28 [ 1 , 2, 4 ] triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 - carboxamide 1 -methyl - 4 - ( 6 -methylpyrazin - 2 - yl) - N - ( 2 - (pyrrolidin - 1 - yl) 4 .29 [1 , 2 ,4 ]triazolo [ 1 , 5- a ]pyridin - 7 - yl )- 1 H -pyrazole - 5 - carboxamide 1 -methyl - 4 - ( 4 -methylpyridin - 2 - yl ) - N - ( 2 - (pyrrolidin - 1 - yl) 4 . 30 [ 1 ,2 , 4 ] triazolo [ 1 , 5 - a ]pyridin -7 - yl) - 1H -pyrazole -5 -carboxamide US 9 ,777 ,000 B2 107 108 TABLE 1- continued Compound name Example No . 1 -methyl - 4 - ( 6 -methylpyridin - 2 - yl) - N - ( 2 - (pyrrolidin - 1 - yl) 4 .31 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1H -pyrazole - 5 -carboxamide 4 - ( 4 , 6 - dimethylpyridin - 2 - yl) - 1 -methyl - N - ( 2 - (pyrrolidin - 1 -yl ) 4 .32 [ 1 , 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 - yl ) - 1 H -pyrazole - 5 -carboxamide 4 - ( 4 - ( difluoromethyl) - 5 - methylthiazol- 2 - yl) - 1 -methyl - N - ( 2 4 . 33 (pyrrolidin - 1 - yl) -[ 1 ,2 ,4 ]triazolo [ 1 ,5 - a ]pyridin -7 -yl ) - 1 H -pyrazole - 5 carboxamide 1 -methyl - N - ( 2 - (pyrrolidin - 1 - yl) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 4 4 . 34 ( 4 - ( trifluoromethyl) thiazol- 2 - yl) - 1H -pyrazole - 5 -carboxamide 4 -( 2 ,5 - dimethylpyrimidin -4 - yl) -N -( 6 -fluoro -2 - (pyrrolidin -1 -yl ) 4 . 35 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1 H -pyrazole - 5 carboxamide 4 - ( 5 -chloro - 4 - ( difluoromethyl )thiazol - 2 - yl) - N - ( 2 - [ (2S ,6R ) - 2 , 6 4 . 36 dimethylmorpholino ) - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl ) - 1 -methyl - 1H pyrazole - 5 -carboxamide 4 - ( 4 - ( difluoromethyl ) - 5 -methylthiazol - 2 - yl) - 1 -methyl - N - ( 2 -phenyl 5 . 1 5 ,6 , 7 , 8 - tetrahydro - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 -yl ) - N - ( 2 - ( 4 - fluorophenyl) - 5 , 6 , 7 , 8 5 . 2 tetrahydro - [ 1, 2 , 4 ]triazolo [ 1 , 5 -a ]pyridin - 7 - yl )- 1- methyl - 1 H -pyrazole - 5 carboxamideomide 4 - ( 5 -chloro - 4 - ( difluoromethyl ) thiazol- 2 - yl) - N - ( 2 - ( 4 - fluorophenyl) 5 . 3 5 , 6 , 7 , 8 - tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H pyrazole - 5 -carboxamide 4 -( 4 ,5 -dimethylthiazol - 2 -yl ) - 1- methyl - N -( 2 -phenyl - 5 ,6 , 7, 8 -tetrahydro 5 . 4 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1H -pyrazole - 5 -carboxamide 4 - ( 4 - (difluoromethyl ) - 5 - vinylthiazol- 2 -yl ) - 1 -methyl - N - ( 2 -phenyl 5 . 5 5 , 6 , 7 , 8 - tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole - 5 carboxamide 4 - ( 4 - ( difluoromethyl) - 5 - ethylthiazol- 2 -yl ) - 1 -methyl - N - ( 2 -phenyl 5 . 6 5 , 6, 7 , 8 - tetrahydro - [ 1, 2 ,4 ] triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 carboxamide 4 - ( 5 -bromo - 4 -methylthiazol - 2 -yl ) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 5 . 7 tetrahydro - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl ) -1H -pyrazole - 5 carboxamide 4 - ( 5 -cyclopropyl - 4 - ( difluoromethyl ) thiazol- 2 - yl) - 1 -methyl - N - ( 2 5 . 8 phenyl- 5 ,6 ,7 , 8 -tetrahydro - [ 1, 2 , 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) - 1H pyrazole - 5 - carboxamide 1 -methyl - N - ( 2 -phenyl - 5 ,6 , 7 , 8 - tetrahydro - [ 1 ,2 , 4 ]triazolo [ 1, 5 - a )pyridin 5 . 9 7 - yl) - 4 - ( 4trifluoromethyl )thiazol - 2 - yl ) - 1 H -pyrazole - 5 -carboxamide 4 - ( 4 -cyanothiazol - 2 - yl) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydro 5 .10 [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1H -pyrazole - 5 -carboxamide 4 - ( 5 - ( 2 -ethoxyethyl ) - 4 -methylthiazol - 2 - yl )- 1 -methyl - N -( 2 -phenyl 5 . 11 5 , 6 ,7 , 8 -tetrahydro - [ 1, 2 ,4 ]triazolo [ 1 , 5 -a ]pyridin - 7 -yl )- 1 H -pyrazole - 5 carboxamide 4 - ( 5 - ethyl- 1 , 3 , 4 - thiadiazol- 2 - yl ) - 1 - methyl- N - ( 2 -phenyl - 5 , 6 , 7 , 8 5 . 12 tetrahydro - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole - 5 carboxamide 4 - ( 5 -bromo - 2 -methylthiazol - 4 -yl ) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 5 . 13 tetrahydro - [ 1 , 2, 4 ] triazolo [ 1, 5 - a ]pyridin - 7- yl ) - 1 H -pyrazole - 5 carboxamide 4 - ( 3 ,6 - dimethylpyrazin - 2 - yl) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 5 . 14 tetrahydro - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl ) -1H -pyrazole - 5 carboxamide 1 -methyl - 4 - ( 3 -methyl - 1 , 2 , 4 - thiadiazol- 5 - yl) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 5 . 15 tetrahydro [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1H -pyrazole - 5 carboxamide 4 - ( 4 - ( difluoromethyl) thiazol- 2 - yl) - N - ( 2 - ( ( R ) - 2 5 . 16 (methoxymethyl ) pyrrolidin - 1 - yl) - 5 ,6 , 7 , 8 -tetrahydro [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl) - 1 -methyl - N - ( 2 - phenyl- 5 ,6 , 7 , 8 5 . 17 tetrahydro - [ 1 , 2, 4 ] triazolo [ 1, 5 - a ]pyridin - 7- yl ) - 1 H -pyrazole - 5 carboxamide 1 -methyl -4 - ( 4 -methylthiazol - 2 - yl )- N - (2 - phenyl - 5 , 6 , 7 , 8 -tetrahydro 5 . 18 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl ) - 1 H -pyrazole - 5 -carboxamide 1 -methyl - 4 - ( 6 -methylpyridin - 2 - yl) - N - ( 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydro 5 . 19 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H - pyrazole - 5 - carboxamide 1 -methyl - 4 - ( 4 -methylpyridin - 2 - yl) - N - ( 2 - phenyl- 5 , 6 , 7 , 8 -tetrahydro 5 . 20 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 - carboxamide 1 -methyl - N - ( 2 - phenyl -5 ,6 , 7 , 8 - tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin 5 . 21 7 - yl) - 4 - ( 6 - (trifluoromethyl ) pyridin - 2 - yl ) - 1 H -pyrazole - 5 - carboxamide 1 -methyl - 4 - ( 3 -methylpyridin - 2 - yl ) - N - ( 2 - phenyl- 5 , 6 , 7 , 8 - tetrahydro 5 .22 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 -carboxamide 4 - ( 4 - fluoropyridin - 2 - yl) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydro 5 . 23 [1 , 2 ,4 ]triazolo [ 1 , 5- a ]pyridin - 7 - yl )- 1 H -pyrazole - 5 - carboxamide 4 - ( 5 - fluoropyridin - 2 -yl ) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydro 5 . 24 [ 1 , 2 ,4 ] triazolo [ 1 ,5 - a ] pyridin - 7 - yl) - 1 H -pyrazole - 5 - carboxamide US 9 ,777 ,000 B2 109 110 TABLE 1 - continued Compound name Example No. 4 - ( 4 -methoxypyridin - 2 -yl ) - 1- methyl - N -( 2 -phenyl - 5 , 6 , 7 , 8 -tetrahydro 5 .25 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1H -pyrazole - 5 - carboxamide 1 -methyl - 4 - ( 5 -methylpyridin - 2 - yl) - N - ( 2 - phenyl- 5 ,6 , 7 , 8 - tetrahydro 5 . 26 [ 1, 2 ,4 ] triazolo [ 1 ,5 - a )pyridin - 7 -yl ) - 1H -pyrazole - 5 -carboxamide 4 - ( 3 -cyanopyridin - 2 -yl ) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 - tetrahydro 5 . 27 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole - 5 - carboxamide 4 - ( 2 , 5 -dimethylthiazol - 4 - yl) - N - ( 2 - ( 4 - fluorophenyl) - 5 , 6 , 7 , 8 - tetrahydro bi5 . 28 [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 5 -chloro -4 - ( difluoromethyl) thiazol - 2 -yl ) - 1 -methyl - N - ( 2 - phenyl 5 . 29 5 , 6 , 7 , 8 - tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 H -pyrazole - 5 ne carboxamide 4 - ( 5 -acetyl - 2 -methylthiazol - 4 - yl) - 1 -methyl - N - ( 2 -phenyl - 5 , 6 , 7 , 8 5 . 30 tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 da carboxamide 4 - ( 5 - ( 1 - hydroxyethyl) - 2 -methylthiazol - 4 - yl) - 1 -methyl - N - ( 2 -phenyl 5 . 31 5 , 6 , 7, 8 - tetrahydro -[ 1 ,2 ,4 ] triazolo [1 ,5 - a ]pyridin -7 -yl )- 1H -pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl ) - N - ( 2 - ( 2 - fluorophenyl) -5 ,6 , 7 ,8 5 . 32 tetrahydro -[ 1 ,2 ,4 ] triazolo [1 ,5 - a ]pyridin - 7 -yl ) - 1 -methyl -1 H -pyrazole - 5 carboxamide 4 - ( 4 - (difluoromethyl ) thiazol- 2 - yl) - N - ( 2 - ( 3 - fluorophenyl ) - 5 , 6 , 7 , 8 5 . 33 tetrahydro - [ 1 , 2 ,4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 - ( 4 - ( difluoromethyl ) thiazol- 2 - yl) - N - ( 2 - ( 2 -methoxyphenyl ) - 5 , 6 , 7 , 8 5 . 34 tetrahydro -[ 1 ,2 ,4 ] triazolo [1 ,5 - a ]pyridin -7 -yl ) - 1 -methyl -1 H -pyrazole - 5 carboxamide 4 -( 5 - cyclopropyl- 4 -( difluoromethyl) thiazol- 2- yl) - N -( 2 -( 4 5 . 35 fluorophenyl )- 5 ,6 ,7 , 8 - tetrahydro - [ 1 , 2, 4 ]triazolo [ 1 ,5 -a ]pyridin - 7 -yl ) - 1 methyl- 1H - pyrazole - 5 -carboxamide 4 - ( 4 - ( difluoromethyl ) - 5 -methylthiazol - 2 - yl) - N - ( 2 - ( 4 - fluorophenyl ) 5 . 36 5 ,6 , 7 ,8 -tetrahydro - [ 1 , 2, 4 ]triazolo [ 1, 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H pyrazole - 5 -carboxamide 4 - ( 5 -chloro - 4 - ( difluoromethyl )thiazol - 2 - yl) - N - ( 2 - ( 3 - fluorophenyl) 5 . 37 5 , 6 , 7 , 8 - tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 ,5 - a ]pyridin - 7 - yl) - 1 -methyl - 1H pyrazole - 5 -carboxamide 4 - ( 5 - cyclopropyl- 4 -methylthiazol - 2 - yl ) - 1 -methyl - N - ( 2 - phenyl- 5 , 6 ,7 ,8 5 . 38 tetrahydro - [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 carboxamide 4 - ( 2 ,5 - dimethylthiazol- 4 - yl) - 1 -methyl - N - ( 2 - phenyl- 5 ,6 , 7 , 8 - tetrahydro 5 . 39 [ 1 , 2, 4 ]triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 -carboxamide 4 - ( 6 -cyanopyridin - 2 - yl) - 1 -methyl - N - ( 2 - phenyl- 5 ,6 , 7 , 8 - tetrahydro 5 .40 [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 H -pyrazole - 5 -carboxamide 4 - ( 4 -cyanothiazol - 2 - yl) - N - ( 2 - (4 - fluorophenyl) - 5 ,6 , 7 , 8 - tetrahydro 5 . 41 [ 1 , 2 ,4 ]triazolo [ 1 , 5 - a ]pyridin - 7 -yl ) - 1 -methyl - 1H -pyrazole - 5 carboxamide 4 -( 5 -cyclopropyl - 4 -( difluoromethyl ) thiazol - 2 - yl) - N - ( 2 -( 3 5 .42 fluorophenyl) -5 , 6 , 7, 8 - tetrahydro -[ 1, 2 ,4 ] triazolo [1 ,5 - a ]pyridin - 7 -yl ) - 1 methyl- 1H -pyrazole - 5 - carboxamide 4 - ( 5 - cyclopropyl- 4 -methylthiazol - 2 -yl )- N - ( 2 - ( 4 - fluorophenyl ) - 5 , 6 , 7 ,8 5 . 43 tetrahydro - [ 1 , 2, 4 ] triazolo [ 1, 5 - a ]pyridin - 7- yl ) -1 -methyl - 1H -pyrazole -5 carboxamide 4 - ( 5 -acetyl - 2 -methylthiazol - 4 - yl) - N - ( 2 - ( 3 - fluorophenyl) - 5 ,6 , 7 , 8 5 . 44 tetrahydro - [ 1 , 2 , 4 ]triazolo [ 1 , 5 - a ]pyridin - 7 - yl) - 1 -methyl - 1 H -pyrazole - 5 carboxamide 4 - ( 4 ,5 - dimethylthiazol- 2 - yl) - 1 -methyl - N - ( 2 - ( pyrrolidin - 1 -yl ) - 5 , 6 , 7 , 8 5 . 45 tetrahydro -[ 1 ,2 , 4 ]triazolo [1 , 5 - a ]pyridin -7 - yl ) - 1 H -pyrazole -5 carboxamide 1 -methyl - N - ( 2 - (pyrrolidin - 1 -yl ) - 5 ,6 , 7 , 8 -tetrahydro - [ 1 , 2 ,4 ]triazolo [ 1 , 5 5 . 46 a ]pyridin - 7 - yl )- 4 - ( 4trifluoromethyl) thiazol - 2 -yl ) - 1 H -pyrazole - 5 carboxamide 1 -methyl - 4 - (6 -methylpyridin - 2 -yl )- N - ( 2 - (pyrrolidin - 1 - yl )- 5 , 6 , 7 ,8 5 . 47 tetrahydro - [ 1 ,2 ,4 ] triazolo [ 1 ,5 - a ]pyridin - 7 -yl ) -1H -pyrazole - 5 carboxamide

In the compound of the above formula (I ), the amide bond ratio of these structures may change , depending on the state is a bond that may be converted to an imide acid bond by 65 of the compound represented by the formula ( I) , namely , a proton tautomeric isomerism , and the generated tautomeric solid state , or a state in which the compound is dissolved in isomer is included in the above formula ( I ) . The abundance a liquid . US 9 ,777 , 000 B2 111 112 at least one of the compound represented by the above [Formula 74 ] formula ( I ) , a pharmaceutically acceptable salt thereof, and a solvate thereof . R2 [ 4 ] A fourth embodiment of the present invention is a N - N N pharmaceutical composition for treating at least one disease or condition selected from the group consisting of certain types of mental disorders and conditions, such as mental ??) disorder , paranoid disorder , and drug - induced psychosis , w anxiety disorders such as panic disorder and obsessive compulsive disorder, motor disorders including Parkinson ' s disease and Huntington ' s disease , mood disorder, neurode The description regarding any given specific tautomeric generative disorder, disorder involving deficits in attention isomer in any given structural formula in the present speci - and /or cognition , obesity , and drug addiction , wherein the fication is not intended to limit a tautomeric isomer to the 15 pharmaceutical composition comprises, as an active ingre any given specific tautomeric isomer , but it is intended to dient, at least one of the compound represented by the above mean that the any given specificic tautomerictautomeric isomer isis a formula ( 1 ) , a pharmaceutically acceptable salt thereof, and representative of the entire set of tautomeric isomers. a solvate thereof, in an effective amount for treating the Specifically , if the compound of Example 1 . 1 . for disease or condition . example, has a compound name “ 1 -methyl - 4 - ( 5 -methylpyri - 20 Examples of the “mental disorders and conditions” that din - 2 - yl) - N - ( 2 -phenylimidazol 1 . 2 - alpyridin - 7 -yl ) - 1H -pyra - can be treated according to the present invention include ( 1 ) zole - 5 - carboxamide, ” its tautomeric isomer , 1 -methyl - 4 - ( 5 paranoid , disorganized , catatonic , undifferentiated , or methylpyridin - 2 - yl) - N -( 2 - phenylimidazo [ 1 , 2 - a ] pyridin - 7 residual schizophrenia , ( 2 ) schizophreniform disorder , ( 3 ) yl) - 1H -pyrazole - 5 - carbimidic acid (which is not paranoid or depressive schizoaffective disorder , (4 ) paranoid od 25 disorder, (5 ) substance - induced mental disorder, for distinguished in termsof E form and Z form ) is also included 25 example , psychosis induced by alcohol , amphetamine , can in the compound of Example 1 . 1 . nabis , cocaine , a hallucinatory drug , an inhalant, opioid , or In the present specification , unless otherwise specified , phencyclidine , ( 6 ) paranoic personality disorder, and ( 7 ) when a cyclic group is substituted with a variable substitu schizotypal personality disorder. However , the mental dis ent, it means that the variable substituent does not bind to a 30 orders and conditions are not limited thereto . specific carbon atom of the cyclic group or to a specific NH In the present specification , unless otherwise specified , group in the cyclic group . For example, it means that the examples of the symptoms of " schizophrenia and schizo variable substituent R * in the following formula A can be phreniform disorder” include ( 1 ) positive symptom , nega substituted with any of carbon atoms i , ii, iii and iv in the tive symptom , and delusional and /or hallucinogenic symp formula A ; the variable substituent R ” in the following 35 tom associated therewith , ( 2 ) disorganized speech ( frequent formula B can be substituted on any of carbon atoms v and off -topic or incoherent speech ) , ( 3 ) flattening of emotion (a vi in the formula B ; and the variable substituent R2 in the significant reduction in the width and strength of emotional following formula C can be substituted on any of carbon expression ) , ( 4 ) alogia ( a reduction in content and amount of atoms vii , viii , ix , and x in the formula C . speech ), (5 ) anhedonia (the disappearance /diminution of 40 ability to experience pleasure ), (6 ) inappropriate affect, ( 7 ) dysphoria ( e. g . depression , anxiety , and anger ), ( 8 ) loss of [Formula 75 ] motivation , (9 ) unsocial personality ( loss of capacity of Formula A obtaining pleasure from social interaction ) , and ( 10 ) a part of cognitive function disorder. However, the schizophrenia 45 and schizophreniform disorder are not limited thereto . im Examples of the “ motor disorders ” that can be treated according to the present invention include ( 1 ) Huntington ' s disease and dyskinesia associated with dopamine agonist therapy, (2 ) Parkinson ' s disease , ( 3 ) restless legs syndrome Formula B 50 (RLS ), and ( 4 ) essential tremor. However, the motor disor ders are not limited thereto . min Examples of the " other disorders ” that can be treated according to the present invention include ( 1 ) obsessive compulsive disorder , ( 2 ) Tourette ' s syndrome, and ( 3 ) tic disorder . However, the other disorders are not limited thereto . Examples of the " anxiety disorders " that can be treated Formula C according to the present invention include ( 1 ) panic disorder, ( 2 ) agoraphobia, ( 3 ) specific phobias, ( 4 ) social phobias , ( 5 ) obsessive - compulsive disorder , ( 6 ) posttraumatic stress dis w man - order , ( 7 ) acute stress disorder , and ( 8 ) generalized anxiety N . viii disorder . However , the anxiety disorders are not limited thereto . vii RZ In the present specification , unless otherwise specified , 65 the term “ drug addiction " means abnormal desire for drugs . [3 ] A third embodiment of the present invention is a phar - In general, the drug addiction has characteristics including maceutical composition comprising, as an active ingredient, motivational disorder such as compulsion to take a desired US 9 ,777 ,000 B2 113 114 drug , and an episode of strong desire for drugs . Examples of striatal medium - sized spiny neurons . However , the neuro the drug addiction include alcohol , amphetamine , cocaine, degenerative disorder and condition are not limited thereto . and opium addiction . In the present specification , unless otherwise specified , In the present specification , unless otherwise specified , the term “ neurotoxic addiction ” indicates intoxication by the term " deficits in attention and / or cognition ” in the 5 neurotoxin . Neurotoxin is any given chemical substance or context of " disorder involving deficits in attention and / or substance thatmay cause neural death , namely, neurological cognition ” means that one or more cognitive functions in a damage. Examples of the neurotoxin include alcohol. When specific individual, such as memory , intellectual, learning , a pregnant woman abuses alcohol, her newborn child would and logical capacity , are below normal level in comparison suffer from alcoholic intoxication and neurological damage , with other individuals of the same age . Moreover , the term 10 which are considered to be fetal alcohol syndrome. Other “ deficits in attention and /or cognition ” means a reduction in examples of the neurotoxin include kainic acid , domoic acid , the functions of any given specific individual, in terms of acromelic acid , certain types of agricultural chemicals ( e . g . one or more cognitive aspects , for example , caused by dichloro diphenyl trichloroethane (DDT ) , certain types of age - related cognitive decline . insecticides (e . g. organophosphorus acids ), volatile organic Examples of the “ disorder involving deficits in attention 15 solvents (e .g . toluene ), metals ( e .g . lead , mercury , arsenic , and/ or cognition ” that can be treated according to the present phosphorus , and aluminum ), certain types of chemical sub invention include (1 ) dementia , such as Alzheimer 's disease, stances used as weapons ( e . g . Agent Orange that is a multiple cerebral infarction , alcoholic dementia or other defoliant, and nerve gas) , and neurotoxic anti- tumor agents . drug -related dementia , dementia associated with intracranial However, the neurotoxin is not limited thereto . tumor or brain damage , dementia associated with Hunting - 20 In the present specification , unless otherwise specified , ton ' s disease or Parkinson ' s disease , or AIDS - related the term “ treat ” used in the context of the phrase " treat the dementia , ( 2 ) delirium , ( 3 ) amnestic disorder , ( 4 ) posttrau disease or condition ” means to recover, alleviate , or suppress matic stress disorder (PTSD ) , (5 ) mental retardation , ( 6 ) progression of the “ disease or condition ” or one or more learning disorder, such as dyslexia , mathematics disorder, or " diseases or conditions. ” In addition , in the present speci disorder of written expression , ( 7 ) attention -deficit hyper - 25 fication , the term " treat ” also includes , depending on con activity disorder ( ADHA ) , and ( 8 ) age - related cognitive ditions of patients , prevention of " disease or condition " decline. However , the disorder involving deficits in attention which includes prevention of the onset of the “ disease or and /or cognition are not limited thereto . condition ” or the onset of any given symptoms associated Examples of the “ mood disorder ” and the “ mood episode” therewith , and reduction of the severity of " disease or that can be treated according to the present invention include 30 condition ” or the any given symptoms associated therewith ( 1 ) major depressive episode (mild level , middle level, or before the onset . In the present specification , the term “ treat” severe level type ), manic episode , mixed affective episode , includes to prevent and improve the recurrence of a certain and hypomanic episode, ( 2 ) atypical depression , ( 3 ) melan - “ disease or condition . ” cholic depression , (4 ) catatonic depression , (5 ) postpartum [5 ] A fifth embodiment of the present invention is a phar mood episode , ( 6 ) postapoplectic depression , ( 7 ) major 35 maceutical composition for treating at least one disease or depressive disorder , ( 8 ) dysthymic disorder/ dysthymia , ( 9 ) condition selected from the group consisting of certain types minor depressive disorder , ( 10 ) premenstrual dysphoric dis - of mental disorders and conditions, such as mental disorder, order, (12 ) postschizophrenic depressive disorder , ( 13 ) paranoid disorder , and drug - induced psychosis , anxiety dis major depressive disorder occurring with paranoid disorder orders such as panic disorder and obsessive - compulsive or mental disorder such as schizophrenia , ( 14 ) bipolar dis - 40 disorder , motor disorders including Parkinson ' s disease and order, such as bipolar disorder type I and bipolar disorder Huntington ' s disease , mood disorder, neurodegenerative type II, and ( 15 ) cyclothymic disorder. However, the mood disorder , disorder involving deficits in attention and /or cog disorder and the mood episode are not limited thereto . nition , obesity , and drug addiction , wherein the pharmaceu In the present specification , unless otherwise specified , tical composition comprises, as an active ingredient, at least the term " neurodegenerative disorder or condition ” means 45 one of the compound represented by the above formula ( 1 ) , nervous function disorder or condition , which is caused by a pharmaceutically acceptable salt thereof, and a solvate neuronal dysfunction and / or neuronal death in the central thereof, in an effective amount for inhibiting PDE10 . nerve system . Examples of the treatment for the aforemen - [ 6 ] A sixth embodiment of the present invention is an agent tioned disorder and condition include administration of a for preventing and /or treating at least one disease or condi drug for enhancing the function of damaged or normally 50 tion selected from the group consisting of certain types of working neurons, so as to prevent neuronal dysfunction mental disorders and conditions such as mental disorder, and / or neuronal death that are under critical conditions, paranoid disorder, and drug - induced psychosis , anxiety dis and / or to compensate the loss of function caused by such orders such as panic disorder and obsessive - compulsive neuronal dysfunction or neuronal death that is under critical disorder, motor disorders including Parkinson ' s disease and conditions , in the aforementioned disorder or condition . 55 Huntington ' s disease , mood disorder , neurodegenerative Examples of the “ neurodegenerative disorder and condi - disorder, disorder involving deficits in attention and /or cog tion " that can be treated according to the present invention nition , obesity , and drug addiction , wherein the agent com include ( 1 ) Parkinson ' s disease , ( 2 ) Huntington ' s disease , prises, as an active ingredient, at least one of the compound ( 3 ) dementia , such as Alzheimer ' s disease , multi - infarct represented by the above formula ( 1 ) , a pharmaceutically dementia , AIDS -related dementia , and frontotemporal 60 acceptable salt thereof , and a solvate thereof. dementia , ( 4 ) neurodegeneration associated with brain dam - [ 7 ] A seventh embodiment of the present invention is an age , ( 5 ) neurodegeneration associated with stroke, and neu - agent for treating at least one disease or condition selected rodegeneration associated with cerebral infarction , (6 ) hypo - from the group consisting of certain types ofmental disor glycemia - induced neurodegeneration , ( 7 ) ders and conditions such as mental disorder, paranoid dis neurodegeneration associated with epileptic seizure , ( 8 ) 65 order and drug - induced mental psychosis , anxiety disorders neurodegeneration associated with neurotoxic addiction , ( 9 ) such as panic disorder and obsessive - compulsive disorder , multiple system atrophy, and ( 10 ) neurodegeneration of motor disorders including Parkinson ' s disease and Hunting US 9 ,777 , 000 B2 115 116 ton ' s disease , mood disorder , neurodegenerative disorder, [ 3 ] or the method according to the embodiment [ 13 ] , disorder involving deficits in attention and / or cognition , wherein the disease or condition is at least one disease or obesity , and drug addiction , wherein the agent comprises, as condition selected from the group consisting of ( 1 ) paranoid , an active ingredient, at least one of the compound repre disorganized , catatonic , undifferentiated , or residual schizo sented by the above formula ( I ) , a pharmaceutically accept- 5 phrenia , ( 2 ) schizophreniform disorder, ( 3 ) paranoid or able salt thereof, and a solvate thereof. depressive schizoaffective disorder, ( 4 ) paranoid disorder , [ 8 ] An eighth embodiment of the present invention is an ( 5 ) substance - induced mental disorder, ( 6 ) psychosis agent for preventing and / or treating diseases related to a induced by alcohol, amphetamine , cannabis , cocaine , a PDE10 receptor, wherein the agent comprises, as an active hallucinatory drug , an inhalant, opioid , or phencyclidine, ( 7 ) ingredient, at least one of the compound represented by the 10 paranoic personality disorder , ( 8 ) schizotypal personality above formula ( I ) , a pharmaceutically acceptable salt disorder , ( 9 ) Huntington ' s disease , ( 10 ) dyskinesia associ thereof, and a solvate thereof . ated with dopamine agonist therapy , ( 11) Parkinson ' s dis [ 9 ] A ninth embodiment of the present invention is an agent ease , ( 12 ) restless legs syndrome, ( 13 ) essential tremor, ( 14 ) for treating diseases related to a PDE10 receptor, wherein obsessive -compulsive disorder, ( 15 ) Tourette ' s syndrome , the agent comprises, as an active ingredient , at least one of 15 ( 16 ) tic disorder , ( 17) panic disorder, (18 ) agoraphobia , (19 ) the compound represented by the above formula ( 1 ) , a specific phobias , ( 20 ) social phobias, ( 21) posttraumatic pharmaceutically acceptable salt thereof, and a solvate stress disorder , (22 ) acute stress disorder, (23 ) generalized thereof. anxiety disorder, ( 24 ) dementia ; Alzheimer ' s disease , mul [ 10 ] Atenth embodiment of the present invention is a PDE 10 tiple cerebral infarction , alcoholic dementia or other drug inhibitor consisting of one or more of the compound repre - 20 related dementia , dementia associated with intracranial sented by the above formula ( I ) , a pharmaceutically accept- tumor or brain damage , dementia associated with Hunting able salt thereof, and a solvate thereof. ton ' s disease or Parkinson ' s disease , AIDS - related demen [ 11 ] An eleventh embodiment of the present invention is use tia , or frontotemporal dementia , (25 ) delirium , ( 26 ) amnestic of at least one of the compound represented by the above disorder, ( 27 ) mental retardation , ( 28 ) learning disorder ; formula ( 1 ) , a pharmaceutically acceptable salt thereof , and 25 dyslexia , mathematics disorder , or disorder of written a solvate thereof, as a pharmaceutical composition . expression , ( 29 ) attention - deficit hyperactivity disorder , ( 30 ) [ 11a ] An 11a - th embodiment of the present invention is use age - related cognitive decline , (31 ) major depressive episode of at least one of the compound represented by the above (mild level , middle level, or severe level type ) , manic formula ( I ) , a pharmaceutically acceptable salt thereof , and episode , mixed affective episode , or hypomanic episode , a solvate thereof, in the production of a pharmaceutical 30 (32 ) atypical depression , (33 ) melancholic depression , ( 34 ) composition . catatonic depression , ( 35 ) postpartum mood episode, ( 36 ) [ 12 ] A twelfth embodiment of the present invention is use of postapoplectic depression , (37 ) major depressive disorder , at least one of the compound represented by the above ( 38 ) dysthymic disorder /dysthymia , ( 39 ) minor depressive formula (1 ) , a pharmaceutically acceptable salt thereof, and disorder, (40 ) premenstrual dysphoric disorder, (41 ) post a solvate thereof, as a PDE10 inhibitor. 35 schizophrenic depressive disorder , (42 ) major depressive [ 13 ] A thirteenth embodiment of the present invention is a disorder occurring with paranoid disorder or mental disorder method for treating at least one disease or condition selected such as schizophrenia, (43 ) bipolar disorder ; bipolar disor from the group consisting of certain types of mental disor der type I and bipolar disorder type II , (44 ) cyclothymic ders and conditions such as mental disorder, paranoid dis - disorder , ( 45 ) neurodegeneration associated with brain dam order and drug - induced psychosis , anxiety disorders such as 40 age , (46 ) neurodegeneration associated with stroke , or neu panic disorder and obsessive -compulsive disorder , motor rodegeneration associated with cerebral infarction , (47 ) disorders including Parkinson ' s disease and Huntington ' s hypoglycemia - induced neurodegeneration , ( 48 ) neurode disease , mood disorder, neurodegenerative disorder, disor - generation associated with epileptic seizure , (49 ) neurode der involving deficits in attention and / or cognition , obesity , generation associated with neurotoxic addiction , (50 ) mul and drug addiction , wherein the method comprises admin - 45 tiple system atrophy , and (51 ) neurodegeneration of striatal istering at least one of the compound represented by the medium - sized spiny neurons. above formula ( I ) , a pharmaceutically acceptable salt In each of the aforementioned embodiments [ 1 ] to [ 15 ] of thereof, and a solvate thereof, in an effective amount for the present invention , when PDE10 inhibitory effect is treating the disease or condition , to a subject in need of measured by an appropriately selected method , for example , treatment for the disease or condition . 50 when it is measured in the after -mentioned Pharmacological [ 14 ] A fourteenth embodiment of the present invention is a Experiment Example 1 (human -derived PDE10 inhibitory method for treating at least one disease or condition selected effect ), it is preferable to use a compound having an IC50 from the group consisting of certain types of mental disor - value of preferably 100 nM or less , more preferably 50 nM ders and conditions such as mental disorder, paranoid dis - or less, even more preferably 10 nM or less, further prefer order and drug - induced psychosis , anxiety disorders such as 55 ably 5 . 0 nM or less , and particularly preferably 1 . 0 nM or panic disorder and obsessive -compulsive disorder, motor less . disorders including Parkinson ' s disease and Huntington ' s In Pharmacological Experiment Example 1 ( human disease, mood disorder , neurodegenerative disorder , disor- PDE10 inhibitory effect) , the compound represented by the der involving deficits in attention and / or cognition , obesity, formula ( I ) of the present invention , or a pharmaceutically and drug addiction , wherein the method comprises admin - 60 acceptable salt thereof, or a solvate thereof has an excellent istering at least one of the compound represented by the PDE10 inhibitory activity . Moreover, the compound repre above formula ( I ) , a pharmaceutically acceptable salt sented by the formula ( I ) of the present invention , or a thereof, and a solvate thereof, in an effective amount for pharmaceutically acceptable salt thereof, or a solvate thereof inhibiting PDE10 , to a subject in need of treatment for the is extremely selective to PDE10 , and thus , is a selective disease or condition . 65 PDE10 inhibitor. [ 15 ] A fifteenth embodiment of the present invention is the In the present specification , unless otherwise specified , pharmaceutical composition according to the embodiment the term " selective PDE10 inhibitor” means a compound US 9 ,777 ,000 B2 117 118 having a significant inhibitory activity on PDE10, rather oyl group , a mono -/ di- C7 - 20 aralkylcarbamoyl group , a than on PDEs 1 to 9 or PDE 11 . mono - /di - heterocyclic carbamoyl group , a Cl. alkylsulfo In one embodiment, the “ selective PDE10 inhibitor” is nyl group , a halogenated C1- 6 alkylsulfonyl group , a C3- 8 preferably a compound having an inhibitory activity on cycloalkylsulfonyl group , a C6- 14 arylsulfonyl group , a C7- 20 PDE10 , which is approximately 1/ 1000 or less of the IC50 5 aralkylsulfonyl group , a heterocyclic sulfonyl group , a values of the compound to inhibit any other PDE enzymes mono - / di- C1- 6 alkylsulfamoyl group , a mono - di- haloge ( e . g . PDE 1A , 2A , 3A , 4A , 4B , 5A , 6 , 7A , 7B , 8A , 9A , and nated C1- 6 alkylsulfamoyl group , a mono - di- C3- 8 11A ) . ( In other word , this compound inhibits the activity of cycloalkylsulfamoyl group , a mono - / di- C6 - 14 arylsulfamoyl PDE10 at an IC50 value that is approximately 1/ 1000 or less of group , a mono -/ di- C7- 20 aralkylsulfamoyl group , and a its IC50 values necessary for inhibition of any other PDE " mono - /di - heterocyclic sulfamoyl group ; R2 represents a enzymes . ) hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl In the present specification , unless otherwise specified , group , a hydroxy C1- 6 alkyl group , or a Cl- , alkoxyl C1- 6 when the term “ the compound of the formula (1 ) ,” “ the alkyl group ; compound represented by the formula ( 1 ) ,” or the like is 15 ring A represented by the following partial structural used , it also refers to “ the compound of the formula (I -a ), ” formula ( II ) : “ the compound of the formula ( 1 - b ) ,” “ the compound of the formula (I - c ), ” “ the compound of the formula (I -d ) ,” and the like , which are the subordinate concepts of the compound [Formula 77 ] of the formula (1 ). ” 20 ( II) [ 16 ] A sixteenth embodiment of the present invention is an intermediate compound represented by the following for mula ( I' ) , or a pharmaceutically acceptable salt thereof, or a solvate thereof: 25 is selected from the group of theheteroaryls consisting of the [ Formula 761 following : (1) 30 N - N [Formula 78 ] ( II - 1)

35

(R )p ( II- 2 )

40 wherein p represents an integer of 0 to 3 ; L represents a hydroxyl group , a halogen atom , a C1-6 alkoxyl group , a C6- 14 aryloxy group , or a C7- 20 aralkyloxy group ;R each independently represents a halogen atom , a hydroxyl group , ( II - 3 ) a nitro group , a cyano group , a C1- 6 alkyl group , a C3- 8 45 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- 6 NARO alkoxyl group , a C1- 6 alkoxylcarbonyl group , a C1- 6 alkoxyl C2- 6 alkenyl group , a hydroxy C1- 6 alkyl group , a C1- 6 ( II - 4 ) alkoxyl C1- 6 alkyl group , a C2- 7 alkanoyl group , a C1- 6 50 alkylthio group , a C1- 6 alkylsulfinyl group , a C1- 6 alkylsul fonyl group , a 3 - to 14 -membered non - aromatic heterocyclic group , a 5 - to 7 -membered monocyclic heteroaryl group , an - NR7R8 group , or a CONR7R8 group wherein R7 and R8 in the — NR ' R $ group and the CONR ' R $ group each 55 ( II - 5 ) independently represent a substituent selected from among a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , a hydroxy C1- 6 alkyl group , a cyanated C1- 6 alkyl group , a C2- 6 alkenyl group , a C2- 6 alkynyl group , a C3- 8 cycloalkyl group , a C6- 14 aryl group , a C7- 20 aralkyl group , 60 ( II - 6 ) a heterocyclic group , a C2- 7 alkanoyl group , a hydroxy C2- 7 alkanoyl group , a halogenated C2- 7 alkanoyl group , a C3- 8 cycloalkylcarbonyl group , a C6- 14 arylcarbonyl group , a C7- 20 aralkylcarbonyl group , a heterocyclic carbonyl group , a mono - / di- C1 - 6 alkylcarbamoyl group , a mono - / di- haloge - 65 nated C1- 6 alkylcarbamoyl group , a mono - / di- C3- 8 R6 cycloalkylcarbamoyl group , a mono -/ di - C6 - 14 arylcarbam US 9 ,777 , 000 B2 10 120 -continued -continued ( II- 7 ) ( II- 17 ) . WA ( II- 18) (II - 8 ) 10

( I -19 ) (II -9 ) 15

( II -20 ) 20

( II-10 ) 25 ( I -21 )

JA-????????“ N ( II- 11 ) 30 ( I -22 )

( II-12 ) 35 MIN ( II- 23 )

N

?I/4 40

( I -13 ) ( II- 24)

45

Mis IN - N ( II- 14 ) R6 30 ( II- 25 ) .? ( II -15 ) 55 ( II -26 )

N

60 N (II - 16 ) ( II- 27 ) ?JJJJJJ4?WIN 65 tN US 9 ,777 ,000 B2 121 122 -continued - continued ( II- 28 ) ( II - 38 ) 77 (II - 29 ) (II - 39) 10

( II - 30 ) 15 ( II -40 )

N NA N NIN

Porti 20 (II - 31) ( II -41 ) NIN 25 = - Z Z

( II - 42 ) ( II -32 )

30

( II -43 ) (II - 33 ) 35

N: 'N = 40 ( II - 34 ) provided that when the ring A is represented by the formula ( II -31 ) , p represents an integer of 1 to 3 ; and Rº represents laa hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 45 alkyl group , or a hydroxy C1- 6 alkyl group . [ 16 - 1 ] (II -35 ) Preferably , the intermediate compound of the above embodiment [ 16 ] is an intermediate compound represented 50 by the above formula ( I' ) wherein p and L have the same N definitions as those described in the embodiment [ 16 ] ; RI each independently represents a halogen atom , a hydroxyl group , a nitro group , a cyano group , a C1- 6 alkyl group , a

( II - 36 ) C3- 8 cycloalkyl group , a halogenated C1- 6 alkyl group , a C2- a 6

55 alkenyl group , a C1- 6 alkoxyl group , a halogenated C1- a6

alkoxyl group , a C1-6 alkoxylcarbonyl group , a hydroxy C1-a6 z= alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C1- 6 alkoxyl

z C2- 6 alkenyl group , a C2- 7 alkanoyl group, a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , an - NR ' R $ group , or a CONR ’ RS group wherein R7 and R8 in the NR ’RS ( II - 37 ) group and the CONR ' R® group have the same definitions as those described in the above embodiment [ 16 ] ; R2 rep resents a hydrogen atom , a C1- 6 alkyl group , or a haloge 65 nated C1- 6 alkyl group ; ring A represented by the following partial structural formula ( II ): ?

US 9, 777 , 000 B2 123 124 -continued [ Formula 79 ] (II - 13 ) (4) 5 W |?S - N (II - 15 )

?10 Z? is selected from the group of the heteroaryls consisting of the following : ?N ? ( II- 16 ) [ Formula 80] (II - 1)

20 (II - 18 )

( II- 3 ) ??F6 25 (II - 19 )

(II - 4 ) 30 ( II- 21 )

(II - 6) ? 35 ( II- 22 ) ??? 40 (II - 7 ) MIN (II - 24 )

45

( II- 9 )

50 (II - 25 ) ???? (II - 10 ) NENT 55 VA? (II - 27) 7N

(II -12 ) 60 (II - 29 ) N N ?????? ? AN ??? 6 W??S - N US 9 , 777 ,000 B2 125 126 -continued -continued ( II- 30 ) ( II -40 )

z

- N Po ( II -41 ) ( 11 - 31 ) 10

Z

- ZEZ 4 ( II -42 ) 15 ( II -32 )

20 ZEZ ( II -43 ) (II - 33 ) N Z-

25 ?

(II -34 ) provided that when the ring A is represented by the formula ( II -31 ) , p represents an integer of 1 to 3 ; and Rº represents 30 a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , or a pharma ceutically acceptable salt thereof, or a solvate thereof. [ 16 - 1 - 2 ] ( II- 35 ) 35 More preferably, the intermediate compound of the above embodiment [ 16 ] is an intermediate compound represented by the above formula ( I' ) wherein p and L have the same ZN definitions as those described in the embodiment [ 16 ]; R ! each independently represents a halogen atom , a cyano 40 group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halo genated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 ( II -36 ) alkoxyl group , a halogenated C1- 6 alkoxyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C1- 6 Z alkoxyl C2- 6 alkenyl group , a C1- 6 alkylthio group , a C1- 6 45 alkylsulfonyl group , an — NR74R8A group , or a CONR74R8A group wherein R7 and R84 in the - NR74R8A group and the — CONR74R8A group each inde ( II- 37 ) pendently represent a substituent selected from among a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group, a hydroxy C1- 6 alkyl group , a C2- 7 alkanoyl group , a hydroxy C2- 7 alkanoyl group , a halogenated C2- 7 alkanoyl group , a C1- 6 alkylsulfonyl group , and a halogenated C1- 6 N alkylsulfonyl group ; R² represents a hydrogen atom , a C1- 6 (II - 38 ) alkyl group , or a halogenated C1- 6 alkyl group ; 55 ring A represented by the following partial structural formula ( II) :

ZEZ [Formula 81] (11 - 39 ) 60

VE 65 US 9, 777 , 000 B2 127 128 is selected from the group of the heteroaryls consisting of the -continued following : (II - 16 )

[ Formula 82] ?1 (II - 1 )

N: (II - 18 )

( II- 3 ) R6 ARO WA ( II - 19 ) (II - 4 )

( II - 21 ) (II - 6 ) V?R6 Z-Z

(II - 22 ) ?? (I - 17 ) sss8830 N?N (I -24 ) (II - 9 ) 35

? 40 NS?/6 (II - 27 ) (II - 10 )

| 45 (II -30 ) (II - 12 ) \ 50 |

(II -31 ) (II - 13 )

S - N (II - 15 ) 60 ( II -32 )

N? 6 US 9 ,777 ,000 B2 129 130 -continued -continued (II - 33 ) ( II -43 )

N N N = N; (II - 34 ) 10 provided that when the ring A is represented by the formula ( II- 31 ) , p represents an integer of 1 to 3 ; and Ró represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , or a pharma ceutically acceptable salt thereof, or a solvate thereof. (II - 35 ) 15 (16 - 1- 2 -21 Even more preferably , the intermediate compound of the above embodiment [ 16 ] is an intermediate compound rep resented by the above formula ( I' ) wherein p , L , R2 , R " , and N ring A represented by the partial structural formula ( II ) have 20 the same definitions as those described in the embodiment [ 16 - 1 - 2 ] provided that when the ring Ais represented by the (II - 36 ) formula (II - 31) , p represents an integer of 1 to 3 ; andReach independently represents a C2- 7 alkanoyl group , and has the same definitions as those described in the embodiment 25 [ 16 - 1 - 2 ], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 16 - 1 - 31 Further preferably , the intermediate compound of the ( II- 37 ) above embodiment [ 16 ] is an intermediate compound rep 30 resented by the above formula ( I' ) wherein p and L have the same definitions as those described in the embodiment [ 16 ] ; R ' each independently represents a halogen atom , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halo genated C -4 alkyl group , a C2- 6 alkenyl group , a C1- 6 (II - 38 ) 35 alkoxyl group , a halogenated C1- 6 alkoxyl group , a hydroxy C1- 6 alkyl group , a C1- 6 alkoxyl C1- 6 alkyl group , a C1- 6 alkoxyl C2- 6 alkenyl group , a C1- 6 alkylthio group , a C1- 6 alkylsulfonyl group , an — NR74R84 group , or a _ CONR74R8A group wherein R74 and R84 in the 40 — NR74R8A group and the — CONR74R8A group have the same definitions as those described in the above embodi (II - 39 ) ment [ 16 - 1 - 2 ]; R² represents a hydrogen atom , a C1- 6 alkyl group , or a halogenated C1- 6 alkyl group ; ring A represented by the following partial structural 45 formula ( II) : N V = ( II - 40 ) [Formula 83 ]

N 50

(II - 41 ) 55 is selected from the group of theheteroaryls consisting of the NNZEZ following: (II - 42 ) 60 [Formula 84 ] ( II - 1 )

N NE? 65 US 9. 777 , 000 B2 131 132 -continued - continued ( II- 3 ) ( II -18 ) - R6 . (II - 4 ) ( II- 19 )

( II- 6 ) ST ( II - 21 ) ZZ ( I -7 ) ( II- 22 ) Wis WIN (II - 9 ) ( II -24 )

N?

IN V

( II-10 ) 35 ( II -31 )

(II - 12 ) 40 ( II -32 )

N

45 ?I/A .( II- 13 ) ( II- 33 ) 50

( II- 15 ) ( II -34 ) 55

??4??? ( II- 16 ) ( II- 35 ) ?now > ?s8 US 9 ,777 , 000 B2 133 134 -continued (11 -36 ) (Formula 85] (II )

N A (II - 37 ) 10 is selected from the group of the heteroaryls consisting of the following: (II - 39 ) 15 [Formula 86 ] ( II - 1 ) ? v= (II - 42 ) 20

( II - 4 ) ZEZ N: 25 provided that when the ring A is represented by the formula ( II - 31) , p represents an integer of 1 to 3 ; and Rº represents 30 ( II - 6 ) a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , or a pharma ceutically acceptable salt thereof, or a solvate thereof. [ 16 -1 - 3 - 2 ] 35 Still further preferably , the intermediate compound of the R6 above embodiment [ 16 ] is an intermediate compound rep ( II - 16 ) resented by the above formula ( I' ) wherein p , L , R² , Rº, and ring A represented by the partial structural formula ( II) have the same definitions as those described in the embodiment 40 [ 16 -1 - 3 ] provided that when the ring A is represented by the formula ( II -31 ) , p represents an integer of 1 to 3 ; andReach independently represents a C2 - 7 alkanoyl group , and has the ( II - 19 ) same definitions as those described in the embodiment [ 16 - 1 - 3 ] , or a pharmaceutically acceptable salt thereof, or a 45 solvate thereof. [ 16 - 1 - 4 ] Particularly preferably , the intermediate compound of the ( II -31 ) above embodiment [ 16 ] is an intermediate compound rep - 50 resented by the above formula ( I' ) wherein p and L have the same definitions as those described in the embodiment [ 16 ] ; R each independently represents a halogen atom , a cyano group , a C1- 6 alkyl group , a C3- 8 cycloalkyl group , a halo genated C1- 6 alkyl group , a C2- 6 alkenyl group , a C1- 6 55 ( II -32 ) alkoxyl group , a C1- 6 alkoxyl C1- 6 alkyl group , or a C1- 6 alkoxyl C2- 6 alkenyl group , and more specifically , R ' rep resents fluorine, chlorine , a cyano group, a methyl group , an ethyl group , an isopropyl group , a cyclopropyl group , a ZA difluoromethyl group , a trifluoromethyl group , a vinyl " ( II - 33 ) group , a methoxy group , an ethoxyethyl group , a 2 - ethoxyvinyl group , or the like; R2 represents a hydrogen atom or a C1- 6 alkyl group , and more specifically , R ? represents a hydrogen atom , a methyl group , or the like ; 65 ring A represented by the following partial structural formula ( II) : US 9, 777 ,000 B2 135 136 - continued azol - 5 - yl group , a 5 - ethyl - 1 , 3 , 4 - thiadiazol- 2 - yl group , a ( II- 34 ) 5 -methyl - 1 , 3 , 4 - thiadiazol- 2 -yl group , a 5 - ( 2 - ethoxyvinyl) 4 methylthiazol- 2 - yl group , a 4 -methylpyrimidin - 2 - yl group , a 4 ,6 -dimethylpyrimidin -2 -yl group , a 4 -methylpyrimidin - 2 5 yl group , a 2 , 5 ,6 - trimethylpyrimidin - 4 -yl group , a 2 ,5 - dim ethylpyrimidin - 4 - yl group , a 2 ,6 - dimethylpyrimidin - 4 - yl group , a 2 ,6 -dimethoxypyrimidin - 4 - yl group , a 2 -methylpy ( II- 35 ) rimidin - 4 -yl group , a 2 -methoxypyrimidin - 4 - yl group , a 5 ,6 -dimethylpyrimidin -4 -yl group , a 5 - chloro - 2 -methylpy 10 rimidin - 4 -yl group , a 5 - chloropyrimidin - 4 -yl group , a N ; 5 - fluoro - 2 -methylpyrimidin - 4 - yl group , a 5 - fluoro - 2 methoxypyrimidin - 4 - yl group , a 5 - fluoro - 6 -methylpyrimi din - 4 - yl group , a 5 -methylpyrimidin - 4 -yl group , a 5 -methoxypyrimidin - 4 - yl group , a 6 -methylpyrimidin - 4 -yl 15 group , a 6 -methoxy - 5 -methylpyrimidin - 4 - yl group , a provided that when the ring A is represented by the formula 4 -methylpyridazin - 3 -yl group , a 5 -methylpyridazin - 3 - yl ( II -31 ) , p represents an integer of 1 to 3 ; and Rº represents group , a 6 -methylpyridazin -3 -yl group , a pyridazin -3 - yl a hydrogen atom or a C1- 6 alkyl group , and more specifically, group , a 3 - cyanopyridin - 2 - yl group , a 3 - cyano - pyridin - 2 - yl Rº represents a hydrogen atom , a methyl group , or the like , group , a 3 -methylpyridin - 2 - yl group , a 3 -methoxypyridin or a pharmaceutically acceptable salt thereof, or a solvate 20 2 - yl group , a 4 ,6 - dimethylpyridin - 2 - yl group , a 4 - fluoro thereof. pyridin - 2 - yl group , a 4 -methylpyridin - 2 - yl group , a 4 -meth [ 16 - 1 - 4 - 2 ] ylpyridin - 2 - yl group , a 4 -methoxypyridin - 2 - yl group , a More particularly preferably , the intermediate compound 4 -methoxy -pyridin - 2 - yl group , a 5 - cyanopyridin - 2 - yl group , of the above embodiment [ 16 ] is an intermediate compound a 5 - fluoropyridin - 2 - yl group , a 5 -methylpyridin - 2 -yl group , represented by the above formula (I ' ) wherein p , L , R², Rº, 25 a 5 -methylpyridin - 2 - yl group , a 6 -( trifluoromethyl) pyridin and ring A represented by the partial structural formula ( II ) 2 - yl group , a 6 -cyano -pyridin - 2 - yl group , a 6 -methylpyri have the same definitions as those described in the embodi- din - 2 - yl group , a 6 -methoxypyridin - 2 - yl group , a 3 ,6 - dim ment [ 16 - 1 - 4 ) provided that when the ring A is represented ethylpyrazin - 2 - yl group , a 3 ,6 -dimethyl - pyrazin - 2 -yl group , by the formula (II - 31 ), p represents an integer of 1 to 3 ; and a 3 -methylpyrazin - 2 - yl group , a 3 -methoxypyrazin - 2 -yl Reach independently represents a C2- 7 alkanoyl group , and 30 group , a 5 -methylpyrazin -2 -yl group , a 6 -methylpyrazin - 2 has the same definitions as those described in the embodi - yl group , or a 6 -methoxypyrazin -2 -yl group , or a pharma ment [ 16 - 1 - 4 ], and more specifically , R ' represents fluorine, ceutically acceptable salt thereof, or a solvate thereof. chlorine , a cyano group , a methyl group , an ethyl group , an [ 16 - 2 ] isopropyl group , a tert -butyl group , a cyclopropyl group , a An intermediate compound represented by the following difluoromethyl group , a trifluoromethyl group , a vinyl 35 formula ( I' - a ) , or a pharmaceutically acceptable salt thereof, group , a methoxy group , an ethoxyethyl group , a or a solvate thereof: 2 - ethoxyvinyl group , an acetyl group , or the like , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [Formula 87 ] [ 16 - 1 - 51 40 Even more particularly preferably , the intermediate com R2 ( I' - a ) pound of the above embodiment [ 16 ] is an intermediate compound represented by the above formula (I ' ) wherein p , N - N L , R ' , R², Rº, and ring A have the same definitions as those described in the above embodiment ( 16 - 1 - 4 - 2 ), and a spe - 45 cific ring A group , in which the definitions of the above described p , R ', and ring A are combined , represents a 1 - methyl- 1H - imidazol - 4 -yl group , a 4 - ( difluoromethyl) - 5 A ethylthiazol- 2 - yl group , a 4 - (difluoromethyl ) - 5 - vinylthi - -- ( R ') p azol- 2 -yl group , a 4 -( difluoromethyl ) - 5 -methylthiazol - 2 -yl 50 group , a 4 - ( difluoromethyl ) - 5 -methylthiazol - 2 -yl group , a 4 - (difluoromethyl ) thiazol- 2 - vl group , a 4 - ( difluoromethyl) wherein p , L , R ' , and R have the same definitions as those thiazol- 2 -yl group , a 4 - ( trifluoromethyl) thiazol - 2 -yl group , a described in the above embodiment [ 16 ] ; 4 - ( trifluoromethyl) thiazol- 2 -yl group , a 4 , 5 -dimethylthi ring A ' represented by the following partial structural azol- 2 - yl group , a 4 -tert -butylthiazol - 2 - yl group , a 4 - ethyl- 55 formula (IT ' ) : thiazol- 2 - yl group , a 4 -cyanothiazol - 2 - yl group , a 4 -meth ylthiazol- 2 - yl group , a 4 -methylthiazol - 2 - yl group , a 5 - ( 2 ethoxyethyl) - 4 -methylthiazol - 2 -yl group , a 5 -chloro - 4 [Formula 88 ] ( difluoromethyl) thiazol- 2 - yl group , a 5 - chloro - 4 (difluoromethyl ) thiazol- 2 - yl group , a 5 -cyclopropyl - 4 - 60 ( II' ) ( difluoromethyl )thiazol - 2 - yl group , a 5 - cyclopropyl- 4 methylthiazol- 2 - yl group , a 5 - bromo- 4 -methylthiazol - 2 - yl group , a 5 -methylthiazol - 2 - yl group , a thiazol- 2 - yl group , a 2 ,5 -dimethyl - thiazol - 4 -yl group , a 2 -methylthiazol - 4 -yl group , a 5 -acetyl -2 -methylthiazol - 4 -yl group , a 5 -bromo - 2 - 65 methylthiazol - 4 - yl group , a thiazol- 4 - yl group , a 3 - isopro - is selected from the group ofthe heteroaryls consisting of the pyl - 1 , 2 , 4 - thiadiazol- 5 - yl group , a 3 -methyl - 1 , 2 , 4 - thiadi following: US 9, 777 , 000 B2 137 138 ?-continued [ Formula 89] (II - 12 ) (II - 1 )

???? (II - 2) ( II- 13)

(II - 3 ) ?N (II - 14 )

(II - 4 ) 20 0N (II - 15 )

(II - 5 ) 25 ???? ? (II - 16 )

(II -17 )

(II - 7 ) 2????????? (II - 18) -R6

( II- 8 ) (II - 19 )

A0 (II - 9 ) ????????? (II - 20)

1?? 55 (II - 10 ) ( II - 21 ) ????

Z- ( II -11 ) (II - 22 ) ? ?

US 9, 777 , 000 B2 139 140 -continued (II - 23 ) [ Formula 90] ( II )

1 ?? (II - 24 ) is selected from the group of the heteroaryls consisting of the following: ??N - N 15 ??? ? Formula 911 ( II- 1 ) (II - 25 )

20 Ns MANEN (II - 3 ) (II - 26 ) 25 - R6

2?? N ? (II - 4) (II - 27 ) 30 ????? (II - 6 ) NEN 35 1-1-1-11-1 (II - 28 )

|

4=W 40 NS (II - 7) (II - 29 ) NTY 45 ??? (II - 9) (II - 30 )

50

? N - N NA1, ???? )6/ (II -10 ) 55 and R°represents a hydrogen atom, a C . , alkyl group, a halogenated C1- s alkyl group, ora hydroxy Ci- s alkyl group . [ 16- 2 - 2] Preferably , the intermediate compound of the above 60 (II -12 ) embodiment [ 16- 2 ] is an intermediate compound repre sented by the above formula (I - a ) wherein p , L , R ', and R N have the same definitions as those described in the above N embodiment [ 16- 1 ];

?Al6 ring A ' represented by the following partial structural )2?3?R formula (IT ) : US 9 ,777 ,000 B2 141 142 -continued -continued ( II -13 ) ( II -30 )

=1 SN 2 (II -15 ) " and Rº represents a hydrogen atom , a C1- 6 alkyl group , a halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , — N or a pharmaceutically acceptable salt thereof, or a solvate Ro thereof. [ 16 -2 - 3 ] ( II- 16 ) 15 More preferably , the intermediate compound of the above embodiment [ 16 - 2 ] is an intermediate compound repre sented by the above formula ( I' - a ) wherein p , L , R1, and R2 Z have the same definitions as those described in the above embodiment [ 16 - 1 - 2 - 2 ] ; ( II- 18 ) 20 ring A ' represented by the following partial structural formula ( II ') : N NRO 25 [Formula 92] (II - 19 ) ( II )

Al 30 ( II -21 ) is selected from the group of the heteroaryls consisting of the following : N 35 z [Formula 93 ] (II - 22 ) ( II - 1 )

40

N - S ( II- 24 ( II - 3 ) 45 2

=Z N R6 ( II - 4 ) ( II -25 ) 50

N

= ( II -6 ) (II -27 ) 55 RO N

N = N 60 ( II - 29 ) ( II - 7 )

65 US 9, 777 , 000 B2 143 144 -continued -continued (II - 9 ) ( II - 24

N?

??? (II - 27) ??2 (I - 10 , 10 - R6R6 A NAN WS ? (II -30 ) (II - 12 ) . ? N 4?4 AN 20 2??? and R° represents a hydrogen atom, a Clas alkyl group , a halogenated C . , alkyl group, or a hydroxy CL. , allkyl group . (I -13 ) 25 or a pharmaceutically acceptable salt thereof, or a solvate thereof . [16 - 2 - 4] Further preferably , the intermediate compound of the above embodiment [ 16 - 2 ] is an intermediate compound NS | 30 represented by the above formula (I - a) wherein p , L , R ' , and (II - 15 ) R ? have the same definitions as those described in the above embodiment [ 16 - 1 - 3 - 2 ]; ring A ' represented by the following partial structural formula (II ): N?N 35 1 [ Formula 94] (II - 16 ) (II ) NA 40 (I - 18 ) 45 is selected from the group of the heteroaryls consisting of the following :

(II -19 ) 50 [Formula 95] ( II- 1 )

?? (II -21 ) 55 (I - 3 ) ? ??R6

(II - 22 ) (II - 4 )

? N ? 88 US 9 ,777 , 000 B2 145 146 -continued -continued ( II - 6 ) ( II - 21)

u VRO ( II -22 ) (II - 7 ) 10

( II - 24

(11 - 9 ) 15 N — 22 R6; 20 and Ro represents a hydrogen atom , a C1- 6 alkyl group , a Powi halogenated C1- 6 alkyl group , or a hydroxy C1- 6 alkyl group , ( II- 10 ) or a pharmaceutically acceptable salt thereof, or a solvate thereof . [ 16 - 2 - 5 ] N Particularly preferably , the intermediate compound of the above embodiment [ 16 - 2 ] is an intermediate compound represented by the above formula (I ' - a ) wherein p , L , R ', and ( II- 12 ) R have the same definitions as those described in the above embodiment ( 16 - 1 - 4 - 2 ] ; ring A ' represented by the following partial structural N formula ( II' ) ; an 35 [Formula 96 ] ( II- 13 ) ( II' )

40 ( II- 15 ) is selected from the group of the heteroaryls consisting of the 45 following:

[Formula 97 ] (II - 16 ) 50 (II -1 )

- ( II - 4 ) (II - 18 ) 55

N - RO

g ( II - 6 ) ,!( II- 19)

e Ro US 9, 777 ,000 B2 147 148 - continued wherein p, L , R ', and R2 have the same definitions as those ( II- 16 ) described in the above embodiment [ 16 ] ; ring A " represented by the following partial structural TO formula ( II" ):

[Formula 99 ] ( II -19 ) 10 ( II " )

N

and Rº represents a hydrogen atom or a C1- 6 alkyl group , and 15 more specifically , Rº represents a hydrogen atom , a methyl group , or the like , or a pharmaceutically acceptable salt is selected from the group of the heteroaryls consisting of the thereof, or a solvate thereof. following : [ 16 - 2 - 6 ] More particularly preferably , the intermediate compound of the above embodiment [16 -2 ] is an intermediate com pound represented by the above formula ( I' - a ) wherein p , L , [Formula 100 ] R ? , R , and ring A ' have the same definitions as those ( II -31 ) described in the above embodiment ( 16 - 2 - 5 ] , and a specific ring A ' group , in which the definitions of the above described 25 p , R ' , and ring A ' are combined , represents a 1 -methyl - 1H imidazol- 4 -yl group , a 4 -( difluoromethyl ) - 5 -ethylthiazol - 2 yl group , a 4 - (difluoromethyl ) - 5 - vinylthiazol- 2 - yl group , a 4 - (difluoromethyl ) - 5 -methylthiazol - 2 - yl group , a 4 - (difluo romethyl) thiazol- 2 -yl group , a 4 - ( trifluoromethyl) thiazol- 2 - 30 ( II - 32 ) yl group, a 4 , 5 -dimethylthiazol - 2 - yl group , a 4 - tert -butylthi azol- 2 - yl group , a 4 - ethylthiazol- 2 - yl group , a 4 - cyanothiazol- 2 - yl group , a 4 -methylthiazol - 2 - yl group , a 4 -methylthiazol - 2 - yl group , a 5 - ( 2 -ethoxyethyl ) - 4 -methyl thiazol- 2 - yl group , a 5 - chloro - 4 - ( difluoromethyl) thiazol- 2 yl group , a 5 -cyclopropyl - 4 - (difluoromethyl ) thiazol- 2 - yl ( II - 33) group , a 5 -cyclopropyl - 4 -methylthiazol - 2 - yl group , a 5 -bromo - 4 -methylthiazol - 2 -yl group , a 5 -methylthiazol - 2 -yl group , a thiazol- 2 - yl group , a 2 , 5 - dimethyl- thiazol- 4 - yl group , a 2 -methylthiazol - 4 -yl group , a 5 -acetyl - 2 -methyl thiazol- 4 -yl group , a 5 -bromo - 2 -methylthiazol - 4 -yl group , a 40 thiazol- 4 - yl group, a 3 - isopropyl- 1 , 2 , 4 - thiadiazol- 5 - yl group , a 3 -methyl - 1 , 2 , 4 - thiadiazol- 5 - yl group , a 5 - ethyl - 1 , ( II -34 ) 3 , 4 - thiadiazol- 2 - yl group , a 5 -methyl - 1 , 3 , 4 - thiadiazol - 2 - yl group , or a 5 - ( 2 - ethoxyvinyl) 4 -methylthiazol - 2 - yl group , or a pharmaceutically acceptable salt thereof, or a solvate 45 thereof. [ 16 - 3 ] An intermediate compound represented by the following formula (I ' - b ), or a pharmaceutically acceptable salt thereof, ( II - 35) or a solvate thereof: 50 N

[Formula 98 ] ( II - 36 ) (I '- b ) 55 R ?

N - N

( II - 37)

41 (R ') p , ZEZ US 9 ,777 , 000 B2 149 150 - continued represented by the above formula ( I' - b ) wherein p , L , R ' , and ( II -38 ) R² have the same definitions as those described in the above embodiment [ 16 - 1 - 3 - 2 ); and ring A " represented by the following partial structural -391-N formula ( II " ) ; ( II - 39 ) [ Formula 101 ] 10 ( II” ) VEN ( II -40 ) AM - 15 is selected from the group of the heteroaryls consisting of the (II -41 ) 2020 follofollowing : [Formula 102 ] IN EZ ( II - 31) -Z 25 (II - 42)

30 ( II- 32 ) w ( II- 43 ) 35 N ( II - 33 ) v= 80 provided that when the ring A " is represented by the formulaa ( II - 31 ) , p represents an integer of 1 to 3 . [ 16 - 3 - 2 ] ( II - 34 ) Preferably , the intermediate compound of the above embodiment [ 16 - 3 ] is an intermediate compound repre - 45 sented by the above formula ( I' - b ) wherein p , L , R ' , and R ? have the same definitions as those described in the above embodiment [ 16 - 1 ] ; and ring A " represented by the partial structural formula ( II" ) has the same definitions as those ( II - 35 ) described in the above embodiment [ 16 - 3 ] provided that 50 when the ring A " is represented by the formula ( II - 31) , p represents an integer of 1 to 3 , or a pharmaceutically N N acceptable salt thereof, or a solvate thereof. [ 16 - 3 - 3 ] More preferably , the intermediate compound of the above 55 ( II - 36 ) embodiment [ 16 - 3 ] is an intermediate compound repre sented by the above formula ( I '- b ) wherein p , L , R1, and R2 have the same definitions as those described in the above embodiment [ 16 - 1 - 2 - 2 ] ; and ring A " represented by the partial structural formula ( II" ) has the same definitions as 60 those described in the above embodiment [ 16 - 3 ] provided ( II- 37 ) that when the ring A " is represented by the formula ( II -31 ) , p represents an integer of 1 to 3 , or a pharmaceutically acceptable salt thereof, or a solvate thereof. [ 16 - 3 - 4 ) 65 Further preferably , the intermediate compound of the ZEZ above embodiment [ 16 - 3 ] is an intermediate compound US 9 ,777 ,000 B2 151 152 -continued -continued (II -38 ) ( II - 33)

Z

=

( II -34 ) ( II- 39) 10

N V = ( II - 35) 15 (II - 43 ) NN N 20 = N provided that when the ring A " is represented by the formula ( II -31 ) , p represents an integer of 1 to 3 , or a pharmaceuti provided that when the ring A " is represented by the formula cally acceptable salt thereof, or a solvate thereof. ( II -31 ) , p represents an integer of 1 to 3 , or a pharmaceuti- 25 [ 16 - 3 - 6 ) cally acceptable salt thereof, or a solvate thereof. More particularly preferably , the intermediate compound [ 16 - 3 - 5 ] of the above embodiment [ 16 - 3 ] is an intermediate com pound represented by the above formula (I ' - b ) wherein p , L , Particularly preferably , the intermediate compound of the R , R², and ring A " have the same definitions as those above embodiment [ 16 - 3 ] is an intermediatemediate compoundcompound 30 described in the above embodiment [ 16 - 3 - 5 ), and a specific represented by the above formula (I ' - b ) wherein p , L , R ' , and ring A " group , in which the definitions of the above R2 have the same definitions as those described in the above described p , R ' , and ring A " are combined , represents a embodiment [ 16 - 1 - 4 - 2 ); and 4 ,6 -dimethylpyrimidin - 2 -yl group , a 4 -methylpyrimidin - 2 ring A " represented by the following partial structural yl group , a 2 , 5 ,6 - trimethylpyrimidin - 4 - yl group , a 2, 5 -dim 35 ethylpyrimidin - 4 -yl group , a 2 ,6 - dimethylpyrimidin - 4 - yl formula ( II " ) : group , a 2 ,6 -dimethoxypyrimidin -4 -yl group , a 2 -methylpy rimidin - 4 - yl group , a 2 -methoxypyrimidin - 4 -yl group , a 5 ,6 -dimethylpyrimidin - 4 - yl group , a 5 -chloro - 2 -methylpy [Formula 103 ] rimidin - 4 -yl group , a 5 -chloropyrimidin - 4 -yl group , a TTH 40 5 - fluoro - 2 -methylpyrimidin -4 -yl group , a 5 - fluoro - 2 methoxypyrimidin - 4 - yl group , a 5 - fluoro -6 -methylpyrimi din -4 -yl group , a 5 -methylpyrimidin -4 -yl group , a 5 -methoxypyrimidin - 4 - yl group , a 6 -methylpyrimidin - 4 - yl IA" group , a 6 -methoxy - 5 - methylpyrimidin - 4 - yl group , a 45 4 -methylpyridazin - 3 - yl group , a 5 -methylpyridazin - 3 -yl HI group , a 6 -methylpyridazin - 3 -yl group , a pyridazin - 3 -yl group , a 3 -cyano -pyridin - 2 -yl group , a 3 -methylpyridin - 2 -yl group , a 3 -methoxypyridin - 2 - yl group , a 4 , 6 - dimethylpyri is selected from the group of the heteroaryls consisting of the din -2 - yl group , a 4 - fluoropyridin - 2 -yl group , a 4 -methyl following : 50 pyridin - 2 -yl group , a 4 -methoxypyridin -2 -yl group , a 5 -cya nopyridin - 2 -yl group , a 5 - fluoropyridin - 2 -yl group , a 5 -methylpyridin - 2 -yl group , a 6 - ( trifluoromethyl) pyridin - 2 [ Formula 104 ] yl group , a 6 - cyano - pyridin - 2 - yl group , a 6 -methylpyridin 2 - yl group , a 6 -methoxypyridin - 2 - yl group , a 3 , 6 - dimethyl (II - 31 ) 55 pyrazin - 2 -yl group , a 3 -methylpyrazin - 2 -yl group , a 3 -methoxypyrazin - 2 - yl group , a 5 -methylpyrazin - 2 - yl group , a 6 -methylpyrazin - 2 - yl group , a 6 -methylpyrazin - 2 yl group , or a 6 -methoxypyrazin - 2 - yl group , or a pharma ceutically acceptable salt thereof, or a solvate thereof. 60 [ 17 ] (II - 32 ) A seventeenth embodiment of the present invention is illustrated , by way of example , with the below - listed inter mediate compounds that are preferable as the compounds of the above embodiment [ 16 ] represented by the above for 65 mula (I ' ) , the compounds of the above embodiment [ 16 - 2 ] ZEZ represented by the above formula ( I' - a ) , and the compounds of the above embodiment [ 16 - 3 ] represented by the above US 9 ,777 ,000 B2 153 154 formula ( I' - b ) , or pharmaceutically acceptable salts thereof, pound corresponding to ( Example 1 . 1 ) < Step 2 > is obtained . or their solvates. The shown intermediate compounds are It is to be noted that the following compound names are obtained from individual steps with Example numbers cor based on English names obtained in accordance with the responding to compound names. For example , in the case of chemical nomenclature program of Cambridge Soft Chem Example number 1 . 1 - 2 , it means that an intermediate com BioDraw Ultra 12 . 0 .2 . 1076 . TABLE 2 Example Compound name No . methyl 1 -methyl - 4 - ( 5 -methylpyridin - 2 -yl ) - 1H - pyrazole - 5 - carboxylate 1 . 1 - 2 1 -methyl - 4 - ( 5 -methylpyridin - 2 - yl) - 1 H -pyrazole - 5 -carboxylic acid 1 . 1 - 3 methyl 1 -methyl - 4 - ( 4 -methylthiazol - 2 - yl ) - 1H -pyrazole - 5 -carboxylate 1 . 2 - 1 1 -methyl - 4 - ( 4 -methylthiazol - 2 - yl) - 1H -pyrazole - 5 -carboxylic acid 1 . 2 - 2 . methyl 4 - ( 4 - ( difluoromethyl ) thiazol- 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 1 . 3 - 1 carboxylate methyl 4 - (5 -bromo - 4 - (difluoromethyl )thiazol - 2 -yl ) - 1 -methyl -1H 1 . 4 - 1 pyrazole - 5 -carboxylate methyl 4 - ( 4 - ( difluoromethyl) - 5 -methylthiazol - 2 -yl )- 1 -methyl - 1H 1 . 4 - 2 pyrazole - 5 -carboxylate methyl 1 -methyl - 4 - ( 4 - (trifluoromethyl ) thiazol - 2 - yl) - 1H -pyrazole - 5 1 . 5 - 1 carboxylate methyl 1 -methyl - 4 - ( 6 - (trifluoromethyl ) pyridin - 2 - yl ) - 1 H -pyrazole - 5 1 . 6 - 1 carboxylate methyl 4- (5 -chloro -4 -( difluoromethyl) thiazol- 2 - yl) - 1- methyl - 1H 1 . 7 - 1 pyrazole - 5 -carboxylate 4 - ( 5 -chloro - 4 - (difluoromethyl ) thiazol- 2 - yl )- 1 -methyl - 1 H -pyrazole - 5 - 1. 7 -2 carboxylic acid methyl 4 - ( 4 ,5 - dimethylthiazol- 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 2 . 2 - 1 carboxylate 4 - ( 4 , 5 -dimethylthiazol - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 -carboxylic acid 2 . 2 - 2 1- methyl - 4 -( 4- ( trifluoromethyl ) thiazol- 2- yl )- 1H -pyrazole - 5 -carboxylic 2 . 8 - 1 acid methyl 1 -methyl - 4 - (6 -methylpyridin - 2 -yl ) - 1H -pyrazole - 5 -carboxylate 2 . 9 - 1 methyl 1 -methyl - 4 - (5 -methyl - 1 , 3 , 4 - thiadiazol- 2 -yl ) - 1H -pyrazole - 5 2 . 10 - 1 carboxylate 1 -methyl - 4 - ( 5 -methyl - 1, 3 , 4 - thiadiazol- 2 - yl) - 1 H -pyrazole - 5 -carboxylic 2 . 10 - 2 acid methyl 4 - ( 6 -methoxypyridin - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 2 . 11 - 1 carboxylate 4 - ( 6 -methoxypyridin - 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 -carboxylic acid 2 . 11 - 2 methyl 1 -methyl - 4 - ( 2 -methylthiazol - 4 - yl) - 1H - pyrazole - 5 - carboxylate 2 . 12 - 1 methyl 1 -methyl - 4 - ( 6 -methylpyrazin - 2 - yl) - 1H -pyrazole - 5 - carboxylate 2 . 13 - 1 1 -methyl - 4 - (6 -methylpyrazin - 2 - yl ) - 1 H -pyrazole - 5 - carboxylic acid 2 . 13 - 2 methyl 4 - ( 3 - isopropyl- 1 , 2 , 4 -thiadiazol - 5 -yl )- 1 -methyl - 1H -pyrazole - 5 2 . 14 - 1 carboxylate methyl 1- methyl - 4 -( 5 -methylthiazol - 2 -yl ) - 1H -pyrazole -5 - carboxylate 2 . 15 - 1 methyl 1 -methyl - 4 - ( 4 -methylpyrimidin - 2 - yl) - 1 H -pyrazole - 5 2 . 16 - 1 carboxylate 1 -methyl - 4 - ( 4 -methylpyrimidin - 2 - yl) - 1H -pyrazole - 5 -carboxylic acid 2 . 16 - 2 methyl 1 -methyl - 4 - ( 1 -methyl - 1H - imidazol - 4 - yl) - 1 H -pyrazole - 5 2 . 17 - 1 carboxylate 1 -methyl - 4 - ( 4 - ( trifluoromethyl) thiazol- 2 - yl) - 1H -pyrazole - 5 - carboxylic 2 . 19 - 7 acid methyl 1 -methyl - 4 - ( thiazol- 4 -yl ) - 1H -pyrazole - 5 -carboxylate 2 . 25 - 1 methyl 1 -methyl - 4 - (thiazol - 2 - yl) - 1H - pyrazole - 5 - carboxylate 2 . 26 - 1 methyl 4 - ( 4 - tert- butyl ) thiazol - 2 -yl ) - 1 -methyl - 1H -pyrazole -5 2 .27 - 1 carboxylate methyl 1- methyl - 4 -( 3 -methylpyridin -2 - yl) - 1H -pyrazole -5 -carboxylate 3 . 1 - 2 1 -methyl - 4 - ( 3 -methylpyridin - 2 - yl) - 1H -pyrazole - 5 - carboxylic acid 3 . 1 - 3 1 -methyl - 4 - ( 5 -methylpyrazin - 2 - yl) -1H -pyrazole - 5 - carboxylic acid 3 . 2 - 1 1 -methyl - 4 - (6 -methylpyridin - 2 - yl )- 1H -pyrazole - 5 -carboxylic acid 3 . 3 - 1 4 - ( 4 - fluoropyridin - 2 - yl) - 1 -methyl - 1H - pyrazole - 5 - carboxylic acid 3 . 4 - 1 1 -methyl - 4 - ( 4 -methylpyridin - 2 - yl) - 1 H -pyrazole - 5 - carboxylic acid 3 . 5 - 1 1 -methyl - 4 - ( 4 - ( trifluoromethyl) thiazol - 2 -yl ) -1H -pyrazole - 5 -carboxylic 3 . 6 - 1 acid 4 - ( 3 -methoxypyridin - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 -carboxylic acid 3 . 7 - 1 4 -( 5 -fluoropyridin -2 -yl ) - 1 -methyl - 1H -pyrazole -5 -carboxylic acid 3 . 8 - 1 methyl 1 -methyl - 4 - ( 6 -methylpyrazm - 2 -yl ) - 1H -pyrazole - 5 -carboxylate 3 . 9 - 1 1 -methyl - 4 - (6 -methylpyrazin - 2- yl) - 1 H -pyrazole -5 -carboxylic acid 3 . 9 - 2 1 -methyl - 4 - ( 6 - ( trifluoromethyl) pyridin - 2 -yl ) - 1H -pyrazole - 5 -carboxylic 3 . 10 - 1 acid 4 - ( 4 ,6 - dimethylpyridin - 2 - yl) - 1 -methyl - 1 H -pyrazole - 5 - carboxylic acid 3 . 11 - 1 4 - ( 4 -difluoromethyl ) thiazol- 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 -carboxylic 3 . 12 - 1 acid methyl 4 - ( 3 -cyanopyridin - 2 - yl) - 1 -methyl - 1 H -pyrazole - 5 - carboxylate 3 . 13 - 1 4 - (3 -cyanopyridin - 2 - yl )- 1 -methyl - 1H -pyrazole -5 -carboxylic acid 3 . 13 - 2 methyl 4 - ( 3 ,6 - dimethylpyrazin - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 3 . 14 - 1 carboxylate US 9 ,777 ,000 B2 155 156 TABLE 2 - continued Example Compound name No . 4 - ( 3 , 6 -dimethylpyrazin - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 -carboxylic acid 3 . 14 - 2 methyl 4 - ( 4 - ethylthiazol- 2 - yl) - 1 -methyl - 1 H -pyrazole - 5 -carboxylate 3 . 18 - 1 4 - ( 4 - ethylthiazol - 2 - yl) - 1 -methyl - 1 H - pyrazole - 5 - carboxylic acid 3 .18 - 2 methyl 4 -( 2 , 5 - dimethylpyrimidin -4 - yl ) - 1 - methyl - 1H - pyrazole -5 3 . 22 - 1 carboxylate 4 - ( 2 ,5 -dimethylpyrimidin -4 -yl ) - 1 -methyl - 1 H -pyrazole -5 -carboxylic 3 .22 - 2 acid 4 - ( 5 -cyanopyridin - 2- yl) - 1- methyl - 1H -pyrazole - 5 -carboxylic acid 3 . 23 - 1 methyl 1 -methyl - 4 - ( 4 -methylpyridazin - 3 - yl) - 1H - pyrazole - 5 3 . 24 - 1 carboxylate 1 -methyl - 4- ( 4- methylpyridazin - 3 -yl ) - 1H -pyrazole -5 -carboxylic acid 3 . 24 - 2 methyl 1 -methyl - 4 - ( 2 -methylpyrimidin - 4 - yl ) - 1 H -pyrazole - 5 3 .25 - 1 carboxylate 1 -methyl - 4 - ( 2 -methylpyrimidin - 4 - yl) - 1H -pyrazole - 5 - carboxylic acid 3 . 25 - 2 methyl 4 -( 2 - methoxypyrimidin - 4 - yl) - 1 -methyl - 1H -pyrazole -5 3 . 26 - 1 carboxylate 4 - ( 2 -methoxypyrimidin - 4 - yl ) - 1 -methyl - 1H -pyrazole - 5 - carboxylic acid 3 . 26 - 2 methyl 4- (5 - fluoro -2 -methoxypyrimidin -4 - yl ) - 1 - methyl - 1H -pyrazole 3 . 27 - 1 5 - carboxylate 4 - ( 5 - fluoro - 2 -methoxypyrimidin - 4 - yl) - 1 -methyl - 1 H -pyrazole - 5 3 . 27 - 2 carboxylic acid methyl 4 - ( 3 -methoxypyrazin - 2 - yl ) - 1 -methyl - 1H - pyrazole - 5 3 . 28 - 1 carboxylate 4 - ( 3 -methoxypyrazin - 2 - yl) - 1 -methyl - 1H - pyrazole -5 - carboxylic acid 3 .28 - 2 methyl 4- (5 -chloropyrimidin -4 - yl )- 1- methyl - 1H -pyrazole -5 3 . 29 - 1 carboxylate 4 - ( 5 -chloropyrimidin - 4 -yl ) - 1 -methyl - 1H -pyrazole - 5 -carboxylic acid 3 . 29 - 2 methyl 4 - ( 2 , 6 - dimethylpyrimidin - 4 -yl ) - 1 -methyl - 1H -pyrazole - 5 3 . 30 - 1 carboxylate 4- ( 2 ,6 - dimethylpyrimidin -4 - yl) - 1- methyl - 1 H -pyrazole - 5 -carboxylic 3 . 30 - 2 acid methyl 4 - ( 6 -methoxy - 5 -methylpyrimidin - 4 - yl) - 1 -methyl - 1H -pyrazole - 3 .31 - 1 5 -carboxylate 4 - ( 6 -methoxy - 5 -methylpyrimidin - 4 - yl ) - 1 -methyl - 1 H -pyrazole - 5 3 .31 - 2 carboxylic acid methyl 1 -methyl - 4 - ( 3 -methylpyrazin - 2 - yl) - 1H -pyrazole - 5 - carboxylate 3 . 32 - 1 1 -methyl - 4 - ( 3 -methylpyrazin - 2 -yl ) - 1 H -pyrazole - 5 - carboxylic acid 3 . 32 - 2 methyl 1 -methyl - 4 - (5 -methylpyrimidin - 4 - yl ) - 1 H -pyrazole - 5 3 . 33 - 1 carboxylate 1 -methyl - 4 - ( 5 -methylpyrimidin - 4 - yl ) - 1H -pyrazole - 5 - carboxylic acid 3 . 33 - 2 methyl 4 - ( 5 -methoxypyrimidin - 4 - yl ) - 1 -methyl - 1 H - pyrazole -5 3 .34 - 1 carboxylate 4 - (5 -methoxypyrimidin - 4 - yl) - 1 -methyl - 1H - pyrazole - 5 - carboxylic acid 3 . 34 - 2 methyl 4 - ( 5 ,6 -dimethylpyrimidin -4 -yl ) - 1 -methyl -1H -pyrazole - 5 3 . 35 - 1 carboxylate 4 -( 5 ,6 -dimethylpyrimidin -4 -yl ) - 1 - methyl - 1 H -pyrazole -5 - carboxylic 3 . 35 - 2 acid methyl 4 - ( 5 - fluoro - 2 -methylpyrimidin - 4 - yl) - 1 -methyl - 1H -pyrazole - 5 - 3 . 36 - 1 carboxylate 4 -( 5 - fluoro -2 -methylpyrimidin - 4 -yl ) - 1 -methyl - 1H -pyrazole -5 3 . 36 - 2 carboxylic acid methyl 1 -methyl - 4 - ( 2 ,5 ,6 - trimethylpyrimidin - 4 -yl )- 1H -pyrazole - 5 3 . 37 - 1 carboxylate 1 -methyl - 4 - ( 2 ,5 , 6 - trimethylpyrimidin -4 - yl) -1H -pyrazole - 5 -carboxylic 3 . 37 - 2 acid methyl 4 - ( 5 - fluoro -6 -methylpyrimidin - 4 - yl) - 1 -methyl - 1H - pyrazole - 5 3 . 38 - 1 carboxylate 4 - ( 5 - fluoro -6 -methylpyrimidin - 4 -yl ) -1 -methyl - 1 H -pyrazole -5 3 .38 - 2 carboxylic acid methyl 1 -methyl - 4 - (6 -methylpyrimidin - 4 -yl ) - 1H - pyrazole - 5 3 .39 - 1 carboxylate 1 -methyl - 4 - ( 6 -methylpyrimidin - 4 -yl ) - 1H -pyrazole - 5 -carboxylic acid 3 . 39 - 2 methyl 4 - ( 2 , 6 - dimethoxypyrimidin - 4 -yl ) - 1 -methyl - 1H -pyrazole - 5 3 . 40 - 1 carboxylate 4 - ( 2 ,6 -dimethoxypyrimidin - 4 - yl )- 1 -methyl - 1H -pyrazole -5 - carboxylic 3 . 40 - 2 acid methyl 4- (5 -chloro - 2- methylpyrimidin -4 - yl) - 1- methyl - 1H -pyrazole vrazole - 5 - 3 .41 - 1 carboxylate 4 -( 5 -chloro - 2 -methylpyrimidin -4 - yl) - 1 -methyl - 1H -pyrazole -5 3 . 41 - 2 carboxylic acid methyl 4 - ( 6 -methoxypyrazin - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 3 .42 - 1 carboxylate 4 - ( 6 -methoxypyrazin - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 -carboxylic acid 3 .42 - 2 methyl 1 -methyl - 4 - ( 4 -methylpyrimidin - 2 - yl ) - 1 H - pyrazole -5 3 .43 - 1 carboxylate US 9 ,777 ,000 B2 157 158 TABLE 2 - continued Example Compound name No . 1 -methyl - 4 - ( 4 -methylpyrimidin - 2 -yl ) - 1H -pyrazole - 5 -carboxylic acid 3 .43 - 2 methyl 4 - ( 4 , 6 - dimethylpyrimidin - 2 -yl ) - 1 -methyl - 1H -pyrazole - 5 3 .44 - 1 carboxylate 4 - ( 4 ,6 -dimethylpyrimidin - 2 -yl )- 1 -methyl - 1H -pyrazole -5 - carboxylic 3 .44 - 2 acid methyl 1- methyl - 4 -( 6 -methylpyridazin - 3- yl) - 1H -pyrazole -5 3 . 45 - 1 carboxylate 1 -methyl - 4 - ( 6 -methylpyridazin - 3 - yl) - 1H - pyrazole - 5 -carboxylic acid 3 .45 - 2 methyl 1 -methyl - 4 - ( 5 -methylpyridazin - 3 - yl) -1H -pyrazole - 5 3 . 46 - 1 carboxylate 1 -methyl - 4 - ( 5 -methylpyridazin - 3 - yl) - 1H -pyrazole - 5 -carboxylic acid 3 . 46 - 2 methyl 1 -methyl - 4 - (pyridazin - 3 -yl ) - 1 H -pyrazole - 5 - carboxylate 3 . 47 - 1 1 -methyl - 4 - (pyridazin - 3 - yl) - 1H -pyrazole - 5 - carboxylic acid 3 . 47 - 2 methyl 1 -methyl - 4 - ( 4 -methylpyridin - 2 -yl ) - 1 H - pyrazole - 5 - carboxylate 4 . 4 - 1 1 -methyl - 4 - ( 4 -methylpyridin - 2 - yl ) -1H -pyrazole - 5 - carboxylic acid 4 . 4 - 2 methyl 4 - ( 4 -methoxypyridin - 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 4 . 5 - 1 carboxylate 4 - ( 4 -methoxypyridin - 2 - yl )- 1 -methyl - 1H -pyrazole - 5 -carboxylic acid 4 . 5 - 2 methyl 4 - ( 4 ,6 -dimethylpyridin - 2 - yl )- 1 -methyl - 1H -pyrazole - 5 4 . 8 - 1 carboxylate 4 - ( 4, 6 -dimethylpyridin - 2 - yl )- 1 -methyl -1H - pyrazole - 5 -carboxylic acid 4 . 8 - 2 4 - ( 4 - ( difluoromethyl ) - 5 -methylthiazol - 2 - yl) - 1 -methyl - 1 H - pyrazole - 5 4 . 9 - 1 carboxylic acid 1 -methyl - 4 - ( 4- ( trifluoromethyl) thiazol- 2 - yl) - 1H -pyrazole - 5 - carboxylic 4 . 10 - 1 acid methyl 4 -( 4 ,5 -dimethylthiazol - 2- yl ) -1 - methyl - 1 H -pyrazole -5 5 . 4 - 1 carboxylate methyl 4 - ( 4 - ( difluoromethyl) - 5 - vinylthiazol- 2 -yl ) - 1 -methyl - 1H 5 . 5 - 1 pyrazole -5 -carboxylate methyl 4 - ( 4 - (difluoromethyl ) -5 - ethylthiazol - 2 - yl) - 1 -methyl - 1H 5 . 6 - 1 pyrazole - 5 -carboxylate methyl 4 - ( 5 -cyclopropyl - 4 - (difluoromethyl ) thiazol - 2 -yl ) - 1 - methyl- 1H 5 . 8 - 1 pyrazole - 5 - carboxylate 4 - ( 4 -cyanothiazol - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 - carboxylic acid 5 . 10 - 1 methyl 4 - ( 5 - bromo - 4 -methylthiazol - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 5 . 11 - 1 carboxylate ( E ) -methyl 4 - (5 - ( 2 - ethoxyvinyl ) - 4 -methylthiazol - 2 -yl ) - 1 -methyl - 1H 5 .11 - 2 pyrazole - 5 -carboxylate methyl 4 - ( 5 - ( 2 -ethoxyethyl ) - 4 -methylthiazol - 2 - yl) - 1- methyl - 1H 5 . 11 - 3 pyrazole - 5 - carboxylate methyl 4 - ( 5 -ethyl - 1, 3 ,4 - thiadiazol - 2 -yl ) - 1 -methyl - 1 H -pyrazole - 5 5 . 12 - 1 carboxylate methyl 4 - ( 5 -bromo - 2 -methylthiazol - 4 - yl )- 1 -methyl - 1H - pyrazole - 5 5 .13 - 1 carboxylate methyl 1 -methyl - 4 - 3 -methyl - 1 ,2 , 4 -thiadiazol - 5 - yl) - 1H -pyrazole - 5 5 . 15 - 1 carboxylate methyl 4 - ( 5 -bromo - 4 -methylthiazol - 2 -yl ) - 1- methyl -1H -pyrazole - 5 5 . 38 - 1 carboxylate 4 -( 5 - cyclopropyl- 4 -methylthiazol - 2 - yl )- 1 - methyl - 1H -pyrazole -5 5 . 38 - 2 carboxylic acid 4 - ( 2 ,5 - dimethylthiazol- 4 - yl) - 1 -methyl -1H - pyrazole - 5 - carboxylic acid 5 . 39 - 1 4 - ( 6 - cyanopyridin - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 - carboxylic acid 5 . 40 - 1 4 - ( 4 - cyanothiazol - 2 - yl) - 1 -methyl - 1H -pyrazole - 5 - carboxylic acid 5 . 41 - 1 methyl 4 - ( 5 -cyclopropyl -4 -methylthiazol - 2 -yl ) - 1 -methyl - 1H -pyrazole 5 . 43 - 1 5 -carboxylate methyl 4 - ( 5 - acetyl- 2 -methylthiazol - 4 - yl )- 1 -methyl - 1 H -pyrazole - 5 5 . 44 - 1 carboxylate 4 - ( 4 ,5 - dimethylthiazol- 2 - yl) - 1 -methyl -1H - pyrazole - 5 - carboxylic acid 5 . 45 - 1 1 -methyl - 4 - ( 6 -methylpyridin - 2 -yl ) - 1H -pyrazole - 5 -carbonyl chloride 5 . 47 - 1

In all of the above described embodiments , when the term 55 salts such as calcium salts , magnesium salts , and barium " compound ” is used, it also refers to a “ pharmaceutically salts ; and aluminum salts (wherein the salts include diso acceptable salt thereof. " dium salts and dipotassium salts, as well as mono salts ) . There may be a case in which the compound in the present Preferred examples of the salts with organic bases include invention forms an acid addition salt or a salt with a base , salts with methylamine, ethylamine , t -butylamine , t - oc depending on the type of a substituent . Such salts are not 60 tylamine , diethylamine , trimethylamine , triethylamine, particularly limited , as long as they are pharmaceutically cyclohexylamine , dicyclohexylamine , dibenzylamine , etha acceptable salts . Examples of the salts include metal salts , nolamine , diethanolamine, triethanolamine , piperidine , mor ammonium salts , salts with organic bases, salts with inor- pholine, pyridine , picoline , lysine , arginine , ornithine , eth ganic acids, salts with organic acids , and salts with basic or ylenediamine , N -methylglucamine , glucosamine , acidic amino acids. Preferred examples of the metal salts 65 phenylglycinealkylester, guanidine, 2 , 6 -lutidine , etha include : alkaline metal salts , such as lithium salts , sodium nolamine, diethanolamine , triethanolamine , and N , N - diben salts , potassium salts , and cesium salts ; alkaline- earth metal zylethylenediamine . Preferred examples of the salts with US 9 ,777 ,000 B2 159 160 inorganic acids include salts with hydrochloric acid , hydro - hydrolysis or the like , following administration into or on a bromic acid , hydroiodic acid , nitric acid , sulfuric acid , and body, the compound before administration is referred to as phosphoric acid . Preferred examples of the salts with a “ prodrug. ” organic acids include : salts with aliphatic monocarboxylic A “ prodrug” of the compound in the present invention can acids such as formic acid , acetic acid , trifluoroacetic acid , 5 be produced , for example , by subjecting a suitable func propionic acid , butyric acid , valeric acid , enanthic acid , tiontional group present in the compound in the present inven tion to a known method , for example , the method described capric acid , myristic acid , palmitic acid , stearic acid , lactic in Design of Prodrugs , H . Bundgaard (Elsevier , 1985 ) . acid , sorbic acid , and mandelic acid ; salts with aliphatic Specific examples of the “ prodrug ” of the compound in dicarboxylic acids such as oxalic acid , malonic acid , suc< 10 the present invention may include the following ( 1 ) to ( 3 ) , cinic acid , fumaric acid , maleic acid , malic acid , and tartaric but examples are not limited thereto . acid ; salts with aliphatic tricarboxylic acids such as citric ( 1 ) Case in which the compound in the present invention is acid ; salts with aromatic monocarboxylic acids such as substituted with a carboxy group ( COOH ) : the ester benzoic acid and salicylic acid ; salts with aromatic dicar thereof, namely , a compound in which the hydrogen atom of boxylic acids such as phthalic acid ; salts with1 . organicOrganic 15 the carboxy group ( COOH ) is replaced with a “ C1- 6 alkyl carboxylic acids such as cinnamic acid , glycolic acid , pyru group .” vic acid , oxyl acid , salicylic acid , and N -acetyl cysteine ; (2 ) Case in which the compound in the present invention is salts with organic sulfonic acids such as methanesulfonic substituted with a hydroxyl group ( OH ) : the alkanoyloxy acid , benzenesulfonic acid , and p -toluenesulfonic acid ; and or the ether thereof, namely , a compound in which the acid addition salts with acidic amino acids such as aspartic 20 hydrogen atom of the hydroxyl group ( OH ) is replaced acid and glutamic acid . Preferred examples of the salts with with a “ C2- 7 alkanoyl group ” or a “ C2- 7 alkanoyloxymethyl basic amino acids include salts with arginine , lysine, and group. ” ornithine . Preferred examples of the salts with acidic amino ( 3 ) Case in which the compound in the present invention is acids include salts with aspartic acid and glutamic acid . substituted with an amino group ( NH , or — NHR ' Among these salts , pharmaceutically acceptable salts are 25 (wherein R ' = H ) ) : the amide thereof, namely , a compound in preferable . For example , when the compound has an acidic which either hydrogen atom or both hydrogen atoms of the functional group therein , examples of the salts include amino group ( NH , or — NHR ' (wherein R ' + H )) are inorganic salts such as alkaline metal salts ( e. g . sodium salts replaced with “ C2 - alkanoyl groups. ” and potassium salts ) and alkaline -earth metal salts ( e . g . When the compound in the present invention has isomers calcium salts , magnesium salts , and barium salts ) , and 30 such as a geometrical isomer , a configurational isomer , a ammonium salts . When the compound has a basic functional tautomeric isomer , an optical isomer, a diastereomer, a group therein , examples of the salts include : salts with regioisomer , or a rotational isomer, both any one isomer and inorganic acids such as hydrochloric acid , hydrobromic acid , a mixture thereof are included in the compound in the nitric acid , sulfuric acid , and phosphoric acid ; and salts with present invention . Moreover , when the compound in the organic acids such as acetic acid , phthalic acid , fumaric acid , 35 present invention has an optical isomer , an optical isomer oxalic acid , tartaric acid , maleic acid , citric acid , succinic obtained from a racemate is also included in the compound acid , methanesulfonic acid and p - toluenesulfonic acid . in the present invention . The above described salts can be obtained according to an In the case of the compound in the present invention has ordinary method , for example , by mixing the compound in one or more asymmetric carbon atoms, two or more isomers the present invention with a solution containing an appro - 40 can be present. In addition , when the compound in the priate amount of acid or base to form salts of interest , and present invention comprises a “ C2 - 6 alkenyl group , " geo then subjecting the salts to fractionation by filtration , or metrical isomer ( cis / trans or Z / E ) can be present. Moreover , distilling the mixed solvent away from the reaction solution . structural isomers can be mutually converted because of low Moreover, the compound in the present invention or a salt energy barrier, tautomeric isomerism may be generated . An thereof can form a solvate with a solvent such as water , 45 example of such tautomeric isomerism is protonic tauto ethanol, or glycerol. meric isomerism in a compound having an imino , keto , or Handbook of Pharmaceutical Salts : Properties , Selection , oxime group . and Use , Stahl & Wermuth (Wiley -VCH , 2002 ) has been When the compound in the present invention has a published as a review book regarding salts . This book geometrical isomer, a configurational isomer, a diaste includes detailed descriptions regarding salts . 50 reomer , a conformer or the like , these isomers can be each The compound in the present invention can be present in isolated by a known means . an unsolvated state or a solvated state . In the present Furthermore, when the compound in the present invention specification , the term “ solvate ” means a molecular complex is an optically active substance , a racemate can be separated comprising the compound in the present invention and one into a ( + ) form or a ( - ) form [ D form or L form ] according ormore pharmaceutically acceptable solventmolecules ( e . g . 55 to an ordinary optical resolution means. water and ethanol) . When the aforementioned solvent mol- When the compound in the present invention contains an ecule is water, it is particularly referred to as a “ hydrate . " optical isomer , a diastereomer, a regioisomer, a rotational Hereinafter , the descriptions regarding the compound in isomer , or a tautomeric isomer, each isomer can be obtained the present invention include the descriptions regarding the as a single compound according to a known synthetic salt thereof, the solvate thereof, and a solvate of the salt . 60 method or separation method . Examples of the optical The “ prodrug ” of the compound in the present invention resolution method include known methods such as ( 1 ) a is also included in the compound in the present invention . fractional recrystallization method , ( 2 ) a diastereomer For instance , when a certain derivative of the compound in method , and ( 3 ) a chiral column method. the present invention , which may hardly or never exhibit ( 1 ) Fractional recrystallization method : This is a method pharmacological activities of interest , is converted to the 65 which comprises binding an optical resolution agent to a compound in the present invention having the pharmaco - racemate via an ionic bond to obtain a crystalline diaste logical activities of interest , for example , as a result of reomer , then separating this diastereomer by a fractional US 9 ,777 ,000 B2 161 162 recrystallization method , and then subjecting the resultant to The compound in the present invention , which is labeled a neutralization step , as desired , so as to obtain a free or substituted with certain types of isotopes ( e . g . positron optically pure compound . Examples of the optical resolution emission isotopes such as 11C , 18F , 150 and 13N ), can be agent include ( + ) -mandelic acid , ( - ) -mandelic acid , ( + ) used , for example , as a tracer (PET tracer ) in Positron tartaric acid , ( - ) - tartaric acid , ( + ) - 1 -phenethylamine , ( - ) - 1 - 5 Emission Tomography ( PET) , and thus , it is useful in the phenethylamine , cinchonine, (- ) -cinchonidine , and brucine . field such as medical diagnosis . ( 2 ) Diastereomer method : This is a method which com - The compound in the present invention , which is labeled prises binding via a covalent bond (reacting ) an optical or substituted with certain types of isotopes , is useful for resolution agent to a racemate mixture to form a diaste - studies regarding histological distribution of drugs and /or reomer mixture , then subjecting the diastereomer mixture to 10 substrates . For instance, PH and 14C facilitate such labeling a common separation means ( e . g ., fractional recrystalliza - and substitution , and the detection means is easy . Thus, they tion , silica gel column chromatography, and HPLC (high are useful for the aforementioned study purpose . performance liquid chromatography ) ) to separate it into an The compound in the present invention , which is labeled optically pure diastereomer, and then removing the optical with isotopes , can be obtained by a common technique resolution agent by a chemical treatment such as a hydro - 15 known to a person skilled in the art , or by a method similar lysis reaction , so as to obtain an optically pure optical to the synthetic methods described later in Examples . In isomer. For example, when the compound in the present addition , instead of a non - labeled compound , the obtained invention has an intramolecular hydroxyl group or a primary isotope -labeled compound can be used in pharmacological or secondary amino group , the compound and an optically experiments . active organic acid ( e . g ., MTPA [ a -methoxy - a - ( trifluorom - 20 [Method for Producing the Compound in the Present Inven ethyl) phenylacetic acid ) and ( - ) -menthoxyacetic acid ) or the tion ] like are subjected to a condensation reaction , so as to obtain Hereinafter , a method for producing the compound rep a diastereomer of each ester body or amide body . On the resented by the formula ( I) of the present invention will be other hand , when the compound in the present invention has described . The compound represented by the formula ( I ) that a carboxy group , the compound and an optically active 25 is the compound in the present invention , a salt thereof, and amine or an alcohol reagent are subjected to a condensation a solvate thereof can be easily produced by a combination of reaction , so as to obtain a diastereomer of each amide body known general chemical production methods, using , as or ester body . Each of the above separated diastereomers is starting materials or synthetic intermediates , commercially converted to an optical isomer of the original compound by available compounds, or compounds that can be easily subjecting it to an acidic hydrolysis or basic hydrolysis 30 obtained from such commercially available compounds reactionre . according to production methods known from literature . (3 ) Chiral column method : This is a method which They can be produced according to representative produc comprises subjecting a racemate or a salt thereof to chro - tion methods, as described below . In addition , the below matography using a chiral column (optical isomer separatory mentioned production methods are not intended to limit the column ) for direct optical resolution . For example , in the 35 present invention . case of high performance liquid chromatography (HPLC ), a The definitions of p , q , Z , R1, R2, R ’ ,R4 , RS, RÓ, R7, R8, mixture of optical isomers is added to a chiral column of ring A , and fused ring B , which are used in individual CHIRAL Series manufactured by Daicel Corporation , etc ., formulas of the below -mentioned production methods, are and it is then developed by a single use of water, various the same as those described in the formula ( I ) in the above buffers ( e . g . , a phosphate buffer ) , and organic solvents ( e . g ., 40 described embodiments , unless otherwise specified . The ethanol, methanol, isopropanol, acetonitrile , trifluoroacetic definition of M in the production method is metal such as acid , and diethylamine ) , or using a mixed solution thereof, lithium , sodium , or potassium , unless otherwise specified . thereby separating the optical isomer. In addition , for The definition of X in the production method is a halogen example, in the case of gas chromatography , the optical atom , unless otherwise specified . The definition of Y in the isomer can be separated using a chiral column of CP - 45 production method is a hydrogen atom , a hydroxyl group , Chirasil -DeX CB (manufactured by GL Sciences ), etc . ORA, or chlorine , unless otherwise specified . The definition The compound in the present invention may be a crystal . of R4 in the production method is a C1- 6 alkyl group , a C6- 13 Although the crystalline form is either a single crystal or a aryl group , or a C7- 20 aralkyl group , unless otherwise speci crystalline mixture , they are included in the compound in the fied . present invention . 50 Individual raw material compounds used in the produc The compound in the present invention may be a phar - tion of the compound of the formula (1 ) in the below maceutically acceptable cocrystal or a cocrystal salt . Herein , mentioned production methods may form salts . As such the term “ cocrystal” or “ cocrystal salt ” means a crystalline salts , the same salts as those in the above formula ( I ) may be substance composed of two or more unique solids at room included . In addition , each raw material compound used in temperature, which has each different physical properties 55 the production of the compound of the formula ( 1 ) can be ( e . g . structure , melting point, melting heat, absorbency, directly used as a reaction solution , or as a crude product, in solubility , and stability ) . Such a cocrystal or cocrystal salt the subsequent reaction . It can also be isolated from a can be produced according to a known cocrystallization reaction mixture according to an ordinary method , and it can method . be easily purified by known separation means such as The compound in the present invention includes com - 60 extraction , concentration , neutralization , filtration , distilla pounds labeled or substituted with isotopes ( e. g . hydrogen tion , recrystallization , or chromatography. isotopes such as ?H and PH , carbon isotopes such as llc , Examples of the solvent used in the above described 13C , and 14C , chlorine isotopes such as 36C1, fluorine iso recrystallization include : water ; alcohols such as methanol, topes such as 18F , iodine isotopes such as 1231 and 1251, ethanol, 2 - propanol, and butanol; ethers such as diethyl nitrogen isotopes such as 13N and 15N , oxygen isotopes such 65 ether , tetrahydrofuran , and 1, 4 -dioxane ; hydrocarbons such as 150 , 170 , and 180 , phosphorus isotopes such as 32P , and as n -hexane , cyclohexane, and heptane; aromatic hydrocar sulfur isotopes such as " S ) . bons such as benzene , toluene, and xylene ; amides such as US 9 ,777 ,000 B2 163 164 N , N -dimethylformamide , N , N -dimethylacetamide , and 1 ,3 - hydroxyl group ( an alcoholic hydroxyl group , a phenolic dimethyl- 2 - imidazolidinone; halogenated hydrocarbons hydroxyl group , a heterocyclic hydroxyl group , etc . ) , an such as chloroform , methylene chloride , and 1 , 2 - dichlo amino group , a carboxy group , and a thiol group are used as roethane ; nitriles such as acetonitrile ; ketones such as substituents , it is also possible to appropriately protect these acetone and diphenylketone ; esters such as methyl acetate 5 groups in each reaction step , and then to remove the pro and ethyl acetate ; sulfoxides such as dimethyl sulfoxide ; and tective groups at a suitable stage . organic acids such as acetic acid , trifluoroacetic acid ,meth - Examples of the protective groups for the hydroxyl group anesulfonic acid , and p - toluenesulfonic acid . These solvents ( an alcoholic hydroxyl group , a phenolic hydroxyl group , a may be used singly , or may also be used by mixing two or heterocyclic hydroxyl group , etc . ) that can be used herein more solvents at a suitable ratio , for example , at a ratio of 1 : 1 10 include : C1- 6 alkyl groups including, as representative to 1 : 10 . Moreover, when a compound represented by a examples, methyl, ethyl, n -propyl , isopropyl, n -butyl , and formula is commercially available product, the commer tert - butyl; alkoxylalkyl groups including , as representative cially available product may be directly used . Furthermore , examples, methoxymethyl (MOM ) and methoxyethoxym a compound produced by a known method or a method ethyl (MEM ) ; tetrahydropyranyl ( THP ) groups; aralkyl equivalent thereto may also be used 15 groups including , as representative examples, benzyl (Bn ) When a substituent in the formula ( I ) contains a variable and triphenylmethyl ( Tr ) ; silyl groups including, as repre functional group ( e .g . a carboxy group , an amino group , a sentative examples, trimethylsilyl ( TMS ) , triethylsilyl hydroxyl group , a carbonyl group , a mercapto group , a C1- 6 ( TES ) , t - butyldimethylsilyl ( TBDMS ) , and t - butyldiphenyl alkoxylcarbonyl group , a C6- 14 aryloxycarbonyl group , a silyl ( TBDPS ) ; alkanoyl groups including, as representative C7- 20 aralkyloxycarbonyl group , a sulfo group ( S02OH ) , 20 examples , acetyl ( Ac ), ethylcarbonyl, and pivaloyl (Piv ) ; and a halogen atom ) , these functional groups are converted aralkylcarbonyl groups including , as a representative by a known method or a method equivalent thereto , so as to example , benzylcarbonyl; aroyl groups including, as a rep produce various compounds. resentative example , benzoyl (Bz ) ; alkoxylcarbonyl groups When the functional group is a " carboxy group ,” it can be including , as representative examples, methoxycarbonyl, converted according to reactions such as esterification , 25 ethoxycarbonyl, and t -butoxycarbonyl (Boc ) ; and aralky reduction , amidation , or conversion reaction to an optionally loxycarbonyl groups including as a representative example , protected amino group . benzyloxycarbonyl ( Z ). When the functional group is an “ amino group ,” it can be Examples of the protective groups for the amino group converted according to reactions such as amidation , sulfo - A NH , group ) or the imino group ( - NH - group ) that can nylation , nitrosation , alkylation , arylation , or imidation . 30 be used herein include: alkanoyl groups including, as rep When the functional group is a “ hydroxyl group ,” it can resentative examples, acetyl (Ac ) , ethylcarbonyl , and piv be converted according to reactions such as esterification aloyl (Piv ); alkoxylcarbonyl groups including, as represen carbamoylation , sulfonylation , alkylation , arylation , oxida - tative examples , methoxycarbonyl, ethoxycarbonyl, and tion , or halogenation . t -butoxycarbonyl (Boc ) ; allyloxycarbonyl ( Alloc) groups; When the functional group is a “ carbonyl group, ” it can 35 fluorenylmethoxycarbonyl (Fmoc ) groups; phenyloxycarbo be converted according to reactions such as reduction , nyl; aralkyloxycarbonyl groups including , as representative oxidation , imination ( including oximation and conversion to eyexamples , benzyloxycarbonyl ( Z ) , p -methoxybenzyloxycar hydrazone ), ( thio )ketalization , conversion to alkylidene , or bonyl , and p -nitrobenzyloxycarbonyl ; aralkyl groups includ thiocarbonylation . ing , as representative examples, benzyl (Bn ) and triphenyl When the functional group is a “mercapto group ( SH ) ,” 40 methyl ( Tr) ; aroyl groups including as a representative it can be converted according to reactions such as alkylation example , benzoyl (Bz ) ; aralkylcarbonyl groups including as or oxidation . a representative example , benzylcarbonyl; sulfonyl groups When the functional group is a “ C1- 6 alkoxylcarbonyl including , as representative examples , methanesulfonyl group ,” a “ C6- 14 aryloxycarbonyl group ," or a “ C7- 20 aralky - (Ms ) , p -toluenesulfonyl ( Ts) , 2 , 4 - dinitrobenzenesulfonyl loxycarbonyl group ," it can be converted according to 45 (Nos ) , and benzenesulfonyl ( Bs ) ; 2 - trimethylsilyl) reactions such as reduction or hydrolysis . ethoxymethyl (SEM ) groups; phthaloyl (Pht ) groups ; and When the functional group is a “ sulfo group ( SO , OH ) ," N , N - dimethylaminomethylene groups. it can be converted according to reactions such as sulfona Examples of the protective groups for the carboxy group midation or reduction . COOH group ) that can be used herein include : alkyl When the functional group is a “ halogen atom ,” it can be 50 groups including , as representative examples ,methyl , ethyl, converted according to , for example , various types of n -propyl , isopropyl , n -butyl , and tert -butyl ; alkenyl groups nucleophilic substitution reactions or various types of cou - including, as a representative example , allyl; aryl groups pling reactions . including, as a representative example , phenyl ( Ph ); aralkyl In each of the above described reactions, when a com groups including , as representative examples , benzyl (Bn ) pound is obtained in the free state , it may be converted to 55 and triphenylmethyl ( Tr ) ; and silyl groups including, as salts according to an ordinary method . When the compound representative examples, trimethylsilyl ( TMS ), triethylsilyl is obtained in the form of salts , the salts may also be ( TES ), t- butyldimethylsilyl (TBDMS ) , and t- butyldiphenyl converted to a free body or other salts according to an silyl ( TBDPS ) . ordinary method. Examples of the protective groups for the thiol group Conversion of these functional groups can be carried out 60 ( SH group ) that can be used herein include: alkyl group according to the method described , for example , in Richard including , as representative examples , methyl, ethyl, n - pro C . Larock et al. , Comprehensive Organic Transformations, pyl, isopropyl , n -butyl , and tert- butyl ; aralkyl groups includ 2nd edition , published in October , 1999 , Wiley - VCH . ing , as representative examples , benzyl (Bn ) and triphenyl Moreover , in each reaction in the method for producing methyl ( Tr ) ; alkanoyl groups including , as representative the compound represented by the formula ( I) of the present 65 examples, acetyl ( Ac ), ethylcarbonyl, and pivaloyl (Piv ) ; invention , and in each reaction in the synthesis of raw and aroyl groups including , as a representative example , material compounds, when reactive groups such as a benzoyl (Bz ). US 9 ,777 ,000 B2 165 166 A method for introducing and /or removing such protec - described in Greene et al. , “ Protective Groups in Organic tive groups can be carried out, as appropriate , depending on Synthesis, 4th edition , 2007 , John Wiley & Sons, " or various the type of a group to be protected or a protective group . types of published study papers. Introduction and /or removal of protective groups can be Reaction conditions applied to the below -mentioned pro carried out according to the method described , for example , 5 duction methods are determined as follows, unless otherwise in Greene et al. , “ Protective Groups in Organic Synthesis , specified . That is , the reaction temperature is in a range from 4th edition , 2007 , John Wiley & Sons. " - 78° C . to a temperature at which a solvent is refluxed . When the protective groups are acyl type protective When the temperature is not particularly described , it is groups such as : alkanoyl groups including , as representative room temperature (0° C . to 35º C . ). The reaction time is a examples, acetyl (Ac ), ethylcarbonyl, and pivaloyl (Piv ); 10 period of time in which the reaction sufficiently progresses. alkoxylcarbonyl groups including , as representative Moreover , the reaction in each step of the production examples, methoxycarbonyl, ethoxycarbonyl, t- butoxycar method can be carried out in the absence of a solvent, or bonyl (Boc ) ; and aroyl groups including , as a representative after raw material compounds have been dissolved or sus example , benzoyl ( Bz) , as a method for removing the pended in a suitable solvent that is irrelevant to the reaction . protective groups, the protected group is hydrolyzed using a 15 Specific examples of such a solvent that is irrelevant to the suitable base such as an alkali metal hydroxide including reaction include : water ; saturated hydrocarbon solvents such lithium hydroxide , sodium hydroxide , or potassium hydrox - as cyclohexane and hexane ; aromatic hydrocarbon solvents ide , so that the protective group can be removed . such as benzene , chlorobenzene, toluene, and xylene ; alco When the protective groups are: alkoxylalkyl type pro hol solvents such as methanol, ethanol, 1 -propanol , 2 -pro tective groups including , as representative examples, 20 panol, tert- butyl alcohol, and 2 -methoxyethanol ; polar methoxymethyl (MOM ) , methoxyethoxymethyl (MEM ) , amide solvents such as N , N -dimethylformamide , N , N - dim and tetrahydropyranyl ( THP ) ; alkoxylcarbonyl type protec - ethylacetamide , hexamethylphosphoric triamide , and 1, 3 tive groups including , as a representative example , t- butoxy - dimethyl- 2 - imidazolidinone ; sulfoxide solvents such as carbonyl (Boc ) ; aralkyloxycarbonyl type protective groups dimethyl sulfoxide ; nitrile solvents such as acetonitrile and including, as representative examples, benzyloxycarbonyl 25 propionitrile ; ether solvents such as diethyl ether, diisopro ( Z ) and p -methoxybenzyloxycarbonyl ; or silyl type protec - pyl ether, diphenyl ether, tetrahydrofuran , 1 , 4 - dioxane, and tive groups including , as representative examples, trimeth - 1 , 2 -dimethoxyethane ; ester solvents such as methyl acetate , ylsilyl ( TMS) , triethylsilyl ( TES ) , and t -butyldimethylsilyl e thyl acetate , and butyl acetate ; ketone solvents such as ( TBDMS) , suitable acids such as acetic acid , hydrochloric acetone and methyl ethyl ketone ; halogenated hydrocarbon acid , hydrobromic acid , sulfuric acid , phosphoric acid , tri - 30 solvents such as dichloromethane , chloroform , carbon tet fluoroacetic acid , or trifluoromethanesulfonic acid , or a rachloride , and 1 , 2 - dichloroethane ; basic solvents such as combination of these acids are used to remove the protective triethylamine , N ,N -diisopropylethylamine , pyridine, and groups . lutidine ; acid anhydrides such as acetic anhydride ; organic Moreover, the above described silyl type protective acids such as formic acid , acetic acid , propionic acid , groups can also be removed using suitable fluoride ion ( F ) 35 trifluoroacetic acid , and methanesulfonic acid ; and inorganic generation reagents, such as tetrabutyl ammonium fluoride acids such as hydrochloric acid and sulfuric acid . A single or hydrogen fluoride . type of solvent may be used alone, or two or more types of Aralkyloxycarbonyl groups including, as representative solvents may appropriately be selected depending on reac examples , benzyloxycarbonyl ( Z ) , p -methoxybenzyloxycar tion conditions, and may be then mixed at an appropriate bonyl, and p -nitrobenzyloxycarbonyl , and aralkyl groups 40 ratio before use . including, as a representative example , benzyl (Bn ) , can be Specific examples of the base ( or deoxidizer) used in the removed by hydrolysis using, for example , a palladium method for producing the compound in the present invention carbon (Pd - C ) catalyst. include inorganic bases such as lithium hydroxide , sodium Furthermore, the above described benzyl group can also hydroxide, potassium hydroxide, magnesium hydroxide , be removed by Birch reduction using metallic sodium in 45 lithium carbonate , sodium carbonate , potassium carbonate , liquid ammonia . cesium carbonate , calcium carbonate, and sodium hydrogen The triphenylmethyl ( Tr) group can be removed by using carbonate ; organic bases such as triethylamine, N , N -diiso a suitable acid such as acetic acid , hydrochloric acid , hyd - propylethylamine , tributylamine , cyclohexyldimethylamine, robromic acid , sulfuric acid , phosphoric acid , trifluoroacetic pyridine , lutidine , 4 -dimethylaminopyridine (DMAP ) , N , N acid , or trifluoromethanesulfonic acid , or using a combina - 50 dimethylaniline, N -methylpiperidine , N -methylpyrrolidine , tion of these acids . Further, the protective group can also be N -methylmorpholine , 1 , 5 - diazabicyclo [ 4 . 3 . 01- 5 -nonene , removed by Birch reduction using metallic sodium or metal- 1 , 4 - diazabicyclo [ 2 . 2 .2 ]octane , 1 , 8 - diazabicyclo [ 5 . 4 .01 - 7 lic lithium in liquid ammonia , or by hydrolysis using a undecene, and imidazole ; metal alkoxides such as sodium palladium carbon catalyst. methoxide , sodium ethoxide , potassium tert -butoxide , and The sulfonyl ( S02 – ) group can be removed , for 55 sodium tert -butoxide ; alkali metal hydrides such as sodium example , by performing one - electron reduction using Na/ an - hydride and potassium hydride ; metal amides such as thracene or Na/ naphthalene at a low temperature , or by sodium amide , lithium diisopropyl amide , and lithium hex performing Birch reduction using metallic sodium or metal- amethyl disilazide ; and organic lithium reagents such as lic lithium in liquid ammonia . methyl lithium , n -butyl lithium , sec -butyl lithium , and tert Moreover , among the sulfonyl groups , a 2 -nitrobenzene - 60 butyl lithium . Moreover, specific examples of the acid or sulfonyl (Ns ) group can be removed under mild conditions acid catalyst used in the method for producing the com in which , for example , it is reacted with thiol in the presence pound in the present invention include : inorganic acids such of a basic reagent such as potassium carbonate or triethyl- as hydrochloric acid , sulfuric acid , nitric acid , hydrobromic amine . acid , and phosphoric acid ; organic acids such as acetic acid , The above described methods for removing protective 65 trifluoroacetic acid , oxalic acid , phthalic acid , fumaric acid , groups are provided for illustrative purpose only . Deprotec - tartaric acid , maleic acid , citric acid , succinic acid , meth tion can be carried out, for example , by applying the method anesulfonic acid , p - toluenesulfonic acid , and 10 - camphor US 9 ,777 , 000 B2 167 168 sulfonic acid ; and Lewis acids such as a boron trifluoride the formula (CA - 2 ) , when L ' = OM ; and it is an acid halide of ether complex , zinc iodide, anhydrous aluminum chloride , the formula (CA - 3 ), when L '= X ]: anhydrous zinc chloride, and anhydrous iron chloride. How ever, examples are not necessarily limited thereto . The salt of the formula ( I ) can be produced according to 5 [Formula 106 ] a known method . For example , when the compound of the formula ( I ) is a basic compound, the salt thereof can be R ? produced by adding an inorganic acid (mineral acid ) such as N - N hydrochloric acid , hydrobromic acid , nitric acid , sulfuric RAO acid , or phosphoric acid , or an organic acid such as formic < Step1 > acid , acetic acid , trifluoroacetic acid , phthalic acid , fumaric acid , oxalic acid , tartaric acid , maleic acid , citric acid , succinic acid , malic acid , methanesulfonic acid , benzene ( A - 1 ) sulfonic acid , or p - toluenesulfonic acid , to the compound . When the compound of the formula ( I ) is an acidic com pound , the salt thereof can be produced by adding an organic best base such as ammonia , trimethylamine, triethylamine, pyri R? he dine , picoline , 2 , 6 - lutidine, ethanolamine, diethanolamine , t triethanolamine , cyclohexylamine , dicyclohexylamine , N N ( R ), N , N - diisopropylethylamine , N , N - dibenzylethylenediamine , RAO ( A - 3) or N , N - dialkylaniline , or an inorganic base such as lithium < Step2 > carbonate , sodium carbonate , potassium carbonate , cesium carbonate , lithium hydroxide, sodium hydroxide , potassium hydroxide , or sodium hydrogen carbonate , to the compound . The compound represented by the formula ( I ) of the R2 present invention can be obtained by a condensation reaction N - N of a carboxylic acid derivative represented by a formula An (CA ) ( wherein it is a carboxylic acid of a formula (CA - 1 ) , when L ' = OH ; it is a carboxylate of a formula ( CA - 2 ) , when Hydrolysis L ' = OM ; and it is an acid halide of a formula (CA - 3 ) , when 30 < Step3 > L ' = X ] with amine represented by a formula ( AM ) . N LA [Formula 105 ] ( A - 4 ) R4 N R2 NH2 N N N N - N HO MO q ( R ) ( AM ) < Step4 > N A A (CA - 1 ) (CA - 2) (CA ) R 2 N - N N - N VA 9R N i A A ( R ) (CA - 3 ) 60 < Step 1 > Hereinafter , methods for producing the compounds rep - < Case of W = Boronic Acid Ester > resented by the formula (CA ) , the formula ( AM ), and the Using the compound represented by the formula ( A - 1 ) , a formula ( I ) will be described . reaction is carried out according to a known method, for < Production Method A > example , the method described in “ The Journal of Organic Method for producing a carboxylic acid derivative repre- 65 Chemistry, 60 , 7508 -2665 , 1995 ," in a temperature range sented by the formula (CA ) [wherein it is a carboxylic acid from 0° C . to a temperature at which a solvent is refluxed , of the formula (CA - 1 ), when L ' = OH ; it is a carboxylate of using a solvent irrelevant to the reaction , such as toluene , US 9 ,777 ,000 B2 169 170 N , N - dimethylformamide, dimethyl sulfoxide, or 1 , 4 - diox - Maruzen , " and “ Journal of Medicinal Chemistry , 48 ( 20 ) , ane , or using a mixed solvent thereof, in the presence of a pp . 6326 -6339 , 2005 , ” in a temperature range from 0° C . to diboron ester such as bis ( pinacolato )diboron or bis ( neopen - a temperature at which a solvent is refluxed , using a solvent tylglycolato )diboron , in the presence of a palladium catalyst irrelevant to the reaction , such as toluene, xylene, N , N such as palladium acetate (II ) , tetrakis (triphenylphosphine ) 5 dimethylformamide , N , N -dimethylacetamide , dimethoxy palladium , tris (dibenzylideneacetone )dipalladium , [ 1 , 1 ' -bis ( diphenylphosphino ) ferrocene dichloropalladium ( II ) , or a ethane , acetonitrile ( acetonitrile /water ) , 1 , 4 - dioxane ( 1 , 4 [ 1, 1 '- bis (diphenylphosphino ) ferrocene ]dichloropalladium dioxane /water ) , or tetrahydrofuran (tetrahydrofuran /water ) , ( II ) - dichloromethane complex , in the presence or absence of or using a mixed solvent thereof, in the presence of a a phosphine reagent such as triphenylphosphine , tris ( tert - 10 palladium catalyst such as palladium acetate ( II ) (Pd butyl) phosphine , tris (o - tolyl) phosphine , or 2 - dicyclohexyl (OAC ) 2 ), tetrakis ( triphenyl phosphine) palladium (Pd phosphino - 2 ', 6 '- dimethoxybiphenyl , and an organic or inor (PPhz ) 4) , tris( dibenzylidene acetone )dipalladium ganic base such as triethylamine , N , N ( ( dba ) 3Pd2) , bis ( dibenzylidene acetone ) palladium diisopropylethylamine , potassium carbonate , or potassium (( dba )2Pd ), or [ 1, 1' - bis (diphenyl phosphino ) ferrocene ]di acetate , or in the presence or absence of tetramethylammo - 15 Chloropalladiumchloropalladium ( II ) (P Pd (appidppf )] Cl212) , a phosphine reagent such nium chloride , tetrabutylammonium chloride , etc . , which is as triphenyl phosphine , tris ( tert- butyl ) phosphine , tris ( 0 used instead of the phosphine reagent, so as to produce the tolyl) phosphine , 2 -dicyclohexylphosphino - 2 ', 6 ' -dimethoxy boronic acid ester represented by the formula ( A - 2 ) . biphenyl, or 2- dicyclohexylphosphino -2 ' ,4 ' , 6 '- triisopropyl < Case of W = Boronic Acid > biphenyl, and an organic or inorganic base such as Using the compound represented by the formula ( A - 1 ) , 20 triethylamine, N , N -diisopropylethylamine , potassium phos according to a known method , for example , the method phate , potassium carbonate , or cesium carbonate , so as to described in “ Chemische Berichte , 42 , 3090 , 1909 , " trialkyl produce a compound represented by the formula ( A - 4 ) . borate such as trimethyl borate or triisopropyl borate is Otherwise, using tetramethylammonium chloride , tetrabu added to a solvent irrelevant to the reaction , such as toluene , tylammonium chloride , or the like , instead of the phosphine tetrahydrofuran , or 1 , 4 - dioxane , or to a mixed solvent 25 reagent, the compound represented by the formula ( A - 4 ) can thereof, in the presence of alkyl lithium such as n -butyl - be produced by the same method as described above . lithium or sec -butyllithium , a Grignard reagent such as < Step 3 > isopropyl magnesium chloride , or metallic magnesium , and - 78° C . to room temperature . Thereafter, an acid such as 30 hydrochloric acid or sulfuric acid is added to the reaction Using the compound represented by the formula ( A -4 ) solution , and the reaction is then carried out in a temperature obtained in < Production Method A > < Step 2 > , a reaction is range from 0° C . to a temperature at which a solvent is carried out according to a known method , for example , the refluxed , so as to produce the boronic acid represented by method described in " Jikken Kagaku Koza , 4th edition , 22 , the formula ( A - 2 ) . 5 Organic Synthesis IV , Acid , Amino Acid , and Peptide , pp . < Case of W = Trifluoroborate > 1 -43 , 1992 , Maruzen ," in a temperature range from 0° C . to Using the boronic acid ester or boronic acid represented a temperature at which a solvent is refluxed , using a solvent by the formula ( A - 1 ) , a reaction is carried out according to inactive to the reaction, such as water, methanol, ethanol, a known method , for example , the method described in 2 -propanol , N , N - dimethylformamide , 1, 4 -dioxane , or tetra “ Chemical Reviews, 108 , 288 - 325 , 2008 . ” in a temperature 40 hydrofuran , or using a mixed solvent thereof, in the presence range from 0° C . to a temperature at which a solvent is of a base such as lithium hydroxide , sodium hydroxide , refluxed , using a solvent irrelevant to the reaction , such as potassium hydroxide , lithium carbonate , sodium carbonate , methanol, ethanol, or water , or using a mixed solvent or potassium carbonate , so as to produce a compound thereof, in the presence of potassium hydrogen difluoride represented by the formula (CA - 1 ) or the formula (CA - 2 ) , (KHF » ) , so as to produce the trifluoroborate represented by 45 depending on a difference in a post- treatment step after the formula ( A - 2 ) . completion of the reaction . < Case of W = N -Methyliminodiacetic Acid (MIDA ) < Case of R4 = Tert -Butyl Group > Borate > Using the compound represented by the formula ( A -4 ) Using the boronic acid represented by the formula ( A - 1 ) , obtained in < Production Method A > , the com a reaction is carried out according to a known method , for 50 pound is reacted with an acid such as hydrochloric acid or example , the method described in " Journal of Organome - trifluoroacetic acid to produce the compound represented by tallic Chemistry, 307 ( 1 ) , pp . 1 - 6 , 1986 , " in a temperature the formula (CA - 1 ) . range from 0° C . to a temperature at which a solvent is < Case of R4 = C7- 20 Aralkyl Group ( e . g . Benzyl Group ) > refluxed , using a solvent irrelevant to the reaction , such as Using the compound represented by the formula ( A -4 ) benzene , toluene , xylene , or dimethyl sulfoxide , or using a 55 obtained in < Production Method A > < Step 2 > , a reaction is mixed solvent thereof, in the presence of N - methylimino - carried out according to a known method , for example , the diacetic acid (MIDA ) , so as to produce an N -methylimino method described in “ Jikken Kagaku Koza , 4th edition , 26 , diacetic acid (MIDA ) borate represented by the formula Organic Synthesis VIII , Asymmetric Synthesis, Reduction , ( A - 2 ) . Sugar, and Labeling Compound , pp . 159 - 266 , 1992 , Maru < Step 2 > 60 zen ," in a temperature range from 0° C . to a temperature at Using the compound represented by the formula ( A -2 ) which a solvent is refluxed , using a solvent irrelevant to the obtained in < Production Method A > < Step 1 > and the reaction , such as an alcohol solvent such as methanol, halogenated heteroaryl derivative represented by the for ethanol, or 2 - propanol, or an ether solvent such as diethyl mula ( A - 3 ) , a reaction is carried out according to a known ether , tetrahydrofuran , 1 , 2 - dimethoxyethane , or 1 , 4 -diox method , for example , the methods described in “ Jikken 65 ane , or a polar solvent such as ethyl acetate or methyl Kagaku Koza , 5th edition , 18 , Organic Compound Synthesis acetate , or using a mixed solvent thereof, in the presence of VI - Organic Synthesis using Metal — , pp . 327 -352 , 2004 , a catalyst such as palladium -carbon (Pd - C ) , Raney nickel US 9 ,777 ,000 B2 171 172 (Raney -Ni ) , or platinum oxide ( Pt20 ), in a hydrogen gas atmosphere , so as to produce the compound represented by Using the compound represented by the formula ( B - 1 ) the formula (CA - 1 ) . < Step 4 > and the compound represented by the formula ( B - 2 ) , a Using the compound represented by the formula (CA - 2 ) 5 reaction is carried out according to a known method , for obtained in < Production Method A > < Step 3 > , a reaction is example , the method described in “ European Journal of carried out according to a known method , for example , the Medicinal Chemistry, 52 , pp . 137 - 150 , 2012 , ” in a tempera method described in “ Journal of the American Chemical ture range from 0° C . to a temperature at which a solvent is Society , 109 ( 24 ) , pp . 7488 -7494 , 1987, ” in a temperature refluxed , using a solvent inactive to the reaction , such as range from 0° C . to a temperature at which a solvent is 10 methanol, ethanol, or 2 -propanol , or using a mixed solvent refluxed , using a halogenating agent such as thionyl chlo thereof, so as to produce a compound represented by the ride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride , formula (B - 3 ). phosphorus trichloride, phosphorus pentachloride, or phos < Step 2 > phorus tribromide , and using a solvent inactive to the reaction , such as dioxane , tetrahydrofuran , benzene , toluene, 15 Using the compound represented by the formula ( B - 3 ) dichloromethane , 1 , 2 - dichloroethane, or chloroform , or obtained in < Production Method B > < Step 1 > , a reaction is using a mixed solvent thereof, in the presence or absence of carried out according to < Production Method A > < Step 3 > , a base such as triethylamine , N , N -diisopropylethylamine , or so as to produce the compound represented by the formula N , N -dimethylaminopyridine , so as to produce the com ( B - 4 ) . pound represented by the formula (CA - 3 ). 20 < Step 3 > < Production Method B > Using the compound represented by the formula ( B - 4 ) Methods for producing amines represented by a formula obtained in < Production Method B > < Step 2 > , a reaction is ( AM - 1 ) and a formula (AM - 2 ): Case in which a fused ring carried out according to a known method , for example , the B is an imidazo [ 1 , 2 - a ]pyridine ring (formula ( AM - 1 ) ) or a method described in “ Strategic Applications of Named 5 ,6 , 7 , 8 -tetrahydroimidazo [ 1 , 2 - a ]pyridine ring ( formula 25 Reactions in Organic Synthesis, Elsevier Academic Press , (AM - 2 )) : 2005 , pp . 116 - 117 , Curtius Rearrangement, ” in a tempera ture range from 0° C . to a temperature at which a solvent is refluxed , using a solvent inactive to the reaction , such as [Formula 107 ] toluene or benzene , or using a mixed solvent thereof, and 30 using diphenylphosphoryl azide (DPPA ), in the presence of HN . COORA a base such as triethylamine . Thereafter, the resulting com pound is reacted with alcohol such as methanol, ethanol, R tert- butyl alcohol, or benzyl alcohol, so as to produce the (B - 2 ) = = compound represented by the formula (B -5 ) . (R3 ) < Step1> 35 < Step 4 > ( B -1 ) Using the compound represented by the formula (B -5 ) COOR4 obtained in < Production Method B > < Step 3 > , the com Hydrolysis pound is reacted with a protective group COORA) by a < Step2 > 40 method that depends on the type of the protective group , (R ') a according to a known method , for example , the method (B -3 ) described in “ Protective Groups in Organic Synthesis 4th COOH Curtius edition , 2007 , John Wiley & Sons, Greene et al ., " so as to rearrangement produce the compound represented by the formula ( AM - 1 ) , R < Step3 > 45 from which the COOR4 group is removed . < Step 5 > ( R ") Using the compound represented by the formula (AM - 1 ) ( B - 4 ) obtained in < Production Method B > < Step 4 > , a reaction is ZI ORA carried out according to a known method , for example , the Deprotection 50 method described in “ Journal of Medicinal Chemistry , 48 R4 < Step4 > ( 10 ) , pp . 3586 - 3640 , 2005 , ” in a temperature range from 0° C . to a temperature at which a solvent is refluxed , using a (R3 ) ? y = solvent irrelevant to the reaction , such as an alcohol solvent ( B -5 ) such as methanol, ethanol, or 2 - propanol, or an ether solvent NH2 55 such as diethyl ether , tetrahydrofuran , 1 , 2 -dimethoxyethane , Reduction or 1 , 4 - dioxane, or a polar solvent such as ethyl acetate or Re < Step5 > methyl acetate , or using a mixed solvent thereof, in the presence of concentrated hydrochloric acid , in the presence (R ') a of a catalyst such as platinum oxide ( Pt , 0 ) , and in a ( AM - 1 ) hydrogen gas atmosphere , so as to produce the compound = NH represented by the formula (AM - 2 ) . < Production Method C > Alternative method for producing amine represented by (R ') ? 65 the formula (AM -2 ) [ the case of R + = C6- 14 aryl group ] and (AM - 2) method for producing amine represented by the formula (AM -3 ) : US 9 ,777 , 000 B2 173 174 [ Formulaen 108 ] 1938 2.97 . 00 B2 HN COORA H COORA ( C - 1 ) Reduction < Step1 > < Step2 > ( R ) ( R3) q ( B - 1 ) ( C - 2 ) - COORA - COORA Br < StenStep3 > < Step4 > ( R ) (R3 ) ? (C - 3 ) ( C - 4 ) COORA COOH Curtius Br Hydrolysis Br — rearrangement < Steps < Step6 > ( R ' ) a ( C - 5 ) = (C -6 ) = ORA R4B (OR )2 ORA ( C - 8 ) R4 - Br < Step7 > (Rº ) a (R3 ) ? KOYOY( C - 9 ) ( C - 7 ) Deprotection < Step9 > Deprotection < Step8 > NH , NH2 Br R4 (Rº ) q (R ) ( AM - 3 ) ( AM - 2 )

< Step 1 > hydrogen carbonate, or potassium carbonate , so as to pro Using the compound represented by the formula ( B - 1 ) duce the compound represented by the formula ( C - 4 ) . and the compound represented by the formula ( C - 1) , a 45 < StepUsing 4 > the compound represented by the formula ( C - 4 ) reaction is carried out according to < Production Method B > obtained in < Production Method C > < Step 3 > and isopropyl < Step 1 > , so as to produce the compound represented by the magnesium chloride , a reaction is carried out according to a formula ( C - 2 ) . known method, for example, the method described in “ Inter < Step 2 > 50 national Publication WO2007 / 121390 , ” in a temperature Using the compound represented by the formula ( C - 2) range from - 30° C . to a temperature at which a solvent is obtained in < Production Method C > < Step 1 > , a reaction refluxed , using a solvent irrelevant to the reaction , such as can be carried out according to < Production Method B > ether , tetrahydrofuran , dioxane , or 1 , 2 - dimethoxyethane , or < Step 5 > , so as to produce the compound represented by the using a mixed solvent thereof, so as to produce the com formula ( C - 3 ) . 55 pound represented by the formula ( C - 5 ) . < Step 3 > < Step 5 > Using the compound represented by the formula ( C - 3 ) Using the compound represented by the formula ( C - 5 ) obtained in < Production Method C > < Step 2 > and N -bro obtained in < Production Method C > < Step 4 > , a reaction is mosuccinimide (NBS ) , a reaction is carried out according to carried out according to < Production Method A > < Step 3 > , a known method , for example , the method described in 60 so as to produce the compound represented by the formula “ Journal of Heterocyclic Chemistry , 39 (4 ) , pp . 733 -735 , ( C -6 ). 2002 , ” in a temperature range from 0° C . to a temperature at < Step 6 > which a solvent is refluxed , using a solvent irrelevant to the Using the compound represented by the formula ( C -6 ) reaction , such as a halogenated solvent such as dichlo - obtained in < Production Method C > < Step 5 > , a reaction is romethane, chloroform , or 1, 2 -dichloroethane , or using a 65 carried out according to < Step 3 > , mixed solvent thereof, in the presence of a base such as so as to produce the compound represented by the formula sodium hydrogen carbonate , sodium carbonate , potassium (C - 7 ). US 9 ,777 , 000 B2 175 176 < Step 7 > < Step 1> Using the compound represented by the formula (C -7 ) obtained in < Production Method C > < Step 6 > and the Using the compound represented by the formula (B - 1) boranic acid derivative represented by the formula ( C - 8 ) , a and the thioisocyanate compound represented by the for reaction is carried out according to < Production Method A > 5 mula ( D - 1 ), a reaction is carried out according to a known < Step 2 > , so as to produce the compound represented by the method , for example , the method described in “ The Journal formula ( C - 9 ) . of Organic Chemistry , 65 ( 5 ), pp . 1566 - 1568 , 2000, ” in a < Step 8 > temperature range from 0° C . to a temperature at which a Using the compound represented by the formula ( C - 9 ) solvent is refluxed , using a solvent irrelevant to the reaction , obtained in < Production Method C > < Step 7 > , a reaction is 10 such as ether, tetrahydrofuran , dioxane, or 1 , 2 - dimethoxy carried out according to < Production Method B > < Step 4 > , ethane , or using a mixed solvent thereof, so as to produce the so as to produce the compound represented by the formula compound represented by the formula (D - 2 ). (AM - 2 ) . < Step 9 > < Step 2 > Using the compound represented by the formula ( C - 7 ) Using the compound represented by the formula ( D - 2 ) obtained in < Production Method C > < Step 6 > , a reaction is obtained in < Production Method D > < Step 1 > and hydrox carried out according to < Production Method B > < Step 4 > , ylamine hydrochloride , a reaction is carried out according to so as to produce the compound represented by the formula a known method , for example, the method described in ( AM - 3 ) . < Production Method D > “ Synthesis , ( 11) , pp . 1649 - 1652 , 2003, ” in a temperature Methods for producing amines represented by a formula 20 range from 0° C . to a temperature at which a solvent is ( AM - 4 ) and a formula ( AM - 5 ) : Case in which a fused ring refluxed , using a solvent irrelevant to the reaction , such as B is a triazolo [ 1 , 2 - a ]pyridine ring ( formula ( AM - 4 ) ) or a methanol, ethanol, or 2 - propanol, or using a mixed solvent 5 ,6 , 7 , 8 -tetrahydrotriazolo [ 1 , 2 - a ]pyridine ring ( formula thereof, so as to produce the compound represented by the (AM -5 ) ) : formula (D - 3 ) .

[Formula 109 ] = 8 HN - COOR4 R40 vN = RAOR40 .. - COOR4 ( D - 1) < Stepl > S N < Step2 > (Rºq (R3 ) um ( B - 1 ) YYET( D - 2 ) COORA COORA HN Br Hydrolysis < Step3 > < Step4 > (R ) ( R ) a (D - 3) = ( D - 4 ) = COOH Cutius ORA Br Rearrangement Br Introduction of R4 < Step5 > < Step 6 > R ) (R3 ) * ( D - 5 ) = KOTY(D - 6 ) ORA NH2 Deprotection R4 R4 < Step7 > NN. N N (R3 ) (Rº ) ( D - 7 ) y = (AM -4 ) < Step8 > Reduction < Step10 > Reduction

ORA NH Deprotection R4 N < Step9 > N . N N - (R3 ) Korum( D - 8 ) ( AM - 5 ) US 9 ,777 , 000 B2 177 178 < Step 3 > line ) , a reaction is carried out according to a known method , Using the compound represented by the formula ( D - 3 ) for example, the method described in “ Organic Synthesis , obtained in < Production Method D > < Step 2 > , isoamy 78 , p . 23 , 2002, ” in a temperature range from 0° C . to a nitrile , and copper bromide (CuBr2 ), a reaction is carried out temperature at which a solvent is refluxed , using a solvent according to a known method , for example , the methods irrelevant to the reaction , such as toluene, xylene , N ,N described in " The Journal of Organic Chemistry , 42 ( 14 ) , pp . dimethylformamide, N , N -dimethylacetamide , dimethoxy 2426 - 2431, 1977 ," in a temperature range from 0° C . to a ethane , acetonitrile (acetonitrile / water) , dioxane (dioxanel temperature at which a solvent is refluxed , using a solvent water ), or tetrahydrofuran (tetrahydrofuran /water ) , or using irrelevant to the reaction , such as acetonitrile , or using a 10 , mixed solvent thereof, so as to produce the compound 10 a mixed solvent thereof, in the presence of a Pd catalyst such represented by the formula ( D - 4 ) . as tris (dibenzylideneacetone )dipalladium (( dba ) 3Pd ), a < Step 4 > phosphine reagent such as 4 , 5' - bis (diphenylphosphino )- 9, 9' Using the compound represented by the formula ( D - 4 ) dimethylxanthene (XANTPHOS ) , and an organic or inor obtained in < Production Method D > < Step 3 . a reaction is 15 ganic base such as triethylamine , N , N - diisopropylethylam carried out according to < Production Method A > < Step 3 > , ine, potassium phosphate , potassium carbonate , or cesium so as to produce the compound represented by the formula carbonate , so as to produce the compound represented by the ( D - 5 ) . formula (D - 7 ) . < Step 5 > < Step 7 > Using the compound represented by the formula ( D -5 ) 20 Using the compound represented by the formula (D - 7) obtained in < Production Method D > < Step 4 > , a reaction is obtained in < Production Method D > < Step 6 ) , a reaction is carried out according to < Production Method B > < Step 3 > , so as to produce the compound represented by the formula carried out according to < Production Method B > < Step 4 > , ( D - 6 ). so as to produce the compound represented by the formula < Step 6 > 25 (AM -4 ). < Case of R4 = C6- 14 Aryl Group or 5 - to 7 -Membered < Step 8 > Monocyclic Heteroaryl Group > Using the compound represented by the formula ( D - 7 ) Using the compound represented by the formula ( D -6 ) obtained in < Production Method D > < Step 6 > , a reaction is obtained in < Production Method D > and the 2n carried out according to < Production Method B > < Step 5 > , boranic acid derivative represented by the formula ( C - 8 ) , a so as to produce the compound represented by the formula reaction is carried out according to < Production Method A > < Step 2 > , so as to produce the compound represented by the (D - 8 ). formula ( D - 7 ) . < Step 9 > < Case of R4 = 3 - to 14 -Membered Non - Aromatic Heterocy Using the compound represented by the formula (D - 8 ) clic Group > 35 obtained in < Production Method D > < Step 8 > , a reaction is Using the compound represented by the formula (D -6 ) carried out according to < Production Method B > < Step 4 > , obtained in < Production Method D > < Step 5 > and a non - so as to produce the compound represented by the formula aromatic heterocyclic compound ( e . g . a 3 - to 8 -membered (AM - 5 ) . ring non - aromatic heterocyclic compound such as aziridine , 40 pyrrolidine , piperazine, piperidine , or morpholine ), a reac Using the compound represented by the formula (AM -4 ) tion is carried out in the absence of a solvent at an outside obtained in < Production Method D > < Step 7 > , a reaction is temperature of approximately 100° C . to 150° C . , so as to carried out according to < Production Method B > < Step 5 > , produce the compound represented by the formula ( D - 7 ). so as to produce the compound represented by the formula Alternatively , using the compound represented by the 45 (AM -5 ) . formula ( D - 6 ) obtained in < Production Method D > < Step 5 > < Production Method E > and a non -aromatic heterocyclic compound ( e. g . a 3 - to Alternativemethod for producing compounds represented 8 -membered ring non -aromatic heterocyclic compound such by formula ( D - 7 ) and formula (D - 8 ) in < Production Method as aziridine , pyrrolidine , piperazine , piperidine, or morpho D > (wherein R * halogen atom ) .

[ Formula 110 ] 0 0 0 - NH2

HON (Rº ) COORA HNT - COOR4 R4 Y ( E - 1 ) ( E -3 ) < Step1 > < Step2 > HN ( B - 1 ) (R3 ) ? (E - 2 ) US 9 ,777 , 000 B2 179179 180 9 0927- continued 0 2

COOH _ COORA Curtius Hydrolysis R4 — Rearrangement R4 – < Step3 > NN < Step4 > (R ) , (R3 ) (Rº ) q (E - 3 ) ( E - 5 ) ( D - 7 ) see < Production < Step5 > Reduction < Step8 > Reduction < Step9> Method D > < Step8 >

COORA COOH Curtius LORA px Hydrolysis R4 Rearrangement R44 < Stepo > < Step7 > ( R ) a ( R ) (Rº ) q ( ES - 6 ) = ( E - 7 ) = TY( D - 6 )

30 < Step 1 > ethylaminopropyl) carbodiimide hydrochloride (WSC .HCI ) , Using the compound represented by the formula ( B - 1 ) 1 - hydroxybenzotriazole (HOBT ) , benzotriazol- 1 - yloxytris and the compound represented by the formula ( E - 1 ) , a (dimethylamino )phosphonium hexafluorophosphate (BOP reaction is carried out according to a known method , for ze reagent) , bis ( 2 -oxo - 3 - oxazolidinyl) phosphinic chloride example , the method described in “ Journal of Heterocyclic (BOP - Cl) , 2 - chloro - 1 , 3 - dimethylimidazolinium hexafluoro Chemistry, 12 ( 1 ) , pp . 107 - 110 , 1975 , " in a temperature phosphate (CIP ) , or 4 - ( 4 , 6 - dimethoxy - 1 , 3 , 5 - triazin - 2 - yl) -4 range from 0° C . to a temperature at which a solvent is methylmorpholinium chloride (DMTMM ), and in the pres refluxed , using a solvent irrelevant to the reaction , such as ence or absence of a base such as triethylamine or pyridine , methylene chloride or chloroform , or using a mixed solvent 40 so as to produce the compound represented by the formula thereof, so as to produce the compound represented by the ( E - 4 ). formula ( E - 2 ) . < Step 3 > < Step 2 > Using the compound represented by the formula (E -4 ) Using the compound represented by the formula ( E - 2 ) obtained in < Production Method E > < Step 2 > , a reaction is obtained in < Production Method E > < Step 1 > and the 45 carried out according to < Production Method A > < Step 3 > , compound represented by the formula ( E - 3 ) (wherein Y = H , so as to produce the compound represented by the formula OH , OR4, or Cl) , a reaction is carried out according to a known method , for example , the method described in “ Jour nal of Heterocyclic Chemistry , 12 ( 1 ), pp . 107 - 110 , 1975 ." < Step 4 > In the case of < Y = OR4, H , or Cl> , the reaction is carried out 50 Using the compound represented by the formula ( E - 5 ) in a temperature range from 0° C . to a temperature at which obtained in < Production Method E > < Step 3 > , a reaction is a solvent is refluxed , using a solvent irrelevant to the carried out according to < Production Method B > < Step 3 > , reaction that is selected from among methylene chloride , so as to produce the compound represented by the formula chloroform , acetonitrile , methanol, N -methylpyrrolidone ( D - 7 ) . and the like, or using a mixed solvent thereof, in the 55 < Step 5 > presence of a base such as sodium hydroxide or sodium methoxide , so as to produce the compound represented by Using the compound represented by the formula ( E - 4 ) the formula ( E - 4 ) . In the case of < Y = OH > , the reaction is obtained in < Production Method E > < Step 2 > , a reaction is carried out in a temperature range from 0° C . to a tempera carried out according to < Production Method B > < Step 5 > , ture at which a solvent is refluxed , in a solvent irrelevant to 60 so as to produce the compound represented by the formula the reaction , such as a halogenated solvent such as dichlo (E -6 ) . romethane or chloroform , an ether solvent such as diethyl < Step > ether or tetrahydrofuran , an aromatic hydrocarbon solvent Using the compound represented by the formula ( E -6 ) such as toluene or benzene , a polar solvent such as N , N - obtained in < Production Method E > < Step 5 > , a reaction is dimethylformamide, or an alcohol solvent such as methanol, 65 carried out according to < Production Method A > < Step 3 > , ethanol, or 2 -propanol , in the presence of a condenser such so as to produce the compound represented by the formula as 1 ,3 -dicyclohexylcarbodiimide (DCC ), 1- ethyl- 3 -( 3 -dim - ( E -7 ). US 9 ,777 ,000 B2 181 182 < Step 7 > - continued Using the compound represented by the formula ( E - 7 ) obtained in < Production Method E > < Step 6 ) , a reaction is N ORA carried out according to < Production Method B > < Step 3 > , Rx Deprotection so as to produce the compound represented by the formula < Step5 > ( D - 8 ). < Step 8 > (R™ ) a Using the compound represented by the formula ( E - 5 ) ( F - 5 ) obtained in < Production Method E > < Step 3 > , a reaction is 10 carried out according to < Production Method B > < Step 5 , NH2 so as to produce the compound represented by the formula ( E - 7 ). < Step 9 > 15 (R ) Using the compound represented by the formula ( D - 7 ) obtained in < Step 4 > , the same ( AM - 6 ) reaction as that in < Production Method D > < Step 8 > is carried out, so as to produce the compound representedesented by 20 the formula ( D -8 ). Step 1 < Production Method F > Using the compound represented by the formula ( B - 1 ) Method for producing amine represented by formula and the compound represented by the formula (F - 1) , a ( AM - 6 ) : the synthesis of an imidazolo [ 1 , 2 - a ]pyridine ring reaction is carried out according to a known method , for ( AM - 6 ) in a case in which Z = CR and R = a halogen atom 25 example , the method described in “ Russian Chemical Bul in the fused ring B (wherein R + ua halogen atom ): letin , 54 , 470 , 2005 , ” in a temperature range from 0° C . to a temperature at which a solvent is refluxed , using a pyridine solvent in the presence of thionyl chloride, so as to produce 30 the compound represented by the formula (F - 2 ). [Formula 111 ] Using the compound represented by the formula ( F - 2 ) obtained in < Production Method F > < Step 1 > , a reaction is R 35 carried out according to a known method , for example , the method described in “ Russian Chemical Bulletin , 54 , 470 , H (R ?) ? COORA 2005 , " in a temperature range from 0° C . to a temperature at ( F - 1 ) then which a solvent is refluxed , using N -methyl - 2 -pyrrolidone < Step1 > as a solvent in the presence of trimethyl phosphite , so as to 40 produce the compound represented by the formula ( F - 3 ) . ( B - 1 ) < Step 3 > Using the compound represented by the formula (F -3 ) R4 (R ) COORA obtained in < Production Method F > < Step 2 > , a reaction is 45 carried out according to < Production Method A > < Step 3 > , < Step2 > so as to produce the compound represented by the formula ( F -4 ). of < Step 4 > ( F - 2 50 Using the compound represented by the formula ( F - 4 ) obtained in < Production Method F > < Step 3 > , a reaction is _ COORA carried out according to < Production Method B > < Step 3 > , so as to produce the compound represented by the formula Hydrolysis ( F - 5 ). < Step3 > 55 < Step 5 > (R3 ) Using the compound represented by the formula ( F - 5 ) ( F -3 ) obtained in < Production Method F > < Step 4 > , a reaction is carried out according to < Production Method B > < Step 4 > , COOH so as to produce the compound represented by the formula Curtius 60 (AM -6 ). Rearrangement < Production Method G > < Step4 > Method for producing compound represented by formula (R3 ) ( I ) : a condensation reaction of an amine represented by a ( F - 4 ) 65 formula (AM ) with carboxylic acid derivatives represented by a formula (CA - 1 ), a formula (CA - 2 ) , and a formula (CA - 3 ) . US 9 ,777 , 000 B2 183 184

[ Formula 112 ]

P2 N - N N - N MO R4O . < Step1 > NA ARP (CA - 2 ) ( A - 4 )

R2 - NH2 R ? N - N Z - N R4 N N - N HO (R3 < Step2> ( AM ) a( R3 ?A R! ) XRP (CA - 1 )

N - N < Step3 >

A V (R ) ( CA - 3 )

< Step 1 > (HATU ) , and in the presence or absence of a base such as The ester represented by the formula ( A - 4 ) is converted to N , N -diisopropylethylamine , triethylamine , or pyridine , so as a carboxylate (CA - 2 ) by the method described in < Produc - to produce the compound represented by the formula (I ) . tion Method A > < Step 3 > . Thereafter, using the amine represented by the formula (AM ), a reaction is carried out Using the carboxylic acid represented by the formula according to a known method , for example , the method (CA - 1 ) and the amine represented by the formula (AM ), a described in " Jikken Kagaku Koza , 4th edition , 22 , Organic 55 reaction is carried out according to a known method , for Synthesis IV , Acid , Amino Acid , and Peptide , pp . 191 - 309, example , the method described in " Jikken Kagaku Koza , 4th 1992 , Maruzen , " in a temperature range from 0° C . to a edition , 22 , Organic Synthesis IV , Acid , Amino Acid , and temperature at which a solvent is refluxed , in a solvent Peptide, pp . 191 - 309, 1992 , Maruzen ," in a temperature irrelevant to the reaction , such as a halogenated solvent such range from 0° C . to a temperature at which a solvent is as dichloromethane or chloroform , an ether solvent such as ou refluxed , in a solvent irrelevant to the reaction , such as a diethyl ether or tetrahydrofuran , an aromatic hydrocarbon halogenated solvent such as dichloromethane or chloroform , solvent such as toluene or benzene , a polar solvent such as an ether solvent such as diethyl ether or tetrahydrofuran , an N , N - dimethylformamide, or an alcohol solvent such as aromatic hydrocarbon solvent such as toluene or benzene , a methanol, ethanol, or 2 -propanol , in the presence of a 65 polar solvent such as N , N - dimethylformamide , or an alcohol condenser such as 2 - ( 1H - 7 - azabenzotriazol- 1 - yl ) - 1 , 1 , 3 , 3 solvent such as methanol, ethanol, or 2 -propanol , in the tetramethyluronium hexafluorophosphate methanaminium presence of a condenser such as 1 , 3 -dicyclohexylcarbodi US 9 ,777 ,000 B2 185 186 imide (DCC ), 1 -ethyl -3 - ( 3 -dimethylaminopropyl ) carbodi imide hydrochloride (waruuWSC .HCI ) , 1h -hydroxybenzotriazole awhonzatwinzolo [Formula 113 ] (HOBT ) , benzotriazol- 1 - yloxytris (dimethylamino )phospho nium hexafluorophosphate (BOP reagent) , bis ( 2 -oxo -3 -ox - 5 X N - N azolidinyl) phosphinic chloride (BOP - CI ) , 2 - chloro - 1 , 3 - dim ethylimidazolinium hexafluorophosphate (CIP ) , 4 - (4 ,6 (R 'la dimethoxy - 1, 3, 5 -triazin - 2- yl ) - 4 -methylmorpholinium chloride (DMTMM ), polyphosphoric acid (PPA ), or 2 -( 1H 10 7 -azabenzotriazol - 1- yl ) - 1, 1, 3 ,3 - tetramethyluronium hexafluorophosphate methanaminium (HATU ), and in the (I " ) presence or absence of a base such as triethylamine , N , N - 15 diisopropylethylamine , or pyridine, so as to produce the compound represented by the formula (I ) .

Otherwise , as an alternativemethod , using the carboxylic R4 N - N acid represented by the formula (CA - 1) and the amine represented by the formula (AM ), a reaction is carried out I according to a known method , for example, the method 25 described in “ International Publication No . WO2005/ * 034867 ” or “ Bioorganic & Medicinal Chemistry Letters , 14 (R ) ( 4 ) , pp . 983 - 988, 2004, ” in a temperature range from 0° C . to a temperature at which a solvent is refluxed , in a solvent 30 < Case of Rt - a C6- 14 Aryl Group or a 5 - to 7 -Membered irrelevant to the reaction , such as pyridine, in the presence Monocyclic Heteroaryl Group > of phosphoryl chloride, so as to produce the compound represented by the formula ( I) . Using the compound represented by the formula ( I ) and 35 the boranic acid derivative represented by the formula (C -8 ), < Step 3 > a reaction is carried out according to < Production Method Using the acid halide represented by the formula (CA - 3) A > < Step 2 > , so as to produce the compound represented by and the amine represented by the formula (AM ), a reaction 40 the formula (I ) . is carried out according to a known method, for example , the method described in “ Jikken Kagaku Koza , 4 'h edition , 22 , < Case of R4- a 3 - to 14 -Membered Non - Aromatic Hetero Organic Synthesis IV , Acid , Amino Acid , and Peptide, pp. cyclic Group > 144 - 146 , 1992 ,Maruzen ,” in a temperature range from 0° C . 4. Using the compound represented by the formula (I ' " ) and to a temperature at which a solvent is refluxed , in a solvent irrelevant to the reaction , such as a halogenated solvent such a non -aromatic heterocyclic compound (e .g . a 3 - to 8 -mem as dichloromethane , chloroform , or 1 ,2 -dichloroethane , an bered ring non - aromatic heterocyclic compound such as ether solvent such as diethyl ether, tetrahydrofuran , or aziridine, pyrrolidine , piperazine, piperidine, or morpho 1 , 4 - dioxane , an aromatic hydrocarbon solvent such as tolu line ) , a reaction is carried out according to < Production ene or benzene, or a polar solvent such as N , N -dimethyl Method D > < Step 6 > < Case of R4 = a 3 - to 14 -membered formamide, in the presence of a base such as triethylamine , 55 nonhon - aromatic heterocyclic group > , so as to produce the N , N -diisopropylethylamine , pyridine, or 4 - dimethylamin compound represented by the formula (I ) . < Production Method I> opyridine , so as to produce the compound represented by the Method for producing compound represented by formula formula (I ) . 60 (I ) : a method comprising performing a condensation reac tion between an amine represented by a formula (AM ) and < Production Method H > carboxylic acid derivatives represented by a formula (CA Method for producing compound represented by formula 1 -2 ) ,a formula (CA -2 -2 ) , and a formula (CA - 3- 2 ), and then ( I) : a synthetic method from formula (I ' ' ) ( in case of " introducing Het that corresponds to a ring A portion into the R + = halogen ) to formula (I ). reaction product . US 9 ,777 , 000 B2 187 8970 621 188 [Formula 114 ] 157

D2 R4 N N — N R2 (R ) N N - N < Step1 > R40 . / MO ( I' " - 2 ) < Step4 > ( A - 4 - 2 ) (CA - 2 - 2 ) Z - N (R ) R4 N ( AM ) N - N

N - N ZN ?? (R ') a oy < Step2> (I " - 3 ) ( CA - 1 - 2 ) < Step5 > A R2 N - N (R ' (A - 3 ) < Step3 > R4 N (CA - 3 - 2 ) zuN - N 2 - N (R3 ) No ALR

45 < Step 1 > < Step 4 > The ester represented by the formula ( A -4 - 2 ) is converted Using the compound represented by the formula ( I' " -2 ) to the carboxylate represented by the formula ( CA - 2 - 2 ) by obtained in < Production Method I > < Step 1 > , or < Produc performing a reaction according to < Production Method A > 50 < Step 3 > . Thereafter, using the amine represented by the tion Method I > < Step 2 > , or < Production Method I > < Step formula (AM ) , a reaction is carried out according to < Pro 3 > , a reaction is carried out according to < Production duction Method G > < Step 1> , so as to produce the com Method A > < Step 1 > , so as to produce the compound pound represented by the formula (I ' " - 2 ). represented by the formula ( I " - 3 ) . < Step 2 > 55 Using the carboxylic acid represented by the formula < Step 5 > (CA - 1 - 2 ) and the amine represented by the formula ( AM ), Using the compound represented by the formula (1 - 3 ) a reaction is carried out according to < Step 4 > and the G > < Step 2 > , so as to produce the compound represented by compound represented by the formula ( A - 3 ) , a reaction is the formula ( I' " - 2 ) . carried out according to < Production Method A > < Step 2 > , < Step 3 > so as to produce the compound represented by the formula Using the acid halide represented by the formula (CA - 3 2 ) and the amine represented by the formula ( AM ) , a reaction is carried out according to < Production Method G > 65 < Production Method J> < Step 3 > , so as to produce the compound represented by the Alternative method for producing compound represented formula ( It" - 2 ) . by formula ( I' " - 3 ) in < Production Method I > . US 9 ,777 , 000 B2 189 US 9, 7 , 000 12 10190 [Formula 115 ] R N - N N - N RAO ?? < Step1 >

W ( A - 4 - 3 ) ( CA - 2 - 3 ) - NH

N - N ( R ) ?? (AM ) N - N < Step2 >

(Rola (CA - 1 - 3 ) ( I '" - 3 )

1N - N < Step3 >

( CA - 3 - 3)

< Step 1 > tiapine , clozapine, ziprasidone, risperidone, paliperidone , The ester represented by the formula ( A - 4 - 3 ) is converted perospirone , blonanserin , lurasidone, aripiprazole , sertin to the carboxylate represented by the formula (CA - 2 - 3 ) by 35 dole , amisulpride , iloperidone, bifeprunox, asenapine, melp performing a reaction according to < Production Method A > erone, brexpiprazole , zotepine, etc . ), ( 2) typical antipsy < Step 3 > . Thereafter , using the amine represented by the chotic agents [ specifically , chlorpromazine, formula ( AM ) , a reaction is carried out according to < Pro prochlorperazine, perphenazine , levomepromazine, flu duction Method G > < Step 1 > , so as to produce the com - phenazine , thioridazine , propericiazine , spiperone , moper pound represented by the formula ( I '" - 3 ) . 40 one , haloperidol, timiperone, bromperidol, pimozide , flo < Step 2 > ropipamide, sulpiride, tiapride , sultopride, nemonapride , Using the carboxylic acid represented by the formula oxypertine , etc . ], ( 3 ) selective serotonin reuptake inhibitors ( CA - 1 - 3 ) and the amine represented by the formula (AM ), ( S SRI) [ specifically , escitalopram , citalopram , paroxetine , a reaction is carried out according to < Production Method sertraline , fluvoxamine, fluoxetine , etc . ) , ( 4 ) selective sero G > < Step 2 > , so as to produce the compound represented by 45 tonin /noradrenalin reuptake inhibitors (SNRI ) [ specifically, the formula (I ' " -3 ). milnacipran , duloxetine , venlafaxine, nefazodone , etc . ], ( 5 ) < Step 3 > selective noradrenalin /dopamine reuptake inhibitors (NDRI ) Using the acid halide represented by the formula (CA - 3 [ specifically , bupropion etc . ], ( 6 ) noradrenergic and specific 3 ) and the amine represented by the formula (AM ), a serotonergic antidepressants (NaSSA ) [ specifically , mir reaction is carried out according to < Production Method G > 50 tazapine etc . ], ( 7 ) triazolopyridine antidepressants ( SARI) < Step 3 > , so as to produce the compound represented by the [ specifically , trazodone etc . ], ( 8 ) tetracyclic antidepressants formula ( I " " - 3 ) . [specifically , setiptiline , mianserin , maprotiline, etc . ) , ( 9 ) [Combination Agent Containing the Compound in the Pres tricyclic antidepressants [ specifically , amitriptyline, trimip ent Invention ] ramine , imipramine , nortriptyline , clomipramine , lofe The compound or pharmaceutical composition of the 55 pramine , amoxapine , dosulepin , etc . ] , ( 10 ) other antidepres present invention can be used in combination with other sants [ specifically , NS- 2359, Lu AA21004 , DOV21947 , drugs or agents according to a common method applied in etc . ), ( 11 ) a7 nicotine receptor agonists, ( 12 ) a7 nicotine medical sites. Examples of a drug that can be used in receptor activity modulators , ( 13 ) a7 nicotine receptor par combination with the compound in the present invention tial modulators [ specifically , SSR - 180711 , PNU - 120596 , include (A ) therapeutic agents for mental diseases, and in 60 etc . ], ( 14 ) other PDE inhibitors [PDE1 inhibitor, PDE2 particular, schizophrenia , or for bipolar disorder , obsessive - inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDE7 inhibitor , compulsive disorder, major depression , Parkinson ' s disease , PDE9 inhibitor, etc . ) , ( 15 ) NK2 antagonists, ( 16 ) NK3 Huntington ' s disease, Alzheimer' s disease , cognitive func antagonists , ( 17 ) muscarinic Ml acetylcholine receptor tion disorder and defect of memory , and ( B ) therapeutic activity modulators , ( 18 ) muscarinic M2 acetylcholine agents for diseases occurring together with schizophrenia . 65 receptor activity modulators, ( 19 ) adenosine receptor modu Examples of the above described agent ( A ) include (1 ) lators , (20 ) muscarinic M4 acetylcholine receptor activity atypical antipsychotic agents [ specifically , olanzapine , que - modulators , (21 ) muscarinic M5 acetylcholine receptor US 9 ,777 ,000 B2 191 192 activity modulators , ( 22 ) adenosine receptor modulators , formin , buformin , phenformin , etc . ] , ( viii ) insulin or insulin ( 23 ) glycine transporter 1 (GlyT1 ) inhibitors [ specifically , derivatives [ specifically , insulin zinc suspension , insulin ALX5407 , SSR504734 , etc . ) , ( 24 ) glutamate enhancers lispro , insulin aspart , regular insulin , NPH insulin , insulin [specifically , ampakine ], (25 ) NMDA receptor inhibitors glargine, insulin detemir , mix - type insulin , etc . ], (ix ) a2 specifically ,memantine hydrochloride etc . ) , (26 ) metabolic 5 antagonists [specifically , midaglizole , isaglidole , derigli glutamate receptor modulators (mGlu ) [specifically , CDPPB , MPEP , etc . ], ( 27 ) anti- anxiety agents ( i) benzodi dole , idazoxan , efaroxan , etc . ] ), ( 37) antiobestic drugs ( i ) azepine anti - anxiety agents [specifically , chlordiazepoxide, adrenalin B3 receptor agonists [ specifically , KRP - 204 , TRK diazepam , oxazolam , medazepam , cloxazolam , lorazepam , 380 / TAC - 301 , etc . ], ( ii ) CB - 1 receptor antagonists [ specifi clorazepate dipotassium , prazepam , bromazepam , fludiaz - 10 cally , rimonabant, SR - 147778 , BAY- 65 - 2520 , etc . ] , ( iii ) epam , mexazolam , alprazolam , flutoprazepam , flutazolam , neuropeptide Y (NPY ) receptor antagonists [specifically , ethyl loflazepate, etc . ], ( ii ) thienodiazepine anti -anxiety S -2367 etc . ], ( iv ) anti - feeding drugs [monoamine reuptake agents [ specifically, etizolam , clotiazepam , etc . ] , and ( iii ) inhibitors [ specifically , sibutramine , mazindol, etc . ]] , ( v ) serotonin 5 -HT1A agonists [ specifically , tandospirone etc . ]) , lipase inhibitors [specifically , orilstat , cetilistat, etc. ) , and (28 ) sleep inducing drugs ( i) benzodiazepine sleep inducing 15 (V1 ) peptide Y ( YY) receptor antagonists, etc .) ; (38 ) drugs [ specifically , nitrazepam , estazolam , flurazepam hyperlipidemia -treating agents such as cholesterol- reducing hydrochloride , nimetazepam , flurazepam , haloxazolam , agents ( i) w3 fatty acids [ specifically , ethyl icosapentate flunitrazepam , rilmazafone hydrochloride, lormetazepam , ( EPA -E preparations, for example , product name: Epadel triazolam , etc . ), ( ii ) thienodiazepine sleep inducing drugs (registered trademark ) ) , docosahexaenoic acid (DHA ), a [ specifically , brotizolam etc . ] , ( iii ) non -benzodiazepine 20 mixed preparation of ethyl icosapentate and ethyl docosa sleep inducing drugs [ specifically , zolpidem etc . ], ( iv )mela - hexaenoate ( e. g. product name: LOVAZATM and Omacor tonin receptor agonists [ specifically , ramelteon etc . ]) , ( v ) ( registered trademark ) ) , etc . ] , ( ii ) HMG - CoA reductase cyclopyrrolone sleep inducing drugs [ specifically , zopiclone inhibitors [specifically , atorvastatin , simvastatin , pitavasta etc . ] , (29 ) ß amyloid vaccines , (30 ) B amyloid decomposing tin , itavastatin , fluvastatin , lovastatin , pravastatin , rivastatin , enzymes , etc . , ( 31 ) cerebral function activators ( specifically , 25 rosuvastatin , etc . ] ( iii ) HMG - CoA synthetase inhibitors , ( iv ) aniracetam , nicergoline , etc . ), ( 32 ) cannabinoid modulators , cholesterol absorption inhibitors [ specifically , ezetimibe ) , ( 33 ) choline esterase inhibitors [ specifically , donepezil ( v ) acyl- CoA cholesterol acyl transferase (ACAT ) inhibitors , hydrochloride, rivastigmine, galantamine hydrobromide, ( vi) CETP inhibitors, ( vii ) squalene synthetase inhibitors, etc . ] , ( 34 ) MAO - B inhibitors [ specifically , rasagiline etc . ) (viii ) antioxidants [specifically , probucol etc . ], ( ix ) PPARA ( 35 ) Parkinson ' s disease - treating agents ( i ) dopamine 30 agonists [ specifically , clofibrate , etofibrate , fenofibrate , receptor agonists [ specifically , levodopa , amantadine hydro - bezafibrate , ciprofibrate , gemfibrozil , KRP - 101 , etc . ], ( x ) chloride , bromocriptine mesilate , pergolide mesilate , caber - PPARS agonists , ( xi) LXR agonists , ( xii ) FXR agonists goline , talipexole hydrochloride, pramipexole hydrochloride [ specifically , INT- 747 etc .] , (xiii ) MTTP inhibitors, (xiv ) hydrate , selegiline hydrochloride , ropinirole hydrochloride , squalene epoxidase inhibitors , etc. ) , (39 ) antihypertensive etc . ], ( ii ) monoamine oxidase inhibitors [ specifically , depre - 35 agents ( i ) diuretics [ specifically , trichlormethiazide , hydro nyl, selegiline , remacemide, riluzole , etc . ) , ( iii ) anticholin - chlorothiazide , mefruside , indapamide , meticrane , chlortha ergic drugs [ specifically , trihexyphenidyl , profenamine , lidone , tripamide , furosemide, torasemide , bumetanide, biperiden , piroheptine hydrochloride , methixene hydrochlo - ethacrynic acid , spironolactone , triamteren , eplerenone , ride , mazaticol hydrochloride , etc . ] , ( iv ) COMT inhibitors etc . ], ( ii ) calcium receptor antagonists [ specifically, amlo [specifically , entacapone etc .] , ( v ) therapeutic agents for 40 dipine , felodipine, nicardipine , nifedipine , nimodipine , amyotrophic lateral sclerosis (specifically , riluzole , neuro - nitrendipine , nilvadipine , aranidipine , azelnidipine , mani trophic factors , etc . ] , ( vi) apoptosis inhibitors [ specifically , dipine , barnidipine , efonidipine , cilnidipine , benidipine, dil CPI- 1189 , IDN -6556 , CEP - 1347 , etc .) , and ( vii ) nerve dif tiazem , etc .] , ( iii) angiotensin converting enzyme inhibitors ferentiation / regeneration promoters [ specifically, leteprinim , (ACEI ) [ specifically , captopril, lisinopril, enalapril , delapril , xaliproden ; SR -57746 - A , SB -216763 , etc . ] ) . 45 perindopril, benazepril, trandolapril, quinapril, alacepril , On the other hand , examples of the above described agent imidapril, temocapril , cilazapril, etc . ), (iv ) angiotensin ( B ) include ( 36 ) therapeutic agents for diabetes ( i ) PPARy receptor blockers (ARB ) [ specifically , losartan , olmesartan , stimulants (agonists and inhibitors ) [ specifically , pioglita telmisartan , valsartan , candesartan cilexetil , irbesartan , etc . ) , zone, rosiglitazone, troglitazone, ciglitazone , darglitazone , ( v ) direct renin inhibitors [ specifically , aliskiren etc . ] , (vi ) a englitazone , netoglitazone , etc .] , ( ii ) insulin secretion pro - 50 receptor blockers [specifically , tolazoline , phentolamine , moters [ ( a ) sulfonylurea agents ( specifically , tolbutamide , doxazosin , prazosin , bunazosin , terazosin , urapidil , etc . ), acetohexamide , chlorpropamide , glibenclamide, gliclazide, (vii ) B receptor blockers [specifically , bopindolol, pindolol, glipizide, glimepiride, glipentide, gliquidone, glisolamide , timolol, dichloroisoprenaline, alprenolol, carteolol, inde tolazamide , etc . ), ( b ) non - sulfonylurea agents etc . ], ( iii ) nolol, bunitrolol, penbutolol, propranolol, nadolol, nip rapid - acting insulin secretion promoters ( specifically , nateg - 55 radilol, tilisolol, acebutolol , celiprolol, metoprolol, atenolol, linide , mitiglinide , repaglinide, etc . ), ( iv ) a - glucosidase bisoprolol, betaxolol, practolol , bevantolol, butoxamine , inhibitors [ specifically , acarbose, voglibose , miglitol, carvedilol, amosulalol, arotinolol, labetalol, etc .] , (viii ) aiß camiglibose , adiposin , emiglitate , pradimicin - Q , salbostatin , blockers [ specifically, carvedilol, labetalol, arotinolol, bev etc . ) , ( v ) insulin resistance - improving agents [specifically , antolol, etc . ], and ( ix ) A2 receptor stimulants [specifically , ( a ) PPARy stimulants , ( b ) PTP - 1B inhibitors , ( c ) DPP -4 60 clonidine ,methyldopa , guanfacine , etc . ]) , (40 ) non - steroidal inhibitors [ specifically, sitagliptin , vildagliptin , alogliptin , anti - inflammatory agents [ specifically , meloxicam , teoxi saxagliptin , NVP -DPP -728 , etc . ), ( d ) GLP - 1 and GLP - 1 cam , indomethacin , ibuprofen , celecoxib , rofecoxib , aspirin , agonists [ specifically , exenatide , liraglutide, etc .) , ( e ) 11ß - indomethacin , etc .] , (41 ) disease -modifying antirheumatic HSD inhibitors and the like, (f ) GPR40 agonists , ( g ) drugs (DMARDs ), (42 ) anti -cytokine agents [ specifically , GPR119 agonists , and ( h ) GPR120 agonists ], ( vi ) hepatic 65 TNF inhibitors and MAP kinase inhibitors ) , ( 43 ) steroid gluconeogenesis suppressants [ specifically , glucagon drugs [specifically , dexamethasone , hexestrol, cortisone antagonists etc . ], ( vii) biguanide agents [ specifically , met acetate , etc . ), (44 ) sex hormones or derivatives thereof US 9 ,777 ,000 B2 193 194 [ specifically , progesterone , estradiol , estradiol benzoate , administration , it is administered at a single dose of gener etc . ] , and (45 ) parathyroid hormone (PTH ) . ally approximately 0 . 1 to approximately 20 mg/ kg body By using the drug of the present invention in combination weight, preferably approximately 0 . 2 to 10 mg/ kg body with the existing drugs on the above described diseases, it is weight, and more preferably approximately 0 . 5 to approxi possible to reduce the doses of the existing drugs , and it is 5 mately 10 mg/ kg body weight. It is desirable to administer also possible to reduce the adverse drug reactions of the this dose once or divided over several administrations ( e . g . existing drugs . Naturally , application of the combined - use three times) per day. method using the present drug is not limited to the above When the compound in the present invention is used in described diseases , and the combined drugs are not limited combination with a combined drug , the amounts of both to the above exemplified compounds. 10 agents can be reduced within a safe range , while taking into The administration form of the compound in the present consideration the opposite effects of the agents . invention and the combined drug is not particularly limited . The combination agent of the present invention has low It is appropriate if the compound in the present invention toxicity , and for example , the compound in the present may be combined with the combined drug upon adminis - invention , or ( and ) the above described combined drug can tration . Examples of such an administration form include: 15 be mixed with a pharmacologically acceptable carrier ( 1 ) administration of a single preparation obtained by simul - according to a known method , so as to prepare a pharma taneous formulation of the compound in the present inven - ceutical composition , for example , a tablet ( including a tion and the combined drug , sugar - coated tablet and a film - coated tablet ) , a powder ( 2 ) simultaneous administration of two types of preparations agent, a granule , a capsule ( including a soft capsule ) , a liquid obtained by separately formulating the compound in the 20 agent, an injection , a suppository , a sustained - release agent , present invention and the combined drug via a single admin - etc . These agents can be safely administered via oral or istration route , parenteral administration . ( 3 ) time- lag administration of two types of preparations As a pharmacologically acceptable carrier that may be obtained by separately formulating the compound in the used in the production of the combination agent of the present invention and the combined drug via a single admin - 25 present invention , the same carriers as those used in the istration route , above described pharmaceutical composition of the present ( 4 ) simultaneous administration of two types of preparations invention can be used . obtained by separately formulating the compound in the The mixing ratio between the compound in the present present invention and the combined drug via different invention and the combined drug in the combination agent administration routes , and 30 of the present invention can be selected , as appropriate , ( 5 ) time- lag administration of two types of preparations depending on administration target, administration route , obtained by separately formulating the compound in the disease , etc . It may also be possible to use the above present invention and the combined drug via different described combined drug by mixing two or more types of administration routes ( for example , administration in the combined drugs at an appropriate ratio . order of the compound in the present invention and the 35 The dose of the combined drug can be selected , as combined drug , or in an opposite order ). appropriate , considering a clinically used dose as a standard . Hereinafter , these administration forms are collectively. In addition , the mixing ratio between the compound in the abbreviated as the " combination agent of the present inven - present invention and the combined drug can be selected , as tion .” appropriate , depending on administration target, administra Upon administration of the combination agent of the 40 tion route, target disease , symptoms, combination , etc . For present invention , the combined drug and the compound in instance , when the administration target is a human , the the present invention may be administered at the same time. combined drug may be used at a ratio of 0 .01 to 100 parts Otherwise , after administration of the combined drug , the by weight, based on 1 part by weight of the compound in the compound in the present invention may be administered , or present invention . For instance , the content of the compound after administration of the compound in the present inven - 45 in the present invention in the combination agent of the tion , the combined drug may be administered . In the case of present invention is different depending on the form of a time - lag administration , such a time lag is different depend preparation . The compound in the present invention is used ing on an active ingredient to be administered , dosage form , at a weight percentage of generally approximately 0 . 01 % to and administration method . For example , when the com - 99 . 9 % , preferably approximately 0 . 1 % to 50 % , and more bined drug is administered in advance , there is applied a 50 preferably approximately 0 . 5 % to 20 % , based on the total method which comprises administering the compound in the weight of the preparation . present invention within 1 minute to 3 days , preferably The content of the combined drug in the combination within 10 minutes to 1 day, and more preferably within 15 agent of the present invention is different depending on the minutes to 1 hour , after administration of the combined drug . form of a preparation . The combined drug is used at a weight When the compound in the present invention is administered 55 percentage of generally approximately 0 .01 % to 99 . 9 % , in advance , there is applied a method which comprises preferably approximately 0 . 1 % to 50 % , and more preferably administering the combined drug within 1 minute to 1 day, approximately 0 . 5 % to 20 % , based on the total weight of the preferably within 10 minutes to 6 hours , and more preferably preparation . within 15 minutes to 1 hour, after administration of the The content of an additive such as a carrier in the compound in the present invention . 60 combination agent of the present invention is different The amount of the combined drug is not particularly depending on the form of a preparation . The additive is used limited , as long as it does not cause a problem regarding at a weight percentage of generally approximately 1 % to adverse drug reactions . The daily dose of the combined drug 99. 99 % , and preferably approximately 10 % to 90 % , based is different depending on administration target, administra - on the total weight of the preparation . tion route , target disease , symptoms, etc . For example , when 65 Even when the compound in the present invention and the such a combined drug is administered to a schizophrenia combined drug are formulated separately, the same contents patient ( adult; body weight: approximately 60 kg ) via oral as those described above may be applied . US 9 , 777 , 000 B2 195 196 Since the dose is fluctuated depending on various condi - caprylate , acylcarnitines, and limonene ), gelatinizers , sus tions , as described above , there is a case in which a dose pending agents , emulsifiers , or commonly used suitable lower than the aforementioned dose is sufficient. On the additives or solvents . other hand , there is also a case in which a dose higher than Various dosage forms include a tablet, a capsule , a gran the aforementioned dose range needs to be administered . 5 ule , a powder agent, a pill , an aerosol, an inhalant, an The compound in the present invention can be adminis ointment, a patch , a suppository , an injection , a troche , a tered alone or in a combination with a pharmaceutically liquid preparation , a spirit , a suspension , an extract , and an acceptable carrier , once or divided over multiple adminis elixir. In addition , the pharmaceutical composition of the trations . Examples of a suitable pharmaceutical carrier present invention can be administered to a patient, via oral 10 administration , subcutaneous administration , intramuscular include an inactive solid diluent or filler , a sterilized aqueous administration , intranasal administration , transdermal solution , and various organic solvents. Then , a pharmaceu administration , intravenous administration , intraarterial tical composition formed from these substances can be administration , perineural administration , epidural adminis easily administered in various administration forms such as tration , intrathecal administration , intraventricular adminis a tablet , a powder agent, a lozenge , a liquid preparation , 15 tration , intrarectal administration , inhalation , etc . syrup , or injection . Such a pharmaceutical composition may The compound in the present invention can be formulated comprise additional components such as a flavor, a binder , into an injection administered via parenteral administration , and an excipient, depending on the situation . Accordingly , which includes the use of a common catheter technique or the compound in the present invention can be formulated infusion . To such an injection preparation , a preservative is into a form suitable for oral, buccal, nasal, parenteral (e . g . 20 added , and it can be provided in a unit administration form , intravenous , intramuscular, or subcutaneous) , transdermal for example , in an ampule or in a multiple -dose container . ( e . g . patch ) or rectal administration , or inhalation or insuf- Such a preparation can take a form such as a suspension flation administration . agent in an oily or aqueous vehicle , a liquid agent, or an [Formulation of Preventive and /or Therapeutic Agents of the emulsion , and it may comprise agents for drug formulation , Present Invention ] 25 such as a suspending agent, a stabilizer , and/ or a dispersant . The pharmaceutical agent of the present invention is Otherwise , an active ingredient can be in a powdery form , administered in the form of a pharmaceutical composition . which can be reconstituted with a suitable vehicle , such as The pharmaceutical composition of the present invention a sterilized pyrogen - removed water , before use . When a product solution is necessary , such a product may comprise at least one compound represented by theV 30 solution can be produced by dissolving an isolated inclusion formula (I ) of the present invention , and it is prepared by » complex in water ( or another aqueous medium ) that is in an combining the compound in the present invention with amount sufficient for generation of a solution with strength pharmaceutically acceptable additives . More specifically , necessary for oral or parenteral administration to a patient. various dosage forms can be prepared by appropriately Such a compound can be formulated into a fast dissolving combining the compound in the present invention with 3536 dosage form ( fddf) , which is designed such that an active excipients ( e . g . lactose , sucrose , mannit , crystalline cellu ingredient thereof is released in an oral cavity . Such a lose, silicic acid , corn starch , and potato starch ) , binders preparation is formulated using a matrix comprising fast ( e. g . celluloses (hydroxypropyl cellulose (HPC ) and dissolving gelatin as a base in many cases . Such a dosage hydroxypropylmethyl cellulose (HPMC ) ), and crystalline form is well known, and it can be used to deliver a wide cellulose , sugars ( lactose , mannit, sucrose , sorbitol , eryth - 40 range of drugs. Almost all of such fast dissolving dosage ritol, and xylitol) , starches ( corn starch and potato starch ) , forms utilize gelatin as a carrier or a structure - forming agent. pregelatinized starch , dextrin , polyvinyl pyrrolidone (PVP ), Typically , gelatin is used to impart to a dosage form , macrogol, and polyvinyl alcohol (PVA ) ), lubricants ( e .g . sufficient strength for preventing the preparation from being magnesium stearate , calcium stearate , talc , and carboxym - broken when it is removed from a package . Once such ethyl cellulose ) , disintegrators ( e . g . starches ( corn starch and 45 gelatin is put into the mouth , the dosage form thereof can be potato starch ) , carboxymethyl starch sodium , carmellose , immediately decomposed . Otherwise , in order to obtain the carmellose calcium , croscarmellose sodium , and crospovi- same effects as described above , various types of starches done ) , coating agents ( e . g . celluloses (hydroxypropyl cellu - can be used . lose (HPC ) , hydroxypropylmethyl cellulose (HPMC ) , The compound in the present invention can also be aminoalkylmethacrylate copolymer E , and methacrylic acid 50 formulated into a rectal composition such as a suppository or copolymer -LD ), plasticizers ( e . g . triethyl citrate and mac - retention enema , wherein the rectal composition comprises , rogol) , masking agents (e . g. titanium oxide ), coloring for example , a common suppository base such as cacao agents , flavoring agents , antiseptics ( e . g . benzalkonium butter or other glycerides . chloride and p -oxybenzoic acid ester ) , isotonizing agents In the case of administration via intranasal administration ( e . g . glycerin , sodium chloride , calcium chloride , mannitol, 55 or inhalation , the compound in the present invention is and glucose ) , pH adjusters ( e . g . sodium hydroxide , potas - conveniently delivered in the form of a solution or a sus sium hydroxide , sodium carbonate , hydrochloric acid , sul pension from a pump spray container that is compressed by furic acid , and buffers such as a phosphate buffer ) , stabilizers a patient or is delivered by a pump, or in the form of an ( e . g . sugar, sugar alcohol, and xanthan gum ), dispersants , aerosol spray presentation delivered from a pressurized antioxidants ( e . g . ascorbic acid , butylhydroxyanisole 60 container or a nebulizer using a suitable spraying agent such (BHA ) , propyl gallate , and dl- a - tocopherol) , buffering as dichlorodifluoromethane , trichlorofluoromethane , dichlo agents , preservatives (e . g . paraben , benzyl alcohol, and rotetrafluoroethane , carbon dioxide or another suitable gas. benzalkonium chloride ) , aromatics (e . g . vaniline , 1 -men - In the case of pressurized aerosol, the dosage unit can be thol, and rose oil ) , solubilizers ( e . g . polyoxyethylene hydro - determined by providing a valve for delivering the measured genated castor oil , polysorbate 80 , polyethylene glycol, 65 amount. A pressurized container or a nebulizer may com phospholipid cholesterol, and triethanolamine ) , absorption prise a solution or a suspension of an active compound . A promoters ( e . g . sodium glycolate , sodium edetate , sodium capsule agent and a cartridge agent ( for example , produced