Cycloalkyl 3-oxopiperazine carboxamides and cycloheteralkyl 3-oxopiperazine carboxamides as Nav1.8 inhibitors

Abstract

To provide a compound that inhibits Nav1.8 channel activity and has inhibitory activity on Nav1.8 voltage-gated sodium ion channel activity, which may be useful in the treatment, prevention, management, improvement, control, and suppression of diseases mediated by Nav1.8 channel activity. [Solution] A novel compound represented by structural formula (I) and a pharmaceutically acceptable salt thereof are provided. The compound may be useful in the treatment, prevention, or management of painful disorders, cough disorders, acute pruritic disorders, and chronic pruritic disorders. TIFF2026048891000069.tif57163

Description

[Background technology]

[0001] Voltage-gated sodium channels (VGSCs) are responsible for supplying sodium ions to excitable cells. It intervenes in selective influx and plays a central role in the initiation and propagation of action potentials (Yu et al. al., Genome Biology 4:207 (2003)). Potential dependence Sodium channels play a central role in the initiation and propagation of action potentials in the central nervous system. They are ubiquitous in the skeletal muscle system and peripheral nervous system, and action potentials cause cell contraction in skeletal muscle and It is also ubiquitous in the myocardium (Goldin et al., Ann NY Academia S. ci. 1999 Apr 30; 868:38-50). Functions of VGSC or their Alterations in the expression of can have a significant impact on the excitability of normal cells ("Huang et al., J Neurosci. 2013 Aug 28; 33 (35) :14087-97”, “Emery et al., J Neurosci. 20 15 May 20; 35(20):7674-81, Kist et al. PLoS One. 2016 Sep 6;11(9):e0161789, and , “Schreiber et al., World J Diabetes. 20 15 Apr 15;6(3):432-44).

[0002] The voltage-gated sodium channel forms one α-subchannel that creates an ion-conducting aqueous pore. A unit and at least one that modifies the dynamics and voltage dependence of channel gating It is a multimeric complex characterized by the β subunit of SNS, PN3, or Na. v Na, also known as 1.8v 1.8 contains nine different α subunits It has been identified and characterized in voltage-gated sodium channels in dairy products. (Goldin et al., Neuron. 2000 Nov; 28 (2) :365-8).

[0003] Sodium channel expression can be tissue-specific. v 1.8 Voltage dependent nato Lime ion channels are transmitted from the periphery (e.g., skin, muscles, and joints) through the spinal cord to the central nervous system. It is primarily expressed in sensory neurons involved in transmitting information to the nervous system. Peripheral nociceptive Activation caused by harmful stimuli (thermal, mechanical, and chemical) that activate receptors Sodium channel activity is necessary for the initiation and propagation of potentials, so sodium channels The channel is essential for this process (Catterall et al., Nat Chem Biol. 2017 Apr 13;13(5):455-463). cell Increase in VGSC protein levels on the surface or in VGSC channel activity The changes include migraines, post-ischemic neurodegeneration, epilepsy, and chronic neuropathic and inflammatory pain conditions. This can cause disease conditions such as those described above. In Nav1.7, Nav1.8, and Nav1.9 The acquisition of functional mutations leads to various conditions in which patients experience spontaneous pain in the absence of external stimuli. It manifests in pain syndromes ("Bennett et al., Lancet"). Neurol. 2014 Jun;13(6):587-99”, “Huang et al. al., J Neurosci. 2013 Aug 28;33(35):140 87-97”, “Kist et al., PLoS One. 2016 Sep. 6;11(9):e0161789”, “Emery et al., J Neuro sci. 2015 May 20;35(20):7674-81, and "Sch reiber et al., World J Diabetes. 2015 Ap r 15;6(3):432-44).

[0004] Na v 1.8 Voltage-gated sodium ion channels are involved in neuropathic pain and chronic itching. It is also thought to play a role in various diseases, including inflammatory pain perception. “Belkouch et al., J Neuroinflammation. 2 014 Mar 7;11:45”, “Coward et al., Pain. 2 000 Mar;85(1-2):41-50'', ``Yiangou et al., FEBS Lett. 2000 Feb 11;467(2-3):249-52'', “Black et al., Ann Neurol. 2008 Dec;64(6 ):644-53'', ``Bird et al., Br J Pharmacol. 2015 May;172(10):2654-70", "Liu et al., N euron. 2010 Nov 4;68(3):543-56, and "Zhao et al., J Clin Invest. 2013”).

[0005] Most voltage-gated sodium ion channels are conserved across different subtypes. Therefore, if a drug that does not exhibit subtype selectivity is used, serious side effects may occur. It may occur. Therefore, it is suitable for use in treating nociceptive, cough, or itching disorders. The therapeutic agents being developed require specificity in their actions. For example, the action on the Na v 1.5 sodium ion channel (which is considered important for the regulation of cardiac function) and the action on the Na 1.8 sodium ion channel (which is considered important in disorders caused by inflammatory insults v or itch and malfunction and / or upregulation of the Na 1.8 sodium v ion channel) need to be discriminated between. Therefore, an inhibitor of the Na 1.8 voltage-dependent sodium ion channel activity may be useful for treating or

[0006] preventing diseases, disorders and conditions involving the Na v 1.8 receptor, and / or, in particular, diseases, disorders and conditions resulting from v malfunction of the Na v 1.8 voltage-dependent sodium ion channel (Han et al., J Neurol Neurosurg Psychiatry 2014 May;85(5):4 99-505). Such diseases, disorders and conditions include, but are not limited to, migraine, neurodegeneration after ischemia, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, neuropathic pain, chronic itch and itch disorders, etc.

[0007] Na v 1.8 A potent Na v 1 .8 sodium ion channel activity inhibitor with selective activity against the Na 1.8 receptor and the Na v 1.8 receptor and the Na v1.8 Voltage-gated sodium ions It is useful for treating and preventing diseases, disorders, and conditions in which the channels are involved.

[0008] The role of the Nav1.8 sodium ion channel is discussed below. “Bennett et al., Physical Medicine an dRehabilitation Clinics of North America a, 2001, 12(2):447-459", "Meissner et al. , Br J Sports Med. 2018 May; 52(10):642- 650”, “Legroux-Crespel et al., Neurology. "2016 Feb 2;86(5):473-83" and "Flaxman et al." al., Lancet, 380:2163-2196 (2012).

[0009] Na v 1.8 Compounds useful for treating conditions related to sodium ion channels This is disclosed in: "ACS Med. Chem. Lett. 20 15, 6, 650”, “BJP 2015, 172, 2654”, “PNAS 2007, 104, 8520”, “J. Med. Chem. 2008, 51 , 407", "JPET 2008, 324, 1204", and "Neurop Pharmacology 2010, 59, 201”.

[0010] Na v 1.8 The compound is also disclosed in: WO2009 / 049180 , WO2009 / 049181, WO2009 / 049183, WO2014 / 1208 08, WO2014 / 120815, WO2014 / 120820, WO2015 / 01 0065, and WO2015 / 089361, WO2017 / 209322, US8, 519,137, US9,051,270, US9,108,903, US9,163, 042, US9,783,501, WO2020 / 092667, WO2019 / 014 352, WO2018 / 213426, US8,629,149, and WO2011 / 026240. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] WO2009 / 049180 [Patent Document 2] WO2009 / 049181 [Patent Document 3] WO2009 / 049183 [Patent Document 4] WO2014 / 120808 [Patent Document 5] WO2014 / 120815 [Patent Document 6] WO2014 / 120820 [Patent Document 7] WO2015 / 010065 [Patent Document 8] WO2015 / 089361 [Patent Document 9] WO2017 / 209322 [Patent Document 10] US8,519,137 [Patent Document 11] US9,051,270 [Patent Document 12] US9,108,903 [Patent Document 13] US9,163,042 [License 14] US9,783,501 [License 15] WO2020 / 092667 [License 16] WO2019 / 014352 [License 17] WO2018 / 213426 [License 18] US8,629,149 [License 19] WO2011 / 026240 [Non-licensed literature]

[0012] [Non-licensed Document 1] Yu et al., Genome Biology 4:207 (2003) [Non-licensed Document 2] Goldin et al., Ann NY Acad Sci. 1999 Apr 30; 868:38-50 [Non-licensed Document 3] Huang et al., J Neurosci. 2013 Aug 28; 33 (35):14087-97 [Non-licensed Document 4] Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81 [Non-licensed Document 5] Kist et al., PLoS One. 2016 Sep 6;11(9):e0161789 [Non-licensed Document 6] Schreiber et al., World J Diabetes. 2015 Apr 15;6(3):432-44 [Non-licensed Document 7] Goldin et al., Neuron. 2000 Nov; 28 (2):365-8 [Non-licensed Document 8] Catterall et al., Nat Chem Biol. 2017 Apr 13;13(5):455-463

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Summary of the Invention

Means for Solving the Problems

[0013] This disclosure is based on structural formula I: [ka] This invention relates to a novel compound represented by [formula], as well as its pharmaceutically acceptable salts, hydrates, and solvates. The compound represented by structural formula I and its embodiments are Na v 1.8 Sodium Ion Channel Inhibitors of scleroactivity (or Na v 1.8 inhibitors) and nociceptive, osteoarthritis Peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, itching, atopic dermatitis, allergies Sexual or contact dermatitis, renal failure, cholestasis, pruritus, acute pruritus, chronic pruritus, migraine, post-ischemic Neurodegeneration, epilepsy, pain, inflammatory pain, spontaneous pain, acute pain, acute pain resulting from fractures, musculoskeletal Injury, pancreatitis and renal colic, perioperative pain, postoperative pain, neuropathic pain, postherpetic neuralgia, three It can occur in cephalic neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, sciatica, and 2° or 3° burns. Pain caused by, optic neuritis, cancer and chemotherapy-induced pain, chronic pelvic pain, pain syndromes and complex pain Na v 1.8 Diseases involving sodium ion channel activity, It may be useful in treating and preventing disorders and conditions. In one embodiment, the condition, disease or The disorder is a pain disorder, acute pain disorder, or chronic pain disorder. In another embodiment, the condition The disease or disorder is an acute pain disorder.

[0014] Furthermore, disclosed are the compound of the present invention represented by structural formula I and pharmaceutically acceptable This is a pharmaceutical composition containing a carrier.

[0015] Furthermore, the disclosure includes the effects of administering the compounds and pharmaceutical compositions of this disclosure. Na in the target group that requires it v 1.8 Inhibition of sodium ion channel activity For the treatment, management, prevention, alleviation, improvement, suppression or control of respondable disorders, diseases and conditions It is a method.

[0016] Furthermore, what is disclosed is Na v 1.8 Inhibition of sodium ion channel activity For manufacturing drugs useful in treating responsive diseases, disorders and conditions, using structural formula I This is the use of the compound shown.

[0017] Furthermore, it is also disclosed that these may be useful in treating the disease, disorder, and condition. By administering the compound of this disclosure in combination with another drug in a therapeutically effective dose, these The treatment or prevention of diseases, disorders, and conditions. Furthermore, the chemicals of the present invention are described. It is a method of preparing an object. [Modes for carrying out the invention]

[0018] The provided structure is: [ka] [During the ceremony, One of A and B is (1) Aryl, and, (2) Heteroaryl Independently selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R a Selected from It is substituted with substituents 1 to 5, and, The other of A and B is, (1)C 3-12 Cycloalkyl, (2)C 2-11 Cycloheteroalkyl, (3)-C1-6 Alkyl-C 3-12 Cycloalkyl, (4)-C 1-6 Alkyl-C 2-11 Cycloheteroalkyl, (5)-C 1-6 Alkyl-OC 3-12 Cycloalkyl, and, (6) New C 1-6 Alkyl-OC 2-11 Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R b It is substituted with 1 to 6 substituents selected from; R 1 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) t C(O)R j , (9)-(CH2) t C(O)NR e R j , (10)-(CH2) n NR e C(O)R j , (11)-(CH2) n NR e C(O)OR j , (12)-(CH2) n NR e C(O)N(R e )2, (13)-(CH2) n NR e C(O)NR e R j , (14)-(CH2) n NR e S(O) m R j , (15)-(CH2) n NR e S(O) m N(R e )2, (16)-(CH2) n NR e S(O) m NR e R j , and, (17)-(CH2) n NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R c Substituted with 1 to 5 substituents selected from It is; R 2 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, (4)-C 2-6 Alkenil, (5)-C 2-6 Alkinil, (6) New C 3-6 Cycloalkyl, (7)-C 2-6 Cycloheteroalkyl, (8)-C 1-6 Alkyl-OC 1-6 Alkyl-, (9)-(CH2) s C(O)R j , (10)-(CH2) s C(O)NRe R j 、 (11)-(CH2) s NR e C(O)R j 、 (12)-(CH2) s NR e C(O)OR j 、 (13)-(CH2) s NR e C(O)N(R e )2、 (14)-(CH2) s NR e C(O)NR e R j 、 (15)-(CH2) s NR e S(O) m R j 、 (16)-(CH2) s NR[[ID=5​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; R 3 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, (4)-C 2-6 Alkenil, (5)-C 2-6 Alkinil, (6) New C 3-6 Cycloalkyl, (7)-C 2-6 Cycloheteroalkyl, (8)-C 1-6 Alkyl-OC 1-6 Alkyl-, (9)-(CH2) s C(O)R j , (10)-(CH2) s C(O)NR e R j , (11)-(CH2) s NR e C(O)R j , (12)-(CH2) s NR e C(O)OR j , (13)-(CH2) s NR e C(O)N(R e )2, (14)-(CH2) s NR e C(O)NR e R j , (15)-(CH2) s NR e S(O) m R j , (16)-(CH2) s NR e S(O) m N(R e )2, (17)-(CH2)s NR e S(O) m NR e R j , and, (18)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R d Substituted with 1 to 5 substituents selected from It is; R 4 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, (4)-C 2-6 Alkenil, (5)-C 2-6 Alkinil, (6) New C 3-6 Cycloalkyl, (7)-C 2-6 Cycloheteroalkyl, (8)-C 1-6 Alkyl-OC 1-6 Alkyl-, (9)-(CH2) s C(O)R j , (10)-(CH2) s C(O)NR e R j , (11)-(CH2) s NR e C(O)R j , (12)-(CH2) s NR e C(O)OR j , (13)-(CH2) s NR e C(O)N(R e )2, (14)-(CH2) s NRe C(O)NR e R j , (15)-(CH2) s NR e S(O) m R j , (16)-(CH2) s NR e S(O) m N(R e )2, (17)-(CH2) s NR e S(O) m NR e R j , and, (18)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R f Substituted with 1 to 5 substituents selected from It is and Here, R 4 and R 5 And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; R 5 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, (4)-C 2-6 Alkenil, (5)-C 2-6 Alkinil, (6) New C 3-6 Cycloalkyl, (7)-C 2-6 Cycloheteroalkyl, (8)-C 1-6 Alkyl-OC 1-6 Alkyl-, (9)-(CH2)s C(O)R j , (10)-(CH2) s C(O)NR e R j , (11)-(CH2) s NR e C(O)R j , (12)-(CH2) s NR e C(O)OR j , (13)-(CH2) s NR e C(O)N(R e )2, (14)-(CH2) s NR e C(O)NR e R j , (15)-(CH2) s NR e S(O) m R j , (16)-(CH2) s NR e S(O) m N(R e )2, (17)-(CH2) s NR e S(O) m NR e R j , and, (18)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R f Substituted with 1 to 5 substituents selected from It is and Here, R 5 and R 7 And the carbon atoms to which they are bonded are 4-membered, 5-membered, or 6-membered saturated rings. It can form; R 6 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, (4)-C 2-6 Alkenil, (5)-C 2-6 Alkinil, (6) New C 3-6 Cycloalkyl, (7)-C 2-6 Cycloheteroalkyl, (8)-C 1-6 Alkyl-OC 1-6 Alkyl-, (9)-(CH2) s C(O)R j , (10)-(CH2) s C(O)NR e R j , (11)-(CH2) s NR e C(O)R j , (12)-(CH2) s NR e C(O)OR j , (13)-(CH2) s NR e C(O)N(R e )2, (14)-(CH2) s NR e C(O)NR e R j , (15)-(CH2) s NR e S(O) m R j , (16)-(CH2) s NR e S(O) m N(R e )2, (17)-(CH2) s NR e S(O) m NR e Rj , and, (18)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R g Substituted with 1 to 5 substituents selected from It is and Here, R 6 and R 7 And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; R 7 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, (4)-C 2-6 Alkenil, (5)-C 2-6 Alkinil, (6) New C 3-6 Cycloalkyl, (7)-C 2-6 Cycloheteroalkyl, (8)-C 1-6 Alkyl-OC 1-6 Alkyl-, (9)-(CH2) s C(O)R j , (10)-(CH2) s C(O)NR e R j , (11)-(CH2) s NR e C(O)R j , (12)-(CH2) s NR e C(O)OR j , (13)-(CH2) s NR e C(O)N(Re )2, (14)-(CH2) s NR e C(O)NR e R j , (15)-(CH2) s NR e S(O) m R j , (16)-(CH2) s NR e S(O) m N(R e )2, (17)-(CH2) s NR e S(O) m NR e R j , and, (18)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R g Substituted with 1 to 5 substituents selected from It is; R 8 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 3-6 Cycloalkyl, and, (4)-C 2-6 Cycloheteroalkyl Selected from the group consisting of, Here, each alkyl, cycloalkyl, and cycloheteroalkyl is either substituted or not. or substituted with 1 to 5 substituents selected from halogens; R 9 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6Alkenil, and (4)-C 2-6 Alkinyl Selected from the group consisting of, Here, each alkyl, alkenyl, and alkynyl is either unsubstituted or halogenated. It is substituted with 1 to 5 substituents selected from n; Each R a teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 2-6 Alkenil, (7)-C 2-6 Alkinil, (8)-C 3-6 Cycloalkyl, (9)-C 2-6 Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C 1-6 Alkyl-aryl, (13)-C 1-6 Alkyl-heteroaryl, (14)-C 1-6 Alkyl-C 3-6 Cycloalkyl, (15)-C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (16)-C 2-6 Alkenil-C 3-6 Cycloalkyl, (17)-C 2-6 Alkenil-C 2-6 Cycloheteroalkyl, (18)-C 2-6 Alkenyl-aryl, (19)-C 2-6 Alkenyl heteroaryl, (20)-C 2-6 Alkinyl-C 3-6Cycloalkyl, (21)-C 2-6 Alkinyl C 2-6 Cycloheteroalkyl, (22)-C 2-6 Alkinyl-aryl, (23)-C 2-6 Alkinyl heteroaryl, (24)-OH, (25)-(CH2) p -OC 1-6 Alkyl, (26)-(CH2) p -OC 2-6 Alkenil, (27)-(CH2) p -OC 2-6 Alkinil, (28)-(CH2) p -OC 3-6 Cycloalkyl, (29)-(CH2) p -OC 2-6 Cycloheteroalkyl, (30)-(CH2) p -O-aryl, (31)-(CH2) p -O-heteroaryl, (32)-OC 1-6 Alkyl-C 3-6 Cycloalkyl, (33)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (34)-OC 1-6 Alkyl-aryl, (35)-OC 1-6 Alkyl-heteroaryl, (36)-S(O) r R h , (37)-C 1-6 Alkyl-S(O) r R h , (38)-N(R k )2, (39)-C(O)R L , and, (40)-NRk R L Independently selected from the group consisting of, Here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Al Kill and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups; Each R b teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 1-6 Alkenil, (7)-C 2-6 Alkinil, (8)-C 3-6 Cycloalkyl, (9)-C 2-6 Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C 1-6 Alkyl-aryl, (13)-C 1-6 Alkyl-heteroaryl, (14)-C 1-6 Alkyl-C 3-6 Cycloalkyl, (15)-C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (16)-C 2-6 Alkenil-C 3-6 Cycloalkyl, (17)-C 2-6 Alkenil-C 2-6 Cycloheteroalkyl, (18)-C 2-6 Alkenyl-aryl, (19)-C 2-6 Alkenyl heteroaryl, (20)-C2-6 Alkinyl-C 3-6 Cycloalkyl, (21)-C 2-6 Alkinyl-C 2-6 Cycloheteroalkyl, (22)-C 2-6 Alkinyl-aryl, (23)-C 2-6 Alkinyl heteroaryl, (24)-OH, (25)-(CH2) q -OC 1-6 Alkyl, (26)-(CH2) q -OC 2-6 Alkenil, (27)-(CH2) q -OC 2-6 Alkinil, (28)-(CH2) q -OC 3-6 Cycloalkyl, (29)-(CH2) q -OC 2-6 Cycloheteroalkyl, (30)-(CH2) q -O-aryl, (31)-(CH2) q -O-heteroaryl, (32)-OC 1-6 Alkyl-C 3-6 Cycloalkyl, (33)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (34)-OC 1-6 Alkyl-aryl, (35)-OC 1-6 Alkyl-heteroaryl, (36)-S(O) r R i , (37)-C 1-6 Alkyl-S(O) r R i , (38)-N(R k )2, (39)-C(O)RL , and, (40)-NR k R L Independently selected from the group consisting of, Here, each R b These are either not substituted, or halogen, CF3, OCF3, CN, C H2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6; R c teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R d teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R e teeth, (1) Hydrogen, and (2)C 1-6 Alkyl Selected from; R f teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R g teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R h teeth, (1) Hydrogen, (2)C 1-6 Alkyl, (3)C 3-6 Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; R i teeth, (1) Hydrogen, (2)C 1-6 Alkyl, (3)C 3-6 Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; R j teeth, (1) Hydrogen, (2)C 1-6 Alkyl, (3)C 3-6 Alkenil, (4)C 3-6 Alkinil, (5)C 3-6 Cycloalkyl, (6)C 2-5 Cycloheteroalkyl, (7) Aryl, and, (8) Heteroaryl Selected from; R k teeth, (1) Hydrogen, and (2)C 1-6 Alkyl Selected from; R L teeth, (1) Hydrogen, (2)C 1-6 Alkyl, (3)C 3-6 Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; m is independently selected from 0, 1, and 2; n is independently selected from 2, 3, 4, 5, and 6; p is independently selected from 0, 1, 2, and 3; q is independently selected from 0, 1, 2, and 3; r is selected independently from 0, 1, and 2; s is independently selected from 0, 1, 2, 3, 4, 5 and 6; and, t is independently selected from 0, 1, 2, 3, 4, 5, and 6. It is a novel compound represented by or a pharmaceutically acceptable salt thereof.

[0019] This disclosure further also relates to structural formula I [wherein, One of A and B is (1) Aryl, and, (2) Heteroaryl Independently selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R a Selected from It is substituted with substituents 1 to 5, and, The other of A and B is, (1)C 3-12 Cycloalkyl, (2)C 2-11 Cycloheteroalkyl, (3)-C 1-6 Alkyl-C 3-12 Cycloalkyl, (4)-C 1-6 Alkyl-C 2-11Cycloheteroalkyl, (5)-C 1-6 Alkyl-OC 3-12 Cycloalkyl, and, (6) New C 1-6 Alkyl-OC 2-11 Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R b It is substituted with 1 to 6 substituents selected from; R 1 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) t C(O)R j , (9)-(CH2) t C(O)NR e R j , (10)-(CH2) n NR e C(O)R j , (11)-(CH2) n NR e C(O)OR j , (12)-(CH2) n NR e C(O)N(R e )2, (13)-(CH2) n NR e C(O)NR e R j , (14)-(CH2) n NR e S(O) m R j , (15)-(CH2) n NR e S(O) m N(R e )2, (16)-(CH2) n NR e S(O) m NR e R j , and, (17)-(CH2) n NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R c Substituted with 1 to 5 substituents selected from It is; R 2 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) s C(O)R j , (9)-(CH2) s C(O)NR e R j , (10)-(CH2) s NR e C(O)R j , (11)-(CH2) s NR e C(O)OR j , (12)-(CH2) s NR e C(O)N(R e )2, (13)-(CH2) s NR e C(O)NR e R j , (14)-(CH2) s NR e S(O) m R j , (15)-(CH2) s NR e S(O) m N(R e )2, (16)-(CH2) s NR e S(O) m NR e R j , and, (17)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R d Substituted with 1 to 5 substituents selected from It is Here, R 2 and R 3 And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; and, Here, R 2 and R 4 And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; R 3 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) s C(O)R j , (9)-(CH2) s C(O)NR e R j , (10)-(CH2) s NR e C(O)R j , (11)-(CH2) s NR e C(O)OR j , (12)-(CH2) s NR e C(O)N(R e )2, (13)-(CH2) s NR e C(O)NR e R j , (14)-(CH2) s NR e S(O) m R j , (15)-(CH2) s NR e S(O) m N(R e )2, (16)-(CH2) s NR e S(O) m NR e R j , and, (17)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R d Substituted with 1 to 5 substituents selected from It is; R 4 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) s C(O)R j , (9)-(CH2) s C(O)NR e R j , (10)-(CH2) s NR e C(O)R j , (11)-(CH2) s NR e C(O)OR j , (12)-(CH2) s NR e C(O)N(R e )2, (13)-(CH2) s NR e C(O)NR e R j , (14)-(CH2) s NR e S(O) m R j , (15)-(CH2) s NRe S(O) m N(R e )2, (16)-(CH2) s NR e S(O) m NR e R j , and, (17)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R f Substituted with 1 to 5 substituents selected from It is and Here, R 4 and R 5 And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; R 5 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) s C(O)R j , (9)-(CH2) s C(O)NR e R j , (10)-(CH2) s NR e C(O)R j , (11)-(CH2)s NR e C(O)OR j , (12)-(CH2) s NR e C(O)N(R e )2, (13)-(CH2) s NR e C(O)NR e R j , (14)-(CH2) s NR e S(O) m R j , (15)-(CH2) s NR e S(O) m N(R e )2, (16)-(CH2) s NR e S(O) m NR e R j , and, (17)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R f Substituted with 1 to 5 substituents selected from It is and Here, R 5 and R 7 And the carbon atoms to which they are bonded are 4-membered, 5-membered, or 6-membered saturated rings. It can form; R 6 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) s C(O)R j , (9)-(CH2) s C(O)NR e R j , (10)-(CH2) s NR e C(O)R j , (11)-(CH2) s NR e C(O)OR j , (12)-(CH2) s NR e C(O)N(R e )2, (13)-(CH2) s NR e C(O)NR e R j , (14)-(CH2) s NR e S(O) m R j , (15)-(CH2) s NR e S(O) m N(R e )2, (16)-(CH2) s NR e S(O) m NR e R j , and, (17)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R gSubstituted with 1 to 5 substituents selected from It is and Here, R 6 and R 7 And the carbon atoms to which they are bonded are -C 3-5 Cycloalkyl ring It can form; R 7 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, (4)-C 2-6 Alkinil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7)-C 1-6 Alkyl-OC 1-6 Alkyl-, (8)-(CH2) s C(O)R j , (9)-(CH2) s C(O)NR e R j , (10)-(CH2) s NR e C(O)R j , (11)-(CH2) s NR e C(O)OR j , (12)-(CH2) s NR e C(O)N(R e )2, (13)-(CH2) s NR e C(O)NR e R j , (14)-(CH2) s NR e S(O) m R j , (15)-(CH2) s NRe S(O) m N(R e )2, (16)-(CH2) s NR e S(O) m NR e R j , and, (17)-(CH2) s NR e R j Selected from the group consisting of, Here, each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cyclohete Roalkyl is either unsubstituted or R g Substituted with 1 to 5 substituents selected from It is; R 8 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 3-6 Cycloalkyl, and, (4)-C 2-6 Cycloheteroalkyl Selected from the group consisting of, Here, each alkyl, cycloalkyl, and cycloheteroalkyl is either substituted or not. or substituted with 1 to 5 substituents selected from halogens; R 9 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, (3)-C 2-6 Alkenil, and (4)-C 2-6 Alkinyl Selected from the group consisting of, Here, each alkyl, alkenyl, and alkynyl is either unsubstituted or halogenated. It is substituted with 1 to 5 substituents selected from n; Each R a teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 2-6 Alkenil, (7)-C 2-6 Alkinil, (8)-C 3-6 Cycloalkyl, (9)-C 2-6 Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C 1-6 Alkyl-aryl, (13)-C 1-6 Alkyl-heteroaryl, (14)-C 1-6 Alkyl-C 3-6 Cycloalkyl, (15)-C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (16)-C 2-6 Alkenil-C 3-6 Cycloalkyl, (17)-C 2-6 Alkenil-C 2-6 Cycloheteroalkyl, (18)-C 2-6 Alkenyl-aryl, (19)-C 2-6 Alkenyl heteroaryl, (20)-C 2-6 Alkinyl-C 3-6 Cycloalkyl, (21)-C 2-6 Alkinyl C 2-6 Cycloheteroalkyl, (22)-C 2-6 Alkinyl-aryl, (23)-C 2-6 Alkinyl heteroaryl, (24)-OH, (25)-(CH2) p -OC1-6 Alkyl, (26)-(CH2) p -OC 2-6 Alkenil, (27)-(CH2) p -OC 2-6 Alkinil, (28)-(CH2) p -OC 3-6 Cycloalkyl, (29)-(CH2) p -OC 2-6 Cycloheteroalkyl, (30)-(CH2) p -O-aryl, (31)-(CH2) p -O-heteroaryl, (32)-OC 1-6 Alkyl-C 3-6 Cycloalkyl, (33)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (34)-OC 1-6 Alkyl-aryl, (35)-OC 1-6 Alkyl-heteroaryl, (36)-S(O) r R h , (37)-C 1-6 Alkyl-S(O) r R h , (38)-N(R k )2, (39)-C(O)R L , and, (40)-NR k R L Independently selected from the group consisting of, Here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Al Kill and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups; Each R b teeth, (1) CN, (2) oxo, (3) halogen, (4) -S(O)2C 1-6 alkyl, (5) -C 1-6 alkyl, (6) -C 1-6 alkenyl, (7) -C 2-6 alkynyl, (8) -C 3-6 cycloalkyl, (9) -C 2-6 cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) -C 1-6 alkyl-aryl, (13) -C 1-6 alkyl-heteroaryl, (14) -C 1-6 alkyl-C 3-6 cycloalkyl, (15) -C 1-6 [[ID= cycloheteroalkyl, (16) -C 2-6 alkenyl-C 3-6 cycloalkyl, (17) -C 2-6 alkenyl-C 2-6 cycloheteroalkyl, (18) -C 2-6 alkenyl-aryl, (19) -C 2-6 alkenyl-heteroaryl, < (20) -C 2-6 alkynyl-C 3-6 cycloalkyl, (21) -C 2-6 alkynyl-C 2-6 cycloheteroalkyl, (22) -C 2-6 alkynyl-aryl, (23) -C 2-6 alkynyl-heteroaryl, <00043 (24) -OH, ​(25)-(CH2) q -OC 1-6 Alkyl, (26)-(CH2) q -OC 2-6 Alkenil, (27)-(CH2) q -OC 2-6 Alkinil, (28)-(CH2) q -OC 3-6 Cycloalkyl, (29)-(CH2) q -OC 2-6 Cycloheteroalkyl, (30)-(CH2) q -O-aryl, (31)-(CH2) q -O-heteroaryl, (32)-OC 1-6 Alkyl-C 3-6 Cycloalkyl, (33)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, (34)-OC 1-6 Alkyl-aryl, (35)-OC 1-6 Alkyl-heteroaryl, (36)-S(O) r R i , (37)-C 1-6 Alkyl-S(O) r R i , (38)-N(R k )2, (39)-C(O)R L , and, (40)-NR k R L Independently selected from the group consisting of, Here, each R b These are either not substituted, or halogen, CF3, OCF3, CN, C H2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6; R c teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R d teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R e teeth, (1) Hydrogen, and (2)C 1-6 Alkyl Selected from; R f teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R g teeth, (1)-C 1-6 Alkyl, (2) OH, (3) Halogens, and (4)-OC 1-6 Alkyl Selected from, Here, the alkyl group is either unsubstituted or substituted with one to three halogens; R h is selected from (1) hydrogen, (2) C 1-6 alkyl, (3) C 3-6 cycloalkyl, (4) aryl, and (5) heteroaryl ; R i is selected from (1) hydrogen, (2) C 1-6 alkyl, (3) C 3-6 cycloalkyl, (4) aryl, and (5) heteroaryl ; R j is selected from (1) hydrogen, (2) C 1-6 alkyl, (3) C 3-6 alkenyl, (4) C 3-6 alkynyl, (5) C 3-6 cycloalkyl, (6) C 2-5 cycloheteroalkyl, (7) aryl, and (8) heteroaryl ; R k is selected from (1) hydrogen, and (2) C 1-6 alkyl ; R L is selected from (1) hydrogen, (2) C 1-6 alkyl, (3) C 3-6 cycloalkyl, (4) aryl, and (5) heteroaryl ; m is independently selected from 0, 1, and 2; n is independently selected from 2, 3, 4, 5, and 6; p is independently selected from 0, 1, 2, and 3; q is independently selected from 0, 1, 2, and 3; r is selected independently from 0, 1, and 2; s is independently selected from 0, 1, 2, 3, 4, 5 and 6; and, t is independently selected from 0, 1, 2, 3, 4, 5, and 6. The invention also provides novel compounds represented by or pharmaceutically acceptable salts thereof.

[0020] The compound represented by structural formula I has many embodiments, which are summarized below. The compounds shown are included, as well as the individual diagrams of those compounds. Stereoimers, enantiomers and epimers, as well as their diastereoisomers and This also includes mixtures of enantiomers (which include racemic mixtures).

[0021] In one embodiment, one of A and B is from the group consisting of aryls and heteroaryls. They are independently selected, where aryl and heteroaryl are either unsubstituted or , R a It is substituted with 1 to 5 substituents selected from A and B, and also with one of A and B. For those using -C 3-12 Cycloalkyl, -C 2-11 Cycloheteroalkyl, -C 1-6 a Lukil-C 3-12 Cycloalkyl, -C 1-6 Alkyl-C 2-11 Cycloheteral Kill, -C 1-6 Alkyl-OC 3-12 Cycloalkyl and -C 1-6 Alkyl-O -C 2-11Independently selected from the group consisting of cycloheteralkyls, where alkyl , cycloalkyl and cycloheteroalkyl are either unsubstituted or R b Choose from It is substituted with one to six selected substituents.

[0022] In another embodiment, one of A and B is a group consisting of aryls and heteroaryls. They are independently selected, where aryl and heteroaryl are either not substituted or R a It is substituted with 1 to 5 substituents selected from A and B, and also the other of A and B. One is -C 3-10 Cycloalkyl, -C 2-9 Cycloheteroalkyl, -C 1-6 a Lukil-C 3-12 Cycloalkyl, -C 1-6 Alkyl-C 2-11 Cycloheteral Kill, -C 1-6 Alkyl-OC 3-12 Cycloalkyl and -C 1-6 Alkyl-O -C 2-11 Independently selected from the group consisting of cycloheteralkyls, where alkyl , cycloalkyl and cycloheteroalkyl are either unsubstituted or R b Choose from It is substituted with one to six selected substituents.

[0023] In another embodiment, one of A and B is a group consisting of aryls and heteroaryls. They are independently selected, where aryl and heteroaryl are either not substituted or R a It is substituted with 1 to 5 substituents selected from A and B, and also the other of A and B. One is -C 3-12 Cycloalkyl and -C 2-11 group consisting of cycloheteralkyls Independently selected from, where cycloalkyl and cycloheteroalkyl are substituted. Not done, or R b It is substituted with 1 to 6 substituents selected from the following.

[0024] In another embodiment, one of A and B is a group consisting of aryls and heteroaryls. They are independently selected, where aryl and heteroaryl are either not substituted or R a It is substituted with 1 to 5 substituents selected from A and B, and also the other of A and B. One is -C 3-10 Cycloalkyl and -C 2-9 A group consisting of cycloheteralkyl groups They are independently selected, where cycloalkyl and cycloheteroalkyl are substituted. Either they are not there, or R b It is substituted with 1 to 6 substituents selected from the following.

[0025] In another embodiment, one of A and B is made of phenyl, pyridine, and thiazole. Independently selected from the group, where phenyl, pyridine, and thiazole are substituted Either they are not there, or R a It is substituted with 1 to 5 substituents selected from A and B The other of these is cyclopropane, cyclobutane, cyclopentane, cyclohexane. , bicyclo[3.2.1]-octane, bicyclo[3.1.0]hexane, bicyclo[2 .2.2] Octane, Spiro[2.5] Octane, Bicyclo[1.1.1] Pentane, S Pyro[3.3]heptane, spiro[2.3]hexane, spiro[2.2]pentane, pipe Independently selected from the group consisting of lysine, tetrahydropyran, and chroman, where A The other of B is either not substituted, or R b1 to 6 substitutions selected from It is substituted with the base.

[0026] In another embodiment, one of A and B is made of phenyl, pyridine, and thiazole. Independently selected from the group, where phenyl, pyridine, and thiazole are substituted Either they are not there, or R a It is substituted with 1 to 5 substituents selected from A and B The other of these is cyclopropane, cyclobutane, cyclopentane, cyclohexane. , bicyclo[3.2.1]-octane, bicyclo[3.1.0]hexane, bicyclo[2 .2.2] Octane, Spiro[2.5] Octane, Bicyclo[1.1.1] Pentane, S Pyro[3.3]heptane, spiro[2.3]hexane, spiro[2.2]pentane, pipe Independently selected from the group consisting of lysine and tetrahydropyran, where A and B The other side is either not substituted, or R b Substituted with 1 to 6 substituents selected from It is being done.

[0027] In another embodiment, one of A and B is independent of the group consisting of phenyl and pyridine. Selected, where phenyl and pyridine are either unsubstituted or R a from It is substituted with one to four selected substituents, and the other of A and B is cyclic. Independently selected from the group consisting of lobutane, cyclohexane, tetrahydropyran, and chroman Selected, where cyclobutane, cyclohexane, and tetrahydropyrane are substituted Either they are not there, or R b It is substituted with 1 to 6 substituents selected from the following.

[0028] In another embodiment, one of A and B is independent of the group consisting of phenyl and pyridine. Selected, where phenyl and pyridine are either unsubstituted or R a from It is substituted with one to four selected substituents, and the other of A and B is cyclic. Independently selected from the group consisting of lobutane, cyclohexane, and tetrahydropyran, Here, cyclobutane, cyclohexane, and tetrahydropyrane are either unsubstituted or unsubstituted. Or, R b It is substituted with 1 to 6 substituents selected from the following.

[0029] In one embodiment, A is selected from the group consisting of aryls and heteroaryls, where aryl and heteroaryl are either unsubstituted or R a Select from 1~ It is substituted with a substituent of 5.

[0030] In another embodiment, A is selected from the group consisting of phenyl, pyridine, and thiazole. Here, phenyl, pyridine, and thiazole are either unsubstituted or R a from It is substituted with one to five selected substituents.

[0031] In another embodiment, A is selected from the group consisting of phenyl and pyridine, where F Enyl and pyridine are either unsubstituted or R a 1 to 4 substituents selected from It has been replaced with.

[0032] In one embodiment, B is -C 3-12 Cycloalkyl, -C 2-11 Cycloheteral Kill, -C 1-6 Alkyl-C 3-12 Cycloalkyl, -C 1-6Alkyl-C 2-1 1-Cycloheteroalkyl, -C 1-6 Alkyl-OC 3-12 Cycloalkyl and -C 1-6 Alkyl-OC 2-11 Independently selected from the group consisting of cycloheteralkyls Here, alkyl, cycloalkyl and cycloheteroalkyl are not substituted. , or R b It is substituted with 1 to 6 substituents selected from the following.

[0033] In another embodiment, B is -C 3-10 Cycloalkyl, -C 2-9 Cycloheteral Kill, -C 1-6 Alkyl-C 3-12 Cycloalkyl, -C 1-6 Alkyl-C 2-1 1-Cycloheteroalkyl, -C 1-6 Alkyl-OC 3-12 Cycloalkyl and -C 1-6 Alkyl-OC 2-11 Independently selected from the group consisting of cycloheteralkyls Here, alkyl, cycloalkyl and cycloheteroalkyl are not substituted. , or R b It is substituted with 1 to 6 substituents selected from the following.

[0034] In another embodiment, B is -C 3-12 Cycloalkyl and -C 2-11 Cycloheteron Independently selected from the group consisting of alkyl, where cycloalkyl and cycloheteral Lukil is either not substituted or R b Substituted with 1 to 6 substituents selected from Yes, they are.

[0035] In another embodiment, B is -C3-10 Cycloalkyl and -C 2-9 Cyclohetal Independently selected from the group consisting of lucyl, where cycloalkyl and cycloheteral Kill is either not replaced or R b Substituted with 1 to 6 substituents selected from ru.

[0036] In another embodiment, B is cyclopropane, cyclobutane, cyclopentane, cyclo xane, bicyclo[3.2.1]octane, bicyclo[3.1.0]hexane, bicyclo [2.2.2] Octane, spiro[2.5] Octane, bicyclo[1.1.1] Pentane , spiro[3.3]heptane, spiro[2.3]hexane, spiro[2.2]pentane, Independently selected from the group consisting of piperidine, tetrahydropyran, and chroman, here B is either not substituted, or R b Substituted with 1 to 6 substituents selected from ru.

[0037] In another embodiment, B is cyclopropane, cyclobutane, cyclopentane, cyclo xane, bicyclo[3.2.1]octane, bicyclo[3.1.0]hexane, bicyclo [2.2.2] Octane, spiro[2.5] Octane, bicyclo[1.1.1] Pentane , spiro[3.3]heptane, spiro[2.3]hexane, spiro[2.2]pentane, Independently selected from the group consisting of piperidine and tetrahydropyran, where B is set Not converted, or R b It is substituted with 1 to 6 substituents selected from the following.

[0038] In another embodiment, B is derived from cyclobutane, cyclohexane, and tetrahydropyran. Independently selected from the group, where cyclobutane, cyclohexane, and tetrahydrop Lan and Chroman are either unsubstituted or R b With 1 to 6 substituents selected from It has been replaced.

[0039] In another embodiment, B is derived from cyclobutane, cyclohexane, and tetrahydropyran. Independently selected from the group, where cyclobutane, cyclohexane and tetrahydro Piran is either unsubstituted or R b Substituted with 1 to 6 substituents selected from Yes, they are.

[0040] In one embodiment, R 1 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C2 -6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C1 -6 Alkyl-OC 1-6 Alkyl-,-(CH2) t C(O)R j ,-(CH2) t C(O)NR e R j ,-(CH2) n NR e C(O)R j ,-(CH2) n NR e C(O )OR j ,-(CH2) n NR e C(O)N(R e )2, -(CH2) n NR e C(O) NR e R j ,-(CH2) n NR e S(O) m Rj ,-(CH2) n NR e S(O) m N (R e )2, -(CH2) n NR e S(O) m NR e R j and -(CH2) n NR e R j A group consisting of CH2, alkyl, alkenyl, alkynyl, and cycloid is selected, where each is CH2, alkyl, alkenyl, alkynyl, and cycloid. Roalkyl and cycloheteroalkyl groups are either unsubstituted or R c Selected from It is substituted with substituents 1 to 5.

[0041] In another embodiment, R 1 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 From cycloheteralkyl Selected from the group, where each alkyl, alkenyl, alkynyl, cycloalkyl and Bicycloheteroalkyl groups are either unsubstituted or R c Select from 1 to 5 positions It is being replaced by a substitution compound.

[0042] In another embodiment, R 1 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where each alkyl and cycloalkyl is unsubstituted. or, R c It is substituted with 1 to 5 substituents selected from. One embodiment of this embodiment In the class, R 1 This is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, and here Each alkyl and cycloalkyl group is either unsubstituted or R c Selected from It is substituted with 1 to 3 substituents.

[0043] In another embodiment, R 1 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, each alkyl group is either unsubstituted or R c With 1 to 5 substituents selected from It is replaced. In one class of this embodiment, R 1 It consists of hydrogen and -CH3. Selected from the group, where -CH3 is either unsubstituted or R c Selected from It is substituted with 1 to 3 substituents. In another class of this embodiment, R 1 It is hydrogen. .

[0044] In another embodiment, R 1 is -C 1-6 It is alkyl, and here alkyl is substituted It is not included, or R c It is substituted with 1 to 5 substituents selected from this. In one class of voice, R 1 is -CH3, where -CH3 is not substituted. squid, or R c It is substituted with 1 to 3 substituents selected from the following.

[0045] In one embodiment, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C2 -6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C1 -6 Alkyl-OC 1-6Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O )OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O) NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N (R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, alkynyl, and cycloid is selected, where each is CH2, alkyl, alkenyl, alkynyl, and cycloid. Roalkyl and cycloheteroalkyl groups are either unsubstituted or R d Selected from It is substituted with substituents 1 to 5, where R 2 and R 3 and the carbons that bond them The atom is -C 3-5 A cycloalkyl ring can be formed, and here, R 2 and R 4 And the carbon atoms to which they are bonded are -C 3-5 It is possible to form a cycloalkyl ring. Cut.

[0046] In another embodiment, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or Rd Select from It is substituted with substituents 1 to 5, where R 2 and R 3 and the carbon that binds them together Elementary atoms are -C 3-5 A cycloalkyl ring can be formed, and here, R 2 and R 4 And the carbon atoms to which they are bonded are -C 3-5 Forming a cycloalkyl ring can.

[0047] In another embodiment, R 2 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheterogenous alkyl Ru, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-( CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s N R e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S (O) mN(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and alkyl is selected, where each CH2, alkyl, alkenyl, and alkyl Nyl, cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R d mosquito It is substituted with 1 to 5 substituents selected from, and here, R 2 and R 3 and they The bonded carbon atoms are -C 3-5 It can form a cycloalkyl ring.

[0048] In another embodiment, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e Rj ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R d Select from It is substituted with substituents 1 to 5, and here, R 2 and R 3 and they are combined The carbon atoms present are -C 3-5 It can form a cycloalkyl ring.

[0049] In another embodiment, R 2 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheterogenous alkyl Ru, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-( CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s N R e C(O)ORj ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S (O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and alkyl is selected, where each CH2, alkyl, alkenyl, and alkyl Nyl, cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R d mosquito It is substituted with 1 to 5 substituents selected from, and here, R 2 and R 4 and they The bonded carbon atoms are -C 3-5 It can form a cycloalkyl ring.

[0050] In another embodiment, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NRe R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R d Select from It is substituted with substituents 1 to 5, and here, R 2 and R 4 and they are combined The carbon atoms present are -C 3-5 It can form a cycloalkyl ring.

[0051] In another embodiment, R 2 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6Cycloheterogenous alkyl Ru, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-( CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s N R e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S (O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and alkyl is selected, where each CH2, alkyl, alkenyl, and alkyl Nyl, cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R d mosquito It is substituted with 1 to 5 substituents selected from the above.

[0052] In another embodiment, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R d Select from It is substituted with substituents 1 to 5.

[0053] In another embodiment, R 2 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteral Selected from the group consisting of alkyl, alkenyl, alkynyl, and cyclo Lukyl and cycloheteralkyl are either unsubstituted or R d 1 selected from It is substituted with approximately 5 substituents.

[0054] In another embodiment, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 From cycloheteralkyl Selected from the group, where each alkyl, alkenyl, alkynyl, cycloalkyl and Bicycloheteroalkyl groups are either unsubstituted or R d Select from 1 to 5 positions It is being replaced by a substitution compound.

[0055] In another embodiment, R 2 is hydrogen, deuterium, -C 1-6 Alkyl and -C 3-6 Cyclo Selected from the group consisting of alkyl groups, where each alkyl and cycloalkyl group is substituted. Not done, or R d It is substituted with 1 to 5 substituents selected from this embodiment. In one class, R 2 is a group consisting of hydrogen, deuterium, -CH3, and cyclopropyl. Selected from, where each alkyl and cycloalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0056] In another embodiment, R 2 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where each alkyl and cycloalkyl is unsubstituted. or, R d It is substituted with 1 to 5 substituents selected from. One embodiment of this embodiment In the class, R 2 This is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, and here Each alkyl and cycloalkyl group is either unsubstituted or R d Selected from It is substituted with substituents 1 to 5.

[0057] In another embodiment, R 2 These are hydrogen, deuterium and -C 1-6 Select from the group consisting of alkyl groups. Here, each alkyl and cycloalkyl is either unsubstituted or R d from It is substituted with 1 to 5 selected substituents. In one class of this embodiment, R 2 teeth A selection from the group consisting of hydrogen, deuterium, and -CH3, where each -CH3 is substituted. Not done, or R d Substituted with 1 to 3 substituents selected from. Another embodiment So, R 2 is hydrogen. In another embodiment, R 2 It is deuterium.

[0058] In another embodiment, R 2 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, each alkyl and cycloalkyl is either unsubstituted or R d Selected from It is substituted with substituents 1 to 5. In one class of this embodiment, R 2 Hydrogen and Selected from the group consisting of -CH3, where each -CH3 is either unsubstituted or , R d It is substituted with 1 to 3 substituents selected from the following.

[0059] In another embodiment, R 2 is -C 1-6 It is an alkyl, where each alkyl and cyclo Roalkyl is either unsubstituted or R d Substituted with 1 to 5 substituents selected from In one class of this embodiment, R 2 is -CH3, where -CH 3 is either not substituted, or R d Substituted with 1 to 3 substituents selected from .

[0060] In one embodiment, R 3 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenil , -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl , -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(C H2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NRe R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S( O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s N R e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, and alkini. R, cycloalkyl and cycloheteroalkyl are either unsubstituted or R d from It is substituted with one to five selected substituents.

[0061] In another embodiment, R 3 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NRe C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R d Select from It is substituted with substituents 1 to 5.

[0062] In another embodiment, R 3 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Cyclo-heterogeneous Selected from the group consisting of alkyl, alkenyl, alkynyl, and cyclo Alkyl and cycloheteroalkyl groups are either unsubstituted or R d Selected from It is substituted with substituents 1 to 5.

[0063] In another embodiment, R 3 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C2-6 Cyclo-heteroalkyl or Selected from the following groups, where each alkyl, alkenyl, alkynyl, and cycloalkyl And cycloheteralkyls are either unsubstituted or R d Select from 1 to 5 It is substituted with a substituent.

[0064] In another embodiment, R 3 is hydrogen, deuterium, -C 1-6 Alkyl and -C 3-6 Cyclo Selected from the group consisting of alkyl groups, where each alkyl and cycloalkyl group is substituted. Not done, or R d It is substituted with 1 to 5 substituents selected from this embodiment. In one class, R 3 is a group consisting of hydrogen, deuterium, -CH3, and cyclopropyl. Selected from, where cyclopropyl is either unsubstituted or R d Selected from It is substituted with substituents 1 to 3.

[0065] In another embodiment, R 3 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where each alkyl and cycloalkyl is unsubstituted. or, R d It is substituted with 1 to 5 substituents selected from. One embodiment of this embodiment In the class, R 3 This is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, and here Therefore, cyclopropyl is either unsubstituted or R d 1 to 3 substituents selected from It has been replaced with.

[0066] In another embodiment, R 3These are hydrogen, deuterium and -C 1-6 Select from the group consisting of alkyl groups. Here, each alkyl group is either unsubstituted or R d Select from 1 to 5 It is substituted with a substituent. In one class of this embodiment, R 3 hydrogen, deuterium and -Selected from the group consisting of CH3, where CH3 is either unsubstituted or R d It is substituted with 1 to 3 substituents selected from. In another class of this embodiment, R 3 is hydrogen. In another class of this embodiment, R 3 It is deuterium.

[0067] In another embodiment, R 3 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, each alkyl group is either unsubstituted or R d With 1 to 5 substituents selected from It is replaced. In one class of this embodiment, R 3 It consists of hydrogen and -CH3. Selected from the group, where CH3 is either unsubstituted or R d 1 selected from Substituting with ~3 substituents. In another class of this embodiment, R 3 It is hydrogen.

[0068] In another embodiment, R 3 is -C 1-6 It is an alkyl group, where each alkyl group is substituted It has not been done, or R d It is substituted with 1 to 5 substituents selected from this. In one class of forms, R 3 is -CH3, where -CH3 is substituted Either not, or R dIt is substituted with 1 to 3 substituents selected from the following.

[0069] In one embodiment, R 4 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenil , -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl , -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(C H2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S( O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s N R e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, and alkini. R, cycloalkyl and cycloheteroalkyl are either unsubstituted or R f from It is substituted with 1 to 5 selected substituents, and here, R 4 and R 5 and they The carbon atoms that are bonded are -C 3-5 It can form a cycloalkyl ring.

[0070] In another embodiment, R 4 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NRe R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R f Select from It is substituted with substituents 1 to 5, and here, R 4 and R 5 and they are combined The carbon atoms present are -C 3-5 It can form a cycloalkyl ring.

[0071] In another embodiment, R 4 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheterogenous alkyl Ru, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-( CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s N R e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j,-(CH2) s NR e S (O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and alkyl is selected, where each CH2, alkyl, alkenyl, and alkyl Nyl, cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R f mosquito It is substituted with 1 to 5 substituents selected from the above.

[0072] In another embodiment, R 4 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NRe S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R f Select from It is substituted with substituents 1 to 5.

[0073] In another embodiment, R 4 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteral Selected from the group consisting of alkyl, alkenyl, alkynyl, and cyclo Lukyl and cycloheteralkyl are either unsubstituted or R f 1 selected from It is substituted with approximately 5 substituents.

[0074] In another embodiment, R 4 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 From cycloheteralkyl Selected from the group, where each alkyl, alkenyl, alkynyl, cycloalkyl and Bicycloheteroalkyl groups are either unsubstituted or R f Select from 1 to 5 positions It is being replaced by a substitution compound.

[0075] In another embodiment, R 4 is hydrogen, deuterium, -C 1-6 Alkyl and -C 3-6 Cyclo Selected from the group consisting of alkyl groups, where each alkyl and cycloalkyl group is substituted. Not done, or R f It is substituted with 1 to 5 substituents selected from this embodiment. In one class, R 4 is a group consisting of hydrogen, deuterium, -CH3, and cyclopropyl. Selected from, where each -CH3 and cyclopropyl is either unsubstituted or R f It is substituted with 1 to 3 substituents selected from the following.

[0076] In another embodiment, R 4 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where each alkyl and cycloalkyl is unsubstituted. or, R f It is substituted with 1 to 5 substituents selected from. One embodiment of this embodiment In the class, R 4 This is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, and here Therefore, each -CH3 and cyclopropyl is either unsubstituted or R f Selected from It is substituted with 1 to 3 substituents.

[0077] In another embodiment, R 4 These are hydrogen, deuterium and -C 1-6 Select from the group consisting of alkyl groups. Here, each alkyl group is either unsubstituted or Rf 1 to 5 to be selected It is substituted with a substituent. In one class of this embodiment, R 4 This is hydrogen. In another class of embodiments, R 4 is deuterium. In another class of this embodiment, R 4 is -CH3, where -CH3 is either unsubstituted or R f Select from It is substituted with 1 to 3 substituents.

[0078] In another embodiment, R 4 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, each alkyl group is either unsubstituted or R f With 1 to 5 substituents selected from It is replaced. In one class of this embodiment, R 4 This embodiment is hydrogen. In another class, R 4 is -CH3, where -CH3 is not substituted or , or R f It is substituted with 1 to 3 substituents selected from the following.

[0079] In another embodiment, R 4 is -C 1-6 It is an alkyl group, where each alkyl group is substituted It has not been done, or R f It is substituted with 1 to 5 substituents selected from this. In one class of forms, R 4 is -CH3, where -CH3 is substituted Either not, or R f It is substituted with 1 to 3 substituents selected from the following.

[0080] In one embodiment, R 5 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6Alkenil , -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl , -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(C H2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S( O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s N R e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, and alkini. R, cycloalkyl and cycloheteroalkyl are either unsubstituted or R f from It is substituted with 1 to 5 selected substituents, and here, R 5 and R 7 and they The bonded carbon atoms can form a saturated ring with four, five, or six members.

[0081] In another embodiment, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R f Select from It is substituted with substituents 1 to 5, and here, R 5 and R 7 and they are combined The carbon atoms present can form saturated rings with four, five, or six members.

[0082] In another embodiment, R 5 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheterogenous alkyl Ru, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-( CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s N R e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S (O) m N(R e )2, -(CH2) s NR e S(O) m NR eR j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and alkyl is selected, where each CH2, alkyl, alkenyl, and alkyl Nyl, cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R f mosquito It is substituted with 1 to 5 substituents selected from, and here, R 5 and R 7 and they The bonded carbon atoms can form a five-membered saturated ring.

[0083] In another embodiment, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NRe S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R f Select from It is substituted with substituents 1 to 5, and here, R 5 and R 7 and they are combined The carbon atoms present can form a five-membered saturated ring.

[0084] In another embodiment, R 5 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C13-6 cycloalkyl, -C 2-6 Cycloheteral Kill, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,- (CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s N R e C(O)NRe R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and aldehyde is selected, where each is CH2, alkyl, alkenyl, and aldehyde. Quinyl, cycloalkyl, and cycloheteroalkyl groups are either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0085] In another embodiment, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C13-6 cycloalkyl, -C 2-6 Cycloheteroalkyl, - C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2 ) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C (O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NRe C( O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of is selected, where each CH2, alkyl, alkenyl, alkynyl, Cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R f Select from It is substituted with substituents 1 to 5.

[0086] In another embodiment, R 5 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteral Selected from the group consisting of alkyl, alkenyl, alkynyl, and cyclo Lukyl and cycloheteralkyl are either unsubstituted or R f 1 selected from It is substituted with approximately 5 substituents.

[0087] In another embodiment, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C2-6 From cycloheteralkyl Selected from the group, where each alkyl, alkenyl, alkynyl, cycloalkyl and Bicycloheteroalkyl groups are either unsubstituted or R f Select from 1 to 5 positions It is being replaced by a substitution compound.

[0088] In another embodiment, R 5 is hydrogen, deuterium, -C 1-6 Alkyl and -C 3-6 Cyclo Selected from the group consisting of alkyl, where alkyl and cycloalkyl are substituted Either they are not there, or R f It is substituted with 1 to 5 substituents selected from. In one class, R 5 This is selected from the group consisting of hydrogen, -CH3, and cyclopropyl. Here, each CH3 and cyclopropyl is either unsubstituted or R f Select from It is substituted with 1 to 3 substituents.

[0089] In another embodiment, R 5 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where alkyl and cycloalkyl are either unsubstituted or , or R f It is substituted with 1 to 5 substituents selected from. One of the components of this embodiment In Las, R 5 This is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, where Each CH3 and cyclopropyl is either unsubstituted or R f Select from 1~ It is substituted with a substituent of 3.

[0090] In another embodiment, R 5These are hydrogen, deuterium and -C 1-6 Select from the group consisting of alkyl groups. And here, the alkyl is either unsubstituted or R f Select from 1 to 5 positions It is substituted with a substitution group. In another embodiment, R 5 is hydrogen. In another embodiment, R 5 It is deuterium.

[0091] In another embodiment, R 5 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, the alkyl is either unsubstituted or R f Place with 1 to 5 substituents selected from It is replaced. In another embodiment, R 5 It is hydrogen.

[0092] In another embodiment, R 5 is -C 1-6 It is alkyl, and here alkyl is substituted It is not included, or R f It is substituted with 1 to 5 substituents selected from this. In one class of voice, R 5 is -CH3, where -CH3 is not substituted. squid, or R f It is substituted with 1 to 3 substituents selected from the following.

[0093] In one embodiment, R 6 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenil , -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl , -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(C H2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S( O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s N R e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, and alkini. R, cycloalkyl and cycloheteroalkyl are either unsubstituted or R g from It is substituted with 1 to 5 selected substituents, and here, R 6 and R 7 and they The carbon atoms that are bonded are -C 3-5 It can form a cycloalkyl ring.

[0094] In another embodiment, R 6 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R g Select from It is substituted with substituents 1 to 5, and here, R 6 and R 7 and they are combined The carbon atoms present are -C 3-5 It can form a cycloalkyl ring.

[0095] In another embodiment, R 6 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheterogenous alkyl Ru, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-( CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s N R e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S (O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A group consisting of CH2, alkyl, alkenyl, and alkyl is selected, where each CH2, alkyl, alkenyl, and alkyl Nyl, cycloalkyl and cycloheteroalkyl groups are either unsubstituted or R gmosquito It is substituted with 1 to 5 substituents selected from the above.

[0096] In another embodiment, R 6 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R g Select from It is substituted with substituents 1 to 5.

[0097] In another embodiment, R 6 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteral Selected from the group consisting of alkyl, alkenyl, alkynyl, and cyclo Lukyl and cycloheteralkyl are either unsubstituted or R g 1 selected from It is substituted with substituents ~5. In another embodiment, R 6 is hydrogen, -C 1-6 Alkyl , -C 2-6 Alkenyl, -C 2-6 Alkinyl and -C 3-6 Composed of cycloalkyl groups Selected from the group, where each alkyl, alkenyl, alkynyl and cycloalkyl is, Either not substituted, or R g It is substituted with 1 to 5 substituents selected from the following.

[0098] In another embodiment, R 6 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 From cycloheteralkyl Selected from the group, where each alkyl, alkenyl, alkynyl, cycloalkyl and Bicycloheteroalkyl groups are either unsubstituted or R g Select from 1 to 5 positions It is substituted with a substitution group. In another embodiment, R 6 is hydrogen, -C 1-6 Alkyl, -C2 -6 Alkenyl, -C 2-6 Alkinyl and -C 3-6 Selected from the group consisting of cycloalkyl groups Selected, where each alkyl, alkenyl, alkynyl and cycloalkyl is substituted. Not done, or R g It is substituted with 1 to 5 substituents selected from the following.

[0099] In another embodiment, R 6 is hydrogen, deuterium, -C 1-6 Alkyl and -C 3-6 Cyclo Selected from the group consisting of alkyl, where alkyl and cycloalkyl are substituted Either they are not there, or R g It is substituted with 1 to 5 substituents selected from. In one class, R 6 These are hydrogen, deuterium, -CH3, -CF3, -CH2CH3, and -C Selected from the group consisting of H2F, -CH2OH, and cyclopropyl, where cyclopropyl The pill is either not substituted or R g Substituted with 1 to 5 substituents selected from In another class of this embodiment, R 6 It consists of hydrogen, deuterium, -CH3 and cyclopropyl Selected from the group consisting of R, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0100] In another embodiment, R 6 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where alkyl and cycloalkyl are either unsubstituted or , or R g It is substituted with 1 to 5 substituents selected from. One of the components of this embodiment In Las, R 6 It is hydrogen, -CH3, -CH2CH3, -CH2F and cyclopropyl Selected from the following group, where cyclopropyl is either unsubstituted or R g mosquito It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 6 teeth Selected from the group consisting of hydrogen, -CH3 and cyclopropyl, where cyclopropyl is either not substituted, or R g It is substituted with 1 to 5 substituents selected from the following.

[0101] In another embodiment, R 6 These are hydrogen, deuterium, and C 1-6 Selected from the group consisting of alkyl groups Here, alkyl is either unsubstituted or R g 1 to 5 replacements selected from It is replaced by the base. In one class of this embodiment, R 6 It consists of hydrogen, deuterium, and -CH Selected from the group consisting of 3, -CF3, -CH2CH3, -CH2OH, and -CH2F. In another class of this embodiment, R 6 This is selected from the group consisting of hydrogen and -CH3. In another embodiment, R 6 It is hydrogen.

[0102] In another embodiment, R 6 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, the alkyl is either unsubstituted or R g Place with 1 to 5 substituents selected from It is replaced. In one class of this embodiment, R 6 These are hydrogen, -CH3, and -CH2C Selected from the group consisting of H3 and -CH2F. In another class of this embodiment, R 6 teeth Selected from the group consisting of hydrogen and -CH3. In another embodiment, R 6 It is hydrogen. .

[0103] In another embodiment, R 6 is -C 1-6 Selected from the group consisting of alkyl groups, where a Lukil is either not substituted or R g Substituted with 1 to 5 substituents selected from In one class of this embodiment, R 6 These are -CH3, -CH2CH3 and -CH Selected from the group consisting of 2F. In another class of this embodiment, R 6 is -CH3 ru.

[0104] In one embodiment, R 7 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenil , -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl , -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(C H2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C(O)OR j ,-(CH2) s NR e C(O)N(R e )2, -(CH2) sNR e C(O)NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S( O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s N R e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, and alkini. R, cycloalkyl and cycloheteroalkyl are either unsubstituted or R g from It is substituted with one to five selected substituents.

[0105] In another embodiment, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl-,-(CH2) s C(O)R j ,-(CH2) s C(O)NR e R j ,-(CH2) s NR e C(O)R j ,-(CH2) s NR e C( O)OR j ,-(CH2) s NR e C(O)N(Re )2, -(CH2) s NR e C(O )NR e R j ,-(CH2) s NR e S(O) m R j ,-(CH2) s NR e S(O) m N(R e )2, -(CH2) s NR e S(O) m NR e R j and -(CH2) s NR e R j A selection is made from the group consisting of CH2, alkyl, alkenyl, alkynyl, and cy Chloalkyl and cycloheteroalkyl groups are either unsubstituted or R g Select from It is substituted with substituents 1 to 5.

[0106] In another embodiment, R 7 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteral Selected from the group consisting of alkyl, alkenyl, alkynyl, and cycloal Kill and cycloheteralkyl are either unsubstituted or R g Select from 1~ It is substituted with substituent 5.

[0107] In another embodiment, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 From cycloheteralkyl Selected from the group, where alkyl, alkenyl, alkynyl, cycloalkyl and Cycloheteroalkyl groups are either unsubstituted or R g 1 to 5 replacements selected from It is substituted with the base.

[0108] In another embodiment, R 7 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkeni Ru, -C 2-6 Alkinyl and -C 3-6 Selected from the group consisting of cycloalkyl groups, here Therefore, alkyl, alkenyl, alkynyl and cycloalkyl groups are either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0109] In another embodiment, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl and -C 3-6 Selected from the group consisting of cycloalkyls, where, Kill, alkenyl, alkynyl, and cycloalkyl are either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0110] In another embodiment, R 7 is hydrogen, deuterium, -C 1-6 Alkyl and -C 3-6 Cyclo Selected from the group consisting of alkyl, where alkyl and cycloalkyl are substituted Either they are not there, or R g It is substituted with 1 to 5 substituents selected from. In one class, R 7 These are hydrogen, deuterium, -CH3, -CF3, -CH2CH3, and -C Selected from the group consisting of H2F, -CH2OH, and cyclopropyl, where cyclopropyl The pill is either not substituted or R g Substituted with 1 to 5 substituents selected from In one class of this embodiment, R 7 These are hydrogen, deuterium, -CH3, and -CH2CH 3, selected from the group consisting of -CH2F and cyclopropyl, where cyclopropyl is , not substituted, or R g It is substituted with 1 to 5 substituents selected from the following. In another class of the embodiment, R 7 It is derived from hydrogen, deuterium, -CH3 and cyclopropyl Selected from the group, where the cycloalkyl is either unsubstituted or R g from It is substituted with selected substituents 1 to 5. In another embodiment, R 7 It is hydrogen. In another embodiment, R 7 It is deuterium.

[0111] In another embodiment, R 7 is hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl Selected from the group consisting of, where alkyl and cycloalkyl are either unsubstituted or , or R g It is substituted with 1 to 5 substituents selected from. One of the components of this embodiment In Las, R 7 It is hydrogen, -CH3, -CH2CH3, -CH2F and cyclopropyl Selected from the following group, where cyclopropyl is either unsubstituted or R g mosquito It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 7 teeth Selected from the group consisting of hydrogen, -CH3 and cyclopropyl, where cycloalkyl is either not substituted, or R g It is substituted with 1 to 5 substituents selected from the following. In another embodiment, R 7 It is hydrogen.

[0112] In one embodiment, R 8 is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloal Kill and -C 2-6 Selected from the group consisting of cycloheteralkyls, where each alkyl Cycloalkyl and cycloheteroalkyl are either unsubstituted or halogenated. It is substituted with 1 to 5 substituents selected from the above.

[0113] In another embodiment, R 8 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, the alkyl group is either unsubstituted or has 1 to 5 substituents selected from halogens. It is replaced by R. In another embodiment, 8 It is hydrogen.

[0114] In another embodiment, R 8 is -C 1-6 It is alkyl, and here alkyl is substituted Either it is not present, or it is substituted with 1 to 5 substituents selected from halogens.

[0115] In one embodiment, R 9 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6Selected from the group consisting of alkynyls, where each alkyl, alkenyl and alkynyl The nyl group is either unsubstituted or substituted with 1 to 5 substituents selected from halogens. It is.

[0116] In another embodiment, R 9 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, Here, the alkyl group is either unsubstituted or has 1 to 5 substituents selected from halogens. It is replaced by. In one class of this embodiment, R 9 It consists of hydrogen and CH3. Selected from the group. In another embodiment, R 9 It is hydrogen.

[0117] In another embodiment, R 9 is -C 1-6 It is alkyl, and here alkyl is substituted Either it is not present, or it is substituted with 1 to 5 substituents selected from halogens. In one class of application forms, R 9 is -C 1-6 It is an alkyl group, CH3.

[0118] One embodiment, each R a CN, oxo, halogen, -S(O)2C 1-6 Alkyl , -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Shik Roalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C3 -6 Cycloalkyl, -C 1-6 Alkyl-C2-6 Cycloheteroalkyl, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Cyclohetal Lukil, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, - C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Cyclohe Telolalkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkinyl heteroary -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 a Lukenil, -(CH2) p -OC 2-6 Alkinyl, -(CH2) p -OC 3-6 C Chloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p - O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -S(O) r R h , -C 1-6 Alkyl-S(O) r R h , -N(R k )2, -C(O)R Land -NR k R L mosquito They are independently selected from the following groups, where each R a It is either not substituted, or halog N, CF3, OH, C 1-6 Alkyl and -OC 1-6 1 to 6 selected from alkyl groups It is substituted with a substituent.

[0119] In another embodiment, each R a CN, oxo, halogen, -S(O)2C 1-6 Alki Ru, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 C Chloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1- 6 alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenil, - (CH2) p -OC 2-6 Alkinyl, -(CH2) p -OC 3-6 Cycloalkyl ,-(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl and -(CH2) p Independently selected from the group consisting of -O-heteroaryls, where each R aIt is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and - OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0120] In another embodiment, each R a CN, oxo, halogen, -S(O)2C 1-6 Alki Ru, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 C Chloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -OH, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkinyl, -O -C 3-6 Cycloalkyl, -OC 2-6 Cycloheteroalkyl, -O-aryl and Independently selected from the group consisting of -O-heteroaryls, where each R a It is replaced Either none, or halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 Alkyl It is substituted with 1 to 6 substituents selected from the following.

[0121] In another embodiment, each R a CN, oxo, halogen, -S(O)2C 1-6 Alki Ru, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 3-6 Cycloalkyl, -C 2- 6-cycloheteroalkyl, aryl, heteroaryl, -OH, -OC 1-6 Alkyl ,-OC 3-6 Cycloalkyl and -OC 2-6A group consisting of cycloheteralkyl groups They are independently selected, and here, each R a It is either not substituted, or halogen, CF3 OH, C 1-6 Alkyl and -OC 1-6 Place 1 to 6 substituents selected from alkyl groups. It has been replaced.

[0122] In another embodiment, each R a CN, halogen, -C 1-6 Alkyl, -C 2-6 Al Kenil, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, hetero Roaryl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2- Independently selected from the group consisting of 6 cycloheteralkyls, where each R a is replaced Either not, or halogen, CF3, OH, C 1-6 Alkyl and OC 1-6 Alkyl It is substituted with 1 to 6 substituents selected from the following.

[0123] In another embodiment, each R a CN, halogen, -C 1-6 Alkyl, -C 3-6 Shik Roalkyl, -C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl, -OC 3- 6-cycloalkyl and -OC 2-6 Independently selected from the group consisting of cycloheteralkyl groups. And here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1- 6alkyl and OC 1-6It is substituted with 1 to 6 substituents selected from alkyl groups.

[0124] In another embodiment, each R a CN, halogen, -C 1-6 Alkyl and -OC 1- Independently selected from the group consisting of 6 alkyl groups, where each R a It is either not replaced, Alternatively, halogen, CF3, OH, C 1-6 Alkyl and OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6.

[0125] In another embodiment, each R a is halogen, -C 1-6 Alkyl and -OC 1-6 Al Independently selected from the group consisting of kills, where each R a It is either not substituted, or Halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups Substituting with ~6 substituents. In one class of this embodiment, each R a is halogen , -C 1-6 Alkyl and -OC 1-6 Independently selected from the group consisting of alkyl, Here, each alkyl group is either unsubstituted or contains Cl, F, CF3, OH, CH3 and - Substituted with 1 to 6 substituents selected from OCH3. Another class of this embodiment So, each R a are Br, F, Cl, -CF3, -CH3, -CHF2, -CH2CF3, Independent of the group consisting of -CF2CH3, -OCF3, -OCHF2, and -OCH2CF3 and are selected. In another class of this embodiment, each R a F, Cl, -CF3, -CH 3, -CHF2, -CH2CF3, -CF2CH3, -OCF3, -OCHF2 and -O It is independently selected from the group consisting of CH2CF3. In another class of this embodiment, each R a This is independent of the group consisting of F, Cl, -CF3, -CH3, -CHF2, and -OCF3. It is selected.

[0126] In another embodiment, each R a This includes halogen and -C 1-6 Independent of the group consisting of alkyl groups Selected, where each alkyl is either unsubstituted or halogen, CF3, O H, C 1-6 Alkyl and -OC 1-6 Substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R a This includes halogen and -C 1-6 Alki Independently selected from the group consisting of R, where each R a is either not substituted, or C Substituted with 1 to 6 substituents selected from l, F, CF3, OH, CH3 and -OCH3 In another class of this embodiment, each R a Br, F, Cl, -CF3, -CH 3. Independently selected from the group consisting of -CHF2, -CH2CF3, and -CF2CH3. In another class of this embodiment, each R a F, Cl, -CF3, -CH3, -CHF 2. Selected independently from the group consisting of -CH2CF3 and -CF2CH3. This implementation In another class of state, each R a It consists of F, Cl, -CF3, -CH3, and -CHF2. It is selected independently of the group.

[0127] In another embodiment, each R ais a halogen. In one class of this embodiment, R a is F or Cl. In another embodiment, R a is -C 1-6 It is alkyl, here So, each R a These are either unsubstituted or contain F, Cl, CF3, OH, CH3 and -OC It is substituted with 1 to 6 substituents selected from H3. In one class of this embodiment, , R a These are -CF3, -CH3, or -CHF2.

[0128] One embodiment, each R b CN, oxo, halogen, -S(O)2C 1-6 Alkyl , -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Shik Roalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C3 -6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Cyclohetal Lukil, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, - C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl-C 2-6 Cyclo Heteroalkyl, -C 2-6Alkinyl-aryl, -C 2-6 Alkinyl heteroant -OH, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 2-6 Alkenyl, -(CH2) q -OC 2-6 Alkinyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Cycloheteroalkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3- 6-cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1- 6 alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -S(O) r R i ,- C 1-6 Alkyl-S(O) r R i , -N(R k )2, -C(O)R L and -NR k R L Independently selected from the group consisting of, where each R b is either not substituted or halo Gen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0129] In another embodiment, each R b CN, oxo, halogen, -S(O)2C 1-6 Alki Ru, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 C Chloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1- 6 alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OH, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 2-6 Alkenil, - (CH2) q -OC 2-6 Alkinyl, -(CH2) q -OC 3-6 Cycloalkyl ,-(CH2) q -OC 2-6 Cycloheteroalkyl, -(CH2) q -O-aryl ,-(CH2) q Independently selected from the group consisting of -O-heteroaryls, where each R b These are either not substituted, or contain halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 1 to 6 positions selected from alkyl It is being replaced by a substitution compound.

[0130] In another embodiment, each R b CN, oxo, halogen, -S(O)2C 1-6 Alki Ru, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6Alkinyl, -C 3-6 C Chloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1- 6 alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2-6 Cyclohete Independently selected from the group consisting of R alkyl groups, where each R b It is either not replaced, Alternatively, halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 a Lukil and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0131] In another embodiment, each R b CN, oxo, halogen, -S(O)2C 1-6 Alki Ru, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 C Chloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2-6 Cyclohete Independently selected from the group consisting of R alkyl groups, where each R b It is either not replaced, Alternatively, halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 a Lukil and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0132] In another embodiment, each R b CN, halogen, -C 1-6 Alkyl, -C 1-6 Al Kenil, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, hetero Loaryl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O- C 2-6 Independently selected from the group consisting of cycloheteralkyls, where each R b is, place Either not replaced, or halogen, CF3, OCF3, CN, CH2CF3, CF2C H3, -C 1-6 Alkyl and -OC 1-6 Place 1 to 6 substituents selected from alkyl groups. It has been replaced.

[0133] In another embodiment, each R b CN, halogen, -C 1-6 Alkyl, -C 1-6 Al Kenil, -C 3-6 Cycloalkyl, aryl, heteroaryl and -OC 1-6 Al Independently selected from the group consisting of kills, where each R b It is either not substituted, or Halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0134] In another embodiment, each R b CN, Halogen-C 1-6 Alkyl, -C1-6 Alke Nil, -C 3-6 Cycloalkyl and -OC 1-6 Independently selected from the group consisting of alkyl groups Here, alkyl, alkenyl and cycloalkyl are either unsubstituted or Halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alki Lu and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0135] In another embodiment, each R b is halogen, -C 1-6 Alkyl, -C 1-6 Alkenil , -C 3-6 Cycloalkyl and -OC 1-6 Independently selected from the group consisting of alkyls So, here, each R b It is either not substituted, or contains halogen, CF3, OCF3, CN CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Select from alkyl It is substituted with substituents 1 to 6. In one class of this embodiment, each R b teeth, Halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl and -OC 1-6 Independently selected from the group consisting of alkyls, where each alkyl, alke Nyl and cycloalkyl groups are either unsubstituted or F, Cl, CF3, OCF3, 1 to 6 positions selected from CN, CH2CF3, CF2CH3, -CH3 and -OCH3 It is replaced with a substitution base. In another class of this embodiment, each R b F, Cl, -CH3 , -CF3, -CH2CF3, -CH(CH3)CF3, -CF2CH3, =CH2, A group consisting of chloropropyl, -OCH3, -OCF3, -OCHF2, and -OCH2CF3. They are independently selected, where cyclopropyl is either unsubstituted or F,Cl From CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3 and O-CH3 It is substituted with 1 to 5 selected substituents. In another class of this embodiment, each R b teeth , F, Cl, -CH3, -CF3, -CH2CF3, -CH(CH3)CF3, =CH2 Independently from the group consisting of cyclopropyl, -OCH3, -OCHF2, and -OCH2CF3 Selected, where cyclopropyl is either unsubstituted or F,Cl,CF3 Selected from OCF3, CN, CH2CF3, CF2CH3, -CH3 and O-CH3 It is substituted with substituents 1 to 5.

[0136] In another embodiment, each R b This includes halogen and -C 1-6 Independent of the group consisting of alkyl groups Selected, and here, each R b These are either not substituted, or halogen, CF3, OCF 3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and OC 1-6 Alkyl It is substituted with 1 to 6 substituents selected from. In one class of this embodiment, each R b This includes halogen and -C 1-6 Independently selected from the group consisting of alkyls, where a Lukil is either unsubstituted or F, Cl, CF3, OCF3, CN, CH2CF 3, substituted with 1 to 6 substituents selected from CF2CH3, -CH3 and -OCH3 There is. In another class of this embodiment, each R b F, Cl, -CH3, -CF3, -C Independently selected from the group consisting of H2CF3, -CH(CH3)CF3, and -CF2CH3 In another class of this embodiment, each R b F, Cl, -CH3, -CF3, -C It is independently selected from the group consisting of H2CF3 and -CH(CH3)CF3.

[0137] In another embodiment, each R b is a halogen. In one class of this embodiment, R b is F or Cl. In another class of this embodiment, R b This is F. In another class of form, R b It is Cl.

[0138] In another embodiment, each R b is -C 1-6 It is alkyl, where alkyl is substituted Either not, or F, Cl, CF3, OCF3, CN, CH2CF3, CF2CH 3, It is substituted with 1 to 6 substituents selected from -CH3 and -OCH3. In one class of morphology, R b -CH3, -CF3, -CH2CF3, -CH(CH 3) Selected from CF3 and -CF2CH3. In another class of this embodiment, R b teeth It is selected from -CH3, -CF3, -CH2CF3, and -CH(CH3)CF3. In another class of the embodiment, R b It is -CF3.

[0139] In one embodiment, R c is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Al Selected from the kill, where the alkyl is either unsubstituted or has 1-3 halogens. It has been replaced with.

[0140] In another embodiment, R c is -C 1-6 Selected from alkyl, OH, and halogen, Here, the alkyl group is either unsubstituted or substituted with one to three halogens. In this embodiment, R c C 1-6 Selected from alkyl and halogen, where alkyl The element is either not substituted or is substituted with one to three halogens. In one class, R c is -C 1-6 It is alkyl, and here the alkyl is substituted Either not, or substituted with halogens 1 to 3. Another class of this embodiment , R c It is a halogen.

[0141] In one embodiment, R d is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Al Selected from the kill, where the alkyl is either unsubstituted or has 1-3 halogens. It is replaced by R. In another embodiment, d is -C 1-6 Alkyl, OH, and halogen Selected from, where the alkyl is either unsubstituted or substituted with 1-3 halogens. It is replaced. In another embodiment, R d is -C 1-6 Selected from alkyl and halogen Here, the alkyl group is either unsubstituted or substituted with one to three halogens. In one class of this embodiment, R d is -C 1-6It is alkyl or F. In this embodiment, R d is -C 1-6 It is alkyl, and here the alkyl is substituted It is either absent or substituted with 1 to 3 halogens. In another embodiment, R d Haroge Here, the alkyl is either unsubstituted or substituted with one to three halogens. In one class of this embodiment, R d It is F.

[0142] In one embodiment, R e is hydrogen and C 1-6 Selected from alkyl. In another embodiment R e is hydrogen. In another embodiment, R e C 1-6 It is alkyl.

[0143] In one embodiment, R f is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Al Selected from the kill, where the alkyl is either unsubstituted or has 1-3 halogens. It is replaced by R. In another embodiment, f is -C 1-6 Alkyl, OH, and halogen Selected from, where the alkyl is either unsubstituted or substituted with 1-3 halogens. It is replaced. In another embodiment, R f is -C 1-6 Selected from alkyl and halogen Here, the alkyl group is either unsubstituted or substituted with one to three halogens. In one class of this embodiment, R f is -C 1-6 It is alkyl or F. In this embodiment, R f is -C 1-6It is alkyl, and here the alkyl is substituted It is either absent or substituted with 1 to 3 halogens. In another embodiment, R f Haroge Here, the alkyl is either unsubstituted or substituted with one to three halogens. In one class of this embodiment, R f It is F.

[0144] In one embodiment, R g is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Al Selected from the kill, where the alkyl is either unsubstituted or has 1-3 halogens. It is replaced by R. In another embodiment, g is -C 1-6 Alkyl, OH, and halogen Selected from, where the alkyl is either unsubstituted or substituted with 1-3 halogens. It is replaced. In another embodiment, R g is -C 1-6 Selected from alkyl and halogen Here, the alkyl group is either unsubstituted or substituted with one to three halogens. In one class of this embodiment, R g is -C 1-6 It is alkyl or F. In this embodiment, R g is -C 1-6 It is alkyl, and here the alkyl is substituted It is either absent or substituted with 1 to 3 halogens. In another embodiment, R g Haroge In one class of this embodiment, R g It is F.

[0145] In one embodiment, R h is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, Ally Selected from R and heteroaryl. In another embodiment, R h is hydrogen, C 1-6 Al Kill and C 3-6 Selected from cycloalkyl. In another embodiment, R h hydrogen and C 1-6 Selected from alkyl groups. In another embodiment, R h It is hydrogen. Another implementation form In state, R h C 1-6 It is alkyl.

[0146] In one embodiment, R i is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, Ally Selected from R and heteroaryl. In another embodiment, R i is hydrogen, C 1-6 Al Kill and C 3-6 Selected from cycloalkyl. In another embodiment, R i hydrogen and C 1-6 Selected from alkyl groups. In another embodiment, R i It is hydrogen. Another implementation form In state, R i C 1-6 It is alkyl.

[0147] In one embodiment, R j is hydrogen, C 1-6 Alkyl, C 3-6 Alkenil, C 3-6 a Lukinil, C 3-6 Cycloalkyl, C 2-5 Cycloheteroalkyl, aryl and hetero Selected from Roaryl. In another embodiment, R j is hydrogen, C 1-6 Alkyl, C3 -6 Alkenil, C 3-6 Alkinyl, C 3-6Cycloalkyl and C 2-5 Cyclohete Selected from R alkyl groups. In another embodiment, R j is hydrogen, C 1-6 Alkyl, C3 -6 Cycloalkyl and C 2-5 Selected from cycloheteralkyl. In another embodiment R j is hydrogen and C 1-6 Selected from alkyl groups. In another embodiment, R j is water It is prime. In another embodiment, R j C 1-6 It is alkyl.

[0148] In one embodiment, R k is hydrogen and C 1-6 Selected from alkyl. In another embodiment R k is hydrogen. In another embodiment, R k C 1-6 It is alkyl.

[0149] In one embodiment, R L is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, Ally Selected from R and heteroaryl. In another embodiment, R L is hydrogen, C 1-6 Al Kill and C 3-6 Selected from cycloalkyl. In another embodiment, R L hydrogen and C 1-6 Selected from alkyl. In one class of this embodiment, R L is hydrogen In another class of this embodiment, R L C 1-6 It is alkyl.

[0150] In one embodiment, m is 0, 1, or 2. In another embodiment, m is 0 or 1. In another embodiment, m is 0 or 2. In another embodiment, m is 0. In one embodiment, m is 1. In another embodiment, m is 2.

[0151] In one embodiment, n is 2, 3, 4, 5, or 6. In another embodiment, n is 2, It is 3, 4, or 5. In another embodiment, n is 2, 3, or 4. In another embodiment, In another embodiment, n is 2 or 3. In another embodiment, n is 2 or 4. In yet another embodiment, n is 2 or 4. , n is 2, 3, 4 or 5. In another embodiment, n is 3. In another embodiment In one embodiment, n is 4. In another embodiment, n is 5. In yet another embodiment, n is 6. That is the case.

[0152] In one embodiment, p is 0, 1, 2, or 3. In another embodiment, p is 0, 1 or In another embodiment, p is 2. In another embodiment, p is 0, 1, or 3. In another embodiment, p is It is 1, 2, or 3. In another embodiment, p is 1 or 2. In another embodiment, p is 1 or 3. In another embodiment, p is 0 or 1. In another embodiment, p is 0 or 2. In another embodiment, p is 0 or 3. In another embodiment, p In another embodiment, p is 0. In yet another embodiment, p is 1. In yet another embodiment, p is 2. In another embodiment, p is 3.

[0153] In one embodiment, q is 0, 1, 2, or 3. In another embodiment, q is 0, 1 or In another embodiment, q is 2. In another embodiment, q is 0, 1, or 3. In another embodiment, q is It is 1, 2, or 3. In another embodiment, q is 1 or 2. In the embodiment, q is , 1 or 3. In another embodiment, q is 0 or 1. In another embodiment, q is , 0 or 2. In another embodiment, q is 0 or 3. In another embodiment, q is In another embodiment, q is 0. In yet another embodiment, q is 1. In yet another embodiment, q is 2. In another embodiment, q is 3.

[0154] In one embodiment, r is 0, 1, or 2. In another embodiment, r is 0 or 1. In another embodiment, r is 0 or 2. In another embodiment, r is 0. In one embodiment, r is 1. In another embodiment, r is 2.

[0155] In one embodiment, s is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, s is 0, 1, 2, 3, 4 or 5. In another embodiment, s is 1, 2, 3, 4, 5 or In another embodiment, s is 6. In another embodiment, s is 1, 2, 3, 4, or 5. In another embodiment, In another embodiment, s is 0, 1, 2, 3, or 4. In another embodiment, s is 0, 1, 2, or 3. In another embodiment, s is 1, It is 2 or 3. In another embodiment, s is 0, 1 or 2. In another embodiment, s is 1 or 2. In another embodiment, s is 0. In another embodiment, s is 1 In another embodiment, s is 2. In another embodiment, s is 3. In one embodiment, s is 4. In another embodiment, s is 5. In yet another embodiment, s is 6.

[0156] In one embodiment, t is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, t t is 0, 1, 2, 3, 4 or 5. In another embodiment, t is 1, 2, 3, 4, 5 or In another embodiment, t is 6. In another embodiment, t is 1, 2, 3, 4, or 5. In another embodiment, t is 0, 1, 2, 3, or 4. In another embodiment, t is 0, 1, 2, or 3. In another embodiment, t is 1, It is 2 or 3. In another embodiment, t is 0, 1 or 2. In another embodiment, t is 1 or 2. In another embodiment, t is 0. In another embodiment, t is 1 In another embodiment, t is 2. In another embodiment, t is 3. In one embodiment, t is 4. In another embodiment, t is 5. In yet another embodiment t is 6.

[0157] In another embodiment, structural formula Ia: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is provided.

[0158] In another embodiment, structural formula Ib: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is provided.

[0159] In one class of this embodiment, the pyridyl is [ka] That is the case.

[0160] In another class of this embodiment, the pyridyl is [ka] That is the case.

[0161] In another class of this embodiment, the pyridyl is [ka] That is the case.

[0162] In another embodiment, structural formula Ic: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is provided.

[0163] In another embodiment, structural formula Id: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is provided.

[0164] In another embodiment, structural formula Ie: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is provided.

[0165] In one class of this embodiment, the pyridyl is [ka] That is the case.

[0166] In another class of this embodiment, the pyridyl is [ka] That is the case.

[0167] In another class of this embodiment, the pyridyl is [ka] That is the case.

[0168] In another embodiment, the structural formula If: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is provided.

[0169] Compounds represented by structural formula I are structural formulas Ia, Ib, Ic, Id, and Compounds represented by formula Ie and structural formula If, and their pharmaceutically acceptable salts and hydrates. This includes solvates.

[0170] Another embodiment is structural formula I [wherein, A is (1) Aryl, and, (2) Heteroaryl Selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R a Selected from It is substituted with substituents 1 to 5; B is (1)-C 3-12 Cycloalkyl, (2)-C 2-11 Cycloheteroalkyl, (3)-C 1-6 Alkyl-C 3-12 Cycloalkyl, (4)-C 1-6 Alkyl-C 2-11 Cycloheteroalkyl, (5)-C 1-6 Alkyl-OC 3-12 Cycloalkyl, and, (6) New C 1-6 Alkyl-OC 2-11 Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R bIt is substituted with 1 to 6 substituents selected from; and, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R L m, n, p, q, r, s and t are, As defined above. This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0171] Another embodiment is structural formula I [wherein, A is (1) Phenyl, (2) Pyridine, and (3) Thiazole Selected from the group consisting of, Here, phenyl, pyridine, and thiazole are either unsubstituted or R a Choose from It is substituted with 1 to 5 selected substituents; B is (1) Cyclopropane, (2) Cyclobutane, (3) Cyclopentane, (4) Cyclohexane, (5) Bicyclo[3.2.1]octane, (6) Bicyclo[3.1.0]hexane, (7) Bicyclo[2.2.2]octane, (8) Spiro[2.5]octane, (9) Bicyclo[1.1.1]pentane, (10) Spiro[3.3]heptane, (11) Spiro[2.3]hexane, spiro[2.2]pentane (12) Piperidine, (13) Tetrahydropyran, and (14) Croman Independently selected from the group consisting of, Here, B is either not substituted, or R b Substituted with 1 to 6 substituents selected from It is; R 1 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or R c 1 to 5 substituents selected from It has been replaced with; R 2 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, and (4)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R d Select from It is substituted with 1 to 5 substituents; R 3 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, and (4)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R d Select from It is substituted with 1 to 5 substituents; R4 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, and (4)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R f Select from It is substituted with 1 to 5 substituents; R 5 teeth, (1) Hydrogen, (2) Deuterium, (3)-C 1-6 Alkyl, and (4)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R f Selected from It is substituted with substituents 1 to 5; R 6 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R g Selected from It is substituted with substituents 1 to 5; R 7 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R g Selected from It is substituted with substituents 1 to 5; R 8 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or substituted with one to five elements selected from halogens. It is substituted with the base; R 9 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or substituted with one to five elements selected from halogens. It is substituted with the base; R a teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 2-6 Alkenil, (7)-C 3-6 Cycloalkyl, (8)-C 2-6 Cycloheteroalkyl, (9) Ariel, (10) Heteroaryl, (11)-OH, (12)-OC 1-6 Alkyl, (13)-OC 3-6 Cycloalkyl, and, (14)-OC 2-6 Cycloheteroalkyl Independently selected from the group consisting of, Here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Al Kill and -OC1-6 It is substituted with 1 to 6 substituents selected from alkyl groups; and, Each R b teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 1-6 Alkenil, (7)-C 2-6 Alkinil, (8)-C 3-6 Cycloalkyl, (9)-C 2-6 Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-OH, (13)-OC 1-6 Alkyl, (14)-OC 3-6 Cycloalkyl, and, (15)-OC 2-6 Cycloheteroalkyl Independently selected from the group consisting of, Here, each R b These are either not substituted, or halogen, CF3, OCF3, CN, C H2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6; and, R c , R d , R e , R f , R g , R h , R i , R j , R k , R L , m, n, p, q, r s and t are as defined above. This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0172] Another embodiment is structural formula I [wherein, A is (1) Phenyl, (2) Pyridine, and (3) Thiazole Selected from the group consisting of, Here, phenyl, pyridine, and thiazole are either unsubstituted or R a Choose from It is substituted with 1 to 5 selected substituents; B is (1) Cyclopropane, (2) Cyclobutane, (3) Cyclopentane, (4) Cyclohexane, (5) Bicyclo[3.2.1]octane, (6) Bicyclo[3.1.0]hexane, (7) Bicyclo[2.2.2]octane, (8) Spiro[2.5]octane, (9) Bicyclo[1.1.1]pentane, (10) Spiro[3.3]heptane, (11) Spiro[2]hexane, (12) Spiro[2.2]pentane (13) Piperidine, and (14) Tetrahydropyran Independently selected from the group consisting of, Here, B is either not substituted, or R b Substituted with 1 to 6 substituents selected from It is; R 1 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or R c 1 to 5 substituents selected from It has been replaced with; R 2 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R d Select from It is substituted with 1 to 5 substituents; R 3 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R d Select from It is substituted with 1 to 5 substituents; R 4 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R f Select from It is substituted with 1 to 5 substituents; R 5 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R f Selected from It is substituted with substituents 1 to 5; R 6 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R g Selected from It is substituted with substituents 1 to 5; R 7 teeth, (1) Hydrogen, (2)-C 1-6 Alkyl, and (3)-C 3-6 Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R g Selected from It is substituted with substituents 1 to 5; R 8 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or substituted with one to five elements selected from halogens. It is substituted with the base; R 9 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or substituted with one to five elements selected from halogens. It is substituted with the base; R a teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 2-6 Alkenil, (7)-C 3-6 Cycloalkyl, (8)-C 2-6 Cycloheteroalkyl, (9) Ariel, (10) Heteroaryl, (11)-OH, (12)-OC 1-6 Alkyl, (13)-OC 3-6 Cycloalkyl, and, (14)-OC 2-6 Cycloheteroalkyl Independently selected from the group consisting of, Here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Al Kill and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups; Each R b teeth, (1) CN, (2) Oxo, (3) Halogen, (4)-S(O)2C 1-6 Alkyl, (5)-C 1-6 Alkyl, (6) New C 1-6 Alkenil, (7)-C 2-6 Alkinil, (8)-C 3-6 Cycloalkyl, (9)-C 2-6 Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-OH, (13)-OC 1-6 Alkyl, (14)-OC 3-6 Cycloalkyl, and, (15)-OC 2-6 Cycloheteroalkyl Independently selected from the group consisting of, Here, each R b These are either not substituted, or halogen, CF3, OCF3, CN, C H2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6; and, R c , R d , R e , R f , R g , R h , R i , R j , R k , R L , m, n, p, q, r s and t are as defined above. This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0173] Another embodiment is structural formula I [wherein, A is (1) Phenyl, and (2) Pyridine Selected from the group consisting of, Here, phenyl and pyridine are either unsubstituted or R a Select from 1~ It is substituted with 4 substituents; B is (1)-C 3-12 Cycloalkyl, and, (2)-C 2-11 Cycloheteroalkyl Independently selected from the group consisting of, Here, cycloalkyl and cycloheteroalkyl are either unsubstituted or R b It is substituted with 1 to 6 substituents selected from; R 1 is hydrogen; R 2, R 3 , R 4 and R 5 is either deuterium or hydrogen; R 6 and R 7 is CH3 or hydrogen; R 8 and R 9 is hydrogen; Each R a teeth, (1) Halogen, (2)-C 1-6 Alkyl, and (3)-OC 1-6 Alkyl Independently selected from the group consisting of, Here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Al Kill and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups; Each R b teeth, (1) Halogen, (2)-C 1-6 Alkyl, (3)-C 1-6 Alkenil, (4)-C 3-6 Cycloalkyl, and, (5)-OC 1-6 Alkyl Independently selected from the group consisting of, Here, each R b These are either not substituted, or halogen, CF3, OCF3, CN, C H2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6; and, R c , R d , R e , R f , R g , R h , R i , R j , Rk , R L , m, n, p, q, r s and t are as defined above. This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0174] Another embodiment is structural formula I [wherein, A is (1) Phenyl, and (2) Pyridine Selected from the group consisting of, Here, phenyl and pyridine are either unsubstituted or R a Select from 1~ It is substituted with 4 substituents; B is (1)-C 3-12 Cycloalkyl, and, (2)-C 2-11 Cycloheteroalkyl Independently selected from the group consisting of, Here, cycloalkyl and cycloheteroalkyl are either unsubstituted or R b It is substituted with 1 to 6 substituents selected from; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen; Each R a teeth, (1) Halogen, (2)-C 1-6 Alkyl, and (3)-OC 1-6 Alkyl Independently selected from the group consisting of, Here, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Al Kill and -OC 1-6It is substituted with 1 to 6 substituents selected from alkyl groups; Each R b teeth, (1) Halogen, (2)-C 1-6 Alkyl, (3)-C 1-6 Alkenil, (4)-C 3-6 Cycloalkyl, and, (5)-OC 1-6 Alkyl Independently selected from the group consisting of, Here, each R b These are either not substituted, or halogen, CF3, OCF3, CN, C H2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups It is substituted with substituents 1 to 6; and, R c , R d , R e , R f , R g , R h , R i , R j , R k , R L , m, n, p, q, r s and t are as defined above. This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0175] Na v 1.8 Exemplary but non-limiting examples of compounds useful as inhibitors of channel activity Examples of this include the following compounds: (1) N-((R)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ; (2) N-((S)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ; (3) N-((R)-(3-chloro-4-fluorophenyl)(8,8-difluorophenyl) Cyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-cal Boxamide; (4) N-((S)-(3-chloro-4-fluorophenyl)(8,8-difluorophenyl) Cyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-cal Boxamide; (5) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(8,8-di Fluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (6) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(8,8-di Fluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (7) N-((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl Cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide; (8) N-((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl Cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide; (9) N-((S)-(4-chlorophenyl)(trans-4-(trifluoromethyl Cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide; (10) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (11) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (12) (R)-2-methyl-3-oxo-N-((R)-(trans-4-(trif (Oromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piper Zin-1-carboxamide; (13) (R)-2-methyl-3-oxo-N-((S)-(trans-4-(triph (Oromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piper Zin-1-carboxamide; (14) (2R)-N-((R)-(3-chloro-4-fluorophenyl)((1R, 3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl )-2-methyl-3-oxopiperazine-1-carboxamide; (15) (2R)-N-((S)-(3-chloro-4-fluorophenyl)((1R, 3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl )-2-methyl-3-oxopiperazine-1-carboxamide; (16) (2R)-N-((R)-(3,4-difluorophenyl)(trans-4- (Trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine -1-carboxamide; (17) (2R)-N-((S)-(3,4-difluorophenyl)(trans-4- (Trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine -1-carboxamide; (18) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (19) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (20) N-((R)-(3-chloro-2,4-difluorophenyl)(trans-4 -(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-cal Boxamide; (21) N-((S)-(3-chloro-2,4-difluorophenyl)(trans-4) -(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-cal Boxamide; (22) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)((1 R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl) (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (23) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl) (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (24) N-((R)-(3-chloro-4-fluorophenyl)(4-(trifluoro Methyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine -1-carboxamide; (25) N-((S)-(3-chloro-4-fluorophenyl)(4-(trifluoro Methyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine -1-carboxamide; (26) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(4 ,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1- Carboxamide; (27) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(4 ,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1- Carboxamide; (28) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(4,4- Difluorocyclohexyl(methyl)-2-methyl-3-oxopiperazine-1-carb Xamide; (29) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(4,4- Difluorocyclohexyl(methyl)-2-methyl-3-oxopiperazine-1-carb Xamide; (30) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(2 ,2,2-trifluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-ol Xopiperazine-1-carboxamide; (31) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(2 ,2,2-trifluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-ol Xopiperazine-1-carboxamide; (32) (2R)-N-((R)-(4-chlorophenyl)(1-(2,2,2-tri Fluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-oxopiperazine -1-carboxamide; (33) (2R)-N-((S)-(4-chlorophenyl)(1-(2,2,2-tri Fluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-oxopiperazine -1-carboxamide; (34) N-((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2- Trifluoroethyl)piperidine-4-yl)methyl)-3-oxopiperazine-1- Ruboxamide; (35) N-((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2- Trifluoroethyl)piperidine-4-yl)methyl)-3-oxopiperazine-1- Ruboxamide; (36) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(R )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (37) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(S )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (38) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(R )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (39) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(S )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (40) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans -1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (41) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(trans -1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (42) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis-1 ,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (43) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis-1 ,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (44) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopropyl Perazine-1-carboxamide; (45) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopropyl Perazine-1-carboxamide; (46) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(cis -3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (47) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(cis -3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (48) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-cyclopropylcyclobutyl)methyl)2-methyl-3-oxopiperazi n-1-carboxamide; (49) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) S-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide; (50) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-cyclopropylcyclobutyl)methyl)2-methyl-3-oxopiperazi n-1-carboxamide; (51) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) S-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide; (52) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-1,1-difluorospiro[2,3]hexane-5-yl)methyl)-2-methyl Ru-3-oxopiperazine-1-carboxamide; (53) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) Su-1,1-difluorospiro[2.3]hexane-5-yl)methyl)-2-methyl- 3-Oxopiperazine-1-carboxamide; (54) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-1,1-difluorospiro[2,3]hexane-5-yl)methyl)-2-methyl Ru-3-oxopiperazine-1-carboxamide; (55) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) Su-1,1-difluorospiro[2.3]hexane-5-yl)methyl)-2-methyl- 3-Oxopiperazine-1-carboxamide; (56) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6 ,6-difluorospiro[3,3]heptan-2-yl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (57) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6 ,6-difluorospiro[3,3]heptan-2-yl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (58) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 ,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (59) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 ,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (60) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 -Methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carb Samido; (61) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 -Methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carb Samido; (62) N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3 -(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carb Xamide; (63) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3- Oxopiperazine-1-carboxamide; (64) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3- Oxopiperazine-1-carboxamide; (65) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Pyro[2,3]hexane-5-yl)methyl)-2-methyl-3-oxopiperazine-1 -Carboxamide; (66) (2R)-N-((S)(3-chloro-2,4-difluorophenyl)(spi Ro[2.3]Hexane-5-yl)methyl)-2-methyl-3-oxopiperazine-1- Carboxamide; (67) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide; (68) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide; (69) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 -(trifluoromethyl)bicyclo[1.1.1]pentan-1yl)methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide; (70) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 -(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2- Methyl-3-oxopiperazine-1-carboxamide; (71) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 ,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-cal Boxamide; (72) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 ,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-cal Boxamide; (73) N-((R)-(3-chloro-2,4-difluorophenyl)(3,3-difluorophenyl) (Tylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; (74) N-((S)-(3-chloro-2,4-difluorophenyl)(3,3-difluorophenyl) (Tylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; (75) (2R)-N-((R)-(3,3-dimethylcyclobutyl)(6-(Trif Luoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1 -Carboxamide; (76) (2R)-N-((S)-(3,3-dimethylcyclobutyl)(6-(Trif Luoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1 -Carboxamide; (77) N-((R)-(3-chloro-4-fluorophenyl)(3-(trifluoro Methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine -1-carboxamide; (78) N-((S)-(3-chloro-4-fluorophenyl)(3-(trifluoro Methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine -1-carboxamide; (79) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(3-(to (Lifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (80) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(3-(to (Lifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (81) (2R)-N-((R)-(4-fluoro-3-methylphenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (82) (2R)-N-((S)-(4-fluoro-3-methylphenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (83) (2R)-N-((R)-(4-fluoro-3-methylphenyl)(cis-4 -(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (84) (2R)-N-((S)-(4-fluoro-3-methylphenyl)(cis-4 -(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (85) (2R)-N-((R)-(4-chloro-3-(difluoromethyl)phenyl )(cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (86) (2R)-N-((R)-(4-chloro-3-(difluoromethyl)phenyl )(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (87) (2R)-N-((S)-(4-chloro-3-(difluoromethyl)phenyl )(cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (88) (2R)-N-((S)-(4-chloro-3-(difluoromethyl)phenyl )(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (89) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans -3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (90) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis-3 -(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine -1-carboxamide; (91) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis-3 -(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine -1-carboxamide; (92) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(trans -3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (93) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxo Piperazine-1-carboxamide; (94) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) S-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (95) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) S-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (96) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxo Piperazine-1-carboxamide; (97) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1 -Carboxamide; (98) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) (S-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (99) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) (S-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (100) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( trans-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide; (101) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (R)-Spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (102) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (S)-Spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (103) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( R)-Spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiper Zin-1-carboxamide; (104) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (S)-Spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (105) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (R)-3,3-difluorocyclopentyl)methyl)2-methyl-3-oxopipera Zin-1-carboxamide; (106) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (S)-3,3-difluorocyclopentyl)methyl)2-methyl-3-oxopipera Zin-1-carboxamide; (107) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (R)-(3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (108) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (S)-3,3-difluorocyclopentyl)methyl)2-methyl-3-oxopipera Zin-1-carboxamide; (109) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (110) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis- 3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (111) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (112) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis- 3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (113) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis- 3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (114) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis- 3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (115) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(tran S-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (116) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(tran S-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (117) N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2- (Il)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxo Piperazine-1-carboxamide; (118) N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2- (Iyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-Oxyl Sopiperazine-1-carboxamide; (119) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyri Zin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3- Oxopiperazine-1-carboxamide; (120) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyri Zin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3- Oxopiperazine-1-carboxamide; (121) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)meth (Lu)-2-methyl-3-oxopiperazine-1-carboxamide; (122) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (123) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (124) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)meth (Lu)-2-methyl-3-oxopiperazine-1-carboxamide; (125) (2R)-N-((R or S)-1-(3-chloro-4-fluorophen Nyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl -3-oxopiperazine-1-carboxamide; (126) (2R)-N-((R or S)-1-(3-chloro-4-fluorophen Nyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)-ethyl)-2- Methyl-3-oxopiperazine-1-carboxamide; (127) (2R)-N-((S or R)-1-(3-chloro-4-fluorophen (Nyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)-ethyl)-2-methyl Ru-3-oxopiperazine-1-carboxamide; (128) (2R)-N-((S or R)-1-(3-chloro-4-fluorophen Nyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)-ethyl)-2- Methyl-3-oxopiperazine-1-carboxamide; (129) (2R)-N-((R)-(3-fluoro-4-(trifluoromethoxy) Phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide; (130) (2R)-N-((S)-(3-fluoro-4-(trifluoromethoxy) Phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide; (131) ((2R)-N-((R)-(2-fluoro-4-(trifluoromethoxy) )phenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2 -Methyl-3-oxopiperazine-1-carboxamide; (132) (2R)-N-((S)-(2-fluoro-4-(trifluoromethoxy) Phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide; (133) (2R)-N-((R)-(4-fluoro-3-(trifluoromethyl) (enyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Ru-3-oxopiperazine-1-carboxamide; (134) (2R)-N-((S)-(4-fluoro-3-(trifluoromethyl) ((trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl) Chil-3-oxopiperazine-1-carboxamide; (135) N-((R)-(4-fluoro-3-(trifluoromethyl)phenyl)( trans-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxopiperazi n-1-carboxamide; (136) N-((S)-(4-fluoro-3-(trifluoromethyl)phenyl)( trans-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxopiperazi n-1-carboxamide; (137) (2R)-N-((R)-(3-chloro-2-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (138) (2R)-N-((S)-(3-chloro-2-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (139) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy) (3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-methyl Xopiperazine-1-carboxamide; (140) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy) (3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-methyl Xopiperazine-1-carboxamide; (141) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoro (R)-2-(trifluoromethyl)thiazole-4- Il(methyl)piperazine-1-carboxamide; (142) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoro (Methyl)cyclohexyl)((S)-2-(trifluoromethyl)thiazole-4- Il(methyl)piperazine-1-carboxamide; (143) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (144) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (145) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (146) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (147) (2R)-N-(R)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (148) (2R)-N-(R)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (149) (2R)-N-(S)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (150) (2R)-N-(S)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (151) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(cis-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (152) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(cis-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (153) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(Trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide; and, (154) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(Trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0176] Na v 1.8 Exemplary but non-limiting examples of compounds useful as inhibitors of channel activity Examples of this include the following compounds: (1) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1r ,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-O Xopiperazine-5,5,6,6-d4-1-carboxamide; (2) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1r ,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-O Xopiperazine-5,5,6,6-d4-1-carboxamide; (3) (2R)-N-((1(R or S))-(4-fluoro-3-(trifluoro (methyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H -pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxami Do; (4) (2R)-N-((1(R or S))-(4-fluoro-3-(trifluoro (methyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H -pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxami Do; (5) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1r ,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(fluoromethyl (Lu)-3-oxopiperazine-2-d-1-carboxamide; (6) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)((R) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido;s (7) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((R) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; (8) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)((S) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; (9) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((S) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; (10) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2- (Trifluoromethyl)piperazine-1-carboxamide; (11) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2- (Trifluoromethyl)piperazine-1-carboxamide; and, (12) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(hydroxy Methyl)-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0177] Na v 1.8 Exemplary but non-limiting examples of compounds useful as inhibitors of channel activity Examples of this include the following compounds: (1) N-((R)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ; (2) N-((S)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ; (3) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (4) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (5) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(cis- 3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (6) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(cis- 3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (7) N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3- (Trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboc Samido; (8) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl) -2-methyl-3-oxopiperazine-1-carboxamide; (9) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl (Lu)-2-methyl-3-oxopiperazine-1-carboxamide; (10) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethicone (Pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl) (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (11) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethicone (Pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl )-2-methyl-3-oxopiperazine-1-carboxamide; (12) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(( 3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (13) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(( 3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (14) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(( 3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Tyl)-2-methyl-3-oxopiperazine-1-carboxamide; and, (15) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(( 3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0178] Na v 1.8 Exemplary but non-limiting examples of compounds useful as inhibitors of channel activity Examples of this include the following compounds: (1) N-((R)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ; (2) N-((S)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ; (3) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (4) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (5) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(cis- 3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (6) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(cis- 3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (7) N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3- (Trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboc Samido; (8) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl) -2-methyl-3-oxopiperazine-1-carboxamide; (9) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl (Lu)-2-methyl-3-oxopiperazine-1-carboxamide; (10) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethicone (Pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl) (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (11) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethicone (Pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl )-2-methyl-3-oxopiperazine-1-carboxamide; (12) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(( 3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (13) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(( 3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (14) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(( 3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Tyl)-2-methyl-3-oxopiperazine-1-carboxamide; and, (15) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(( 3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (16) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-O Xopiperazine-5,5,6,6-d4-1-carboxamide; and, (17) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-O Xopiperazine-5,5,6,6-d4-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0179] The specific stereochemistry described above is preferred, but diastereoisomers, enantiomers, Other stereoisomers, including epimers and mixtures thereof, also include Na v Diseases involving 1.8 It may be useful in the treatment of [condition].

[0180] A synthesis method for producing the above compound is disclosed in the following examples. If the details of the synthesis are not provided in the examples, the compound is described herein. By applying the provided synthesis information, those skilled in the fields of medicinal chemistry or synthetic organic chemistry can... Therefore, it is easily manufactured. If the stereochemical center is not defined, the structure is defined as the center. This represents a mixture of stereoisomers. In the case of such compounds, enantiomers, dia Individual stereoisomers, including stereoisomers and mixtures thereof, are also represented by structural formula I. It is a compound that can be found.

[0181] definition "Ac" stands for acetyl, which is CH3C(=O)-.

[0182] Unless otherwise defined, "alkyl" refers to a straight or branched carbon chain. This refers to saturated carbon chains that can be combinations of these: alkoxy and alkanoyl. Other groups with the prefix "alk" are also defined separately for carbon chains. Unless otherwise specified, it can be linear, branched, or a combination thereof. Examples of alkyl groups Examples include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and te Examples include rt-butyl, pentyl, hexyl, heptyl, octyl, and nonyl.

[0183] "Alkenyl" means, unless otherwise defined, at least one carbon-carbon double bond It includes and means a carbon chain that can be linear, branched, or a combination thereof. Examples of alkenyls include vinyl, allyl, isopropenyl, pentenyl, and hexenyl. Examples include 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl. In certain embodiments, the alkenyl is a -C1 alkenyl or =CH2.

[0184] Unless otherwise defined, "alkynyl" refers to a group containing at least one carbon-carbon triple bond. It includes and means a carbon chain that can be linear, branched, or a combination thereof. Examples of alkynyls include ethinyl, propargyl, 3-methyl-1-pentynyl, Examples include 2-heptinyl.

[0185] "Cycloalkyl" refers to saturated monocyclic and bicyclic compounds having a specified number of carbon atoms. This refers to a spirocyclic or cross-linked carbon ring. The cycloalkyl ring is condensed with a phenyl ring. It's fine to do that. 3-12 Cycloalkyls are saturated monocyclic rings having 3 to 12 carbon atoms. This refers to a carbon ring of the form C, bicyclic, spirocyclic, or bridging type. 3-12 Cycloalkyls are It may be condensed with a phenyl ring. C 3-10 Cycloalkyl groups consist of 3 to 10 carbon atoms. This refers to a saturated monocyclic, bicyclic, spirocyclic, or bridging carbon ring having C. 3-10 Cycloalkyls may be condensed with a phenyl ring. Examples of cycloalkyls include cycloalkyls. Clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Yes. In one embodiment, the cycloalkyl is cyclopropyl. In another embodiment, Cycloalkyls include cyclopropane, cyclobutane, cyclopentane, and cyclohexane. Selected from: In another embodiment, the cycloalkyl is cyclopropane, cyclobutane cyclopentane, cyclohexane, bicyclo[3.2.1]octane, bicyclo[3. 1.0]-Hexane, bicyclo[2.2.2]octane, spiro[2.5]octane, bi Cyclo[1.1.1]pentane, spiro[3.3]heptane, spiro[2.3]hexane and are selected from spiro[2.2]pentane. In another embodiment, the cycloalkyl is Selected from cyclobutane and cyclohexane. In another embodiment, cycloalkyl is It is cyclopropane.

[0186] A "cycloheteroalkyl" has a specified number of carbon atoms, and is composed of N, NH, S(S (containing O and SO2) and containing at least one ring heteroatom selected from O It is a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, spirocyclic, or bridging ring or This signifies a ring system. The cycloheteralkyl ring may be fused to a phenyl ring. The heteroalkyl ring is substituted at the ring carbon and / or at the ring nitrogen or ring sulfur. It may be done. C 2-11 Cycloheteralkyls have 2 to 11 carbon atoms. At least one ring selected from N, NH, S (including SO and SO2), and O Saturated or partially unsaturated non-aromatic monocyclic, bicyclic, and spirocyclic compounds containing telo atoms. Or it means a bridging ring or ring system. A cycloheteralkyl ring is a ring carbon and / Alternatively, it may be substituted in the ring nitrogen or ring sulfur. 2-11 Cyclohetal Lukil may be condensed with a phenyl ring. 2-9 Cycloheteralkyl groups are 2-9 It has 1 carbon atom and is selected from N, NH, S (including SO and SO2) and O. A saturated or partially unsaturated non-aromatic monocyclic formula containing at least one ring heteroatom. This refers to a bicyclic, spirocyclic, or bridging ring or ring system. A cycloheteralkyl ring is, The ring carbon and / or the ring nitrogen or ring sulfur may be substituted. C2 -9 The cycloheteralkyl group may be condensed with a phenyl ring. Examples include tetrahydrofuran, pyrrolidine, tetrahydrothiophene, and azetidine. Examples include piperazine, piperidine, morpholine, oxetane, and tetrahydropyran. In one embodiment, the cycloheteralkyl is azetidine, piperidine, pyrrolidine, te Selected from trahydropyran and tetrahydrofuran. In another embodiment, cyclo The teloalkyl is selected from piperidine and tetrahydropyran. In another embodiment, In another embodiment, the cycloheteroalkyl is tetrahydropyran. Roalkyl is chroman.

[0187] "Aryl" refers to a monocyclic, bicyclic, or tricyclic carbon atom containing 6 to 14 carbon atoms. This refers to a cyclic aromatic ring or aromatic ring system, where at least one of the rings is aromatic. Examples of aryls include phenyl and naphthyl. In one embodiment, The aryl is phenyl. In another embodiment, the aryl is selected from phenyl and naphthalene. It will be selected.

[0188] A "heteroaryl" contains 5 to 14 ring atoms, and consists of N, NH, S(SO and S A single ring heteroatom containing O2 and at least one selected from O. This refers to a cyclic, bicyclic, or tricyclic ring or ring system, where a ring containing a heteroatom is used. At least one of the components is aromatic. Examples of heteroaryl compounds include pyrrolyl and isoxa. Zolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thi Asiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanil, to Liazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoisoxazoli Benzoxazolyl, Benzothiazolyl, Benzimidazolyl, Benzofuranyl Nzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofur Examples include nyl. In one embodiment, the heteroaryl is selected from pyridine and thiazole. In another embodiment, the heteroaryl is pyridine. In yet another embodiment, The teloaryl is a thiazole. In another embodiment, the heteroaryl is a pyridine. Pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, thiazole, oxazo Benzofran, benzoxazole, benzothiazole, indole, indazole Selected from , imidazopyridine, thiophene and thiazolopyridine. Another embodiment Therefore, heteroaryl is pyridine.

[0189] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, The halogen is fluorine, chlorine, or bromine. In another embodiment, the halogen is , fluorine or chlorine. In another embodiment, the halogen is fluorine or bromine. In one embodiment, the halogen is fluorine. In another embodiment, the halogen is chlorine. In another embodiment, the halogen is bromine.

[0190] "Me" stands for methyl.

[0191] "Okiso" represents =O.

[0192] "Saturated" means that it contains only single bonds.

[0193] "Unsaturated" means that it contains at least one double or triple bond. In this embodiment, "unsaturated" means containing at least one double bond. In this embodiment, "unsaturated" means that it contains one double bond. Another embodiment In this context, "unsaturated" means that it contains at least one triple bond. Morphologically, "unsaturated" means that it contains one triple bond.

[0194] Variable part (for example, R 1 , R a(etc.) appear more than twice in any of the constituent elements or structural formula I. If such an existence exists, its definition in each existence is independent of its definition in all other existences. Furthermore, combinations of substituents and / or variable parts are such combinations This is only acceptable if it results in a stable compound. The bond in the substituent variable region is transverse. The wavy lines indicate connection points.

[0195] Under the standard nomenclature used throughout this disclosure, the terminal portion of a given side chain is the most It is described first, followed by adjacent functional groups described toward the bonding point. For example, C 1- 5-Alkylcarbonylamino C 1-6 Alkyl substituents are equivalent to the following: [ka] When selecting a compound, a person skilled in the art can choose from various substituents (i.e., R 1 , R 2 (etc.) are chemical structures The selection should be made according to well-known principles regarding bonding and stability. To recognize.

[0196] The term "substituted" is considered to encompass multiple substitutions by a given substituent. It should be. If multiple substituents are disclosed or requested, the substituted compounds The object is independently, either once or multiple times, by one or more of the substituent parts disclosed or requested. It can be substituted. The fact that it can be substituted independently means that the (two or more) substitutions This means that the bases may be the same or may be different.

[0197] The expression "pharmaceutically acceptable" in this specification means that sound medical judgment is used and applicable. If all applicable government regulations are followed, it is safe and suitable for administration to humans and animals. It is used to indicate compounds, materials, compositions, salts and / or dosage forms.

[0198] Compounds represented by structural formula I may contain one or more chiral centers. Therefore, the compounds represented by structural formula I The compounds include racemic compounds and racemic mixtures, single enantiomers, and diastereomers. —It may exist as a mixture or as individual diastereomers. This disclosure is represented by structural formula I. It is intended to encompass all such isomeric forms of the compound.

[0199] Independent synthesis of optical isomers and diastereoisomers or their chromatographic composition By appropriately modifying the methodology disclosed herein, the methodology known in the art can be used. As can be achieved, their absolute stereochemistry is determined by the crystalline product or the crystallized product. Crystalline intermediates (these include, if necessary, chiral centers with known absolute configurations) X-ray beam of a drug (derivatized with a reagent containing an atom heavy enough to perform absolute attribution) It can be determined by crystallography.

[0200] If necessary, the racemic mixture of the compound is prepared so that the individual enantiomers can be isolated. This separation allows for the enantiomerization of a racemic mixture of compounds. A sophisticated compound is coupled to form a diastereoisomer mixture, and then fractional coupling is performed. Individual diastereoisomers can be separated by standard methods such as crystallization or chromatography. This can be carried out by methods well known in the art, such as separating them. The Plipping reaction often involves the formation of salts using enantiomerically pure acids or bases. The diastereomer derivative is then formed by cleavage of the added chiral residue. It can be converted into a pure enantiomer. The racemic mixture of the above compounds is chiral. It is also possible to separate them directly using chromatography with a stationary phase, The method is well known in this field.

[0201] Alternatively, any enantiomer of a compound may be optically pure with a known stereochemistry. By stereoselective synthesis using starting materials or reagents in a method well known in the art, It can be obtained.

[0202] Some of the compounds described herein contain olefin double bonds, and Unless otherwise specified, it is intended to include both E and Z geometric isomers. It is.

[0203] Tautomers exhibit rapid protonation from one atom of the compound to another atom of the compound. It is defined as a compound that undergoes water. Some of the compounds described herein are water They can exist as tautomers with different bonding sites. An example of this is keto-eno. These can be ketones and their enol forms, known as tautomers. These and mixtures thereof are included in the compound represented by structural formula I.

[0204] In compounds represented by general structural formula I, the atoms exhibit their natural isotopic abundance. It is possible, or one or more of the atoms have the same atomic number, but their atomic mass or mass The number differs from the atomic mass or mass number mainly found in nature in certain isotopes. It can be artificially concentrated. This disclosure covers all appropriate isotopic variations of the compound represented by structural formula I. The intention is to encompass species. For example, different isotopic forms of hydrogen (H) include pro Tium 1 H), deuterium ( 2 H) and tritium ( 3 H) is included. Protium is, It is the main hydrogen isotope found in nature. When deuterium is enriched, its in vivo half-life increases. There may be specific therapeutic benefits, such as prolongation or reduction in the required dosage, or Compounds that are useful as standards for characterizing biological samples may be provided. Tritium is radioactive, and therefore, as a tracer in metabolic or kinetic studies... This allows us to provide useful radiolabeled compounds. Isotope enrichment within the range of structural formula I is possible. The compound was prepared by conventional techniques well known to those skilled in the art, or by appropriate isotopes. Using concentrated reagents and / or intermediates as described in the schemes and examples of this specification To prepare the product using a preparation method similar to the one already established, without conducting excessive experiments. It is possible.

[0205] Furthermore, some of the crystalline forms of compounds can exist as polymorphs, and they themselves The body is intended to be included in this disclosure. Furthermore, one of the compounds represented by structural formula I The part can form a solvate with water or a common organic solvent. This is included within the scope of this disclosure.

[0206] It is generally preferable to administer the compound as an enantiomerically pure formulation. The mixture is separated into its individual enantiomers by one of many conventional methods. They can be separated. These methods include chiral chromatography and chiral assisted chromatography. Derivatization with an agent followed by separation by chromatography or crystallization, and dias Examples include the fractional crystallization of teleomer salts.

[0207] salt Where used herein, references to compounds include pharmaceutically acceptable salts. to be used as a precursor to the free compound or its pharmaceutically acceptable salts or This also includes pharmaceutically unacceptable salts when used in other synthetic operations. The intention is understood.

[0208] The compound can be administered in the form of a pharmaceutically acceptable salt. "Pharmacologically acceptable salts" include inorganic or organic bases and inorganic or organic acids. This refers to salts prepared from non-toxic bases or acids. The term "pharmaceutically acceptable salt" is used. The salts of the included basic compounds are generally obtained by reacting the free base with a suitable organic or inorganic acid. This shows a non-toxic salt of the compound of this disclosure, which is prepared by [method]. While not an exhaustive list, typical examples of salt include: vinegar Salts, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates Bromides, camsilates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, e Detoxate, edisylate, estrate, esylate, fumarate, gluceptate, g Luconic acid salt, glutamate salt, glycolyl arsanilate, hexyl resorcinolate, hi Dravamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionic acid Salt, lactate, lactobionate, laurate, malate, maleate, mandelic acid Salts, mesylates, methyl bromides, methyl nitrates, methyl sulfates, mucinates, napsylates Nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (Embonate), palmitate, pantothenate, phosphate / diphosphate, polygalactate Cluturonate, salicylate, stearate, sulfate, acetate, succinate, tannin Salts, tartrates, theoclates, tosylates, triethoidides, trifluoroacetates , and valerate. Furthermore, if the compound represented by structural formula I has an acidic part, Suitable pharmaceutically acceptable salts include, but are not limited to, aluminum, and aluminum. Monium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, ferrous Examples include salts derived from inorganic bases such as manganese, potassium, sodium, and zinc. Preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium It is a lium salt. Examples of salts derived from pharmaceutically acceptable organic non-toxic bases include the following: These include salts of substances: primary amines, secondary amines and tertiary amines, cyclic amines, and Basic ion exchange resins, for example, arginine, betaine, caffeine, choline, N, N -Dibenzylethylenediamine, diethylamine, 2-Diethylaminoethanol, 2- Dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphol N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, i Sopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, Polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine Examples include mine, tripropylamine, and tromethamine.

[0209] Furthermore, if a carboxylic acid (-COOH) group or an alcohol group is present in the compound... If present, drugs containing carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl are used. Scientifically acceptable esters, or O-acetyl, O-pivaloyl, O-benzoyl and Acyl derivatives of alcohols, such as O-aminoacyl, can also be used. (Sustained-release type) For modifying solubility or hydrolysis properties for use as a drug or prodrug formulation. This includes ester and acyl groups known in the art.

[0210] The term "prodrug" refers to a substance that, for example, undergoes hydrolysis in the bloodstream, which can be converted into a parent compound in vivo. A rapidly convertible compound (for example, from a prodrug represented by structural formula I to a compound represented by structural formula I) This means (conversion to a compound or its salt); sufficient discussion is needed, see "T. Higuchi and V. Stella, Pro-drugs as Novel Deliv ery Systems, Vol. 14 of the ACS Sympo sium Series” and “Edward B. Roche, ed., Bio reversible carriers in Drug Design, Amer ican Pharmaceutical Association and Perg. Amon Press, 1987" (These are both included herein by reference.) This disclosure is described in (included). This disclosure describes the production of a novel compound represented by structural formula I. It includes the group.

[0211] Furthermore, solvates and especially hydrates of the compound are also included in this disclosure.

[0212] usefulness The compound, Na v 1.8 Is it a selective inhibitor of sodium ion channel activity? Or, Na v 1.8 It has selective activity as a sodium ion channel blocker. In the application method, the compound is applied to each channel in the Qube® assay system. Functional efficacy (IC) 50 Based on the value, Na v From the 1.5 sodium channel Na v It exhibits at least 10 times selectivity for 1.8 sodium channels, and some In the embodiment, Na v 1.5 Sodium channel v 1.8 sodium chahn It exhibits at least 100 times selectivity for Nell. The compound is Na v 1.8 channel It is a potent inhibitor of activity. The compound and its pharmaceutically acceptable salts are Na v 1.8 Thorium ion channel activity and / or Na v 1.8 Receptor inhibition mediated diseases, It may be effective in treating disorders and conditions.

[0213] Na v 1.8 Sodium ion channel activity and / or Na v 1.8 Receptors are involved The diseases, disorders, or conditions that may be affected include, but are not limited to, nociceptive disorders, osteoarthritis, and terminal disorders. Peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, pruritus, acute itching, chronic itching, hemiplegia Pain, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, perioperative pain, postoperative pain, nerve Transpathogenic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, Cancer and chemotherapy-induced pain, chronic pelvic pain, pain syndromes, and complex regional pain syndromes. There is.

[0214] One or more of these conditions or diseases require a therapeutically effective dose of a compound in the patient. Or by administering a pharmaceutically acceptable salt thereof, treatment, management, prevention, reduction, or relief may be achieved. These conditions, diseases, or impairments can be improved or controlled. Furthermore, these compounds can be improved or controlled. Harm (nociception, osteoarthritis, peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, Itching, acute itching, chronic itching, migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute Pain during intercourse, perioperative pain, postoperative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetes Sexual neuropathy, chronic low back pain, phantom limb pain, cancer and chemotherapy-induced pain, chronic pelvic pain, pain syndromes, Furthermore, treatment, prevention, management, relief, improvement, or control of one or more of the following (complex regional pain syndromes): It can be used to manufacture drugs that may be useful for control.

[0215] A preferred use of the compound is by administering a therapeutically effective dose to patients in need of treatment. It may be used to treat one or more of the following diseases. The compound is used to treat these diseases: (1) Pain state, (2) Itchy condition, and, (3) Coughing It can be used to manufacture drugs for treating one or more of the following conditions.

[0216] In one embodiment, the pain condition is either acute or chronic pain disorder. Another embodiment Therefore, this pain condition is an acute pain disorder.

[0217] The compound may be effective in treating nociception. Nociception or pain is a threat to survival. It is essential and, in many cases, serves a protective function. However, the pain Pain associated with surgical procedures and current treatments to alleviate pain can delay postoperative recovery. This may prolong the hospital stay. 80% of surgical patients experience tissue damage and peripheral nerve damage. They are experiencing postoperative pain due to subsequent inflammation. In many cases, once the wound heals... Because nerve damage leads to persistent neuropathic pain, approximately 10-50% of surgical patients experience postoperative pain. This can lead to chronic pain.

[0218] Compounds represented by structural formula I may be effective in the treatment of osteoarthritis. Arthritis is a type of joint disorder caused by inflammation, destruction, and eventual loss of cartilage within the joint. It is osteoarthritis. The standard treatment for pain associated with osteoarthritis is nonsteroidal anti-inflammatory drugs (NSAIDs). AIDs), for example, celecoxib and diclofenac ("Zeng et al, (This is outlined in "2018"). Patients who do not respond to NSAID therapy are typically, Treatment involves low doses of opioids (e.g., hydrocodone). If the patient becomes resistant to the above treatments... Patients who exhibit these symptoms typically opt for total joint replacement.

[0219] The compound represented by structural formula I may be effective in treating peripheral neuropathy. The disorder is nerve damage caused by chronic hyperglycemia and diabetes. Symptoms include numbness, loss of sensation, and, in some cases, pain in the distal limb (e.g., foot, leg, or hand). It causes pain. It is the most common complication of diabetes. Treatment of painful diabetic neuropathy The standard treatment for this condition is gabapentinoids, such as gabapentin and pregabalin. Some patients respond well to tricyclic antidepressants such as amitriptyline, but others do not respond well to tricyclic antidepressants. The symptoms are significantly relieved with the use of SRI / NRI drugs such as uroxetine (Schreiber et al., World J Diabetes. 2015 Apr 15;6 (3):432-44). Many options are available, but the greatest potential is not Common side effects include limited side effects (e.g., dizziness, nausea).

[0220] The compound represented by structural formula I may be effective in the treatment of hereditary acromegaly. Erythromelalgia of the extremities (IEM) is a condition involving several voltage-gated sodium thyroid receptors, including Nav1.8. It is a chronic pain syndrome associated with channel mutations (Kist et al., PL oS One. 2016 Sep 6; 11(9):e0161789). The patient, The distal areas such as the hands and feet show the classic "glove and stocking" redness pattern, and these It is typically brought on by warm temperatures and exercise. Some patients respond to immersion in cold water. This relieves the burning pain associated with redness. It affects voltage-gated sodium channels. Drug therapies (e.g., lidocaine and mexiletine) are promising, but treating IEM is difficult. There is currently no standard treatment for this.

[0221] The compound represented by structural formula I may be effective in treating neuropathic pain. Harmful pain is pain caused by injury or disease affecting the somatosensory nervous system. Yes. In human patients and animal models of neuropathic pain, primary afferent sensory neurons Damage to the nerves, in addition to activity induced in response to stimuli that are normally harmless, can lead to the formation of nerve tumors. It has been demonstrated that it can trigger spontaneous activity (Colloca et al. al., Nat Rev Dis Primers. 2017 Feb 16;3: 17002; Coward et al., Pain. 2000 Mar;85( 1-2):41-50; Yiangou et al., FEBS Lett. 2 000 Feb 11;467(2-3):249-52; Carter et al ., Phys Med Rehabil Clin N Am. 2001 May; 12(2):447-59). Some nerve injuries increase Nav1.8 expression, This is considered to be the fundamental mechanism of pathological pain (Black et al.) ., Ann Neurol. 2008 Dec;64(6):644-53;Bi rd et al., Br J Pharmacol. 2015 May;172( 10):2654-70). Peripheral nerve damage often occurs after the initial injury has healed. This can also lead to persistent neuropathic pain. Examples of neuropathic pain include, but are not limited to, However, there are conditions such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, and lumbar nerve root disorders. phantom limb pain, cancer and chemotherapy-induced pain, chronic pelvic pain, complex regional pain syndrome and related conditions Examples include neuralgia and pain conditions resulting from gain-of-function mutations in Nav1.8. (Huang et al., J Neurosci. 2013 Aug 28;3 3(35):14087-97; Kist et al., PLoS One. 2 016 Sep 6;11(9):e0161789; Emery et al., J Neurosci. 2015 May 20;35(20):7674-81; and Schreiber et al., World J Diabetes. 2015 Apr 15;6(3):432-44).

[0222] Ectopic activity of sensory neurons, which are normally inactive, is associated with the development and maintenance of neuropathic pain. This is thought to be one of the contributing factors, and it is generally believed to be due to sodium chain reaction in damaged nerves. This is thought to be related to increased Nell activity (Wood et al., Curr O pin Pharmacol. 2001 Feb; 1(1):17-21; Bak er et al., TRENDS in Pharmacological Sci ences, 2001, 22(1): 27-31). Standards for Neuropathic Pain. Treatment varies greatly depending on the specific condition, but the first-line treatment is typically pregabalin. Gabapentin, tricyclic antidepressants (e.g., amitriptyline) and SRI / NRI drugs (e.g.) (For example, duloxetine). Patients who are resistant to these treatments are usually given a low dose of a You will be prescribed a tranquilizer (for example, hydrocodone).

[0223] The compound represented by structural formula I may be effective in the treatment of multiple sclerosis.

[0224] Recent evidence suggests a potential role for Nav1.8 in multiple sclerosis. Nav1.8 expression in this region was isolated from an animal model of multiple sclerosis (EAE model). It has been confirmed in the tissues of patients with multiple sclerosis (MS), and in the postmortem brains of patients with multiple sclerosis (MS). (Shields et al., Ann Neurol. 2012 Feb;) 71(2):186-94; Black et al., Proc Natl A cad Sci US A. 2000 Oct 10;97(21):11598- 602). Furthermore, two types of SCN10A polymorphisms showed a significant association with MS. Roostaei et al., Neurology. 2016 Feb 2; 86 (5):410-7). When Nav1.8 is overexpressed in the cerebellum, mice exhibit behavioral changes. The patient developed a motor disorder associated with ataxia, which was treated by orally administering a selective small molecule Nav1.8 antagonist. It is improved by reaching (Shields et al., PLoS One.) 2015 Mar 6; 10(3)). These studies showed that Nav1.8 antagonists are frequently used. This suggests that it may be a useful treatment for symptoms associated with sclerosing.

[0225] The compound represented by structural formula I may be effective in treating asthma. Asthma is an inflammation of the airways. This condition causes the human airway to become hypersensitive, narrowed, and swollen, and Therefore, breathing becomes difficult. These symptoms are typically triggered by an allergic reaction. (Nair P et al., J Allergy Clin Immu) nol Pract. 2017 May-Jun; 5(3):649-659). pantness In preclinical models of respiration, by removing Nav1.8-containing neurons, or by removing nerves By inhibiting transfibers with small molecules, inflammation of the airways and infiltration of immune cells are reduced. (Talbot et al., Neuron. 2015 Jul 15;87 (2):341-54). Selective Nav1.8 antagonists are triggered by immune cell infiltration. This could be a useful treatment for preventing airway hyperresponsiveness.

[0226] The compound represented by structural formula I may be effective in treating pruritus. Generally, itching is... Pruritus, also known as itching, affects about 4% of the world's population and is a condition characterized by an urge or reflex to scratch. It is an unpleasant sensation that induces gas and is considered to be closely related to pain (Luo et al., Cell Mol Life Sci. 2015 Sep;72 (17): 3201-23). ​​Theories regarding the origin of itching include nociceptors (which sense pain). This suggests the subtle low-frequency activation of neurons; however, some afferent neurons It has been noted that the body preferentially responds to histamine, which induces itching (Schme lz et al., J Neurosci. 1997 Oct 15; 17(2 0):8003-8). At the same time, histamine-responsive neurons cause capsulitis, which triggers pain. It was also found to respond to Ishin (McMahon et al., Trend). s in Neuroscience 1992, 15:497-501). temporary reception Both members of the container potential (TRP) family and nerve growth factor (NGF) are involved in itching. It is known to play a role in pain and discomfort, and clinically, both diseases It is treated with medications such as gabapentin and antidepressants. Therefore, the underlying cause of the pain and itching is The mechanisms are highly interwoven and complex, and there is no distinction between panselective pathways and itch-selective pathways. The fact that things remain as they are continues to be accepted (Ikoma et a l., Nat Rev Neurosci. 2006 Jul; 7(7):535 -47). The role of Nav1.8 in pruritus is constitutively active serine / threotherapy. This study was conducted using mice that genetically modify and express nin kinase BRAF, and here, The serine / threonine kinase BRAF is expressed in neurons that express Nav1.8. This increased the excitability of pruritus receptors, leading to increased spontaneous scratching behavior. (Zhao et al, 2013). In the skin, during inflammation, keratinocytes, Plutogens are released from pyocytes, mast cells, and eosinophils. These molecules are Nav1 It directly acts on free nerve endings that express .8, inducing itching (Riol-Blanco et al., Nature. 2014 Jun 5; 510 (7503): 157-61). Chronic and acute itching can result from many different injuries, diseases, and disorders. It is possible, and it is cutaneous or pruriceptive, neurological, It can be classified as neuropathic or psychogenic; itching can be caused by systemic diseases, skin diseases, and dermal diseases. It can result from both physical and chemical damage to the skin. Pathologically, it can be caused by dry skin, eczema, psoriasis, Chickenpox and shingles, urticaria, scabies, renal failure, cirrhosis, lymphoma, iron deficiency, diabetes, menopause, red blood Conditions such as cytosis, uremia, and hyperthyroidism are associated with tumors, multiple sclerosis, and peripheral neuropathy. It causes itching, as well as neurological disorders such as delusions associated with harm, nerve compression, and obsessive-compulsive disorder. It can be. Medications such as opioids and chloroquine can also cause itching (Ikoma et al., Nat Rev Neurosci. 2006 Jul;7(7) (535-47). Post-burn itching also hinders the healing process, thereby causing lasting fear. This is a very serious clinical problem because it negatively impacts the quality of life (Van Lo ey et al., Br J Dermatol. 2008 Jan;158(1 ):95-100).

[0227] A pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier comprising the compound and a pharmaceutically acceptable carrier. Pharmaceutical compositions that are similarly included within the scope of this disclosure.

[0228] The compound or its pharmaceutically acceptable salt is used in the treatment of painful conditions, itchy conditions and coughing conditions. It could be useful.

[0229] Compounds represented by structural formula I or their pharmaceutically acceptable salts may be contaminated in human patients or other mammals. Used in the manufacture of drugs for treating pain, itching, and coughing in patients. It is possible.

[0230] The method for treating pain is represented by structural formula I, which indicates a therapeutically effective amount for patients who require treatment. Administering a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing said compound This includes. A method for treating itchy conditions involves administering a therapeutically effective amount of structural formula I to patients who require treatment. The compound shown or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing said compound is administered. This includes administering a therapeutically effective dose to patients who require treatment. A compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound This includes administering a substance. Other medical uses of the compound represented by structural formula I are described herein. It is described there.

[0231] The term "painful state" as used in this specification is not limited to the following: This includes: acute pain, perioperative pain, preoperative pain, postoperative pain, neuropathic pain, post-herpes pain. Neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, chronic pelvic pain, vulvar pain, multiple Combined regional pain syndrome and related neuralgia, cancer and chemotherapy-related pain, HIV-related pain Pain and neuropathy, nerve damage, nerve root avulsion injury induced by HIV treatment, Painful traumatic mononeuropathy, painful polyneuropathy, erythromyelitis (erythromyelitis) IGIA, paroxysmal severe pain disorder, small fiber neuropathy, oral burning syndrome, central pain disorder Symptoms (can be caused by virtually any lesion at any level of the nervous system) post-operative pain syndromes (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, stump pain), bone pain and Joint pain (osteoarthritis), pain from repetitive movements, toothache, myofascial pain (muscle injury, fibromyalgia), perioperative Pain during menstruation (general surgery, gynecology), chronic pain, dysmenorrhea, pain related to the angina, and various other conditions. Inflammatory pain caused by various factors (e.g., osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis) (and gout), shoulder tendinitis or bursitis, gouty arthritis, and polymyalgia rheumatica (AOL) Myelitis rheumatica, primary hyperalgesia, secondary hyperalgesia, primary allodynia Secondary allodynia, or another type of pain caused by central sensitization, complex regional pain syndrome. Group, chronic joint pain and related neuralgia, acute pain, migraine, migraine (m igraine headache, headache (headache pain), cluster headache Nonvascular headache, traumatic nerve injury, nerve compression or entrapment, and neuropathic pain.

[0232] The terms "pruritic condition" or "pruritic disorder" as used in this specification are not limited to those used in this specification. It does not include a specific condition, but encompasses a state accompanied by an unpleasant sensation that induces the urge to scratch, such as chronic itching. Includes.

[0233] The terms "cough condition" or "cough disorder" as used herein are not limited to these terms. However, this includes chronic cough, neuropathic cough, or cough resulting from a neurological condition.

[0234] Nav 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases Treatment of the disorder or condition is represented by structural formula I for the subject having the disease, disorder or condition. This means administering a compound. One of the outcomes of the treatment is Na v 1.8 Sodium Ion Channel Activity or Na v 1.8 It may alleviate diseases, disorders, or conditions mediated by receptors. Another outcome of the treatment was Na v 1.8 Sodium ion channel activity or Na v 1.8 receiving It may alleviate diseases, disorders, or conditions mediated by the condition. Another outcome of treatment is Na v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases and disorders Or it may improve the condition. Another outcome of treatment is Na v 1.8 Sodium ions Channel activity or Na v 1.8 By suppressing diseases, disorders, or conditions mediated by receptors It is possible. Another outcome of the treatment is Na v 1.8 Sodium ion channel activity or Na v 1.8 This may involve managing diseases, disorders, or conditions mediated by receptors.

[0235] Another outcome of the treatment is Na v 1.8 Sodium ion channel activity or Na v 1.8 receiving It may help prevent diseases, disorders, or conditions that are mediated by the condition.

[0236] Na v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases Prevention of the disability or condition is expressed in structural formula I for individuals at risk of the disease, disability, or condition. This means administering the compound. One consequence of prevention is that the risk of the disease, disorder, or condition is reduced. In a certain group, Na v 1.8 Sodium ion channel activity or Na v 1.8 receiving It may alleviate diseases, disorders, or conditions in which the condition is mediated. Another consequence of prevention is the disease In individuals at risk of illness, disability, or condition, Na v 1.8 Sodium ion chain Nerve activity or Na v 1.8 Possible by suppressing diseases, disorders, or conditions mediated by receptors. Another outcome of prevention is that in individuals at risk of the disease, disability, or condition, Na v 1 .8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, disorders or It may improve the condition. Another consequence of prevention is that the risk of the disease, disorder, or condition is reduced. Among the target individuals, Na v 1.8 Sodium ion channel activity or Na v 1.8 Reception It may alleviate a disease, disorder, or condition involving the body. Another consequence of prevention is the disease In individuals at risk of disability or condition, Na v 1.8 Sodium Ion Channel Activity or Na v 1.8 Possible management of diseases, disorders, or conditions mediated by receptors. .

[0237] One outcome of the treatment was the pain experienced by the subject immediately before administration of the compound represented by structural formula I. Compared to other methods, this may reduce the amount of pain experienced by the individual. Another outcome of treatment The result was that, compared to the pain experienced by the subject immediately before administration of the compound represented by structural formula I, This may reduce the amount of pain experienced by the subject. Another outcome of the treatment is shown in structural formula I. Compare the pain experienced by the subject to the pain immediately before administration of the compound. It may improve the amount of milk. Another outcome of the treatment is administering the compound represented by structural formula I. By comparing the amount of pain the subject experiences with the pain immediately before the action, the amount of pain the subject experiences can be reduced. This is possible. Another outcome of the treatment is the response immediately before administering the compound represented by structural formula I. This could involve managing the amount of pain experienced by the individual compared to the overall pain level. Another result compared the pain in subjects immediately before administration of the compound represented by structural formula I. This could potentially improve the amount of pain experienced by the individual.

[0238] Another outcome of the treatment is the additional pain experienced by the subject after administration of the compound represented by structural formula I. It may help prevent illness.

[0239] Pain prevention is aimed at reducing pain in individuals at risk of pain, represented by structural formula I. This means administering a compound. Prevention is not limited to surgery or other preventive measures. This includes administering the drug to the subject before the expected painful event occurs. One outcome of prevention is pain It may reduce pain in individuals at risk. Another outcome of prevention is pain It may suppress pain in individuals at risk. Another outcome of prevention is pain It may improve pain in individuals at risk. Another outcome of prevention is pain It may alleviate pain in individuals at risk. Another outcome of prevention is pain This could involve managing pain in individuals at risk.

[0240] The terms “administration” and / or “to administer” a compound refer to the individual requiring treatment. This means providing a compound represented by structural formula I or its prodrug to a body or mammal. This should be understood.

[0241] The administration of the compound represented by structural formula I for carrying out this treatment method is such a treatment or By administering an effective amount of the compound represented by structural formula I to mammals that require prevention To be implemented. The need for prophylactic administration by the methods provided herein is well known. The effective amount of each compound is determined by using the risk factors present. In the analysis, the decision is made by the physician or veterinarian in charge of the case, however, The effective dose depends on various factors, such as the exact disease being treated, the severity of that disease, and the patient. Other illnesses or conditions the patient may have, the selected route of administration, and other conditions the patient may need at the same time. It depends on other drugs and treatments, as well as other factors at the physician's discretion.

[0242] The usefulness of this compound in these diseases or disorders is reported in the literature for animal diseases. This can be demonstrated in the model.

[0243] Dosage and dosage range To provide a compound represented by structural formula I in an effective dose for mammals (especially humans), Any appropriate route of administration can be used. For example, orally, intravenously, by infusion, subcutaneously, or via This involves using the skin, intramuscularly, intradermally, transmucosally, intramucosally, rectally, locally, parenterally, in the eyes, lungs, nose, etc. It can be administered in the following forms: tablets, lozenges, dispersions, suspensions, solutions, capsules, etc. Examples include creams, ointments, and aerosols. Preferably, the compound represented by structural formula I is administered orally. To be given.

[0244] Na v 1.8 Disorders, diseases and / or disorders requiring inhibition of sodium ion channel activity In the treatment or prevention of a condition, the appropriate dosage level is generally the patient's body weight per day. The dosage is approximately 0.0001 to 500 mg per kg, and this is administered as a single or multiple dose. This is possible. In one embodiment, an appropriate dosage level is 1 kg per day of the patient's body weight. This can be approximately 0.001 to 500 mg per gram. In another embodiment, an appropriate dosage level This can range from approximately 0.001 to approximately 250 mg / kg per day. In another embodiment, appropriately The dosage level can range from approximately 0.01 to approximately 250 mg / kg per day. In this context, an appropriate dosage level may be approximately 0.1 to 100 mg / kg per day. In another embodiment, an appropriate dosage level is approximately 0.05–100 mg / kg per day. It is possible. In another embodiment, an appropriate dosage level is approximately 0.1 to 50 mg / day It may be in kg. In another embodiment, an appropriate dosage level is about 0.05 to 0 per day. It may be 0.5 mg / kg. In another embodiment, an appropriate dosage level is about 0 per day It may be 0.5 to 5 mg / kg. In another embodiment, an appropriate dosage level is per day It may be approximately 5-50 mg / kg. When administered orally, the composition is administered to the patient under treatment. To adjust the dosage according to the symptoms, preferably 0.01 to 1000 mg of the active ingredient, In particular, 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0. 75, 1.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 5 0.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 4 00.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 10 It is supplied in the form of a tablet containing 0.0 mg of the active ingredient per day. 1 to 8 times (preferably 1 to 4 times per day, more preferably 1 or 2 times per day) It can be administered in a regimen of (number of doses). This administration regimen provides the optimal therapeutic response. It can be adjusted to that extent.

[0245] However, the specific dosage level and frequency of administration for any particular patient may be changed. It is possible to determine the activity of the specific compound used, its metabolic stability, and its effects. Length, age, weight, general health status, sex, diet, method and timing of administration, elimination rate various factors including drug combinations, the severity of specific conditions, and the recipients receiving treatment. It is understood that it depends on various factors.

[0246] The compound represented by structural formula I is (a) the compound or a pharmaceutically acceptable salt thereof, and (b) A pharmaceutically acceptable carrier, which can be used in a pharmaceutical composition. The compound represented by structural formula I is a pharmaceutical composition containing one or more other active pharmaceutical ingredients. It can be used in the present disclosure. The compounds disclosed herein can also be used in the compounds represented by structural formula I. Alternatively, it may be used in pharmaceutical compositions in which the pharmaceutically acceptable salt is the sole active ingredient. It is possible.

[0247] In the context of pharmaceutical compositions, the term "composition" refers to a combination of an active ingredient (one or more) and inactive components that make up the entire composition. It is intended to include products containing one or more sexually explicit ingredients, and furthermore, optional. From a combination, complexation, or aggregation of two or more components, or from the solution of one or more components From separation, or from another type of reaction or interaction of one or more components, directly or It is intended to include any products that arise indirectly. Therefore, disclosures herein The pharmaceutical composition is a mixture of a compound represented by structural formula I and a pharmaceutically acceptable carrier. It includes any composition manufactured by doing so.

[0248] The compound represented by structural formula I is useful for diseases or conditions. It can be used in combination with other drugs that may be equally useful in treatment or improvement. Such other drugs, in the routes and amounts commonly used with respect to them, have structural formula I. The compounds shown can be administered simultaneously or sequentially. Pain, itching and In the treatment of patients with a cough, two or more drugs are generally administered. The compounds shown are generally those that are already taken with one or more other drugs for these conditions. It can be administered to patients who have the following condition. In many cases, the compound contains one or more anti-pain agents. In patients already being treated with a compound, if the patient's pain is not responding adequately to the treatment... It is administered in certain cases.

[0249] Combination therapy further involves the overlap of the compound represented by structural formula I with one or more other drugs. This also includes therapies administered according to a set schedule. It can also involve combining one or more other active ingredients. When used in this manner, the compound represented by structural formula I and the other active ingredient are used individually. It is also intended that it can be used at a lower dose than in the case of [specific condition]. The pharmaceutical compositions disclosed in the document include one or more compounds in addition to the compound represented by structural formula I. It includes pharmaceutical compositions containing other active ingredients.

[0250] It can be administered in combination with the compound represented by structural formula I, and separately or together. Examples of other active ingredients that can be administered in the pharmaceutical composition are not limited to the above. However, the following can be listed: (i) Opioid agonists; (ii) Opioid antagonists; (iii) Calcium channel blockers; (iv) NMDA receptor agonists; (v) NMDA receptor antagonists; (vi) COX-2 selective inhibitors; (vii) NSAIDs (nonsteroidal anti-inflammatory drugs); (viii) Analgesics; (ix) Sodium channel inhibitors; (x) anti-NGF antibody; (xi)Na v 1.7 Inhibitors; (xii) HCN inhibitors; (xiii) TRPV1 antagonists; (xiv)Na v 1.7 Biological drugs; and, (xv)Na v 1.8 Biological drugs; and, Those pharmaceutically acceptable salts.

[0251] In another embodiment, the pharmaceutical composition includes the following: (1) The compound described in claim 1 or a pharmaceutically acceptable salt thereof; (2) One or more compounds selected from the group consisting of the following, or their pharmaceutically acceptable Salt: (i) Opioid agonists; (ii) Opioid antagonists; (iii) Calcium channel blockers; (iv) NMDA receptor agonists; (v) NMDA receptor antagonists; (vi) COX-2 selective inhibitors; (vii) NSAIDs (nonsteroidal anti-inflammatory drugs); (viii) Analgesics; (ix) Sodium channel inhibitors; (x) anti-NGF antibody; (xi)Na v 1.7 Inhibitors; (xii) HCN inhibitors; (xiii) TRPV1 antagonists; (xiv)Na v 1.7 Biological drugs; and, (xv)Na v 1.8 Biological drugs; and, Those pharmaceutically acceptable salts; and, (3) A pharmaceutically acceptable carrier.

[0252] Nav1.7 biological agents inhibit the function of the Nav1.7 channel ( This means (but is not limited to) antibodies, nanobodies, and peptides. Nav1.8 biological agents are proteins that inhibit the function of the Nav1.8 channel. (This means, but is not limited to, antibodies, nanobodies, and peptides.) do.

[0253] The following are specific compounds that are used in combination with the compound represented by structural formula I. These include: sodium channel inhibitors (this is not limited to lidocaine, but is a possible example). This includes lidocaine such as Inpatch); tricyclic antidepressants (this is not limited to...) However, this includes amitriptyline; and SRI / NRI drugs (this is not limited to...) (Not, but it includes duloxetine).

[0254] Appropriate opioid agonists include, but are not limited to, codeine and fentanyl. Hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine Ne, oxycodone, oxymorphone, buprenorphine, butorphanol, dezosine These include nalbufine, pentazocine, and tramadol.

[0255] Appropriate opioid antagonists include, but are not limited to, naltrexone and naltrexone. Examples include xon.

[0256] Appropriate calcium channel antagonists include, but are not limited to, amlodipine. Diltiazem, felodipine, gabapentin, isradipine, nicardipine, nifedi Examples include pine, nisoldipine, pregabalin, verapamil, and diconicid.

[0257] Appropriate NMDA receptor antagonists include, but are not limited to, ketamine and methadone. These include memantine, amantadine, and dextromethorphan.

[0258] Appropriate COX-2 inhibitors include, but are not limited to, celecoxib and etrico. Examples include xib and parecoxib.

[0259] Appropriate NSAIDs or nonsteroidal anti-inflammatory drugs include, but are not limited to, Aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurvip Ibuprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mef Enamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, pi Examples include roxicam, slindac, and tolmetin.

[0260] Appropriate analgesics include, but are not limited to, acetaminophen and duloxetine. There are things like chins.

[0261] The above combinations include a compound represented by structural formula I and one other active compound. This includes not only single-component compounds, but also combinations with two or more other active compounds. Non-limiting examples include... For example, a combination of two or more active compounds selected from the following: Examples include: opioid agonists; opioid antagonists; calcium channel antagonists. Antidotes; NMDA receptor agonists; NMDA receptor antagonists; COX-2 selective inhibitors; NSA ID (nonsteroidal anti-inflammatory drugs); and analgesics.

[0262] Compounds represented by structural formula I or their pharmaceutically acceptable salts are further used in spinal cord stimulation therapy and It can also be used in combination with skin stimulation therapy.

[0263] Furthermore, Na v 1.8 Diseases, disorders, or conditions mediated by sodium ion channel activity Methods for treating or preventing the condition are also provided, wherein the method is used for patients who require such treatment. Person or Na v 1.8 Therapeutic dose for patients at risk of developing sodium-mediated diseases. Na v 1.8 Sodium ion channel activity inhibitor and a specific amount of one or more effective ingredients This involves administering the medication for several minutes, thereby allowing them to work together to provide effective relief.

[0264] In a further manner, Na v 1.8 Sodium ion channel activity inhibitors and one other type The above active ingredients are combined with at least one pharmaceutically acceptable carrier or excipient. A pharmaceutical composition is provided.

[0265] Therefore, Na v 1.8 Diseases, disorders, or conditions mediated by sodium ion channel activity Na for manufacturing drugs to treat or prevent v 1.8 Sodium Ion Channel The use of an activity inhibitor and one or more active ingredients is provided. Therefore, further development of this disclosure In a similar or alternative manner, Na v 1.8 Sodium ion channel activity is involved. For use simultaneously, separately, or sequentially in the treatment or prevention of a disease, disorder, or condition Na as a combined preparation v 1.8 Sodium ion channel activity inhibitors and one type Products containing more than 100% active ingredients are provided. Such combined preparations are For example, it could come in a twin-pack format.

[0266] A compound represented by structural formula I, used to treat or prevent pain, itchiness, and cough. It can be used in combination with another medicine that is effective in treating the disease, disorder, or condition. To be able to do it is to be understood.

[0267] Furthermore, methods for treating or preventing pain, itching, and coughing are also provided, and here, The method involves providing a specific amount of a compound represented by structural formula I to a patient requiring such treatment. Administer a quantitative amount of another medicine that is effective in treating the disease, disorder, or condition, thereby This includes the fact that they work together to provide effective relief.

[0268] Furthermore, methods for treating or preventing pain, itching, and coughing are also provided, and here, The method involves providing a specific amount of a compound represented by structural formula I to a patient who requires such treatment. Administer a specific amount of another drug useful in treating that particular condition, disorder, or disease, and Therefore, this includes the fact that they work together to provide effective relief.

[0269] The term "therapeutic effective dose" refers to the precise amount determined by researchers, veterinarians, physicians, or other clinicians. A biological or medical response of cells, tissues, systems, animals, or humans (this is a symptom of a disorder that is being treated). This refers to the amount of the compound represented by structural formula I that induces (including relaxation of the state). The novel treatment methods offered are for disorders known to those skilled in the art. The term "mammal" includes humans and companion animals (e.g., dogs and cats). .

[0270] The weight ratio of the compound represented by structural formula I to the second active ingredient can be changed, and It depends on the effective dose of each component. Generally, the effective dose of each component is used. For example, when a compound represented by structural formula I is combined with a COX-2 inhibitor, the structural formula The weight ratio of the compound represented by I to the COX-2 inhibitor is generally about 1000:1 to about 1:1. It is within the range of 000, preferably within the range of about 200:1 to about 1:200. Structure The combination of the compound represented by formula I with another active ingredient is also generally within the range described above. In all cases, the effective dose of each active ingredient should be used.

[0271] Synthesis method The following reaction scheme and examples are based on the chemical formula represented by structural formula I described herein. Methods that can be used for the synthesis of compounds are illustrated. These reaction schemes and examples are These are provided for illustrative purposes only and should not be construed as limiting the invention in any way. It should not be. All substituents are defined above unless otherwise specified. This is a case. Several strategies based on synthetic transformations known in the literature on organic synthesis, structure It can be used to prepare the compound represented by formula I.

[0272] device Reverse-phase chromatography is performed using a Gilson column selected from the following options. Performed with GX-281: Phenomenex Synergi C18 (150m m?30mm?4 microns), YMC-Actus Pro C18 (150mm?30m m?5 microns), Xtimate C18 (150mm?25mm?5 microns), Bo ston Green ODS (150mm? 30mm? 5 microns), XSELECT C18 (150mm? 30mm? 5 microns), and Waters XSELECT C18 (150mm? 30mm? 5 microns). Conditions include high pH (0.1% v / v 10m). 0-100% acetonitrile containing M NH4CO3 or 0.05% NH4OH (Water eluent) or low pH (containing 0.1% v / v TFA and 0-95% acetonitrile / It contains one of the following (water eluent), and in some examples, this is noted.

[0273] SFC chiral partitioning is performed using Sepiate Prep SFC 100 and Multigra. m II (MG II), THAR80 prep SFC, or Waters SF The test was conducted using C (80, 200, or 350).

[0274] LC / MS measurement is performed using one of the following conditions, with UV and MS detectors and Wat Waters Classing Aquity with ers SQD mass spectrometer Shimadzu 2010 or 2020 Mass Spectrometer equipped with a stem. zu 20UV254 and 220nM, or DAD / ELSD and G6110 MSD The procedure was performed using an Agilent 1200 HPLC equipped with: (1) Ascentis Express C18 (3-50 mm) 2.7 μm column, A: 0.05% in water A mobile phase containing TFA and B: 0.05% TFA in acetonitrile is used. The flow rate was 1.8 mL / min, and the ratio changed from 90:10 (A:B) to 5:95 (A:B) over 6 minutes. ], UV detection 210nm; (2) Aquity BEH C18 (1.0-50mm ) 1.7 μm column, A: 0.05% TFA in water, and B: in acetonitrile Use a mobile phase containing 0.05% TFA [at a flow rate of 0.3 mL / min gradient for 2 minutes] [90:10 (A:B) → 5:95 (A:B)], UV detection 215nm; (3)A Gilent YMC J'Sphere H-80 (3-50mm) 5μm column, A: Use a mobile phase containing 0.1% TFA in water, and B: Acetonitrile [gradient] At a flow rate of 1.4 mL / min, over 3.6 minutes, the ratio changes from 95:5 (A:B) to 0:100 (A:B). ), and 0.4 minutes 0:100 (A:B), UV detection 254nm and 220nm, and Agilent 1100 quadrupole mass spectrometer; (4) Agilent TC- C18 (2.1-50 mm) 5 μm column, A: 0.0375% TFA in water, B: Use a mobile phase containing 0.01875% TFA in acetonitrile [gradient 0. At a flow rate of 8 mL / min, starting with 90:10 (A:B) for 0.4 minutes, then gradually increasing to 90:10 over 3 minutes → 0:100 (A:B), and 10:90 (A:B) for 0.6 minutes, UV detection 254n m and 220 nm, and an Agilent 6110 quadrupole mass spectrometer.

[0275] Proton NMR or 1 1H NMR is a standard analytical technique unless otherwise specified. Therefore, Varian 400 ATB PFG 5mm, Nalorac DBG 4 Varian equipped with 00-5 or Nalorac IDG 400-5 probe Unity-Inova 400 MHz NMR Spectrometer, Auto X ID PFG Varian-400MHz MR spectrometer with 5mm probe, PFG 4N Varian 400MHz VNMRS spectrometer with 5mm uc probe, This is the Bruker AvanceIII 50 with PABBO Probe 5mm. Acquired using a 0MHz spectrometer. The results of the spectral analysis are reported. Chemical shift ( The δ) value is reported in delta (δ) units, parts per million (ppm). 1H NMR spectrum The chemical shift related to Toll is referenced at residual non-deuterated solvent (CDCl3(δ 7.26 ppm). (referred to as ), DMSO d-6 (referred to as δ 2.50 ppm), and CD3OD (δ It is given relative to the signal (referenced at 3.31 ppm). Multiple terms are given as The following abbreviations are used for reporting: s = single line, d = double line, t = triple line, q = quadruple line, dd = double line Double lines, m = multiple lines, or overlap of non-equivalent resonances. The coupling constant (J) is reported in Hertz (Hz). It was announced.

[0276] Abbreviation AcOH is acetic acid; Boc is tert-butoxycarbonyl; Ca lc'd is a calculated value; CDI is 1,1'-carbonyldiimidazole; DAST is diethylaminosulfur trifluoride; DCE is dichloroethane. DCM is dichloromethane; DEA is diethanolamine; DI BAL-H is diisobutylaluminum hydride; DIPEA or DIEA is N,N-diisopropylethylamine; DMA is dimethylacetamide. DMF is dimethylformamide; DMSO is dimethyl sulfoxide. dppf is 1,1'-bis(diphenylphosphin)ferrocene; ED C is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; ED CI is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; E t2O is diethyl ether; toluene is ethyl acetate; EtOH is , is ethanol; Et3N is triethylamine; g is grams; h or hr(s) is time(s); HATU is 1-[bis(dimethylamino )-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxy It is a hydroxyphosphate; Hex is hexane; HOAt is , is 1-hydroxy-7-azabenzotriazole; HPLC is a high-performance liquid chromatography It is a matrix; IPA is isopropyl alcohol; iPrMgCl Alternatively, i-PrMgCl is isopropyl magnesium chloride; iPrMgCl -LiCl is an isopropylmagnesium chloride lithium chloride complex; L is , is liter; LAH is lithium aluminum hydride; LC / MS is, Liquid chromatography-mass spectrometry (LRMS) is a low-resolution mass spectrometry method. M is mole; Me is methyl; MeOH is methanol; Me CN is acetonitrile; MeMgBr is methylmagnesium bromide. mg is milligram; mL is milliliter; mmol is millimol Ms-Cl is methanesulfonyl chloride; N is normal; NaHMDS is sodium bis(trimethylsilyl)amide; NH4OAc is , is ammonium acetate; NMO is 4-methylmorpholine N-oxide; NMP is N-methylpyrrolidone; mPa is millipascal; mol % is mole percent; PCC is pyridinium chlorochromate; Pd / C is carbon-supported palladium; Pd(dppf)Cl2 is [1,1-bis(dif It is [enyl-phosphino)-ferrocene]dichloropalladium(II); Pd(PP h3)4 is tetrakis(triphenyl-phosphine)-palladium(0); P d(tBu3P)2 is bis(tri-tert-butylphosphine)-palladium(0) Pet.ether or PE is petroleum ether; PG is a protecting group. PPh3 is triphenylphosphine; ppm is the amount per liter Milligrams; Prep. or prep means preparative; psi is pounds / square It is a square inch; rt or RT is room temperature; SFC is supercritical fluid chromatography. Fee is; TBAF is tetrabutylammonium fluoride; tBuX Phos Pd G3 is [(2-di-tert-butylphosphino-2',4',6' -Triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl) (Nyl) Palladium(II) methane sulfonate; TEA is triethylamine TFA is trifluoroacetic acid; THF is tetrahydrofuran. Ti(OEt)4 is titanium(IV) ethoxide; Ti(OiPr)4 is , titanium(IV) isopropoxide; TLC is thin-layer chromatography. UV stands for ultraviolet light; and v / v stands for volume / volume.

[0277] As shown in Scheme A, the compound represented by structural formula I is Ti(OEt)4 or This involves using a dehydrating agent such as Ti(OiPr)4 to appropriately functionalize aldehyde A-1. By condensing it with tert-butanesulfinamide to obtain intermediate A-2, It is possible to prepare it. Next, intermediate A-2 is reacted with various organometallic nucleophiles A-3. By doing so, it is possible to obtain intermediate A-4, which can then be deprotected under acidic conditions to obtain formula A An amine represented by -5 can be obtained. Next, amine A-5 is subjected to urea coupling. Under the conditions (using triphosgene or CDI as the coupling reagent), piperazine A- By combining with 6, a compound represented by formula A-7 can be obtained. In some embodiments, Protecting groups (e.g., Boc) may need to be removed during the synthesis process. Type A- Aldehydes of type 1 and organometallic compounds of type A-3 are commercially available or suitable starting materials. It can be synthesized from materials and reagents.

[0278] Scheme A [ka] As shown in Scheme B, the compound represented by structural formula I is appropriately functionalized. Activate carboxylic acid B-1 with (COCl)2 or with amine B-2 and amide coupling It can be prepared by performing a process to obtain intermediate B-3. This intermediate is It is suitable for reacting with various organometallic nucleophiles A-3 to obtain intermediate B-4. Then, intermediate B-4 is subjected to a reductive amination reaction in the presence of an amine source and a reducing agent, Form A-5 can be produced. In some cases, tert-butansulfinamide When used as an amine source and deprotection (under an acidic environment) is required after reductive amination. Next, amine A-5 is subjected to urea coupling conditions (with tri as the coupling reagent). When combined with piperazine A-6 under the use of phosgene or CDI, the result is represented by formula A-7. A compound can be obtained. In some embodiments, protecting groups such as Boc are used in the synthesis process. It may be necessary to remove them through the following: Type B-1 carboxylic acids and Type A-3 organogold. The genus is commercially available or can be synthesized from suitable starting materials and reagents.

[0279] Scheme B [ka] [Examples]

[0280] Examples Examples 1A and 1B N-((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoro Methyl)cyclohexyl)methyl)3-oxopiperazine-1-carboxamide, and N-((S)-3-chloro-4-fluorophenyl)(trans-4-(trifluoro Methyl)cyclohexyl)-methyl)-3-oxopiperazine-1-carboxamide [ka] Stage 1: (3-chloro-4-fluorophenyl)(-4-(trifluoromethyl) Chlohexyl Methanone trans-4-(trifluoromethyl)cyclohexanecarboxylic acid (571 mg, 2. A solution prepared by dissolving 91 mmol) in CH2Cl2 (5 mL) was then prepared at 0°C, and the chloride in DCM was added. Oxalyl (2M, 3.64 mL, 7.28 mmol) and one drop of DMF were added. The mixture was heated to room temperature and stirred for 4 hours, then heated to 40°C and stirred for 30 minutes. Next, the mixture was concentrated under reduced pressure to obtain a residue. This residue was then dissolved in THF. (4 mL, Solution A). In a separate flask, copper(I) cyanide (652 mg, 7. Suspend 28 mmol) in THF (4 mL), cool to 0°C, and then add 3 in THF. -Chloro-4-fluorophenylmagnesium bromide (0.5M, 11.64mL, 5 (0.82 mmol) was added. The mixture was stirred at 0°C for 1 hour, and then solution A was added. The mixture was then stirred at 0°C for 4 hours. The reaction product was then mixed with 30 mL of saturated aqueous solution NH4Cl. Quenched and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined and Na2SO4. The compound was dehydrated, filtered, and concentrated under reduced pressure to obtain the title compound.

[0281] LCMS m / z (M+H): Calculated value 308.7, Measured value 309.2. Stage 2: (3-chloro-4-fluorophenyl)(trans-4-(trifluorophenyl) (Cyl)cyclohexyl)methanamine In the microwave tube, (3-chloro-4-fluorophenyl)(trans-4-(triflu Oromethyl(cyclohexyl)methanone (1281mg, 4.15mmol), acetate Monium (2559 mg, 33.2 mmol) and ethanol (15 mL) were added. Heat the mixture in a microwave at 130°C for 20 minutes, let it cool to room temperature, and then cyano Sodium borohydride (287 mg, 4.56 mmol) was added. The reaction mixture was then prepared. The mixture was heated in a microwave oven at 125°C for 20 minutes, and then cooled to room temperature. The resulting reaction product was then... Quench by adding 10% aqueous K2CO3 (30 mL), then ethyl acetate (2 × 30 Extraction was performed using (mL). The organic layer was combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. Thus, the title compound was obtained.

[0282] LCMS m / z (M+H): Calculated value 413.9, Measured value 414.4. Stage 3: Examples 1A and 1B (3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl) chlorophenyl) Chlohexyl(methanamine) (333 mg, 1.075 mmol) in DCM (3 mL) To the dissolved solution, add Et3N (0.749 mL, 5.38 mmol) and tripho at 0°C. Sugen (319 mg, 1.075 mmol) was added. The mixture was stirred at 0°C for 1 hour. Next, piperazine-2-one (215 mg, 2.150 mmol) was added. After stirring at °C for 1 hour, the reaction mixture is heated to room temperature, stirred at room temperature for 1 hour, and then, The residue was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (0-4% Me). The mixture of isomers was purified by elution with OH / DCM, and a mixture of isomers was obtained. Further extraction using FC (OD-H column, 25% EtOH + 0.25% DIPEA cosolvent) Separate them, and compare Example 1A (second eluted fraction) and Example 1B (first eluted fraction). This was obtained.

[0283] Example 1A: LRMS m / z (M+H): calculated value 435.8, found value 436.4. 1H NMR δ (ppm) (500 M Hz, DMSO-d6): 8.01 (s, 1H), 7.53 (dd, J = 7.3, 2.0 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.32 ? 7.27 (m, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.37 (t, J = 9.1 Hz, 1H), 3 .96 ? 3.77 (m, 2H), 3.54 ? 3.41 (m, 2H), 3.14 (td, J = 5.3, 2.6 Hz, 2H), 2.19 (d , J = 8.6 Hz, 1H), 2.06 (d, J = 12.5 Hz, 1H), 1.93 (d, J = 12.4 Hz, 1H), 1.78 (d , J = 12.7 Hz, 1H), 1.65 (q, J = 11.8 Hz, 1H), 1.28 ? 0.87 (m, 5H). Example 1B: LRMS m / z (M+H): Calculated value 435.8, Measured value 436.4. 1H NMR δ (ppm) (500 M Hz, DMSO-d6): 8.01 (s, 1H), 7.53 (dd, J = 7.3, 2.0 Hz, 1H), 7.38 ? 7.26 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 4.44 ? 4.31 (m, 1H), 4.00 ? 3.80 (m, 2H), 3.57 ? 3.42 (m, 2H), 2.51 (p, J = 1.8 Hz, 2H), 2.25 ? 2.13 (m, 1H), 2.08 (s, 1H), 1.93 (d, J = 11.9 Hz, 1H), 1.83 ? 1.74 (m, 1H), 1.71 ? 1.57 (m, 1H), 1.27 ? 0.94 (m, 5H). Table 1: The following examples use appropriate starting materials and reagents, and are based on Examples 1A and 1 It was prepared according to the synthesis procedure for B. [Table 1] TIFF2026048891000020.tif233170TIFF2026048891000021.tif240170TIFF2026048891000022.tif219170 Examples 15A and 15B (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2 -Trifluoroethyl)piperidine-4-yl)methyl)2-methyl-3-oxopiper Radin-1-carboxamide, and (2R)-N-((S)-(3-chloro-4-flu Olophenyl)(1-(2,2,2-trifluoroethyl)piperidine-4-yl)methyl (Lu)-2-methyl-3-oxopiperazine-1-carboxamide [ka] Step 1: 1-(2,2,2-trifluoroethyl)piperidine-4-carbonitride 4-Cyanopiperidine (517 mg, 4.69 mmol) in anhydrous CH2Cl2 (8 mL) ) dissolved in a solution of 2,2,2-trifluoroethyltrifluoromethane-sulfone Et3N (0.744 mL, 5.16 mmol) and Et3N (0.850 mL, 6.10 mL) (mol) was added. The mixture was stirred at room temperature for 3 days, and then diethyl ether and saturates. The separated organic layer was partitioned between aqueous NaHCO3 molecules. The separated organic layer was then dehydrated with Na2SO4. The compound was filtered and concentrated under reduced pressure to obtain the title compound.

[0284] LRMS m / z (M+H): Calculated value 192.2, Measured value 193.1. Stage 2: (3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoro Ethyl)piperidine-4-yl)methaneamine In the microwave tube, 1-(2,2,2-trifluoroethyl)piperidine-4-carbon Trill (380 mg, 1.977 mmol), 0.5 M 3-chloro-4-phosphate in THF Lulorophenylmagnesium bromide (5.93 mL, 2.97 mmol) and THF ( 3 mL) were charged. The mixture was heated at 100 °C for 15 minutes in a microwave oven, cooled to room temperature, and then MeOH (2 mL) and NaBH4 (224 mg, 5.93 mmol) were added. The reaction was stirred at room temperature for 3 hours, then quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over Na2SO 4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0 - 5% MeOH / DCM) to obtain the title compound.

[0285] LRMS m / z (M + H): Calculated value 324.7, Measured value 325.2. Stage 3: Examples 15A and 15B (3 - chloro - 4 - fluorophenyl)(1 - (2,2,2 - trifluoro - ethyl) piperidin - 4 - yl)methanamine (150 mg, 0.462 mmol) was dissolved in CH2Cl 2 (3 mL). To the solution, at 0 °C, Et3N (0.322 mL, 2.309 mm ol) and triphosgene (137 mg, 0.462 mmol) were added. The mixture was stirred at 0 °C for 1 hour, then (R) - 3 - methylpiperazin - 2 - one (105 mg, 0.924 mmol) was added. After stirring at 0 °C for 1 hour, the reaction was warmed to room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ( eluted with 0 - 4% MeOH / DCM) to obtain a mixture. The mixture was further separated by SFC (OD - H column, 25% EtOH co - solvent) to obtain Example 15A (the fraction eluted first) and Example 15B (the fraction eluted second).

[0286] Example 15A: LRMS m / z (M+H): Calculated value 464.9, Measured value 465.4. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.31 (s, 1H), 7.15 ? 7.10 (m, 2H), 6.54 (s, 1H), 5.34 (s, 1H), 4.74 (d, J = 6.5 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.27 (d, J = 13.2 Hz, 1H), 3.48 (dt, J = 11.6, 5.7 Hz, 1H), 3.30 (d, J = 11.9 Hz, 1H), 3.16 ? 3.08 (m, 1H), 3.05 (d, J = 10.5 Hz, 1H), 2.97 (q, J = 9.6 Hz, 3H), 2.30 (td, J = 11.2, 3 .3 Hz, 2H), 1.69 (d, J = 25.0 Hz, 4H), 1.52 (d, J = 7.0 Hz, 3H). Example 15B: LRMS m / z (M+H): calculated value 464.9, found value 465.4. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.35 (d, J = 6.7 Hz, 1H), 7.16 ? 7.09 (m, 2H), 6.07 (s, 1 H), 5.10 (s, 1H), 4.61 (t, J = 8.2 Hz, 1H), 4.44 (q, J = 6.9 Hz, 1H), 4.27 (d, J = 12.8 Hz, 1H), 3.46 (td, J = 11.5, 4.1 Hz, 1H), 3.30 (d, J = 12.0 Hz, 1H), 3.1 9 ? 3.11 (m, 1H), 2.99 (tt, J = 23.4, 12.5 Hz, 4H), 2.41 ? 2.26 (m, 2H), 1.82 (d , J = 11.5 Hz, 1H), 1.64 (d, J = 21.0 Hz, 4H), 1.55 (d, J = 7.0 Hz, 3H). Table 2: The following examples use appropriate starting materials and reagents, and are based on Example 15A and Example 15A. It was prepared according to the synthesis procedure for 15B. [Table 2] Examples 18A, 18B, 18C, and 18D (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(R)-(1 ,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl)-3-ol Xopiperazine-1-carboxamide, (2R)-N-((R)-(3-chloro-4-f Luorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)pipette Lysine-4-yl(methyl)-3-oxopiperazine-1-carboxamide, (2R)- N-((S)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-to (Lifluoropropan-2-yl)piperidine-4-yl)methyl)-3-oxopiperazi n-1-carboxamide, and (2R)-N-((S)-(3-chloro-4-fluoro Phenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidine -4-yl)methyl)-3-oxopiperazine-1-carboxamide [ka] Step 1: tert-butyl 4-(3-chloro-4-fluorobenzoyl)piperidi n-1-carboxylate tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carb A solution prepared by dissolving xylate (542 mg, 1.990 mmol) in THF (8 mL) At 0°C, 3-chloro-4-fluorophenylmagnesium bromide (0.5) in THF (M, 7.96 mL, 3.98 mmol) was added. The mixture was stirred at 0°C for 30 minutes. Next, the mixture was heated to room temperature for 2 hours. Then, the reaction mixture was mixed with saturated aqueous solution NH4Cl. It was pounded and extracted with diethyl ether. The separated organic layer was dehydrated with Na2SO4. The compound was filtered and concentrated under reduced pressure to obtain the title compound.

[0287] LRMS m / z (M+H): Calculated value 341.8, Measured value 342.4. Stage 2: (3-chloro-4-fluorophenyl)(piperidine-4-yl)methanone Hydrochloride tert-butyl 4-(3-chloro-4-fluorobenzoyl)piperidine-1-ca Luboxylate (680 mg, 1.989 mmol) mixed with CH2Cl2 (3 mL) and MeO2 A solution of 1,4-dioxane dissolved in H (1 mL) is then mixed with HCl (4 M, 3 mL, 12. (00 mmol) was added. The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. Thus, the title compound was obtained.

[0288] LRMS m / z (M+H): Calculated value 241.7, Measured value 242.2. Stage 3: (3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoro Propan-2-yl piperidine-4-yl methanone (3-chloro-4-fluorophenyl)(piperidine-4-yl)methanone hydrochloride D A solution dissolved in MF (5 mL) contains 1,1,1-trifluoropropane-2-yl Lifluoromethanesulfonate (636 mg, 2.58 mmol) and Et3N (1.1 0.8 mL (7.95 mmol) was added. The mixture was heated to 50°C for 20 hours, and then... Then, it was cooled to room temperature, quenched with H2O, and extracted with ethyl acetate. The bed was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was collected in silica gel. Purified by Lamb chromatography (eluted with 0-40% ethyl acetate / hexane), and then labeled. A mixed product was obtained.

[0289] LRMS m / z (M+H): Calculated value 337.7, Measured value 338.3. Stage 4: (S)-N-((Z)-(3-chloro-4-fluorophenyl)(1-(1 ,1,1-trifluoropropan-2-yl)piperidine-4-yl)-methylene)-2 -Methylpropane-2-sulfinamide In the microwave tube, (3-chloro-4-fluorophenyl)(1-(1,1,1-trif Luoropropan-2-yl)piperidine-4-yl)methanone (188mg, 0.557 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (135 mg , 1.113 mmol) and titanium(IV) isopropoxide (1 mL, 3.38 mmol) l) was added. The mixture was heated in a microwave oven at 120°C for 30 minutes. Then, saturated Aqueous solution of NaHCO3 (10 mL) and ethyl acetate (30 mL). The mixture is heated in a room. The mixture was stirred at warm temperature for 20 minutes, and then filtered through a Celite® pad. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was silica. Purified by gel column chromatography (elution with 0-20% ethyl acetate / hexane), The title compound was obtained.

[0290] LRMS m / z (M+H): Calculated value 440.9, Measured value 441.4. Stage 5: (S)-N-((3-chloro-4-fluorophenyl)(1-(1,1,1 -Trifluoropropan-2-yl)piperidine-4-yl)methyl)-2-methylprop Pan-2-sulfinamide (isomer A and isomer B) (S)-N-((Z)-(3-chloro-4-fluorophenyl)(1-(1,1,1- Trifluoropropan-2-yl)piperidine-4-yl)methylene)-2-methylprop Pan-2-sulfinamide (174 mg, 0.395 mmol) with THF (1 mL) NaBH4 (59.7 mg, 1.578 mg) was dissolved in a solution of MeOH (500 μL). (ol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and then saturated with ethyl acetate. The mixture was partitioned between aqueous NaHCO3 solutions. The organic layer was separated and then washed with brine. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (elution with 40% ethyl acetate in hexane) to obtain the title compound. It was done.

[0291] Isomer A (first eluted fraction): LRMS m / z (M+H): Calculated value 442.9, Measured value 443.4; And, Isomer B (second eluted fraction): LRMS m / z (M+H): Calculated value 442.9, Measured value 443.4. Stage 6: (3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoro Propan-2-yl piperidine-4-yl methanamine hydrochloride (S)-N-((3-chloro-4-fluorophenyl)(1-(1,1,1-triflu) Olopropan-2-yl)piperidine-4-yl)methyl)-2-methylpropan-2- Sulfinamide (isomer A, 48 mg, 0.108 mmol) is converted to CH2Cl2 (500 A solution prepared by dissolving 1,4-dioxane in (μL) and MeOH (500 μL) is then mixed with HCl (4 (M, 1 mL, 4.00 mmol) was added. The mixture was stirred at room temperature for 2 hours, then The solution was concentrated under reduced pressure. The resulting residue was washed with hexane (2 × 10 mL) and filtered to obtain a solvent. The compound was removed and dehydrated under reduced pressure to obtain the title compound.

[0292] LRMS m / z (M+H): Calculated value 338.8, Measured value 339.3. Stage 7: Examples 18A and 18B (3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropane- 2-yl)piperidine-4-yl)methanamine HCl (41.5 mg, 0.111 mg) A solution of (mol) dissolved in CH2Cl2 (2 mL) was prepared, and at 0°C, Et3N (0.092 mL, 0.664 mmol) and triphosgene (32.8 mg, 0.111 mmol) It was added. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine- 2-one (18.94 mg, 0.166 mmol) was added. After stirring at 0°C for 1 hour, The reaction mixture was then heated to room temperature for one hour and concentrated under reduced pressure. The resulting residue was silica gel. The mixture was purified by column chromatography (elution with 0-4% MeOH / DCM). The mixture was then subjected to SFC(OJ-H column, 20%(EtOH + 0.2% DIPE). A) Separate with a co-solvent, and obtain Example 18A (the first fraction to be eluted) and Example 18B ( The second fraction that eluted was obtained.

[0293] Example 18A: LRMS m / z (M+H): Calculated value 478.9, Measured value 479.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.31 (s, 1H), 7.12 (d, J = 6.9 Hz, 2H), 6.39 (s, 1H), 5.1 2 (s, 1H), 4.66 (s, 1H), 4.51 (s, 1H), 4.24 (d, J = 13.3 Hz, 1H), 3.57 ? 3.46 (m , 1H), 3.31 (d, J = 11.4 Hz, 1H), 3.23 ? 3.07 (m, 2H), 2.94 (s, 2H), 2.56 (s, 1H) ), 2.36 (s, 1H), 1.76 (d, J = 11.6 Hz, 1H), 1.63 (s, 2H), 1.49 (d, J = 7.0 Hz, 3 H), 1.37 (s, 2H), 1.23 (s, 3H). Example 18B: LRMS m / z (M+H): Calculated value 478.9, Measured value 479.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.30 (s, 1H), 7.12 (d, J = 6.9 Hz, 2H), 6.25 (s, 1H), 5.0 1 (s, 1H), 4.66 (s, 1H), 4.47 (s, 1H), 4.24 (d, J = 12.9 Hz, 1H), 3.52 (t, J = 7 .8 Hz, 1H), 3.31 (d, J = 9.6 Hz, 1H), 3.23 ? 3.08 (m, 2H), 2.99 (s, 1H), 2.86 (s , 1H), 2.55 (s, 1H), 2.38 (s, 1H), 1.79 (d, J = 12.2 Hz, 1H), 1.63 (s, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.36 (s, 2H), 1.24 (s, 3H). Step 8: Examples 18C and 18D Examples 18C and 18D use isomer B from step 5, and Example 18A and Prepared according to the synthesis procedure for Example 18B. Example 18C (first eluted fraction) And Example 18D (the second fraction to elute) was obtained using an SFC (OD-H column, 15% (E Separation was performed using tOH + 0.2% DIPEA (co-solvent).

[0294] Example 18C: LRMS m / z (M+H): Calculated value 478.9, Measured value 479.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.40 (dd, J = 7.0, 2.0 Hz, 1H), 7.19 ? 7.13 (m, 1H), 7.09 (t, J = 8.6 Hz, 1H), 6.27 (d, J = 3.3 Hz, 1H), 5.38 (d, J = 6.5 Hz, 1H), 4.59 ( t, J = 7.9 Hz, 1H), 4.52 (d, J = 6.9 Hz, 1H), 4.29 (d, J = 12.5 Hz, 1H), 3.45 (t d, J = 11.6, 4.2 Hz, 1H), 3.33 ? 3.25 (m, 1H), 3.21 ? 3.09 (m, 2H), 2.95 (d, J = 10.0 Hz, 1H), 2.89 (d, J = 9.2 Hz, 1H), 2.58 (t, J = 10.7 Hz, 1H), 2.33 (s, 1H) , 1.83 (d, J = 12.3 Hz, 1H), 1.66 (d, J = 8.9 Hz, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.40 ? 1.30 (m, 2H), 1.22 (d, J = 6.2 Hz, 3H). Example D: LRMS m / z (M+H): calculated value 478.9, found value 479.4. 1H NMR δ (ppm) (500 MHz , クロロホルム-d): 7.39 (d, J = 6.6 Hz, 1H), 7.19 ? 7.13 (m, 1H), 7.10 (t, J = 8 .6 Hz, 1H), 6.27 (s, 1H), 5.34 (d, J = 16.6 Hz, 1H), 4.60 (d, J = 7.7 Hz, 1H), 4 .52 (s, 1H), 4.29 (d, J = 12.8 Hz, 1H), 3.46 (dt, J = 11.4, 5.8 Hz, 1H), 3.29 (d , J = 12.1 Hz, 1H), 3.22 ? 3.10 (m, 2H), 3.00 (s, 1H), 2.84 (s, 1H), 2.54 (s, 1H ), 2.39 (t, J = 10.4 Hz, 1H), 1.86 (d, J = 13.1 Hz, 1H), 1.73 ? 1.57 (m, 2H), 1. 55 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.1 Hz, 2H), 1.24 (d, J = 6.1 Hz, 3H). Examples 19A, 19B, 19C, and 19D (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans-1,1 -Difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxo Piperazine-1-carboxamide, (2R)-N-((S)-(3-chloro-4-fluor (Lofenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl) (2R)-N-(( R)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2. 5] Octane-6-yl(methyl)-2-methyl-3-oxopiperazine-1-carb Thamide, and (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis -1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide [ka] Stage 1: (3-chloro-4-fluorophenyl)(1,1-difluorospiro[2. 5) Octane-6-yl)methanone 1,1-Difluorospiro[2.5]octane-6-carboxylic acid (318 mg, 1.6 (72 mmol) was dissolved in CH2Cl2 (4 mL) and then (C) in DCM was added at 0°C. OCl)2 (2M, 1.672 mL, 3.34 mmol) and one drop of DMF were added. The mixture was heated to room temperature, stirred for 4 hours, and then heated to 40°C for 30 minutes. The mixture was then concentrated under reduced pressure. The resulting residue was then dissolved again in THF (4 mL). Solution A was then prepared. In a separate reaction flask, copper(I) cyanide (374 mg, 4... Suspend 18 mmol) in THF (4 mL), cool to 0°C, and then add ( 3-Chloro-4-fluorophenyl)magnesium bromide (0.5M, 6.69mL, 3.34 mmol) was added. The mixture was stirred at 0°C for 1 hour, and then added to solution A. The mixture was then stirred at 0°C for 2 hours, and then heated to room temperature for 2 hours. The resulting reaction mixture was acetic acid. The mixture was partitioned between ethyl acetate and saturated aqueous solution NH4Cl, and filtered using a Celite® pad. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to form a title sample. A mixed product was obtained.

[0295] LRMS m / z (M+H): Calculated value 302.7, Measured value 302.9. Stage 2: (3-chloro-4-fluorophenyl)(1,1-difluorospiro[2. 5) Octan-6-yl)methanamine hydrochloride In the microwave tube, (3-chloro-4-fluorophenyl)(1,1-difluorospiron [2.5] Octane-6-yl)methanone (506 mg, 1.672 mmol), acetate Charge with monium (1031 mg, 13.37 mmol) and ethanol (10 mL). The mixture was heated in a microwave at 125°C for 15 minutes, then cooled to room temperature, and then... Sodium borohydride (126 mg, 2.006 mmol) was added. Heat the contents in a microwave at 125°C for 15 minutes, then let it cool to room temperature, and add 30 mL of 10 The mixture was quenched with % aqueous K2CO3 and extracted with ethyl acetate (2 × 30 mL). The resulting organic layer was then extracted. The mixture was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was then treated with diethyl E. The title compound was obtained by treating it with HCl (2M, 2mL) in a tere solution and filtering off the resulting solid. Ta.

[0296] LRMS m / z (M+H): Calculated value 303.7, Measured value 304.0. Stage 3: Examples 19A, 19B, 19C, and 19D (3-chloro-4-fluorophenyl)(1,1-difluorospiro[2.5]octa) (6-yl)methanamine hydrochloride (160 mg, 0.527 mmol) is added to CH2Cl2 (3 mL) of suspension is prepared, and at 0°C, triphosgene (156 mg, 0.527 ml) is added. (0.367 mL, 2.63 mmol) and Et3N were added. The mixture was then 0 Stir at °C for 1 hour, then add (R)-3-methylpiperazine-2-one (90 mg, 0. 790 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, and then left at room temperature for 1 hour. The temperature was raised and the mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The mixture was purified by elution with 0-4% MeOH / DCM to obtain a mixture. This mixture was then converted to SFC. (Separated using an AD-H column with 20% (EtOH + 0.2% DIPEA) as a cosolvent.) Example 19A (first eluted fraction), Example 19B (second eluted fraction), Implementation Example 19C (the third eluted fraction) and Example 19D (the fourth eluted fraction) were obtained. Ta.

[0297] Example 19A: LRMS m / z (M+H): Calculated value 443.9, Measured value 444.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.31 (d, J = 6.8 Hz, 1H), 7.15 - 7.11 (m, 2H), 6.19 (d, J = 15.9 Hz, 1H), 4.92 (s, 1H), 4.64 (t, J = 8.2 Hz, 1H), 4.43 (s, 1H), 4.22 (d, J = 12.7 Hz, 1H), 3.51 (td, J = 11.5, 4.2 Hz, 1H), 3.37 ? 3.29 (m, 1H), 3.14 (dd d, J = 14.4, 11.2, 3.6 Hz, 1H), 2.02 ? 1.93 (m, 1H), 1.72 ? 1.60 (m, 4H), 1.48 ( dd, J = 7.0, 4.2 Hz, 3H), 1.29 ? 1.18 (m, 3H), 1.07 (dt, J = 20.4, 7.7 Hz, 3H). Example 19B: LRMS m / z (M+H): Calculated value 443.9, Measured value 444.3. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.31 (d, J = 6.5 Hz, 1H), 7.16 ? 7.11 (m, 2H), 6.02 (s, 1 H), 4.81 (s, 1H), 4.66 (t, J = 8.4 Hz, 1H), 4.39 (d, J = 6.5 Hz, 1H), 4.22 (d, J = 14.6 Hz, 1H), 3.56 ? 3.47 (m, 1H), 3.36 ? 3.29 (m, 1H), 3.15 (ddd, J = 14.5, 11.2, 3.7 Hz, 1H), 1.98 (d, J = 12.6 Hz, 1H), 1.73 ? 1.59 (m, 4H), 1.48 (d, J = 7.1 Hz, 3H), 1.29 ? 1.21 (m, 4H), 0.99 (td, J = 7.9, 3.8 Hz, 2H). Example 19C: LRMS m / z (M+H): Calculated value 443.9, Measured value 444.3. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.34 (d, J = 6.9 Hz, 1H), 7.18 ? 7.05 (m, 2H), 5.99 (s, 1 H), 4.96 (s, 1H), 4.68 (t, J = 8.0 Hz, 1H), 4.41 (d, J = 6.8 Hz, 1H), 4.28 (d, J = 12.9 Hz, 1H), 3.47 (td, J = 11.6, 4.3 Hz, 1H), 3.30 (d, J = 11.8 Hz, 1H), 3.1 6 (ddd, J = 14.5, 11.3, 3.7 Hz, 1H), 1.92 (d, J = 13.1 Hz, 1H), 1.77 ? 1.58 (m, 4H), 1.56 (d, J = 7.1 Hz, 3H), 1.51 (d, J = 15.2 Hz, 1H), 1.30 ? 1.08 (m, 3H), 1 .06 (t, J = 8.6 Hz, 2H). Example 19D: LRMS m / z (M+H): Calculated value 443.9, Measured value 444.3. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.38 (s, 1H), 7.19 ? 7.09 (m, 2H), 6.06 (s, 1H), 5.12 (s, 1H), 4.66 (s, 1H), 4.43 (s, 1H), 4.29 (d, J = 12.3 Hz, 1H), 3.47 (t, J = 11.0 H z, 1H), 3.30 (d, J = 11.5 Hz, 1H), 3.16 (t, J = 12.1 Hz, 1H), 1.97 (d, J = 12.6 Hz, 1H), 1.80 ? 1.58 (m, 4H), 1.55 (d, J = 6.9 Hz, 3H), 1.29 ? 1.20 (m, 4H), 0.9 9 (t, J = 8.6 Hz, 2H). Examples 20A, 20B, 20C, and 20D (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3 -(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide (20A), (R)-N-((R)-(3-Chloro-2,4-Diph Luorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2 -Methyl-3-oxopiperazine-1-carboxamide(20B), (R)-N-((S )-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl) Cyclobutyl(methyl)-2-methyl-3-oxopiperazine-1-carboxamide(2 0C), and (R)-N-((R)-(3-chloro-2,4-difluorophenyl)( cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide (20D)

change

[0298] LRMS m / z (M+H): Calculated value 298.6, Measured value 299.1. Stage 2: (R,E)-N-((3-chloro-2,4-difluorophenyl)(3-( Trifluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfine Amido In the microwave tube, (3-chloro-2,4-difluorophenyl)(3-(trifluoro Methyl(cyclobutyl)methanone (1.7g, 5.69mmol), (R)-(+)-2 -Methyl-2-propanesulfinamide (1.035g, 8.54mmol) and tetra Laetoxytitanium (10.46 mL, 11.39 mmol) was charged. The reaction mixture was then added. Heat in a microwave at 105°C for 1 hour, then cool to room temperature, and add H2O (30 mL). It was then poured into 50 mL of ethyl acetate (50 mL). The mixture was stirred for 10 minutes. Next, the separated organic layer was filtered using a Celite® pad. The compound was dehydrated with O4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0299] LRMS m / z (M+H): Calculated value 401.8, Measured value 402.3. Stage 3: (R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2 -Sulfinamide (isomer A), (R)-N-((S)-(3-chloro-2,4-diph (Cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl) Tylpropane-2-sulfinamide (isomer B-1), (R)-N-((R)-(3- Chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl (Lu)methyl)-2-methylpropane-2-sulfinamide (isomer B-2), and, ( R)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-( Trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfine Amide (isomer C) (R,E)-N-((3-chloro-2,4-difluorophenyl)(3-(trifluoro Methyl(cyclobutyl)methylene)-2-methylpropane-2-sulfinamide(2 (0.2g, 5.48 mmol) dissolved in THF (10mL) and MeOH (2mL) NaBH4 (0.207 g, 5.48 mmol) was added to the solution at 0°C. The mixture Stir at 0°C for 1 hour, then raise the temperature to room temperature for 1 hour, and mix with ethyl acetate and saturated aqueous NaH The CO3 was distributed between the layers. The separated organic layer was dehydrated with Na2SO4, filtered, and then removed under reduced pressure. The residue was concentrated below. The obtained residue was subjected to silica gel column chromatography (0-40% acetate). The mixture was purified by elution with chill / hexane to obtain a mixture. This mixture was then sFC(AD-H The fractions were separated using a column (with 10% MeOH as a cosolvent), and isomer A (the first fraction to elute) was obtained. Isomer B (the second fraction to elute) and isomer C (the third fraction to elute) were obtained. Isomer B was converted to SFC (IF-H column, 30% EtOH + 0.25% DIPEA cosolvent). Further separation was performed to obtain isomer B-1 (the first fraction to elute) and isomer B-2 (the second fraction to elute). The fraction obtained was the fraction eluted into the solution.

[0300] Stage 4: (S)-(3-chloro-2,4-difluorophenyl)(trans-3-( Trifluoromethyl(cyclobutyl)methanamine hydrochloride (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3 -(trifluoromethyl)-cyclobutyl)-methyl)-2-methylpropane-2-s Rufinamide (isomer A, 125 mg, 0.310 mmol) is dissolved in CH2Cl2 (1 mL). The solution dissolved in ) was cooled to 0°C, and then HCl (4M, 1 mL (4 mmol) was added. The mixture was stirred at 0°C for 2 hours, and then under reduced pressure. The solution was concentrated. The resulting residue was washed with diethyl ether (2 × 5 mL), filtered, and labeled. A mixed product was obtained.

[0301] LRMS m / z (M+H): Calculated value 299.7, Measured value 300.2. Stage 5: Example 20A (S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoro (L-methyl)cyclobutyl)methanamine hydrochloride (59 mg, 0.197 mmol) To the suspension in H2Cl2 (4 mL), add triphosgene (58.4 mg, 0) at 0°C. 0.197 mmol) and Et3N (0.082 mL, 0.591 mmol) were added. The mixture is stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one ( 29.2 mg (0.256 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour. Next, the mixture was heated to room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was then collected in a silica gel container. Purified by microchromatography (elution with 0-4% MeOH / DCM), Example 20A Obtained.

[0302] LRMS m / z (M+H): Calculated value 439.8, Measured value 440.3. 1H NMR δ (ppm) (500 MHz, chloroform m-d): 7.22 (q, J = 8.0 Hz, 1H), 6.97 (t, J = 8.2 Hz, 1H), 6.57 (d, J = 28.5 Hz, 1H), 5.37 ? 5.21 (m, 1H), 5.01 (dd, J = 10.7, 8.4 Hz, 1H), 4.56 ? 4.43 (m, 1H), 4.18 (d, J = 13.2 Hz, 1H), 3.54 ? 3.43 (m, 1H), 3.32 (d, J = 11.1 Hz, 1H), 3.20 ? 3.08 (m, 1H), 3.00 ? 2.82 (m, 2H), 2.36 (d, J = 5.9 Hz, 1H), 2.28 ? 2.17 (m, 1H), 2.09 (q, J = 9.9, 6.9 Hz, 1H), 1.97 ? 1.88 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H ). Step 6: Examples 20B, 20C, and 20D Examples 20B, 20C, and 20D show different isomers obtained in step 3. The body was used as the starting material and prepared according to the synthesis procedure for Example 20A.

[0303] Example 20B (obtained from isomer C): LRMS m / z (M+H): Calculated value 439.8, Measured value 440 3. ¹H NMR δ (ppm) (500 MHz, chloroform-d): 7.22 (q, J = 7.5 Hz, ¹H), 6.97 (t , J = 8.3 Hz, 1H), 6.38 (d, J = 28.8 Hz, 1H), 5.24 (s, 1H), 5.03 (dd, J = 10.9, 8.2 Hz, 1H), 4.44 (d, J = 6.6 Hz, 1H), 4.22 (d, J = 13.4 Hz, 1H), 3.45 (td, J = 11.5, 3.7 Hz, 1H), 3.30 (d, J = 11.7 Hz, 1H), 3.21 ? 3.11 (m, 1H), 3.00 ? 2.84 ( m, 2H), 2.37 (dt, J = 12.8, 6.5 Hz, 1H), 2.28 ? 2.18 (m, 1H), 2.11 (q, J = 10.1, 7.1 Hz, 1H), 1.99 ? 1.88 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H). Example 20C (obtained from isomer B-1): LRMS m / z (M+H): Calculated value 439.8, Measured value 440.3. ¹H NMR δ (ppm) (500 MHz, chloroform-d): 7.21 (td, J = 8.2, 6.0 Hz, ¹H ), 7.02 ? 6.92 (m, 1H), 6.34 (s, 1H), 4.98 (d, J = 8.0 Hz, 1H), 4.94 ? 4.87 (m, 1H), 4.39 (q, J = 7.1 Hz, 1H), 4.17 (d, J = 13.6 Hz, 1H), 3.51 (td, J = 11.5, 4. 2 Hz, 1H), 3.32 (dq, J = 11.7, 3.6 Hz, 1H), 3.15 (ddd, J = 14.2, 11.1, 3.6 Hz, 1 H), 2.83 (dt, J = 17.6, 8.8 Hz, 1H), 2.72 (p, J = 8.9 Hz, 1H), 2.35 (dtd, J = 11 .9, 8.3, 3.7 Hz, 1H), 2.16 ? 2.06 (m, 1H), 2.06 ? 1.98 (m, 1H), 1.93 ? 1.85 (m, 1H), 1.48 (d, J = 7.1 Hz, 3H). Example 20D (obtained from isomer B-2): LRMS m / z (M+H): Calculated value 439.8, Measured value 440.3. ¹H NMR δ (ppm) (500 MHz, chloroform-d): 7.25 - 7.19 (m, ¹H), 7.00 - 6 .93 (m, 1H), 6.35 (s, 1H), 5.19 (s, 1H), 4.97 (t, J = 8.8 Hz, 1H), 4.42 (q, J = 6.9 Hz, 1H), 4.24 (d, J = 12.8 Hz, 1H), 3.46 (td, J = 11.6, 4.2 Hz, 1H), 3.34 ? 3.27 (m, 1H), 3.16 (ddd, J = 14.3, 11.2, 3.6 Hz, 1H), 2.83 (dt, J = 17.6, 8.8 Hz , 1H), 2.74 (p, J = 9.0 Hz, 1H), 2.31 (dtd, J = 11.9, 8.2, 3.8 Hz, 1H), 2.16 ? 2 .09 (m, 1H), 2.04 (ddd, J = 12.0, 8.1, 3.8 Hz, 1H), 1.97 ? 1.88 (m, 1H), 1.52 (d (J = 7.1 Hz, 3H). Table 3: The following examples use appropriate starting materials and reagents, and include Examples 20A and 2 The preparation was carried out according to the synthesis procedures for Example 0B, Example 20C, and Example 20D. [Table 3] TIFF2026048891000029.tif239170TIFF2026048891000030.tif37170 Example 26 N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(tri Fluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboxamide [ka] (S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoro (Methyl)cyclobutyl)methanamine hydrochloride (70 mg, 0.208 mmol) In a solution prepared by dissolving in 2Cl2 (3 mL), Et3N (0.116 mL, 0.83) was added at 0°C. 3 mmol) and triphosgene (61.8 mg, 0.208 mmol) were added. Stir the mixture at 0°C for 1 hour, then add piperazine-2-one (27.1 mg, 0.271 mmol). l) was added. The reaction mixture was then stirred at 0°C for 1 hour and then heated to room temperature for 1 hour. The residue was then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (0-4%). The sample was purified by elution with MeOH / DCM to obtain Example 26.

[0304] LRMS m / z (M+H): Calculated value 425.8, Measured value 426.4. 1H NMR δ (ppm) (500 MHz, chlorophosphene) Lum-d): 7.22 (q, J = 8.1 Hz, 1H), 6.98 (t, J = 8.3 Hz, 1H), 6.51 (d, J = 23.9 H z, 1H), 5.03 (dd, J = 10.8, 7.9 Hz, 1H), 4.08 (s, 2H), 3.68 (t, J = 5.1 Hz, 2H), 3.43 (s, 2H), 3.04 ? 2.84 (m, 2H), 2.37 (q, J = 9.7, 6.5 Hz, 1H), 2.28 ? 2.18 ( m, 1H), 2.09 (d, J = 13.5 Hz, 1H), 2.00 ? 1.83 (m, 2H). Examples 27A and 27B (R or S)-N-((S)-(3-chloro-2,4-difluorophenyl)(t Lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3 -Oxopiperazine-1-carboxamide, and (S or R)-N-((S)-( 3-Chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl) Clobutyl(methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxami Do [ka] (S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoro (Methyl)cyclobutyl)methanamine hydrochloride (95.8 mg, 0.285 mmol) In a solution prepared by dissolving CH2Cl2 (4 mL), add Et3N (0.199 mL, 1.2 mL) at 0°C. (425 mmol) and triphosgene (85 mg, 0.285 mmol) were added. Stir the mixture at 0°C for 1 hour, then add 3-cyclopropylpiperazine-2-one (51.9 mg). (0.371 mmol) was added. After stirring at 0°C for 1 hour, the reaction mixture was left at room temperature for 1 hour. The temperature was raised to [temperature] and the mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. Purification by (elution with 0-4% MeOH / DCM) yielded a mixture of isomers. The mixture of the body was further separated using SFC (OD-H column, 30% MeOH cosolvent). Examples 27A (the first fraction to be eluted) and 27B (the second fraction to be eluted) were obtained. It was done.

[0305] Example 27A: LRMS m / z (M+H): Calculated value 465.8, Measured value 466.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.21 (td, J = 8.2, 6.0 Hz, 1H), 6.98 (t, J = 8.3 Hz, 1H), 6.52 (s, 1H), 5.11 (d, J = 8.3 Hz, 1H), 5.03 ? 4.96 (m, 1H), 4.15 (d, J = 6.8 H z, 1H), 4.03 (d, J = 13.2 Hz, 1H), 3.51 ? 3.43 (m, 1H), 3.42 ? 3.30 (m, 2H), 2.9 4 (dq, J = 9.9, 5.1 Hz, 1H), 2.86 (dt, J = 16.5, 8.5 Hz, 1H), 2.37 (d, J = 6.3 H z, 1H), 2.28 ? 2.17 (m, 1H), 2.11 (s, 1H), 1.94 ? 1.84 (m, 1H), 1.27 ? 1.21 (m, 1H), 0.66 (dt, J = 9.5, 4.7 Hz, 1H), 0.57 (ddt, J = 12.9, 8.5, 4.9 Hz, 2H), 0.47 (q, J = 7.4, 5.3 Hz, 1H). Example 27B: LRMS m / z (M+H): Calculated value 465.8, Measured value 466.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.20 (td, J = 8.2, 6.0 Hz, 1H), 7.01 ? 6.92 (m, 1H), 6.66 (s, 1H), 5.22 (d, J = 8.0 Hz, 1H), 5.04 (dd, J = 11.0, 8.0 Hz, 1H), 4.18 ? 4.08 (m, 2H), 3.47 ? 3.39 (m, 1H), 3.38 ? 3.31 (m, 2H), 2.95 (ddt, J = 14.7, 9.8, 5. 0 Hz, 1H), 2.86 (dt, J = 16.7, 8.7 Hz, 1H), 2.36 (dt, J = 12.8, 6.5 Hz, 1H), 2.2 9 ? 2.20 (m, 1H), 2.11 (dq, J = 13.4, 7.0, 6.2 Hz, 1H), 1.99 ? 1.88 (m, 1H), 1.3 2 ? 1.27 (m, 1H), 0.74 ? 0.67 (m, 1H), 0.61 (ddt, J = 21.8, 8.3, 4.3 Hz, 2H), 0. 51 (dq, J = 10.1, 5.1 Hz, 1H). Examples 28A and 28B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(spiro[2 .3]Hexane-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carb Xamide and (2R)-N-((S)(3-chloro-2,4-difluorophenyl) (Spiro[2,3]hexane-5-yl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide [ka] Example 28A: (2R)-N-((R or S)-(3-chloro-2,4-diflu Olophenyl)(spiro[2,3]hexane-5-yl)methyl)-2-methyl-3-ol Xopiperazine-1-carboxamide Diethylzinc in hexane (1M, 2.215 mL, 2.215 mmol) is converted to CH2C A solution of TFA (0) in 5 mL of CH2Cl2 (0) was added to a solution at 0°C. (0.171 mL, 2.215 mmol) was added dropwise. The mixture was stirred for 1 hour, and then Next, diiodomethane (0.179 mL, 2.215 mmol) was added. Then, 4 After 0 minutes have elapsed, (2R)-N-((R or S)( 3-Chloro-2,4-difluorophenyl)(3-methylene-cyclobutyl)methyl)- 2-Methyl-3-oxopiperazine-1-carboxamide (Example 25A, 170 mg, 0.443 mmol) was added. The reaction mixture was stirred for 2 hours, and then saturated aqueous solution NH4 Quenched with Cl. The separated organic layer was dehydrated (MgSO4), filtered, and then... The residue was concentrated. The obtained residue was subjected to silica gel column chromatography (0-3% MeOH / C). The sample was purified by elution with H2Cl2 to obtain Example 28A.

[0306] LRMS m / z (M+H): Calculated value 397.9, Measured value 398.3. 1H NMR δ (ppm) (500 MHz, chlorophosphene) Lum-d): 7.21 (q, J = 8.1 Hz, 1H), 6.95 (t, J = 8.4 Hz, 1H), 6.35 (s, 1H), 5.00 (dq, J = 15.4, 7.6 Hz, 2H), 4.38 (q, J = 7.1 Hz, 1H), 4.18 (d, J = 15.3 Hz, 1H), 3.56 ? 3.45 (m, 1H), 3.35 ? 3.27 (m, 1H), 3.14 (ddd, J = 14.2, 11.2, 3.6 Hz, 1H ), 2.86 (h, J = 7.1 Hz, 1H), 2.28 ? 2.15 (m, 1H), 2.08 (d, J = 8.3 Hz, 1H), 2.01 ? 1.94 (m, 1H), 1.83 (dd, J = 11.5, 6.6 Hz, 1H), 1.48 (t, J = 7.0 Hz, 3H), 0.53 ? 0.35 (m, 4H). Example 28B: (2R)-N-((S or R)-(3-chloro-2,4-diflu Olophenyl)(spiro[2,3]hexane-5-yl)methyl)-2-methyl-3-ol Xopiperazine-1-carboxamide Example 28B uses Example 25B as the starting material and follows the synthesis method described in Example 28A. The preparations were carried out in the order listed.

[0307] LRMS m / z (M+H): Calculated value 397.9, Measured value 398.3. 1H NMR δ (ppm) (500 MHz, chlorophosphene) Lum-d): 7.25 ? 7.19 (m, 1H), 6.95 (q, J = 8.3, 7.6 Hz, 1H), 6.46 (s, 1H), 5.07 (d, J = 6.5 Hz, 2H), 4.39 (q, J = 6.9 Hz, 1H), 4.23 (d, J = 13.4 Hz, 1H), 3.45 ( td, J = 11.5, 4.2 Hz, 1H), 3.31 ? 3.26 (m, 1H), 3.19 ? 3.12 (m, 1H), 2.87 (d, J = 8.1 Hz, 1H), 2.24 ? 2.17 (m, 1H), 2.13 ? 2.07 (m, 1H), 2.02 ? 1.94 (m, 1H), 1. 87 (dd, J = 11.5, 6.7 Hz, 1H), 1.51 (d, J = 7.1 Hz, 3H), 0.44 (t, J = 9.5 Hz, 4H ). Examples 29A and 29B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans- 3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide, and (2R)-N-((S)-(3-Chloro-2,4-Diflu Olophenyl)(trans-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl Chil-3-oxopiperazine-1-carboxamide [ka] Stage 1: (3-chloro-2,4-difluorophenyl)(trans-3-(difluoro Methyl(cyclobutyl)methanone 3-(difluoromethyl)cyclobutane-1-carboxylic acid (1.00g, 6.66mm) A solution of (C) in CH2Cl2 (15 mL) was prepared by dissolving (C) in CH2Cl2 at 0°C. OCl)2 (2M, 3.66 mL, 7.33 mmol) and one drop of DMF were added. The mixture was heated to room temperature for 4 hours, and then concentrated under reduced pressure. The resulting residue was THF Solution A was prepared by dissolving it in (6 mL). In another flask, 2-chloro-1,3 -Difluoro-4-iodobenzene (2.74g, 9.99mmol) in THF (20m The solution dissolved in L) was cooled to -20°C, and then the isopropyl magnesium in THF was added. A lithium chloride-lithium chloride complex (1.3 M, 7.69 mL, 9.99 mmol) was added. The resulting mixture was stirred at -20°C for 2 hours, then heated to 0°C, and subsequently, Copper(I) cyanide (1.193 g, 13.32 mmol) was added. The mixture was then heated to 0°C. The mixture was stirred for 30 minutes, and then solution A was added. The reaction mixture was kept at 0°C for 2 hours, and then... Then, raise the temperature to room temperature for 1 hour, quench with saturated aqueous solution NH4Cl (40 mL), and ethyl acetate Extraction was performed using a 2x30 mL solution. The resulting organic layer was combined, dehydrated with Na2SO4, filtered, and reduced. The residue was concentrated under pressure. The obtained residue was subjected to silica gel column chromatography (0-20% acetic acid). The mixture was purified by elution with ethyl / hexane to obtain a trans / cis mixture. Separation was performed using SFC (AD-H column, 10% MeOH cosolvent) to obtain the title compound (tra). The lance isomer (the second fraction eluted from SFC) was obtained.

[0308] LRMS m / z (M+H): Calculated value 280.6, Measured value 281.3. Stage 2: (R)-N-((E)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethyl)cyclobutyl)methylene)-2-methylpropane-2 -Sulfinamide In the microwave tube, (3-chloro-2,4-difluorophenyl)(trans-3-(di Fluoromethyl(cyclobutyl)methanone (180 mg, 0.641 mmol), (R) -2-methyl-2 propanesulfinamide (117 mg, 0.962 mmol), te Traethoxytitanium (0.403 mL, 1.924 mmol) and Toluene (1.5 mL) The mixture was then heated in a microwave oven at 105°C for 1 hour, and then cooled to room temperature. Next, H2O (20 mL) and ethyl acetate (20 mL) were added. The mixture The mixture was stirred for 10 minutes and then filtered through a Celite® pad. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0309] LRMS m / z (M+H): Calculated value 383.8, Measured value 384.3. Stage 3: (R)-N-((3-chloro-2,4-difluorophenyl)(trans- 3-(difluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfite Namido (R)-N-((E)-(3-chloro-2,4-difluorophenyl)(trans-3 -(difluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfite Dissolve naamide (246 mg, 0.641 mmol) in THF (4 mL) and water (200 μL). To the dissolved solution, add NaBH4 (72.7 mg, 1.923 mmol) at -78°C. The mixture was added. The mixture was stirred at -78°C for 3 hours, and then slowly heated to room temperature. The separated organic layer was partitioned between ethyl acetate and saturated aqueous solution NaHCO3. The compound was dehydrated with O4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0310] LRMS m / z (M+H): Calculated value 385.8, Measured value 386.4. Stage 4: (3-chloro-2,4-difluorophenyl)(trans-3-(difluoro Methyl(cyclobutyl)methanamine hydrochloride (R)-N-((3-chloro-2,4-difluorophenyl)(trans-3-(diph Luoro-methyl)cyclobutyl)methyl)2-methylpropane-2-sulfinamide (167 mg, 0.433 mmol) was dissolved in CH2Cl2 (1 mL) to make a solution, and then 0 At °C, HCl (4M, 1 mL, 4.00 mmol) was added to 1,4-dioxane. The mixture was stirred at 0°C for 2 hours, and then concentrated under reduced pressure. The resulting residue was diethyl ester. The sample was washed with ether (2 × 8 mL) and filtered to obtain the title compound.

[0311] LRMS m / z (M+H): Calculated value 281.7, Measured value 282.3. Stage 5: Examples 29A and 29B (3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl) Cyclobutyl(methanamine) hydrochloride (130 mg, 0.462 mmol) in DCM (5 m To the solution dissolved in (L), add Et3N (0.257 mL, 1.846 mmol) at 0°C. Triphosgene (137 mg, 0.462 mmol) was added. The mixture was incubated at 0°C for 1 Stir for a while, then add (R)-3-methylpiperazine-2-one (52.7 mg, 0.4 62 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, and then heated in a room for 1 hour. The mixture was heated to a warm temperature, and the reaction mixture was concentrated under reduced pressure. The resulting residue was then collected in a silica gel column. The mixture of isomers was purified by chromatography (elution with 0-4% MeOH / DCM). The mixture was obtained. Further analysis of the mixture using SFC (AD-H column, 20% EtOH cosolvent) After separation, Example 29A (the first fraction to elute) and Example 29B (the second fraction to elute) Draw points)がgetられた.

[0312] Example 29A: LRMS m / z (M+H): Calculated value 421.8, Measured value 422.5. 1H NMR δ (ppm) (500 MHz, DMSO-d6): 7.20 (d, J = 5.6 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 5.86 (td, J = 57.1, 3.7 Hz, 1H), 4.96 (s, 1H), 4.37 (s, 1H), 4.20 ? 4.15 (m, 1H), 3.51 (td, J = 11.3, 4.0 Hz, 1H), 3.36 ? 3.29 (m, 1H), 3.16 (t, J = 12.2 Hz, 1H), 2.75 (d, J = 40.6 Hz, 2H), 2.28 (d, J = 6.0 Hz, 1H), 2.19 ? 2.09 (m, 1H), 2.01 (s, 1H), 1 .90 ? 1.78 (m, 1H), 1.48 (d, J = 7.0 Hz, 3H). Example 29B: LRMS m / z (M+H): Calculated value 421.8, Measured value 422.5. 1H NMR δ (ppm) (500 MHz, DMSO-d6): 7.21 (q, J = 7.0 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.24 (s, 1H) , 5.86 (td, J = 57.1, 3.7 Hz, 1H), 5.05 ? 4.99 (m, 1H), 4.39 (s, 1H), 4.22 (d, J = 13.4 Hz, 1H), 3.54 ? 3.41 (m, 1H), 3.30 (d, J = 9.8 Hz, 1H), 3.17 (t, J = 10. 9 Hz, 1H), 2.87 ? 2.63 (m, 2H), 2.28 (dt, J = 12.2, 6.0 Hz, 1H), 2.12 (dd, J = 1 7.8, 10.9 Hz, 1H), 2.01 (s, 1H), 1.90 ? 1.81 (m, 1H), 1.73 (s, 1H), 1.51 (d, J = 7.0 Hz, 3H). Examples 30A and 30B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-(tri Fluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl- 3-Oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-C (Lolo-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1. 1]Pentan-1-yl(methyl)-2-methyl-3-oxopiperazine-1-carb Thamid [ka] Step 1: N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1 .1]Pentan-1-carboxamide 3-(trifluoromethyl)bicyclo[1.1.1]penta in DCM (12 mL) A mixture of n-1-carboxylic acid (300 mg, 1.666 mmol) is subjected to N2 under CDI ( 540 mg (3.33 mmol) was added at 25°C. The mixture was then stored under N2 at 25°C. Stir for 1 hour, then add N,O-dimethylhydroxylamine hydrochloride (244 mg, 2. Add 498 mmol) and triethylamine (0.696 mL, 5.00 mmol). The reaction mixture was stirred under N2 at 25°C for 12 hours, and then concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography (ISCO® registered trademark); 12 g SepaFlash(registered trademark) Silica Flash Column; The title compound was obtained by purification with an eluent (10-50% ethyl acetate / petroleum ether).

[0313] 1 H NMR (CDCl3, 400MHz) δ 3.67 (s, 3H), 3.18 (s, 3H), 2.48-2.07 (m, 6H). Stage 2: (3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl )Bicyclo[1.1.1]pentan-1-yl)methanone 1-bromo-3-chloro-2,4-difluorobenzene (85) in THF (2 mL) A mixture of 6 mg and 3.76 mmol of isopropyl magnesium chloride under N2 conditions. Add 2.90 mL of 3.76 mmol of 1.3 M toluene solution over 2 hours at 0°C. Next, N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1. 1.1] Pentane-1-carboxamide (280 mg, 1.255 mmol) is added at 0°C. The reaction mixture was then stirred under N2 at 20°C for 16 hours. It was dissolved in (20 mL) and HCl (20 mL). The organic layer was separated, and the aqueous layer was Back-extraction was performed with SiO (3 × 20 mL). The organic layers were combined and dissolved in brine (20 mL). The sample was washed, dehydrated with anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified using Prep-TLC (silica gel, petroleum ether / ethyl acetate = 9 / 1). The title compound was obtained.

[0314] 1 H NMR (500 MHz, CDCl3) δ 7.62-7.67 (m, 1H), 7.07-7.11 (m, 1H), 2.41 (s, 6H). Stage 3: (3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl )Bicyclo[1.1.1]pentan-1-yl)methanamine (3-chloro-2,4-difluorophenyl)(3-(tri) in EtOH (2 mL) Fluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanone (120 mg, A mixture of 0.386 mmol) and ammonium acetate (447 mg, 5.79 mmol) Sodium borohydride (36.4 mg, 0.579 mmol) was added at 25°C. The reaction mixture was then stirred under microwaves at 130°C for 10 minutes. The substance is concentrated to remove most of the EtOH, and then treated with 2N NaOH until the pH is > 10. The organic layers were extracted with ethyl acetate (2 × 20 mL). The resulting organic layers were combined and dehydrated with anhydrous sodium 2SO4. The mixture was then filtered and concentrated under reduced pressure to obtain the title compound.

[0315] LRMS m / z (M-16): Calculated value 311.1, Measured value 294.9. Stage 4: Examples 30A and 30B CDI (62.4 mg, 0.385 mmol) and (3-chloro) in DCM (2 mL) -2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1] A mixture of pentan-1-yl)methaneamine (100 mg crude) was stirred at 20°C for 1 hour. Next, (R)-3-methylpiperazine-2-one (47.6 mg, 0.417 mg) (mol) was added. The resulting mixture was stirred at 20°C for 16 hours. Then the mixture Reverse-phase HPLC (75:25 → 45:55; water (0.1% TFA): MeCN (0. The mixture of isomers was purified with 1% TFA to obtain a mixture of isomers. Further separation was performed using an AD-H column (5%-40% EtOH + 0.05% DEA cosolvent). Next, Example 30A (the first fraction to elute) and Example 30B (the second fraction to elute) This was obtained.

[0316] Example 30A: LRMS m / z (M+H): Calculated value 451.1, Measured value 452.0. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.27-7.42 (m, 1H), 7.11-7.15 (m, 1H), 6.66-6.68 (m, 1H), 5.34-5 .36 (m, 1H), 4.65 (d, J=7.0 Hz, 1H), 3.94-4.14 (m, 1H), 3.20-3.42 (m, 3H), 1.89 (s, 6H), 1.41 (d, J=7.0 Hz, 3H). Example 30B: LRMS m / z (M+H): Calculated value 451.1, Measured value 452.0. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.24-7.41 (m, 1H), 7.14 (t, J=8.4 Hz, 1H), 5.35 (s, 1H), 4.42-4 .69 (m, 1H), 3.90-4.13 (m, 1H), 3.34-3.43 (m, 1H), 3.24-3.30 (m, 2H), 1.90 (s, 6 H), 1.41 (d, J=7.0 Hz, 3H). Table 4: The following examples use appropriate starting materials and reagents, and are based on Example 30A and Example 30A. It was prepared according to the synthesis procedure for 30B. [Table 4] TIFF2026048891000037.tif105170 Examples 36A, 36B, 36C, and 36D (2R)-N-((R)-(4-fluoro-3-methylphenyl)(trans-4-( Trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide, (2R)-N-((S)-(4-Fluoro-3-methylphenyl) (trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3- Oxopiperazine-1-carboxamide, (2R)-N-((R)-(4-fluoro-3 -methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)methyl)-2 -Methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S) -(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclophenyl) Xyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka] Step 1: N-methoxy-N-methyl-4-(trifluoromethyl)cyclohexane- 1-Carboxamide 4-(trifluoromethyl)cyclohexane-1-carbone in DMF (40 mL) Acid 1 (4g, 20.39 mmol) and HATU (11.63g, 30.6 mmol) The mixture contains N,O-dimethylhydroxylamine hydrochloride (2.98 g, 30.6 mmol). The mixture was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours. Then, water (300 mL) was added. Add ) and extract the mixture with ethyl acetate (3 × 20 mL). Combine the organic layers and bleed. Washed with a line (100 mL), dehydrated with Na2SO4, and filtered. The filtrate was then subjected to reduced pressure. Evaporate the product and then use flash silica gel chromatography (ISCO( Registered Trademark); 12 g SepaFlash (Registered Trademark) Silica Flash Column; Purified with eluent (13% petroleum ether / ethyl acetate), the title compound was obtained. Obtained.

[0317] LRMS m / z (M+H): Calculated value 339.1, Measured value 240.1. Stage 2: (4-fluoro-3-methylphenyl)(4-(trifluoromethyl)cycline Rohexyl Methanon N-methoxy-N-methyl-4-(trifluoromethyl) methyl phosphate in THF (3 mL) A mixture of (4-) hexane-1-carboxamide (500 mg, 2.090 mmol) Fluoro-3-methylphenyl)magnesium bromide (13.79 mL, 6.90 mm) (1 ol) was added at 0°C. The resulting mixture was stirred at 20°C for 18 hours. Then, water (1 (5 mL) was added, and the mixture was extracted with ethyl acetate (2 × 8 mL). The organic layer was then mixed. Wash with brine (15 mL), dehydrate with Na2SO4, filter, and the filtrate under reduced pressure. The product was evaporated. The resulting crude product was subjected to flash silica gel chromatography (ISC). O(Registered Trademark); 12 g SepaFlash(Registered Trademark) Silica Flask h Column; Purified with eluent (4% petroleum ether / ethyl acetate) to obtain the title compound This was obtained.

[0318] LRMS m / z (M+H): Calculated value 288.1, Measured value 289.1. Stage 3: (4-fluoro-3-methylphenyl)(4-(trifluoromethyl)cycline Rohexyl Methanamine NH4OAc (802 mg, 10.41 mmol) and NaBH3CN (65.4 mg) (1.041 mmol) in a microwave chamber, (4-fluoro-3-methylphenyl (4-(trifluoromethyl)cyclohexyl)methanone (200 mg, 0.694 mg) The solution was prepared by dissolving (mol) in EtOH (4 mL) and adding it to the reaction mixture. The reaction mixture was stirred and heated in a low-wave reactor at 130°C for 15 minutes. Shrink to remove most of the EtOH, treat with 2N NaOH until pH > 10, and then acetic acid Extraction was performed with ethyl acetate (2 × 20 mL). The resulting organic layers were combined, dehydrated with Na₂SO₄, and filtered. The compound was then concentrated under reduced pressure to obtain the title compound.

[0319] LRMS m / z (M+H): Calculated value 289.1, Measured value 290.1. Stage 4: Examples 36A, 36B, 36C, and 36D (4-fluoro-3-methylphenyl)(4-(trifluoro) in DMF (1 mL) Methyl(cyclohexyl)methanamine (150 mg crude) and CDI (168 mg, 1 A mixture of 0.037 mmol) and DIEA (0.272 mL, 1.555 mmol) is used. Stir at °C for 1 hour, then add (R)-3-methylpiperazine in DMF (0.5 mL). -2-one (71.0 mg, 0.622 mmol) was added. The resulting mixture was stored at 20°C. Stir for 1 hour, then reverse-phase HPLC (53:47 → 33:67; water (0.1%) The TFA is purified with MeCN (0.1% TFA), followed by freeze-drying to obtain the isomers. A mixture was obtained. The mixture of the isomers was then subjected to SFC (OD-H column, 40% EtOH). Further separation was performed using a co-solvent, resulting in Example 36A (the first fraction eluted) and Example 36B (2 Example 36C (third fraction) and Example 36D (fourth fraction) The resulting fraction was obtained.

[0320] Example 36A: LRMS m / z (M+H): Calculated value 429.2, Measured value 430.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.89 (br s, 1H), 7.16-7.18 (m, 1H), 7.09-7.15 (m, 1H), 6. 99-7.06 (m, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.46 (q, J=7.2 Hz, 1H), 4.31 (t, J=9.6 Hz, 1H), 3.88-3.95 (m, 1H), 2.93-3.15 (m, 3H), 2.19 (m, 4H), 2.00-2.05 (m, 1H), 1.89-1.93 (m, 1H), 1.70-1.76 (m, 1H), 1.59-1.63 (m, 1H), 0.82-1.26 (m, 8H). Example 36B: LRMS m / z (M+H): Calculated value 429.2, Measured value 430.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.19-7.24 (m, 1H), 7.18 (t, J=6.5 Hz, 1H), 6.99 (t, J=9.0 Hz, 1H), 4.83-4.89 (m, 2H), 4.56 (q, J=7.0 Hz, 1H), 4.01-4.61 (m, 1H), 3.17-3.3 2 (m, 3H), 2.28 (s, 3H), 2.19-2.23 (m, 1H), 2.10 (td, J=4.5, 11.5 Hz, 1H), 1.88- 1.97 (m, 1H), 1.72-1.81 (m, 2H), 1.64-1.72 (m, 1H), 1.55-1.64 (m, 2H), 1.42 (d, J=7.0 Hz, 3H), 1.30-1.40 (m, 1H), 1.26 (dd, J=4.5, 13.5 Hz, 1H). Example 36C: LRMS m / z (M+H): Calculated value 429.2, Measured value 430.3. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.19-7.24 (m, 1H), 7.16-7.19 (m, 1H), 7.00 (t, J=9.0 Hz, 1H), 4.84-4.89 (m, 2H), 4.54 (q, J=7.0 Hz, 1H), 3.99-4.08 (m, 1H), 3.28-3.31 (m, 1H), 3.16-3.27 (m, 2H), 2.28 (s, 3H), 2.19-2.22 (m, 1H), 2.11 (m, 1H), 1.88-1.9 6 (m, 1H), 1.71-1.81 (m, 2H), 1.63-1.70 (m, 1H), 1.55-1.63 (m, 2H), 1.35 (d, J=7 0 Hz, 4H). Example 36D: LRMS m / z (M+H): calculated value 429.2, found value 430.3. 1H NMR δ (ppm) (500 MHz, クロロホルム-d): 7.05 (d, J=7.5 Hz, 1H), 6.99-7.02 (m, 1H), 6.86 (t, J=9.0 Hz, 1H), 4.43 (q, J=7.0 Hz, 1H), 4.29 (d, J=10.0 Hz, 1H), 3.88-3.96 (m, 1H), 3. 16-3.21 (m, 1H), 3.05-3.16 (m, 2H), 2.15 (s, 3H), 2.04-2.08 (m, 1H), 1.93-2.03 ( m, 1H), 1.86-1.93 (m, 1H), 1.72-1.78 (m, 1H), 1.56-1.66 (m, 1H), 1.25 (d, J=7.0 Hz, 5H), 0.93-1.14 (m, 2H), 0.79-0.84 (m, 1H) Table 5: The following examples use appropriate starting materials and reagents, and include Examples 36A and 3 The preparation was carried out according to the synthesis procedures for 6B, Example 36C, and Example 36D. [Table 5] TIFF2026048891000040.tif226170TIFF2026048891000041.tif216170TIFF2026048891000042.tif235170TIFF2026048891000043.tif135170 Examples 44A, 44B, 44C, and 44D (2R)-N-((R or S)-(3-chloro-4-fluorophenyl)(cis- 3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3- Oxopiperazine-1-carboxamide (44A), (2R)-N-((S or R) -(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroetho Xy(cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxami (44B), (2R)-N-((R or S)-(3-chloro-4-fluorophenicol (trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)- 2-Methyl-3-oxopiperazine-1-carboxamide(44C), and (2R)- N-((S or R)-(3-chloro-4-fluorophenyl)(trans-3-(2 ,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide (44D) [ka] Stage 1: Benzyl 3-(2,2,2-trifluoroethoxy)cyclobutane-1- Carboxylate A suspension prepared by suspending NaH (0.389 g, 9.72 mmol) in THF (10 mL). Benzyl 3-hydroxycyclobutane-1-carboxylate (1.67g, 8.1 0 mmol) was added at 0°C for 10 minutes. Then, 2,2,2-trifluoroethyl Trifluoromethanesulfonate (1.231 mL, 8.91 mmol) was added, The mixture was stirred at 20°C for 16 hours. The reaction product was quenched with saturated aqueous solution NH4Cl and vinegar. Extraction was performed with ethyl acid (3 × 10 mL). The resulting organic layers were combined and washed with brine (10 mL). The residue was then dehydrated with Na2SO4, filtered, and evaporated under reduced pressure. Purified by LC (silica gel, ethyl acetate / petroleum ether = 1 / 10, v / v), and then labeled. A mixed product was obtained.

[0321] 1 H NMR (500 MHz, CDCl3) δ 7.35-7.38 (m, 5H), 5.14-5.16 (m, 2H), 4.34 (q, J=6.5 Hz, 1H), 3.70-3.78 (m, 2H), 3.06-3.14 (m, 1H), 2.51-2.63 (m, 2H), 2.29-2.38 (m, 2H). Step 2: 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxylic acid Benzyl 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxy A solution prepared by dissolving rate (550 mg, 1.908 mmol) in MeOH (10 mL) Under an N2 atmosphere, Pd / C (203 mg) was added. The reaction mixture was degassed and H2 The mixture is returned to the container and filled (3 times), and the reaction mixture is stirred at 20°C under H2 (15 psi) for 12 hours. Next, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound.

[0322] 1 H NMR (500 MHz, CDCl3) δ 10.05 (br s, 1H), 4.35 (q, J=6.5 Hz, 1H), 3.66-3.85 ( m, 2H), 3.01-3.17 (m, 1H), 2.56-2.64 (m, 2H), 2.31-2.45 (m, 2H). Step 3: N-methoxy-N-methyl-3-(2,2,2-trifluoroethoxy) Clobutan-1-carboxamide 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxylic acid (370m A solution prepared by dissolving (g, 1.867 mmol) in DCM (5 mL) was then mixed with CDI (303 mg, 1.867 mmol) was added at 20°C. The mixture was stirred for 1 hour, and then TEA (0.521 mL, 3.73 mmol) and N,O-dimethylhydroxylamine hydrochloride (182 mg, 1.867 mmol) was added. The reaction mixture was then incubated at 20°C for a further 1 The mixture was stirred for 2 hours, and then water (10 mL) was added. The reaction mixture was then collected in a DCM (3 × 5 m²). Extraction was performed using L). The organic layers were combined, dehydrated with Na2SO4, filtered, and the filtrate was removed under reduced pressure. The compound was then evaporated to obtain the title compound.

[0323] LRMS m / z (M-16): Calculated value 241.1, Measured value 242.1. Stage 4: (3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoro Ethoxycyclobutyl Methanone A solution of 4-bromo-2-chloro-1-fluorobenzene dissolved in THF (2 mL). Isopropyl magnesium chloride in THF (2M, 1.741mL, 3.48mm (1 ol) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour, and then THF(1 N-methoxy-N-methyl-3-(2,2,2-trifluoroethoxy)- in mL A mixture of cyclobutane-1-carboxamide (420 mg crude) was added. The reaction Stir the mixture at 20°C for 2 hours, then quench with saturated aqueous solution NH4Cl (5 mL), and Et Extraction was performed with OAc (3 x 5 mL). The organic layers were combined, dehydrated with Na2SO4, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography. ISCO®; 12 g SepaFlash®; Silica F lash Column; Purified with eluent (4% ethyl acetate / petroleum ether), title A compound was obtained.

[0324] 1 H NMR (400 MHz, CD3OD) δ 8.02-8.08 (m, 1H), 7.88-7.96 (m, 1H), 7.37 (t, J=8.8 Hz, 1H), 4.09-4.24 (m, 1H), 3.96-4.09 (m, 1H), 3.86 (q, J=9.2 Hz, 2H), 2.56-2.64 (m, 2H), 2.37-2.48 (m, 2H). Stage 5: (3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoro Ethoxycyclobutyl methaneamine (3-chloro-4-fluorophenyl)(3-(2,2,2) in EtOH (3 mL) - Trifluoroethoxy(cyclobutyl)methanone (250 mg, 0.805 mmol) A mixture of NH4OAc (930 mg, 12.07 mmol) and NaBH3CN (76 mg) (g, 1.207 mmol) was added at 20°C. The mixture was microwaved (Biota The mixture was stirred at 130°C for 10 minutes under a GE Initiator. Then, the reaction mixture was prepared. The solution is concentrated to remove most of the EtOH, and then treated with 2N NaOH until the pH is > 12. Extraction was performed with SiO2 (3 × 5 mL). The resulting organic layers were combined and dehydrated with Na2SO4, then filtered. The filtrate was then concentrated under reduced pressure to obtain the title compound.

[0325] LRMS m / z (M+H): Calculated value 311.1, Measured value 312.0. Stage 6: (2R)-N-((3-chloro-4-fluorophenyl)(cis-3-(2 ,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide (isomer A), and (2R)-N-((3-chloro-4 -Fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclob (Cyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (isomer B) CDI (260 mg, 1.604 mmol) and (3-chloro- 4-Fluorophenyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl) A mixture of tanamine (250 mg crude) was stirred at 20°C for 1 hour. Then, (R)- 3-methylpiperazine-2-one (101 mg, 0.882 mmol) was added. The mixture was stirred at 20°C for 2 hours. The solid was then filtered off, and the filtrate was subjected to reverse-phase HP testing. LC(58:42 → 28:72;Water(0.1%TFA):MeCN(0.1%TFA After purification using ), two isomers were obtained.

[0326] The first isomer to elute: (2R)-N-((3-chloro-4-fluorophenyl)(cis -3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide (isomer A).

[0327] LRMS m / z (M+H): Calculated value 451.1, Measured value 452.2. The second isomer to elute: (2R)-N-((3-chloro-4-fluorophenyl)(t Lance-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-meth Ru-3-oxopiperazine-1-carboxamide (isomer B).

[0328] LRMS m / z (M+H): Calculated value 451.1, Measured value 452.2. Stage 7: Examples 44A, 44B, 44C, and 44D Isomer A (150 mg, 0.332 mmol) was subjected to SFC (AS-H column, 30% EtOH + 0.1% NH3H2O) (cosolvent) was divided and Example 44A (first eluted) The fraction obtained was Example 44B (the second fraction to be eluted).

[0329] Example 44A: LRMS m / z (M+H): Calculated value 451.1, Measured value 452.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.40-7.46 (m, 1H), 7.23-7.31 (m, 1H), 7.17 (t, J=8.5 Hz, 1H), 4 .62-4.68 (m, 1H), 4.48-4.53 (m, 1H), 3.95-4.04 (m, 2H), 3.82 (q, J=9.0 Hz, 2H), 3.32-3.38 (m, 1H), 3.17-3.29 (m, 2H), 2.48-2.55 (m, 1H), 2.19-2.29 (m, 1H), 2.11 -2.18 (m, 1H), 1.76-1.82 (m, 1H), 1.63-1.70 (m, 1H), 1.36-1.42 (m, 3H). Example 44B: LRMS m / z (M+H): Calculated value 451.1, Measured value 452.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.40-7.46 (m, 1H), 7.23-7.31 (m, 1H), 7.17 (t, J=8.5 Hz, 1H), 4 .62-4.68 (m, 1H), 4.56 (q, J=7.2 Hz, 1H), 4.01-4.07 (m, 1H), 3.96-4.01 (m, 1H), 3.82 (q, J=9.0 Hz, 2H), 3.32-3.36 (m, 1H), 3.17-3.27 (m, 2H), 2.48-2.55 (m, 1H), 2.20-2.27 (m, 1H), 2.09-2.19 (m, 1H), 1.76-1.83 (m, 1H), 1.65-1.72 (m, 1H), 1.3 7-1.43 (m, 3H). Isomer B (100 mg, 0.221 mmol) was subjected to SFC (OJ-H column, 20% (E) (tOH + 0.1% NH3H2O) was divided with cosolvent) and Example 44C (the first to elute) The fractions 44D (the second fraction to be eluted) and Example 44D (the second fraction to be eluted) were obtained.

[0330] Example 44C: LRMS m / z (M+H): Calculated value 451.1, Measured value 452.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): δ 7.42-7.48 (m, 1H), 7.24-7.62 (m, 1H), 7.15-7.20 (m, 1H), 4.6 4-4.70 (m, 1H), 4.54 (q, J=7.0 Hz, 1H), 4.27 (q, J=6.0 Hz, 1H), 4.00-4.07 (m, 1H ), 3.82 (q, J=9.0 Hz, 2H), 3.32-3.35 (m, 1H), 3.17-3.26 (m, 2H), 2.66-2.75 (m, 1 H), 2.21 (t, J=6.5 Hz, 2H), 1.91-2.01 (m, 2H), 1.36-1.42 (m, 3H). Example 44D: LRMS m / z (M+H): Calculated value 451.1, Measured value 452.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): δ 7.41-7.47 (m, 1H), 7.23-7.31 (m, 1H), 7.16-7.21 (m, 1H), 4.6 6-4.72 (m, 1H), 4.48-4.53 (m, 1H), 4.26 (q, J=6.0 Hz, 1H), 3.98-4.04 (m, 1H), 3. 81 (q, J=9.0 Hz, 2H), 3.32-3.36 (m, 1H), 3.15-3.27 (m, 2H), 2.67-2.75 (m, 1H), 2 .21 (t, J=6.5 Hz, 2H), 1.90-2.01 (m, 2H), 1.34-1.40 (m, 3H). Examples 45A and 45B N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(to Lance-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine -1-Carboxamide and N-((S)-(5-chloro-6-(trifluoromethyl)p Lysine-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl) -3-Oxopiperazine-1-Carboxamide

Chem.

[0331] ​​LRMS m / z (M+H): Calculated value 207.5, Measured value 208.0. Stage 2: 5-Chloro-6-(trifluoromethyl)picolinealdehyde THF (10 mL) and water (5 mL) containing 3-chloro-2-(trifluoromethyl) 6-Vinylpyridine (1.922g, 9.26mmol) and NMO (2.169g, 18 A mixture of 0.52 mmol) and OsO4 (4.63 mL, 0.463 mmol) was prepared at 20°C. The mixture was stirred for 12 hours. Then, NaIO4 (5.94 g, 27.8 mmol) was added, and The mixture was stirred at 20°C for a further 2 hours. Then, water (60 mL) was added and mixed. The substance was extracted using DCM (3 x 40 mL). The resulting organic layer was combined and dehydrated with Na2SO4, then filtered. The filtrate was then concentrated under reduced pressure to obtain the title compound.

[0332] LRMS m / z (M+H): Calculated value 209.6, Measured value 210.0. Stage 3: (5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-( Trifluoromethyl(cyclohexyl)methanone 5-Chloro-6-(trifluoromethyl)picolinealdehyde (600 mg crude), 4-methyl-N'-(4-(trifluoromethyl)cyclohexylidene)benzenesulfone Dissolve nohydrazide (1915 mg, 5.73 mmol) in dioxane (20 mL). Cs2CO3 (1866 mg, 5.73 mmol) was added to the solution at 15°C. The reaction mixture was heated to 100°C for 12 hours, filtered, and the filtrate was concentrated. The resulting residue The residue was subjected to flash silica gel chromatography (ISCO®); 20 g Se paFlash (registered trademark) Silica Flash Column; Eluent 1 The title compound was obtained by purification with 0% ethyl acetate / petroleum ether.

[0333] 1 1H NMR (400 MHz, CDCl3) δ 8.12 - 8.18 (m, 1H), 7.98 - 8.04 (m, 1H), 4.02 (t, J = 3.6 Hz, 1H), 2.06 - 2.20 (m, 5H), 1.72 - 1.77 (m, 4H). Stage 4: (5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-( Trifluoromethyl(cyclohexyl)methanamine (5-Chloro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethyl)cyclohexyl)methanone (130 mg, 0.36 mmol) and NH4OAc (417.89 mg, 5.42 mmol) in EtOH (2 mL) were added NaBH3CN (34.07 mg, 0.542 mmol) at 20 °C. The reaction mixture was stirred under microwave (Biotage Initiator) at 130 °C for 10 minutes, then concentrated to remove most of the EtOH, treated with 2N NaOH until pH > 12, and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound. H3CN(34.07mg、0.542mmol)を20℃で添加した。その反応混合物 を、マイクロ波(Biotage Initiator)下、130℃で10分間撹拌し 、次いで、濃縮して大部分のEtOHを除去し、pH>12になるまで2N NaOHで処理し、EtOAc(3×5mL)で抽出した。その有機層を合してNa2SO4で脱水 し、濾過し、その濾液を減圧下で濃縮して標題化合物が得られた。 し、濾過し、その濾液を減圧下で濃縮して、標題化合物が得られた。 且濾液を減圧下で濃縮して、標題化合物が得られた。

[0334] LRMS m / z (M + H): Calculated 360.1, Found 361.1. [[ID=2 (28]] Stage 5: N-((5-chloro-6-(trifluoromethyl)pyridine-2-yl)( trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazi n-1-carboxamide [ A mixture of CDI (90 mg, 0.554 mmol) and (5-chloro -6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethyl)cyclo hexyl)methanamine (100 mg crude) in DMF (1.5 mL) was stirred at 20 °C for 1 hour. Then piperazin-2-one (30.5 mg, 0.305 mmol) was added. The reaction The mixture is stirred at 20°C for 1 hour, then the solid is filtered off, and the filtrate is prepared using prep-H PLC(53:47 → 23:67;Water(0.1%TFA):MeCN(0.1%TF Purification using A)) yielded two isomers.

[0335] First isomer eluted: N-((5-chloro-6-(trifluoromethyl)pyridine-2 -yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxy Sopiperazine-1-carboxamide (trans-isomer).

[0336] LRMS m / z (M+H): Calculated value 486.1, Measured value 487.2. Second isomer eluted: N-((5-chloro-6-(trifluoromethyl)pyridine- 2-yl)(cis-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxo -Piperazine-1-carboxamide (cis-isomer).

[0337] LRMS m / z (M+H): Calculated value 486.1, Measured value 487.1. Stage 6: Examples 45A and 45B N-((5-chloro-6-(trifluoromethyl)pyridine-2-yl)(trans- 4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1- Ruvoxamide (80 mg, 0.164 mmol) is processed in Chiral-SFC (column DA). ICEL CHIRALPAK IC, 30%(EtOH+0.1%NH3H2O) The fractions were divided into two parts (solvent) and Example 45A (the first fraction eluted) and Example 45B (the second fraction eluted). The resulting fraction was obtained.

[0338] Example 45A: LRMS m / z (M+H): Calculated value 486.1, Measured value 487.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.99-8.05 (m, 1H), 7.56-7.62 (m, 1H), 4.66-4.72 (m, 1H), 4.05 ( s, 2H), 3.57-3.66 (m, 2H), 3.33 (br s, 2H), 2.05-2.13 (m, 2H), 1.87-2.02 (m, 3H) , 1.28-1.40 (m, 2H), 1.06-1.27 (m, 3H). Example 45B: LRMS m / z (M+H): Calculated value 486.1, Measured value 487.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.99-8.05 (m, 1H), 7.56-7.62 (m, 1H), 4.66-4.72 (m, 1H), 4.05 ( s, 2H), 3.57-3.66 (m, 2H), 3.33 (br s, 2H), 2.04-2.14 (m, 2H), 1.87-2.02 (m, 3H) , 1.27-1.41 (m, 2H), 1.06-1.26 (m, 3H). Table 6: The following examples use appropriate starting materials and reagents, and are based on Example 45A and Example 45A. It was prepared according to the synthesis procedure for 45B. [Table 6] Examples 47A, 47B, 47C, and 47D (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl)pyri Zin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2- Methyl-3-oxopiperazine-1-carboxamide (47A), (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopropyl Perazine-1-carboxamide (47B), (2R)-N-((S or R)-(5- Chloro-6-(trifluoromethyl)pyridine-2-yl)(trans-3-(triflu) Oromethyl(cyclobutyl)me...

Claims

1. Structural formula I: 【Chemistry 1】 [During the ceremony, One of A and B is (1) Aryl, and, (2) Heteroaryl Independently selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R ａ Selected from It is substituted with substituents 1 to 5, and, The other of A and B is, (1) C ３－１２ Cycloalkyl, (2) C ２－１１ Cycloheteroalkyl, (3)-C １－６ Alkyl-C ３－１２ Cycloalkyl, (4)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl, (5)-C １－６ Alkyl-O-C ３－１２ Cycloalkyl, and, (6)-C １－６ Alkyl-O-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R ｂ It is substituted with 1 to 6 substituents selected from; R １ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｔ C(O)R ｊ 、 (9)-(CH ２ ) ｔ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｎ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｎ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｎ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｎ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｎ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｎ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｎ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｎ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｃ Substituted with 1 to 5 substituents selected from It is; R ２ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, (4)-C ２－６ Alkenil, (5)-C ２－６ Alkinil, (6)-C ３－６ Cycloalkyl, (7)-C ２－６ Cycloheteroalkyl, (8)-C １－６ Alkyl-O-C １－６ Alkyl-, (9)-(CH ２ ) ｓ C(O)R ｊ 、 (10)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (14)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (17)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (18)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｄ Substituted with 1 to 5 substituents selected from It is Here, R ２ and R ３ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form, and Here, R ２ and R ４ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; R ３ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, (4)-C ２－６ Alkenil, (5)-C ２－６ Alkinil, (6)-C ３－６ Cycloalkyl, (7)-C ２－６ Cycloheteroalkyl, (8)-C １－６ Alkyl-O-C １－６ Alkyl-, (9)-(CH ２ ) ｓ C(O)R ｊ 、 (10)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (14)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (17)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (18)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｄ Substituted with 1 to 5 substituents selected from It is; R ４ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, (4)-C ２－６ Alkenil, (5)-C ２－６ Alkinil, (6)-C ３－６ Cycloalkyl, (7)-C ２－６ Cycloheteroalkyl, (8)-C １－６ Alkyl-O-C １－６ Alkyl-, (9)-(CH ２ ) ｓ C(O)R ｊ 、 (10)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (14)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (17)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (18)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｆ Substituted with 1 to 5 substituents selected from It is and Here, R ４ and R ５ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; R ５ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, (4)-C ２－６ Alkenil, (5)-C ２－６ Alkinil, (6)-C ３－６ Cycloalkyl, (7)-C ２－６ Cycloheteroalkyl, (8)-C １－６ Alkyl-O-C １－６ Alkyl-, (9)-(CH ２ ) ｓ C(O)R ｊ 、 (10)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (14)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (17)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (18)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｆ Substituted with 1 to 5 substituents selected from It is and Here, R ５ and R ７ And the carbon atoms to which they are bonded are 4-membered, 5-membered, or 6-membered saturated rings. It can form; R ６ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, (4)-C ２－６ Alkenil, (5)-C ２－６ Alkinil, (6)-C ３－６ Cycloalkyl, (7)-C ２－６ Cycloheteroalkyl, (8)-C １－６ Alkyl-O-C １－６ Alkyl-, (9)-(CH ２ ) ｓ C(O)R ｊ 、 (10)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (14)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (17)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (18)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｇ Substituted with 1 to 5 substituents selected from It is and Here, R ６ and R ７ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; R ７ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, (4)-C ２－６ Alkenil, (5)-C ２－６ Alkinil, (6)-C ３－６ Cycloalkyl, (7)-C ２－６ Cycloheteroalkyl, (8)-C １－６ Alkyl-O-C １－６ Alkyl-, (9)-(CH ２ ) ｓ C(O)R ｊ 、 (10)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (14)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (17)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (18)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｇ Substituted with 1 to 5 substituents selected from It is; R ８ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, and, (4)-C ２－６ Cycloheteroalkyl Selected from the group consisting of, Here, each alkyl, cycloalkyl, and cycloheteroalkyl is either substituted or not. or substituted with 1 to 5 substituents selected from halogens; R ９ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, and (4)-C ２－６ Alkinyl Selected from the group consisting of, Here, each alkyl, alkenyl, and alkynyl is either unsubstituted or halogenated. It is substituted with 1 to 5 substituents selected from n; Each R ａ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C ２－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C １－６ Alkyl-aryl, (13)-C １－６ Alkyl-heteroaryl, (14)-C １－６ Alkyl-C ３－６ Cycloalkyl, (15)-C １－６ Alkyl-C ２－６ Cycloheteroalkyl, (16)-C ２－６ Alkenyl-C ３－６ Cycloalkyl, (17)-C ２－６ Alkenyl-C ２－６ Cycloheteroalkyl, (18)-C ２－６ Alkenyl-aryl, (19)-C ２－６ Alkenyl heteroaryl, (20)-C ２－６ Alkinyl-C ３－６ Cycloalkyl, (21)-C ２－６ Alkinyl C ２－６ Cycloheteroalkyl, (22)-C ２－６ Alkinyl-aryl, (23)-C ２－６ Alkynyl heteroaryl, (24)-OH, (25)-(CH ２ ) ｐ -O-C １－６ Alkyl, (26)-(CH ２ ) ｐ -O-C ２－６ Alkenil, (27)-(CH ２ ) ｐ -O-C ２－６ Alkinil, (28)-(CH ２ ) ｐ -O-C ３－６ Cycloalkyl, (29)-(CH ２ ) ｐ -O-C ２－６ Cycloheteroalkyl, (30)-(CH ２ ) ｐ -O-aryl, (31)-(CH ２ ) ｐ -O-heteroaryl, (32)-OC １－６ Alkyl-C ３－６ Cycloalkyl, (33)-OC １－６ Alkyl-C ２－６ Cycloheteroalkyl, (34)-OC １－６ Alkyl-aryl, (35)-OC １－６ Alkyl-heteroaryl, (36)-S(O) ｒ R ｈ 、 (37)-C １－６ Alkyl-S(O) ｒ R ｈ , (38)-N(R ｋ ) ２ 、 (39)-C(O)R Ｌ , and, (40)-NR ｋ R Ｌ Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; Each R ｂ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C １－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C １－６ Alkyl-aryl, (13)-C １－６ Alkyl-heteroaryl, (14)-C １－６ Alkyl-C ３－６ Cycloalkyl, (15)-C １－６ Alkyl-C ２－６ Cycloheteroalkyl, (16)-C ２－６ Alkenyl-C ３－６ Cycloalkyl, (17)-C ２－６ Alkenyl-C ２－６ Cycloheteroalkyl, (18)-C ２－６ Alkenyl-aryl, (19)-C ２－６ Alkenyl heteroaryl, (20)-C ２－６ Alkinyl-C ３－６ Cycloalkyl, (21)-C ２－６ Alkinyl-C ２－６ Cycloheteroalkyl, (22)-C ２－６ Alkinyl-aryl, (23)-C ２－６ Alkynyl heteroaryl, (24)-OH, (25)-(CH ２ ) ｑ -O-C １－６ Alkyl, (26)-(CH ２ ) ｑ -O-C ２－６ Alkenil, (27)-(CH ２ ) ｑ -O-C ２－６ Alkinil, (28)-(CH ２ ) ｑ -O-C ３－６ Cycloalkyl, (29)-(CH ２ ) ｑ -O-C ２－６ Cycloheteroalkyl, (30)-(CH ２ ) ｑ -O-aryl, (31)-(CH ２ ) ｑ -O-heteroaryl, (32)-OC １－６ Alkyl-C ３－６ Cycloalkyl, (33)-OC １－６ Alkyl-C ２－６ Cycloheteroalkyl, (34)-OC １－６ Alkyl-aryl, (35)-OC １－６ Alkyl-heteroaryl, (36)-S(O) ｒ R ｉ 、 (37)-C １－６ Alkyl-S(O) ｒ R ｉ , (38)-N(R ｋ ) ２ 、 (39)-C(O)R Ｌ , and, (40)-NR ｋ R Ｌ Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; R ｃ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｄ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｅ teeth, (1) Hydrogen, and (2) C １－６ Alkyl Selected from; R ｆ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｇ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｈ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; R ｉ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; R ｊ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Alkenil, (4) C ３－６ Alkinil, (5) C ３－６ Cycloalkyl, (6) C ２－５ Cycloheteroalkyl, (7) Aryl, and, (8) Heteroaryl Selected from; R ｋ teeth, (1) Hydrogen, and (2) C １－６ Alkyl Selected from; R Ｌ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; m is independently selected from 0, 1, and 2; n is independently selected from 2, 3, 4, 5, and 6; p is independently selected from 0, 1, 2, and 3; q is independently selected from 0, 1, 2, and 3; r is selected independently from 0, 1, and 2; s is independently selected from 0, 1, 2, 3, 4, 5 and 6; and, t is independently selected from 0, 1, 2, 3, 4, 5, and 6. A compound represented by or a pharmaceutically acceptable salt thereof.

2. Structural formula I: 【Chemistry 2】 [During the ceremony, One of A and B is (1) Aryl, and, (2) Heteroaryl Independently selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R ａ Selected from It is substituted with substituents 1 to 5, and, The other of A and B is, (1)-C ３－１２ Cycloalkyl, (2)-C ２－１１ Cycloheteroalkyl, (3)-C １－６ Alkyl-C ３－１２ Cycloalkyl, (4)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl, (5)-C １－６ Alkyl-O-C ３－１２ Cycloalkyl, and, (6)-C １－６ Alkyl-O-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R ｂ It is substituted with 1 to 6 substituents selected from; R １ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｔ C(O)R ｊ 、 (9)-(CH ２ ) ｔ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｎ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｎ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｎ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｎ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｎ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｎ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｎ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｎ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｃ Substituted with 1 to 5 substituents selected from It is; R ２ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｓ C(O)R ｊ 、 (9)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｄ Substituted with 1 to 5 substituents selected from It is Here, R ２ and R ３ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; and, Here, R ２ and R ４ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; R ３ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｓ C(O)R ｊ 、 (9)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｄ Substituted with 1 to 5 substituents selected from It is; R ４ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｓ C(O)R ｊ 、 (9)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｆ Substituted with 1 to 5 substituents selected from It is and Here, R ４ and R ５ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; R ５ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｓ C(O)R ｊ 、 (9)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｆ Substituted with 1 to 5 substituents selected from It is and Here, R ５ and R ７ And the carbon atoms to which they are bonded are 4-membered, 5-membered, or 6-membered saturated rings. It can form; R ６ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｓ C(O)R ｊ 、 (9)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｇ Substituted with 1 to 5 substituents selected from It is and Here, R ６ and R ７ And the carbon atoms to which they are bonded are -C ３－５ Cycloalkyl ring It can form; R ７ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, (4)-C ２－６ Alkinil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7)-C １－６ Alkyl-O-C １－６ Alkyl-, (8)-(CH ２ ) ｓ C(O)R ｊ 、 (9)-(CH ２ ) ｓ C(O)NR ｅ R ｊ 、 (10)-(CH ２ ) ｓ NR ｅ C(O)R ｊ 、 (11)-(CH ２ ) ｓ NR ｅ C(O)OR ｊ 、 (12)-(CH ２ ) ｓ NR ｅ C(O)N(R ｅ ) ２ 、 (13)-(CH ２ ) ｓ NR ｅ C(O)NR ｅ R ｊ 、 (14)-(CH ２ ) ｓ NR ｅ S(O) ｍ R ｊ 、 (15)-(CH ２ ) ｓ NR ｅ S(O) ｍ N(R ｅ ) ２ 、 (16)-(CH ２ ) ｓ NR ｅ S(O) ｍ NR ｅ R ｊ , and, (17)-(CH) ２ ) ｓ NR ｅ R ｊ Selected from the group consisting of, Here, each CH ２ , alkyl, alkenyl, alkynyl, cycloalkyl and cyclohex Roalkyl is either unsubstituted or R ｇ Substituted with 1 to 5 substituents selected from It is; R ８ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, and, (4)-C ２－６ Cycloheteroalkyl Selected from the group consisting of, Here, each alkyl, cycloalkyl, and cycloheteroalkyl is either substituted or not. or substituted with 1 to 5 substituents selected from halogens; R ９ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ２－６ Alkenil, and (4)-C ２－６ Alkinyl Selected from the group consisting of, Here, each alkyl, alkenyl, and alkynyl is either unsubstituted or halogenated. It is substituted with 1 to 5 substituents selected from n; Each R ａ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C ２－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C １－６ Alkyl-aryl, (13)-C １－６ Alkyl-heteroaryl, (14)-C １－６ Alkyl-C ３－６ Cycloalkyl, (15)-C １－６ Alkyl-C ２－６ Cycloheteroalkyl, (16)-C ２－６ Alkenyl-C ３－６ Cycloalkyl, (17)-C ２－６ Alkenyl-C ２－６ Cycloheteroalkyl, (18)-C ２－６ Alkenyl-aryl, (19)-C ２－６ Alkenyl heteroaryl, (20)-C ２－６ Alkinyl-C ３－６ Cycloalkyl, (21)-C ２－６ Alkinyl C ２－６ Cycloheteroalkyl, (22)-C ２－６ Alkinyl-aryl, (23)-C ２－６ Alkynyl heteroaryl, (24)-OH, (25)-(CH ２ ) ｐ -O-C １－６ Alkyl, (26)-(CH ２ ) ｐ -O-C ２－６ Alkenil, (27)-(CH ２ ) ｐ -O-C ２－６ Alkinil, (28)-(CH ２ ) ｐ -O-C ３－６ Cycloalkyl, (29)-(CH ２ ) ｐ -O-C ２－６ Cycloheteroalkyl, (30)-(CH ２ ) ｐ -O-aryl, (31)-(CH ２ ) ｐ -O-heteroaryl, (32)-OC １－６ Alkyl-C ３－６ Cycloalkyl, (33)-OC １－６ Alkyl-C ２－６ Cycloheteroalkyl, (34)-OC １－６ Alkyl-aryl, (35)-OC １－６ Alkyl-heteroaryl, (36)-S(O) ｒ R ｈ 、 (37)-C １－６ Alkyl-S(O) ｒ R ｈ , (38)-N(R ｋ ) ２ 、 (39)-C(O)R Ｌ , and, (40)-NR ｋ R Ｌ Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; Each R ｂ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C １－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C １－６ Alkyl-aryl, (13)-C １－６ Alkyl-heteroaryl, (14)-C １－６ Alkyl-C ３－６ Cycloalkyl, (15)-C １－６ Alkyl-C ２－６ Cycloheteroalkyl, (16)-C ２－６ Alkenyl-C ３－６ Cycloalkyl, (17)-C ２－６ Alkenyl-C ２－６ Cycloheteroalkyl, (18)-C ２－６ Alkenyl-aryl, (19)-C ２－６ Alkenyl heteroaryl, (20)-C ２－６ Alkinyl-C ３－６ Cycloalkyl, (21)-C ２－６ Alkinyl-C ２－６ Cycloheteroalkyl, (22)-C ２－６ Alkinyl-aryl, (23)-C ２－６ Alkynyl heteroaryl, (24)-OH, (25)-(CH ２ ) ｑ -O-C １－６ Alkyl, (26)-(CH ２ ) ｑ -O-C ２－６ Alkenil, (27)-(CH ２ ) ｑ -O-C ２－６ Alkinil, (28)-(CH ２ ) ｑ -O-C ３－６ Cycloalkyl, (29)-(CH ２ ) ｑ -O-C ２－６ Cycloheteroalkyl, (30)-(CH ２ ) ｑ -O-aryl, (31)-(CH ２ ) ｑ -O-heteroaryl, (32)-OC １－６ Alkyl-C ３－６ Cycloalkyl, (33)-OC １－６ Alkyl-C ２－６ Cycloheteroalkyl, (34)-OC １－６ Alkyl-aryl, (35)-OC １－６ Alkyl-heteroaryl, (36)-S(O) ｒ R ｉ 、 (37)-C １－６ Alkyl-S(O) ｒ R ｉ , (38)-N(R ｋ ) ２ 、 (39)-C(O)R Ｌ , and, (40)-NR ｋ R Ｌ Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; R ｃ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｄ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｅ teeth, (1) Hydrogen, and (2) C １－６ Alkyl Selected from; R ｆ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｇ teeth, (1)-C １－６ Alkyl, (2) OH, (3) Halogens, and (4) - OC １－６ Alkyl Selected from, Here, the alkyl is either unsubstituted or substituted with one to three halogens; R ｈ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; R ｉ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; R ｊ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Alkenil, (4) C ３－６ Alkinil, (5) C ３－６ Cycloalkyl, (6) C ２－５ Cycloheteroalkyl, (7) Aryl, and, (8) Heteroaryl Selected from; R ｋ teeth, (1) Hydrogen, and (2) C １－６ Alkyl Selected from; R Ｌ teeth, (1) Hydrogen, (2) C １－６ Alkyl, (3) C ３－６ Cycloalkyl, (4) Aryl, and, (5) Heteroaryl Selected from; m is independently selected from 0, 1, and 2; n is independently selected from 2, 3, 4, 5, and 6; p is independently selected from 0, 1, 2, and 3; q is independently selected from 0, 1, 2, and 3; r is selected independently from 0, 1, and 2; s is independently selected from 0, 1, 2, 3, 4, 5 and 6; and, t is independently selected from 0, 1, 2, 3, 4, 5, and 6. A compound represented by or a pharmaceutically acceptable salt thereof.

3. A is, (1) Aryl, and, (2) Heteroaryl Selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R ａ Selected from It is substituted with substituents 1 to 5; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. A is, (1) Phenyl, (2) Pyridine, and (3) Thiazole Selected from the group consisting of, Here, phenyl, pyridine, and thiazole are either unsubstituted or R ａ Choose from It is substituted with one to five selected substituents; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. A is, (1) Phenyl, and (2) Pyridine Selected from the group consisting of, Here, phenyl and pyridine are either unsubstituted or R ａ Select from 1 to It is substituted with four substituents; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. B is, (1)-C ３－１２ Cycloalkyl, (2)-C ２－１１ Cycloheteroalkyl, (3)-C １－６ Alkyl-C ３－１２ Cycloalkyl, (4)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl, (5)-C １－６ Alkyl-O-C ３－１２ Cycloalkyl, and, (6)-C １－６ Alkyl-O-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R ｂ Substituted with 1 to 6 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. B is, (1) Cyclopropane, (2) Cyclobutane, (3) Cyclopentane, (4) Cyclohexane, (5) Bicyclo[3.2.1]octane, (6) Bicyclo[3.1.0]hexane, (7) Bicyclo[2.2.2]octane, (8) Spiro[2.5]octane, (9) Bicyclo[1.1.1]pentane, (10) Spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) Piperidine, (13) Tetrahydropyran, and (14) Croman Independently selected from the group consisting of, Here, B is either not substituted, or R ｂ Substituted with 1 to 6 substituents selected from Being; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. B is, (1) Cyclopropane, (2) Cyclobutane, (3) Cyclopentane, (4) Cyclohexane, (5) Bicyclo[3.2.1]octane, (6) Bicyclo[3.1.0]hexane, (7) Bicyclo[2.2.2]octane, (8) Spiro[2.5]octane, (9) Bicyclo[1.1.1]pentane, (10) Spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) piperidine, and (13) Tetrahydropyran Independently selected from the group consisting of, Here, B is either not substituted, or R ｂ Substituted with 1 to 6 substituents selected from Being; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. B is, (1)-C ３－１２ Cycloalkyl, and, (2)-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, cycloalkyl and cycloheteroalkyl are either unsubstituted or R ｂ Substituted with 1 to 6 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. B is, (1) Cyclobutane, (2) Cyclohexane, and (3) Tetrahydropyran Independently selected from the group consisting of, Here, cyclobutane, cyclohexane, and tetrahydropyran are not substituted. , or R ｂ Substituted with 1 to 6 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R １ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or R ｃ 1 to 5 substituents selected from It is replaced by; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ２ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ３ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ４ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｆ Select from It is substituted with 1 to 5 substituents; R ５ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｆ Selected from It is substituted with substituents 1 to 5; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R ２ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ３ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ４ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｆ Select from It is substituted with 1 to 5 substituents; R ５ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｆ Selected from It is substituted with substituents 1 to 5; R ６ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｇ Selected from It is substituted with substituents 1 to 5; and, R ７ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｇ Selected from It is substituted with substituents 1 to 5; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. R ８ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or has one to five substitutions selected from halogens. It is substituted with the base; and, R ９ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or has one to five substitutions selected from halogens. It is substituted with the base; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. A is, (1) Aryl, and, (2) Heteroaryl Selected from the group consisting of, Here, aryl and heteroaryl are either unsubstituted or R ａ Selected from It is substituted with substituents 1 to 5; and, B is, (1)-C ３－１２ Cycloalkyl, (2)-C ２－１１ Cycloheteroalkyl, (3)-C １－６ Alkyl-C ３－１２ Cycloalkyl, (4)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl, (5)-C １－６ Alkyl-O-C ３－１２ Cycloalkyl, and, (6)-C １－６ Alkyl-O-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, alkyl, cycloalkyl and cycloheteroalkyl are either unsubstituted or Or, R ｂ Substituted with 1 to 6 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. R １ is hydrogen; R ２ , R ３ , R ４ and R ５ is either deuterium or hydrogen; R ６ and R ７ CH ３ or hydrogen; and, R ８ and R ９ It is hydrogen; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ It is hydrogen; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

18. Each R ａ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C ２－６ Alkenil, (7)-C ３－６ Cycloalkyl, (8)-C ２－６ Cycloheteroalkyl, (9) Ariel, (10) Heteroaryl, (11)-OH, (12)-O-C １－６ Alkyl, (13)-O-C ３－６ Cycloalkyl, and, (14)-O-C ２－６ Cycloheteroalkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ Substituted with 1 to 6 substituents selected from alkyl groups; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

19. Each R ａ teeth, (1) Halogen, (2)-C １－６ Alkyl, and (3)-O-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ Substituted with 1 to 6 substituents selected from alkyl groups; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

20. Each R ａ teeth, (1) Halogens, and (2)-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ Substituted with 1 to 6 substituents selected from alkyl groups; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

21. Each R ｂ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C １－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-OH, (13)-O-C １－６ Alkyl, (14)-O-C ３－６ Cycloalkyl, and, (15)-O-C ２－６ Cycloheteroalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

22. Each R ｂ teeth, (1) Halogen, (2)-C １－６ Alkyl, (3)-C １－６ Alkenil, (4)-C ３－６ Cycloalkyl, and, (5)-O-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23. Each R ｂ teeth, (1) Halogens, and (2)-C １－６ Alkyl Independently selected from the group consisting of, Here, alkyl is either unsubstituted or halogen, CF ３ OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

24. A is, (1) Phenyl, (2) Pyridine, and (3) Thiazole Selected from the group consisting of, Here, phenyl, pyridine, and thiazole are either unsubstituted or R ａ Choose from It is substituted with one to five selected substituents; B is, (1) Cyclopropane, (2) Cyclobutane, (3) Cyclopentane, (4) Cyclohexane, (5) Bicyclo[3.2.1]octane, (6) Bicyclo[3.1.0]hexane, (7) Bicyclo[2.2.2]octane, (8) Spiro[2.5]octane, (9) Bicyclo[1.1.1]pentane, (10) Spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane (12) Piperidine, (13) Tetrahydropyran, and (14) Croman Independently selected from the group consisting of, Here, B is either not substituted, or R ｂ Substituted with 1 to 6 substituents selected from It is; R １ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or R ｃ 1 to 5 substituents selected from It has been replaced with; R ２ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ３ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ４ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｆ Select from It is substituted with 1 to 5 substituents; R ５ teeth, (1) Hydrogen, (2) Deuterium, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｆ Selected from It is substituted with substituents 1 to 5; R ６ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｇ Selected from It is substituted with substituents 1 to 5; R ７ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｇ Selected from It is substituted with substituents 1 to 5; R ８ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or has one to five substitutions selected from halogens. It is substituted with the base; R ９ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or has one to five substitutions selected from halogens. It is substituted with the base; R ａ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C ２－６ Alkenil, (7)-C ３－６ Cycloalkyl, (8)-C ２－６ Cycloheteroalkyl, (9) Ariel, (10) Heteroaryl, (11)-OH, (12)-O-C １－６ Alkyl, (13)-O-C ３－６ Cycloalkyl, and, (14)-O-C ２－６ Cycloheteroalkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; and, Each R ｂ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C １－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-OH, (13)-O-C １－６ Alkyl, (14)-O-C ３－６ Cycloalkyl, and, (15)-O-C ２－６ Cycloheteroalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

25. A is, (1) Phenyl, (2) Pyridine, and (3) Thiazole Selected from the group consisting of, Here, phenyl, pyridine, and thiazole are either unsubstituted or R ａ Choose from It is substituted with one to five selected substituents; B is, (1) Cyclopropane, (2) Cyclobutane, (3) Cyclopentane, (4) Cyclohexane, (5) Bicyclo[3.2.1]octane, (6) Bicyclo[3.1.0]hexane, (7) Bicyclo[2.2.2]octane, (8) Spiro[2.5]octane, (9) Bicyclo[1.1.1]pentane, (10) Spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) piperidine, and (13) Tetrahydropyran Independently selected from the group consisting of, Here, B is either not substituted, or R ｂ Substituted with 1 to 6 substituents selected from It is; R １ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or R ｃ 1 to 5 substituents selected from It has been replaced with; R ２ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ３ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｄ Select from It is substituted with 1 to 5 substituents; R ４ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, each alkyl and cycloalkyl is either unsubstituted or R ｆ Select from It is substituted with 1 to 5 substituents; R ５ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｆ Selected from It is substituted with substituents 1 to 5; R ６ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｇ Selected from It is substituted with substituents 1 to 5; R ７ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, and (3)-C ３－６ Cycloalkyl Selected from the group consisting of, Here, alkyl and cycloalkyl are either unsubstituted or R ｇ Selected from It is substituted with substituents 1 to 5; R ８ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or has one to five substitutions selected from halogens. It is substituted with the base; R ９ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or has one to five substitutions selected from halogens. It is substituted with the base; R ａ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C ２－６ Alkenil, (7)-C ３－６ Cycloalkyl, (8)-C ２－６ Cycloheteroalkyl, (9) Ariel, (10) Heteroaryl, (11)-OH, (12)-O-C １－６ Alkyl, (13)-O-C ３－６ Cycloalkyl, and, (14)-O-C ２－６ Cycloheteroalkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; and, Each R ｂ teeth, (1) CN, (2) Oxo, (3) Halogen, (4) - S(O) ２ C １－６ Alkyl, (5)-C １－６ Alkyl, (6)-C １－６ Alkenil, (7)-C ２－６ Alkinil, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-OH, (13)-O-C １－６ Alkyl, (14)-O-C ３－６ Cycloalkyl, and, (15)-O-C ２－６ Cycloheteroalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

26. A is, (1) Phenyl, and (2) Pyridine Selected from the group consisting of, Here, phenyl and pyridine are either unsubstituted or R ａ Select from 1 to It is substituted with four substituents; B is, (1)-C ３－１２ Cycloalkyl, and, (2)-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, cycloalkyl and cycloheteroalkyl are either unsubstituted or R ｂ It is substituted with 1 to 6 substituents selected from; R １ is hydrogen; R ２ , R ３ , R ４ and R ５ is either deuterium or hydrogen; R ６ and R ７ CH ３ or hydrogen; R ８ and R ９ is hydrogen; Each R ａ teeth, (1) Halogen, (2)-C １－６ Alkyl, and (3)-O-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; and, Each R ｂ teeth, (1) Halogen, (2)-C １－６ Alkyl, (3)-C １－６ Alkenil, (4)-C ３－６ Cycloalkyl, and, (5)-O-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

27. A is, (1) Phenyl, and (2) Pyridine Selected from the group consisting of, Here, phenyl and pyridine are either unsubstituted or R ａ Select from 1 to It is substituted with four substituents; B is, (1)-C ３－１２ Cycloalkyl, and, (2)-C ２－１１ Cycloheteroalkyl Independently selected from the group consisting of, Here, cycloalkyl and cycloheteroalkyl are either unsubstituted or R ｂ It is substituted with 1 to 6 substituents selected from; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ is hydrogen; Each R ａ teeth, (1) Halogen, (2)-C １－６ Alkyl, and (3)-O-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Al Kill and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; and, Each R ｂ teeth, (1) Halogen, (2)-C １－６ Alkyl, (3)-C １－６ Alkenil, (4)-C ３－６ Cycloalkyl, and, (5)-O-C １－６ Alkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, C H ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ Selected from alkyl groups It is substituted with substituents 1 to 6; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

28. below: (1) N-((R)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ； (2) N-((S)-3-chloro-4-fluorophenyl)(trans-4-(trif Luoromethyl(cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide) ； (3) N-((R)-(3-chloro-4-fluorophenyl)(8,8-difluorophenyl) Cyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-cal Boxamide; (4) N-((S)-(3-chloro-4-fluorophenyl)(8,8-difluorophenyl) Cyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-cal Boxamide; (5) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(8,8-di Fluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (6) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(8,8-di Fluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (7) N-((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl Cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide; (8) N-((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl Cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide; (9) N-((S)-(4-chlorophenyl)(trans-4-(trifluoromethyl Cyclohexyl(methyl)-3-oxopiperazine-1-carboxamide; (10) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (11) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (12) (R)-2-methyl-3-oxo-N-((R)-(trans-4-(trif (Oromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piper Zin-1-carboxamide; (13) (R)-2-methyl-3-oxo-N-((S)-(trans-4-(trif (Oromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piper Zin-1-carboxamide; (14) (2R)-N-((R)-(3-chloro-4-fluorophenyl)((1R, 3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl )-2-methyl-3-oxopiperazine-1-carboxamide; (15) (2R)-N-((S)-(3-chloro-4-fluorophenyl)((1R, 3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl )-2-methyl-3-oxopiperazine-1-carboxamide; (16) (2R)-N-((R)-(3,4-difluorophenyl)(trans-4- (Trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide; (17) (2R)-N-((S)-(3,4-difluorophenyl)(trans-4- (Trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide; (18) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (19) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxy Sopiperazine-1-carboxamide; (20) N-((R)-(3-chloro-2,4-difluorophenyl)(trans-4 -(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-cal Boxamide; (21) N-((S)-(3-chloro-2,4-difluorophenyl)(trans-4 -(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-cal Boxamide; (22) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)((1 (R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl) (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (23) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 (R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl) (Cyl)-2-methyl-3-oxopiperazine-1-carboxamide; (24) N-((R)-(3-chloro-4-fluorophenyl)(4-(trifluoro Methyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine -1-Carboxamide; (25) N-((S)-(3-chloro-4-fluorophenyl)(4-(trifluoro Methyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine -1-Carboxamide; (26) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(4 ,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1- Carboxamide; (27) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(4 ,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1- Carboxamide; (28) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(4,4- Difluorocyclohexyl(methyl)-2-methyl-3-oxopiperazine-1-carb Xamide; (29) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(4,4- Difluorocyclohexyl(methyl)-2-methyl-3-oxopiperazine-1-carb Xamide; (30) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(2 ,2,2-trifluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-ol Xopiperazine-1-carboxamide; (31) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(2 ,2,2-trifluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-ol Xopiperazine-1-carboxamide; (32) (2R)-N-((R)-(4-chlorophenyl)(1-(2,2,2-tri Fluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide; (33) (2R)-N-((S)-(4-chlorophenyl)(1-(2,2,2-tri Fluoroethyl)piperidine-4-yl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide; (34) N-((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2- Trifluoroethyl)piperidine-4-yl)methyl)-3-oxopiperazine-1- Ruboxamide; (35) N-((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2- Trifluoroethyl)piperidine-4-yl)methyl)-3-oxopiperazine-1- Ruboxamide; (36) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(R )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (37) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(S )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (38) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(R )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (39) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(S )-(1,1,1-trifluoropropan-2-yl)piperidine-4-yl)methyl) -3-oxopiperazine-1-carboxamide; (40) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans -1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (41) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(trans -1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (42) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis-1 ,1-difluorospiro[2.5]octan-6-yl(methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (43) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis-1 ,1-difluorospiro[2.5]octan-6-yl(methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (44) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(tra ns-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopropyl Perazine-1-carboxamide; (45) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(tra ns-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopropyl Perazine-1-carboxamide; (46) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(cis -3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiper Zin-1-carboxamide; (47) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)(cis -3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiper Zin-1-carboxamide; (48) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-cyclopropylcyclobutyl)methyl)2-methyl-3-oxopiperazi n-1-carboxamide; (49) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) S-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide; (50) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-cyclopropylcyclobutyl)methyl)2-methyl-3-oxopiperazi n-1-carboxamide; (51) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) S-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide; (52) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-1,1-difluorospiro[2,3]hexane-5-yl)methyl)-2-methyl Lu-3-oxopiperazine-1-carboxamide; (53) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) Su-1,1-difluorospiro[2.3]hexane-5-yl)methyl)-2-methyl- 3-oxopiperazine-1-carboxamide; (54) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-1,1-difluorospiro[2,3]hexane-5-yl)methyl)-2-methyl Lu-3-oxopiperazine-1-carboxamide; (55) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) Su-1,1-difluorospiro[2.3]hexane-5-yl)methyl)-2-methyl- 3-oxopiperazine-1-carboxamide; (56) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6 ,6-difluorospiro[3,3]heptan-2-yl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (57) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6 ,6-difluorospiro[3,3]heptan-2-yl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (58) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 ,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (59) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 ,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (60) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 -Methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carbbox Thamid; (61) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 -Methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carbbox Thamid; (62) N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3 -(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carb Xamide; (63) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3- Oxopiperazine-1-carboxamide; (64) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(tra lance-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3- Oxopiperazine-1-carboxamide; (65) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(S Pyro[2,3]hexane-5-yl)methyl)-2-methyl-3-oxopiperazine-1 - Carboxamide; (66) (2R)-N-((S)(3-chloro-2,4-difluorophenyl)(spi Ro[2.3]Hexane-5-yl)methyl)-2-methyl-3-oxopiperazine-1- Carboxamide; (67) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide; (68) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxop Perazine-1-carboxamide; (69) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 -(trifluoromethyl)bicyclo[1.1.1]pentan-1yl(methyl)-2-methyl Chill-3-oxopiperazine-1-carboxamide; (70) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 -(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2- Methyl-3-oxopiperazine-1-carboxamide; (71) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(3 ,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-cal Boxamide; (72) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(3 ,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-cal Boxamide; (73) N-((R)-(3-chloro-2,4-difluorophenyl)(3,3-difluorophenyl) (Tylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; (74) N-((S)-(3-chloro-2,4-difluorophenyl)(3,3-difluorophenyl) (Tylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; (75) (2R)-N-((R)-(3,3-dimethylcyclobutyl)(6-(Trif Luoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1 - Carboxamide; (76) (2R)-N-((S)-(3,3-dimethylcyclobutyl)(6-(Trif Luoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1 - Carboxamide; (77) N-((R)-(3-chloro-4-fluorophenyl)(3-(trifluoro Methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine -1-Carboxamide; (78) N-((S)-(3-chloro-4-fluorophenyl)(3-(trifluoro Methyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine -1-Carboxamide; (79) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(3-(t (Lifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (80) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(3-(t (Lifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (81) (2R)-N-((R)-(4-fluoro-3-methylphenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (82) (2R)-N-((S)-(4-fluoro-3-methylphenyl)(trans -4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (83) (2R)-N-((R)-(4-fluoro-3-methylphenyl)(cis-4 -(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (84) (2R)-N-((S)-(4-fluoro-3-methylphenyl)(cis-4 -(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (85) (2R)-N-((R)-(4-chloro-3-(difluoromethyl)phenyl (cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (86) (2R)-N-((R)-(4-chloro-3-(difluoromethyl)phenyl (Trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (87) (2R)-N-((S)-(4-chloro-3-(difluoromethyl)phenyl (cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-o Xopiperazine-1-carboxamide; (88) (2R)-N-((S)-(4-chloro-3-(difluoromethyl)phenyl (Trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (89) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(trans -3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (90) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis-3 -(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide; (91) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis-3 -(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine -1-Carboxamide; (92) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(trans -3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (93) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxo Piperazine-1-carboxamide; (94) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) S-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (95) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) S-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (96) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( Lance-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxo Piperazine-1-carboxamide; (97) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( Lance-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1 - Carboxamide; (98) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(C) (S-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (99) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(C) (S-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1- Ruboxamide; (100) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( trans-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine- 1-Carboxamide; (101) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (R)-Spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (102) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (S)-Spiro[2,2]pentan-1-yl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (103) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( R)-Spiro[2,2]pentan-1-yl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (104) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (S)-Spiro[2,2]pentan-1-yl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (105) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (R)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (106) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (S)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (107) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (R)-(3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (108) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (S)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopipera Zin-1-carboxamide; (109) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (110) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis- 3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (111) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (112) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis- 3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazi n-1-carboxamide; (113) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(cis- 3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (114) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(cis- 3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3 -Oxopiperazine-1-carboxamide; (115) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(tran S-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (116) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(tran S-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (117) N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2- (Iyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxo Piperazine-1-carboxamide; (118) N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2- (Iyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxy Sopiperazine-1-carboxamide; (119) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyri (Zin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3- Oxopiperazine-1-carboxamide; (120) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyri (Zin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3- Oxopiperazine-1-carboxamide; (121) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl L)-2-methyl-3-oxopiperazine-1-carboxamide; (122) (2R)-N-((R or S)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (123) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (124) (2R)-N-((S or R)-(5-chloro-6-(trifluoromethyl (Tyl)pyridine-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl L)-2-methyl-3-oxopiperazine-1-carboxamide; (125) (2R)-N-((R or S)-1-(3-chloro-4-fluorophen (Nyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl -3-oxopiperazine-1-carboxamide; (126) (2R)-N-((R or S)-1-(3-chloro-4-fluorophen (Nyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)-ethyl)-2- Methyl-3-oxopiperazine-1-carboxamide; (127) (2R)-N-((S or R)-1-(3-chloro-4-fluorophen (Nyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)-ethyl)-2-methyl Lu-3-oxopiperazine-1-carboxamide; (128) (2R)-N-((S or R)-1-(3-chloro-4-fluorophen (Nyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)-ethyl)-2- Methyl-3-oxopiperazine-1-carboxamide; (129) (2R)-N-((R)-(3-fluoro-4-(trifluoromethoxy) Phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Chill-3-oxopiperazine-1-carboxamide; (130) (2R)-N-((S)-(3-fluoro-4-(trifluoromethoxy) Phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Chill-3-oxopiperazine-1-carboxamide; (131) ((2R)-N-((R)-(2-fluoro-4-(trifluoromethoxy) )phenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2 -Methyl-3-oxopiperazine-1-carboxamide; (132) (2R)-N-((S)-(2-fluoro-4-(trifluoromethoxy) Phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl Chill-3-oxopiperazine-1-carboxamide; (133) (2R)-N-((R)-(4-fluoro-3-(trifluoromethyl) ((trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl) Lu-3-oxopiperazine-1-carboxamide; (134) (2R)-N-((S)-(4-fluoro-3-(trifluoromethyl) ((trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl) Chill-3-oxopiperazine-1-carboxamide; (135) N-((R)-(4-fluoro-3-(trifluoromethyl)phenyl)( trans-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxopiperazi n-1-carboxamide; (136) N-((S)-(4-fluoro-3-(trifluoromethyl)phenyl)( trans-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxopiperazi n-1-carboxamide; (137) (2R)-N-((R)-(3-chloro-2-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (138) (2R)-N-((S)-(3-chloro-2-fluorophenyl)(tran S-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopipette Radin-1-carboxamide; (139) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy) ((3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (140) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy) ((3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (141) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoro (R)-2-(trifluoromethyl)thiazole-4- Il(methyl)piperazine-1-carboxamide; (142) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoro (S)-2-(trifluoromethyl)thiazole-4- Il(methyl)piperazine-1-carboxamide; (143) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (144) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)( (3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (145) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (146) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)( (3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl) Methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (147) (2R)-N-(R)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (148) (2R)-N-(R)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (149) (2R)-N-(S)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (150) (2R)-N-(S)-(3-chloro-2,4-difluorophenyl)( Lance-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-O Xopiperazine-1-carboxamide; (151) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(cis-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (152) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(cis-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl -3-oxopiperazine-1-carboxamide; (153) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(Trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl Chill-3-oxopiperazine-1-carboxamide; And, (154) (2R)-N-((R or S)-(3-chloro-2,4-difluoro (Phenyl)(Trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl Chill-3-oxopiperazine-1-carboxamide; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

29. below, (1) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1r ,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-O Xopiperazine-5,5,6,6-d4-1-carboxamide; (2) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1r ,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-O Xopiperazine-5,5,6,6-d4-1-carboxamide; (3) (2R)-N-((1(R or S))-(4-fluoro-3-(trifluoro (methyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H -pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxami D; (4) (2R)-N-((1(R or S))-(4-fluoro-3-(trifluoro (methyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H -pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxami D; (5) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1r ,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(fluoromethyl (Lu)-3-oxopiperazine-2-d-1-carboxamide; (6) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)((R) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; s (7) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((R) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; (8) (R)-N-((R)-(3-chloro-2,4-difluorophenyl)((S) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; (9) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((S) -Croman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxa Mido; (10) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2- (Trifluoromethyl)piperazine-1-carboxamide; (11) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2- (Trifluoromethyl)piperazine-1-carboxamide; And, (12) (R)-N-((S)-(3-chloro-2,4-difluorophenyl)((1 r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(hydroxy Methyl)-3-oxopiperazine-1-carboxamide; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

30. The compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier A pharmaceutical composition containing these ingredients.

31. Na ｖ 1. Treatment of disorders, conditions, or diseases that respond to inhibition of 8-channel activity is required. A compound according to claim 1 or for preparing a drug useful for the treatment of mammals The use of that pharmaceutically acceptable salt.

32. For the treatment, prevention, or control of painful disorders, cough disorders, acute itchy disorders, or chronic itchy disorders. Use of the compound described in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product.

33. The use according to claim 32, wherein the disorder is a painful disorder.

34. Claim 3, wherein the pain disorder is selected from acute pain, inflammatory pain, or neuropathic pain. Use as described in 3.

35. For use in therapeutic applications, the compound described in claim 1 or the pharmaceutically acceptable thereof salt.

36. Na ｖ 1. Treatment or prevention of disorders, conditions, or diseases that respond to inhibition of channel activity is necessary. A method for treating or preventing the disorder, condition, or disease in a patient, which is effective in treatment. The method comprising administering an amount of the compound described in claim 1 or a pharmaceutically acceptable salt thereof, method.

37. If the aforementioned disorder is selected from painful disorders, cough disorders, acute itchy disorders, or chronic itchy disorders, please The method described in item 36.

38. The method according to claim 37, wherein the disorder is a painful disorder.

39. Claim 3, wherein the pain disorder is selected from acute pain, inflammatory pain, or neuropathic pain. The method described in 8.

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